Sulfonyl derivatives

专利摘要:
The present invention is of general formula (I) [Wherein, R 1 means a hydrogen atom, a hydroxyl group, a nitro group or the like. R 2 and R 3 each independently represent a hydrogen atom, a halogen atom and the like. R 4 and R 5 each independently represent a hydrogen atom, a halogen atom and the like. Q <1> means the saturated or unsaturated 5-6 membered cyclic hydrocarbon group etc. which may have a substituent. Q 2 means a single bond, an oxygen atom, or the like. Q 3 means any of the following groups. T 1 means a carbonyl group or the like. X 1 and X 2 each independently represent a methine group or a nitrogen atom.] Sulfonyl derivatives, salts thereof or solvates thereof; And their application as medicaments. These compounds are excellent anticoagulants with strong FXa inhibitory action, fast, sufficient and oral side effects that can be achieved by oral administration and have a sustained antithrombotic effect.
公开号:KR20010015639A
申请号:KR1020007003295
申请日:1998-09-30
公开日:2001-02-26
发明作者:고바야시쇼조；코모리야사토시；이토마사유키；나가타츠토무；모치즈키아키요시；하기노야노리아스；나가하라타카야스；호리노하루히코
申请人:스즈키 다다시；다이이찌 세이야꾸 가부시기가이샤；
IPC主号:

专利说明:

Sulfonyl derivatives {SULFONYL DERIVATIVES}
Unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reclosure after blood circulation reconstruction, and thrombus formation in extracorporeal circulation Since anticoagulation of blood is one of the important factors, there is a need for an excellent anticoagulant that has excellent dose responsiveness, sustainability, low risk of bleeding, low side effects, and immediate effect even after oral administration. (Trombosis Research; Thrombosis Research, Vol. 68, pp. 507-512, 1992).
In the study of anticoagulants based on various mechanisms of action, FXa inhibitors are likely to be excellent anticoagulants. The blood coagulation system is a series of reactions in which a large amount of thrombin is produced through amplification by a multistage enzymatic reaction to produce insoluble fibrin. In the endogenous system, after a multi-step reaction following activation of the contact factor, the activation factor IX activates the factor X on the phospholipid membrane in the presence of activation factor VIII factor and calcium ion. In the exogenous system, factor VII activates factor X in the presence of tissue factors. That is, activation of FXa of factor X in the coagulation system is an essential reaction in thrombin generation. X factor FXa, activated at both endogenous and exogenous systems, decomposes prothrombin to produce thrombin. Thrombin production is further amplified because the thrombin produced activates upstream clotting factors. As mentioned above, since the coagulation system higher than FXa is divided into endogenous and exogenous, inhibition of coagulation enzymes higher than FXa does not sufficiently inhibit the production of FXa, and as a result, it produces thronbin. In addition, since the coagulation system is a self-amplifying reaction, inhibition of coagulation system can be more efficiently achieved by inhibiting FXa located at a higher level than inhibiting the generated toronbin (Trombosis Research, Vol. 5). , 617-629, l979).
Another advantage of FXa inhibitors is that there is a large discrepancy between the effective dose of the thrombus model and the dose that extends the bleeding time in the experimental bleeding model. From these results, FXa inhibitors are anticoagulants with a low risk of bleeding. Is considered.
Although various compounds have been reported as FXa inhibitors, in general, antitronron III and antithrombin III dependent pentasaccharides cannot inhibit the prothrombinase complex, which plays a practical role in thrombus formation in vivo. Known (Trombosis Research; Thombosis Research, Vol. 68, pp. 507-512, 1992; Journal of Clinical Investigation, Vol. 71, pp. 1383-1389, 1983; Mebio; Mebio; , August, pp. 92-97). Oral administration is not effective. Teak anticoagulant peptides (TAP) isolated from vampire mites or leeches (Science; Science, Vol. 248, pp. 593-596, 1990.) and antistatin (AST) (Journal of Biologic Chemistry; Journal of Biological Chemistry, Vol. 263, pp. 10162-10137, 1988) also inhibited FXa and showed antithrombotic effects from venous thrombosis models to arterial thrombosis models, but these are polymeric peptides and have no effect on oral administration. In view of this, development of low molecular weight FXa inhibitors that directly inhibit coagulation factors in antithrombin III independence has been performed.
An object of the present invention is to provide a novel compound having strong FXa inhibitory effect, fast and sufficiently sustained antithrombogenic effect in oral administration, low side effects, and useful as an excellent anticoagulant.
The present invention is a novel sulfonyl derivative or salt thereof capable of oral administration that inhibits the activating coagulation factor (hereinafter abbreviated as "FXa") and exhibits strong anticoagulant action, and a blood coagulation inhibitor or thrombi containing the same as an active ingredient, or A prophylactic and / or therapeutic agent for embolism.
In light of the above situation, the present inventors intensively examined the synthesis and pharmacological action of novel FXa inhibitors, and as a result, the novel sulfonyl derivatives, salts thereof or solvates thereof showed strong FXa inhibitory action and strong anticoagulant action, and orally administered. In addition, the present invention has been found to be highly effective and consistently inhibit FXa, exhibit strong anticoagulant action, antithrombotic action, high safety, and useful as a drug for preventing and treating various diseases caused by thrombosis and embolism.
The present invention provides a sulfonyl derivative, a salt thereof, or a solvate thereof represented by the following general formula (I).

[Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbon A carbonyloxy group or a group A ¹ -B ^1- (wherein A ¹ is an amino group which may have one or two substituents, a saturated or unsaturated 5-6 membered cyclic hydrocarbon group or substituent which may have a substituent) It means a saturated or unsaturated 5- to 6-membered heterocyclic group which may have, B ¹ means a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group, or an alkylenecarbonyloxy group.) Means.
R ² and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group. Moreover, R <^2> or R <^3> may become one with R <^1>, and may form a C1-C3 alkylene group or alkenylene group.
R ⁴ and R ⁵ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (except when R ⁴ and R ⁵ are hydrogen atoms at the same time).
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent, or a saturated or unsaturated 2 group which may have a substituent It means a cyclic or tricyclic condensed cyclic group.
Q ² is a single bond, an oxygen atom, a sulfur atom, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched carbon atom 2 to An alkynylene group of 6, group-N (R ⁶ ) -CO- (wherein R ⁶ means a hydrogen atom or an alkyl group), group-N (R ⁷ )-(CH ₂ ) m- (wherein R ⁷ means a hydrogen atom or an alkyl group, m means an integer of 0 to 6), or
group

(This group is a divalent saturated or unsaturated 5 to 6 membered cyclic hydrocarbon group which may have a substituent, a divalent saturated or unsaturated 5 to 6 membered heterocyclic group which may have a substituent, or a divalent that may have a substituent. Saturated or unsaturated bicyclic condensed cyclic group means ← C means that the carbon atom of this group is bonded with Q <^1> .
Q ³ means any one of the following groups.

(In these groups, when the carbon atom to which R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ is not adjacent to the nitrogen atom, each independently,
Hydrogen atom,
Hydroxy,
Alkyl group,
Alkoxy Group,
Alkoxyalkyl group,
Alkoxyalkyloxy group,
Hydroxyalkyl group,
Hydroxyalkyloxy group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylsulfonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonylalkyl group,
Carboxyl group,
Carboxyalkyl group,
Carboxyalkyloxy group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkyloxy group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An amino group which may have l or 2 substituents,
An aminoalkyl group which may have one or two substituents in the amino group portion,
An aminoalkyloxy group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
Aminoalkylcarbonyloxy groups which may have one or two substituents in the amino group moiety,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyloxy group which may have one or two substituents in the amino group moiety, or
A ² -B ^2- (In the group, A ² means a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent. B ² means a single bond, a carbonyl group or an alkylene group.
When the carbon atoms to which R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are bonded are adjacent to the nitrogen atom, they are each independently,
Hydrogen atom,
Alkyl group,
Hydroxyalkyl group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylsulfonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonylalkyl group,
Carboxyl group,
Carboxyalkyl group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxyalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An aminoalkyl group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group moiety, or
Group A ³ -B ^3- (where A ³ means a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent B ³ means a single bond, a carbonyl group or an alkylene group.
In addition, R ⁸ and R ⁹ , R ¹⁰ and R ¹¹ , R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ are saturated or unsaturated 5 to 7 members which may be substituted together with the carbon atoms constituting the ring. Or a saturated or unsaturated 5 to 7 membered heterocyclic group which may have a cyclic hydrocarbon group or a substituent of
R ¹⁴ and R ¹⁷ are each independently,
Hydrogen atom,
Alkyl group,
Hydroxyalkyl group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group, alkoxyl group,
Alkoxyalkyl group,
Alkoxyalkylcarbonyl group,
Alkoxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonyl group,
Alkylsulfonylalkyl group,
Carboxyalkyl group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An amino group which may have l or 2 substituents,
An aminoalkyl group which may have one or two substituents in the amino group portion,
Aminoalkyloxy groups which may have one or two substituents in the amino group moiety,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
An aminoalkyloxycarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group moiety, or
It means the aminocarbonyloxyalkyl group which may have one or two substituents in an amino-group part.
In addition, R ¹⁴ may be a saturated or unsaturated 5- to 7-membered heterocyclic group which may be substituted with a carbon atom constituting a ring and R ¹⁴ bonded to R ¹² or R ¹³ to form a ring. good.
In addition, R ¹⁷ means a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent together with the carbon atom constituting the ring and R ¹⁷ bonded to R ¹⁵ or R ¹⁶ . You may also
a, b, d, e and g each independently represent an integer of 0 or 1. c means an integer from 0 to 3. f, h and i each independently represent an integer of 1 to 3. Provided that the sum of a, b and c means an integer of 2 or 3, the sum of d and e means an integer of 0 or l, and the sum of f, g and h means an integer of 3 to 5 .)
T ¹ is a carbonyl group, a group -CH (R ¹⁸ )-(where R ¹⁸ is a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, hetero Means an arylalkyl group or an aminoalkyl group which may have a substituent in the amino group portion.) Or group -C (= NOR ¹⁹ )-(wherein R ¹⁹ represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group) , An aminoalkyl group which may have a substituent on a heteroaryl group, a heteroarylalkyl group or an amino group portion.
X ¹ and X ² each independently represent a methine group or a nitrogen atom.]
The present invention also provides a medicament comprising the sulfonyl derivative represented by the general formula (l), a salt thereof, or a solvate thereof as an active ingredient.
Moreover, this invention is sulfonyl derivative represented by the said General formula (l), its salt, or its solvate; And it provides a pharmaceutical composition containing a pharmaceutically acceptable carrier.
Moreover, this invention provides use as a medicine of the sulfonyl derivative, its salt, or its solvate represented by the said General formula (l).
In addition, the present invention provides a method for treating a disease caused by a thrombus or embolism, comprising administering a sulfonyl derivative represented by the general formula (l), a salt thereof, or a solvate thereof to a patient.
Best Mode for Carrying Out the Invention
The substituent of the sulfonyl derivative of this invention represented by general formula (I) is demonstrated.
^Examples of halogen atoms in R ¹ include fluorine, chlorine, bromine and iodine atoms.
As an alkyl group, a linear, branched or cyclic C1-C6 alkyl group is meant, and a methyl group, an ethyl group, isopropyl group, a cyclopropyl group, etc. are mentioned, for example.
The hydroxyalkyl group means a group consisting of a hydroxy group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. The alkylene group includes a methylene group, an ethylene group, a trimethylene group, a propylene group, a cyclohexylene group, and the like. Can be mentioned. As a hydroxyalkyl group, a hydroxymethyl group, a hydroxyethyl group, etc. are mentioned, for example.
The alkoxyl group means the group which consists of the above-mentioned alkyl group of C1-C6 and an oxygen atom, For example, a methoxyl group, an ethoxyl group, an isopropoxyl group, etc. are mentioned.
An alkoxyalkyl group means the group comprised by said C1-C6 alkoxyl group and said C1-C6 alkylene group, For example, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group etc. are mentioned.
A carboxyalkyl group means the group comprised with a carboxyl group and said C1-C6 alkylene group, For example, a carboxymethyl group, a carboxyethyl group, etc. are mentioned.
An alkylcarbonyl group means the group which consists of said C1-C6 alkyl group and a carbonyl group, For example, a methylcarbonyl group, an ethylcarbonyl group, etc. are mentioned.
The alkoxycarbonyl group means a group consisting of the alkoxyl group having 1 to 6 carbon atoms and a carbonyl group, and examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
An alkoxycarbonylalkyl group means the group comprised by said alkoxycarbonyl group and said alkylene group, For example, a methoxycarbonylethyl group, an ethoxycarbonylmethyl group, etc. are mentioned.
An alkylcarbonyloxy group means the group which consists of said C1-C6 alkyl group, a carbonyl group, and an oxygen atom, For example, a methylcarbonyloxy group, an ethylcarbonyloxy group, an isopropylcarbonyloxy group, etc. are mentioned. have.
In the groups A ^l -B ^l- , A ^l is an amino group which may have one or two substituents, a saturated or unsaturated 5-6 membered cyclic hydrocarbon group or substituent which may have a substituent, or saturated or unsaturated Means a 5 to 6 membered heterocyclic group.
Therefore, when A ¹ means an amino group which may have one or two substituents, B ¹ means a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group. , Group A ¹ -B ¹ -means, for example, a group as shown in the following group (A).
Group (A):
An amino group which may have one or two substituents,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminoalkyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group portion,
Aminocarbonylalkyloxy group which may have one or two substituents in the amino group portion, aminoalkylcarbonyl group which may have one or two substituents in the amino group portion,
An aminoalkylcarbonyloxy group which may have one or two substituents in the amino group portion;
Hereinafter, group represented by group (A) is demonstrated.
The aminocarbonyl group which may have one or two substituents in an amino group part means the group which consists of the amino group and carbonyl group which may have one or two substituents.
The aminoalkyl group which may have one or two substituents in the amino group portion means a group consisting of an amino group which may have one or two substituents and an alkylene group having 1 to 6 carbon atoms as described above, and examples of the aminoalkyl group include, for example, For example, an aminomethyl group, an aminoethyl group, etc. are mentioned.
The aminocarbonylalkyl group which may have one or two substituents in the amino group moiety means a group consisting of the aminocarbonyl group which may have the above substituent and the alkylene group having 1 to 6 carbon atoms described above, and the aminocarbonylalkyl group For example, an aminocarbonylmethyl group, an aminocarbonylethyl group, etc. are mentioned.
The aminocarbonylalkyloxy group which may have one or two substituents in the amino group moiety means a group consisting of the aminocarbonylalkyl group which may have the above substituents and an oxygen atom, and as the aminocarbonylalkyloxy group, for example, It means an aminocarbonyl methoxyl group and an aminocarbonyl ethoxyl group.
The aminoalkylcarbonyl group which may have one or two substituents in the amino group part means the group which consists of the aminoalkyl group and carbonyl group which may have the said substituent, and an aminoalkylcarbonyl group, for example, aminomethylcarbonyl group, amino Ethyl carbonyl group etc. are mentioned.
The aminoalkylcarbonyloxy group which may have one or two substituents in an amino group part means the group which consists of the aminoalkylcarbonyl group which may have the said substituent, and an oxygen atom, and an aminoalkylcarbonyloxy group, for example, Aminomethylcarbonyloxy group, an aminoethylcarbonyloxy group, etc. are mentioned.
Moreover, as a substituent which can be substituted by an amino group, the following group (l) is mentioned, for example.
Group (1):
Alkyl group,
Alkenyl,
Halogenoalkyl group,
Halogenoalkenyl group,
Hydroxyalkyl group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Alkoxy Group,
Alkoxyalkyl group,
Alkoxyalkylcarbonyl group,
Alkoxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonyl group,
Alkylsulfonylalkyl group,
Carboxyalkyl group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
Trifluoromethylsulfonyloxyalkenyl group, and
Period a ^1- b ^1-
(In the group, a ¹ is saturated or may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group. It means an unsaturated 5-6 membered cyclic hydrocarbon group or a saturated or unsaturated 5-6 membered heterocyclic group.
b ¹ is a single bond, carbonyl group, alkylene group, carbonylalkyl group, carbonylalkyloxy group, alkylenecarbonyloxy group, alkyleneaminocarbonyl group, alkyleneaminocarbonylalkyl group, alkyleneaminosulfonyl group or alkyleneaminosulfur Phenyl group.).
Here, the substituent which can be substituted by the amino group in group (l) is demonstrated.
The alkyl group means the same as described above.
Alkenyl group means a linear, branched, cyclic C2-C6 alkenyl group, For example, a vinyl group, an aryl group, etc. are mentioned.
The halogenoalkyl group means a group consisting of a halogen atom and the alkylene group described above, and examples thereof include a chloromethyl group and a bromoethyl group.
The halogeno alkenyl group means a group composed of a halogen atom and a linear or branched alkenylene group having 2 to 6 carbon atoms. Examples thereof include a chloroethenyl group and a bromopropenyl group. In addition, the position of a double bond is not specifically limited.
A hydroxyalkyl group means a group consisting of a hydroxy group and a linear, branched, cyclic alkylene group having 2 to 6 carbon atoms, and examples thereof include a hydroxyethyl group and a hydroxypropyl group.
The hydroxyalkylcarbonyl group means a group composed of the hydroxyalkyl group and the carbonyl group described above, and examples thereof include a hydroxymethylcarbonyl group and a hydroxyethylcarbonyl group.
The hydroxyalkylsulfonyl group means a group composed of the hydroxyalkyl group and sulfonyl group described above, and examples thereof include hydroxymethylsulfonyl group, hydroxyethylsulfonyl group and the like.
Alkoxyl groups mean the same as described above.
The alkoxyalkyl group means the group comprised by the alkoxyl group mentioned above, and a linear, branched, cyclic C2-C6 alkylene group, For example, a methoxyethyl group, an ethoxyethyl group, a methoxypropyl group, etc. are mentioned. have.
The alkoxyalkylcarbonyl group means a group constituted by the alkoxyalkyl group and the carbonyl group described above, and examples thereof include methoxyethylcarbonyl group, ethoxymethylcarbonyl group, and the like.
An alkoxyalkylsulfonyl group means the group comprised by the alkoxyalkyl group and sulfonyl group mentioned above, For example, a methoxymethylsulfonyl group, an ethoxymethylsulfonyl group, etc. are mentioned.
A formyl alkyl group means the group comprised with a formyl group and the C1-C6 alkylene group mentioned above, For example, a formyl methyl group, a formyl ethyl group, etc. are mentioned.
A formyl alkylcarbonyl group means the group which consists of said formyl alkyl group and a carbonyl group, For example, a formyl methyl carbonyl group, a formyl ethyl carbonyl group, etc. are mentioned.
A formyl alkylsulfonyl group means the group comprised by said formyl alkyl group and a sulfonyl group, For example, a formyl methyl sulfonyl group, a formyl ethyl sulfonyl group, etc. are mentioned.
The alkylcarbonyl group means a group composed of the alkyl group and the carbonyl group described above, and examples thereof include methylcarbonyl group and ethylcarbonyl group.
An alkylcarbonylalkyl group means the group comprised by said alkylcarbonyl group and the C1-C6 alkylene group mentioned above, For example, a methylcarbonylmethyl group, an ethylcarbonylmethyl group, etc. are mentioned.
An alkylsulfonyl group means the group comprised by the alkyl group and sulfonyl group mentioned above, For example, a methylsulfonyl group, an ethylsulfonyl group, etc. are mentioned.
An alkylsulfonylalkyl group means the group comprised by said alkylsulfonyl group and the C1-C6 alkylene group mentioned above, For example, a methylsulfonylmethyl group, an ethylsulfonylmethyl group, etc. are mentioned.
Carboxyalkyl group means the same as described above.
The carboxyalkylcarbonyl group means a group composed of the carboxyalkyl group and the carbonyl group described above, and examples thereof include a carboxymethylcarbonyl group and a carboxyethylcarbonyl group.
A carboxyalkylsulfonyl group means the group comprised by the carboxyalkyl group and sulfonyl group mentioned above, For example, a carboxymethylsulfonyl group, a carboxyethylsulfonyl group, etc. are mentioned.
The carboxyalkylcarbonylalkyl group means a group constituted by the above-mentioned carboxyalkylcarbonyl group and the above-mentioned alkyl group having 1 to 6 carbon atoms, and examples thereof include a carboxymethylcarbonylmethyl group and a carboxyethylcarbonylmethyl group.
The carboxyalkylsulfonylalkyl group means a group composed of the aforementioned carboxyalkylsulfonyl group and an alkylene group having 1 to 6 carbon atoms as described above, and examples thereof include a carboxymethylsulfonylmethyl group and a carboxyethylsulfonylmethyl group.
The alkoxycarbonyl group and the alkoxycarbonylalkyl group mean the same as described above.
The alkoxycarbonylalkylcarbonyl group means a group composed of the alkoxycarbonylalkyl group and the carbonyl group described above, and means, for example, a methoxycarbonylethylcarbonyl group, an ethoxycarbonylmethylcarbonyl group, and the like.
The alkoxycarbonylalkylsulfonyl group means a group composed of the alkoxycarbonylalkyl group and sulfonyl group described above, and means, for example, a methoxycarbonylethylsulfonyl group, an ethoxycarbonylmethylsulfonyl group, and the like.
The trifluoromethylsulfonyloxyalkenyl group means a group consisting of a trifluoromethylsulfonyloxy group and a linear or branched alkenylene group having 2 to 6 carbon atoms. For example, trifluoromethylsulfonyloxyvinyl Group, a trifluoromethylsulfonyloxyaryl group, etc. are mentioned.
And in a ^first means a heterocyclic group of the cyclic hydrocarbon group or a saturated or unsaturated 5-6 won in a substituent a good source of 5~6 saturated or unsaturated group such as a halogen atom - group a ¹ -b ^1. Here, as a saturated or unsaturated 5-6 membered cyclic hydrocarbon group, a cyclopentyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, a phenyl group etc. are mentioned, for example. Can be mentioned. In addition, when there exist a plurality of structural isomers like a cyclopentenyl group, all of these are included.
The saturated or unsaturated 5-6 membered heterocyclic group is a cyclic group containing at least 1 hetero atom, and a hetero atom includes an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of the saturated or unsaturated 5 to 6 membered heterocyclic group include a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, a pyrazinyl group, a tetrahydropyrazinyl group, an imidazolyl group, a pyrazolinyl group, Oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyrimidinyl group, tetrahydropyrimidinyl group , Pyridazinyl group, tetrahydropyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, thio Morpholinyl group, tetrazolyl group, tetrazinyl group, triazolyl group, triazinyl group, etc. are mentioned. In addition, when a some structural isomer exists like a pyranyl group, all of them are included.
b ¹ is a single bond, carbonyl group, alkylene group, carbonylalkyl group, carbonylalkyloxy group, alkylenecarbonyloxy group, alkyleneaminocarbonyl group, alkyleneaminocarbonylalkyl group, alkyleneaminosulfonyl or alkyleneaminosulfur Although meant a phenylyl group, an alkylene group means the same as described above.
The carbonylalkyl group means a group composed of a carbonyl group and an alkylene group having 1 to 6 carbon atoms described above, and examples thereof include a carbonylmethyl group and a carbonylethyl group.
The carbonylalkyloxy group means a group composed of the above carbonylalkyl group and an oxygen atom, and examples thereof include a carbonylmethoxy group and a carbonylethoxy group.
The alkylene carbonyloxy group means a group composed of the above-mentioned alkyl group having 1 to 6 carbon atoms, carbonyl group and oxygen atom, and examples thereof include a methylene carbonyloxy group and an ethylene carbonyloxy group.
The alkylene aminocarbonyl group means a group consisting of the alkylene group having 1 to 6 carbon atoms described above, an imino group and a carbonyl group, and examples thereof include a methyleneaminocarbonyl group, an ethyleneaminocarbonyl group, and the like.
An alkylene amino carbonyl alkyl group means the group comprised by said alkylene amino carbonyl group and the C1-C6 alkylene group mentioned above, For example, a methylene amino carbonyl methyl group, an ethylene amino carbonyl methyl group, etc. are mentioned. .
An alkylene amino sulfonyl group means the group comprised by the C1-C6 alkylene group, an imino group, and a sulfonyl group mentioned above, For example, a methylene amino sulfonyl group, an ethylene amino sulfonyl group, etc. are mentioned.
In addition, an alkylene amino sulfonyl alkyl group means group comprised by said alkylene amino sulfonyl group and the C1-C6 alkylene group mentioned above, For example, a methylene amino sulfonyl methyl group, ethylene amino sulfonyl methyl group, etc. Can be mentioned.
Next, a description will be given of the substituent that can be substituted with heterocyclic group which may have a substituent of the ¹ of a saturated or unsaturated 5-6 won as a cyclic hydrocarbon group or a saturated or unsaturated 5-6 won. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom. The alkoxyl group, alkyl group, alkoxycarbonyl group and aminocarbonyl group mean the same as described above.
Group a ¹ -b ¹ - Examples, it is the presence of various, depending on the combination of a ¹ and b ^1, and for example, there may be mentioned the same groups as follows.
A saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered heterocyclic group and a carbonyl group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group and an alkylene group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered heterocyclic group and a carbonylalkyl group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group and a carbonylalkyloxy group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered heterocyclic group and an alkylenecarbonyloxy group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group and an alkyleneaminocarbonyl group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered heterocyclic group and an alkyleneaminocarbonylalkyl group which may have a substituent,
A group consisting of a 5-6 membered cyclic hydrocarbon group and an alkyleneaminosulfonyl group which may have a substituent, and
The group which consists of a saturated or unsaturated 5- or 6-membered heterocyclic group and alkyleneaminosulfonylalkyl group which may have a substituent.
Moreover, as a substituent which can be substituted by an amino group, the thing of the following group (2) other than the said group (l) is mentioned.
County (2):
An amino group which may have l or 2 substituents selected from the above-mentioned group (l),
An aminoalkyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminocarbonyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminocarbonylalkylcarbonyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminocarbonylalkylsulfonyl group which may have one or two substituents selected from the group (1) in the amino group portion,
An aminoalkylcarbonyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminosulfonyl group which may have one or two substituents selected from the group (l) in the amino group portion,
An aminosulfonylalkyl group which may have one or two substituents selected from the group (1) in the amino group portion,
An aminoalkylsulfonyl group which may have one or two substituents selected from the group (1) in the amino group portion,
An aminosulfonylalkylcarbonyl group which may have one or two substituents selected from the group (l) in the amino group portion, and
An aminosulfonylalkylsulfonyl group which may have one or two substituents selected from the group (1) in the amino group portion.
Below, the substituent of group 2 is demonstrated.
The aminocarbonyl group, aminocarbonylalkyl group and aminoalkylcarbonyl group in this group (2) means the same thing as what was demonstrated previously.
The aminoalkyl group which may have a substituent means the group comprised by the amino group which may have a substituent, and a linear, branched, or cyclic C2-C6 alkylene group, As an aminoalkyl group, it is aminoethyl group, aminopropyl, for example. And the like can be mentioned.
The aminocarbonylalkylcarbonyl group which may have a substituent means the group which consists of the aminocarbonylalkyl group and carbonyl group which may have a substituent, and an aminocarbonylalkylcarbonyl group is an aminocarbonylmethylcarbonyl group, aminocarbonylethyl, for example. Carbonyl group etc. are mentioned.
The aminocarbonylalkylsulfonyl group which may have a substituent means the group comprised by the aminocarbonylalkyl group and sulfonyl group which may have a substituent, As an aminocarbonylalkylsulfonyl group, For example, an aminocarbonylmethylsulfonyl group, Aminocarbonyl ethyl sulfonyl group etc. are mentioned.
The aminosulfonyl group which may have a substituent means the group comprised by the amino group and sulfonyl group which may have a substituent.
The aminosulfonylalkyl group which may have a substituent means the group which consists of the aminosulfonyl group which may have the said substituent, and the C1-C6 alkylene group mentioned above, and an aminosulfonylalkyl group is an aminosulfonyl, for example. A methyl group, an aminosulfonyl ethyl group, etc. are mentioned.
The aminoalkylsulfonyl group which may have a substituent means the group which consists of the amino group which may have a substituent, and the C1-C6 alkylene group and sulfonyl group which were mentioned above, and an aminoalkylsulfonyl group is an aminomethylsulfonyl group, for example. And aminoethylsulfonyl group.
The aminosulfonylalkylcarbonyl group which may have a substituent means the group which consists of the aminosulfonylalkyl group and carbonyl group which may have the said substituent, and an aminosulfonylalkylcarbonyl group is aminosulfonylmethylcarbonyl group, amino, for example. A sulfonyl ethyl carbonyl group, etc. are mentioned.
The aminosulfonylalkylsulfonyl group which may have a substituent means the group comprised by the aminosulfonylalkyl group and sulfonyl group which may have the said substituent, and an aminosulfonylalkylsulfonyl group is aminosulfonylmethyl, for example. A sulfonyl group, an aminosulfonyl ethyl sulfonyl group, etc. are mentioned.
In addition, although A <^1> means the saturated or unsaturated 5-6 membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, Here, as a saturated or unsaturated 5-6 membered cyclic hydrocarbon group, it is a, for example. And cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group and phenyl group. In addition, when a some structural isomer exists like a cyclopentenyl group, all of them are included.
A saturated or unsaturated 5-6 membered heterocyclic group is a cyclic group containing at least 1 hetero atom, and a hetero atom includes an oxygen atom, a nitrogen atom, and a sulfur atom. As a 5-6 membered heterocyclic group which is saturated or unsaturated, a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a pyrazolinyl group, an oxazolyl group, an oxazolinyl group, thia Zolyl group, thiazolinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, An oxadiazinyl group, a morpholinyl group, a thiadinyl group, a thiadiazinyl group, a thimorpholinyl group, a triazolyl, a triazinyl group, etc. are mentioned. In addition, when a plurality of structural isomers exist like a pyranyl group, all of them are included.
When A ¹ represents a saturated or unsaturated 5 to 6 membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, B ¹ represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or In the meaning of an alkylenecarbonyloxy group, group A ¹ -B ¹ -means, for example, a group or the like as represented by the following group (B).
Group (B):
Saturated or unsaturated 5-6 membered cyclic hydrocarbon group or heterocyclic group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group and a carbonyl group which may have a substituent,
A group consisting of a saturated or unsaturated 5-6 membered cyclic hydrocarbon group or heterocyclic group and alkylene group which may have a substituent,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, and a carbonyl and alkylene group,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, a carbonyl group, an alkylene group and an oxygen atom,
A group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, an alkylene group and a carbonyl group,
Saturated or unsaturated 5-6 membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, A group comprised by alkylene group, carbonyl group, and oxygen atom.
Below, group shown by the group (B) is demonstrated.
As a group which consists of a cyclic hydrocarbon group and a carbonyl group in the group which consists of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, and a carbonyl group, it is cyclopentylcarbonyl group, phenylcarbonyl group, for example. Etc. can be mentioned. Moreover, as group comprised by a heterocyclic group and a carbonyl group, a furyl carbonyl group, thienyl carbonyl group, a pyridyl carbonyl group, etc. are mentioned, for example.
In the group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or a heterocyclic group and an alkylene group which may have a substituent, the group composed of a cyclic hydrocarbon group and an alkylene group means the above-mentioned cyclic hydrocarbon group and carbon number l described above. The group comprised from the alkylene group of -6 is meant, for example, a cyclohexyl methyl group, a benzyl group, etc. are mentioned. In addition, the group comprised by the heterocyclic group and the alkylene group means the group comprised by the said heterocyclic group and the C1-C6 alkylene group mentioned above, For example, a furyl methyl group, thienyl ethyl group, a pyridyl propyl group, etc. Can be mentioned.
In the group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent or a carbonyl group and an alkylene group, the group consisting of a cyclic hydrocarbon group, a carbonyl group and an alkylene group is the aforementioned cyclic hydrocarbon group The group which consists of a carbonyl group and the C1-C6 alkylene group mentioned above is mentioned, for example, a cyclopentadienyl carbonylmethyl group, a phenylcarbonylethyl group, etc. are mentioned. In addition, the group which consists of a heterocyclic group, a carbonyl group, and an alkylene group means the group which consists of said heterocyclic group, a carbonyl group, and the C1-C6 alkylene group mentioned above, For example, a furyl carbonyl methyl group, thienyl car A carbonyl ethyl group, a pyridyl carbonyl propyl group, etc. are mentioned.
The group consisting of a cyclic hydrocarbon group, a carbonyl group, an alkylene group and an oxygen atom in the group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or a heterocyclic group, a carbonyl group, an alkylene group and an oxygen atom which may have a substituent Group which consists of a cyclic hydrocarbon group, a carbonyl group, and an alkylene group, and an oxygen atom is mentioned, For example, a cyclopentyl carbonyl methoxy group, a phenylcarbonyl ethoxy group, etc. are mentioned. In addition, the group which consists of a heterocyclic group, a carbonyl group, an alkylene group, and an oxygen atom means the group which consists of the group which consists of said heterocyclic group, a carbonyl group, and an alkylene group, and an oxygen atom, for example, a furyl carbonyl methoxy group, thi A vinyl carbonyl ethoxy group, a pyridyl carbonyl propoxy group, etc. are mentioned.
In the group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, or an alkylene group and a carbonyl group, the group consisting of a cyclic hydrocarbon group, an alkylene group and a carbonyl group is the aforementioned cyclic hydrocarbon group and alkyl group. It means group comprised by the ethylene group and carbonyl group, For example, a cyclohexyl methyl carbonyl group, a phenyl ethyl carbonyl group, etc. are mentioned. In addition, the group which consists of a heterocyclic group, an alkylene group, and a carbonyl group means the group which consists of the group which consists of said heterocyclic group, an alkylene group, and a carbonyl group, for example, a furylmethylcarbonyl group, thienyl ethylcarbonyl group, and pyridylpropyl Carbonyl group etc. are mentioned.
The group consisting of a cyclic hydrocarbon group, an alkylene group, a carbonyl group and an oxygen atom in a group consisting of a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or a heterocyclic group, an alkylene group, a carbonyl group and an oxygen atom which may have a substituent The group consisting of a group consisting of a cyclic hydrocarbon group, an alkylene group and a carbonyl group and an oxygen atom means a cyclohexadienylmethylcarbonyloxy group, a phenylethylcarbonyloxy group, and the like. In addition, the group which consists of a heterocyclic group, an alkylene group, a carbonyl group, and an oxygen atom means the group which consists of the group which consists of said heterocyclic group, an alkylene group, and a carbonyl group, and an oxygen atom, for example, a furylmethylcarbonyloxy group, a tier And a ethyl ethylcarbonyloxy group, a pyridyl propylcarbonyloxy group, and the like.
Moreover, the substituent of the following group (3) is mentioned as a substituent which can be substituted with a saturated or unsaturated 5-6 membered cyclic hydrocarbon group or heterocyclic group.
County (3):
Hydroxy,
Alkyl group,
Alkoxy Group,
Hydroxyalkyl group,
Alkoxyalkyl group,
Halogen atom,
Cyanogi,
Nitro Group,
Carboxyl group,
Alkoxycarbonyl group,
Formyl,
Heteroaryl group,
Heteroarylalkyl group,
Alkyl imino group,
Amidino,
Guanidino,
Amino (hydroxyimino) alkyl group,
Amino (alkoxyimino) alkyl group,
Amino (aryloxyimino) alkyl group,
An amino group which may have one or two substituents,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyloxy group which may have one or two substituents in the amino group portion,
An aminoalkyl group which may have one or two substituents in the amino group portion,
An aminoalkyloxy group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
Aminoalkylcarbonyloxy groups which may have one or two substituents in the amino group moiety, and
Oxygen atom.
In addition, the number of substituents which can be substituted is 1-3.
Below, the substituent which can be substituted by the saturated or unsaturated 5- or 6-membered heterocyclic group of group (3) is demonstrated.
The alkyl group, alkoxyl group, hydroxyalkyl group, alkoxyalkyl group, halogen atom and alkoxycarbonyl mean the same as those described for R ¹ .
Heteroaryl group means the aromatic monovalent group containing at least 1 hetero atom, For example, a pyridyl group, a furyl group, thienyl group, etc. are mentioned.
Heteroarylalkyl group means the group comprised by said heteroaryl group and the C1-C6 alkylene group mentioned above, For example, a pyridylmethyl group, a furylethyl group, thienylmethyl group, etc. are mentioned.
The alkylimino group means a group composed of the alkyl group and the nitrogen atom described above, and examples thereof include methylimino group and ethylimino group.
An amino (hydroxy imino) alkyl group means the group which the amino group and the hydroxy imino group couple | bonded with the same carbon atom of the alkyl group mentioned above, For example, an amino (hydroxy imino) methyl group, an amino (hydroxy imino) ethyl group, etc. are mentioned. Can be.
The amino (alkoxyimino) alkyl group means a group in which an amino group and an alkoxyimino group are bonded to the same carbon atom of the alkyl group described above. Here, an alkoxy imino group means the bivalent group comprised from the alkoxyl group and imino group which were demonstrated previously. As an amino (alkoxy imino) alkyl group, an amino (methoxy imino) methyl group, an amino (ethoxy imino) methyl group, etc. are mentioned, for example.
The amino (aryloxyimino) alkyl group refers to a group in which an amino group and an aryloxyimino group are bonded to the same carbon atom of the alkyl group described above. Here, an aryloxyimino group means the bivalent group comprised with an aryl group and an imino group. Here, as an aryl group, a phenyl group, a naphthyl group, anthryl group, a phenanthryl group, etc. are mentioned, for example. As an amino (aryloxy imino) alkyl group, an amino (phenoxy imino) methyl, an amino (naphthyloxy imino) methyl group, etc. are mentioned, for example.
The aminocarbonyl group which may have one or two substituents in an amino group part means the group which consists of the amino group and carbonyl group which may have one or two substituents.
The aminoalkyl group which may have one or two substituents in the amino group portion means a group consisting of an amino group which may have one or two substituents and an alkylene group having 1 to 6 carbon atoms as described above. For example, an aminomethyl group, an aminoethyl group, etc. are mentioned.
The aminocarbonylalkyl group which may have one or two substituents in the amino group moiety means a group consisting of the aminocarbonyl group which may have the above substituent and the alkylene group having 1 to 6 carbon atoms described above, and the aminocarbonylalkyl group For example, an aminocarbonylmethyl group and an aminocarbonylethyl group are mentioned.
The aminocarbonylalkyloxy group which may have one or two substituents in the amino group moiety means a group consisting of the aminocarbonyl aalkyl group which may have a substituent in the amino group moiety described above and an oxygen atom, and represents an aminocarbonylalkyloxy group. For example, an aminocarbonyl methoxyl group and an aminocarbonyl ethoxyl group mean.
The aminoalkylcarbonyl group which may have one or two substituents in the amino group moiety means a group consisting of the aminoalkyl group and carbonyl group which may have a substituent in the amino group moiety described above, and the aminoalkylcarbonyl group may be, for example, aminomethyl Carbonyl group, aminoethylcarbonyl group, etc. are mentioned.
The aminoalkylcarbonyloxy group which may have one or two substituents in the amino group moiety means a group consisting of an aminoalkylcarbonyl group and an oxygen atom which may have a substituent in the amino group moiety described above. For example, an aminomethylcarbonyloxy group, an aminoethylcarbonyloxy group, etc. are mentioned.
The aminoalkyloxy group which may have one or two substituents in the amino group portion means a group composed of an amino group which may have a substituent, and a linear, branched, cyclic alkylene group having 2 to 6 carbon atoms and an oxygen atom. For example, an aminoethyloxy group, an aminopropyloxy group, etc. are mentioned.
In addition, the oxygen atom can be a substituent when the cyclic hydrocarbon group is a keto compound. In the case of a heterocyclic group or a bicyclic or tricyclic condensed cyclic group, an oxygen atom is bonded to a nitrogen atom or a sulfur atom constituting the ring and becomes an N-oxide or an S-oxide and becomes a keto compound. to be.
In the present invention, when R ¹ is one of R ² or R ³ and does not mean an alkylene group or alkenylene group having ¹ to ³ carbon atoms, a hydrogen atom, an alkyl group, a hydroxyalkyl group, a group A ¹ -B ^1- desirable.
Examples of the halogen atom in R ² and R ³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The alkyl group means a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms, and examples thereof include methyl group, ethyl group, isopropyl group, cyclopropyl group, heptyl group and octyl group.
The hydroxyalkyl group means a group composed of a hydroxy group and a linear, branched or cyclic C1-8 alkylene group, and examples thereof include a hydroxymethyl group and a hydroxyethyl group.
The alkoxyalkyl group means a group composed of the alkyl group and the oxygen atom described above and a linear, branched or cyclic alkylene group having 1 to 8 carbon atoms, and examples thereof include methoxymethyl group, methoxyethyl group, ethoxymethyl group and the like. Can be. In addition, R <^2> or R <^3> becomes ^one with R <^1>, and means the C1-C3 alkylene group or alkenylene group, but this is group of general formula (I), for example.

Means the following.


In the present invention, when R ² or R ³ together with R ¹ do not mean an alkylene group or alkenylene group having 1 to 3 carbon atoms, R ² and R ³ are preferably a hydrogen atom or an alkyl group.
In the present invention, it is preferable that R ¹ and R ² or R ³ become one to mean an alkylene or alkenylene group having 1 to ³ carbon atoms.
Examples of the halogen atom in R ⁴ and R ⁵ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The alkyl group and the alkoxyl group mean the same as those described for R ¹ . In the present invention, R ⁴ and R ⁵ are preferably halogen atoms, and among them, fluorine atom, chlorine atom and bromine atom are preferable.
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent, and a saturated or unsaturated bicyclic group which may have a 5-6 membered heterocyclic group or substituent which may have a substituent. Or a tricyclic condensed cyclic group.
Here, as a saturated or unsaturated 5-6 membered cyclic hydrocarbon group, a cyclopentyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, a phenyl group etc. are mentioned, for example. Can be mentioned. In addition, when a some structural isomer exists like a cyclopentenyl group, all of them are included.
The saturated or unsaturated 5-6 membered heterocyclic group is a cyclic group containing at least 1 hetero atom, and a hetero atom includes an oxygen atom, a nitrogen atom, and a sulfur atom. As a saturated or unsaturated 5-6 membered heterocyclic group, it is a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a pyrazolinyl group, an oxazolyl group, an oxazolinyl group, thiazolyl, for example. Group, thiazolinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxa Diazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, thiamorpholinyl group, triazolyl, triazinyl group, etc. are mentioned. In addition, when a plurality of structural isomers exist, such as a pyranyl group, all of them are included.
The saturated or unsaturated bicyclic or tricyclic condensed cyclic group which may have a substituent may be: (1) The saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have the above substituents condensed, (2) may have the above substituents. Condensed with a saturated or unsaturated 5-6 membered cyclic hydrocarbon group and a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent, ③ a saturated or unsaturated 5-6 membered complex which may have a substituent It means that the summoned group is condensed. For example, in (1), an indenyl group, an indanyl group, a naphthyl group, tetrahydro naphthyl group, anthryl group, a phenanthryl group, etc. are mentioned. As (2), a benzofuranyl group, indoryl group, indolinyl group, quinolyl group, benzodiazinyl group, tetrahydroisoquinolyl group, etc. are mentioned. As a thing of (3), a naphthyridinyl group, a tetrahydro thieno pyridyl group, a tetrahydro thiazolo pyridyl group, a tetrahydro pyridino pyridyl group, etc. are mentioned.
As a substituent which can be substituted with said cyclic hydrocarbon group, a heterocyclic group, a bicyclic or tricyclic condensed cyclic group, the thing of the following group (4) is mentioned.
County (4):
Hydroxy,
Alkyl group,
Alkenyl,
Halogenoalkyl group,
Halogenoalkenyl group,
Alkoxy Group,
Hydroxyalkyl group,
Alkoxyalkyl group,
Halogen atom,
Cyanogi,
Nitro Group,
Carboxyl group,
Alkoxycarbonyl group,
Formyl,
Heteroaryl group,
Heteroarylalkyl group,
Alkyl imino group,
Amidino,
Guanidino,
Amino (hydroxyimino) alkyl group,
Amino (alkoxyimino) alkyl group,
Amino (aryloxyimino) alkyl group,
An amino group which may have l or 2 substituents,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyloxy group which may have one or two substituents in the amino group portion,
An aminoalkyl group which may have one or two substituents in the amino group portion,
An aminoalkyloxy group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
An aminoalkylcarbonyloxy group which may have one or two substituents in the amino group portion,
Oxygen atom,
Trifluoromethylsulfonyloxy group,
Trifluoromethylsulfonyloxyalkenyl group,
Boric acid group (-B (OH ₂ )),
5-6 membered saturated or unsaturated substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group Saturated or optionally substituted with 1 to 3 substituents selected from the group consisting of a cyclic hydrocarbon group and a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group Unsaturated 5- to 6-membered heterocyclic group.
In addition, the number of substituents which can be substituted is 1-7. The substituent of this group (4) means the same thing as what was described by group (1)-group (3).
In the present invention, as Q ¹ , a phenyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, and pyrrolidi which may have a substituent Preferred are a nyl group, a tetrahydrothienopyridyl which may have a substituent, and a tetrahydrothiazolopyridyl group which may have a substituent.
In Q ² , examples of the linear or branched alkylene group having ¹ to 6 carbon atoms include methylene group, ethylene group, trimethylene group, propylene group, tetramethylene group, butylene group, pentamethylene group and hexa Methylene group etc. are mentioned.
As a linear or branched C2-C6 alkenylene group, a vinylene group, a propenylene group, butenylene, pentenylene group, etc. are mentioned, for example. In addition, the position of a double bond is not specifically limited.
Examples of the linear or branched alkynylene group having 2 to 6 carbon atoms include propynylene group, butynylene group, pentynylene group, hexynylene group and the like.
Next term:

This group may be a divalent saturated or unsaturated 5 to 6 membered cyclic hydrocarbon group which may have a substituent, a divalent saturated or unsaturated 5 to 6 membered heterocyclic group which may have a substituent, or a divalent that may have a substituent. Saturated or unsaturated bicyclic condensed cyclic group, ← C represents a bond of the carbon atom and Q ¹ of this group, for example, thiophene, furan, pyran, pyrrole, pyrrolidine, pyrroline, Imidazole, imidazoline, imidazolidine, pyrazole, pyrazolidine, thiazole, oxazole, oxathiolan, benzene, pyridine, piperidine, piperazine, morpholine, thiomorpholine, pyrazine, pyri Divalent groups derived from midine, pyridazine, triazine, tetraazine, thiadiazine, dithiazine, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene and the like, and the like. It may have a substituent. As a substituent, the same thing as what was mentioned in the former group (4) is mentioned.
The alkyl groups of R ⁶ and R ^{7 in} the groups -N (R ⁶ ) -CO- and group-N (R ⁷ )-(CH ₂ ) _m -are linear, branched or cyclic C 1-6 carbon atoms. An alkyl group is meant and a methyl group, an ethyl group, isopropyl group, a cyclopropyl group, etc. are mentioned, for example. As the group -N (R ⁶ ) -CO-, the group ← N (R ⁶ ) -CO- (← represents a bond between the nitrogen atom of this group and Q ¹ ) is preferable, and the group -N (R ⁷ As (CH ₂ ) m-, the group ← N (R ⁷ )-(CH ₂ ) m-(where ← represents a bond between the nitrogen atom of this group and Q ¹ ) is preferable.
In the present invention, Q ² is a single bond, a carbonyl group, a group

Is preferably represented by
group

Among the groups represented by benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazolin, furan, thiophene, pyrrole, oxazole, oxa Preference is given to divalent groups derived from sleepy, thiadiazole, cyclopentane, cyclopentene, cyclohexane, cyclohexene.
Alkyl group, alkoxyl group, alkoxyalkyl group, hydroxyalkyl group, hydroxyalkyloxy group, hydroxy in R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ as a substituent in Q ³ Alkylcarbonyl group, hydroxyalkylsulfonyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, Carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, amino group which may have one or two substituents, and a substituent in the amino group part aminoalkyl group which may have 1 or 2, aminoalkylcarbonyl group which may have 1 or 2 substituents in amino group part, amino group part Aminoalkylcarbonyloxy group which may have one or two substituents, aminocarbonyl group which may have one or two substituents in the amino group portion, aminocarbonylalkyl which may have one or two substituents in the amino group portion And the aminocarbonylalkyloxy group which may have one or two substituents in the amino group portion means the same as described above for R ¹ .
The alkoxyalkyloxy group means a group composed of the alkoxyalkyl group and the oxygen atom described above, and examples thereof include methoxymethyloxy group, methoxyethyloxy group, ethoxymethyloxy group and the like.
A carboxyalkyl group means the group comprised with a carboxyl group and the C1-C6 alkylene group mentioned above, For example, a carboxymethyl group, a carboxyethyl group, etc. are mentioned.
A carboxyalkyloxy group means the group which consists of said carboxyalkyl group and an oxygen atom, For example, a carboxy methoxyl group, a carboxy ethoxyl group, etc. are mentioned.
The alkoxycarbonylalkyloxy group means a group composed of the alkoxycarbonylalkyl group described above and an oxygen atom, and examples thereof include a methoxycarbonylethyl group and an ethoxycarbonylethyl group.
The aminoalkyloxy group which may have one or two substituents in the amino group moiety means a group consisting of an amino group which may have a substituent and a linear, branched or cyclic C2-C6 alkylene group and an oxygen atom, for example Examples of the aminoalkyloxy group include an aminoethoxyl group, an aminopropoxyl group, and the like. In the group A ² -B ^2- , A ² is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent. Or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent, but as the saturated or unsaturated 5-6 membered cyclic hydrocarbon group, for example, a cyclopentyl group, a cyclopentenyl group, A cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, a phenyl group, etc. are mentioned. In addition, when a some structural isomer exists like a cyclopentenyl group, all of them are included.
The saturated or unsaturated 5-6 membered heterocyclic group is a cyclic group containing at least 1 hetero atom, and a hetero atom includes an oxygen atom, a nitrogen atom, and a sulfur atom. As a 5-6 membered heterocyclic group which is saturated or unsaturated, a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, a pyrazinyl group, tetrahydropyrazinyl group, an imidazolyl group, a pyrazolyl group , Oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyrimidinyl group, tetrahydropyrimididi Nyl group, pyridazinyl group, tetrahydropyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, Thiomorpholinyl group, tetrazolyl group, tetrazinyl group, triazolyl, triazinyl, etc. are mentioned. In addition, when a some structural isomer exists like a pyranyl group, all of them are included.
B ² means a single bond, a carbonyl group or an alkylene group, and an alkylene group means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.
Group A ² -B ² - roneun may be a group such as, for example, as follows. Saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent, Saturated or unsaturated group which may consist of the saturated or unsaturated 5-6 membered heterocyclic group and carbonyl group which may have a substituent, and a substituent may have A group consisting of a 5-6 membered cyclic hydrocarbon group and an alkylene group.
In addition, R ⁸ and R ⁹ , R ¹⁰ and R ¹¹ , R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ are saturated or unsaturated 5 to 7 members which may be substituted together with the carbon atoms constituting the ring. Although it means the saturated or unsaturated 5-7 membered heterocyclic group which may have a cyclic hydrocarbon group or a substituent, Here, as a saturated or unsaturated 5-7 membered cyclic hydrocarbon group, it is a cyclopentyl group, A cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, a phenyl group, etc. are mentioned. In addition, when a some structural isomer exists like a cyclopentenyl group, all of them are included.
The saturated or unsaturated 5 to 7 membered heterocyclic group is a cyclic group including at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. As a saturated or unsaturated 5-7 membered heterocyclic group, it is a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, a pyrazinyl group, tetrahydropyrazinyl group, an imidazolyl group, a pyrazolinyl group, for example. , Oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, oxatriazolyl group, thiadiazolyl group, prazanyl group, pyranyl group, pyridyl group, pyrimidinyl group, tetrahydropyrimidinyl group , Pyridazinyl group, tetrahydropyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, thio Morpholinyl group, tetrazolyl group, tetrazinyl group, triazolyl group, triazinyl group, etc. are mentioned. In addition, when there exist several isomers like a pyranyl group, all of them are included.
a, b, d, e and g each independently represent an integer of 0 or l. c means an integer from 0 to 3. f, h and i each independently represent an integer of 1 to 3. Provided that the sum of a, b and c means an integer of 2 or 3, the sum of d and e means an integer of 0 or 1, and the sum of f, g and h means an integer of 3 to 5 ).
An alkyl group, alkoxyl group, hydroxyalkylcarbonyl group, hydroxyalkylsulfonyl group, alkoxyalkylcarbonyl group, alkoxyalkylsulfonyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group in R ¹⁴ and R ¹⁷ as a substituent of Q ³ , Alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonyl Alkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, amino group which may have one or two substituents, aminoalkylcarbonyl group which may have one or two substituents in the amino group moiety, and one or two substituents in the amino group moiety A good aminoalkyloxycarbonyl group, one or two substituents in the amino group portion Good aminocarbonyl group, a substituent to the amino group portion of one or two or import good aminocarbonyl group, and a substituent to the amino group portion 1 or may have two good aminocarbonyl-oxy group means that previously such as that described in R ¹ do.
A hydroxyalkyl group means a group consisting of a hydroxy group and a linear, branched or cyclic alkylene group having 2 to 6 carbon atoms, and examples thereof include a hydroxyethyl group and a hydroxypropyl group.
An alkoxyalkyl group means the group comprised with the alkoxyl group mentioned above, and a linear, branched, or cyclic C2-C6 alkylene group, For example, a methoxyethyl group, an ethoxyethyl group, etc. are mentioned.
The aminoalkyl group which may have one or two substituents in the amino group portion means a group consisting of an amino group which may have a substituent described above and a linear, branched or cyclic alkylene group having 2 to 6 carbon atoms. For example, an aminoethyl group, an aminopropyl group, etc. are mentioned.
The aminoalkyloxy group which may have one or two substituents in the amino group moiety means a group consisting of an amino group which may have a substituent and a linear, branched or cyclic C2-C6 alkylene group and an oxygen atom, for example For example, an aminoethoxyl group, an amino propoxyl group, etc. are mentioned as an aminoalkyloxy group.
In the groups A ³ -B ^3- , A ³ means a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent, Here, as a saturated or unsaturated 5-6 membered cyclic hydrocarbon group, a cyclopentyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, a phenyl group, etc. are mentioned, for example. Can be mentioned. In addition, when a some structural isomer exists like a cyclopentenyl group, all of them are included.
The saturated or unsaturated 5 to 6 membered heterocyclic group is a cyclic group including at least one heteroatom, and examples of the heteroatom include an oxygen atom, a nitrogen atom and a sulfur atom. As a 5-6 membered heterocyclic group which is saturated or unsaturated, a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, a pyrazinyl group, tetrahydropyrazinyl group, an imidazolyl group, a pyrazolyl group , Oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyrimidinyl group, tetrahydropyrimididi Nyl group, pyridazinyl group, tetrahydropyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, Thiomorpholinyl group, tetrazolyl group, tetrazinyl group, triazolyl, triazinyl group, etc. are mentioned. In addition, when there exist several isomers like a pyranyl group, all of them are included.
B ³ means a single bond, a carbonyl group or an alkylene group, and the alkylene group means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.
Group A ³ -B ³ - as, for example, there may be mentioned gideung as described below. Saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, Saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group and carbonyl group which may have a substituent, and saturated or unsaturated A group consisting of a 5-6 membered heterocyclic group and an alkylene group.
R ¹⁴ and R ¹² , R ¹⁴ and R ¹³ , R ¹⁷ and R ¹⁵ , R ¹⁷ and R ¹⁶ may have a substituent together with the carbon atom constituting the ring and the nitrogen atom to which R ¹⁴ or R ¹⁷ bonds. A good saturated or unsaturated 5 to 7 membered heterocyclic group is meant, but the saturated or unsaturated 5 to 7 membered heterocyclic group is a cyclic group including at least one hetero atom, and the hetero atom is an oxygen atom. And nitrogen atoms and sulfur atoms. As a saturated or unsaturated 5-7 membered heterocyclic group, it is a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, a pyrazinyl group, tetrahydropyrazinyl group, an imidazolyl group, a pyrazolinyl group, for example. , Oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyrimidinyl group, tetrahydropyrimididi Nyl group, pyridazinyl group, tetrahydropyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiadidinyl group, thiadiazinyl group, Thiomorpholinyl group, tetrazolyl group, tetrazinyl group, triazolyl group, triazinyl group, etc. are mentioned. Moreover, when there exist several structures now, such as a pyranyl group, it is contained all.
In the present invention, Q ³ is

(In these groups, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , a, b, c, d, e, f, g, h And i are as described above.) Among them, as Q ³ ,
group

(In which R ⁸ , R ⁹ , a, b and c are the same as before).
T ¹ is a carbonyl group,
-CH (R ¹⁸ )-
(R ¹⁸ means a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have a substituent on an amino group portion) Or
Group -C (= NOR ¹⁹ )-
(R ¹⁹ means a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have a substituent on an amino group portion.).
Herein, the alkyl group, carboxyalkyl group, alkoxycarbonyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, and aminoalkyl group in R ¹⁸ or R ¹⁹ may be the same as those described for R ¹ . it means. In the present invention, a carbonyl group is preferable as T ¹ .
In the present invention, the group in general formula (I)

end

or

Means,
R ⁴ means a halogen atom.
In the present invention, as Q ¹ , a cyclopentyl group which may have a substituent, a cyclohexyl group which may have a substituent, a cyclopentenyl group which may have a substituent, a cyclohexenyl group which may have a substituent, and a substituent may have Phenyl group, pyrrolidinyl group which may have a substituent, piperidinyl group which may have a substituent, imidazolyl group which may have a substituent, thiazolyl group which may have a substituent, thiadiazolyl group which may have a substituent, A pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, a thiazolidinyl group which may have a substituent, a morpholinyl group which may have a substituent, and a substituent Good piperazinyl group, thiomorpholinyl group which may have a substituent, pyrrolyl group which may have a substituent, thienyl group which may have a substituent, may have a substituent Furanyl group, tetrahydropyrimidinyl group which may have a substituent, tetrahydrofuranyl group which may have a substituent, tetrahydrothienyl group which may have a substituent, sulfolanyl group which may have a substituent, and imide which may have a substituent Zolinyl group, thiazolinyl which may have a substituent, oxazolyl group which may have a substituent, oxadiazinyl group which may have a substituent, triazinyl group which may have a substituent, tetragenyl group which may have a substituent, and a substituent Pyrazinyl group which may have a substituent, pyrazolyl group which may have a substituent, pyrazolinyl group which may have a substituent, pyrazolidinyl group which may have a substituent, thienopyridyl group which may have a substituent, and a substituent A good tetrahydrothienopyridyl group, the thiazolopyridyl group which may have a substituent, the tetrahydro thiazolopyri may have a substituent Groups are preferred.
Examples of the substituent include a hydroxy group, an alkyl group, a hydroxyalkyl group, a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group, formyl group, an alkylsulfonyl group, an amino group which may have one or two substituents, and a substituent on an amino group portion. Aminosulfonyl group which may have one or two, aminoalkyl group which may have one or two substituents in an amino group part, an oxygen atom, a trifluoromethyl group, a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyan Aminocarbonyl group which may have one or two substituents in the no group, nitro group, carboxyl group, alkoxycarbonyl group or amino group portion, aminosulfonyl group which may have one or two substituents in the amino group portion, and one substituent in the amino group portion Or 1 to 3 substituents selected from the group consisting of two aminoalkyl groups and trifluoromethyl which may have two Cyclic hydrocarbon group of 5~6 good source of saturated or unsaturated; And one or two substituents in the aminocarbonyl and amino group moieties which may have one or two substituents in the halogen atom, hydroxy group, amino group, alkoxyl group, alkyl group, cyano group, nitro group, carboxyl group, alkoxycarbonyl group and amino group portion. Saturated or unsaturated 5 which may have 1 to 3 substituents selected from the group consisting of an aminosulfonyl group which may have, and an aminoalkyl group which may have one or two substituents in the amino group portion, and a trifluoromethyl group. A 6-membered heterocyclic group is preferable.
In the present invention, as Q ² , a single bond, a carbonyl group, a group

Is preferably represented by
group

Among the groups represented by benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazolin, furan, thiophene, pyrrole, oxazole, oxa Preferred are divalent groups derived from sleepy, thiadiazole, cyclopentane, cyclopentene, cyclohexane, cyclohexene.
Q ³

[Wherein R ⁸ , R ⁹ , a, b and c are the same as electricity]
Means;
It is especially preferable when T <^1> means a carbonyl group.
In the sulfonyl derivatives of the present invention, optical isomers or stereoisomers derived from sub-carbon atoms may be present, but all of the optical isomers, stereoisomers, and mixtures thereof are included in the present invention.
The salt of the sulfonyl derivative of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, mineral salts such as hydrochloride, hydrobromide, hydrochloride, phosphate, nitrate, sulfate, benzoate, and methane Euphonic acid salts such as sulfonates, 2-hydroxyethane sulfonates, p-toluene sulfonates and acetates, propane salts, oxalates, malonates, succinate salts, glutalates, artitic salts, tartarate salts, maleic acid salts And organic carboxylates such as malate and mandelate. The solvate is not particularly limited as long as it is pharmaceutically acceptable. Specific examples thereof include a hydrate and an ethanolate.
Below, the preferable compound in the sulfonyl derivative of this invention is given.
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazin-2-carboxylic acid hydrochloride
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) nicotinyl] piperazine hydrochloride
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
l- [4- (2-aminopyridin-5-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- [imidazol-4 (5) -yl] benzoyl] piperazine hydrochloride
1- [4- [2-aminoimidazol-4-yl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazin hydrochloride
2- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
2- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-l-yl] carbonyl] phenyl] -1 -methylpyridinium iodide
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride
l-[(E) -4-chlorostyrylsulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride
2- [4-[[4-[(E) -4-chlorostyrylsulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
3- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -1 -methylpyridinium iodide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-hydroxy-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-4- [4- (pyridin-4-yl) benzoyl] piperazine
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazin-2-carboxylic acid
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-3-yl) benzoyl] piperazine hydrochloride
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4- [4-[[2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
4- [4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
2-carbamoyl-4-[(E) -4-chlorostyrylsulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
1- [trans-4- (aminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
l-[[(6RS) -6-aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl} sulfonyl] pipe Razine Hydrochloride
1-[(7-aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4-[[(3S) -pyrrolidin-3-yl] oxy] benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4-[(3RS) -pyrrolidin-3-yl] benzoyl] piperazine hydrochloride
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] pipe Razine Hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno [3,2c] pyridin-2-yl ) Carbonyl] Piperazine Hydrochloride
2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) Carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine- 2-yl) carbonyl] piperazine
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (1-pyrrolin-2-yl) -4,5,6,7-tetrahydrothieno [3,2 -c] pyridin-2-yl] carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] pipe Razine Hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-formyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] piperazine
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine hydrochloride
2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6,6-dimethyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridinium iodide
2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridine N-oxide
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -l-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- I) carbonyl] piperazine trifluoroacetate
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -l-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (2-hydroxyethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl] carbonyl] piperazine hydrochloride
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (pyridin-3-yl) methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl] carbonyl] piperazine hydrochloride
1-[(E) -4-chlorostyrylsulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[(IRS) -4- (pyridin-4-yl) -3-cyclohexenyl] carbonyl] piperazine hydrochloride
Cis-, trans-1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[4- (pyridin-4-yl) cyclohexanyl] carbonyl] piperazine hydrochloride
6-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -2,2-dimethyl-1,2,3,4-tetrahydroisoquinolin Nium iodide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (l, 2,3,6-tetrahydropyridin-4-yl) benzoyl] piperazine hydrochloride
1-[[(E) -2- (6-chloropyridin-3-yl) vinyl] sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-methyl-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -2-methylphenyl] pyridine N-oxide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-methylpyridin-4-yl) benzoyl] piperazine hydrochloride
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -2-methylpyridine N-oxide
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl-2-[[2-morpholin-4-yl) ethylamino] carbonyl] piperazin-1-yl] car Carbonyl] phenyl] pyridine N-oxide
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[2- (dimethylamino) ethylamino] carbonyl] piperazin-1-yl] carbonyl] Phenyl] pyridine N-oxide
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-1- [4- (pyridin-2-yl) benzoyl] piperazine
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-carboxymethyl-1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
1- [4-[(3RS) -1-acetimidoylpyrrolidin-3-yl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-acetoxymethylpyrrolidin-4-yl) benzoyl] piperazine
l-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-hydroxymethylpyridin-4-yl) benzoyl] piperazine hydrochloride
2-hydroxymethyl-4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (2-aminoimidazol-4-yl) benzoyl] piperazine
2-[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-4-yl] carbonyl-4-phenyl] -6-methylpyridine N-oxide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (6-methylpyridin-2-yl) benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (3-aminopyridin-2-yl) benzoyl] piperazine hydrochloride
4- [4-[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-4-yl] carbonyl] -3-methylphenyl] pyridine N-oxide
l- [2-tert-butoxycarbonyl-4- (pyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
1- [2-carboxy-4- (pyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
1- (4-amidinobenzoyl) -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -l- [4- [imidazol-4 (5) -yl] benzoyl] piperazine hydrochloride
1- [4- (2-aminopyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
1- [4- (2 aminothiazol-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
2-carbamoyl-4-[(E) -4-chlorostyrylsulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4- [5-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] pyridin-2-yl] pyridine N-oxide
2-amino-4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine Noxide
4- [4-[[4-[(E) -4-chlorostyrylsulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-l- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
2-carboxymethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
2- [4-[[2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
2-methyl-4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -2,3-methyl-4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
2- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-hydroxymethyl-3-methylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2,3-dimethylpiperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2,6-dimethyl-1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2,2-dimethyl-1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
2- [4-[[4-[(6chloronaphthalen-2-yl) sulfonyl] -2,2-dimethylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-oxo-1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -2,3-dicarbamoyl-4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-methyl-3- [2- (morpholin-4-yl) ethylamino] carbonyl] -4- [4- (pyridine-4 -Yl) benzoyl] piperazine hydrochloride
4- [4-[[4- (6-chloronaphthalen-2-yl) sulfonyl-3-methyl-2-[[2- (morpholin-4-yl) ethylamino] carbonyl] piperazin-1 -Yl] carbonyl] phenyl] pyridine N-oxide
2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4- [4-[[2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -6-methylpiperazin-1-yl] carbonyl] phenyl] pyridine N-jade Seed
2- [4-[[2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -6-oxopiperazin-1-yl] carbonyl] phenyl] pyridine N-jade Seed
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] -1,2,3,4-tetrahydroquinoxaline hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] decahydroquinoxaline hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-[(ethoxycarbonylmethylsulfonylamino) methyl] -2-methyl-4- [4- (pyridin-2-yl) benzoyl Piperazine Hydrochloride
2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -3-oxo-1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -3- (imidazol-4-yl) methyl-2-oxo-4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] -7-oxodecahydropyrido [3,4-b] pyrazine hydrochloride
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-l-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -6-methyl-l-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] -2-[[2- (morpholin-4-yl) ethylamino] carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) carbonyl] Piperazine Hydrochloride
2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-1-[(6-methyl-5,6,7,8-tetrahydropyrido-1, 6-naphthyridin-2-yl) carbonyl] piperazine hydrochloride
The sulfonyl derivative manufacturing method of this invention is demonstrated below.
The sulfonyl derivatives, salts thereof, and solvates thereof of the present invention can be prepared by a combination of well-known general chemical preparation methods, and representative synthesis methods are described below.
Moreover, when it is necessary to protect substituents, such as a nitrogen atom, a hydroxyl group, and a carboxyl group, when synthesize | combining the sulfonyl derivative of this invention, you may be protected by the general protecting group which can remove when needed conventionally known, and these protecting groups When necessary, it can remove according to the organic chemical general method shown by the following manufacturing methods. In addition, the starting materials required can be obtained by a general synthetic method of organic chemistry, and the preparation method of these starting materials is shown in the reference example. Furthermore, these starting materials can be synthesized by applying the method illustrated in the reference example.
Hereinafter, the protecting group and deprotection method of substituents, such as a nitrogen atom, a hydroxyl group, and a carboxyl group, are demonstrated.
Suitable protecting groups for nitrogen atoms of amino and alkylamino groups include conventional acyl protecting groups, that is, alkanoyl groups such as acetyl groups or methoxycarbonyl groups, ethoxycarbonyl groups, alkoxycarbonyl groups such as tertiary butoxycarbonyl groups, or benzyloxycarbonyl groups, para Aroyl groups such as arylmethyl groups such as methoxybenzyloxycarbonyl groups, para (ortho) nitrobenzyloxycarbonyl groups, arylmethyl groups such as benzyl groups, triphenylmethyl groups, or benzoyl groups are suitable. The deprotection method of these protecting groups depends on the chemical properties of the protecting groups employed. For example, acyl protecting groups such as alkanoyl groups, alkoxycarbonyl groups or aroyl groups include lithium hydroxide, sodium hydroxide or alkali hydroxides such as potassium hydroxide. It can be hydrolyzed and deprotected by using a suitable base.
In addition, substituted methoxycarbonyl protecting groups such as tert-butoxycarbonyl groups or paramethoxybenzyloxycarbonyl groups are suitable acids such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethane It can be removed by sulfonic acid or a combination of these acids. In addition, arylmethoxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, para (ortho) nitrobenzyloxycarbonyl group and arylmethyl groups such as benzyl group can be removed by hydrolysis using a palladium / carbon catalyst. In addition, the benzyl group may be converted into a nitrogen-hydrogen bond by removing the benzyl group by Birch reduction using metal sodium in liquid ammonium. The triphenylmethyl group can be removed by a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Moreover, benzyl group can be removed by birch reduction using metal sodium in liquid ammonium, and can also be removed by hydrolysis using a palladium-carbon catalyst.
As a protecting group of other amino groups, in the case of a primary amino group, it can protect by a butaroyl group type, and can remove it with hydrazine, dimethylaminopropylamine, etc.
As a suitable protecting group of a hydroxyl group, an acyl type protecting group and an ether type protecting group are mentioned. As an acyl type protecting group, alkanoyl groups, such as an acetyl group, and aroyl groups, such as a benzoyl group, are suitable. As an ether type protecting group, arylmethyl groups, such as a benzyl group, silyl ether groups, such as a tertiary butyldimethylsilyl group, methoxymethyl group, Tetrahydropyranyl group etc. are mentioned.
Removal of these protecting groups depends on the chemical nature of the protecting group employed. For example, acyl groups, such as an alkanoyl group and an aroyl group, can be removed by hydrolyzing with a suitable base, such as alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. The arylmethyl type protecting group can be removed by hydrolysis using a palladium / carbon catalyst, and silyl groups such as tertiary butyldimethylsilyl group can be removed by hydrofluoric acid salts such as tetrabutylammonium fluoride.
In addition, a methoxymethyl group, tetrahydropyranyl group, etc. can be removed by acetic acid, hydrochloric acid, etc. In addition, the hydroxyl group substituted by the aryl group can be protected by a methyl group, and can be removed by Lewis acid, such as aluminum chloride and phosphorus tribromide, trimethylsilyl iodide, and hydrogen bromide.
The carboxyl group can be protected by esterification. Methyl, methyl ester and the like can be removed by hydrolysis with a suitable base such as alkali hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and in tertiary butyl ester, by treatment with trifluoroacetic acid or hydrochloric acid, The tertiary butyl group can be removed. Moreover, as an arylmethyl type ester, such as a benzyl group, an arylmethyl group can be removed by hydrolysis using a palladium / carbon catalyst.
[Manufacturing Method-1]
Compound represented by general formula (Ia)
Q ¹ -Q ² -T ¹ -Q ^3a (Ia)
[Wherein, Q ¹ , Q ² and T ¹ are as described above. Q ^3a means any one of the following groups.

Wherein R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , a, b, c, d, e, f, g, h and i Is as described above.]]
It represented the nitrogen atom of Q ^3a by the general formula (IIa) acid halides

[In formula, R <^1> , R <^2> , R <^3> , R <^4> , R <^5> , X <^1> , X <^2> is as above-mentioned in general formula (Ia) and general formula (IIa). Halo means a halogen atom such as chlorine, bromine or iodine.] Sulfonyl derivative represented by formula (I) by sulfonylation

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q ¹ , Q ² , Q ³ , T ¹ , X ¹ and X ² are as described above.
<Synthesis of Compound Represented by General Formula (Ia)>
The compound represented by general formula (Ia) can be synthesize | combined by a series of operation by a well-known technique.
For example, a compound represented by general formula (IIIa) which can be synthesized by applying a known method or a known method.
Q ^3b -H (IIIa)
[Q ^3b means any one of the following groups.

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , a, b, c, d, e, f, g, h and i in the group R ²¹ is a general nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl, benzyl, and the like. Activator of carboxylic acid represented by general formulas (IVa) to (IVd) which can synthesize nitrogen atom to which hydrogen atom of Q ^3b bonds by application of the known technique
Q ¹ -Q ^2b -COOH (IVa)
Q ¹ -N (R ²⁰ )-(CH ₂ ) _ml -COOH (IVb)
Q ¹ -O-(CH ₂ ) _ml -COOH (IVc)
Q ¹ -S-(CH ₂ ) _ml -COOH (IVd)
[Wherein, Q ¹ is as described above. R ²⁰ means a linear or branched alkylene group or a general nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl, benzyl and the like. Q ^2b is a single bond, linear or branched alkylene group having 1 to 6 carbon atoms, linear or branched alkenylene group having 2 to 6 carbon atoms, linear or branched carbon group having 2 to 6 carbon atoms or

(This group means the same as described above.) M1 means an integer of 1 to 6.] Compounds represented by the general formula (Ib) acylated by
Q ¹ -Q ² -T ² -Q ^3b (Ib)
Wherein Q ¹ , Q ² , Q ³ and T ¹ are as described above.
In addition, when the nitrogen source of the compound Q ^3b of the general formula (IIIa) self design nitrogen atom to form an amide bond, a nitrogen atom of the compound Q ^3b of the general formula (IIIa) by the general formula (Ⅴa) ~ (Ⅴd) Compound shown
Q ¹ -Q ² -CHL ¹ R ¹⁸ (Va)
^{Q 1 - N (R 20)} - (CH 2) m1 - CHL 1 R 18 (Vb)
_{^{Q 1 - O - (CH 2}} ) m1 - CHL 1 R 18 (Vc)
_{^{Q 1 - S - (CH 2}} ) m1 - CHL 1 R 18 (Vd)
[Wherein, Q ¹ , Q ^2b , R ¹⁸ , R ²⁰ and m 1 are as described above. L ¹ means an organic chemically used leaving group such as chlorine, bromine, oxo, methylsulfonyloxy group and paratoluenesulfonyloxy group.]
The compound represented by general formula (Ib) can be synthesize | combined by the method of alkylating with
Further, when the nitrogen atom of Q ^3b of the compound represented by the general formula (IIIa) is an amine having a primary or secondary degree, the carbonyl compound represented by the general formulas (VIa) to (VId)
Q ¹ -Q ^2b -C (= O) R ¹⁸ (VIa)
^{Q 1 - N (R 20)} - (CH 2) m1 - C (= O) R 18 (VIb)
_{^{Q 1 - O - (CH 2}} ) m1 - C (= O) R 18 (VIc)
_{^{Q 1 - S - (CH 2}} ) m1 - C (= O) R 18 (VId)
[Wherein, Q ¹ , Q ^2b , R ¹⁸ , R ²⁰ and m 1 are the same as described above].
Primary or general formula represented by general formulas (VIIa) to (VIId) which can be synthesized by the compound represented by general formula (IIIa), reagents such as 1,1'-carbonyldiimidazole, and the application of a known technique Compound of secondary amine represented by (VIIe)
Q ¹ -Q ^2b -NH ₂ (VIIa)
Q ¹ -N (R ²⁰ )-(CH ₂ ) _{m 2} -NH ₂ (VIIb)
Q ¹ -O-(CH ₂ ) _{m 2} -NH ₂ (VIIc)
Q ¹ -S-(CH ₂ ) _{m 2} -NH ₂ (VIId)

[Wherein, Q ¹ , Q ^2b , and R ²⁰ are as described above. m2 means 2-6 the integer. group

Means a 5 to 6 heterocyclic group which may have a substituent.)] To react to form a urea derivative, or an isocyanate derivative or a carboxylic acid represented by general formulas (IVa) to (IVd). Compounds represented by the general formula (Ib) can be produced by reacting the produced isocyanate with an amine represented by the general formula (IIIa).
An aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group, or an alkenyl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is present in the structure of the compound Q ¹ represented by General Formula (Ib). In this case, it is also possible to couple with an aryl compound substituted with a boric acid group using a transition metal catalyst.
When an alkenyl group exists in the structure of Q <^1> of the compound represented by general formula (Ib), it is also possible to couple | bond with the aryl group substituted by the halogen atom or the trifluoromethanesulfonyloxy group using a transition metal catalyst.
Similarly, when an aryl group substituted with a boric acid group is present in the structure of Q ¹ of the compound represented by the formula (Ib), a coupling reaction may be performed with an alkenyl compound substituted with a halogen atom or a trifluoromethanesulfonyloxy group. When an aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is present in the structure of compound Q ¹ represented by formula (Ib), a coupling reaction is performed using an alkenyl compound and a transition metal catalyst to general formula (Ib). It is also possible to obtain the displayed compounds. When the compound represented by general formula (Ib) obtained in this way is protected by the nitrogen atom of Q <^3b>, the compound represented by general formula (Ia) can be obtained by deprotecting as needed.
For example, as a suitable activator of the carboxylic acid represented by General Formulas (IVa) to (IVd), the carboxylic acid represented by General Formulas (IVa) to (IVd) may be substituted with chloroformic acid ether such as isobutyl chloroformate. By reacting with a mixed acid anhydride such as one obtained as anhydride, an acid halide such as acyl chloride prepared using a halide such as thionyl chloride, a phenol such as paranitrophenol, a pentafluorophenyltrifluoroacetate, or the like. Active esters obtained by reaction with the obtained active esters, N-hydroxybenztriazole or N-hydroxysuccinimide, or N, N'-dicyclohexylcarbodiimido or N- (3 Reaction product with -dimethylaminopropyl) -N'-ethylcarbodiido hydrochloride, reaction product with diethyl cyanophosphonic acid (Shioiri's method), tripe And the like can be given: phosphine and 2, 2'-pyrido reaction product with the quality disulfide pitdeu (向 山 法 Mukaiyama's method).
The compound represented by the general formula (Ib) by reacting the activator of the carboxylic acid thus obtained and the compound represented by the general formula (IIIa) or a salt thereof at -78 ° C to 150 ° C in an inert solvent usually in the presence of a suitable base. Get
Specific bases include carbonates, alkoxides, hydroxides or hydrides of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, or n- Organometallic bases represented by alkyllithium such as butyllithium, dialkylaminolithium such as lithium diisopropylamine, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
Examples of inert solvents include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, and N, N-dimethyl. Amide solvents such as formamide, N, N-dimethylacetamido, N-methylpyrrolidin-2-one, and the like, and in addition, sulfoxide solvents such as dimethyl sulfoxide and sulfolane if appropriate. Ketone solvents, such as acetone and methyl ethyl ketone, can be used.
When the nitrogen atom of the compound Q ^3b represented by the general formula (IIIa) is a nitrogen atom that forms an amide bond, the compound represented by the general formulas (Va) to (Vd) and -78 ° C to The reaction can be carried out at 150 DEG C to alkylate the nitrogen atom to obtain a compound represented by the general formula (Ib). Specific bases include alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, or dihydrides such as alkyllithium such as hydrides or n-butyllithium and lithium diisopropylamine. Organometallic bases represented by alkylaminolithium, or organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); and the like.
As the inert solvent, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane, amide solvents such as N, N-dimethylformamide, and the like are preferable.
For example, when the nitrogen atom of the compound Q ^3b represented by the general formula (IIIa) is a primary or secondary amine, an organic acid such as acetic acid, a mineral acid such as hydrochloric acid, or a Lewis such as aluminum chloride is usually necessary in an inert solvent. In the presence of an acid, imine is formed with a carbonyl compound represented by general formulas (VIa) to (VId) at -20 ° C to 150 ° C, and this imine is in an inert solvent, sodium borohydride, sodium cyanoborohydride, The compound represented by general formula (Ib) can be obtained by hydrogenating at 10 degreeC-110 degreeC with borohydride reducing agents, such as sodium triacetoxy borohydride, or catalytic reduction catalysts, such as a palladium / carbon catalyst.
Examples of inert solvents include halogenated carbon such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, benzene solvents such as toluene, N, N-dimethylformamide and N Amide solvents such as, N-dimethylacetamide and N-methylpyrrolidin-2-one are optimal.
When the nitrogen atom of compound Q ^3b represented by general formula (IIIa) is a primary or secondary amine, the primary or secondary amines represented by general formulas (VIIa) to (VIId) may be represented by general formula (VIIe). It is also possible to induce a urea derivative by reacting a compound, which is a secondary amine, and a reagent reactant such as 1,1'-carbonyldiimidazole. If the reaction requires a compound represented by the general formula (VIIa) or the secondary amine represented by the general formula (VIIa) to (VIId) or a compound represented by the general formula (IIIa) to a reagent such as carbonyldiimidazole, In the presence of a base, it can synthesize | combine by making it react in order in inert solvent.
Examples of inert solvents include halogenated carbon such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, benzene solvents such as toluene, N, N-dimethylformamide and N And amide solvents such as N-dimethylacetamide and N-methylpyrrolidin-2-one. Preferably dichloromethane, tetrahydrofuran, toluene and the like.
Examples of the base include carbonates, hydroxides or pyridines of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydroxides, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methyl Organic bases such as morpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like. The reaction may be performed in the range of -70 ° C to 110 ° C.
When the nitrogen atom of the compound Q ^3b represented by the general formula (IIIa) is a primary or secondary amine, the compound represented by the general formula (Ib) is a compound represented by the general formula (IIIa) and an isocyanate derivative in an inert solvent. It can obtain by making it react in the range of -20 degreeC-100 degreeC.
The isocyanate derivative is an acid halogenated carboxylic acid represented by the general formula (IVa) with an acid halide such as thionyl chloride or oxaryl chloride at -20 ° C to 110 ° C in an inert solvent such as tetrahydrofuran, chloroform or toluene. Subsequently, it reacts with sodium azide in the range of 0 degreeC-80 degreeC in inert solvents, such as tetrahydrofuran, chloroform, or toluene, and it heats at 20 degreeC-100 degreeC, or is represented by General formula (IVa). The resulting carboxylic acid is reacted at -20 ° C to 110 ° C in an inert solvent such as tetrahydrofuran, chloroform, or toluene to form a mixed anhydride in chloroformate esters such as isobutyl chloroformate and in the range of 0 ° C to 80 ° C. Reacted with sodium azide at and then heated to 20 ° C. to 100 ° C .; Alternatively, the carboxylic acid represented by the general formula (IVa) is made into hydrazide through -ester at -20 ° C to 110 ° C in an inert solvent such as tetrahydrofuran, chloroform or toluene, and further, nitric acid or alkyl ester thereof. After reacting to make acyl azide, it can synthesize | combine by the method of heating at 20 degreeC-150 degreeC, etc. in solvent, such as chloroform, dichloroethane, toluene, xylene, and N, N- dimethylformamide.
The carboxylic acid represented by the general formula (IVa) is diphenylphosphoryl azide and 10 ° C in an inert solvent such as chloroform, tetrahydrofuran, toluene, N, N-dimethylformamide in the presence of triethylamine and the like. The compound represented by general formula (Ib) can be manufactured by making it react in the range of -140 degreeC, and then reacting with the amine represented by general formula (IIIa).
An aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group, or an alkenyl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is present in the structure of the compound Q ¹ represented by General Formula (Ib). In the case of a biphasic solvent such as benzene-water and toluene-water, an amide solvent such as N, N-dimethylformamide, an ether solvent such as tetrahydrofuran, dimethoxyethane, sodium carbonate, sodium hydroxide, barium hydroxide, In the presence of a base such as potassium phosphate or cesium carbonate, using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0), an aryl derivative substituted with a boric acid group in a range of 20 ° C. to 150 ° C. and 0.5 hour to 120 The time coupling reaction can be carried out.
When an alkenyl group is present in the structure of Q ¹ of the compound represented by formula (Ib), an aryl in which a halogen atom or a trifluoromethanesulfonyloxy group is substituted in the presence of a suitable base using a transition metal catalyst such as acetic acid / palladium Coupling reaction can be carried out for 0.5 to 120 hours in the range of 20 degreeC-150 degreeC in amide type solvents, such as group and N, N- dimethylformamide.
Similarly, when an aryl group substituted with a boric acid group is present in the structure of Q ¹ of the compound represented by formula (Ib), an allyl derivative substituted with a halogen atom, a trifluoromethanesulfonyloxy group, a halogen atom, and a trifluoromethane sulfide Coupling may be carried out with an aryl derivative substituted with a phenyl derivative. If an aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is present in the structure of compound Q ¹ , coupling is performed using an alkenyl compound and a transition metal catalyst. By reacting, the compounds represented by general formula (Ib) can be obtained.
If this procedure the nitrogen compound Q ^3b of the general formula (Ib) thus obtained is self-protected by deprotection as needed, to obtain the compound represented by the general formula (Ia).
<Synthesis of Compounds Represented by General Formula (IIa)>
The sulfonic acid halide represented by general formula (IIa) is conventionally reported in various methods such as halogenation of the corresponding sulfonic acid represented by general formula (IIb) or sulfonylhalogenation of unsaturated bonds represented by general formula (IIC). Chemistry of Sulfonic Acids Esters and their Derivatives, Edited by S. Patai and Z. Rappoport, 1991 John Wiley & Sons Ltd.


[In formulas (IIb) and (IIC), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ and X ² are as described above.]
For example, the sulfonic acid represented by general formula (IIb) is represented by general formula (IIa) by reacting thionyl halide with thionyl halide at a temperature of 0 ° C to 150 ° C for 0.5 to 24 hours in the presence of N, N-dimethylformamide. Sulfonate halides can be synthesized.
At this time, the reaction system may be diluted with an inert solvent such as dichloromethane, chloroform, hydrogen tetrachloride, N-methylpyrrolidin-2-one, dimethyl sulfoxide and sulfolane.
In addition, the compound represented by the general formula (IIc) having an unsaturated bond is reacted with thionyl halide or chlorosulfonic acid at a temperature of 0 ° C. to 150 ° C. for 0.5 to 24 hours in an inert solvent such as N, N-dimethylformamide. The sulfonic acid halide represented by Formula (IIa) can be synthesized.
The compound represented by the general formula (Ia) synthesized by the above-described method or the like is usually -78 ° C in the sulfonic acid halide represented by the general formula (IIa) synthesized by the above-described method or the like in an inert solvent in the presence of a suitable base. The compound of general formula (I) can be obtained by making it react at -150 degreeC.
Specific bases include carbonates, alkoxides, hydroxides or hydrides of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, or n- Organometallic bases represented by alkyllithium such as butyllithium, dialkylaminolithium such as lithium diisopropylamide, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamido, N, N-dimethylacetamide, N-methylpyrrolidine 2-one, dimethyl sulfoxide, sulfolane, acetone, etc. are mentioned.
[Manufacturing Method-1- (1)]
When the nitrogen atom of Q ^3a in the general formula (Ia) to be sulfonylated is a primary or secondary amine, the carbonate, hydroxide or pyridine of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide as a base, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) The same organic base is optimal, and as the solvent, in addition to an inert solvent, an alcohol solvent such as ethanol and butanol, and an ester solvent such as ethyl acetate can be used.
[Manufacturing Method-1- (2)]
When the nitrogen atom of Q ^3a in the general formula (Ia) to be sulfonated is a nitrogen atom constituting an amino group, an alkoxide of an alkali metal or an alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride, potassium hydride as a base, Or hydrides or organometallic bases represented by alkyllithium such as n-butyllithium, dialkylaminolithium such as lithium diisopropylamide, or diazabicyclo [5.4.0] undec-7-ene (DBU) Organic bases such as
Tetrahydrofuran, 1,2- diethoxyethane, dioxane, N, N- dimethylformamide, etc. are mentioned as an inert solvent.
[Manufacturing Method-2]
A method for producing a sulfonyl derivative (I) by acylating a nitrogen atom of compound Q ^3a represented by general formula (VIIIa) with a carboxylic acid represented by general formula (IVa) or an activator thereof.
Q ¹ -Q ² -COOH (IVa)
[Wherein Q ¹ and Q ² are as described above.]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a are as described above.]
The sulfonic acid halide represented by the general formula (IIa) in an inert solvent in the presence of a suitable base or primary or secondary amine or amido nitrogen atom of the compound represented by the general formula (IIIa).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Halo are as described above.]
By sulfonylating at -78 ° C to 150 ° C by the general formula (IIIb)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3b are as described above.
Specific bases include carbonates, alkoxides, hydroxides or hydrides of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, or n- Organometallic bases represented by alkyllithium such as butyllithium, dialkylaminolithium such as lithium diisopropylamide, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine- 2-one dimethyl sulfoxide, sulfolane, acetone, etc. are mentioned.
If this procedure the nitrogen compound Q ^3b shown by the general formula (VIIIb) obtained is self-protected by deprotection as needed, to obtain the compound represented by the general formula (VIIIa).
Moreover, the compound represented by general formula (VIIIa) can be obtained by removing the nitrogen protecting group of the compound represented by general formula (VIIIc) by a suitable method.

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , X ¹ , and X ² are as described above. Q ^3c means any of the following groups.]

Wherein R ²² represents a hydrogen atom,
Alkyl group,
A hydroxy group protected by a methoxymethyl group or tetrahydropyranyl group,
A hydroxyalkyl group protected by a methoxymethyl group or tetrahydropyranyl group,
Alkoxy Group,
Alkoxyalkyl group,
Dialkoxyalkyl group,
Dialkylamino group,
Monoalkylamino group which protected the amino group by the tertiary butoxycarbonyl group,
Dialkylaminoalkyl group,
Monoalkylaminoalkyl group which protected the amino group by the tertiary butoxycarbonyl group,
Dialkylaminocarbonyl group,
Dialkylaminocarbonylalkyl group,
Dialkylaminocarbonyloxy group,
Monoalkylaminoalkyloxy group which protected the amino group by the tertiary butoxycarbonyl group, or
A dialkyl amino carbonyl alkyl oxy group etc. are meant.
When the carbon atoms to which R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are bonded are not adjacent to the nitrogen atom, they are each independently
Hydrogen atom,
Alkyl group,
A hydroxy group protected by a methoxymethyl group or tetrahydropyranyl group,
A hydroxyalkyl group protected by a methoxymethyl group or tetrahydropyranyl group,
Alkoxy Group,
Alkoxyalkyl group,
Dialkoxyalkyl group,
Dialkylamino group,
Monoalkylamino group which protected the amino group by the tertiary butoxycarbonyl group,
Dialkylaminoalkyl group,
Monoalkylaminoalkyl group which protected the amino group by the tertiary butoxycarbonyl group,
Monoalkylaminoalkyl group which protected the amino group by the tertiary butoxycarbonyl group,
Dialkylaminocarbonyl group,
Dialkylaminocarbonylalkyl group,
Dialkylaminoalkyloxy group,
Monoalkylaminoalkyloxy group which protected the amino group by the tertiary butoxycarbonyl group,
Or a dialkylaminocarbonylalkyloxy group.
When the carbon atoms to which R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are bonded are adjacent to the nitrogen atom, they are each independently
Hydrogen atom,
Alkyl group,
A hydroxyalkyl group in which a hydroxy group is protected by a methoxymethyl group or tetrahydropyranyl group, etc.,
Alkoxyalkyl group,
Dialkoxyalkyl group,
Dialkylaminoalkyl group,
Monoalkylaminoalkyl groups in which an amino group is protected by a tertiary butoxycarbonyl group,
Dialkylaminocarbonyl group,
It means a dialkylaminocarbonylalkyl group or a dialkylaminoalkyloxy group.
R ²³ and R ²⁴ , R ²⁵ and R ²⁶ may be a single saturated or unsaturated 5 to 7 membered heterocyclic ring or a saturated or unsaturated 5 to 7 membered heterocyclic ring which may have a substituent. May mean tableware or R ²⁷
Alkyl group,
A hydroxyalkyl group protecting a hydroxy group,
A hydroxyalkylcarbonyl group protecting a hydroxy group,
A hydroxyalkylsulfonyl group protecting a hydroxy group,
Alkoxyalkyl group,
Alkoxyalkylcarbonyl group,
Alkoxyalkylsulfonyl group,
Alkylcarbonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonyl group,
Alkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
Dialkylaminoalkyl group,
Monoalkylaminoalkyl group which protected the amino group by the tertiary butoxycarbonyl group,
Dialkylaminocarbonyl group,
A dialkyl amino carbonyl alkyl group etc. are meant.
In addition, R <^25> and R <^27> or R <^26> and R <^27> may mean together the saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent.
R ²⁸ means tertiary butoxycarbonyl group, benzyl group or triphenylmethyl group. j and k mean an integer of 0 or 1. l means the integer of 1-3. Provided that the sum of k and l means an integer from 1 to 4.)
General formula (IIIb) obtained by a known method or its application
Q ^3c -H (IIIb)
Amino compounds represented by
[Wherein, Q ^3c is as described above.]
Formula (IXa) obtained by reacting with alkylsulfonic acid halide in the presence of a suitable base

[Wherein, R ³ and Q ^3c are as described above.]
The carbonyl compound represented by the general formula (XIa) in an inert solvent in the presence of a sulfonamide represented by

[Wherein, R ² , R ⁴ , R ⁵ , R ²² , X ¹ and X ² are as described above. ]
Reacted with alcohol (XIIa)

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ²² , Q ^3c , X ¹ and X ² are as described above. ] And converting the alcohol of the alcohol represented by the general formula (XIIa) to methanesulfonyloxy group or the like in the presence of a suitable base, or to halogen atoms by phosphorus halide or triphenylphosphine / halogenated carbon According to the method, the compound represented by the general formula (VIIIc) can be obtained by leaving the group and leaving methanesulfonic acid or hydrogen halide in the presence of a suitable base.
The amino compound obtained by the known method represented by the general formula (IIIb) or its application is reacted with an alkylsulfonic acid halide which may have a substituent in an inert solvent in the presence of a suitable base at -78 ° C to 150 ° C, thereby providing a general formula (IXa The sulfonamido compound represented by) can be obtained.
Examples of the base include carbonates of alkali or alkaline earth metals such as sodium carbonate and potassium carbonate, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine and diisopropylethyl. Amines, organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); and the like.
Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine- 2-one etc. can be mentioned, According to the kind of base to be used, dimethyl sulfoxide, sulfolane, acetone, etc. can be used.
Represented by the general formula (XIIa) by reacting the sulfonamide represented by the general formula (IXa) with a carbonyl compound represented by the general formula ( A) in an inert solvent at -78 ° C to 110 ° C in an inert solvent. Alcohol compounds can be obtained.
Specific bases include hydrides of alkali metals or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, or alkyllithium such as n-butyllithium and dialkylaminolithium such as lithium diisopropylamide. The organometallic base etc. which are represented by these are mentioned.
Tetrahydrofuran, 1,2-dimethoxyethane, dioxane, etc. are mentioned as an inert solvent.
Hydroxy groups of alcohols represented by the general formula (XIIa) are carbonates or pyridine, alkali, or alkaline earth metals such as sodium carbonate and potassium carbonate, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, Dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran in the presence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) , Triphenylphosph such as phosphorus halide or triphenylphosphine dibromide such as phosphorus pentachloride at -20 ° C to 110 ° C in solvents such as 1,2-dimethoxyethane, dioxane, toluene and N, N-dimethylformamide Treated with a pin halogen complex to form a halide, and the resulting halide leaves the hydrogen halide in the presence of basic, e.g., dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethok Ethane, dioxane, toluene, N, N-dimethylformamido, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, in dimethyl sulfoxide, sodium carbonate, potassium carbonate, sodium ethoxide, Carbonates, alkoxides, hydroxides or hydrides of alkali or alkaline earth metals such as potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, alkyllithium such as n-butyllithium, lithium diisopropylamine and Organometallic bases represented by the same dialkylaminolithium, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] The compound represented by the general formula (VIIIc) can be obtained by treating the compound with an organic base such as Undec-7-ene (DBU) at -78 ° C to 150 ° C.
Moreover, the hydroxy group of the alcohol body represented by general formula (XIIa) is a carbonate or pyridine, 2,6- lutidine, collidine, 4-dimethylaminopyridine, triethyl of an alkali metal or alkaline earth metal such as sodium carbonate and potassium carbonate. Dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, in the presence of an organic base such as amine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), 1 Alkyl or aryl sulfonic acid ester derivatives by treating with an alkyl or aryl sulfonate such as methanesulfonic acid chloride at -20 ° C to 110 ° C in a solvent such as, 2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, etc. The compound represented by the general formula (VIIIc) can be obtained by leaving the alkyl or arylsulfonic acid ester derivative away from the alkyl or arylsulfonic acid ester derivative in the presence of basic. That is, for example, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamido, N, N-dimethylacetamide, N-methyl Alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride in an inert solvent such as pyrrolidin-2-one and dimethyl sulfoxide Organometallic bases represented by carbonates, alkoxides, hydroxides or hydrides, or alkyllithium such as n-butyllithium, dialkylaminolithium such as lithium diisopropylamine, or pyridine, 2,6-lutidine, collidine And organic bases such as 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU) Compound represented by general formula (VIIIc) by treatment at ℃ Get
In addition, the compound represented by general formula (VIIIc) makes the sulfonamide represented by general formula (IXa) into a silyl compound by silyl halogen compounds, such as trimethylsilyl chloride, in an inert solvent in presence of a suitable base, Furthermore, in presence of a base, It can obtain by making it react with the carbonyl compound represented by general formula (XIa) in an inert solvent, and then processing under basic aqueous conditions in acidic condition (Peterson reaction). That is, the sulfonamide represented by general formula (IXa) is -78 degreeC-110 degreeC, for example, sodium ethoxide and potassium butoxide in solvents, such as tetrahydrofuran, a 1, 2- dimethoxyethane, a dioxane, etc. , An hydride of an alkali metal or an alkaline earth metal such as sodium hydride or potassium hydride, or an organometallic base represented by an alkyl lithium such as n-butyllithium or a dialkylaminolithium such as lithium diisopropylamine, An alkylsilyl chloride such as trimethylsilyl chloride is used to form a silyl compound, and then condensation with a carbonyl compound represented by the general formula ( A) under the same conditions, followed by treatment under basic conditions under acidic conditions to give the general formula (VIIIc). Compounds can be obtained.
Removal of the nitrogen atom protecting group of the compound represented by the general formula (VIIIc) can be removed according to a method generally used. That is, in the case of the tertiary butoxycarbonyl group, it can be removed by a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. In addition, arylmethyl groups such as benzyl groups can be removed by hydrogenolysis using a palladium / carbon catalyst, and triphenylmethyl groups are suitable acids such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, tri It can be removed by fluoromethanesulfonic acid or a combination of these acids. In the liquid ammonium, benzyl groups may be removed by birch reduction using sodium metal, or may be removed by hydrogenolysis using a palladium / carbon catalyst.
The protecting group of the compound of formula (VIIIc) may be removed to obtain a compound represented by formula (VIIIa). For example, suitable activators of the carboxylic acid represented by the general formula (IVa) are those obtained by reacting the carboxylic acid represented by the general formula (IVa) with an chloroformic acid ether such as isobutyl chloroform as anhydride. Mixed acid anhydrides, acid halides such as acyl chlorides prepared using inorganic acid halides such as thionyl chloride, phenols such as paranitrophenol, active esters obtained by reacting pentafluorophenyl-trifluoroacetate, N Active esters obtained by reaction with hydroxybenztriazole or N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N, usually used for amino acid synthesis Reaction product with '-ethylcarbodiimide hydrochloride, reaction product with diethyl cyanophosphonic acid (Shioiri's method), triphenylphosphine and 2,2'-dipyridyl And the like can be mentioned reaction products (Mukaiyama's 法) of the feed.
The sulfonyl derivative represented by the general formula (I) is reacted with the activator of the carboxylic acid thus obtained and the compound represented by the general formula (VIIIa) at -78 ° C to 150 ° C in an inert solvent in the presence of a suitable base. You can get it.
Examples of the base include carbonates, alkoxides, hydroxides or hydrides of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, or n-butyl Organometallic bases represented by alkyllithium such as lithium, dialkylaminolithium such as lithium diisopropylamide, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methyl Organic bases such as morpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine- 2-one, dimethyl sulfoxide, sulfolane, acetone, etc. are mentioned.
[Manufacturing Method-2- (1)]
Compound represented by general formula (VIIIa) to be acylated

In which the nitrogen atom of Q ^3a of [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a is as described above] is a primary or secondary amine, As carbonates, hydroxides or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmol of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide Organic bases such as porin, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like are optimal. In addition to the inert solvent, alcohol solvents such as ethanol and butanol, acetate ethyl Ester solvents, such as ester, can also be used.
[Manufacturing Method-2- (2)]
Compound represented by general formula (VIIIa) to be acylated

^Wherein the nitrogen atom of Q ^3a of [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a is as described above] is a nitrogen atom forming an amide bond, For example, alkoxides of alkali or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride, potassium hydride, or alkyllithium such as hydrides or n-butyllithium, di-dipropyl, such as lithium diisopropylamide Organometallic bases represented by alkylaminolithium, or organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); and the like. As the inert solvent, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and N, N-dimethylformamide are preferable.
[Manufacturing Method-3]
Compound represented by general formula (VIIIa)

^Wherein the nitrogen atom of Q ^3a in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a is as described above is a nitrogen atom forming an amide bond. The nitrogen atom of the compound represented by (VIIIa) is represented by general formulas (Va) to (Vd).
Q ¹ -Q ^2b -CHL ¹ R ¹⁸ (Va)
^{Q 1 - N (R 20)} - (CH 2) m1 - CHL 1 R 18 (Vb)
_{^{Q 1 - O - (CH 2}} ) m1 - CHL 1 R 18 (Vc)
_{^{Q 1 - S - (CH 2}} ) m1 - CHL 1 R 18 (Vd)
Wherein Q ¹ , Q ^2b , R ¹⁸ , R ²⁰ , m ¹ and L ¹ are the same as described above. A method for producing the sulfonyl derivative of the present invention by alkylation.
When the nitrogen atom of Q ^3a of the compound represented by general formula (VIIIa) is a nitrogen atom of an amide bond, the nitrogen atom of Q ^3a of the compound represented by general formula (VIIIa) is represented by general formulas (Va) to (Vd) By alkylation with a compound, a sulfonyl derivative represented by the general formula (I) can be synthesized. That is, the compound represented by the general formula (VIIIa) is reacted with the compound represented by the general formulas (Va) to (Vd) for 0.5 hour to 120 hours at -78 ° C to 150 ° C in an inert solvent in the presence of a suitable base to provide nitrogen. Alkylation of an atom can be performed and the sulfonyl derivative represented by general formula (I) can be obtained.
Examples of the base include alkoxides or hydrides of alkali metals or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, or alkyllithium such as n-butyllithium, lithium diisopropylamide Organometallic bases represented by dialkylaminolithium such as, or organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU), and the like, and examples of the inert solvents include tetrahydrofuran, 1 , 2-dimethoxyethane, toluene, dioxane, N, N-dimethylformamide and the like are preferable.
[Manufacturing Method-4]
Compound represented by general formula (VIIIa)

^Wherein the nitrogen atom of Q ^3a of [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a is as described above] is a primary or secondary amine, Carbonyl compound represented by (VIa)-(VId)
Q ¹ -Q ^2b -C (= O) R ¹⁸ (VIa)
^{Q 1 - N (R 20)} - (CH 2) m1 - C (= O) R 18 (VIb)
_{^{Q 1 - O - (CH 2}} ) m1 - C (= O) R 18 (VIc)
_{^{Q 1 - S - (CH 2}} ) m1 - C (= O) R 18 (VId)
[Wherein, Q ¹ , Q ^2b , R ¹⁸ , R ²⁰ and m1 are as described above.] A method for producing a sulfonyl derivative (I) by forming an imine and reducing the same.
When the nitrogen atom of compound Q ^3b represented by general formula (VIIIa) is an amine, the compound represented by general formula (VIIIa) and the carbonyl compound represented by general formulas (VIa) to (VId) are usually required in an inert solvent. In the presence of organic acids such as acetic acid, mineral acids such as hydrochloric acid, or Lewis acids such as aluminum chloride, imine is formed at -20 ° C to 150 ° C for 0.5 hours to 120 hours, and the imine produced is added to sodium borohydride or cyanide in an inert solvent. Sulfate represented by the general formula (I) by hydrogenating a boron hydride reducing agent such as sodium borohydride or sodium triacetoxy borohydride or a catalytic reduction catalyst such as palladium / carbon catalyst for 0.5 hours to 120 hours Ponyl derivatives can be obtained.
Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine- 2-one, dimethyl sulfoxide, sulfolane and the like are preferred.
[Manufacturing Method-5]
Compound represented by general formula (VIIIa)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a are as described above), Q ^3a in the formula (VIIIa) is a primary or secondary amine. Any compound of the secondary amine represented by the primary or general formula (VIIe) represented by general formula (VIIa)-(VIId) using reagents, such as carbonyldiimidazole, for the compound represented by
Q ¹ -Q ^2b -NH ₂ (VIIa)
^{Q 1 - N (R 20)} - (CH 2) m1 - NH 2 (VIIb)
Q ¹ -O-(CH ₂ ) _{m 2} -NH ₂ (VIIc)
Q ¹ -S-(CH ₂ ) _{m 2} -NH ₂ (VIId)

[Wherein, Q ¹ , Q ^2b , R ²⁰ and m 2 and
group

Is the same as described above.] To form a urea derivative.
When compound Q ^3a represented by general formula (VIIIa) is an amine, the compound of the primary amine represented by general formula (VIIa)-(VIId) or secondary amine represented by general formula (VIIe) and 1,1'- It is possible to induce the sulfonyl derivative of the present invention represented by the general formula (I) to be a urea derivative by reacting a reagent such as carbonyldiimidazole.
The reaction is carried out in a reagent such as carbonyldiimidazole, a primary amine compound represented by formulas (VIIa) to (VIId) or a secondary amine compound represented by formula (VIIe) and a compound represented by formula (VIIIa). If necessary, it can be synthesized by reacting sequentially in an inert solvent in the presence of a base. Inert solvents include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine- 2-one, dimethyl sulfoxide, sulfolane, etc. are mentioned, Preferably they are chloromethane, tetrahydrofuran, toluene, etc.
Bases include carbonates, hydroxides or pyridines of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydroxides or pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methyl Organic bases such as morpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like, and the reaction may be performed in the range of -70 ° C to 110 ° C.
[Manufacturing Method-6]
Compound represented by general formula (VIIIa)

^Wherein the nitrogen atom of Q ^3a of [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and Q ^3a is as described above] is a primary or secondary amine, Isocyanate derivatives (Q ¹ -Q ^2b -N = C = O), wherein Q ¹ and Q ^2b are as described above. Or carboxylic acids represented by general formulas (IVa) to (IVd).
Q ¹ -Q ^2b -COOH (IVa)
^{Q 1 - N (R 20)} - (CH 2) m1 - COOH (IVb)
_{^{Q 1 - O - (CH 2}} ) m1 - COOH (IVc)
_{^{Q 1 - S - (CH 2}} ) m1 - COOH (IVd)
[Wherein, Q ¹ , Q ^2b , R ²⁰ and m ¹ are the same as described above]; a sulfide represented by the general formula (I) having a urea group by reacting an isocyanate generated from the amine represented by the general formula (VIIIa). Method of Making Ponyl Derivatives.
If the Q ^3a compound represented by the general formula (VIIIa) is an amine, the sulfonyl derivative represented by the formula (I) can be obtained by 0.5 hours at ~120 sigan in an inert solvent, -20 ℃ ~100 ℃.
An isocyanate derivative can be synthesize | combined from the carboxylic acid represented by general formula (IVa)-(IVd). That is, the carboxylic acid represented by general formulas (IVa) to (IVd) is an acid halide with thionyl chloride, oxaryl chloride, or the like, and reacts with sodium azide in an inert solvent in the range of 0 ° C to 60 ° C. Heating followed by heating; A method of reacting the carboxylic acid represented by the general formula (IVa) with chloroformate esters such as isobutyl chloroformate, making it a mixed acid anhydride, and reacting with sodium azide, followed by heating; Alternatively, the carboxylic acid represented by the formulas (IVa) to (IVd) is guided to hydrazide via-ester at -20 ° C to 110 ° C in an inert solvent such as tetrahydrofuran, chloroform or toluene, and then nitrous acid Alternatively, the alkyl ester may be reacted with an acyl azide to be synthesized by a method of heating to 20 ° C. to 150 ° C. in a solvent such as chloroform, dichloroethane, toluene, xylene, N, N-dimethylformamide, or the like.
The carboxylic acid represented by the general formulas (IVa) to (IVd) is reacted with diphenylphosphoryl azido in a range of 10 ° C. to 100 ° C. in an inert solvent in the presence of a base such as triethylamine. The sulfonyl derivative represented by general formula (I) can be manufactured by making it react with the amine represented by VIIIa).
[Manufacturing Method-7]
General formula (I) by coupling reaction using transition metal catalyst

A sulfonyl derivative represented by [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q ¹ , Q ² , Q ³ , T ¹ , X ¹ and X ² are as described above.] How to.
An aryl group in which a halogen atom or a trifluoromethanesulfonyloxy group is substituted in the structure of Q ¹ of the sulfonyl derivative represented by general formula (I), or an alkenyl group in which a halogen atom or trifluoromethanesulfonyloxy group is substituted When present, the transition metal catalyst may be used for the coupling reaction with an aryl compound substituted with a boric acid group.
If there alkenyl groups in the structure of Q ^1-sulfonyl derivative represented by the general formula (I) it is also possible to a halogen atom or a trifluoromethyl group is methanesulfonyloxy ring substituted aryl group and coupling using a transition metal catalyst.
Similarly, when an aryl group substituted with a boric acid group is present in the structure of the sulfonyl derivative Q ¹ represented by Formula (I), an aryl compound or a halogen atom or a trifluoromethanesulfonyl substituted with a halogen atom or a trifluoromethanesulfonyloxy group The oxy group can be reacted with a substituted alkenyl compound.
When the aryl group in which the halogen atom or trifluoromethanesulfonyloxy group is substituted in the structure of the sulfonyl derivative Q ¹ represented by the general formula (I) is coupled with an alkenyl compound and a transition metal catalyst, the general formula (I It is also possible to obtain the sulfonyl derivative represented by).
The sulfonyl derivative represented by general formula (I) thus obtained can be deprotected as necessary to obtain a compound represented by general formula (Ia).
An aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group, or an alkenyl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is present in the structure of the sulfonyl derivative Q ¹ represented by formula (I). Sodium bicarbonate, sodium hydroxide, barium hydroxide in a two-phase solvent such as benzene-water and toluene-water, an amide solvent such as N, N-dimethylformamide, and an ether solvent such as tetrahydrofuran or dimethoxyethane And an aryl derivative having a boric acid group substituted at 20 ° C. to 150 ° C. using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0) in the presence of a base such as potassium phosphate or cesium carbonate. The coupling reaction can be carried out for 120 hours.
When an aryl group having a boric acid group is present in the structure of the sulfonyl derivative Q ¹ represented by formula (I), an aryl compound or a halogen atom or a trifluoromethanesulfonyloxy substituted with a halogen atom or a trifluoromethanesulfonyloxy group The coupling reaction may be performed with an alkenyl compound substituted with a group.
In addition, if any group is alkenyl to the structure of the sulfonyl derivative Q ¹ represented by the general formula (I) include methanesulfonyl Suitable bases presence, halogen atom or trifluoromethyl group, using a transition metal catalyst such as palladium acetate sulfonyl-oxy group It is also possible to carry out coupling reaction for 0.5 to 120 hours in the range of 20 degreeC-150 degreeC among amide type solvents, such as a substituted aryl group and N, N- dimethylformamide.
Similarly, when an aryl group substituted with a boric acid group is present in the structure of the sulfonyl derivative Q ¹ represented by formula (I), an aryl derivative substituted with a halogen atom or a trifluoromethanesulfonyloxy group, or a halogen atom or trifluoromethane The sulfonyloxy group may be subjected to a coupling reaction with a substituted alkenyl derivative.
When a aryl group in which a halogen atom or a trifluoromethanesulfonyloxy group is substituted in the structure of the sulfonyl derivative Q ¹ represented by the general formula (I) exists, the alkenyl compound and the transition gold catalyst are used for coupling to form a general formula. The sulfonyl derivative represented by (I) can be obtained. The sulfonyl derivative represented by the general formula (I) thus obtained can be deprotected as necessary to obtain a sulfonyl derivative represented by the general formula (I) obtained by converting a substituent.
[Manufacturing Method-8]
Method for producing amide oxime sulfonamide
Formula (I)

T of the sulfonyl derivative represented by [wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q ¹ , Q ² , Q ³ , T ¹ , X ¹ and X ² are as described above.] ¹ -Q ³

[Wherein, R ⁸ , R ⁹ , R ¹² , R ¹³ and R ¹⁴ are as described above. n means an integer of 1 or 2. p means an integer of 1 to 3. q means an integer from 0 to 3. Provided that the sum of p and q means an integer of 3 or 4.], and R ⁸ , R ⁹ , R ¹² , of R ¹ , Q ¹ , Q ² , and Q ³ in Formula (I). The sulfonyl derivative represented by general formula (I) when there is no substituent having an amine group, an alkylamine group, an amide group, a hydroxy group, or a carboxylic acid group on R ¹³ , R ¹⁴ and a substituent which may be substituted on these In an inert solvent, a halogenating agent such as phosphorus pentachloride or an alkylating agent such as meerinin reagent is reacted at -30 ° C to 140 ° C, preferably in a halogen solvent such as chloroform at 0 ° C to 80 ° C. Iminochloride or imino ether, and in the iminochloride or imino ether in an inert solvent at 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C., in the presence of a base catalyst, if necessary, in hydroxyl Reacting general formula (I) by reacting alkoxyamine or these salts which may have an amine or a substituent Displayed can be obtained sulfonyl derivative.
Examples of inert solvents include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and aromatic solvents such as benzene and toluene. Alkyl halide solvents are preferred.
Examples of the base include carbonates, alkoxides, hydroxides or hydrides of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, or n-butyl Organometallic bases represented by alkyllithium such as lithium, dialkylaminolithium such as lithium diisopropylamine, or pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methyl Organic bases such as morpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
[Manufacturing Method-9]
N-oxide
In the sulfonyl derivative represented by general formula (I), R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a heterocyclic aromatic ring or aliphatic tertiary containing a nitrogen atom on a substituent which may be substituted on these When amine is present, sulfonyl derivatives represented by the general formula (I) may be selected from ketone solvents such as water, acetate and acetone, benzene solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and dimethoxyethane. Or a peroxide such as hydrogen peroxide, metachloroperbenzoic acid, or tert-butylhydroperoxide in a halogenated alkyl solvent such as dichloromethane, chloroform, carbon tetrachloride, or the like at -40 ° C to 60 ° C for 0.5 to 120 hours, preferably -20 ° C. By reacting at -20 degreeC, the sulfonyl derivative represented by general formula (I) of an N-oxide derivative can be obtained.
[Manufacturing Method-10]
Quaternization of nitrogen atoms
In the sulfonyl derivative represented by general formula (I), R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a heterocyclic aromatic ring or aliphatic containing a nitrogen atom on a substituent which may be substituted on these In the presence of tertiary amines, sulfonyl derivatives represented by the general formula (I) include amide solvents such as 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, and N, N-dimethylform. Among amide solvents such as amide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one, and sulfoxide solvents such as dimethyl sulfoxide and sulfolane, such as methyl iodide and ethyl iodide The sulfonyl derivative represented by general formula (I) of a quaternary amine can be obtained by making alkyl halide react at -10 degreeC-150 degreeC, Preferably 0 degreeC-80 degreeC.
[Manufacturing Method-11]
Sulfoxide and sulfonation
In the sulfonyl derivative represented by the general formula (I), when there is a heterocyclic or aliphatic thioether containing a sulfur atom on R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a substituent substitutable for these, The sulfonyl derivatives represented by the general formula (I) include ketone solvents such as water, acetic acid and acetone, benzene solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and dimethoxyethane, or dichloromethane; In a halogenated alkyl solvent such as chloroform and carbon tetrachloride, peroxides such as hydrogen peroxide, metachloroperbenzoic acid, or tert-butylhydroperoxide are reacted at -40 ° C to 60 ° C for 0.5 to 120 hours, preferably -20 to 20 ° C. The sulfonyl derivative represented by general formula (I) of a sulfoxide or a sulfone can be obtained by doing this.
[Manufacturing Method-12]
Amidino-1
In the sulfonyl derivative represented by general formula (I), when there is a nitrile group on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable therewith, it is amidino according to a general method commonly used. Can be converted to a group. For example, a sulfonyl derivative containing an amidino group represented by the general formula (I) may be optionally substituted with aliphatic ether solvents such as diethyl ether, halogenated alkyl solvents such as chloroform and dichloromethane, and aprotic properties such as benzene. In a solvent or a mixed solvent thereof, in the presence of hydrogen halides such as hydrogen chloride and hydrogen bromide, an equivalent to excess amount of C1-4 alcohols such as methanol, ethanol, propanol, etc., at -10 ° C to 60 ° C for 3 hours to 120 The iminoether body obtained by making it act as an iminoether body for a time is made into C1-C4 alcohols, such as ethanol and a propanol, Aliphatic ether solvents, such as diethyl ether, Halogenated alkyl solvents, such as chloroform, Ratio, such as benzene Ammonium, a monoalkylamine which may have a substituent, or a dialkylamine which may have a substituent in solvents, such as a protic solvent, dimethylformamide, and dimethyl sulfoxide, Is a general formula (I) having an amidino group by reacting these carbonates and acetates at −10 ° C. to 140 ° C. for 0.5 hour to 200 hours, preferably in ethanol at −8 ° C. to 30 ° C. for 10 to 96 hours. The sulfonyl derivative shown can be obtained.
[Manufacturing Method-13]
Amidino-2
In the sulfonyl derivative represented by the general formula (I), in the case where there is a primary or secondary amino group on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable therewith, a generally used method This can be converted into a substituted amidino group. For example, a sulfonyl derivative containing an amidino group represented by the general formula (I) may be optionally substituted with aliphatic ether solvents such as diethyl ether, halogenated alkyl solvents such as chloroform and dichloromethane, and aprotic properties such as benzene. Imine ether, imino chloride or these salts synthesized from an amide compound or a nitrile compound in a solvent or a mixed solvent in the presence of a base, if necessary, at -10 ° C to 140 ° C for 0.5 to 200 hours, preferably By making it react for 10 to 96 hours at 0 degreeC-80 degreeC, the sulfonyl derivative represented by general formula (I) which has an amidino group can be obtained. Bases include sodium carbonate, potassium carbonate, sodium, sodium hydroxide, carbonates, hydroxides or pyridine of alkali or alkaline earth metals such as potassium hydroxide, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N Organic bases such as -methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
[Manufacturing Method-14]
N-nitrilation
In the sulfonyl derivative represented by the general formula (I), in the case where there is a primary or secondary amine on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable therewith, it is generally used. Depending on the method, this can be cyanoated.
For example, the sulfonyl derivative represented by the general formula (I) is preferably -10 ° C to 110 ° C in the presence of salts and bases such as acetate sodium in alcohol solvents such as methanol, ethanol and propanol, if necessary. Preferably, the sulfonyl derivative represented by the general formula (I) having a nitrile group on a nitrogen atom can be obtained by reacting cyanide bromide at 0 ° C to 60 ° C.
Specific bases include carbonates, hydroxides or pyridines of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydroxides, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
[Manufacturing Method-15]
Amidoxime or carboxamide-O-alkyl oxime
In the sulfonyl derivative represented by the general formula (I), when a nitrile group is present on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable therewith, this is according to a general method used. It can be planted or carboxamide-O-alkyl oxime. For example, if necessary, sulfonyl derivatives represented by the general formula (I) include alcohol solvents such as methanol, ethanol and propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as chloroform and dichloromethane. Aprotic solvents such as toluene, amide solvents such as N, N-dimethylformamide, solvents such as dimethyl sulfoxide, or a mixed solvent thereof, preferably at -10 ° C to 110 ° C, preferably 0 ° C to Sulfur represented by the general formula (I) having an amidoxime or carboxamide-O-alkyloxime group by reacting hydroxylamine or an alkoxyamine or a salt thereof, which may have a hydroxylamine or a substituent, if necessary at 60 ° C. Ponyl derivatives can be obtained.
Specific bases include carbonates, hydroxides or pyridines of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydroxides, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
[Manufacturing Method-16]
Guanidine
In the sulfonyl derivative represented by the general formula (I), in the case where there is a primary or secondary amine on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable therewith, it is generally used. Depending on the method, this can be converted to a substituted or unsubstituted guanidine group.
For example, sulfonyl derivatives represented by the general formula (I) having primary or secondary amines may be substituted with aliphatic ether solvents such as diethyl ether, halogenated hydrocarbons such as chloroform and dichloromethane, and aprotons such as benzene. -10 ° C to -N in a solvent or a mixed solvent thereof, if necessary, in the presence of a base catalyst, N, N'-di-tert-butoxycarbonylthiourea and N, N'-dicyclohexylcarbodiimide as a condensing agent After reacting at 140 ° C for 0.5 to 200 hours, preferably at 0 ° C to 80 ° C for 10 to 96 hours, the tertiary butoxycarbonyl group which is usually used is removed to be represented by the general formula (I) which is a guanidino compound. Sulfonyl derivatives can be synthesized. Specific bases include carbonates, hydroxides or pyridines of alkali or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydroxides, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N- Organic bases such as methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like.
[Manufacturing Method-17]
Nitrogen Atom Protector Removal
In the sulfonyl derivative represented by the general formula (I), when an acylamino group or an alkoxycarbonylamino group is present on R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a substituent which may be substituted on these, water, lower alcohol Alternatively, an amino substance can be obtained by hydrolyzing at a temperature of 0 ° C. to 80 ° C. with an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide as a base in tetrahydrofuran or a mixture of these solvents.
The nitrogen atom to which an acyl protecting group such as a tertiary butoxycarbonyl group or paramethoxybenzyloxycarbonyl group is bonded may be a halogenated alkyl solvent such as dichloromethane, chloroform or carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane or dioxane. Among aromatic solvents such as ether solvents, benzene and toluene, suitable acids such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or combinations of these acids By removing the acyl protecting group from the nitrogen atom at 0 ° C to 80 ° C.
In addition, the nitrogen atom to which the arylmethoxycarbonyl group such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, and para (ortho) nitrobenzyloxycarbonyl group binds is ethanol, tetrahydrofuran, acetic acid, N, N-dimethylformamide and the like. By hydrogenolysis using palladium carbon, these arylmethoxycarbonyl groups can be removed from the nitrogen atom and converted into nitrogen-hydrogen bonds.
Nitrogen atoms to which silyl protecting groups such as trimethylsilyl or tert-butyldimethylsilyl are bonded include ethers such as halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane and dioxane In an aromatic solvent such as a solvent, benzene, or toluene, hydrofluoric acid such as hydrochloric acid and tetrabutylammonium fluoride can be reacted at 0 ° C. to 80 ° C. to remove the silyl group from the nitrogen atom and convert it into a nitrogen-hydrogen bond. .
The nitrogen atom to which the benzyl group binds is removed from the solvent such as ethanol, tetrahydrofuran or acetic acid by catalytic reduction using a palladium carbon catalyst at 0 ° C. to 80 ° C. or by birch reduction using metal sodium in liquid ammonium. Can be converted to a nitrogen-hydrogen bond
The nitrogen atom to which the triphenyl group binds is removed by tricyclic group by catalytic reduction using a palladium carbon catalyst at 0 ° C. to 80 ° C. or by birch reduction using liquid sodium in liquid ammonium in a solvent such as ethanol, tetrahydrofuran or acetic acid. Can be converted to a nitrogen-hydrogen bond.
The nitrogen atom to which the triphenylmethyl group bonds is triphenyl by catalytic reduction using a palladium carbon catalyst or the like in a solvent such as ethanol, tetrahydrofuran or acetate at 0 ° C. to 80 ° C., or by birch reduction using metal sodium in liquid ammonium. The methyl group can be removed and converted into a nitrogen-hydrogen bond.
In addition, the silyl group is removed at a temperature of 0 ° C. to 80 ° C. by a suitable acid such as acetate, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetate, trifluoromethanesulfonic acid or a combination of these acids to form a nitrogen-hydrogen bond. Can be converted to
[Manufacturing Method-18]
Ester hydrolysis
In the sulfonyl derivative represented by the general formula (I), when there is an alkoxycarbonyl group on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable for these, alkoxy protected by methyl, ethyl ester or the like The carbonyl group can be converted to carboxylic acid by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. In the case of tertiary butyl esters, tertiary butyl groups can be removed by treatment with trifluoroacetic acid or hydrochloric acid, and in the case of arylmethyl group esters such as benzyl groups, arylmethyl groups may be obtained by hydrolysis using a palladium carbon catalyst. Can be removed to obtain carboxylic acid.
[Manufacturing Method-19]
In the sulfonyl derivative represented by the general formula (I), an acyloxy group, an arylmethyloxy group, a silyl ether group, and methoxy on R ¹ , Q ¹ , Q ² , Q ³ , and T ¹ or a substituent substitutable therefor When there is a methyl group or tetrahydropyranyl group, acyl groups such as alkanoyl group and aroyl group can be removed by hydrolysis with a suitable base such as alkali hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
The arylmethyl type protecting group can be removed by hydrogenolysis using a palladium carbon catalyst, and silyl ether groups such as tertiary butyldimethylsilyl group can be removed by hydrofluoric acid salts such as tetrabutylammonium fluoride. In addition, a methoxymethyl group, tetrahydropyranyl group, etc. can be removed with acetic acid, hydrochloric acid, etc.
[Manufacturing Method-20]
In the sulfonyl derivative represented by the general formula (I), when an amino group is present on R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a substituent substitutable thereto, the acyl halide or carboxylic acid usually used It can be acylated by the method using an activator, and can also acylate according to methods, such as reductive alkylation.
Moreover, the sulfonyl derivative represented by general formula (I) which becomes a urea derivative can be manufactured by making sulfonylation, isocyanate, or isocyanate derived from carboxylic acid react with sulfonic acid chloride.
[Manufacturing Method-21]
In the sulfonyl derivative represented by the general formula (I), when there is a carboxyl group on R ¹ , Q ¹ , Q ² , Q ³ , T ^1, or a substituent substitutable thereto, the active ester method or mixed acid anhydride which is usually used It can convert into a carbamoyl group, an alkyl carbamoyl group, or a dialkyl carbamoyl group by the method etc., and can be converted into a hydroxyl group, an aldehyde group by reduction. The converted hydroxy group or the aldehyde group may be subjected to functional group conversion such as conversion to an amino group or conversion to an alkylamino group by forming an ether bond by applying a conventional organic chemical method. Moreover, after converting a carboxyl group into ester directly or by a conventional method, or making it into a mixed acid anhydride, it can reduce and convert into an alcohol.
[Manufacturing Method-22]
Formation of phenol
In the sulfonyl derivative represented by the general formula (I), when there is a methoxy group substituted with an aryl group on R ¹ , Q ¹ , Q ² , Q ³ , T ¹ or a substituent substitutable thereto, dichloromethane, chloroform, Trimethylsilyl iodide at -78 ° C to 110 ° C in a halogenated alkyl solvent such as carbon tetrachloride, a benzene solvent such as toluene, a Lewis acid such as aluminum chloride or phosphorus tribromide, or a halogenated alkyl solvent or an ether solvent. By removing the methyl group can be converted to a hydroxyl group.
The sulfonyl derivatives represented by the general formula (I) of the present invention, their salts and solvates thereof have specific and superior FXa inhibitory effects and are useful as anticoagulants, blood clots, embolism prevention and / or treatment.
Since the sulfonyl derivative of the present invention exerts an effect even by oral administration, it can be administered by oral or parenteral methods.
The dosage of the sulfonyl derivative of the present invention may be appropriately increased or decreased depending on the symptoms, age, weight, and the like of the patient.
The sulfonyl derivative of the present invention may also be used as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.
In general, in the case of oral administration, 1 to 1000 mg / day, preferably 5 to 300 mg / day, per adult.
There is no restriction | limiting in particular as a dosage form, A tablet, a capsule, powder, a granule, suspension, a syrup, a dry syrup, etc. are mentioned, for example.
These can be prepared by known formulation techniques with additives such as conventional excipients, lubricants, binders and the like.
In the case of parenteral administration, there is no restriction | limiting in particular as a dosage form, For example, an ointment, an injection, a suppository etc. are mentioned. In the case of administration by injection, 0.1-100 mg / day, preferably 0.5-30 mg / day, per adult, may be injected subcutaneously, intravenously, or intravenously.
Although the sulfonyl derivative of this invention is demonstrated in detail, taking a reference example, an Example, and a test example as an example, this invention is not limited to these.
Example
Hereinafter, the sulfonyl derivative of the present invention and a method for producing the same will be described in detail. In addition, the raw compound of the sulfonyl derivative of the present invention also contains a novel compound, these compounds and their preparation method will be described with reference examples.
In the preparation of the compound, silica gel column chromatography used Melx silica gel 60 or silica gel for Yamazen medium pressure chromatography as a carrier.
In addition, nuclear magnetic resonance spectrum (NMR) was used as tetrahydromethylsilane as an internal standard.
Reference Example 1 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride and trifluoroacetic acid salt
tert-butylpiperazinecarboxylate (856 mg) was dissolved in dichloromethane (20 mL), triethylamine (0.77 mL) and 6-chloro-2-naphthylsulfonylchloride (1.20 g) were added and at room temperature Stir for 5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with IN hydrochloric acid. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in saturated ethanol (10 ml), concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain the hydrochloride (1.62 g, quant.) Of the title compound as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.1-3.4 (8H, m), 7.75 (lH, dd, J = 8.8, 2.0 Hz),
7.86 (lH, dd, J = 8.8, l.5 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.26-8.32 (2H, m),
8.56 (lH, s), 8.63 (2H, broad singlet).
MS (FAB) m / z: 311 [(M + H) ⁺ , Cl ³⁵ ], 313 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: C ₁₄ H _l5 ClN ₂ O ₂ S.HC1.0.lH ₂ O
Calc .: C, 48.17; H, 4.68, Cl, 20.31; N, 8.03; S, 9.19.
Anal: C, 47.91; H, 4.68; Cl, 20.41; N, 7.80; S, 9.21.
In addition, trifluoroacetic acid was obtained by treating with trifluoroacetic acid instead of saturated ethanol.
Elemental Analysis: C ₁₄ H _l5 ClN ₂ O ₂ S.CF ₃ CO ₂ H
Calc .: C, 45.24; H, 3.80, Cl, 8.35; F, 13.42; N, 6.59; S, 7.55.
Anal: C, 44.84; H, 3.80; Cl, 8.27; F, 13.72; N, 6. 29; S, 7.50.
Reference Example 2 4- (4-pyridyl) benzoic acid hydrochloride
At room temperature, 4-bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboronic acid (10.0 g) were dissolved in toluene (250 mL) and water (250 mL), and tetrakis (triphenylphosphine) palladium ( 0) (5.00 g) and anhydrous sodium carbonate (25.4 g) were added sequentially, and it heated and refluxed at 120 degreeC for 19 hours. After cooling to room temperature, ethyl acetate and water were added to separate the aqueous layer. In addition, the organic layer was extracted twice with water. After all the obtained aqueous layers were combined, concentrated hydrochloric acid was added to this solution to make acid, and the mixture was washed with ethyl acetate again. Solvent distillation to 100 mL of the aqueous layer precipitated a colorless solid, which was collected by filtration and dried under reduced pressure to obtain the title compound (8.37 g, 59%).
¹ H-NMR (DMSO-d ₆ ) δ: 8. 11 (2H, d, J = 8. 8 Hz),
8.14 (2H, d, J = 8 Hz), 8.35 (2H, d, J = 6.6 Hz), 8.97 (2H, d, J = 6.6 Hz).
Elemental _{analysis: C l2 H 9 NO 2} HCl a 0.3 H ₂ O
Calc .: C, 59.79; H, 4. 43; N, 5.81
Anal: C, 59.87; H, 4. 35; N, 5.53
MS (FAB) m / z: 200 (M + H) ⁺ .
Reference Example 3 1-tert-butoxycarbonyl-4- [4- (4-pyridyl) benzoyl] piperazine
4- (4-pyridyl) benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended in N, N-dimethylformamide (40 mL) and 1-hydroxybenzo Triazole (374 mg) and N-methylmorpholine (336 µl) were added and ice-cooled, followed by addition of 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg). The solvent was distilled off, and the residue was purified by silica gel column chromatography (2% methanol-dichloromethane) and washed with hexane to obtain the title compound (905 mg, 89%).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.40-3.91 (8H, m),
7.51 (2H, d, J = 5.9 Hz), 7.53 (2H, d, J = 8.l Hz), 7.69 (2H, d, J = 8.l Hz),
8.69 (2H, doublet, J = 5.9 Hz).
Elemental Analysis: as C _{2 l} H ₂₅ N ₃ O ₃
Calc .: C, 68.64; H, 6.86, N, 11.44.
Anal: C, 68.48; H, 6. 84; N, 11.17.
Reference Example 4 1- [4- (4-pyridyl) benzoyl] piperazine 2trifluoroacetic acid salt
1-tert-butoxycarbonyl-4- [4- (4-pyridyl) benzoyl] piperazine (944 mg) was dissolved in dichloromethane (30 mL) to give trifluoroacetic acid (30 mL) under ice-cooling. It added and stirred for 1 hour at room temperature. The solvent was distilled off, and tetrahydrofuran was added and it solidified, and the title compound (l.28g, 100%) was obtained as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.1-3.3 (4H, br s), 3.5-4.0 (4H, m),
7.65 (2H, d, J = 7.8 Hz), 7.95-8.05 (4H, m), 8.79 (2H, d, J = 5.4 Hz),
8.95-9.10 (lH, br s)
Reference Example 5 4-tert-butoxycarbonyl-2-ethoxycarbonyl-1- [4- (4-pyridyl) benzoyl] piperazine
1,2-dibromopropionic acid (58.0 g) was dissolved in toluene (150 ml), and toluene solution of N, N'-dibenzylethylenediamine (53.5 g) and triethylamine (53 ml) under ice-cooling Toluene 50 ml) was added dropwise. Toluene (100 mL) was added to this reaction liquid, it stirred at room temperature for 14 hours, toluene (100 mL) was added again, and it stirred at 60-80 degreeC for 4 hours. The insolubles were removed by filtration, the filtrate was washed with water and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in acetic acid (200 ml), 10% palladium / carbon (about 50% water content, 40 g) was added, and contact reduction was carried out at room temperature for 4 hours at 4 atmospheres. The catalyst was removed by filtration, and dichloromethane and saturated aqueous potassium carbonate solution were added to the residue obtained by distillation under reduced pressure, the organic layer was separated, and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in dichloromethane (350 ml), under ice-cooling, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (46.5 g) was added, and the temperature was gradually decreased to room temperature. The mixture was stirred for 14 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-2% methanol-dichloromethane) and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (5.82 g, 10%) ) The title compound was obtained in the same manner as the Reference Example 3 using this and 4- (4-pyridyl) benzoic acid hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.2-1.4 (3H, m), 1.46 (9H, s), 2.7-5.4 (7H, m),
7.51 (2H, d, J = 5.2 Hz), 7.59 (2H, d, J = 7.6 Hz), 7.69 (2H, d, J = 7.6 Hz),
8.69 (2H, doublet, J = 5.2 Hz).
MS (FAB) m / z: 440 (M + H) ⁺ .
Reference Example 6 6- (4-pyridyl) nicotinic acid hydrochloride
6-Chloronicotinic acid (535 mg) and diethyl (4-pyridyl) borane (500 mg) were dissolved in tetrahydrofuran (20 mL), and under an argon atmosphere, tetrabutylammonium bromide (546 mg) and potassium hydroxide ( 570 mg), tetrakis (triphenylphosphine) palladium (0) (392 mg), and water (0.5 mL) were added, and it heated and refluxed for 6 hours. Dilute hydrochloric acid was added to the reaction solution, acidified, water and ethyl acetate were poured and extracted, and the aqueous layer was distilled off under reduced pressure. The residue was purified by synthetic adsorbent chromatography (Diion HP-20, water-50% acetonitrile-water), diluted hydrochloric acid was added to the obtained fractions to make acid, solvent distilled, tetrahydrofuran was added, and the precipitate was filtered. Compound (269 mg, 32%) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 8.45-8.55 (2H, m), 8.65 (2H, d, J = 6.8 Hz),
9.03 (2H, doublet, J = 6.8 Hz), 9.27 (lH, s).
MS (FAB) m / z: 201 (M + H) ⁺
Reference Example 7 Methyl 4- (3-pyridyl) benzoate
Methyl 4-bromobenzoate (5.04 g) and diethyl-3-pyridylborane (2.30 g) were dissolved in tetrahydrofuran (100 mL), and under an argon atmosphere, tetrabutylammonium bromide (2.51 g) and potassium hydroxide ( 2.63 g), tetrakis (triphenylphosphine) palladium (0) (1.8 g), and water (1 mL) were added and heated to reflux for 2 hours. After cooling the reaction solution, an aqueous ammonium chloride solution and ethyl acetate were added, the organic layer was separated, and dried over anhydrous magnesium sulfate. The residue obtained after solvent distillation was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The solvent was distilled off, methanol and ethanol 1N hydrochloric acid were added to the residue, and the solvent was distilled once again, tetrahydrofuran was added, the precipitated solid was collected by filtration and dried to give the title compound (1.76 g, 45%) as a colorless solid. Got it.
¹ H-NMR (DMSO-d ₆ ) δ: 3.91 (3H, s), 8.0-8.1 (3H, m),
8.1-8.15 (2H, m), 8.75-8.85 (lH, m), 8.85-8.95 (lH, m), 9.25-9.3 (lH, m).
Reference Example 8 4- (3-pyridyl) benzoic acid hydrochloride
At room temperature, methyl 4- (3-pyridyl) benzoate (1.76 g) was dissolved in a mixed solvent of 1N hydrochloric acid (50 mL) and dioxane (50 mL), and the solvent was distilled off under reduced pressure after heating under reflux for 4 hours. Tetrahydrofuran was added to the residue, and the resultant was washed to obtain the title compound (1.55 g, 93%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 7.95-8.0 (3H, m), 8.10 (2H, d, J = 8.3 Hz),
8.65-8.75 (lH, m), 8.8-8.9 (lH, m), 9.22 (lH, d, J = 2.0 Hz)
Reference Example 9 Methyl 4- (2-aminopyridin-5-yl) benzoate
In the same reaction as in Reference Example 2, 4- (2-aminopyridin-5-yl) benzoic acid was obtained using 5-bromo-2-aminopyridine and 4-carboxyphenylboronic acid as raw materials.
The resulting 4- (2-aminopyridin-5-yl) benzoic acid (684 mg) was dissolved in methanol (50 mL) at room temperature, concentrated sulfuric acid (1 mL) was added thereto, and the mixture was heated to reflux for 2 hours, and then weakly alkaline with an aqueous sodium hydrogencarbonate solution. I did. Water and ethyl acetate were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Hexane was added to the residue to crystallize to obtain the title compound (243 mg, 23%).
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.57 (2H, br s),
6.60 (1H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz),
7.72 (lH, dd, J = 8.8, 2.4 Hz), 8.09 (2H, d, J = 8.8 Hz),
8.38 (lH, d, J = 2.4 Hz).
MS (FAB) m / z: 229 (M + H) ⁺ .
Elemental Analysis: C ₁₃ H _l2 N ₂ O ₂
Calc .: C, 68.41; H, 5.30, F, 12.27.
Anal: C, 68.78; H, 5. 45; M, 12.09.
Reference Example 10 Methyl 4- [2- (tert-butoxycarbonylamino) pyridin-5-yl] benzoate
At room temperature, 4- (2-aminopyridin-5-yl) methyl benzoate (200 mg) was suspended by adding tert-butanol (20 mg), and di-tert-butyldicarbonato (286 mg) was added thereto for 24 hours. Stirred. After distilling off the solvent, the residue was purified by silica gel column chromatography (1% methanol-dichloromethane) to obtain the title compound (155 mg, 54%) as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 3.95 (3H, s),
7.63 (2H, d, J = 8.3 Hz), 7.92 (lH, dd, J = 8.8, 2.4 Hz),
8.07 (lH, d, J = 8.8 Hz), 8.09 (lH, br s), 8.12 (2H, d, J = 8.3 Hz),
8.55 (lH, d, J = 2.4 Hz).
MS (FAB) m / z: 329 (M + H) ⁺ .
Elemental Analysis: C ₁₈ H ₂₀ N ₂ O ₄
Calc .: C, 65.84; H, 6. 14, N, 8.53;
Anal: C, 65.67; H, 6.02; N, 8.40.
Reference Example 11 4- [2- (tert-butoxycarbonylamino) pyridin-5-yl] benzoic acid
At room temperature, 4- [2- (tert-butoxycarbonylamino) pyridin-5-yl] methyl benzoate (250 mg) was suspended in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), 1N sodium hydroxide aqueous solution (8 ml) was added, and it stirred for 5 hours. Aqueous citric acid solution was added to make the reaction solution slightly acidic, saturated brine and n-butanol were added, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the crude product was obtained to give the title compound (120 mg, 49%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.49 (9H, s), 7.83 (2H, d, J = 8.3 Hz),
7.91 (1H, d, J = 8.8 Hz), 8.02 (2H, d, J = 8.3 Hz),
8.13 (lH, dd, J = 8.8, 2.4 Hz), 8.65 (1H, d, J = 2.4 Hz), 9.95 (lH, s),
12.99 (1H, broad singlet).
Reference Example 12 1- [4- [2- (tert-butoxycarbonylamino) pyridin-5-yl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
4- [2- (tert-butoxycarbonyl) amino] pyridine benzoic acid (74 mg) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetic acid salt (110 mg) It is suspended in a mixed solvent of dichloromethane (20 ml) and N, N-dimethylformamide (1 ml), 1-hydroxybenzotriazole (35 mg) and N-methylmorpholine (34 µl) are added, and ice-cooled. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (68 mg) was added. After stirring for 6 hours at room temperature, the solvent was distilled off and the residue was purified by silica gel column chromatography (1% methanol-dichloromethane). The solvent was distilled off to obtain the title compound (l28 mg, 90%).
¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 3.00-3.30 (4H, m), 3.50-4.10 (4H, m),
7.39 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.8 Hz), 7.60 (1H, dd, J = 8.8, 2.0 Hz),
7.71 (1H, dd, J = 8.8, 1.5 Hz), 7.84 (lH, dd, J = 8.8, 2.4 Hz), 7.88 (lH, br s),
7.9-8.0 (3H, m), 8.03 (1H, d, J = 8.8 Hz), 8.31 (lH, s),
8.46 (lH, d, J = 2.4 Hz).
Reference Example 13 4- (4-Aminophenyl) benzoic Acid Hydrochloride
In the same manner as in Reference Example 2, the title compound was obtained using 4-bromoaniline and 4-carboxyphenylboronic acid as raw materials.
¹ H-NMR (DMSO-d ₆ ) δ: 7.31 (2H, d, J = 7.3 Hz), 7.75-7.85 (4H, m),
8.09 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 213 (M ^&lt; ^{+ &} gt ^; ).
Elemental _{analysis: C 13 H 11 NO 2 ·} HCl
Calc .: C, 62.53; H, 4.84, N, 5.61; Cl, 14.20.
Anal: C, 62.33; H, 4.83; N, 5.50; Cl, 14.14.
Reference Example 14 4- [4- (tert-butoxycarbonylamino) phenyl] methylbenzoate
In the same reaction as in Reference Example 9 and Reference Example 10, the title compound was obtained using 4- (4-aminophenyl) benzoic acid hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 3.94 (3H, s), 6.56 (lH, br s),
7.46 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.3 Hz),
8.08 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 328 (M + H) ⁺ .
Elemental Analysis: C _l9 H ₂₁ NO ₄
Calc .: C, 69.71; H, 6.47, N, 4.28.
Anal: C, 69.49; H, 6. 44; N, 4.42.
Reference Example 15 4- [4- (tert-butoxycarbonylamino) phenyl] benzoic acid
Methyl 4- [4- (tert-butoxycarbonylamino] phenyl] benzoate (501 mg) was obtained in the same manner as in Reference Example 11 to obtain the title compound (426 mg, 89%).
¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 6.57 (lH, br s),
7.47 (2H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz),
8.13 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 314 (M + H) ⁺ .
Elemental Analysis: C _l8 H _l9 NO ₄
Calc .: C, 68.99; H, 6.11, N, 4.47.
Anal: C, 68.91; H, 6. 27; N, 4.24.
Reference Example 16 1- [4- [4- (tert-butoxycarbonylamino) phenyl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same reaction as in Reference Example 12, 4- [4- (tert-butoxycarbonylamino) phenyl] benzoic acid (l50 mg) and l-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluor The title compound (303 mg, 100%) was obtained using roacetate (203 mg) as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 2.90-3.30 (4H, m), 3.50-4.10 (4H, m),
6.56 (lH, s), 7.35 (2H, d, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz),
7.49 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz),
7.59 (lH, dd, J = 8.8, 2.0 Hz), 7.76 (lH, dd, J = 8.8, 2.0 Hz),
7.90-7.95 (3H, m), 8.30 (lH, broad singlet).
Reference Example 17 Methyl 4-acetylbenzoate
Methyl 4-acetylbenzoate (3.28 g) was dissolved in a mixed solvent of tetrahydrofuran (100 ml) and methanol (7 ml) at room temperature, and trimethylsilyl diazomethane (2.0 M hexane solution, 12 ml) was cooled on ice. I dripped slowly. After heating up to room temperature and stirring for 30 minutes, the solvent was distilled off. Sodium bicarbonate and ether were added to the residue, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off and crystallized with hexane to obtain the title compound (2.90g, 82%).
¹ H-NMR (CDCl ₃ ) δ: 2.65 (3H, s), 3.96 (3H, s),
8.01 (2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz).
MS (EI) m / z: 178 M ⁺ .
Elemental Analysis: C ₁₀ H ₁₀ O ₃
Calc .: C, 67.41; H, 5.66.
Anal: C, 67.28; H, 5.53.
Reference Example 18 Methyl 4-bromoacetylbenzoate
At 15 ° C., methyl 4-acetylbenzoate (2.23 g) was dissolved in acetic acid hydrobromic acid solution (30%, 10 mL). Bromine was slowly dripped at this reaction liquid so that 15 degreeC may be maintained. After stirring for 10 minutes, the reaction solution was cooled to 4 ° C, a mixed solvent of methanol (50 mL) and water (50 mL) was added to crystallize, and the mixture was washed with hexane. Filtration gave the title compound (2.29 g, 71%) as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 4.47 (2H, s),
8.05 (2H, d, J = 8.8 Hz), 8.16 (2H, d, J = 8.8 Hz).
MS (FAB) m / z: 257 [(M + H) ⁺ , ⁷⁹ Br], 259 [(M + H) ⁺ , ⁸¹ Br
Elemental Analysis: C ₁₀ H ₉ BrO ₃
Calc .: C, 46.72; H, 3.53.
Anal: C, 46.36; H, 3.63.
Reference Example 19 Methyl 4- (2-aminothiazol-4-yl) benzoate
Methyl 4-bromoacetylbenzoate (1.00 g) and thiourea (296 mg) were dissolved in isopropanol (100 mL) at room temperature and heated to reflux for 15 minutes. Under stirring at the same temperature, anhydrous sodium carbonate (206 mg) was added to the reaction solution, and the mixture was heated to reflux for 20 minutes. After the reaction was completed, water (50 ml) was added thereto under ice cooling, and the precipitated solid was collected by filtration. This was dissolved in water and dichloromethane, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off and the precipitated pale yellow solid was washed with ether to give the title compound (634 mg, 70%).
¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 4.96 (2H, br s), 6.88 (1H, s),
7.85 (2H, d, J = 8.8 Hz), 8.05 (2H, d, J = 8.8 Hz).
MS (FAB) m / z: 235 (M + H) ⁺ .
Reference Example 20 4- (2-aminothiazol-4-yl) benzoic acid
At room temperature, methyl 4- (2-aminothiazol-4-yl) benzoate (300 mg) was suspended in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL). Aqueous sodium hydroxide solution (10 ml) was added to the reaction solution, and the mixture was stirred for 1 hour. In addition, N, N-dimethylformamide (5 ml) was added, and the mixture was heated to reflux for 6 hours. After completion of the reaction, the solvent was distilled off, water and 1N hydrochloric acid were added sequentially, and the precipitated pale yellow solid was collected by filtration to obtain the title compound (229 mg, 69%) as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ: 7.30 (lH, br s), 7.87 (2H, d, J = 8.3 Hz),
7.95-8.00 (2H, m).
MS (FAB) m / z: 221 (M + H) ⁺ .
Elemental Analysis: C ₁₀ H ₈ N ₂ O ₂ S · 0.75HC1 · 0.6H ₂ O
Calc .: C, 46.48; H, 3.88, N, 10.84; Cl, 10.29; S, 12.41.
Anal: C, 46.36; H, 4. 12, N, 10.64; Cl, 10.05; S, 12.33.
Reference Example 21 Methyl 4- (imidazol-4-yl) benzoate
At room temperature, methyl 4-bromoacetylbenzoate (2 g) was dissolved in formamide (100 mL) and stirred at 180 ° C. for 90 minutes. After completion of the reaction, the reaction solution was ice-cooled, dissolved in water and 1N hydrochloric acid, and purified by synthetic adsorption chromatography (Diion HP-20, water-50% acetonitrile-water). The crude product thus obtained was purified by silica gel column chromatography (5% methanol-dichloromethane) to obtain the title compound (844 mg, 54%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 7.46 (lH, s), 7.75 (lH, s),
7.86 (2H, m), 8.07 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 203 (M + H) ⁺ .
Reference Example 22 Methyl 4- [1-triphenylmethylimidazol-4 (5) -yl] benzoate
Methyl 4- (imidazol-4-yl) benzoate (828 mg) was dissolved in dichloromethane (50 mL), under ice-cooling, diisopropylethylamine (856 µl) and triphenylmethylchloride (1.37 g) were added. It stirred at room temperature for 16 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography (dichloromethane) to give the title compound (1.08 g, 59%) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 3.90 (3H, s), 7.15-7.22 (6H, m),
7.23 (lH, d, J = 1.5 Hz), 7.30-7.40 (15H, m), 7.52 (1H, d, J = 1.5 Hz),
7.79 (2H, d, J = 8.3 Hz), 8.01 (2H, d, J = 8.3 Hz).
MS (FAB) m / z: 445 (M + H) ⁺ ,
Reference Example 23 4- [1-triphenylmethylimidazol-4- (5) -yl] benzoic acid
At room temperature, 4- [l-triphenylmethylimidazol-4 (5) -yl] methyl benzoate (1.04 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), followed by 3N hydroxide. Aqueous sodium solution (6 ml) was added, and the mixture was stirred for 5 hours. Tetrahydrofuran and methanol were solvent distilled under reduced pressure, an aqueous citric acid solution was added to make the reaction solution slightly acidic, water and dichloromethane were added, and the organic layer was separated. After washing with saturated brine, drying with anhydrous sodium sulfate, the solvent was distilled off to obtain the title compound (1.13 g, quant.) As a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 7.15-7.22 (6H, m), 7.23 (lH, d, J = l. 5 Hz),
7.30-7.40 (9H, m), 7.69 (lH, d, J = 1.5 Hz), 7.81 (2H, d, J = 8.3 Hz)
8.10 (2H, doublet, J = 8.3 Hz).
Reference Example 24 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- [1-triphenylmethylimidazol-4 (5) -yl] benzoyl] piperazine
In the same reaction as in Reference Example 12, 4- [1-triphenylmethylimitazol-4 (5) -yl] benzoic acid (371 mg) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine The title compound (560 mg, 90%) was obtained as a colorless glassy solid using hydrochloride (300 mg) as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 2.90-3.30 (4H, m), 3.50-4.10 (4H, m),
7.15-7.20 (6H, m), 7.28 (2H, d, J = 8.3 Hz), 7.30-7.40 (9H, m),
7.49 (lH, d, J = l.0 Hz), 7.59 (lH, dd, J = 8.8, 2.0 Hz),
7.71 (2H, d, J = 8.3 Hz), 7.75 (lH, dd, J = 8.8, 1.5 Hz), 7.90-7.95 (3H, m),
8.29 (hl, br s).
MS (FAB) m / z: 723 (M + H) ⁺ .
Reference Example 25 4- [2-aminoimidazol-4-yl] benzoic acid hydrochloride
At room temperature, 4-bromoacetylbenzoate (1.37 g) and acetylguanidine (1.62 g) were suspended in acetonitrile and heated to reflux for 16 hours. The solvent was distilled off under reduced pressure, water was added, the precipitated insolubles were collected by filtration, washed with ethanol to obtain 4- [2-aminoimidazol-4-yl] methyl benzoate. This was dissolved in a mixed solvent of dioxane (10 mL) and 1N hydrochloric acid (10 mL) and heated to reflux for 8 hours. The solvent was distilled off, tetrahydrofuran was added to the residue, and the residue was filtered to give the title compound (500 mg, 39%).
¹ H-NMR (DMSO-d ₆ ) δ: 7.55-7.65 (3H, m), 7.80 (2H, d, J = 8.3 Hz)
7.98 (2H, doublet, J = 8.3 Hz), 12.2-13.3 (3H, m).
MS (FAB) m / z: 204 (M + H) ⁺ .
Elemental Analysis: C ₁₀ H ₉ N ₃ O _{2 ·} HC1 · 0.5H ₂ O
Calc .: C, 48.30; H, 4. 46; N, 16.90; Cl, 14.26.
Anal: C, 48.03; H, 4.10; N, 16.49; Cl, 14.12.
Reference Example 26 1- [4-Bromo-2- (tert-butoxycarbonyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
4-bromophthalic anhydride (1.96 g) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (3.00 g) were suspended in dichloromethane (200 mL) under ice-cooling, Ethylamine (3.76 ml) was added and the mixture was stirred for 20 minutes. Dilute hydrochloric acid and dichloromethane were added, the organic layer was separated, and dried over anhydrous sodium sulfate. After the solvent was concentrated to 200 ml, N, N-diisopropyl-O-tert-butylisourea (2.6 g) was added under ice cooling, followed by stirring at room temperature for 3 days. Dilute hydrochloric acid and dichloromethane were added, the organic layer was separated, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to give the title compound as a colorless solid (1. 78 g, 35%).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 2.90-3.40 (6H, m), 3.80-4.00 (2H, m),
7.01 (lH, d, J = 8.3 Hz), 7.59 (lH, dd, J = 8.3, 2.0 Hz), 7.61 (lH, dd, J = 8.3, 2.0 Hz),
7.76 (lH, dd, J-8.8, 2.0 Hz), 7.85-7.95 (3H, m), 8.00 (lH, d, J-2.0 Hz),
8.29 (hl, br s).
Reference Example 27 1- [2-tert-butoxycarbonyl-4- (pyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same reaction as in Reference Example 7, 1- [4-bromo-2- (tert-butoxycarbonyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine and diethyl The title compound was obtained using (4-pyridyl) borane as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.80-3.50 (6H, m), 3.80-4.00 (2H, m),
7.40 (lH, d, J = 7.8 Hz), 7.60 (lH, dd, J = 8.8, 2.0 Hz),
7.77 (lH, dd, J = 8.3, 1.5 Hz), 7.87 (lH, dd, J = 7.8, 2.0 Hz), 7.90-7.95 (3H, m),
8.10 (2H, d, J = 6.8 Hz), 8.25 (lH, d, J = 2.0 Hz), 8.31 (lH, br s),
8.90 (2H, doublet, J = 6.8 Hz).
MS (FAB) m / z: 592 (M + H) ⁺ .
Elemental _{analysis: C 3l H 30 ClN 3 O} 5 S · HC1 · 0.2H 2 O-THF
Calc .: C, 59.69; H, 5. 64; N, 5.97; Cl, 10.07; S, 4.55.
Anal: C, 59.55; H, 5. 45; N, 5.87; Cl, 9.97; S, 4.68.
Reference Example 28 5- (4-Pyridyl) thiophene-2-carboxylic acid hydrochloride
In the same reaction as in Reference Example 6, 5-bromothiophene-2-carboxylic acid and diethyl (4-pyridyl) borane were used as starting materials to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 7.87 (1H, d, J = 3.9 Hz), 8.17 (lH, d, J = 3.9 Hz),
8.29 (2H, d, J = 6.8 Hz), 8.88 (2H, d, J = 6.8 Hz).
MS (FAB) m / z: 206 (M + H) ⁺ .
Elemental _{analysis: C l0 H 7 NO 2 S} · HC1 · 0.8H ₂ O as a
Calc .: C, 46.90; H, 3.78; N, 5.47; Cl, 13.84; S, 12.52.
Anal: C, 46-77; H, 3.76; N, 5.27; Cl, 13.83; S, 12.56.
Reference Example 29 5- (4-pyridyl) furan-2-carboxylic acid hydrochloride
In the same manner as in Reference Example 6, 5-bromofuran-2-carboxylic acid and diethyl (4-pyridyl) borane were used as raw materials to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 7.49 (lH, d, J = 3.4 Hz), 7.80-7.90 (lH, m),
8.20-8.30 (2H, m), 8.85-8.95 (2H, m).
Reference Example 30 4- (2-pyridyl) benzoic acid hydrochloride
2- (p-tolyl) pyridine (17.2 g) was added to water (200 mL), potassium permanganate (21.0 g) was added, and the mixture was heated to reflux for 18 hours. The precipitate was filtered off, dichloromethane was added to the filtrate, the aqueous layer was separated, and made acidic with 2N hydrochloric acid. The acidic aqueous solution was concentrated, and the precipitates were collected by filtration, washed with water and ethyl acetate to obtain the title compound (7.07 g, 35%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 7.60 (lH, t, J = 5.9 Hz), 8.08 (2H, d, J = 7.8 Hz),
8.17 (2H, m), 8.21 (2H, doublet, J = 7.8 Hz), 8.78 (lH, d, J = 4.9 Hz).
MS (El) m / z: 199 M ⁺ .
Reference Example 31 1-[(E) -4-chlorostyrylsulfonyl) piperazine hydrochloride
In the same manner as in Reference Example 1, tert-butyll-piperazinecarboxylate and (E) -4-chlorostyrylsulfonyl chloride were used as raw materials to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.20 (4H, br s), 3.33-3.38 (4H, m),
7.47 (2H, s), 7.53 (lH, d, J = 8.8 Hz), 7.82 (lH, d, J = 8.8 Hz).
Elemental Analysis: C ₁₂ H _l5 ClN ₂ O ₂ SHCl
Calc .: C, 44.59; H, 4.99, Cl, 21.94; N, 8.67; S, 9.92.
Anal: C, 44.42; H, 4.78, Cl, 21.83; N, 8.68; S, 9.87.
Reference Example 32 4- (2,4-Diamino-6-pyrimidinyl) benzoic acid hydrochloride
6-Chloro-2, 4-diaminopyrimidine (434 mg) was dissolved in toluene (9 mL), 4-carboxyphenylboronic acid (667 mg), ethanol (2.5 mL), sodium carbonate (635 mg), water (3.0 mL) and bis (triphenylphosphine) palladium (II) dichloride (65 mg) were added, and the mixture was heated to reflux for 24 hours under an argon gas atmosphere. Ethyl acetate and water were added to separate the aqueous layer, 2N hydrochloric acid was added to make acidic, the insolubles were collected by filtration, washed with water and tetrahydrofuran and dried to obtain the title compound (371 mg, 54%).
¹ H-NMR (DMSO-d ₆ ) δ: 6.43 (lH, s), 7.30-7.80 (2H, br),
7.96 (2H, d, J = 7.8 Hz), 8.12 (2H, d, J = 7.8 Hz), 8.27 (2H, br s),
12.77 (1 H, br), 13.33 (l H, br).
MS (EI) m / z: 230 M ⁺ .
Elemental Analysis: As C ₁₁ H ₁₀ N ₄ O ₂ S · 0.95HCl · 1.9H ₂ O
Calc .: C, 44.17; H, 4,97; Cl, 11.26; N, 18.73.
Anal: C, 44.33; H, 4.97; Cl, 11.32; N, 18.65.
Reference Example 33 1-tert-Butoxycarbonyl-4- [4- (2-pyridyl) benzoyl] piperazine
In the same manner as in Reference Example 3, the title compound was obtained using 4- (2-pyridyl) benzoic acid hydrochloride and tert-butyl 1 -piperazinecarboxylate obtained in Reference Example 30 as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.43 (4H, br), 3.51 (2H, br)
3.76 (2H, br), 7.28 (lH, d, J = 5.9 Hz), 7.52 (2H, d, J = 7.8 Hz),
7.76 (lH, m), 7.79 (1H, m), 8.05 (2H, d, J = 7.8 Hz),
8.71 (lH, d, J = 4.9).
MS (FAB) m / z: 368 (M + H) ⁺ .
Elemental _{analysis: C 2l H 25 N 3 O} 3 · 0.lH 2 O
Calc .: C, 68.31; H, 6.88; N, 11.38;
Anal: C, 68.26; H, 6. 86; N, 11.42.
Reference Example 34 2- [4-[[4- (tert-butoxycarbonyl) piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
Dichloromethane solution (8 mL of dichloromethane) of 1-tert-butoxycarbonyl-4- [4- (2-pyridyl) benzoyl] piperazine (517 mg) was metachloroperbenzoic acid (789 mg) at -10 ° C. ) Was added and stirred for 24 hours. Diluted with dichloromethane, a small amount of aqueous sodium thiosulfate solution and saturated brine were added thereto, the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the title compound (415 mg, 77%).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.47 (6H, br), 3.76 (2H, br),
7.29 (lH, m), 7.34 (lH, t, J = 7.8 Hz), 7.44 (1H, dd, J = 7.8, 2.0 Hz),
7.52 (2H, d, J = 7.8 Hz), 7.90 (2H, d, J = 7.8 Hz), 8.35 (lH, d, J = 5.9 Hz).
MS (FAB) m / z: 384 (M + H) ⁺ .
Reference Example 35 2- [4-[(1-piperazinyl) carbonyl] phenyl] pyridine N-oxide
2- [4-[[4- (tert-butoxycarbonyl) piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide was dissolved in dichloromethane (2.5 mL) and saturated ethanol hydrochloride solution was added. It stirred at room temperature for 1 hour. After distilling a solution under reduced pressure, water was added to make an aqueous solution. Acetone was added to this aqueous solution until the liquid became cloudy, and the precipitates were collected by filtration and washed with acetone to obtain the title compound (274 mg, 81%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.17 (4H, br s), 3.50-3.95 (4H, br),
7.43 (lH, d, J = 3.9 Hz), 7.44 (lH, d, J = 3.9 Hz), 7.57 (2H, d, J = 8.8 Hz),
7.66 (lH, t, J = 3.9 Hz), 7.92 (2H, d, J = 8.8 Hz), 8.36 (1H, t, J = 3.9 Hz),
9.21 (2H, broad singlet).
MS (FAB) m / z: 284 (M + H) ⁺ .
Reference Example 36 1- (tert-butoxycarbonyl) -4- [4- (3-pyridyl) benzoyl] piperazine
The title compound was obtained in the same manner as in Reference Example 3 using 4- (3-pyridyl) benzoic acid hydrochloride and tert-butyl 1 -piperazinecarboxylate obtained in Reference Example 8 as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.35-3.85 (8H, br),
7.38 (lH, dd, J = 7.8, 4.9 Hz), 7.52 (2H, d, J = 8.3 Hz),
7.63 (2H, d, J = 8.3 Hz), 7.88 (lH, m), 8.62 (1H, dd, J = 1.5, 4.9 Hz),
8.84 (lH, d, J = 2.0 Hz).
Reference Example 37 3- [4-[[4- (tert-butoxycarbonyl) piperazin] -1-yl] carbonyl] phenyl] pyridine N-oxide
In the same manner as in Reference Example 34, 1- (tert-butoxycarbonyl) -4- [4- (3-pyridyl) benzoyl] piperazine was used as a raw material to obtain a title compound as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.35-4.83 (8H, br), 7.38 (1H, m),
7.47 (lH, m), 7.49-7.65 (4H, m), 8.23 (lH, dd, J = 6.4, 1.5 Hz),
8.47 (1H, t, J = 1.5 Hz).
MS (FAB) m / z: 384 (M + H) ⁺ .
Elemental analysis: C _{2 l} H ₂₅ N ₃ O ₄ as 0.25 H ₂ O
Calc .: C, 65.02; H, 6.63; N, 10.83.
Anal: C, 65.30; H, 6.65; N, 10.43.
Reference Example 38 2-hydroxy 4- (4-pyridyl) benzoic acid
4-amino-2-hydroxybenzoic acid (5.04 g) was dissolved in water (22.5 mL) and 47% hydrobromic acid aqueous solution (22.5 mL). An aqueous solution of sodium nitrite (2.26 g) (15.0 ml) was added dropwise while maintaining the reaction solution at 5 ° C. or lower and stirred for 30 minutes in ice-cooling. The reaction solution was gradually added to a solution obtained by dissolving copper bromide (5.63 g) in a 47% aqueous hydrogen bromide solution (15 mL) under ice-cooling and stirred at room temperature for 150 minutes. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-10% methanol-dichloromethane) to obtain a crude product of 4-bromo-2-hydroxybenzoic acid (5.51 g).
Using this crude product (298 mg), the title compound (70 mg, 21%) was obtained in the same manner as the Reference Example 6.
¹ H-NMR (DMSO-d ₆ ) δ: 7.30-7.40 (2H, m), 7.78 (2H, d, J = 4.4 Hz),
7.92 (lH, d, J = 6.3 Hz), 8.69 (2H, d, J = 5.9 Hz).
MS (FAB) m / z: 216 (M + H) ⁺ .
Reference Example 39 4-Bromo-3-hydroxybenzoic Acid
3-hydroxybenzoic acid (5.00 g) was suspended in acetic acid (24.5 mL), and an acetic acid solution (5 mL) of bromine (1.9 mL) was added dropwise with ice cooling, followed by stirring at room temperature for 33 hours. The reaction solution was ice-cooled, and the precipitates were collected by filtration and washed with acetic acid to obtain the title compound (1.68 mg, 21%).
¹ H-NMR (DMSO-d ₆ ) δ: 7.28 (lH, dd, J = 7.8, 2.0 Hz),
7.51 (lH, d, J = 2.0 Hz), 7.59 (lH, d, J = 8.3 Hz), 10.54 (lH, br s),
12.84 (1H, broad singlet)
Reference Example 40 Methyl 4-bromo-3-methoxybenzoate
In the same manner as in Reference Example 17, 4-bromo-3-hydroxybenzoic acid was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 3.92 (3H, s), 3.96 (3H, s),
7.51 (1H, dd, J = 8.3, 2.0 Hz), 7.55 (lH, d, J = 2.0 Hz), 7.61 (lH, d, J = 8.8 Hz).
Reference Example 41 3-methoxy-4- (4-pyridyl) benzoic acid
The reaction was performed in the same manner as in Reference Example 7 using 4-bromo-3-methoxybenzoate and diethyl (4-pyridyl) borane. The title compound was obtained in the same manner as the Reference Example 8 using the obtained crude product.
¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 7.65-7.75 (3H, m),
8.20 (2H, d, J = 5.4 Hz), 8.94 (2H, d, J = 6.3 Hz).
MS (FAB) m / z: 230 (M + H) ⁺ .
Reference Example 42 4-tert-Butoxycarbonyl-1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine
Under ice-cooling, 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and 6-chloro-2-naphthylsulfonylchloride (588 mg) were dissolved in dichloromethane (18 mL), and Isopropylethylamine (0.59 mL) was added, and it stirred at room temperature for 63 hours. The residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (688 mg, 71%).
¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7. 1 Hz), 1.38 (9H, s), 2.80-4.70 (9H, m),
7.55 (1H, dd, J = 8.6, 2.2 Hz), 7.77 (lH, dd, J = 8.6, 1.7 Hz),
7.85-7.90 (3H, m), 8.33 (lH, s).
MS (FAB) m / z: 483 [(M + H) ⁺ , Cl ³⁵ ], 485 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 43 4-tert-Butoxycarbonyl-2-ethoxycarbonyl-1- [4- (3-pyridyl) benzoyl] piperazine
In the same manner as in Reference Example 12, 4- (3-pyridyl) benzoic acid and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine were used as raw materials to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (3H, m), 1.46 (9H, s), 2.70-4.80 (8H, m),
5.35 (lH, br), 7.35-7.70 (5H, m), 7.85-7.95 (lH, m),
8.64 (2H, doublet of doublets, J = 4.6, 1.7 Hz), 8.86 (1H, s).
MS (FAB) m / z: 440 (M + H) ⁺ .
Reference Example 44 Methyl N-tert-Butoxycarbonyltranexumate
Thionyl chloride (1 ml) was added dropwise to methanol (20 ml) under ice-cooling, followed by addition of tranexyl acid (2.04 g), followed by heating to reflux for 3 hours. The residue obtained by distillation of the reaction solution under reduced pressure was triturated with ether and filtered to give colorless crystals (2.31 g).
The obtained crystals (2.10 g) were dissolved in dichloromethane (40 mL), and N-methylmorpholine (1.2 mL) was added. Dichloromethane solution (3 mL of dichloromethane) of di-tert- butyl dicarbonato (2.51 g) was added under ice cooling, and it stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1). Further recrystallization in a mixed solvent of hexane and ethyl acetate to give colorless crystals (2.09g, 65%).
¹ H-NMR (CDCl ₃ ) δ: 0.90-1.10 (2H, m), 1.40-1.60 (12H, m),
1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 2.24 (lH, m), 2.98 (2H, m),
3.66 (3 H, s), 4.58 (1 H, br).
Elemental Analysis: C ₁₄ H ₂₅ NO ₄
Calc .: C, 61.97; H, 9. 29; N, 5.16.
Anal: C, 62.15; H, 9. 42; N, 5.12.
Reference Example 45 trans-4- (N-tert-butoxycarbonyl aminomethyl) cyclohexylmethanol
M-N-tert-butoxycarbonyltranexum acid methyl (1.00 g) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and methanol (2 mL), and sodium borohydride (0.44 g) was added under ice cooling to room temperature. Stirred for 24 hours. The reaction solution was concentrated under reduced pressure after adding water, and ethyl acetate and dilute hydrochloric acid were added to separate the organic layer. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (once; dichloromethane to dichloromethane: methanol = 20: 1, twice; hexane: ethyl acetate = 3: l). Then, colorless crystals (0.74 g, 82%) were obtained. In addition, part of the mixture was recrystallized in a mixed solvent of hexane and ethyl acetate to obtain colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 0.90-1.10 (4H, m), 1.30-1.60 (12H, m),
1.80-2.00 (4H, m), 2.98 (2H, m), 3.45 (2H, d. J = 6.4 Hz), 4.59 (1H, br).
Elemental Analysis: C ₁₃ H ₂₅ NO ₃
Calc .: C, 64.17; H, 10.33, N, 5.76.
Anal: C, 64.31; H, 10.03; N, 5.74.
Reference Example 46 trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexanecarboxyaldehyde
trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylmethanol (0.20 g) was dissolved in dichloromethane (5 mL), pyridinium chlorochloromate (0.23 g) was added, and 3 hours at room temperature. After stirring, the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (0.15 g, 76%).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (2H, m), 1.27 (2H, m), 1.40-1.60 (lH, m),
1.44 (9H, s), 1.88 (2H, m), 2.02 (2H, m), 2.18 (1H, m),
3.00 (2H, t, J = 6.4 Hz), 4.61 (1H, br), 9.62 (lH, s).
MS (FAB) m / z: 242 (M + H) ⁺ .
Reference Example 47 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylmethyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexanecarboxyaldehyde (0.13 g) was dissolved in dichloromethane (7 mL) and 1-[(6-chloronaphthalen-2-yl) sulfonyl ] Piperazine trifluoroacetic acid salt (0.24 g), triethylamine (78 microliters), and sodium triacetoxy borohydride (0.17 g) were added, and it stirred at room temperature under argon gas atmosphere for 11 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, diluted with dichloromethane, and the organic layer was separated and taken up. After drying over anhydrous sodium sulfate, the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (0.29 g, 100%).
¹ H-NMR (CDCl ₃ ) δ: 0.70-0.90 (4H, m), 1.30-1.50 (2H, m),
1.42 (9H, s), 1.70-1.80 (4H, m), 2.09 (2H, d, J = 7.3 Hz),
2.46 (4H, m), 2.92 (2H, m), 3.08 (4H, m), 4.53 (lH, br),
7.56 (1H, dd, J = 8.8, 2.0 Hz), 7.78 (lH, dd, J = 8.8, 2.0 Hz),
7.80-8.00 (3H, m), 8.30 (1H, s).
MS (FAB) m / z: 536 [(M + H) ⁺ , Cl ³⁵ ], 538 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 48 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same reaction as in Reference Example 11 and Reference Example 12, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.00 (2H, m), 1.40-1.60 (3H, m),
1.42 (9H, s), 1.60-1.70 (2H, m), 1.70-1.90 (2H, m), 2.30 (lH, m),
2.95 (2H, m), 3.07 (4H, m), 3.58 (2H, br), 3.70 (2H, br),
4.57 (lH, m), 7.58 (1H, doublet of doublets, J = 8.8, 2.0 Hz),
7.75 (lH, dd, J = 8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.30 (lH, s).
MS (FD) m / z: 549 (M ⁺ , Cl ^{+ 35} ), 551 (M ⁺ , Cl ³⁷ ).
Reference Example 49 N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycinebenzyl ester
In the same reaction as in Reference Example 11 and Reference Example 12, the title compound was obtained using methyl N-tert-butoxycarbonyltranexum acid and glycinebenzyl ester as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (2H, m), 1.44 (9H, s), 1.40-1.60 (3H, m),
1.80-1.90 (2H, m), 1.90-2.00 (2H, m), 2.10 (lH, m), 2.98 (2H, m),
4.08 (2H, d, J = 4.9 Hz), 4.57 (lH, br), 5.19 (2H, s), 5.97 (lH, m),
7.30-7.40 (5H, m).
Elemental Analysis: C ₂₂ H ₃₂ N ₂ O ₅
Calc .: C, 65.32; H, 7.97; N, 6.93.
Anal: C, 65.05; H, 7.89; N, 7.16.
Reference Example 50 1- [N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycyl] -4-[(6-chloronaphthalen-2-yl) sulphate Ponyl] Piperazine
N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycinebenzyl ester (0.22 g) is suspended in tetrahydrofuran (11 ml) and 10% palladium / carbon (about 50% moisture content, 50 mg) was added and atmospheric pressure reduction was carried out at room temperature for 14 hours. After filtration of the catalyst, the solvent was distilled off under reduced pressure. The obtained residue was reacted in the same manner as in Reference Example 12 to obtain the title compound (0.32 g, 98%).
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.00 (2H, m), 1.30-1.50 (3H, m),
1.43 (9H, s), 1.80-2.00 (4H, m), 2.06 (1H, m), 2.95 (2H, m),
3.10-3.20 (4H, m), 3.52 (2H, m), 3.74 (2H, m), 3.94 (2H, d, J = 4.4 Hz),
4.54 (lH, m), 6.40 (lH, m), 7.59 (lH, dd, J = 8.8, 2.0 Hz),
7.74 (lH, dd, J = 8.8, 1.5 Hz), 7.80-8.00 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 607 [(M + H) ⁺ , Cl ³⁵ ], 609 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 51 1-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride
Homopiperazine (5 g) was dissolved in tetrahydrofuran (100 mL) at room temperature, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (12.3 g) was added slowly, and it stirred for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography (10-20% methanol-dichloromethane), ethanol 1N hydrochloric acid was added, the solvent was distilled off, solidified by addition of ethanol, powder (7.46 g) Got. This was carried out and reacted as in Reference Example 1 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.00 (2H, br s), 3.10-3.30 (4H, m),
3.30-3.50 (2H, m), 3.55-3.65 (2H, m), 7.72 (1H, d, J = 8.8 Hz),
7.89 (1H, d, J = 8.3 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.22-8.28 (2H, m),
8.56 (lH, s), 9.29 (2H, broad singlet).
MS (FAB) m / z: 325 (M + H) ⁺ .
Elemental Analysis: C ₁₅ H _l7 ClN ₂ O ₂ S.HCl
Calc .: C, 49.89; H, 5.02; N, 7.75; Cl, 19.63.
Anal: C, 49.94; H, 5.05; N, 7.47; Cl, 19.65.
Reference Example 52 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine
In the same manner as in Reference Example 48, the title compound was obtained using methyl N-tert-butoxycarbonyltranexomate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride.
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.00 (2H, m), 1.40-1.60 (3H, m),
1.43 (9H, s), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.30-2.40 (1H, m),
2.97 (2H, m), 3.30-3.50 (4H, m), 3.60-3.80 (4H, m),
4.64 (lH, br), 7.50-7.60 (1H, m), 7.70-7.80 (1H, m),
7.80-8.00 (3H, m), 8.33 and 8.35 (1, each s).
MS (FAB) m / z: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 53 Methyl 4- (N-tert-butoxycarbonylaminomethyl) benzoate
The title compound was obtained using 4-aminomethylbenzoic acid as a reference example 44 as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.91 (3H, s), 4.37 (2H, d, J = 5.4 Hz),
4.92 (1H, broad singlet), 7.35 (2H, doublet, J = 8.3 Hz), 8.00 (2H, doublet, J = 8.3 Hz).
Elemental Analysis: C ₁₄ H _l9 NO ₄
Calc .: C, 63.38; H, 7.22; N, 5.28.
Anal: C, 63.20; H, 7.02; N, 5.58.
Reference Example 54 1- [4- (N-tert-butoxycarbonylaminomethyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
As in Reference Example 48, the title compound was obtained using methyl 4- (N-tert-butoxycarbonylaminomethyl) benzoate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.00-3.30 (4H, br), 3.40-4.00 (4H, br),
4.31 (2H, d, J = 5.9 Hz), 4.90 (lH, br), 7.27 (4H, m),
7.59 (lH, dd, J = 8.8, 1.5 Hz), 7.75 (lH, d, J = 8.8 Hz), 7.90-8.00 (3H, m),
8.30 (lH, s).
MS (FAB) m / z: 544 [(M + H) ⁺ , C 1 ³⁵ ], 546 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 55 Methyl 3- (N-tert-butoxycarbonylaminomethyl) benzoate
Methyl 3-methylbenzoate (1.00 g) was dissolved in carbon tetrachloride (10 ml), N-bromosuccinimide (1.22 g) and 2,2'-azobisisobutylonitrile (catalyst amount) were added, and a mercury lamp was added. It heated and refluxed for 1 hour, examining. The insoluble matter was filtered off, and the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give a colorless oil (1.34 g). The resulting colorless oil (0.62 g) was dissolved in N, N-dimethylformamide (10 mL), sodium azide (0.38 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent under reduced pressure was dissolved in tetrahydrofuran (15 mL), triphenylphosphine (0.75 g) was added, and the mixture was stirred at an external temperature of about 50 ° C. for 5 hours. About 28% aqueous ammonia (7 ml) was added to the reaction solution, followed by further stirring for 2 hours. The reaction solution was concentrated under reduced pressure, extracted with ether, diluted hydrochloric acid, and acidified to separate the aqueous layer. Dilute sodium hydroxide aqueous solution was added to this, and it made alkaline, and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the residue obtained by distillation of the solvent under reduced pressure was dissolved in dichloromethane (7 ml), di-tert-butyldicarbonate (0.45 g) was added under ice cooling, and the solvent was stirred for 3 days at room temperature. The residue obtained by distillation under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (0.29 g, 35%).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.91 (3H, s), 4.36 (2H, d, J = 5.9 Hz),
4.97 (lH, br), 7.40 (1H, t, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz),
7.90-8.00 (2H, m).
MS (FAB) m / z: 266 (M + H) ⁺ .
Reference Example 56 Methyl 4-cyanomethylbenzoate
Methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved in dichloromethane (20 mL), triethylamine (0.9 mL) was added, followed by dichloromethane solution of methanesulfonyl chloride (0.70 g) under ice-cooling (dichloromethane). 5 ml) was added. After stirring at room temperature for 15 hours, the reaction solution was diluted with dichloromethane and washed with water. It dried with anhydrous sodium sulfate, the residue obtained by distilling a solvent under reduced pressure was dissolved in acetonitrile (l2 ml), potassium cyanide (0.80 g) and 18-crown-6 (0.16 g) were added, and it stirred at room temperature for 40 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane and washed with water. After drying over anhydrous sodium sulfate, the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane) to obtain colorless crystals (0.91 g, 86%). Part of the mixture was recrystallized in a mixed solvent of hexane and ethyl acetate to obtain colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 3.82 (2H, s), 3.93 (3H, s),
7.42 (2H, doublet, = 8.3 Hz), 8.06 (2H, doublet, J = 8.3 Hz).
Elemental Analysis: C ₁₀ H ₉ NO ₂
Calc .: C, 68.56; H, 5. 18; N, 8.00.
Anal: C, 68.39; H, 5. 29; N, 8.08.
Reference Example 57 Methyl 4- [2- (tert-butoxycarbonylamino) ethyl] benzoate
Methyl 4-cyanomethylbenzoate (0.20 g) was dissolved in a mixed solution of methanol (15 mL) and chloroform (0.4 mL), platinum dioxide (33 mg) was added, and contact reduction was performed at room temperature for 3 hours at 3 atmospheres. . The catalyst was removed by celite filtration and the solvent was distilled off under reduced pressure. The obtained residue was suspended in dichloromethane (5 ml), triethylamine (160 µl) was added thereto, and dichloromethane solution (dichloromethane 2 ml) of di-tert-butyl dicarbonate (0.29 g) under ice-cooling was added. It stirred at 13 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to obtain the title compound (0.28 g, 88%).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.86 (2H, t, J = 6.8 Hz)
3.39 (2H, m), 3.91 (3H, s), 4.53 (lH, br), 7.27 (2H, d, J = 8.3 Hz),
7.98 (2H, doublet, J = 8.3 Hz).
Elemental Analysis: C ₁₅ H ₂₁ NO ₄
Calc .: C, 64.50; H, 7. 58; N, 5.01.
Anal: C, 64.43; H, 7. 35; N, 4.97.
Reference Example 58 1- [4- [2- (tert-Butoxycarbonylamino) ethyl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
As in Reference Example 48, methyl 4- [2- (tert-butoxycarbonylamino) ethyl] benzoate, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used to obtain the title compound. Got it.
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.79 (2H, t, J = 6.8 Hz),
3.10 (4H, br), 3.35 (2H, m), 3.40-4.00 (4H, br), 4.50 (lH, br),
7.18 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.59 (lH, dd, J = 8.8, 2.0 Hz),
7.75 (lH, dd, J = 8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 558 [(M + H) ⁺ , Cl ³⁵ ], 560 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 59 (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene
In the same reaction as in Reference Example 55, the title compound was obtained using (2RS) -6-methoxycarbonyl-2-toluenesulfonyloxymethyl-1,2,3,4-tetrahydronaphthalene as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60 (1H, m), 1.46 (9H, s), 1.90-2.10 (2H, m),
2.50 (lH, dd, J = 17.1, 10.7 Hz), 2.70-3.00 (3H, m), 3.10-3.30 (2H, m),
3.89 (3H, s),
4.68 (lH, br), 7.12 (lH, d, J = 7.8 Hz), 7.70-7.80 (2H, m).
Elemental Analysis: C _l8 H ₂₅ NO ₄
Calc .: C, 67.69; H, 7.89; N, 4.39.
Anal: C, 67.78; H, 7.61; N, 4.12.
Reference Example 60 1-[[(6RS) -6- (N-tert-Butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl] -4- [(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same reaction as in Reference Example 48, (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene, 1-[( The title compound was obtained using 6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride.
¹ H-NMR (CDCl ₃ ) δ: 1.30-1.60 (lH, m), 1.45 (9H, s), 1.80-2.00 (2H, m),
2.43 (1H, dd, J = 16.6, 10.7 Hz), 2.70-2.90 (3H, m), 3.00-3.20 (6H, m),
3.50-3.90 (4H, br), 4.69 (lH, br), 6.90-7.10 (3H, m),
7.59 (lH, dd, J = 8.8, 2.0 Hz), 7.75 (lH, dd, J = 8.8, 2.0 Hz),
7.90-8.00 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 598 [(M + H) ⁺ , Cl ³⁵ ], 600 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 61 (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene
(2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (0.47 g) dissolved in dichloromethane (10 mL) Then, diisobutylaluminum hydride (0.95 M hexane solution, 3.6 ml) was added dropwise at an external temperature of -78 ° C, and stirred at that temperature for 90 minutes. Methanol was added to the reaction solution, the temperature was raised to room temperature, the insolubles were filtered through celite filtration, and the filtrate was concentrated under reduced pressure. Diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give colorless crystals (0.31 g, 72%). . Part of the mixture was recrystallized in a mixed solvent of hexane and ethyl acetate to obtain colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60 (lH, m), 1.46 (9H, s), 1.60-1.70 (1H, m),
1.90-2.00 (2H, m), 2.45 (lH, dd, J = 16.6, l0.7 Hz), 2.70-2.90 (3H, m),
3.10-3.30 (2H, m), 4.62 (2H, d, J = 5.9 Hz), 4.67 (1H, br), 7.00-7.20 (3H, m).
Elemental Analysis: C ₁₇ H ₂₅ NO ₃
Calc .: C, 70.07; H, 8. 65; N, 4.81.
Anal: C, 70.21; H, 8.49; N, 4.75.
Reference Example 62 1-[[(6RS) -6- (N-tert-Butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] methyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] piperazine
(2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene as a raw material, the same as in Reference Example 46 and Reference Example 47 The reaction gave the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.30-1.50 (lH, m), 1.44 (9H, s), 1.80-2.00 (2H, m),
2.40 (1H, m), 2.51 (4H, br), 2.60-2.90 (3H, m), 3.09 (6H, br), 3.39 (2H, s),
4.67 (1 H, br), 6.90-7.00 (3 H, m), 7.56 (lH, d, J = 8.8 Hz),
7.77 (1H, doublet, J 8.8 Hz), 7.80-8.00 (3H, m), 8.28 (1H, s).
MS (FAB) m / z: 584 [(M + H) ⁺ , Cl ³⁵ ], 586 [(M + H) ⁺ , C 1 ³⁷ )
Reference Example 63 (2RS) -2- (tert-Butyldimethylsilyloxymethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene
(2RS) -2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (1.71 g) was dissolved in N, N-dimethylformamide (5 mL) and cooled on ice. Imidazole (0.81 g) and tert-butyldimethylsilyl chloride (1.81 g) were added, and it stirred at room temperature for 14 hours. Methanol was added to the reaction solution, and the residue was concentrated under reduced pressure and diluted with ethyl acetate. After washing with water, the resultant was dried over anhydrous sodium sulfate, and the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain a pale yellow solid (2.20 g, 85%).
¹ H-NMR (CDCl ₃ ) δ: 0.06 (6H, s), 0.91 (9H, s), 1.40-1.60 (lH, m),
1.90-2.10 (2H, m), 2.53 (lH, dd, J = 17.1, 10.3 Hz), 2.80-3.00 (3H, m),
3.58 (2H, d, J = 5.9 Hz), 3.89 (3H, s), 7.14 (lH, d, J = 7.8 Hz),
7.70-7.80 (2H, m).
MS (FAB) m / z: 335 (M + H) ⁺ .
Reference Example 64 (2RS) -2- (tert-Butyldimethylsilyloxymethyl) -6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene
As in Reference Example 61, the title compound was obtained using (2RS) -2- (tert-butyldimethylsilyloxymethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.91 (9H, s), 1.30-1.50 (lH, m),
1.50-1.60 (lH, m), 1.90-2.10 (2H, m), 2.48 (lH, m), 2.70-2.90 (3H, m),
3.58 (2H, m), 4.62 (2H, doublet, J = 5.9 Hz), 7.09 (3H, m).
MS (FAB) m / z: 307 (M + H) ⁺ .
Reference Example 65 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl) -1,2,3,4-tetrahydronaphthalene
(2RS) -2- (tert-Butyldimethylsilyloxymethyl) -6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (1.00 g) was dissolved in dichloromethane (10 mL) and triethylamine (0.5 ml) was added and ice-cooled. Dichloromethane solution (1 mL of dichloromethane) of methanesulfonyl chloride (0.39 g) was added thereto, stirred at room temperature for 9 hours, and washed with water and dried over anhydrous sodium sulfate. The title compound (1.10 g, 83%) was obtained in the same manner as the Reference Example 59 using the residue obtained by distillation of the solvent under reduced pressure.
¹ H-NMR (CDCl ₃ ) δ: 0.06 (6H, s), 0.91 (9H, s), 1.40-1.60 (lH, m),
1.46 (9H, s), 1.90-2.00 (2H, m), 2.45 (1H, m), 2.70-2.90 (3H, m),
3.57 (2H, m), 4.24 (2H, m), 4.76 (lH, br), 7.00-7.10 (3H, m).
MS (FAB) m / z: 406 (M + H) ⁺ .
Reference Example 66 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene
(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl) -1,2,3,4-tetrahydronaphthalene (1.09 g) was added to tetrahydrofuran It dissolved in (10 mL) and added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 4.0 mL), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-2: 1) to obtain a colorless solid (0.77 g, 98%). Part of the mixture was recrystallized in a mixed solvent of hexane and ethyl acetate to obtain colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60 (2H, m), 1.46 (9H, s), 1.90-2.10 (2H, m),
2.48 (lH, dd, J = 16.6, 10.7 Hz), 2.70-3.00 (3H, m), 3.6-3.7 (2H, m),
4.24 (2H, doublet, J = 5.4 Hz), 4.78 (1H, br), 7.00-7.10 (3H, m).
Elemental Analysis: C ₁₇ H ₂₅ NO ₃
Calc .: C, 70.07; H, 8. 65; N, 4.81.
Anal: C, 70.02; H, 8.61; N, 4.46.
Reference Example 67 1-[[(2RS) -6- (N-tert-Butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] methyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] piperazine
(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (0.17 g) was dissolved in dichloromethane (5 mL) , N-methylmorpholine N-oxide (0.13 g) and Molecular Sieves 4A (active fraction powder, 0.18 g) were added, and ruthenium tetrapropylammonium tetrachloride (10 mg) was added under ice-cooling, and 1 was added at room temperature. It stirred for hours. Ether was added to the reaction solution, the insolubles were removed by celite filtration, and the filtrate was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane) to obtain an aldehyde to obtain the title compound (0.14 g, 41%) by the same reaction as in Reference Example 47.
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (1H, m), 1.44 (9H, s), 1.80-2.00 (2H, m),
2.20-2.40 (3H, m), 2.50-2.60 (4H, m), 2.60-2.80 (3H, m), 3.11 (4H, m),
4.20 (2H, d, J = 5.4 Hz), 4.79 (lH, br), 6.94 (3H, m), 7.57 (lH, dd, J = 8.8, 1.5 Hz),
7.79 (lH, dd, J = 8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.31 (lH, s).
MS (FAB) m / z: 584 [(M + H) ⁺ , Cl ³⁵ ], 586 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 68 1-[[(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] carbonyl] -4- [(6-chloronaphthalen-2-yl) sulfonyl] piperazine
(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (0.21 g) was added to carbon tetrachloride (2 ml) and acetonitrile ( 2 ml), dissolved in water (3 ml), sodium peridate (0.48 g) and ruthenium trichloride hydrate (4 mg) were added and stirred for 90 minutes. The reaction solution was diluted with dichloromethane, the organic layer was separated and dried over anhydrous sodium sulfate. Ether was added to the residue obtained by distilling a solvent under reduced pressure, an insoluble matter was removed, and the filtrate was distilled under reduced pressure. The title compound (0.11 g, 25%) was obtained in the same manner as the Reference Example 12 using the obtained carboxylic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.70-2.00 (2H, m), 2.60-2.90 (4H, m),
2.95 (lH, m), 3.11 (4H, m), 3.64 (2H, m), 3.76 (2H, m),
4.22 (2H, d, J = 5.4 Hz), 4.82 (lH, br), 6.90-7.10 (3H, m),
7.59 (lH, d, J = 8.8 Hz), 7.77 (lH, d, J = 8.8 Hz), 7.90-8.00 (3H, m),
8.31 (1 H, s).
MS (FD) m / z: 59-7 [M &lt; + &gt;, Cl ³⁵ ], 599 [M ⁺ , C1 ³⁷ ].
Reference Example 69 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene
The title compound was obtained in the same manner as the Reference Example 65 as 2-hydroxymethyl-7-methoxycarbonylnaphthalene (1.01 g) as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.98 (3H, s),
4.50 (2H, d, J = 5.4 Hz), 4.99 (lH, br), 7.53 (lH, d, J = 8.3 Hz),
7.80-7.90 (3H, m), 8.04 (lH, doublet of doublets, J = 8.3, 1.0 Hz), 8.57 (1H, s).
Elemental Analysis: C _l8 H ₂₁ NO ₄
Calc .: C, 68.55; H, 6.71; N, 4.44.
Found C, 68.54; H, 6. 70; N, 4.46.
Reference Example 70 1-[[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] pipe Razin
As in Reference Example 48, the title compound was obtained using 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.12 (4H, br), 3.50-4.00 (4H, br),
4.45 (2H, d, J = 5.9 Hz), 5.01 (lH, br), 7.34 (lH, d, J = 7.8 Hz),
7.45 (lH, d, J = 8.3 Hz), 7.50-7.60 (lH, m), 7.66 (lH, s), 7.70-7.80 (4H, m),
7.90-8.00 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 594 [(M + H) ⁺ , Cl ³⁵ ], 596 [(M + H) ⁺ , C1 ³⁷ ]
Reference Example 71 1-[[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] methyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
The title compound was obtained in the same manner as the Reference Example 61 and the Reference Example 67 using 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.50-2.70 (4H, m), 3.10 (4H, br),
3.61 (2H, s), 4.44 (2H, d, J = 5.4 Hz), 4.92 (1H, br), 7.30-7.40 (2H, m),
7.50-7.70 (3H, m), 7.70-7.90 (3H, m), 7.90-8.00 (3H, m), 8.29 (lH, s).
MS (FAB) m / z: 580 [(M + H) ⁺ , Cl ³⁵ ], 582 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 72 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene
The title compound was obtained in the same manner as in Reference Example 45 and Reference Example 65 using dimethyl 2,6-naphthaledicarboxylic acid as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.98 (3H, s) 4.50 (2H, d, J = 5.4 Hz),
4.99 (lH, br), 7.47 (1H, d, J = 8.3 Hz), 7.75 (1H, s), 7.84 (lH, d, J = 8.8 Hz),
7.92 (lH, d, J = 8.8 Hz), 8.06 (1H, d, J = 8.3 Hz), 8.58 (lH, s).
Elemental Analysis: C ₁₈ H ₂₁ NO ₄
Calc .: C, 68.55; H, 6.71; N, 4.44.
Anal: C, 68.93; H, 6. 70; N, 4.29.
Reference Example 73 Methyl 4-[[(3S) -tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate
Methyl 4-hydroxybenzoate (l.01 g), (3R) -1-tert-butoxycarbonyl-3-pyrrolidinol (l.36 g) triphenylphosphine (l.73 g) was added to tetrahydrofuran (50 Ml). 40% azodicarboxylic-acid diethyltoluene solution (2.87 ml) was dripped at this solution, and it stirred at room temperature for 20 hours. Ethyl acetate and 10% aqueous potassium carbonate solution were added to the reaction mixture, the organic layer was separated, washed with 10% aqueous potassium carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (1.60 g, 76%).
¹ H-NMR (CDCl ₃ ) δ: (9H, s), 2.00-2.20 (2H, m), 3.40-3.70 (4H, m),
3.89 (3H, s), 4.96 (lH, br s), 6.88 (2H, d, J = 8.8 Hz), 7.90-8.00 (2H, m).
Reference Example 74 4-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid
The title compound was obtained in the same manner as in Reference Example 11 using methyl 4-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.47 (9H, each s), 2.10-2.20 (2H, m),
3.40-3.70 (4H, m), 5.00-5.10 (lH, m), 6.98 (2H, d, J = 8.8 Hz),
7.97 (2H, doublet, J = 8.8 Hz).
Reference Example 75 1- [4-[[(3S) -1-tert-Butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine
4-[[((3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] in the same reaction as in Reference Example 12] The title compound was obtained using piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.00-3.20 (4H, m),
3.40-3.80 (8H, m), 4.88 (lH, br s), 6.82 (2H, d, J = 8.3 Hz),
7.20-7.30 (2H, m), 7.60 (lH, dd, J = 8.7, 1.9 Hz), 7.76 (lH, dd, J = 8.5, 1.7 Hz),
7.90-7.95 (3H, m), 8.30 (lH, s).
Elemental Analysis: C ₃₀ H ₃₄ ClN ₃ O ₆ S
Calc .: C, 60.04; H, 5.71; N, 7.00.
Anal: C, 60.05; H, 5.69; N, 6.80.
Reference Example 76 Methyl 3-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate
As in Reference Example 73, the title compound was obtained using methyl 3-hydroxybenzoate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m),
3.40-3.70 (4H, m), 3.92 (3H, s), 4.96 (lH, br s), 7.07 (lH, d, J = 7.8 Hz),
7.30-7.40 (lH, m), 7.53 (lH, d, J = 2.0 Hz), 7.65 (lH, m).
MS (FAB) m / z: 322 (M + H) ⁺ .
Reference Example 77 3-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid
As in Reference Example 74, the title compound was obtained using methyl 3-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m),
3.35-3.65 (4H, m), 5.04 (lH, br s), 7.05-7.15 (lH, m), 7.30-7.40 (lH, m),
7.53 (lH, s), 7.62 (1H, d, J = 7.3 Hz).
MS (FAB) m / z: 308 (M + H) ⁺ .
Reference Example 78 1- [3-[[(3S) -1-tert-Butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine
As in Reference Example 75, the title compound was obtained using 3-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m),
2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (lH, brs), 6.80-6.90 (3H, m),
7.20-7.30 (lH, m), 7.60 (lH, dd, J = 8.8, 1.5 Hz),
7.76 (1H, doublet of doublets, J = 8.5, 1.7 Hz), 7.90-7.95 (3H, m), 8.30-8.35 (lH, m).
MS (FAB) m / z: 600 [(M + H) ⁺ , Cl ³⁵ ], 602 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 79 4-[[(3R) -l-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] methyl benzoate
As in Reference Example 73, the title compound was obtained using methyl 4-hydroxybenzoate and (3S) -l-tert-butoxycarbonyl-3-pyrrolidinol as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.05-2.25 (2H, m), 3.40-3.70 (4H, m),
3.89 (3H, s), 4.96 (lH, br s), 6.88 (2H, d, J = 8.8 Hz), 7.90-8.00 (2H, m).
MS (FAB) m / z: 322 (M + H) ⁺ .
Reference Example 80 4-[[(3R) -l-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid
The title compound was obtained in the same manner as in Reference Example 74 using methyl 4-[[(3R) -l-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 and 1.48 (9H, each s), 2.10-2.25 (2H, m),
3.40-3.70 (4H, m), 4.98 (1H, broad s), 6.91 (2H, d, J = 8.8 Hz),
8.00-8.10 (2H, m).
MS (FAB) m / z: 308 (M + H) ⁺ .
Reference Example 81 1- [4-[[(3R) -1-tert-Butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine
As in Reference Example 75, the title compound was obtained using 4-[[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.00-3.20 (4H, m),
3.40-3.80 (8H, m), 4.89 (lH, br s),
6.82 (2H, d, J = 8.3 Hz), 7.20-7.30 (2H, m), 7.58 (lH, dd, J = 8.8, 2.0 Hz),
7.74 (1H, doublet of doublets, J = 8.5, 1.7 Hz), 7.90-7.95 (3H, m), 8.30 (1H, s).
MS (FAB) m / z: 600 [(M + H) ⁺ , Cl ³⁵ ], 602 [(M + H) ⁺ , C1 ³⁷ ]
Reference Example 82 Methyl 3-[[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate
As in Reference Example 73, the title compound was obtained using methyl 3-hydroxybenzoate and (3S) -1-tert-butoxycarbonyl-3-pyrrolidinol as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.05-2.25 (2H, m),
3.40-3.70 (4H, m), 3.92 (3H, s), 4.95 (lH, br s), 7.07 (lH, d, J = 7.8 Hz),
7.30-7.40 (lH, m), 7.50-7.55 (lH, m), 7.60-7.70 (lH, m).
MS (FAB) m / z: 322 (M + H) ⁺ .
Reference Example 83 3-[[(3R) -l-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid
As in Reference Example 74, the title compound was obtained using methyl 3-[[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.05-2.25 (2H, m), 3.45-3.70 (4H, m),
4.97 (lH, br s), 7.10-7.15 (lH, m), 7.35-7.45 (lH, m), 7.58 (lH, s),
7.70-7.75 (lH, m).
MS (FAB) m / z: 308 (M + H) ⁺ .
Reference Example 84 1- [3-[[(3R) -1-tert-Butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine
As in Reference Example 75, the title compound was obtained using 3-[[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m),
2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (lH, brs), 6.80-6.90 (3H, m),
7.20-7.30 (lH, m), 7.60 (lH, dd, J = 8.5, 1.7 Hz), 7.76 (lH, dd, J = 8.5, 2.0 Hz),
7.90-7.95 (3H, m), 8.30-8.35 (lH, m).
MS (FAB) m / z: 600 [(M + H) ⁺ , C 1 ³⁵ ], 602 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 85 4- (2-Amino-5-pyrimidyl) benzoic acid
In the same reaction as in Reference Example 2, the title compound was obtained using 2-amino-5-bromopyrimidine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 7.81 (2H, d, J = 8.8 Hz), 8.00 (2H, d, J = 8.8 Hz)
8.84 (2 H, s).
MS (FAB) m / z: 216 (M + H) ⁺ .
Reference Example 86 1-tert-Butoxycarbonyl-4-[(methoxycarbonyl) methylene] piperidine
Methyl dimethylphosphono acetate (1.8 ml) was dissolved in tetrahydrofuran (40 ml), and 60% oily sodium hydride (450 mg) was added under ice cooling, and the mixture was stirred as it was. Tetrahydrofuran solution (10 mL of tetrahydrofuran) of 1- (tert-butoxycarbonyl) -4-piperidone (2.05 g) was added, stirred at room temperature for 30 minutes, diluted with ethyl acetate, and 2N hydrochloric acid was added. did. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the title compound (2.35 g, 92%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.28 (2H, t, J = 5.9 Hz)
2.94 (2H, t, J = 5.9 Hz), 3.48 (2H, t, J = 5.9 Hz), 3.50 (2H, t, J = 5.9 Hz),
3.70 (3H, s), 5.72 (1H, s).
Elemental Analysis: C ₁₃ H ₂₁ NO ₄
Calc .: C, 61.16; H, 8. 29; N, 5.49.
Anal: C, 61.14; H, 8.34; N, 5.20.
Reference Example 87 (1-tert-butoxycarbonylpiperidin-4-yl) methyl acetate
1-tert-butoxycarbonyl-4-[(methoxycarbonyl) methylene] piperidine (875 mg) was dissolved in ethanol (10 mL) and 10% palladium / carbon (about 50% water content, 730 Mg) was added and atmospheric pressure reduction was performed at room temperature for 3 days. The catalyst was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (871 mg, 99%).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (2H, m), 1.45 (9H, s), 1.65 (2H, m),
1.93 (1H, m), 2.25 (2H, d, J = 6.8 Hz), 2.72 (2H, br), 3.68 (3H, s),
4.08 (2H, broad singlet).
MS (FAB) m / z: 258 (M + H) ⁺ .
Reference Example 88 (1-tert-butoxycarbonylpiperidin-4-yl) acetic acid
As in Reference Example 11, the title compound was obtained using (1-tert-butoxycarbonylpiperidin-4-yl) methyl acetate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, m), 1.45 (9H, s), 1.73 (2H, m)
1.94 (lH, m), 2.29 (2H, d, J = 6.8 Hz), 2.72 (2H, m), 4.10 (2H, br).
MS (EI) m / z: 243 M ⁺ .
Reference Example 89 1-[(1-tert-butoxycarbonylpiperidin-4-yl) acetyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same reaction as in Reference Example 12, (l-tert-butoxycarbonylpiperidin-4-yl) acetic acid and l-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as raw materials. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, m), 1.43 (9H, s), 1.63 (2H, m),
1.91 (lH, m), 2.14 (2H, d, J = 6.8 Hz), 2.66 (2H, m), 3.07 (4H, br s),
3.56 (2H, br), 3.67 (2H, br), 4.02 (2H, br),
7.58 (lH, dd, J = 8.8, 2.0 Hz), 7.75 (lH, d, J = 8.8 Hz),
7.91 (lH, d, J = 8.8 Hz), 7.93 (lH, d, J = 8.8 Hz), 7.92 (lH, s), 8.30 (lH, s).
MS (FAB) m / z: 536 [(M + H) ⁺ , Cl ³⁵ ), 538 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 90 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid
The title compound was obtained in the same manner as in Reference Example 86, Reference Example 87, and Reference Example 88 after obtaining an aldehyde body by using the l-tert-butoxycarbonylisonifecotinate as a raw material and by the same reaction as in Reference Example 61. .
¹ H-NMR (CDCl ₃ ) δ: 1.10 (2H, m), 1.41 (1H, m), 1.45 (9H, s)
1.60 (2H, q, J = 7.8 Hz), 1.66 (2H, m), 2.39 (2H, t, J = 7.8 Hz),
2.67 (2H, m), 4.09 (2H, br).
MS (FAB) m / z: 258 (M + H) ⁺ .
Reference Example 91 1- [3- (1-tert-Butoxycarbonylpiperidin-4-yl) propionyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin
In the same reaction as in Reference Example 12, 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin hydrochloride The title compound was obtained as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, m), 1.35 (1H, m), 1.44 (9H, s),
1.47 (2H, q, J = 7.8 Hz), 1.57 (2H, m), 2.24 (2H, t, J = 7.8 Hz),
2.61 (2H, m), 3.07 (4H, br s), 3.50 (2H, br s), 3.71 (2H, br s),
4.04 (2H, br), 7.58 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.75 (1H, doubled, J = 8.8, 2.0 Hz),
7.90 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 8.30 (1H, s).
MS (FAB) m / z: 550 [(M + H) ⁺ , C 1 ³⁵ ], 552 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 92 (E) -3- (4-pyridyl) acrylic acid
The title compound was obtained in the same manner as the Reference Example 86 and the Reference Example 88 using isonicotinaldehyde as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 6.79 (1H, d, J = 16.6 Hz),
7.56 (1H, d, J = 16.6 Hz), 7.66 (2H, d, J = 5.9 Hz), 8.62 (2H, d, J = 5.9 Hz),
12.72 (1H, broad singlet).
MS (EI) m / z: 149 M ⁺ .
Reference Example 93 1-methoxycarbonyl-3-pyrroline
3-Pyrroline (1.1 mL) was dissolved in dichloromethane (20 mL), triethylamine (2.6 mL) was added thereto under ice cooling, and methyl chloroformate (1.2 mL) was added thereto, followed by stirring at room temperature for 17 hours. The residue obtained by distillation of the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (0.95 g, 52%).
¹ H-NMR (CDCl ₃ ) δ: 3.73 (3H, s), 4.00-4.20 (4H, m), 5.70-5.90 (2H, m).
Reference Example 94 Methyl 4-trifluoromethanesulfonyloxybenzoate
Methyl 4-hydroxybenzoate (1.99 g) was dissolved in dichloromethane (20 mL), pyridine (2.4 mL) and trifluoromethanesulfonic anhydride (3.0 mL) were added under ice-cooling. After stirring at room temperature for 6 hours, pyridine (1.5 mL) and trifluoromethanesulfonic anhydride (1.0 mL) were added, and the mixture was stirred for 5 hours. Dichloromethane and aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, washed with 10% citric acid aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (5% ethyl acetate-hexane) to obtain the title compound (3.22 g, 86%).
¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 7.36 (2H, d, J = 8.8 Hz),
8.15 (2H, doublet, J = 8.8 Hz).
MS (FAB) m / z: 285 (M + H) ⁺ .
Reference Example 95 Methyl 4- (l-methoxycarbonylpyrrolidin-3-yl) benzoate
Methyl 4-trifluoromethanesulfonyloxybenzoate (l.05g), 1-methoxycarbonyl-3-pyrroline (1.0g), lithium chloride (0.51g), palladium (II) acetate (53mg), Tri (2-furyl) phosphine (100 mg) was dissolved in N, Ndimethylformamide (25 mL), diisopropylethylamine (2.8 mL) was added, and the mixture was heated at 90 DEG C for 11 hours in an argon gas atmosphere. It stirred at 100 degreeC for 7 hours. The solvent was distilled off under reduced pressure, dichloromethane and water were added to the obtained residue, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-5: 1). This was dissolved in methanol (30 mL), 10% palladium / carbon (about 50% moisture, 186 mg) and ammonium formate (197 mg) were added, and the mixture was heated to reflux for 2 hours. After filtration of the catalyst, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate-toluene) to obtain the title compound (241 mg, 25%).
¹ H-NMR (CDCl ₃ ) δ: 1.95-2.10 (1H, m), 2.25-2.35 (1H, m), 3.30-3.35 (4H, m),
3.55-3.75 (1H, m), 3.72 and 3.73 (3H, each s), 3.80-3.90 (1H, m),
3.91 (3H, s), 7.30 (2H, d, J = 3.8 Hz), 8.00 (2H, d, J = 8.3 Hz).
MS (FAB) m / z: 264 (M + H) ⁺ .
Reference Example 96 4- (1-tert-butoxycarbonylpyrrolidin-3-yl) benzoic acid
Methyl 4- (1-methoxycarbonylpyrrolidin-3-yl) benzoate (0.24 g) was dissolved in methanol (10 mL), 8N hydrochloric acid (30 mL) was added, and the mixture was heated to reflux for 40 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in N, N-dimethylformamide (30 ml), 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (0.30 g) was added, and diiso Propylethylamine (0.40 ml) was added and the mixture was stirred at room temperature for 15 hours. The residue obtained by distillation of the solvent under reduced pressure was partitioned between ethyl acetate and 100% citric acid aqueous solution, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-10% methanol-dichloromethane) to obtain the title compound (234 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, m), 1.90-2.00 (1H, m), 2.20-2.30 (1H, m),
3.20-3.90 (5H, m), 7.20-7.30 (2H, m), 8.00-8.10 (2H, m).
MS (EI) M / z: 291 M ⁺ .
Reference Example 97 1- [4-[(3RS) -1-tert-Butoxycarbonylpyrrolidin-3-yl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] Piperazine
In the same manner as in Reference Example 12, 4- (1-tert-butoxycarbonylpyrrolidin-3-yl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as raw materials. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.47 and 1.60 (9H, each s), 1.80-2.00 (1H, m),
2.10-2.20 (1H, m), 3.00-4.00 (13H, m), 7.10-7.30 (4H, m),
7.55-7.65 (1H, m), 7.70-7.80 (1H, m), 7.85-8.00 (3H, m), 8.30 (1H, s).
Reference Example 98 5-benzimidazole carboxylic acid methyl hydrochloride
In the same manner as in Reference Example 44, the title compound was obtained using 5-benzimidazole carboxylic acid as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.93 (3H, s), 7.96 (1H, d, J = 8.8 Hz),
8.12 (1H, d. J = 8.8 Hz), 8.40 (1H, s), 9.66 (1H, s).
Elemental Analysis: C ₉ H ₈ N ₂ O ₂ -HCl
Calc .: C, 50.84; H, 4. 27; N, 13.17; Cl, 16.67.
Anal: C, 50.64; H, 4. 22; N, 13. 12; Cl, 16.59.
Reference Example 99 N-triphenylmethyl-5-benzimidazole carboxylic acid methyl
As in Reference Example 22, the title compound was obtained using 5-benzimidazole carboxylic acid methyl hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 3.75 (2H, s), 3.89 (1H, s), 6.49 (1 / 3H, d, J = 8.8 Hz),
7.1-7.4 (16H, m), 7.61 (1 / 3H, dd, J = 8.8, 1.5 Hz), 7.78 (2 / 3H, d, J = 8.8 Hz),
7.87 (2 / 3H, dd, J = 8.8, 1.5 Hz), 7.96 (1 / 3H, s), 8.02 (2 / 3H, s).
MS (FAB) m / z: 419 (M + H) ⁺ .
Reference Example 100 Thiazolo [5,4-c] pyridine-2-carboxylic acid sodium salt
Thiazolo [5,4-c] pyridine-2-carboxylic acid ethyl (0.6 lg) was dissolved in tetrahydrofuran (12 mL), 1N aqueous sodium hydroxide solution (3 mL) was added thereto, followed by stirring at room temperature for 30 minutes. , Insolubles were collected by filtration. It used for the next reaction without purification.
¹ H-NMR (DMSO-d ₆ ) δ: 7.95 (1H, d, J = 5.9 Hz),
8.57 (1 H, d, J = 5.9 Hz), 9.27 (1 H, s).
Reference Example 101 1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] -4-[( 6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same manner as in Reference Example 47, 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine, 1-[(6-chloro The title compound was obtained using naphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.53-2.62 (4H, m), 2.72 (2H, bra),
3.10 (4H, br s), 3.59 (2H, s), 3.66 (2H, br s), 4.38 (2H, s), 6.54 (lH, s),
7.57 (1H, dd, J = 8.8, 2.0 Hz), 7.76 (1H, dd, J = 8.8, 2.0 Hz),
7.87-7. 94 (3H, m), 8.29 (1H, s).
MS (FAB) M / z: 562 [(M + H) ⁺ , C 1 ³⁵ ], 564 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 102 3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionic acid
5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the same manner as Reference Example 86, Reference Example 87, and Reference Example 88 As a raw material, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.70 (2H, t, J = 7.3 Hz),
2.76 (2H, broad s), 3.09 (2H, t, J = 7.3 Hz), 3.70 (2H, s), 4.40 (2H, s), 6.51 (1H, s).
MS (FD) m / z: 311M ⁺ .
Reference Example 103 (E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) acrylic acid
In the same manner as in Reference Example 86 and Reference Example 88, 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine was used as a raw material. , The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.85 (2H, br a), 3.73 (2H, br s),
4.47 (2H, s), 6.12 (1H, d, J = 15.4 Hz), 6.98 (1H, s), 7.77 (1H, d, J = 15.4 Hz).
MS (ED) m / z: 309 M ⁺ .
Reference Example 104 1-[(E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) prop Phenoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same manner as in Reference Example 12, (E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) acrylic acid And 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.80 (2H, br s)
3.12 (4H, t, J = 4.9 Hz), 3.46-3.86 (6H, m), 4.41 (2H, s),
6.39 (1H, d, J = 15.1 Hz), 6.83 (1H, s), 7.55-7.78 (3H, m),
7.89-7.92 (3H, m), 8.30 (1H, s).
MS (FD) m / z: 601 (M ⁺ , Cl ³⁵ ), 603 (M ⁺ , Cl ³⁷ )
Reference Example 105 1- [3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionyl] -4 -[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionic acid (445 mg) in tetrahydrofuran (10 ml) It melt | dissolved in and N-methylmorpholine (170 microliters) and isobutyl chloroformate (210 microliters) were dripped sequentially at -20 degreeC. After stirring at −20 ° C. for 10 minutes, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (607 mg) previously dissolved in dichloromethane (10 mL) was added. After stirring at -20 ° C for 10 minutes, the reaction solution was heated to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloroethane, washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography ( Hexane: ethyl acetate = 4: 1-2: 1) to obtain the title compound (625 mg, 72%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.53 (2H, t, J = 7.5 Hz),
2.68 (2H, br s), 2.99-3.10 (6H, m), 3.51-3.55 (2H, m), 3.64 (2H, brs),
3.72-3.77 (2H, m), 4.34 (2H, s), 6.43 (1H, s), 7.59 (1H, dd, J = 8.8, 2.0, Hz),
7.74 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.30 (1H, s).
MS (FAB) m / z: 604 [(M + H) ⁺ , C 1 ³⁵⁰ ], 606 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 106 3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propanal
3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) ethyl propionate (1.68 g) obtained in Reference Example 102 was diluted with After dissolving in methane (100 mL) and stirring for 10 minutes at -78 ° C, diisobutylaluminum hydride (0.98 M hexane solution, 7.50 mL) was slowly added dropwise. After stirring at -78 ° C for 10 minutes, methanol (50 ml) was added and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was added with dichloromethane and saturated aqueous ammonium chloride solution and filtered through celite. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (935 mg, 55%).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.76 (2H, br s), 2.81 (2H, t, J = 7.3 Hz),
3.09 (2H, t, J = 7.3 Hz), 3.69 (2H, br s), 4.39 (2H, s), 6.49 (1H, s),
9.81 (1 H, s).
MS (FAB) m / z: 295 M ⁺ .
Reference Example 107 1- [3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propyl] -4- (6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same manner as in Reference Example 47, 3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propanal and 1- The title compound was obtained using [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.69-1.79 (2H, m), 2.36 (2H, t, J = 7.3 Hz),
2.49-2.54 (4H, m), 2.65-2.75 (4H, m), 3.10 (4H, br s), 3.67 (2H, br s),
4.37 (2H, s), 6.39 (1H, s), 7.57 (1H, dd, J = 8.8, 2.0 Hz),
7.78 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.30 (1H, s).
MS (FD) m / z: 589 (M ⁺ , C 1 ³⁵ ), 591 (M ⁺ , C1 ³⁷ )
Reference Example 108 2-Aminomethyl-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine
5-tert-butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (2.10 g) was dissolved in tetrahydrofuran (100 mL) After adding triphenylphosphine (2.66 g) and phthalimide (1.15 g), diethyl azodicarboxylic acid (1.28 mL) was dripped, and it stirred at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a colorless solid. This was dissolved in ethanol (40 mL), hydrazine hydrate (0.39 mL) was added, and the mixture was heated to reflux for 5 hours. The precipitated solid was filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 25: 1) to obtain the title compound (448 mg, 21%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 2.72 (2H, m), 3.60 (2H, m)
3.80 (2H, s), 4.32 (2H, s), 6.64 (1H, s).
MS (FD) m / z: 268 M ⁺ .
Reference Example 109 1- [N-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] carba Moyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
5-tert-butoxycarbonyl-2-aminomethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (150 mg) was dissolved in tetrahydrofuran (100 mL), Under ice-cooling, carbonyldiimidazole (136 mg) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in toluene (50 mL). Triethylamine (0.23 mL) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (356 mg) were added under ice cooling, and it stirred at room temperature overnight. Diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1) to obtain the title compound (303 mg, 89%).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.70 (2H, br s), 3.07 (4H, t, J = 4.9 Hz),
3.48 (4H, t, J = 4.9 Hz), 3.66 (2H, br s), 4.36 (2H, br s),
4.39 (2H, d, J = 5.4 Hz), 4.69 (1H, t, J = 5.4 Hz), 6.58 (1H, s),
7.58 (1H, dd, J = 8.8, 2.0 Hz), 7.74 (1H, dd, J = 8.8, 2.0 Hz),
7.87-7.93 (3H, m), 8.30 (1H, s).
MS (FD) m / z: 604 (M ⁺ , C 1 ³⁵ ), 606 (M ⁺ , C 1 ³⁷ )
Reference Example 110 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] piperazine
As in Reference Example 12, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid, 1-[(6-chloronaphthalene -2-yl) sulfonyl] piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.79 (2H, br s),
3.12 (4H, t, J = 4.9 Hz), 3.68 (2H, br s), 3.84 (4H, t, J = 4.9 Hz),
4.42 (2H, broad singlet), 6.91 (1H, doublet), 7.59 (1H, doublet of doublets, J = 8.8, 2.0 Hz),
7.75 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.90-7.97 (3H, m), 8.30 (1H, s).
MS (FD) m / z: 575 (M ⁺ , Cl ³⁵ ), 577 (M ⁺ , Cl ³⁵ )
Reference Example 111 1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine
As in Reference Example 12, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid, 1-[(6-chloronaphthalene 2-yl) sulfonyl] -3-ethoxycarbonyl piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 1.47 (9H, s), 2.35-2.46 (1H, m),
2.55-2.64 (1H, m), 2.80 (2H, br s), 3.15-3.20 (1H, m), 3.69 (2H, br s),
3.75-3.85 (1H, m), 4.12 (2H, q, J = 7.3 Hz), 4.20-4.36 (2H, m),
4.39-4.48 (3H, m), 6.96 (1H, s), 7.59 (1H, dd, J = 8.8, 2.0 Hz),
7.75 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.32 (1H, s).
MS (FAB) m / z: 648 [(M + H) ⁺ , Cl ³⁵ ], 650 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 112 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-cyano-4,5,6,7-tetrahydrothieno [3,2-c] Pyridin-2-yl) carbonyl] piperazine
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] pipe Razine hydrochloride (195 mg), triethylamine (0.2 mL) and sodium acetate (118 mg) were suspended in ethanol, cyanide bromide (114 mg) was added, and the mixture was stirred at room temperature for 2 hours. Dichloromethane was added and washed with the residue obtained by concentrating a reaction liquid under reduced pressure. After drying over anhydrous sodium sulfate, the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the title compound (51 mg, 28%).
¹ H-NMR (CDCl ₃ ) δ: 2.93-2.98 (2H, m), 3.11-3.14 (4H, m),
3.49-3.55 (2H, m), 3.81-3.84 (4H, m), 4.29 (2H, s), 6.89 (1H, s),
7.59 (1H, dd, J = 8.8, 2.0 Hz), 7.75 (1H, dd, J = 8.8, 2.0 Hz),
7.90-7.94 (3H, m), 8.30 (1H, s).
MS (FAB) m / z: 501 [(M + H) ⁺ , C 135], 503 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 113 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl]- 4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (283 mg) was dissolved in benzene (10 mL), and Ethylamine (0.14 mL) and azide diphenylphosphoryl (0.21 g) were added, and the mixture was heated to reflux for 2 hours. After cooling the reaction solution to room temperature, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (347 mg) was added, and the mixture was heated to reflux overnight. After cooling the reaction solution to room temperature, dichloromethane and 3N sodium hydroxide aqueous solution were added, and the organic layer was extracted. The extracted organic layer was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-2: 1) to obtain the title compound (284 mg, 48%).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.65 (2H, br s), 3.10 (4H, t, J = 4.9 Hz),
3.57 (4H, t, J = 4.9 Hz), 3.64 (2H, br s), 4.27 (2H, s), 6.15 (1H, br s),
7.58 (1H, dd, J = 8.8, 2.0 Hz), 7.73 (1H, dd, J = 8.8, 2.0 Hz),
7.87-7. 93 (3H, m), 8.28 (1H, s).
MS (FAB) m / z: 591 [(M + H) ⁺ , Cl ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].
Reference Example 114 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) -N-methylcarbox Barmoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl] -4-[(6 Chloronaphthalen-2-yl) sulfonyl] piperazine (147 mg) was dissolved in N, N-dimethylformamide (10 mL), 60% oily sodium hydride (22 mg) was added, and the mixture was stirred at room temperature for 30 minutes. I was. Methyl iodide (0.023 mL) was added to the reaction solution, the mixture was stirred at room temperature for 90 minutes, and the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (43 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.63 (2H, br s), 3.01 (4H, t, J = 4.9 Hz),
3.13 (3H, s), 3.40 (4H, t, J = 4.9 Hz), 3.67 (2H, br s), 4.31 (2H, s),
6.21 (lH, br s), 7.58 (lH, dd, J = 8.8, 2.0 Hz), 7.72 (1H, dd, J = 8.8, 2.0 Hz),
7.88-7.95 (3H, m), 8.27 (lH, s).
MS (FAB) m / z: 605 [(M + H) ⁺ , C 1 ³⁵ ], 607 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 115 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] piperazine
6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid, 1-[(6-chloronaphthalene, as in Reference Example 12 The title compound was obtained using the 2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.84 (2H, br s), 3.19 (4H, br),
3.72 (2H, t, J = 5.4 Hz), 3.87 (2H, br s), 4.54 (2H, s), 4.63 (2H, brs),
7.57 (lH, dd, J = 8.8, 2.0 Hz), 7.76 (lH, dd, J = 8.8, 2.0 Hz),
7.87-7.94 (3H, m), 8.30 (lH, s)
MS (FAB) m / z: 577 [(M + H) ⁺ , C 1 ³⁵ ], 579 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 116 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine
6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (742 mg). 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-ethoxycarbonylpiperazine hydrochloride (1.00 g), benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium ( 1.50 g) was dissolved in N, N-diethylformamido (30 mL), triethylamine (0.40 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (505 mg, 30%).
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.37 (3H, m), 1.47 (9H, s), 2.45-2.60 (lH, m),
2.62-2.71 (1H, m), 2.75-2.90 (2H, m), 3.65-3.94 (3H, m), 4.19-4.31 (2H, m),
4.45-4.72 (4H, m), 5.35 (1 / 2H, brs), 5.71-5.77 (1 / 2H, m), 6.72 (1H, br s),
7.58 (lH, dd, J = 8.8, 2.0 Hz), 7.77 (lH, dd, J = 8.8, 2.0 Hz),
7.88-7.92 (3H, m), 8.33 (lH, s).
MS (FAB) m / z: 649 [(M + H) ⁺ , C 1 ³⁵ ], 651 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 117 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-car Bamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalene 2-yl) sulfonyl] -2-ethoxycarbonylpiperazine (487 mg) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL) and 1N aqueous sodium hydroxide solution (3 mL) were added, It stirred at room temperature for 4 hours. 1N hydrochloric acid was added, pH was adjusted to 1-2, ethyl acetate was added, and the organic layer was separated and taken. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (5 ml), and N-methylmorpholine (0.09 ml) and isobutyl chloroformate (0.11 ml) were added dropwise at -20 ° C. . After stirring at −20 ° C. for 10 minutes, ammonia-dichloromethane solution (0.50 ml) was added, and after stirring at −20 ° C. for 10 minutes, ethanolic 1N hydrochloric acid (10 ml) was added to raise the reaction solution to room temperature. The reaction solution was concentrated under reduced pressure, and then the residue was dissolved in dichloroethane and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to obtain the title compound (317 mg, 68%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (9H, s), 2.39-2.86 (4H, m), 3.60-3.80 (4H, m),
4.25-4.34 (lH, m), 4.36-4.44 (1 / 2H, m), 4.62 (2H, brs), 4.97 (1 / 2H, br s),
5.44-5.52 (1 / 2H, m), 6.19 (1 / 2H, br s), 7.30-7.39 (lH, m),
7.63-7.85 (3H, m), 8.15 (lH, d, J = 8.8 Hz), 8.20-8.29 (2H, m), 8.48 (lH, s).
MS (FAB) m / z: 620 [(M + H) ⁺ , Cl ³⁵ ], 622 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 118 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [ (E) -4-chlorostyrenesulfonyl] piperazine
6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid, 1-[(E) -4, as in Reference Example 12 The title compound was obtained using -chloro styrenesulfonyl) piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.87 (2H, br s), 3.31 (4H, m),
3.75 (2H, br s), 3.90 (2H, br s), 4.57 (2H, br s), 4.68 (2H, s),
6.64 (lH, d, J = 15.6 Hz), 7.28-7.35 (5H, m).
MS (FAB) m / z: 553 [(M + H) ⁺ , C 1 ³⁵ ], 555 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 119 (3S) -3-Amino-1-tert-butoxycarbonylpyrrolidine
In the same manner as in Reference Example 59, the title compound was obtained using (3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (1.50 g) as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.98-2.11 (2H, m), 2.95-3.10 (lH, m),
3.26-3.60 (4H, m).
MS (FAB) m / z: 187 (M + H) ⁺ .
Reference Example 120 (3S) -3-[(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine trifluoroacetic acid salt
In the same manner as in Reference Example 1, the title compound was obtained using (3S) -3-amino-1-tert-butoxycarbonylpyrrolidine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.80 (lH, m), 1.88-1.99 (lH, m),
2.95-3.28 (4H, m), 3.75-3.84 (1H, m), 7.71 (1H, m), 7.91 (lH, m),
8.10-8.30 (4H, m), 8.53 (lH, s), 8.91 (lH, br s), 9.06 (1H, br s).
Reference Example 121 (3S) -1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl]- 3-[(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine
In the same manner as in Reference Example 47, 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and (3S) -3- [ The title compound was obtained using (6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine trifluoroacetate as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.52-1.63 (lH, m), 2.03-2.12 (lH, m),
2.19-2.27 (lH, m), 2.35-2.54 (2H, m), 2.73-2.85 (3H, m),
3.59 (lH, d, J = 13.9 Hz), 3.66 (lH, d, J = 13.9 Hz), 3.70 (2H, br s),
3.88-3.95 (lH, m), 4.39 (2H, s), 4.99 (1 / 2H, s), 5.02 (1 / 2H, s),
6.49 (1H, s), 7.55 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.82-7.90 (4H, m), 8.40 (1H, s).
MS (FD) m / z: 561 (M ⁺ , Cl ³⁵ ), 563 (M ⁺ , Cl ³⁷ )
Reference Example 122 (3S) -1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] -3-[(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine
As in Reference Example 12, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid, (3S) -3- (6 -Chloro naphthalen-2-yl) sulfonamide] pyrrolidine trifluoroacetate was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.80-2.08 (2H, m), 2.75 (2H, brs),
3.48-3.87 (6H, m), 3.88-4.05 (lH, m), 4.37 (2H, br s), 6.09 (lH, br s),
7.05-7.15 (lH, m), 7.55 (lH, dd, J = 8.8, 1.5 Hz), 7.79-7.91 (4H, m),
8.41 (lH, s).
MS (FAB) m / z: 576 [(M + H) ⁺ , C 1 ³⁵ ], 578 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 123 (35) -3-Amino-1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine
(3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine was dissolved in trifluoroacetic acid, and then concentrated under reduced pressure, and diethyl ether was added to remove the liquid on the precipitate. Using the obtained residue, a crude product of sulfonamide was obtained in the same manner as in Reference Example 1. The title compound was obtained by azation and reduction as in Reference Example 55.
¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.53 (3H, m), 1.72-1.83 (lH, m),
2.81-2.89 (lH, m), 3.20-3.39 (4H, m), 7.69 (lH, dd, J = 8.8, 1.9 Hz),
7.87 (1H, d, J = 8.8 Hz), 8.12 (lH, d, J = 8.8 Hz), 8.21 (lH, s),
8.26 (lH, d, J = 8.8 Hz), 8.39 (lH, s).
MS (FAB) m / z: 311 [(M + H) ⁺ , Cl ³⁵ ], 313 ((M + H) ⁺ , C1 ³⁷ ]
Reference Example 124 (3S) -3-[[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] Amino] -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine
5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine, (3S) -3-amino, in the same manner as in Reference Example 47 The title compound was obtained using -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.60-1.69 (1H, m), 1.95-2.05 (lH, m),
2.72 (2H, broad singlet), 3.11 (lH, dd, J = 10.3, 4.4 Hz), 3.30-3.46 (4Hm),
3.68 (2H, br s), 3.72 (2H, s), 4.36 (2H, s), 6.44 (lH, s),
7.56 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.86-7.91 (4H, m), 8.36 (lH, s).
MS (FD) m / z: 561 (M ⁺ , C 1 ³⁵ ), 563 (M ⁺ , C1 ³⁷ )
Reference Example 125 (3S) -3-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino ] -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine
As in Reference Example 12, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid, (3S) -3-amino- The title compound was obtained using 1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.90-2.00 (lH, m),
2.11-2.22 (lH, m), 2.80 (2H, br s), 3.32-3.42 (lH, m), 3.44-3.57 (3H, m),
3.71 (2H, broad singlet), 4.38 (2H, d, J = 1.5 Hz), 4.40-4.49 (lH, m),
5.80-5.87 (1H, m), 6.96 (1H, s), 7.54 (1H, dd, J = 8.8, 1.5 Hz),
7.83-7.89 (3H, m), 7.90 (1H, d, J = 8.8 Hz), 8.37 (lH, s).
MS (FD) m / z: 576 [(M + H) ⁺ , Cl ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 126 1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalen-2-yl) sulfonyl] homopiperazine
As in Reference Example 12, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid, 1-[(6-chloronaphthalene -2-yl) sulfonyl] homopiperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.01 (2H, br s), 2.78 (2H, br s),
3.37-3.54 (4H, m), 3.68 (2H, broad singlet), 3.78 (2H, t, J = 6.l Hz),
3.86 (2H, t, J = 6. 1 Hz), 4.39 (2H, s), 6.88 (lH, br s),
7.55 (lH, dd, J = 8.8, 2.0 Hz), 7.75-7.80 (lH, m),
7.83-7.90 (3H, m), 8.33 (lH, s).
MS (FD) m / Z: 589 (M ⁺ , C1 ³⁵ ), 591 (M ⁺ , C1 ³⁷ )
[Reference Example 127] # 4-benzylamino-1-tert-butoxycarbonylpiperidine
Dissolve 1-tert-butoxycarbonyl-4-piperidone (7.00 g) in dichloromethane (500 mL), add benzylamine (4.03 mL), sodium triacetoxyborohydride (11.91 g) and overnight at room temperature Stirred. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: l) to obtain the title compound (7.46 g, 76%).
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.37 (2H, m), 1.45 (9H, s), 1.80-1.90 (2H, m),
2.62-2.70 (lH, m), 2.75-2.85 (lH, m), 2.98-3.07 (lH, m), 3.78-3.90 (3H, m),
3.95-4.10 (lH, m), 7.21-7.34 (5H, m).
MS (FD) m / z: 290 M ⁺ .
Reference Example 128 4-Amino-1-tert-butoxycarbonylpiperidine acetate
4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) is dissolved in methanol (2 mL) and acetic acid (30 mL), 10% palladium / carbon (about 50% water content, 3.06 g) ) And contact reduction was carried out overnight at medium pressure (3 atm). After filtration of the catalyst, the filtrate was distilled under reduced pressure, and the obtained residue was solidified with ethyl acetate to obtain the title compound (2.23 g, 57%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.23 (2H, m), 1.39 (9H, s), 1.69-1.77 (2H, m),
1.80 (3H, s), 2.50 (2H, s), 2.67-2.88 (2H, m), 3.80-3.90 (1H, m).
Elemental Analysis: Cl ₀ H ₂₀ N ₂ O ₂ -CH ₃ CO ₂ H
Calc .: C, 53.16; H, 9.37; N, 10.33.
Anal: C, 53.51; H, 9. 10; N, 9.93.
REFERENCE EXAMPLE 129 X4-[(6-chloronaphthalen-2-yl) sulfonamido] piperidine trifluoroacetic acid salt
As in Reference Example 1, the title compound was obtained by using 4-amino-1-tert-butoxycarbonylpiperidine hydrochloride and 6-chloro-2-naphthylsulfonyl chloride as raw materials.
¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.60 (2H, m), 1.68-1.78 (2H, m),
2.81-2.95 (2H, m), 3.10-3.20 (2H, m), 3.29-3.40 (lH, m),
7.70 (lH, dd, J = 8.8, 2.0 Hz), 7.91 (lH, dd, J = 8.8, 2.0 Hz),
8.11-8.15 (2H, m), 8.21 (lH, s), 8.31 (lH, br s), 8.50 (lH, s),
8.55 (1H, broad singlet).
MS (FAB) m / z: 325 [(M + H) ⁺ , C 1 ³⁵ ], 327 [(M + H) ⁺ , C 1 ³⁷ ].
Reference Example 130 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-cyanobenzofuran-2-yl) carbonyl] piperazine
In the same manner as in Reference Example 12, the title compound was obtained using 6-cyanobenzofuran-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 3.21 (4H, s), 3.95 (4H, s), 7.32 (lH, d, J = l.0 Hz),
7.55 (lH, dd, J = 8.3, 1.0 Hz), 7.59 (lH, dd, J = 8.8, 2.0 Hz),
7.72 (lH, d, J = 8.3 Hz), 7.77 (lH, dd, J = 8.8, 2.0 Hz), 7.81 (lH, s),
7.88-7.95 (3H, m), 8.32 (lH, s).
MS (FAB) m / z: 480 [(M + H) ⁺ , Cl ³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 131 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-([5-cyanobenzothiophen-2-yl) carbonyl] piperazine
The title compound was obtained in the same manner as in Reference Example 12 using 5-cyanobenzothiophene-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 3.18 (4H, s), 3.89 (4H, s), 7.43 (1H, d, J = 2.0 Hz),
7.60 (lH, d, J = 8.8 Hz), 7.73-7.80 (2H, m), 7.85-7.95 (4H, m), 8.10 (lH, s),
8.32 (lH, s).
MS (FAB) m / z: 496 [(M + H) ⁺ , C 1 ³⁵ ], 498 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 132 (1RS) -4-Trifluoromethanesulfonyloxy-3-cyclohexenecarboxylic acid ethyl
Diisopropylamine (0.99 mL) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (1.59 M hexane solution, 3.70 mL) was added dropwise at -78 ° C. 4-oxocyclohexanecarboxylic acid ethyl (1.00 g) dissolved in tetrahydrofuran (5 ml) was added dropwise, stirred for 15 minutes, and then N-phenyltrifluoromethanesulfone dissolved in tetrahydrofuran (5 ml) was added. Mid (2.10g) was dripped, and it stirred for 1 hour after heating up to 0 degreeC. The reaction mixture was concentrated under reduced pressure, and the residue was purified by neutral alumina column chromatography (hexane: ethyl acetate = 9: 1) to obtain the title compound (838 mg, 47%).
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.88-1.99 (1H, m),
2.10-2.18 (lH, m), 2.38-2.50 (4H, m), 2.55-2.64 (lH, m),
4.16 (2H, q, J = 7.3 Hz), 5.77 (lH, broad singlet).
MS (FAB) m / z: 303 (M + H) ⁺ .
Reference Example 133 (1RS) -4- (4-Pyridyl) -3-cyclohexenecarboxylic acid ethyl
In the same manner as in Reference Example 7, (1RS) -4-trifluoromethanesulfonyloxy-3-cyclohexene carboxylic acid ethyl was used as a starting material, to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 1.80-1.91 (lH, m),
2.19-2.25 (1H, m), 2.40-2.57 (4H, m), 2.59-2.67 (lH, m),
4.17 (2H, q, J = 7.3 Hz), 6.36 (lH, br s),
7.26 (2H, doublet of doublets, J = 4.9, 1.5 Hz), 8.53 (2H, doublet of doublets, J = 4.9, 1.5 Hz).
MS (FAB) m / z: 232 (M + H) ⁺ .
Reference Example 134 (1RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid
The title compound was obtained in the same manner as Reference Example 8 using (1RS) -4- (4-pyridyl) -3-cyclohexene carboxylic acid as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.82 (1H, m), 2.10-2.19 (lH, m),
2.42-2.65 (5H, m), 6.99 (lH, br s), 8.02 (2H, d, J = 6.8 Hz),
8.80 (2H, doublet, J = 6.8 Hz).
MS (FAB) m / z: 204 (M + H) ⁺ .
[Reference Example 135] cis-, trans-4- (4-pyridyl) cyclohexanecarboxylic acid
As in Reference Example 87, the title compound was obtained using (1RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid as a raw material.
MS (FAB) m / z: 206 (M + H) ⁺ .
Reference Example 136 6-methoxy-3,4-dihydroisoquinoline
3-methoxyphenethylamine (75.0 g) was dissolved in tetrahydrofuran (100 mL), formic acid (60 mL) and acetic anhydride (108 mL) were added under ice-cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to separate the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in benzene (200 mL), and phosphorus oxychloride (140 mL) was added dropwise with ice cooling. After stirring at 70 ° C. for 15 minutes, ice was added, 2N hydrochloric acid was added, and the mixture was stirred for 1 hour under ice cooling. The aqueous layer was separated, neutralized by addition of potassium carbonate, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to obtain the title compound (13.5 g, 17%).
¹ H-NMR (CDCl ₃ ) δ: 2.72 (2H, t, J = 7.3 Hz), 3.72 (2H, t, J = 7.3 Hz),
3.83 (3H, s), 6.68 (lH, d, J = 2.4 Hz), 6.79 (1H, dd, J = 8.3, 2.4 Hz),
7.22 (1H, doublet, J = 8.3 Hz), 8.25 (h, s).
MS (FAB) m / z: 162 (M + H) ⁺ .
Reference Example 137 6-methoxy-1,2,3,4-tetrahydroisoquinoline
6-methoxy-3,4-dihydroisoquinoline (10.4 g) was dissolved in methanol (100 mL), water (10 mL) was added, and sodium borohydride (6.10 g) was added, followed by 15 minutes at room temperature. Stirred. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane, and washed with water, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 15) to obtain the title compound (7.95 g, 76%).
¹ H-NMR (CDCl ₃ ) δ: 2.79 (2H, t, J = 5.9 Hz), 3.12 (2H, t, J = 5.9 Hz),
3.76 (3H, s), 3.96 (2H, s), 6.62 (lH, s), 6.70 (lH, dd, J = 8.3, 2.4 Hz),
6.92 (1H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 164 (M + H) ⁺ .
Reference Example 138 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
6-methoxy-1,2,3,4-tetrahydroisoquinoline (7.75 g) was dissolved in dimethyl sulfide (20 mL), aluminum chloride (19.0 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. . Dichloromethane and dilute hydrochloric acid were added, the aqueous layer was separated, saturated aqueous sodium bicarbonate solution was added, the mixture was weakly alkaline and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the residue obtained by distillation of the solvent under reduced pressure was dissolved in saturated ethanol hydrochloride (100 ml), ethyl acetate was added to the residue obtained by distillation of the solvent under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (7.91 g). , 90%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 5.9 Hz), 3.43 (2H, m), 4.25 (2H, s),
6.76 (lH, d, J = 2.0 Hz), 6.83 (1H, dd, J = 8.3, 2.0 Hz), 7.15 (lH, d, J = 8.3 Hz),
9.71 (3H, broad singlet).
MS (FAB) m / z: 150 (M + H) ⁺ .
Reference Example 139 2-tert-Butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline
6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.87 g) was dissolved in methanol (100 mL), triethylamine (4.67 mL), di-tert-butyldicarbonate (13.95 g ) Was added and stirred at room temperature for 3 hours. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1) to obtain the title compound (9.96 g, 94%).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.75 (2H, t, J = 5.9 Hz),
3.61 (2H, t, J = 5.9 Hz), 4.48 (2H, s), 6.25 (lH, br s),
6.64 (1H, d, J = 2.4 Hz), 6.70 (1H, br s), 6.93 (lH, d, J = 7.8 Hz).
Reference Example 140 2-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline
As in Reference Example 94, the title compound was obtained using 2-tert-butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydro isoquinoline as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.87 (2H, t, J = 5.9 Hz),
3.66 (2H, t, J = 5.9 Hz), 4.59 (2H, s), 7.06 (lH, br s),
7.08 (lH, d, J = 8.3 Hz), 7.17 (lH, d, J = 8.3 Hz).
Elemental Analysis: C ₁₅ H ₁₈ F ₃ NO ₅ S
Calc .: C, 47.24; H, 4.76; F, 14.94; N, 3.67; S, 8.41.
Anal: C, 47.34; H, 4.72; F, 15.25; N, 3.42; S, 8.65.
Reference Example 141 2-tert-Butoxycarbonyl-6-methoxycarbonyl-1,2,3,4-tetrahydro isoquinoline
2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline (1.34 g) is dissolved in methanol (50 mL) and triethylamine (0.73 Ml), palladium (II) acetate (40 mg) and 1,3- (diphenylphosphine) propane (145 mg) were added, and the mixture was stirred overnight at 70 ° C under a carbon monoxide stream. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the title compound (665 mg, 65%).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.88 (2H, m), 3.66 (2H, br s),
3.91 (3H, s), 4.62 (2H, s), 7.17 (lH, d, J = 7.8 Hz), 7.83 (lH, s),
7.84 (lH, d, J = 7.8 Hz).
Reference Example 142 1-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] -4-[(6-chloronaphthalene-2- (Yl) sulfonyl] piperazine
As in Reference Example 48, 2-tert-butoxycarbonyl-6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline, 1-[(6-chloronaphthalen-2-yl) sulfonyl ] Piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.76 (2H, t, J = 5.4 Hz), 3.09 (4H, br),
3.60 (2H, t, J = 5.4 Hz), 3.77 (4H, br), 4.52 (2H, s), 7.12-7.2S (3H, m),
7.59 (lH, dd, J = 8.8, 2.0 Hz), 7.75 (lH, dd, J = 8.8, 2.0 Hz),
7.88-7.95 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 570 [(M + H) ⁺ , C 1 ³⁵ ], 572 [(M + H) ⁺ , Cl ³⁷ ]
Reference Example 143 4- (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) benzoic acid
4- (1-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine (3.59 g) in 1,2-dimethoxyethane (30 mL) It dissolved, and 4-carboxyphenylboronic acid (3.60g), lithium chloride (1.38g), tetrakistriphenylphosphinepalladium (0.62g), and an aqueous sodium carbonate solution (2M, 16.3ml) were added, and it was made into 2 in argon gas atmosphere. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue obtained by distillation of the solvent under reduced pressure was subjected to silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1). The resulting compound was purified by trituration with hexane and ethyl acetate in a mixed solvent (hexane: ethyl acetate = 5: 1) to obtain the title compound (462 mg, 14%).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.56 (2H, br s), 3.66 (2H, m),
4.12 (2H, broad s), 6.19 (lH, broad), 7.47 (2H, doubled, J = 8.3 Hz),
8.07 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 304 (M + H) ⁺ .
Reference Example 144 4- (1-tert-butoxycarbonylpiperidin-4-yl) benzoic acid
As in Reference Example 87, the title compound was obtained using 4- (1-tert-butoxycarbonyl-l, 2,3,6-tetrahydropyridin-4-yl) benzoic acid as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.60-1.71 (2H, m), 1.80-1.89 (2H, m),
2.69-2.90 (3H, m), 4.20-4.35 (2H, m), 7.31 (2H, d, J = 8.3 Hz),
8.05 (2H, doublet, J = 8.3 Hz).
MS (FAB) m / z: 306 (M + H) ⁺ .
Reference Example 145 1- [4- (1-tert-butoxycarbonyl-l, 2,3,6-tetrahydropyridin-4-yl) benzoyl] -4-[(6-chloronaphthalene-2- (Yl) sulfonyl] piperazine
In the same manner as in Reference Example 12, 4- (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) benzoic acid, 1-[(6-chloronaphthalen-2-yl ) Sulfonyl] piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.48 (2H, br s), 3.10 (4H, br)
3.62 (2H, t, J = 5.9 Hz), 3.70 (4H, br), 4.08 (2H, br s), 6.05 (lH, bra),
7.25 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.59 (lH, dd, J = 8.8, 2.0 Hz),
7.75 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.90-7.96 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 596 [(M + H) ⁺ , C 1 ³⁵ ], 598 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 146 1- [4- (1-tert-butoxycarbonylpiperidin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same manner as in Reference Example 12, 4- (1-tert-butoxycarbonylpiperidin-4-yl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as raw materials. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.49-1.63 (2H, m), 1.72-1.80 (2H, m),
2.59-2.68 (1H, m), 2.71-2.86 (2H, m), 2.92-3.30 (4H, m), 3.45-4.95 (4H, m),
4.16-4.31 (2H, m), 7.18 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz),
7.59 (lH, dd, J = 8.8, 2.0 Hz), 7.75 (lH, dd, J = 8.8, 2.0 Hz),
7.90-7.94 (3H, m), 8.30 (lH, s).
MS (FAB) m / z: 598 [(M + H) ⁺ , C 1 ³⁵ ], 600 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 147 (3RS) -3-Amino1-tert-butoxycarbonylpyrrolidine
3-aminopyrrolidine (0.54 g) was dissolved in methanol (30 mL) under ice-cooling, diisopropylethylamine (720 µl) and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (0.84g) was added, it gradually heated up to room temperature and stirred for 11 hours. The residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-5% methanol-dichloromethane) to obtain the title compound (0.59 g, 94%).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.00-2.30 (2H, m), 3.10-4.00 (5H, m).
Reference Example 148 (3RS) -1-tert-Butoxycarbonyl-3-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine
As in Reference Example 1, the title compound was obtained using (3RS) -3-amino-1-tert-butoxycarbonylpyrrolidine as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.60-2.10 (2H, m), 3.00-3.50 (4H, m),
3.88 (lH, br), 4.96 (lH, br), 7.50-7.60 (1H, m), 7.80-7.90 (4H, m),
8.43 (lH, s),
MS (FAB) m / z: 411 ((M + H) ⁺ , C 1 ³⁵ ], 413 [(M + H) ⁺ , C 1 ³⁷ ]
Reference Example 149 (3RS) -1-tert-Butoxycarbonyl-3- [4- (4-pyridyl) benzamido] pyrrolidine
As in Reference Example 12, the title compound was obtained using (3RS) -3-amino-1-tert-butoxycarbonylpyrrolidine and 4- (4-pyridyl) benzoic acid as raw materials.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.90-2.10 (1H, m), 2.20-2.30 (1H, m),
3.30-3.40 (1H, m), 3.40-3.60 (2H, m), 3.70-3.80 (lH, m), 4.65-4.75 (lH, m),
6.25-6.35 (lH, m), 7.52 (2H, d, J = 5.9 Hz), 7.71 (2H, d, J = 8.3 Hz),
7.88 (2H, doublet, J = 8.3 Hz), 8.70 (2H, doublet, J = 5.4 Hz).
MS (FAB) m / z: 368 (M + H) ⁺ .
Reference Example 150 # 6-Chloro-N-methoxy-N-methylnicotinamide
Under ice-cooling, 6-chloronicotinic acid (5.00 g) was suspended in dichloromethane (150 mL), and catalytic amounts of N, N-dimethylformamide and oxaryl chloride (5.30 mL) were added, followed by stirring at room temperature for 23 hours. The reaction solution was concentrated, and the obtained residue was dissolved in dichloromethane (100 mL), and N, O-dimethylhydroxylamine hydrochloride (6.18 g), and triethylamine (13.3 mL) were added under ice cooling. After stirring for 6 hours at room temperature, the mixture was diluted with dichloromethane (150 mL) and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (6.08 g, 96%).
¹ H-NMR (CDCl ₃ ) δ: 3.39 (3H, s), 3.56 (3H, s), 7.39 (lH, d, J = 8.3 Hz),
8.03 (lH, dd, J = 8.3, 2.4 Hz), 8.78 (lH, d, J = 2.4 Hz).
Reference Example 151 6-Chloronicotinaldehyde
6-Chloro-N-methoxy-N-methylnicotinamide (500 mg) was dissolved in tetrahydrofuran (8 mL), and diisobutylaluminum hydride (0.95 M hexane solution, 2.88) at -78 ° C under argon atmosphere. Ml) was added dropwise, stirred for 3 hours, and then stirred at room temperature for 2 hours. The reaction solution was cooled to −20 ° C., saturated brine (2 mL) was added thereto, stirred for 30 minutes, and the insolubles were filtered off and washed with ethyl acetate. The combined filtrate and washings were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (346 mg, 98%) as a crude product, which was used in the next reaction without purification.
¹ H-NMR (CDCl ₃ ) δ: 7.52 (lH, d, J = 8.3 Hz), 8.14 (lH, dd, J = 8.3, 2.2 Hz),
8.87 (lH, d, J = 2.2 Hz), 10.10 (lH, s).
Reference Example 152 1-tert-Butoxycarbonyl-4-methanesulfonylpiperazine
N-tert-butoxycarbonylpiperazine (2.00 g) was dissolved in dichloromethane (40 mL), triethylamine (1.78 mL) was added, and methanesulfonyl chloride (0.91 mL) was added dropwise under ice-cooling. . After stirring for 1 hour under ice cooling, the mixture was diluted with dichloromethane (20 ml), and washed with an aqueous 5% citric acid solution, water, and brine. After drying over anhydrous magnesium sulfate, the residue obtained by distillation of the solvent under reduced pressure was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the title compound (2.58 g, 91%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.79 (3H, s), 3.19 (4H, t, J = 5.l Hz),
3.55 (4H, t, J = 5.l Hz).
Reference Example 153 1-tert-butoxycarbonyl-4-[[(2RS) -2- (6-chloropyridin-3-yl) -2-hydroxyethyl] sulfonyl] piperazine
1-tert-butoxycarbonyl-4-methanesulfonylpiperazine (838 mg) was dissolved in tetrahydrofuran (8 ml), and tert-butyllithium (1.7 M pentane solution, l.72 ml) was added, followed by stirring for 2 hours. Tetrahydrofuran solution (4 mL of tetrahydrofuran) of 6-chloronicotinaldehyde (346 mg) was added dropwise, and after stirring at -78 ° C for 3 hours, isopropanol (l mL) was added, and the temperature was raised to room temperature, followed by ethyl acetate. Diluted. After washing with water and saturated brine, drying over anhydrous sodium sulfate, and distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to obtain the title compound (532 mg, 54%).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.11 (lH, dd, J = 14.1,2.2 Hz),
3.21 (lH, dd, J = 14.1, 9.8 Hz), 3.23-3.33 (4H, m), 3.52-3.57 (4H, m),
3.70 (1H, broad s), 5.37 (lH, broad bre), 7.36 (1H, d, J = 8.3 Hz),
7.72 (lH, dd, J = 8.3, 2.4 Hz), 8.41 (lH, d, J = 2.4 Hz).
MS (FAB) m / z: 405 (M + H) ⁺ .
Reference Example 154 1-tert-Butoxycarbonyl-4-[[(E) -2- (6-chloropyridin-3-yl) ethyl] sulfonyl] piperazine
1-tert-butoxycarbonyl-4-[[(2RS) -2- (6-chloropyridin-3-yl) -2-hydroxyethyl] sulfonyl] piperazine (465 mg) was diluted with dichloromethane (10 ML), N-methylmorpholine (0.152 mL) and N, N-dimethyl-4-aminopyridine (14.1 mg) were added, and p-toluenesulfonyl chloride (263 mg) was cooled under ice with argon atmosphere. Added. After stirring at room temperature for 2 hours, N, N-dimethyl-4-aminopyridine (141 mg) was added, and the mixture was stirred at room temperature for 3 hours. Dilution with dichloromethane (20 ml), washing with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, drying with anhydrous sodium sulfate, and distilling off the solvent under reduced pressure gave silica gel column chromatography (dichloromethane: methanol = 100). : 1) gave the title compound (414 mg, 93%).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.19 (4H, br), 3.55 (4H, br),
6.73 (lH, d, J = 15.6 Hz), 7.40 (lH, d, J = 8.3 Hz), 7.43 (5H, d, J = 15.6 Hz),
7.76 (1H, doublet of doublets, J = 8.3, 2.5 Hz), 8.50 (1H, (1H, d, J = 2.5 Hz).
Elemental Analysis: As C ₁₆ H ₂₂ ClN ₃ O ₃ S
Calc .: C, 49.54; H, 5.72; N, 10.83; Cl, 9.14; S, 8.27.
Anal: C, 49.54; H, 5.73; N, 10.63; C1, 9.44; S, 8.15.
Reference Example 155 1- (4-Bromo-2-methylbenzoyl) -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
In the same manner as in Reference Example 12, 4-bromo-2-methylbenzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.80-4.10 (8H, m),
6.89 (lH, d, J = 8.3 Hz), 7.30 (lH, dd, J = 8.3, 2.0 Hz), 7.35 (1H, d, J = 2.0 Hz),
7.60 (1H, dd, J = 8.8, 2.0 Hz), 7.74 (lH, dd, J = 8.8, 2.0 Hz),
7.90-7.95 (3H, m), 8.30 (1H, broad singlet).
MS (FAB) m / z: 507 [(M + H) ⁺ , Br ⁷⁹ ], 509 [(M + H) ⁺ , Br ⁸¹ ].
Reference Example 156 3-methyl-4- (4-pyridyl) benzoic acid hydrochloride
In the same manner as in Reference Example 6, 4-bromo-3-methylbenzoic acid was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.36 (3H, s), 7.50 (lH, d, J = 7.8 Hz),
7.92 (lH, d, J = 7.8 Hz), 7.97 (lH, s), 8.08 (2H, d, J = 6.4 Hz),
8.99 (2H, doublet, J = 6.4 Hz).
MS (FAB) m / z: 214 (M + H) ⁺ .
Reference Example 157 4- (2-methyl-4-pyridyl) benzoic acid hydrochloride
In the same manner as in Reference Example 2, the title compound was obtained using 4-bromo-2-methylpyridine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.81 (3H, s), 8.10-8.16 (4H, m),
8.23 (lH, dd, J = 6.4, 1.5 Hz), 8.36 (lH, d, J = 1.5 Hz), 8.85 (1H, d, J = 6.4 Hz).
MS (FAB) m / z: 214 (M + H) ⁺ .
Reference Example 158 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine
N, N'-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved in toluene (250 ml), and 3-methylethyl bromotonate (7..0 ml) was added dropwise under ice-cooling. It stirred at room temperature for 24 hours. Triethylamine (2.0 ml) was added, after stirring at room temperature for 71 hours, the insolubles were filtered off and the filtrate was distilled under reduced pressure. 10% hydrochloric acid (300 ml) was added to the obtained residue, and the precipitate was filtered. Ethyl acetate was added to the filtrate to separate the aqueous layer, and potassium carbonate was added to make alkaline. Ethyl acetate was added to the mixture, the organic layer was separated, washed with saturated brine, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (10.7 g, 62%).
¹ H-NMR (CDCl ₃ ) δ: 2.30-2.70 (8H, m), 3.11 (1H, br s), 3.40-3.80 (4H, m),
3.60 (3H, s), 7.20-7.40 (10H, m).
MS (FAB) m / z: 339 (M + H) ⁺ .
Reference Example 159 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine
Dissolve 1,4-dibenzyl-2-methoxycarbonylmethylpiperazine (2.04 g) in acetic acid (40 mL), add 10% palladium / carbon (containing about 50% water, 2.00 g) and at room temperature Contact reduction was performed at 4 atmospheres for 4 hours. The catalyst was filtered off, and dichloromethane and saturated potassium carbonate aqueous solution were added to the residue obtained by distillation under reduced pressure, and the precipitated insoluble matter was filtered, and the organic layer was separated and taken out. After washing with saturated brine, it was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (30 ml), 6-chloro-2-naphthylsulfonyl chloride (782 mg) was added, stirred at 0 ° C for 2 hours, triethylamine (410 µl) was added at 0 ° C. Furthermore, it stirred for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-3% methanol-dichloromethane) to obtain the title compound (759 mg, 33%).
¹ H-NMR (CDCl ₃ ) δ: 1.71 (lH, br s), 2.15-2.55 (4H, m), 2.90-3.05 (2H, m),
3.15-3.25 (lH, m), 3.60-3.70 (5H, m), 7.55-7.60 (lH, m), 7.75-7.80 (lH, m),
7.85-7.95 (3H, m), 8.30 (lH, s).
(FAB) m / z: 383 [(M + H) ⁺ , Cl ³⁵ ], 385 [(M + H) ⁺ , C1 ³⁷ ].
Reference Example 160 4-tert-butoxycarbonyl-1-[(3-chloro-1-propyl) sulfonyl] piperazine
1-tert-butoxycarbonylpiperazine (3.00 g) and triethyl amine (2.24 mL) were dissolved in dichloromethane (40 mL) under an argon atmosphere and ice-cooled, and 3-chloro-l-propanesulfonic acid chloride (1.96 g) was added and it stirred for 10 minutes at room temperature under ice-cooling for 20 minutes. The reaction solution was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the title compound (4.36 g, 83%).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 2.27-2.33 (2H, m), 3.08 (2H, t, J = 7.3 Hz),
3.26 (4H, t, J = 4.9 Hz), 3.53 (4H, t, J = 4.9 Hz), 3.69 (2H, t, J = 6.l Hz).
MS (FAB) m / z: 327 (M + H) ⁺
Elemental Analysis: C ₁₂ H ₂₃ ClN ₂ O ₄ S
Calc .: C, 44.10; H, 7.09, Cl, 10.85; N, 8.57; S, 9.81.
Anal: C, 44.18; H, 7. 11; Cl, 10.69; N, 8.23; S, 9.76.
Reference Example 161 4-tert-Butoxycarbonyl-1-[(3-hydroxy-1-propyl) sulfonyl] piperazine
4-tert-butoxycarbonyl-1-[(3-chloro-1-propyl) sulfonyl] piperazine (1.18 g) was dissolved in N, N-dimethylformamide (10 mL) and potassium acetate (1.06). g) was added, and after stirring at room temperature for 2 hours, the mixture was heated and stirred at 100 ° C for 3 hours. Dilution with ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution were added, followed by stirring. The organic layer was separated, washed with 5% citric acid aqueous solution, water, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (20 ml), water (5 ml) and lithium hydroxide monohydrate (221 mg) were added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate and saturated brine were added, the organic layer was separated, and then extracted with ethyl acetate from the aqueous layer. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the title compound (944 mg, 84%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.04-2.11 (2H, m), 3.06 (2H, t, J = 7.6 Hz),
3.25 (4H, t, J = 4.9 Hz), 3.53 (4H, t, J = 4.9 Hz), 3.80 (2H, q, J = 5.4 Hz).
MS (FAB) m / z: 309 (M + H) ⁺ .
Elemental Analysis: C ₁₂ H ₂₄ N ₂ O ₅ S
Calc .: C, 46.74; H, 7. 84; N, 9.08; S, 10.40.
Anal: C, 46.80; H, 7.92; N, 9.05; S, 10.59.
Reference Example 162 4-tert-Butoxycarbonyl-1-[(3-methoxymethyloxy-1-propyl) sulfonyl] piperazine
4-tert-butoxycarbonyl-1-[(3-hydroxy-1-propyl) sulfonyl] piperazine (3.00 g) was dissolved in dichloromethane (60 mL) and diisopropylethylamine (2.72 mL) ) Was added and methoxymethyl chloride (1.11 mL) was added under ice-cooling. After stirring at room temperature for 20 hours, the mixture was diluted with dichloromethane, washed with water, 5% citric acid aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (3.32 g, 97%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.06-2.13 (2H, m), 3.03 (2H, m),
3.25 (4H, t, J = 4.9 Hz), 3.36 (3H, s), 3.52 (4H, t, J = 4.9 Hz),
3.63 (2H, t, J = 5.4 Hz), 4.61 (2H, s).
MS (FAB) m / z: 353 (M + H) ⁺ .
Elemental Analysis: C ₁₄ H ₂₈ N ₂ O ₆ S
Calc .: C, 47.71; H, 8.01; N, 7.95; S, 9.10.
Anal: C, 47.77; H, 8. 18; N, 7.97; S, 9.16.
Reference Example 163 4-tert-butoxycarbonyl-1-[(E) -4-chloro-β- [2- (methoxymethyloxy) ethyl] -β-styrylsulfonyl] piperazine and 4- tert-butoxycarbonyl-1-[(Z) -4-chloro-β- [2- (methoxymethyloxy) ethyl] -β-styrylsulfonyl] piperazine
In an argon atmosphere, 4-tert-butoxycarbonyl-1-[(3-methoxymethyloxy-1-propyl) sulfonyl] piperazine (800 mg) is dissolved in tetrahydrofuran (10 ml), Tert-butyllithium (1.7 M hexane solution, 1.47 ml) was added dropwise at 78 deg. C, and stirred at -78 deg. Trimethylsilyl chloride (0.317 mL) was added, and after stirring at -78 ° C for 90 minutes, tert-butyllithium (1.7M hexane solution, 1.47 mL) was added dropwise and stirred at -78 ° C for 90 minutes. The tetrahydrofuran solution (8 ml of tetrahydrofuran) of p-chlorobenzaldehyde (352 mg) was dripped at -78 degreeC, and after stirring for 2 hours, it returned to room temperature over 15 hours and stirred for 6 hours. Under ice-cooling, 5% citric acid solution (20 ml) and ethyl acetate (150 ml) were added, and the organic layer was separated and washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-2: 1) to obtain the title compound E (307 mg, 28%), Z. (751 mg, 70%) was obtained.
E body:
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.87 (2H, t, J = 7.3 Hz), 3.21-3.28 (4H, m),
3.35 (3H, s), 3.46-3.56 (4H, m), 3.80 (2H, t, J = 7.3 Hz), 4.60 (2H, s),
7.40 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.54 (lH, s).
Z body:
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.77 (2H, dt, J = 6.4, 1.0 Hz),
2.91-2.98 (4H, m), 3.19-3.25 (4H, m), 3.38 (3H, s),
3.82 (2H, t, J = 6.4 Hz), 4.66 (2H, s), 7.07 (lH, s),
7.32 (2H, doublet, J = 8.6 Hz), 7.35 (2H, doublet, J = 8.6 Hz).
Example 1 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride.
At room temperature, 1- [4- (4-pyridyl) benzoyl] piperazine ditrifluoroacetate (1.19 g) was suspended in dichloromethane (100 mL), followed by diisopropylethylamine (1.68 mL) and 6 -Chloro-2-naphthylsulfonylchloride (691 mg) was added. After stirring at room temperature for 2 hours, the reaction solution was purified by silica gel column chromatography (2% methanol-dichloromethane), and the obtained fraction was added with ethanolic 1N hydrochloric acid to make weak acid, and then the solvent was distilled off. The resultant colorless solid was washed with tetrahydrofuran to give the title compound (1.05 g, 81%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.95-3.25 (4H, m), 3.43 (2H, br s), 3.60 (2H, br s),
7.56 (2H, d, J = 8.3 Hz), 7.74 (lH, dd, J = 8.8, 2.5 Hz),
7.83 (1H, dd, J = 8.8, 2.0 Hz), 8.01 (2H, d, J = 8.3 Hz), 8.19 (1H, d, J = 8.8 Hz),
8.25-8.40 (4H, m), 8.51 (1H, s), 8.94 (2H, d, J = 6.8 Hz).
MS (FAB) m / z: 492 [(M + H) ⁺ , Cl ³⁵ ], 494 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₆ H ₂₂ N ₃ O ₃ ClS.HC1.0.5H ₂ O
Calc .: C, 58.10; H, 4.50; N, 7.82; Cl, 13.19; S, 5.97.
Anal: C, 58.12; H, 4.67; N, 7.66; Cl, 13.12; S, 6.10.
Example 2 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
4-tert-butoxycarbonyl-2-ethoxycarbonyl-l- [4- (4-pyridyl) benzoyl] piperazine (5l4 mg) is dissolved in dichloromethane (30 mL) and cooled on ice with trifluoro Roacetic acid (30 mL) was added and stirred at room temperature for 45 minutes. The residue obtained by distilling the solvent was suspended in dichloromethane (100 ml) under ice-cooling, and diisopropylethylamine (1.02 ml) and 6-chloro-2-naphthylsulfonyl chloride (366 mg) were added. After stirring at room temperature for 1 hour, the reaction solution was purified by silica gel column chromatography (1% methanol-dichloromethane), and ethanol 1N hydrochloric acid was added to the obtained fraction to make it slightly acidic, and then the solvent was distilled off. The colorless solid obtained was washed with ethanol to give the title compound (308 mg, 43%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.30 (3H, m), 2.60-5.40 (9H, m)
7.50 (2 / 3H, d, J = 8.3 Hz), 7.57 (4 / 3H, d, J = 7.8 Hz),
7.74 (lH, dd, J = 9.0, 1.7 Hz), 7.83 (lH, d, J = 8.8 Hz),
8.00 (2 / 3H, d, J = 7.8 Hz), 8.04 (4 / 3H, d, J = 8.3 Hz),
8.19 (lH, d, J = 8.8 Hz), 8.25-8.35 (4H, m), 8.55 (lH, s),
8.92 (2H, doublet, J = 4.9 Hz).
MS (FAB) m / z: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₉ H ₂₆ N ₃ O ₅ ClS.HC1.0.5H ₂ O.
Calc .: C, 57.15; H, 4,63; N, 6.89; Cl, 11.63; S, 5.26.
Anal: C, 56.95; H, 4.68; N, 6.70; Cl, 11.36; S, 5.30.
Example 3 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine-2-carboxylic acid hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride (152 mg) obtained in Example 2 The solution was dissolved in ice-cold mixture in a mixed solvent of ethanol (1 ml), tetrahydrofuran (1 ml) and water (1 ml), 1N aqueous sodium hydroxide solution was added dropwise, and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to make it slightly acidic, and the precipitated colorless solid was collected by filtration and dried to obtain the title compound (62 mg, 42%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.65-5.30 (7H, m), 7.49 (4 / 5H, d, J = 7.7 Hz),
7.56 (6 / 5H, d, J = 8.3 Hz), 7.74 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, d, J = 8.3 Hz), 7.95-8.05 (2H, m), 8.19 (1H, d, J = 8.3 Hz),
8.20-8.35 (4H, m), 8.53 (lH, s), 8.92 (2H, d, J = 5.4 Hz).
MS (FAB) m / z: 536 [(M + H) ⁺ , C 1 ³⁵ ], 538 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₂ N ₃ O ₅ ClS.0.9HC1.1.2H ₂ O.
Calc .: C, 54.92; H, 4. 32; N, 7. 12; Cl, 11.41; S, 5.43.
Anal: C, 54.94; H, 4. 42; N, 6.83; Cl, 11.31; S, 5.33.
Example 4
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) nicotinyl] piperazine hydrochloride
6- (4-pyridyl) nicotinic acid hydrochloride (96 mg) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetic acid salt (150 mg) in dichloromethane (10 mL). Suspension was added, 1-hydroxybenzotriazole (48 mg) and N-methylmorpholine (155 µl) were added, and ice-cooled to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (102 mg) ) Was added, followed by stirring at room temperature for 16 hours. Since the reaction was slow, N, N-dimethylformamide (10 ml) was added to the reaction solution, and the mixture was stirred for 3 days. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography (1% methanol-dichloromethane). The solvent was distilled off, tetrahydrofuran and ethanol 1N hydrochloric acid were added to the residue, and the precipitated crystals were collected by filtration and dried to obtain the title compound (105 mg, 55%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.25 (4H, m), 3.46 (2H, br s), 3.76 (2H, br s),
7.74 (lH, dd, J = 8.5, 1.7 Hz), 7.83 (1H, d, J = 8.8 Hz),
8.07 (lH, dd, J = 7.8, 1.5 Hz), 8.19 (lH, d, J = 8.8 Hz), 8.28 (lH, s),
8.29 (lH, d, J = 8.8 Hz), 8.42 (lH, d, J = 8.3 Hz),
8.51 (lH, s), 8.65 (2H, d, J = 6.4 Hz), 8.80 (1H, m), 9.01 (2H, d, J = 5.9 Hz).
MS (FAB) m / z: 493 [(M + H) ⁺ , C 1 ³⁵ ], 495 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₅ H _2l N ₄ O ₃ ClS-HCIH ₂ O
Calc .: C, 54.85; H, 4. 42; N, 10.23; Cl, 12.95; S, 5.86.
Anal: C, 54.57; H, 4.51; N, 10.06; Cl, 13.08; S, 5.87.
Example 5 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 4, 4- (3-pyridyl) benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetate were used as raw materials to obtain the title compound as a colorless solid. Got it.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.25 (4H, m), 3.47 (2H, br s), 3.73 (2H, br s),
7.51 (2H, d, J = 8.3 Hz), 7.73 (lH, dd, J = 8.8, 2.0 Hz), 7.8-7.9 (3H, m),
7.92 (lH, dd, J = 7.8,5.4 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.25-8.30 (2H, m),
8.50 (lH, s),
8.55-8.65 (lH, m), 8.75-8.85 (lH, m), 9.14 (lH, d, J = 2.0 Hz).
MS (FAB) m / z: 492 [(M + H) ⁺ , Cl ³⁵ ], 494 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₂ N ₃ O ₃ ClS.0.85HC1H ₂ O
Calc .: C, 57.72; H, 4.63; N, 7.77; Cl, 12.12; S, 5.93.
Anal: C, 57.44; H, 4. 62; N, 7.68; Cl, 11.99; S, 5.83.
Example 6 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine (300 mg) obtained in Example 1 was added to dichloromethane (10 mL). It dissolved, 3-chloroperbenzoic acid (382g) was added at -20 degreeC, and it stirred at -20 degreeC for 21 hours. An aqueous solution of sodium sulfite was added to decompose the excess peroxide, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by distillation of the solvent was purified by silica gel column chromatography (2-5% methanol-dichloromethane). After distilling off the solvent, ether was added to solidify and filtered to obtain the title compound (200 mg, 63%) as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 2.90-3.40 (4H, m), 3.40-4.20 (4H, m),
7.43 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 7.3 Hz), 7.55-7.65 (3H, m),
7.76 (lH, dd, J = 8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.26 (2H, d, J = 7.3 Hz),
8.31 (1 H, s).
MS (FAB) m / z: 508 [(M + H) ⁺ , C 1 ³⁵ ], 510 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₂ N ₃ O ₄ ClS.0.8H ₂ O
Calc .: C, 59.78; H, 4.55; N, 8.04; Cl, 6.79; S, 6.14.
Anal: C, 59.82; H, 4. 45; N, 7.94; Cl, 6.85; S, 6.29.
Example 7 1- [4- (2-aminopyridin-5-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
To a mixed solvent of dichloromethane (1 ml) and ethanol (1 ml), 1- [4- [2-tert-butoxycarbonylamino) pyridin-5-yl) benzoyl] -4-[(6-chloronaphthalene 2-yl) sulfonyl] piperazine (128 mg) was dissolved, and under cooling with ice, saturated ethanol hydrochloride solution (10 ml) was added, the mixture was stirred at room temperature for 1 minute, the solvent was distilled off, and isopropanol was added to crystallize. The precipitated crystals were filtered and dried to afford the title compound (88 mg, 68%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.20 (4H, m), 3.30-3.90 (4H, m),
7.05 (1 / 2H, d, J = 8.8 Hz), 7.06 (1 / 2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.3 Hz),
7.67 (2H, d, J = 8.3 Hz), 7.73 (lH, d, J = 8.3 Hz), 7.82 (lH, d, J = 8.8 Hz),
7.90-8.10 (2H, br), 8.18 (lH, d, J = 8.3 Hz), 8.25-8.35 (4H, m), 8.50 (lH, s).
MS (FAB) m / z: 507 [(M + H) ⁺ , Cl ³⁵ ], 509 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₆ H ₂₃ ClN ₄ O ₃ S.HC1.1.2H ₂ O.0.8iPrOH.
Calc .: C, 55.56; H, 5.52; N, 9.13; Cl, 11.55; S, 5.22.
Anal: C, 55.40; H, 5. 24; N, 8.85; Cl, 11.79; S, 5.50.
Example 8 1- [4- (4-aminophenyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
1- [4- [4- (tert-butoxycarbonylamino) phenyl] benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin in the same manner as in Example 7 As a raw material, the title compound was obtained as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.20 (4H, m), 3.25-3.80 (4H, m),
6.68 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz),
7.54 (2H, d, J = 8.3 Hz), 7.73 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.18 (lH, dd, J = 8.8 Hz), 8.25-8.40 (2H, m),
8.50 (1H, broad singlet).
MS (FAB) m / z: 506 [(M + H) ⁺ , Cl ₃₅ ], 508 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₄ ClN ₃ O ₃ S.0.2HCl
Calc .: C, 63.18; H, 4.75; N, 8. 19; Cl, 8.29; S, 6.25.
Anal: C, 62.93, H, 4.93; N, 7.91; Cl, 7.99; S, 6.36.
Example 9 1- [4- (2-aminothiazol-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
The title compound was prepared in the same manner as in Example 4, using 4- (2-aminothiazol-4-yl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials Got it.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m),
7.26 (lH, s), 7.41 (2H, d, J = 8.3 Hz), 7.73 (lH, dd, J = 8.8, 2.0 Hz),
7.79 (2H, d, J = 8.3 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.18 (lH, d, J = 8.8 Hz),
8.25-8.30 (2H, m), 8.50 (lH, br s).
MS (FAB) m / z: 513 [(M + H) ⁺ , C 1 ³⁵ ], 515 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H _2l N ₄ O ₃ ClS ₂ .HC1.0.3H ₂ O
Calc .: C, 51.95; H, 4.11; N, 10.10; Cl, 12.78; S, 11.56.
Anal: C, 51.99; H, 4. 19; N, 10.03; Cl, 12.61; S, 11.45.
Example 10 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- [imidazol-4 (5) -yl] benzoyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- [1-triphenylmethylimidazol-4 (5) -yl] benzoyl] piperazine in dichloromethane (5 mL) (303 mg) was dissolved and saturated hydrochloric acid ethanol solution (30 mL) was added under ice-cooling. After stirring for 3 hours at room temperature, the solvent was distilled off, ether was added for crystallization, and the resulting crystals were filtered to give the title compound (307 mg, 76%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m)
7.47 (2H, d, J = 8.3 Hz), 7.74 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.19 (lH, d, J = 8.8 Hz),
8.22 (1H, d, J = l.0 Hz), 8.25-8.30 (2H, m), 8.50 (lH, m),
9.22 (lH, d, J = 1.0 Hz).
MS (FAB) m / z: 481 [(M + H) ⁺ , C 1 ₃₅ ], 483 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H _2l ClN ₄ O ₃ S.HC1.0.4H ₂ O
Calc .: C, 54.94; H, 4.38; N, 10.68; Cl, 13.52; S, 6.11.
Anal: C, 54.98; H, 4. 29; N, 10.62; Cl, 13.56; S, 6.14.
Example 11 1- [4- (2-aminoimidazol-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 4, 4- (2-aminoimidazol-4-yl) benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as the starting compounds. Got.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m),
7.39 (2H, d, J = 8.3 Hz), 7.47 (1H, s), 7.49 (2H, br s),
7.67 (2H, d, J = 8.3 Hz), 7.73 (lH, dd, J = 8.8, 2.5 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.18 (lH, d, J = 8.8 Hz),
8.25-8.30 (2H, m), 8.50 (lH, br s).
MS (FAB) m / z: 496 [(M + H) ⁺ , Cl ³⁵ ], 498 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₂ N ₅ O ₃ ClS-HCl
Calc .: C, 54.14; H, 4. 35; N, 13.15; Cl, 13.32; S, 6.02.
Anal: C, 53.94; H, 4. 39; N, 12.82; Cl, 13.27; S, 6.07.
Example 12 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -1 -methylpyridinium iodide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl obtained in Example 1 in a mixed solvent of benzene (10 mL) and methanol (10 mL). ] Piperazine (300 mg) was dissolved at room temperature, methyl iodide (1 mL) was added to the reaction solution, and the same amount of methyl iodide was added three times every 24 hours and refluxed for 4 days. The reaction solution was distilled off under reduced pressure, and the obtained residue was washed with methanol, collected by filtration and dried to give the title compound (229 mg, 58%) as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (2H, br s), 3.13 (2H, br s), 3.43 (2H, br s),
3.75 (2H, broad s), 4.34 (3H, s), 7.59 (2H, d, J = 8.8 Hz),
7.74 (lH, dd, J = 8.8, 2.4 Hz), 7.85 (lH, dd, J = 8.8, 2.0 Hz),
8.08 (2H, d, J = 8.8 Hz), 8.19 (lH, d, J = 8.8 Hz),
8.25-8.30 (2H, m), 8.45-8.55 (3H, m), 9.03 (2H, d, J = 6.8 Hz).
Elemental Analysis: As C ₂₇ H ₂₅ N ₃ O ₃ ClIS · H ₂ O
Calc .: C, 49.74; H, 4. 17; N, 6.45.
Anal: C, 49.60; H, 4.09; N, 6.23.
Example 13 3- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
In the same manner as in Example 6, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine obtained in Example 5 was used as a raw material. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.90-3.40 (4H, m), 3.40-4.20 (4H, m), 7.50-7.60 (lH, m),
7.40-7.45 (3H, m), 7.54 (2H, d, J = 8.3 Hz), 7.60 (lH, dd, J = 8.8, 2.0 Hz),
7.76 (lH, dd, J = 8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.22 (lH, d, J = 5.9 Hz),
8.31 (lH, d, J = 2.0 Hz), 8.43 (1H, broad singlet).
MS (FAB) m / z: 508 [(M + H) ⁺ , Cl ³⁵ ], 510 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₂ N ₃ O ₄ ClIS.H ₂ O
Calc .: C, 59.37; H, 4. 60; N, 7.99; C1, 6.74; S, 6.10.
Anal: C, 59.48; H, 4.69; N, 7.74; Cl, 6.73; S, 6.07.
Example 14 1- [2-carboxy-4- (pyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine
1- [2-tert-butoxycarbonyl-4- (pyridin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride in dichloromethane (50 mL) (250 mg) was dissolved, and trifluoroacetic acid (50 mL) was added dropwise with ice cooling. After stirring at room temperature for 5 hours, the solvent was distilled off, the residue was dissolved in methanol, the resulting solution was left in a refrigerator for 1 day, the precipitated colorless solid was collected by filtration and dried to give the title compound (550 mg, 28%). Was obtained as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.40 (6H, m), 3.65-3.75 (2H, m),
7.41 (lH, d, J = 7.8 Hz), 7.70-7.75 (3H, m), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
8.00 (lH, dd, J = 7.8, 1.5 Hz), 8.15-8.30 (4H, m), 8.50 (lH, br s),
8.67 (2H, doublet, J = 5.9 Hz), 13.29 (1H, broad singlet).
MS (FAB) m / z: 536 [(M + H) ⁺ , Cl ³⁵ ], 538 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: C ₂₇ H ₂₂ ClN ₃ O ₅ S.0.5H ₂ O
Calc .: C, 59.50; H, 4. 25; N, 7.71; Cl, 6.50; S, 5.88.
Anal: C, 59.54; H, 4. 30; N, 7.37; C1, 6.35; S, 5.89.
Example 15 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-4-yl) thiophen-2-yl] carbonyl] piperazine hydrochloride
5- (pyridin-4-yl) thiophene-2-carboxylic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] pipet obtained in the same manner as in Example 4, and obtained in Reference Example 28. The title compound was obtained by using azine hydrochloride.
¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (4H, br s), 3.74 (4H, br s),
7.52 (lH, d, J = 3.9 Hz), 7.73 (lH, dd, J = 8.8, 2.5 Hz),
7.83 (lH, dd, J = 8.8, 2.0 Hz), 8.03 (1H, d, J = 3.9 Hz),
8.10-8.15 (2H, m), 8.18 (lH, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.51 (lH, s),
8.88 (2H, doublet, J = 6.8 Hz).
MS (FAB) m / z: 498 [(M + H) ⁺ , Cl ³⁵ ], 500 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₄ H ₂₀ ClN ₃ O ₃ S ₂ HC1H ₂ O
Calc .: C, 52.17; H, 4. 20; N, 7.61; Cl, 12.83; S, 11.61.
Anal: C, 52.04; H, 4. 22; N, 7.22; Cl, 12.74; S, 11.57.
Example 16 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-4-yl) furan-2-yl] carbonyl] piperazine hydrochloride
5- (pyridin-4-yl) furan-2-carboxylic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine obtained in the same manner as in Example 4 and obtained in Reference Example 29 The title compound was obtained using hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.13 (4H, br s), 3.30-4.00 (4H, m),
7.21 (lH, d, J = 3.9 Hz), 7.71 (lH, d, J = 8.8 Hz), 7.75-7.80 (lH, m),
7.83 (lH, d, J = 8.8 Hz), 6.10-8.30 (5H, m), 8.51 (lH, s), 8.85-8.90 (2H, m).
MS (FAB) m / z: 482 [(M + H) ⁺ , Cl ³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₀ ClN ₃ O ₄ S · HC1 · H ₂ O
Calc .: C, 53.74; H, 4. 32; N, 7.83; Cl, 13.22; S, 5.98.
Anal: C, 53.51; H, 4. 36; N, 7.57; Cl, 13.21; S, 5.97.
Example 17 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 4, using 4- (pyridin-2-yl) benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride obtained in Reference Example 30 as a starting material. The compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (4H, br), 3.60-4.00 (4H, br),
7.46 (3H, br), 7.73 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
7.94-8.05 (2H, br), 8.08 (2H, d, J = 8.8 Hz), 8.18 (lH, d, J = 8.8 Hz),
8.28 (2H, doublet, J = 8.8 Hz), 8.50 (1H, s), 8.70 (1H, br).
MS (FAB) m / z: 492 [(M + H) ⁺ , C 1 ³⁵ ], 494 [(M + H) ⁺ , Cl ³⁵ ]
Elemental Analysis: As C ₂₆ H ₂₂ ClN ₃ O ₃ S.0.9HC1H2O
Calc .: C, 57.53; H, 4. 62; Cl, 12.41; N, 7.74; S, 5.91.
Anal: C, 57.55; H, 4.52; Cl, 12.64; N, 7.61; S, 6.03.
Example 18 1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
The title compound was obtained according to the method of Example 17 using 4- (2-pyridyl) benzoic acid hydrochloride and 1-[(E) -4-chlorostyrylsulfonyl] piperazine hydrochloride obtained in Reference Example 31 as raw materials.
¹ H-NMR (DMSO-d ₆ ) δ: 3.19 (4H, br), 3.46 (2H, br), 3.75 (2H, br),
7.36 (lH, d, J = 15.6 Hz), 7.44 (1H, d, J = 15.6 Hz), 7.50-7.58 (lH, br),
7.53 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.82 (2H, d, J = 7.8 Hz),
8.13 (2H, m), 8.15 (2H, d, J = 7.8 Hz), 8.75 (lH, d, J = 4.9 Hz).
MS (FAB) m / z: 468 [(M + H) ⁺ , C 1 ³⁵ ], 470 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₂ ClN ₃ O ₃ S.HC1.0.3EtOH.0.3H ₂ O
Calc .: C, 56.42 H, 4.89; Cl, 13.54; N, 8.02; S, 6.12.
Anal: C, 56.51 H, 4.83; Cl, 13.46; N, 8.10; S, 5.99.
Example 19 2- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
In the same manner as in Example 6, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine obtained in Example 17 was used as a raw material. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, br), 3.63 (2H, br), 3.67 (2H, br),
7.27 (lH, m), 7.33 (lH, t, J = 8.8 Hz), 7.39-7.41 (lH, br),
7.40 (2H, d, J = 7.8 Hz), 7.60 (lH, d, J = 8.8 Hz), 7.77 (lH, d, J = 8.8 Hz),
7.83 (2H, d, J = 7.8 Hz), 7.93 (lH, d, J = 3.BHz), 7.94 (lH, s),
8.31 (lH, s), 8.33 (lH, d, J = 5.9 Hz).
MS (FAB) m / z: 508 [(M + H) ⁺ , C 1 ³⁵ ], 510 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₂ ClN ₃ O ₄ S
Calc .: C, 61.47; H, 4. 37; Cl, 6.98; N, 8. 27; S, 6.31.
Anal: C, 61.32; H, 4. 46; Cl, 7.21; N, 8.13; s, 6.02.
Example 20 2- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -1-methylpyridinium iodide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine obtained in the same manner as in Example 12 and obtained in Example 17 as a raw material The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.93-3.23 (4H, br), 3.54 (2H, br),
3.82 (2H, br), 4.30 (3H, s), 7.50 (2H, d, J = 8.8 Hz), 7.53 (lH, m),
7.70 (2H, d, J = 8.8 Hz), 7.70 (lH, br), 7.84-7.92 (4H, m),
8.15 (lH, t, J = 6.8 Hz), 8.26 (1H, s), 8.52 (lH, t, J = 6.8 Hz),
9.29 (lH, d, J = 5.9 Hz).
Elemental Analysis: C ₂₇ H ₂₅ ClIN ₃ O ₃ S.1.6H ₂ O
Calc .: C, 48.93; H, 4. 29; N, 6.34.
Anal: C, 48.81; H, 4.06; N, 6.31.
Example 21 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride
4- (2,4-diamino-6-pyrimidyl) benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine obtained in the same manner as in Example 4 and obtained in Reference Example 32 The title compound was obtained using hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.14 (4H, br), 3.45 (2H, br s), 3,73 (2H, br s),
6,36 (1H, s), 7,54 (2H, d, J = 7.8 Hz), 7.74 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, d, J = 8.8 Hz), 7.83 (lH, s), 7.84 (2H, d, J = 7.8 Hz),
8.18 (lH, J = 8.8 Hz), 8.18-8.35 (3H, br), 8.27 (lH, s), 8.28 (lH, d, J = 8.8 Hz),
8.50 (lH, s), 12.64 (lH, br s).
MS (FAB) m / z: 523 [(M + H) ⁺ , C 1 ³⁵ ], 525 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₅ H ₂₃ ClN ₆ O ₃ S.HC1.1.4H ₂ O
Calc .: C, 51.36; H, 4. 62; Cl, 12.13; N, 14.37; S, 5.48.
Anal: C, 51.38; H, 4.54; Cl, 12.24; N, 14.23; S, 5.55.
Example 22 1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride
4- (2,4-diamino-6-pyrimidyl) benzoic acid hydrochloride obtained in the same manner as in Example 21, and 1-[(E) -4-chlorostyrylsulfonyl obtained in Reference Example 31 The title compound was obtained using piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.18 (4H, br), 3.43 (2H, br), 3.76 (2H, br),
4.0 (2H, br), 6.37 (lH, s), 7.84 (2H, d, J = 15.6 Hz), 7.44 (lH, J = 15.6 Hz),
7.53 (2H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.82 (1H, d, J = 8.8 Hz),
7.88 (1H, d, J = 8.8 Hz), 8.23 (lH, br s), 8.32 (lH, br s), 12.58 (lH, br s).
MS (FAB) m / z: 499 [(M + H) ⁺ , C 1 ³⁵ ], 501 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₃ H ₂₃ ClN ₆ O ₃ S · lHC2 · 1.4H ₂ O
Calc .: C, 48.64; H, 4.79; Cl, 13.73; N, 14.80; S, 5.65.
Anal: C, 48.46; H, 4.56; Cl, 13.53; N, 14.54; S, 5.72.
Example 23 2- [4-[[4- (E) -4-chlorostyrylsulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
2- [4-[(l-piperazinyl) carbonyl] phenyl] pyridine N-oxide hydrochloride and (E) -4-chlorostyrylsulfonylchloride obtained in the same manner as in Example 1 and obtained in Reference Example 35. The title compound was obtained as a raw material.
¹ H-NMR (CDCl ₃ ) δ: 3.10-3.40 (4H, br), 3.66 (2H, br)
3.89 (2H, br), 6.65 (1H, d, J = 15.6 Hz), 7.28 (lH, m), 7.34 (lH, t, J = 7.8 Hz),
7.39-7.48 (6H, m), 7.50 (2H, d, J = 7.8 Hz), 7.88 (2H, d, J = 7.8 Hz),
8.34 (lH, d, J = 5.9 Hz).
MS (FD) m / z: 483 (M ⁺ , C 1 ³⁵ ), 485 (M ⁺ , Cl ³⁷ )
Elemental Analysis: As C ₂₄ H ₂₂ ClN ₃ O ₄ S.0.5H ₂ O
Calc .: C, 58.47; H, 4. 70; Cl, 7.19; N, 8.52; S, 6.50.
Anal: C, 58.49; H, 4.80; Cl, 7.29; N, 8.31; S, 6.34.
Example 24 1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
Under ice-cooling, piperazine (727 mg) was dissolved in dichloromethane (10 mL), and (E) -4-chlorostyrylsulfonyl chloride (500 mg) was slowly added. After stirring at room temperature for 1 hour, the reaction solution was diluted with dichloromethane (100 ml), washed with saturated aqueous sodium bicarbonate solution, 5% aqueous citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling a solvent under reduced pressure was suspended in N, N-dimethylformamide (10 ml), and 4- (4-pyridyl) benzoic acid (420 mg) and N, N-dimethyl-4 obtained in Reference Example 2 -Aminopyridine (309 mg) was added. Under ice-cooling, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (405 mg) was added, and the reaction solution was stirred at room temperature for 68 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 70: 1) to recrystallize the colorless solid with a mixed solvent of ethyl acetate and hexane, and recrystallized with ethyl acetate to give colorless acicular crystals. (185 mg) was obtained. On the other hand, saturated hydrochloric acid-ethanol (4 ml) was added to the filtrate, and the obtained residue was recrystallized from methanol-ethyl acetate to give the title compound (200 mg) as colorless needles.
¹ H-NMR (DMSO-d ₆ ) δ: 3.17 (2H, br s), 3.23 (2H, br s),
3.48 (2H, br s), 3.77 (2H, br s), 7.36 (lH, d, J = 15.3 Hz),
7.44 (lH, d, J = 15.3 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.74 (2H, d, J = 8.3 Hz),
7.82 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.8 Hz), 8.32 (2H, d, J = 6.6 Hz),
8.95 (2H, doublet, J = 6.6 Hz).
MS (FAB) m / z: 4 68 [(M + H) ⁺ , Cl ³⁵ ], 470 [(M + H) ⁺ , Cl ³⁷ ]
Elemental analysis: as _{C 24 H 22 ClN 3 O 3} S · HCl · 0.2H 2 O · 0.22CH 3 CO 2 CH 2 CH 3
Calc .: C, 56.66; H, 4.81; Cl, 13.44; N, 7.97; S, 6.08.
Anal: C, 56.68; H, 4.79; Cl, 13.43; N, 8.04; S, 6.14.
Example 25 4- [4-[[4-[(E) -4-chlorostyrylsulfonyl] piperazin-1-yl] carbonyl] phenyl] -1 -methylpyridinium iodide
In the same manner as in Example 12, using 1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine obtained in Example 24 as a raw material, The title compound was obtained.
1 H-NMR (DMSO-d 6) 6: 3.04-3. 87 (BH, br), 4.35 (3H, s),
7.3 S (lH, d, J = 15.6 Hz), 7.44 (lH, d, J = 15.6 Hz),
7.53 (2H, d, J = 8.3 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.8 Hz),
8.13 (2H, d, J = 8.3 Hz), 8.53 (2H, d, J = 6.8H7), 9.05 (2H, d, J = 7.3 Hz).
Elemental Analysis: C ₂₅ H ₂₅ ClIN ₃ O ₃ S 0.5H ₂ 0
Calc .: C, 48.52; H, 4. 23; N, 6.79.
Anal: C, 48.68; H, 4.13; N, 6.41.
Example 26 3- [4-[[4-[(E) -4-chlorostyrylsulfonyl] piperazin-l-yl] carbonyl] phenyl] pyridine N-oxide
After removing the protecting group by the same reaction as in Example 7, the title compound was obtained by reacting with (E) -4-chlorostyrylsulfonylchloride in the same manner as in Example 23.
¹ H-NMR (CDCl ₃ ) δ: 3.26 (4H, br), 3.52-4.00 (4H, br),
6.64 (lH, d, J = 15.6 Hz), 7.45-7.52 (7H, m), 7.52 (2H, d, J = 2.0 Hz),
7.57 (2H, d, J = 2.0 Hz), 8.22 (lH, dt, J = 6.3, 1.6 Hz), 8.44 (lH, t, J = 1.6 Hz).
MS (FAB) m / z: 484 [(M + H) ⁺ , Cl ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₂ ClN ₃ O ₃ S.0.5H ₂ O
Calc .: C, 58.47; H, 4. 70; Cl, 7.19; N, 8.52; S, 6.50.
Anal: C, 58.49; H, 4. 66; Cl, 7.40; N, 8.54; s, 6.56.
Example 27 1-[(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine hydrochloride
According to the method of Example 17, using 4- (3-pyridyl) benzoic acid hydrochloride obtained in Reference Example 8 and 1-[(E) -4-chlorostyrylsulfonyl] piperazine hydrochloride obtained in Reference Example 31 as a raw material The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3. 08-3.29 (4H, br), 3. 42-3. 85 (4H, broad singlet),
7.35 (lH, d, J = 15.6 Hz), 7.43 (1H, d, J = 15.6 Hz), 7.52 (2H, d, J = 8.3 Hz),
7.59 (2H, d, J = 8.3 Hz), 7.80-7.93 (5H, m), 8.54 (lH, d, J = 6.8 Hz),
8.78 (lH, d, J = 4.5 Hz), 9.13 (1H, d, J = 2.0 Hz).
MS (FAB) m / z: 468 [(M + H) ⁺ , Cl ³⁵ ], 470 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₂ ClN ₃ O ₃ S.HC1.1.3H ₂ O
Calc .: C, 54.61; H, 4.89; N, 7.96; Cl, 13.43; S, 6.07.
Anal: C, 54.82; H, 4.80; N, 7.91; Cl, 13.14; S, 6.14.
Example 28 3- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -1-methylpyridinium iodide
In the same manner as in Example 12, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine obtained in Example 5 was used as a raw material. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.50-3.80 (8H, m), 4.44 (3H, s),
7.57 (2H, d, J = 8.3 Hz), 7.74 (1H, dd, J = 8.6, 2.0 Hz),
7.84 (lH, dd, J = 8.8, 1.5 Hz), 7.94 (2H, d, J = 8.3 Hz), 8.10-8.30 (4H, m),
8.51 (1H, s), 8.90 (lH, d, J = 7.8 Hz), 9.01 (1H, d, J = 5.9 Hz), 9.45 (lH, s).
MS (FAB) m / z: 506 [(M + H) ⁺ , Cl ³⁵ ], 508 [(M + H) ⁺ , Cl ³⁷ ]
Example 29 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-hydroxy-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 4, 2- (hydroxy-4- (4-pyridyl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride obtained in Reference Example 38 were prepared. The title compound was obtained as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.40 (8H, m), 7.25-7.40 (3H, rn),
7.70-7.80 (1H, m), 7.80-7.90 (lH, m), 8.15-8.25 (3H, m),
6.25-8.35 (2H, m), 8.50-8.60 (lH, m), 8.91 (2H, d, J = 6.4 Hz),
10.41 (lH, broad singlet).
MS (FAB) m / z: 535 [(M + H) ⁺ , C 1 ³⁵ ], 537 [(M + H) ⁺ , C 1 ³⁷ ],
Elemental analysis: as C ₂₆ H ₂₂ ClN ₃ O ₄ S · lHC1 · 1.7H ₂ O
Calc .: C, 53.96; H, 4. 62; N, 7. 26; Cl, 12.86; S, 5.54.
Anal: C, 53.62; H, 4.58; N, 7.34; Cl, 13.10; S, 5.94.
Example 30 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-methoxy-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 4, 3-methoxy-4- (4-pyridyl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride obtained in Reference Example 41 were used as starting materials. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-4.00 (8H, m), 3.81 (3H, s),
7.08 (1H, d, J = 8.8 Hz), 7.17 (lH, s), 7.55 (1H, d, J = 8.8 Hz),
7.74 (lH, dd, J = 8.8, 2.0 Hz), 7.83 (lH, d, J = 8.3 Hz), 8.04 (2H, d, J = 6.3 Hz),
8.19 (lH, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.52 (lH, s),
8.85 (2H, doublet, J = 6.3 Hz).
MS (FAB) m / z: 522 [(M + H) ⁺ , Cl ³⁵ ], 524 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₇ H ₂₄ ClN ₃ O ₄ S.0.8HC1.1.7H ₂ O
Calc .: C, 55.74; H, 4.89; N, 7.22; Cl, 10.97; S, 5.51.
Anal: C, 55.59; H, 4. 90; N, 7.23; Cl, 10.90; S, 5.52.
Example 31 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-hydroxy-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
Boron tribromide (115 µl) was dissolved in dichloromethane (1 ml), and 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3 obtained in Example 30 at an ambient temperature of about -78 ° C. Dichloromethane (dichloromethane: 4 ml) of -methoxy-4- (pyridin-4-yl) benzoyl] piperazine (105 mg) was added dropwise and stirred for 23 hours while gradually warming to room temperature. Dichloromethane and water were added, stirred for a while, and sodium bicarbonate was added thereto to make the reaction solution alkaline and the organic layer was separated. The aqueous layer was extracted again with dichloromethane, the organic layers were combined and washed with saturated brine. The residue obtained by drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-3% methanol-dichloromethane). The crude crude obtained was dissolved in tetrahydrofuran and solidified by adding ethanol hydrochloride. The precipitated solid was filtered, bitten and dissolved in a mixed solvent of methanol, the insolubles were filtered off, and the filtrate was distilled under reduced pressure to obtain the title compound (36 mg, 30%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.80 (8H, m), 6.85-6.95 (lH, m),
7.01 (lH, d, J = 1.4 Hz), 7.49 (lH, d, J = 8.8 Hz), 7.72 (lH, dd, J = 8.8, 2.0 Hz),
7.81 (lH, dd, J = 8.5, 1.7 Hz), 7.94 (2H, d, J = 6.4 Hz), 8.19 (lH, d, J = 8.8 Hz),
8.25-8.30 (2H, m), 8.51 (lH, s), 8.75 (2H, d, J = 5.9 Hz), 10.67 (lH, s).
MS (FAB) m / z: 508 [(M + H) ⁺ , C 1 ³⁵ ], 510 [(M + H) ⁺ , C 1 ³⁷ ].
Example 32 1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-4- [4- (pyridin-4-yl) benzoyl] piperazine
By the same reaction as in Example 7, 4-tert-butoxycarbonyl-l-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine was used as a raw material, and a protecting group After removal, the title compound was obtained in the same manner as in Example 4 by reaction with 4- (4-pyridyl) benzoic acid hydrochloride.
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.10 (3H, m), 3.00-4.00 (8H, m), 4.60-4.80 (lH, m),
7.42 (2H, d, J = 7.8 Hz), 7.47 (2H, d, J = 5.9 Hz), 7.50-7.60 (lH, m),
7.64 (2H, d, J = 8.3 Hz), 7.70-7.80 (lH, m), 7.85-7.95 (3H, m),
8.33 (lH, s), 8.69 (2H, s).
MS (FAB) m / z: 564 [(M + H) ⁺ , C 1 ³⁵ ], 566 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₉ H ₂₆ ClN ₃ O ₅ S.0.3H ₂ O
Calc .: C, 60.78; H, 4. 70; N, 7.33; Cl, 6.80; S, 5.60.
Anal: C, 60.84; H, 4. 84; N, 6.98; Cl, 7.03; S, 5.70.
Example 33 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazin-2-carboxylic acid
In the same manner as in Example 3, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-4- [4- (pyridin-4-yl) benzoyl] piperazine was used as a raw material. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.70-5.00 (7H, m), 7.40-7.50 (2H, m),
7.65-7.75 (2H, m), 7.85-8.25 (8H, m), 8.50-8.60 (2H, m), 8.80-8.95 (2H, m).
MS (FAB) m / z: 536 [(M + H) ⁺ , Cl ³⁵ ], 538 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₂ CIN ₃ O ₅ S.0.3HC1H ₂ O
Calc .: C, 57.40; H, 4. 34; N, 7.44; Cl, 8.16; S, 5.68.
Anal: C, 57.16; H, 4. 35; N, 7.36; Cl, 7.92; S, 6.08.
Example 34 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l- [4- (pyridin-3-yl) benzoyl] piperazine
By the same reaction as in Example 2, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.15-1.30 (3H, m), 2.60-4.60 (8H, m), 5.33 (lH, br),
7.40-7.55 (3H, m), 7.70-7.85 (4H, m), 8.05-8.10 (1H, m),
8.19 (1H, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.50-8.65 (2H, m), 8.91 (lH, s).
MS (FAB) m / z: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₉ H ₂₆ ClN ₃ O ₅ S.0.1HC1.0.5H ₂ O.
Calc .: C, 60.40; H, 4. 74; N, 7. 29; Cl, 6.76; S, 5.56.
Anal: C, 60.67; H, 4.61; N, 7.30; Cl, 6.89; S, 5.51.
Example 35 2-Carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-3-yl) benzoyl] piperazine hydrochloride
4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l- [4- (pyridin-3-yl) benzoyl] piperazine (426 mg) as in Example 3 As a raw material, the ester was hydrolyzed to obtain a crude product, which was then suspended in N, N-dimethylformamide (35 mL). Under ice-cooling, di-tert-butyl dicarbonate (646 mg), pyridine (370 µl) and ammonium bicarbonate (196 mg) were added, and the mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol-dichloromethane), and the eluate was dissolved in tetrahydrofuran and solidified with ethanol hydrochloride. This was dissolved in a mixed solution of water and methanol, the insolubles were filtered off, and the filtrate was distilled off under reduced pressure to obtain the title compound (302 mg, 65%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-4.50 (6H, m), 5.08 (lH, br), 7.40-7.60 (2H, m),
7.65-7.85 (3H, m), 7.92 (2H, d, J = 7.8 Hz), 8.00-8.10 (1H, m),
8.20 (2H, d, J = 8.8 Hz), 8.25-8.35 (2H, m), 8.49 (lH, s),
8.80 (1H, d, J = 7.8 Hz), 8.88 (lH, d, J = 5.4 Hz), 9.25 (lH, s).
MS (FAB) m / z: 535 [(M + H) ⁺ , Cl ³⁵ ), 537 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₇ H ₂₃ ClN ₄ O ₄ S · lHC1 · 1.7H ₂ O
Calc .: C, 53.54; H, 4.58; N, 9.25; Cl, 12.29; S, 5.29.
Anal: Cr 53.36: H, 4.71; N, 9.07; Cl, 12.17; S, 5.50.
Example 36 2-Carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 35, 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1- [4- (pyridin-4-yl) benzoyl] piperazine was used as a raw material. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-2.70 (2H, m), 3.20-3.80 (2H, m),
4.10-4.50 (2H, m), 5.07 (lH, br s), 7.40-7.55 (2H, m), 7.60-7.65 (1H, m),
7.67 (lH, s), 7.72 (lH, dd, J = 8.8, 2.4 Hz), 7.78 (1H, dd, J = 8.8, 2.4 Hz),
8.04 (2H, d, J = 8.8 Hz), 8.20 (1H, d, J = 8.8 Hz), 8.25-8.35 (4H, m),
8.49 (lH, s), 8.95 (2H, d, J = 5.4 Hz).
MS (FAB) m / z: 535 [(M + H) ⁺ , C 1 ³⁵ ], 537 [(M + H) ⁺ , Cl ₃₇ ]
Elemental Analysis: C ₂₇ H ₂₃ ClN ₄ O ₄ S.HC1.1.8H ₂ O
Calc .: C, 53.70; H, 4.61; N, 9.28; Cl, 11.74; S, 5.31.
Anal: C, 53.87; H, 4.40; N, 8.89; Cl, 11.81; S, 5.23.
Example 37 4- [4-[[2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-jade Seed
In the same manner as in Example 7, 2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4-pyridin-4-yl) benzoyl] piperazine was used as a raw material. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-4.50 (6H, m), 5.04 (lH, br), 7.30-7.90 (10H, m),
8.10-8.30 (5H, m), 8.48 (lH, s).
MS (FAB) m / z: 551 [(M + H) ⁺ , Cl ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: C ₂₇ H ₂₃ ClN ₄ O ₅ S.0.8H ₂ O
Calc .: C, 57.35; H, 4. 39; N, 9.91; C1, 6.27; S, 5.67.
Anal: C, 57.64; H, 4.50; N, 9.48; Cl, 6.37; S, 5.71.
Example 38 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazin-1-yl] carbonyl] phenyl] pyridine N- Oxid
By the same reaction as in Example 37, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.30-1.40 (3H, m), 2.30-4.70 (8H, m), 5.47 (lH, br s),
7.40-7.80 (8H, m), 7.92 (1H, s), 7.94 (2H, s), 8.26 (2H, d, J = 6.8 Hz),
8.48 (lH, s).
MS (FAB) m / z: 580 [(M + H) ⁺ , C 1 ³⁵ ], 582 [(M + H) ⁺ , Cl ³⁷ ]
As _{C 29 H 26 ClN 3 O 6} S · l.3H 2 O: Elemental Analysis
Calc .: C, 57.72; H, 4.78; N, 6.96; Cl, 5.87; S, 5.31.
Anal: C, 57.99; H, 4.75; N, 6.56; Cl, 5.98; S, 5.43.
Example 39 4- [4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide
By the same reaction as in Example 3, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.30-4.50 (6H, m), 5.22 (lH, br s), 7.35-7.50 (2H, m),
7.70-7.90 (6H, m), 8.19 (lH, d, J = 8.8 Hz), 8.25-8.30 (4H, m), 8.53 (lH, s),
13.42 (1 H, broad singlet).
Elemental Analysis: C ₂₇ H ₂₂ ClN ₃ O ₆ S.0.2HC1.1.7H ₂ O
Calc .: C, 54.97; H, 4. 37; N, 7. 12; Cl, 7.21; S, 5.44.
Anal: C, 55.07; H, 4.40; N, 6.82; Cl, 7.16; S, 5.47.
Example 40 2-Carbamoyl-4-[(E) -4-chlorostyrylsulfonyl]-[1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
2-carbamoyl-4-[[2- (4-chlorophenyl) -2-ethoxyethyl] sulfonyl]-[1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
The title compound was obtained by the method of Example 2 and Example 35.
2-carbamoyl-4-((E) -4-chlorostyrylsulfonyl]-[l- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
¹ H-NMR (CDCl ₃ ) δ: 2.80-4.80 (6H, m), 5.32 (lH, br),
7.04 (lH, d, J = 15.6 Hz), 7.40-7.50 (3H, m), 7.60-7.80 (4H, m),
7.95-8.05 (2H, m), 8.20 (2H, br), 8.81 (2H, br).
MS (FAB) m / z: 511 [(M + H) ⁺ , Cl ³⁵ ], 513 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₅ H ₂₃ ClN ₄ O ₄ S.0.9HC1.1.8H ₂ O
Calc .: C, 52.11; H, 4.81; N, 9.72; Cl, 11.69.
Anal: C, 52.28; H, 4.83; N, 9.44; Cl, 11.51.
2-carbamoyl-4-[[2- (4-chlorophenyl) -2-ethoxyethyl] sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.20 (3H, m), 2.95-4.70 (6H, m), 5.34 (lH, br),
7.38 (4H, s), 7.65-7.85 (2H, m), 8.05-8.15 (2H, m), 8.40-8.50 (2H, m),
8.91 (2H, doublet, J = 5.9 Hz).
MS (FAB) m / z: 557 [(M + H) ⁺ , C 1 ³⁵ ], 559 [(M + H) ⁺ , C 1 ³⁷ ].
Elemental Analysis: C ₂₇ H ₂₉ ClN ₄ O ₅ S.HC1.2.5H ₂ O.
Calc .: C, 50.78; H, 5.52; N, 8.77; Cl, 11.10; S, 5.02.
Anal: C, 50.61; H, 5. 38; N, 8.68; Cl, 11.27; S, 5.07.
Example 41 1- [trans-4- (aminomethyl) cyclohexylmethyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 7.
¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.00 (4H, m), 1.48 (lH, m), 1.60-1.90 (5H, m),
2.60 (2H, m), 2.90-3.10 (4H, m), 3.14 (2H, m), 3.52 (2H, m), 3.77 (2H, m),
7.75 (lH, dd, J = 8.8, 2.0 Hz), 7.85 (lH, d, J = 8.8 Hz), 7.99 (3H, br),
8.21 (lH, d, J = 8.8 Hz), 8.30-8.40 (2H, m), 8.56 (lH, s), 10.46 (lH, br).
MS (FAB) m / z: 436 [(M + H) ⁺ , Cl ³⁵ ], 438 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₂ H ₃₀ ClN ₃ O ₂ S · 2HC1 · 3 / 4H ₂ O
Calc .: C, 50.58; H, 6. 46; N, 8.04; Cl, 20.36; S, 6.14.
Anal: C, 50.74; H, 6. 48; N, 7.76; Cl, 20.09; S, 6.19.
Example 42 1- [trans-4- (aminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] Using the piperazine as a raw material, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.00 (2H, m), 1.20-1.40 (2H, m),
1.48 (lH, m), 1.50-1.70 (2H, m), 1.70-1.90 (2H, m), 2.44 (lH, m),
2.59 (2H, m), 2.96 (4H, m), 3.55 (4H, m), 7.72 (lH, dd, J = 8.8, 2.0 Hz),
7.81 (1H, d, J = 8.3 Hz), 7.90 (3H, br), 8.16 (lH, d, J = 8.8 Hz),
8.20-8.30 (2H, m), 8.49 (lH, s).
MS (FAB) m / z: 450 [(M + H) ⁺ , C 1 ³⁵ ], 452 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂₈ ClN ₃ O ₃ S.0.9HC1.1.5H ₂ O
Calc .: C, 51.83; H, 6. 31; N, 8.24; Cl, 13.21; S, 6.29.
Anal: C, 51.63; H, 6. 22; N, 7.97; Cl, 13.32; S, 6.17.
Example 43 1- [N- [trans-4- (aminomethyl) cyclohexylcarbonyl] glycyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycyl] -4-[(6-chloronaphthalene-2 -Yl) sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.00 (2H, m), 1.20-1.40 (2H, m),
1.50 (lH, m), 1.60-1.80 (4H, m), 2.10 (lH, m), 2.62 (2H, m),
2.90-3.10 (4H, m), 3.40-3.60 (4H, m), 3.83 (2H, d, J = 5.4 Hz),
7.70-7.90 (3H, m), 7.93 (3H, br), 8.17 (1H, d, J = 8.3 Hz), 8.20-8.30 (2H, m),
8.49 (lH, s).
MS (FAB) m / z: 507 [(M + H) ⁺ , C 1 ³⁵ ], 509 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₄ H _3l ClN ₄ O ₄ S.HCl
Calc .: C, 53.04; H, 5.93; N, 10.31; Cl, 13.05; S, 5.90.
Anal: C, 52.90; H, 5.98; N, 10.29; Cl, 12.98; S, 5.91.
Example 44 1- [trans-4- (aminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyllhomopiperazine hydrochloride
In the same manner as in Example 7, 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] Homopiperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.1.0 (2H, m), 1.30-1.50 (2H, m),
1.50-1.90 (7H, m), 2.40-2.80 (3H, m), 3.20-3.70 (8H, m), 7.60-7.70 (lH, m),
7.80-8.00 (4H, m), 8.10-8.20 (lH, m), 8.20-8.30 (2H, m),
8.52 and 8.53 (lH, each s).
MS (FAB) m / z: 464 [(M + H) ⁺ , Cl ³⁵ ], 466 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₃ H ₃₀ ClN ₃ O ₃ SHCl
Calc .: C, 55.20; H, 6. 24; N, 8.40; Cl, 14.17; S, 6.41.
Anal: C, 55.42; H, 6. 18; N, 8. 26; Cl, 14.11; S, 6.53.
Example 45 1- [4- (aminomethyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [4- (N-tert-butoxycarbonylaminomethyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as a raw material. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.20 (4H, br), 3.30-3.80 (4H, br),
4.03 (2H, s), 7.37 (2H, d, J = 7.3 Hz), 7.50 (2H, d, J = 7.3 Hz),
7.72 (1H, d, J = 8.8 Hz), 7.82 (lH, d, J = 6.8 Hz), 8.18 (lH, d, J = 8.8 Hz),
8.20-8.40 (2H, m), 8.43 (3H, br), 8,49 (lH, s).
MS (FAB) m / z: 444 [(M + H) ⁺ , Cl ³⁵ ], 446 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂₂ ClN ₃ O ₃ S · HC1 · H ₂ O
Calc .: C, 53.02; H, 5.06; N, 8.43; Cl, 14.23; S, 6.43.
Anal: C, 53.06; H, 5. 30; N, 8.32; Cl, 14.20; S, 6.44.
Example 46 1- [3- (aminomethyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
The ester was hydrolyzed in the same manner as in Example 3 using methyl 3- (N-tert-butoxycarbonylaminomethyl) benzoate as a raw material, followed by reaction in the same manner as in Examples 4 and 7 to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (4H, br), 3.20-3.80 (4H, br),
4.00 (2H, s), 7.30-7.60 (4H, m), 7.73 (lH, d, J = 8.8 Hz),
7.83 (lH, d, J = 8.8 Hz), 8.10-8.60 (7H, m).
MS (FAB) m / z: 444 [(M + H) ⁺ , Cl ³⁵ ] 446 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₂ H ₂₂ ClN ₃ O ₃ S · HC1 · 1 / 4H ₂ O
Calc .: C, 54.49; H, 4.88; N, 8.67; Cl, 14.62; S, 6.61.
Anal: C, 54.64; H, 4.95; N, 8.52; Cl, 14.59; S, 6.70.
Example 47 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3- [N- (l-pyrrolin-2-yl) aminomethyllbenzoyl] piperazine hydrochloride
2-methoxy-l-pyrroline (35 mg) was dissolved in dimethylformamide (2 mL), and 1- [3- (aminomethyl) benzoyl] -4-[(6-chloronaphthalen-2-ylsulfonyl ] Piperazine Hydrochloride (0.10 g) and triethylamine (44 µl) were added and stirred for 3 days at room temperature The reaction solution was concentrated under reduced pressure, diluted with methanol, 1N hydrochloric acid was added, and the solvent was distilled off under reduced pressure. The residue was purified by gel filtration chromatography (Sephadex LH-20, Φ 15 × 300 mm, methanol) and then solidified with a mixed solvent of methanol and ether to obtain a colorless solid (0.11 g, 91%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.04 (2H, m), 2.81 (2H, t, J = 7.8 Hz),
3.18 (4H, br), 3.20-3.80 (5H, m), 4.10 (1H, br), 4.51 (2H, d, J = 5.9 Hz),
7.30-7.50 (4H, m), 7.72 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, d, J = 8.8 Hz),
8.18 (1H, d, J = 8.8 Hz), 8.20-8.30 (2H, m), 8.50 (lH, s),
10.01 (lH, t, J = 5.9 Hz), 10.06 (lH, s).
MS (FAB) m / z: 511 [(M + H) ⁺ , Cl ³⁵ ], 513 [(M + H) ⁺ , Cl ³⁷ ]
As _{C 26 H 27 ClN 4 O 3} S · HC1 · CH 3 OH · 4 / 5H 2 O: Elemental Analysis
Calc .: C, 54.60; H, 5. 70; N, 9.43; Cl, 11.94; S, 5.40.
Anal: C, 54.84; H, 5.47; N, 9.13; Cl, 11.86; S, 5.48.
Example 48 1- [4- (2-aminoethyl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [4- (2- (tert-butoxycarbonylamino) ethyl] benzoyl] -4-((6-chloronaphthalen-2-yl) sulfonyl] piperazine As a raw material, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.20 (8H, m), 3.40-3.90 (4H, br),
7.28 (4H, s), 7.72 (lH, dd, J = 8.8, 2.4 Hz), 7.81 (lH, dd, J = 8.8, 2.0 Hz),
8.02 (3H, br), 8.17 (lH, d, J = 8.3 Hz), 8.20-8.30 (2H, m), 8.49 (lH, s).
MS (FAB) m / z: 458 [(M + H) ⁺ , Cl ³⁵ ], 460 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₃ H ₂₄ ClN ₃ O ₃ S.HC1 · 1 / 2CH ₃ OH · 1 / 2H ₂ O
Calc .: C, 54.34; H, 5. 43; N, 8.09; Cl, 13.65; S, 6.17.
Anal: C, 54.43; H, 5. 26; N, 7.92; Cl, 13.58; S, 6.24.
Example 49 1-[[(6RS) -6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen2-yl) Sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl ] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.50 (lH, m), 1.90-2.10 (2H, m),
2.40-2.60 (lH, m), 2.60-3.00 (5H, m), 3.03 (4H, m), 3.40-3.80 (4H, br)
7.00-7.10 (3H, m), 7.73 (1H, dd, J = 8.8, 2.0 Hz),
7.81 (1H, doublet of doublets, J = 8.8, 1.5 Hz), 8.05 (3H, br),
8.18 (1H, d, J = 8.3 Hz), 8.20-8.30 (2H, m), 8.49 (lH, s).
MS (FAB) m / z: 498 [(M + H) ⁺ , Cl ³⁵ ], 500 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₆ H ₂₈ ClN ₃ O ₃ S.HC1 · 3 / 2H ₂ O
Calc .: C, 55.61; H, 5. 74; N, 7.48; Cl, 12.63; S, 5.71.
Anal: C, 55.64; H, 5.53; N, 7.77; Cl, 12.79; S, 5.76.
Example 50 1-[[(6RS) -6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl] methyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] methyl] Using the 4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.50 (lH, m), 2.00-2.10 (2H, m),
2.40-2.60 (lH, m), 2.60-3.00 (7H, m), 3.00-3.20 (2H, m),
3.30-3.50 (2H, m), 3.82 (2H, m), 4.22 (2H, br), 7.00-7.10 (lH, m),
7.25 (2H, s), 7.73 (lH, dd, J = 8.8, 2.4 Hz), 7.81 (1H, dd, J = 8.8, 1.5 Hz),
8.00-8.40 (6H, m), 8.52 (lH, s), 11.08 (lH, br).
MS (FAB) m / z: 484 [(M + H) ⁺ , C 1 ³⁵ ], 486 [(M + H) ⁺ , C 1 ³⁷ 1
Elemental Analysis: As C ₂₆ H ₃₀ ClN ₃ O ₂ S.2HCl
Calculated value; C, 56.07; H, 5.79; N, 7.54; Cl, 19.10; S, 5.76.
Anal: C, 56.04; H, 5.79; N, 7.52; Cl, 18.95; S, 5.80.
Example 51 1-[[(2RS) -6-Aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl] methyl] -4-[(6-chloronaphthalen-2-yl) Sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] methyl] The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.50 (lH, m), 2.00-2.20 (lH, m),
2.20-2.40 (lH, m), 2.40-2.60 (1H, m), 2.75 (2H, m), 2.90-3.30 (7H, m),
3.60-3.70 (2H, m), 3.70-4.00 (4H, m), 7.04 (lH, d, J = 7.8 Hz),
7.10-7.30 (2H, m), 7.74 (1H, m), 7.86 (1H, d, J = 8.8 Hz),
8.20-8.50 (6H, m), 8.56 (1H, s), 10.69 (lH, br).
MS (FAB) m / z: 484 [(M + H) ⁺ , Cl ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₃₀ ClN ₃ O ₂ S · 2HC1 · 1 / 2H ₂ O
Calc .: C, 55.18; H, 5.88; N, 7. 42; Cl, 18.79; S, 5.66.
Anal: C, 55.34; H, 5. 70; N, 7.31; Cl, 18.76; S, 5.85.
Example 52 1-[[(2RS) -6-aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl ) Sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] carbonyl ] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.55 (lH, m), 1.80-1.90 (1H, m), 2.60-2.90 (4H, m),
2.90-3.10 (5H, m), 3.50-3.80 (4H, m), 3.90 (2H, s), 7.05 (lH, d, J = 7.8 Hz),
7.10-7.20 (2H, m), 7.71 (lH, d, J = 8.8 Hz), 7.82 (lH, d, J = 8.3 Hz),
8.10-8.40 (6H, m), 8.50 (lH, s).
MS (FAB) m / z: 498 [(M + H) ⁺ , Cl ³⁵ ], 500 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₈ CIN ₃ O ₃ S · 2HC1 · 0.8H ₂ O
Calc .: C, 56.15; H, 5.58; N, 7.55; Cl, 14.02; S, 5.76.
Anal: C, 55-93; H, 5. 22; N, 7.37; Cl, 14.26; S, 5.70.
Example 53 1-[(7-aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[7-N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfur The title compound was obtained based on phonyl] piperazine.
¹ H-NMR (DMSO-d ₆ ) δ: 3.10 (4H, br), 3.30-3.90 (4H, br)
4.18 (2H, s), 7.46 (lH, d, J = 8.8 Hz), 7.69 (lH, d, J = 8.8 Hz),
7.73 (lH, d, J = 8.8 Hz), 7.83 (lH, d, J = 6.8 Hz), 7.89 (1H, s),
7.90-8.00 (3H, m), 8.19 (lH, d, J = 8.8 Hz), 8.20-8.30 (2H, m),
8.50 (4H, broad singlet).
MS (FAB) m / z: 494 [(M + H) ⁺ , Cl ³⁵ ], 496 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₄ ClN ₃ O ₃ S.HC1 · 3 / 4H ₂ O
Calc .: C, 57.41; H, 4.91; N, 7.72; Cl, 13.03; S, 5.89.
Anal: C, 57.40; H, 4.87; N, 7.71; Cl, 13.09; S, 5.89.
Example 54 1-[(7-aminomethylnaphthalen-2-yl) methyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[[7-N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] methyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl ] Piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.92 (2H, m), 3.22 (2H, m), 3.83 (2H, m)
4.20 (2H, d, J = 5.4 Hz), 4.51 (2H, br), 7.60-7.90 (4H, m),
7.90-8.40 (7H, m), 8.52 (lH, s), 8.57 (3H, br), 11.52 (lH, br).
MS (FAB) m / z: 480 [(M + H) ⁺ , C 1 ³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₆ H ₂₆ ClN ₃ O ₂ S · 2HC1 · 1 / 4H ₂ O
Calc .: C, 56.02; H, 5. 15; N, 7.54; Cl, 19.08; S, 5.75.
Anal: C, 55.88; H, 5. 45; N, 7.34; Cl, 18.90; S, 5.69.
Example 55 1-[(6-aminomethylnaphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 3, Example 4 and Example 7 using 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.09 (4H, br), 3.40-3.90 (4H, br),
4.19 (2H, s), 7.47 (lH, d, J = 8.3 Hz), 7.66 (lH, d, J = 8.3 Hz),
7.73 (lH, d, J = 9.3 Hz), 7.83 (lH, d, J = 8.8 Hz), 7.90-8.10 (4H, m),
8.19 (lH, d, J = 8.8 Hz), 8.20-8.30 (2H, m), 8.40-8.60 (4H, m).
MS (FAB) m / z: 494 [(M + H) ⁺ , Cl ³⁵ ], 496 [(M + H) ⁺ , C ³⁷ ].
Elemental Analysis: C ₂₆ H ₂₄ ClN ₃ O ₃ S.HC1 · 3 / 4H ₂ O · 1 / 5Et ₂ O
Calc .: C, 57.60; H, 5. 14; N, 7.52; Cl, 12.69; S, 5.74.
Anal: C, 57.64; H, 5. 10; N, 7. 12; Cl, 12.69; S, 5.82.
Example 56 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[-4-[[(3S) -pyrrolidin-3-yl] oxy] benzoyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [4-[[(3S) -l-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalene- 2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.05-2.25 (2H, m), 3.00-3.10 (4H, m),
3.20-3.70 (8H, m), 5.16 (lH, br s), 6.95 (2H, d, J = 8.8 Hz),
7.31 (2H, d, J = 8.3 Hz), 7.70-7.75 (lH, m), 7.82 (lH, dd, J = 8.5, 1.7 Hz),
8.18 (2H, d, J = 8.8 Hz), 8.20-8.30 (2H, m), 8.50 (lH, s).
MS (FAB) m / z: 500 [(M + H) ⁺ , Cl ³⁵ ], 502 [(M + H) ⁺ , Cl ³⁷ ]
Example 57 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-[[(3S) -pyrrolidin-3-yl] oxy] benzoyl] piperazine hydrochloride
By the same reaction as in Example 56, 1- [3-[[(3S) -l-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalene- 2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m),
3.20-3.80 (8H, m), 5.11 (lH, br s), 6.90-6.95 (3H, m),
7.00-7.05 (1H, m), 7.30-7.35 (lH, m), 7.72 (lH, dd, J = 8.8, 2.0 Hz),
7.81 (lH, dd, J = 8.5, 1.7 Hz), 8.18 (2H, d, J = 8.8 Hz),
8.25-8.30 (2H, m), 8.50 (lH, s).
MS (FAB) m / z: 500 [(M + H) ⁺ , Cl ³⁵ ], 502 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: C ₂₅ H ₂₆ ClN ₃ O ₄ S.HC1.H ₂ O
Calc .: C, 54.15; H, 5. 27; N, 7.58; Cl, 12.79; S, 5.78.
Anal: C, 53.84; H, 5. 19; N, 7.33; Cl, 12.72; S, 5.86.
Example 58 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4-[[(3R) -pyrrolidin-3-yl] oxy] benzoyl] piperazine hydrochloride
By the same reaction as in Example 56, 1- [4-[[(3R) -l-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalene- 2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.05-2.25 (2H, m), 3.00-3.10 (4H, m)
3.20-3.70 (8H, m), 5.16 (1H, broad s), 6.96 (2H, d, J = 8.8 Hz),
7.31 (2H, d, J = 8.8 Hz), 7.74 (1H, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 1.5 Hz), 8.18 (lH, d, J = 8.8 Hz), 8.25-8.30 (2H, m),
8.50 (lH, s).
MS (FAB) m / z: 500 [(M + H) ⁺ , Cl ³⁵ ], 502 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₅ H ₂₆ ClN ₃ O ₄ S.2HC1.0.8H ₂ O
Calc .: C, 53.80; H, 5.20; N, 7.53; Cl, 13.97; S, 5.74.
Anal: C, 53.84; H, 5.05; N, 7.51; Cl, 13.79; S, 5.74.
Example 59 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4- [3-[[(3R) -pyrrolidin-3-yl] oxy] benzoyl] piperazine hydrochloride
In the same manner as in Example 56, 1- [3-[[(3R) -l-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4-[(6-chloronaphthalene-2- (I) sulfonyl] piperazine as a raw material, to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m),
3.20-3.80 (8H, m), 5.11 (lH, br s), 6.90-6.95 (2H, m), 7.00-7.05 (lH, m),
7.30-7.35 (1H, m), 7.74 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 1.5 Hz), 8.18 (2H, d, J = 8.8 Hz), 8.25-8.30 (2H, m),
8.50 (1 H, s).
MS (FAB) m / z: 500 [(M + H) ⁺ , C 1 ³⁵ ), 502 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: C ₂₅ H ₂₆ ClN ₃ O ₄ S.HC1.H ₂ O
Calc .: C, 54.15; H, 5. 27; N, 7.58; Cl, 12.79; S, 5.78.
Anal: C, 53.91; H, 5. 14; N, 7.37; Cl, 12.62; S, 5.67.
Example 60 1- [4- (2-aminopyrimidin-5-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl] sulfonyl] piperazine hydrochloride
In the same manner as in Example 4, 4- (2-amino-5-pyrimidyl) benzoic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, br), 3.56 and (each 2H, br),
4.70-5.45 (3H, br), 7.40 (2H, d, J = 8.8 Hz), 7.67 (2H, d, J = 8.8 Hz),
7.73 (1H, dd, J = 8.8, 2.0 Hz), 7.82 (lH, d, J = 8.8 Hz),
8.18 (1H, d, J = 8.8 Hz), 8.27 (1H, s), 8.28 (lH, d, J = 8.8 Hz),
8.50 (1 H, s), 8.72 (l H, s).
MS (FAB) m / z: 508 [(M + H) ⁺ , C 1 ³⁵ ], 510 [(M + H) ⁺ , C 1 ³⁷ ].
Elemental Analysis: As C ₂₅ H ₂₂ ClN ₅ O ₃ S · lHC1 · 0.7H ₂ O
Calc .: C, 53.55; H, 4.40; Cl, 13.28; N, 12.49; S, 5.72.
Anal: C, 53.59; H, 4.58; Cl, 13.02; N, 12.58; S, 5.89.
Example 61 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(piperidin-4-yl) acetyl] piperazin hydrochloride
In the same manner as in Example 7, 1-[(l-tert-butoxycarbonylpiperidin-4-yl) acetyl] -4-[(6-chloronaphthalen-2-yl] sulfonyl] piperazine The title compound was obtained as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (2H, m), 1.71 (2H, m), 1.87 (lH, m),
2.20 (2H, d, J = 6.8 Hz), 2.78 (2H, br), 2.96 (4H, br s), 3.14 (2H, m),
3.52 (4H, br s), 4.02 (2H, br), 7.73 (lH, doublet of doublets, J = 88,2.0 Hz),
7.81 (lH, d, J = 8.8 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.28 (lH, d, J = 8.8 Hz),
8.26 (lH, s), 8.50 (lH, s), 8.54 (lH, br), 8.75 (lH, br).
MS (FAB) m / z: 436 [(M + H) ⁺ , C 1 ³⁵ ], 438 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C _{2 l} H ₂₆ ClN ₃ O ₃ S · l.1HCl·l.lH ₂ O
Calc .: C, 50.86; H, 5.96; Cl, 15.01; N, 8.47; S, 6.47.
Anal: C, 51.07; H, 5. 74; Cl, 14.75; N, 8.36; S, 6.50.
Example 62 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4- [3- (piperidin-4-yl) propionyl] piperazin hydrochloride
In the same manner as in Example 7, 1- [3- (l-tert-butoxycarbonylpiperidin-4-yl) propionyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl ] Piperazine as a raw material to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (2H, m), 1.50 (lH, m), 1.51 (2H, m),
1.89 (2H, m), 2.36 (2H, m), 2.88 (2H, m), 3.08 (4H, m), 3.64 (4H, m),
4.04 (2H, br), 7.58 (1H, doublet of doublets, J = 8.8, 2.0 Hz), 7.82 (lH, doubled, J = 8.8, 2.0 Hz),
8.05 (1H, d, J = 8.8 Hz), 8.06 (lH, s), 8.09 (1H, d, J = 8.8 Hz), 8.42 (1H, s).
MS (FAB) m / z: 450 [(M + H) ⁺ , Cl ³⁵ ), 452 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂₈ ClN ₃ O ₃ S · 8.HCI · 0.9H ₂ O
Calc .: C, 49.68; H, 5.99; Cl, 18.66; N, 7.90; S, 6.03.
Anal: C, 49.45; H, 5. 70; Cl, 18.63; N, 7.72; S, 6.04.
Example 63 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(E) -3- (pyridin-3-yl) propenyl] piperazin hydrochloride
In the same manner as in Example 4, the title compound was obtained using (E) -3- (3-pyridyl) acrylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials. .
¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (4H, m), 3.69 (2H, br), 3.85 (2H, br),
7.51 (2H, s), 7.70 (1H, dd, J = 8.8, 2.0 Hz), 7.83 (lH, dd, J = 8.8, 2.0 Hz),
7.89 (1H, dd, J = 7.8, 5.4 Hz), 8.16 (lH, d, J = 8.8 Hz), 8.22 (lH, d, J = 2.0 Hz),
8.26 (lH, d, J = 8.8 Hz), 8.51 (lH, s), 8.67 (1H, d, J = 7.8 Hz), 8.77 (lH, d, J = 5.4 Hz),
9.13 (lH, s).
MS (FAB) M / z: 442 [(M + H) ⁺ , C 1 ³⁵ ], 444 [(M + H) ⁺ , C 1 ³⁷ ],
Elemental Analysis: C ₂₂ H ₂₀ ClN ₃ O ₃ S, HC1, 1 / 4H ₂ O
Calc .: C, 54.72; H, 4. 49; N, 8.70; Cl, 14.68; S, 6.64.
Anal: C, 54.81; H, 4. 43; N, 8.54; Cl, 14.68; S, 6.74.
Example 64 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(E) -3- (pyridin-4-yl) propenyl] piperazin hydrochloride
In the same manner as in Example 4, the title compound was obtained using (E) -3- (4-pyridyl) acrylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials. .
¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (4H, m), 3.68 (2H, br), 3.82 (2H, br),
5.76 (lH, s), 7.48 (lH, d, J = 15.lHz), 7.65 (lH, d, J = 15.lHz),
7.72 (lH, dd, J = 8.8, 2.0 Hz), 7.83 (lH, dd, J = 8.8, 2.0 Hz),
8.11 (2H, broad s), 8.16 (lH, d, J = 8.8 Hz), 8.24 (lH, s),
8.27 (lH, d, J = 8.8 Hz), 8.52 (lH, s), 8.82 (2H, d, J = 5.9 Hz).
MS (FAB) m / z: 442 [(M + H) ⁺ , C 1 ³⁵ ], 444 [(M + H) ⁺ , C 1 ³⁷ ],
Elemental Analysis: As C ₂₂ H ₂₀ CIN ₃ O ₃ S.HC1 · 1 / 5H ₂ O
Calc .: C, 54.82; H, 4. 48; Cl, 14.71; N, 8.72; S, 6.65.
Anal: C, 54.77; H, 4.41; Cl, 14.71; N, 8.50; S, 6.77.
Example 65 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(pyridin-4-yl) acetyl] piperazine hydrochloride
In the same manner as in Example 4, 4-pyridylacetic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (2H, br), 3.04 (2H, br), 3.57 (2H, br),
3.62 (2H, br), 4.00 (2H, s), 7.71 (2H, d, J = 5.9 Hz),
7.74 (lH, dd, J = 8.8, 3.0 Hz), 7.83 (lH, dd, J = 8.8, 2.0 Hz),
8.18 (lH, d, J = 8.8 Hz), 8.27 (lH, s), 8.29 (lH, d, J = 8.8 Hz),
8.53 (lH, s), 8.72 (2H, d, J = 5.9 Hz).
MS (FAB) m / z: 430 [(M + H) ⁺ , Cl ³⁵ ], 432 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C _{2 l} H ₂₀ CIN ₃ O ₃ S · HC1 · 0.3H ₂ O
Calc .: C, 53.46; H, 4.61; Cl, 15.03; N, 8.91; S, 6.80.
Anal: C, 53.28; H, 4. 49; Cl, 15.18; N, 8.91; S, 6.75.
Example 66 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4- [4-[(3RS) -pyrrolidin-3-yl) benzoyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [4-[(3RS) -l-tert-butoxycarbonylpyrrolidin-3-yl] benzoyl] -4-[(6-chloronaphthalen-2-yl ) Sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.85-1.95 (1H, m), 2.30-2.40 (lH, m),
3.00-3.90 (13H, m), 7.72 (lH, dd, J = 8.6, 2.2 Hz),
7.80 (lH, dd, J = 8.8, 2.0 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz),
8.18 (1H, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.49 (lH, s).
MS (ERB) m / z: 484 [(M + H) ⁺ , Cl ³⁵ ], 486 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₅ H ₂₆ ClN ₃ O ₃ S.HC1 · 3 / 2H ₂ O
Calc .: C, 54.84; H, 5.52; N, 7.67; Cl, 12.95; S, 5.86.
Anal: C, 55.00; H, 5.53; N, 7.48; Cl, 13.23; S, 5.97.
Example 67 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(isoquinolin-7-yl) carbonyl] piperazine hydrochloride
Methyl 7-isoquinolinecarboxylate (206 mg) was dissolved in 4N hydrochloric acid, heated to reflux for 4 hours, and then the residue and 1-[(6-chloronaphthalen-2-yl) sulfonyl] obtained by distilling off the solvent. The title compound (298 mg, 62%) was obtained by the same method as Example 4 using piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.95-3.25 (4H, m), 3.40-3.60 (2H, m),
3.70-3.90 (2H, m), 7.73 (lH, dd, J = 8.8, 2.0 Hz), 7.84 (lH, d, J = 8.8 Hz),
8.05 (lH, d, J = 7.3 Hz), 8.20 (lH, d, J = 8.8 Hz), 8.25-8.35 (3H, m),
8.41 (lH, d, J = 6.4 Hz), 8.45 (lH, s), 8.52 (lH, s), 8.71 (1H, d, J = 6.4 Hz),
9.79 (lH, s).
MS (FAB) m / z: 465 [(M + H) ⁺ , Cl ³⁵ ], 467 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₀ ClN ₃ O ₃ S.HC1.2.2H ₂ O
Calc .: C, 53.18; H, 4.72; N, 7.75; Cl, 13.08; S, 5.92.
Anal: C, 53.11; H, 4. 70; N, 7.60; Cl, 13.01; S, 6.16.
Example 68 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(quinolyl-2-yl) carbonyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 4, using quinoline-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials.
¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (2H, m), 3.17 (2H, m), 3.62 (2H, m)
3.83 (2H, m), 7.61 (1H, d, J = 8.3 Hz), 7.60-7.80 (2H, m), 7.80-7.90 (2H, m),
7.95 (lH, d, J = 8.3 Hz), 8.00 (lH, d, J = 7.3 Hz), 8.18 (lH, d, J = 8.8 Hz),
8.20-8.40 (2H, m), 8.43 (lH, d, J = 8.3 Hz), 8.51 (lH, s).
Elemental Analysis: As C ₂₄ H ₂₀ ClN ₃ O ₃ S
Calc .: C, 61.87; H, 4.33; N, 9.02; Cl, 7.61; S, 6.88.
Anal: C, 61.76; H, 4. 20; N, 8.73; Cl, 7.65; S, 6.99.
Example 69 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(4-hydroxyquinolin-2-yl) carbonyl] piperazin hydrochloride
The title compound was obtained in the same manner as in Example 4, using 4-hydroxyquinoline-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrazine hydrochloride as raw materials.
¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.30 (4H, br), 3.53 (2H, br),
3.77 (2H, br), 6.45 (lH, s), 7.48 (1H, t, J = 7.3 Hz), 7.70-7.90 (4H, m),
8.10-8.40 (4H, m), 8.52 (1H, s).
MS (FAB) m / z: 482 [(M + H) ⁺ , Cl ³⁵ ], 484 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₀ ClN ₃ O ₄ S.9 / 10HC1.1 / 3CH ₃ OH.3 / 2H ₂ O.
Calc .: C, 52.90; H, 4. 60; N, 7.61; Cl, 12.19; S, 5.80.
Anal: C, 53.17; H, 4.59; N, 7.39; Cl, 12.31; S, 6.07.
Example 70 1-[(6-chloronaphthalen-2-yl] sulfonyl] -4-[(8-hydroxyquinolin-7-yl) carbonyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 4, using 8-hydroxyquinoline-7-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.30 (4H, br), 3.35 (2H, br),
3.79 (2H, br), 7.39 (lH, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.3 Hz),
7.60-7.90 (3H, m), 8.10-8.40 (3H, m), 8.50 (1H, s), 8.60 (lH, d, J = 7.8 Hz),
8.96 (lH, d, J = 4.4 Hz).
MS (FAB) m / z: 482 [(M + H) ⁺ , C 1 ³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₀ CIN ₃ O ₄ SHCICH ₃ OH 1 / 4H ₂ O
Calc .: C, 54.11; H, 4.63; N, 7.57; Cl, 12.78; S, 5.78.
Anal: C, 54.40; H, 4. 84; N, 7.66; Cl, 13.04; S, 5.99.
Example 71 1-[(benzimidazol-5-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride
Examples 3, 4 and 10 using methyl N-triphenylmethyl-5-benzimidazole carboxylate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials The reaction was carried out in the same manner as to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.08 (4H, br), 3.30-4.00 (4H, br),
7.48 (lH, d, J = 8,3 Hz), 7.60-7.90 (4H, m), 8.10-8.30 (3H, m),
8.50 (lH, s), 9.51 (1H, s).
MS (FAB) m / z: 455 [(M + H) ⁺ , C 1 ³⁵ ], 457 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₂ H ₁₉ ClN ₄ O ₃ S · HC1 · 5 / 4H ₂ O
Calc .: C, 51.42; H, 4.41; N, 10.90; Cl, 13.80; S, 6.24.
Anal: C, 51.53; H, 4.40; N, 10.71; Cl, 13.61; S, 6.40.
Example 72 1-[(benzimidazol-5-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride
The title compound by the same method as in Example 7 using methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride as a raw material Got.
¹ H-NMR (DMSO-d ₆ ) δ: 1.67 (1H, m), 1.93 (lH, m), 3.20-3.90 (8H, m),
7.44 (1 / 2H, m), 7.54 (1 / 2H, m), 7.68 (lH, m), 7.80-8.00 (3H, m),
8.10-8.30 (3H, m), 8.49 (1 / 2H, s), 8.55 (1 / 2H, s),
9.56 and 9.57 (lH, each s).
MS (FAB) m / z: 469 [(M + H) ⁺ , Cl ³⁵ ], 471 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₃ H _2l ClN ₄ O ₃ S.HC1.0.3CH ₃ OH.H ₂ O.
Calc .: C, 52.50; H, 4.76; N, 10.51; Cl, 13.30; S, 6.01.
Anal: C, 52.31; H, 4. 66; N, 10.50; Cl, 13.34; S, 6.01.
Example 73 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(thiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
In the same manner as in Example 4, using sodium thiazolo [5,4-c] pyridine-2-carboxylate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.10-3.30 (4H, m), 3.84 (2H, m),
4.32 (2H, m), 7.69 (lH, dd, J = 8.8, 2.0 Hz), 7.83 (lH, dd, J = 8.8, 2.0 Hz),
8.10-8.30 (4H, m), 8.51 (1H, s), 8.79 (lH, d, J = 5.9 Hz), 9.62 (lH, s).
MS (FAB) m / z: 473 [(M + H) ⁺ , C 1 ³⁵ ], 475 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C _{2 l} H _l7 ClN ₄ O ₃ S _{2 ·} HCl
Calc .: C, 49.51; H, 3.56; N, 11.00; Cl, 13.92; S, 12.59.
Anal: C, 49.45; H, 3.71; N, 11.20; Cl, 13.67; S, 12.55.
Example 74 1-[(E) -4-chlorostyrylsulfonyl] -4-[(thiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
The title compound was prepared in the same manner as in Example 4, using sodium thiazolo [5,4-c] pyridine-2-carboxylate and 1-[(E) -4-chlorostyrylsulfonyl) piperazine hydrochloride as starting materials. Got.
¹ H-NMR (DMSO-d ₆ ) δ: 3.30 (4H, m), 3.87 (2H, m), 4.35 (2H, m),
7.3S (lH, d, J = 15.6 Hz), 7.40-7.50 (3H, m), 7.79 (lH, d, J = 8.3 Hz),
8.2 (lH, d, J = 5.9 Hz), 8.77 (lH, d, J = 5.9 Hz), 9.59 (1H, s).
MS (FAR) m / z: 449 [(M + H) ⁺ , Cl ³⁵ ], 451 [(M + H) ⁺ , Cl ³⁷ ].
A _{C l9 H l7 ClN 4 O 3} S 2 · 1 / 2HCl: elemental analysis
Calc .: C, 48.85; H, 3.78; N, 11.99; Cl, 11.38; S, 13.73.
Anal: C, 49.18; H, 3.80; N, 12.20; Cl, 11.05; S, 13.84.
Example 75 1-[(6-chloronaphthalen-2-yl) sulfonyl-4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) Methyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl]- The title compound was obtained using 4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.82-2.88 (4H, m), 2.91-2.99 (4H, m),
3.28-3.36 (2H, m), 3.47-3.55 (4H, m), 4.02 (2H, br s), 6.58 (lH, s),
7.11 (lH, dd, J = 8.8, 2.0 Hz), 7.81 (lH, dd, J = 8.8, 2.0 Hz),
7.23-7.28 (3H, m), 8.49 (lH, s), 9.42 (2H, br s).
MS (FAB) m / z: 462 [(M + H) ⁺ , Cl ³⁵ ], 464 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂ Cl ₄ N ₃ O ₂ S _{2 ·} 2HC1 · 1.5H ₂ O
Calc .: C, 47.02; H, 5.20; Cl, 18.93; N, 7.48; S, 11.41.
Anal: C, 47.18; H, 5.41; Cl, 18.59; N, 7.37; S, 11.33.
Example 76 1-[(6-chloronaphthalen-2-yl) sulfonyl-4- [trans-3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine- 2-yl) propenyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [trans-3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Profenonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.95-3.10 (6H, m), 3,32-3.51 (3H, m),
3.60-3.80 (3H, m), 4.12 (2H, s), 6.75 (lH, d, J = 15.l Hz), 7.19 (lH, s),
7.50 (lH, d, J = l5.lHz), 7.70 (lH, dd, J = 8.8,2.4 Hz),
7.81 (lH, dd, J = 8.8, 2.0 Hz), 8.15 (1H, d, J = 8.8 Hz),
8.22 (1H, doublet, J = 2.0 Hz), 8.50 (1H, s), 9.53 (2H, broad singlet).
MS (FAB) m / z: 502 [(M + H) ⁺ , C 1 ³⁵ ], 504 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₄ ClN ₃ O ₃ S ₂ .HCI.0.5H ₂ O.
Calc .: C, 52.65; H, 4.79; Cl, 12.95; N, 7.67; S, 11.71.
Anal: C, 52.36; H, 4.88; Cl, 12.63; N, 8.01; S, 11.39.
Example 77 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) propionyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propy Onyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.80-3.60 (16H, m), 4.12 (2H, br s),
7.11 (lH, br s), 7.74 (1H, dd, J = 8.8, 2.0 Hz), 7.83 (lH, dd, J = 8.8, 2.0 Hz),
8.20 (lH, s), 8.25-8.30 (2H, m), 8.53 (lH, s), 9.67 (2H, br s).
MS (FAB) m / z: 504 [(M + H) ₊ , C 1 ³⁵ ], 506 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₆ ClN ₃ O ₃ S ₂ 1.2HC1.1.3H ₂ O
Calc .: C, 50.46; H, 5. 26; Cl, 13.65; N, 7.36.
Anal: C, 50.83; H, 5. 26; Cl, 13.43; N, 6.97.
Example 78 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) propyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propyl ] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.07 (2H, m), 2.72-2.80 (2H, m),
2.82-3.21 (8H, m), 3.35 (2H, broad s), 3.51 (2H, d, J = 11.5 Hz),
3.82 (2H, d, J = 11.5 Hz), 4.06 (2H, s), 6.66 (lH, s),
7.74 (lH, dd, J = 8.8, 1.5 Hz), 7.85 (lH, dd, J = 8.8, 1.5 Hz),
8.20 (lH, d, J = 8.8 Hz), 8.25-8.39 (2H, m), 8.55 (1H, s), 9.50 (2H, br s),
11.26 (lH, broad singlet).
MS (ERB) m / z: 490 [(M + H) ⁺ , Cl ³⁵ ], 492 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₈ ClN ₃ O ₂ S _{2 ·} 2HC1 · 1.6H ₂ O
Calc .: C, 48.71; H, 5.65; Cl, 17.97; N, 7.10; S, 10.84.
Anal: C, 49.01; H, 5.77; Cl, 17.62; N, 6.96; S, 10.82.
Example 791 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) methyl] carbamoyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl ] Carbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.78-2.86 (2H, br s), 2.88-2.94 (4H, m),
3.99-3.35 (2H, m), 3,37-3.42 (4H, m), 4.03 (2H, br s),
4.19 (2H, d, J = 5.4 Hz), 6.62 (1H, s), 7.2S (lH, t, J = 5.4 Hz),
7.72 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
8.16 (lH, d, J = 8.8 Hz), 8.22-8.26 (2H, m), 8.50 (lH, s), 9.27 (2H, br s).
Elemental Analysis: As C ₂₃ H ₂₅ ClN ₄ O ₃ S ₂ HC1 .1.3H ₂ O
Calc .: C, 48.90; H, 5. 10; Cl, 12.55; N, 9.92.
Anal: C, 49.02; H, 5.20; Cl, 12.50; N, 9.76.
Example 80 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Carbonyl] Piperazine Hydrochloride
In the same manner as in Example 7, 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.99-3.05 (2H, m), 3.08 (4H, t, J = 4.6 Hz)
3.35-3.40 (2H, m), 3.71 (4H, t, J = 4.6 Hz), 4.11 (2H.s),
7.17 (lH, s), 7.71 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.22-9.28 (3H, m), 8.50 (lH, s),
9.38 (2H, broad singlet).
MS (FAB) m / z: 476 [(M + H) ⁺ , Cl ³⁵ ], 478 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental analysis: as C ₂₂ H ₂₃ ClN ₃ O ₃ S ₂ HC1 3 / 2H ₂ O
Calc .: C, 48.98; H, 4.86; Cl, 13.14; N, 7.79; S, 11.89.
Anal: C, 48.96; H, 4.67; Cl, 13.21; N, 7.74; S, 11.93.
Example 81 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l-[(4,5,6,7-tetrahydrothieno [3,2- c] pyridin-2-yl) carbonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7.0 Hz), 2.38-2.58 (lH, m),
2.65-2.72 (lH, m), 3.04 (2H, br s), 3.29-3.43 (3H, m), 3.70 (lH, br s),
4.01-4.30 (6H, m), 5.18 (1H, broad s), 7.27 (lH, s),
7.73 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, d, J = 8.8 Hz), 8.26 (1H, s),
8.29 (1 H, s), 8.54 (l H, s), 9.59 (2 H, br s).
MS (FAB) m / z: 548 [(M + H) ⁺ , Cl ³⁵ ], 550 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₅ H ₂₆ N ₃ ClO ₅ S _2. 1.2HC1.0.6H ₂ O.
Calc .: C, 49.83; H, 4.75; Cl, 12.94; N, 6.97; S, 10.64.
Anal: C, 49.62; H, 4.71; Cl, 13.30; N, 7.19; S, 10.56.
Example 82 2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine -2-yl) carbonyl] piperazine hydrochloride
Following the same reaction as in Example 3, 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-l-[(4,5,6,7-tetrahydrothieno [ The title compound was obtained using 3,2-c] pyridin-2-yl) carbonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-2.53 (lH, m), 2.58-2.69 (lH, m),
3.04 (2H, broad s), 3.29-3.83 (4H, m), 4.07-4.32 (4H, m), 4.90-5.20 (1H, m),
7.03-7.30 (lH, m), 7.71 (lH, dd, J = 8.8, 2.4 Hz),
7.81 (lH, d, J = 8.8 Hz), 8.81 (1H, d, J = 8.8 Hz), 8.20-9.29 (2H, m),
8.52 (lH, s), 9.58 (2H, broad singlet).
MS (FAB) m / z: 520 [(M + H) ⁺ , Cl ³⁵ ], 522 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₃ H ₂₂ N ₃ ClO ₅ S ₂ 1.2HC10.8H ₂ O
Calc .: C, 47.78; H, 4. 32; Cl, 13.49; N, 7.27; S, 11.09.
Anal: C, 47.41; H, 4. 36; Cl, 13.81; N, 7.14; S, 11.01.
Example 83 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothieno [3,2 -c] pyridin-2-yl) carbonyl] piperazine
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-cyano-4,5,6,7-tetrahydrothieno) [3,2- in methanol (4 mL) c] a dichloromethane solution (dichloromethane: 1 ml) of pyridin-2-yl) carbonyl] piperazine (41 mg) is added, and hydroxylamine hydrochloride (28 mg) and triethylamine (0.55 ml) are added, Stir at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (dichloromethane-dichloromethane: methanol = 100: 3) to obtain the title compound (14 mg, 32%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.74-2.79 (2H, m), 3.06 (4H, s), 3.35-3.38 (2H, m),
3.71 (4H, s), 4.07 (2H, s), 5.32 (2H, s), 7.08 (lH, s),
7.71 (lH, dd, J = 8.8, 1.6 Hz), 7.81 (lH, dd, J = 8.8, 1.6 Hz), 8.16 (lH, s),
8.23-8.25 (2H, m), 8.33 (lH, br s), 8.49 (lH, s).
MS (FAB) m / z: 534 [(M + H) ⁺ , Cl ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ].
Example 84 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) carbamoyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbon Barmoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.83 (2H, br s), 2.99 (4H, br s),
3.30 (2H, br s), 3.54 (4H, br s), 4.00 (2H, s), 6.33 (lH, s),
7.70 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (1H, d, J = 8.8 Hz),
8.16 (lH, d, J = 8.8 Hz), 8.22 (1H, s), 8.26 (lH, d, J = 8.8 Hz),
8.50 (lH, s), 9.18 (2H, broad singlet), 9.82 (1H, s).
MS (FAB) m / z: 491 [(M + H) ⁺ , C 1 ³⁵ ], 493 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂₃ N ₄ ClO ₃ S ₂ HC1 0.3H ₂ O
Calc .: C, 49.59; H, 4.65; Cl, 13.31; N, 10.51; s, 12.03.
Anal: C, 49.32; H, 4.63; Cl, 13.34; N, 10.81; S, 12.03.
Example 85 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N-methyl-N- (4,5,6,7-tetrahydrothieno [3,2-c ] Pyridin-2-yl) carbamoyl] piperazine hydrochloride
In the same manner as in Example 7, 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl)- N-methylcarbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.83 (2H, t, J = 5.4 Hz), 2.97 (4H, br s),
3.10 (3H, s), 3.28-3.41 (6H, m), 4.00 (2H, s), 6.35 (lH, s),
7.72 (lH, dd, J = 8.8, 2.0 Hz), 7.81 (lH, dd, J = 8.8, 2.0 Hz),
8.17 (lH, d, J = 8.8 Hz), 8.23-8.31 (2H, m), 8.50 (lH, s), 9.28 (2H, br s)
MS (FAB) m / z: 505 [(M + H) ⁺ , C 1 ³⁵ ], 507 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₃ H ₂₅ N ₄ ClO ₃ S _2. 1.lHC ₁ .0.5H ₂ O
Calc .: C, 49.85; H, 4.93; Cl, 13.43; N, 10.11; S, 11.57.
Anal: C, 49.55; H, 4.92; Cl, 13.23; N, 10.13; S, 11.83.
Example 86 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (1-pyrrolin-2-yl) -4,5,6,7-tetrahydrothier No [3,2-c] pyridin-2-yl] carbonyl] piperazine hydrochloride
As in Example 47, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 The title compound was obtained using -yl) carbonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.07-2.18 (2H, m), 2.90-3.11 (8H, m),
3.62 (2H, t, J = 6.8 Hz), 3.72 (4H, br), 3.80 (2H, t, J = 5.9 Hz),
3.99 (2H, t, J = 5.9 Hz), 4.62 (lH, br s), 4.73 (lH, br s),
7.10 (lH, s), 7.50 (lH, s), 7.72 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.18 (lH, d, J = 8.8 Hz), 8.22-8.28 (2H, m),
8.51 (lH, s), 10.37 (1H, broad singlet), 10.53 (1H, broad singlet).
MS (FAB) m / z: 542 [(M + H) ⁺ , Cl ³⁵ ], 544 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₆ H ₂₇ ClN ₄ O ₃ S ₂ 1.3HC1.0.4H ₂ O
Calc .: C, 52.25; H, 4.91; Cl, 13.64; N, 9.37; S, 10.73.
Anal: C, 52.34; H, 5.03; Cl, 13.56; N, 9.36; S, 10.74.
Example 87 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl Carbonyl l Piperazine Hydrochloride
1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] in the same manner as in Example 7. The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.01 (2H, t, J = 5.9 Hz), 3.11 (4H, br)
3.44 (2H, br s), 3.74 (2H, br s), 4.32-4.46 (4H, m),
7.71 (lH, dd, J = 8.6, 2.0 Hz), 7.83 (lH, dd, J = 8.8 Hz, 2.0 Hz),
8.15 (lH, d, J = 8.8 Hz), 8.23 (lH, s), 8.26 (lH, d, J = 8.8 Hz),
8.30 (lH, s).
MS (FAB) m / z: 477 [(M + H) ⁺ , Cl ³⁵ ], 479 [(M + H) ⁺ , Cl ³⁷ ]
Elemental analysis; C _{2 l} H _{2 l} ClN ₄ O ₃ S _2. HC1 .0.2H ₂ O as
Calc .: C, 48.78; H, 4. 37; Cl, 13.71; N, 10.84; S, 12.40.
Anal: C, 48.60; H, 4.50; Cl, 13.58; N, 10.62; S, 12.29.
Example 88 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo [5,4 -c] pyridin-2-yl) carbonyl] piperazine hydrochloride; And 1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalene-2 -Yl) sulfonyl] piperazine
In the same manner as in Reference Example 112 and Example 83, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-terahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride as a raw material, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride and 1-[(6-carbamoyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine was obtained.
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride
¹ H-NMR (DMSO-d ₆ ) δ: 2.77 (2H, br s), 3.09 (4H, br),
3.48 (2H, t, J = 5.4 Hz), 3.73 (2H, br s), 4.30-4.50 (4H, m),
5.61 (lH, br s), 7.71 (lH, doublet of doublets, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8 Hz, 2.0 Hz), 8.15 (lH, d, J = 8.8 Hz),
8.22 (lH, d, J = 1.5 Hz), 8.25 (lH, d, J = 8.8 Hz), 8.50 (lH, s),
8.53 (hl, br s).
MS (FAB) m / z: 535 [(M + H) ⁺ , Cl ³⁵ ], 537 [(M + H) ⁺ , C1 ³⁷ ]
1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalene-2- (Yl) sulfonyl] piperazine
¹ H-NMR (DMSO-d ₆ ) δ: 2.75 (2H, br s), 3.09 (4H, br),
3.63 (2H, t, J = 5.9 Hz), 3.73 (2H, br s), 4.39 (2H, br s),
4.59 (2H, s), 6.17 (2H, s), 7.70 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8 Hz, 2.0 Hz), 8.14 (lH, d, J = 8.8 Hz),
8.21 (lH, d, J = 1.5 Hz), 8.25 (lH, d, J = 8.8 Hz), 8.50 (lH, s).
MS (FAB) m / z: 520 [(M + H) ⁺ , C 1 ³⁵ ], 522 [(M + H) ⁺ , Cl ³⁷ ]
As _{C 22 H 22 CIN 5 O 4} S 2 · H 2 O: Elemental Analysis
Calc .: C, 49.11; H, 4.50; N, 13.02.
Anal: C, 48.98; H, 4. 12; N, 12.83.
Example 89 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (1-pyrroline-2-yl) -4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride
In the same manner as in Example 47, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-Tile) carbonyl] piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.07-2.15 (2H, m), 2.94-3.16 (8H, m),
3.63 (2H, t, J = 7.3 Hz), 3.75 (2H, br s), 3.90 (2H, br s),
4.39 (2H, broad singlet), 4.93 (2H, doublet), 7.70 (lH, doublet of doublets, J = 8.8, 2.0 Hz),
7.83 (1H, dd, J = 8.8 Hz, 2.0 Hz), 8.15 (lH, d, J = 8.8 Hz),
8.22 (lH, d, J = 2.0 Hz), 8.25 (lH, d, J = 8.8 Hz), 8.50 (lH, s).
MS (FAB) M / Z: 544 [(M + H) ⁺ , Cl ³⁵ ], 546 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: As C ₂₅ H ₂₆ CIN ₅ O ₃ S ₂ 1.4HC1 CH ₃ OH
Calc .: C, 49.79; H, 5.05; Cl, 13.57; N, 11.17; S, 10.23.
Anal: C, 49.44; H, 4.78; Cl, 13.63; N, 10.83; S, 10.15.
Example 90 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-formyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine
In the same manner as in Example 4, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-Tile) carbonyl] piperazine hydrochloride and formic acid were used as starting materials to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.74-2.88 (2H, m), 3.10 (4H, br),
3.31 (2H, s), 3.66-3.86 (4H, m), 4.64-4.73 (2H, m),
7.69 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
8.14 (lH, d, J = 8.8 Hz), 8.15-8.22 (2H, m), 8.24 (lH, d, J = 8.8 Hz),
8.50 (1 H, s).
MS (FAB) m / z: 505 [(M + H) +, ClP], 507 [(M + H) +, C1 37]
Elemental analysis: as C ₂₂ H _2l ClN ₄ O ₄ S _{2 ·} 1 / 5H ₂ O
Calc .: C, 51.95; H, 4. 24; Cl, 6.97; N, 11.02; S, 12.61.
Anal: C, 52.18; H, 4. 30; Cl, 6.69; N, 10.71; S, 12.21.
Example 91 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 in dichloromethane (10 mL) -Yl) carbonyl] piperazine hydrochloride (400 mg) was suspended, triethylamine (0.22 mL) and acetic acid (0.05 mL) were added and stirred at room temperature for 5 minutes, followed by 30% aqueous formaldehyde solution (0.08 mL) and Sodium triacetoxy borohydride (264 mg) was added, and it stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in saturated hydrochloric acid ethanol solution (1 mL), the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from hexane and ethyl acetate to obtain the title compound (298 mg, 71%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.89 (3H, s), 3.10 (6H, br), 3.32-3.81 (4H, m),
4.30-4.81 (4H, m), 7.71 (lH, dd, J = 8.8, 2.0 Hz),
7.82 (lH, dd, J = 8.8, 2.0 Hz), 8.15 (lH, d, J = 8.8 Hz), 8.20-8.28 (2H, m),
8.50 (lH, s), 11.28 (lH, br s).
MS (FAB) m / z: 491 [(M + H) ⁺ , Cl ³⁵ ], 493 [(M + H) ⁺ , C1 ³⁷ ]
Elemental Analysis: As C ₂₂ H ₂₃ ClN ₄ O ₃ S ₂ .HC1.0.6H ₂ O
Calc .: C, 49.09; H, 4.72; Cl, 13.17; N, 10.41; S, 11.91.
Anal: C, 48.88; H, 4.78; Cl, 13.26; N, 10.42; S, 12.03.
Example 92 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6,6-dimethyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridinium iodide
N-N-dimethylformamide (20 mL) in 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride (200 mg) was dissolved. Methyl iodide (0.05 mL) and potassium carbonate (79 mg) were added, and the mixture was stirred overnight at 80 ° C. The reaction solution was concentrated under reduced pressure, and then water was added to the residue to precipitate a precipitate. This was dissolved in a mixed solution of dichloromethane and methanol (1: 1), and ethyl acetate was added to precipitate the precipitate, which was filtered to obtain the title compound (144 mg, 56%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.05-3.23 (12H, m), 3.77 (2H, t, J = 5.9 Hz),
4.40 (2H, broad s), 4.79 (2H, broad s), 7.71 (1H, dd, J = 8.8, 2.0 Hz),
7.83 (lH, dd, J = 8.8, 2.0 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.20-8.27 (2H, m),
8.32 (lH, s).
MS (FD) m / z: 505 (M ⁺ , Cl ³⁵ ), 507 (M ⁺ , Cl ³⁷ )
Elemental Analysis: As C ₂₃ H ₂₆ ClIN ₄ O ₃ S _{2 ·} 1 / 2CH ₃ CO ₂ CH ₂ CH ₃
Calc .: C, 44.35; H, 4. 47; N, 8.28.
Anal: C, 44.52; H, 4. 23; N, 8.01.
Example 93 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine N-oxide
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine hydrochloride (400 mg) was suspended in acetone (10 mL), 1N aqueous sodium hydroxide solution (0.38 mL) and 30% aqueous hydrogen peroxide solution (3.50 mL) were added, followed by stirring at room temperature for 8 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by synthetic adsorbent chromatography (diamond ion HP-20, water-water: acetonitrile = 2: 5) to obtain the title compound (84 mg, 39%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.83-2.90 (lH, m), 3.10 (5H, br), 3.20-3.47 (4H, m),
3.61-3.83 (3H, m), 4.28-4.50 (3H, m), 4.78-4.85 (lH, m),
7.69 (1H, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
8.14 (lH, d, J = 8.8 Hz), 8.19-8,27 (2H, m), 8.50 (1H, s)
MS (FD) m / z: 506 (M ⁺ , C 1 ³⁵ ), 508 (M ⁺ , Cl ³⁷ )
Example 94 2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbonyl] piperazine trifluoroacetic acid salt
1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] dissolved in dichloromethane (1 mL) 2-Carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine (303 mg) was added to trifluoroacetic acid (1 ml), followed by concentration under reduced pressure, and the precipitate precipitated. The residue was washed with diethyl ether to give the title compound (263 mg, 83%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.39-2.70 (2H, m), 2.92-3.06 (2H, m),
3.42-3.77 (4H, m), 4.25-4.50 (7 / 2H, m), 4.97 (1 / 2H, br s),
5.35-5.44 (1 / 2H, m), 6.14 (1 / 2H, br s), 7.30-7.39 (lH, m),
7.66-7.73 (2H, m), 7.77-7.82 (lH, m),
8.16 (1H, d, J = 8.8 Hz), 8.21-8.28 (2H, m), 8.49 (lH, s), 9.26 (2H, br s).
MS (FAB) m / z: 520 [(M + H) ⁺ , Cl ³⁵ ], 522 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₂ H ₂₂ ClN ₅ O ₄ S ₂ .CF ₃ CO ₂ H.0.6H ₂ O
Calc .: C, 44.29; H, 3.73; Cl, 5.40; F, 9.55; N, 10.67; S, 9.77.
Anal: C, 44.59; H, 3.79; Cl, 5.26; F, 9.54; N, 10.28; S, 9.72.
Example 95 2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride
In the same manner as in Example 91, 2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -l-[(4,5,6,7-tetrahydrothiazolo [5, 4-c) pyridin-2-yl) carbonyl] piperazine trifluoroacetate was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.37-2.70 (2H, m), 2.91 (3H, s), 3.00-3.78 (6H, m),
4.28-4.77 (7 / 2H, m), 4.97 (1 / 2H, br s), 5.40-5.50 (1 / 2H, m),
6.14 (1 / 2H, br s), 7.32-7.40 (lH, m), 7.68-7.75 (2H, m), 7.77-7.83 (lH, m),
8.15 (lH, d, J = 8.8 Hz), 8.21-8.28 (2H, m), 8.49 (lH, s).
MS (FAB) m / z: 534 [(M + H) ⁺ , Cl ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₃ H ₂₄ ClN ₅ O ₄ S ₂ HC1 2.5 H ₂ O
Calc .: C, 44.88; H, 4.91; Cl, 11.52; N, 11.38; S, 10.42.
Anal: C, 44.83; H, 4.99; Cl, 11.65; N, 11.31; S, 10.46.
Example 96 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (2-hydroxyethyl) -4,5,6,7-tetrahydrothiazolo [5 , 4-C] pyridin-2-yl] carbonyl] piperazine hydrochloride
1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] pipe The crude product obtained in the same manner as in Example 91 using lazine hydrochloride (132 mg) and glyoxylic acid hydrate (82 mg) was suspended in tetrahydrofuran (50 mL), and triethylamine (0.22 mL) and ethyl were obtained. Chloroformate (0.03 mL) was added under ice-cooling, stirred at room temperature for 15 minutes, and then sodium borohydride (50 mg) and water (10 mL) were added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 3) was dissolved in saturated ethanol (1 mL), concentrated under reduced pressure, and triturated with ethyl acetate to give the title compound (52 mg, 33%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (4H, br s), 3.20-3.57 (6H, m), 3.69-3.87 (4H, m),
4.34-4.82 (4H, m), 5.38 (1H, broad singlet),
7.71 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8 Hz, 2.0 Hz),
8.15 (lH, d, J = 8.8 Hz), 8.22 (1H, s), 8.25 (lH, d, J = 8.8 Hz),
8.50 (1H, s), 10.48 (lH, br s).
MS (FAB) m / z: 521 [(M + H) ⁺ , Cl ³⁵ ], 523 [(M + H) ⁺ , C 1 ³⁷ ]
As in Example 91, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- Using the 2-yl] carbonyl] piperazine hydrochloride as a raw material, the compounds of Examples 97, 98 and 99 were obtained.
Example 97 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (pyridin-2-yl) methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride
¹ H-NMR (DMSO-d ₆ ) δ: 3.07-3.17 (6H, m), 3.63 (2H, t, J = 6.3 Hz),
3.74 (2H, br s), 4.39 (2H, br s), 4.58 (2H, s), 4.61 (2H, s),
7.50-7.64 (lH, m), 7.67-7.73 (2H, m), 7.82 (lH, dd, J = 8.8, 1.5 Hz),
7.97 (1H, m), 8.15 (lH, d, J = 8.8 Hz), 8.22 (lH, d, J = 1.5 Hz),
8.25 (lH, d, J = 8.8 Hz), 8.50 (lH, s), 8.69 (lH, d, J = 4.9 Hz).
MS (FAB) m / z: 568 [(M + H) ⁺ , C 1 ³⁵ ], 570 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₆ ClN ₅ O ₃ S ₂ .2HC1.0.8H ₂ O.
Calc .: C, 49.48; H, 4.55; C1, 16.23; N, 10.68; S, 9.78.
Anal: C, 49.72; H, 4. 48; Cl, 16.31; N, 10.86; S, 9.53.
Example 98 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (pyridin-3-yl) methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride
¹ H-NMR (DMSO-d ₆ ) δ: 3.03-3.27 (6H, m), 3.40-3.81 (4H, m)
3.74 (2H, br s), 4.40 (2H, br s), 4.50 (2H, s), 4,70 (2H, s),
7.70 (1H, dd, J = 8.8, 2.4 Hz), 7.82 (lH, dd, J = 8.8),
8.15 (lH, d, J = 8.8 Hz), 8.22 (1H, s), 8.25 (lH, d, J = 8.8 Hz),
8.50 (lH, s), 8.73 (lH, d, J = 7.8 Hz), 8.93 (lH, d, J = 4.4 Hz).
MS (FAB) m / z: 568 [(M + H) ⁺ , C 1 ³⁵ ], 370 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₇ H ₂₆ ClN ₅ O ₃ S ₂ .2.9HC1.4.5H ₂ O
Calc .: C, 42.96; H, 5.06; Cl, 18.32; N, 9.28.
Anal: C, 42.97; H, 4. 84; Cl, 18.19; N, 9.23.
Example 99 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[6- (pyridin-4-yl) methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride
¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (4H, br s), 3.19 (2H, br s),
3.64 (2H, br s), 3.74 (2H, br s), 4.41 (2H, br s), 4.49 (2H, s),
4.80 (2H, s), 7.69 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
8.15 (lH, d, J = 8.8 Hz), 8.21 (1H, d, J = 2.0 Hz), 8.25 (lH, d, J = 8.8 Hz),
8.41 (2H, d, J = 6.3 Hz), 8.50 (1H, s), 9.04 (2H, d, J = 6.3 Hz).
MS (FAB) m / z: 568 [(M + H) ⁺ , Cl ³⁵ ], 570 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₆ ClN ₅ O ₃ S ₂ .2.7HC1.6.0H ₂ O.
Calc .: C, 41.86; H, 5. 30; Cl, 16.93; N, 9.04; S, 8.28.
Anal: C, 42.05; H, 4.98; Cl, 16.92; N, 9.37; S, 8.61.
Example 100 1-[(E) -4-chlorostyrylsulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carb Carbonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] The title compound was obtained using -4-[(E) -4-chlorostyrylsulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 3.04 (2H, br s), 3.23 (4H, br), 3.47 (2H, br s),
3.77 (2H, broad singlet), 4.35-4.50 (2H, m), 7.33 (lH, d, J = 15.6 Hz),
7.43 (1H, d, J = 15.6 Hz), 7.49 (lH, d, J = 8.3 Hz), 7.79 (lH, d, J = 8.3 Hz),
9.57 (2H, broad singlet).
MS (FAB) m / z: 453 [(M + H) ⁺ , Cl ³⁵ ], 455 [(M + H) ⁺ , Cl ³⁷ ]
Elemental _{analysis: C l9 H 2l ClN 4 O} 3 S 2 · HCI · 0.3H ₂ O as a
Calc .: C, 46.12; H, 4. 60; Cl, 14.33; N, 11.32; S, 12.96.
Anal: C, 46.42; H, 4. 66; Cl, 14.38; N, 11.02; S, 13.02.
Example 101 1-[(E) -4-chlorostyrylsulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] piperazine hydrochloride
As in Example 91, [(E) -4-chlorostyrylsulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] The title compound was obtained using carbonyl] piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.92 (3H, s), 3.01-3.32 (6H, br), 3.35-3.88 (4H, m),
4.29-4.84 (4H, m), 7.33 (lH, d, J = 15.6 Hz), 7.49 (lH, d, J = 15.6 Hz),
7.49 (1H, d, J = 8.3 Hz), 7.79 (1H, d, J = 8.3 Hz), 11.31 (1H, br s).
MS (FAB) m / z: 467 [(M + H) ⁺ , Cl ³⁵ ], 469 [(M + H) ⁺ , Cl ³⁷ ]
Elemental analysis: As C ₂₀ H ₂₃ CIN ₄ O ₃ S ₂ .HC1.0.2H ₂ O
Calc .: C, 47.37; H, 4. 85; Cl, 13.98; N, 11.05; S, 12.65.
Anal: C, 47.30; H, 4.92; Cl, 14.05; N, 11.03; S, 12.49.
Example 102 (3S) -3-[(6-chloronaphthalen-2-yl) sulfonamide] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine -2-yl) methyl] pyrrolidine hydrochloride
In the same manner as in Example 7, (3S) -1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Methyl] -3-[(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine was used as a raw material to obtain the title compound.
[α] D = −69.72 ° C. (25 ° C., c = l.00, CH ₃ OH).
¹ H-NMR (DMSO-d ₆ at 100 ° C.) δ: 1.88-1.89 (lH, m), 2.10-2.25 (lH, m),
3.02-3.07 (2H, m), 3.10-3.50 (6H, m), 4.02 (lH, s), 4.12 (2H, s),
4.45 (2H, s), 7.12 (lH, s), 7.65 (lH, d, J = 8.3 Hz), 7.91 (lH, d, J = 8.3 Hz),
8.10 (lH, d, J = 8.3 Hz), 8.14 (1H, s), 8.16 (1H, d, J = 8.3 Hz),
8.18 (hl, br s), 8.48 (1H, s), 9.65 (2H, br s).
MS (FD) m / z: 461 (M ⁺ , Cl ³⁵ ), 463 (M ⁺ , C1 ³⁷ )
Elemental analysis: C ₂₂ H ₂₄ ClN ₃ O ₂ S ₂ .2.lHCl H ₂ O
Calc .: C, 47.47; H, 5.09; Cl, 19.74; N, 7.55; S, 11.52.
Anal: C, 47.55; H, 5.13; Cl, 19.85; N, 7.45; S, 11.48.
Example 103 (3S) -3-[(6-chloronaphthalen-2-yl) sulfonamide] -1-[(4, S, 6,7-tetrahydrothieno [3,2-c] pyridine -2-yl) carbonyl] pyrrolidine hydrochloride
In the same manner as in Example 7, (3S) -l-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Carbonyl] -3-[(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine as a raw material to obtain the title compound.
[a] _D = −62.70 ° (25 ° C., c = l.00, CH ₃ OH).
¹ H-NMR (DMSO-d ₆ at 100 ° C.) δ: 1.82-1.90 (lH, m), 1.96-2.05 (lH, m),
3.05 (2H, t, J = 6.0 Hz), 3.42-3.S7 (2H, m), 3.60-3.72 (2H, m),
3.84-3.90 (lH, m), 4.12 (2H, s), 4.45 (2H, s), 7.25 (lH, s),
7.64 (lH, dd, J = 8.3,1.6 Hz), 7.90 (1H, dd, J = 8.3,1.6 Hz),
7.97 (lH, d, J = 5.6 Hz), 8.08 (lH, d, J = 8.7 Hz),
8.12 (lH, s), 8.14 (lH, d, J = 8.7 Hz), 8.47 (1H, s), 9.55 (2H, br s).
MS (FAB) m / z: 476 [(M + H) ⁺ , Cl ³⁵ ], 478 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₂ H ₂₂ ClN ₃ O ₃ S ₂ as HCl
Calc .: C, 51.56; H, 4.52; Cl, 13.84; N, 8.20; S, 12.51.
Anal: C, 51.25; H, 4.61; Cl, 13.68; N, 7.98; S, 12.36.
Example 104 (3S) -1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-[[(4,5,6,7-tetrahydrothieno [3,2-c] Pyridin-2-yl) methyl] amino] pyrrolidine hydrochloride
In the same manner as in Example 7, (3S) -3-[[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2- Il) methyl] amino] -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine was used as a raw material to obtain the title compound.
[a] _D = + 34. 82 ° (25 ° C., c = l.00, CH ₃ OH).
¹ H-NMR (DMSO-d ₆ ) δ: 1.98-2.20 (2H, m), 2.99-3.04 (2H, m),
3.19-3.26 (lH, m), 3.30-3.50 (3H, m), 3.61-3.72 (lH, m), 3.52-3.60 (lH, m),
4.13 (2H, s), 4.29 (2H, s), 7.09 (lH, s), 7.71 (lH, dd, J = 8.8, 2.0 Hz),
7.89 (1H, dd, J = 8.8, 2.0 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.25 (1H, d, J = 2.0 Hz),
8.30 (lH, s), 8.57 (lH, s), 9.55 (2H, br s), 9.7-10.0 (lH, m).
MS (FD) m / z: 461 (M ⁺ , Cl ³⁵ ), 463 (M ⁺ , C1 ³⁷ )
Elemental Analysis: As C ₂₂ H ₂₄ ClN ₃ O ₂ S ₂ .2HC1.0.2H ₂ O
Calc .: C, 49.06; H, 4.94; Cl, 19.75; N, 7.80; S, 11.91.
Anal: C, 48.88; H, 4.97; Cl, 19.65; N, 7.67; S, 11.84.
Example 105 (3S) -3-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino] -1-[(6-chloro Naphthalen-2-yl) sulfonyl] pyrrolidine hydrochloride
In the same manner as in Example 7, (3S) -3-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Carbonylamino] -l-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a raw material to obtain the title compound.
[α] _D = + 33.56 ° (25 °, c = l.00, CH ₃ OH).
¹ H-NMR (DMSO-d ₆ ) δ: 1.85-1.95 (lH, m), 1.95-2.05 (lH, m),
3.04 (2H, m), 3.24-3.40 (lH, m), 3.41-3.53 (3H, m), 4.04-4.24 (3H, m),
7.34 (lH, s), 7.67 (lH, d, J = 8.8 Hz), 7.84 (lH, d, J = 8.8 Hz),
8.03 (lH, d, J = 8.8 Hz), 8.17 (lH, s), 8.22 (1H, d, J = 8.8 Hz),
8.27 (lH, d, J = 5.7 Hz), 8.50 (lH, s), 9.59 (1H, br s), 9.71 (lH, br s).
MS (FAB) m / z: 476 [(M + H) ⁺ , Cl ³⁵ ], 478 [(M + H) ⁺ , C 1 ³⁷ ]
Example 106 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Carbonyl] Homopiperazine Hydrochloride
In the same manner as in Example 7, 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.83 (2H, br s), 3.04 (2H, t, J = 5.4 Hz),
3.30-3.59 (6H, m), 3.60-3.88 (4H, m), 4.14 (2H, s), 7.20 (lH, br s),
7.69 (lH, dd, J = 8.8, 2.0 Hz), 7.84 (lH, d, J = 8.8 Hz), 8.10 (1H, d, J = 8.8 Hz),
8.17-8.21 (2H, m), 8.50 (1H, s), 9.57 (2H, br s).
MS (FAB) m / z: 490 [(M + H) ⁺ , Cl ³⁵ ], 492 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₃ H ₂₅ ClN ₃ O ₃ S ₂ .1.lHC1 .0.2H ₂ O.
Calc .: C, 51.66; H, 4.99; Cl, 13.92; N, 7.86.
Anal: C, 51.46; H, 4.61; Cl, 13.55; N, 8.05.
Example 107 4-[(6-chloronaphthalen-2-yl) sulfonamido] -l-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2- I) carbonyl] piperidine hydrochloride
In the same manner as in Example 4, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid and 4-[(6 The title compound was obtained using -chloronaphthalen-2-yl) sulfonamido] piperidine trifluoroacetic acid as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.26-1.38 (2H, m), 1.58-1.65 (2H, m),
2.93-3.13 (4H, m), 3.29-3.40 (3H, m), 3.90-4.05 (2H, m), 4.11 (2H, s),
7.16 (lH, s), 7.68 (lH, dd, J = 8.0, 2.0 Hz), 7.92 (lH, dd, J = 8.8, 2.0 Hz),
8.07 (lH, d, J = 7.3 Hz), 8.13 (2H, d, J = 8.8 Hz), 8.20 (1H, d, J = 7.3 Hz),
8.23 (lH, s), 8.51 (1H, s), 9.71 (2H, br s)
MS (FAB) m / z: 490 [(M + H) ⁺ , C 1 ³⁵ ], 492 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₃ H ₂₅ ClN ₃ O ₃ S ₂ .2.4HC1.3H ₂ O.
Calc .: C, 43.67; H, 5. 32; Cl, 19.05; N, 6.64.
Anal: C, 43.85; H, 5. 10; Cl, 19.07; N, 6.63.
Example 108 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethylbenzofuran-2-yl) carbonyl] piperazine
In the same manner as in Example 83, using 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-cyanobenzofuran-2-yl) carbonyl] piperazine as a raw material The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (4H, s), 3.83 (4H, br), 5.90 (2H, br),
7.34 (lH, s), 7.64-7.75 (3H, m), 7.83 (1H, dd, J = 8.8, 2.0 Hz), 7.89 (1H, s),
8.17 (1H, d, J = 8.8 Hz), 8.23 (lH, d, J = 1.5 Hz), 8.26 (lH, d, J = 8.8 Hz),
8.51 (lH, s), 9.77 (lH, s).
MS (FAB) m / z: 513 [(M + H) ⁺ , C 1 ³⁵ ], 515 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₄ H _2l ClN ₄ O ₅ S · 1 / 5H ₂ O
Calc .: C, 55.80; H, 4. 18; Cl, 6.86; N, 10.70; S, 6.21.
Anal: C, 55.65; H, 4. 25; Cl, 6.81; N, 10.70; S, 6.37.
Example 109 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethylbenzothiophen-2-yl) carbonyl] piperazine
In the same manner as in Example 83, 1-((6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-cyanobenzothiophen-2-yl) carbonyl] piperazine was used as a raw material. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (4H, s), 3.77 (4H, s), 5.87 (2H, br s),
7.67 (lH, s), 7.71 (lH, d, J = 2.0 Hz), 7.75 (lH, d, J = 8.8 Hz),
7.83 (1H, dd, J = 8.8, 2.0 Hz), 7.94 (lH, d, J = 8.8 Hz), 8.15 (lH, s),
8.17 (lH, d, J = 8.8 Hz), 8.25 (lH, d, J = 8.8 Hz), 8.29 (lH, d, J = 8.3 Hz),
8.50 (lH, s), 9.68 (lH, s).
MS (FAB) m / z: 529 [(M + H) ⁺ , Cl ³⁵ ], 531 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H _2l N ₄ ClO ₄ S ₂ .0.3H ₂ O.
Calc .: C, 53.94; H, 4.07; N, 10.48.
Anal: C, 54.22; H, 4. 17; N, 10.23.
Example 110 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[(lRS) -4- (pyridin-4-yl) -3-cyclohexene] carbonyl] piperazine Hydrochloride
In the same manner as in Example 12, (lRS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride The title compound was obtained as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.60 (lH, m), 1.80-1.90 (lH, rn),
2.25-2.58 (5H, m), 2.80-2.90 (lH, m), 2.91-3.10 (lH, m), 3.46-3.72 (4H, m),
6.94 (1H, broad s), 7.71 (lH, dd, J = 8.8, 2.0 Hz), 7.82 (lH, dd, J = 8.8, 2.0 Hz),
7.96 (2H, d, J = 6.8 Hz), 8.15 (lH, J = 8.8 Hz), 8.24 (1H, J = 2.0 Hz),
8.27 (1H, J = 8.8 Hz), 8.50 (1H, s), 8.76 (2H, d, J = 6.8 Hz).
MS (ERB) m / z: 496 [(M + H) ⁺ , Cl ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₆ ClN ₃ O ₃ S.HC1.1.3H ₂ O
Calc .: C, 56.18; H, 5. 37; Cl, 12.75; N, 7.56; S, 5.77.
Anal: C, 56.03; H, 5. 29; Cl, 12.67; N, 7.41; S, 5.77.
Example 111 1-[(E) -4-chlorostyrylsulfonyl] -4-[[(1RS) -4- (pyridin-4-yl) -3-cyclohexene] carbonyl] piperazine hydrochloride
The reaction was carried out in the same manner as in Reference Example 12, using (lRS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid and 1-[(E) -4-chlorostyrylsulfonyl) piperazine hydrochloride as raw materials. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.59-1.70 (lH, m), 1.90-1.98 (lH, m),
2.31-2.56 (4H, m), 2.90-3.00 (lH, m), 3.13 (4H, br s), 3.50-3.63 (4H, m),
6.98 (lH, br s), 7.35 (lH, d, J = 15.6 Hz), 7.44 (lH, d, J = 15.6 Hz),
7.51 (2H, d, J = 8.3 Hz), 7.80 (lH, J = 8.3 Hz), 7.97 (lH, J = 6.8 Hz),
8.77 (lH, J = 6.8 Hz).
MS (FAB) m / z: 472 [(M + H) ⁺ , Cl ³⁵ ], 474 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₆ ClN ₃ O ₃ S.0.9HCl.2.3H ₂ O.
Calc .: C, 52.77; H, 5.81; Cl, 12.33; N, 7.69; S, 5.87.
Anal: C, 52-61; H, 5.80; Cl, 12.54; N, 7.44; S, 6.05.
Example 112 cis-, trans-l-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[4- (pyridin-4-yl) cyclohexane] carbonyl] piperazine hydrochloride
Reaction was performed in the same manner as in Reference Example 12, and cis-, trans-4- (4-pyridyl) cyclohexanecarboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as raw materials. To give the title compound.
MS (FAB) m / z: 498 [(M + H) ⁺ , C 1 ³⁵ ], 500 ((M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₆ H ₂₈ ClN ₃ O ₃ S.1.3HCl.2H ₂ O.
Calc .: C, 53.71; H, 5.77; Cl, 14.02; N, 7.23; S, 5.51.
Anal: C, 53.70; H, 5. 70; Cl, 14.21; N, 7.13; S, 5.72.
Example 113 cis-, trans-l-[(E) -4-chlorostyrylsulfonyl] -4-[[4- (pyridin-4-yl) cyclohexane] carbonyl] piperazine hydrochloride
Reaction was carried out in the same manner as in Reference Example 12, using cis-, trans-4- (4-pyridyl) cyclohexanecarboxylic acid and 1-[(E) -4-chlorostyrylsulfonyl) piperazine hydrochloride as starting materials. The compound was obtained.
MS (FAB) m / z: 474 [(M + H) ⁺ , C 1 ³⁵ ], 476 (M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₈ CIN ₃ O ₃ S · 2HC1 · 0.8H ₂ O
Calc .: C, 54.17; H, 5.83; Cl, 14.66; N, 7.80; S, 6.03.
Anal: C, 54.21; H, 6. 20; Cl, 15.03; N, 7.51; S, 6.18.
Example 114 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] piperazine hydrochloride
In the same manner as in Example 7, 1-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] -4-[(6-chloro The title compound was obtained using naphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.89-3.29 (4H, m), 3.20-3.83 (8H, m),
4.25 (2H, s), 7.10-7.25 (3H, m), 7.71 (lH, d, J = 8.3 Hz),
7.81 (lH, d, J = 8.3 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.15-8.25 (2H, m),
8.49 (lH, s), 9.54 (2H.brs).
MS (FAB) m / z: 470 [(M + H) ⁺ , Cl ³⁵ ], 472 [(M + H) ⁺ , Cl ³⁷ ].
Elemental Analysis: As C ₂₄ H ₂₄ ClN ₃ O ₃ S.HC1.2.0H ₂ O
Calc .: C, 53.14; H, 5.39; Cl, 13.07; N, 7.75; s, 5.91.
Anal: C, 53.43; H, 5. 43; Cl, 13.15; N, 8.07; S, 5.55.
Example 115 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] Piperazine Hydrochloride
In the same manner as in Example 91, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] The title compound was obtained using piperazine hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.88 (3H, s), 2.90-3.80 (13H, m), 4.12-4.56 (lH, m),
7.19 (lH, s), 7.20 (2H, d, J = 6.8 Hz), 7.72 (lH, dd, J = 8.8, 2.0 Hz),
7.81 (lH, d, J = 8.8 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.24-8.28 (2H, m),
8.49 (lH.s), 10.93 (lH, brs).
MS (FAB) m / z: 484 [(M + H) ⁺ , C 1 ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₄ H ₂₄ ClN ₃ O ₃ S.HC1.2.3H ₂ O
Calc .: C, 53.44; H, 5.67; Cl, 12.62; N, 7.48; S, 5.71.
Anal: C, 53.71; H, 5.81; Cl, 12.37; N, 7. 26; S, 5.62.
Example 116 6-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -2,2-dimethyl-1,2,3,4- Tetrahydroisoquinolinium iodide
In the same manner as in Example 92, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl ) Carbonyl] piperazine hydrochloride was used as a raw material to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.90-3.85 (18H, m), 4.61 (2H, s)
7.19 (1H, d, J = 7.8 Hz), 7.24 (lH, d, J = 7.8 Hz), 7.28 (1H, s),
7.72 (1H, dd, J = 8.8, 1.5 Hz), 7.81 (lH, d, J = 8.8 Hz),
8.17 (lH, d, J = 8.8 Hz), 8.20-8.31 (2H, m), 8.50 (lH, s).
Elemental Analysis: As C ₂₆ H ₂₉ ClIN ₃ O ₃ SH ₂ O
Calc .: C, 48.49; H, 4. 85; N, 6.53.
Anal: C, 48.66; H, 4.96; N, 6.39.
Example 117 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (1,2,3,6-tetrahydropyridin-4-yl) benzoyl] piperazine hydrochloride
In the same manner as in Reference Example 7, 1- [4- (l-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) benzoyl] -4-[(6-chloro The title compound was obtained using naphthalen-2-yl) sulfonyl] piperazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (2H, br s), 3.05 (4H, br), 3.30 (2H, br s),
3.35-3.78 (6H, m), 6.24 (1H, broad s), 7.32 (2H, d, J = 8.3 Hz),
7.47 (2H, d, J = 8.3 Hz), 7.71 (lH, dd, J = 8.8, 2.0 Hz),
7.81 (lH, dd, J = 8.8, 2.0 Hz), 8.17 (lH, d, J = 8.8 Hz),
8.22-8.28 (2H, m), 8.49 (lH, s), 9.25 (2H, br s).
MS (FAB) m / z: 496 [(M + H) ⁺ , C 1 ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₆ ClN ₃ O ₃ S.HC1 · 2 / 5H ₂ O
Calc .: C, 57.86; H, 5. 19; Cl, 13.14; N, 7.79; S, 5.94.
Anal: C, 57.91; H, 5. 19; Cl, 12.91; N, 7.75; S, 5.78.
Example 118 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (piperidin-4-yl) benzoyl] piperazin hydrochloride
Reaction was performed in the same manner as in Reference Example 7, and 1- [4- (l-tert-butoxycarbonylpiperidin-4-yl) benzoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] Using the piperazine as a raw material, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.78-1.94 (4H, m), 2.80-3.21 (7H, m),
3.30-3.84 (6H, m), 7.23 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz),
7.71 (lH, dd, J = 8.8, 2.0 Hz), 7.80 (lH, dd, J = 8.8, 2.0 Hz),
8.17 (lH, d, J = 8.8 Hz), 8.22-8.27 (2H, m), 8.49 (1H, s), 8.78-9.00 (2H, m).
MS (FAB) m / z: 498 [(M + H) ⁺ , Cl ³⁵ ], 500 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₆ H ₂₈ ClN ₃ O ₃ S.HC1 · 3 / 5H ₂ O
Calc .: C, 57.27; H, 5.58; Cl, 13.00; N, 7.71; S, 5.88.
Anal: C, 57.23; H, 5.52; Cl, 12.90; N, 7.60; S, 5.83.
Example 119 (3RS) -3-[(6-chloronaphthalen-2-yl) sulfonamido] -l- [4- (pyridin-4-yl) benzoyl] pyrrolidine hydrochloride
(3RS) -l-tert-butoxycarbonyl-3-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine is dissolved in saturated ethanol, stirred for 8 hours at room temperature, and the solvent is Distillation under reduced pressure. The title compound was obtained in the same manner as in Example 4 using the obtained residue and 4- (4-pyridyl) benzoic acid as starting materials.
¹ H-NMR (DMSO-d ₆ ) δ: 1.70-2.10 (2H, m), 3.00-3.65 (4H, m),
3.75-3.90 (lH, m), 7.50-8.40 (13H, m), 8.95-9.05 (2H, m)
MS (FAB), n / z: 492 [(M + H) ⁺ , C 1 ³⁵ ], 494 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₆ H ₂₂ ClN ₃ O ₃ S.HC1.1.8H ₂ O
Calc .: C, 55.68; H, 4.78; N, 7.49; Cl, 12.64; S, 5.72.
Anal: C, 55.62; H, 4.94; N, 7.67; Cl, 12.76; S, 5.79.
Example 120 (3RS) -1-[(6-chloronaphthalen-2-yl) sulfonyl] -3- [4- (pyridin-4-yl) benzamido] pyrrolidine hydrochloride
(3RS) -l-tert-butoxycarbonyl-3- [4- (4-pyridyl) benzamido] pyrrolidine was dissolved in saturated ethanol hydrochloride, stirred at room temperature for 4 hours, and then the solvent was decompressed. The title compound was obtained in the same manner as in Reference Example 1 using 6-chloro-2-naphthylsulfonyl chloride as a starting material.
¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.10 (2H, m), 3.00-3.60 (4H, m),
4.15-4.25 (lH, m), 7.57 (1H, dd, J = 8.8, 2.0 Hz), 7.73 (2H, d, J = 8.8 Hz),
7.85 (lH, dd, J = 8.8, 2.0 Hz), 7.90 (2H, d, J = 8.8 Hz), 7.9S-8.05 (2H, m),
8.18 (lH, d, J = 8.8 Hz), 8.30-8.40 (3H, m), 8.50 (1H, s),
8.98 (2H, doublet, J = 6.4 Hz).
MS (FAB) m / z: 492 [(M + H) ⁺ , Cl ³⁵ ], 494 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₆ H ₂₂ ClN ₃ O ₃ S.0.8HC1.0.8H ₂ O
Calc .: C, 58.31; H, 4.59; N, 7.85; Cl, 11.92; S, 5.99.
Anal: C, 58.27; H, 4.68; N, 7.80; Cl, 11.94; S, 6.04.
Example 121 1-[[(E) -2- (6-chloropyridin-3-yl) ethylene] sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine
Tert-part in the same manner as in Example 7 using 1-tert-butoxycarbonyl-4-[[(E) -2- (6-chloropyridin-3-yl) ethylene] sulfonyl] piperazine as a raw material The oxycarbonyl group was removed and reacted in the same manner as the residue Reference Example 116 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.10-3.31 (4H, br), 3.40-3.84 (4H, br),
7.50 (lH, d, J = 15.9 Hz), 7.52 (1H, d, J = 15.9 Hz),
7.46 (3H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.3 Hz), 8.28-8.33 (3H, m),
8.79 (lH, d, J = 2.0 Hz), 8.94 (2H, d, J = 6.4 Hz).
MS (FAB) m / z: 469 [(M + H) ⁺ , C 1 ³⁵ ], 471 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₃ H ₂₁ CIN ₄ O ₃ SHCl0.4H ₂ O
Calc .: C, 53.89; H, 4. 48; N, 10.93; Cl, 13.83; S, 6.26.
Anal: C, 53.95; H, 4. 47; N, 11.02; Cl, 13.91; S, 6.39.
Example 122 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-methyl-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
The reaction was carried out in the same manner as in Reference Example 7, and the title compound was obtained using 1- (4-bromo-2-methylbenzoyl) -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material. .
¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 2.80-4.00 (8H, m),
7.36 (lH, d, J = 8.3 Hz), 7.73 (lH, dd, J = 8.8, 2.4 Hz), 7.75-7.85 (2H, m),
7.88 (lH, s), 8.18 (1H, d, J = 8.8 Hz), 8.20-8.30 (4H, m), 8.50 (lH, br s),
8.90 (2H, doublet, J = 6.8 Hz).
MS (FAB) m / z: 506 [(M + H) ⁺ , C 1 ³⁵ ], 508 [(M + H) ⁺ , Cl ³⁷ ]
Example 123 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -3-methylphenyl] pyridine N-oxide
In the same manner as in Example 6, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-methyl-4- (pyridin-4-yl) benzoyl] piperazine was used as a raw material. , The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 2.80-4.20 (8H, m), 7.16 (lH, d, J = 8.3 Hz),
7.38 (lH, J = 8.3 Hz), 7.41 (lH, br s), 7.48 (2H, d, J = 6.8 Hz),
7.61 (1H, dd, J = 8.8, 1.5 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.91-7.97 (3H, m),
8.28 (2H, doublet, J = 6.8 Hz), 8.31 (hl, br s).
MS (FAB) m / z: 522 [(M + H) ⁺ , C 1 ³⁵ ], 524 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₇ H ₂₄ ClN ₃ O ₄ SH ₂ O
Calc .: C, 60.05; H, 4. 85; Cl, 6.56; N, 7.78; S, 5.94.
Anal: C, 59.98; H, 4.89; Cl, 6.51; N, 7.48; S, 5.92.
Example 124 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-methyl-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 4, using 3-methyl-4- (4-pyridyl) benzoic acid hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 3.08 (4H, br), 3.47 (2H, br),
3.72 (2H, br), 7.26-7.37 (3H, m), 7.73 (lH, doublet of doublets, J = 8.8, 2.0 Hz),
7.83 (lH, dd, J = 8.8, 2.0 Hz), 7.86 (2H, d, J = 6.8 Hz),
8.18 (lH, d, J = 8.8 Hz), 8.25-8.29 (2H, m), 8.50 (lH, br s),
8.87 (2H, doublet, J = 6.8 Hz).
MS (FAB) m / z: 506 [(M + H) ⁺ , C 1 ³⁵ ], 508 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₄ ClN ₃ O ₃ S.0.9HC1.1.7H ₂ O
Calc .: C, 56.95; H, 5.01; Cl, 11.83; N, 7.38; S, 5.63.
Anal: C, 57.08; H, 5.04; Cl, 11.75; N, 7.37; S, 5.49.
Example 125 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -piperazin-1-yl] carbonyl] -2-methylphenyl] pyridine N-oxide
In the same manner as in Example 6, using 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-methyl-4- (pyridin-4-yl) benzoyl piperazine as a raw material, The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 3.13 (4H, br), 3.63 (2H, br),
3.86 (2H, br), 7.15-7.28 (5H, m), 7.60 (lH, d, J = 8.8 Hz),
7.76 (lH, d, J = 8.8 Hz), 7.90-7.96 (3H, m), 8.26 (2H, d, J = 6.8 Hz),
8.31 (lH, s).
MS (FAB) m / z: 522 [(M + H) ⁺ , Cl ³⁵ ], 524 [(M + H) ⁺ , Cl ³⁵ ].
Elemental Analysis: As C ₂₇ H ₂₄ ClN ₃ O ₄ SH ₂ O
Calc .: C, 60.05; H, 4. 85; Cl, 6.56; N, 7.78; S, 5.94.
Anal: C, 59.71; H, 4.68; Cl, 6.87; N, 7.63; S, 5.91.
Example 126 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-methylpyridin-4-yl) benzoyl] piperazine hydrochloride
The title compound was obtained in the same manner as in Example 4 using 4- (2-methyl-4-pyridyl) benzoic acid hydrochloride as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.76 (3H, s), 3.00-3.90 (8H, m),
7.56 (2H, d, J = 8.3 Hz), 7.74 (lH, dd, J = 8.8, 2.4 Hz),
7.83 (lH, dd, J = 8.8, 2.0 Hz), 8.00 (2H, d, J = 8.3 Hz), 8.14 (1H, d, J = 6.4 Hz),
8.19 (lH, d, J = 8.8 Hz), 8.22-8.29 (3H, m), 8.51 (lH, br s),
8.80 (1H, doublet, J = 6.4 Hz).
MS (FAB) m / z: 506 [(M + H) ⁺ , Cl ³⁵ ], 508 [(M + H) ⁺ , Cl ³⁵ ]
Elemental Analysis: As C ₂₇ H ₂₄ ClN ₃ O ₃ SHCl 2H ₂ O
Calc .: C, 56.06; H, 5.05; Cl, 12.26; N, 7. 26; S, 5.54.
Anal: C, 55.84; H, 5.03; Cl, 12.26; N, 6.87; S, 5.54.
Example 127 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -piperazin-1-yl] carbonyl] phenyl] -2-methylpyridine N-oxide
In the same manner as in Example 6, using 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-methylpyridin-4-yl) benzoyl] piperazine as a raw material, The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.58 (3H, s), 3.13 (4H, br), 3.65 (2H, br),
3.84 (2H, br), 7.34 (lH, doublet of doublets, J = 6.8, 2.4 Hz), 7.41 (2H, d, J = 8.3 Hz),
7.45 (lH, d, J = 2.4 Hz), 7.56-7.62 (3H, m), 7.76 (lH, dd, J = 8.8, 2.0 Hz),
7.91-7.96 (3H, m), 8.28-8.32 (2H, m).
MS (FAB) m / z: 522 [(M + H) ⁺ , Cl ³⁵ ), 524 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: As C ₂₇ H ₂₄ ClN ₃ O ₄ SH ₂ O 0.05 CH ₂ Cl ₂
Calc .: C, 59.69; H, 4.83; Cl, 7.16; N, 7.72; S, 5.89.
Anal: C, 59.47; H, 4.87; Cl, 6.98; N, 7.48; S, 6.10.
Example 128 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[2- (morpholin-4-yl) ethylaminoIcarbonyl] pipe Lazine-l-yl] carbonyl] phenyl] pyridine N-oxide
In the same manner as in Example 4, 4- [4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N The title compound was obtained using -oxide and 4- (2-aminoethyl) morpholine as starting materials.
¹ H-NMR (CDCl ₃ ) δ: 2.22 (4H, s), 2.35-2.80 (6H, br), 3.20-3.90 (3H, br),
3.74 (4H, s), 4.20-4.60 (lH, br), 5.25-5.50 (lH, br), 6.80-7.20 (lH, br),
7.45-7.70 (7H, m), 7.76 (lH, d, J = 8.5 Hz), 7.85-7.95 (3H, m),
8.26 (2H, doublet, J = 6.9 Hz), 8.32 (1H, s).
MS (FAB) m / z: 664 [(M + H) ⁺ , C 1 ³⁵ ], 666 [(M + H) ⁺ , Cl ³⁷ ]
Example 129 4- [4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[2- (dimethylamino) ethylamino] carbonyl] piperazin-l- Il] carbonyl] phenyl] pyridine N-oxide
In the same manner as in Example 4, 4- [4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N The title compound was obtained using -oxide and 2- (dimethylamino) ethylamine as starting materials.
¹ H-NMR (CDCl ₃ ) δ: 2.29 (6H, s), 2.35-2.75 (6H, br), 3.35-3.90 (3H, br),
4.40-4.60 (1H, br), 5.25-5.50 (lH, br), 7.00-7.20 (lH, br),
7.45-7.65 (7H, m), 7.77 (lH, dd, J = 8.8, 1.4 Hz), 7.85-7.95 (3H, m),
8.26 (2H, doublet, J = 7.3 Hz), 8.34 (1H, s).
MS (FAB) rr, / z: 622 [(M + H) ⁺ , C 1 ³⁵ ], 624 [(M + H) ⁺ , Cl ³⁷ ]
A _{C 3l H 32 N 5 O 5} S · 0.05CH 2 Cl 2 · 2H 2 O: Elemental Analysis
Calc .: C, 56.30; H, 5.49; N, 10.57; Cl, 5.89; S, 4.84.
Anal: C, 56.27; H, 5. 37; N, 10.39; Cl, 6.01; S, 4.91.
Example 130 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-l- [4- (pyridin-2-yl) benzoyl] piperazine
The reaction was carried out in the same manner as in Reference Example 116, using 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine and 4- (2-pyridyl) benzoic acid hydrochloride as raw materials. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-4.50 (11H, m), 5.06 (lH, br s),
7.30-7.50 (3H, m), 7.72 (lH, dd, J = 8.8, 2.0 Hz), 7.80-7.85 (lH, m),
7.85-7.95 (lH, m), 7.98 (lH, d, J = 7.8 Hz), 8.10 (2H, d, J = 8.3 Hz),
8.18 (1H, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.51 (1H, s), 8.65-8.70 (1H, m).
MS (FAB) m / 7: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , C 1 ³⁷ ]
Elemental Analysis: C ₂₉ H ₂₆ ClN ₃ O ₅ S · l.lH ₂ O
Calc .: C, 59.66; H, 4.87; N, 7.20; Cl, 6.07; S, 5.49.
Anal: C, 59.53; H, 4.61; N, 7.05; Cl, 6.33; S, 5.70.
Example 131 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-carboxymethyl-1-[4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
In the same manner as in Reference Example 3, 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-l- [4- (pyridin-2-yl) benzoyl] piperazine Using as the raw material, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30-4.50 (8H, m), 5.05 (1H, br s),
7.35-7.40 (lH, m), 7.43 (2H, d, J = 8.8 Hz), 7.72 (1H, d, J = 8.3 Hz),
7.81 (lH, d, J = 8.8 Hz), 7.85-7.90 (1H, m), 7.97 (lH, d, J = 7.8 Hz),
8.08 (2H, d, J = 8.8 Hz), 8.17 (lH, d, J = 8.8 Hz), 8.25-8.30 (2H, m),
8.49 (1 H, s), 8.63-8.70 (1 H, m).
MS (FAB) m / z: 550 [(M + H) ⁺ , Cl ³⁵ ], 552 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₈ H ₂₄ ClN ₃ O ₅ S.0.4HC1.0.9H ₂ O
Calc .: C, 57.90; H, 4.55; N, 7.23; Cl, 8.55; S, 5.52.
Anal: C, 57.76; H, 4. 26; N, 7.02; C1, 8.44; S, 5.27.
Example 132 2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride
Reaction was carried out in the same manner as in Reference Example 35, and 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-carboxymethyl-l- [4- (pyridin-2-yl) benzoyl] piperazine was used as a raw material. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.20-4.50 (8H, m), 5.10 (lH, br s),
6.96 (2H, broad s), 7.45-7.55 (3H, m), 7.70-7.85 (3H, m), 8.05-8.35 (6H, m),
8.50 (lH, s), 8.81 (lH, d, J = 4.9 Hz).
MS (FAB) m / z: 549 [(M + H) ⁺ , Cl ³⁵ ], 551 [(M + H) ⁺ , Cl ³⁷ ]
Elemental Analysis: C ₂₈ H ₂₅ ClN ₄ O ₄ S.lHC3.1.5H ₂ O
Calc .: C, 53.94; H, 4. 74; N, 8.99; Cl, 13.08; S, 5.14.
Anal: C, 53.85; H, 4.87; N, 8.80; Cl, 13.19; S, 5.27.
Example 133 1-[(Z) -4-chloro-β- (2-hydroxyethan-1-yl) -β-styrylsulfonyl] -4- [4- (pyridin-2-yl) benzoyl Piperazine Hydrochloride
Under ice-cooling, 4-tert-butoxycarbonyl-l-[(Z) -4-chloro-β- [2- (methoxymethyloxy) ethyl] -β-styrylsulfonyl] piperazine (355 mg) was added. It dissolved in ethanol (3 ml), saturated ethanol hydrochloride (6 ml) was added, and it stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was reacted in the same manner as in Example 4 to obtain the title compound (285 mg, 65%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.58 (2H, t, J = 6.6 Hz), 3.06 (4H, br s),
3.15-3.60 (4H, br), 3.68 (2H, t, J = 6.6 Hz), 7.24 (lH, s),
7.38 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.47-7.57 (3H, m),
8.02-8.10 (2H, m), 8.14 (2H, d, J = 8.3 Hz), 8.74 (lH, d, J = 4.4 Hz).
MS (FAB) m / z: 512 (M + H) ⁺ .
Example 134 1-[(E) -4-chloro-β- (2-hydroxyethan-1-yl) -β-styrylsulfonyl] -4- [4- (pyridin-2-yl) benzoyl Piperazine Hydrochloride
In the same manner as in Example 133, 4-tert-butoxycarbonyl-l-[(E) -4-chloro-β- [2- (methoxymethoxy) ethyl) -β-styrylsulfonyl] pipe The title compound was obtained using raazine as a raw material.
¹ H-NMR (DMSO-d ₆ ) δ: 2.74 (2H, t, J = 7.3 Hz), 3.27 (4H, br s),
3.37-3.85 (6H, m), 7.45 (lH, s), 7.50-7.60 (5H, m),
7.68 (2H, d, J = 8.3 Hz), 8.06-8.17 (4H, m), 8.75 (1H, d, J = 4.9 Hz).
MS (FAB) m / z: 512 (M + H) ⁺ .
Elemental Analysis: As C ₂₆ H ₂₆ ClN ₃ O ₄ S · lHC1 · 0.8H ₂ O
Calc .: C, 55.12; H, 5.11; N, 7. 42; Cl, 13.14; S, 5.66.
Anal: C, 55.22; H, 5. 21; N, 7.20; Cl, 12.97; S, 5.66.
Test Example 1 Measurement of Ki Value for FXa
5 µl of sample solution, 5 µl of purified water, 100 mM Tris 200 mM sodium chloride, 0.2% BSA (pH 7.4) buffer 40 µl in 96-well microplate, dissolved in 0.05 U / ml human FXa (Enzyme Research, measurement buffer) Dilution) 10 microliters were aliquoted, 40 microliters S2222 (Chromogenix, final concentration: 75, 150, 300, 600 microM) was added, and the increase of absorbance at 405 nm was measured for 15 minutes at room temperature. Four first-order regression equations (Y = aX + b) were obtained from the reciprocal of the reaction rate and the inhibitor concentration (Dixon Plot), and the median of six values obtained by solving the simultaneous equation was Ki.
The Ki values for the compounds of Example 91 and Example 93, FXa, were 6.6 nM and 10.9 nM, respectively.
Test Example 2 Measurement of Ki Value for Thrombin
5 µl of sample solution, 5 µl of purified water, 100 mM Tris 200 mM sodium chloride, 0.2% BSA (pH 7.4) buffer 40 µl in 96-well microplate, dissolved in 5 U / ml human thrombin (Sigma Chemical, measurement buffer) Dilution) 10 microliters were dispensed, 40 microliters S2266 (Chromogenix, final concentration: 50, 100, 200, 400 microM) was added, and the increase in absorbance at 405 nm was measured for 15 minutes at room temperature. Four first-order regression equations (Y = aX + b) were obtained at the inverse of the reaction rate and inhibitor concentration (Dixon Plot), and the median of six values obtained by solving the simultaneous equation was Ki.
The Ki values for the compounds of Examples 91 and 93, thrombin, were 0.4 μM and 3.3 μM, respectively.
Test Example 3 Measurement of FXa Inhibitory Action (IC ₅₀ Value)
1) Reaction rate method
Dissolve in 96-well microplates with 10 μl of sample solution, 100 mM Tris. Dilution) 10 microliters were dispensed, and 40 microliters of S2222 (Chromogenix) was added, and the increase in absorbance (mOD / min) was measured at 405 nm at room temperature. The percent inhibition of each sample was calculated by the following equation, and the final concentration of the sample was plotted on the horizontal axis of the logarithmic probability plot and the percent inhibition was plotted on the vertical axis to obtain 50% inhibition concentration (IC ₅₀ ).
% Inhibition = (1-sample OD ÷ control OD) × 100
The compound of Example 92 showed a FXa 50% inhibition concentration, 7.8 nM.
2) end point method
100 μl of sample solution, 280 μl of 100 mM Tris · 200 mM sodium chloride (pH 7.4) buffer and 100 μl of 1 mM S2222 (Chromogenix) solution were mixed and warmed at 37 ° C. to 0.625 U / ml of human FXa 20 µl of HFXa-1011, dissolved and diluted with a measuring buffer) was added thereto, warmed at 37 ° C for 15 minutes, and then 100 µl of 1M citric acid was added, and the absorbance was measured at 405 nm. Instead of the sample, only the diluting solvent of the sample was added as a blank, and 1M citric acid was added before FXa as a control. The sample concentration when 50% of FXa activity was decreased (IC ₅₀ value) was used as an index of FXa inhibitory activity.
The compounds of Example 6 and Example 19 exhibited FXa 50% inhibitory concentration, 125 nM and 72 nM, respectively.
Test Example 4 Measurement of Thrombin Inhibitory Action (IC ₅₀ Value)
1) Reaction rate method
10 μl of sample solution in 96-well microplate, 40 μl of 100 mM Tris · 200 mM sodium chloride · 0.2% BSA (pH 7.4) buffer, 10 μl of 4 U / ml human thrombin (Sigma Chemical, dissolved and diluted with measurement buffer) Was injected, and 40 µl of 500 µM S2266 (Chromogenix) was added, and the increase in absorbance (mOD / min) at 405 nm was measured at room temperature. Obtain the% inhibition for each sample by the following equation, to a plot of% inhibition agent to a final concentration of the sample, and the vertical axis on the horizontal axis on page log probability was determined the 50% inhibitory concentration (IC _50).
% Inhibition = (OD of 1-sample OD ÷ control) × 100
The thrombin 50% inhibitory concentration of the compound of Example 19 was 1.9 μM.
2) Endpoint method
1 U / ml of human thrombin (Sigma Chemical Co., Ltd.) Dissolved and diluted with a buffer for measurement) 20 μl was added and warmed at 37 ° C. for 10 minutes, and then 100 μl of 1M citric acid was added to measure absorbance at 405 nm. Instead of the specimen, only the diluting solvent of the sample was added to the blank, and 1M citric acid was added before thrombin as a control. The concentration of the sample at 50% inhibition of thrombin activity was determined (IC ₅₀ ) and used as an index of thrombin inhibition.
The thrombin 50% inhibitory concentration of the compound of Example 92 was 200 μM or more.
Test Example 5 Measurement of Prolongation of Coagulation Time (Measurement of Prothrombin Time)
20 μl of plasma and 20 μl of sample solution are mixed, and 40 ml of synprastin (Organon Teknika) is added to measure the coagulation time. The concentration of the sample (CT2), which doubled the plasma coagulation time, was obtained as an index of anticoagulant action.
The compound of Example 92 showed 0.35 μM CT2.
Test Example 6 Oral Administration Test
1) method
The sample was dissolved or suspended in 0.5% (w / v) methyl cellulose solution, and orally administered (10 ml / kg) to 8-11 week old rats (Wistar male rats (Japan SL Inc.)) fasted overnight. After the administration of the sample, under anhalose anesthesia, blood containing 1/10 of 3.13% (w / v) sodium citrate was collected from the jugular vein, and rats were awakened at the time of blood collection. In addition, after 6 hours the blood was fed again. Plasma was centrifuged in each blood sample and blood antiFXa activity and prothrombin time extension were measured.
2) How to measure
2-1) Determination of anti-FXa activity in plasma
Dispense 5 μl of plasma into a 96 well plate, and place in 100 mM Tris.200 mM sodium chloride.0.2% BSA pH 7.4 buffer, water, and 0.1 U / ml human factor Xa solution (dissolved and diluted with measurement buffer). 55 μl of the mixture of 1: 2 and 40 μl of 750 μM S-2222 were added. After stirring for 10 seconds with a plate mixer, the increase in absorbance (mOD / min) at 405 nm was measured at room temperature. The inhibition rate was calculated as follows.
% Inhibition =
(Average of OD of control corresponding to OD ÷ sample bodily blood time of 1-sample) * 100
2-2) Measurement of Prolongation of Coagulation Time in Oral Administration
40 μl of cinplastin (Organon Teknika, USA) was added to 20 μl of plasma, and the coagulation time was measured. The ratio of the prothrombin time after sample administration to the prothrombin time before sample administration was used as an index of the coagulation time extension action.
3) results
The compound of Example 110 showed 70% of anti-FXa activity in plasma 1 hour after 30 mg / kg oral administration of the sample, and prothrombin time was extended by 1.18 times.
Test Example 7 Antithrombogenic Effect Test in TIC Tromboplastin-Induced Rat DIC Model
Rats were anesthetized with halosene, and blood was collected (platelet count, anti-FXa activity, TAT measurement) using 3.13% (w / v) sodium citrate for 1/10 in the jugular vein, and then the samples were orally administered. Intraperitoneal anesthesia (1 ml / kg) with nembutal (50 mg / ml sodium pentobarbital, Abbott Laboratories,) at a suitable time after sample administration and 0.2 U / ml of tissue thromboplastin (Thromboplastin C plus, Dade). Diagnostics of PR Inc.) was injected intravenously in the femoral vein for 1 minute at 2.5 to 3.0 ml / kg / min, and blood was collected from the jugular vein 10 minutes later (for platelet count and anti-FXa activity measurement), and 20 minutes later. (For TAT measurement). Platelet count, plasma anti-FXa activity and TAT concentration of each blood sample were measured. Platelet counts were measured with an automatic hemocytometer and measurement of anti-FXa activity in plasma was the same as that in Test Example 7.
In addition, the measurement of TAT (Thrombin-anti Thrombin = complex) was performed using the EnzygnostR TAT micro kit (made by the Beringberg company).
By orally administering 30 mg / kg of the compound of Example 95, clear anti-FXa action in plasma was recognized, and the decrease of platelet count and the increase of TAT concentration were suppressed (Tissue thromboplastin administration was 1 hour after sample administration).
The sulfonyl derivatives of the present invention exhibit anticoagulant action by good FXa inhibition. Therefore, the sulfonyl derivatives of the present invention do not act on any platelet, and various diseases caused by blood clots and embolisms, for example, cerebral infarction, cerebral embolism, electrocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis and the like. It is possible to treat or prevent vocal vascular coagulation syndrome, thrombus formation after replacement of artificial stool, reclosure after blood circulation reconstruction, thrombus formation during extracorporeal circulation, and blood coagulation during blood collection.

权利要求:
Claims (19)
[1" claim-type="Currently amended] Formula (I)

[Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbon A carbonyloxy group or group A ¹ -B ^1- (wherein A ¹ is an amino group which may have one or two substituents, a saturated or unsaturated 5-6 membered cyclic hydrocarbon group or substituent which may have a substituent) It means a saturated or unsaturated 5- to 6-membered heterocyclic group which may have, B ¹ means a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group, or an alkylenecarbonyloxy group.) Means.
R ² and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group. Moreover, R <^2> or R <^3> may become one with R <^1>, and may form a C1-C3 alkylene group or alkenylene group.
R ⁴ and R ⁵ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (except when R ⁴ and R ⁵ are hydrogen atoms at the same time).
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent, or a saturated or unsaturated 2 group which may have a substituent It means a cyclic or tricyclic condensed cyclic group.
Q ² is a single bond, an oxygen atom, a sulfur atom, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched carbon atom 2 to An alkynylene group of 6, group-N (R ⁶ ) -CO- (wherein R ⁶ means a hydrogen atom or an alkyl group), group-N (R ⁷ )-(CH ₂ ) m- (wherein R ⁷ means a hydrogen atom or an alkyl group, m means an integer of 0 to 6), or
group

(This group is a divalent saturated or unsaturated 5 to 6 membered cyclic hydrocarbon group which may have a substituent, a divalent saturated or unsaturated 5 to 6 membered heterocyclic group which may have a substituent, or a divalent that may have a substituent. Saturated or unsaturated bicyclic condensed cyclic group means ← C means that the carbon atom of this group is bonded with Q <^1> .
Q ³ means any one of the following groups.

(In these groups, when the carbon atom to which R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ is not adjacent to the nitrogen atom, each independently,
Hydrogen atom,
Hydroxy,
Alkyl group,
Alkoxy Group,
Alkoxyalkyl group,
Alkoxyalkyloxy group,
Hydroxyalkyl group,
Hydroxyalkyloxy group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylsulfonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonylalkyl group,
Carboxyl group,
Carboxyalkyl group,
Carboxyalkyloxy Group
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkyloxy group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An amino group which may have l or 2 substituents,
An aminoalkyl group which may have one or two substituents in the amino group portion,
An aminoalkyloxy group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
Aminoalkylcarbonyloxy groups which may have one or two substituents in the amino group moiety,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyloxy group which may have one or two substituents in the amino group moiety, or
A ² -B ^2- (In the group, A ² means a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent. B ² means a single bond, a carbonyl group or an alkylene group.
When the carbon atoms to which R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are bonded are adjacent to the nitrogen atom, they are each independently,
Hydrogen atom,
Alkyl group,
Hydroxyalkyl group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylsulfonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonylalkyl group,
Carboxyl group,
Carboxyalkyl group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxyalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An aminoalkyl group which may have one or two substituents in the amino group portion,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group moiety, or
A ³ -B ^3- (In the group, A ³ means a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-6 membered heterocyclic group which may have a substituent. B ³ means a single bond, a carbonyl group or an alkylene group.
In addition, R ⁸ and R ⁹ , R ¹⁰ and R ¹¹ , R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ are saturated or unsaturated 5 to 7 members which may be substituted together with the carbon atoms constituting the ring. Or a saturated or unsaturated 5 to 7 membered heterocyclic group which may have a cyclic hydrocarbon group or a substituent of
R ¹⁴ and R ¹⁷ are each independently,
Hydrogen atom,
Alkyl group,
Hydroxyalkyl group,
Hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl group,
Alkoxy Group,
Alkoxyalkyl group,
Alkoxyalkylcarbonyl group,
Alkoxyalkylsulfonyl group,
Formyl,
Formylalkyl groups,
Formylalkylcarbonyl group,
Formylalkylsulfonyl group,
Alkylcarbonyl group,
Alkylcarbonylalkyl group,
Alkylsulfonyl group,
Alkylsulfonylalkyl group,
Carboxyalkyl group,
Carboxyalkylcarbonyl group,
Carboxyalkylsulfonyl group,
Carboxyalkylcarbonylalkyl group,
Carboxyalkylsulfonylalkyl group,
Alkoxycarbonyl group,
Alkoxycarbonylalkyl group,
Alkoxycarbonylalkylcarbonyl group,
Alkoxycarbonylalkylsulfonyl group,
An amino group which may have l or 2 substituents,
An aminoalkyl group which may have one or two substituents in the amino group portion,
Aminoalkyloxy groups which may have one or two substituents in the amino group moiety,
Aminoalkylcarbonyl groups which may have one or two substituents in the amino group moiety,
An aminoalkyloxycarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonyl group which may have one or two substituents in the amino group portion,
An aminocarbonylalkyl group which may have one or two substituents in the amino group moiety, or
It means the aminocarbonyloxyalkyl group which may have one or two substituents in an amino-group part.
In addition, R ¹⁴ may be a saturated or unsaturated 5- to 7-membered heterocyclic group which may be substituted with a carbon atom constituting a ring and R ¹⁴ bonded to R ¹² or R ¹³ to form a ring. good.
In addition, R ¹⁷ means a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent together with the carbon atom constituting the ring and R ¹⁷ bonded to R ¹⁵ or R ¹⁶ . You may also
a, b, d, e and g each independently represent an integer of 0 or 1. c means an integer from 0 to 3. f, h and i each independently represent an integer of 1 to 3. Provided that the sum of a, b and c means an integer of 2 or 3, the sum of d and e means an integer of 0 or l, and the sum of f, g and h means an integer of 3 to 5 .)
T ¹ is a carbonyl group,
-CH (R ¹⁸ )-
(R ¹⁸ means a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have a substituent on an amino group portion) Or
-C (= NOR ¹⁹ )-
(R ¹⁹ means a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group which may have a substituent on the amino group portion.).
X ¹ and X ² each independently represent a methine group or a nitrogen atom.] A sulfonyl derivative, a salt thereof, or a solvate thereof.
[2" claim-type="Currently amended] The group of formula (I) according to claim 1

end

or

[Wherein R ² , R ⁴ , R ⁵ , X ¹ and X ² are as described above.] A sulfonyl derivative, salt thereof or solvate thereof.
[3" claim-type="Currently amended] The sulfonyl derivative, salt thereof or solvate thereof according to claim 1 or 2, wherein R ⁴ represents a halogen atom.
[4" claim-type="Currently amended] The method of claim 1 to claim any one of the preceding claims 3 above, which may have a Q ¹ substituent, a phenyl group, a substituent is also good imidazolyl group, which may have a substituent, a pyridyl group, which may have a substituent, a pyrimidinyl group, a substituent A sulfonyl derivative, a salt thereof, or a solvate thereof, which means a pyrrolidinyl group which may have, a tetrahydrothienopyridyl which may have a substituent, or a tetrahydrothiazolopyridyl group which may have a substituent.
[5" claim-type="Currently amended] The sulfonyl derivative according to any one of claims 1 to 4, a salt thereof, or a solvate thereof, wherein Q ^{2 means} a single bond, a phenylene group, a cyclohexylene group, or a cyclohexenylene group.
[6" claim-type="Currently amended] The compound of any one of claims 1 to 5, wherein Q ³ is

[Wherein R ⁸ , R ⁹ , a, b and c are as described above] Sulfonyl derivatives, salts thereof or solvates thereof.
[7" claim-type="Currently amended] The sulfonyl derivative, salt thereof or solvate thereof according to any one of claims 1 to 6, wherein T ¹ represents a carbonyl group.
[8" claim-type="Currently amended] A pharmaceutical comprising the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof, or a solvate thereof as an active ingredient.
[9" claim-type="Currently amended] An activated blood coagulation factor X inhibitor according to any one of claims 1 to 7, wherein the sulfonyl derivative, its salt, or solvate thereof is an active ingredient.
[10" claim-type="Currently amended] A blood coagulation inhibitor comprising the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof, or a solvate thereof as an active ingredient.
[11" claim-type="Currently amended] A prophylactic and / or therapeutic agent for thrombus or embolism, comprising the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof, or a solvate thereof as an active ingredient.
[12" claim-type="Currently amended] A cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, or pancreatic blood vessels using the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof, or a solvate thereof as an active ingredient. Anticoagulant syndrome, thrombus formation after artificial stool replacement, reclosure after blood circulation reconstruction, thrombus formation during extracorporeal circulation or blood clotting during blood collection.
[13" claim-type="Currently amended] A pharmaceutical composition comprising the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier.
[14" claim-type="Currently amended] Use of the sulfonyl derivative according to any one of claims 1 to 7, a salt thereof, or a solvate thereof as a medicament.
[15" claim-type="Currently amended] Use of a sulfonyl derivative, a salt thereof, or a solvate thereof according to any one of claims 1 to 7 as an activated blood coagulation factor inhibitor.
[16" claim-type="Currently amended] Use of the sulfonyl derivative according to any one of claims 1 to 7, its salts, or solvates thereof as an anticoagulant.
[17" claim-type="Currently amended] Use of the sulfonyl derivative according to any one of claims 1 to 7, its salt, or solvate thereof as a prophylactic and / or therapeutic agent for thrombus or embolism.
[18" claim-type="Currently amended] A method for treating a disease caused by a thrombus or embolism, comprising administering a sulfonyl derivative, a salt thereof, or a solvate thereof according to any one of claims 1 to 7 to a patient.
[19" claim-type="Currently amended] A cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, characterized by administering a sulfonyl derivative, a salt thereof, or a solvate thereof according to any one of claims 1 to 7 to a patient. , Disruptive vascular coagulation syndrome, Thrombus formation after artificial fecal replacement, Reclosure after blood circulation reconstruction, Thrombus formation during circulating in vitro or blood clotting at blood collection.

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JP4256065B2|2009-04-22|

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NO20001636D0|2000-03-29|

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WO1999016747A1|1999-04-08|

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US6525042B1|2003-02-25|

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CA2304285A1|1999-04-08|

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AT314347T|2006-01-15|

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IL135180D0|2001-05-20|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-09-30|Priority to JP9-267117

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1997-09-30|Priority to JP26711797

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1998-09-30|Application filed by 스즈키 다다시, 다이이찌 세이야꾸 가부시기가이샤

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1998-09-30|Priority to PCT/JP1998/004411

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2001-02-26|Publication of KR20010015639A

优先权:

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申请号 | 申请日 | 专利标题

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JP9-267117|1997-09-30|

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JP26711797|1997-09-30|

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PCT/JP1998/004411|WO1999016747A1|1997-09-30|1998-09-30|Sulfonyl derivatives|