Composition containing diarylalkane derivative as the active ingredient for treating or preventing p

专利摘要:
PURPOSE: Provided is a composition for the treatment or prevention of pancreatitis which comprises a diarylalkane derivative or a pharmacologically acceptable salt thereof as an active ingredient; to usage of a diarylalkane derivative or a pharmacologically acceptable salt thereof to prepare an agent for the treatment or prevention of pancreatitis; or to a method for the treatment or prevention of pancreatitis which comprises administering to warm-blooded animals in need of such treatment or prevention an effective amount of a diarylalkane derivative or a pharmacologically acceptable salt thereof. CONSTITUTION: A diarylalkane derivative represented by the following formula: A wherein, R¬1: a hydrogen atom, a halogen atom; R¬2, R¬3: a hydrogen atom, a halogen atom, a C1-C4 alkoxy group; R¬4: a substituted or unsubstituted 5- or 6-membered cyclic amino group which may further contain an oxygen or sulfur atom; A: a C1-C4 alkylene group U, or a pharmacologically acceptable salt thereof has excellent pancreatitis inhibitory activity and is therefore useful as a composition for the treatment or prevention of pancreatitis.
公开号:KR20000057309A
申请号:KR1019990704745
申请日:1997-11-27
公开日:2000-09-15
发明作者:아사이후미또시；후지모또고이찌
申请人:가와무라 요시부미；상꾜 가부시키가이샤；
IPC主号:

专利说明:

COMPOSITION CONTAINING DIARYLALKANE DERIVATIVE AS THE ACTIVE INGREDIENT FOR TREATING OR PREVENTING PANCREATITIS}
Conventionally, diaryl alkane derivatives are known to have cellotonin 2 receptor antagonism, inhibit platelet aggregation, and be useful as agents for the treatment or prevention of circulatory diseases, for example, J. Med. Chem., 35, 189 (1992), ibid., 33, 1818 (1990), Japanese Unexamined Patent Publication No. 6-234736, Japanese Unexamined Patent Publication No. 6-306025, and the like. Not.
The present invention is a composition for treating or preventing pancreatitis containing a diarylalkane derivative or a pharmacologically acceptable salt thereof as an active ingredient, a diarylalkane derivative or a pharmacologically acceptable for preparing a preparation for the treatment or prevention of pancreatitis. The present invention relates to a method of treating or preventing pancreatitis, wherein the use of a salt thereof, or an effective amount of a diarylakan derivative or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal.
The present inventors have long studied the pharmacological action of a series of diarylalkane derivatives. As a result, it was found that the diaryl alkane derivative has an excellent pancreatitis inhibitory effect and is useful as a pancreatitis treatment or prophylactic agent, and thus, the present invention has been completed.
The present invention is a composition for the treatment or prevention of pancreatitis containing a diaryl alkane derivative or a pharmacologically acceptable salt thereof as an active ingredient, a diaryl alkane derivative or a pharmacologically acceptable for preparing a preparation for the treatment or prevention of pancreatitis. The present invention provides a method for treating or preventing pancreatitis by using a salt thereof, or administering a diarylalkane derivative or an effective amount of a pharmacologically acceptable salt thereof to a warm-blooded animal.
The diaryl alkane derivative which is an active ingredient of the present invention, the general formula (I)
Has
In the above formula,
R ¹ represents a hydrogen atom or a halogen atom,
R ² and R ³ are the same or different and represent a hydrogen atom, a halogen atom or a C ₁ -C ₄ alkoxy group,
R ⁴ may be substituted, and may be a 5 to 6 membered cyclic amino group which may contain an oxygen or sulfur atom (the substituent is a C ₁ -C ₂₀ aliphatic acyl which may include a hydroxy group or a double bond as a substituent on a carbon atom) An oxy group, and a substituent on a nitrogen atom represents a C ₁ -C ₄ alkyl group.)
A represents a C ₁ -C ₄ alkylene group.
The halogen atoms of R ¹ , R ² and R ³ may be, for example, fluorine, chlorine, bromine or iodine atoms, preferably fluorine, chlorine or bromine atoms, and more preferably fluorine or chlorine atoms.
The C ₁ -C ₄ alkoxy group of R ² and R ³ may be, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy group, preferably Preferably it is a methoxy group or an ethoxy group, Especially preferably, it is a methoxy group.
The 5 to 6 membered cyclic amino group which may contain an oxygen or sulfur atom of R ⁴ may be a pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl group, preferably pyrrolidinyl, piperidinyl or It is a morpholinyl group, More preferably, it is a pyrrolidinyl or a piperidinyl group, Especially preferably, it is a pyrrolidinyl group. Also preferably, the cyclic amino group is bonded to A as its carbon atom.
C ₂₀ aliphatic acyloxy group, it may comprise a double bond, C ₁ that - an also contain a double bond substituents of the carbon atoms stab C ₁ in the R ⁴ C ₂₀ aliphatic acyl portion, for example, formyl, acetyl, Propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, myristoyl, palmitoyl, stearo It may be a 1, icosanoyl, acryloyl, metaacryloyl, crotonoyl, oleoyl, or linoleoyl group, preferably a C ₂ -C ₅ aliphatic acyl group, a C ₈ -C ₁₈ aliphatic acyl group , Acryloyl group, crotonoyl group, oleoyl group or linoleoyl group, more preferably C ₈ -C ₁₈ aliphatic acyl group, even more preferably octanoyl group, decanoyl group, lauroyl group, myristo Diary, palmitoyl group or stearoyl group, particularly preferably deca A journal or diary in Slough.
The C ₁ -C ₄ alkyl group which is a substituent on the nitrogen atom of R ⁴ may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl group, preferably methyl or ethyl group It is especially preferably a methyl group.
Furthermore, R ⁴ may be substituted. Specific examples of 5 to 6 membered cyclic amino groups which may contain oxygen or sulfur atoms include, for example, pyrrolidinyl, methylpyrrolidinyl, ethylpyrrolidinyl, propylpyrrolidinyl, isopropylpyrrolidinyl, butylpyrroli Diyl, hydroxypyrrolidinyl, formyloxypyrrolidinyl, acetoxypyrrolidinyl, propionyloxypyrrolidinyl, butyryloxypyrrolidinyl, valeryloxypyrrolidinyl, pivaloyloxypyrrolidinyl, hexa Noyloxypyrrolidinyl, heptanoyloxypyrrolidinyl, octanoyloxypyrrolidinyl, nonanoyloxypyrrolidinyl, decanoyloxypyrrolidinyl, undecanoyloxypyrrolidinyl, lauroyloxypyrrolidinyl, myristoyloxypi Lolidinyl, Palmitoyloxypyrrolidinyl, Stearoyloxypyrrolidinyl, Icosanoyloxypyrrolidinyl, Acryloyloxypyrrolidinyl, Methacryloyloxypyrrolidinyl, Crotonoyl jade Pyrrolidinyl, oleoyloxypyrrolidinyl, linoleoyloxypyrrolidinyl, 1-methyl-hydroxypyrrolidinyl, 1-methyl-formyloxypyrrolidinyl, 1-methyl-acetoxypyrrolidinyl, 1 -Methyl-propionyloxypyrrolidinyl, 1-methyl-butyryloxypyrrolidinyl, 1-methyl-valeryloxypyrrolidinyl, 1-methyl-pivaloyloxypyrrolidinyl, 1-methyl-hexanoyloxypy Lolidinyl, 1-methyl-3,3-dimethylbutyryloxypyrrolidinyl, 1-methyl-heptanoyloxypyrrolidinyl, 1-methyl-octanoyloxypyrrolidinyl, 1-methyl-nonanoyloxypyrrolidinyl , 1-methyl-decanoyloxypyrrolidinyl, 1-methyl-undecanoyloxypyrrolidinyl, 1-methyl-lauroyloxypyrrolidinyl, 1-methyl-myristoyloxypyrrolidinyl, 1-methyl-palmi Toyloxypyrrolidinyl, 1-methyl-stearoyloxypyrrolidinyl, 1-methyl-icosanoyloxypyrrolidinyl, 1-methyl-acryloyloxypyrrolidinyl, 1-methyl-methac Royloxypyrrolodinyl, 1-methyl-crotonoyloxypyrrolidinyl, 1-methyl-oleoyloxypyrrolidinyl, 1-methyl-linoleroyloxypyrrolidinyl, 1-ethyl-hydroxypyrrolidinyl, 1-ethyl-acetoxypyrrolidinyl, 1-ethyl-propionyloxypyrrolidinyl, 1-ethyl-butyryloxypyrrolidinyl, 1-ethyl-valeryloxypyrrolidinyl, 1-ethyl-pivalo Yloxypyrrolidinyl, 1-ethyl-octanoyloxypyrrolidinyl, 1-ethyl-nonanoyloxypyrrolidinyl, 1-ethyl-decanoyloxypyrrolidinyl, 1-ethyl-undecanoyloxypyrrolidinyl, 1- Ethyl-lauroyloxypyrrolidinyl, 1-ethyl-myristoyloxypyrrolidinyl, 1-ethyl-palmitoyloxypyrrolidinyl, 1-ethyl-stearoyloxypyrrolidinyl, 1-ethyl-acryloyloxypy Lolidinyl, 1-ethyl-crotonoyloxypyrrolidinyl, 1-ethyl-linoreoyloxypyrrolidinyl, piperidinyl, methylpiperidinyl, ethylpiperidinyl, propylpi Lidinyl, isopropylpiperidinyl, butylpiperidinyl, hydroxypiperidinyl, acetoxypiperidinyl, propionyloxypiperidinyl, butyryloxypiperidinyl, valeryloxypiperidinyl, pivaloyl Oxypiperidinyl, decanoyloxypiperidinyl, lauroyloxypiperidinyl, myristoyloxypiperidinyl, palmitoyloxypiperidinyl, stearoyloxypiperidinyl, acryloyloxypiperidinyl , Linoreoyloxypiperidinyl, 1-methyl-hydroxypiperidinyl, 1-methyl-acetoxypiperidinyl, 1-methyl-propionyloxypiperidinyl, 1-methyl-butyryloxypiperidinyl , 1-methyl-valeryloxypiperidinyl, 1-methyl-pivaloyloxypiperidinyl, 1-methyl-decanoyloxypiperidinyl, 1-methyl-lauroyloxypiperidinyl, 1-methyl Myristoyloxypiperidinyl, 1-methyl-palmitoyloxypiperidinyl, 1-methyl-stearoyloxypiperidinyl, 1-meth -Acryloyloxypiperidinyl, 1-methyl-linoleoyloxypiperidinyl, 1-ethyl-hydroxypiperidinyl, 1-ethyl-acetoxypiperidinyl, 1-ethyl-propionyloxypiperididi Neyl, 1-ethyl-butyryloxypiperidinyl, 1-ethyl-valeryloxypiperidinyl, 1-ethyl-pivaloyloxypiperidinyl, 1-ethyl-decanoyloxypiperidinyl, 1-ethyl Lauroyloxypiperidinyl, 1-ethyl-myristoyloxypiperidinyl, 1-ethyl-palmitoyloxypiperidinyl, 1-ethyl-stearoyloxypiperidinyl, 1-ethyl-acryloyl Oxypiperidinyl, 1-ethyl-linoreoyloxypiperidinyl, morpholinyl, 4-methylmorpholinyl, 4-ethylmorpholinyl, 4-propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl, thiomorpholinyl, 4-methylthiomorpholinyl, 4-ethylthiomorpholinyl, 4-propylthiomorpholinyl, 4-isopropylthiomorpholinyl, 4-butylthiomorph Polynyl One can,
Preferably, pyrrolidinyl, methylpyrrolidinyl, ethylpyrrolidinyl, hydroxypyrrolidinyl, acetoxypyrrolidinyl, propionyloxypyrrolidinyl, valeryloxypyrrolidinyl, pivaloyloxypyrrolidinyl , Octanoyloxypyrrolidinyl, decanoyloxypyrrolidinyl, undecanoyloxypyrrolidinyl, lauroyloxypyrrolidinyl, myristoyloxypyrrolidinyl, palmitoyloxypyrrolidinyl, stearoyloxypyrrolidinyl, acryl Royloxypyrrolidinyl, linoreoyloxypyrrolidinyl, 1-methyl-hydroxypyrrolidinyl, 1-methyl-acetoxypyrrolidinyl, 1-methyl-propionyloxypyrrolidinyl, 1-methyl-valeryl Oxypyrrolidinyl, 1-methyl-pivaloyloxypyrrolidinyl, 1-methyl-octanoyloxypyrrolidinyl, 1-methyl-decanoyloxypyrrolidinyl, 1-methyl-undecanoyloxypyrrolidinyl, 1- Methyl-lauroyloxypyrrolidinyl, 1-methyl-myristoyloxypyrrole Ridinyl, 1-methyl-palmitoyloxypyrrolidinyl, 1-methyl-stearoyloxypyrrolidinyl, 1-methyl-acryloyloxypyrrolidinyl, 1-methyl-linoreoyloxypyrrolidinyl, 1-ethyl Hydroxypyrrolidinyl, 1-ethyl-acetoxypyrrolidinyl, 1-ethyl-propionyloxypyrrolidinyl, 1-ethyl-valeryloxypyrrolidinyl, 1-ethyl-pyvaloyloxypyrrolidinyl, 1-ethyl-decanoyloxy-pyrrolidinyl, 1-ethyl-lauroyloxypyrrolidinyl, 1-ethyl-myristoyloxypyrrolidinyl, 1-ethyl-palmitoyloxypyrrolidinyl, 1-ethyl-stea Loyloxypyrrolidinyl, 1-ethyl-linoreoyloxypyrrolidinyl, piperidinyl, methylpiperidinyl, ethylpiperidinyl, hydroxypiperidinyl, acetoxypiperidinyl, propionyloxypiperidinyl, Valeryloxypiperidinyl, pivaloyloxypiperidinyl, decanoyloxypiperidinyl, lauroyloxypiperidinyl, myristoyloxypi Lidinyl, palmitoyloxypiperidinyl, stearoyloxypiperidinyl, acryloyloxypiperidinyl, linoreyloxypiperidinyl, 1-methyl-hydroxypiperidinyl, 1-methyl-acetoxy Piperidinyl, 1-methyl-propionyloxypiperidinyl, 1-methyl-valeryloxypiperidinyl, 1-methyl-pivaloyloxypiperidinyl, 1-methyl-decanoyloxypiperidinyl, 1 -Methyl-lauroyloxypiperidinyl, 1-methyl-myristoyloxypiperidinyl, 1-methyl-palmitoyloxypiperidinyl, 1-methyl-stearoyloxypiperidinyl, 1-methyl- Acryloyloxypiperidinyl, 1-methyl-linoleoyloxypiperidinyl, 1-ethyl-hydroxypiperidinyl, 1-ethyl-acetoxypiperidinyl, 1-ethyl-propionyloxypiperidinyl , 1-ethyl-valeryloxypiperidinyl, 1-ethyl-pivaloyloxypiperidinyl, 1-ethyl-decanoyloxypiperidinyl, 1-ethyl-lauroyloxypiperidinyl, 1-- Ethyl-me Stoyloxypiperidinyl, 1-ethyl-palmitoyloxypiperidinyl, 1-ethyl-stearoyloxypiperidinyl, 1-ethyl-linoleoyloxypiperidinyl, morpholinyl, 4-methylmor Polyyl, 4-ethylmorpholinyl, thiomorpholinyl, 4-methylthiomorpholinyl or 4-ethylthiomorpholinyl group,
More preferably, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-3-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4- Acetoxy-2-pyrrolidinyl, 4-propionyloxy-2-pyrrolidinyl, 4-valeryloxy-2-pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidinyl, 4-octanoyl Oxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyl Oxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-acetoxy-2-pyrrolidinyl , 1-methyl-4-propionyloxy-2-pyrrolidinyl, 1-methyl-4-valeryloxy-2-pyrrolidinyl, 1-methyl-4-pyvaloyloxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1 -Methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4- Mitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-acetoxy 2-pyrrolidinyl, 1-ethyl-4-decanoyloxy-2-pyrrolidinyl, 1-ethyl-4-lauroyloxy-2-pyrrolidinyl, 1-ethyl-4-myristoyloxy -2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-ethyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperididi Neyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 4-hydroxy-2-piperidinyl, 1 -Methyl-4-hydroxy-2-piperidinyl, 2-morpholinyl, 3-morpholinyl, 4-methyl-2-morpholinyl, 4-methyl-3-morpholinyl, 4-ethyl- 2-morpholinyl, 2-thiomorpholinyl or 4-methyl-2-thiomorpholinyl group,
Even more preferably, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-py Lolidinyl, 1-methyl-4-acetoxy-2-pyrrolidinyl, 1-methyl-4-pivaloyloxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl , 1-methyl-4-decanoyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl , 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperididi Neyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1 -Methyl-4-piperidinyl, 2-morpholinyl, 4-methyl-2-morpholinyl or 2-thiomorpholinyl group,
Even more preferably, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrrolidinyl , 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl , 4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl-4 -Decanoyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4 Palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl- 2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl group,
Especially preferably, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl or 1-methyl-4-lauroyloxy-2 -A pyrrolidinyl group.
The C ₁ -C ₄ alkylene group of A may be, for example, methylene, ethylene, propylene, trimethylene, tetramethylene group, preferably a C ₁ to C ₃ alkylene group, more preferably methylene or ethylene group And particularly preferably an ethylene group.
Compound (I), which is an active ingredient of the present invention, can be converted into a corresponding pharmacologically acceptable acid addition salt by treating with acid according to a conventional method. Examples of such acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, organic acids such as acetic acid, benzoic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid and citric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluene Although addition salt by sulfonic acids, such as sulfonic acid, is mentioned, Preferably it is a hydrochloride salt.
In addition, the compound (I) and the pharmacologically acceptable salts thereof are left in the air, whereby water may be absorbed and adsorbed water may adhere or become a hydrate. Such salts are also included as the active ingredient of the present invention.
In addition, when a subsidiary carbon exists in the molecule | numerator of compound (I), there exists an optically active substance and the mixture of arbitrary ratios, These were also included as an active ingredient of this invention.
In the compound having the formula (I), Preferably,
(1) a compound in which R ₁ is a hydrogen atom, a fluorine atom or a chlorine atom,
(2) a compound in which R ¹ is a hydrogen atom or a fluorine atom,
(3) a compound in which R ² and R ³ are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or an ethoxy group;
(4) a compound in which R ² is a hydrogen atom, a fluorine atom or a chlorine atom, and R ³ is a methoxy group;
(5) a compound in which R ² is a hydrogen atom or a fluorine atom, and R ³ is a methoxy group,
(6) Pyrrolidinyl group, piperidinyl group, morpholinyl group, or thiomorpholinyl group, in which R ⁴ may be substituted (the substituent is a hydroxy group, a C ₂ to C ₅ aliphatic acyl group as a substituent on a carbon atom) An oxy group, a C ₈ to C ₁₈ aliphatic acyloxy group, acryloyl group, crotonoyl group, oleoyl group or linoleoyl group, and a substituent on a nitrogen atom represents a methyl group or an ethyl group.
(7) R ⁴ is a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group which may be substituted (the substituent represents a hydroxy group or a C ₈ to C ₁₈ aliphatic acyloxy group as a substituent on a carbon atom, A compound having a magnetic group)
(8) R ⁴ is 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrroli Denyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrroli Dinyne, 4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl- 4-decanoyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl- 4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl A compound which is a 2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl group,
(9) R ⁴ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauro Yloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl or 1-methyl-4-lauroyloxy A compound which is a 2-pyrrolidinyl group,
(10) A compound wherein A is a C ₁ -C ₃ alkylene group,
(11) a compound in which A is a methylene group or an ethylene group, or
(12) A compound wherein A is an ethylene group
Can be mentioned.
It is also preferable to combine any one selected from the group consisting of (1)-(2), (3)-(5), (6)-(9) and (10)-(12), for example It can be mentioned.
(13) R ¹ is a hydrogen atom, a fluorine atom or a chlorine atom,
R ² and R ³ are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or an ethoxy group,
A pyrrolidinyl group, a piperidinyl group, a morpholinyl group or a thiomorpholinyl group in which R ⁴ may be substituted (the substituent may be a hydroxy group, a C ₂ -C ₅ aliphatic acyloxy group, a C _8- A C ₁₈ aliphatic acyloxy group, acryloyl group, crotonoyl group, oleoyl group or linoleoyl group, and a substituent on a nitrogen atom represents a methyl group or an ethyl group.),
A is a C ₁ -C ₃ alkylene group,
(14) R ¹ is a hydrogen atom or a fluorine atom,
R ² is hydrogen, fluorine or chlorine and R ³ is a methoxy group
A pyrrolidinyl group, a piperidinyl group, or a morpholinyl group in which R ⁴ may be substituted (the substituent represents a hydroxy group or a C ₈ -C ₁₈ aliphatic acyloxy group as a substituent on a carbon atom, and as a substituent on a nitrogen atom) Methyl group.),
A is a methylene group or an ethylene group,
(15) R ¹ is a hydrogen atom or a fluorine atom,
R ² is hydrogen, fluorine or chlorine and R ³ is a methoxy group,
R ⁴ is 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrrolidinyl, 4- Decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4- Stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl-4-decanoyl Oxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyl Oxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-pipe Ridinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl group,
A is an ethylene group,
(16) R ¹ is hydrogen or fluorine
R ² is hydrogen or fluorine and R ³ is a methoxy group
R ⁴ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2 -Pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl or 1-methyl-4-lauroyloxy-2-py It is a rolledinyl group,
A is an ethylene group.
As a preferable compound in general formula (I), the compound shown in following Table 1 and Table 2 can be illustrated concretely.

In the table, abbreviated symbols indicate the following groups.
Dec: Decano Diary
Et: ethyl group
Lau: Lauro Diary
Me: Methyl group
Mor: Morpholinyl group
Myr: Myristoyl
Oct: Octanoyl group
Pal: Palmitoyl group
Pdec: Pentadecanoyl Diary
Pip: piperidinyl group
Pyr: pyrrolidinyl group
Ste: Stearoyl group
Tdec: tridecanoyl diary
Tmor: thiomorpholinyl group
Udec: Undecanoo Diary
Among these compounds,
Preferred are compound numbers 1-5, 1-6, 1-7, 1-8, 1-13, 1-14, 1-16, 1-17, 1-26, 1-27, 1-28, 1-29, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-60, 1- 61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-88, 1-89, 1-90, 1-91, 1-92, 1-99, 1-100, 1-101, 1-114, 1-116, 1-132, 1-133, 1-134, 1-135 and 1-139;
More preferably, compound numbers 1-13, 1-14, 1-16, 1-17, 1-27, 1-28, 1-29, 1-33, 1-34, 1-35, 1-38 , 1-39, 1-40, 1-41, 1-60, 1-61, 1-62, 1-63, 1-88, 1-89, 1-90, 1-91, 1-92, 1 Compounds of -100, 1-101, 1-114 and 1-116,
Even more preferred are the compound numbers 1-13, 1-14, 1-16, 1-17, 1-33, 1-34, 1-35, 1-38, 1-39, 1-40, 1- 41, 1-60, 1-90, 1-91, 1-92, 1-100, 1-101 and 1-114;
Especially preferred is
Compound Number: 1-13
4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
Compound Number: 1-14
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
Compound Number: 1-16
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
Compound Number: 1-17
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
Compound Number: 1-33
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
Compound Number: 1-34
4-decanoyloxy-2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
Compound Number: 1-35
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
Compound Number: 1-38
4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
Compound Number: 1-39
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine,
Compound number: 1-40
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine
And
Compound number: 1-41
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine
The compound of the is mentioned.
Compounds having the formula (I) as an active ingredient of the present invention are prepared according to known methods (for example, JP-A-6-234736, JP-A-6-306025, etc.), or It was easily prepared according to the method.

In said formula, R <^1> , R <^2> , R <^3> , R <^4> and A have the same meaning as the said definition, R <^4a> may be substituted and may contain 5-6 membered cyclic amino group which may contain oxygen or a sulfur atom The substituent is a C ₁ -C ₂₀ aliphatic acyloxy group which may include a hydroxy group which may be protected as a substituent on a carbon atom or a double bond, and the nitrogen atom of the ring is protected.), Z is a hydroxy group, a halogen atom (preferably chlorine, bromine or iodine atom), C ₁ ~ C ₆ alkane sulfonyloxy group (C ₁ ~ C ₆ alkane may be, for example, methane, ethane, propane, butane, pentane, hexane, preferably it is methane or ethane), or C ₁ ~ C ₆ represents an alkyl, C ₁ ~ C ₆ alkoxy, or C ₆ ~ C ₁₀ aryl alcohol with a halogen may be substituted sulfonyl oxy.
The C ₁ to C ₆ alkyl group which is a substituent of the C ₆ to C ₁₀ arylsulfonyloxy group is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethyl Linear or branched chain alkyl groups having 1 to 6 carbon atoms such as butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and are preferred. Preferably it is a C1-C4 linear or branched alkyl group, Especially preferably, it is a methyl group.
The C ₁ -C ₆ alkoxy group, which is a substituent of the C ₆ -C ₁₀ arylsulfonyloxy group, refers to a group in which the "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isoprop Foxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy , 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3 C1-C6 linear or branched alkoxy groups, such as -dimethylbutoxy, are preferable, It is a C1-C4 linear or branched alkoxy group, Especially preferably, it is a methoxy group.
The C ₆ to C ₁₀ aryl group of the C ₆ to C ₁₀ arylsulfonyloxy group may be, for example, a phenyl or naphthyl group, and is preferably a phenyl group.
The protecting group of the hydroxyl group of R ^4a is, for example, a cyclic ether group such as tetrahydrofuranyl or tetrahydropyranyl group, methoxymethyl group, methoxyethoxymethyl group, C ₆ to C ₁₀ aryl-methyl group, C ₆ to C ₁₀ aryl-methyloxycarbonyl group, carbamoyl group, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-hexylcarbamoyl, N, N-dimethylcarbamoyl, N, Substituted with C ₁ to C ₆ alkyl such as N-diethylcarbamoyl, N, N-diisopropylcarbamoyl, N, N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl group Such as carbamoyl group, trimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl group C ₁ ~ C _6, and a substituent selected from the group consisting of alkyl and phenyl can silyl date having three wind Tetrahydropyranyl, methoxymethyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl, N, N-dimethylcarbamoyl or t-butyldimethylsilyl group.
The protecting group of the nitrogen atom of the cyclic amino group of R ^4a is, for example, a C ₁ to C ₁₀ alkoxy-carbonyl group, a C ₁ to C ₅ alkanoyl group, a C ₆ to C ₁₀ aryl-methyl group, a C ₆ to C ₁₀ aryl- Methyloxycarbonyl group, preferably t-butoxycarbonyl, acetyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bro Mobenzyloxycarbonyl group.
C ₆ ~ C ₁₀ aryl-methyl, and C ₆ ~ C ₁₀ aryl-oxy-methyl-C ₆ ~ C ₁₀ aryl group is a carbonyl group, and for example, the number of phenyl or naphthyl date example, preferably a phenyl group. Further, the C ₆ to C ₁₀ aryl group may have a substituent, these may be, for example, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen, preferably methyl, methoxy group or fluorine or chlorine It is an atom.
The C ₁ to C ₁₀ alkoxy-carbonyl group is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl 1 to 10 carbon atoms such as t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl group It may be a straight chain or branched chain alkoxy-carbonyl group, preferably a straight chain or branched chain alkoxy-carbonyl group having 1 to 8 carbon atoms, more preferably a straight chain or branched chain alkoxy-carbonyl group having 1 to 4 carbon atoms, particularly preferably Ethoxy-carbonyl or t-butoxy-carbonyl group.
The C ₁ to C ₅ alkanoyl group may be, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl group, preferably an acetyl group.
The first step A1 was prepared by reacting a compound having formula (II) with a compound having formula (III) as a step of preparing a compound having formula (IV).
When Z represents a halogen atom, a C ₁ to C ₆ alkanesulfonyloxy group or a C ₆ to C ₁₀ arylsulfonyloxy group, the reaction is carried out in the presence of a base in an inert solvent. Moreover, it is preferable that the hydroxyl group contained in raw material compound (III) is protected.
Bases used are preferably alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, alkali metal bicarbonates such as potassium bicarbonate, sodium fluoride, alkali metal fluorides such as potassium fluoride, sodium hydride, potassium hydride, lithium hydride Alkali metal hydrides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, alkali metal alkoxides such as lithium methoxide, pyridine, picoline, triethylamine, N-methylmorpholine, 4-dimethyl Organic amines such as aminopyridine, more preferably alkali metal carbonates, alkali metal fluoride salts, alkali metal hydrides or alkali metal alkoxides.
The inert solvent to be used is not particularly limited unless it is involved in the reaction, for example, hydrocarbons such as hexane, benzene, toluene, methylene chloride, chloroform, halogenated hydrocarbons such as 1,2-dichlorethane, ether, tetrahydro Ethers such as furan, dioxane, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, N, N-dimethylacetoamide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethyl Amides such as phosphoramide, sulfoxides such as dimethyl sulfoxide, or a mixed solvent thereof, and are preferably ethers, ketones, amides or sulfoxides.
The reaction temperature varies depending on the type of raw materials (II) and (III), solvents and bases, and is usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 80 ° C.), and the reaction time varies depending on the reaction temperature. Minutes to 48 hours (preferably 1 to 24 hours).
When Z represents a hydroxyl group, this reaction is carried out in the presence of azodicarboxylic acid C ₁ to C ₄ alkyl esters such as triphenylphosphine, methyl azodicarboxylic acid and ethyl azodicarboxylic acid in an inert solvent. Moreover, it is preferable that the hydroxyl group contained in raw material compound (III) is protected.
The inert solvent used may be the same as described above, but is preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers.
The reaction temperature varies depending on the type of raw material compounds (II) and (III), solvents and bases, but is usually -20 ° C to 100 ° C (preferably 10 ° C to 80 ° C), and the reaction time varies depending on the reaction temperature, etc. 30 minutes to 48 hours (preferably 1 to 24 hours).
After the completion of the reaction, the target compound (IV) of the reaction was collected from the reaction mixture according to a conventional method. For example, if an insoluble matter is present, it is filtered off properly and the solvent is evaporated under reduced pressure or the solvent is evaporated under reduced pressure, and then water is added to the residue, and the organic solvent is incompatible with water such as ethyl acetate. After extraction and drying with anhydrous magnesium sulfate or the like, the solvent can be obtained by evaporation, and if necessary, it can be further purified by conventional methods such as recrystallization, column chromatography and the like.
Step A2 is performed as desired.
Reaction (a): reaction for removing the protective group of a hydroxyl group contained in R ⁴ a,
Reaction (b): reaction which acylates the hydroxyl group etc. which were produced | generated by reaction (a),
Reaction (c): reaction for removing the protecting group of the nitrogen atom contained in R ⁴ a, and
Reaction (d): It includes the reaction which converts the alkoxycarbonyl group contained in R <^{4a> to} a methyl group, or the reaction which converts an alkanoyl group to an alkyl group, and changes order suitably.
Reaction (a):
The reaction for removing the protecting group of the hydroxy group contained in R ⁴ a in the reaction (a) depends on the type of protecting group and is performed by a method well known in organic synthetic chemistry.
When the protecting group of the hydroxy group is an arylmethyl group or an arylmethyloxycarbonyl group, an inert solvent (preferably alcohols such as methanol, ethanol, isopropanol, ethers such as ether, tetrahydrofuran, dioxane, toluene, benzene, xylene and Catalytic reduction catalyst (preferably palladium) in the same aromatic hydrocarbons, aliphatic hydrocarbons such as hexane, cyclohexane, esters such as ethyl acetate, butyl acetate, fatty acids such as acetic acid or a mixture of organic solvents and water thereof In the presence of carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-valium sulfate, etc., the corresponding compound (IV) is hydrogen (usually 1 to 10 atm, Preferably 1 to 3 atmospheres).
The reaction temperature is usually 0 ° C to 100 ° C (preferably 20 ° C to 80 ° C), and the reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 48 hours (preferably 1 to 24 hours).
When the protecting group of the hydroxy group is a methoxymethyl group, methoxyethoxymethyl group or cyclic ether group, for example, an inert solvent (hydrocarbons such as hexane, benzene, halogenated hydrocarbons such as methylene chloride, chloroform, esters such as ethyl acetate) , Ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane, or a mixed solvent of organic solvents and water thereof, preferably esters, ethers or Among the halogenated hydrocarbons), the corresponding compound (IV) can be converted into an acid (e.g., an organic acid such as hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, Lewis acids such as boron trifluoride, strongly acidic cation exchange resins such as Dow X 50W, and the like. It is inorganic or organic acid, more preferably hydrochloric acid, sulfuric acid or trifluoroacetic acid.) And is accomplished by reaction.
The reaction temperature is usually -10 deg. C to 100 deg. C (preferably -5 deg. C to 50 deg. C), and the reaction time varies depending on the reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
In addition, when treating compound (IV) with an acid like this reaction, the acid addition salt of compound (I) can also be obtained with removal of a protecting group.
After completion of the reaction, the target compound of the reaction was taken from the reaction mixture according to a conventional method. For example, it is obtained by neutralizing the reaction mixture as appropriate, and removing an insoluble matter by filtration, then adding an organic solvent that is not mixed with water such as ethyl acetate, and washing with water, followed by evaporation of the solvent. . If desired, the desired compound can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography.
In the case of the carbamoyl group in which the protecting group of the hydroxyl group may be substituted, it can be removed by reduction or hydrolysis.
When removing by reduction, for example, in an inert solvent (preferably ethers such as ether, tetrahydrofuran, dioxane), a reducing agent (preferably metal hydride reducing agent such as lithium aluminum hydride or lithium borohydride) ) Can be removed by reacting the compound (IV). The reaction temperature varies depending on the solvent and the like, and is usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 80 ° C.), and the reaction time depends on the reaction temperature, but usually 30 minutes to 24 hours (preferably 1 hour to 16 hours). ) to be. After completion of the reaction, the reaction product can be taken from the reaction mixture by a conventional method, for example, by the same operation as that of taking the compound of step A1 described above.
When removing by hydrolysis, it can hydrolyze with either an acid or an alkali. The solvent to be used is not limited as long as it does not inhibit the reaction. However, alcohols such as water, methanol and ethanol or ethers such as dioxane and tetrahydrofuran or a mixed solvent of the organic solvent and water (preferably water or alcohols) ) to be. The acid to be used is preferably a mineral acid such as hydrochloric acid or sulfuric acid, and the alkali to be used is preferably a hydroxide of an alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, and barium hydroxide. The reaction temperature varies depending on the reaction conditions, but is usually 0 ° C to 100 ° C (preferably 10 ° C to 80 ° C), and the reaction time varies depending on the reaction temperature, but usually 30 minutes to 48 hours (preferably 1 hour to 16 hours). Time). After completion of the reaction, the reaction product can be taken from the reaction mixture by a conventional method, for example, by the same operation as that of taking the compound of step A1 described above.
When the protecting group of the hydroxy group is a trisubstituted silyl group, it can be easily removed by treating in an inert solvent, for example, in the presence of an acid, an alkali or a fluoride.
In the case of removal by acid, for example, the acid used may be an organic acid such as acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, inorganic acids such as hydrochloric acid, hydrofluoric acid, sulfuric acid, boron trifluoride ether complex, and the like. Lewis acids (preferably hydrochloric acid), and the solvent used is, for example, tetrahydrofuran, ethers such as dioxane, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, chloroform, alcohols such as methanol and ethanol Hydrocarbons such as hexane, cyclohexane, or mixtures thereof, or a mixed solvent of organic solvents and water (preferably ethers, in particular dioxane). The reaction temperature varies depending on the reaction conditions, but is usually -50 ° C to 100 ° C (preferably -5 ° C to 80 ° C), and the reaction time varies depending on the reaction temperature, but usually 10 minutes to 48 hours (preferably 30 minutes to 16 hours). After completion of the reaction, the reaction product can be taken from the reaction mixture in a conventional manner, for example by the same operation as for collecting the compound of step A1 described above.
In the case of removing the silyl groups with alkali, the alkali used is for example alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or alkali metal carbonates (preferably alkali metal carbonates, in particular potassium carbonate) such as potassium carbonate, The inert solvent is preferably alcohols such as methanol or ethanol or alcohols containing water. The reaction temperature depends on the reaction conditions, but is usually 0 ℃ to 100 ℃ (preferably 5 ℃ to 80 ℃), the reaction time depends on the reaction temperature, but usually 10 minutes to 48 hours (preferably 30 minutes to 16 Time). After completion of the reaction, the reaction product can be taken from the reaction mixture in a conventional manner, for example by the same operation as for collecting the compound of step A1 described above.
When the silyl group is removed in the presence of fluoride, the reagents for generating fluorine ions used are, for example, tetrabutylammonium fluoride, HF pyridine complex, potassium fluoride (preferably tetrabutylammonium fluoride). ), The solvent is, for example, tetrahydrofuran, ethers such as dioxane, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, chloroform, alcohols such as methanol and ethanol, hydrocarbons such as hexane and cyclohexane Or a mixture of these or a mixed solvent of these and water (preferably ethers, in particular tetrahydrofuran). In addition, when a water-soluble salt such as potassium fluoride is used in a mixture of water and an insoluble solvent, for example, a mixed solvent of methylene chloride and water, the use of crown ethers such as 18-crown-6 can be used to accelerate the reaction progress. . The reaction temperature varies depending on the reaction conditions, but is usually -70 ° C. to 100 ° C. (preferably -20 ° C. to 50 ° C.), and the reaction time varies depending on the reaction temperature, but usually 10 minutes to 48 hours (preferably 30 minutes). To 16 hours). After completion of the reaction, the reaction product can be taken from the reaction mixture by conventional methods, for example by the same operation as that of taking the compound of step A1 described above.
Reaction (b):
The reaction which acylates the hydroxyl group in reaction (b) is performed by the method well known in organic synthetic chemistry. For example, inert solvents (preferably aromatic hydrocarbons such as benzene, toluene, halogenated hydrocarbons such as methylene chloride, chloroform, esters such as ethyl acetate, ethers such as tetrahydrofuran, dioxane, acetone, methylethyl Among ketones such as ketones, and amides such as N, N-dimethylacetoamide), base or nonexistent (bases are preferably triethylamine, pyridine, diethylisopropylamine, 4-dimethylaminopyridine, etc.). Organic tertiary amines).
Acylating agents used include acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide, isobutyryl chloride, valeryl chloride, pivaloyl chloride, hexanoyl chloride, 3,3-dimethylbutyryl chloride, heptanoyl Chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, isocanoyl chloride, acryloyl chloride, methacryloyl chloride, C ₂ -C ₂₀ aliphatic acyl halides, which may have double bonds such as crotonoyl chloride, linoleroyl chloride, mixed acid anhydrides of formic acid and acetic acid, acetic anhydride, propionic anhydride, butanoic anhydride, valeric anhydride, Pivalic anhydride, Hexanoic anhydride, Heptanoic anhydride, Octanoic anhydride Nonanoic anhydride, decanoic acid anhydride, lauric acid anhydride, myristic acid anhydride, palmitic anhydride, acrylic acid anhydride, methacrylic acid anhydride, crotonic acid, that may have a double bond, such as anhydrous linoleic acid C ₂ - C ₂₀ carboxylic acid Anhydrides are mentioned.
In addition, the reaction which acylates a hydroxy group includes a corresponding hydroxy compound and a carboxylic acid (for example, acetic acid, propionic acid, butanoic acid, valeric acid, hexanoic acid, 3,3-dimethylbutanoic acid, heptanoic acid, octanoic acid, C ₂ -C ₂₀ aliphatic carboxylic acids which may have double bonds such as nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosane acid, acrylic acid, methacrylic acid, crotonic acid, linolenic acid) Is reacted in the same manner as in the case where Z in the A1 step is a hydroxyl group.
The reaction temperature is usually -10 deg. C to 50 deg. C (preferably 0 deg. C to 30 deg. C), and the reaction time depends on the reaction temperature, but is usually 15 minutes to 20 hours (preferably 30 minutes to 10 hours).
After completion of the reaction, the reaction product can be taken from the reaction mixture by conventional methods, e.g., if insolubles are present, appropriately separated by filtration and, if the reaction solution is acidic or alkaline, neutralized appropriately. By the same operation as for extracting the compound of step A1.
Reaction (c):
The reaction for removing the protecting group of the nitrogen atom contained in R ⁴ a in the reaction (c) depends on the type of protecting group and is performed by a method well known in organic synthetic chemistry.
When the protecting group of the nitrogen atom is an arylmethyl group or an arylmethoxycarbonyl group, the reaction is carried out in the same manner as in the removal reaction when the hydroxy protecting group in the reaction (a) of step A2 is an arylmethyl group.
When the protecting group of the nitrogen atom is a t-butoxycarbonyl group, the same reaction as in the removal reaction in the case where the protecting group of hydroxy in the reaction (a) of the present step is a methoxymethyl group or the like is performed.
In addition, when the protecting group of the nitrogen atom is an alkoxycarbonyl moiety, an inert solvent (preferably alcohols such as methanol, ethanol, ethers such as terahydrofuran, dioxane, water or water and a mixed solvent of the organic solvent) ), Reacted with a base (preferably alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal carbonates such as sodium carbonate, potassium carbonate) and by hydrolysis, the corresponding protecting groups were removed.
The reaction temperature varies depending on the solvent and the like, and is usually 0 ° C. to 100 ° C. (preferably room temperature to 60 ° C.), and the reaction time depends on the reaction temperature and the like, but usually 30 minutes to 24 hours (preferably 1 hour to 16 hours). to be.
After completion of the reaction, the reaction product can be taken from the reaction mixture by a conventional method, for example, by the same operation as the method of collecting the compound of this step of the above-mentioned method A.
Reaction (d):
The reaction for converting the alkoxycarbonyl group contained in R ⁴ a in the reaction (d) into a methyl group or an alkanoyl group into an alkyl group is carried out in an inert solvent (preferably ether such as ether, tetrahydrofuran, dioxane), By reacting with a reducing agent (preferably an alkali metal aluminum hydride such as lithium aluminum hydride).
The reaction temperature varies depending on the solvent and the like, and is usually 0 ° C. to 100 ° C. (preferably room temperature to 80 ° C.), and the reaction time depends on the reaction temperature and the like, but usually 30 minutes to 24 hours (preferably 1 hour to 16 hours). to be.
After completion of the reaction, the reaction product can be taken from the reaction mixture by a conventional method, for example, by the same operation as that of collecting the compound of step A1 described above.
In addition, compound (I) can be converted into a pharmacologically acceptable salt by treating with an acid by a conventional method. For example, in an inert solvent (preferably ethers such as ethers, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, halogenated hydrocarbons such as methylene chloride, chloroform) and 5 minutes to 1 minute at room temperature. It can obtain by making time react and distilling a solvent off under reduced pressure. In addition, the hydrochloride of compound (I) can be obtained by adsorbing compound (I) or its acid addition salt to an acidic resin column (for example, CM- Sephadex C-25 (registered trademark), etc.) and eluting diluted hydrochloric acid. .
The raw material compound (II) was prepared by a known or known method (for example, JP-A-55-20740, JP-A-2-304022, JP-A-6-234736, Japanese Patent Laid-Open No. 6-306025 and the like).
Compound (I) is useful as a pancreatitis treatment or prophylactic agent (preferably for pancreatitis treatment) because of its excellent pancreatitis suppressing action and low toxicity.
Hereinafter, the present invention will be described in more detail with reference to Test Examples, Preparation Examples, and Formulation Examples, but the scope of the present invention is not limited thereto.
[Test Example 1]
Inhibition of choline deficiency Ethionine-induced pancreatitis
Choline deficiency ethione expression (CDE expression) induced pancreatitis in mice was induced by some modifications of Lombardi et al. [Lombardi et al, Am. J. Pathol., 79, 465-480 (1975)]. That is, the choline deficiency formula (CDE formula) to which 0.5% (w / w) DL-ethionine was added was given to ICR type | system | group female mouse (Nihon Charles River, 3 weeks old), and pancreatitis was induced. About 64 ml of blood was collected from the mouse heart under ether anesthesia 64 hours after the CDE expression addition. The blood was left to coagulate for 2 hours at room temperature and centrifuged (12,000 rpm, 10 minutes) to obtain serum. The amylase activity in this serum was measured using an amylase activity measurement kit (amylase B-test and Cocoa, Wacopecun Yagyo Bridge) as an index of pancreatitis. The test drug was suspended in a 0.5% (w / w) tragant solution and administered 6 times a day twice a day from 1 hour before the start of the CDE expression.
The amylase activity (IU / ml) of the serum of mice to which the test compound was administered is shown in Tables 3, 4 and 5. In addition, the control group represents the group given the CDE expression and induced pancreatitis but did not receive the test drug, and the normal group represents the group given the conventional diet without giving the CDE expression.
compoundDose (mg / kg)JesusAmylase Activity (IU / mL) Compound of Preparation Example 31030151535.032.1 Control-2071.7 Normal-207.4
compoundDose (mg / kg)JesusAmylase Activity (IU / mL) Compound of Preparation Example 4103010 948.430.5 Compound of Preparation Example 21030101053.731.2 Control-2064.7 Normal-206.6
compoundDose (mg / kg)HydrothermalAmylase Activity (IU / mL) Compound of Preparation Example 181030101025.721.8 Control group-101048.0 8.7
[Test Example 2]
Inhibition of cellulose induced pancreatitis
Induction of experimental acute pancreatitis in rats is described by Otsugi et al. [Otuki et al, Dig. Dis. Sci., 35, 242-250 (1990)]. That is, cellulose (20 µg / kg) was repeated four times per hour and administered intraperitoneally to the wister rats (Nippon SLC, body weight about 200 g). 3 hours after the final administration, the blood obtained from the jugular vein was allowed to stand at room temperature for 2 hours to coagulate blood after centrifugation (12,000 rpm, 10 minutes) under ether anesthesia. The amylase activity in this serum was measured using an amylase activity measurement kit (amylase B test, Wakoko, Wakokoyakugokyo) and used as an index of pancreatitis. The test drug was suspended in 0.5% (W / V) tragant solution and orally administered 30 minutes before the start of cellulose injection. The control group induces pancreatitis but does not receive the test drug.
compoundDose (mg / kg)HydrothermalAmylase Activity (IU / mL) Compound of Preparation Example 3103010015151543.634.931.7 Control-1548.7
[Production Example 1]
(2R, 4R) -2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride ( Exemplary Compound No. 1-14)
(a) (2R, 4R) -1-ethoxycarbonyl-2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydrate Roxypyrrolidine
399 mg of 4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenol was dissolved in 8 ml of N, N-dimethylacetoamide, and under ice cooling, 363 mg of potassium t-butoxide and (2S, 718 mg of 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine was added, and it stirred at 40 degreeC for 5 hours. 50 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with water and brine sequentially. The ethyl acetate layer was dehydrated using anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/7) to give 535 mg (yield 76%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean
(2R, 4R) -1-ethoxycarbonyl-2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in step (a) above. 201 mg of 4-hydroxypyrrolidine was dissolved in 4 ml of tetrahydrofuran, stirred under ice-cooling, and dropped into a mixed solution of 53 mg of lithium aluminum hydride and 4 ml of tetrahydrofuran, followed by heating to reflux for 30 minutes. Thereafter, the reaction solution was ice-cooled to add sodium sulfate · 10 hydrate to decompose excess hydride. The insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was purified using silica gel column chromatography (eluent: methylene chloride / methanol = 4/1) to give 139 mg of a colorless oil (yield 80%). Got.
(c) (2R, 4R) -2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean hydrochloride
(2R, 4R) -2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4- obtained by the same method as in step (b) above. 246 mg of hydroxy-1-methylpyrrolidine was dissolved in 5 ml of ethyl acetate, and 0.25 ml of 4N hydrogen chloride-ethyl acetate solution was added and allowed to stand at room temperature. The precipitated crystals were separated by filtration and dried to obtain 210 mg (yield 78%) of the title compound as colorless crystals.
Melting point: 128-129 ° C.
[Production Example 2]
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methyl Pyrrolidine hydrochloride (Example Compound No. 1-17)
(a) (2R, 4R) -1-ethoxycarbonyl-2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl ] -4-hydroxypyrrolidine
622 mg of 4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenol was dissolved in 7 ml of N, N-dimethylacetoamide, and 343 mg of potassium t-butoxide and ( 678 mg of 2S, 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine was extracted by reaction in the same manner as in Preparation Example 1 (a). The obtained oily substance was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3) to give 552 mg (yield 52%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-Fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy- 1-methylpyrrolidine
(2R, 4R) -1-ethoxycarbonyl-2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] obtained in step (a) above. 551 mg of phenoxy] ethyl] -4-hydroxypyrrolidine, 20 ml of tetrahydrofuran and 140 mg of lithium aluminum hydride were used and reacted in the same manner as in Preparation Example 1 (b). The obtained concentrate was purified using silica gel column chromatography (elution solvent: methylene chloride / methanol = 3/2) to give 405 mg (yield 84%) of the title compound as a colorless oil.
(c) (2R, 4R) -2 [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1 Methylpyrrolidine hydrochloride
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4 obtained in the step (b) above. 399 mg of -hydroxy-1-methylpyrrolidine was dissolved in 5 ml of ethyl acetate, and 0.38 ml of 4N hydrogen chloride-ethyl acetate solution was added to precipitate crystals. The solvent was removed under reduced pressure, and the obtained solid was dissolved in a small amount (about 0.5 ml) of methylene chloride, and then 5 ml of ethyl acetate was added and left at room temperature. The precipitated crystals were separated by filtration and dried to give 359 mg (yield 82%) of the title compound as colorless crystals.
Melting point: 128-130 ° C.
[Manufacture example 3]
(2R, 4R) -4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
(a) (2R, 4R) -4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine (example Compound number 1-38)
(2R, 4R) -4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in Example 68 of JP-A-6-234736. 388 mg of 1-methylpyrrolidine was dissolved in 5 ml of pyridine, 543 mg of lauric anhydride and 40 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was separated and extracted with ethyl acetate and water. The ethyl acetate layer was dehydrated on magnesium sulfate and concentrated under reduced pressure to obtain an oily substance. This was purified using silica gel column chromatography (eluent: ethyl acetate) to obtain 549 mg (yield 94%) of the standard compound as a colorless oil.
(b) (2R, 4R) -4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
(2R, 4R) -4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpi obtained in step (a) above 535 mg of lollidine was dissolved in 6 ml of dioxane, and 0.75 ml of 4N hydrogen chloride-dioxane solution was added and concentrated under reduced pressure. This was dissolved in 1 ml of ethyl acetate, and 10 ml of ether was added and stirred. The precipitated crystals were filtered and dried in vacuo to give 446 mg (yield 78%) of the title compound as colorless crystals.
Luminous intensity: [alpha] _D -2.1 degrees (c = 1.19, methanol).
Melting point: 73-74 ℃.
[Production Example 4]
(2R, 4R) -2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride ( Exemplary Compound No. 1-16)
(a) (2R, 4R) -1-ethoxycarbonyl-2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydrate Roxypyrrolidine
170 mg of 2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenol were dissolved in 4 ml of N, N-dimethylacetoamide, and 101 mg of potassium t-butoxide and (2S, 4R) under ice-cooling. N-N-dimethylacetoamide solution (2 mL) of 199 mg))-2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine was added sequentially under ice-cooling and at room temperature It stirred for 3 hours and again at 40 degreeC for 12 hours. 150 mL of ethyl acetate and 60 mL of 1N hydrochloric acid were added to the reaction solution for separation. The ethyl acetate layer was washed with water and brine sequentially, and dehydrated using anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily substance. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 7/3) to obtain 184 mg (yield 62%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean
(2R, 4R) -1-ethoxycarbonyl-2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in step (a) above. 180 mg of 4-hydroxypyrrolidine was reacted and extracted in the same manner as in Preparation Example 1 (b) using 47 mg of lithium aluminum hydride and 10 ml of tetrahydrofuran, and the concentrate was purified by silica gel column chromatography (elution solvent: Purification using methylene chloride / methanol = 4/1) gave 101 mg (yield 65%) of the title compound as a colorless oil.
(c) (2R, 4R) -2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean hydrochloride
(2R, 4R) -2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1 obtained in step (b) above. 101 mg of -methylpyrrolidine was dissolved in 3 ml of ethyl acetate, and 0.10 ml of 4N hydrogen chloride-ethyl acetate solution was added and concentrated. The obtained oily substance was dissolved in a small amount of ethyl acetate, and crystallized when it stood at room temperature. This was filtered and dried to give 86 mg (yield 78%) of the title compound as colorless crystals.
Melting point: 98-100 ° C.
Production Example 5
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride ( Exemplary Compound No. 1-91)
(a) (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- [2- (4-fluorophenyl) Ethyl] phenoxy] ethyl] pyrrolidine
248 mg of 4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenol was dissolved in 10 ml of N, N-dimethylacetoamide, and 125 mg of potassium t-butoxide and (2S, 4R) under ice-cooling. 405 mg of) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- (2-chloroethyl) pyrrolidine was added and stirred at room temperature for 3 hours. 150 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with water and brine sequentially. The ethyl acetate layer was dehydrated using anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 433 mg (yield 73%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean
(2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- [2- (4- obtained in step (a) above) 398 mg of fluorophenyl) ethyl] phenoxy] ethyl] pyrrolidine was dissolved in 10 ml of tetrahydrofuran, stirred under ice-cooling, and added dropwise into a mixed liquid of 81 mg of lithium aluminum hydride and 10 ml of tetrahydrofuran. After refluxing for 1 hour and ice-cooling, sodium sulfate 10 hydrate is added to decompose excess hydride. The insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was purified using silica gel column chromatography (eluent: methylene chloride / methanol = 7/3) to give 151 mg of a title compound as a colorless oil (yield 59%). Got.
(c) (2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean hydrochloride
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1 obtained in step (b) above. 138 mg of -methylpyrrolidine was dissolved in 4 ml of ethyl acetate, and 0.15 ml of 4N hydrogen chloride-ethyl acetate solution was added and concentrated. The obtained oily substance was dissolved in 5 ml of ethyl acetate, and when left to stand at room temperature, crystals precipitated. This was filtered and dried to give 66 mg (yield 43%) of the title compound as colorless crystals.
Melting point: 70-73 ℃.
[Manufacture example 6]
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (Example Compound No. 1 -139)
(a) (2R, 4R) -1-t-butoxycarbonyl-2- [2- [4-fluoro-2- [2-4-fluorophenyl) ethyl] phenoxy] ethyl] -4- Hydroxypyrrolidine
687 mg of 4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenol was dissolved in 12 ml of N, N-dimethylacetoamide, 212 mg of potassium t-butoxide was added under ice cooling, 10 Stirred for a minute. 687 mg of (2S, 4R) -2- (2-chloroethyl) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine was added to the obtained solution, and the mixture was stirred at room temperature for 14 hours. 135 mg of potassium t-butoxide was added to the reaction mixture, the mixture was stirred at 40 ° C for 4 hours, and 300 ml of ethyl acetate was added to the reaction mixture, followed by washing with water and brine sequentially. The ethyl acetate layer was dehydrated using anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3) to give 571 mg (yield 74%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride
(2R, 4R) -1-t-butoxycarbonyl-2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] obtained in step (a) above. 570 mg of ethyl] -4-hydroxypyrrolidine was dissolved in 5 ml of ethyl acetate, and crystals precipitated when 30 ml of 4N hydrogen chloride-ethyl acetate solution was added and stirred at room temperature for 30 minutes. This was filtered, washed with ethyl acetate and dried to give 381 mg (yield 78%) of the title compound as colorless crystals.
Melting point 186-187 캜.
[Manufacture example 7]
(2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (Example Compound No. 1-132)
(a) (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl ] Pyrrolidine
1090 mg of 4-fluoro-2- (2-phenylethyl) phenol, (2S, 4R) -2- (2-bromoethyl) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy 1870 mg of pyrrolidine and 566 mg of potassium t-butoxide were reacted in 10 ml of N, N-dimethylacetoamide in the same manner as in Preparation Example 6 (a), and extracted to obtain an oil. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give 2090 mg (yield 84%) of the title compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride
(2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- (2-phenylethyl) obtained in step (a) above. 600 mg of phenoxy] ethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was left at room temperature for 1 hour. The solid obtained by depressurizingly removing the solvent was dissolved in a small amount of a mixture of methylene chloride and methanol, and crystallized when standing still by adding 10 ml of ethyl acetate. This was filtered and dried to give 270 mg (yield 67%) of the title compound as colorless crystals.
Melting point 151-152 캜.
[Manufacture example 8]
(2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (Example Compound No. 1-90 )
(a) (2R, 4R) -1-t-butoxycarbonyl-2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine
Preparation Example 7 (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- (2-phenyl) obtained in step (a). 1490 mg of ethyl) phenoxy] ethyl] pyrrolidine was dissolved in 15 ml of tetrahydrofuran, 0.79 ml of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the oily concentrate was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 1115 mg (yield 95%) of the title compound as a colorless solid.
(b) (2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine
(2R, 4R) -1-t-butoxycarbonyl-2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydrate obtained in step (a) above 1115 mg of roxypyrrolidine was reacted in the same manner as in Preparation Example 1 (b) using 20 ml of tetrahydrofuran and 200 mg of lithium aluminum hydride, and the concentrate obtained after workup was subjected to silica gel column chromatography Methylene / methanol = 5/1) was used to obtain 540 mg (yield 61%) of the title compound as a colorless solid.
(c) (2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride
(2R, 4R) -2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine 540 obtained in step (b) above. The mg was dissolved in 5 ml of ethyl acetate, and crystals precipitated when 0.60 ml of 4N hydrogen chloride-ethyl acetate solution was added. This was filtered and dried to give 515 mg (yield 86%) of the title compound as colorless crystals.
Melting point 121-122 ° C.
[Manufacture example 9]
(2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1-methylpyrroli Dean Hydrochloride (Example Compound No. 1-92)
(a) (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] pyrrolidine
2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenol 400 mg, (2S, 4R) -2- (2-bromoethyl) -1-t-butoxycarbonyl 690 mg of 4-t-butyldimethylsilyloxypyrrolidine and 208 mg of potassium t-butoxide were reacted in 5 ml of N, N-dimethylacetoamide in the same manner as in Preparation Example 5 (a), followed by extraction. Obtained an oil. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to obtain 580 mg (yield 63%) of the title compound as a colorless oil.
(b) (2R, 4R) -1-t-butoxycarbonyl-2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl ] -4-hydroxypyrrolidine
(2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- [2- [2- [2- (3,4-difluoro) obtained in step (a) above 580 mg of phenyl) ethyl] -4-fluorophenoxy] ethyl] pyrrolidine was dissolved in 5 ml of tetrahydrofuran, 0.31 ml of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the oily concentrate was purified using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give the title compound (280 mg, yield 61%) as a colorless solid.
(c) (2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1- Methylpyrrolidine
(2R, 4R) -1-t-butoxycarbonyl-2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluoro obtained in step (b) above 280 mg of phenoxy] ethyl] -4-hydroxypyrrolidine was reacted in the same manner as in Preparation Example 1 (b) using 5 ml of tetrahydrofuran and 50 mg of lithium aluminum hydride. Purification was carried out using silica gel column chromatography (eluent: methylene chloride / methanol = 10/1) to obtain 140 mg (yield 63%) of the title compound as a colorless solid.
(d) (2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1- Methylpyrrolidine hydrochloride
(2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydrate obtained in step (c) above. 140 mg of oxy-1-methylpyrrolidine was dissolved in 5 ml of ethyl acetate, and crystals precipitated when 0.15 ml of 4N hydrogen chloride-ethyl acetate solution was added. This was filtered and dried to give 113 mg (yield 73%) of the title compound as colorless crystals.
Melting point 93-94 ° C.
[Production Example 10]
(2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (example Compound number 1-133)
(2R, 4R) -1-t-butoxycarbonyl-2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluoro obtained in Preparation Example 9 (b). 83 mg of rophenoxy] ethyl] -4-hydroxypyrrolidine was dissolved in 2 ml of dioxane, and 2 ml of 4N hydrogen chloride-dioxane solution was added, and the crystals were allowed to stand at room temperature for 1 hour to precipitate. This was filtered and dried to give 55 mg (yield 77%) of the title compound as colorless crystals.
Melting point 170-171 캜.
[Production Example 11]
(2R, 4R) -2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (Example Compound No. 1-136 )
(a) (2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrroli Dean
520 mg of 6-fluoro-2- (2-phenylethyl) phenol was dissolved in 10 ml of N, N-dimethylacetoamide, 300 mg of potassium t-butoxide, (2S, 4R) -2- (2-chloro The reaction was carried out in the same manner as in Production Example 5 (a), using 820 mg of ethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine, and extraction was performed to obtain an oil. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain 984 mg (yield 81%) of the title compound as an oil.
(b) (2R, 4R) -2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine
(2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-octyloxy obtained in step (a) above. The concentrate obtained by reacting in the same manner as in Preparation Example 1 (b) using 984 mg of carbonylpyrrolidine, 200 mg of lithium aluminum hydride, and 20 ml of tetrahydrofuran, was subjected to silica gel column chromatography (elution solvent: Purification using methylene chloride / methanol = 5/1) gave 319 mg (yield 53%) of the title compound as an oil.
(c) (2R, 4R) -2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride
(2R, 4R) -2- [2- [6-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine obtained in step (b). The mg was dissolved in 10 ml of ethyl acetate, and 0.23 ml of 4N hydrogen chloride-ethyl acetate solution was added. The solvent was removed under reduced pressure, and the obtained oily substance was recrystallized using ethyl acetate, filtered and dried to obtain 320 mg (yield 91%) of the title compound as colorless crystals.
Melting point 136-138 캜.
[Manufacture example 12]
2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (Example Compound No. 1-134)
(a) 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine
175 mg of 4-fluoro-2- (2-phenylethyl) phenol was dissolved in 5 ml of N, N-dimethylacetoamide, stirred under ice-cooling, and 130 mg of potassium t-butoxide was added. 220 mg of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride was added to the reaction liquid, and it stirred at room temperature for 5 hours and then at 55 degreeC for 6 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed sequentially with water and brine. The extract was dehydrated and concentrated under reduced pressure to obtain an oil, which was purified using silica gel column chromatography (eluent: methylene chloride / methanol = 5/1) to obtain 83.8 mg (yield 32%) of the title compound as an oil. .
(b) 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
83.8 mg of 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine obtained in step (a) was dissolved in a small amount of ethyl acetate, and 4 When 0.06 ml of N hydrogen chloride-ethyl acetate solution was added, crystals were precipitated. After standing, the mixture was filtered and dried to give 68.9 mg (yield 74%) of the title compound as colorless crystals.
Melting point 149-151 캜.
[Production Example 13]
3- [4-fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine hydrochloride (Example Compound No. 1-135)
(a) 1-t-butoxycarbonyl-3- [4-fluoro-2- (2-phenylethyl) phenoxy] methylpiperidine
175 mg of 4-fluoro-2- (2-phenylethyl) phenol was dissolved in 5 ml of N, N-dimethylacetoamide, stirred under ice-cooling, and 100 mg of potassium t-butoxide was added and stirred for 10 minutes. 330 mg of 1-t-butoxycarbonyl-3-tosyloxymethylpiperidine was added to the reaction mixture, stirred at room temperature for 3 days, diluted with ethyl acetate, washed sequentially with water and brine, and the extract was dehydrated and dried. After concentration under reduced pressure, an oily substance was obtained. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 291 mg (yield 87%) of the title compound as an oil.
(b) 3- [4-fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine
291 mg of 1-t-butoxycarbonyl-3- [4-fluoro-2- (2-phenylethyl) phenoxy] methylpiperidine obtained in step (a), 100 mg of lithium aluminum hydride, tetrahydro The reaction product was reacted in the same manner as in Preparation Example 1 (b) using 10 mL of furan, and the obtained concentrate was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 10/1), followed by 89.8 mg (39% yield) of the compound were obtained as an oily substance.
(c) 3- [4-fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine hydrochloride
89.8 mg of 3- [4-fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine obtained in step (b) was dissolved in a small amount of ethyl acetate, and 4N hydrogen chloride-acetic acid When 0.07 ml of ethyl solution was added, crystals precipitated. This was filtered and dried to give 81.7 mg (yield 82%) of the title compound as colorless crystals.
Melting point 193-196 ° C.
Production Example 14
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1 Methylpyrrolidine hydrochloride (Example Compound No. 1-41)
(a) (2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyl jade C-1-methylpyrrolidine
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in Preparation step 2 (b). 513 mg of 4-hydroxy-1-methylpyrrolidine was dissolved in 10 ml of pyridine, and 652 mg of lauric anhydride was added at room temperature. 48 mg of 4-dimethylaminopyridine was added here, and it stirred at room temperature for 30 minutes, and stirred at 40 degreeC for 1 hour. Ethyl acetate was added and diluted with the reaction solution, washed twice with 1N hydrochloric acid, followed by brine, and the extract was dehydrated and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluate: methylene chloride / methanol = 5/1) to give 684 mg (yield 91%) of the titled compound as a colorless oil.
(b) (2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyl jade C-1-methylpyrrolidine Hydrochloride
(2R, 4R) -2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4 obtained in the step (a) above. -684 mg of lauroyloxy-1-methylpyrrolidine was dissolved in 10 ml of dioxane, and 0.45 ml of 4N hydrogen chloride-dioxane solution was added and concentrated under reduced pressure. Hexane was added thereto to crystallize, and the filtrate was dried to give 485 mg (yield 67%) of the title compound as colorless crystals.
Melting Point 49-53 ℃
[Production Example 15]
(2R, 4R) -2- [2- [4-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (Example Compound No. 1-137)
(a) (2R, 4R) -2- [2- [4-chloro-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine
500 mg of 4-chloro-2- (2-phenylethyl) phenol was dissolved in 10 ml of N, N-dimethylacetoamide, 270 mg of potassium t-butoxide under ice-cooling, and (2S, 4R) -2- (2 Reaction and extraction were carried out in the same manner as in Production Example 1 (a), using 520 mg of -chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine to obtain an oily substance. This was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give 260 mg (yield 29%) of the title compound as an oil.
(b) (2R, 4R) -2- [2- [4-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine
(2R, 4R) -2- [2- [4-chloro-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrroli obtained in step (a) above 260 mg of dean was reacted in the same manner as in Preparation Example 1 (b) using 10 ml of tetrahydrofuran and 70 mg of lithium aluminum hydride, and the resultant was subjected to post-treatment, followed by silica gel column chromatography (eluent: methylene chloride / Methanol = 5/1) was used to obtain 103 mg (yield 46%) of the title compound as a colorless solid.
Melting point 65-68 ℃
[Production Example 16]
(2R, 4R) -2- [2- [4-bromo-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (Example Compound No. 1-138)
(a) (2R, 4R) -2- [2- [4-bromo-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine
500 mg of 4-bromo-2- (2-phenylethyl) phenol was dissolved in 10 ml of N, N-dimethylacetoamide, 220 mg of potassium t-butoxide under ice-cooling, and (2S, 4R) -2- ( Reaction and extraction were carried out in the same manner as in Production Example 1 (a), using 440 mg of 2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine to obtain an oily substance. This was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain 280 mg (yield 34%) of the title compound as an oil.
(b) (2R, 4R) -2- [2- [4-bromo-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine
(2R, 4R) -2- [2- [4-bromo-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypi obtained in step (a) above 280 mg of lollidine was reacted in the same manner as in Preparation Example 1 (b) using 10 ml of tetrahydrofuran and 70 mg of lithium aluminum hydride, and the resultant was subjected to silica gel column chromatography (elution solvent: methylene chloride). / Methanol = 5/1) was used to obtain 113 mg (yield 46%) of the title compound as a colorless solid.
Melting point 63-66 ℃
[Production Example 17]
(2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (Example Compound No. 1-140)
(a) (2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine
680 mg of 5-chloro-2- (2-phenylethyl) phenol was dissolved in 10 ml of N, N-dimethylacetoamide, 360 mg of potassium t-butoxide was added under ice cooling, followed by stirring for 10 minutes. 1000 mg of (2S, 4R) -2- (2-chloroethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine was added to the reaction solution, in the same manner as in Preparation Example 5 (a). Reaction and extraction gave an oil. This was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 1.38 g (yield 91%) of the title compound as an oil.
(b) (2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine
(2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-dimethylcarbamoyloxy-1-octyloxycarb obtained in step (a) above. Reaction was carried out in the same manner as in Preparation Example 1 (b) using 1380 mg of carbonylpyrrolidine, 450 mg of lithium aluminum hydride, and 20 ml of tetrahydrofuran, and the obtained concentrate was subjected to silica gel column chromatography (elution solvent: chloride). Methylene / methanol = 5/1) was used to obtain 256 mg (yield 30%) of the title compound as a colorless solid.
(c) (2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylphyllolidine hydrochloride
256 mg of (2R, 4R) -2- [2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine obtained in step (b) Was dissolved in 5 ml of ethyl acetate, and 0.18 ml of 4N hydrogen chloride-ethyl acetate solution was added. The solvent was removed under reduced pressure, and the obtained oily substance was dissolved in 10 ml of ethyl acetate and left to stand, resulting in the precipitation of crystals. This was filtered and dried to give 183 mg (yield 65%) of the title compound as colorless crystals.
Melting Point 99-102 ℃
[Production Example 18]
(2R, 4R) -4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (Example Compound No. 1- 13)
(a) (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine
500 mg of 2- [2- (3-methoxyphenyl) ethyl] phenol was dissolved in 20 ml of N, N-dimethylacetoamide, 270 mg of potassium t-butoxide was added under ice cooling, followed by stirring for 15 minutes. 1190 mg of (2S, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- (p-toluenesulfonyloxy) ethyl] pyrrolidine was added to the reaction solution, and Preparation Example 5 (a) The reaction was carried out in the same manner as in the step, and extracted to obtain an oil. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 860 mg (yield 78%) of the title compound as an oil.
(b) (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine
(2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in step (a) above. 853 mg of pyrrolidine was stirred in hydrogen stream at 60 ° C. for 7 hours using 85 mg of 5% palladium-carbon catalyst in 6 ml of ethanol to remove the benzyl group. The reaction mixture was cooled, the catalyst was filtered off, and the concentrate obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the title compound (650 mg, yield 93%). ) Was obtained as a colorless oil.
(c) (2R, 4R) -4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine
(2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] obtained in step (b) above. The concentrate obtained by the same reaction as in Preparation Example 1 (b) using pyrrolidin 640 mg, 176 mg of lithium aluminum hydride and 30 ml of tetrahydrofuran was subjected to silica gel column chromatography (elution solvent: methylene chloride / Methanol = 10/1) was used to obtain 523 mg (yield 95%) of the title compound as a colorless oil.
(d) (2R, 4R) -4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
520 mg of (2R, 4R) -4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine obtained in the step step Was dissolved in 5 ml of dioxane and 1.1 ml of 4N hydrogen chloride-dioxane solution was added. The solution was removed under reduced pressure, the resulting oil was dissolved in 2 ml of methylene chloride, 40 ml of ethyl acetate was added, and the mixture was left at room temperature to precipitate crystals. This was filtered and dried to obtain 420 mg (yield 73%) of the title compound as colorless crystals.
Melting Point 100-102 ℃
[Example 1]
Capsule
20.0 mg of compound of Preparation Example 3
Lactose 158.7
Corn Starch 70.0
Magnesium Stearate 1.3
250 mg
The powder of the above formulation is mixed, passed through a 60-mesh sieve, and then the powder is put into 250 mg No. 3 gelatin capsule to make a capsule.
[Example 2]
refine
20.0 mg of compound of Preparation Example 3
Lactose 154.0
Corn Starch 25.0
Magnesium Stearate 1.0
200 mg
The powder of the said prescription is mixed, it is compressed into a tableting machine, and it turns into a tablet of 200 mg.
This tablet may be coated with sugar as necessary.
The compound having the formula (I) is useful as a therapeutic or prophylactic agent (preferably a therapeutic agent) for pancreatitis because of its excellent pancreatitis inhibitory action and low toxicity. Moreover, the compound whose R <^4> is an acyloxy-heterocyclyl group (especially an aliphatic acyloxy pyrrolidinyl group) has the characteristic that there is little irritation to the stomach.
The compound (I) and pharmacologically acceptable salts thereof of the present invention, when used as a pancreatitis treatment or prophylactic agent, may be mixed with itself or with an appropriately pharmacologically acceptable excipient, diluent, and the like, and used in tablets, capsules, granules, powders or syrups. It can be administered orally or parenterally by injection or the like.
These agents include excipients (e.g., sugar derivatives such as lactose, white sugar, glucose, mannite, sorbet; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low Degree of substitution Cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and internal crosslinked carboxymethyl cellulose sodium: gum arabic: dextran: fulan: hard silicic anhydride, synthetic silicic acid Silicate derivatives such as aluminum and magnesium metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate), binders (e.g., excipients; gelatin; polyvinylpi Lollidon; macrogol etc.), disintegrant (for example, said excipient; croscarmellose sodium, Chemically modified starches such as sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, cellulose derivatives, and the like, lubricants (eg, talc; stearic acid; calcium stearate, magnesium stearate; Colloidal silica; waxes such as gums, geolo; boric acid; glycol; carboxylic acids such as fumaric acid, adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; sodium lauryl sulfate, Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above excipients; Alcohols such as butanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and clesol; thimerosal Acetic anhydride; sorbic acid; It was prepared by the method. The amount varies depending on the symptoms, age, administration method, etc., but in the case of oral administration, the lower limit 1 mg (preferably 10 mg) and the upper limit 1000 mg (preferably 500 mg) per intravenous administration The lower limit of 0.5 mg (preferably 5 mg) and the upper limit of 500 mg (preferably 250 mg) per dose is preferably administered to an adult 1-3 times a day depending on the symptoms.

权利要求:
Claims (28)
[1" claim-type="Currently amended] [Formula I]
[Wherein, R ¹ represents a hydrogen atom or a halogen atom,
R ² and R ³ are the same or different and represent a hydrogen atom, a halogen atom or a C ₁ -C ₄ alkoxy group,
R ⁴ represents a 5 to 6 membered cyclic amino group which may be substituted and may contain an oxygen or sulfur atom (the substituent on the carbon atom represents a C ₁ -C ₂₀ aliphatic acyloxy group which may include a hydroxy group or a double bond) And a substituent on the nitrogen atom represents a C ₁ -C ₄ alkyl group.)
A represents a C ₁ -C ₄ alkylene group.] A composition for the treatment or prophylaxis of pancreatitis containing a diarylalkane derivative having a pharmacologically acceptable salt thereof as an active ingredient.
[2" claim-type="Currently amended] The method according to claim 1, wherein the active ingredient,
R ¹ is a arylalkane derivative or a pharmacologically acceptable salt thereof which is a hydrogen atom, a fluorine atom or a chlorine atom.
[3" claim-type="Currently amended] The method according to claim 1, wherein the active ingredient,
R ¹ is a arylalkane derivative or a pharmacologically acceptable salt thereof which is a hydrogen atom or a fluorine atom.
[4" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 3,
A composition wherein R ² and R ³ are the same or different and a arylalkane derivative or a pharmacologically acceptable salt thereof which is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or an ethoxy group.
[5" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 3,
A composition wherein R ² is a hydrogen atom, a fluorine atom or a chlorine atom, and R ³ is a aryl group or a pharmacologically acceptable salt thereof.
[6" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 3,
The composition wherein R <^2> is a hydrogen atom and a fluorine atom, and R <^3> is a arylalkane derivative whose methoxy group is a pharmacologically acceptable salt.
[7" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 6,
R ⁴ may be substituted with a pyrrolidinyl group, a piperidinyl group, a morpholinyl group or a thiomorpholinyl group (as examples of the substituent on the carbon atom as a hydroxyl group, C ₂ to C ₅ aliphatic acyloxy group, C ₈ to C _{18 represents an} aliphatic acyloxy group, acryloyl group, crotonoyl group, oleoyl group or linoleoyl group, and a substituent on the nitrogen atom represents a methyl group or an ethyl group.) A composition which is a diarylalkane derivative or a pharmacologically acceptable salt thereof. .
[8" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 6,
R ⁴ may be substituted with a pyrrolidinyl group, a piperidinyl group or a morpholinyl group (The substituent on the carbon atom represents a hydroxy group or a C ₈ to C ₁₈ aliphatic acyloxy group, and the substituent on the nitrogen atom represents a methyl group. A phosphorus diarylalkane derivative or a pharmacologically acceptable salt thereof.
[9" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 6, wherein
R ⁴ is 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrrolidinyl, 4 -Decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4 Stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl-4-deca Noyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-palmi Toyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2- Diarylalkane derivatives which are piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl groups or pharmacologically acceptable thereof A salt.
[10" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 6, wherein
R ⁴ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy- 2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl or 1-methyl-4-lauroyloxy-2- A diarylalkane derivative which is a pyrrolidinyl group or a pharmacologically acceptable salt thereof.
[11" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 10, wherein
A composition is a arylalkane derivative wherein A is a C ₁ -C ₃ alkylene group or a pharmacologically acceptable salt thereof.
[12" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 10, wherein
A composition wherein A is a diaryl alkane derivative which is a methylene group or an ethylene group or a pharmacologically acceptable salt thereof.
[13" claim-type="Currently amended] The active ingredient according to any one of claims 1 to 10, wherein
A is a aryl alkane derivative which is an ethylene group, or its pharmacologically acceptable salt.
[14" claim-type="Currently amended] The method of claim 1, wherein the active ingredient
4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-decanoyloxy-2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine,
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine or
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine or The composition is a pharmacologically acceptable salt thereof.
[15" claim-type="Currently amended] [Formula I]
[Wherein, R ¹ represents a hydrogen atom or a halogen atom,
R ² and R ³ are the same or different and represent a hydrogen atom, a halogen atom or a C ₁ -C ₄ alkoxy group,
R ⁴ represents a 5 to 6 membered cyclic amino group which may be substituted and may contain an oxygen or sulfur atom (the substituent on the carbon atom represents a C ₁ -C ₂₀ aliphatic acyloxy group which may include a hydroxy group or a double bond) And a substituent on the nitrogen atom represents a C ₁ -C ₄ alkyl group.)
A represents a C ₁ -C ₄ alkylene group.] A method of treating or preventing pancreatitis wherein an effective amount of a diarylalkane derivative having a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal.
[16" claim-type="Currently amended] The compound according to claim 15, wherein in formula (I),
A method for treating or preventing pancreatitis wherein R ¹ is hydrogen, fluorine or chlorine.
[17" claim-type="Currently amended] The compound according to claim 15, wherein in formula (I),
A method of treating or preventing pancreatitis wherein R ¹ is a hydrogen atom or a fluorine atom.
[18" claim-type="Currently amended] The compound according to any one of claims 15 to 17, wherein in formula (I):
A method for treating or preventing pancreatitis wherein R ² and R ³ are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or an ethoxy group.
[19" claim-type="Currently amended] The compound according to any one of claims 15 to 17, wherein in formula (I):
A method for treating or preventing pancreatitis wherein R ² is a hydrogen atom, a fluorine atom or a chlorine atom, and R ³ is a methoxy group.
[20" claim-type="Currently amended] The compound according to any one of claims 15 to 17, wherein in formula (I):
A method for treating or preventing pancreatitis wherein R ² is a hydrogen atom or a fluorine atom and R ³ is a methoxy group.
[21" claim-type="Currently amended] The compound according to any one of claims 15 to 20, wherein in formula (I):
R ⁴ may be substituted with a pyrrolidinyl group, a piperidinyl group, a morpholinyl group or a thiomorpholinyl group (as examples of the substituent on the carbon atom as a hydroxyl group, C ₂ to C ₅ aliphatic acyloxy group, C ₈ to C ₁₈ aliphatic acyloxy group, acryloyl group, crotonoyl group, oleoyl group or linoleoyl group, and a substituent on the nitrogen atom represents a methyl group or an ethyl group).
[22" claim-type="Currently amended] The compound according to any one of claims 15 to 20, wherein in formula (I):
R ⁴ may be substituted with a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group (wherein the substituent represents a hydroxy group or a C ₈ to C ₁₈ aliphatic acyloxy group as a substituent on a carbon atom, and a substituent on a nitrogen atom) Represents a methyl group) A method for the treatment or prevention of phosphorus pancreatitis.
[23" claim-type="Currently amended] The compound according to any one of claims 15 to 20, wherein in formula (I):
R ⁴ is 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-octanoyloxy-2-pyrrolidinyl, 4 -Decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4 Stearoyloxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-octanoyloxy-2-pyrrolidinyl, 1-methyl-4-deca Noyloxy-2-pyrrolidinyl, 1-methyl-4-lauroyloxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-palmi Toyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2- A method for the treatment or prevention of pancreatitis which is a piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl or 4-methyl-2-morpholinyl group.
[24" claim-type="Currently amended] The compound according to any one of claims 15 to 20, wherein in formula (I):
R ⁴ is 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-decanoyloxy-2-pyrrolidinyl, 4-lauroyloxy- 2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoyloxy-2-pyrrolidinyl or 1-methyl-4-lauroyloxy-2- A method for the treatment or prevention of pyrrolidinyl group pancreatitis.
[25" claim-type="Currently amended] The compound according to any one of claims 15 to 24, wherein in formula (I):
A method for treating or preventing pancreatitis wherein A is a C ₁ -C ₃ alkylene group.
[26" claim-type="Currently amended] The compound according to any one of claims 15 to 24, wherein in formula (I):
A method for treating or preventing pancreatitis wherein A is a methylene group or an ethylene group.
[27" claim-type="Currently amended] The compound according to any one of claims 15 to 24, wherein in formula (I):
A method of treating or preventing pancreatitis wherein A is an ethylene group.
[28" claim-type="Currently amended] The compound of claim 15, wherein the compound of formula (I)
4-hydroxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine,
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-decanoyloxy-2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-decanoyloxy-2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
4-lauroyloxy-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine,
2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine,
2- [2- [2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine or
2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine How to treat or prevent pancreatitis.

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同族专利:

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公开号 | 公开日

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NZ336003A|2001-02-23|

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NO992552D0|1999-05-27|

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CN1245426A|2000-02-23|

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NO992552L|1999-07-19|

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AU5067198A|1998-06-22|

---

HU9904002A3|2001-01-29|

---

IL130103D0|2000-06-01|

---

WO1998023271A1|1998-06-04|

---

AU717679B2|2000-03-30|

---

EP0958817A1|1999-11-24|

---

ID21653A|1999-07-08|

---

CZ189299A3|1999-09-15|

---

HU9904002A2|2000-04-28|

---

CA2273085A1|1998-06-04|

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:
1996-11-28|Priority to JP31774696

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1996-11-28|Priority to JP96-317746

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1997-11-27|Application filed by 가와무라 요시부미, 상꾜 가부시키가이샤

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2000-09-15|Publication of KR20000057309A

优先权:

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申请号 | 申请日 | 专利标题

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JP31774696|1996-11-28|

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JP96-317746|1996-11-28|