Methods and compositions for the treatment and prevention of hyperuricemia

专利摘要:
Insulin sensitivity enhancers, such as troglitazone, can treat and / or prevent hyperuricemia, and are therefore used for the treatment or prevention of diseases such as gout, urolithiasis, hyperuremic nephropathy and leish-Nihan syndrome.
公开号:KR19990045531A
申请号:KR1019980050484
申请日:1998-11-24
公开日:1999-06-25
发明作者:도시히꼬 후지와라；고이찌 이와사끼；히로요시 호리꼬시
申请人:가와무라 요시부미；상꾜 가부시키가이샤；
IPC主号:

专利说明:

Methods and compositions for the treatment and prevention of hyperuricemia
The present invention relates to methods and compositions for treating or preventing hyperuricemia, wherein the active ingredient is an insulin-resistant enhancing substance, commonly referred to as an "insulin sensitizer."
Hyperuricemia is a disease characterized by abnormally high concentrations of uric acid in the plasma. Plasma is saturated at 7.0 mg / dl of uric acid, and if the concentration of uric acid in the blood reaches or exceeds this concentration due to metabolic disorders associated with uric acid, then the symptom that appears is termed “hyperacidemia”. When the concentration of uric acid in the blood exceeds a certain level, uric acid may precipitate out of the monosodium urate and deposit in various tissues such as the joint cavity or the kidney. Such deposition can cause gout, nephropathy or vasculature. Hyperuricemia can occur due to decreased excretion of uric acid, excessive production of uric acid, or both. It can also lead to other diseases such as enzymatic abnormalities in purine metabolism. These are all so-called "primary causes". Other diseases, such as disorders of the hematopoietic organs and nephropathy, and administration of a medicament such as pyrazineamide or thiazide, lead to so-called hyperuremic acid called "secondary cause".
Examples of diseases caused by hyperuricemia include gout (including acute gouty arthritis and chronic gout stone arthritis), urolithiasis, hyperuricemia nephropathy (chronic gout nephropathy, acute hyperuricemia nephropathy) and Leshe-Nyhan syndrom).
Early treatment of hyperuricemia symptoms, especially gout, consists of administering analgesics such as colchicine and / or analgesic anti-inflammatory agents such as indomethacin. It is common practice to treat the long-term problems of hyperuricemia by controlling diet, for example by limiting the intake of alcohol or by controlling caloric intake. However, when these dietary treatments do not have sufficient effect, for example, prophylactic administration of analgesics such as colchicine, or uric acid excretion such as probeneside, sulfinpyrazone, ketophenylbutazone, bucolom or benzbromarin These disorders can be treated by administering accelerators or by inhibiting uric acid synthesis inhibitors such as allopurinol.
In recent years, insulin sensitivity enhancers have been used for the prevention or treatment of diabetes. As used herein, the term "insulin sensitivity enhancer" refers to a compound capable of improving the impaired activity of insulin even when endogenous insulin is present. A broad range of compounds includes "insulin sensitivity enhancers". Typical examples include various thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds. These are described, for example, below:
WO 94/01433 (= Japanese Patent Publication No. Hei 6-80667), Japanese Patent Publication No. Hei 4-69383, WO 92/02520 (= Japanese Laid-Open Publication (PCT) No.6-500538), WO 91/07107 (= Japanese Laid-open Patent No. Hei 3-170478 = Japanese Laid-Open Patent No. Hei 7-8862 ), US Patent No. 5 132 317 (= Japanese Patent Laid-Open No. Hei 3-90071), U.S. Patent No. Hei. Patent No. 4 897 405 (= Japanese Patent Laid-Open No. Hei 2-292272), WO 89/08651 (= Japanese Patent Laid-Open No. Hei 1-272574), U.S. Pat. Patent Nos. 5 061 717, 5 120 754, 5 223 522 (= Japanese Patent Laid-Open No. Hei 1-272573), U.S. Patent Nos. 5 002 953, 5 194 443, 5 232 925, 5 260 445 (= Japanese Patent Laid-Open No. Hei 1-131169), U.S. Patent No. Patent No. 4 918 091 (= Japanese Patent Laid-Open No. Sho 64-13076), U.S. Patent No. Patent No. 4 897 393, 4 948 900 (= Japanese Patent Laid-Open No. Sho 64-56675 = Japanese Patent Publication No. Hei 5-5832), U.S. Patent No. Patent No. 4 873 255 (= Japanese Patent Laid-Open No. Sho 64-38090), U.S. Patent No. 4 703 052 (= Japanese Patent Laid-Open No. Sho 61-271287 = Japanese Patent Publication No. Hei 5-86953), U.S. Patent No. Patent No. 4 687 777 (= Japanese Patent Laid-Open No. Sho 61-267580 = Japanese Patent Publication No. Hei 5-31079), U.S. Patent No. Patent No. 4 725 610 (= Japanese Patent Laid-Open No. Sho 61-85372 = Japanese Patent Publication No. Hei 5-66956), U.S. Patent No. Patent No. 4 572 912 (= Japanese Patent Laid-Open No. 60-51189 = Japanese Patent Publication No. 2-31079), U.S. Patent No. 60-51189. Patent No. 4 461 902 (= Japanese Patent Laid-Open No. Sho 58-118577 = Japanese Patent Publication No. 2-57546), U.S. Pat. Patent No. 4 287 200, 4 340 605, 4 438 141, 4 444 779 (= Japanese Patent Publication No. Sho 55-22636 = Japanese Patent Publication No. Sho 62-42903), EP 0 708 098A (Japanese Patent Publication No. Hei 9 -48779), EP 0 676 398A (= Japanese Patent Laid-Open No. Hei 7-330728), WO 95/18125, EP 0 745 600A, EP 0 332 332A (= Japanese Laid-Open Patent No. Hei 1-272574) and EP 0 604 983A (= Japanese Patent Laid-Open No. Hei 6-247945).
For example, 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione (hereinafter "troglitazone") is , Thiazolidine derivatives capable of enhancing insulin activity, and are known for the treatment and / or prevention of diabetes. Fujiwara et al., "Diabetes", 37, 1459 (1988); Hofmann C.A. et al., "Diabetes Care", 15, 1075 (1992). It has also been reported that the compounds have antioxidant activity and are therefore useful for the treatment of insulin-dependent diabetes mellitus (type 1 diabetes: IDDM) ["Tonyobyo (Diabetes)", 37 (2), 127-129 ( 1994).
However, it has already been reported that any of the compounds are useful for treating or preventing hyperuricemia.
For example, there are reports of clinical trial values regarding the relationship between administration of CS-045 (= troglitazone) and uric acid. According to this report, before administration of triglitazone, the concentration of uric acid is 4.7 ± 1.7, which is slightly reduced to 4.4 ± 1.4 after administration. This reduction is a normal change to be expected, and administration of triglitazone is not effective in treating or preventing hyperuricemia ["Rinsho lyaku (Clinical Medicine)", 9, Suppl. 3 (July issue), 14 (1993). ].
There is also a report on the relationship between hyperuricemia and insulin resistance. This means only a simple relationship, not that insulin sensitizers are effective in the treatment or prevention of hyperuricemia ["Tonyobyo (Diabetes)", 40, an extra number, 239, 2PO41 (1997), "Sougo Rinsho (Clinic All- round) ", 46 (8), 2128-2130 (1997) and" Mebio ", 14 (9), 90-96 (1997).
For example, 1- (3-bromobenzo [b] furan-2-ylsulfonyl) -hydantoin (Japanese Patent Laid-Open No. Hei 6-211657) or benzopyran derivative (Japanese Patent Laid-Open No. Sho 63-107971) For example, ethyl {[5-chloro-3- (2-methylphenyl) -4-oxo-4H-1-benzopyran-7-yl] oxy} acetate has been reported to be effective for the prevention and treatment of hyperuricemia. These are completely different from the structure of the compound of this invention.
Applicants have surprisingly found that certain classes of compounds that are insulin sensitivity enhancers can treat and / or prevent hyperuricemia.
Brief summary of the invention
It is an object of the present invention to provide a method for treating or preventing hyperuricemia.
Another object of the present invention is to provide a composition for treating or preventing hyperuricemia.
Still other objects and advantages of the present invention will become apparent from the following description.
The present invention therefore provides a method of treating or preventing peruuremia in a mammal having peruricemia, which comprises administering to said mammal an insulin sensitivity enhancer in an amount effective to alleviate or prevent peruuremia.
The invention also provides a composition comprising an effective amount of an insulin sensitivity enhancer, as a composition for treating or preventing hyperuricemia in a mammal having hyperuricemia.
Detailed description of the invention
In particular, the insulin sensitivity enhancer used in the present invention may be a thiazolidinedione compound, an iminothiazolidinone compound, a diiminothiazolidine compound, a thioxothiazolidinone compound, an iminotriazole compound, an oxazolidinedione compound. , Isoxazolidinedione compound and oxadiazolidinedione compound are preferably selected from the group consisting of thiazolidinedione compounds. Also included are pharmaceutically acceptable salts of these compounds.
Examples of insulin sensitivity enhancers that may be used in the present invention are as follows:
(I) Japanese Patent Laid-Open No. Sho 60-51189 (Japanese Patent Publication No. Hei 2-31079), U.S. As described in Patent No. 4 572 912 and European Patent Publication No. 139421 A:
(1) thiazolidine derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof:
[In the above formula:
R ^1a and R ^2a are the same or different and each represents a hydrogen atom or a C _1-5 alkyl group;
R ^3a is a hydrogen atom, a C _1-6 aliphatic acyl group, a C _6-8 cycloalkylcarbonyl group, an unsubstituted or a naphthoyl group or a benzoyl group substituted with one or more substituents selected from the group consisting of the substituents defined below A heterocyclic acyl group, a phenylacetyl group, a phenylpropionyl group, a phenylpropionyl group substituted with one or more halogen atoms, wherein the summoning portion is a 4 to 7 membered ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms; Phenylacetyl group, cinnamoyl group, C _2-7 alkoxycarbonyl group or benzyloxycarbonyl group;
(The above substituent χ is a C _1-4 alkyl group, C _1-4 alkoxy group, hydroxy group, halogen atom, amino group, C _1-4 monoalkylamino group, dialkylamino group or nitro group in which each alkyl group is C _1-4 ) ;
R ^4a and R ^5a are the same or different and each represents a hydrogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, or R ^4a and R ^5a simultaneously represent a C _1-4 alkylenedioxy group;
Y ^a and Z ^a are the same or different and each represents an oxygen atom or an imino group;
n ^a represents an integer of 1 to 3;
In the compound of formula 1, the definition of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , Y ^a , Z ^a and n ^a , types of pharmaceutically acceptable salts, methods of preparing compounds of formula 1, Details such as examples and manufacturing examples are disclosed in Japanese Patent Laid-Open No. Sho 60-51189 (Japanese Patent Publication No. Hei 2-31079), US Patent No.4572912, and European Patent Publication No. 139421A, which are incorporated herein by reference.
More specifically, when R ^1a , R ^2a , R ^4a , or R ^5a is an alkyl group, it may be a C _1-5 straight or branched alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl and 2-ethylpropyl groups. Among them, a C _1-4 alkyl group is preferred, and a methyl group is most preferred.
R ^3a represents a C _1-6 aliphatic acyl group, which may be a straight or branched chain group. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl and hexanoyl groups.
When R ^3a represents a cycloalkylcarbonyl group, it is C _6-8 (ie, C _5-7 in the cycloalkyl group). Examples of such groups include cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl groups.
When R ^3a represents a heterocyclic acyl group, it is a group in which the heterocyclic group is attached to a carbonyl group. The heterocyclic moiety is 4 to 7, more preferably a 5 or 6 membered ring, selected from the group consisting of 1 to 3, more preferably 1 or 2 and most preferably 1 is a nitrogen, oxygen or sulfur atom Hetero atom. When there are three hetero atoms in the heterocyclic group, they are all preferably nitrogen atoms, or preferably 1 or 2 nitrogen atoms and correspondingly 2 or 1 oxygen and / or sulfur atoms. The heterocyclic group is preferably aromatic. Examples of preferred heterocyclic acyl groups include furoyl (more preferably 2-furoyl), tenoyl (more preferably 3-tenoyl), 3-pyridinecarbonyl (nicotinoyl) and 4-pyridinecarbonyl And (isonicotinoyl) groups.
When R ^3a represents an alkoxycarbonyl group, it is a straight or branched alkoxycarbonyl group having an alkoxy moiety of C _1-6 , ie having 2 to 7 carbon atoms, for example methoxycarbonyl, ethoxycarbonyl, propoxycar Carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups, among which C _2-4 alkoxy Carbonyl groups are preferred, and ethoxycarbonyl groups are most preferred.
When the substituent χ is an alkyl group, it may be a C _1-4 straight or branched alkyl group, examples of which include the alkyl groups exemplified in connection with R ^1a and R ^2a .
When the substituent χ is an alkoxy group, it may be a C _1-4 straight or branched alkoxy group, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t- Butoxy groups, most preferably methoxy groups.
When the substituent χ represents a halogen atom, it may be, for example, a fluorine, chlorine, bromine or iodine atom.
When the substituent χ represents a C _1-4 alkylamino group, it may be straight or branched, for example methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino or t- It is a butylamino group, and among these, a methylamino group is the most preferable.
When the substituent χ represents a dialkylamino group in which each alkyl moiety is C _1-4 , these are straight or branched chain groups, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diiso Butylamino, di-sec-butylamino, di-t-butylamino, N -methyl- N -ethylamino, N -methyl- N -propylamino, N -methyl- N -isopropylamino, N -methyl- N -Butylamino, N -methyl- N -isobutylamino, N -methyl- N- sec-butylamino, N -methyl- N- t-butylamino, N -ethyl- N -propylamino, N -ethyl- N -isopropylamino, N - ethyl - N - bupil amino, N-ethyl-N-iso-butylamino, N-ethyl-N -sec- butyl amino, N - ethyl - N -t- butyl amino, N - propyl - N -isopropylamino, N -propyl- N -butylamino, N -propyl- N -isobutylamino, N -propyl- N- sec-butylamino, N -propyl- N- t-butylamino, N -iso Propyl- N -butyl- Mino, N -isopropyl- N -isobutylamino, N -isopropyl- N- sec-butylamino, N -isopropyl- N- t-butylamino, N -butyl- N -isobutylamino, N -butyl N- sec-butylamino, N -butyl- N- t-butylamino, N -isobutyl- N- sec-butylamino, N -isobutyl- N- t-butylamino and N- sec-butyl- N It is a -t- butylamino group, Among these, a dimethylamino group is preferable.
When R ^4a and R ^5a represent an alkoxy group, it may be a C _1-5 straight or branched alkoxy group, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-part Oxy, t-butoxy and pentyloxy groups, among which C _1-4 alkoxy groups are preferred, and methoxy groups are most preferred.
When R ^4a and R ^5a together represent an alkylenedioxy group, it is C _1-4 , examples include methylenedioxy, ethylenedioxy, propylenedioxy, trimethylenedioxy and tetramethylenedioxy groups, these Of these, methylenedioxy and ethylenedioxy groups are preferred.
Preferred examples of the compound of formula 1 include:
(2) A compound in which R ^1a represents a C _1-4 alkyl group.
(3) A compound in which R ^2a represents a hydrogen atom or a C _1-3 alkyl group.
(4) A compound in which R ^3a represents a hydrogen atom, a C _1-4 aliphatic acyl group, an unsubstituted benzoyl or naphthoyl group, or a C _2-4 alkoxycarbonyl group.
(5) A compound in which R ^4a represents a C _1-4 alkyl group.
(6) A compound in which R ^5a represents a hydrogen atom or a C _1-3 alkyl group.
(7) the following compounds:
[R ^1a represents a C _1-4 alkyl group,
R ^2a represents a hydrogen atom or a C _1-3 alkyl group,
R ^3a represents a hydrogen atom, a C _1-4 aliphatic acyl group, an unsubstituted benzoyl or naphthoyl group, or a C _2-4 alkoxycarbonyl group,
R ^4a represents a C _1-4 alkyl group,
R ^5a represents a hydrogen atom or a C _1-3 alkyl group.
(8) A compound in which R ^3a represents a hydrogen atom, an acetyl group, a benzoyl group, or an ethoxycarbonyl group.
(9) the following compounds:
[R ^1a represents a C _1-4 alkyl group,
R ^2a represents a hydrogen atom or a C _1-3 alkyl group,
R ^3a represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group,
R ^4a represents a C _1-4 alkyl group,
R ^5a represents a hydrogen atom or a C _1-3 alkyl group.
(10) A compound in which R ^1a represents a methyl group.
(11) A compound in which R ^2a represents a hydrogen atom or a methyl group.
(12) A compound in which R ^3a represents a hydrogen atom, an acetyl group, or an ethoxycarbonyl group.
(13) A compound in which R ^4a represents a methyl group or a t-butyl group.
(14) A compound in which R ^5a represents a hydrogen atom or a methyl group.
(15) the following compounds:
[R ^1a represents a methyl group,
R ^2a represents a hydrogen atom or a methyl group,
R ^3a represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group,
R ^4a represents a methyl group or a t-butyl group,
R ^5a represents a hydrogen atom or a methyl group.
(16) a compound selected from:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone),
ii) 5- [4- (6-hydroxy-2-methyl-7-t-butylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iv) 5- [4- (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
v) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and
vi) 5- [4- (6-ethoxycarbonyl-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.
(II) Japanese Patent Laid-Open No. Sho 61-267580 (Japanese Patent Publication No. Hei 5-66956) and U.S. Patent No. 4 687 777 describes the following:
(1) thiazolidine derivatives of formula (2) and their pharmaceutically acceptable salts:
In the compound of the formula (2), details such as types of pharmaceutically acceptable salts, preparation methods, examples of compounds and preparation examples are given in Japanese Patent Laid-Open No. Sho 61-267580 (Japanese Patent Laid-Open No. Hei 5-66956), U.S. Pat. Patent No. 4 687 777, which is incorporated herein by reference.
Preferred examples of the compound of formula 2 include:
(2) a compound selected from the following;
i) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
ii) 5- {4- [2- (4-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
iii) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione (hereinafter referred to as "pioglitazone") and
iv) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione.
(III) Japanese Patent Laid-Open No. Sho 61-271287 (Japanese Patent Publication No. Hei 5-86953) and U.S. In patent No. 4 703 052 the following is described:
(1) a compound of Formula 3 or a pharmaceutically acceptable salt thereof:
[In the above formula;
Represents a single or double bond,
n ^c represents 0, 1 or 2,
X ^c is an oxygen atom, a sulfur atom, a sulfinyl group Or sulfonyl groups Represents;
R ^c represents a hydrogen atom, a methyl group or an ethyl group;
R ^1c is a C _5-7 cycloalkyl group, methyl group, pyridyl group, thienyl group, furyl group, naphthyl group, p -biphenylyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, formula C ₆ H ₄ W ^2c (wherein W ^2c represents a hydrogen atom, a hydroxy group, a halogen atom (eg, a fluorine, chlorine or bromine atom), a C _1-4 alkyl group, a C _1-4 alkoxy group or a C _1-4 alkylthio group) or a formula alk-W ^1c (wherein, alk is C _1-6 alkylene group, ethyl or isopropyl dengi Li represents a propylidene, W ^1c is coming hydrogen atom, a hydroxy group, C _1-4 alkoxy, C _1-4 alkylthio, pyridinium Dill group, furyl group, thienyl group, tetrahydrofural group, tetrahydrothienyl group, naphthyl group, C _5-7 cycloalkyl group or formula C ₆ H ₄ W ^2c (wherein W ^2c is the same as defined above) A C _5-7 cycloalkyl group substituted with;
R ^2c represents a hydrogen atom or a methyl group;
R ^3c represents a hydrogen atom, a C _1-6 alkyl group, a formula C ₆ H ₄ W ^2c (wherein W ^2c is the same as defined above) or a benzyl group;
R ^4c represents a hydrogen atom,
or
R ^1c and R ^2c together form a C _4-6 alkylene group; R ^3c and R ^4c both represent a hydrogen atom;
or
R ^3c and R ^4c together form a C _4-6 alkylene group; R ^1c and R ^2c both represent a hydrogen atom;
or
R ^2c and R ^3c together form a C _4-6 alkylene group; R ^1c and R ^4c both represent a hydrogen atom.
In the compounds of the formula (3), details such as the definitions of R ^1c , R ^2c , R ^3c , W ^1c , W ^2c and alk, types of pharmaceutically acceptable salts, preparation methods and preparation examples of the compounds of formula (3) are described in Japan. Patent Publication No. Sho 61-271287 (Japanese Patent Publication No. Hei 5-86953), US Patent No. 4 703 052, which are incorporated herein by reference.
For example, when R ^1c or W ^1c is a cycloalkyl group, it may be a cyclopentyl, cyclohexyl or cycloheptyl group.
When W ^2c represents an alkyl group or an alkoxy group, or W ^1c represents an alkoxy group, this may be the same as the definitions and examples for the substituent χ above.
When W ^1c or W ^2c is an alkylthio group, it may be a C _1-4 straight or branched alkylthio group, for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec -Butylthio and t-butylthio groups, with methylthio groups being most preferred.
When alk represents a C _1-6 alkyl group, it may be C _1-6 straight or branched chain, for example methylene, methylmethylene, ethylene, ethylidene, propylene, isopropylidene, propylidene, trimethylene, tetramethylene , 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, hexamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1-dimethyltetramethylene and 2 A 2, 2-dimethyl tetramethylene group is contained, Among these, a C _1-4 linear or branched alkylene group is preferable, and a methylene or ethylene group is more preferable.
When R ^3c represents a C _1-6 alkyl group, it may be C _1-6 , preferably C _1-4 straight or branched chain, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3 -Dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups. Among them, C _1-4 alkyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups are preferred, and methyl groups are most preferred.
When R ^1c and R ^2c or R ^2c and R ^3c or R ^3c and R ^4c represent C _4-6 alkylene groups, they may be straight or branched chain groups, for example tetramethylene, 1-methyl-trimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, hexamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1-dimethyl-tetramethylene and 2,2-dimethyltetramethylene Contains groups.
When W ^1c or W ^2c represents a C _1-4 alkoxy group or W ^2c represents a halogen atom or a C _1-4 alkyl group, these may be the same as the above examples for the substituent χ.
Preferred examples of the compound of formula 3 include:
(2) The compound described in (1), wherein R ^c represents a hydrogen atom, Represents a single bond, and n ^c represents 0 or 1.
(3) As the compound described in (2), each of R ^2c , R ^3c and R ^4c represents a hydrogen atom, R ^1c represents a hydrogen atom, a cyclohexyl group, formula C ₆ H ₄ W ^2c (wherein W ^2c is A hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, or alk-W ^1c (wherein alk represents a C _1-4 alkylene group, ethylidene group or isopropylidene group, and W ^1c is A compound which represents a hydrogen atom, a hydroxyl group, a C _1-4 alkoxy group, a cyclohexyl group, or a formula C ₆ H ₄ W ^2c (wherein W ^2c is the same as defined above).
(4) The compound described in (3), wherein X ^c represents an oxygen atom, R ^1c represents a cyclohexyl group, cyclohexylmethyl group, benzyl group, fluorobenzyl group, C _1-4 alkyl group, hydroxymethyl group, methoxy The compound which shows a methyl group or an ethoxy ethyl group.
(5) The compound described in (4), wherein R ^1c represents a benzyl group.
(6) The compound described in (5), wherein 5-[(2-benzyl-2,3-dihydrobenzofuran-5-yl) methyl] thiazolidine-2,4-dione or 5-[(2 -Benzyl-3,4-dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione (englitazone) or a salt thereof, preferably a sodium salt thereof.
(7) The compound described in (2), wherein R ^2c and R ^3c together form a tetramethylene group, R ^1c and R ^4c each represent a hydrogen atom, and X ^c represents an oxygen atom.
(8) As the compound described in (2), (a) R ^1c and R ^2c together form a pentamethylene group, R ^3c and R ^4c each represent a hydrogen atom, and X ^c represents an oxygen atom; Or (b) R ^3c and R ^4c together form a pentamethylene group, R ^1c and R ^2c each represent a hydrogen atom, and X ^c represents an oxygen atom.
(9) The compound described in (3), wherein n ^c represents 0, R ^1c represents a hydrogen atom, a methyl group or a benzyl group, and X ^c represents a sulfur atom or a sulfonyl group To represent a compound.
(IV) Japanese Patent Publication No. Hei 1-131169 or U.S. In patent No. 5 002 953, No. 5 914 443, No. 5 232 925 or No. 5 260 445 are described:
(1) a compound of formula 4 and pharmaceutically acceptable salts thereof:
[In the above formula:
A ^1d represents a substituted or unsubstituted aromatic heterocyclic group,
R ^1d represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl portion of the aralkyl group may be substituted or unsubstituted) or a substituted or unsubstituted aryl group,
R ^2d and R ^3d each represent a hydrogen atom or together form a bond,
A ^2d represents a benzene ring having up to 5 substituents in total,
n ^d represents an integer of 2 to 6;
In the compound of formula (4), the definition of A ^1d , R ^1d , R ^2d , R ^3d , A ^2d and n ^d, the kind of pharmaceutically acceptable salts, the preparation method of the compound of formula (4), preparation examples and preferred compounds Details of Japanese Patent Publication No. Hei 1-131169 or US Pat. No. 5 002 953, No. 5 194 443, No. 5 232 925 or No. 5 260 445, which are incorporated herein by reference.
For example, when A ^1d represents a substituted or unsubstituted aromatic heterocyclic group, it is a single aromatic ring that is a 5 to 7 membered ring, wherein 1 to 3 atoms are selected from the group consisting of nitrogen, oxygen and sulfur atoms. Or may be a fused ring system in which at least one of the rings is an aromatic heterocyclic group and the ring is an aromatic heterocyclic group or a carbocyclic aryl group as defined above. When there are three hetero atoms in the aromatic heterocyclic group, it is preferable that all are nitrogen atoms, or 1 or 2 are nitrogen atoms and the corresponding 2 or 1 are oxygen and / or sulfur atoms.
Examples of monocyclic aromatic heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadia Zolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Preferred groups are 5- to 7-membered aromatic heterocyclic groups, which have at least one nitrogen atom and optionally additional nitrogen, oxygen and sulfur atoms. Examples of such groups include pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, Thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Among these, pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups are more preferable.
The various aromatic heterocyclic groups mentioned above may form fused rings with other ring groups, and examples of such fused ring systems include indolyl, benzofuryl, benzothienyl, benzoxazolyl, benzoimidazolyl, isoquinolyl, Quinolyl and quinoxalyl groups.
Such aromatic heterocyclic groups may be unsubstituted or substituted with one or more substituents selected from the group consisting of substituents π to be defined below. There is no particular limitation on the number of substituents, but there may be limitations on the number of substitutable positions and sometimes steric hindrance. However, in general, when the group is substituted, 1 to 3 substituents are preferred.
Substituent π is selected from the group consisting of:
[Halogen atoms such as fluorine, chlorine, bromine or iodine atoms;
C _1-6 alkyl groups such as those defined and exemplified in R ^3c above;
C _1-6 haloalkyl group, which any alkyl group defined and exemplified for R ^3c is substituted with one or more of the above halogen atoms, such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluor Chloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,2-trichloroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 3-fluoropropyl, 4-chlorobutyl, 5-fluoropentyl and 6-fluorohexyl groups;
C _1-6 alkoxy group (which may be C _1-6 , preferably C _1-4 straight or branched chain) such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -Butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyl-oxy, 2-methylbutoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2 -Methylpentyloxy, 1-methylpentyloxy, 3,3-dimethyl-butoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylpart Oxy, 2,3-dimethylbutoxy and 2-ethylbutoxy groups, among which C _1-4 alkoxy groups, in particular methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups Preferably, a methoxy group is most preferred;
C _1-6 aliphatic carboxyl acyl groups such as those defined and exemplified with respect to R ^1d ;
C _1-6 alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, sec-butanesulfonyl, t-butanesulfonyl, pentanesul Phenyl, isopentansulfonyl, neopentanesulfonyl, 2-methylbutane-sulfonyl, 1-ethylpropanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2-methylpentanesul Ponyl, 1-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethyl-butanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3- Dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl and 2-ethylbutanesulfonyl groups;
C _1-6 haloalkanesulfonyl groups such as fluoromethanesulfonyl, chloromethanesulfonyl, bromomethanesulfonyl, iodomethanesulfonyl, trifluoromethanesulfonyl, trichloromethanesulfonyl, 2-fluoro Roethanesulfonyl, 2-chloroethanesulfonyl, 2-bromoethanesulfonyl, 2-iodoethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, 2,2-difluoroethanesulfonyl , 2,2,2-trichloroethanesulfonyl, 2,2-dichloroethanesulfonyl, 2,2-dibromo-ethanesulfonyl, 3-fluoropropanesulfonyl, 4-chlorobutanesulfonyl, 5 -Fluoropentanesulfonyl and 6-fluorohexanesulfonyl groups;
Hydroxyl group, carboxy group;
Alkoxycarbonyl groups which are C _1-6 in the alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-carbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbon Carbonyl, t-butoxy-carbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, 4 -Methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxy-carbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbon Carbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethyl-butoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl and 2-ethylbutoxycarbonyl among these, C _2-5 alkoxycarbonyl group, especially methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl Is carbonyl, butoxycarbonyl and isobutoxy groups are preferred, the methoxycarbonyl group is most preferred;
C _1-6 acylamino group (acyl moiety may be any of C _1-6 acyl groups included in the group represented by R ^1d );
C _1-6 alkanesulfonylamino group (alkanesulfonyl moiety may be any of the alkanesulfonyl groups exemplified above);
C _1-6 haloalkanesulfonylamino group (the haloalkanesulfonyl moiety may be any of the haloalkanesulfonyl groups exemplified above);
Amino groups, cyano groups, and
Alkylenedioxy groups such as those defined and exemplified with respect to R ^4d ;
A C _1-8 alkylene group (fused with an aryl or heterocyclic ring to form a cycloalkyl group), which may be any of the alkylene groups defined and exemplified for alk and may be a higher group such as hexamethylene and octamethylene have].
When R ^1d represents an alkyl group, it is preferably C _1-6 and may be any of the groups defined and exemplified for R ^3c .
When R ^1d represents an acyl group, it may be for example:
[Aliphatic acyl groups, preferably: C _1-25 , more preferably C _1-20 , more preferably C _1-6 , most preferably C _1-4 alkanoyl groups (eg formyl, acetyl , Butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl and stearoyl groups, acetyl among them Group is most preferred); C _2-6 halogenated alkanoyl groups, especially halogenated acetyl groups (eg, chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups); Lower alkoxyalkanoyl groups, wherein the alkoxy moiety is C _1-5 , preferably C _1-3 , and the alkanoyl moiety is C _2-6 , preferably an acetyl group (eg, methoxyacetyl group); Or unsubstituted homologues of the groups, in particular C _3-6 alkenoyl or alkinoyl groups [eg acryloyl, methacryloyl, propioloyl, crotonoyl, isocrotonoyl and ( E ) -2 -Methyl-2-butenoyl group;
Aromatic acyl groups, preferably arylcarbonyl groups, wherein the aryl moiety has C _6-14 , more preferably C _6-10 , more preferably C ₆ or C ₁₀ , most preferably C ₆ ring, and Bocyclic group (which is unsubstituted or has 1 to 5, preferably 1 to 3 substituents selected from the group consisting of said substituents π), preferably: an unsubstituted group (eg benzoyl, α-naphthoyl and β-naphthoyl group); Halogenated arylcarbonyl groups (eg, 2-bromo-benzoyl and 4-chlorobenzoyl groups); Each alkyl substituent is C _1-5 , preferably C _1-4 , a lower alkyl-substituted arylcarbonyl group (eg, 2,4,6-trimethylbenzoyl and 4-toluoyl group); Lower alkoxy-substituted arylcarbonyl groups (eg, 4-anisoyl groups), wherein each alkoxy substituent is preferably C _1-5 , preferably C _1-4 ; Nitro-substituted arylcarbonyl groups (eg, 4-nitrobenzoyl and 2-nitrobenzoyl groups); Lower alkoxycarbonyl-substituted arylcarbonyl groups wherein each alkoxycarbonyl substituent is C _2-6 [eg, 2- (methoxycarbonyl) benzoyl group]; Or an aryl substituent is the same as defined above except that the aryl group is not itself substituted with an aryl group when further substituted with an aryl group, an aryl-substituted arylcarbonyl group (eg, 4-phenylbenzoyl group);
Alkoxycarbonyl groups, in particular C _2-7 , more preferably C _2-5 , are unsubstituted (eg methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups) or halogen atoms or tri -A substituted silyl group, that is, a group substituted with a tri (lower alkylsilyl) group (eg, 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl group);
Alkenyloxycarbonyl groups (eg, vinyloxycarbonyl and allyloxycarbonyl groups), wherein the alkenyl moiety is C _2-6 , preferably C _2-4 ; And
Aralkyloxycarbonyl group, wherein the aralkyl moiety is the same as the following definitions and examples, and when the aryl ring is substituted, it is preferable to have one or two lower alkoxy or nitro substituents (eg benzyloxycarbonyl, 4 -Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl group).
When R ^1d represents an aralkyl group, it is preferably a group in which the C _1-6 alkyl group is an alkyl group substituted with one or more, preferably 1 to 3 aryl groups, which are one or more substituents selected from the group consisting of said substituents π, Preferably it may be substituted with one to three. Preferred examples of the aralkyl group include C _1-4 substituted with 1 to 3 aryl groups, more preferably C _1-3 , most preferably C ₁ or C ₂ alkyl groups, which are unsubstituted (eg, Benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl groups) or aryl Moieties may be substituted by lower alkyl groups, lower alkoxy groups, nitro groups, halogen atoms, cyano groups, or C _1-3 alkylenedioxy groups, preferably methylenedioxy groups [eg, 4-methylbenzyl, 2,4 , 6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzoyl, 4-bromobenzyl , 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl and piperonyl group].
When R ^1d represents a substituted or unsubstituted aryl group, it is a carbocyclicaryl group which is a ring of C _6-14 , preferably C _6-10 , most preferably C ₆ or C ₁₀ . The group may have a single aromatic ring or may have two or more fused aromatic rings. The group may be unsubstituted or substituted with one or more substituents selected from the group consisting of the substituents π as defined above. There is no particular limitation on the number of substituents, but there may be limitations on the number of substitutable positions and sometimes steric hindrance. However, in general, when the group is substituted, 1 to 3 substituents are preferred. Examples of the unsubstituted group include phenyl, 1-naphthyl, 2-naphthyl, indenyl, phenanthrenyl and anthracenyl groups, among them, phenyl and naphthyl groups are preferred, and phenyl groups are most preferred.
Examples of the unsubstituted group include 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,3,4 -Trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl , 4-ethoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3 -Dimethyl-phenyl, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,6-dimethyl-phenyl, 3,4,5-trimethylphenyl, 2,4,5-tri Methylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4- Chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichloro- Neyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4,5-trichloro-phenyl, 2,4,5-trichlorophenyl, 2,3,4- Trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-tri-chlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro Rophenyl, 2,4-difluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 3, 4,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4-bis (trifluoro Methyl) phenyl, 2,3-bis (trifluoromethyl) phenyl, 3,4-bis (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) -phenyl, 2,6-bis ( Trifluoromethyl) phenyl, 3,4,5-tris (trifluoromethyl) phenyl, 2,4,5-tris- (trifluoromethyl) phenyl, 2-acetamidophenyl, 3-acetamido Phenyl, 4-acet Not shown, phenyl, and a 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, and 4-methoxycarbonyl phenyl group.
When A ^2d represents a benzene ring having a total number of substituents of 5 or less, it is preferably selected from the group consisting of the substituents π defined above.
Preferred examples of the compound of formula 4 include:
(2) The compound described in (1), wherein A ^1d represents a substituted or unsubstituted, single ring or fused ring aromatic heterocyclic group having 4 or more heteroatoms selected from oxygen, sulfur and nitrogen atoms.
(3) The compound described in (1) or (2), wherein A ^1d represents a group of formula (a), formula (b) or formula (c):
(a) (b) (c)
[Wherein, R ^4d and R ^5d each independently represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group; Or R ^4d and R ^5d together with the carbon atom to which they are attached form a benzene ring, wherein each carbon atom of the benzene ring may be substituted or unsubstituted; In the group of the formula (a), X ^d represents an oxygen or sulfur atom.
(4) The compound described in (3), wherein each of R ^4d and R ^5d independently represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted phenyl group.
(5) The compound described in (4), wherein R ^4d and R ^5d together form a group of formula (d):
(d)
[Wherein R ^6d and R ^7d each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group or an alkoxy group].
(6) The compound described in (5), wherein each of R ^6d and R ^7d represents a hydrogen atom.
(7) The compound described in any one of (1) to (6), wherein A ^2d represents the formula (e) below:
(e)
[Wherein R ^8d and R ^9d each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group or an alkoxy group].
(8) The compound described in (7), wherein each of R ^8d and R ^9d represents a hydrogen atom.
(9) the compound described in (1) which is the following formula (f) and a pharmaceutically acceptable salt thereof:
(f)
[Wherein A ^1d , R ^1d , R ^2d , R ^3d and n ^d are the same as defined in formula (4) of (1), and R ^8d and R ^9d are as defined in formula (a) of (7) same].
(10) The compound described in any of (1) to (9), wherein n ^d is an integer of 2 or 3.
(11) The compound described in any one of (1) to (10), wherein R ^1d is a methyl group.
(12) The compound of (1) selected from:
i) 5- (4- {2- [N-methyl-N- (2-benzothiazolyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
ii) 5- (4- {2- [N-methyl-N- (2-pyrimidinyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
iii) 5- (4- {2- [N-methyl-N- (4,5-dimethylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
iv) 5- {4- [2- (N-methyl-N-thiazol-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
v) 5- (4- {2- [N-methyl-N- (4-phenylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
vi) 5- (4- {2- [N-methyl-N- (4-phenyl-5-methylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
vii) 5- (4- {2- [N-methyl-N- (4-methyl-5-phenylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
viii) 5- (4- {2- [N-methyl-N- (5-phenyloxazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
ix) 5- (4- {2- [N-methyl-N- (4,5-dimethyloxazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
x) 5- {4- [2- (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xi) 5- {4- [2- (N-acetyl-N-pyrimidin-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xii) 5- {4- [2- (N-benzothiazol-2-yl-N-benzylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xiii) 5- {4- [3- (N-methyl-N-benzoxazol-2-ylamino) propoxy] benzyl} thiazolidine-2,4-dione, and
xiv) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione (hereinafter referred to as "rosiglitazone").
(13) The compound described in (1), wherein 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) -ethoxy] benzyl} thiazolidine-2,4-dione (Loziglitazone).
In (2) to (11), details such as definitions of R ^4d , R ^5d , R ^6d , R ^7d , R ^8d and R ^9d are described in Japanese Patent Laid-Open No. Hei 1-131169 or US Pat. No. 5 002 953, No. 5 194 443, No. 5 194 925 or No. 5 260 445, which are incorporated herein by reference.
(V) Japanese Patent Publication No. Hei 9-48779 and European Patent Publication No.708098A describe the following:
(1) an oxime derivative of the formula (5) and a pharmaceutically acceptable salt thereof:
[In the above formula:
R ^1e represents a hydrogen atom or a C _1-6 straight or branched alkyl group,
R ^2e represents a C _2-6 straight or branched alkylene group,
R ^3e is a hydrogen atom, a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain alkoxy group, a C _1-4 straight or branched chain alkylthio group, a halogen atom, a nitro group, an amino group, a C _1- group _{A four} straight or branched monoalkylamino group, a C _1-4 straight or branched dialkylamino group, a C _6-10 aryl group or a C _7-12 aralkyl group,
X ^e represents a C _6-10 aryl group unsubstituted or substituted with 1 to 3 of the substituents α defined below, or a C _1-3 heteroaromatic group unsubstituted or substituted with 1 to 3 of the substituents α defined below,
(The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain acyl Oxy groups, (v) C _1-4 straight or branched alkoxy groups, (vi) C _1-4 straight or branched alkylenedioxy groups, (vii) C _7-12 aralkyloxy groups, (viii) C _{1 -4} straight or branched alkylthio group, (ix) C _1-4 straight or branched alkylsulfonyl group, (x) halogen atom, (xi) nitro group, (xii) amino group, (xiii) C _1-4 straight chain Or a branched monoalkylamino group, (xiv) a straight or branched dialkylamino group in which each alkyl group is C _1-4 , (xv) a C _7-12 aralkyl group, (xvi) an unsubstituted or substituent β as defined below. substituted with one or more substituents selected from the group C _6-10 aryl group, (xvii) substituted C is unsubstituted or one substituent selected from the group consisting of substituents β defined above _6-10 aryloxy , (Xviii) substituted with one or more substituents selected from the group consisting of substituents β defined an unsubstituted or a C _6-10 arylthio group, selected from the group consisting of (xix) unsubstituted or substituents β defined below a C _6-10 arylsulfonyl group optionally substituted with one substituent, (xx) an unsubstituted or a substituted with one or more substituents selected from the group consisting of substituents β defined C _6-10 arylsulfonyl group (for the amino nitrogen atom is part Unsubstituted or substituted with a C _1-6 straight or branched alkyl group) (xxi) heteroaromatic group, (xxii) heteroaryloxy group, (xxiii) heteroarylthio group, (xxiv) heteroarylsulfonyl group or (xxv) hetero Aromatic sulfonylamino group (where the nitrogen atom of the amino portion is unsubstituted or substituted with a C _1-6 straight or branched alkyl group);
(The above substituent β is a C _1-6 straight or branched chain alkyl group, C _1-4 straight or branched chain haloalkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom or C _1-4 straight or branched chain alkyl group. A lendioxy group);
Y ^e represents an oxygen atom, a sulfur atom or a group of the formula> NR ^4e (wherein R ^4e represents a hydrogen atom, a C _1-6 straight or branched alkyl group or a C _1-8 straight or branched acyl group),
Z ^e is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl or 3 , 5-dioxooxazolidin-2-ylmethyl group].
In the compound of formula 5, R^1e, R^2e, R^3e, R^4e, α, β, X^e, Y^eAnd Z^eDefinitions, types of pharmaceutically acceptable salts, methods for preparing compounds of formula (5), examples of compounds, and preparations are given in Japanese Patent Laid-Open No. Hei 9-48779 and European Patent Publication No. 708098A, incorporated herein by reference.
For example, when R ^3e , substituent α or substituent β represent a C _1-4 alkoxy group or halogen atom, or when R ^3e or substituent α represent a mono- or di-alkylamino group, these are defined above with respect to substituent χ and It may be the same as the example.
When R ^3e , substituent α or substituent β represent an alkylenedioxy group, they may be the same as the above definitions and examples for R ^4a and R ^5a .
When R ^3e or substituent α represents an alkylthio group, they may be the same as the above definitions and examples for W ^2c .
When R ^3e , substituent α, substituent β or R ^4e represent a C _1-6 alkyl group, they may be identical to the above definitions and examples for R ^3c .
When X ^e or the substituent α represents a heteroaromatic group, this may be the same as the above definition and example for A ^1d .
When R ^3e or substituent α represents an aralkyl group, or when R ^3e , X ^e or substituent α represents an aryl group, they may be the same as the above definitions and examples for R ^1d .
When R ^2e represents a C _2-6 straight or branched alkylene group, it may be selected from the alkylene groups exemplified and exemplified above for alk.
When substituent α or substituent β represent a haloalkyl group, the alkyl moiety may be a C _1-6 , preferably C _1-3 straight or branched chain group. There is no particular limitation on the number of halogen atoms, but there may be a limit on the number of substitutable positions; In general, however, one to three halogen atoms are preferred. Examples of such groups include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2,2,2-trichloro Roethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 2,2-dibromoethyl, 3-bromo -Propyl, 3-chloropropyl, 3-fluoropropyl, 3-iodopropyl, 4-bromobutyl, 4-chlorobutyl, 4-fluorobutyl, 4-iodobutyl, 5-bromopentyl, 5 -Chloropentyl, 5-fluoropentyl, 5-iodopentyl, 6-bromohexyl, 6-chlorohexyl, 6-fluorohexyl and 6-iodohexyl groups, among which trifluoromethyl , 2-bromoethyl, 2-chloroethyl and 2-fluoroethyl groups are preferred.
When the substituent α represents an acyloxy group, it is C _1-4 and may be a straight or branched chain aliphatic group. Examples of such groups include formyloxy, acetoxy, propionyloxy, butyryloxy and isobutyryloxy groups.
When the substituent α represents an aralkyloxy, aryloxy, arylthio, arylsulfonyl, arylsulfonylamino, heteroaryloxy, heteroarylthio, heteroarylsulfonyl or heteroarylsulfonylamino group, aralkyl, aryl or hetero The aryl moiety may be the same as defined and illustrated above.
When the substituent α represents a C _1-8 acyl group, aliphatic or carbocyclic aromatic groups are preferred, examples of which include:
[Aliphatic acyl groups, preferably C _1-8 , more preferably C _1-6 , most preferably C _1-4 alkanoyl groups such as propyl, acetyl, propionyl, butyryl, isobutyryl , Pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl and octanoyl groups, among these, an acetyl group is most preferred; C _2-6 allogenated alkanoyl groups, especially halogenated acetyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups; Lower alkoxyalkanoyl groups, such as methoxyacetyl groups, wherein the alkoxy moiety is C _1-5 , preferably C _1-3 , and the alkanoyl moiety is C _2-6 , preferably the acetyl group; And unsubstituted homologues of the groups, in particular C _3-6 alkenoyl or alkinoyl groups, such as acryloyl, methacryloyl, propionyl, crotonoyl, isocrotonoyl and ( E ) -2-methyl -2-butenoyl group; And
Aromatic acyl groups, preferably arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl groups; Halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl group; Lower alkyl-substituted arylcarbonyl groups such as 4-toluyl group; Lower alkoxy-substituted arylcarbonyl groups such as 4-anisoyl group; Nitro-substituted acrylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl groups; And lower alkoxycarbonyl-substituted arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl group.
Preferred examples of the compound of formula 5 include:
(2) The compound described in (1), wherein R ^1e represents a hydrogen atom or a C _1-4 straight or branched alkyl group.
(3) The compound described in (1), wherein R ^1e represents a hydrogen atom or a C _1-3 straight or branched alkyl group.
(4) The compound described in (1), wherein R ^1e represents a hydrogen atom, a methyl group, or an ethyl group.
(5) The compound described in (1), wherein R ^1e represents a methyl or ethyl group.
(6) The compound described in (1), wherein R ^2e represents a C _2-5 straight or branched alkylene group.
(7) The compound described in (1), wherein R ^2e represents a C ₂ or C ₃ straight or branched chain alkylene group.
(8) The compound described in (1), wherein R ^2e represents an ethylene, trimethylene or methylethylene group.
(9) The compound described in (1), wherein R ^2e represents an ethylene group.
(10) The compound described in (1), wherein R ^3e represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a methoxy group, an ethoxy group, a methylthio group, an ethylthio group, or a halogen atom.
(11) The compound described in (1), wherein R ^3e represents a hydrogen atom.
(12) The compound described in (1), wherein X ^e is an unsubstituted or substituted C _1-6 aryl group substituted with 1 to 3 substituents selected from the group consisting of α, or 1 to 3 is nitrogen, oxygen or A heteroaromatic group having a 5 to 10 membered ring (which may have 1 or 2 rings) which is a hetero-atom selected from the group consisting of sulfur atoms and substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α compound,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain. Acyloxy groups, (v) C _1-4 straight or branched alkoxy groups, (vi) C _1-4 straight or branched alkylenedioxy groups, (vii) C _7-12 straight or branched chain aralkyloxy groups, (viii) a C _1-4 straight or branched alkylthio group, (ix) a C _1-4 straight or branched alkylsulfonyloxy group, (x) a halogen atom, (xi) a C _7-12 aralkyl group, (xii) A phenyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituted β, (xiii) a phenoxy group substituted with one or more substituents selected from the group consisting of unsubstituted or substituted β, (xiv) an unsubstituted or substituted β A phenylthio group substituted with one or more substituents selected from the group, (xv) unsubstituted or substituted β selected from the group consisting of A phenylsulfonyl substituted with one or more substituent groups, (xvi) A is substituted at least one group selected from the group consisting of unsubstituted or substituents β, is substituted by a nitrogen atom is unsubstituted or C _1-6 linear or branched alkyl group of the amino part phenylsulfanyl Phenylamino group, (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfonyl group, (xviii) nitrogen atom unsubstituted or C _1-6 straight chain Or a pyridylsulfonylamino group in which the nitrogen atom of the imidazolyl group and / or (xix) amino moiety substituted with a branched alkyl group is unsubstituted or substituted with a C _1-6 straight or branched alkyl group;
The substituent β is a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain haloalkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom or a C _1-4 straight or branched chain alkylenedi Oxy group].
(13) The compound described in (1), wherein X ^e is an unsubstituted or substituted C _6-10 aryl group substituted with 1 to 3 substituents selected from the group consisting of α or 1 to 3 nitrogen, oxygen or sulfur atoms A compound having a 5 to 10 membered ring (which may have 1 or 2 rings) which is a hetero-atom selected from the group consisting of and having a heteroaromatic group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents a ,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain. Alkanoyloxy groups, (v) C _1-4 straight or branched chain alkoxy groups, (vi) C _1-4 straight or branched chain alkylenedioxy groups, (vii) C _7-12 straight or branched chain aralkyloxy groups (viii) a C _1-4 straight or branched alkylthio group, (ix) a C _1-4 straight or branched alkylsulfonyloxy group, (x) a fluorine, chlorine or bromine atom, (xi) C _7-12 A phenyl group substituted with one or more substituents selected from the group consisting of an alkyl group, (xii) unsubstituted or substituent β, (xiii) a phenoxy group substituted with one or more substituents selected from the group consisting of unsubstituted or substituent β, (xiv) Or a group consisting of a phenylthio group, (xv) unsubstituted or substituent β substituted with one or more substituents selected from the group consisting of substituent β A phenylsulfonyl group substituted with one or more substituents selected from (xvi) unsubstituted or substituted β and one or more substituted, nitrogen atoms of the amino moiety unsubstituted or substituted with a C _1-6 straight or branched chain alkyl group Phenylsulfonylamino group, (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfonyl group, (xviii) nitrogen atom unsubstituted or C _{1- An} imidazolyl group substituted with a ₆ straight-chain or branched alkyl group and / or a pyridylsulfonylamino group substituted with an unsubstituted or C _1-6 straight-chain or branched-chain alkyl group with the nitrogen atom of the amino moiety;
The substituent β is a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain haloalkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom or a C _1-4 straight or branched chain alkylenedioxy Group;
(14) The compound described in (1), wherein phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, wherein X ^e is substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α, Compounds exhibiting indolyl, quinolyl or isoquinolyl groups,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain. Alkanoyloxy groups, (v) C _1-4 straight or branched alkoxy groups, (vi) methylenedioxy groups, (vii) C _7-12 aralkyloxy groups, (viii) C _1-4 straight or branched chain alkyls Thio group, (ix) C _1-4 straight or branched chain alkylsulfonyl group, (x) fluorine, chlorine or bromine atom, (xi) C _7-12 aralkyl group, (xii) unsubstituted or methyl, trifluoromethyl , A phenyl group substituted with one or more substituents selected from the group consisting of methoxy, fluoro and methylenedioxy groups, (xiii) unsubstituted or selected from the group consisting of methyl, trifluoromethyl, methoxy, fluoro and methylenedioxy groups Phenoxy groups, (xiv) unsubstituted or substituted with one or more substituents, methyl, trifluoromethyl, methoxy, fluoro and methylenedioxe Phenylsulfo substituted with one or more substituents selected from the group consisting of groups, (xv) unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, fluoro and methylenedioxy groups One or more substituted and one or more substituted, nitrogen atoms of an amino moiety unsubstituted or C _1-6 straight or branched chain, selected from the group consisting of a nil, (xvi) unsubstituted or methyl, trifluoromethyl, methoxy, fluoro and methylenedioxy group A phenylsulfonylamino group substituted with one or more substituents selected from the group substituted by an alkyl group, (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfo group, (xviii) a nitrogen atom is unsubstituted or C _1-6 straight or branched of the imidazolyl group, or (xix) amino moiety substituted with a chain alkyl group nitrogen atom ratio Indicates a flute dilsul sulfonyl group substituted with a ring or a C _1-6 straight or branched chain alkyl group.
(15) The compound described in (1), wherein phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, wherein X ^e is substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α , A compound representing an indolyl, quinolyl or isoquinolyl group,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain. Alkanoyloxy groups, (v) C _1-4 straight or branched alkoxy groups, (vi) methylenedioxy, benzyloxy, phenethyloxy or naphthylmethoxy groups, (vii) C _1-4 straight or branched chain alkyls Thio, (viii) C _1-4 straight or branched chain alkylsulfonyl group, (ix) fluorine, chlorine or bromine atom, (x) benzyl group, (xi) unsubstituted or methyl, trifluoromethyl, methoxy, A phenyl group substituted with one or more substituents selected from the group consisting of fluoro and methylenedioxy groups, (xii) an unsubstituted or one or more substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, fluoro and methylenedioxy groups Substituted phenoxy groups, (xiii) phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylami Furnace, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino or N -methylpyridylphenylsulfonylamino group and / or ( xiv) an imidazolyl group unsubstituted or substituted with a C _1-6 straight or branched alkyl group.
16 as the compounds described in (1), X ^e is, substituted with one to three substituents selected from the group consisting of an unsubstituted or substituted α, phenyl, naphthyl, pyridyl, indolyl, quinolyl or A compound representing an isoquinolyl group,
[The above substituents α each represent (i) a C _1-3 straight or branched alkyl group, (ii) trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, formyloxy or acetoxy group, (iii C _1-3 straight or branched alkoxy group, (iv) methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl or ethylsulfonyl group, (v) fluorine, chlorine or bromine atom, (vi) benzyl , Phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylamino, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, N -methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and And / or N -methylpyridylsulfonylamino group.
(17) The compound described in (1), wherein phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, wherein X ^e is substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α. A compound representing a group,
[Each of the above substituents α is methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, acetoxy, methoxy, ethoxy, isopropoxy, methylenedioxy, benzyloxy, methylthio, ethylthio, methylsul Phenyl, ethylsulfonyl, chlorine, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyri Dilsulfonylamino and / or N -methylpyridylsulfonylamino group.
(18) The compound described in (1), wherein X ^e represents a phenyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α,
[Each of the above substituents α is methyl, hydroxy, acetoxy, chlorine, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylamino, pyridyl, pyridyloxy, Pyridylthio and / or pyridylsulfonyl groups.
(19) A compound described in (1), wherein X ^e represents a pyridyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α,
[The above substituents α each represent methoxy, ethoxy, isopropoxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsul Phenylamino and / or N -methylphenylsulfonylamino group.
(20) The compound described in (1), wherein Y ^e is an oxygen atom, a sulfur atom or a formula> NR ^4e (wherein R ^4e is a hydrogen atom, a C _1-3 straight or branched alkyl group or a C _2-5 straight chain or Branched alkanoyl groups).
(21) The compound described in (1), wherein Y ^e represents an oxygen atom.
(22) The compound described in (1), wherein Z ^e is 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl or 3,5-di A compound showing an oxooxazolidin-2-ylmethyl group.
(23) The compound described in (1), wherein Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl group.
(24) The compound described in (1), wherein Z ^e represents 2,4-dioxothiazolidin-5-ylmethyl.
(25) The compound described in (1), wherein R ^1e represents a hydrogen atom or a C _1-4 straight or branched alkyl group,
R ^2e represents a C _2-5 straight or branched alkylene group,
R ^3e represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a methoxy group, an ethoxy group, a methylthio group, an ethylthio group or a halogen atom,
X ^e is a C _6-10 aryl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α, or 5 to 5 wherein hetero is atom selected from the group consisting of nitrogen, oxygen and sulfur atoms A 10-membered ring (which may have one or two rings) and an unsubstituted or substituted heteroaromatic group substituted with 1 to 3 substituents selected from the group consisting of α,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain. Acyloxy group, (v) C _1-4 straight or branched alkoxy group, (vi) C _1-4 straight or branched chain alkylenedioxy group, (vii) C _7-12 aralkoxy group, (viii) C _{1 -4} straight or branched chain alkylthio group, (ix) C _1-4 straight or branched chain alkylsulfonyl group, (x) halogen atom, (xi) C _7-12 aralkyl group, (xii) unsubstituted or substituted β One or more substituents selected from the group consisting of a phenyl group substituted with one or more substituents selected from the group consisting of (xiii) unsubstituted or substituted β or a phenoxy group substituted with one or more substituents selected from the group consisting of (xiv) an unsubstituted or substituent β At least one substituent selected from the group consisting of a phenylthio group, (xv) unsubstituted or substituted β A phenyl sulfonyl group, (xvi) an unsubstituted or substituted by substituents β at least one substituent selected from the group consisting of and substituted by nitrogen atoms which is unsubstituted or C _1-6 linear or branched alkyl group of the amino part phenylsulfonyl group, (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfonyl groups, (xviii) nitrogen atom unsubstituted or C _1-6 straight or branched chain The nitrogen atom of the imidazolyl group and / or (xix) amino moiety substituted with an alkyl group represents a pyridylsulfonylamino group substituted with an unsubstituted or C _1-6 straight or branched chain alkyl group;
The substituent β is a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain haloalkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom or a C _1-4 straight or branched chain alkylenedi An oxy group],
Y ^e represents an oxygen atom, a sulfur atom or a group of the formula> NR ^4e (wherein R ^4e represents a hydrogen atom, a C _1-3 straight or branched alkyl group or a C _2-5 straight or branched alkanoyl group),
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxothiazolidin-5-ylmethyl or 3,5-dioxooxazolidin-2-ylmethyl group .
(26) The compound described in (1),
R ^1e represents a hydrogen atom or a C _1-4 straight or branched alkyl group,
R ^2e represents a C _2-5 straight or branched alkylene group,
R ^3e represents a hydrogen atom,
X ^e is a C _6-10 aryl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α, or 5 wherein 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms To a 10-membered ring (which may have one or two rings) and an unsubstituted or substituted heteroaromatic group substituted with 1 to 3 substituents selected from the group consisting of α,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain egg. Carnoyloxy group, (v) C _1-4 straight or branched alkoxy group, (vi) C _1-4 straight or branched chain alkylenedioxy group, (vii) C _7-12 aralkyloxy group, (viii) C _1-4 straight or branched chain alkylthio group, (ix) C _1-4 straight or branched chain alkylsulfonyl group, (x) fluorine, chlorine or bromine atom, (xi) C _7-12 aralkyl group, (xii) non- A phenyl group substituted with one or more substituents selected from the group consisting of rings or substituents beta, (xiii) an unsubstituted or phenoxy group substituted with one or more substituents selected from the group consisting of beta, (xiv) an unsubstituted or substituent beta A phenylthio group substituted with one or more substituents selected from (xv) unsubstituted or one selected from the group consisting of Phenylsulfonyl group substituted with the above substituents, (xvi) unsubstituted or substituted with at least one substituent selected from the group consisting of phenyl, and the nitrogen atom of the amino moiety is unsubstituted or substituted with C _1-6 straight or branched chain alkyl group Sulfonylamino groups, (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfonyl groups, (xviii) nitrogen atom unsubstituted or C _1-6 An imidazolyl group substituted with a straight or branched alkyl group and / or a pyridylsulfonylamino group substituted with an unsubstituted or C _1-6 linear or branched alkyl group with a nitrogen atom of the amino moiety;
The substituent β is a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain haloalkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom or a C _1-4 straight or branched chain alkylenedioxy Represents a group],
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxothiazolidin-5-ylmethyl group.
(27) The compound described in (1),
R ^1e represents a hydrogen atom or a C _1-3 straight or branched alkyl group,
R ^2e represents a C ₂ or C ₃ straight or branched alkylene group,
R ^3e represents a hydrogen atom,
X ^e represents a phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, indolyl, quinolyl or isoquinolyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α ,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain egg. Carnoyloxy group, (v) C _1-4 straight or branched alkoxy group, (vi) methylenedioxy group, (vii) C _7-12 aralkyloxy group, (viii) C _1-4 straight or branched chain alkyl tea Oxi, (ix) C _1-4 straight or branched chain alkylsulfonyl group, (x) fluorine, chlorine or bromine atom, (xi) C _7-12 aralkyl group, (xii) phenyl group (methyl, trifluoromethyl, meth) (Xiii) a phenoxy group (phenyl moiety may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy group), (xiv) Phenylthio group (phenyl moiety may be substituted with methyl, trifluoromethyl, methoxy, fluoro and methylenedioxy group), (xv) phenylsulfonyl group (phenyl moiety is methyl, trifluoromethyl, May be substituted with a methoxy, fluoro or methylenedioxy group), (xvi) phenylsulfonylamino group (phenyl moiety may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy group, amino Moieties of nitrogen may be substituted with C _1-6 straight or branched chain alkyl groups), (xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyri Dylsulfonyl group, (xviii) nitrogen atom unsubstituted or imidazolyl group substituted with C _1-6 straight or branched chain alkyl group and / or (xix) nitrogen atom of unsubstituted or C _1-6 straight or branched chain A pyridylsulfonylamino group substituted with an alkyl group],
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(28) The compound described in (1),
R ^1e represents a hydrogen atom, a methyl group or an ethyl group,
R ^2e represents an ethylene, trimethylene or methylethylene group,
R ^3e represents a hydrogen atom,
X ^e represents a phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, indolyl, quinolyl or isoquinolyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α ,
[The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain egg. A cannoyloxy group, (v) a C _1-4 straight or branched alkoxy group, (vi) a methylenedioxy, benzyloxy, phenethyloxy or naphthylmethoxy group, (vii) a C _1-4 straight or branched chain alkyl tea Group, (viii) C _1-4 straight or branched chain alkylsulfonyl group, (ix) fluorine, chlorine or bromine atom, (x) benzyl group, (xi) phenyl group (methyl, trifluoromethyl, methoxy, fluoro Or methylenedioxy group), (xii) phenoxy group (phenyl moiety may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy group), (xiii) phenylthio, phenyl alkylsulfonyl, phenylsulfonyl amino, N - phenyl sulfonyl amino, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, P Dilsul sulfonyl, -5-pyrimidin dilsul, N - methyl-pyridyl phenylsulfonyl amino and / or (xiv) represents an imidazolyl unsubstituted or substituted by C _1-6 straight-chain or branched-chain alkyl group,
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(29) The compound described in (1),
R ^1e represents a hydrogen atom, a methyl group or an ethyl group,
R ^2e represents an ethylene, trimethylene or methylethylene group,
R ^3e represents a hydrogen atom,
X ^e represents a phenyl, naphthyl, pyridyl, indolyl, quinolyl or isoquinolyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α,
[The above substituents α each represent (i) a C _1-3 straight or branched alkyl group, (ii) trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, formyloxy or acetoxy group, (iii) C _1-3 straight or branched alkoxy group, (iv) methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl or ethylsulfonyl group, (v) fluorine, chlorine or bromine atom, (vi) benzyl, Phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -Methylphenylsulfonylamino, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, N -methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and / Or an N -methylpyridylsulfonylamino group;
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(30) As a compound described in (1),
R ^1e represents a hydrogen atom, a methyl group or an ethyl group,
R ^2e represents an ethylene group,
R ^3e represents a hydrogen atom,
X ^e represents a phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituents α,
[The above substituents α are (i) methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, acetoxy, methoxy, ethoxy, isopropoxy, methylenedioxy, benzyloxy, methylthio, ethylthio, Methylenesulfonyl, ethylenesulfonyl, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio, pyridylsul Phenyl, pyridylsulfonylamino and / or N -methylpyridylsulfonylamino group;
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(31) The compound described in (1),
R ^1e represents a methyl group or an ethyl group,
R ^2e represents an ethylene group,
R ^3e represents a hydrogen atom,
X ^e represents a phenyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α,
[The above substituent α is methyl, hydroxy, acetoxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N -methylphenylsulfonylamino, pyridyl, pyridyloxy, Pyridylthio and / or pyridylsulfonyl;
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(32) The compound described in (1),
R ^1e represents a methyl or ethyl group,
R ^2e represents an ethylene group,
R ^3e represents a hydrogen atom,
X ^e represents a pyridyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituted α,
[The above substituent α is methoxy, ethoxy, isopropoxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonyl Amino and / or N -methylphenylsulfonylamino;
Y ^e represents an oxygen atom,
Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(33) The compound described in (1), wherein the compound is selected from:
i) 5- [4- {2-[(1-biphenyl-4'-ylethylidene) aminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
ii) 5- [4- (2-{[1- (4-phenylsulfonylphenyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (2-{[1- (4-pyrid-2'-ylphenyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione (hereinafter "compound A "),
iv) 5- [4- (2-{[1- (4-pyrid-3'-ylphenyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
v) 5- [4- (2-{[1- (4-pyrid-4'-ylphenyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
vi) 5- [4- (2-{[1- (2-phenyl-5-pyridyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
vii) 5- [4- (2-{[1- (2-methoxy-5-pyridyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
viii) 5- [4- (2-{[1- (2-ethoxy-5-pyridyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione,
ix) 5- [4- (2-{[1- (2-isopropoxy-5-pyridyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione, and
x) 5- [4- (2-{[1- (2-benzyl-5-pyridyl) ethylidene] aminooxy} ethoxy) benzyl] thiazolidine-2,4-dione.
(VI) WO95 / 18125 describes the following:
(1) isoxazolidinedione derivatives of formula (6) and pharmaceutically acceptable salts thereof:
[Wherein,
R ^f represents a substituted aromatic hydrocarbon group, a substituted cyclic aliphatic hydrocarbon group, a substituted heterocyclic group, a substituted fused heterocyclic group or a group of formula 6a:
^Wherein R ^1f represents a substituted aromatic hydrocarbon group, a substituted cyclic aliphatic hydrocarbon group, a substituted heterocyclic group, a substituted fused heterocyclic group, and R ^2f and R ^3f are the same or Different and each represents a hydrogen atom or a lower alkyl group, and X ^f represents an oxygen atom, a sulfur atom or a secondary amino group);
R ^4f represents a hydrogen atom or a lower alkyl group;
R ^5f represents a lower alkyl group;
P ^f and Q ^f each represent a hydrogen atom or together form a bond].
In the compound of formula 6, the definitions of R ^f , R ^1f , R ^2f , R ^3f , R ^4f , R ^5f , P ^f and Q ^f , types of pharmaceutically acceptable salts, methods of preparing compounds of formula 6, compounds of Details such as examples and preparations are described in WO95 / 18125 and incorporated herein by reference.
More specific examples of the aromatic hydrocarbon group represented by R ^f and R ^1f include the aryl groups defined above and exemplified for R ^1d .
When R ^f or R ^1f represents a heterocyclic group or a fused heterocyclic group, it may be any of the fused heterocyclic groups defined and exemplified above with respect to the aromatic heterocyclic group or A ^1d . Alternatively, R ^f and R ^1f may represent a non-aromatic (preferably saturated) heterocyclic group, which may be a 5 to 7 membered ring, wherein 1 to 3 are selected from the group consisting of nitrogen, oxygen and sulfur atoms It may be a hetero-atom, preferably at least one is nitrogen. Examples of such groups include pyrrolidinyl, piperidinyl, piperazinyl, N -methylpiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, thiazolidinyl, diazolidinyl, oxolanil, Thiolanil and perhydropyridyl groups.
When R ^f and R ^1f represent a cyclic aliphatic hydrocarbon group, it is preferably a cycloalkyl group having a C _3-8 membered ring, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo It contains an octyl group, Among these, cyclopentyl and cyclohexyl group are preferable. Alternatively, it may preferably be a cycloalkenyl group having a C _5-8 membered ring, such as a cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group.
Any of the above groups represented by R ^f or R ^1f may be substituted or unsubstituted. If substituted, the group may be substituted with any groups conventionally used in the art, such as those defined and exemplified with respect to substituent α.
When R ^2f , R ^3f , R ^4f , or R ^5f represent an alkyl group, it is C _1-6 , more preferably a C _1-4 lower alkyl group, and is the same as defined and exemplified above with respect to R ^3c and the substituents χ. can do.
Preferred examples of the compound of formula 6 include:
(2) The compound described in (1), wherein R ^4f is a hydrogen atom and R ^5f is a lower alkyl group.
(3) The compound described in (2), wherein R ^f is a phenyl group which may be substituted, and 5- or 6- having 1 or 2 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen atoms. A compound which represents an aromatic ring heterocyclic group or a fused aromatic heterocyclic group which may be substituted and is formed by fusing the aromatic heterocyclic ring and the benzene ring.
(4) The compound described in (3), wherein R ^f is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms selected from the group consisting of a phenyl group, sulfur, oxygen and a nitrogen atom, or the aromatic heterocycle A compound showing a fused aromatic heterocyclic group formed by fusing a ring and a benzene ring.
(5) The compound described in (3), wherein R ^f represents a fused aromatic heterocyclic group or a phenyl group formed by fusing a 5- or 6-membered heterocyclic ring having a sulfur atom with a benzene ring.
(6) The compound described in (2), wherein R ^f represents a phenyl, benzothienyl or 1-methyl-1- (2-pyridylthio) methyl group.
(7) The compound described in (2), wherein R ^f represents a phenyl group.
(8) The compound described in (2), wherein R ^f represents a group of the following formula (6a):
[Formula 6a]
(9) The compound described in (8), wherein R ^1f is a phenyl group which may be substituted or a 5- or 6-membered aromatic which may be substituted with 1 to 2 heteroatoms selected from the group consisting of sulfur, oxygen and nitrogen atoms Compound which shows a heterocyclic group.
(10) The compound described in (8), wherein R ^1f represents a 5- or 6-membered aromatic heterocyclic group having 1 to 2 hetero atoms selected from the group consisting of sulfur, oxygen, and nitrogen atoms.
(11) The compound described in (8), wherein R ^1f represents a 5- or 6-membered aromatic heterocyclic group having a nitrogen atom.
(12) The compound described in (8), wherein R ^1f represents a pyridyl group.
(13) the compound described in (1), selected from:
i) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione,
ii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzylidene} -3,5-isoxazolidinedione,
iii) 4- {4- [2- (2-benzothienyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione, and
iv) 4- [4- (2- {5-methyl-2- [1- (2-pyridylthio) ethyl] -4-oxazolyl} ethoxy) benzyl] -3,5-isoxazolidinedione .
(VII) Japanese Patent Application Publication No. Hei 7-330728 or European Patent Publication No.676398A describes the following:
(1) a heterocyclic compound of Formula 7 and a pharmaceutically acceptable salt thereof:
[Wherein,
X ^g is an indole, indolin, azaindole, azaindolin, imidazopyridine or imidazopyrimidine ring, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below Group;
Y ^g represents oxygen or sulfur atom;
Z ^g is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3 , 5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group;
R ^g is selected from the group consisting of a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an unsubstituted or a substituent ε as defined below An amino group substituted with the above substituents, or a C _7-11 linear or branched aralkyl group;
(The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain alkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic Aliphatic acyl group or C _7-11 aromatic acyl group);
m ^g represents an integer of 1 to 5,
(Said substituent δ is a C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, phenylthio, C _1-4 straight or branched Substituted with one or more substituents selected from the group consisting of an amino group, an unsubstituted or substituent Φ substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined above C _6-10 aryl group or C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of an unsubstituted or substituent Φ;
(The substituent Φ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent ε defined below. An amino group substituted with one or more substituents selected from the group consisting of
In compounds of formula (7), R ^g , X ^g , Y ^g , m ^g and Z ^g and details such as substituents δ, ε and Φ, types of pharmaceutically acceptable salts, methods of preparing compounds of formula (7), compounds of Examples and production examples are described in Japanese Patent Application Laid-Open No. Hei 7-330728 or European Patent Publication No. 676398A, which is incorporated herein by reference.
For example, when R ^g , substituent δ or substituent Φ represent C _1-4 alkyl or alkoxy, this may be as defined and exemplified above with respect to substituent χ. When R ^g or substituent ε represents an aralkyl group, it may be as defined and exemplified above with respect to R ^1d . When the substituent δ represents an alkylthio group, it may be as defined and exemplified above with respect to W ^2c . When substituent δ or substituent ε represents an aryl group, it may be as defined and exemplified above with respect to R ^1d . When the substituent ε represents a C _1-11 straight or branched aliphatic acyl group, a C _8-12 aromatic aliphatic acyl group or a C _7-11 aromatic acyl group, it is in the corresponding group, defined and exemplified above for R ^1d . Can be selected.
Preferred examples of the compound of formula 7 include:
(2) Indole, indolin, azaindole, imidazopyridine, the compound described in (1), wherein X ^g is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ defined below Or a compound showing an imidazopyrimidine ring group,
[The substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 linear or branched group From the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined below, or a substituent Φ defined below A C _6-10 aryl group substituted with one or more substituents selected or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituent Φ defined below;
The substituent Φ is a C _1-4 straight or branched chain alkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an unsubstituted or substituent ε defined below. An amino group substituted with one or more substituents selected from the group consisting of;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group Acyl group or C _7-11 aromatic acyl group.
(3) the compound described in (1), wherein X ^g is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ defined below; Compound which shows a dazopyrimidine ring group;
[The above substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 straight chain or branched group From the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined below, or a substituent Φ defined below A C _6-10 aryl group substituted with one or more substituents selected, or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituent Φ defined below;
The substituent Φ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent ε defined below An amino group substituted with one or more substituents selected from the group consisting of;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group Acyl group or C _7-11 aromatic acyl group.
(4) A compound as described in (1), wherein X ^g is an indole, indolin, imidazopyridine ring group substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below. Compound represented;
[The substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 linear or branched group 1 selected from the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined below, or a substituent Φ as defined below To C _6-10 aryl group substituted with 3 to 3 substituents, or C _7-11 straight or branched chain aralkyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituent Φ as defined below. ;
The substituent Φ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent ε as defined below. An amino group substituted with one or more substituents selected from the group consisting of;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group Acyl group or C _7-11 aromatic acyl group.
(5) The compound described in (1), wherein X ^g represents an indolin or imidazopyridine ring group substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below. ;
[Said substituent δ is a C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a phenylthio, coming C _1-4 straight-chain or branched-chain alkylthio, tri Fluoromethyl group or phenyl group.
(6) The compound described in (1), wherein X ^g represents an imidazopyridine ring group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituent δ defined below;
[The above substituent δ represents a methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, fluorine, chlorine, phenylthio, methylthio, ethylthio or a phenyl group].
(7) The compound described in (1), wherein R ^g represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, or a halogen atom.
(8) The compound described in (1), wherein R ^g represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom, or a chlorine atom.
(9) The compound described in (1), wherein R ^g represents a hydrogen atom or a methoxy group.
(10) The compound described in (1), wherein R ^g represents a hydrogen atom.
(11) The compound described in (1), wherein Y ^g represents an oxygen atom.
(12) The compound described in (1), wherein Z ^g is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl or 2,4- A compound showing a dioxooxazolidin-5-ylmethyl group.
(13) The compound described in (1), wherein Z ^g represents a 2,4-dioxothiazolidine-5-ylidenylmethyl or 2,4-dioxothiazolidin-5-ylmethyl group.
(14) The compound described in (1), wherein Z ^g represents a 2,4-dioxothiazolidin-5-ylmethyl group.
(15) As the compound described in (1):
X ^g represents an indole, indolin, azaindole, imidazopyridine or imidazopyrimidine ring group substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below;
Y ^g represents oxygen or sulfur atom;
Z ^g is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3 , 5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group;
R ^g represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group or a halogen atom,
m ^g is a compound showing the integer of 1-5,
[The substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 linear or branched group From the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined below, or a substituent Φ defined below A C _6-10 aryl group substituted with one or more substituents selected, or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituent Φ defined below;
The substituent Φ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group, unsubstituted or substituted substituent ε An amino group substituted with one or more substituents selected from the group consisting of;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group Acyl group or C _7-11 aromatic acyl group.
(16) As the compound described in (1):
X ^g represents an indole, indolin, imidazopyridine or imidazopyrimidine ring group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below;
Y ^g represents an oxygen atom;
Z ^g represents a 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl group ;
R ^g represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group or a halogen atom;
m ^g is a compound showing the integer of 1-5,
[The substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 linear or branched group From the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε as defined below, or a substituent Φ defined below A C _6-10 aryl group substituted with one or more substituents selected, or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituent Φ defined below;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group An acyl group or a C _7-11 aromatic acyl group;
The substituent Φ is composed of a C _1-4 straight or branched chain alkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an unsubstituted or substituent ε defined above. Amino group substituted with at least one substituent selected from the group consisting of
(17) As the compound described in (1):
X ^g represents an indole, indolin or imidazopyridine ring group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ defined below;
Y ^g represents an oxygen atom;
Z ^g represents a 2,4-dioxothiazolidine-5-ylidenylmethyl or 2,4-dioxothiazolidin-5-ylmethyl group;
R ^g represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom;
m ^g is a compound showing the integer of 1-5,
[The substituent δ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, C _1-4 linear or branched group Selected from the group consisting of an amino group substituted with one or more substituents selected from the group consisting of a chain alkylthio group, a trifluoromethyl group, a nitro group, an unsubstituted substituent ε defined below, or a substituent Φ defined below A C _6-10 aryl group substituted with 1 to 3 substituents, or a C _7-11 straight or branched chain aralkyl group substituted with 1 to 3 substituents selected from the group consisting of unsubstituted or substituent Φ as defined below. ;
The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic aliphatic group An acyl group or a C _7-11 aromatic acyl group;
The substituent Φ is a C _1-4 straight or branched chain alkyl group, a C _1-4 straight or branched chain alkoxy group, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an unsubstituted or substituent ε as defined above. Amino group substituted with one or more substituents selected from the group consisting of:
(18) As the compound described in (1):
X ^g represents an indoline or imidazopyridine ring group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below;
Y ^g represents an oxygen atom;
Z ^g represents a 2,4-dioxothiazolidin-5-ylmethyl group;
R ^g represents a hydrogen atom or a methoxy group;
m ^g is a compound showing the integer of 1-5,
[Said substituent δ is a C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a phenylthio, coming C _1-4 straight-chain or branched-chain alkylthio, tri Fluoromethyl group or phenyl group.
(19) As a compound described in (1):
X ^g represents an imidazopyridine ring group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ defined below;
Y ^g represents an oxygen atom;
Z ^g represents a 2,4-dioxothiazolidin-5-ylmethyl group;
R ^g represents a hydrogen atom;
m ^g is a compound showing the integer of 1-5,
[The substituent δ is a methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, benzyloxy group, fluorine atom, chlorine atom, phenylthio group, methylthio group, ethylthio group or Phenyl group].
(20) the compound described in (1), selected below:
i) 5- {4- (3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
ii) 5- {4- (5-chloro-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
iii) 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
iv) 5- {4- (5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
v) 5- {4- (5-ethoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
vi) 5- {4- (5-isopropoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione, and
vii) 5- [4- (1-methylindolin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.
(VIII) European Patent Publication No. 745600A describes the following:
(1) a fused heterocyclic compound of Formula 8 and a pharmaceutically acceptable salt thereof:
[Wherein:
X ^h represents a benzimidazole ring group unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of substituents γ as defined below,
Y ^h represents oxygen or sulfur atom,
z ^h is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3 , 5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group;
R ^h is selected from the group consisting of a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an unsubstituted or substituent η defined below An amino group substituted with one or more substituents, or a C _7-11 straight or branched chain aralkyl group,
m ^h represents an integer of 1 to 5;
(Said substituents γ are C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, phenylthio, C _1-4 straight or branched From the group consisting of an amino group substituted with one or more substituents selected from the group consisting of chain alkylthio groups, trifluoromethyl groups, nitro groups, unsubstituted substituents as defined below, or substituents defined by A C _6-10 aryl group substituted with one or more substituents selected, or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents selected from the group consisting of unsubstituted or substituents λ defined below);
(The above substituent η is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic Aliphatic acyl group or C _7-11 aromatic acyl group);
(The substituent λ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent η defined above. An amino group substituted with at least one substituent selected from the group consisting of
In compounds of formula (8), R ^h , X ^h , Y ^h , Z ^h and definitions of substituents γ, η and λ and m ^h , types of pharmaceutically acceptable salts, methods of preparing compounds of formula (8), examples of compounds And details such as preparation examples are described in European Patent Publication No. 745600A, which is incorporated herein by reference.
When R ^h , substituent γ or substituent λ represent an alkyl or alkoxy group, it is C _1-4 and may be any corresponding group defined and exemplified above with respect to substituent χ. When R ^h , substituent γ or substituent η represent an aralkyl group, this may be as defined and exemplified above with respect to R ^1d . When substituent γ or substituent η represents a halogen atom, it may be as defined and exemplified above with respect to substituent χ. When substituent γ represents an alkylthio group, it may be as defined and exemplified above with respect to W ^2c . When the substituent γ represents an aryl group, it may be as defined and exemplified above with respect to R ^1d . When the substituent η represents a C _1-11 straight or branched aliphatic acyl group, a C _8-12 aromatic aliphatic acyl group or a C _7-11 aromatic acyl group, it is in the corresponding group defined and exemplified above for R ^1d . Can be selected.
When the substituent η represents a C _1-8 alkyl group, it may be a straight or branched chain group, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl Neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl and octyl groups. Of these, C _1-4 alkyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups are preferred, and most preferred are methyl groups.
Preferred examples of the compound of formula 8 include:
(2) The compound described in (1), wherein R ^h represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, or a halogen atom.
(3) The compound described in (1), wherein Y ^h represents an oxygen atom.
(4) The compound described in (1), wherein Z ^h is 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxothiazolidine-5-ylidenylmethyl or 2,4- A compound showing a dioxooxazolidin-5-ylmethyl group.
(5) As the compound described in (1):
R ^h represents a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group or a halogen atom,
Y ^h represents an oxygen atom,
Z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxothiazolidine-5-ylidenylmethyl or 2,4-dioxooxazolidin-5-ylmethyl group compound.
(6) The compound described in (1), wherein Z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxothiazolidine-5-ylidenylmethyl group.
7 as a compound described in (1), R ^h is a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a compound showing a fluorine atom or a chlorine atom.
(8) The compound described in (1), wherein m ^h represents an integer of 1 to 3.
(9) As the compound described in (1):
Y ^h represents an oxygen atom,
Z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxothiazolidine-5-ylidenylmethyl group,
R ^h represents a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom,
m ^h represents an integer of 1 to 3;
(10) A compound described in (1), wherein X ^h represents a benzimidazole ring group substituted with 1 to 5 substituents selected from the group consisting of unsubstituted or substituents γ as defined below,
[Wherein the substituents γ are C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a phenylthio, coming C _1-4 straight-chain or branched-chain alkylthio, tri Fluoromethyl group, hydroxy group, acetoxy group, benzyl group or phenyl group.
(11) The compound described in (1), wherein Z ^h represents a 2,4-dioxooxazolidin-5-ylmethyl group.
(12) The compound described in (1), wherein R ^h represents a hydrogen atom, a methyl group, or a methoxy group.
(13) As the compound described in (1):
X ^h represents a benzimidazole ring group substituted with 1 to 5 substituents selected from the group consisting of unsubstituted or substituents γ as defined below;
[Wherein the substituents γ are C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a phenylthio, coming C _1-4 straight-chain or branched-chain alkylthio, tri Fluoromethyl group, hydroxy group, acetoxy group, benzyl group or phenyl group;
Y ^h represents an oxygen atom,
Z ^h represents a 2,4-dioxooxazolidin-5-ylmethyl group,
R ^h represents a hydrogen atom, a methyl group or a methoxy group,
m ^h represents an integer of 1 to 3;
(14) The compound described in (1), wherein X ^h represents an unsubstituted or benzimidazole ring group substituted with 1 to 5 substituents selected from the group consisting of substituents γ defined below;
[The substituent γ is methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, fluorine, chlorine, phenylthio, methylthio, ethylthio, Hydroxy group, acetoxy group, benzyl group or phenyl group.
(15) The compound described in (1), wherein R ^h represents a hydrogen atom.
(16) The compound described in (1), wherein m ^h represents 1 or 2.
(17) As the compound described in (1):
X ^h represents a benzimidazole ring group unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of substituents γ as defined below;
[The substituent γ is methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, fluorine, chlorine, phenylthio, methylthio, ethylthio, Hydroxy group, acetoxy group, benzyl group or phenyl group;
Y ^h represents an oxygen atom;
z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl group;
R ^h represents a hydrogen atom;
m ^h represents 1 or 2;
(18) The compound described in (1), wherein X ^h represents a benzimidazole ring group substituted with 1 to 5 substituents selected from the group consisting of unsubstituted or substituent γ as defined below;
[The substituent γ represents a methyl, methoxy, hydroxy, acetoxy or benzyl group].
(19) The compound described in (1), wherein m ^h represents 1.
(20) As a compound described in (1):
X ^h represents a benzimidazole ring group unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of substituents γ as defined below;
[The substituent γ represents a methyl group, a methoxy group, a hydroxy group, an acetoxy group or a benzyl group],
Y ^h represents an oxygen atom,
Z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl group,
R ^h represents a hydrogen atom,
m ^h is 1;
(21) The compound described in (1), selected below:
i) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
ii) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (hereinafter referred to as "Compound B"),
iii) 5- [4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iv) 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-2,4-dione,
v) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and
vi) 5- [4- (5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione.
(IX) Japanese Patent Application Publication No. Hei 1-272574 and European Patent Publication No.332332A describe the following:
(1) a compound of formula 9 and pharmaceutically acceptable salts thereof:
[In the above formula:
Represents a single bond or a double bond;
V ⁱ represents a formula —CH═CH—, —N═CH— or —CH═N— group or a sulfur atom;
W ⁱ represents a group> CH 2,>CHOH,>CO,> C = NOR ⁱ or -CH = CH-,
X ⁱ represents a sulfur or oxygen atom or a group> NR ¹ⁱ , -CH = N- or -N = CH-,
Y ^{i represents a} formula = CH- group or a nitrogen atom,
Z ⁱ is 1 or 2 substituents selected from the group consisting of hydrogen atom, C _1-7 alkyl group, C _3-7 cycloalkyl group, phenyl group, naphthyl group, pyridyl group, furyl group, thienyl group or C _1-3 alkyl group Substituted phenyl group, trifluoromethyl group, C _1-3 alkoxy group, fluorine atom, chlorine atom and bromine atom,
Z ¹ⁱ represents a hydrogen atom or a C _1-3 alkyl group,
R ⁱ and R ¹ⁱ each independently represent a hydrogen atom or a methyl group,
n ⁱ represents 1, 2 or 3;
In the compound of formula 9, definition of V ⁱ , W ⁱ , X ⁱ , Y ⁱ , Z ⁱ , Z ¹ⁱ , R ⁱ , R ¹ⁱ and n ⁱ , types of pharmaceutically acceptable salts, process for preparing compounds of formula 9 , Details such as examples and preparation examples of the compound are described in Japanese Patent Application Laid-Open No. Hei 1-272574 and European Patent Publication No. 332332A, incorporated herein by reference.
For example, when Z ⁱ represents a C _1-7 alkyl group or a substituent on a phenyl group represented by Z ¹ⁱ or Z ⁱ represents a C _1-3 alkyl group, it is one of the corresponding groups defined and exemplified above with respect to substituent η. Can be selected. When Z ⁱ represents a C _3-7 cycloalkyl group, it can be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
Preferred examples of the compound of formula 9 include:
(2) As the compound described in (1), the broken line does not have a bond, and W ⁱ represents a group> CO or> CHOH.
(3) The compound described in (2), wherein V ⁱ represents a chemical formula -CH = CH- or -CH = N- group or a sulfur atom, and n ⁱ represents 2.
(4) As the compound described in (3), X ⁱ represents an oxygen atom, Y ⁱ represents N forming an oxazol-4-yl group, Z ⁱ represents (2-thienyl), (2-furyl ), Phenyl, substituted phenyl or naphthyl group, and Z ¹ⁱ represents a 5-methyl group.
(5) The compound described in (4), wherein V ⁱ represents a chemical formula -CH = N- group or a sulfur atom, and Z ⁱ represents a 2-phenyl group.
(6) As the compound described in (1), V ⁱ represents a group of the formula -CH = CH-, W ⁱ represents a group of formula> CO, Z ⁱ represents 2- (2-furyl), 2-phenyl, 2- The compound which shows a (4-methylphenyl) or 2- (2-naphthyl) group.
(7) The compound described in (3), wherein X ⁱ represents oxygen or a sulfur atom, and Y ⁱ represents a nitrogen atom forming an oxazol-5-yl group, thiazol-4-yl group or thiazol-5-yl group Indicative compound.
(8) The compound described in (3), wherein X ⁱ represents a group of the formula -CH = N-, and Y ⁱ represents CH forming pyrid-2-yl; Or X ⁱ represents an oxygen atom and Y ⁱ represents CH forming a fur-2-yl group.
(9) The compound described in (1), which is 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} thiazolidine-2,4-dione compound.
(X) Japanese Patent Application Publication No. Hei 6-247945 and European Patent Publication No. 604983A describe the following:
(1) a naphthalene derivative of the formula (10) and a pharmaceutically acceptable salt thereof:
[In the above formula:
Is a chemical formula or Represents a group of
-X ^j -represents an oxygen or sulfur atom;
= Y ^j -represents = N- or the formula = CR ^5j- ;
R ^1j , R ^2j , R ^3j , R ^4j and R ^5j are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy group or an arylcarbonyloxy group , Carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, alkylaminocarbonyl group, arylaminocarbonyl group, amino group, alkylamino group, alkanoylamino group, arylcarbonylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group or Trihalomethyl group,
R ^6j represents a hydrogen atom, a substituted alkyl group or a substituted aryl group,
n ^j represents 0 or an integer of 1 to 3;
Represents a single bond or a double bond.
In compounds of Formula 10, definitions of A ^j , X ^j , Y ^j , R ^1j , R ^2j , R ^3j , R ^4j , R ^5j , R ^6j and n ^j , types of pharmaceutically acceptable salts, compounds of formula 10 Details of the preparation method, examples of the compounds, and preparation examples are given in Japanese Patent Application Laid-Open No. Hei 6-247945 and European Patent Publication No. 604983A, incorporated herein by reference.
When R ^1j , R ^2j , R ^3j , R ^4j or R ^5j represent a halogen atom, an alkyl group, an aryl group or an alkoxy group, it may be as defined and exemplified above with respect to each substituent χ, R ^3c or R ^4a . R ^1j , R ^2j , R ^3j , R ^4j or R ^5j are an alkoxyalkoxy group, aryloxy group, alkanoyloxy group, arylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, alkylaminocarbonyl group, arylaminocarbonyl group, alkaline When representing a noylamino group or an arylcarbonylamino group, each portion of these groups may be as defined and exemplified above.
When R ^1j , R ^2j , R ^3j , R ^4j or R ^5j represent an alkylamino group, it may be a mono- or di-alkylamino group as defined and exemplified above with respect to the substituent χ.
When R ^1j , R ^2j , R ^3j , R ^4j or R ^5j represent a trihalomethyl group, it may be a trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl group, preferably Trifluoromethyl group.
Preferred examples of the compound of formula 10 include:
(2) As the compound described in (1), each of R ^1j , R ^2j , R ^3j , R ^4j and R ^5j is independently a hydrogen atom, a halogen atom, a C _1-8 alkyl group, a C _6-12 aryl group, C _1-8 alkoxy group, C _2-6 alkoxyalkoxy group, C _6-12 aryloxy group, C _2-9 alkanoyloxy group, C _7-13 arylcarbonyloxy group, carboxyl group, C _2-9 alkoxycarbonyl group, C _7-13 aryloxycarbonyl group, carbamoyl group, C _2-9 alkylaminocarbonyl group, C _7-13 arylaminocarbonyl group, amino group, C _1-8 alkylamino group, C _2-9 alkanoylamino group, C _7-13 aryl Carbonylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group or trihalomethyl group, R ^6j is selected from the group consisting of hydrogen atom, unsubstituted or phenyl group, halogen atom, nitro group and cyano group substituted with one or more substituents, C _1-8 alkyl, or unsubstituted or C _1-8 alkyl group, a halogen atom, a nitro group, and cyano The compound represents a C _6-12 aryl optionally substituted from the group consisting of a group with one or more substituent selected.
(3) As the compound described in (1):
R ^1j , R ^2j , R ^3j , R ^4j and R ^5j are each independently hydrogen atom, halogen atom, C _1-8 alkyl group, C _1-8 alkoxy group, C _2-6 alkoxyalkoxy group, C _2-9 al Carbonyloxy group, C _7-13 arylcarbonyloxy group, carboxyl group, C _2-9 alkoxycarbonyl group, carbamoyl group, C _2-9 alkylaminocarbonyl group, C _7-13 arylaminocarbonyl group, amino group, C _1-8 alkyl Amino group, C _2-9 alkanoylamino group, C _7-13 arylcarbonylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group or trihalomethyl group;
R ^6j represents a C _6-12 aryl group which may be substituted with a hydrogen atom, a C _1-8 alkyl group or a halogen atom.
(4) As the compound described in (1):
-X ^j -represents an oxygen atom;
Y ⁱ represents a group of the formula = CR ^5j- ;
R ^1j , R ^2j , R ^3j , R ^4j and R ^5j are each independently hydrogen atom, halogen atom, C _1-5 alkyl group, C _1-5 alkoxy, C _2-6 alkoxyalkoxy group, C _2-6 alkano Iloxy group, carboxyl group, C _2-6 alkoxycarbonyl group, C _7-13 arylaminocarbonyl group, amino group, C _2-6 alkanoylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group or trihalomethyl group ;
R ^6j represents a C _6-12 aryl group which may be substituted with a hydrogen atom, a C _1-5 alkyl group or a halogen atom.
(5) The compound described in (1),
Silver chemical formula Represents a group of;
-X ^j -represents an oxygen atom and Y ^j represents the formula = CR ^5j- ;
R ^1j , R ^2j , R ^3j and R ^4j each independently represent a hydrogen atom or a halogen atom;
R ^5j represents a hydrogen atom;
R ^6j represents a hydrogen atom;
n ^j represents 1;
Represents a single bond.
(6) The compound as described in (1), which is 5- [6- (2-fluorobenzyloxy) -2-naphthyl-methyl] thiazolidine-2,4-dione.
Any compound of Formula 1 to Formula 10, or a pharmaceutically acceptable salt thereof, may be used in the form of various isomers, for example stereoisomers based on asymmetric carbon atoms [eg, the 2 position of the chroman ring, or If the carbon atom at position 5 of the thiazolidine ring of the compound of formula 1 can be present in the form of asymmetric carbon atoms, the stereoisomers based on such asymmetric carbon atoms and mixtures thereof in any proportion are all represented by the same formula Can be. The present invention therefore encompasses both these isomers and mixtures thereof.
In each compound of Formula 1 to Formula 10 and pharmaceutically acceptable salts thereof, for example, the 2,4-dioxothiazolidin-5-ylmethyl ring has various tautomers. In Formulas 1 to 10, these tautomers and mixtures thereof in any ratio are all represented by the same formula. Accordingly, the present invention includes both such isomers and mixtures thereof.
In the present invention, when any compound of Formula 1 to Formula 10 or a pharmaceutically acceptable salt thereof forms solvates (eg hydrates), they are also included in the present invention. For example, when left in air or recrystallized in the presence of water, each compound of Formula 1 to Formula 10 and its pharmaceutically acceptable salts will form a hydrate and absorb water. The present invention also includes such solvents.
The present invention is all prodrugs, i.e. derivatives of the compounds of the formulas (1) to (10), which are converted into compounds of the formulas (1) to (10) or pharmaceutically acceptable salts thereof under physiological conditions.
Preferred examples of the compounds of the present invention and pharmaceutically acceptable salts thereof represented by each of the formulas (1) to (10) include:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone),
ii) 5- [4- (6-hydroxy-2-methyl-7-t-butylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iv) 5- [4- (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
v) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
vi) 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
vii) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
viii) 5- {4- [2- (4-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
ix) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione (pioglitazone),
x) 5- {4- [2- (6-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
xi) 5-[(2-benzyl-2,3-dihydrobenzofuran-5-yl) methyl] thiazolidine-2,4-dione,
xii) 5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione (englitazone),
xiii) 5- (4- {2- [N-methyl-N- (2-benzothiazolyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xiv) 5- (4- {2- [N-methyl-N- (2-pyrimidinyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xv) 5- (4- {2- [N-methyl-N- (4,5-dimethylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xvi) 5- {4- [2- (N-methyl-N-thiazol-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xvii) 5- (4- {2- [N-methyl-N- (4-phenylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xviii) 5- (4- {2- [N-methyl-N- (4-phenyl-5-methylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xix) 5- (4- {2- [N-methyl-N- (4-methyl-5-phenylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xx) 5- (4- {2- [N-methyl-N- (5-phenyloxazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xxi) 5- (4- {2- [N-methyl-N- (4,5-dimethyloxazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxii) 5- {4- [2- (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xxiii) 5- {4- [2- (N-acetyl-N-pyrimidin-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xxiv) 5- (4- {2- [N- (2-benzothiazolyl) -N-benzylamino] ethoxy} benzyl) thiazolidine-2,4-dione,
xxv) 5- (4- {3- [N-methyl-N- (2-benzoxazolyl) amino] propoxy} benzyl) thiazolidine-2,4-dione,
xxvi) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl) thiazolidine-2,4-dione (rosiglitazone),
xxvii) 5- (4- {2- [1- (4-biphenylyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
xxviii) 5- (4- {2- [1- (4-phenylsulfonylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxix) 5- (4- {2- [I- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione (Compound A),
xxx) 5- (4- {2- [1- (4-pyrid-3'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
xxxi) 5- (4- {2- [1- (4-pyrid-4'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxii) 5- (4- {2- [l- (2-phenyl-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxiii) 5- (4- {2- [1- (2-methoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxiv) 5- (4- {2- [1- (2-ethoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxv) 5- (4- {2- [1- (2-isopropoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxvi) 5- (4- {2- [1- (2-benzyl-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxvii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidine-dione,
xxxviii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzylidene} -3,5-isoxazolidinedione,
xxxix) 4- {4- [2- (2-benzothienyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione,
xl) 4- [4- (2- {5-methyl-2- [1- (2-pyridylthio) ethyl] -4-oxazolyl} ethoxy) benzyl] -3,5-isoxazolidinedione .
xli) 5- {4- (3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xlii) 5- {4- (5-chloro-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xliii) 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xliv) 5- {4- (5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
xlv) 5- {4- (5-ethoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xlvi) 5- {4- (5-isopropoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
xlvii) 5- [4- (1-methylidone-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xlviii) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xlix) 5- [4- (6-methoxy-l-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (Compound B),
1) 5- [4- (5-methoxy-l-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
li) 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-2,4-dione,
lii) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
liii) 5- [4- (5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
liv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} thiazolidine-2,4-dione, and
lv) 5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione;
Among these, the following compounds and pharmaceutically acceptable salts thereof are more preferable:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone),
ii) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
iv) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione (pioglitazone),
v) 5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione (englitazone),
vi) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione (rosiglitazone),
vii) 5- (4- {2- [1- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione (Compound A),
viii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione,
ix) 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
x) 5- [4- (1-methylidone-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xi) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xii) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (Compound B),
xiii) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
xiv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} thiazolidine-2,4-dione, and
xv) 5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione;
Of these, the following compounds and their pharmaceutically acceptable salts are most preferred:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone),
ii) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione (pioglitazone),
iii) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione (rosiglitazone),
iv) 5- (4- {2- [1- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxylbenzyl) thiazolidine-2,4-dione (Compound A) and
v) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (Compound B).
The concentration of uric acid in the patient's blood is measured by conventional methods. In particular, blood is collected for a predetermined period of time before and after administration of the medicament to a patient with hyperuricemia, such as by the ureasease catalase method (Kageyama: Clin. Chim. Acta., 31, 421-426 (1971)). The measurement kit used in this method is commercially available ("Uricolor 400", trade name; Ono Pharmaceutical).
Insulin sensitivity enhancers used in the present invention can be administered in various forms. There are no particular restrictions on the dosage form, but it will depend on the dosage form as well as the severity of the patient's age, sex or other condition and / or disease. For example, for oral administration, the compounds can be used in the form of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions or capsules. For intravenous administration, the compounds may be used in the form of injections with or without conventional adjuvants such as glucose or amino acids. If necessary, administration may be by intramuscular injection, intradermal injection, subcutaneous injection or intraperitoneal injection only. In situ administration can be done with suppositories. Oral administration is generally preferred.
The various formulations can be formulated using known auxiliaries commonly used in the art, such as excipients, binders, disintegrants, lubricants, solubilizers, correctors, coatings and the like.
For tablet formulations, various carriers known in the art can be used. Examples include: excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; Binders such as water, ethanol, propanol, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone sugar; Dry starch, sodium alginate, agar powder, naminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose Disintegrants such as; Disintegration aids such as saccharose, stearin, cacao butter and hydrogenated oils; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Wetting agents such as glycerin and starch; Absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol. If desired, tablets may be coated (eg, sugar-coated, gelatin-coated, enteric-coated or film-coated) and the tablets may be formed into bilayer or multilayer tablets.
For pill formulations, various carriers known in the art can be used. Examples include excipients such as glucose, lactose, starch, cacao oil, hydrogenated vegetable oil, kaolin and talc; Binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; And disintegrants such as laminaran ager.
For suppository formulations, various carriers known in the art can be used. Examples include polyethylene glycol, cacao oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.
When formulated with injections, sterile solutions or suspensions which are isotonic with blood are preferred. For liquid, emulsion or suspension formulations, any diluent conventionally used in the art can be used. Examples include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, propoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In such cases, sodium chloride, glucose or glycerin may be included in an amount sufficient to prepare an isotonic solution or in an amount sufficient to add conventional dissolution aids, buffers, smoothing agents and the like. In addition, coloring agents, preservatives, aroma chemicals, flavoring agents, sweetening agents and / or other agents may be added if necessary.
There is no particular limitation on the amount of active ingredient to be included in the pharmaceutical formulation. The amount can be freely selected as required, but in general, it is preferable to include 1 to 70% by weight, preferably 1 to 30% by weight, of the compound based on the total weight of the composition.
The dose of insulin sensitivity enhancer varies depending on the condition, age, weight and condition of the patient, as well as the route of administration and the like. In the case of oral administration, it is preferable to administer to the adult patient in a single or single dose, depending on the symptoms, in an amount of 0.1 mg (preferably 1 mg) or more and 1000 mg (preferably 500 mg) or less per day. In the case of intravenous administration, it is preferable to administer to the adult patient in a single or single dose, depending on the symptoms, in an amount of at least 0.01 mg (preferably 0.1 mg) and 500 mg (preferably 200 mg) per day.
The invention will be explained in more detail by the following examples, which illustrate the activity of the compounds of the invention followed by formulations.
Example
Treatment of Hyperuricemia (H.U.)
Four adult patients with diabetes and peruricemia and blood uric acid concentrations of at least 7.0 mg / dl are administered orally 200 mg of troglitazone twice daily (in the morning and in the evening). This administration is continued for 4 weeks. Blood is collected before and after administration, and blood uric acid concentration is measured.
The results are shown in the table below.
patientHistory of gout, including complicationsUses accompanying another treatment of H.U.Blood uric acid concentration (mg / dl) 0 weeks4 weeks 1 (male)nonenone7.25.2 2 (male)nonenone7.65.3 3 (female)nonenone7.95.6 4 (male)nonenone7.25.2
As is clear from the table above, by administering troglitazone to a patient with hyperuricemia whose blood uric acid concentration is 7.0 mg / dl or more, the blood uric acid concentration can be reduced below the normal range of 6.0 mg / dl.
exam
Acute toxicity
Acute toxicity testing of troglitazone is carried out in conventional manner. In particular, 300 mg / kg of triglitazone was orally administered to three ddY mice (males) and observed for 5 days. All survived.
Formulation Example 1
Powder
The powder is obtained by mixing 5 g troglitazone, 895 g lactose and 100 g corn starch in a blender.
Formulation Example 2
Granules
5 g of troglitazone, 895 g of lactose and 100 g of low-substituted hydroxypropyl cellulose are mixed, 300 g of 10% w / v aqueous solution of hydroxypropyl cellulose is added, the resulting mixture is kneaded and an extruded granulator is used. The granules are obtained by granulating and kneading the dough, and then drying the granulated product.
Formulation Example 3
Capsule
5 g of troglitazone, 115 g of lactose, 58 g of cornstarch and 2 g of magnesium stearate are mixed in a V-type mixer, and the resulting mixture is charged into a No. 3 capsule at a ratio of 180 mg to obtain a capsule.
Formulation Example 4
refine
5 g of troglitazone, 90 g of lactose, 34 g of cornstarch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, followed by tableting of the resulting mixture with a tableting machine to obtain a tablet.
Formulation Example 5
Powder
5 g of pioglitazone, 895 g of lactose and 100 g of cornstarch are mixed in a blender to give a powder.
Formulation Example 6
Granules
5 g of rosiglitazone, 865 g of lactose and 100 g of low-substituted hydroxypropyl cellulose are mixed, 300 g of 10% w / v hydroxypropyl cellulose aqueous solution is added, the resulting mixture is kneaded, and an extruded granulator is used. The granules are obtained by granulating and kneading the dough, followed by drying the granulated product.
Formulation Example 7
Capsule
5 g of Compound A, 115 g of lactose, 58 g of cornstarch and 2 g of magnesium stearate are mixed in a V-type mixer, and the resulting mixture is filled in No. 3 capsules at a ratio of 180 mg to obtain a capsule.
Formulation Example 8
refine
5 g of Compound A, 90 g of lactose, 34 g of cornstarch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, followed by compression of the resulting mixture with a tableting machine to obtain a tablet.
In accordance with the present invention, insulin sensitivity enhancers such as troglitazone are able to treat and / or prevent hyperuricemia, and thus are used for the treatment or prevention of diseases such as gout, urolithiasis, hyperuricemia nephropathy and Lesh-Nihan syndrome.

权利要求:
Claims (21)
[1" claim-type="Currently amended] Use of an insulin sensitivity enhancer in the manufacture of a medicament for the treatment or prevention of hyperuricemia.
[2" claim-type="Currently amended] The method of claim 1, wherein the insulin sensitivity enhancer is a thiazolidinedione compound, an iminothiazolidinone compound, a diiminothiazolidine compound, a thioxothiazolidinone compound, an iminotriazole compound, an oxazolidinedione compound, Use selected from the group consisting of a sazolidinedione compound and an oxadiazolidinedione compound.
[3" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is selected from the group consisting of a thiazolidinedione compound, an iminothiazolidinone compound, and a diiminothiazolidine compound.
[4" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is selected from the group consisting of thiazolidinedione compounds.
[5" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is of formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]
[In the above formula:
R ^1a and R ^2a are the same or different and each represents a hydrogen atom or a C _1-5 alkyl group;
R ^3a is a hydrogen atom, a C _1-6 aliphatic acyl group, a C _6-8 cycloalkylcarbonyl group, an unsubstituted or substituted benzoyl or naphthoyl group with one or more of the substituents χ defined below, wherein the heterocyclic moiety is 1-3 Heterocyclic acyl groups having 4 to 7 membered rings which are nitrogen and / or oxygen and / or sulfur hetero-atoms, phenylacetyl groups, phenylpropionyl groups, phenylacetyl or phenylpropionyl groups substituted with one or more halogen atoms, cinnamoyl group , C _2-7 alkoxycarbonyl group or benzyloxycarbonyl group;
(The above substituent χ is a C _1-4 alkyl group, C _1-4 alkoxy group, hydroxy group, halogen atom, amino group, C _1-4 monoalkylamino group, dialkylamino group or nitro group in which each alkyl group is C _1-4 ) ;
R ^4a and R ^5a are the same or different and each represents a hydrogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, or R ^4a and R ^5a both represent a C _1-4 alkylenedioxy group;
Y ^a and Z ^a are the same or different and each represents an oxygen atom or an imino group;
n ^a represents an integer of 1 to 3;
[6" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 2 or a pharmaceutically acceptable salt thereof.
[Formula 2]
[7" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 3 or a pharmaceutically acceptable salt thereof:
[Formula 3]
[In the above formula;
Represents a single or double bond,
n ^c represents 0, 1 or 2,
X ^c represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group;
R ^c represents a hydrogen atom, a methyl group or an ethyl group;
R ^1c is a C _5-7 cycloalkyl group, methyl group, pyridyl group, thienyl group, furyl group, naphthyl group, p -biphenylyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, formula C ₆ H ₄ W ^2c (wherein W ^2c represents a hydrogen atom, a hydroxy group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group or a C _1-4 alkylthio group) or alk-W ^1c wherein alk is C _1-6 alkylene group, ethylidene group or isopropylidene group, W ^1c represents a hydrogen atom, hydroxy group, C _1-4 alkoxy group, C _1-4 alkylthio group, pyridyl group, furyl group, thienyl group, tetrahydro Fu ralgi, a tetrahydro-thienyl group, a naphthyl group, C _5-7 cycloalkyl group or a group represented by the formula C ₆ H ₄ W ^2c a C _5-7 cycloalkyl group substituted represent a (wherein, W ^2c is as defined above)) Represents;
R ^2c represents a hydrogen atom or a methyl group;
R ^3c represents a hydrogen atom, a C _1-6 alkyl group, a formula C ₆ H ₄ W ^2c (wherein W ^2c is the same as defined above) or a benzyl group;
R ^4c represents a hydrogen atom,
or
R ^1c and R ^2c together form a C _4-6 alkylene group, and R ^3c and R ^4c both represent a hydrogen atom;
or
R ^3c and R ^4c together form a C _4-6 alkylene group, and R ^1c and R ^2c both represent a hydrogen atom;
or
R ^2c and R ^3c together form a C _4-6 alkylene group, and both R ^1c and R ^4c represent a hydrogen atom.
[8" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 4 or a pharmaceutically acceptable salt thereof.
[Formula 4]
[In the above formula:
A ^1d represents a substituted or unsubstituted aromatic heterocyclic group,
R ^1d represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl portion of the aralkyl group may be substituted or unsubstituted) or a substituted or unsubstituted aryl group,
R ^2d and R ^3d each represent a hydrogen atom or together form a bond,
A ^2d represents a benzene ring having up to 5 substituents in total,
n ^d represents an integer of 2 to 6;
[9" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 5 or a pharmaceutically acceptable salt thereof:
[Formula 5]
[In the above formula:
R ^1e represents a hydrogen atom or a C _1-6 straight or branched alkyl group,
R ^2e represents a C _2-6 straight or branched alkylene group,
R ^3e is a hydrogen atom, a C _1-6 straight or branched chain alkyl group, a C _1-4 straight or branched chain alkoxy group, a C _1-4 straight or branched chain alkylthio group, a halogen atom, a nitro group, an amino group, a C _1- group _{A four} straight or branched monoalkylamino group, a C _1-4 straight or branched dialkylamino group, a C _6-10 aryl group or a C _7-12 aralkyl group,
X ^e represents a C _6-10 aryl group unsubstituted or substituted with 1 to 3 of the substituents α defined below, or a C _1-3 heteroaromatic group unsubstituted or substituted with 1 to 3 of the substituents α defined below,
(The above substituents α each represent (i) a C _1-6 straight or branched chain alkyl group, (ii) a C _1-4 straight or branched chain haloalkyl group, (iii) a hydroxy group, and (iv) a C _1-4 straight or branched chain acyl Oxy groups, (v) C _1-4 straight or branched alkoxy groups, (vi) C _1-4 straight or branched alkylenedioxy groups, (vii) C _7-12 aralkyloxy groups, (viii) C _{1 -4} straight or branched alkylthio group, (ix) C _1-4 straight or branched alkylsulfonyl group, (x) halogen atom, (xi) nitro group, (xii) amino group, (xiii) C _1-4 straight chain Or a branched monoalkylamino group, (xiv) at least one of a straight or branched chain dialkylamino group wherein each alkyl group is C _1-4 , (xv) a C _7-12 aralkyl group, (xvi) unsubstituted or a substituent β as defined below a substituted C _6-10 aryl group, (xvii) an unsubstituted or a substituted by one or more of substituents β defined C _6-10 aryloxy group, (xviii) an unsubstituted or to one or more of the defined substituents β Substituted C _6-10 Arylthio group, (xix) an unsubstituted or a C _6-10 arylsulfonyl group optionally substituted with a substituent in more than one of the defined substituents β, (xx) substituted by one or more of substituents β defined below or unsubstituted C _{6 -10} arylsulfonylamino group (the nitrogen atom of the amino moiety is unsubstituted or substituted with a C _1-6 straight or branched chain alkyl group) (xxi) heteroaromatic group, (xxii) heteroaryloxy group, (xxiii) heteroarylthio group, (xxiv) heteroarylsulfonyl group or (xxv) heteroaromatic sulfonylamino group, wherein the nitrogen atom of the amino moiety is unsubstituted or substituted with a C _1-6 straight or branched chain alkyl group;
(The above substituent β is a C _1-6 straight or branched chain alkyl group, C _1-4 straight or branched chain haloalkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom or C _1-4 straight or branched chain alkyl group. A lendioxy group);
Y ^e represents an oxygen atom, a sulfur atom or a group of the formula> NR ^4e (wherein R ^4e represents a hydrogen atom, a C _1-6 straight or branched alkyl group or a C _1-8 straight or branched acyl group),
Z ^e is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl or 3 , 5-dioxooxazolidin-2-ylmethyl group].
[10" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 6 or a pharmaceutically acceptable salt thereof:
[Formula 6]
[Wherein,
R ^f represents a substituted aromatic hydrocarbon group, a substituted cyclic aliphatic hydrocarbon group, a substituted heterocyclic group, a substituted fused heterocyclic group or a group of formula 6a:
[Formula 6a]
^Wherein R ^1f represents a substituted aromatic hydrocarbon group, a substituted cyclic aliphatic hydrocarbon group, a substituted heterocyclic group, a substituted fused heterocyclic group, and R ^2f and R ^3f are the same or Different and each represents a hydrogen atom or a lower alkyl group, and X ^f represents an oxygen atom, a sulfur atom or a secondary amino group);
R ^4f represents a hydrogen atom or a lower alkyl group;
R ^5f represents a lower alkyl group;
P ^f and Q ^f each represent a hydrogen atom or together form a bond].
[11" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 7 or a pharmaceutically acceptable salt thereof.
[Formula 7]
[Wherein,
X ^g is an indole, indolin, azaindole, azaindolin, imidazopyridine or imidazopyrimidine ring, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of substituents δ as defined below Group;
Y ^g represents oxygen or sulfur atom;
Z ^g is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3 , 5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group;
R ^g is substituted with one or more of a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an unsubstituted or substituent ε as defined below An amino group or a C _7-11 linear or branched aralkyl group;
(The substituent ε is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain alkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic Aliphatic acyl group or C _7-11 aromatic acyl group);
m ^g represents an integer of 1 to 5,
(Said substituent δ is a C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, phenylthio, C _1-4 straight or branched C _6-10 aryl or unsubstituted, substituted with one or more of the chain alkylthio group, trifluoromethyl group, nitro group, unsubstituted or amino group substituted with one or more of the above-described substituents ε Or a C _7-11 straight or branched chain aralkyl group substituted with one or more substituents Φ;
(The substituent Φ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent ε defined below. An amino group substituted with one or more of).
[12" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 8 or a pharmaceutically acceptable salt thereof.
[Formula 8]
[Wherein:
X ^h represents a benzimidazole ring group unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of substituents γ as defined below,
Y ^h represents oxygen or sulfur atom,
z ^h is 2,4-dioxothiazolidine-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3 , 5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group;
R ^h is selected from the group consisting of a hydrogen atom, a C _1-4 straight or branched alkyl group, a C _1-4 straight or branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an unsubstituted or substituent η defined below An amino group substituted with one or more substituents, or a C _7-11 straight or branched chain aralkyl group,
m ^h represents an integer of 1 to 5;
(Said substituents γ are C _1-4 linear or branched alkyl group, C _1-4 straight or branched chain alkoxy group, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, phenylthio, C _1-4 straight or branched C _6-10 aryl substituted with a chain alkylthio group, trifluoromethyl group, nitro group, unsubstituted or substituted with one or more of the substituents η as defined below, amino group, unsubstituted or with one or more of the substituents λ defined below A C _7-11 straight or branched chain aralkyl group unsubstituted or substituted with one or more of the substituents λ defined below);
(The above substituent η is a C _1-8 straight or branched chain alkyl group, C _7-11 straight or branched chain aralkyl group, C _6-10 aryl group, C _1-11 straight or branched chain aliphatic acyl group, C _8-12 aromatic Aliphatic acyl group or C _7-11 aromatic acyl group);
(The substituent λ is a C _1-4 straight or branched chain alkyl group, C _1-4 straight or branched chain alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or unsubstituted or substituent η defined above. An amino group substituted with one or more of).
[13" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 9 or a pharmaceutically acceptable salt thereof:
[Formula 9]
[In the above formula:
Represents a single bond or a double bond;
V ⁱ represents a formula —CH═CH—, —N═CH— or —CH═N— group or a sulfur atom;
W ⁱ represents a group> CH 2,>CHOH,>CO,> C = NOR ⁱ or -CH = CH-,
X ⁱ represents a sulfur or oxygen atom or a group> NR ¹ⁱ , -CH = N- or -N = CH-,
Y ^{i represents a} formula = CH- group or a nitrogen atom,
Z ⁱ is a phenyl group substituted with one or two substituents selected from a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a phenyl group, a naphthyl group, a pyridyl group, a furyl group, a thienyl group, or a C _1-3 alkyl group, Trifluoromethyl group, C _1-3 alkoxy group, fluorine atom, chlorine atom and bromine atom,
Z ¹ⁱ represents a hydrogen atom or a C _1-3 alkyl group,
R ⁱ and R ¹ⁱ each independently represent a hydrogen atom or a methyl group,
n ⁱ represents 1, 2 or 3;
[14" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is a compound of Formula 10 or a pharmaceutically acceptable salt thereof:
[Formula 10]
[In the above formula:
Is a chemical formula or Represents a group of
-X ^j -represents an oxygen or sulfur atom;
= Y ^j -represents = N- or the formula = CR ^5j- ;
R ^1j , R ^2j , R ^3j , R ^4j and R ^5j are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy group or an arylcarbonyloxy group , Carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, alkylaminocarbonyl group, arylaminocarbonyl group, amino group, alkylamino group, alkanoylamino group, arylcarbonylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group or Trihalomethyl group,
R ^6j represents a hydrogen atom, a substituted alkyl group or a substituted aryl group,
n ^j represents 0 or an integer of 1 to 3;
Represents a single bond or a double bond.
[15" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is or a pharmaceutically acceptable salt thereof:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
ii) 5- [4- (6-hydroxy-2-methyl-7-t-butylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iv) 5- [4- (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
v) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
vi) 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
vii) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
viii) 5- {4- [2- (4-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
ix) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
x) 5- {4- [2- (6-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
xi) 5-[(2-benzyl-2,3-dihydrobenzofuran-5-yl) methyl] thiazolidine-2,4-dione,
xii) 5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione,
xiii) 5- (4- {2- [N-methyl-N- (2-benzothiazolyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xiv) 5- (4- {2- [N-methyl-N- (2-pyrimidinyl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xv) 5- (4- {2- [N-methyl-N- (4,5-dimethylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xvi) 5- {4- [2- (N-methyl-N-thiazol-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xvii) 5- (4- {2- [N-methyl-N- (4-phenylthiazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xviii) 5- (4- {2- [N-methyl-N- (4-phenyl-5-methylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xix) 5- (4- {2- [N-methyl-N- (4-methyl-5-phenylthiazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xx) 5- (4- {2- [N-methyl-N- (5-phenyloxazol-2-yl) amino] ethoxy} benzyl) thiazolidine-2,4-dione,
xxi) 5- (4- {2- [N-methyl-N- (4,5-dimethyloxazol-2-yl) amino] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxii) 5- {4- [2- (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xxiii) 5- {4- [2- (N-acetyl-N-pyrimidin-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
xxiv) 5- (4- {2- [N- (2-benzothiazolyl) -N-benzylamino] ethoxy} benzyl) thiazolidine-2,4-dione,
xxv) 5- (4- {3- [N-methyl-N- (2-benzoxazolyl) amino] propoxy} benzyl) thiazolidine-2,4-dione,
xxvi) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl) thiazolidine-2,4-dione,
xxvii) 5- (4- {2- [1- (4-biphenylyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
xxviii) 5- (4- {2- [1- (4-phenylsulfonylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxix) 5- (4- {2- [I- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxx) 5- (4- {2- [1- (4-pyrid-3'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
xxxi) 5- (4- {2- [1- (4-pyrid-4'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxii) 5- (4- {2- [l- (2-phenyl-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxiii) 5- (4- {2- [1- (2-methoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxiv) 5- (4- {2- [1- (2-ethoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxv) 5- (4- {2- [1- (2-isopropoxy-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxvi) 5- (4- {2- [1- (2-benzyl-5-pyridyl) ethylideneaminooxy] ethoxy} benzyl) -thiazolidine-2,4-dione,
xxxvii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidine-dione,
xxxviii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzylidene} -3,5-isoxazolidinedione,
xxxix) 4- {4- [2- (2-benzothienyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione,
xl) 4- [4- (2- {5-methyl-2- [1- (2-pyridylthio) ethyl] -4-oxazolyl} ethoxy) benzyl] -3,5-isoxazolidinedione .
xli) 5- {4- (3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xlii) 5- {4- (5-chloro-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xliii) 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xliv) 5- {4- (5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
xlv) 5- {4- (5-ethoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
xlvi) 5- {4- (5-isopropoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} -thiazolidine-2,4-dione,
xlvii) 5- [4- (1-methylidone-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xlviii) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xlix) 5- [4- (6-methoxy-l-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
1) 5- [4- (5-methoxy-l-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
li) 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-2,4-dione,
lii) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
liii) 5- [4- (5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
liv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} thiazolidine-2,4-dione, or
lv) 5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione.
[16" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
ii) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
iii) 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
iv) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
v) 5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione,
vi) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
vii) 5- (4- {2- [1- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxy} benzyl) thiazolidine-2,4-dione,
viii) 4- {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} -3,5-isoxazolidinedione,
ix) 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione,
x) 5- [4- (1-methylidone-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xi) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xii) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
xiii) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidine-2,4-dione,
xiv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} thiazolidine-2,4-dione, or
xv) 5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione.
[17" claim-type="Currently amended] Use according to claim 1, wherein the insulin sensitivity enhancer is or a pharmaceutically acceptable salt thereof:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
ii) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
iii) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
iv) 5- (4- {2- [1- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxylbenzyl) thiazolidine-2,4-dione, or
v) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.
[18" claim-type="Currently amended] A composition for treating or preventing hyperuricemia in a mammal having hyperuricemia, comprising an effective amount of an insulin sensitivity enhancer.
[19" claim-type="Currently amended] 19. The method of claim 18, wherein the insulin sensitivity enhancer is a thiazolidinedione compound, an iminothiazolidinone compound, a diiminothiazolidine compound, a thioxothiazolidinone compound, an iminotriazole compound, an oxazolidinedione compound, A composition selected from the group consisting of a sazolidinedione compound and an oxadiazolidinedione compound.
[20" claim-type="Currently amended] 19. The composition of claim 18, wherein the insulin sensitivity enhancer is a thiazolidinedione compound.
[21" claim-type="Currently amended] The composition of claim 18 wherein the insulin sensitivity enhancer is or a pharmaceutically acceptable salt thereof:
i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
ii) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione,
iii) 5- {4- [2- (N-methyl-N-pyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione,
iv) 5- (4- {2- [1- (4-pyrid-2'-ylphenyl) ethylideneaminooxy] ethoxylbenzyl) thiazolidine-2,4-dione, or
v) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-11-25|Priority to JP32318297

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1997-11-25|Priority to JP97-323182

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1998-11-24|Application filed by 가와무라 요시부미, 상꾜 가부시키가이샤

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1999-06-25|Publication of KR19990045531A

优先权:

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申请号 | 申请日 | 专利标题

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JP32318297|1997-11-25|

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JP97-323182|1997-11-25|