WO1999030739A1

WO1999030739A1 - Leukemia remedy

Info

Publication number: WO1999030739A1
Application number: PCT/JP1998/005657
Authority: WO
Inventors: Yukiko Tokumitsu; Kouichi Tamoto
Original assignee: Sankyo Company, Limited
Priority date: 1997-12-16
Filing date: 1998-12-15
Publication date: 1999-06-24
Also published as: AU1507799A

Abstract

A leukemia preventive or remedy containing an insulin resistance improver as the active ingredient.

Description

Specification

Leukemia treatment [Technical field]

The present invention relates to a preventive or therapeutic agent for leukemia containing an insulin sensitizer as an active ingredient, a composition for preventing or treating leukemia containing an insulin sensitizer as an active ingredient, a method for preventing or treating leukemia, The present invention relates to a method for preventing or treating leukemia in which a medicament for treatment is used, or a pharmacologically effective amount of an insulin resistance improving substance is administered to a warm-blooded animal.

[Prior art]

Leukemia is a disease based on the systematic and unrestricted growth of hematopoietic tissues and is regarded as a malignant tumor of hematopoietic tissues. Clinically, abnormal blood cells that are not normally found in peripheral blood appear, causing leukemia cells to proliferate and infiltrate into the bone marrow and other systemic organs.Therefore, various infections, anemia, bleeding, It is characterized by various organ disorders due to infiltration. The incidence is increasing worldwide, and the major causes of leukemia are genetic factors and viral infections such as retroviruses. Currently, treatments for leukemia include chemotherapy, radiation therapy, immunotherapy, and combinations thereof.

Conventionally, as leukemia therapeutic agents, for example, in acute leukemia, which accounts for about 80% of leukemia in Japan, antimetabolites cytarabine (Ara-C), 6-mercaptopurine (6-MP), methotrexet ( MXM), anticancer antibiotics daunorubicin (DNR), idarubicin (IDR), alkylating agent cyclophosphamide (CY), plant alkaloid vincristine (VCR), podophyllotoxin derivative etoposide (VP Alkylating agents such as busulfan (BUS) and dimustine (ACU) are used in chronic leukemia, which accounts for about 20%. However, these therapeutic agents have various side effects such as nausea, vomiting, myelosuppression, liver damage, mucosal damage, myocardial damage, alopecia, hemorrhagic cystitis, and peripheral neuropathy. Therefore, a prophylactic or therapeutic agent which has a main effect of anti-leukemia and has few side effects has been desired. By the way, an insulin sensitizer has an action of improving such a condition when the action of insulin is incomplete despite the presence of endogenous insulin. Compounds having various structures are known as such an insulin resistance improving substance. Examples thereof include thiazolidinedione compounds, oxazolidinedione compounds, isooxazolidinedione compounds, and oxaziazolidinedione compounds. These are described, for example, in U.S. Pat. No. 4,729,129 (Japanese Patent Laid-Open No. 60-511189, Japanese Patent Publication No. 2-31079, EP 139421A); U.S. Pat. No. 4,703,052 (JP-A-61-271287, Japanese Patent Publication No. 5-86953); U.S. Pat. Nos. 5,0029,53, 51,94443, 523 No. 2925, No. 5260445 (Japanese Unexamined Patent Publication (Kokai) No. 1-13169); EP 07080

98 A (Japanese Patent Application Laid-Open No. 9-48779) WO 95/1 18 125; EP 06763 98 A (Japanese Patent Application Laid-Open No. 7-330728) EP 0745600A; EP 033233 2 A (Japanese Patent Application Laid-Open No. 11-272574) EP 0604983 A ( WO 94 01 433 (Japanese Patent Application Laid-Open No. 6-80667); Japanese Patent Application Laid-Open No. 4-69383; WO 92 02520 (Japanese Patent Application Laid-Open No. 6-500538); WO 91/07107 US Pat. No. 5,323,171 (JP-A-3-90071); US Pat. No. 4,897,405 (JP-A-2-292272); WO 89/0865 1 (Japanese Unexamined Patent Publication No. 1-27254); U.S. Pat. Nos. 5,061,717, 5, 20754, 5223 522 (Japanese Unexamined Patent Publication No. 11-272573); U.S. Pat. U.S. Pat. No. 4,973,934, No. 4,948,900 (Japanese Unexamined Patent Publication No. Sho 64-56675, Japanese Patent Publication No. 5-5832); U.S. Pat. No. 4,873,255 (Japanese Unexamined Patent Publication No. Sho 64-3) U.S. Patent No. 4725610 (JP-A-6-85372, Japanese Patent Publication No. 5-66956); U.S. Patent No. 4,461,902 U.S. Pat. Nos. 4,287,200, 4,340,605, 4,438,141 and 4,444,779 (Japanese Unexamined Patent Publication No. 55-22636, Japanese Patent Publication No. 62) — 42903);

At present, insulin sensitizers are used as preventive or therapeutic agents for diabetes, It is known that it can be used for prevention or treatment of various diseases such as diabetic complications. For example, Japanese Patent Application Laid-Open No. Sho 60-511189 (U.S. Pat. No. 4,572,912, EP 1339421 A, etc.) discloses 5— [4— (6 —Hydroxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] thiazolidin-12,4-dione (hereinafter referred to as “troglitazone”) has an activity to enhance insulin action. It has been known as a thiazolidine derivative and as a preventive and / or therapeutic agent for diabetes [Diabetes, 37, 1459 (1988); Diabetes Care, 15, 1075 (1992)]. -On the other hand, Japanese Patent Application Laid-Open Nos. Hei 6-172, 339, Hei 9-124 623, Hei 9-1 368 777 and Hei 9-1 944 67, and Natl. Acad. Sci., 94, 237 (1997), WO974017, WO98292120 and WO98 as published after the priority date of the present application. 39006 describes a thiazolidinedione compound and an oxazolidinedione compound, and also discloses that these compounds have anticancer activity. However, leukemia is not disclosed as a specific disease, and there is no description or suggestion that the insulin sensitizer is useful for the prevention or treatment of leukemia. In addition, since the sensitivity of cancer cells to a drug may vary depending on the type of cancer, for example, a therapeutic agent for breast cancer or knee cancer is not always useful as a therapeutic agent for leukemia.

Also, as disclosed on or after the priority date of the present application, retinoide compounds having a thiazolidinedione structure are described in Chem. Pharm. Bull., 45 (11), 1805 (1997). Have a leukemia cell differentiation inducing activity. However, these retinoid compounds having a thiazolidinedione structure are not included in the claims of the present application, and there is no direct description that they can be used as therapeutic agents for leukemia.

Further, as published on or after the priority date of the present application, WO 9255,988 and WO 98,291,13 describe thiazolidinedione compounds, and these compounds are used for leukemia. It is also disclosed that it can be a therapeutic agent. However, these conjugates have been used as agonists or activators of PPARγ (Peroxisome Prolator if Activated Receptor). On the other hand, the compound of the present application The use of PPARγ is not limited to use as an agonist or activator of PPARγ.

[Disclosure of the Invention]

The present inventors have conducted intensive studies on the pharmacological activity of the insulin sensitizer, and found that the insulin sensitizer significantly improves leukemia and is useful as a preventive or therapeutic agent for leukemia. We have completed the present invention.

In particular, the insulin sensitizer is a thiazolidinedione compound, an iminothiazol idinone compound, a diiminothiazolidine compound, a thioxothiazol idinone compound, or an iminotriazole. Compounds, oxazolidinedione compounds, isoxazolidinedione compounds, and oxadiazol idinedione compounds, preferably thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds. And oxadiazolidinedione compounds, more preferably thiazolidinedione compounds, iminothiazolidinone compounds and diiminothiazolidine compounds, particularly preferably thiazolidinedione compounds. Are compounds and Okisazoriji Njion compounds, and optimally about prophylactic or therapeutic agents of leukemia containing compound is a thiazolidinedione compound as an active ingredient. The thiazolidinedione compound and the like include pharmacologically acceptable salts thereof.

Specific examples of such an insulin sensitizer include the following compounds.

(I) Japanese Patent Application Laid-open No. Sho 60-51 189 (Japanese Patent Publication No. 2-31079), U.S. Patent No. 4,572,921 and EP 1 394 221 A has (1) General formula (I)

Where:

_R h and a are the same or different and each represent a hydrogen atom or a T alkyl group having 1 to 5 carbon atoms,

R ^3a is a hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 6 to 8 carbon atoms, ^a benzoyl or naphthoyl group optionally having a substituent (a) ^a (The substituent (a) ³ is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an amino group, a 1 to 4 carbon atoms. A monoalkylamino group having the same or different, and each alkyl is a dialkylamino group or a nitro group having 1 to 4 carbon atoms.), A hetero atom composed of a nitrogen atom, an oxygen atom and a sulfur atom A 4- to 7-membered heterocyclic acyl group containing 1 to 3 heteroatoms selected from the group, a phenylacetyl group, a phenylpropionyl group, and a phenylacetyl group substituted with at least one halogen. Or Hue - Rupuropioniru group, cinnamoyl group, an alkoxycarbonyl alkylsulfonyl group or a benzyl O alkoxycarbonyl group having 2 to 7 carbon atoms,

R ^4a and R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, or R ^4a and R ^5a together represent Represents an alkylenedioxy group having the number 1 to 4,

Y ^a及Pi Za are the same or different and each represents an oxygen atom or an imino group,

na represents an integer of 1 to 3. ]

Or a pharmacologically acceptable salt thereof. In the compound having the general formula ^{(I), R la, R} 2a, R 3a, R 4a, R 5a, Y a, exemplary Z a, defined represented by _n a and substituents _{(a) a,} pharmacologically Acceptable salt seeds Details of the compound, the method for producing the compound having the general formula (I), compound examples, examples, and the like are described in the above-mentioned publications.

In the above formula, when R ^la , R ^2a , R ^4a or R ^5a represents an alkyl group, the group is a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl, Ethynole, propyl, isopropyl, butynole, isobutynole, s-butyl, t-butynole, pentynole, 1-methylbutynole, 2-methylinobutynole, 3-methylinobutynole, 1-ethylpropyl, 2-ethylpropyl. It is preferably an alkyl group having 1 to 4 carbon atoms, and most preferably a methyl group. -

When R ^3a represents an aliphatic acyl group having 1 to 6 carbon atoms, the group is a linear or branched aliphatic acyl group, for example, formyl, acetyl, propionyl, butyrinole, Isobutyryl, pivaloyl, linolenic, linolenic and hexanol.

When R3a represents a cycloalkylcarbonyl group, the group is a group having 6 to 8 carbon atoms (for example, the cycloalkyl moiety has 5 to 7 carbon atoms), for example, cyclopentylcanolebonyl and cyclohexyl. Xylcarbonyl and cycloheptylcarbonyl.

When R ^3a represents a heterocyclic acyl group, the group is a group in which a heterocyclic group is bonded to a carbonyl group. The heterocyclic moiety is a 4- to 7-membered ring, preferably a 5- or 6-membered ring, and has 1 to 3, preferably 1 or 2, selected from a heteroatom group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. , But optimally has one heteroatom. If the heterocyclic moiety has three heteroatoms, preferably all are nitrogen atoms or one or two are nitrogen atoms and accordingly two or one are oxygen and / or sulfur atoms. The heterocyclic moiety is preferably an aromatic ring. Preferably, the heterocyclic acyl group is a furoyl (preferably 2-furyl), tenyl (preferably 3-tenol), 3-pyridinecarbonyl (nicotinoyl), 4-pyridinecarbonyl (isonicotinol) group.

When R3a represents an alkoxycarbonyl group, the group is a straight-chain or branched-chain alkoxycanolebonyl group having 1 to 6 alkoxy moieties, that is, having a total of 2 to 7 carbon atoms. Toxiccarbonyl, ethoxycanolebonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobut These are xycarbonyl, S-butoxycarbonyl, t-butoxycarbonyl, pentynoleoxycarbonyl and hexyloxycarbonyl. It is preferably an alkoxycarbonyl group having 2 to 4 carbon atoms, and most preferably an ethoxycarbonyl group.

When the substituent (a) a represents an alkyl group, the group is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, the alkyl groups exemplified as R ^la and R ^2a Is the same as

When the substituent (a) a represents an alkoxy group, the group is a linear or branched alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy. , Isobutoxy, s-butoxy, t-butoxy. Preferably, it is a methoxy group.

Substituent (a) When ^a represents ^a halogen atom, the atom is fluorine, chlorine, bromine, or iodine.

When the substituent (a) a represents a monoalkylamino group, the group is a linear or branched alkylamino group having 1 to 4 carbon atoms, for example, methylamino, ethylamino, propylamino, isopropylamino. Mino, butyramino, isobutylamino, s-butylamino, t-butylamino. Preferably, it is a methylamino group.

When the substituent (a) a represents a dialkylamino group, the group is a linear or branched dialkylamino group in which each alkyl moiety has 1 to 4 carbon atoms, such as dimethylamino, getylamino, Dipropylamino, diisopropylamino, dibutylamino, disobutylamino, di-s-butylamino, di-t-butylamino, N-methyl-1-N-ethynoleamino, N-methyl-1-N-propylamino, N-methyl-1-N-isopropylamino Mino, N-methyl-N-butylamino, N-methinolay N-isobutylamino, N-methyl-N-s-butylamino, N-methylinolate N-t-butynoleamino, N-ethinole N-propynoleamino, N-ethinole N- Isopropylamino, N-ethyl-1N-butylamino, N-ethyl-1N-isobutylamino, N Echiru one N- s-Buchiruamino, N- Echiru N- t-Bed Chiruamino, N- propyl one N- isopropyl § amino, N- propyl one N- butyl L-amino, N-propyl-N-isobutynoleamino, N-propyl-N-s-butylamino, N-propyl-N-t-butylamino, N-isopropyl-N-butylamino, N-isopropyl-N-isobutyl Namino, N-isopropyl-N-s-butylamino, N-isopropyl-N-tert-butylamino, N-butyl-N-isobutylamino, N-butyl-N-s-butylamino, N-butyl-N-t-butylamino, N-isobutyl-N-s-butylamino, Nf-sobutyl-N-t-butylamino, N-s-butyl-N-t-butylamino. Preferably, it is a dimethylamino group. '

When R ^4a or R ^5a represents an alkoxy group, the group is a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, s-butoxy, t-butoxy, and pentyloxy. It is preferably an alkoxy group having 1 to 4 carbon atoms, and most preferably a methoxy group.

When R ^4a and R ^5a together represent an alkylenedioxy group, the group is an alkylenedioxy group having 1 to 4 carbon atoms, for example, methylenedioxy, ethylenedioxy, propylenedioxy, tri Methylenedioxy and tetramethylenedioxy. Preferably, they are a methylenedioxy group and an ethylenedioxy group. Among the compounds having the general formula (I), preferred compounds are shown below.

(2) The compound wherein Rla is an alkyl group having 1 to 4 carbon atoms.

(3) The compound wherein Rla is a methyl group.

(4) The compound wherein R2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

(5) The compound wherein R2a is a hydrogen atom or a methyl group.

(6) The compound wherein R3a is a hydrogen atom, an aliphatic acryl group having 1 to 4 carbon atoms, a benzoyl or naphthoyl group having no substituent, or an alkoxycarbonyl group having 2 to 4 carbon atoms.

(7) The compound wherein R3a is a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group.

(8) The compound wherein R3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group.

(9) The compound wherein R ^4a is an alkyl group having 1 to 4 carbon atoms. (10) The compound wherein is a methyl group or a t_butyl group.

(11) The compound, wherein R ^5a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

(12) The compound wherein R ^5a is a hydrogen atom or a methyl group.

However, in R ^la , in the order of (2), (3), in R ^2a , in the order of (4), (5), in R ^3a , in the order of (6)-(8), and in ( 9) and (10), and in R5a, (11) and (12) are ranked in favorable order. Also, select from 2 to 5 from (2)-(3), (4)-(5), (6)-(8), (9)-(10) and (1 1)-(12), Arbitrary combinations of these are also suitable, and such combinations are shown below, for example.

(13) Rla is an alkyl group having 1 to 4 carbon atoms,

R ^2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ^3a is a hydrogen atom, an aliphatic acyl group having 1 to 4 carbon atoms, a benzoyl or naphthoyl group having no substituent Or an alkoxycarbonyl group having 2 to 4 carbon atoms,

R is an alkyl group having 1 to 4 carbon atoms,

A compound in which R ^5a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

(14) R ^la is an alkyl group having 1 to 4 carbon atoms,

R ^2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ^3a is a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group,

R ^4a is an alkyl group having 1 to 4 carbon atoms,

(15) Rla is a methyl group,

R ^2a is a hydrogen atom or a methyl group,

R ^3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group; R ^4a is a methyl group or a t-butyl group; A compound wherein R ^5a is a hydrogen atom or a methyl group.

Further preferred compounds are shown below.

(16) 5- [4- (6-hydroxy2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] thiazolidine-12,4-dione (hereinafter referred to as troglitazone),

5- [4- (6-hydroxy-2-methynole-1 7-t-butynolechroman-12-ylmethoxy) benzyl] thiazolidine-1,2,4-dione (hereinafter referred to as compound C),-

5- [4- (6-hydroxy-1-ethyl-5,7,8-trimethymerecroman-1-inolemethoxy) benzinole] thiazolidine-1,2,4-dione,

5— [4— (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-inolemethoxy) benzinole] thiazolidine-1,2, dione,

5- [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] thiazolidine-1,2,4-dione and

5- [4- (6-ethoxycarbonyloxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] thiazolidine-12,4-dione (hereinafter referred to as compound D).

(I I) JP-A-61-267580 (Japanese Patent Publication No. 5-66956) and U.S. Pat.

(1) General formula (I I.)

Or a pharmacologically acceptable salt thereof. The above publications describe the types of pharmacologically acceptable salts of the compound having the general formula (II), the method for producing the compound having the general formula (II), details of compound examples, examples, and the like. I have. Among the compounds having the general formula (II), suitable compounds are shown below. (2) 5- {4- [2- (3-ethyl-1-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione,

5— {4— [2- (4-Ethyl-1-2-pyridyl) ethoxy] benzyl} —2,4-thiazolidinedione,

5— {4 -— [2- (5-ethyl-1-pyridyl) ethoxy] benzyl} 1-2,4-thiazolidinedione (hereinafter referred to as “pioglitazone”) and

5— {4- [2- (6-ethyl-2-pyridyl) ethoxy] benzyl) -2,4-thiazolidinedione.

(I I I) JP-A-61-271287 (Japanese Patent Publication No. 5-86953) and U.S. Pat.

(1) — General formula (I I I)

[Where,

Dashed lines represent single bonds or non-bonds,

n ^c is 0, 1 or 2;

X ^c is an oxygen atom, a sulfur atom, a sulfier group (s = o) a sulfol group (s (= o) (= o)),

R ^c is a hydrogen atom, a methyl group or an ethyl group,

R ^k is a hydrogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a methyl-substituted cycloalkyl group having 6 to 8 carbon atoms, a pyridyl group, a cyenyl group, a furyl group, a naphthyl group, a p-biphenylyl group A tetrahydrobranyl group, a tetrahydrocenyl group, a tetrahydrobiranyl group, a C ₆ HW ^2c group [W ^2c is a hydrogen atom, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 4 carbon atoms, An alkoxy group having 1 to 4 carbon atoms or an alkylthio group having 1 to 4 carbon atoms. Or a 1 k-W ^le group [a 1 k is an alkyl having 1 to 6 carbon atoms A hydrogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a pyridyl group, a furyl group, a phenyl group; A tetrahydrofuryl group, a tetrahydrophenyl group, a naphthyl group, a cycloalkyl group having 5 to 7 carbon atoms, or a C ₆ H ₄ W2c group. ]

R ^2C is a hydrogen atom or a methyl group,

R ^3c is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a C ₆ H ₄ W 2e group or a benzyl group, and — R ^4C is a hydrogen atom,

When RIC and R2c are taken together they form an alkylene group having 4 to 6 carbon atoms, and R4e are each a hydrogen atom,

When R3c and are together they form an alkylene group having 4 to 6 carbon atoms, Rlc and R2e are each a hydrogen atom,

If R2C and _R k are summer together, they form an alkylene group which have a 3 or 4 carbon atoms, Rlc and R4c are each hydrogen atom. ]

Or a pharmacologically acceptable salt thereof.

In the compound having the general formula ^{(III), R e, R} lc, R 2c, R 3c, R {\ X c, Wk,, exemplary definitions indicated by _n e and a 1 k, acceptable pharmacologically Details of the type of salt, the method for producing the compound having the above general formula (III), examples, and the like are described in the above publications.

In the above formula, if R ^lc or Wlc is a cycloalkyl group, said group is a heptyl group cyclopentyl Le, cyclohexane cyclohexyl, cyclohexylene.

When W2c represents an alkyl group or an alkoxy group, and represents a alkoxy group, these are the same as those described above for the substituent (a) a.

When Wlc or represents an alkylthio group, the group is a linear or branched alkylthio group having 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s —Butylthio and t-butylthio. Preferably it is a methylthio group.

When a 1 k represents an alkylene group having 1 to 6 carbon atoms, the group has 1 to 6 carbon atoms. A linear or branched alkylene group having two or more groups, for example, methylene, methylenolemethylene, ethylene, ethylidene, propylene, isopropylidene, propylidene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene , 3-methyltrimethylene, pentamethylene, hexamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1dimethyltetramethylene, and 2,2-dimethyltetramethylene. Preferably, it is a linear or branched alkylene group having 1 to 4 carbon atoms, and most preferably, a methylene group or an ethylene group. —

When R ^3c represents an alkyl group having 1 to 6 carbon atoms, the group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethynolepropynole, hexinole, 4-methylinopentane, 3-methyl Norepentinole, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutynole, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- Dimethylbutyl and 2-ethylbutyl. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, and most preferably a methyl group.

Rlc and R2c together or R3C and R together form an alkylene group having _{4 to} 6 carbon atoms, or R2e and R3c together have 3 to 4 carbon atoms When it represents an alkylene group, the group is a linear or branched alkylene group, such as tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyl / retrimethylene, pentamethylene, Xamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene.

Among the compounds having the above general formula (III), suitable compounds are shown below.

(2) Re is a hydrogen atom,

The dashed line is unjoined, The compound according to (1), wherein nc is 0 or 1.

(3) R ^2c , R ^3c and R are hydrogen atoms,

R ^k is a hydrogen atom, cyclohexyl, C ₆ H ^ W2c (W ^2e is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group.) Or a 1 k—Wlc [a 1k is an alkylene group having 1 to 4 carbon atoms, an ethylidene group or an isopropylidene group, and Wle is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a cyclohexyl group or a C ₆ W ^2e . ] The compound according to (2), wherein ―

(4) X ^c is an oxygen atom,

(3) Rlc is a cyclohexyl group, a cyclohexylmethyl group, a benzyl group, a fluorobenzyl group, an alkyl group having 1 to 4 carbon atoms, a hydroxymethyl group, a methoxymethyl group or an ethoxyxyl group. Compound.

The compound according to (4), wherein (5) is a benzyl group.

(6) 5-[(2-Benzyl-2,3-dihydrobenzofuran-5-inole) methyl] thiazolidine-1,4, dione, 5— [(2-Benzyl-1,3,4-dialdehyde mouth-1H —Benzopyran-6-inole) Methinole] Thiazolidine-1,2,4-dione

(Hereinafter, referred to as “englitazone”) or a sodium salt thereof.

(7) The compound according to (2), wherein R2c and R3c together form a — (CH ₂ ) ₄ — group, R ^k and R ^4c are each a hydrogen atom, and X ^e is an oxygen atom.

(8) (a) Rlc and R2c together form one (CH ₂ ) _{5 group} ,

_R 3c and are each a hydrogen atom,

X ^c is an oxygen atom, or

(b) and R ^ Gar the cord _(C H ₂₎ 5 is formed,

Rk and R2c are each a hydrogen atom,

The compound according to (2), wherein X ^c is an oxygen atom.

(9) n ^c is 0,

R ^lc is a hydrogen atom, a methyl group or a benzyl group,

X ^c is a sulfur atom or a sulfonyl group (S (= θ) (= 0)) (3) A compound as described.

(IV) Japanese Patent Application Laid-Open No. 1-11319, U.S. Pat.No. 5,002,533, No. 5,194,443, No. 5,232,925 and No. 5,260,445 Is

(1) General formula (IV)

[Where,

Aid represents a substituted or unsubstituted aromatic heterocyclic group;

R ^ld represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl moiety may be substituted or unsubstituted), or a substituted or unsubstituted aryl group;

R ^2d and R ^M are the same or different and represent a hydrogen atom, or R ^2d and R ^M together represent a bond;

AM represents a benzene ring having a total of up to 5 substituents; and

n ^d represents an integer in the range of 2 to 6. ]

Or a pharmaceutically acceptable salt thereof.

With the compounds having the general formula ^{(IV), A ld, R} ld, R 2d, exemplary definitions represented by RA ^2d及Pi n ^d, pharmaceutically acceptable type of salt, the general formula (IV) Details of the method for producing the compound, examples thereof, and suitable compounds are described in the above publications.

When A is a substituted or unsubstituted aromatic heterocyclic group, the group is a 5- to 7-membered aromatic containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom in the ring. A monocyclic group or a condensed ring in which at least one ring is the aromatic heterocyclic group described above and the other ring is an aromatic heterocyclic group or an aromatic hydrocarbon group. If the aromatic heterocyclic group contains three heteroatoms, preferably all are nitrogen atoms, one or two are nitrogen atoms and accordingly two or one are oxygen and Z or sulfur atoms . In the case of a monocyclic aromatic heterocyclic group, for example, furyl, chenyl, pyrrolyl, aze Bur, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxoxadazolyl, triazolyl, tetrazolyl, thiaziazolyl, pyriel, pyridyl, pyridazinyl, pyrimidinyl, pyrazil. It is preferably an aromatic heterocyclic group having 5 to 7 members and having at least one nitrogen atom, and optionally having another nitrogen atom, oxygen atom or sulfur atom. Said groups are preferably, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiaziazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrimidinyl, . Most preferred are, for example, pyridyl, imidazolyl, oxazolyl, pyrazinyl, thiazolyl.

The various aromatic heterocyclic groups described above may form fused rings with other ring groups, such as indolyl, benzofurinole, benzochenyl, benzoxazolinole, benzimidazolyl, isoquinolyl, quinolyl, quinoxalyl. is there.

The above aromatic heterocyclic group may be unsubstituted or substituted with one or more substituents (a) d selected from the following substituents (a). There is no particular limitation on the number of substitutions, except for the number of substitutionable positions and steric hindrance. Generally, 1 to 3 substitutions are preferred.

The substitution (a) d is selected from:

Halogen atom, fluorine, chlorine, bromine, iodine atom;

An alkyl group having 1 to 6 carbon atoms, for example, the same groups as described for R ^3e above;

A haloalkyl group having 1 to 6 carbon atoms, for example, a group in which the alkyl group described for R ^3e is substituted with one or more halogen atoms, for example, fluoromethyl, chloromethyl, bromomethyl, bromomethyl, trifluoromethyl; , Trichloromethinole, 2-funoleolechinore, 2-chloroethinole, 2-bromoethenole, 2-bromoethyl, 2,2,2-triphneoleolochinole, 2,2-diphneoleolochinole, 2, 2, 2-trichloroethinole, 2, 2-dichloroethynole, 2, 2-dibromoethynole, 3-fluoropropynole, 4-chlorobutynole, 5-pentyl pentyl, 6-hexolepentyl An alkoxy group having 1 to 6 carbon atoms, wherein the group is a linear or branched group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1-ethylpropoxy, hexyloxy, 4-methylinolepentinole Oxy, 3-methylinopentene / reoxy, 2-methylinopentynoleoxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy , 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and 2-ethylbutoxy. Preferably it is an alkoxy group having 1 to 4 carbon atoms, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, most preferably a methoxy group;

An aliphatic acyl group having 1 to 6 carbon atoms, for example, the same groups as described in R ^ld below;

Alkanesulfonyl groups having 1 to 6 carbon atoms, such as methanesulfonyl, ethanesulfonyl, prono ヽ. And sulfonyl. Sulphonyl, butanesul honinole, isobutane sulphoninole, s-butanes sulphoninole, t-butanes sulphoninole, pentans sulphonyl, isopentans sulphoninole, pentans sulphoninole, 2-methinole butanesulphoninole , 1 — Etino Reprono ,.ノレへへへへレへレへレノノノButanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethynolebutanesulfonyl, 2,3-dimethylbutanesulfonyl, 2-ethylbutanesulfonyl;

Haloalkanesulfonyl group having 1 to 6 carbon atoms, such as fluoromethane snorehoninole, chloromethaneszolehoninole, bromomethanesnolehoninole, eodomethane snorehoninole, trifnoroleolomethanesulfonyl, trichloromethanesulfonyl, 2—funolenesoloethanesnorenole , 2-cloth ethanes solehoninole, 2-bromoetane sonolehoninole, 2-ryodoethanesnolehoninole, 2, 2-2 Nolehoninole, 2,2-difluoroethanesnorefonyl, 2,2,2-trichloroethane ethanenorefoni / le, 2,2-dichloroethanes / lehoninole, 2,2-dibromoethanes norefonyl, 3-fluoro Propanesulfonyl, 4-chlorobutanesulfonyl, 5-funenole-opening pentans-norefoninole, 6-fu / leo-opening hexaneszolehoninole group;

A hydroxy group;

Carboxy group;

An alkoxycarbonyl group in which the alkoxy moiety has 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycanolebonyl, butoxycarboninole, isobutoxycanoleboninole, s-butoxycanolebonyl, t-butoxy force / Leponyl, Pentyloxycarbonyl, Isopentinocarbonyl, Neopentinoleoxycanoleboninole, 2-Methinolebutoxycanole Boninole, 1-Ethinolepropoxycanoleboninole, Hexy / Reoxycanolebon Ninole, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutyl Toxoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxy force / reponyl, and 2-ethylbutoxycarbonyl group. It is preferably an alkoxycanolebonyl group having 2 to 5 carbon atoms, more preferably a methoxycanoleboninole, ethoxycanoleboninole, propoxycarbonyl, isopropoxycarbonyl, butoxycarbyl, or isobutoxycarbonyl group. , Optimally a methoxycarbonyl group;

An acylamino group having 1 to 6 carbon atoms, wherein the acyl portion is an acyl group having 1 to 6 carbon atoms included in the group described in R ^ld ;

An alkane sulfonylamino group having 1 to 6 carbon atoms, wherein the alkane sulfonyl moiety is a group described above;

A haloalkanesulfonylamino group having 1 to 6 carbon atoms, wherein the haloalkanesulfonyl moiety is a group described above;

An amino group;

Cyano group; An alkylenedioxy group, for example, the same groups as those described when R4a and R5a are linked to each other to indicate an alkylenedioxy group;

An alkylene group having 1 to 8 carbon atoms (which forms a cycloalkyl group condensed with an aromatic ring or a heterocyclic ring), a a group described in 1k and higher groups such as hexamethylene and octamethylene;

It is.

When Rid represents an alkyl group, it is preferably a group having 1 to 6 carbon atoms, and is the same group as described for R ^3c above.

When Rid represents an acyl group, for example, an aliphatic acyl group, an alkanol group having 1 to 25 carbon atoms, preferably 1 to 20 carbon atoms, more preferably 1 to 6 carbon atoms, Optimally, it has 1 to 4 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl, isoptyryl, pivaloyl, norkurelyl, isovaleryl, hexanoyl, heptanyl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl) A stearoyl group, most preferably an acetyl group); a halogenated alkanoyl group having 2 to 6 carbon atoms, particularly a halogenated acetyl group (for example, chloroacetylinole, dichloroacetyl, trichloroacetyl, trifrenoleroacetyl);

A lower alkoxyalkanoyl group in which the alkoxy moiety has i to 5 carbon atoms (preferably 1 to 3) and the alkanol moiety has 2 to 6 carbon atoms (preferably an acetyl group), for example, methoxyacetyl Groups or unsaturated similar groups of these groups, especially alkenoyl and alkynyl groups having 3 to 6 carbon atoms (for example acryloyl, methacryloyl, propioloyl, crotonyl, isocrotonyl, (E) —2-methyl) One 2-butenyl group);

An aromatic acyl group, preferably an arylcarbonyl group, wherein the aryl moiety has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, and more preferably 6 or 1 0, optimally 6, and the carbocyclic group is unsubstituted or has 1 to 5, preferably 1 to 3, substituents (a) d as defined above. Preferably, an unsubstituted group (eg, benzoyl, α-naphthoyl, / 3-naphthoyl group); a halogenated aryl group (eg, 2-bromobenzoyl, 4-cyclobenzoyl group); A lower alkyl-substituted arylcarbonyl group, wherein the alkyl-substituted group has 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms (eg, 2, 4, 6-trimethylbenzoyl, 4-toluoyl group);

A lower alkoxy-substituted arylcarbonyl group, wherein the alkoxy-substituted group preferably has 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms (eg, 4-anisyl group); nitro-substituted arylarylcarbonyl group (eg, 4 —Nitrobenzoyl, 2-nitrobenzoyl group);

A lower alkoxycarbonyl-substituted arylcarbonyl group, wherein the alkoxycarbonyl-substituted group preferably has 2 to 6 carbon atoms [eg, 2- (methoxycarbonyl) benzoyl group];

Aryl-substituted arylcarbonyl group, and the aryl-substituted moiety is as described above, except that the substituted moiety is further substituted with an aryl group (for example, a 4-phenyl-2-benzoyl group) ;

An alkoxycarbonyl group, preferably having 2 to 7 carbon atoms, more preferably having 2 to 5 carbon atoms, and an unsubstituted group (for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl group) or A halogen atom or a tri-substituted silyl group, for example, a tri (lower alkylsilyl) group (eg, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl group);

An alkenyloxycarbonyl group, wherein the alkenyl moiety has 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms (for example, a buroxycarbonyl or aryloxycarbonyl group);

An aralkyl moiety as described below, wherein the aryl ring is preferably substituted with one or two lower alkoxy, nitro (e.g., benzylinoleoxycanolebonyl) , 4-methoxybenzyloxycarbonyl, 3,4-dimethoxypentinoleoxycarbonyl (2-nitrobenzyloxycanolebonyl, 4-nitrobenzyloxycarbonyl));

It is.

When R ^ld represents an aralkyl group, preferably an alkyl having 1 to 6 carbon atoms Is a group substituted with at least one, preferably 1 to 3, aryl (the aryl is substituted with one or more, preferably 1 to 3 selected from the substituent π). You. Preferably, the aralkyl group has 1 to 4 carbon atoms, more preferably 1 to 3, and most preferably 1 or 2 alkyl, wherein the alkyl is 1 to 3 unsubstituted aryl. Groups substituted with (e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylenopineol, α-naphthinolemethinole, naphthinolemethinole, diphenyl / lemethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl group or lower alkyl, lower alkoxy, nitro, halogen, cyano, alkylenedioxy having 1 to 3 carbon atoms, preferably methylenedioxy, or an aryl-substituted group (eg, 4— Methylbenzyl, 2, 4, 6—trimethylbenzinole, 3, 4, 5—trimethinolebenzinole, 4-methoxybenzyl, 4-meth Xyphenenolesiphenylenolemethinole, 2-nitrobenzole, 4-nitrobenzole, 4-clozenbenzole, 4-bromobenzinole, 4-cyanobenzinole, 4-cyanobenzirdiphenylmethyl, bis (2-nitrophenyl ) Methyl, piperonyl group).

When Rid represents a substituted or unsubstituted aryl group, it is a carbocyclic aryl group having 6 to 14, preferably 6 to 10, and most preferably 6 or 10 carbon atoms. The group is one aromatic ring group or two or more fused aromatic ring groups. The group is unsubstituted or substituted with one or more substituents selected from the substituents (a) d. There is no particular limitation on the number of substitutions except for the number of substitutionable positions and steric hindrance. Generally, one to three substitutions are preferred. Examples of the unsubstituted aryl group include phenyl, 1-naphthyl, 2-naphthyl, indenyl, phenanthrenyl, and anthracenyl groups, preferably phenyl and naphthyl groups, and most preferably phenyl group. Substituted aryl groups include, for example, .2- methoxypheno ^, 3- methoxyphenone, 4-methoxyphenone, 2,4-dimethoxyphenone, 2,3 -dimethoxyphenone, 2, 5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 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- ___________________, 2-methinolephen, 2- 4-methinolephen, 2, 4-dimethinolephen, 2, 3-dimethinophen, two , 5-Dimethinolephenyl, 3, 4-Dimethinolephenyl, 3, 5-Dimethinolephenyl, 2, 6-Dimethinolephene, 3, 4, 5-Trimethinolephene, 2, 4, 5-trimethinolephene 2,3,4-trimethinolephen, 2,3,5-trimethylpheninole, 2,3,6-trimethinolephen, 2,4,6-trimethinolephen, 2—Black mouth, 2_4 mouth, 2, 4—Jikro mouth, 2, 3—Dik mouth, 2,5—Dichloro , 3, 4-dichloropheninole,

3, 5-dichloro mouth, 2, 6—dichloro feline, 3, 4, 5—triclo mouth, 2, 4, 5—triclo mouth, 2, 3, 4—triclo mouth Phenyl, 2, 3, 5—Triclophenyl, 2, 3, 6—Triclophenyl, 2,

4, 6-triclonal feninole, 2-funenol feninole, 3-funenol feninole, 4-fluorophenyl, 2, 4-difluorophenyl, 2, 3-difluoropheninole, 3, 4 —Diphnoleolopheninole, 3, 5—Diphneololofeninole, 2, 6—Diphneololofeninole, 3, 4, 5—Trifnoleolofenenole, 2, 4, 5—Trifonoleolophenyl, 2 — Trifluoromethylphenyl, 3— trifluoromethylphene, 4—trinoleolomethinolefeninole, 2,4-bis (trinoleolomethinole) phenyl, 2,3-bis (triflule Phenyl, 3,4-bis (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl, 2,6-bis (trifluoronoreomethyl) phenyl, 3,4,5-tri (Methyl triphnoleo) phenyl, 2, 4, 5-tris (trifluoromethyl) phenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-methoxycarbonylphenyl, 3-methyl Toxicarboyurphenyl is a 4-methoxycarbonyloleboninolephen group.

When AM is a benzene ring having a maximum of 5 substitutions, it is preferably a group selected from the above substitutions (a) d. Among the compounds having the general formula (IV), suitable compounds are shown below.

The compound according to (1), wherein (2) represents a substituted or unsubstituted monocyclic or condensed aromatic heterocyclic group containing up to 4 heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom in the ring. .

(3) A "is the formula ( _a ), ( _b ) or (c)

(a) (b) (c)

[Where,

R ^4d and R ^5d are the same or different and represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group, or R ^4d and R ^5d are the same or different and are bonded to a carbon atom; R5 <! Together with the carbon atom to which they are attached form a benzene ring, and together each of the carbon atoms denoted by R ^4d and R ^5d, whether substituted or unsubstituted And in the formula (a), X <> represents an oxygen atom or a sulfur atom. ] The compound according to (1) or (2), wherein

(4) The compound according to (3), wherein R and are the same or different and each represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted phenyl group.

(5) R and R5d together form the equation (d)

(d)

(Wherein R ^6d and R ^7d are the same or different and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl or alkoxy group).

(6) The compound according to (5), wherein both R ^6d and represent a hydrogen atom.

(7) A is the formula ( _e )

(e)

(Wherein R ^8d and R ^9d are the same or different and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl or alkoxy group), and any one of (1) to (6) The compound described in one item.

(8) The compound according to (7), wherein R ^8d and R ^M are the same or different and each represent a hydrogen atom.

Equation (9)

[Where,

_{_{A, Rld, R 2d, R}} 3d and _n d is Ri as Der as defined with respect to formula (IV) (i), R ^8d and R ^9d are as defined with respect to formula (e) of (7). ] The compound according to (1) or a pharmacologically acceptable salt thereof.

(10) The compound according to any one of (1) to (9), wherein _η represents an integer of 2 or 3.

(11) The compound according to any one of (1) to (10), wherein R ^ld represents a methyl group.

(1 2) 5— {4-(2— [N-methyl-1-N— (2-benzothiazolyl) amino] ethoxy) benzyl {^} thiazolidine-1,2,4-dione,

5— {4-(2- [Ν-methyl-1- (2-pyrimidinyl) amino] ethoxy) benzyl; [thiazolidine-1,2,4-dione,

5— {4- [2- (Ν-methinole-1-yl— [2- (4,5-dimethinolethiazolyl)] amino] benzyl] thiazolidine-1,2-dione,

5-{4— (2-[Ν-methyl-1-Ν (2-thiazolyl) amino] etho Xy) benzyl} thiazolidine-1,2-dione,

5 — {4-[2 — (N-methyl-1-N— [2 — (4 — pheninolethiazolyl)] amino] ethoxy] benzyl} thiazolidine-1,2,4-dione,

5-{4-1 [2-(N-methyl-1-N-[2-(4-phenyl-5-methylthiazolyl)] amino] benzyl] thiazolidine-1, 4-dione;

5-{4-1 [2-(N-methyl-1-N-[2-(4-methynole-5-phenyl azolyl)] amino] ethoxy] benzyl} thiazolidine-1, 4-dione;

5-{4 — [2 — (N-methyl-N— [2 — (5 —phenyloxazolyl)] amino] ethoxy] benzyl} thiazolidine-1, 2, 4-dione;

5-{4-[2-(N-methyl-1-N-[2-(4, 5-dimethyloxazolyl)] amino] ethoxy] benzyl} thiazolidine-1, 4-dione,

5 — {4 — [2 — (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-1, 4-dione,

5— {4- (2- [N-acetyl-N- (2-pyrimidinyl) amino] ethoxy) benzyl} thiazolidine-1,2,4-dione,

5 — {4-(2 — [N- (2-benzothiazolyl) -N-benzylamino] ethoxy) benzyl) thiazolidine- 1, 2, 4-dione,

5 — {4-(3 — [N-methyl-N- (2-benzoxazolyl) amino] propoxy) benzyl} thiazolidine-1, 2, 4-dione and

5-{4 — (2 — [N-methyl-N- (2-pyridyl) amino] ethoxy) benzyl} thiazolidine-1, 2, 4-dione (hereinafter referred to as “mouth diglitazone”) ( 1) The compound as described in the above.

(1 3) 5 — {4 — (2 — [N-methyl-1-N— (2-pyridyl) amino] ethoxy) benzyl} thiazolidine-1,2,4-dione (mouth diglitazone) .

In the above (2) to (1 1), R, R5d , RM, is the definition of the group represented by _R 7d R8d and _R 9d, in the above publications ^{^{such, R 5, R 6, R}} 7, R 8 and R ⁹ It is described as.

Japanese Patent Application Laid-Open No. 9-487779 and EP 70809 A (1) — General formula (V)

(V)

[Where,

R ^le represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms,

R ^2e represents a linear or branched alkylene group having 2 to 6 carbon atoms,

R ^3e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, Straight-chain or branched alkylthio group having 1 to 4 carbon atoms, halogen atom, nitro group, amino group, straight-chain or branched monoalkylamino group having 1 to 4 carbon atoms, identical or different Wherein each alkyl has a linear or branched dialkylamino group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or 7 to 12 carbon atoms Represents an aralkyl group,

X ^e also have 1 to 3 substituents (a) Ariru group or 1 to 3 substituents having 6 to 10 carbon atoms that may have a ^e (a) ^e Shows a good aromatic heterocyclic group,

Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, and (ii) a linear or branched alkyl group having 1 to 4 carbon atoms. A chain halogenated alkyl group, (iii) a hydroxy group, (i V) a straight or branched chain acyloxy group having 1 to 4 carbon atoms, and (V) a 1 to 4 carbon atoms. A linear or branched alkoxy group, (V i) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms, (V ii) a carbon number of 7 to 12 carbon atoms (V iii) a linear or branched alkylthio group having 1 to 4 carbon atoms, (i X) a carbon number

A linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (X) a halogen atom, (xi) a nitro group, (xii) an amino group, and (xiii) a charcoal. A linear or branched monoalkylamino group having 1 to 4 prime numbers,

(X i V) the same or different, each alkyl having 1 to 4 carbon atoms, a linear or branched dialkylamino group, (XV) an aralkyl group having 7 to 12 carbon atoms, (XV i) an aryl group having 6 to 10 carbon atoms which may have a substituent (b) e; (XV ii) an aryl group having 6 to 10 carbon atoms which may have a substituent (b) e 1 Ariruokishi group having zero, and the (xviii) substituents (b) § Li one thio group having 1 0 having 6 to carbon atoms which may have a ^e, (X ix) substituent (b) e Arylsulfonyl group having 6 to 10 carbon atoms which may have (XX) arylsulfonyl group having 6 to 10 carbon atoms which may have (b) ^e ; A mino group (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms),

(xXi) an aromatic heterocyclic group, (XXii) an aromatic heterocyclic oxy group, (XXiii) an aromatic heterocyclic thio group, (XXiV) an aromatic heterocyclic sulfonyl group, and

(XXV) represents an aromatic heterocyclic sulfonylamino group (the nitrogen atom of the amino moiety may be substituted with linear or branched alkyl having 1 to 6 carbon atoms).

Here, the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain alkyl group having 1 to 4 carbon atoms. An alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom or a linear or branched alkylenedioxy group having 1 to 4 carbon atoms,

Y ^e is an oxygen atom, a sulfur atom or a group having the formula> N— (wherein, R 4e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a carbon atom having 1 to 6 carbon atoms) Represents a straight-chain or branched-chain acyl group having eight.

Z ^e is 2, 4-di O Kiso thiazolidine one 5-Ili Deyuru methyl, 2, 4-di O Kiso thiazolidine one 5- Irumechiru group, 2, 4-di O Kiso O hexa oxazolidine one 5 - Irumechiru group or It represents a 3,5-dioxooxadiazolidine-12-methyl group. ]

Or a pharmacologically acceptable salt thereof. In the compound having the general formula (V), examples of the definitions represented by R ^le , R ^2e , R ^3e , R, (a) ^e , (b) e, xe, _Y e, and _Z e are pharmacologically acceptable. Details of the types of salts, methods for producing compounds having the above general formula (V), examples of compounds, examples, and the like are described in the above publications.

RK when the substituent (a) e and the substituent (b) e are an alkoxy group having 1 to 4 carbon atoms, a halogen atom or R3e, and the substituent ( _a ) e is a mono- or di-alkylamino group. These are the same as those described above for the substitution (a) a. When the substituted component (a) e and the substituted component (b) e each represent an alkylenedioxy group, this is the same as the case where R ^4a and R ^5a together represent an alkylenedioxy group. is there.

When R ^3e and the substituent (a) e represent an alkylthio group, this is the same as that described for W2e above.

When RK R ^3e , the substituted component (a) e, the substituted component (b) e, and R represent an alkyl group having 1 to 6 carbon atoms, this is the same as described above for R ^3e .

When X ^e and the substituent (a) e represent an aromatic heterocyclic group, this is the same as described above for Aid.

When the RK substitution (a) e represents an aralkyl group, or R3e, x, and the substitution ( _a ) e represents an aryl group, these are the same as those described in the above.

When R ^2e represents a linear or branched alkylene group having 2 to 6 carbon atoms, this is the same as described above for a 1 k.

When the substituted component (a) e and the substituted component (b) e represent a halogenated alkyl group, the alkyl moiety is a straight or branched chain having 1 to 6, preferably 1 to 3 carbon atoms. Alkyl. The number of halogen atoms is not particularly limited except for the case where the number of substitutable positions is limited. Generally, one to three substitutions are preferred. These include, for example, trifluoromethyl, trichloromethyl, difluoromethylinole, dichloromethinole, jib mouth mometinole, phnoreolomethinole, chloromethinole, bromomethyl, odomethyl, 2,2,2-trichloroethyl, 2,2,2-triethyl Funoleolechinore, 2-bromoethinolle, 2-chloroethinolle, 2-funoleolechinore, 2-odoethyl, 2,2-jib mouth Moetinolle, 3-bromopropinole, 3-kuroguchi Propyl, 3-fluoropropyl, 3-chloropropyl, 4-bromobutyl, 4-chlorobutyl, 4-fluorobutynole, 4-chlorobutyl, 5-bromopentinole, 5-chloropentinole, 5-funolenopentinole, 5-yonopentinole Dopentinole, 6-bromohexynole, 6-chlorohexynole, 6-hexolenohexenole, 6-hexhexoleno group, preferably trifluoromethyl, 2-bromoethyl, 2-chloroethyl, 2 —It is a funoleoletinole group.

When the substituent (a) e represents an acyloxy group, the group is a linear or branched aliphatic acyloxy group having 1 to 4 carbon atoms. For example, a formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy group.

Substituent (a) ^e is alkylsulfonyl, aralkyloxy, aryloxy, arylthio, arylsulfonyl, arylsulfonylamino, aromatic heterocyclic oxy, aromatic heterocyclic thio, aromatic heterocyclic sulfonyl, aromatic When it is a heterocyclic sulfonylamino group, the alkyl, aralkyl, aryl, and aromatic heterocyclic moieties are the same as those described above.

When R ^4e represents an acyl group having 1 to 8 carbon atoms, it is preferably aliphatic or carbocyclic aromatic, and examples thereof are as follows.

In the case of an aliphatic acyl group, it is preferably an alkanoyl group having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 4 carbon atoms, such as honoremil, Acetyl, propionyl, butyrinole, isobutylinole, pivaloisle, norrelyl, isovaleryl, hexanoyl, heptanyl, octanoyl; most preferably, acetyl; halogenated alkanol having 2 to 6 carbon atoms, particularly halogen. Acetyl group, for example, chloroacetyl, dichloroacetyl, trifluoroacetyl, trifluoroacetyl group; the alkoxy moiety has 1 to 5, preferably 1 to 3 carbon atoms, and the alkanol moiety has 2 to 6 carbon atoms. , Preferably an acetyl group, a lower alkoxyalkanoyl group having Or an unsaturated analogous group of these groups, in particular, an alkenyl or alkynyl group having 3 to 6 carbon atoms, such as acryloyl, methacryloyl, propio-lenole, crotonyl, isocrotonyle, (E) — 2-Methyl-1-2-butenoy Group);

In the case of an aromatic acyl group, it is preferably an arylcarbonyl group such as benzoyl, α-naphthyl,] 3-naphthoyl group; Benzoyl group; lower alkyl-substituted arylcarbonyl group, for example, 4-toluoyl group; lower alkoxy-substituted arylcarbonyl group, for example, 4-anisyl group; nitro-substituted arylcarbonyl group, for example, 412 Tolbenzoyl, 2-nitrobenzoyl group; lower alkoxycarbonyl-substituted arylcarbonyl group, for example, 2- (methoxycarbonyl) benzoyl group.

Among the compounds having the general formula (V), suitable compounds are shown below.

(2) The compound according to (1), wherein Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.

(3) The compound according to (1), wherein Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.

(4) The compound according to (1), wherein Rle represents a hydrogen atom, a methyl group or an ethyl group.

(5) The compound according to (1), wherein Rle represents a methyl group or an ethyl group.

(6) The compound according to (1), wherein R2e represents a linear or branched alkylene group having 2 to 5 carbon atoms.

(7) The compound according to (1), wherein R2e represents a linear or branched alkylene group having 2 to 3 carbon atoms.

(8) The compound according to (1), wherein R2e represents an ethylene group, a trimethylene group or a methylethylene group.

(9) The compound according to (1), wherein R2e represents an ethylene group.

(10) R ^3e has a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, and 1 or 2 carbon atoms The compound according to (1), which represents an alkylthio group or a halogen atom.

(11) The compound according to (1), wherein R ^3e represents a hydrogen atom.

(12) Xe is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a) ^e , or 1 to 3 substituents (a) ^e You can do it 5- to 10-membered ring with 1 to 3 nitrogen, oxygen and sulfur or sulfur atoms

A heteroaromatic group (consisting of one or two rings),

Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, or (ii) a linear alkyl group having 1 to 4 carbon atoms. Or (iii) a hydroxy group, (iv) a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and (V) a 1 to 4 carbon atom. A linear or branched alkoxy group having 1 to 4 carbon atoms; (V i) a linear or branched alkylene dioxy group having 1 to 4 carbon atoms;

(vii) an aralkyloxy group having 7 to 12 carbon atoms, (V iii) a linear or branched alkylthio group having 1 to 4 carbon atoms, and (ix) a 1 to 4 carbon atoms. A linear or branched alkylsulfonyl group having

(X) a halogen atom, (X i) an aralkyl group having 7 to 12 carbon atoms,

(xii) a phenyl group optionally having a substituent (b) e; (Xii 1) a phenoxy group optionally having a (b) e; (Xiv) a substituent (b) e (XV) a phenylsulfonyl group optionally having a substituent (b) ^e ; (XV i) optionally having a substituent (b) ^e A phenylsulfonylamino group (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms), (XVii) a furyl group, a phenyl group An oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, (XV iii) an imidazolyl group (a linear or branched nitrogen atom having 1 to 6 carbon atoms) May be substituted with an alkyl of the formula:), and Represents a (X ix) pyridyl sulfonyl § amino group (the nitrogen atom of Amino moiety may be substituted with a straight-chain or branched alkyl having 1 to 6 carbon atoms.),

Here, the substituent (b) e is a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkyl halide having 1 to 4 carbon atoms. A linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom or a linear or branched alkylenedioxy group having 1 to 4 carbon atoms The compound according to (1). (13) Xe has 1 to 3 substituents (a) aryl group having 6 to 10 carbon atoms which may have ^e , or 1 to 3 substituents (a) ⁶ 5- to 10-membered ring having 1 to 3 nitrogen, oxygen and / or sulfur atoms which may be

A heteroaromatic group (consisting of one or two rings),

Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms. A branched alkyl halide group, (iii) a hydroxy group, (iv) a linear or branched alkanoyloxy group having 1 to 4 carbon atoms, and (V) a carbon number 1 A linear or branched alkoxy group having from 4 to 4,

(V i) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms, (V ii) an aralkyloxy group having 7 to 12 carbon atoms, (V iii) a C 1 to 4 carbon atom Linear or branched alkylthio groups having

(ix) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (X) a fluorine atom, a chlorine atom, a bromine atom, and (Xi) a carbon atom having 7 to 12 carbon atoms. (Xii) a phenyl group optionally having a substituent (b) ^e , (Xiii) a phenoxy group optionally having a substituent (b) ^e ,

(Xiv) a phenylthio group optionally having a substituent (b) e, (XV) a phenylsulfonyl group optionally having a (b) e substituent, (XVi) a substituent

(b) a phenylsulfonylamino group optionally having e (the nitrogen atom of the amino moiety may be substituted by linear or branched alkyl having 1 to 6 carbon atoms) ), (XV ii) furyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, ( _xv iii) imidazolyl (nitrogen atoms are carbon atoms) And / or (X i X) a pyridylsulfonylamino group (where the nitrogen atom of the amino moiety is a carbon atom). And may be substituted with linear or branched alkyl having 1 to 6).

Here, the substituent (b) ^e is a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched halo having 1 to 4 carbon atoms. Genated alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom or linear or branched alkylenedioxy group having 1 to 4 carbon atoms The compound according to (1), which represents a group.

(14) X ^e force S 1 to 3 substituents (a) phenyl group, naphthyl group, imidazolyl group, oxazolyl group, pyridyl group, indrill group, quinolyl group which may have ^e Or represents an isoquinolyl group,

Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms. A branched alkyl halide group, (iii) a hydroxy group, (iv) a linear or branched alkanoyloxy group having 1 to 4 carbon atoms,

(V) a linear or branched alkoxy group having 1 to 4 carbon atoms, (Vi) a methylenedioxy group, (Vii) an aralkyloxy group having 7 to 12 carbon atoms, (Viii A) straight-chain or branched alkylthio group having 1 to 4 carbon atoms, (ix) a straight-chain or branched alkylsulfonyl group having 1 to 4 carbon atoms, and (X) fluorine. Atom, chlorine atom, bromine atom,

(X i) an aralkyl group having 7 to 12 carbon atoms; (X ii) a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy). ), (Xiii) a phenoxy group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (Xiv) a phenylthio group (the phenyl May be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy.), (XV) a phenylsulfonyl group (the phenyl is methyl, trifluoromethyl, methoxy, (XV i) a phenylsulfonylamino group (where phenyl is methyl, trifluoromethyl) The nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms.), (XV ii) furyl, chenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, (XV iii) imida A zolyl group (a nitrogen atom may be substituted by a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms), and a no or (X i X) pyridylsulfonyl amino group (an amino moiety May be substituted with linear or branched alkyl having 1 to 6 carbons.).) The compound according to (1), wherein

(1 5) X ^e is from 1-3 substituents (a) a phenyl group which may have a ^e, naphthyl group, an imidazolyl group, Okisazoriru group, a pyridyl group, an indolyl group, a key Noryl group or Isokinoriru group Show,

Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms. A branched alkyl halide group, (iii) a hydroxy group, (iv) a linear or branched alkyloxy group having 1 to 4 carbon atoms,

(V) a linear or branched alkoxy group having 1 to 4 carbon atoms, (V i) a methylenedioxy group, a benzyloxy group, a phenethyloxy group, a naphthylmethoxy group, (V ii) a carbon number of 1 to 4 A linear or branched alkylthio group having 1 to 4 carbon atoms, (V iii) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (ix) a fluorine atom, a chlorine atom, Bromine atom,

(X) a benzyl group, (Xi) a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xii) a phenoxy group (the phenyl group) May be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy.), (Xiii) phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenyl Enylsulfonylamino, furyl, cheninole, oxazolinole, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino, N-methylpyridylsulfonylamino And / or (X i V) imidazolyl group (the nitrogen atom has 1 carbon atom) 6 may be substituted by straight-chain or branched alkyl having.) Shows a (1) compound described.

(16) Xe is a phenyl group, a naphthyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a), Here, the substituent (a) e is (i) a linear or branched alkyl group having 1 to 3 carbon atoms, (ii) a trifluoromethyl group, a difluoromethyl group, or a fluoromethyl group. (Iii) a linear or branched alkoxy group having 1 to 3 carbon atoms, (iv) a methylenedioxy group, a benzyloxy group, a methylthio group; an ethylthio group, a methyl group. Sulfonyl group, ethylsulfonyl group, (V) fluorine atom, chlorine atom, bromine atom, (V i) benzyl group, phenyl group, 4-methylphenyl group, 4-trifurenoleolomethinolephenylinole group, 4-me Toxiphenyl group, 4-phenylenophenyl group, 3,4-methylenedioxyphenyl group, phenoxy group, phenylthio group, phenylsulfonyl group, phenyl Nilsnolephonylamino, N-methylphenylsnolephonylamino, furyl, chenyl, oxazolyl, thiazolyl, imidazolyl, N-methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridyl The compound according to (1), which represents a sulfonyl group, a pyridylsulfonylamino group and / or an N-methylpyridylsulfonylamino group.

(1 7) X ^e is from 1-3 substituents (a) a phenyl group which may have a ^e, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group,

Here, the substituent (a) ^e is a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a hydroxy group, an aceethoxy group, a methoxy group, an ethoxy group, an isopropoxy group, a methylenedioxy group, a benzyloxy group, a methylthio group, Ethylthio group, methylsulfonyl group, ethylsulfonyl group, chlorine atom, benzyl group, phenyl group, phenoxy group, phenylinolethio group, phenylsulfonyl group, phenylinolesulfonylamino group, N-methylphenylsulfonylamino group The compound according to (1), which represents a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, a pyridylsulfonylamino group and / or an N-methylpyridylsulfonylamino group.

(1 8) X ^e represents 1 to 3 substituents (a) may have a ^e-phenylene group,

Here, the substituent (a) e is a methyl group, a hydroxy group, an acetoxy group, a chlorine atom, a benzyl group, a phenyl group, a phenoxy group, a phenylthio group, a phenyl group. The compound according to (1), which represents a sulfonyl group, a phenylsulfonylamino group, an N-methylphenylsulfonylamino group, a pyridyl group, a pyridyloxy group, a pyridylthio group and / or a pyridylsulfonyl group.

(19) ^Xe is a pyridyl group optionally having 1 to 3 substituents (a) e,

Here, the substituent (a) ^e is a methoxy group, an ethoxy group, an isopropoxy group, a benzyloxy group, a methinorethio group, an ethylthio group, a methylsnolehoninole group, a ethinolesnolehoninole group, a benzinole group, or a feninole group. (1) The compound according to (1), which represents a phenyl group, a phenoxy group, a phenylinolethio group, a phenylsulfonyl group, a phenylsulfonylamino group and / or an N-methylphenylsulfonylamino group.

(20) Y ^e is an oxygen atom, a sulfur atom or a group having the formula> N—R ^4e (wherein, is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms or A linear or branched alkynyl group having 2 to 5 carbon atoms.).

(21) The compound according to (1), wherein Ye represents an oxygen atom.

(22) Z ^e force 2, 4-di O Kiso thiazolidine one 5- Irumechiru group, 2, 4-di O Kiso O hexa oxazolidine one 5- Irumechiru group or 3, 5-di-O Kiso O hexa di § oxazolidinedione — The compound according to (1), which represents a 2-ylmethyl group.

(23) Z ^e force 4-di O Kiso thiazolidine one 5- Irumechiru group or 2, 4-di-O Kiso O hexa oxazolidine - 5 Irumechiru a group (1) compounds described.

(24) Z ^e force 2, 4-di O Kiso thiazolidine - 5 Irumechiru a group (1) compounds described.

(25) Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms;

R ^2e represents a linear or branched alkylene group having 2 to 5 carbon atoms;

R ^3e is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, halogen Indicates an atom; ^Xe has 1 to 3 substituents (a) aryl group having 6 to 10 carbon atoms which may have e, or 1 to 3 substituents (a) ^e 5- to 10-membered ring having 1 to 3 nitrogen, oxygen, and sulfur or sulfur atoms which may be

A heteroaromatic group (consisting of one or two rings),

(V ii) an aralkyloxy group having 7 to 12 carbon atoms, (V iii) a linear or branched alkylthio group having 1 to 4 carbon atoms, (i X) a carbon number of 1 to 4 A linear or branched alkylsulfonyl group having

(X) a halogen atom, (X i) an aralkyl group having 7 to 12 carbon atoms,

(xii) a phenyl group optionally having a substituent (b) e, (X iii) a phenoxy group optionally having a (b) e substituent, (X i V) a substituent (b) e A phenylthio group which may have (XV) a phenylsulfonyl group which may have a substituent (b) ^e , and (XV i) which may have a substituent (b) ^e A phenylsulfonylamino group (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms), (XVii) a furyl group, a phenyl group Group, oxazolyl group, isoxazolyl group, thiazolyl group, pyridyl group, pyridyloxy group, pyridylthio group, pyridylsulfonyl group, (XV iii) imidazolyl group (the nitrogen atom has a linear or branched structure having 1 to 6 carbon atoms) It may be substituted by a branched alkyl.) Z or (X i X) pin lysyl sulfonyl § amino group (the nitrogen atom of Amino moiety may be substituted with a straight-chain or branched alkyl having 1 to 6 carbon atoms) indicates,

Here, the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a straight-chain or branched halogen group having 1 to 4 carbon atoms. Alkyl group, linear or branched chain having 1 to 4 carbon atoms Alkoxy group, halogen atom or straight or branched chain having 1 to 4 carbon atoms

^Ye is an oxygen atom, a sulfur atom or a group having the formula> N—R ^4e (wherein is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms or a carbon atom having 2 carbon atoms, A linear or branched alkyl group having from 5 to 5);

Ze force S 2,4-Dioxothiazolidine-1-ylmethyl group, 2,4-dioxoxazolidine-1-5-ylmethyl group or 3,5-dioxoxazodiazolidine—2— A compound represented by the formula (1);

(26) R ^le represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms;

R ^3e represents a hydrogen atom;

X ^e is have Ariru group, or 1 to 3 of substituents (a) ^e having 1 0 having 6 to carbon atoms which may have 1 to 3 substituents (a) e 5- to 10-membered ring having 1 to 3 nitrogen, oxygen, and / or sulfur atoms

A heteroaromatic group (consisting of one or two rings),

(iX) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (X) a fluorine atom, a chlorine atom, a bromine atom, and (Xi) a carbon atom of 7 to 12 carbon atoms. An aralkyl group having the formula (Xii) a substituent (b) e optionally having a (Xiii) a phenoxy group optionally having a substituent (b) ^e ;

(XiV) a substituted thiol group which may have (b) e, (XV) a phenylsulfonyl group which may have (b) ^e , (XV i)

(b) a phenylsulfonylamino group optionally having ^e (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms) ), (XV ii) a furyl group, a cyenyl group, an oxazolyl group, an isooxazolyl group, a thiazolyl group, a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, and Or a (X i X) pyridylsulfonylamino group (where the nitrogen atom of the amino moiety has 1 carbon atom). And may be substituted with linear or branched alkyl having from 6 to 6).

Here, the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain alkyl group having 1 to 4 carbon atoms. Alkyl group, linear or branched alkyloxy group having 1 to 4 carbon atoms, halogen atom or linear or branched alkylenedioxy group having 1 to 4 carbon atoms Shows;

Y ^e represents an oxygen atom;

Z ^e force S2,4-Dioxothiazolidine-1-ylmethyl group or 2,4-dioxoxazolidine-15-ylmethyl group; the compound according to (1).

(27) Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms;

R ^2e represents a linear or branched alkylene group having 2 or 3 carbon atoms;

R ^3e represents a hydrogen atom;

X ^e is from 1-3 substituents (a) ^e a phenyl group which may have a naphthyl group, an imidazolyl group, Okisazoriru group, a pyridyl group, indolyl group, key Noryl group or Isokinoriru group,

Here, the substitution component (a) ^e is (i) a linear group having 1 to 6 carbon atoms. Or (ii) a linear or branched halogenated alkyl group having 1 to 4 carbon atoms, (iii) a hydroxy group, (iv) a 1 to 4 carbon atoms. A linear or branched alkanoyloxy group having four,

(V) a linear or branched alkoxy group having 1 to 4 carbon atoms, (vi) a methylenedioxy group, (V ii) an aralkyloxy group having 7 to 12 carbon atoms, (V iii) A linear or branched alkylthio group having 1 to 4 carbon atoms, (ix) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, and (X) a fluorine atom , Chlorine atom, bromine atom,

(X i) an aralkyl group having 7 to 12 carbon atoms; (xii) a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy) (Xiii) a phenoxy group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (Xiv) a phenyloxy group (the phenyl May be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy.), (XV) phenylsulfonyl group (the phenyl is substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy) ), (XVi) a phenylsulfonylamino group (the phenyl is methyl, trifluoromethyl, methyl The nitrogen atom of the amino moiety may be substituted by a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms.), (XV ii) ) Furyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, (XV iii) imidazolyl (nitrogen has 1 to 6 carbon atoms) And (X i X) a pyridylsulfonyl amino group (where the nitrogen atom of the amino moiety is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms). It may be substituted by a branched alkyl.)

Y ^e represents an oxygen atom;

Z ^e force S 2,4-Dioxothiazolidine-1-5-ylmethyl group; the compound according to (1). (28) R ^le represents a hydrogen atom, a methyl group or an ethyl group;

R2e represents an ethylene group, a trimethylene group or a methylethylene group;

R ^3e represents a hydrogen atom;

X ^e is from 1-3 substituents (a) ⁶ a phenyl group which may have a naphthyl group, Imidazoriru group, Okisazoriru group, a pyridyl group, indolyl group, key Noryl group or Isokinoriru group,

(X) a benzyl group, (X i) a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy. :), (xii) a phenoxy group (the phenyl group) The phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy.), (Xiii) phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methyl Phenylsulfonylamino, furyl, chenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino, N-methylpyridylsulfonylamino , And / or (X i V) imidazolyl group (the nitrogen atom has 1 to Which may be substituted by straight-chain or branched alkyl having 6).

Y ^e represents an oxygen atom;

Z ^e represents a 2,4-dioxothiazolidine-5 f-methyl group; the compound according to (1). (29) R ^le represents a hydrogen atom, a methyl group or an ethyl group;

R 2e represents an ethylene group, a trimethylene group or a methylethylene group;

R ^3e represents a hydrogen atom;

X ^e represents a phenyl group, a naphthyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a) ^e , wherein the substituent (a) e is (I) a linear or branched alkyl group having 1 to 3 carbon atoms, (ii) a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a hydroxy group, a formyloxy group, an acetoxy group, (iii) a linear or branched alkoxy group having 1 to 3 carbon atoms, (iv) methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, (V ) Fluorine atom, chlorine atom, bromine atom, (vi) benzyl group, pheninole group, 4-methynolephenyl group, 4-trifluoromethylphenyl group, 4-methoxyphenyl Phenyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, Furyl, chenyl, oxazolyl, thiazolyl, imidazolyl, N-methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and Z or N-methylpyridylsulfonyl Represents a mino group;

Y ^e represents an oxygen atom;

Z ^e represents a 2,4-dioxothiazolidine-15-ylmethyl group; the compound according to (1).

(30) R ^le represents a hydrogen atom, a methyl group or an ethyl group;

R2e represents an ethylene group;

R ^3e represents a hydrogen atom;

X ^e represents a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a) ^e ,

Here, the substituent (a) e is a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a hydroxy group, an acetoxy group, a methoxy group, an ethoxy group, Isopropoxy group, methylenedioxy group, benzyloxy group, methylthio group, ethynolethio group, methylsulfonyl group, ethylsulfonyl group, chlorine atom, benzyl group, phenyl group, phenoxy group, phenylthio group, phenylsulfonyl group, phenylsulfonyl An amino group, an N-methylphenylsulfonylamino group, a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, a pyridylsulfonylamino group and / or an N-methylpyridylsulfonylamino group;

Y ^e represents an oxygen atom;

( ^E ) The compound according to (1), wherein the compound exhibits a 2,4-dioxothiazolidine-1-5-methyl group.

(31) represents a methyl group or an ethyl group;

R2e represents an ethylene group;

R ^3e represents a hydrogen atom;

X ^e represents a phenyl group which may have 1 to 3 substituents (a) ⁶ ,

Here, the substituent (a) e is a methyl group, a hydroxy group, an aceethoxy group, a chlorine atom, a benzinole group, a phenyl group, a phenoxy group, a phenylthio group, a phenylsulfoninole group, a phenylsolehoninoleamino group , N-methinorefenylsulfoninoleamino, pyridyl, pyridyloxy, pyridylthio and Z or pyridylsulfonyl;

Y ^e represents an oxygen atom;

(32) represents a methyl group or an ethyl group;

R2e represents an ethylene group;

R ^3e represents a hydrogen atom;

X ^s represents a pyridyl group optionally having 1 to 3 substituents (a) e,

Here, the substituent (a) e is a methoxy group, an ethoxy group, an isopropoxy group, a benzyloxy group, a methylthio group, an ethylthio group, a methylsulfonyl group, A tinolesulfonyl group, a benzyl group, a phenyl group, a phenoxy group, a phenylthio group, a phenylenolesnorefinole group, a phenylszolefony / reamino group, and a Z or N-methinolephenylsulfonylamino group;

Y ^e represents an oxygen atom;

Z ^e represents a 2,4-dioxothiazolidine-1-ylmethyl group; the compound according to (1).

(3 3) 5— {4— (2 — [([1- (4-Bifyuniryl) ethylidene] amino] ethoxy] ethoxy) benzyl} thiazolidine-1,2,4-dione,

5— {4— (2 — [([1— (4 一 1 ニ 1 ニ 1 ニ 2 ニ 4 フ 2 オン 4 レ 2 ェ 4 レ 2 ニ 4 エ 4 ニ 4 エ 4 ニ 4 ニ 4 ニ 4 ニ 4 ニ 4 ニ 2 ニ 4 ニ 4 ニ 2 ニ 4 ニ 4 エ 2 ニ 444 エ 2 ニ 444 (4

5-{4- [2-([(1- [4- (2-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine-1,2,4-dione (hereinafter referred to as "compound A"). ),

5— {4— [2 — ([(1— [4— (3-pyridyl) phenyl] ethylidene) amino] oxy) ethoxy] benzyl} thiazolidine-1,2, dione,

5-{4-[2— ([(1— [4— (4-pyridyl) phenyl] ethylidene) amino] oxy) ethoxy] benzyl} thiazolidine-1,2,4-dione,

5— {4- (2-[([1- (2-phenyl-5-pyridyl) ethylidene] amino] ethoxy] ethoxy) benzyl} thiazolidine-1,2, dione,

5— {4— (2 — [([1— (2-Methoxy-5-pyridyl) ethylidene] amino) ethoxy] benzyl) thiazolidine-1,2-dione,

5-{4-(2— [([1— (2-ethoxy-1-5-pyridyl) ethylidene] amino] ethoxy] ethoxy) benzyl} thiazolidine-1, 4-dione,

5— {4— (2 — [([1- (2-isopropoxy-5-pyridyl) ethylidene] amino) ethoxy] benzyl) thiazolidine-1,2-dione and

5-{4-(2-[([1-(2-benzyl-1-pyridyl) ethylidene] amino] ethoxy] ethoxy) benzyl} thiazolidine-1, 2, 4-dione. (VI) WO 9 5 1 8 1 25 (1) — General formula (VI)

(VI)

[Where,

R ^{ is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted fused heterocyclic group, or formula

[Where,

R ^lf is an ^optionally substituted aromatic hydrocarbon group, optionally substituted, cycloaliphatic hydrocarbon group, optionally substituted! /, Heterocyclic group or optionally substituted, fused complex a Hajime Tamaki, R ^2f and R ³ f are the same or different, a hydrogen atom or a lower alkyl group, X ^f is a group represented by an oxygen atom, a sulfur atom or a secondary amino group,

R ^4f is a hydrogen atom or a lower alkyl group,

R ^5f is lower alkyl;

P ^f and Q ^f are the same or different and are a hydrogen atom, or P ^f and Q ^f together represent a bond. ]

Or a pharmacologically acceptable salt thereof is described.

In the compound having the general formula (VI), examples of the definitions represented by R ^f , R ^lf , R ² R ^3f , R ^4f , R ^5f , P ^f and Q ^f , types of pharmacologically acceptable salts, Details of the production method of the compound having the general formula (VI), compound examples, examples, and the like are described in the above publications.

The aromatic hydrocarbon groups represented by R ^f and R ^lf are the same as those described above for R ^ld . When R ^f and R ^lf represent a heterocyclic group or a fused heterocyclic group, they are an aromatic heterocyclic group or an aromatic fused heterocyclic group, and are the same as those described for R ^{1 (i} . When R ^f and R ^lf represent a non-aromatic heterocyclic group, it has 5 to 7 carbon atoms, of which 1 to 3 are hetero atoms selected from nitrogen, oxygen and sulfur atoms. And preferably at least one is a nitrogen atom, such as pyrrolidinyl, piperidinyl, piperazinyl, N-methinolepidrazenole, monoreforinyl, thiomonoreolininole, oxosazolidinyl, thiazolidinyl, diazolidinyl, oxorazonyl, thioxoranyl, thioxoranyl, thioxolanyl Group.

When Rf and ^Rlf represent a cyclic aliphatic hydrocarbon group, they are preferably a cycloalkyl group, and more preferably a group having 3 to 8 carbon atoms. For example, they are cyclopropyl, cyclobutynole, cyclopentynole, cyclohexynole, cyclohepty / le, and cyclooctyl groups, preferably cyclopentyl and cyclohexyl groups. Alternatively, it is a cycloalkenyl group, preferably a group having 5 to 8 carbon atoms. For example, cyclopenteninole, cyclohexeninole, cycloheptininole, cycloocteninole group.

The above groups represented by R ^f and R ^lf may be substituted or unsubstituted. When substituted, the group may be substituted with groups commonly used in the art, for example as described above for the substituent (a) ^e .

^{^{R 2f, R 3 f, R}} «, may exhibit R ⁵ f is an alkyl group, preferably 1 to 6 carbon atoms, more preferably a lower alkyl group having 1 to 4 carbon, atoms, e.g. R ^3c and substitution (a) ^Same as described in a.

Among the compounds having the above general formula (VI), suitable compounds are shown below.

(2) The compound according to (1), wherein R ^4f is a hydrogen atom and R ^5f is a lower alkyl group.

(3) Rf may be substituted with a fuunyl group, a sulfur atom, an oxygen atom, and a 5- or 6-membered optionally substituted aromatic heterocyclic group containing one or two heteroatoms selected from a nitrogen atom, Or the compound according to (2), which is a condensed aromatic heterocyclic group which is obtained by condensing an aromatic heterocyclic ring and a benzene ring.

(4) R 1 is selected from a fluorine group, a sulfur atom, an oxygen atom and a nitrogen atom. Or a 5- or 6-membered aromatic heterocyclic group containing two hetero atoms, or a condensed aromatic heterocyclic group obtained by condensing an aromatic complex ring and a benzene ring. Compound o

(5) The compound according to (3), wherein Rf is a furyl group or a condensed aromatic heterocyclic group in which a benzene ring and a 5- or 6-membered heterocyclic ring containing a sulfur atom are condensed. '

(6) The compound according to (2), wherein Rf is a phenyl group, a benzophenyl group, or a 1-methyl-1- (2-pyridylthio) methyl group.

(7) The compound according to (2), wherein Rf is a phenyl group.

(8) Rf

(2) The compound according to (2).

(9) Rlf is a phenyl group which may be substituted, or a 5- or 6-membered optionally substituted aromatic heteroatom containing one or two hetero atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom or an atom atom. The compound according to (8), which is a cyclic group.

(10) The compound according to (8), wherein R ^lf is a 5- or 6-membered aromatic heterocyclic group containing one or two hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom.

(11) The compound according to (8), wherein (5) is a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom.

(12) The compound according to (8), wherein Rlf is a pyridyl group.

(1 3) 4— [4 -— [2- (2-phenyl-1-5-methyl-4-oxazolinole) ethoxy] benzyl] —3,5-isoxazolidinedione

4- [4— [2 -— (2-phenyl-1-5-methyl-4-oxazolyl) ethoxy] benzylidene] —3,5-isoxazolidinedione,

4- [4- [2- (2-nzochenyl-5-methyl-4-oxazolyl) ethoxy] benzyl] -1-3,5-isoxoxazolidinedione and

4— [4— [2- [5-Methyl- [2- (2-pyridylthio) ethyl-1 4-oxazolyl) ethoxy] benzyl] —3,5-Isoxazolidinedione (1) The compound according to (1), wherein

(V I I) Japanese Patent Application Laid-Open No. 7-3300728 and EP

(1) General formula (VII)

[Where,

は represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindolin ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings represent one to three substituents (a) g described later. May have,

Yg represents an oxygen atom or a sulfur atom,

Is 2,4-dioxothiazolidine-15-yridenylmethyl group, 2,4-dioxothiazolidine-15-ylmethyl group, 2,4-dioxoxazolidine-15

—Ylmethyl group, 3,5-dioxooxadiazolidine-12T-methyl group or N-hydroxypereidomethyl group;

R8 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom A hydroxy group, a dinitro group, a substituted group (b) an amino group optionally having S (the substituted group (b) i is a straight-chain or branched chain having 1 to 8 carbon atoms) Alkyl group, linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, straight chain having 1 to 11 carbon atoms, Represents a branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms. A linear or branched aralkyl group having at most 11

m «represents an integer from 1 to 5,

Here, the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, A trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) g (the substituent (b) g is a straight-chain or branched-chain having 1 to 8 carbon atoms) Alkyl groups, linear or branched aralkyl groups having 7 to 11 carbon atoms, aryl groups having 6 to 10 carbon atoms, and linear groups having 1 to 11 carbon atoms are also available. Or a branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms.) c) an aryl group having 6 to 10 carbon atoms which may have g (the substituent (c) 8 is a linear or branched alkyl group having 1 to 4 carbon atoms, C1-C4 linear or branched alkoxy group, halogen atom, hydroxy group, nitro group, phenyl A trifluoromethyl group, a substituted moiety (b) an amino group optionally having 5), or a substituted moiety (c) a linear chain having 7 to 11 carbon atoms optionally having S Represents a branched or branched aralkyl group. ]

Or a pharmacologically acceptable salt thereof.

In the compound having the general formula (VII), RS, XS, YS, substitution (a) S, substitution (b) S, substitution (c) 8 and mg are exemplified. Details of acceptable salts, methods for producing compounds having the above general formula (VII), examples of compounds, examples, and the like are described in the above publications.

For example, when RS, the substituent (a) S, and the substituent (c) S represent an alkyl group or an alkoxy group having 1 to 4 carbon atoms, they are the same as those described above for the substituent (a) a. The same is true.

When R8, the substitution (a) S and the substitution (c) g represent a halogen atom, they are the same as those described for the substitution (a) a above.

RS, Substituent (a) When S represents an aralkyl group, it is the same as that described above for R ^{1 (j} ).

Substituent (a) When S represents an alkylthio group, it is the same as that described in above.

When the substituent (a) S and the substituent (b) g represent an aryl group, they are the same as those described for Rid above.

Substituted (b) straight-chain or branched-chain fat having 6 to 11 carbon atoms Aliphatic group, araliphatic aliphatic group having 8 to 12 carbon atoms or 7 to 12 carbon atoms

When referring to an aromatic acyl group having 11 ones, it is as described for R ^ld above.

When the substituted group (b) g represents an alkyl group having 1 to 8 carbon atoms, the group is a linear or branched alkyl group, for example, methyl, ethyl, propyl, isopropylinole, butynole. , Isobutynole, s-butynole, t-butynole, pentynole, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3, 3- Dimethinolebutyl, 2, 2-dimethylbutynole, 1, 1-Dimethynolebutynole, 1, 2-dimethylbutynole, 1, 3-dimethylbutynole, 2, 3-dimethinolebutyl, 2-ethylbutyl, heptyl, octyl group is there. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and most preferably a methyl group.

Among the compounds having the above general formula (VII), suitable compounds are shown below.

(2) represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have one to three substituents (a) 8 described later. May be

Here, (a) K is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a fluorothio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, An amino group which may have a substituent (b) g (the substituent (b) 8 is a linear or branched alkyl group having 1 to 8 carbon atoms, and a carbon atom having 7 to 1 carbon atoms; A linear or branched aralkyl group having one, an aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms Group, araliphatic acyl group having 8 to 12 carbon atoms or 7 to 1 carbon atoms An aromatic acyl group having 1) is selected from an aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) g; Wherein the substituent (c) S is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms. Group, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, an amino group which may have a substituent (b) g), or at least one substituent (c) 8 (1) The compound according to (1), which represents a linear or branched aralkyl group having 7 to 11 carbon atoms which may be possessed.

(3) XS represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings may have 1 to 3 substituents (a) g described below,

Here, the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. , A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, b) an amino group optionally having 8 (the substituent (b) S is a linear or branched alkyl group having 1 to 8 carbon atoms, and a substituted or unsubstituted alkyl group having 7 to 11 carbon atoms; Linear or branched aralkyl group having 6 to 10 carbon atoms, linear or branched aliphatic acryl group having 1 to 11 carbon atoms, carbon Araliphatic acyl group having the number 8 to 12 or carbon number 7 to 1 Represents an aromatic acyl group having 1), an aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) g (the substituent ( c) 6 is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group A nitro group, a phenyl group, a trifluoromethyl group, an amino group optionally having a substituent (b) g), or a carbon number optionally having at least one substituent (c) 8 The compound according to (1), which represents a linear or branched aralkyl group having 7 to 11 groups.

(4) XS represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) δ described below, (A) 6 is linear or branched having 1 to 4 carbon atoms Branched alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, 1 to 4 carbon atoms Linear or branched alkylthio group, trifluoromethyl group, nitro group, substituted (b) amino group which may have S (the substituted (b) g is A linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched aralkyl group having 7 to 11 carbon atoms, and 6 to 10 carbon atoms; An aryl group having 1 to 11 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic aliphatic acyl group having 8 to 12 carbon atoms, or a 7 to 11 carbon atom Represents an aromatic acyl group having), 1 to 3 substituents (c) S An aryl group having 6 to 10 carbon atoms which may have (the substituted (c) g is a linear or branched alkyl group having 1 to 4 carbon atoms; A straight-chain or branched-chain alkoxy group having 1 to 4 halogen atoms, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, and an amino group optionally having a substituent (b) S (1) a linear or branched aralkyl group having 7 to 11 carbon atoms which may have 1 to 3 substituents (c) g; Compound.

(5) Xg represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) g described below;

Here, the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. A benzyloxy group, a halogen atom, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a fujyl group; Compound.

(6) Xg represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) す described below;

Here, the substituent (a) g is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group. The compound according to (1), which represents an ethylthio group or a phenyl group. (7) R5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom The compound according to (1), which shows

(8) The compound according to (1), wherein R8 represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom. ·

(9) The compound according to (1), wherein R8 represents a hydrogen atom or a methoxy group.

(10) The compound according to (1), wherein RS represents a hydrogen atom.

(11) The compound according to (1), wherein YS represents an oxygen atom.

(1 2) ZS is 2,4-dioxothiazolidine-15-iridylmethyl group, 2,4-dioxothiazolidine-15-ylmethyl group or 2,4-dioxoxazozolidine-1-5— The compound according to (1), which represents a methyl group.

(13) The compound according to (1), wherein ZS represents a 2,4-dioxothiazolidine-15-yridenylmethyl group or a 2,4-dioxothiazolidine-15fmethyl group.

(14) The compound according to (1), wherein Zg represents a 2,4-dioxothiazolidine-1-ylmethyl group.

(1 5) XI! Represents an indole ring group, an indoline group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings may have 1 to 3 substituents (a) g described later. ,

Υϋ represents an oxygen atom or a sulfur atom,

Zg is 2,4-dioxothiazolidine-1-5-idylmethyl group, 2,4-dioxothiazolidine-15-ylmethyl group, 2,4-dioxoxazolidine-15-ylmethyl group, 3,5-dioxo Oxadiazolidine-12-methyl group or N-hydroxyperidomethyl group;

R8 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom;

m? is an integer from 1 to 5,

Here, the substituent (a) 8 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms. Alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group An amino group which may have a substituent (b) ϋ (the substituent (b) 6 is a linear or branched alkyl group having 1 to 8 carbon atoms, A linear or branched aralkyl group having 1 carbon atom, an aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic alkyl having 1 to 11 carbon atoms Represents an aromatic aliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.), And having at least one substituent (c) S Aryl group having 6 to 10 carbon atoms (optionally c) S is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxy, Group, a nitro group, a phenyl group, a trifrenorelomethyl group, a substituted group (b) an amino group optionally having S), or at least one substituted group (c) S The compound according to (1), which represents a straight-chain or branched aralkyl group having a good carbon number of 7 to 11.

(16) represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings each have 1 to 3 substituents to be described later.

(a) may have S,

Y8 represents an oxygen atom,

Z g represents a 2,4-dioxothiazolidine-15-ylenylmethyl group, a 2,4-dioxothiazolidine-15-ylmethyl group or a 2,4-dioxoxazolidine-15f-methyl group;

Rg represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom;

mS represents an integer of 1 to 5,

Here, the substituent (a) S is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. , Benzyloxy group, halogen atom, hydroxy group, acetoxy group, Phenylthio group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group, amino group optionally substituted (b) S (The substituted (b) 8 is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched aralkyl group having 7 to 11 carbon atoms. An aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, and an aromatic aliphatic acyl group having 8 to 12 carbon atoms A group or an aromatic acyl group having 7 to 11 carbon atoms.), An aryl having 6 to 10 carbon atoms optionally having at least one substituent (c) g A group (wherein the substituted (c) g is a linear or branched alkyl group having 1 to 4 carbon atoms; A straight or branched alkoxy group having up to 4 groups, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoronoreomethyl group, and a substituent (b) S A good amino group) or a straight-chain or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substitution moiety (c) g. Compound.

(17) represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) g described below;

YS represents an oxygen atom,

Z g represents a 2,4-dioxothiazolidine-15-yridenylmethyl group or a 2,4-dioxothiazolidine-15-ylmethyl group;

RS represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom,

m? is an integer from 1 to 5,

Here, the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. Benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group, substitution An amino group which may have a moiety (b) S (the substituted moiety (b) 6 is a linear or branched alkyl group having 1 to 8 carbon atoms, 7 to 11 carbon atoms) Linear or branched aral with Kill group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, aromatic fatty acid having 8 to 12 carbon atoms An aromatic acyl group or an aromatic acyl group having 7 to 11 carbon atoms. ), 1 to 3 substituted (c) aryl groups having 6 to 10 carbon atoms which may have S (the substituted (c) 6 has 1 to 4 carbon atoms) Linear or branched alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, triphenylenomethyl A group, a substituent (b) an amino group optionally having S), or a straight-chain having 7 to 11 carbon atoms optionally having 1 to 3 substituents (c) g; Alternatively, the compound according to (1), which represents a branched aralkyl group.

(18) XS represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) 6 described below;

Y8 represents an oxygen atom,

Z g represents a 2,4-dioxothiazolidine-1-5-methyl group; Rg represents a hydrogen atom or a methoxy group;

m8 represents an integer of 1 to 5,

Here, the substituent (a) S is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. (1) The compound according to (1), which represents a benzyloxy group, a halogen atom, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group. .

(19) X S represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) 8 described below;

YS represents an oxygen atom,

Z S represents a 2,4-dioxothiazolidine-1-5-ylmethyl group;

R8 represents a hydrogen atom,

m? is an integer from 1 to 5,

Here, the substituted component (a) S represents a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, The compound according to (1), which represents a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or a phenyl group.

(20) 5- {4-(3-Methylimidazo [4,5-b] pyridine-1-ylmethoxy) benzyl} thiazolidine_2,4-dione,

5— [4— (5-chloro-1--3-imidazo [4,5-b] pyridine-12-ylmethoxy) benzyl] thiazolidine-1,4-dione,

5- [4- (5-Methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl / le] thiazolidine-1, 4-dione,

5- [4-(5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5- [4 -— (5-ethoxy-1-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5- [4- (5-Isopropoxy-1-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-1, 2,4-dione and

5— [4— (1-Methylindoline-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione

The compound according to (1), wherein

(VIII) Japanese Patent Application Laid-Open No. 9-295970 and EP 745 600 A include (1) —general formula (VIII)

[Where,

X ^h represents a benzimidazole ring group, which may have 1 to 5 substituents (a) k described below;

Y ^h represents an oxygen atom or a sulfur atom,

Z ^h is a 2,4-dioxothiazolidine-15-yridenylmethyl group, a 2,4-dioxothiazolidine-15-ylmethyl group, a 2,4-dioxoxazolidine-15-ylmethyl group, 3,5-dioxoxaziazolidine-1-ylmethyl group or N—Hydroxyperidomethyl group,

R ¹¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom A hydroxy group, a nitro group, an amino group which may have a substituent (b) h (the substituent (b) h is a linear or branched chain having 1 to 8 carbon atoms). Alkyl group, linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, straight chain having 1 to 11 carbon atoms Represents a branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms. A linear or branched aralkyl group having at most 11

m ^h represents an integer of 1 to 5,

Here, the substituent (a) h is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, ) Amino group which may have a 'group (the substituent (b) h is a linear or branched alkyl group having 1 to 8 carbon atoms; and a substituted or unsubstituted alkyl group having 7 to 11 carbon atoms). A linear or branched aralkyl group having 6 to 10 carbon atoms, a linear or branched aliphatic acryl group having 1 to 11 carbon atoms, Araliphatic acyl group having 8 to 12 carbon atoms or 7 to 11 carbon atoms An aromatic Ashiru group having pieces.), Substituents (c) § Li Ichiru group having 1 0 having 6 to carbon atoms which may have a ^h (the substituent (c) ^h is the number of carbon atoms Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl Group, trifluoromethyl group, substituted (b) amino group optionally having h), or (c) straight chain having 7 to 11 carbon atoms optionally having h It represents a chain or branched aralkyl group. ]

Or a pharmacologically acceptable salt thereof.

In the compound having the general formula (VIII), R ^h , X ^h , Y ^h , Examples of the definitions represented by (a) h, (b) h, ( _c ) h and _m h, types of pharmacologically acceptable salts, and compounds of the general formula (VIII) Details of the production method, compound examples, examples and the like are described in the above publications.

When R ^h , substitution (a) h and substitution ( _c ) h represent an alkyl group or an alkoxy group having 1 to 4 carbon atoms, they are the same as those described in the above substitution (a) ³ It is.

When R ^h , the substituted moiety (a) h, and the substituted moiety (b) h represent an aralkyl group, they are the same as those described above for R ^{1 (i} ).

When R ^h , substitution (a) h, and substitution (c) h represent a halogen atom, they are the same as those described for the substitution (a) a above.

Substituents (a) When ^h represents an alkylthio group, it is the same as described above in.

When the substituted moiety (a) h and the substituted moiety ( _b ) h represent an aryl group, they are the same as those described in above.

Substituent (b) h is a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms or 7 to 11 carbon atoms

When the substitution (b) h represents an alkyl group having 1 to 8 carbon atoms, it is the same as that described for the substitution (b) g above.

Among the compounds having the general formula (VIII), suitable compounds are shown below.

(2) Rh is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom The compound according to (1), which shows

(3) The compound according to (1), wherein Yh represents an oxygen atom.

(4) Z ^h 2,4-dioxothiazolidine-1-ylmethyl group, 2,4-dioxothiazolidine-15-ylidurmethyl group or 2,4-dioxoxazolidin-5-ylmethyl The compound according to (1), which represents a group. (5) Rh is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom Indicates that

Y ^h represents an oxygen atom,

Z ^h force Shows 2,4-dioxothiazolidine-1-ylmethyl group, 2,4-dioxothiazolidine-15-ylidurmethyl group or 2,4-dioxoxazolidin-5-ylmethyl group ( 1) The compound as described.

(6) Z ^h force 2, 4-di O Kiso thiazolidine _ 5- Irumechiru group or 2, 4-di-O Kiso thiazolidine showing an 5- Iridenirumechiru group (1) compounds described.

(7) The compound according to (1), wherein Rh represents a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom.

The compound according to (1), wherein (8) represents an integer of 1 to 3.

(9) Y ^h represents an oxygen atom,

Z ^h force; a 2,4-dioxothiazolidine-1-5-methyl group or a 2,4-dioxothiazolidine-1-5-ylidenylmethyl group;

R ^h is a hydrogen atom, a methyl group, main butoxy group, an ethoxy group, a fluorine atom or a chlorine atom,

The compound according to (1), wherein mh represents an integer of 1 to 3.

(10) Χΐ · represents 1 to 5 benzodimidazole ring groups which may have the following substituents (a) h,

Wherein the substituent (a) ^h is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, Benzyloxy, halogen, phenylthio, linear or branched alkylthio having 1 or 4 carbon atoms, trifluoromethyl, hydroxy, acetyl, benzyl, phenyl or phenyl (1) The compound described in (1).

(11) The compound according to (1), which represents a 2,4-dioxoxazolidine-15-ylmethyl group.

(12) The compound according to (1), wherein Rh represents a hydrogen atom, a methyl group or a methoxy group. (1 3) represents 1 to 5 substituents (a) a benzodimidazole ring group optionally having h,

Wherein the substituent (a) h is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, Benzyloxy, halogen, phenylthio, linear or branched alkylthio having 1 or 4 carbon atoms, trifluoromethyl, hydroxy, acetoxy, benzyl, phenyl or phenyl Represents a group,

Y ^h represents an oxygen atom,

Z ¹¹ represents a 2,4-dioxoxazolidine-1-ylmethyl group; R ^h represents a hydrogen atom, a methyl group or a methoxy group;

The compound according to (1), wherein is an integer of 1 to 3.

(1 4) X ^h is 1 to indicate the five following substituents (a) ¹¹ may have a base Nzui Midazo Ichiru ring group,

Where the substitution (a) h is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group (1) The compound according to (1), which represents an ethylthio group, a hydroxy group, an acetyl group, a benzyl group or a fuzyl group.

(15) The compound according to (1), wherein Rh represents a hydrogen atom.

The compound according to (1), wherein (16) represents 1 or 2.

(17) Xh represents 1 to 5 substituents (a) a benzodimidazole ring group optionally having ^h ,

Where the substituent (a) h is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, Represents a methylthio group, an ethylthio group, a hydroxy group, an acetyl group, a benzyl group or a phenyl group;

Yh represents an oxygen atom,

Z ^h represents a 2,4-dioxothiazolidine_5-ylmethyl group;

R ^h represents a hydrogen atom,

(1) The compound according to (1), wherein mh represents 1 or 2. (18) X ^h has 1 to 5 substituents (a) a benzodimidazole ring group optionally having ^h ,

(1) The compound according to (1), wherein (a) h represents a methyl group, a methoxy group, a hydroxy group, an acetyl group or a benzyl group.

(19) The compound according to (1), wherein mh represents 1. '

(20) χΊ is 1 to 5 substituted (a) a benzimidazoyl ring group optionally having ^h ,

Here, the substituent (a) h represents a methyl group, a methoxy group, a hydroxy group, an acetate group or a benzyl group;

Y ^h represents an oxygen atom,

Z ^h represents a 2,4-dioxothiazolidine-1-ylmethyl group;

R ^h represents a hydrogen atom,

The compound according to (1), wherein mh represents 1.

(21) 5— [4 -— (1-Methylbenzimidazole_2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5- [4-(6-Methoxy-1-1-methinolevene-2-azo-methyl-2-benzyl) benzyl] thiazolidine-1,4-dione (hereinafter referred to as “Compound B” 5.),

5— [4— (5-Methoxy-1—Methynolebenzi midazo 1—2-Inolemethoxy) benzyl] thiazolidine-1,2,4-dione,

5— [4— (1-Benzylbenzimidazole-5-ylmethoxy) benzyl] thiazolidine-1,4-dione,

5-[4-(5-Hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-1, 2,4-dione and

The compound according to (1), which is 5- [4-(5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione.

(I X) JP-A 1-27254 and EP 332332A include:

(1) General formula (IX)

[Where,

Dotted lines indicate binding or no binding,

Vi is —CH = CH—, one N-CH—, one CH-N— or a sulfur atom, and Wi is〉 CH ₂ ,>CHOH,>CO,> C = NORi or one CH = CH— ,

X ^[ is a sulfur atom, an oxygen atom,〉 NRli, one CH-N— or —N = CH—, Y is = CH— or a nitrogen atom,

Zi represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a pyridyl group, a furyl group, a phenyl group, or the same or different carbon atoms. An alkyl having 1 to 3 carbon atoms, trifluoromethyl, an alkoxy having 1 to 3 carbon atoms, a fuunyl group mono- or di-substituted by a group that is fluorine, chlorine or bromine,

Zli is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

Ri and Rii are the same or different and are a hydrogen atom or a methyl group,

n ¹ is 1, 2 or 3. ]

Or a pharmacologically acceptable salt thereof.

In the compounds having the above general formula (IX), Vi, Wi, X 〖, Yi, Zi, ZLI, Ri, Rli及Pi _n i exemplary definitions represented by the type of acceptable salts pharmacologically, upper following general Details of the production method of the compound having the formula (IX), compound examples, examples, and the like are described in the above publications.

For example, when Zi is an alkyl group having 1 to 7 carbon atoms or a Zli group or a phenyl group represented by Zi is an alkyl group having 1 to 3 carbon atoms, these are the above-mentioned substitution groups (b) Same as described for g.

When Zi represents a cycloalkyl group having 3 to 7 carbon atoms, Propinole, cyclopentinole, cyclopentyl, cyclohexinole, and cycloheptinole groups.

Among the compounds having the general formula (IX), suitable compounds are shown below.

(2) The dotted line indicates no binding,

The compound according to (1), wherein W ′ is> CO or> CHOH. '

(3) Vi is —CH = CH—, —CH = N— or a sulfur atom,

The compound according to (2), wherein ni is 2.

(4) Xi is an oxygen atom,

Υ 'is a nitrogen atom forming an oxazole-4-hydroxyl group,

Z ¹ is a 2-phenyl group, a 2-furyl group, a phenyl group, a substituted phenyl group or a naphthyl group;

The compound according to (3), wherein Zli is a methyl group.

(5) Vi is -CH = N- or a sulfur atom,

The compound according to (4), wherein Zi is phenyl.

(6) Vi is -CH = CH-,

Wi is> CO,

The compound according to (1), wherein Zi is a 2- (2-furyl) group, a 2-fuel group, a 2- (4-methylphenyl) group or a 2- (2-naphthyl) group.

(7) Xi is an oxygen atom or a sulfur atom,

(3) The compound according to (3), wherein 1 is a nitrogen atom forming an oxazole- ^1- yl, thiazole-4-yl or thiazol-15-yl group.

(8) Xi is —CH = N—, and Yi is a CH group forming a pyridyl 2 _yl group,

Or (3) the compound according to (3), wherein Xi is an oxygen atom, and Yi is a CH group forming a fluor-2-yl group.

(9) The compound according to (1), which is 5— {4-—3- (5-Methynole-1-phenyl-2-oxyl-1-propyl) propionyl] benzyl} thiazolidine-1,2, dione.

(X) JP 6-247945 and EP 604983 A include: (1) General formula (X)

[In the above general formula (X),

Represents

-XJ — represents an oxygen or sulfur atom,

= Υί represents = Ν— or -CR ⁵ j—,

^{^{Rij, R 2), R 3}} i, and R ⁵ j are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, Ariru group, alkoxy group, alkoxyalkoxy group, Ariruo alkoxy group, alkanoyloxy Noi Ruo alkoxy group, § Reelcarbonyloxy group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, alkamoyl 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 ^fi j represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group,

n i represents an integer from 0 to 3,

The dotted line indicates that the bond at that portion may be a double bond. ]

Or a pharmacologically acceptable salt having the formula:

In the compounds having the above general formula (X), A〗, Xj, ^{^{Y〗, RKRKR 3] ', R 4}} ]', R 5 j, exemplary definitions represented by R ⁶ j and nj, is pharmacologically acceptable Details of the type of salt, the method for producing the compound having the above general formula (X), compound examples, examples and the like are described in the above publications. Rij, R, R, R, R 5 j halogen atom, an alkyl group, § Li Ichiru group, indicating § alkoxy group, R6j alkyl groups, indicating Ariru group, these upper Symbol substituent of ( a) ^Same as described for ^a , R ^3c and R.

RU, R ² j, RKR "and R ⁵ j are alkoxyalkoxy, aryloxy, alkanoyloxy, arylcarbonyl, alkoxycarbonyl, aryloxycarbyl, alkyl When it represents an aminocarbonyl group, an arylaminocarbonyl group, an alkanoylamino group, or an arylcarbonylamino group, each part of these groups is the same as described above.

When R! J, R ² j, R, R, and R ⁵ represent an alkylamino group, this is a mono- or di-alkylamino group, and is the same as that described in (a) ^a above. is there.

R ^l KR ² KRK

When represents a trihalomethyl group, this is a trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl group, preferably a trifluoromethyl group.

Among the compounds having the general formula (X), suitable compounds are shown below. (2) R2] ′, R3j, R4j and R5j are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, An alkoxy group having 1 to 8 carbon atoms, an alkoxyoxy group having 2 to 6 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, an alkanoyloxy group having 2 to 9 carbon atoms An arylcarbonyloxy group having 7 to 13 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 9 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, carbamoyl Group, alkylaminocarbonyl group having 2 to 9 carbon atoms, arylaminocarbonyl group having 7 to 13 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, carbon number Represents an alkanoylamino group having 2 to 9 carbon atoms, an arylcarbonylamino group having 7 to 13 carbon atoms, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group, or a trihalomethyl group. ,

R ⁶ j is an alkyl group having 1 to 8 carbon atoms which may have one or more substituents selected from a hydrogen atom, halogen, nitro and cyano, or halogen, nitro A compound according to (1), which represents an aryl group having 6 to 12 carbon atoms which may have one or more substituents, selected from cyano and cyano.

(3) R R2j, RK and R ⁵ j are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, alkoxy group having 1 to 8 carbon atoms having 1 to 8 carbon atoms, or 2 carbon atoms An alkoxyalkoxy group having 6 carbon atoms, an alkanoyloxy group having 2 to 9 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 9 carbon atoms A carbamoyl group, an alkylaminocarbonyl group having 2 to 9 carbon atoms, an arylaminocarboyl group having 7 to 13 carbon atoms, an amino group, an alkylamino group having 1 to 8 carbon atoms, Alkanoylamino having 2 to 9 carbons, arylcarbonylamino having 7 to 13 carbons, ethylenedioxymethyl, formyl, shear Group, a nitro group, or a trihalomethyl group and table,

The compound according to (1), wherein R ⁶ j represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may be substituted with halogen.

(4)-xi — represents an oxygen atom,

YJ represents = CR ⁵ j—,

R ² j, R ^y K and R 5j ′ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, 2 to 6 carbon atoms An alkoxyalkoxy group having 2 to 6 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, and an arylaminocarbonyl group having 7 to 13 carbon atoms , An amino group, an alkanoylamino group having 2 to 6 carbon atoms, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group,

The compound according to (1), wherein R 6j represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may be substituted with halogen.

( Five )

Represents

-XJ — represents an oxygen atom,

YJ

Represents

R ² KR and R ⁴ j are the same or different and represent a hydrogen atom or a halogen atom,

R ⁵ j represents a hydrogen atom,

R ⁶ j represents a hydrogen atom,

nJ represents 1,

The compound according to (1), wherein the bond at the site indicated by the dotted line is a single bond.

(6) The compound according to (.1), which is 5- [6- (2-fluorobenzyloxy) -12-naphthylmethyl] thiazolidine-1,4-dione.

In the compounds having the general formulas (I) to (X) or the pharmaceutically acceptable salts thereof, when various isomers, for example, stereoisomers based on asymmetric carbon atoms are present (for example, the general formula The carbon atom at the 2-position of the chroman ring and the 5-position carbon atom of the thiazolidine ring and the oxazolidine ring of the compound having (I) is an asymmetric carbon atom.); The stereoisomers based on carbon atoms and the equivalent and unequal mixtures of these isomers are all represented by a single formula. Accordance connexion, mixtures _c such stereoisomers both encompassed by the present invention of these isomers及Pico these isomers, the general formula with an optically divided raw material (I) to (X) The compound having the general formulas (I) to (X) can be optically resolved by a conventional optical resolution method or separation method, if desired.

Further, in the compounds having the general formulas (I) to (X) or pharmacologically acceptable salts thereof, for example, 2,4-dioxothiazolidine-1-5-^-methyl group, 2,4-dioxo Oxazolidine-5-methyl group, 3,5-dioxoxazia Various tautomers are considered to exist in the zolidine-1-ylmethyl group. In the above general formulas (I) to (X), the tautomers and the equivalent and unequal mixtures of the isomers are all represented by a single formula. Therefore, both of these isomers and mixtures of these isomers are included in the present invention.

Further, in the present invention, when the compound having the general formula (I) to (X) or a pharmaceutically acceptable salt thereof forms a solvate (for example, a hydrate), all of these are included. It is a thing. For example, the compound having the general formulas (I) to (X) or a pharmacologically acceptable salt thereof is left in the air or recrystallized, thereby absorbing water and adsorbing water. However, hydrates may form. The present invention includes such a solvate.

Furthermore, the present invention also includes all compounds that are converted into the compounds having the above general formulas (I) to (X) or pharmacologically acceptable salts thereof by metabolizing in vivo, so-called prodrugs. .

In the compound of the present invention having the general formulas (I) to (X),

Preferably,

5-[4-(6-hydroxy-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) benzyl] thiazolidine-1,2,4-dione (troglitazone),

5-[4- (6-hydroxy-1-2-methinole 7-t-butynolechroman-1-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5— [4— (6-hydroxy-1-2-ethynole-5,7,8-trimethylchroman 1-2— ^ f-methoxy) benzyl] thiazolidine-1,2, dione,

5— [4— (6-Hydroxy-1-isobutyl_5,7,8-trimethylchroman-1-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5— [4— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] thiazolidine-1,2, dione,

5- [4- (6-ethoxycarbonyloxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] thiazolidine-1, 4-dione,

5— {4-[2- (3-ethynole-1-pyridyl) ethoxy] benzyl} — 2,4-thiazolidinedione, 5— {4- [2- (4-Ethyl-2-pyridyl) ethoxy] benzyl} 1-, 4-thiazolidinedione,

5— {4— [2— (5-ethynole-1-pyridyl) ethoxy] benzyl} —2,4-thiazolidinedione (pioglitazone),

5— {4— [2— (6-ethynole-2-pyridyl) ethoxy] benzyl} —2,4-thiazolidinedione,

5-[(2-Benzyl-2,3-dihydrobenzofuran-5-yl) methyl] thiazolidine-1, 4-dione,

5 — [(2-benzinole-1,4-dihydro2H-benzopyran-1-6-inole) methyl] thiazolidine-1,4-dione (englitazone),

5— {4— (2— [N-methyl-1-N— (2-benzothiazolyl) amino] ethoxy) benzyl) thiazolidine-1,2, dione,

5-{4-(2- [N-methyl-N- (2-pyrimidinyl) amino] ethoxy) benzyl} thiazolidine-1, 2, 4-dione,

5— {4- [2_ (N-methyl-N— [2- (4,5-dimethylthiazolyl)] amino] benzyl] thiazolidine-1 2,4-dione;

5-{4-(2- [N-methyl-1-N- (2-thiazolyl) amino] ethoxy) benzyl} thiazolidine-1, 4-dione,

5-{4- [2 -— (N-methyl-1-N- [2- (4-phenylthiazolyl)] amino) ethoxy] benzyl} thiazolidine-1,2,4-dione,

5-{4- [2 -— (N-methyl-1-N- [2- (4-phenyl-5-methinolethiazolyl)] amino] ethoxy] benzyl} thiazolidine-1,2, dione,

5-{4-[2-(N-methyl-1-N-[2-(4-methyl-1-phenolethia zolyl)] amino] ethoxy] benzyl} thiazolidine-1, 4-dione;

5— {4- [2- (N-methyl-1-N— [2- (5-phenyloxazolinole)] amino] ethoxy] benzyl} thiazolidine-1,2,4-dione,

5-{4- [2_ (N-methyl-N- [2- (4,5-dimethyloxazolyl)] amino] benzyl] thiazolidine-1,2,4-dione,

5- {4- [2- (2-Pyrimidinylamino) ethoxy] benzyl} thiazoly Gin one, two, four diones,

5— {4- (2- [N-acetyl-N- (2-pyrimidinyl) amino] ethoxy) benzyl} thiazolidine—2,4-dione;

5— {4- (2 -— [N- (2-benzothiazolyl) -1-N-benzinoleamino] ethoxy) benzyl} thiazolidine-1, 4-dione,.

5— {4- (3 -— [N-methyl-1-N— (2-benzoxazolyl) amino] propoxy) benzyl} thiazolidine-1,2, dione,

5-{4- (2- [N-methyl-N- (2-pyridyl) amino] ethoxy) benzyl] thiazolidine-1,4-dione (mouth diglitazone),

5-{4-(2-[([1-(4-biphenyl) ethylidene] amino) oxy] ethoxy) benzyl} thiazolidine- 1, 2, 4-dione,

5— {4— (2— [([1-(4-pheninolenesolehoninolefuenoinole) ethylidene] amino] ethoxy] ethoxy) benzyl} thiazolidine-1,2, dione,

5-{4- [2-([(1- [4- (2-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine-1,2, dione (compound A),

5-{4- [2 — ([(1— [4- (3-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine-1,2,4-dione,

5-{4-[2-([(1-[4-(4-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine- 1, 2, 4-dione,

5-{4- (2-([[1- (2-phenyl-1-5-pyridyl) ethylidene] amino) oxy] ethoxy) benzyl} thiazolidine-1,2, dione,

5— {4— (2 — [([1— (2—Methoxy-5—pyridyl) ethylidene] amino) ethoxy] ethoxy) benzyl} thiazolidine-1,2,4-dione,

5— {4 -— (2-[([1- (2-ethoxy-1-pyridyl) ethylidene] amino) oxy] ethoxy) benzyl} thiazolidine-1,2,4-dione,

5— {4— (2 — [([1- (2-isopropoxy-5-pyridyl) ethylidene] amino] ethoxy] benzyl) thiazolidine-1,2, dione,

5— {4— (2— [([1-(2-benzyl-5-pyridyl) ethylidene Mino) oxy] ethoxy) benzyl} thiazolidine-1,2,4-dione,

4 -— {4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl} —3,5-isoxazolidinedione,

4- {4- [2- (2-Feninole-5-methyl-14-oxazolyl) ethoxy] benzylidene} —3,5-isoxazolidinedione,

4— {4- [2- (2-Benzoenyl-1-5-methyl-4-oxazolyl) ethoxy] benzyl} —3,5-isoxazolidinedione,

4- {4-(2- [5-Methyl-2- (2-pyridylthio) ethyl-4-oxosazolyl] ethoxy) benzyl} 1-3,5-isoxazolidinedione

5- [4- (3-Methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-1, 4_dione,

5- [4- (5-chloro-1-3-methinoreimidazo [4,5-b] pyridine-1-ylmethoxy) benzyl] thiazolidine _ 2,4-dione,

5- [4-(5-Methoxy-1-3-methylimidazo [4,5-b] pyridine-1-ylmethoxy) benzyl] thiazolidine-1,4-dione.,

5-[4-(5-Hydroxy- 1-3-methylimidazo [4, 5-b] pyridine-1-2-methoxy) benzyl] thiazolidine-1, 4-dione,

5— [4— (5-ethoxy-1-methylimidazo [4,5-b] pyridine-1-ylmethoxy) benzyl] thiazolidine-1,2-dione,

5— [4— (5-Isopropoxy-1-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-1,2, dione,

5— [4- (1-methylindoline-2-ylmethoxy) benzyl] thiazolidin-1 2,4-dione,

5-[4-(1-methinolebenzi midazonole 1-2-inolemethoxy) benzinole] thiazolidine-1, 4-dione,

5-[4--(6-Methoxy 1-methylbenzimidazol_2-ylmethoxy) benzyl] thiazolidine-1, 2, 4-dione (Compound B),

5— [4— (5-Methoxy-1-methylbenzimidazole_2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione, 5— [4— (1—benzinolebenzi midazo 1-5—inolemethoxy) benzyl] thiazolidine-1 2,4 dione,

5— [4— (5-hydroxy-1,4,6,7-tetramethylbenzimidazo-one-2-y-methoxy) benzyl] thiazolidine-1,2-dione,

5— [4— (5-acetoxy-1,4,6,7-tetramethylbenzimidazol-1-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5— {4- [3 -— (5_Methyl-1-phenyloxazol_-4-yl) propionyl] benzyl} thiazolidine-1,2, dione and

5— [6— (2-Fluorobenzyloxy) -1-2-naphthylmethyl] thiazolidin-1,2,4-dione

And a pharmacologically acceptable salt thereof.

More preferably,

5-[4--(6-hydroxy-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) benzyl] thiazolidine-1, 4-dione (troglitazone),

5-[4--(6-ethoxycarbonyloxy_2,5,7,8-tetramethylchroman-1-dimethoxy) benzyl] thiazolidine-1, 4-dione,

5- {4- [2- (5-ethyl-1-pyridyl) ethoxy] benzyl} —2,4-thiazolidinedione (pioglitazone),

5 — [(2-Benzyl-1,3,4-dihydro2 2-benzopyran-1,6-inole) methyl] thiazolidine-1,2,4-dione (englitazone),

5— {4— (2 -— [Ν-methyl-1- (2-pyridyl) amino] ethoxy) benzyl) thiazolidine-1,2-dione (mouth diglitazone),

5-{4-[2— ([(1-[4-(2-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine-1,2,4-dione (compound 、),

4 1 {4-[2— (2—Feniru 5—Methinole 1—oxazolyl) Benzyl]-3,5-isoxazolidinedione,

5- [4-(5-Methoxy-3- 3-methylimidazo [4,5-b] pyridine-1 2 f-methoxy) benzyl] thiazolidine-1, 4-dione,

5— [4— (1-Methylindoline-2-ylmethoxy) benzyl] thiazolidin-1 2,4-dione,.

5-[4-(1-methylbenzimidazole- 1-2-methoxy) benzyl] thiazolidine-1, 2, 4-dione,

5- [4- (6-Methoxy-1- 1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-1, 4-dione (Compound B),

5— [4— (5-hydroxy-1,4,6,7-tetramethylbenzimidazo-lu-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5— {4- [3- (5-Methyl-1-phenylenoxazole / le-4-ynole) propionyl] benzyl} thiazolidine-1,2,4-dione and

5— [6— (2-Fluorobenzyloxy) -1-2-naphthylmethyl] thiazolidin-1,2,4-dione

And a pharmacologically acceptable salt thereof.

Particularly preferably,

5— [4— (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine_2,4-dione (troglitazone),

5— {4— [2— (5-ethyl-1-2-pyridyl) ethoxy] benzinole} —2,4-thiazolidinedione (pioglitazone),

5— {4-(2- [N-methyl-N- (2-pyridyl) amino] ethoxy) benzyl] thiazolidine-1,4-dione (mouth diglitazone),

5-{4-1 [2-([(1-[4-(2-pyridyl) phenyl] ethylidene) amino] oxy) ethoxy] benzyl} thiazolidine-1,2, dione (compound A) and

5— [4— (6—Methoxy 1—Methynolebenzi midazo 1—Yrmethoxy) benzyl] thiazolidine — 2,4 dione (Compound B), And a pharmacologically acceptable salt thereof.

Most preferably,

5- [4- (6-hydroxy-1,2,5,7,8-tetramethinolechroman-12-ylmethoxy) benzyl] thiazolidine-1 a compound that is 2,4-dione (troglitazone) and its pharmacologically acceptable Salt.

[Industrial applicability]

The insulin resistance improving substance of the present invention is useful as an agent for preventing or treating leukemia. The insulin sensitizer of the present invention is administered in various forms. The administration form is not particularly limited, but is determined according to various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. Examples include oral administration by tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules or capsules, and parenteral administration by injections or suppositories. In the case of injections, they are administered intravenously, alone or mixed with normal replacement fluids such as glucose and amino acids, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. It is. A preferred dosage form is oral administration.

These various preparations are prepared by using known auxiliaries which are commonly used in the field of pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, dissolving agents, flavoring agents, coating agents, etc. It can be formulated.

A wide variety of carriers conventionally known in the art can be used as tablets in the form of tablets, such as lactose, sucrose, glucose, starch, sodium chloride, urea, calcium carbonate, kaolin, crystalline cellulose, and caic acid. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder for polyvulpioridone sugar, dried starch , Sodium alginate, Agar powder, Laminaran powder, Sodium hydrogen carbonate, Calcium carbonate, Polyoxyethylene sorbitan fatty acid esters, Sodium lauryl sulfate, Stearic acid monoglyceride, Starch, Lactose and other disintegrants, Sucrose, Stearin, Cocoa batata First, hydrogenation Disintegration inhibitors such as quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal keic acid, and purified talc And lubricating agents such as stearate, boric acid powder and polyethylene glycol. Further, the tablets may be tablets coated with a usual coating as necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets, or multi-layer tablets. Can be tablets.

For molding into pills, a wide variety of carriers conventionally known in the art can be used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; Powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar. ■

For shaping in the form of suppositories, various carriers conventionally known in the art can be used widely, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc. Can be mentioned.

When prepared as an injection, the liquid preparation and the suspension are preferably sterilized and isotonic with blood. When forming these liquid preparations, emulsions and suspensions, they are used as diluents. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. . In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, and soothing agents may be used. An agent may be added. If necessary, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be added.

The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually 1 to 70% by weight in the whole composition. / ₀ , preferably 1-30% by weight.

In the present invention, the dose of the insulin sensitizer is different depending on symptoms, age, administration method and the like.For example, in the case of oral administration, the lower limit is ◦. It is preferable to administer lOOmg (preferably 50mg) once or in several divided doses depending on the symptoms. For intravenous administration, a lower limit of 0.1 mg (preferably 0.1 mg) and a maximum of 50 mg (preferably 20 mg) once or daily for adults per day It is desirable to administer the drug in several divided doses according to the symptoms. Next, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples.

[Best mode for carrying out the invention]

Example 1 Human Leukemia Cell Growth Inhibitory Effect

As a culture solution of human leukemia cells, an RPMI 1640 solution containing 10% of non-activated fetal bovine serum and 50 g / m1 of kanamycin was used. That is, human leukemia cell KU

8 1 2 (2 X 105 cells 1) was added to a final concentration of 2 μM troglitazone (compound name: 5— [4— (6—hydroxy-1,2,5,7,8—tetramethylchroman). The mixture was placed in a 1 ml culture medium containing (l-methoxy) benzyl] thiazolidine-1,4-dione) and cultured in a carbon dioxide incubator at 37 ° C for 96 hours. The cell proliferation of human leukemia cells was determined every 24 hours by measuring the number of viable cells in a culture solution containing troglitazone and a culture solution without troglitazone by the trypan blue staining method. The human leukemia cell growth inhibitory activity (inhibition rate) by troglitazone was calculated by the following formula, and the results are shown in Table 1. In Table 1, "contact time" indicates the contact time between human leukemia cell KU812 and troglitazone.

Human leukemia cell proliferation inhibitory activity (%) = [1 vitritazone-added group viable cells Z untreated group viable cells] X 100

table 1

Human leukemia cell growth inhibitory activity Contact time (hours) 24 48 72 96 Growth inhibitory activity (%) 0 1 2.3 27. 0 46.0 As evident from Table 1, the compound of the present invention is an excellent human. It showed an inhibitory effect on the growth of leukemia cells.

[Test example]

Test Example 1. Acute toxicity

Acute toxicity was measured according to standard methods. That is, 3 d dY mice (male) Ritazone was orally administered at a dose of 30 Omg Z kg, and observed for 5 days, all of which survived. Similarly, the acute toxicity of Compounds C and D was determined to be SOO mg Z kg or more for oral administration.

[Formulation example]

A preparation containing the insulin resistance improving substance of the present invention as an active ingredient can be produced, for example, by the following method.

Formulation Example 1. Powder

A powder is obtained by mixing 5 g of troglitazone, 8995 g of lactose and 100 g of corn starch in a blender.

Formulation Example 2. Granules

Glitazone (5 g), lactose (865 g) and low-substituted hydroxypropyl Pilcell mouth (100 g) are mixed, and then kneaded with 100% aqueous hydroxypropylcellulose (300 g). . This is granulated using an extrusion granulator and dried to obtain granules.

Formulation Example 3. Capsule

5 g of troglitazone, 15 g of lactose, 58 g of corn starch and 2 g of magnesium stearate were mixed using a V-type mixer, and then mixed into a No. 3 capsule.

Filling by O mg gives capsules.

Formulation Example 4. Tablet

After mixing 5 g of troglitazone, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate with a blender, tablets are obtained with a tablet machine.

Formulation Example 5. Powder

A powder is obtained by mixing 5 g of pioglitazone, 8995 g of lactose and 100 g of corn starch in a blender.

Formulation Example 6. Granules

After mixing 5 g of oral diglitazone, 8665 g of lactose, and 100 g of low-substituted hydroxypropylcell mouth, add 300 g of a 10% aqueous solution of hydroxypropylcellulose and knead the mixture. . This is extruded using an extruder and granulated. Is obtained.

Formulation Example 7. Capsule

After mixing 5 g of compound A, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate using a V-type mixer, fill capsules No. 3 with 18 O mg each to obtain capsules. . '

Formulation Example 8. Tablet

5 g of Compound A, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed with a blender, and the mixture is compressed with a tablet machine to give tablets.

Claims

Claims A prophylactic or therapeutic agent for leukemia containing an insulin sensitizer as an active ingredient.

2. In claim 1, wherein the insulin sensitizer is a thiazolidinedione compound, an iminothiazolidinone compound, a diiminothiazolidine compound, a thioxothiazolidinone compound, an iminotriazole compound, or an oxazolidinedione compound. An agent for preventing or treating leukemia, which is a compound selected from the group consisting of isoxazolidinedione compounds and oxaziazolidinedione compounds.

3. In claim 1, the insulin sensitizer is selected from the group consisting of a thiazolidinedione compound, an oxazolidinedione compound, an isoxazolidinedione compound, and an oxadiazolidinedione compound. Or a preventive or therapeutic agent for leukemia.

4. The preventive or therapeutic agent for leukemia according to claim 1, wherein the insulin sensitizer is a compound selected from the group consisting of a thiazolidine compound, an iminothiazolidinone compound and a diiminothiazolidine compound.

5. The preventive or therapeutic agent for leukemia according to claim 1, wherein the insulin sensitizer is a thiazolidinedione compound or an oxazolidinedione compound.

6. The preventive or therapeutic agent for leukemia according to claim 1, wherein the insulin sensitizer is a thiazolidinedione compound.

7. In claim 1, the insulin sensitizer is a compound represented by the general formula (I):

[Where,

Rla and R2a are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms;

R ^3a is a hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 6 to 8 carbon atoms, ^a benzoyl or naphthoyl group optionally having a substituent (a) ^a (The substituent (a) a is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an amino group, a 1 to 4 carbon atoms. A monoalkylamino group having the same or different, and each alkyl is a dialkylamino group or a nitro group having 1 to 4 carbon atoms.), A hetero atom composed of a nitrogen atom, an oxygen atom and a sulfur atom A 4- to 7-membered heterocyclic acyl group containing 1 to 3 heteroatoms selected from the group, a phenylacetyl group, a phenylpropionyl group, and a phenylacetyl group substituted with at least one halogen. Or phenylpropionyl group, cinnamoyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms or a benzyloxycarbonyl group,

R ^4a and R 5a are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, or R ^4a and R ^5a together Represents an alkylenedioxy group having 1 to 4 carbon atoms,

Y ^a and Z ^a are the same or different and each represent an oxygen atom or an imino group;

n ^a is an integer of 1 to 3. ]

A prophylactic or therapeutic agent for leukemia, which is a thiazolidine derivative or a pharmacologically acceptable salt thereof.

8. In claim 7, Rla is an alkyl group having 1 to 4 carbon atoms. Or a prophylactic or therapeutic agent for leukemia.

9. The preventive or therapeutic agent for leukemia according to claim 7, wherein ^Ria is a methyl group.

10. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 9, wherein R ^2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

11. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 9, wherein R ^2a is a hydrogen atom or a methyl group.

12. In any one of claims 7 to 11, wherein R ^3a represents a hydrogen atom, an aliphatic acyl group having 1 to 4 carbon atoms, or a benzoyl group having no substituent. Or a preventive or therapeutic agent for leukemia, which is a naphthoyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms.

13. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 11, wherein R ^3a is a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group.

14. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 11, wherein R ^3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group.

15. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 14, wherein R ^4a is an alkyl group having 1 to 4 carbon atoms.

16. The preventive or therapeutic agent for leukemia according to any one of claims 7 to 14, wherein R ^4a is a methyl group or a t-butyl group.

1 7. In any one of the ranges paragraph 7 to the first 6 of claims, R ⁵ a is prophylactic or therapeutic agent for leukemia is an alkyl group having 1 to 3 hydrogen atom or carbon.

1 8. The prophylactic or therapeutic agent for leukemia according to any one of claims 7 to 16, wherein R5a is a hydrogen atom or a methyl group.

1 9. In claim 1, the insulin sensitizer is a compound of the general formula (II)

(Π)

A prophylactic or therapeutic agent for blood disease, which is a thiazoli derivative or a pharmacologically acceptable salt thereof having the formula:

20. In claim 1, the insulin sensitizer is a compound of the general formula (I I I)

[Where,

Dashed lines represent single bonds or non-bonds,

n ^c is 0, 1 or 2;

X ^c is an oxygen atom, a sulfur atom, a sulfiel group (S = 〇), a sulfur group (SΟθ) (= θ)),

R ^c is a hydrogen atom, a methyl group or an ethyl group,

R ^lc is a hydrogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a methyl-substituted cycloalkyl group having 6 to 8 carbon atoms, a pyridyl group, a chenyl group, a furyl group, Nafuchinore group, p- Bifueyurinore groups, tetrahydrofuranyl Honoré group, Tetorahi Doroche group, tetrahydropyrazole El group, C ₆ H ₄ W2c group [W ^2c represents a hydrogen atom, arsenic Dorokishi group, a fluorine atom, a chlorine atom, a bromine atom, the number of carbon atoms An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or an alkylthio group having 1 to 4 carbon atoms. Or a 1 k—Wlc group [ _a 1 k is an alkylene group having 1 to 6 carbon atoms, an ethylidene group or an isopropylidene group, and W ^k is a hydrogen atom, a hydroxy group, _a C 1 to C 4 group. An alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a pyridyl group, a furyl group, a phenyl group, a tetrahydrofuryl group, a tetrahydrophenyl group, a naphthyl group, a cycloalkyl group having 5 to 7 carbon atoms or C _{6 {is a} W2c group. ]

R ^2c is a hydrogen atom or a methyl group,

R ^3c is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a C ₆ H ₄ group or a benzyl group,

R ^4c is a hydrogen atom,

When Rlc and R2c are joined together they form an alkylene group having 4 to 6 carbon atoms, and R3e is each a hydrogen atom,

When R ^3c and R are taken together, they form an alkylene group having 4 to 6 carbon atoms, Rlc and R 2c are each a hydrogen atom,

_{When R} and _R k are joined together, they form an alkylene group having 3 or 4 carbon atoms, and R ^lc and R ^4c are each a hydrogen atom. ]

Or a pharmacologically acceptable salt thereof, a prophylactic or therapeutic agent for leukemia.

21. In claim 1, the insulin sensitizer is a compound of the general formula (IV)

[Where,

Aid represents a substituted or unsubstituted aromatic heterocyclic group; R ^ld represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl moiety may be substituted or unsubstituted), or a substituted or unsubstituted aryl group;

R2d and may be the same or different, represent a hydrogen atom, or R ^2d and R ^M represents a bond together;

AM represents a benzene ring having a total of up to 5 substituents; and

n ^d represents an integer in the range of 2 to 6. ]

22. In claim 1, the insulin sensitizer is a compound of the general formula (V)

(V)

[Where,

R ^3e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, Linear or branched alkylthio group having 1 to 4 carbon atoms, halogen atom, nitro group, amino group, linear or branched monoalkylamino group having 1 to 4 carbon atoms, identical or Differently, each alkyl is a linear or branched dialkylamino group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Represents a group,

X ^e is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a) e or 1 to 3 substituents (a) e Shows a good aromatic heterocyclic group,

Here, the substituted component (a) e is (i) a linear or branched compound having 1 to 6 carbon atoms. A branched alkyl group; (ii) a linear or branched alkyl halide group having 1 to 4 carbon atoms; (iii) a hydroxy group; and (iv) a straight chain having 1 to 4 carbon atoms. A linear or branched alkoxy group, (V) a linear or branched alkoxy group having 1 to 4 carbon atoms, (V i) a linear or branched alkoxy group having 1 to 4 carbon atoms. A branched alkylenedioxy group, (V ii) an aralkyloxy group having 7 to 12 carbon atoms, and (V iii) a linear or branched alkylthio group having 1 to 4 carbon atoms. (Ix) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (X) a halogen atom, (xi) a nitro group, (xii) an amino group, and (xiii) a carbon number of 1. A linear or branched monoalkylamino group having from 4 to 4

(Xiv) a straight or branched dialkylamiso group having the same or different alkyls each having 1 to 4 carbon atoms; (XV) an aralkyl group having 7 to 12 carbon atoms; XV i) an aryl group having 6 to 10 carbon atoms which may have a substituent (b) e; (XV ii) carbon number optionally having a substituent (b) e 6 to 1 0 Ariruokishi group having a (xviii) substituents (b) Ariruchio group having 6 to 1 0 carbon atoms which may have a ^e, (X i X) substituent (b) ^e Arylsulfonyl group having 6 to 10 carbon atoms which may be present, arylsulfonyl group having 6 to 10 carbon atoms optionally having ( _xx ) substitution (b) e A mino group (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms), (XXi ) Aromatic heterocyclic group, (XX ii) aromatic heterocyclic oxy group, (XX iii) aromatic heterocyclic thio group, (XX i V) aromatic heterocyclic sulfonyl group, and (XXV) aromatic heterocyclic sulfonyl It represents an amino group (the nitrogen atom of the amino group may be substituted with linear or branched alkyl having 1 to 6 carbon atoms).

Here, the substituent (b) e is a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkyl halide having 1 to 4 carbon atoms. A linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms A dioxy group,

Y ^e is an oxygen atom, a sulfur atom or a group having the formula> N—R (wherein is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a group having 1 to 6 carbon atoms) Represents a straight-chain or branched-chain acyl group having eight.

Z ^e is 2, 4-di O Kiso thiazolidine one 5-Ili Deyuru methyl, 2, 4-di-O Kiso thiazolidine one 5- Irumechiru group, 2, 4-di O Kiso O hexa oxazolidine one 5 - Irumechiru group or It represents a 3,5-dioxooxadiazolidine-12-methyl group. ]

A prophylactic or therapeutic agent for leukemia, which is an oxime derivative or a pharmacologically acceptable salt thereof.

23. In claim 1, the insulin sensitizer is a compound of the general formula (VI)

[Where,

R ^f is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted fused heterocyclic group, or the following general formula:

[Where,

Rlf is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted cycloaliphatic hydrocarbon group, a substituted or heterocyclic group or a substituted or fused heterocyclic group. There, R2f and _R 3f are the same or different, a hydrogen atom or a lower alkyl group,

X ^f is a group represented by an oxygen atom, a sulfur atom or a secondary amino group, R ⁴ⁱ is a hydrogen atom or a lower alkyl group,

R ^5f is lower alkyl;

P ^f and 0 ′ are the same or different and are a hydrogen atom, or P ^f and Q ^f together represent a bond. ]

A prophylactic or therapeutic agent for leukemia, which is an isoxoxazolidinedione derivative or a pharmacologically acceptable salt thereof.

24. In claim 1, the insulin sensitizer is a compound of the general formula (V I I)

(νπ)

[Where,

Χ8 represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindrin ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have one to three substituents (a) S described later. May have,

YS represents an oxygen atom or a sulfur atom,

Is a 2,4-dioxothiazolidine-1-5-ylmethyl group, a 2,4-dioxothiazolidine-1-5-ylmethyl group, a 2,4-dioxoxazolidine-15-ylmethyl group, A 5-dioxoxaziazolidine-12-methyl group or an N-hydroxyperidomethyl group;

RS represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, A hydroxy group, a nitro group, an amino group which may have a substituent (b) g (the substituent (b) S is a linear or branched alkyl group having 1 to 8 carbon atoms) A straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a straight-chain or branched aralkyl group having 1 to 11 carbon atoms, A branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms) or 7 to 7 carbon atoms. A linear or branched aralkyl group having at most 11

m? represents an integer from 1 to 5,

Here, the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, Benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenyl group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group, substituted group (B) an amino group optionally having g (the substituent (b) 8 is a linear or branched alkyl group having 1 to 8 carbon atoms, and 7 to 11 carbon atoms) A linear or branched aralkyl group having 6 to 10 carbon atoms, a linear or branched aliphatic acryl group having 1 to 11 carbon atoms An araliphatic acyl group having 8 to 12 carbon atoms or 7 to 11 carbon atoms And an aryl group having 6 to 10 carbon atoms which may have a substituent (c) g (the substituent (c) g has 1 to 4 carbon atoms). Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoro group A methyl group, a substituted group (b) an amino group optionally having e), or a substituted group (c) a linear or branched group having 7 to 11 carbon atoms optionally having S; A chain aralkyl group is shown. ]

A prophylactic or therapeutic agent for leukemia, which is a heterocyclic compound having the formula or a pharmacologically acceptable salt thereof.

25. In claim 1, the insulin sensitizer is a compound of the general formula (V I I I)

X ^h — (CH ₂ ) _m h-'(vm)

[Where,

Xh represents a benzimidazole ring group, which may have 1 to 5 substituents (a) described below; Υ ¹ · represents an oxygen atom or a sulfur atom,

Zeta ¹ "is 2, 4-di O Kiso thiazolidine one 5-Ili Deyuru methyl, 2, 4-di O Kiso thiazolidine one 5- Irumechiru group, 2, 4-di O Kiso O hexa oxazolidine one 5 - Irumechiru group , 3,5-dioxooxadiazolidine-12-methyl group or ゥ -hydroxyperidomethyl group;

^Rh is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom A hydroxy group, a nitro group, an amino group optionally having a substituent (b) h (the substituent (b) h is a linear or branched alkyl having 1 to 8 carbon atoms) Group, a linear or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a linear or branched aralkyl group having 6 to 10 carbon atoms A branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.) Or 7 to 7 carbon atoms 1 represents a linear or branched aralkyl group having one,

mil represents an integer from 1 to 5,

Here, the substituent (a) h is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, (Substituted (b) Ί is a linear or branched alkyl group having 1 to 8 carbon atoms, and has 7 to 11 carbon atoms.) Linear or branched aralkyl group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acryl group having 1 to 11 carbon atoms, carbon Araliphatic acyl group having 8 to 12 carbon atoms or 7 to 11 carbon atoms An aromatic Ashiru group having.), Substituents (c) Ariru group having 1 0 having 6 to carbon atoms which may have a ^h (the substituent (c)

¹¹ is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, Nitro, phenyl, trifluoromethyl, substituted (b) h An optionally substituted amino group) or a substituted (c) linear or branched aralkyl group having 7 to 11 carbon atoms which may have an ^h . ]

Or a pharmacologically acceptable salt thereof, which is a condensed heterocyclic compound having the formula (I) or a pharmacologically acceptable salt thereof.

26. In claim 1, the insulin sensitizer is a compound of the general formula (IX)

[Where,

Dotted lines indicate binding or no binding,

Vi is —CH = CH—, —N = CH—, one CH = N— or a sulfur atom, and is> CH ₂ ,>CHOH,>CO,> C = NOR ⁱ or one CH = CH—,

Xi is a sulfur atom, an oxygen atom,> NR ^U , —CH = N— or —N-CH—, Yi is = CH— or a nitrogen atom,

Zi represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a pyridyl group, a furyl group, a phenyl group, or the same or different carbon atoms. An alkyl having 1 to 3 carbon atoms, trifluoromethyl, an alkoxy having 1 to 3 carbon atoms, a phenyl group mono- or disubstituted by a group that is fluorine, chlorine or bromine,

Ζϋ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

Ri and are the same or different and are a hydrogen atom or a methyl group,

ni is 1, 2 or 3. ]

27. In Claim 1, the insulin sensitizer is a compound of the general formula (X)

[In the above general formula (X),

Represents

-xi represents an oxygen atom or a sulfur atom,

= YJ one represents = N— or = CR ⁵ j—

^{R! J, R 2 i R} 3 j, R 4) and R ⁵⁾ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, § Li Ichiru group, alkoxy group, alkoxyalkoxy group, Ariruo alkoxy group, Alkanoyloxy group, arylcarbonyl 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 ⁶ j represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group,

n i represents an integer from 0 to 3,

The dotted line indicates that the bond at that portion may be a double bond. ]

A prophylactic or therapeutic agent for leukemia, which is a naphthalene derivative or a pharmacologically acceptable salt thereof.

28. In claim 1, the insulin sensitizer is:

5- [4_ (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-1,4-dione (troglitazone), 5- [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] thiazolidine-1, 4-dione,

5- [4— (6-ethoxycarbonyloxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-1, 4-dione,

5— {4— [2— (5-ethyl-1-pyridyl) ethoxy] benzyl} —2,4-thiazolidinedione (pioglitazone),

5 — [(2-Benzyl-1,3,4-dihydro 2H—Benzopyran-1,6-yl) methinole] Thiazolidine-1,2,4-dione (englitazone),

5- (4- (2- [N-methyl-N- (2-pyridyl) amino] ethoxy) benzyl) thiazolidine-1,2,4-dione (mouth diglitazone),

5- {4--1-[[((1-[4- (2-pyridyl) phenyl] ethylidene) amino] oxy] ethoxy] benzyl} thiazolidine-1,2, dione (compound A),

4-1 {4-1 [2- (2-Feninole-5-methinole 4-oxazolinole) ethoxy] benzyl} —3,5-isoxazolidinedione,

5— {4— (5-Methoxy-1-3-methylimidazo [4,5-b] pyridine-12-ylmethoxy) benzyl} thiazolidine-1,2-dione,

5- [4- (1-methylindoline-2-ylmethoxy) benzyl] thiazolidin-1,2,4-dione,

5- [4- (1-Methylbenzimidazole-l_2-ylmethoxy) benzyl] thiazolidine-l, 4-dione,

5— [4— (6-Methoxy-1-methylbenzimidazole-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione (Compound B),

5— [4— (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione,

5— {4— [3 -— (5-Methyl-1-phenyl-2-oxazole) -propioninole] benzyl} thiazolidine-1,2-dione or

5-[6-(2-Fluorobenzyloxy) 1-2-naphthylmethyl] thiazolidin-1, 2, 4-dione And a therapeutic or prophylactic agent for leukemia, which is a pharmacologically acceptable salt thereof.

29. In Claim 1, the insulin sensitizer is:

5- [4- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-1,4-dione (troglitazone) and its pharmaceutically acceptable salts An agent for treating or preventing leukemia.