JPH10212247A - Therapeutic agent for autoimmune disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preventive or therapeutic agent for autoimmune diseases except I type diabetes as systemic lupus erythematosus, that contains a substance improving resistance to insulin as an active ingredient and has excellent effect with side-effects reduced. SOLUTION: This autoimmune disease agent is prepared by formulating a substance that can improve the resistance to insulin, a thiazolidinedione of the formula [R<1a> and R<2a> are H, a 1-5C alkyl; R<3a> is H, a 1-6C aliphatic acyl, a 6-8C cycloalkylcarbonyl, (substituted) benzoyl; R<4a> and R<5a> are H, a 1-5C alkyl, a 1-5C alkoxy; Y<a> , Z<a> are each O, imino; n<a> is an integer of 1-3] as an active ingredient. This preparation is useful as a preventive and therapeutic agent for autoimmune diseases as rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (except I type diabetes) with reduced side effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a composition for treating or preventing an autoimmune disease (excluding type I diabetes) containing an insulin sensitizer as an active ingredient, and an autoimmune disease (provided that the composition is an autoimmune disease). , Except type I diabetes)), their use for the manufacture of a medicament for the treatment or prevention of
Alternatively, the present invention relates to a method for treating or preventing an autoimmune disease (however, excluding type I diabetes) in which a pharmacologically effective amount thereof is administered to a warm-blooded animal.

[0002]

2. Description of the Related Art An autoimmune disease causes an immune response to a self component that is not normally observed.
It is considered a condition that results in various tissue and / or dysfunctions. Autoimmune diseases are roughly classified into systemic autoimmune diseases and organ-specific diseases according to their characteristics. Representative examples of systemic autoimmune diseases include, for example, systemic lupus erythematosus, rheumatoid arthritis, etc.,
Representative examples of the organ-specific autoimmune diseases include Hashimoto's disease and juvenile-onset diabetes.

[0003] As the mechanism of cell tissue damage, mainly the mechanism of damage through antibodies, immune complexes and the like (hereinafter referred to as the mechanism).
It is called "disorder mechanism through humoral immunity." ) And cell-mediated cytototopathology (T-lymphocytes)
xicity; hereinafter, referred to as “disorder mechanism through cell-mediated immunity”. )are categorized. In general, it is considered that the mechanism of injury through humoral immunity is important in systemic autoimmune diseases, and the mechanism of injury through cell-mediated immunity is important in organ-specific autoimmune diseases ing.

However, with the recent development of immunology, cytotoxic cells mainly composed of lymphocytes gather in the vicinity of target cells in the mechanism of impairment through cell-mediated immunity, and ultimately directly reach the target cells. In addition to damaging target cells upon contact with, the cytotoxic cells become inflammatory cytokines (T
Release humoral factors such as NF, IL-1, LT, etc.
It has been clarified that the target cells may be damaged indirectly through the above. On the other hand, it is also evident that the mechanism of humoral immunity involving killer lymphocytes, neutrophils, platelets, and the like also involves, for example, the mechanism of antibody-dependent cellular cytotoxicity (ADCC). (Department of Pathology, Supplement 1, pp. 91-105 (1995)
Year)). Therefore, regardless of whether the disease is a systemic autoimmune disease or an organ-specific autoimmune disease, infiltration of cytotoxic cells, mainly lymphocytes, in the target organ or target organ damage mechanism in the autoimmune disease is various. It is considered important in causing organizational and functional disorders. Therefore, the target organ or the compound that suppresses infiltration of lymphocytes in the target organ is useful as a prophylactic or therapeutic agent for an autoimmune disease.

At present, steroids, non-steroidal anti-inflammatory drugs, immunosuppressants and the like are used for the treatment of autoimmune diseases (Today's Therapeutic Guideline, Medical Shoin, p. 577 (1996)). Further, recently, production inhibitors of TNFα and IL-1, which are inflammatory cytokines, and action inhibitors have been developed. Also, for the purpose of inhibiting the infiltration of cytotoxic lymphocytes into the target organ or target organ,
Various mouse monoclonal antibodies against cell adhesion factors (ICAM-1, VCAM-1, etc.) have been developed and DBA /
Therapeutic effects have been reported in various animal models such as 2 mice (Yagi et al., Diabetes, 44, 744 (1
995); Baron et al., J. Clin. Invest., Vol. 93,
1700 (1994)). However, any of the therapeutic agents or methods have drawbacks such as insufficient effect and strong side effects. Further, a prophylactic or therapeutic drug for an autoimmune disease having a clinically superior effect and weaker side effects has been desired.

[0006] Recently, insulin sensitizers have been known as preventive or therapeutic agents for diabetes. Here, the insulin sensitizer is a compound that improves the state in which the action of insulin is incomplete despite the presence of endogenous insulin. Such insulin sensitizers encompass a wide range of compounds. Representative examples include, for example, thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds, oxadiazolidinedione compounds, and the like,
They are described, for example, in WO 94/01433 (= Japanese Unexamined Patent Publication No.
No. 80667); JP-A-4-69383; WO 92
/ 02520 (= Tokuhyo Hei 6-500538); WO 9
1/07107 (= JP-A-3-170478 = Japanese Patent Publication No. 7-8862); U.S. Pat. No. 5,132,317 (= JP-A-3-90071); U.S. Pat. No. 4,897,405 (= JP-A-2-292272); WO 89/08651
(= JP-A-1-272574); U.S. Pat.
717, 5120754, and 5223522 (= Japanese Patent Laid-Open No.
-272573); U.S. Pat.
No. 94443, 5232925, 5260445 (= JP-A-1-131169); US Pat.
(= JP-A-64-13076); U.S. Pat.
393, 4948900 (= JP-A-64-56675 = JP-B-5-5832); U.S. Patent No. 4,873,255
(= JP-A-64-38090); U.S. Pat.
052 (= Japanese Patent Laid-Open No. 61-271287 = 5-8)
No. 6953); U.S. Pat.
U.S. Pat. No. 4,256,610 (Japanese Patent Application Laid-Open No. Sho 61-85372 = Japanese Patent Publication No. 5-66956); U.S. Pat.
(= Japanese Patent Application Laid-Open No. S60-51189 = Japanese Patent Publication No. 2-31079
US Pat. No. 4,461,902 (= JP-A-58-11).
No. 8577 = Japanese Patent Publication No. 2-57546); U.S. Pat.
287200, 4340605, 4438141, 44
44779 (= JP-A-55-22636 = JP-B-62)
EP-070898A (= JP-A-9-48779); EP 0676398A (= JP-A-7-330728); WO 95/18125; E
P 0745600A; EP 0332332A (= Japanese Patent Laid-Open No. 1-272574); EP0604983A (=
JP-A-6-247945). Note that “=” indicates a correspondence.

[0007] For example, 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (hereinafter referred to as "troglitazone") Is a thiazolidine derivative having an activity of enhancing insulin action, and is known as a preventive and / or therapeutic agent for diabetes (Fujiwara et al., Diabetes, 37, 1459 (1988); Hofma
nn CA et al., diabetes Care, 15, 1075 (1992
Year) ). Further, since the compound has an antioxidant effect, insulin-dependent diabetes (type I diabetes: IDD
It has been reported that it is also useful as a therapeutic agent for M) (Diabetes, Vol. 37, No. 2, pp. 127-129 (1994)).

[0008] However, there is no report that troglitazone suppresses tissue infiltration of lymphocytes, and it is said that troglitazone is useful as a preventive and / or therapeutic agent for autoimmune diseases except insulin-dependent diabetes (type I diabetes). There is no report. At present, insulin-dependent diabetes mellitus (type I diabetes) is considered to be one of autoimmune diseases, and troglitazone has been reported to be useful for treating insulin-dependent diabetes. The report that the compound is useful for is based on the antioxidant action of the compound. Thus, these known facts even teach that troglitazone suppresses lymphocyte tissue infiltration and is useful as a prophylactic or therapeutic agent for autoimmune diseases (excluding type I diabetes). , Not even suggestive. Further, other insulin sensitizers are also known to be useful for diabetes, but are not known to inhibit lymphocyte tissue infiltration.

[0009]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on the pharmacological activity of an insulin sensitizer, and as a result, have found that the inhibitor suppresses the infiltration of lymphocytes into pancreatic β cells. From this, autoimmune diseases (however,
Excludes type I diabetes. The present invention has been found out to be useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for the present invention.

That is, the present invention relates to, for example, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Sjogren's syndrome, systemic scleroderma, mixed connective tissue disease,
Diseases classified as systemic autoimmune diseases such as dermatomyositis;
And Hashimoto's disease, primary myxedema, thyrotoxicosis, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Ad
dison disease, male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, pemphigus vulgaris, sympathetic ophthalmitis, multiple sclerosis, autoimmunity Hemolytic anemia, idiopathic thrombocytopenic purpura, post-myocardial infarction syndrome, rheumatic fever, lupus hepatitis, primary biliary cirrhosis, Behcet's disease, CRES
It is useful as a prophylactic or therapeutic agent for autoimmune diseases (excluding type I diabetes) such as diseases classified as organ-specific autoimmune diseases such as T syndrome.

[0011]

Means for Solving the Problems The present invention relates to a composition for treating or preventing an autoimmune disease (excluding type I diabetes) containing an insulin sensitizer as an active ingredient, and an autoimmune disease ( Provided that they are used for the manufacture of a medicament for the treatment or prevention of type I diabetes;
Alternatively, there is provided a method for treating or preventing an autoimmune disease (however, excluding type I diabetes) wherein a pharmacologically effective amount thereof is administered to a warm-blooded animal.

In particular, the insulin sensitizer is a thiazolidinedione compound, an oxazolidinedione compound, an isoxazolidinedione compound, or an oxadiazolidinedione compound, preferably a thiazolidinedione compound as an active ingredient. The present invention relates to a prophylactic or therapeutic agent for an immune disease (excluding type I diabetes). The thiazolidinedione compound and the like include pharmacologically acceptable salts thereof.

[0013] Examples of such an insulin resistance improving substance include the following compounds.

(I) JP-A-60-51189 (JP-B-2-31079), US Pat. No. 4,457,291
No. 2 and EP-A-139421, (1) The general formula (I)

[0015]

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Wherein R ^1a and R ^2a are the same or different and each represent a hydrogen atom or a C ₁ -C ₅ alkyl group;
^3a is a hydrogen atom, a C ₁ -C ₆ aliphatic acyl group, a C ₆ -C
₈ cycloalkylcarbonyl group, benzoyl or naphthoyl group which may have a substituent (the substituent is
₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen atom, amino, mono--C ₁ -C ₄ alkylamino, di -C ₁ -C ₄ alkylamino or nitro group. ), A 4- to 7-membered heterocyclic acyl group containing 1 to 3 heteroatoms selected from a heteroatom group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenylacetyl group, a phenylpropionyl group, and at least one A phenylacetyl or phenylpropionyl group, a cinnamoyl group, a C ₂ -C ₇ alkoxycarbonyl group or a benzyloxycarbonyl group substituted with a halogen atom, wherein R ^4a and R ^5a are the same or different and are each a hydrogen atom,
₁ -C ₅ alkyl group or one showing a C ₁ -C ₅ alkoxy group, or R ^4a and R ^5a together indicates C ₁ -C ₄ alkylenedioxy group, Y ^a and Z ^a are the same or different and each represents an oxygen atom or an imino group, n ^a represents an integer of 1 to 3. Or a pharmacologically acceptable salt thereof. In the compound having the above general formula (I), R ^1a , R ^2a , R ^3a , R
^4a, R ^5a, Y ^a, exemplary definitions represented by Z ^a and n ^a,
Details of types of pharmacologically acceptable salts, methods for producing the compound having the above general formula (I), examples of compounds, examples, and the like are described in the above publications.

Among the compounds having the general formula (I), preferred compounds are shown below. (2) The compound wherein R ^1a is a C ₁ -C ₄ alkyl group.

(3) R ^2a is a hydrogen atom or C ₁ -C ₃
Compounds that are alkyl groups.

(4) A compound wherein R ^3a is a hydrogen atom, a C ₁ -C ₄ aliphatic acyl group, a benzoyl or naphthoyl group having no substituent or a C ₂ -C ₄ alkoxycarbonyl group.

(5) The compound wherein R ^4a is a C ₁ -C ₄ alkyl group.

(6) R ^5a is a hydrogen atom or C ₁ -C ₃
Compounds that are alkyl groups.

(7) R ^1a is a C ₁ -C ₄ alkyl group, R ^2a is a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ^3a is a hydrogen atom, a C ₁ -C ₄ aliphatic group. Group acyl group, unsubstituted benzoyl or naphthoyl group or C
A ₂ -C ₄ alkoxycarbonyl group, R ^4a is, C ₁
-C ₄ alkyl group, wherein R ^5a is a hydrogen atom or C _1-
A compound which is a C ₃ alkyl group.

(8) R ^3a is a hydrogen atom, an acetyl group,
Compounds that are a benzoyl group or an ethoxycarbonyl group.

(9) R ^1a is a C ₁ -C ₄ alkyl group, R ^2a is a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ^3a is a hydrogen atom, an acetyl group, a benzoyl group or A compound which is an ethoxycarbonyl group, R ^4a is a C ₁ -C ₄ alkyl group, and R ^5a is a hydrogen atom or a C ₁ -C ₃ alkyl group.

(10) The compound wherein R ^1a is a methyl group.

(11) The compound wherein R ^2a is a hydrogen atom or a methyl group.

(12) The compound wherein R ^3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group.

(13) The compound wherein R ^4a is a methyl group or a t-butyl group.

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

(15) R ^1a is a methyl group, and R ^2a
Is a hydrogen atom or a methyl group, and R ^3a is a hydrogen atom,
An acetyl group or an ethoxycarbonyl group, wherein R ^4a is
A compound which is a methyl group or a t-butyl group, and wherein R ^5a is a hydrogen atom or a methyl group.

(16) i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone), ii) 5 -[4- (6-hydroxy-2-methyl-7-
t-butylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iii) 5- [4- (6-hydroxy-2-ethyl-
5,7,8-trimethylchroman-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, iv) 5- [4- (6-hydroxy-2-isobutyl-
5,7,8-trimethylchroman-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, v) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and vi ) 5- [4- (6-ethoxycarbonyloxy-
2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.

(II) JP-A-61-267580 (Japanese Patent Publication No. 5-66956) and US Pat. No. 4,687,777.
(1) General formula (II)

[0033]

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A thiazolidine derivative having the formula or a pharmaceutically acceptable salt thereof is described.

Details of the pharmacologically acceptable salts of the compounds having the above general formula (II), production methods, compound examples, examples and the like are described in the above publications.

Among the compounds having the general formula (II), preferred compounds are shown below.

(2) i) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione; ii) 5- {4- [2- (4- Ethyl-2-pyridyl)
Ethoxy] benzyl} -2,4-thiazolidinedione; iii) 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione (hereinafter referred to as “pioglitazone”). ) And iv) 5- {4- [2- (6-ethyl-2-pyridyl)
Ethoxy] benzyl} -2,4-thiazolidinedione,
A compound selected from:

(III) JP-A-61-271287 (JP-B 5-86953) and US Pat. No. 47030
No. 52 includes: (1) General formula (III)

[0039]

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[Wherein the broken line represents a single bond or a non-bond, n ^c is 0, 1 or 2, and X ^c is O, S, S = O, S
(= O) (= O), wherein R ^c is H, CH ₃ or C ₂ H ₅
Wherein R ^1c is independently H, C ₅ -C ₇ cycloalkyl, C ₆ -C ₈ methyl-substituted cycloalkyl, pyridyl,
Thienyl, furyl, naphthyl, p- biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, ^{_{tetrahydropyranyl, C 6 H 4 W 2c [}} W 2c is H, OH, F, C
l, Br, a C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ thioalkyl] or alk-W ^1c
[Alk is C ₁ -C ₆ alkylene, ethylidene or isopropylidene; W ^1c is H, OH, C ₁ -C ₄ alkoxy, C ₁ -C ₄ thioalkyl, pyridyl, furyl,
Thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, C ₅ -C ₇ cycloalkyl or C ₆ H ₄
In W ^2c is] in R ^2c is H or CH _3, R ^3c is H, C ₁
-C ₆ alkyl, with C ₆ H ₄ W ^2c or benzyl, R ^4c is H, when R ^1c and R ^2c are taken together, they form a C ₄ -C ₆ alkylene, R ^3c and R ^4c are each H, when R ^3c and R ^4c are taken together, they form a C ₄ -C ₆ alkylene, R ^1c and R
^2c are each H, when R ^2c and R ^3c are taken together, they form a C ₃ -C ₄ alkylene, R
^1c and R ^4c are each H. Or a pharmacologically acceptable salt thereof.

In the compound having the general formula (III), examples of the definitions represented by R ^1c , R ^2c , R ^3c , W ^1c , W ^2c and alk, the types of pharmacologically acceptable salts, Details of the production method, examples, and the like of the compound having III) are described in the above publications.

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

(2) R ^c is H, dashed line is non-bonded, n
The compound according to (1), wherein ^c is 0 or 1.

(3) R ^2c , R ^3c and R ^4c are each H
Wherein R ^1c is H, cyclohexyl, C ₆ H ₄ W ^2c (W ^2c is H, F, Cl, Br, CH ₃ or CH ₃ O) or alk-W ^1c [alk is C ₁ -C ₄ alkylene , Ethylidene or isopropylidene, wherein W ^1c is H, OH, C _1-
C ₄ alkoxy, cyclohexyl or ^{_{C 6 H 4 W 2c] (}} 2) The compound according.

(4) The compound according to (3), wherein X ^c is O, and R ^1c is cyclohexyl, cyclohexylmethyl, benzyl, fluorobenzyl, C ₁ -C ₄ alkyl, hydroxymethyl, methoxymethyl or ethoxyethyl.

(5) The compound according to (4), wherein R ^1c is benzyl.

(6) 5-[(2-benzyl-2,3-
Dihydrobenzofuran-5-yl) methyl] thiazolidine-2,4-dione, 5-[(2-benzyl-3,4-
Dihydro-2H-benzopyran-6-yl) methyl] thiazolidine-2,4-dione (hereinafter referred to as “englitazone”) or a sodium salt thereof (5).
A compound as described.

(7) R ^2c and R ^3c together form (CH ₂ ) ₄
Wherein R ^1c and R ^4c are each H and X ^c is O.

(8) (a) R ^1c and R ^2c together form (CH
₂ ) to form ₅ , R ^3c and R ^4c are each H and X ^c is O
Or (b) when R ^3c and R ^4c together form (CH ₂ ) ₅
Wherein R ^1c and R ^2c are each H and X ^c is O.

(9) The compound according to (3), wherein n ^c is 0, R ^1c is H, CH ₃ or benzyl, and X ^c is S or S (＝ O) (＝ O).

(IV) JP-A-1-131169,
U.S. Pat. Nos. 5,295,953, 5,194,443, 52
Nos. 32925 and 5260445 include: (1) General formula (IV)

[0052]

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Wherein A ^1d represents a substituted or unsubstituted aromatic heterocyclic group; R ^1d represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (wherein the aryl moiety is represents even or it may be unsubstituted) or substituted or unsubstituted aryl group; or R ^2d and R ^3d each represents a hydrogen R ^2d and R ^3d represents a bond together; a ^2d in total 5 It represents a benzene ring having a substituent of up pieces; and n ^d represents an integer ranging from 2-6. Or a pharmaceutically acceptable salt thereof.

[0054] In the compound having the general formula ^{(IV), A 1d, R} 1d, R 2d, an exemplary definition represented by R ^3d, A ^2d and n ^d, pharmaceutically acceptable type of salt, the general formula Details of the method for producing the compound having (IV), examples thereof, suitable compounds, and the like are described in the above publications.

Among the compounds having the general formula (IV), preferred compounds are shown below.

(2) A description according to (1), wherein A ^1d represents a substituted or unsubstituted monocyclic or condensed-ring aromatic heterocyclic group containing up to 4 heteroatoms selected from oxygen, sulfur and nitrogen in the ring. Compound.

(3) A ^1d is represented by the formula (a), (b) or (c)

[0058]

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[In the formula, R ^4d and R ^5d each independently represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group, or when R ^4d and R ^5d are each bonded to a carbon atom, ^4d and R ^5d together with the carbon atom to which they are attached form a benzene ring, and together each carbon atom represented by R ^4d and R ^5d may be substituted or unsubstituted. And (1) or (2), wherein X ^d represents oxygen or sulfur in the moiety of formula (a).

(4) The compound according to (3), wherein R ^4d and R ^5d each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group.

(5) R ^4d and R ^5d together form formula (d)

[0062]

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(3) The compound according to (3), wherein R ^6d and R ^7d each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.

(6) The compound according to (5), wherein both R ^6d and R ^7d represent hydrogen.

(7) A ^2d is the formula (e)

[0066]

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(Wherein R ^8d and R ^9d each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy), and any one of the above items (1) to (6) Compound.

(8) The compound according to (7), wherein R ^8d and R ^9d each represent hydrogen.

(9) Equation (f)

[0070]

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[Wherein A ^1d , R ^1d , R ^2d , R ^3d and n ^d
Is as defined for formula (IV) in (1),
^8d and R ^9d are as defined for formula (e) in (7)) or a pharmaceutically acceptable salt thereof.

[0072] (10) n ^d represents an integer of 2 or 3 (1) to any one of the preceding compound according to (9).

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

(12) i) 5- {4- [2- (N-methyl-N- (2-benzothiazolyl) amino) ethoxy]
Benzyl} thiazolidine-2,4-dione, ii) 5- {4- [2- (N-methyl-N- (2-pyrimidinyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione, iii) 5- {4- [2- (N-methyl-N- (2-
[4,5-dimethylthiazolyl)] amino) ethoxy]
Benzyl {thiazolidine-2,4-dione, iv) 5- {4- (2- (N-methyl-N- (2-thiazolyl) amino) ethoxy] benzyl} thiazolidine-
2,4-dione, v) 5- {4- [2- (N-methyl-N- (2- [4-
Phenylthiazolyl]) amino) ethoxy] benzyl
Thiazolidine-2,4-dione, vi) 5- {4- [2- (N-methyl-N- (2- [4
-Phenyl-5-methylthiazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, vii) 5- {4- [2- (N-methyl-N- (2-
[4-methyl-5-phenylthiazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, viii) 5- {4- [2- (N-methyl-N- (2-
[5-phenyloxazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, ix) 5- {4- [2- (N-methyl-N- (2-
[4,5-dimethyloxazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, x) 5- {4- [2- (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-2,4 -Dione, xi) 5- {4- [2- (N-acetyl-N- (2-pyrimidinyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione, xii) 5- {4- [2- ( N- (2-benzothiazolyl) -N-benzylamino) ethoxy] benzyl {thiazolidine-2,4-dione, xiii) 5- {4- [3- (N-methyl-N- (2-
Benzoxazolyl) amino) propoxy] benzyl) thiazolidine-2,4-dione, and xiv) 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-
The compound according to (1), which is selected from 2,4-dione (hereinafter, referred to as "BRL-49653").

(13) 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione (BRL-4965)
The compound according to (1), which is 3).

In the above (2) to (11),
Examples of the definitions of R ^4d , R ^5d , R ^6d , R ^7d , R ^8d and R ^9d are described in detail in the above publications.

(V) JP-A-9-48779 and European Patent Publication No. 708098 disclose: (1) Formula (V)

[0078]

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[Wherein, R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R ^2e represents a linear or branched alkyl group having 2 to 6 carbon atoms. R ^3e represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms, Linear alkoxy group, linear or branched alkylthio group having 1 to 4 carbon atoms, halogen atom, nitro group, amino group, linear or branched chain having 1 to 4 carbon atoms Monoalkylamino group, linear or branched dialkylamino group having the same or different alkyls each having 1 to 4 carbon atoms, aryl group having 6 to 10 carbon atoms or 7 to 7 carbon atoms Have 12 An aralkyl group, X ^e is 1 to 3 substituents to aryl groups or 1 having three to ten C 6 carbon atoms which may have a substituent alpha alpha
Wherein the substituent α is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, and (ii) a 1 to 1 carbon atom. 4
A straight or branched alkyl halide group having one, (iii) a hydroxy group, (iv) a carbon atom of 1
A straight-chain or branched-chain acyloxy group having 1 to 4 carbon atoms, (v) a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, (vi) a 1 to 4 carbon atoms. A linear or branched alkylenedioxy group having (vii) an aralkyloxy group having 7 to 12 carbon atoms; (viii) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms An alkylthio group, (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,
(Xiii) a straight-chain or branched monoalkylamino group having 1 to 4 carbon atoms; (xiv) a straight-chain or branched alkyl group having the same or different and each alkyl having 1 to 4 carbon atoms. Dialkylamino group,
(Xv) an aralkyl group having 7 to 12 carbon atoms,
(Xvi) an aryl group having 6 to 10 carbon atoms which may have a substituent β, (xvii) a substituent β
An aryloxy group having 6 to 10 carbon atoms which may have: (xviii) an arylthio group having 6 to 10 carbon atoms which optionally has a substituent β;
(Xx) an arylsulfonyl group having 6 to 10 carbon atoms optionally having a substituent β, and (xx) an arylsulfonylamino group having 6 to 10 carbon atoms optionally having a substituent β. (The nitrogen atom of the amino moiety may be substituted with a linear or branched alkyl having 1 to 6 carbon atoms), (xxi) a heteroaromatic ring group, (xxii) a heteroaromatic oxy group , (X
(xxiii) a heteroaromatic ring thio group, (xxiv) a heteroaromatic ring sulfonyl group, and (xxv) a heteroaromatic ring sulfonylamino group (the nitrogen atom of the amino moiety is a straight-chain or branched-chain having 1 to 6 carbon atoms. May be substituted with alkyl.).

Here, the substituent β is a straight-chain or branched alkyl having 1 to 6 carbon atoms, a straight-chain or branched alkyl halide having 1 to 4 carbon atoms, number 1 to 4 pieces of a straight-chain or branched alkoxy, having 1 to halogen or carbon represents straight-chain or branched alkylenedioxy having four, Y ^e represents an oxygen atom, a sulfur Atom or formula> NR ^4e
Wherein R ^4e is a hydrogen atom and has 1 to 6 carbon atoms
A linear or branched alkyl group having 1 to 8 carbon atoms, or a linear or branched acyl group having 1 to 8 carbon atoms. ) Indicates, Z ^e is 2,4-dioxo-thiazolidin-5-Iridenirumechiru group, 2,4-dioxothiazolidin-5-ylmethyl group, 5-2,4-oxooxazolidin-ylmethyl group or a 3,5 It represents a dioxooxadiazolidine-2-ylmethyl group. ] Or a pharmacologically acceptable salt thereof.

In the compound having the above general formula (V), examples of the definitions represented by R ^1e , R ^2e , R ^3e , R ^4e , α, β, X ^e and Y ^e , the types of pharmacologically acceptable salts Details of the production method of the compound having the general formula (V), compound examples, examples, and the like are described in the above publications.

Among the compounds having the general formula (V), preferred compounds are shown below. (2) The compound according to (1), wherein R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.

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

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

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

(6) R ^2e represents a linear or branched alkylene group having 2 to 5 carbon atoms (1)
A compound as described.

(7) R ^2e represents a linear or branched alkylene group having 2 to 3 carbon atoms (1)
A compound as described.

(8) The compound according to (1), wherein R ^2e represents an ethylene group, a trimethylene group or a methylethylene group.

(9) The compound as described in (1), wherein R ^2e represents an ethylene group.

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

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

(12) X ^e is 1 to 3 substituted α
An aryl group having 6 to 10 carbon atoms which may have a nitrogen atom, an oxygen atom and / or a sulfur atom which may have 1 to 3 substituents α.
5- to 10-membered ring (consisting of one or two rings)
Wherein the substituent α is (i) a linear or branched alkyl having 1 to 6 carbons, (ii) a linear having 1 to 4 carbons (Iii) hydroxy, (iv) linear or branched acyloxy having 1 to 4 carbon atoms, (v) 1 carbon atom
(Vi) a linear or branched alkylenedioxy having 1 to 4 carbon atoms; (vii) a linear or branched alkylenedioxy having 1 to 4 carbon atoms; Having aralkyloxy, (vi
ii) linear or branched alkylthio having 1 to 4 carbons, (ix) linear or branched alkylsulfonyl having 1 to 4 carbons,
(X) a halogen atom, (xi) a carbon number of 7 to 12.
(Xiii) phenyl optionally having a substituent β, (xiii) phenoxy optionally having a substituent β, (xiv) phenylthio optionally having a substituent β, (Xv) phenylsulfonyl optionally having a substituent β, (xvi) phenylsulfonylamino optionally having a substituent β (the nitrogen atom in the amino portion is a straight chain having 1 to 6 carbon atoms) Or it may be substituted by a branched alkyl.),
(Xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, (xvii
i) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms) and / or (xix) pyridylsulfonylamino (nitrogen atom in the amino moiety) Represents 1 to 6 carbon atoms
May be substituted with a straight-chain or branched-chain alkyl. ), Where the substituent β has 1 carbon atom
Linear or branched alkyl having 1 to 4 carbon atoms, linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkyl having 1 to 4 carbon atoms, The compound according to (1), which represents a branched alkoxy, a halogen, or a linear or branched alkylenedioxy having 1 to 4 carbon atoms.

(13) X ^e is 1 to 3 substituted α
An aryl group having 6 to 10 carbon atoms which may have a nitrogen atom, an oxygen atom and / or a sulfur atom which may have 1 to 3 substituents α.
5- to 10-membered ring (consisting of one or two rings)
Wherein the substituent α is: (i) a linear or branched alkyl having 1 to 6 carbons, (ii) a linear having 1 to 4 carbons Alkyl or halogenated alkyl halides, (iii)
Hydroxy, (iv) linear or branched alkanoyloxy having 1 to 4 carbon atoms, (v)
Linear or branched alkoxy having 1 to 4 carbons, (vi) linear or branched alkylenedioxy having 1 to 4 carbons, (vi
i) aralkyloxy having 7 to 12 carbon atoms,
(Viii) linear or branched alkylthio having 1 to 4 carbons, (ix) linear or branched alkylsulfonyl having 1 to 4 carbons, (x) fluorine atom , Chlorine atom, bromine atom,
(Xi) aralkyl having 7 to 12 carbon atoms,
(Xii) phenyl optionally having a substituent β,
(Xiii) phenoxy optionally having a substituent β,
(Xiv) phenylthio optionally having a substituent β, (xv) phenylsulfonyl optionally having a substituent β, (xvi) phenylsulfonylamino optionally having a substituent β (amino moiety May be substituted by linear or branched alkyl having 1 to 6 carbons.), (Xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, Pyridylthio, pyridylsulfonyl, (xviii) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms), and / or
Or (xix) pyridylsulfonylamino (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms), wherein the substituent β is Straight-chain or branched alkyl having 1 to 6 carbons, straight-chain or branched alkyl halide having 1 to 4 carbons, straight-chain having 1 to 4 carbons The compound according to (1), which represents linear or branched alkoxy, halogen, or linear or branched alkylenedioxy having 1 to 4 carbon atoms.

(14) X ^e is 1 to 3 substituted α
Phenyl group, naphthyl group, imidazolyl group, oxazolyl group, pyridyl group, indolyl group, which may have
A quinolyl group or an isoquinolyl group;
Is selected from: (i) a linear or branched alkyl having 1 to 6 carbons, (ii) a linear or branched alkyl halide having 1 to 4 carbons, (iii) (Vi) straight-chain or branched alkanoyloxy having 1 to 4 carbon atoms, (v) straight-chain or branched alkoxy having 1 to 4 carbon atoms, (vi) ) Methylenedioxy, (vii) aralkyloxy having 7 to 12 carbons, (viii) straight-chain or branched alkylthio having 1 to 4 carbons, (i
x) linear or branched alkylsulfonyl having 1 to 4 carbon atoms, (x) fluorine atom, chlorine atom, bromine atom, (xi) aralkyl having 7 to 12 carbon atoms, (xii) Phenyl, which may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy;
ii) phenoxy (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xiv) phenylthio (the phenyl is methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy) (Xv) phenylsulfonyl (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy),
(Xvi) phenylsulfonylamino (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy. The nitrogen atom in the amino moiety is linear or branched having 1 to 6 carbon atoms. May be substituted with a branched alkyl).
(Xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy,
Pyridylthio, pyridylsulfonyl, (xviii)
Imidazolyl (the nitrogen atom may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms) and / or (xix) pyridylsulfonylamino (where the nitrogen atom of the amino moiety is a carbon atom (1) may be substituted with linear or branched alkyl having 1 to 6).

(15) X ^e is 1 to 3 substituted α
Phenyl group, naphthyl group, imidazolyl group, oxazolyl group, pyridyl group, indolyl group, which may have
A quinolyl group or an isoquinolyl group;
Is selected from: (i) a linear or branched alkyl having 1 to 6 carbons, (ii) a linear or branched alkyl halide having 1 to 4 carbons, (iii) (Vi) straight-chain or branched alkanoyloxy having 1 to 4 carbon atoms, (v) straight-chain or branched alkoxy having 1 to 4 carbon atoms, (vi) ) Methylenedioxy, benzyloxy, phenethyloxy, naphthylmethoxy, (vii) linear or branched alkylthio having 1 to 4 carbons, (viii) linear having 1 to 4 carbons Or a branched alkylsulfonyl, (ix) a fluorine atom, a chlorine atom, a bromine atom, (x) benzyl, (xi) phenyl (the phenyl is methyl, trifluoromethyl (Xii) phenoxy (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (Xii
i) phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino,
Furyl, thienyl, oxazolyl, isoxazolyl,
Thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino,
N-methylpyridylsulfonylamino, and / or
(Xiv) imidazolyl (the nitrogen atom has 1 to 6 carbon atoms)
May be substituted with a straight-chain or branched-chain alkyl. The compound according to (1), wherein

(16) X ^e is 1 to 3 substituents α
Represents a phenyl group, a naphthyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have the following formula: wherein the substituent α is (i) a linear or branched group having 1 to 3 carbon atoms. Branched alkyl, (ii)
Trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, formyloxy, acetoxy,
(Iii) linear or branched alkoxy having 1 to 3 carbon atoms, (iv) methylenedioxy,
Benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, (v) fluorine, chlorine, bromine, (vi) benzyl, phenyl, 4-
Methylphenyl, 4-trifluoromethylphenyl, 4
-Methoxyphenyl, 4-fluorophenyl, 3,4-
Methylenedioxyphenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino,
N-methylphenylsulfonylamino, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, N-methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and / or N-methylpyridylsulfonylamino (1). Compound.

(17) X ^e is 1 to 3 substituted α
Represents a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group which may have a substituent α, wherein methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, acetoxy, methoxy, ethoxy, iso Propoxy, methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio , Pyridylsulfonyl, pyridylsulfonylamino and / or N
The compound according to (1), which represents -methylpyridylsulfonylamino.

(18) X ^e is 1 to 3 substituted α
Represents a phenyl group which may have: wherein the substituent α is methyl, hydroxy, acetoxy, a chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino,
The compound according to (1), which represents N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio and / or pyridylsulfonyl.

(19) X ^e is 1 to 3 substituted α
Represents a pyridyl group which may have: wherein the substituent α is methoxy, ethoxy, isopropoxy,
The compound according to (1), which represents benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino and / or N-methylphenylsulfonylamino.

(20) Y ^e is an oxygen atom, a sulfur atom or a group having the formula> NR ^4e (where R ^4e is a hydrogen atom, a linear or branched chain having 1 to 3 carbon atoms) Which is an alkyl group or a linear or branched alkanoyl group having 2 to 5 carbon atoms.).

(21) The compound described in (1), wherein Y ^e represents an oxygen atom.

[0102] The (22) Z ^e is 2,4-dioxo-thiazolidin-5-ylmethyl group, 2,4-di-oxooxazolidin-5-ylmethyl group or a 3,5-dioxo oxadiazolidin-2-ylmethyl group The compound according to (1) above.

[0103] (23) Z ^e shows a 2,4-dioxo-thiazolidin-5-ylmethyl group or a 2,4-dioxo-oxazolidinedione 5-ylmethyl group (1) compounds described.

[0104] (24) Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group (1) compounds described.

(25) R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R ^2e represents a linear or branched alkyl group having 2 to 5 carbon atoms. R ^3e represents a hydrogen atom;
X ^e represents a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, an alkylthio group having 1 to 2 carbon atoms, or a halogen atom; An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents α, or a nitrogen atom, an oxygen atom and / or 1 to 3 substituents which may have α. A 5- to 10-membered heteroaromatic ring (comprising one or two rings) having 1 to 3 sulfur atoms, wherein the substituent α is (i) a carbon atom having 1 carbon atom
(Ii) straight-chain or branched alkyl halide having 1 to 4 carbon atoms, (iii) hydroxy, (iv) carbon number. Linear or branched acyloxy having 1 to 4 carbon atoms, (v) linear or branched alkoxy having 1 to 4 carbon atoms, (vi) having 1 to 4 carbon atoms Linear or branched alkylenedioxy, (vii) aralkyloxy having 7 to 12 carbon atoms, (vi
ii) linear or branched alkylthio having 1 to 4 carbons, (ix) linear or branched alkylsulfonyl having 1 to 4 carbons,
(X) a halogen atom, (xi) a carbon number of 7 to 12.
(Xiii) phenyl optionally having a substituent β, (xiii) phenoxy optionally having a substituent β, (xiv) phenylthio optionally having a substituent β, (Xv) phenylsulfonyl optionally having a substituent β, (xvi) phenylsulfonylamino optionally having a substituent β (the nitrogen atom in the amino portion is a straight chain having 1 to 6 carbon atoms) Or it may be substituted by a branched alkyl.),
(Xvii) furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, (xvii
i) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms) and / or (xix) pyridylsulfonylamino (nitrogen atom in the amino moiety) Represents 1 to 6 carbon atoms
Which may be substituted with a straight-chain or branched-chain alkyl having two carbon atoms.
Linear or branched alkyl having 1 to 4 carbon atoms, linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkyl having 1 to 4 carbon atoms, A branched alkoxy, a halogen or a linear or branched alkylenedioxy having 1 to 4 carbon atoms; ^Ye is an oxygen atom, a sulfur atom or a group having the formula> NR ^4e ( In the formula, R ^4e is a hydrogen atom,
It represents a linear or branched alkyl group having 1 to 3 carbon atoms or a linear or branched alkanoyl group having 2 to 5 carbon atoms. ); Z ^e
Is a 2,4-dioxothiazolidine-5-ylmethyl group,
The compound according to (1), which represents a 2,4-dioxooxazolidin-5-ylmethyl group or a 3,5-dioxooxadiazolidin-2-ylmethyl group.

(26) R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R ^2e represents a linear or branched alkyl group having 2 to 5 carbon atoms. R ^3e represents a hydrogen atom; X ^e represents 1 to 3 aryl groups having 6 to 10 carbon atoms which may have a substituent α, or 1 to 3 Represents a 5- to 10-membered (single or bicyclic) heteroaromatic ring group having 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms which may have a substituent α. Wherein the substituted α is (i) a linear or branched alkyl having 1 to 6 carbons,
i) a linear or branched alkyl halide having 1 to 4 carbon atoms, (iii) hydroxy,
(Iv) linear or branched alkanoyloxy having 1 to 4 carbon atoms, (v) linear or branched alkoxy having 1 to 4 carbon atoms,
(Vi) linear or branched alkylenedioxy having 1 to 4 carbon atoms, (vii) aralkyloxy having 7 to 12 carbon atoms, (viii) straight-chain having 1 to 4 carbon atoms Linear or branched alkylthio having 1 to 4 carbon atoms, (ix) linear or branched alkylsulfonyl having 1 to 4 carbon atoms, (x) fluorine atom, chlorine atom, bromine atom, (xi) carbon number An aralkyl having 7 to 12 (xii) substituents β
(Xiii) a substituted β
(Xiv) a substituent β
(Xv) a substituted β
(Xvi) phenylsulfonyl optionally having
Phenylsulfonylamino optionally having a substituent β (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms), (xvii ) Furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl,
(Xviii) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms) and / or (xix) pyridylsulfonylamino (nitrogen in the amino moiety The atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms.)
Is a straight-chain or branched alkyl having 1 to 6 carbons, a straight-chain or branched alkyl halide having 1 to 4 carbons, 1 to 4 carbons
Straight-chain or branched alkoxy having pieces, having 1 to halogen or carbon represents straight-chain or branched alkylenedioxy having four; Y ^e represents an oxygen atom; Z ^e is The compound according to (1), which represents a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group.

(27) R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms; R ^2e represents a linear or branched alkyl group having 2 to 3 carbon atoms. R ^3e represents a hydrogen atom; X ^e represents a phenyl group, a naphthyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, which may have 1 to 3 substituents α. Represents an indolyl group, a quinolyl group or an isoquinolyl group, wherein the substituent α is (i) a linear or branched alkyl having 1 to 6 carbons, and (ii) a linear or branched alkyl having 1 to 4 carbons. (Iii) hydroxy, (iv) linear or branched alkanoyloxy having 1 to 4 carbon atoms, (v) 1 to 4 carbon atoms Straight with pieces Jo or branched alkoxy, (vi) methylenedioxy, (vii)
Aralkyloxy having 7 to 12 carbon atoms,
(Viii) linear or branched alkylthio having 1 to 4 carbons, (ix) linear or branched alkylsulfonyl having 1 to 4 carbons, (x) fluorine atom , Chlorine atom, bromine atom,
(Xi) aralkyl having 7 to 12 carbon atoms,
(Xiii) phenyl (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xiii) phenoxy (the phenyl is methyl, trifluoromethyl, methoxy, fluoro or methylene) (Xiv) phenylthio (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (x
v) phenylsulfonyl (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xvi) phenylsulfonylamino (the phenyl is methyl, trifluoromethyl, methoxy, fluoro Or a nitrogen atom in the amino moiety having 1 carbon atom.
And may be substituted by straight-chain or branched-chain alkyl having from 6 to 6. ), (Xvii) frills,
Thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, (xviii) imidazolyl (where the nitrogen atom is substituted by a linear or branched alkyl having 1 to 6 carbon atoms) And / or (xix) pyridylsulfonylamino (the nitrogen atom of the amino moiety may be substituted by a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms); Y ^e represents an oxygen atom; Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group; (1) compounds described.

(28) R ^1e 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;
^e is a phenyl group, naphthyl group, imidazolyl group, oxazolyl group, which may have 1 to 3 substituents α,
A pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group, wherein the substituent α is (i) a linear or branched alkyl having 1 to 6 carbon atoms,
(Ii) a linear or branched alkyl halide having 1 to 4 carbon atoms, (iii) hydroxy, (iv) a linear or branched alkanoyl having 1 to 4 carbon atoms. Oxy, (v) carbon number 1
Linear or branched alkoxy having 4 to 4 carbon atoms, (vi) methylenedioxy, benzyloxy, phenethyloxy, naphthylmethoxy, (vii) linear or branched chain having 1 to 4 carbon atoms (Viii) a linear or branched alkylsulfonyl having 1 to 4 carbon atoms, (i)
(x) fluorine atom, chlorine atom, bromine atom, (x) benzyl, (xi) phenyl (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xii) Phenoxy (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), (xiii) phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, furyl, thienyl Oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino, N-methylpyridylsulfonylamino, and / or (xiv) imidazolyl (the nitrogen atom has 1 to 6 carbon atoms) . That that may be substituted with a straight-chain or branched alkyl) indicates; Y ^e represents an oxygen atom; indicates a Z ^e is 2,4-dioxo-thiazolidin-5-ylmethyl group; ( The compound according to 1).

(29) R ^1e 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;
^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 α, wherein the substituent α is
(I) linear or branched alkyl having 1 to 3 carbons, (ii) trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, formyloxy, acetoxy, (iii) 1 to 3 carbons Linear or branched alkoxy having
v) methylenedioxy, benzyloxy, methylthio,
Ethylthio, methylsulfonyl, ethylsulfonyl,
(V) a fluorine atom, a chlorine atom, a bromine atom, (vi) benzyl, phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, Phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, furyl, thienyl, oxazolyl, thiazolyl,
Imidazolyl, N- methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, shows a pyridyl sulfonylamino and / or N- methyl-pyridyl sulfonylamino; Y ^e represents an oxygen atom; Z ^e
Represents a 2,4-dioxothiazolidine-5-ylmethyl group; the compound according to (1).

(30) R ^1e represents a hydrogen atom, a methyl group or an ethyl group; R ^2e represents an ethylene group; R ^3e represents a hydrogen atom; X ^e has 1 to 3 substituted α. Represents a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group, wherein the substituent α is methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, acetoxy, methoxy, ethoxy, isopropoxy, methylene Dioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl , Pyridylsulfonylua Mino and / or N- methyl pyridylsulfonyl an amino; Y ^e represents an oxygen atom; Z ^e is 2,4 indicates a dioxothiazolidin-5-ylmethyl group; (1) compounds described.

[0111] (31) R ^1e represents a methyl or ethyl group; R ^2e represents an ethylene group; R ^3e represents a hydrogen atom; X ^e is also have three substituents α from 1 Represents a good phenyl group, wherein the substituted α is methyl, hydroxy, acetoxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio and / or indicate the pyridyl sulfonyl; Y ^e represents an oxygen atom; Z ^e is 2,4-dioxothiazolidin -5
-Represents an ylmethyl group; the compound of (1).

(32) R ^1e represents a methyl group or an ethyl group; R ^2e represents an ethylene group; R ^3e represents a hydrogen atom; even if X ^e has 1 to 3 substituted α. Represents a good pyridyl group, wherein the substituent α is methoxy, ethoxy, isopropoxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino and / or Represents N-methylphenylsulfonylamino;
Y ^e represents an oxygen atom; Z ^e represents a 2,4-dioxothiazolidin-5-ylmethyl group; (1) compounds described.

(33) i) 5- [4- [2-[[[1-
(4-biphenylyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, ii) 5- [4- [2-[[[1- (4-phenylsulfonylphenyl) ethylidene] amino] oxy ] Ethoxy] benzyl] thiazolidine-2,4-dione, iii) 5- [4- [2-[[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine- 2,4-dione (hereinafter, referred to as 2,4-dione)
It will be referred to as "Compound A". ), Iv) 5- [4- [2-[[[1- [4- (3-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, v) 5- [ 4- [2-[[[1- [4- (4-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, vi) 5- [4- [2-[[ [1- (2-phenyl-5
-Pyridyl) ethylidene] amino] oxy] ethoxy]
Benzyl] thiazolidine-2,4-dione, vii) 5- [4- [2-[[[1- (2-methoxy-
5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, viii) 5- [4- [2-[[[1- (2-ethoxy-5-pyridyl) ethylidene] amino] Oxy] ethoxy] benzyl] thiazolidine-2,4-dione, ix) 5- [4- [2-[[[1- (2-isopropoxy-5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine -2,4-dione, and x) 5- [4- [2-[[[1- (2-benzyl-5-
(1) The compound according to (1), which is selected from pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione.

(VI) WO95 / 18125 includes: (1) General formula (VI)

[0115]

Embedded image

[In the formula, 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. Ring group, or the following general formula

[0117]

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[Wherein, R ^1f represents an ^optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group. A ring group, R ^2f and R ^3f may be the same or different and each is a hydrogen atom or a lower alkyl group, and X ^f is 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 a lower alkyl, P ^f and Q ^f are each a hydrogen atom, or P ^f and Q ^f together represent a bond] An isoxazolidinedione derivative or a pharmaceutically acceptable salt thereof is described.

In the compound having the above general formula (VI), R ^f , R ^1f , R ^2f , R ^3f , R ^4f , R ^5f , P ^f and Q
Examples of the definition shown by ^f , the type of pharmacologically acceptable salt,
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.

Among the compounds having the general formula (VI), preferred 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 is a 5- or 6-membered aromatic heterocyclic group containing 1 to 2 heteroatoms selected from a phenyl group, a sulfur atom, an oxygen atom and a nitrogen atom which may be substituted. The compound according to (2), which is a cyclic group or a condensed aromatic heterocyclic group which is obtained by condensing an aromatic heterocyclic ring and a benzene ring and may be substituted.

(4) ^Rf is a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from a phenyl group, a sulfur atom, an oxygen atom and a nitrogen atom, or The compound according to (3), which is a condensed aromatic heterocyclic group formed by condensing with a benzene ring.

(5) The compound according to (3), wherein R ^f is a phenyl 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 R ^f is a phenyl group, a benzothienyl group, or a 1-methyl-1- (2-pyridylthio) methyl group.

(7) The compound according to (2), wherein R ^f is a phenyl group.

(8) R ^f

[0128]

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The compound according to (2), which is

(9) R ^1f is an ^optionally substituted phenyl group or a 5- or 6-membered optionally substituted aromatic group containing 1 or 2 heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom. The compound according to (8), which is a heterocyclic group.

(10) The compound according to (8), wherein R ^1f 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) 5 or 6 wherein R ^1f contains a nitrogen atom
The compound according to (8), which is a membered aromatic heterocyclic group.

(12) R ^1f is a pyridyl group (8)
A compound as described.

(13) i) 4- [4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl] -3,5-isoxazolidinedione; ii) 4- [4- [ 2- (2-phenyl-5-methyl-
4-oxazolyl) ethoxy] benzylidene] -3,5
-Isoxazolidinedione, iii) 4- [4- [2- (2-benzothienyl-5-
Methyl-4-oxazolyl) ethoxy] benzyl]-
3,5-isoxazolidinedione, and iv) 4- [4- [2- [5-methyl- [2- (2-pyridylthio) ethyl-4-oxazolyl) ethoxy] benzyl] -3,5-isoxazolidinedione The compound according to (1), which is selected from:

(VII) JP-A-7-330728 and EP-A-676398 disclose (1) the general formula (VII)

[0136]

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[In the formula, X ^g represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group. (A)
Y ^g represents an oxygen atom or a sulfur atom, and Z ^g represents a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidine-5-ylmethyl group, 4-dioxooxazolidine-5-ylmethyl group, 3,5-dioxooxadiazolidine-2
-Ylmethyl group or N-hydroxyureidomethyl group, wherein R ^g is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms,
Or a straight-chain or branched-chain alkoxy group, a halogen atom, a hydroxy group, a nitro group, and an amino group which may have a substituent (b) (the substituent (b) has 1 carbon atom).
A straight-chain or branched alkyl group having 7 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 linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms. ) Or 7 to 1 carbon atoms
Represents a linear or branched aralkyl group having one, and ^mg represents an integer of 1 to 5, wherein the substituent (a) is a linear or branched aralkyl group 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 Having a linear or branched alkylthio group, a trifluoromethyl group,
A nitro group, an amino group which may have a substituent (b) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, a carbon atom having 7 to 11 carbon atoms); Linear or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.), Aryl having 6 to 10 carbon atoms which may have a substituent (c) Groups (the substituent (c) 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, halogen) Atom, hydroxy group, nitro group, phenyl group A trifluoromethyl group, an amino group optionally having a substituent (b)), or a linear or branched chain having 7 to 11 carbon atoms optionally having a substituent (c) Represents an aralkyl group. Or a pharmacologically acceptable salt thereof.

In the compound having the general formula (VII), the definitions represented by R ^g , X ^g , Y ^g , Z ^g , the substitution (a), the substitution (b), the substitution (c) and ^ng Example,
Details of pharmacologically acceptable salts, methods for producing compounds having the above general formula (VII), examples of compounds and examples are described in the above publications.

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

(2) X ^g 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) Wherein the substituent (a) 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. Branched alkoxy, benzyloxy, halogen, hydroxy, acetoxy, phenylthio, linear or branched alkylthio having 1 to 4 carbon atoms, trifluoromethyl, nitro An amino group optionally having a substituent (b) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, Having A linear or branched aralkyl group, an aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, and 8 to 12 carbon atoms. Araliphatic acyl group or aromatic acyl group having 7 to 11 carbon atoms.), And aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (The substituent (c) 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 , A hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, an amino group optionally having a substituent (b)), or a carbon number optionally having at least one substituent (c) Has 7 to 11 A linear or branched aralkyl group (1) compounds described.

(3) X ^g represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents (a) described later. Where the substitution (a) 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 acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, and an amino group optionally having a substituent (b) The substituent (b) is a straight-chain 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 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or a 7 to 11 carbon atom Yes That an aromatic acyl group.)
An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c)
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, Phenyl group, trifluoromethyl group,
An amino group optionally having a substituent (b)), or a carbon atom having 7 carbon atoms optionally having at least one substituent (c)
(1) The compound according to (1), which represents a straight-chain or branched aralkyl group having from 11 to 11.

(4) X ^g represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described below. The substituent (a) 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, or a benzyloxy group. , A halogen atom, a hydroxy group,
An acetoxy 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 optionally having a substituent (b) The substituent (b) has 1 to 8 carbon atoms.
Linear or branched alkyl groups having 7 to 11 carbon atoms, linear or branched aralkyl groups having 7 to 11 carbon atoms, aryl groups having 6 to 10 carbon atoms, 1 to 1 carbon atoms A linear or branched aliphatic acyl group having 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms is shown. ) An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (c) (the substituent (c) may be a linear or substituted aryl group having 1 to 4 carbon atoms) Branched alkyl group, carbon number 1
A straight-chain or branched alkoxy group having 4 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)), Or 1 to 3 substitutions (c)
The compound according to (1), which represents a linear or branched aralkyl group having 7 to 11 carbon atoms which may have

(5) X ^g represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) to be described later. ) 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, Phenylthio group, 1 to 4 carbon atoms
Linear or branched alkylthio groups having
The compound according to (1), which represents a trifluoromethyl group or a phenyl group.

(6) X ^g represents an imidazopyridine ring group, and these rings have 1 to 3 substituents (a)
Wherein the substituent (a) 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. The compound according to (1), which represents a group, a methylthio group, an ethylthio group or a phenyl group.

(7) R ^g is a hydrogen atom, 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. The compound according to (1), which represents a group or a halogen atom.

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

(9) The compound as described in (1), wherein R ^g represents a hydrogen atom or a methoxy group.

(10) The compound according to (1), wherein R ^g represents a hydrogen atom.

(11) The compound according to (1), wherein Y ^g represents an oxygen atom.

(12) Z ^g represents a 2,4-dioxothiazolidine-5-ylenylmethyl group, a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group ( The compound according to 1).

(13) The compound according to (1), wherein Z ^g represents a 2,4-dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxothiazolidine-5-ylmethyl group. (14) The compound according to (1), wherein Z ^g represents a 2,4-dioxothiazolidin-5-ylmethyl group.

(15) X ^g 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) May have
Y ^g represents an oxygen atom or a sulfur atom, and Z ^g is 2,4-
Dioxothiazolidine-5-yridenylmethyl group, 2,
A 4-dioxothiazolidine-5-ylmethyl group, 2,
4-dioxooxazolidin-5-ylmethyl group,
A 3,5-dioxooxadiazolidine-2-ylmethyl group or an N-hydroxyureidomethyl group, wherein R ^g is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, Represents a linear or branched alkoxy group having 1 to 4 carbon atoms or a halogen atom, and ^mg represents an integer of 1 to 5, wherein the substituent (a) is a group having 1 to 4 carbon atoms. Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group A straight-chain 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) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, Linear or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.), And 6 to 10 carbon atoms optionally having at least one substituent (c). Aryl group having 1 to 4 carbon atoms (the substituent (c) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms) An alkoxy 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)),
Or the compound according to (1), which represents a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c).

(16) X ^g represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents (a) described later. Y ^g represents an oxygen atom, and Z ^g represents a 2,4-dioxothiazolidine-5-ylenylmethyl group, 2,4-dioxothiazolidine-5-yl.
Ylmethyl group or 2,4-dioxooxazolidine-5
And R ^g represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms,
Represents a linear or branched alkoxy group having 1 to 4 carbon atoms or a halogen atom, and ^mg represents an integer of 1 to 5, wherein the substituent (a) is a group having 1 to 4 carbon atoms. A linear or branched alkyl group having
Linear or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, linear or branched having 1 to 4 carbon atoms Chain alkylthio group, trifluoromethyl group, nitro group, substitution (b)
(Substituted (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 7 to 11 carbon atoms) A branched aralkyl group, 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 fat having 8 to 12 carbon atoms An acyl group or an aromatic acyl group having 7 to 11 carbon atoms), and an aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) The component (c) 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 group,
A phenyl group, a trifluoromethyl group, an amino group optionally having a substituent (b)), or a straight chain having 7 to 11 carbon atoms optionally having at least one substituent (c). The compound according to (1), which represents a chain or branched aralkyl group.

(17) X ^g represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later, and Y ^g represents an oxygen atom, Z ^g is 2,4-dioxo-thiazolidin-5-Iridenirumechiru group or 2,4
-Dioxothiazolidine-5-ylmethyl group;
^g represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom, and ^mg represents an integer of 1 to 5, wherein the substituent (a) is a straight-chain having 1 to 4 carbon atoms. Or a branched alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, Linear or branched alkylthio, trifluoromethyl, nitro, and optionally substituted amino groups (substituted (b) having 1 to 8 carbon atoms) Linear or branched alkyl group having 7 to 11 carbon atoms, linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, Has 11 A linear or 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.) 1 to 3 An aryl group having 6 to 10 carbon atoms which may have a substituent (c) (the substituent (c) is a linear 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, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, and a substituent (b). (1) The compound according to (1), which represents an amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have 1 to 3 substituents (c).

(18) X ^g represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described below, and Y ^g represents an oxygen atom. And Z ^g is 2,4-dioxothiazolidine-
Represents a 5-ylmethyl group, R ^g represents a hydrogen atom or a methoxy group, ^mg represents an integer of 1 to 5, wherein the substituent (a) is a straight-chain or 1- to 4-carbon atom. A branched alkyl group, 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 alkyl group having 1 to 4 carbon atoms, Shows a branched alkylthio group, trifluoromethyl group or phenyl group (1)
A compound as described.

(19) X ^g represents an imidazopyridine ring group, these rings may have 1 to 3 substituents (a) described below, Y ^g represents an oxygen atom, and Z
^g represents a 2,4-dioxothiazolidin-5-ylmethyl group, R ^g represents a hydrogen atom, m ^g is an integer of 1 to 5, wherein the substituent (a) is a methyl group, an ethyl group The compound according to (1), which represents isopropyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, fluorine, chlorine, phenylthio, methylthio, ethylthio or phenyl.

(20) i) 5- {4- (3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione; ii) 5- [4- (5 -Chloro-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iii) 5- [4- (5-methoxy-3-methylimidazo [4,5 -B] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iv) 5- [4- (5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] Thiazolidine-2,4-dione, v) 5- [4- (5-ethoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, vi) 5- [4- (5-Isopropoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and vii) 5- [4- (1 -Methylindoline-2-ylmethoxy) benzyl] thiazolidine-2,4-dione;
The compound according to (1), which is selected from the group consisting of:

(VIII) European Patent Publication No. 7
No. 45600 includes: (1) General formula (VIII)

[0159]

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[Wherein, X ^h represents a benzimidazole ring group, which may have 1 to 5 substituents (a) described below, and Y ^h represents an oxygen atom or a sulfur atom. ,
Z ^h is a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxooxazolidine-5-ylmethyl group, a 3,5-dioxooxadiazo group Represents a lysine-2-ylmethyl group or an N-hydroxyureidomethyl group, and R ^h is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and having 1 to 4 carbon atoms A linear or branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) has 1 to 8 carbon atoms) Straight or branched alkyl group having 7 to 11 carbon atoms, straight or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, not having 1 carbon atom A linear or branched aliphatic acyl group having 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms) or 7 to 1 carbon atoms
A straight or branched aralkyl group having 1; m ^h represents an integer of 1 to 5; wherein the substituent (a) is a straight or branched aralkyl group 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 Having a linear or branched alkylthio group, a trifluoromethyl group,
A nitro group, an amino group which may have a substituent (b) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, a carbon atom having 7 to 11 carbon atoms); Linear or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.), Aryl having 6 to 10 carbon atoms which may have a substituent (c) Groups (the substituent (c) 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, halogen) Atom, hydroxy group, nitro group, phenyl group A trifluoromethyl group, an amino group optionally having a substituent (b)), or a linear or branched chain having 7 to 11 carbon atoms optionally having a substituent (c) Represents an aralkyl group. Or a pharmacologically acceptable salt thereof.

In the compound having the general formula (VIII), the definitions represented by R ^h , X ^h , Y ^h , Z ^h , the substitution (a), the substitution (b), the substitution (c) and m ^h And the types of pharmacologically acceptable salts, and the general formula (VII)
Details of the production method of the compound having I), compound examples, examples, and the like are described in the above publications.

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

[0163] (2) R ^h is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, straight-chain or branched alkoxy having 1 to 4 carbon atoms The compound according to (1), which represents a group or a halogen atom.

(3) The compound according to (1), wherein Y ^h represents an oxygen atom.

(4) Z ^h represents a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group ( The compound according to 1).

[0166] (5) R ^h is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, straight-chain or branched alkoxy having 1 to 4 carbon atoms represents a group or a halogen atom, Y ^h represents an oxygen atom, Z ^h is 2,4-dioxo-thiazolidin-5-ylmethyl group, 2,4-dioxothiazolidin-5-Iridenirumechiru group or 2,4-dioxo Oxazolidine-5
-The compound according to (1), which represents an ylmethyl group.

(6) The compound described in (1), wherein Z ^h represents a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group.

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

(8) The compound according to (1), wherein m ^h is an integer of 1 to 3.

(9) Y ^h is an oxygen atom, Z ^h is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group, and R ^h is a hydrogen atom Or a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom, and m ^h represents an integer of 1 to 3.

[0171] (10) X ^h represents a good benzimidazole ring group which may have 1 to 5 below substituents (a), wherein the substituent (a) is from 1 to 4 carbon atoms 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 phenylthio group, a 1 to 4 carbon atoms. The compound according to (1), which has a linear or branched alkylthio group, trifluoromethyl group, hydroxy group, acetoxy group, benzyl group or phenyl group.

(11) The compound described in (1), wherein Z ^h represents a 2,4-dioxooxazolidin-5-ylmethyl group.

(12) The compound according to (1), wherein R ^h represents a hydrogen atom, a methyl group or a methoxy group.

[0174] (13) X ^h represents a good benzimidazole ring group which may have 1 to 5 below substituents (a), wherein the substituent (a) is from 1 to 4 carbon atoms 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 phenylthio group, a 1 to 4 carbon atoms. A linear or branched alkylthio group, trifluoromethyl group, hydroxy group, acetoxy group, benzyl group or phenyl group, Y ^h represents an oxygen atom, and Z ^h represents 2,4-dioxooxazolidine. -5 represents a -5-ylmethyl group, R ^h represents a hydrogen atom, a methyl group or a methoxy group, and m ^h represents 1 to 3
The compound according to (1), which represents an integer of

[0175] (14) X ^h represents 1 to 5 substituents have the following substituents: (a) a benzimidazole ring group, wherein the substituents (a) include methyl group, ethyl group, isopropyl Group, methoxy group, ethoxy group, propoxy group, isopropoxy group, benzyloxy group, fluorine atom, chlorine atom, phenylthio group, methylthio group, ethylthio group, hydroxy group, acetoxy group, benzyl group or phenyl group (1) A compound as described.

(15) The compound described in (1), wherein R ^h represents a hydrogen atom.

(16) The compound according to (1), wherein m ^h is 1 or 2.

[0178] (17) X ^h represents 1 to 5 substituents have the following substituents: (a) a benzimidazole ring group, wherein the substituents (a) include methyl group, ethyl group, 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, methylthio group, ethylthio group, a hydroxy group, an acetoxy group, a benzyl group or a phenyl group, Y ^h Represents an oxygen atom, and Z ^h is 2,
Represents a 4-dioxothiazolidine-5-ylmethyl group,
The compound according to (1), wherein R ^h represents a hydrogen atom and m ^h represents 1 or 2.

[0179] (18) X ^h represents 1 to 5 substituents have the following substituents: (a) a benzimidazole ring group, wherein the substituent (a) represents a methyl group, a methoxy group,
The compound according to (1), which represents a hydroxy group, an acetoxy group or a benzyl group.

(19) The compound described in (1), wherein m ^h is 1.

[0181] (20) X ^h represents 1 to 5 substituents have the following substituents: (a) a benzimidazole ring group, wherein the substituent (a) represents a methyl group, a methoxy group,
A hydroxy group, an acetoxy group or a benzyl group;
^h represents an oxygen atom, Z ^h represents a 2,4-dioxothiazolidin-5-ylmethyl group, R ^h represents a hydrogen atom, m ^h represents 1 (1) compound described.

(21) i) 5- [4- (1-Methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, ii) 5- [4- (6-methoxy-1-methylbenz) Imidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (hereinafter, referred to as "compound B"), iii) 5- [4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] Thiazolidine-2,4-dione, iv) 5- [4- (1-benzylbenzimidazole-
5-ylmethoxy) benzyl] thiazolidine-2,4-
Dione, v) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and vi) 5- [4- ( 5-acetoxy-1,4,6,7-
Tetramethylbenzimidazol-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione.

(IX) JP-A-1-272574 and European Patent Publication No. 332332 disclose: (1) General formula (IX)

[0184]

Embedded image

[Wherein the dotted line indicates a bond or no bond;
V ⁱ is -CH = CH -, - N = CH -, - CH = an N- or S, W ⁱ is _{CH 2, CHOH, CO, C} =
NOR ⁱ or CH = CH, and X ⁱ is S, O, N
R ¹ⁱ , —CH ＝ N— or —N ＝ CH—, and Y ⁱ
Is CH or N, Z ⁱ is hydrogen, (C ₁ -C ₇ )
Alkyl, (C ₃ ~C ₇₎ cycloalkyl, phenyl,
Phenyl mono- or di-substituted by naphthyl, pyridyl, furyl, thienyl or the same or different (C ₁ -C ₃ ) alkyl, trifluoromethyl, (C ₁ -C ₃ ) alkoxy, fluoro, chloro or bromo Wherein Z ¹ⁱ is hydrogen or (C ₁ -C ₃ ) alkyl, R ⁱ and R ¹ⁱ are each independently hydrogen or methyl, and n ⁱ is 1, 2 or 3. Or a pharmacologically acceptable salt thereof.

In the compounds having the general formula (IX), V ⁱ , W ⁱ , X ⁱ , Y ⁱ , Z ⁱ , Z ¹ⁱ , R ⁱ and n ⁱ
Illustrative of the definition shown, the type of pharmacologically acceptable salt,
Details of the production method of the compound having the general formula (IX), compound examples, examples, and the like are described in the above publications.

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

(2) The dotted line indicates no connection, and W ⁱ
Is (CO) or CHOH.

[0189] (3) V ⁱ is -CH = CH -, - CH =
The compound according to (2), wherein the compound is N- or S, and n ⁱ is 2.

(4) X ⁱ is O, Y ⁱ is N for forming an oxazol-4-yl group, and Z ⁱ is (2
-Thienyl), (2-furyl), phenyl, substituted phenyl or naphthyl, and Z ¹ⁱ is 5-methyl.

[0191] (5) V ⁱ is -CH = N-or S, and Z ⁱ is 2-phenyl (4) compounds according.

[0192] (6) V ⁱ is -CH = CH-, W
ⁱ is CO, and Z ⁱ is 2- (2-furyl), 2-
Phenyl, 2- (4-methylphenyl) or 2-
The compound according to (1), which is (2-naphthyl).

(7) The compound according to (3), wherein X ⁱ is O or S, and Y ⁱ is N which forms an oxazol-5-yl, thiazol-4-yl or thiazol-5-yl group. .

[0194] (8) X ⁱ is -CH = N-, and if Y ⁱ is CH forming a pyrid-2-yl group, or X ⁱ is O and Y ⁱ is fur-2 The compound according to (3), which is CH forming an yl group.

(9) 5- {4- [3- (5-methyl-
2-phenyloxazol-4-yl) propionyl]
Benzyl dithiazolidine-2,4-dione (1)
A compound as described.

(X) JP-A-6-247945 and European Patent Publication No. 604983 disclose: (1) General formula (X)

[0197]

Embedded image

[In the above general formula (X),

[0199]

Embedded image

Represents [0200], -X ^j - represents -O- or -S-, = Y ^j - is = N- or = CR ^5j - represents, R ^1j, R
^2j , ^R3j , ^R4j and ^R5j each independently represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy group, an arylcarbonyloxy group, a 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 , a nitro group, or a trihalomethyl group, R ^6j represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, n ^j
Represents an integer of 0 to 3, and the dotted line represents that the bond of the portion may be a double bond. ] Or a pharmaceutically acceptable salt thereof.

In the compound having the general formula (X), X ^j , Y ^j , R ^1j , R ^2j , R ^3j , R ^4j , R ^5j , R ^6j
And the definitions of n ^j , the types of pharmacologically acceptable salts, methods for producing the compounds having the above general formula (X), examples of compounds, examples, and the like are described in the above publications.

Among the compounds having the general formula (X), suitable compounds are shown below. (2) R ^1j , R ^2j , R ^3j , R ^4j and R ^5j each independently represent a hydrogen atom, a halogen atom, a C ₁ -C ₈ alkyl group, a C ₆ -C ₁₂ aryl group, a C ₁ -C ₁₂ an alkoxy group having C _8, alkoxyalkoxy group C ₂ ~C _6, C ₆ ~C
₁₂ aryloxy groups, C ₂ -C ₉ alkanoyloxy groups, C ₇ -C ₁₃ arylcarbonyloxy groups, carboxyl groups, C ₂ -C ₉ alkoxycarbonyl groups,
Aryloxycarbonyl group ₇ -C _13, a carbamoyl group, alkylaminocarbonyl group C ₂ ~C _9, C ₇ ~
C ₁₃ arylaminocarbonyl group, amino group, C _1-
Alkylamino group C _8, C ₂ alkanoylamino groups -C _9, arylcarbonylamino group C ₇ -C _13, ethylenedioxy methyl group, a formyl group, a cyano group, a nitro group, or a trihalomethyl group, R ^6j is a hydrogen atom;
C ₁ -C ₈ which may have one or more substituents selected from a phenyl group, a halogen atom, a nitro group and a cyano group.
Or a C ₆ -C ₁₂ aryl group which may have one or more substituents selected from C ₁ -C ₈ alkyl groups, halogen atoms, nitro groups and cyano groups (1) A compound as described.

(3) R ^1j , R ^2j , R ^3j , R ^4j and R ^5j
Are each independently a hydrogen atom, a halogen atom, C _1-
Alkyl C _8, alkoxy group of C ₁ ~C _8, C ₂ ~
A C ₆ alkoxyalkoxy group, a C ₂ -C ₉ alkanoyloxy group, a C ₇ -C ₁₃ arylcarbonyloxy group, a carboxyl group, a C ₂ -C ₉ alkoxycarbonyl group, a carbamoyl group, a C ₂ -C ₉ alkylaminocarbonyl group, arylaminocarbonyl group C ₇ -C _13, an amino group, an alkylamino group of C ₁ ~C _8, C ₂ ~
Alkanoylamino groups of C _9, arylcarbonylamino group C ₇ -C _13, ethylenedioxy methyl group, a formyl group, a cyano group, a nitro group, or a trihalomethyl group, R ^6j represents a hydrogen atom; C ₁ -C The compound according to (1), which represents an alkyl group of ₈ ; or a C _{6 to} C ₁₂ aryl group optionally substituted with a halogen atom.

(4) -X ^j- represents -O-, Y ^j represents = CR ^5j- , and R ^1j , R ^2j , R ^3j , R ^4j and R
^5j is each independently a hydrogen atom, a halogen atom, C ₁
Alkyl group -C _5, alkoxy groups C ₁ ~C _5, C ₂
Alkoxyalkoxy groups -C _6, alkanoyloxy groups of C ₂ -C _6, a carboxyl group, an alkoxycarbonyl group having C ₂ -C _6, arylaminocarbonyl group C ₇ -C _13, amino group, C ₂ -C ₆ Represents an alkanoylamino group, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group, wherein R ^6j is a hydrogen atom; a C ₁ -C ₅ alkyl group; The compound according to (1), which represents a good C ₆ -C ₁₂ aryl group.

(5)

[0206]

Embedded image

-X ^j- represents -O-, Y ^j represents = CR ^5j- , and R ^1j , R ^2j , R ^3j and R ^4j each independently represent a hydrogen atom or a halogen atom. Wherein R ^5j represents a hydrogen atom, R ^6j represents a hydrogen atom, n ^j represents 1, and the bond at the site indicated by the dotted line is a single bond.

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

In the compounds having the general formulas (I) to (X) or the pharmaceutically acceptable salts thereof, various isomers such as stereoisomers based on asymmetric carbon atoms exist (for example, In the compounds having the general formula (I), the carbon atom at the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms.) And in the general formulas (I) to (X), Stereoisomers based on asymmetric carbon atoms and equal and unequal mixtures of these isomers are all represented by a single formula. Therefore, the present invention includes all these isomers and mixtures of these isomers.

Further, in the compounds having the general formulas (I) to (X) or pharmacologically acceptable salts thereof, for example, various tautomers may be added to the 2,4-dioxothiazolidine-5-ylmethyl ring. The existence of a body is considered. 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, the present invention includes all these isomers and mixtures of these isomers.

Further, in the present invention, when the compound having the general formulas (I) to (X) or a pharmacologically acceptable salt thereof forms a solvate (for example, a hydrate), these are all included. It is a thing. For example, the general formula (I)
Or when the compound having (X) or a pharmacologically acceptable salt thereof is left in the air or recrystallized to absorb water and adhere to adsorbed water or form a hydrate. There is. The present invention includes such a solvate.

The present invention also includes all compounds which are converted into the compounds having the above general formulas (I) to (X) or pharmacologically acceptable salts by metabolism in the living body, so-called prodrugs. It is a thing.

In the compounds of the present invention having the general formulas (I) to (X), preferably, i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2) -Ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone), ii) 5- [4- (6-hydroxy-2-methyl-7-
t-butylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iii) 5- [4- (6-hydroxy-2-ethyl-
5,7,8-trimethylchroman-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, iv) 5- [4- (6-hydroxy-2-t-butyl-
5,7,8-trimethylchroman-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, v) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, vi) 5- [4- (6-ethoxycarbonyloxy-
2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, vii) 5- {4- [2- (3-ethyl-2-pyridyl) ethoxy] benzyl}- 2,4-thiazolidinedione, viii) 5- {4- [2- (4-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione, ix) 5- {4- [2- (5 -Ethyl-2-pyridyl)
Ethoxy] benzyl {-2,4-thiazolidinedione (pioglitazone), x) 5- {4- [2- (6-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione, xi) 5- [(2-benzyl-2,3-dihydrobenzofuran-5-yl) methyl] thiazolidine-2,4-dione, xii) 5-[(2-benzyl-3,4-dihydro-2)
H-benzopyran-6-yl) methyl] thiazolidine-
2,4-dione (englitazone), xiii) 5- {4- [2- (N-methyl-N- (2-
Benzothiazolyl) amino) ethoxy] benzyl {thiazolidine-2,4-dione; xiv) 5- {4- [2- (N-methyl-N- (2-pyrimidinyl) amino) ethoxy] benzyl} thiazolidine-2,4- Dione, xv) 5- {4- [2- (N-methyl-N- (2-
[4,5-dimethylthiazolyl)] amino) ethoxy]
Benzyl {thiazolidine-2,4-dione, xvi) 5- {4- (2- (N-methyl-N- (2-thiazolyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione, xvi) 5- {4- [2- (N-methyl-N- (2-
[4-phenylthiazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, xviii) 5- {4- [2- (N-methyl-N- (2
-[4-phenyl-5-methylthiazolyl]) amino)
Ethoxy] benzyl {thiazolidine-2,4-dione, xix) 5- {4- [2- (N-methyl-N- (2-
[4-methyl-5-phenylthiazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, xx) 5- {4- [2- (N-methyl-N- (2- [5
-Phenyloxazolyl]) amino) ethoxy] benzyl {thiazolidine-2,4-dione, xxi) 5- {4- [2- (N-methyl-N- (2-
[4,5-dimethyloxazolyl]) amino) ethoxy] benzyl} thiazolidine-2,4-dione, xxii) 5- {4- [2- (2-pyrimidinylamino) ethoxy] benzyl} thiazolidine-2,4 -Dione, xxiii) 5- {4- [2- (N-acetyl-N-
(2-pyrimidinyl) amino) ethoxy] benzyl {thiazolidine-2,4-dione, xxiv) 5- {4- [2- (N- (2-benzothiazolyl) -N-benzylamino) ethoxy] benzyl} thiazolidine-2 Xxv) 5- {4- [3- (N-methyl-N- (2-benzoxazolyl) amino) propoxy] benzyl) thiazolidine-2,4-dione, xxvi) 5- {4- [2 -(N-methyl-N- (2-
Pyridyl) amino) ethoxy] benzyl {thiazolidine-2,4-dione (BRL-49653), xxvii) 5- [4- [2-[[[1- (4-biphenylyl) ethylidene] amino] oxy] ethoxy] benzyl Thiazolidine-2,4-dione, xxviii) 5- [4- [2-[[[1- (4-phenylsulfonylphenyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, xxix ) 5- [4- [2-[[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione (compound A), xxx) 5- [4- [2-[[[1- [4- (3-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine- 2,4-dione, xxxi) 5- [4- [2-[[[1- [4- (4-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, xxxii ) 5- [4- [2-[[[1- (2-phenyl-5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, xxxiii) 5- [4- [2 -[[[1- (2-Methoxy-5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, xxxiv) 5- [4- [2-[[[1- (2 -Ethoxy-5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, xxxv) 5- [4- [2-[[[1- (2-isopropoxy-5) Pyridyl) ethylidene] amino] oxy]
Ethoxy] benzyl] thiazolidine-2,4-dione, xxxvi) 5- [4- [2-[[[1- (2-benzyl-5-pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2, 4-dione, xxxvii) 4- [4- [2- (2-phenyl-5-
Methyl-4-oxazolyl) ethoxy] benzyl]-
3,5-isoxazolidinedione, xxxviii) 4- [4- [2- (2-phenyl-5
-Methyl-4-oxazolyl) ethoxy] benzylidene] -3,5-isoxazolidinedione, xxxix) 4- [4- [2- (2-benzothienyl-
5-methyl-4-oxazolyl) ethoxy] benzyl]
-3,5-isoxazolidinedione, xl) 4- [4- [2- [5-methyl- [2- (2-pyridylthio) ethyl-4-oxazolyl) ethoxy] benzyl] -3,5-isoxazolidinedione , Xli) 5- {4- (3-methylimidazo [4,5-
b] pyridin-2-ylmethoxy) benzyl {thiazolidine-2,4-dione, xlii) 5- [4- (5-chloro-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine -2,4-dione, xliii) 5- [4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xliv) 5- [4- (5-hydroxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xlv) 5- [4- (5-ethoxy-3-methyl) Imidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xlvi) 5- [4- (5-isopropoxy-3-) Chiruimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xlvii) 5- [4- (1- methyl-indoline-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione; xlviii) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione, xlix) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (compound B), 1) 5- [4- ( 5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, li) 5- [4- (1-benzylbenzimidazole-
5-ylmethoxy) benzyl] thiazolidine-2,4-
Dione, lii) 5- [4- (5-hydroxy-1,4,6,7
-Tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, liii) 5- [4- (5-acetoxy-1,4,6,
7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] Benzyl @ thiazolidine-2,4-dione, or lv) 5- [6- (2-fluorobenzyloxy) -2
[Naphthylmethyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof.

In the compounds of the present invention having the general formulas (I) to (X), more preferably, i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman- 2-ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone), ii) 5- [4- (6-acetoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) benzyl]
Thiazolidine-2,4-dione, iii) 5- [4- (6-ethoxycarbonyloxy-
2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, iv) 5- {4- [2- (5-ethyl-2-pyridyl)
Ethoxy] benzyl} -2,4-thiazolidinedione (pioglitazone), v) 5-[(2-benzyl-3,4-dihydro-2H-
Benzopyran-6-yl) methyl] thiazolidine-2,
4-dione (engritazone), vi) 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-
2,4-dione (BRL-49653), vii) 5- [4- [2-[[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2, 4-dione (compound A), viii) 4- [4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl] -3,5
-Isoxazolidinedione, ix) 5- {4- (3-methylimidazo [4,5-b]
Pyridin-2-ylmethoxy) benzyl {thiazolidine-2,4-dione, x) 5- [4- (1-methylindoline-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xi) 5- [4- (1-methylbenzimidazole-2
-Ylmethoxy) benzyl] thiazolidine-2,4-dione, xii) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (compound B), xiii ) 5- [4- (5-hydroxy-1,4,6,
7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, xiv) 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] Benzyl @ thiazolidine-2,4-dione, or xv) 5- [6- (2-fluorobenzyloxy) -2
[Naphthylmethyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof.

In the compounds of the present invention having the above general formulas (I) to (X), optimally: i) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2) -Ylmethoxy) benzyl] thiazolidine-2,4-dione (troglitazone), ii) 5- {4- [2- (5-ethyl-2-pyridyl)
Ethoxy] benzyl} -2,4-thiazolidinedione (pioglitazone), iii) 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-
2,4-dione (BRL-49653), iv) 5- [4- [2-[[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2, 4-dione (compound A), or v) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (compound B), or a compound thereof. It is a pharmacologically acceptable salt.

[0216]

BEST MODE FOR CARRYING OUT THE INVENTION The insulin sensitizer used in the present invention is administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, degree of disease, and the like. For example, tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of injections, they are administered intravenously, alone or as a mixture with normal replenishers such as glucose and amino acids.
It is administered subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally. Preferably it is oral administration.

[0219] These various preparations are prepared according to a conventional method into a base drug, a known auxiliary such as an excipient, a binder, a disintegrant, a lubricant, a dissolving agent, a flavoring agent, a coating agent and the like which can be usually used in the field of known pharmaceutical preparations. It can be formulated using an agent. When molding into tablets, widely known carriers in this field can be used as carriers, for example, lactose,
Excipients such as sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, Methylcellulose, potassium phosphate, polyvinylpyrrolidone sugar binder, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,
Disintegrating agents such as stearic acid monoglyceride, starch, lactose,
Disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite and colloidal silica Examples thereof include adsorbents such as acids, lubricants such as purified talc, stearates, powdered boric acid, and polyethylene glycol. Further, the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.

In the form of pills, those conventionally known in the art can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; Examples thereof include a gum arabic powder, a tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar.

In the case of molding into a suppository, a wide variety of carriers conventionally known in the art can be used as the carrier, such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glyceride and the like. 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 diluted. As the agent, any one commonly used in this field can be used, for example, water, ethyl alcohol,
Examples include 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 a normal solubilizing agent may be used.
A buffer, a soothing agent and the like may be added. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be added as necessary.

The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the whole composition. Is appropriate. Furthermore, autoimmune diseases are classified into systemic autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic scleroderma, mixed connective tissue disease, and dermatomyositis. And Hashimoto's disease
Primary myxedema, thyrotoxicosis, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Addison's disease,
Male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, bullous pemphigoid, sympathetic ophthalmitis, multiple sclerosis, autoimmune hemolytic anemia And organ-specific autoimmune diseases such as idiopathic thrombocytopenic purpura, myocardial infarction syndrome, rheumatic fever, lupus hepatitis, primary biliary cirrhosis, Behcet's disease, and CREST syndrome.

In the present invention, the dosage of the insulin sensitizer is different depending on symptoms, age, administration method and the like. 1 mg) and, as an upper limit, 1000 mg (preferably 500 mg) in one or several divided doses.
In the case of intravenous administration, for adults, the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 500 mg (preferably 200 mg) once or several times a day. It is desirable to administer according to.

Next, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples.

[0224]

EXAMPLE 1 Inhibitory Effect of Lymphocyte Infiltration Streptozotocin 40 was administered to 8-week-old DBA / 2 mice.
mg / kg was administered intraperitoneally for 5 days to induce autoimmunity against islet β cells. For 38 days from the first day of administration of streptozotocin, troglitazone was administered at a concentration of 0.2% in F2 powder feed (240 mg / kg).
/ Day). The mice in the control group received only powdered feed during this time.

Before starting the administration of streptozotocin, during the drug administration period, and on the last day of the drug administration, blood was collected from the tail vein, and the blood was centrifuged. Table 1 shows the results. In the table, the vertical axis represents the blood glucose level (mg / dl) of the plasma, and the horizontal axis represents time (days).

[0226]

[Table 1]

The mice used above were measured for blood glucose level on the last day of drug administration and then sacrificed, and the pancreas was excised and fixed in Bouin. A tissue section of this pancreas was prepared, and the degree of lymphocyte infiltration into the pancreatic islets was observed under an optical microscope. The ratio (%) of the number of pancreatic islets in which lymphocytes were infiltrated to the total number of pancreatic islets under observation was calculated, and this was defined as the degree of lymphocyte infiltration.
In addition, each mouse was treated with 0-40 lymphocyte infiltration.
Table 2 shows the ratio (%) of the number of mice classified into each range to the total number of troglitazone-administered groups and control groups.

[0228]

[Table 2] 程度 Degree of lymphocyte infiltration Experimental group 0-40% 40-60% ────────────────────────────────── Control group 37.5 62.5 Troglitazone administration group 100 0 ６２ As shown in Table 2 above, in the control group, 62 .
40% lymphocyte infiltration into pancreatic islets of 5% of mice
However, in the troglitazone-administered group, the degree of infiltration of lymphocytes into pancreatic islets of all mice was 40% or less. From these results, troglitazone suppressed infiltration of lymphocytes into target cells. Further, Tables 1 and 2 show that troglitazone suppressed the infiltration of lymphocytes into target cells and suppressed the development of autoimmune diseases.

Example 2 Inhibition of Adjuvant Arthritis Bone Destruction
Action Winder et al. Method (Arthritis Rheum., Vol. 12, No.
P. 472, 1969). One group consisted of 5 Lewis rats (female, 8-10 weeks old, weighing 160-
Using 200 g, Charles River, Japan, an adjuvant (Mycobacterium butyricu) was injected into the skin of the right hind footpad of the rat.
m. of heat-killed bacteria) 100 μg / 0.05 ml / paw was injected to induce arthritis. 0 days of injection of adjuvant
Up to day 20 as a day, rats received 0.2% troglitazone, 0.05% pioglitazone, BRL, respectively.
A powder feed mixed with 0.005% of -49653 was administered, and the rats of the control group were administered only the powder feed during the same period. On the 21st day, the rats were sacrificed, and the right hind paw (injection paw) was cut. Then, soft X-ray photography was performed, and the state of bone destruction was observed. The score of bone destruction was “0” for “normal” in which no bone destruction occurred, “joint destruction, bone destruction,
The most advanced state of "deformation and ossification" was evaluated as 4 points, and evaluated on a 5-point scale of 0, 1, 2, 3, and 4, and 2 points from the calcaneus and tarsal bone to the metatarsal bone I went about places.
Therefore, the score per animal was a total of two points from the calcaneus and the tarsal bone to the metatarsal, and the maximum score was eight points.

The results are shown in Table 3.

[0231]

[Table 3] ────────────────────────────────── Experimental group Bone destruction score-(point) Bone destruction suppression Rate (%) 対 照 Control group 7.4 ± 0.4 Troglitazone administration group 5.4 ± 0.2 ^* 27.0 Pioglitazone administration group 4.4 ± 1.0 40.5 BRL-49653 administration group 4.8 ± 1.2 35.1 ─────────── ─────────────────────── *: P <0.05 vs control group.

As is clear from Table 3, the troglitazone-administered group showed a significant inhibitory effect on bone destruction as compared with the control group (Wilcoxon test method). Pioglitazone administration group,
The BRL-49653 administration group also showed suppression of bone destruction.

Example 3 Inhibitory Effect on Lymphocyte Infiltration Streptozotocin 40 was administered to 8-week-old DBA / 2 mice.
mg / kg was administered intraperitoneally for 5 days to induce autoimmunity against islet β cells. For 38 days from the first day of administration of streptozotocin, pioglitazone was administered at a concentration of 0.2% in F2 powder feed (236 mg / kg).
/Day). The mice in the control group received only powdered feed during this time. Before the start of streptozotocin administration, during the drug administration period,
Blood was collected from the tail vein on the last day of drug administration, the blood was centrifuged, and the blood glucose level of the obtained plasma was measured with a glucose analyzer (manufactured by Sinotest). Table 4 shows the results. In the table, the vertical axis represents the blood glucose level (mg / dl) of the plasma, and the horizontal axis represents time (days).

[0234]

[Table 4]

The mice used above were measured for blood glucose levels on the last day of drug administration and then sacrificed, and the pancreas was excised and fixed in Bouin. A tissue section of this pancreas was prepared, and the degree of lymphocyte infiltration into the pancreatic islets was observed under an optical microscope. The ratio (%) of the number of pancreatic islets in which lymphocytes were infiltrated to the total number of pancreatic islets under observation was calculated, and this was defined as the degree of lymphocyte infiltration.
In addition, each mouse was treated with 0-40 lymphocyte infiltration.
Table 5 shows the ratio (%) of the number of mice classified in each range to the total number of pioglitazone-administered groups and control groups.

[0236]

[Table 5] 程度 Degree of lymphocyte infiltration 0-40% 40- 60% ────────────────────────────────── Control group 37.5 62.5 Pioglitazone administration group 1000 ─よ う As shown in Table 5 above, in the control group, 62.
40% lymphocyte infiltration into pancreatic islets of 5% of mice
In contrast, in the pioglitazone-administered group, the degree of infiltration of lymphocytes into pancreatic islets of all mice was 40% or less. From these results, pioglitazone suppressed the infiltration of lymphocytes into target cells.

[0237] Furthermore, Tables 4 and 5 show that pioglitazone suppressed the infiltration of lymphocytes into target cells and suppressed the development of autoimmune diseases.

Example 4 Inhibitory Effect on Lymphocyte Infiltration Streptozotocin 40 was administered to 8-week-old DBA / 2 mice.
mg / kg was administered intraperitoneally for 5 days to induce autoimmunity against islet β cells. For 31 days from the first day of administration of streptozotocin, BRL-49653 or Compound A was added to F2 powder feed at a concentration of 0.1% (BRL, respectively).
-49653: 125 mg / kg / day, Compound A: 94
(mg / kg / day). The mice in the control group received only powdered feed during this time.

Before starting the administration of streptozotocin, during the drug administration period, on the last day of the drug administration, blood was collected from the tail vein, the blood was centrifuged, and the blood glucose level of the obtained plasma was measured with a glucose analyzer (manufactured by Sinotest). Table 6 shows the results. In the table, the vertical axis represents the blood glucose level (mg / dl) of the plasma, and the horizontal axis represents time (days).

[0240]

[Table 6]

The mice used above were measured for blood glucose levels on the last day of drug administration and then sacrificed, and the pancreas was excised and fixed in Bouin. A tissue section of this pancreas was prepared, and the degree of lymphocyte infiltration into the pancreatic islets was observed under an optical microscope. The ratio (%) of the number of pancreatic islets in which lymphocytes were infiltrated to the total number of pancreatic islets under observation was calculated, and this was defined as the degree of lymphocyte infiltration.
In addition, each mouse was treated with 0-40 lymphocyte infiltration.
Table 7 shows the ratio (%) of the number of mice classified in each range to the total number of BRL-49653 or Compound A-administered groups.

[0242]

[Table 7] 程度 Degree of lymphocyte infiltration 0-40% 40- 60% ────────────────────────────────── Control group 55.6 44.4 BRL-49653 administration group 100 0 Compound A administration group 100 0 よ う As shown in Table 7 above, In the control group, 40%
In the group to which BRL-49653 and Compound A were administered, lymphocyte infiltration was observed in all mice in the group to which BRL-49653 and Compound A were administered, whereas the infiltration of lymphocytes to ６０60% of islets reached 44.4%. Less than 40% of the islets were observed. That is, BRL-49653 and Compound A suppressed infiltration of lymphocytes into target cells. Furthermore, as is clear from Tables 6 and 7, BRL-49653 and Compound A suppressed the infiltration of lymphocytes into target cells and suppressed the development of autoimmune diseases.

Example 5 Inhibition of Adjuvant Arthritis Bone Destruction
Action Winder et al. Method (Arthritis Rheum., Vol. 12, No.
P. 472, 1969). One group consisted of 5 Lewis rats (female, 8-10 weeks old, weighing 160-
Using 200 g, Charles River, Japan, an adjuvant (Mycobacterium butyricu) was injected into the skin of the right hind footpad of the rat.
m. of heat-killed bacteria) 100 μg / 0.05 ml / paw was injected to induce arthritis. 0 days of injection of adjuvant
Until the 20th day as a day, rats were administered a powdered feed containing 0.1% of compound A and 0.1% of compound B, and rats of the control group were administered only powdered feed during the same period. On the 21st day, the rats were sacrificed, and the right hind paw (injection paw) was cut. Then, soft X-ray photography was performed, and the state of bone destruction was observed. The score of bone destruction was “0” for “normal” in which no bone destruction occurred, “joint destruction, bone destruction,
The most advanced state of "deformation and ossification" was evaluated as 4 points, and evaluated on a 5-point scale of 0, 1, 2, 3, and 4, and 2 points from the calcaneus and tarsal bone to the metatarsal bone I went about places.
Therefore, the score per animal was a total of two points from the calcaneus and the tarsal bone to the metatarsal, and the maximum score was eight points.

The results are shown in Table 8.

[0245]

[Table 8] 群 Experimental group Bone destruction score-(point) Bone destruction suppression Rate (%) 対 照 Control group 8.0 ± 0.0 Compound A administration Group 6.6 ± 0.7 17.5 Compound B administration group 6.6 ± 0.8 17.5 ─────────────────────────よ う As is clear from Table 8, the compound A administration group and the compound B administration group showed a tendency to suppress bone destruction as compared with the control group (Wilcoxon test method).

[Test Example] Test Example 1. Acute toxicity Acute toxicity was measured according to a conventional method. That is, troglitazone was orally administered to three ddY mice (male) at a dose of 300 mg / kg and observed for 5 days, but all survived.
Similarly, as a result of measuring the acute toxicity of the compounds of Exemplified Compound Nos. 2, 3, 4, and 10, all of
g / kg or more.

[Preparation Examples] A preparation containing the insulin sensitizer of the present invention or a pharmacologically acceptable salt thereof as an active ingredient can be produced, for example, by the following method.

Formulation Example 1 When mixed powders troglitazone 5g, lactose 895g and corn starch 100g in a blender, powder is obtained.

Formulation Example 2 After mixing 5 g of granule troglitazone, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose,
300 g of a 10% aqueous solution of hydroxypropylcellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain a granule.

Formulation Example 3 5 g of troglitazone capsule , 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate
Was mixed using a V-type mixer, and then 1
A capsule is obtained by filling 80 mg each.

Formulation Example 4 Tablets 5 g of troglitazone, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, and the mixture is compressed with a tablet machine to obtain tablets.

Formulation Example 5 When mixed powders pioglitazone 5g, lactose 895g and corn starch 100g in a blender, powder is obtained.

Formulation Example 6 After mixing 5 g of granule BRL-49653, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 10% aqueous solution of hydroxypropylcellulose 30
Add 0 g and knead. This is granulated using an extrusion granulator and dried to obtain a granule.

Formulation Example 7 5 g of capsule compound A, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate were mixed using a V-type mixer, and then 180 mg was placed in a No. 3 capsule.
By filling each, capsules are obtained.

Formulation Example 8 5 g of tablet compound A, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, and the mixture is compressed with a tablet machine to give tablets.

[0256]

The insulin sensitizer of the present invention comprises:
It is useful as a prophylactic or therapeutic agent for autoimmune diseases (excluding type I diabetes).

Continuing from the front page (72) Inventor Toshimichi Hosokawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Junichiro Fukushige 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Daigo Minakoshi 1-2-5 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (20)

[Claims] 1. An autoimmune disease containing an insulin sensitizer as an active ingredient (excluding type I diabetes).
Prophylactic or therapeutic agents. 2. The autoimmunity according to claim 1, wherein the insulin sensitizer is a compound selected from the group consisting of a thiazolidinedione compound, an oxazolidinedione compound, an isoxazolidinedione compound and an oxadiazolidinedione compound. An agent for preventing or treating a disease (excluding type I diabetes). 3. The autoimmune disease according to claim 1, wherein the insulin sensitizer is a compound selected from thiazolidinedione compounds (excluding type I diabetes).
Prophylactic or therapeutic agents. 4. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (I): [Wherein, R ^1a and R ^2a are the same or different and each represent a hydrogen atom or a C ₁ -C ₅ alkyl group, and R ^3a is a hydrogen atom, a C ₁ -C ₆ aliphatic acyl group, a C _6-
A C ₈ cycloalkylcarbonyl group, a benzoyl or naphthoyl group which may have a substituent (the substituent is
C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen atom, amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino or nitro group. ), A 4- to 7-membered heterocyclic acyl group containing 1 to 3 heteroatoms selected from a heteroatom group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenylacetyl group, a phenylpropionyl group, and at least one phenylacetyl or phenylpropionyl group substituted with a halogen atom, a cinnamoyl group, C ₂ -C ₇ alkoxycarbonyl group or benzyloxycarbonyl group, R ^4a and R ^5a are the same or different, a hydrogen atom, C ₁ -
Or shows a C ₅ alkyl group or a C ₁ -C ₅ alkoxy group, or R ^4a and R ^5a together indicates C ₁ -C ₄ alkylenedioxy group, Y ^a and Z ^a are the same or different represents an oxygen atom or an imino group, n ^a represents an integer of 1 to 3. Or an autoimmune disease which is a pharmacologically acceptable salt thereof (provided that I
Excluding type 2 diabetes. ) A prophylactic or therapeutic agent. 5. The method of claim 1, wherein the insulin sensitizer is represented by the general formula (II): Or a prophylactic or therapeutic agent for an autoimmune disease (excluding type I diabetes), which is a compound having the formula: or a pharmacologically acceptable salt thereof. 6. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (III): Wherein the dashed line represents a single bond or a non-bond, n ^c is 0,
In 1 or 2, X ^c is O, S, S = O, S (= O) (=
O) wherein R ^c is H, CH ₃ or C ₂ H ₅ and R ^1c
Separate the H, C ₅ ~C ₇ cycloalkyl, C ₆ -C ₈
Methyl-substituted cycloalkyl, pyridyl, thienyl, furyl, naphthyl, p-biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C
₆ H ₄ W ^2c [W ^2c is H, OH, F, Cl, Br, C ₁ ~
C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ thioalkyl] or alk-W ^1c [alk is C ₁ ~
C ₆ alkylene, ethylidene or isopropylidene; W ^1c is H, OH, C ₁ -C ₄ alkoxy, C ₁ -C _4
4 Thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, C ₅
-C ₇ cycloalkyl or C ₆ H ₄ W ^2c] in R ^2c
Is H or CH ₃ , R ^3c is H, C ₁ -C ₆ alkyl, C
₆ H ₄ W ^2c or benzyl, wherein R ^4c is H, R ^1c and R
^{If 2c} is taken together, they form a C ₄ -C ₆ alkylene, R ^3c and R ^4c are each H, R
When ^{the 3c} and R ^4c are taken together, they C ₄ ~
C ₆ alkylene to form, R ^1c and R ^2c are each H, when R ^2c and R ^3c are taken together, they form a C ₃ -C ₄ alkylene, R ^1c and R ^4c Is H, respectively. Or a pharmacologically acceptable salt thereof, for a prophylactic or therapeutic agent for an autoimmune disease (however, excluding type I diabetes). 7. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (IV): [In the formula, A ^1d represents a substituted or unsubstituted aromatic heterocyclic group; R ^1d represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (wherein the aryl moiety may be substituted or unsubstituted) R ^2d and R ^3d each represent hydrogen or R ^2d and R ^3d together represent a bond; A ^2d represents a total of up to 5 Represents a substituted benzene ring; and n ^d is 2 to
Represents an integer in the range of 6. Or a pharmacologically acceptable salt thereof, for a prophylactic or therapeutic agent for an autoimmune disease (however, excluding type I diabetes). 8. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (V): [Wherein, R ^1e represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R ^2e represents a linear or branched alkyl group having 2 to 6 carbon atoms. R ^3e represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms. Alkoxy group, carbon number 1
A straight or branched alkylthio group having 1 to 4 carbon atoms, a halogen atom, a nitro group, an amino group,
A straight-chain or branched monoalkylamino group having 1 to 4 carbon atoms, a straight-chain or branched dialkylamino group having the same or different alkyl groups each having 1 to 4 carbon atoms, to an aryl group or an aralkyl group having 12 or C 7 -C having 10, X ^e is C 6 carbon atoms which may have a three substituents α from 1 to aryl groups having 10 Or 1 to 3
Represents a heteroaromatic ring group optionally having a substituent α, wherein the substituent α is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) A) straight-chain or branched alkyl halide group having 1 to 4 carbon atoms, (iii) hydroxy group,
v) a linear or branched acyloxy group having 1 to 4 carbon atoms; (v) a linear or branched alkoxy group having 1 to 4 carbon atoms;
i) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms, (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,
(X) a halogen atom, (xi) a nitro group, (xi
(xiii) a linear or branched monoalkylamino group having 1 to 4 carbon atoms,
(Xiv) linear or branched dialkylamino groups having the same or different alkyls each having 1 to 4 carbon atoms, (xv) aralkyl groups having 7 to 12 carbon atoms, (xvi) substituted an aryl group having 6 to 10 carbon atoms which may have β, (x
vii) 6 to 1 carbon atoms optionally having a substituent β
An aryloxy group having 0, (xviii) an arylthio group having 6 to 10 carbon atoms optionally having a substituent β, and (xix) having 6 to 10 carbon atoms optionally having a substituent β. (Xx) an arylsulfonylamino group having 6 to 10 carbon atoms which may have a substituent β (the nitrogen atom in the amino portion is a straight-chain having 1 to 6 carbon atoms) Or (xxi) a heteroaromatic ring group, (xxii) a heteroaromatic oxy group, (xxiii) a heteroaromatic thio group,
(Xxiv) a heteroaromatic sulfonyl group, and (xxiv)
v) a heteroaromatic ring sulfonylamino group (the nitrogen atom in the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms). Here, the substituent β is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons, four having straight-chain or branched alkoxy, having 1 to halogen or carbon represents straight-chain or branched alkylenedioxy having four, Y ^e represents an oxygen atom, a sulfur atom or the formula A group having> N—R ^4e , wherein R ^4e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a linear or branched alkyl group having 1 to 8 carbon atoms, shows a branched acyl group.) indicates, Z ^e is 2,4-dioxo-thiazolidin-5-Iridenirumechiru group, 2,4-dioxothiazolidin-5-ylmethyl group, 2,4-dioxo-oxazolidinedione -5-ylmethyl group 3,5-dioxo oxadiazolidinediones 2-
Shows an ylmethyl group. Or an agent for preventing or treating an autoimmune disease (however, excluding type I diabetes), which is an oxime derivative or a pharmacologically acceptable salt thereof. 9. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (VI): [Wherein, 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: [Wherein, R ^1f is an ^optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group. Yes,
R ^2f and R ^3f may be the same or different and each is a hydrogen atom or a lower alkyl group, and X ^f is 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 a lower alkyl, P ^f and Q ^f are each a hydrogen atom, or P ^f and Q ^f together represent a bond. Or a pharmacologically acceptable salt thereof for an autoimmune disease (excluding type I diabetes). 10. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (VII): [In the formula, X ^g represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group. Y ^g represents an oxygen atom or a sulfur atom, and Z ^g represents a 2,4-dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxothiazolidine-5-ylmethyl group. , 2,4-dioxooxazolidin-5-ylmethyl group, 3,5-dioxooxadiazolidine-2-ylmethyl group or N-hydroxyureidomethyl group, wherein R ^g is a hydrogen atom, having 1 to 4 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 A group or an amino group which may have a substituent (b) (the substituent (b) may be a straight-chain or branched alkyl group having 1 to 8 carbon atoms, 7 to 11 carbon atoms) A straight or branched aralkyl group having 6 to 10 carbon atoms, a straight or branched aliphatic acyl group having 1 to 11 carbon atoms, and 8 carbon atoms Represents an araliphatic acyl group having from 12 to 12 or an aromatic acyl group having from 7 to 11 carbon atoms.) Or a linear or branched aralkyl group having from 7 to 11 carbon atoms; ^mg represents an integer of 1 to 5, wherein the substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, and 1 to 4 carbon atoms.
Linear or branched alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group having 1 to 4 carbon atoms, 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) (the substituent (b) 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-chain fat having 1 to 11 carbon atoms An aromatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms), and 6 carbon atoms which may have a substituent (c). Or 10 Wherein the substituent (c) is a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group, amino group optionally having substituent (b)) or carbon number optionally having substituent (c) 7 to 11
And a straight-chain or branched-chain aralkyl group. Or a pharmacologically acceptable salt thereof, for a prophylactic or therapeutic agent for an autoimmune disease (however, excluding type I diabetes). 11. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (VIII): [Wherein, X ^h represents a benzimidazole ring group, which may have 1 to 5 substituents (a) described below, Y ^h represents an oxygen atom or a sulfur atom, and Z ^h Is a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxooxazolidine-5-ylmethyl group, a 3,5-dioxooxadiazolidine- A 2-ylmethyl group or an N-hydroxyureidomethyl group; R ^h is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear chain having 1 to 4 carbon atoms; Or a branched alkoxy group, a halogen atom, a hydroxy group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) is a straight-chain having 1 to 8 carbon atoms). Chain-like or A branched alkyl group, a straight or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a straight chain having 1 to 11 carbon atoms 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) or a straight chain having 7 to 11 carbon atoms. A linear or branched aralkyl group; m ^h represents an integer of 1 to 5; wherein the substituent (a) is a linear or branched aralkyl group having 1 to 4 carbon atoms. Alkyl group, 1 to 4 carbon atoms
Linear or branched alkoxy group, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group having 1 to 4 carbon atoms, 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) (the substituent (b) 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-chain fat having 1 to 11 carbon atoms An aromatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms), and 6 carbon atoms which may have a substituent (c). Or 10 Wherein the substituent (c) is a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Group, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group, amino group optionally having substituent (b)) or carbon number optionally having substituent (c) 7 to 11
And a straight-chain or branched-chain aralkyl group. Or an agent for preventing or treating an autoimmune disease (however, excluding type I diabetes), which is a condensed heterocyclic compound having the formula: 12. The compound of claim 1, wherein the insulin sensitizer is represented by the general formula (IX): [Wherein the dotted line indicates no bond or a bond, V ⁱ is -CH = CH -, - N = CH -, - CH = an N- or S, W ⁱ is _{CH 2, CHOH, CO, C} = NOR ⁱ or CH = CH, X ⁱ is S, O, NR ¹ⁱ , -CH = N- or -N = C
H-, Y ⁱ is CH or N, Z ⁱ is hydrogen, (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ )
1 by a group which is cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl or the same or different (C ₁ -C ₃ ) alkyl, trifluoromethyl, (C ₁ -C ₃ ) alkoxy, fluoro, chloro or bromo;
Z ¹ⁱ is hydrogen or (C ₁ -C ₃ ) alkyl, R ⁱ and R ¹ⁱ are each independently hydrogen or methyl, and ⁿⁱ is 1, 2 or 3. Or a pharmacologically acceptable salt thereof, for a prophylactic or therapeutic agent for an autoimmune disease (however, excluding type I diabetes). 13. The method according to claim 1, wherein the insulin sensitizer is represented by the general formula (X): [In the above general formula (X), Wherein -X ^j -represents -O- or -S-, = Y ^j -represents = N- or = CR ^5j- , and R ^1j , R ^2j , R ^3j , R ^4j and R ^5j are Each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group,
Alkoxy group, alkoxyalkoxy group, aryloxy group, alkanoyloxy group, arylcarbonyloxy group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, alkylaminocarbonyl group, arylaminocarbonyl group, amino group, alkylamino Group, alkanoylamino group, arylcarbonylamino group, ethylenedioxymethyl group,
Formyl group, a cyano group, a nitro group, or a trihalomethyl group, R ^6j represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, n ^j is from 0 to 3 Represents an integer, and the dotted line indicates that the bond of the portion may be a double bond. ) Or a pharmacologically acceptable salt thereof, which is a prophylactic or therapeutic agent for an autoimmune disease (however, excluding type I diabetes). 14. An autoimmune disease caused by an inhibitory effect on lymphocyte infiltration containing the insulin sensitizer according to claim 1 selected from claims 1 to 13 as an active ingredient (provided that: Prophylactic or therapeutic agent for type I diabetes). 15. A systemic autoimmune disease containing the insulin sensitizer according to claim 1 selected from [claim 1] to [claim 13] as an active ingredient (excluding type I diabetes). ) A prophylactic or therapeutic agent. 16. An organ-specific autoimmune disease comprising the insulin sensitizer of claim 1 as an active ingredient, wherein the substance is selected from the claims 1 to 13 (provided that:
Excludes type I diabetes. ) A prophylactic or therapeutic agent. (17) A preventive or therapeutic agent for rheumatoid arthritis, comprising the insulin sensitizer according to (1) selected from [1] to [13] as an active ingredient. (18) A preventive or therapeutic agent for juvenile rheumatoid arthritis, comprising the insulin sensitizer according to (1) selected from [1] to [13] as an active ingredient. (19) A preventive or therapeutic agent for systemic lupus erythematosus comprising the insulin sensitizer according to (1) selected from [1] to [13] as an active ingredient. (20) A preventive or therapeutic agent for Hashimoto's disease, comprising the insulin sensitizer according to (1) selected from [1] to [13] as an active ingredient.