MXPA98009928A - Therapeutic agent for autoinmu diseases - Google Patents
Therapeutic agent for autoinmu diseasesInfo
- Publication number
- MXPA98009928A MXPA98009928A MXPA/A/1998/009928A MX9809928A MXPA98009928A MX PA98009928 A MXPA98009928 A MX PA98009928A MX 9809928 A MX9809928 A MX 9809928A MX PA98009928 A MXPA98009928 A MX PA98009928A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- carbon atoms
- straight
- branched chain
- benzyl
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 201000010099 disease Diseases 0.000 title claims description 25
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- 230000002708 enhancing Effects 0.000 claims abstract description 10
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 372
- 125000001424 substituent group Chemical group 0.000 claims description 170
- 125000000217 alkyl group Chemical group 0.000 claims description 151
- -1 C-1 monoalkylamino Chemical group 0.000 claims description 149
- 150000001875 compounds Chemical class 0.000 claims description 125
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 96
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 125000005843 halogen group Chemical group 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
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- 150000003839 salts Chemical class 0.000 claims description 42
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- 125000002252 acyl group Chemical group 0.000 claims description 39
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 39
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 37
- 230000029578 entry into host Effects 0.000 claims description 36
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- GXPHKUHSUJUWKP-UHFFFAOYSA-N Troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 229960001641 troglitazone Drugs 0.000 claims description 21
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 20
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 19
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- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 18
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 17
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- 125000002947 alkylene group Chemical group 0.000 claims description 16
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 15
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- 125000001931 aliphatic group Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 14
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- 238000000034 method Methods 0.000 claims description 12
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 11
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- 239000000470 constituent Substances 0.000 claims description 10
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 9
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- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
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- MJAMNJNCEOHYIU-UHFFFAOYSA-N 1,2-oxazolidine-3,4-dione Chemical class O=C1CONC1=O MJAMNJNCEOHYIU-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
A preventive or therapeutic agent for autoimmune diseases (excluding type I diabetes) containing an insulin resistance enhancing substance as an active ingredient is disclosed.
Description
THERAPEUTIC AGENT FOR AUTOIMMUNE DISEASES
TECHNICAL FIELD OF THE INVENTION
The present invention relates to ositions for the treatment or prevention of autoimmune diseases (excluding type I diaLets) which contain as their active ingredient a substance that improves insulin resistance »when used for the preparation of pharmaceutical products for the treatment or prevention of autoimmune diseases (excluding type I diabetes) »or a method of treatment or prevention method for autoimmune diseases (excluding type I diabetes) > administering pharmacologically effective amounts thereof to warm-blooded animals.
BACKGROUND OF THE INVENTION
It is believed that autoimmune diseases include immune responses to the body's own onents that are not observed under normal conditions, which result in a pathological condition that causes various tissue disorders and / or functional disorders. Autoimmune diseases are broadly classified into systemic autoimmune diseases and autoimmune diseases specific to organs according to their characteristics. Typical examples of systemic autoimmune diseases include systemic lupus erythematosus and chronic rheumatoid arthritis. On the other hand »typical examples of organ-specific autoimmune diseases include Hashimoto's disease and juvenile-type diabetes. The mechanism of disorder in the cells of the tissues is classified mainly in a mechanism of disorder mediated by antibodies and immune lements (known as the "mechanism of disorder mediated by humoral immunity") and a mechanism of disorder mediated by T lymphocytes and other cell C-mediated cell-mediated cytotoxicity »known as the" mechanism of cell mediated immunity disorder "). In general »the mechanism of humoral immunity mediated disorder is considered important in systemic autoimmune diseases. whereas the mechanism of disorder mediated by cellular immunity is considered important in organ-specific autoimmune diseases. However, due to recent advances in the field of immunology, it has been clearly shown that in the mechanism of cell mediated immunity disorder "in addition to cytotoxic cells consisting mainly of lymphocytes accumulating near target cells followed by direct contact finally with the target cells to damage them, the cytotoxic cells also release humoral factors such as inflammatory cytokines (such as TNF »IL-1 and L) which indirectly deteriorate the target cells as a result of their mediation. On the other hand »also in the disorder mediated by humoral immunity» it has been clearly shown that it exists »for example. an antibody-dependent cell-mediated cytotoxicity mechanism (ADCC) in the case of the involvement of cells such as killer lymphocytes, neutrophils and platelets CByourigakutaikei, Supl. 1 »pp. 91-105 (1995) 3. Thus »in the mechanism of internal organ organ or objective organ disorder in autoimmune diseases» regardless of whether they are systemic autoinmune diseases or organ-specific autoimmune diseases »the invasion by cytotoxic cells consisting mainly of lymphocytes is considered important in terms of causing various tissue and functional disorders. For this reason. ounds that inhibit the invasion of lymphocytes into the target organ or target organ mechanisms mentioned above are useful as agents for the prevention or treatment of autoimmune diseases. Currently, steroids, non-steroidal anti-inflammatory agents, immunosuppressants and others are used in the treatment of autoimmune diseases (Konnichinochiryoushishin »Igaku Shoin» P. 577 (1996) 3. In addition »agents have recently been developed which inhibit the production and action of inflammatory cytokines such as TNFa and IL-1. More »several types of mouse monoclonal antibodies for cell adhesion factors (such as ICAM-1 and VCAM-1) have been developed for the purpose of inhibiting the invasion of cytotoxic lymphocytes in the target internal organs and target organs. The therapeutic effects of these monoclonal antibodies have been reported in several animal models such co or DBA / 2 mice (yagi and other »Diabetes» 44 »744 (1995); Baron and others. J. Clin. Invest. »93, 1700 < 1994) D. However, none of these therapeutic agents or therapeutic methods exhibit adequate effects, and they also have the disadvantage of presenting serious adverse effects. There is therefore a desire for a preventive or therapeutic agent for autoimmune diseases that has excellent clinical efficacy and less adversity. In recent years, it has been known that substances that improve insulin resistance function as agents to prevent or treat diabetes. Here »substances that improve insulin resistance refer to compounds that improve the impaired action of insulin despite the presence of endogenous insulin. These substances that improve insulin resistance include a wide range of compounds. Typical examples include various compounds of tiasoli &nadione »oxazolidinedione compounds» isoxazolidinedione compounds and oxadiazolidinedione compounds. These are described in WO 94/01433 C = Japanese patent application (Kokai) No. Hei 6-B0667) »Japanese patent application (Kokai) No. Hei 4-693S3, WO 92/02520 < = Japanese patent application (Kohyo) No. Hei 6-50053B), WO 91/07107 (= Japanese patent application (Kokai) No. Hei 3-17047S = Japanese patent publication (Kokoku) No. Hei 7-B862) , EU patent No. 5 132 317 (= Japanese patent application (Kokai) No. Hei 3-90071), US patent. No. 4 897 405 < = Japanese patent application (Kokai) No. Hei 2-292272), WO B9 / 0655 (= Japanese patent application (Kokai) No. Hei 1-272574), US patents. Nos. 5 061 717 »5 120 754, 5 223 522 (= Japanese patent application (Kokai) No. Hei 1-272573), US patents. Nos. 5 002 953, 5 194 443, 5 232 925 »5 260 445 (= Japanese patent application (Kokai) No. Hei 1-131169), US patent. No. 4,918,091 (= Japanese patent application (Kokai) No. Sho 64-13076>, US Patent Nos. 4 897 393, 4 94B 900 (= Japanese Patent Application (Kokai) No. Sho 64-56675 = Japanese Patent Publication (Kokoku) Kfo. Hei 5-5B32), U.S. Patent No. 4 B73 255 (= Japanese Patent Application (Kokai) No. Sho 64-38090) »U.S. Patent No. 4,703,052 ( = Japanese Patent Application (Kokai) No. Sho 61-271287 = Japanese Patent Publication (Kokoku) No. Hei 5-86953), US Patent No. 4 687 777 (= Japanese Patent Application (Kokai) No. Sho 61-2675B0 = Japanese Patent Publication (Kokoku) No. Hei 5-31079), U.S. Patent No. 4,725,610 (= Japanese Patent Application (Kokai) No. Sho 61-85372 = Japanese Patent Publication (Kokoku) No. Hei 5-66956), U.S. Patent No. 4 572 912 (= Japanese Patent Application (Kokai) No. Sho 60-51189 = Japanese Patent Publication (Kokoku) No. Hei 2-31079), U.S. Pat. No. 4 461 902 (= patent application) and Japanese (Kokai) No. Sho 58-11B577 = Japanese Patent Publication (Kokoku) No. Hei 2-57546), US Patents. Nos. 4 287 200, 4 340 605, 4 438 141 »4 444 779 (= Japanese patent application (Kokai) No. Sho 55-22636 = Japanese patent publication (Kokoku) No. Sho 62-42903), EP 0 708 098A (= Japanese patent application (Kokai) No. Hei 9-48779), EP 0 676 39BA (= Japanese patent application {Kokai) No. Hei 7-330728), WO 95 / 1B125, EP O 745 600A, EP O 332 332A < = Japanese patent application (Kokai) No. Hei 1-272574) and EP 0 604 9B3A (= Japanese patent application (Kokai) No. Hei 6-247945), etc. In addition »the equal sign" = "indicates the corresponding patent or patents. For example, 5-C4- (6-hydroxy-2, 5, 7,8-tetramethyl-chroman-2-ylmethoxy) benzyl thiazolidino-2 »4-dione (known as" troglitazone ") is a thiazolidine derivative having an activity that improves the effects of insulin and that is known as an agent for the treatment and / or prevention of diabetes CFujiwara et al., Diabetes »37, 1459 (1988); Hof ann C.A. and others, Diabetes Care, 15 »1075 (1992) 3. Moreover, since said compound has antioxidant effects, it has also been reported to be useful as a therapeutic drug for insulin-dependent diabetes mellitus (type I diabetes).; IDDM) CTounyoubyou, Vol. 37, No. 2 »pp 127-129 (1994) 3. However, there are no reports that troglitazone inhibits tissue invasion by lymphocytes and that it is useful as a preventive and / or therapeutic agent for autoimmune diseases with the exception of diabetes-dependent diabetes mellitus. insulin (type I diabetes). Currently »insulin-dependent diabetes mellitus (type I diabetes) is considered a type of autoimmune disease. Although there is only one report indicating that troglitazone is useful for the treatment of insulin-dependent diabetes mellitus, it points out that the discovery that troglitazone is useful for the treatment or prevention of insulin-dependent diabetes mellitus is based on the antioxidant effects possessed by said compound. Thus, these known facts do not teach or suggest that troglitazone inhibits the invasion of tissues by lymphocytes "or that it is useful as a preventive or therapeutic agent for diseases15 autoimmune (excluding type I diabetes). Moreover, although it is known that other substances that improve insulin resistance are useful for the treatment and prevention of diabetes, it is known that these compounds inhibit the invasion of tissues by lymphocytes. DESCRIPTION OF THE INVENTION
As a result of more serious research about the pharmacological activity of substances that improve
In the case of insulin resistance, the present inventors discovered that said substances inhibit the invasion of lymphocytes in pancreatic S cells. From this it was also discovered that said substances are useful as preventive or therapeutic agents (preferably therapeutic agents) for autoimmune diseases (excluding type I diabetes) and are achieved in the present invention. Namely the present invention is useful as an agent preventive or therapeutic of autoimmune diseases (excluding type I diabetes) including »for example» diseases classified as systemic autoimmune diseases such as systemic lupus erythematosus, chronic rheumatoid arthritis, juvenile rheumatoid arthritis »Sjbgren's syndrome» systemic scleriasis »connective tissue disease and mixed dermatomyositis, and diseases classified as organ-specific autoimmune diseases such as Hashimoto's disease, primary ixedema, thyrotoxia, pernicious anemia »ulcerative colitis» autoimmune atrophic gastritis »Addison's idiopathic disease» male infertility »Goodp's syndrome asture »acute progressive globular nephritis» myasthenia gravis, multiple iositis, pemphigus vulgaris, pemphigoid bolus, sympathetic ophthalmia, multiple sclerosis, autoimmune olymetic anemia »idiopathic thrombocytopenic purpura» post iocardial infarction syndrome »rheumatic fever, lupoid hepatitis, primary biliary cirrhosis »Behcet syndrome. and Crest syndrome. The present invention provides compositions for the treatment or prevention of autoimmune diseases (excluding type I diabetes) which contain as their active ingredient a substance that improves insulin resistance, its use for the preparation of armaceutical products for the treatment or prevention of diseases autoimmune 5 (excluding type I diabetes), or a method of treatment or prevention for autoimmune diseases (excluding type I diabetes) »administering armagologically and ectively amounts of these to warm-blooded animals. The present invention relates to an agent for the prevention or treatment of autoimmune diseases (excluding type I diabetes). Substances of the active ingredient that improve insulin resistance include thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinodone compounds and
oxadiazoli &oodone, and preferably thiazolidinedione compounds. Moreover, the pharmacologically acceptable salts of the thiazolidinedione compounds "etc. they are included in the thiazolidinedione compounds mentioned above and so on. Said insulin resistance enhancing substances include, for example, the following compounds. (I) In Japanese Patent Application (Kokai) No. Sho 60-51189 Japanese Patent Publication (Kokoku) No. Hei 2-310793, the US patent. No. 4 572 912 and the publication of
European Patent No. 139421A, it is described: (1) a thiazolidine derivative of the formula (I): 10
Cen where RA * and R53 »may be the same or different and each represents a hydrogen atom or an alkyl group of Cx-
R3"represents a hydrogen atom" an aliphatic acyl group of C -Cβ, a cycloalkylcarbonyl group of C-Ca a benzoyl or naphthoyl group which may have a substituent (the substituent is an alkyl group of C ^ -C ^ __, alkoxy of C_ -C? or hydroxyl, a halogen atom or an amino group, onoalkylamino of C ^ -C ^ 'dialkylamino of CA-C4 or a nitro group), a heterocyclic acyl group of 4 to 7 members containing from 1 to 3 heterogeneous atoms selected from the group of heterogeneous atoms consisting of nitrogen, oxygen and sulfur atoms, a phenylacetyl group, a phenylpropionyl group, a phenylacetyl or phenylpropionyl group substituted with at least one halogen atom, a cinnamoyl group, a group alkoxycarbonyl of Ca-C ^ or a benzyloxycarbonyl group; R- * a and RSßl may be the same or different and each represents a hydrogen atom; an alkyl group of C ^ -C ^ or an alkoxy group of C ^ -Cs »or - * and Ra * taken together represent a alkylene dioxy group of C -C ", Y" and Zß can be the same or different and each represents an oxygen atom or an imino group, and * is an integer from 1 to 33 or a pharmacologically acceptable salt thereof. compounds of the order í I), the defining details of H1 *, Rs », R3-, R - **, Rs», ¥ * »Z- and n«, the type of pharmacologically acceptable salts »the procedure for the preparation of the compounds of the formula (I) »the examples of the compounds» the examples »etc. are described in the publications mentioned above .. Of said compounds of the formula (I), the preferable compounds are shown below: (2) those wherein R3- * is an alkyl group of
(3) those in which R3 ** is a hydrogen atom or an alkyl group of Cx-C3 »(4) those in which R3β is a hydrogen atom» an aliphatic acyl group of Ca-C4, a benzoyl group or unsubstituted naphthoyl or an alkoxycarbonyl group of C. ^ C ^ "(5) those in which R- * b is an alkyl group of
(6) those in which Rs * is a hydrogen atom or an alkyl group of (7) those in which R3-5 * is an alkyl group of a hydrogen atom or an alkyl group of
A hydrogen atom, an aliphatic acyl group of C ^ -C ^ "an unsubstituted benzoyl or naphthoyl group or an alkoxycarbonyl group of C ^ -C ^ * R- * 4" is an alkyl group of C ^ - C ^, and RSβ is a hydrogen atom or an alkyl group of
(8) those in which R3ß is a hydrogen atom, or an acetyl, benzoyl or ethoxycarbonyl group, (9) those in which R3 - "- is an alkyl group of C ^ -C ^, Rsa" is an atom of hydrogen or an alkyl group of
3ß is a hydrogen atom »an acetyl group, benzoyl or ethoxycarbonyl, R-» «is ur? alkyl group of C ^ -C ^ * and jjsa is a hydrogen atom or an alkyl group of Cx-C3, (10) those in which R-LJa is a methyl group »(11) those in which Sß is a hydrogen atom or a methyl group. (12) those in which 3ß is a hydrogen atom ", or an acetyl or ethoxycarbonyl group" (13) those in which LR ^ ß is a methyl or t-butyl group "(14) those in which Rs" is a hydrogen atom or a methyl group "(15) those in which R-1- * is a methyl group, Raß is a hydrogen atom or a methyl group, R3» is a hydrogen atom or an acetyl group or ethoxycarbonyl, * -β is a methyl or t-butyl group, and RSβ is a hydrogen atom or a methyl group »i lß) esee selected from: i) 5-C4- (6-hydroxy-2.5.7, S-tetrame-ilchroman-2-ylmethoxy) benzyl L. iazolidino-2,4-dione (roglitazone) »ii) 5-C4-α6-hydroxy-2-methyl-7-t-butyl-roman-2-ylmethoxy) benzyl 3-tlazoli iño-2,4-dione, iii) 5-C4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmeto i) benzyl L-thiazolidino-2,4-dione, iv) 5-C4 - (6-hydroxy-isobutyl-5, 7, 8-trimethylchroman-2-ylmethoxy) benzyl-3-aiazolidino-2 »4-dione, v) 5-C4- (6-acetoxy-2,5» 7,8 -tetramethylchroman-2-ylmethoxy) benzyl 3-thiazolidino-2,4-dione, and vi) 5-C4- (6-ethoxycarbonyloxy-, 5, 7, 8-tetramethyl-chroman-2-ylmethyl) benzyl thiazolidino-2,4 -Diona. (II) In the Japanese patent application (Kokai) No. Sho 61-267580 Japanese Patent Publication (Kokoku) No. Hei 5-66956) and the US patent. No. 4 687 777 describes: (1) a thiazolidine derivative of the formula (II):
or a pharmacologically salt thereof. Details of the type of pharmacologically acceptable salts, the preparation procedure, examples of compounds, examples, etc. of the compound of the formula (II) are described in the publications mentioned above. Of said compounds of the formula (II), the preferable compounds are shown below: (2) a compound selected from: i) 5-. { 4-C2- (3-ethyl-2-pyridyl) ethoxy benzyl} -2,4- iazolidinedione »ii) 5-. { 4-C2- (4-ethyl-2-pyridyl) ethoxy-3-benzyl} -2,4-iazolidinedione, iii) 5- [4-C2- (5-ethyl-2-pyridyl) ethoxy-3-benzyl} -2,4-thiazolidinedione (hereinafter referred to as "pioglitazone"), and iv) 5-. { 4-C2- (6-ethyl-2-pyridyl) ethoxy-3-benzyl} -2,4-thiazolidinedione. (III) In the Japanese patent application (Kokai) No. Sho 61-271287 C Japanese patent publication C Kokoku) No. Hei 5-86953D and the US patent. No. 4,703,052 is described: (1) a compound of the formula (III):
Een where the broken line represents a single bond or a non-bond, n ° ee O, 1 or 2, Xa is an O, S. S = 0 or S (= 0) (= 0), R ° is an H, CH3 or C ^ K ^ »R-1-0 is independently H, cycloalkyl of Cjg-Cy, methylcycloalkyl of CG-Ce» pyridyl »thienyl» furyl »naphthyl, p-biphenylyl» tetrahydrofuranyl »tetrahydrothienyl, tetrahydropyranyl, C ^ H ^ W30 Cen where WSa is H, OH »F» Cl, Br, C ^ -C ^ alkyl, C ^ -C ^ alkoxy or Cx-C ^ thioalkyl or alq-W C! where alk is a C? -C?, ethylidene or isopropylidene alkylene, W3- "is H" OH "C? -Cycloalkyl, thioalkyl of C ^ -C ^ furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, cycloalkyl. of C3-C ^ o CeH ^ S3 <; = 3, 530 is H or CH3 »R3c = is H, C ^ -C ^ alkyl, C ^ H ^ W350 or benzyl, R- * O is H, in case -0 and R530 are taken together, they form an alkylene of ^ -C ,. , R ay - * "3 eon each H, in case that R3 ° and R- * a are taken together, they form an alkylene of C ^ -Cß,? O and j; s are JI, in case R520 and R3 < = are taken together < RTI ID = 0.0 > they < / RTI > form a C3-C ^ alkylene and R-* a are each H3, or a pharmaceutically acceptable salt thereof In the compounds of the formula (III), the details of the definition of R * -0 »R52 * 5, R3e, W3-0.s < 3 and alq, the type of pharmacologically acceptable salts, the process for the preparation of the compounds of the formula (III), examples , etc. are described in the aforementioned publications.From said compounds of the formula (III), the preferable compounds are shown below: (2) those described in (1), in which R "is H, the dotted line it is a non-bond and it is 0 or 1 »(3) those described in (2), where those Rsa» R is and R- * c are each H »ic is H» ciciohexyl »C ^ H ^ 530 ( where Wacs is H »F, Cl, Br, CH3 or CH3?) or alq- 3-0 Een where alq is Alkylene of C ^ -C ^ ethylidene or isopropylidene, and Wxa is H, OH, C ^ -C ^ alkoxy, cyclohexyl, or C ^ H ^ 4 ^ a! 3, (4) those described in (3), in which Xo ee O, R-1- * 3 is cyclohexyl »cyclo and ylmethyl, benzyl, fluorobenzyl» C 1 -C 4 alkyl, hydroxymethyl, methoxymethyl or ethoxyethyl (5) those described in (4), in which io is benzyl. (6) those described in (5), which are: 5-C (2-benzyl-2, 3-ihydrobenzofuran-5-yl) methyl thiazolidino-, 4-dione, 5-E (2-benzyl-3, 4-dihydro-2H-benzopyran-6-yl) I-thiazolidino-2,4-dione (hereinafter referred to as "englitazone") or a sodium salt thereof, (7) those described in (2), in which R3a and R3 ° taken together form (CH ^) ^ »R-1-0 and ** 0 are each H and X« = is O. (8) (a) those described in (2), in which ( a) O and SC taken together form (CHSS) B, R3! and R- * ß are each H and Xo is O, or (b) R3, a and R- »a taken together form (CH ^), ^ R3-0 and 530 are each H and Xo is O» y ( 9) those described in (3), in which nß is 0 »(IV) In the Japanese patent application (Kokai) No. Hei 1-131169 and in the US patents Nos. 5,002,953, 5,194,443, 5,232 925 or 5 260 445 disclose: (1) a compound of the formula (IV):
Een where A < a represents an optionally substituted or unsubstituted aromatic heterocyclic group, α "a represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (wherein the aryl portion may be substituted or unsubstituted) or an aryl group optionally substituted or unsubstituted »R53 ** and R3, a each represent a hydrogen atom or Ra, a and R3 < taken together form a link »A58 ** represents a benzene ring that has not more than 5 sustituyent.es in total; and n? is an integer from 2 to 63 or a pharmaceutically acceptable salt thereof. In the compound of the formula (IV), the details of the definitions of A3 - **, RXdl, Rss «a» R3t »A53 * and n?» The type of pharmaceutically acceptable salts »the process for the preparation of the compound of formula (IV) »examples thereof, preferable compounds, etc., are described in the publications mentioned above. Of said compounds of the formula (IV), the preferable compounds are shown below: (2) those deesritoe in (1), in which A3- "a represents an optionally substituted or unsubstituted aromatic heterocyclic group of a single ring or from a condensed ring 4 or fewer heterogeneous atoms selected from nitrogen »oxygen and sulfur» (3) those described in (1) or (2), in which
A3- * represents a portion of formula (a), (b) or (c):
(a) (b) (c) Cen where R- *? and Rs < a each independently represents a hydrogen atom »an alkyl group or an aryl group optionally substituted or unsubstituted, or in the event that R" *** and Radl are each attached to a carbon atom, can together form a ring of benzene with the carbon atoms to which they are attached and additionally each carbon atom bound to R- *? and Ra "* can be substituted or unsubstituted and X" * in the portion of the formula (a) represents oxygen or sulfur »(4) those described in (3). in which R - *" * and E < 3 each independently represents hydrogen, alkyl or an optionally substituted phenyl group, (5) those described in (3) 'in which "*** and Rsa taken together represent a portion of the formula (d):
(wherein Re? and R ', a each independently represent hydrogen »halogen, optionally substituted alkyl or alkoxy)' '(6) those described in (5), in which Rtídl and R-7-a repreeentan amboe hydrogen, (7) those described in any of (1) to (6), in which A53 ** represents a portion of the formula (e):
(wherein Rset and 3"each independently represent hydrogen, halogen, optionally substituted alkyl or alkoxy)" (8) those described in (7), in which βd and s> a represent each hydrogen, (9) those described in (1) of the formula (f)
Cen where A * - **, R3-, Raca, R3? Ayn «* have the same meanings as those defined for formula (IV) of (1), and f3« a and R? D have the same meanings as those defined for the formula (e) of (7) 3 or a pharmacologically acceptable salt thereof »
(10) those described in any of (1) to (9), in which n < * represents an integer of 2 or 3 »(11) those described in any of (D a (10), in which R3- * 3- represents a methyl group» (12) those described in (1) selected from i) 5-. { 4-C2- (N-methyl- - (-benzthiazolyl) min) ethoxy-3-benzyl) lazolidin-2 »4-dione» ii) 5-- £ 4-C2- (N-ethyl-N- (2-pyrimidinyl lamino> ethoxy-3-benzyl.] thiazolidino-2'-ione »iii) 5-. {4-C2- (N-methyl-N- (2-C4,5-dimethylthiazoyl) amino) ethoxy-3-benzyl .thiazolidino-2'-4-ione, iv) 5-. {4- (2- (N-me-il-N- (2-thiazolyl) amino) -ethoxy-benzyl} - iazolidino-2 »4 -dione »v) 5-. {4-C2- (N-met.il-N- (2-E4-f niltiazolyl) amino) -ethoxy-3-benzyl} -thiazolidino-2-dion, vi) 5-. { 4-C2- (N-methyl-N- (2-C4-phenyl-5-methylthiazolyl) amino) ethoxy-3-benzyl} thiazolidino-2,4-dione »vii) 5-. { 4-E2- (N-p? Ethyl-N- (2-E4-methyl-5-phenylthiazolyl-3-methyl) ethoxy-benzyl} -thiazolidino-2'-4-dione »vii?) 5-. { 4-C2- (N-ethyl-N- (2-C5-phenyloxazolyl) to ino) -ethoxy-3-benzyl} thiazolidino-2 »4-dione» ix) 5-. { 4-C2- (N-methyl-N- (2-C4,5-dimethyloxazolyl) -a ino) ethoxy-3-benzyl} thiazolidino-2,4-dione, x) 5-. { 4-E2- (2-pyrimidinylamino) ethoxy3benzyl >; -thiazolidino-2, - ione »xi) 5-. { 4-E2- (N-acetyl-N- < 2-pyrimidinyl) amino) ethoxy-benzyl} thiazolidino- »-dione» xii) 5 ~. { 4-C2- (N- (2-benzothiazolyl) -N-benzylamino) -ethoxy benzyl} thiazolidino-2,4-dione »xiii) 5-. { 4-C3- (N-methyl-N- (2-benzoxa? Olyl) amino) -propoxy-3-benzyl} thiazolidino-2,4-dione and xiv) 5- 4-C2- (N-methyl-N- (2-pyridyl) amin) ethoxy 3-benzyl} thiazolydin-2 »4-dione (hereinafter referred to as" BRL-49653")»
(13) those described in (1) which is 5-. { 4-C2- (N-methyl-N- (2-pyridyl) amino) ethoxy-3-benzyl} thiazolidino-2,4-dione (BRL-49653). In (2) to (11) mentioned above »the details of the definition of R - *« *. 3 *, Rß < a »R" 7 *, 6"* and RT" are described in the publications mentioned above. (V) Japanese Patent Application (Kokai) No. Hei 9-48779 and European Patent Publication No. 70B09BA are described (1) an oxime derivative of the formula (V):
(V)
Cen where: R * represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, 53 * represents a straight or branched chain alkylene group having from 2 to 6 carbon atoms, R3ß represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a straight chain alkylthio group or branched having from 1 to 4 carbon atoms, a halogen atom »a nitro group» an amino group, a straight or branched chain monoalkylamino group having from 1 to 4 carbon atoms, a straight or branched chain dialkylamino group wherein the alkyls have from 1 to 4 carbon atoms "an aryl group having from 6 to 10 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms" X * represents an aryl group having 6 to 12 carbon atoms; to 10 carbon atoms and that can of having from 1 to 3 substituents a »or an aromatic heterocyclic group which may have from 1 to 3 ac substituents. The substituent ot represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms »(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms» (iii) a hydroxyl group, (iv) a straight or branched chain acyloxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a group straight or branched chain alkylenedioxy having from 1 to 4 carbon atoms, (vii) an aralkyloxy group having from 7 to 12 carbon atoms "(viii) a straight chain alkylthio group
0 branched having 1 to 4 carbon atoms, (i) a straight or branched chain alkylsulfonyl group having
1 to 4 carbon atoms »(x) a halogen atom» (xi) a nitro group »(xii) an amino group, (xiii) a straight or branched chain monoalkylamino group having from 1 to 4 carbon atoms, (xiv) a straight or branched chain dialkylamino group in which the alkyls may be the same or different and each having from 1 to 4 carbon atoms, () an aralkyl group having from 7 to 12 carbon atoms. vi > an aryl group having from 6 to 10 carbon atoms "which can have a substituent β" (xvii) an aryloxy group having from 6 to 10 carbon atoms "which can have a substituent β" (xviii) a group arylthio having from 6 to 10 carbon atoms, which can have a substituent ß "(xix) an arylsulfonyl group having from 6 to 10 carbon atoms" which can have a substituent ß, (x) an arylsulfonyl group having 6 to 10 carbon atoms, which may have a substituent B, (the nitrogen atom of the amino portion may be substituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms ), i xi) a heteroaromatic group, (xxii) an aromatic heterocyclic group "(xxiii) an aromatic heterocyclicthio group, (xxiv) an aromatic heterocyclylsulonyl group or (xxv) an aromatic heterocyclylsulinylamino group (the nitrogen atom of the amino can be substituted with a gr a straight or branched chain alkyl having from 1 to 6 carbon atoms). The substituent β represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms »a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms; Yß represents an oxygen atom, a sulfur atom or a group of the > NR- * "(n where - * ß repreeenta a hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms or a straight or branched chain acyl group having 1 to B atoms carbon) "and Z * represents a 2,4-dioxothiazolidin-5-ylidenemethyl group" a 2,4-dioxothiazolidin-5-methyl group. a 2,4-dioxooxazolidin-5-ylmethyl group or a 3,5-dioxo-oxazolidin-5-yl ethyl group3 or a pharmacologically acceptable salt thereof. In the compounds of the formula (V) »the details of the definition of X, RSß» R3ß, R- * ß »a» ß »Xß, Y» and Zß, the pharmacologically acceptable salt type »the procedure for the preparation of the compound of the formula (V), the examples of the compounds, the examples, etc., are described in the publications mentioned above. Of said compound of the formula (V), preferred compounds are shown below: (2) those described in (1), in which R3- * represents a hydrogen atom or uri straight or branched chain alkyl group having from 1 to 4 carbon atoms "(3) those described in (1), in which R3 -" * represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 3 carbon atoms (4) those described in (1), in which R3 - ** represents a hydrogen atom »a methyl group or an ethyl group.
(5) those described in (1), wherein Rlß represents a methyl or ethyl group. (6) those described in (1), in which Raß represents a straight or branched chain alkylene group having from 2 to 5 carbon atoms, (7) those described in (1), in which Ra * represents a straight or branched chain alkylene group having 2 or 3 carbon atoms »(8) those deesritos in íl), in which a * represents an ethylene group» tri ethylene or methylmethylene, (9) those described in (1) , wherein R33 * "represents an ethylene group" (10) that is described in (1), wherein R3 * represents a hydrogen atom »a straight or branched chain alkyl group having 1 to 4 carbon atoms »An alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms or a halogen atom, (11) those described in (1), in which R3β represents a hydrogen atom, (12) those described in (1), in which X * 'represents an aryl group having from 6 to 10 atoms of carbon, which may have 1 to 3 substituents cx or an aromatic heterocyclic group of 5 to 10 members (comprising doe rings) having 1 to 3 nitrogen atoms »oxygen and / or sulfur» and which may have 1 to 3 selected substituents a. The substituent x represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms »(iii) a hydroxyl group. (iv) a straight or branched chain acyloxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a chain alkylenedioxy group straight or branched having 1 to 4 carbon atoms »(vii) an aralkyloxy group having 7 to 12 carbon atoms, (viii) a straight chain alkylthio group
0 branched having 1 to 4 carbon atoms »(i) a straight or branched chain alkylsulfonyl group having
1 to 4 carbon atoms, (?) A halogen atom »(xi) an aralkyl group having from 7 to 12 carbon atoms» (xii) a phenyl group which may have a substituent ß »(xiii) a phenoxy group may have a substituent β "(xiv) a phenylthio group which may have a substituent β, (xv) a phenylsulfonyl group which may have a substituent β, (xvi) a phenylsulfonylamine group which may have a β-substituent (the nitrogen atom of the amino portion can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) "(xvii) a furyl» thienyl »oxazolyl» isoxazolyl, thiazolyl »pyridyl, pyridyloxy» pyridylidene group pyridylsul onyl »(xviii) an imidazolyl group (the nitrogen atom can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and / or (xix) a pyridylsulphonyl group ino (the nitrogen of the amino portion can be substituted with a group straight or branched chain alkyl having from 1 to 6 carbon atoms). The substituent ß represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms »a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms "(13) those described in (1), in which X * represents an aryl group which has 6 to 10 carbon atoms which may have 1 to 3 substituents ot or an aromatic heterocyclic group of 5 to 10 members (comprising one or two rings) having 1 to 3 nitrogen atoms »oxygen and sulfur, and which may have 1 to 3 substituents. The substituents a represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms »(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms» (iii) a hydroxyl group »(iv) a straight or branched chain alkanoyloxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms "(vi) a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms" (vii) an aralkoxy group which has from 7 to 12 carbon atoms »(viii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms»
(ix> a straight or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms, (x) fluorine, chlorine or bromine atoms, (xi) an aralkyl group having from 7 to 12 carbon atoms "( xii) a phenyl group which may have a substituent ß, (xiii) a phenoxy group which may have a substituent ß, (xiv) a phenylthio group which may have a substituent ß, (xv) a phenylsulfonyl group which may have a substituent ß , (xvi) a phenylsulfonylamino group which may have a substituent ß (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (vii > furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio or pyridylsulfonyl group (viii) an imidazolyl group (the nitrogen atom can be substituted with a straight or branched chain alkyl group having 6 carbon atoms) ) and / or (xix) a pyridyl group ulf nilamino (the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms). The substituent ß represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms »a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms. (14) those described in (1) "in which X" represents a phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, indolyl, quinolyl or isoquinolyl group and these groups optionally have 1 to 3 substituents cx. Substituent o, represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms "(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms" (iii) a hydroxyl group, (iv) a straight or branched chain alsanoyloxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a methylenedioxy group, (vii) an aralkylkoxy group having from 7 to 12 carbon atoms "(viii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (i> a straight-chain alkylsulfonyl group or branched having 1 to 4 carbon atoms, (x) a fluorine »chlorine or bromine atom (xi) an aralkyl group having 7 to 12 carbon atoms» (xii) a phenyl group (the phenyl group) can be substituted with methyl »trifluoromethyl, methoxy, fluoro and methylenedioxy)» (xiii) a phenoxy group (the phenyl group it can be substituted with methyl »trifluoromethyl» methoxy »fluoro or methylenedioxy)» (xiv) a phenylthio group (the phenyl group can be substituted with methyl, trifluoromethyl »methoxy. fluoro or methylenedioxy), (v) a phenylsulfonyl group (the phenyl group may be substituted with methyl, tri-loromethyl, methoxy, fluoro or methylenedioxy) "(xvi) a phenylsulfonylamino group (the phenyl group may be substituted with methyl» tri-loromethyl, methoxy »fluoro or methylenedioxy, and the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xvii) a furyl» thienyl »oxazolyl» isoxazolyl group »Thiazolyl, pyridyl» pyridyloxy, pyridylthio or pyridylsulfonyl, (xviii) an imidazolyl group (the nitrogen atom can be substituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms) and / or (xix) a pyridylsulfonylamino group (the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (15) those described in (1) »wherein * represents a g phenyl "naphthyl, imidazolyl, oxazolyl, pyridyl" indolyl "quinolinyl or isoquinolyl" and these groups optionally have 1 to 3 substituents a. The substituent c, represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms. (ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms »(iii) a hydroxyl group, (iv) a straight or branched chain alkanoyloxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a methylenedioxy group » benzyloxy or naphthylmethoxy »(vii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms» (viii) a straight or branched chain alkylenyl group having from 1 to 4 carbon atoms, (i) a fluorine, chlorine or bromine atom, (x) a benzyl group, (xi) a phenyl group (the phenyl group may be substituted with methyl »tri-loromethyl, methoxy, fluoro or methylenedioxy), (xii) a phenoxy group (the phenyl group can be substituted with methyl, tri-loromethyl, methoxy, fluoro or methylenedioxy) "(xiii) a phenylthio phenylsulfonyl phenylsulphonylane-N-methylphenylsulfonylamino, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyl-oxyl, pyridylthio group. pyridylsul onyl »pyridylsul-onylamino, or N-methylpyridylsulfonyl ino and / or (xiv) an imidazolyl group (the nitrogen atom can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) "(16) those described in (1), in wherein Xß represents a phenyl, naphthyl, pyridyl, indolyl, quinolyl or ioquinolyl group, and eetos group optionally has from 1 to 3 substituents a. The substituent represents (i) a straight or branched chain alkyl group having from 1 to 3 carbon atoms, (ii) a trifluoromethyl »difluoromethyl» fluoromethyl »hydroxyl group for iloxy or acetoxy group (iii) a chain alkoxy group straight or branched having 1 to 3 carbon atoms, (iv) a methylenedioxy, benzyloxy »methylthio» ethylthio »methylsul onyl or ethylene sulfyl group (v) a fluorine, chlorine or bromine atom and (vi) a benzyl group »Phenyl» 4-methylphenyl. 4- tri-loromethyl-enyl, 4-methoxyphenyl, 4-fluoro-enyl, 3,4-methylenedium-ifnyl »phenoxy» phenylthio »phenylsulfonyl» phenylisulfonylamino »N-methylphenylsulfonylamino, furyl, thienyl» oxazolyl, thiazolyl, imidazolyl »N-methylimidazolyl» pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and / or N-ethylpyridylsulfonylamino. (17) those described in (1), in which X * represents a phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl group, and these groups have 1 to 3 cx constituents. The substituent c <; represents a methyl, ethyl, isopropyl, tri-lornomethyl, hydroxyl, acetoxy, methoxy, ethoxy, isopropoxy, methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulphenyl, chloro, benzyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, phenylsulfonylamino group. -methylphenylene onylamino, pyridyl, pyridyloxy »pyridylthio» pyridylsulfonyl »pyridylsulfonylamino and / or N-mepyridylsulfonylamino. (18) those described in (1), in which X "represents a phenyl group which may have from 1 to 3 substituents ex The substituent a represents a methyl group" hydroxy "acetoxy» chloro, benzyl »phenyl» phenoxy »phenylthio Phenylsulfonyl, phenylsulphonyl, N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio and / or pyridylsulfonyl (19) those described in (1) »in which X * represents a pyridyl group which may have from 1 to 3 substituents a. substituent cx represents a methoxy group »ethoxy, isopropoxy» benzyloxy »methylthio» ethylthio »methylsulfonyl» ethylsul onyl »benzyl, phenyl» phenoxy, phenylthio »phenylsulfonyl» phenylsulfonylamino and / or N-methyl enylsulfilamino (20) those dessritoe in (1) ), in which Ym represents an oxygen or sulfur atom or a group of the formula " N-R- * a (wherein R - * «* represents a hydrogen atom, a straight or branched chain alkyl group which has 1 to 3 carbon atoms or a group straight or branched chain alkanoyl having from 2 to 5 carbon atoms), (21) those described in (1), in which Y "represents an oxygen atom" (22) the compound described in (1) "in which Z * represents a 2,4-dioxothiazolidin-5-ylmethyl group, a 2,4-ioxo-oxazolidin-5-ylmethyl group or a 3,5-dioxo-oxazolidin-2-ylmethyl group (23) those described in (1) »In which Z" represents a 2,4-dioxothiazolidin-5-ylmethyl group or a 2,4-dioxo-oxazolidin-5-ylmethyl group, (24) those described in (1), in which Z * represents a group 2,4 -dioxothiazolidin-5-ylmethyl. (25) those described in (1) 'in which R3- * represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms »Raß represents an alkylene group having 2 to 5 carbon atoms; R ß represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms »an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms or a halogen atom; X ** represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents x 'or a 5- to 10-membered aromatic heterocyclic group (comprising one or two rings) having from 1 to 3 nitrogen atoms »oxygen and / or sulfur» and which may have 1 to 3 cx. The substituent ex represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms »(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms» (iii) a hydroxyl group »(iv) a straight or branched chain acyloxy group having from 1 to. 4 carbon atoms »Cv) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms» (vi) a straight or branched chain alkylene group i having from 1 to 4 carbon atoms, (vii) an aralkyloxy group having from 7 to 12 carbon atoms, (viii) a straight chain alkylthio group
0 branched having 1 to 4 carbon atoms, (ix) a straight or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms, (x) a halogen atom »(xi) an aralkyl group having 7 to 12 carbon atoms »(xii) a phenyl group which may have a substituent β» (xiii) a phenoxy group which may have a substituent β »(xiv) a phenylthio group which may have a substituent β» (xv) a phenylsulfonyl group which may have a substituent ß "(xvi) a phenylsulinylamino group which may have a substituent ß (the nitrogen atom of the amino portion may be substituted with a straight or branched chain alkyl group having from 1 to 6 atoms carbon), xvii) a furyl »thienyl» oxazolyl, isoxazolyl »thiazolyl» pyridyl »pyridyloxy» pyridylthio or pyridylsulfoyl group (xviii) an imidazolyl group (the nitrogen atom of the amino portion can be substituted with an alkyl group of Straight or branched chain that has 1 to 6 carbon atoms)? or (xix) a pyridylsulfonylamino group (the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having
1 to 6 carbon atoms). The ester ß represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms; Y ** represents an oxygen or sulfur atom or a group of the formula > N- "** (wherein R - ** represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 3 carbon atoms or a straight or branched chain alkanoyl group having from 2 to 5 carbon atoms), and Z ~ represents a 2,4-dioxothiazolidin-5-ylmethyl group, a 2,4-dioxo-oxazolidin-5-ylmethyl group or a 3'-dioxo-oxazolidin-5-ylmethyl group »(26) described in (1) »in which
R3- * represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms »RSβ represents a straight or branched chain alkylene group having from 2 to 5 carbon atoms» S3ß represents a hydrogen atom »ß represents an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents or an aromatic heterocyclic group of 5 to 10 members (comprising one or doe rings) having from 1 to 3 nitrogen atoms »oxygen atoms and / or sulfur atoms» and which may have 1 to 3 substituents cx. The substituent x represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms »
(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms "(iii) a hydroxyl group" (iv) a straight or branched chain alkanoyloxy group having from 1 to 4 carbon atoms, ( v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms, (vii) an aralkyloxy group having from 7 to 12 carbon atoms, (viii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms "(ix) a straight or branched chain alkylene sulfonyl group having from 1 to 4 carbon atoms, ( x> a fluorine »chlorine or bromine atom (xi) an aralkyl group having from 7 to 12 carbon atoms» (xii) a phenyl group which may have a substituent ß »(xiii) a phenoxy group which may have a substituent ß »(xiv) a phenylthio group which may have a substituent ß, (xv> an enylsulfonyl group which can be and having a substituent ß, (xvi) a phenylsulfonylamino group which may have a substituent ß (the nitrogen atom of the amino portion may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xvii) a furyl, thienyl »oxazolyl» isoxazolyl, thiazolyl, pyridyl, pyridyloxy »pyridylthio or pyridylenesulfonyl group (xviii) an imidazolyl group (the nitrogen atom of the amino portion can be substituted with a straight chain alkyl group or branched having 1 to 6 carbon atoms) and / or (xix) a pyridyl-sulphonylamino group (the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) ). The β-ester represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms "a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms »a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms; Y "* represents an oxygen atom" and Zß represents a group, 4-dioxothiazolidin-5-ylmethyl or a 2,4-ioxothiazolidin-5-yl ethyl group. (27) those described in (1), in which R3 - "* represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 3 carbon atoms; R53 ** represents a chain alkylene group straight or branched having 2 to 3 carbon atoms, a »represents a hydrogen atom, X» represents a phenyl group »naphthyl, imidazolyl» oxazolyl, pyridyl »indolyl, quinolyl or isoquinolyl» and these groups optionally have from 1 to 3 substituents c.The substituent a represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms "(ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms, (iii) a hydroxyl group "(iv) a straight or branched chain alkanoyloxy group having from 1 to 4 carbon atoms" (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, ( vi) a methylenedioxy group, (vii) an aralkyloxy group having 7 12 carbon atoms, (viii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (ix) a straight or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms "(x ) a fluorine »chlorine or bromine atom (xi) an aralkyl group having from 7 to 12 carbon atoms» (xii) a phenyl group (the phenyl group can be substituted with methyl »trifluoromethyl» methoxy »fluoro and methylenedioxy) , (xiii) a phenoxy group (the phenyl group can be substituted with methyl »trifluoromethyl» methoxy, fluoro or methylenedioxy), (xiv) a phenylthio group (the phenyl group can be substituted with methyl »trifluoromethyl» ptetoxy »fluoro or methylenedioxy) (x) an enylsulfonyl group (the phenyl group can be substituted with methyl »trifluoromethyl» methoxy »fluoro or methylenedioxy), (xvi) a phenylsulfilamino group (the phenyl group can be substituted with methyl, trifluoroethyl» methoxy » fluoro or methylenedioxy »and the nitrogen atom of the amino portion can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xvii) a furyl »thienyl» oxazolyl »isoxazolyl» thiazolyl »pyridyl» pyridyloxy »pyridylthio or pyridylsulfonyl group, (xviii) an imidazolyl group (the nitrogen atom can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and / or (xix) a pyridylsulphonylamino group (the nitrogen atom of the amino portion can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) »Y * represents an oxygen atom» and Zß represents a 2 »4-dioxothiazolidin-5-ylmethyl group» (28 ) those described in (1), where R3- »represents a hydrogen atom,» a methyl group or an ethyl group »aβ represents an ethylene, trimethylene or methylene group, R3β represents a hydrogen atom. X * represents a phenyl, naphthyl, imidazolyl »oxazolyl» pyridyl »indolyl, quinolyl or isoquinolyl group, and these groups optionally have from 1 to 3 substituents. The substituent cx represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms, (iii) a hydroxyl group, (iv) a straight or branched chain alkanoyloxy group having from 1 to 4 carbon atoms "(v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a methylenedioxy »benzyloxy» phenethyloxy or naphthylmethoxy group (vii) an aralkylthio group having from 1 to 4 carbon atoms, (viii) a straight or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms, (ix) a fluorine atom »chlorine or bromine» (x) a benzyl group »(xi) a phenyl group (the phenyl group can be substituted by methyl» trifluoromethyl »methoxy» fluoro and methylenedioxy) »(xii) a phenoxy group (the phenyl group) can be substituted with methyl »trifluoromethyl» methoxy, fluoro or methylenedioxy) "(xiii) a phenylthio phenylsulfonyl phenylsulphonylamino N-ethylphenylsulphonylamino group» furyl »thienyl» oxazolyl, isoxazolyl, thiazolyl »pyridyl, pyridyloxy» pyridylthio »pyridylsulfonyl, pyridylsulphonylamino or N-methylpyridylsulfonylamino and / or an imidazolyl group ( the nitrogen atom can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms); Y * represents an oxygen atom, and Z * represents a 2,4-dioxothiazolidin-5-ylmethyl group, (29) those described in (1) »where Rl represents a hydrogen atom» a methyl group or a group ethyl »Rsaß represents an ethylene group» trimethylene or ethylethylene »R3ß represents a hydrogen atom» Xß represents a phenyl group »naphthyl, pyridyl» indolyl, quinolyl or isoquinolyl and these groups optionally have from 1 to 3 substituents »The constituent x represents ( i) a straight or branched chain alkyl group having from 1 to 3 carbon atoms, (ii) a trifluoromethyl, difluoromethyl, luoromethyl, hydroxyl, formyloxy or acetoxy group; (iii) a straight or branched chain alkoxy group having from 1 to 3 carbon atoms »(iv) a methylenedioxy, benzyloxy, methylthio» ethylthio, methylsulphonyl or ethylsulonyl group »(v) a fluorine, chlorine or bromine atom» (vi) a benzyl group »phenyl» 4-methylphenyl »4-trifluoro ethylfe nyl, 4-methoxyphenyl, 4-chlorophenyl, 3,4-methylenedioxyphenyl, phenoxy. phenylthio »phenylsulfonyl» phenylsulfonylamino »N-methylphenylsulfonylamino, furyl, thienyl, oxazolyl» thiazolyl * imidazolyl »N-methylimidazolyl» pyridyl »pyridyloxy» pyridylthio, pyridylsulfonyl, pyridylsulphonyl and / or N-methylpyridylsulphonylamino. Yß represents an oxygen atom, and Z "represents a 2,4-dioxothiazolidin-5-ylmethyl group (30) those described in (1), in which R3-" represents a hydrogen atom, a methyl group or a ethyl group »Raß repreeenta. an ethylene group, R3 * represents a hydrogen atom, X «* represents a phenyl group» naphthyl. pyridyl, quinolyl or isoquinolyl and these groups optionally have 1 to 3 substituents x. The substituent a represents a methyl, ethyl, isopropyl, trifluoromethyl, hydroxyl, acetoxy »methoxy, ethoxy» isopropoxy, ethylene xi, taenzyloxy »methylthio» ethylthio »ethylene sulfonyl» ethylene sulphonyl, chloro, benzyl, phenyl, phenoxy, phenylthio group » phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino »pyridyl» pyridyloxy, pyridylthio, pyridylsul nyl, pyridylsulfonylamino and / or N-ethylpyridylsulfonylamino. Y- represents an oxygen atom, and Z ~ represents a 2,4-ioxo-azozolidin-5-ylmethyl group, (31) those described in (1), in which R3- * represents a methyl or ethyl group »= a "* Represents an ethylene group" R3"represents a hydrogen atom" Y. "represents a phenyl group which may have from 1 to 3 substituents cx Substituent a represents a methyl group» hydroxyl »acetoxy» a chlorine atom »benzyl »Phenyl» phenoxy »phenylthio, phenylsulfonyl, phenylsulinylamino» N-ptethylphenylsulphonylamino, pyridyl »pyridyloxy» pyridylthio and / or pyridylsul onyl »? * Represents an oxygen atom» and Z * represents a group 2 »4-dioxothiazolidin-5-phenyl ethyl »(32) those described in (1), in which R3- * represents a methyl or ethyl group» R53 * represents an ethylene group, RS »represents a hydrogen atom» X * represents a pyridyl group which may have 1 to 3 substituents a The substituent ex represents a methoxy-ethoxy group isopropoxy, benzyloxy, methylthio »ethylthio, nile metilsul 'ethylsulfonyl, benzyl» phenyl, phenoxy, phenylthio, phenylsulfonyl "phenylsulfonylamino and / or N etilpiridiIsul onilamino; Yß represents an oxygen atom »and Zß represents a group 2» 4-dioxo-azozolidin-5-ylmethyl »and (33) those described in (1) selected from: i) 5-C4-C2-CCCl- (4-biphenylyl) ) ethylidene-3-amino-3-ethoxy-benzyl thiazolidino-2,4-dione »ii) 5-C4-EL2-CCCl- (4-phenylsulfonyl-phenyl) -ethylidene-3-amino- or -i-3-benzyl-3-azole-2,4-ione, iii) 5-C4- C2-CCCl- (2-pyridyl > phenyl-3-ethylidene-3-aminooxy-ethoxy-benzyl-3-aiazolidino-, 4-ione (hereinafter referred to as "compound A"), iv) 5-E4-C2-CECl- (3-pyridyl) phenyl-3-ethylidene-3-aminoloxy letoxy 3-benzyl 3-azozolidino-, 4-dione »V) 5-E4-E2-CCEl-. { 4-plridyl) fer.il 3e-ylidene-amino-3-oxo-3-ethoxy-3-benzyl-3-thiazolidino-2,4-dione, vi) 5-C4-C2-CCCl- (2-phenyl-5-pyridyl) ethylidene-3-aminooieo-3-benzyl-iazolidino- »- dione »vii) 5-C4-C2-C Cl- (2-methoxy-5-pyridyl) ethylidene-3-amino-3-oxytoxy-Ibhenyl-3-thiazole-2,4-dione, viii) 5-E4-E2-CCCl- (-ethoxy- 5-pyridyl) ethylidene-3-amino-3-oxo-ethoxy-3-benzyl thiazolidino-2 »4-dione, ix) 5-C4-C2-ECCl- (2-isopropoxy-5-pyridyl) -ethylidene-3-aminoloxy-Detox-3-benzyl-3-aiazolidine-2,4-dione and x >; 5-C4-C2-ECCl- (2-benzyl-5-pyridyl) ethylidene-3-amino or 3-di-benzyl-D-thiazolidino-2'-dione (VI) In document W095 / 18125 there is described (1) a derivative of isooxazolidinedione of the formula (VI):
Cen where * represents an optionally substituted aromatic hydrocarbon group »a cycloaliphatic hydrocarbon group optionally substituted» an optionally substituted heterocyclic group »an optionally substituted fused heterocyclic group or a group of the following formula:
Where R3 - ** represents an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or a fused heterocyclic group optionally substituted, 58 * 1 and 3 * are the same or different and each represents a hydrogen atom or a lower alkyl group, * represents an oxygen atom, a sulfur atom or a secondary amino group), R - *** represents a hydrogen atom or a lower alkyl group »3 *" represents an alkyl group lower and P ** and O. * "each represent a hydrogen atom or
P * and Q * taken together represent a bond 3 or a pharmacologically acceptable salt thereof. In the compound of the. formula (VI), the details of the definition of R * S R3 - **, R3 * 1, R3 **, R - ***, 3 **, P * > and Q *% the type of pharmacologically acceptable salt, the procedure for. preparation of the compound of. Formula (VI), examples of compounds, examples, etc., are described in the publications mentioned above. Of said compounds of the formula (VI), the preferred compounds are shown below. (2) those described in (1) »in which R *** - is a hydrogen atom and R * 'is a lower alkyl group» (3) those described in (2). wherein R * is an optionally substituted phenyl group, an optionally substituted 5 or 6-membered aromatic heterocyclic group containing one or doe heterogeneous atoms selected from sulfur atoms »oxygen and nitrogen» or an optionally substituted fused aromatic heterocyclic group substituted in the which the aromatic heterocyclic ring described above is condensed with a benzene ring. (4) those described in (3) »in which R * is a phenyl group» a 5- or 6-membered aromatic heterocyclic group containing one or two heterogeneous atoms selected from sulfur atoms »oxygen and nitrogen» or a heterocyclic group condensed aromatic in which the aromatic heterocyclic ring described above is condensed with a benzene ring. (5) those described in (3) »in which R *" is a phenyl group or a condensed aromatic heterocyclic group in which a 5- or 6-membered heterocyclic ring containing a sulfur atom is condensed with a benzene ring (6) those described in (2), in which * is a phenyl, benzothienyl or l-ethyl-1- (2-pyridylthio) methyl group, (7) those described in (2), in which R * represents a phenyl group »(8) those described in (2), in which cualee * is a group of the formula:
(9) those described in (8), wherein R3- * is an optionally substituted phenyl group or an optionally substituted 5 or 6-membered aromatic heterocyclic group containing one or two heterogeneous atoms selected from sulfur, oxygen and nitrogen atoms »(10) those described in (8), in which R3- * 'is a 5- or 6-membered aromatic heterocyclic group containing one or two heterogeneous atoms selected from sulfur atoms» oxygen and nitrogen, (11) those described in (8), in which R3 - ** is a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom »(12) those described in (8), in which R3- *" represents a pyridyl group , (13) those described in (1), selected from: i) 4-E4-C2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy benzyl3-3,5-ieoxazolidinedione »ii) 4-C4- C2- (-phenyl-5-methyl-4-oxazolyl) ethoxy benzyl-ide l-3 »5-ioxaazolidinedione.» Iii) 4-C4-C2- (2-benzothienyl-5-methyl-4) -oxazolyl) ethoxy-3-benzyl-3-3-5-isoxazolidinedione and iv) 4-C4-C2-C5-methyl-C2- (2-pyridylthio) ethyl-4-oxazolyl) ethoxy-3-benzyl-3, 3, 5-ioxazolidinedione. (VII) Japanese Patent Application (Kokai No. Hei 7-330728 and European Patent Publication No. 67639BA) describes (1) a heterocyclic compound of the formula (VII)
Cen where: »represents an indole ring group» an indoline ring group, an azaindol ring group »an azaindoline ring group» an imidasopyridine ring group or an imidazopyrimine ring group »and these ring groups can have from 1 to 3 substituent portions (a) described later »Y» represents an oxygen or sulfur atom; 2 < ar represents a 2'4-dioxothiazolidin-5-ylidenemethylmethyl-2'4-dioxothiazolidin-5-ylmethyl, 2,4-dioxo-oxazolidin-5-ylmethyl-3'-5-dioxanediazolidin-2-ylmethyl or N-hydroxyureidomethyl group; Rβ represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms» a halogen atom »a group hydroxyl »a nitro group» an amino group which may have a substituent (b) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atom »a straight or branched chain aralkyl group which has from 7 to 11 carbon atoms »an aryl group having from 6 to 10 carbon atoms» a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms »an aromatic-aliphatic acyl group having from B to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms »» is an integer from 1 to 5; The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom , a hydroxyl group »an acetoxy group» a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a trifluoromethyl group» a nitro group, an amino group which may have a substituent (b) (substituent (b) represents uri straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight or branched chain aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms »an aliphatic aromatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 1 to 4 carbon atoms; to 11 carbon atoms), a group of ilo having 6 to 10 carbon atoms which may have a substituent (c) (substituent (c) represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, a straight-chain alkoxy group or branched having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a tri-loromethyl group or an amino group which may have a substituent (b)) or an aralkyl group of straight or branched chain having from 7 to 11 carbon atoms 3 or a pharmacologically acceptable salt thereof. In the compound of the formula (VID, the details of the definition of R », X», Y », the substituent (a), the substituent (b), the substituent (s) yi», the pharmacologically acceptable salt type The process for the preparation of the compound of the formula (VII), the examples of the compounds, the examples, etc., are described in the publications mentioned above, of said compound of the formula (VII), the compounds which are preferred. are shown below (2) those described in Cl), in which Xa represents an indole ring group. ring of indoline ring of "azaindol ring" of imidazopyridine ring or of ring of idazopyrimidine, and these rings may have from 1 to 3 substituents (a) described later. The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alsoxi group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxyl group »an acetoxy group» a phenylthio group »a straight or branched chain alkylthio group having from 1 to 4 carbon atoms» a tri-loromethyl group »a nitro group, an amino group which may have a substituent (b ) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight or branched chain aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms »a straight or branched chain aliphatic acyl group having 1 to 11 carbon atoms, an aliphatic aromatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 10 carbon atoms; to 11 carbon atoms), an aryl group having from 6 to 10 carbon atoms which may have at least one substituent (c) (substituent (c) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a straight chain or straight alkoxy group which has from 1 to 4 carbon atoms a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a tri-loromethyl group or an amino group which may have a sti uyen e (b)) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms which may have at least one constituent (c), (3) those described in (1), in which »represents an indole ring group, of indoline ring "of imidasopyridine ring or of imidazopyrimidine ring" and these rings may have from 1 to 3 substituents (a) described later. The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom »A hydroxyl group» an acetoxy group, a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a tri-loromethyl group» a nitro group »an amino group which may have a substituent (b) ) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms »a straight or branched chain aralkyl group having from 7 to 11 carbon atoms» an aryl group having 6 to 10 carbon atoms »a straight or branched chain aliphatic acyl group having 1 to 11 carbon atoms, an aromatic-aiiphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 10 carbon atoms; to 11 carbon atoms) »a group ar ilo having 6 to 10 carbon atoms which may have at least one substituent (c) (substituent (c) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, an alkoxy group of straight or branched chain having from 1 to 4 carbon atoms »a halogen atom» a hydroxyl group »a nitro group, a phenyl group» a trifluoromethyl group or an amino group which may have a substituent (b)) or a group straight or branched chain aralkyl having from 7 to 11 carbon atoms which can have at least one substituent (c) '(4) those described in (1)' in which X * represents an indole ring group or of imidazopyridine ring and these rings can have from 1 to 3 substituents (a) described later. The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms» a benzyloxy group »a halogen atom »A hydroxyl group» an acetoxy group, a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a tri-loromethyl group» a nitro group, an amino group which may have a substituent (b ) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms »a straight or branched chain aralkyl group having from 7 to 11 carbon atoms» an aryl group having 6 to 10 carbon atoms »a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms» an aliphatic aromatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 10 carbon atoms; to 11 carbon atoms), an aryl group having from 6 to 10 carbon atoms which may have at least one substituent (c) (substituent (c) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom »a hydroxyl group» a nitro group »a phenyl group, a tri-loromethyl group or an amino group which may have a substituent (b) ) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms which may have from 1 to 3 substituents (c), (5) those described in (1), in which X 'represents a group of "indoline ring or imidazopyridine ring" and these rings may have 1 to 3 substituents (a) described later. The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom »A phenylthio group» a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, a tri-loromethyl group or a phenyl group »(6) those described in (1), wherein» represents a ring group of imidazopyridine and the ring can have from 1 to 3 substituents (a) described later. The substituent (a) represents a methyl, ethyl, isopropyl, methoxy, ethoxy group. propoxy »isopropoxy or benzyloxy, a fluorine or chlorine atom, or a phenylthio group» methylthio »ethylthio or phenyl» (7) those described in (1) »wherein R * represents a hydrogen atom, a chain alkyl group straight or branched having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atom or a halogen atom, (8) those described in (1), in which Rflf represents a hydrogen atom , a methoxy group "an ethoxy group", a fluorine atom or a chlorine atom, (9) those described in (1), in which R "represents a hydrogen atom or a methoxy group, (10) those described in (1) ), in which »represents a hydrogen atom» (11) those described in (1), in which Y »repreeenta an oxygen atom, (12) those described in (1 >; »In which Z» represents a 2,4-dioxothiazolidin-5-ylidenemethyl, 2,4-dioxo-azozolidin-5-ylmethyl or 2'4-dioxo-oxazolidin-5-ylmethyl group (13) those described in (1) , in which Z "represents a 2,4-dioxothiazolidin-5-ylidenemethyl or 2,4-dioxothiazolidin-5-ylmethyl group" (14) esae described in (1) "wherein Zs represents a group 2» 4-dioxothiazolidin-5 -ylmethyl, (15) those described in (1), in which X4 * represents a group of indole ring, indoline ring, azaindole ring, imidazopyridine ring or imidazopyrimidine ring, and ether rings may have from 1 to 3 euetituyentes (a) described after, 5B
? «F represents an oxygen or sulfur atom; Z9 represents a 2,4-dioxothiazolidin-5-ylidenyl ethyl group »2» 4-dioxothiazolidin-5-ylmethyl »2,4-dioxooxazolidin-5-ylmethyl, 3,5-diooxadiazolidin-2-ylmethyl or N-hydroureture ethyl , R "represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms" a straight or branched chain alsoxi group having from 1 to 4 carbon atoms or a halogen atom, and 9 represents an integer from 1 to 5; The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom »A hydroxyl group, an acetoxy group, a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, a tri-loromethyl group, a nitro group, an amino group which may have a substituent (b) ) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms »a straight or branched chain aralkyl group having from 7 to 11 carbon atoms» an aryl group having 6 to 10 carbon atoms »an aliphatic straight or branched chain acyl group having from 1 to 11 carbon atoms» an aromatic-aliphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 10 carbon atoms; 11 carbon atoms), a group of ilo having 6 to 10 carbon atoms which can have a substituent ic) (the substituent (s) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom »a hydroxyl group» a nitro group, a phenyl group »a trifluoromethyl group or an amino group which may have a substituent (b)) or a straight-chain aralkyl group or branched having from 7 to 11 carbon atoms which can have at least one substituent (c) '(16) those described in (1), in which X' represents an indole ring group of imidazopyridine ring or "imidazopyrimidine ring" and these rings can have from 1 to 3 substituents (a) described later »Y9 represents an oxygen atom» Z9 represents a 2,4-dioxothiazolidin-5-ylidenemethyl group »2» 4-dioxothiazolidin-5 -methylmethyl or 2,4-dioxooxazolidin-5-ylmethyl »R9 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms "a straight or branched chain alkoxy group having 1 to 4 carbon atoms or a halogen atom" represents 9 an integer from 1 to 5; The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alsoxi group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom »A hydroxy group» an acetoxy group, a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a trifluoromethyl group» a nitro group »an amino group which can have a substituent (b) (the substituent (to) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight or branched chain aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to to 10 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms "an aromatic-aliphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms), an aryl group or having 6 to 10 carbon atoms which may have a substituent (c) (substituent (c) represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain alkoxy group or branched having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a tri-loromethyl group or an amino group which may have a substituent (b)) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms which may have at least one substituent (c), (17) ) The compound described in (1), in which X9 represents an indoline ring group of indoline ring or of imidazopyridine ring and these rings can have from 1 to 3 (a) described later constituents. Oxygen atom »Z9 represents a group 2» 4-dioxothiazolidin-5-ylidene ethyl or 2 »4-dioxothiazolidin-5-ylmethyl» OI represents a hydrogen atom »a methoxy group» an ethoxy group »a fluorine atom or a chlorine atom »m9 represents an integer from 1 to 5. The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms» a straight or branched chain alkoxy group having 1 to 4 carbon atoms. to 4 carbon atoms »a benzyloxy group» a halogen atom »a group hydroxyl »an acetoxy group» a phenylthio group »a straight or branched chain alkylthio group having from 1 to 4 carbon atoms» a trifluoromethyl group »a nitro group, an arnino group which may have a substituent (b) (the substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms »a straight or branched chain aralkyl group having from 7 to 11 carbon atoms» «an aryl group having from 6 to 10 carbon atoms »a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms» an aromatic aliphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms carbon), an aryl group having from 6 to 10 carbon atoms which may have a substituent (c) (substituent (c) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group that has e from 1 to 4 carbon atoms »a halogen atom» a hydroxyl group »a nitro group» a phenyl group »a trifluoromethyl group or an amino group which may have a substituent (b)) or a straight-chain aralkyl group or branched that has 7 to 11 carbon atoms that can have 1 to 3 substituents (c) >; (18) those described in (1), in which Xa represents an indoline ring or imidazopyridine ring group, and these rings may have from 1 to 3 substituents (a.) Described later, Y9 represents an oxygen atom »Z < * represents a group 2'-dioxothiazolidin-5-ylmethyl, R * represents a hydrogen atom or a methoxy group »? s9 represents an integer from 1 to 5. The substituent (a) represents a straight or branched chain alkyl group which has from 1 to 4 carbon atoms "a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group" a halogen atom "a phenylthio group" a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a tri-luoromethyl group or a phenyl group» (19) those described in (1), in which X "represents an imidazopyridine ring group" and the ring may have from 1 to 3 substituents (a) described later »Y9 represents an oxygen atom» Z9 represents a 2,4-dioxothiazolidin-5-ylmethyl group »R« represents a hydrogen atom »m9 represents an integer from 1 to 5. The substituent (a) represents a methyl group »ethyl» isopropyl »methoxy» ethoxy »propox i »isopropoxy or benzyloxy» a fluorine or chlorine atom »or a phenylthio group» methylthio, ethylthio or phenyl »(20) those described in (1), selected from: i) 5-. { 4- (3-methylimidazoE4 »5-b3pyridin-2-yl-ethoxy) -benzyl} thiazolidino- »4- ione» ii) 5-C4- (5-chloro-3-methylimidazoE4 »5-b3pyridin-2-ylmethoxy) benzyl 3-thiazolidino-2» 4-dione »iii) 5- 4- (5-methoxy) 3- ethylimidazo-4'-5-ta-3-pyridin-2-ylmethoxy) -benzyl thiazolidino-2 »4-dione» iv) 5-C4- (5-hydroxy-3-methylimide? Or C4,5-b3pyridin-2-) ylmethoxy) encylDiazolidino -2,4- ione, v) 5- 4- (5-ethoxy-3-methylimidazoC4 »5-to3pyridin-2-ylmethoxy) benzyl thiazolidino-, 4-dione» vi) 5- 4- (5-isopropoxy-3 - ethylimidazoC4 »5-b3pyridin-2-ylmethoxy) -benzyl 3-thiazolidino-, 4-dione and. vii) 5- 4- (1-methylindolin-2-ylmethoxy) benzyl-thiazolidino-2'-4-dione.
(VIII) European Patent No. 745600A describes (1) a condensed heterocyclic compound of the formula (VIII):
(VIII)
Cen where: X * 1 represents a benzimidazole ring group »and the group can have from 1 to 5 e) substituents (a) described later»? H represents an oxygen or sulfur atom, Z * »represents a group 2» 4- dioxothiazolidin-5-ylidenemethyl »2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxo-oxazolidin-5-ylmethyl» 3 »5-ioxaadiasolidin-methyl-ethyl or
N-hydrouretic acid; R 1 ^ represents a hydrogen atom »a straight or branched chain alkyl group having from 1 to 4 carbon atoms» a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom »a hydroxyl group »a nitro group» an amino group which may have a substituent (to) (the substituent (to) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms »a straight-chain aralkyl group or branched chain having from 7 to 11 carbon atoms »an aryl group having from 6 to 10 carbon atoms» a straight or branched chain aliphatic acyl group having from I to 11 carbon atoms »an aromatic-aliphatic acyl group has from B to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms »m? it is an integer from 1 to 5; The substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group» a halogen atom »A hydroxyl group, an acetoxy group, a phenylthio group, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms» a trifluoromethyl group »a nitro group» an amino group which may have a solvent (b) (substituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight or branched chain aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to at 10 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms »an aliphatic aromatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms), an aryl group or having 6 to 10 carbon atoms which a solvent may have (c) (the constituent (c) represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, a straight or branched chain alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a trifluoromethyl group or an ino group which may have a substituent (b) > or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms which may have a solvent (c) »or a pharmacologically acceptable salt thereof. ? represents a hydrogen atom »a straight or branched chain alkyl group having from 1 to 4 carbon atoms» a straight or branched chain alkoxy group having from 1 to 4 carbon atoms »a halogen atom» a group
The hydroxyl group, a nitro group, an amino group which is unsubstituted or is substituted by at least one substituent selected from the group consisting of eta-defined constituents, or a straight or branched-chain aralkyl group having at least one substituent thereof. to 11 carbon atoms; and 20? represents an integer from 1 to 5; In the compound of the formula (VIII), the details of the definition of R? »X * 1» ** »Z", the substituent (a), the constituent (b>, the constituent (c) and m? the type of pharmacologically acceptable salt »the procedure for
The preparation of the compound of the formula (VII), the examples of the compounds, the examples, etc., are described in the publication mentioned above. Of said compound of the formula (VIII), the preferred compounds are shown below: (2) those described in (1), in which R * >; represents a hydrogen atom »a straight or branched chain alkyl group having from 1 to 4 carbon atoms» an alcohol group having 1 to 4 carbon atoms or a halogen atom. (3) those described in (1), in which Yh represents an oxygen atom »(4) those described in (1)» in which Z * 1 represents a 2,4-dioxothiazolidin-5-ylidenemethyl group »2 4-dioxothia? Olidin-5-ylmethyl or 2'-4-dioxooxazolidin-5-ylmethyl "(5) that is described in (1)" wherein R ** represents a hydrogen atom "a straight-chain alkyl group or branched having 1 to 4 carbon atoms »an alkoxy group having 1 to 4 carbon atoms or a halogen atom,? represents an oxygen atom, and Z? represents a 2,4-ioxothiazolidin-5-ylmethyl group »2» 4-ioxothiazolidin-5-ylidenemethyl or 2,4-dioxo-oxazolidin-5-ylmethyl, (6) those described in (1), in which Z * 1 represents a 2'4-dioxothiazolidin-5-ylmethyl or 2,4-dioxothiazolidin-5-ylidenemethyl group "(7) those described in (1), in which R ** represents a hydrogen atom" a methyl group "a group methoxy »an ethoxy group, a fluorine or chlorine atom» (B) those described in (1) »in which m ** is an integer from 1 to 3» (9) those described in (1), in which ? is an oxygen atom, Z * represents a group 2 »4-dioxothiazolidin-5-ylmethyl or 2» 4-dioxothiazolidin-5-ylidenemethyl »R * 1 represents a hydrogen atom, a methyl group, a methoxy group» a group ethoxy »a fluorine or chlorine atom» and mh is an integer of 1 to 3 »(10) those described in (1), wherein X ** represents a toencimidazole ring group which may have from 1 to 5 substituents Ca) described below, the substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms» a benzyloxy group »A halogen atom» a phenylthio group »a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, a trifluoromethyl group, a hydroxyl group, a asei group, a benzyl group or a phenyl group. (11) those described in (1), in which Z ** represents a 2,4-dioxothiazolidin-5-ylmethyl group * (12) those described in (1), in which R * 1 represents a hydrogen atom »A methyl group or a methoxy group, (13) those described in (1), in which X * 1 represents a benzimidazole ring group which may have from 1 to 5 substituents (a), the substituent (a) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms "a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a toenzyloxy group" a halogen atom, a phenylthio group "a straight or branched chain alkylthio group having from 1 to 4 carbon atoms »a trifluoromethyl group» a hydroxyl group »an acetoxy group» a benzyl group or a phenyl group »? represents an oxygen atom »Z * 1 represents a 2,4-ioxothiazolidin-5-ylmethyl group» Rh represents a hydrogen atom »a methyl or methoxy group» and m * represents an integer from 1 to 3; (14) those described in (1) 'in which X * 1 represents a benzimidazole ring group which may have from 1 to 5 substituents (a) »the substituent (a) represents a methyl, ethyl, isopropyl» methoxy group , ethoxy »propoxy» isopropoxy or benzyloxy »a fluorine or chlorine atom» or a phenylthio group »methylthio» ethylthio »hydroxyl, acetoxy» benzyl or phenyl (15) those described in (1), in which R ** represents a hydrogen atom, (16) those described in (1), in which * 1 is 1 or 2 (17) those described in (1), wherein Xh represents a benzimidazole ring group which may have from 1 to 5 substituents a), the substituent (a) represents a methyl, ethyl, isopropyl group »methoxy» etho? i »propoxy» isopropoxy or ^ O benzyloxy »a fluorine or chlorine atom» or a phenylthio group, methylthio , ethylthio, hydroxyl, acetoxy, benzyl or phenyl »And? represents an oxygen atom »Z ** represents a group 2» 4-dioxothiazolidin-5-ylmethyl »15 R * represents a hydrogen atom» and * ^ represents 1 or 2 »(18) those described in (1), in those which n represents a ring group of toencimidazole which may have from 1 to 5 e) elements, said substituent (a) represents a methyl group »methoxy, hydroxyl, acetoxy or benzyl, (19) those described in (1), wherein m ** is 1, (20) those described in (1), wherein X * »25 represents a benzimidazole ring group which may have from 1 to 5 substituents (a).
said substituent (a) represents a methyl group »methoxy» hydroxyl »acetoxy or benzyl, Y * represents an oxygen atom, Z * 1 represents a group 2» 4-dioxothiazolidin-5-ylmethyl,? repreeenta a hydrogen atom "and m is 1 **" (21) those described in (1), seleccionadoe i) 5-C4- (1-me ylbenzimidazol-2-ylmethoxy) benci13- thiazolidine-2,4-dione; ii) 5-C4- (-methoxy-1-methylbenzimidazol-2-ylmethoxy) -benayl-3-thiazolidino-, 4-ione. (Hereinafter called "Compound B"), iii) 5-C4- (5-methoxy-1-metilbencimidazol- -ilmetoxi > - benzyl thiazolidine-2"4- iona iv) 5-C4-Í l-bencilbencimidazol-5 -ylmethoxy) benzyl-thiazolidino- »-dione; v) 5-C4-í 5-hydroxy-1,4 '6"7-tetrametilbencimidazol- - ylmethoxy) benzyl thiazolidine-2" 4- iona and vi) 5-C4-Í 5- ketoxy-1,4, 6, 7- emethylbenzimidazol-2-ylmethoxy) benzyl iazoli ino-2,4-dione. (IX) In the. Japanese patent application (Kokai) No. Hei 1-272574 and European patent No. 332332A describes (1) a compound of the formula (IX):
Cen where the broken line represents a bond or a non-bond »Va- is -CH = CH-, -N = CH-, -CH = N- or S, W1 is CHa» CHOH, CO, C = NOR3- or CH = CH, X1 is S, O »NR3 - * -, -CH = N- or -N = CH-, Y5- is CH or N» 2a- is hydrogen »C ^ C alkyl, C3-C cycloalkyl , »Phenyl» naphthyl »pyridyl» furyl, thienyl or phenyl substituted with one or two substituents selected from the group consisting of
Cx-C3 »trifluoromethyl and C ^ -C3 alkoxy groups and fluorine atoms» chlorine or bromine which may be the same or different »Z -3- is hydrogen or C ^ -C3 alkyl, R4- and R3- 5- repreeentan each independently hydrogen or methyl, and n * - is 1, 2 or 33 or a pharmacologically acceptable salt thereof. In the compound of the formula (IX), the details of the definition of Va-, W3-, X1, Y1, Z5- »Z3-5-» R1, R3 - * - and * - »the type of pharmacologically acceptable salt , the process for the preparation of the compound of the formula (IX), the examples of the compounds »loe examplee» etc. are described in the publications mentioned above. Of said compound of the formula (IX), the preferred compounds are shown below: (2) those described in (1), in which the broken line represents a non-bond and W3- is CO or CHOH, (3) those described in (2), in which Va- is -LO CH = CH-, -CH = N- or S, and n * - ee 2, (4) those described in (3), in which X * - is O and Y * - ee N to form an oxazol-4-yl group, Z4- is (2-thienyl), (2-furyl), phenyl »substituted phenyl or naphthyl, and Z i is 5- methyl, (5) those described in (4), in which V * - is -
CH = N- or S, and Z * - ee 2-phenyl, (6) those described in (1), in which V5- is -
CH = CH-, W * - ee CO and Z * -ee 2- (2-furyl), 2-phenyl »2-Í4- > ethylphenyl) or 2- (-na il), (7) those described in (3), in which Xi is O or S and Y * - is N to form an oxazol-5-yl, thiazolyl group or thiazol-5-yl, (5) those described in (3), in which Xa-is-CH = N- and Y3- is CH to form a pyridyl-or -X3- is O and Y3- is
CH 2 to form a fur-2-yl group (9) those described in (1). which is 5-. { 4-C3- (5-methyl-2-phenyloxazol-4-yl) propioni1 benzyl} lazolidino-2 »4- dione. (X) Japanese patent application (Kokai) No. 6-247945 and European patent No. 604983A describe (1) a naphthalene derivative of the formula IX):
-X = J- represents -O- or -S- »15 = Y * - represents = N- or = CRS ^ -, R13, Ra =, R3a, R-43" and RsA each independently represent a hydrogen atom , a halogen atom "át an alkyl, aryl" alkoxy "alkoxyalkoxy, aryloxy, alkanoyloxy" arilcartooniloxi "carboxyl" alkoxycarbonyl "20 aryloxycarbonyl" carbamoyl "alkylaminocarbonyl" arylaminocarbonyl, amino »alkylamino, alkanoylamino" arylcarbonylamino, ethylenedioxy ethyl "formyl" cyano , nitro or trihalomethyl, RSSS represents a hydrogen atom "group 25 optionally substituted alkyl or n3 optionally substituted aryl group" is an integer from O to 3, and the broken line represents a bond may be a double bond three or pharmacologically acceptable salt thereof In the compound of the formula (X), the details of the definition of A = * »Xa, á, 3 ^, 3 *, R3Í, R" * = », RS: i, e ^ y *, the type of pharmacologically acceptable salt, the procedure for the preparation of the compound of the formula (X) »the examples of the compounds, the examples» etc. »are described in the publications mentioned above .. Of said compound of the formula (X), the preferred compounds are shown below: (2) those described in (1), wherein R- ^, ias, Raa, - »S and R = each independently represent a hydrogen atom, a halogen atom or an alkyl group of Cx-Ce >; aryl of Ce-CiJ3, alkoxy of Cj_-CT, alkoxyalkoxy of C3-C6 »aryloxy of CG-C: 1_13, alkanoyloxy of C ^ ->, arylcarphoonyloxy of C ^ - i CJL3» carboxyl »alkoxicartoonyl of C2-C9 , aryloxycarbonyl
Cy-CX3, carbamoyl »C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 arylaminocarbonyl amino, Cx-Cß alkylamino» C 1 -C 6 alkanoylamino »arylcarbonylamino group, ethylenedioxymethyl, formyl cyano. nitro or trihalogen ethyl, and R63 represents a hydrogen atom »an alkyl group of C -Cβ which may have one or more substituents selected from a phenyl group, a halogen atom, a nitro group and a cyano group; or an aryl group of Ce-C12 which may have one or more substituents selected from an alkyl group of C-C3, a halogen atom, a nitro group and a cyano group, (3) those described in (1), which R: i »Ra3, 3 '» R- * and 53 * each independently represent a hydrogen atom »a halogen atom or an alkyl group of 0X-Cβ» Cx-Cß alkoxy »CS-alkanoyloxy alkoxy-alkoxy -CT, C-CX3 arylcarbonyloxy, carboxyl »C3-Cß alkoxycarbonyl, sarbamoyl, C2-CT alkylaminocarbonyl, C7-CX3 arylaminocarbonyl» amino »alkylamino of Cx-CB. C 7 -C 4 alkanoylamino C 1 -C 3 arylcarbonylamino > ethylenedioxy ethyl »formyl. cyano. nitro or ethyl trihalogen »and
Res represents a hydrogen atom »an alkyl group of Cx-Ca or an aryl group of Cf-C12 which can be substituted with a halogen atom» (4) those described in (1), in which -X3- repreeenta- O- »Y3- represents = CRS: 5-» R3-3", R33" »R33, - * 3 and RSa each independently represent a hydrogen atom, a halogen atom or an alkyl group of C -C3» alkoxy of Cx-C? C3-C6-alkoxyalkoxy »C3-C6-alkanoyloxy» carboxyl, C2-CT-alkoxycarbonyl. arylcarbonyl of C ^ -C3, amino »alkanoylamino of Ca-C?» ethylenedioxymethyl, formyl, cyano, nitro or trihalogenomethyl, and * 33"represents a hydrogen atom, an alkyl group of C -Cs, or an aryl group of Ce-C :: to which can be substituted with a halogen atom »(5) those described in (1)» in which "(flp-48) represents (f2) -X3- represents -O-» 5 Yá represents = CR = 3- »Ri3X R533", R3a and R "* 3" each independently represent a hydrogen atom or a halogen atom, RS: S represents a hydrogen atom,? .OR * 33 represents a hydrogen atom. hydrogen »n3 is 1 and the broken line, repreeenta a bond which is a single bond» or (6) esae described in íl), which is 5-C6- (2- 15 fluorobenzyloxy) -2-na tylmethyl thiazolidin- 2,4-dione It should be noted that in the compounds of formulas (I) to (X) or the pharmacologically acceptable salts thereof, in the case where several isomers, for example,
> stereographed eroe that refer to carbon atoms
Or asymmetric there are (for example) the carbon atoms in the 2-position of the chroman ring and in the 5-position of the thiazolidine ring of the compounds of the formula (I) are the asymmetric carbon atoms), the stereoisomers that result from these asymmetric carbon atoms and mixtures that contain a
The same or not equal amount of these isomers are all represented by the individual formula in formulas (I) to (X). Therefore, the active ingredients of the present invention include all these isomers and the mixture thereof. Furthermore, in the compounds of the formulas (I) to (X) or 5, the archaeologically acceptable salts thereof, for example in the 2,4-dioxothiazolidin-5-ylmethyl ring, it is possible to contemplate the existence of several tautomers . In the formulas (I) to (X), all tautomers and mixtures containing an equal or non-equal amount of these iomeroe are
? .O represented by the individual formula. Therefore, the present invention includes all ethers and mixtures of these isomers. Moreover, in the present invention, in which the compounds of the formulas (I) to (X) or the salts
Pharmacologically acceptable substances thereof form solvates (eg hydrates), said solvates are also included in the present invention. For example, when the compounds of the formulas (I) to (X) or pharmacologically acceptable salts thereof are allowed to settle in
the atmosphere or recrystallize »absorb moisture to carry adsorbed water or to form hydrates. Said solvates are also included in the present invention. Furthermore, the present invention includes all the components that are converted. those of the formulas (I) a
(X) or archaeologically acceptable salts of the same being being metabolized in the living body, that is to say, pro-drugs. The compounds of formulas (I) to (X) of the present invention preferably include i) 5-C4- (6-hydroxy-2 »5» 7 »8-tetramethylchroman-2-ylmethoxy) benzyl-3-thiazolidino-2» 4-dione (troglitazone) »ii) 5- C4- (6-hydroxy-2-methyl-7-t-foutylchroman-2-ylmethoxy) benzyl 3-thiazolidino-2» -dione »iii) 5-E4- (6-hydroxy) -2-ethyl-5 »7» B-trimethylchroman-2-ylmethoxy) benzyl 3-thiazolidino-, 4-dione, ^^. 0 iv) 5-C4-Í 6-hydroxy-2-isobutyl-5 »7» Bt imethylcrornan - 9 2-ylmeto i) benzyl-azozolidino-2,4-dione »v) 5-C4- (-acetoxy-2» 5 »7,8-emethylchroman-2-ylmethoxy) benzyl 3-thiazolidino-2» 4-dione »and vi) 5-E4- (6- toxicartoonyloxy-2,5, 7, B-tetramethyl-15 chroman-2-ylmethoxy) benzyl-3-aiazolidino-2 »4-dione» vii) 5-. { 4-E2- (3-ethyl-2-pyridyl) ethoxy benzyl} -2 »4- thiazolidinedione» viii) 5-. { 4-E2- (-ethyl-2-pyridyl) ethoxy toencyl} -2'4-thiazolidinedione »JO i) 5- [4-E2- (5-ethyl-2-pyridyl) ethoxy-toencyl} -2 »4- thiazolidinedione (pioglitazone)» X) 5-. { 4-C2- (6-ethyl-2-pyridyl) ethoxy-3-octyl} -2'4-iazolidinedione »xi) 5-C (2-toencyl-2» 3-dihydrobenzofuran-5-
-yl) methyl-3-thiazolidino-2,4-dione, xii) 5- C (-to-ethyl-3'-ihydro-H-benzopyran-6-yl) methyl thiazolidino-2'-dione (englitazone) »xiii) 5 -. { 4-C2- (N-me-il-N- (2-t-benzothiazolyl) amino) to i 3-benzyl) thiazolidino-2 »4-dione» xiv) 5-Í4-E2- (N-ethyl-N- (-pyrimidinyl) amino) ethoxy-3-benzyl} -thiazolidino- »4-dione» xv) 5-. { -E2- (-methyl- - { -E4 »5- imethylthi z -yl3amino and oxy-3-benzyl} -thiazolidino-2» 4-dione »xvi) 5-. { 4- (2- (N-ethyl-N- (2-yiazolyl-lamino) -ethoxy-3-benzyl} -thiazolidino-2-dione »lO xvii) 5 ~ [4-C2- (-methyl-N- (2- C4-phenylazolyl > amino) -ethoxy benzyl}. Iazolidino-2 »4-dione» xviii) 5-. {4-C2- (N-methyl-N- (2-C4-phenyl-5-methylthiazolyl amino) etho benzyl.) - iazolidino-2 »4-dione» xix) 5-C4-C2- (N-methyl-N-C2-C4-methyl-5- phenylthiazolyl) amino-letoxy-toencyl} thiazolidino-2 »4- ione» x) 5-. { 4-C2- (N-methyl-N-C2-C5-phenyloxazolyl-lamino-ethoxy-benzyl} -thiazolidino-2 »4-dione» I XXi) 5-. { 4-C2-IN-methyl-N-2-C4,5-dimethyloxazolyl-3) -amino) etho3benzyl > thiazolidino-2,4-dione, 20 xxii) 5 - £ 4-C2- (2-pyrimidinylamino) ethoxy-3-benzyl} - iazolidino-2,4-dione, xxiii) 5-. { 4-E2- (N-acetyl-N- (2-pyrimidinyl the inol-ethoxy benzyl}. Iazolidino-2 »4-dione» xxiv) 5-. {4-E2- (N- (2-benzothiazolyl) -benzylamino) -25-ethoxy-3-benzyl} -thiazolidino-2 »4-dione» xxv) 5-. { 4-C3- (N-methyl-N- (2-benzoxazolyl lamino) - Bl
propoxy 3-benzyl} iazolidino-, 4-dione xxvi) 5-. { 4-C2- (N-methyl- - (2-pyridyl) amin) et i 3- benzyl} iazolidino-2,4-dione (BRL-496531 »xxvii) 5-E4-C2-CCCl- (-biphenylyl) ethylideneamino3-oxo3-ethoxy-benzyl-3-thiazolidino-, 4-dione» xxviii) 5-C4-C2-CC Cl- (4 phenylsulfylphenyl) ethylidene-3-amino-3-oxo-3-ethoxy-benzyl thiazolidino- »4-ione» xxix) 5-C4-C2-C Cl- (2-pyridyl) phenyl-3-ethylidene-3-amino-3-yloxy-benzyl-3-thiazolidino-2-dione (compound Al »xxx) 5-C4-C2-CCCl- (3-pyridyl) phenyl3-ethylidene-3-amino-3-ethoxy-3-benzyl thiazolidino-, 4-dione, xxxi) 5-C4-C2-CCCl- (4-pyridyl) phenyl-3-ethylidene-3-aminoxy-3-oxoxy-benzyl-azole; - iona, xxxii) 5-C4-C2-CCLl- < 2- nyl-5-pyridyl) ethylidene3-amino3o3e oi Ibenzyl 3-azozolidino- »-dione» xviii) 5-C4-C2-ECCl- (-ethoxy-5-pyridyl) -lilyne-3-amino-loxy-texoxy-Ibencyl-3-thiazolidino-2,4 -diona > x iv) 5-C4-C2-CCCl- (-ethoxy-5-pi idyl) and illden -amino3oxyethoxy Ibenzyl 3-thiazolidino-2,4-dione "xxxv) 5-C4-C2-CCCl- (2-isopropoxy-5) -pyridyl) ethylidene-3-amino-3e-oxy-3-benzyl-3-azozolidine-2,4-ione and xxxvi) 5-C4-E2-CECl- (2-benzyl-5-pyridyl) -ethylidene-3-amino-3-ene-3-benzyl-3-aiazolidino-2-4-ane xxxvii) 4-C4-E2- (2-enyl-5-ethyl-4-xazolyl) ethoxy-3-benzyl 3-3, 5-isoxazolidinedione »xxxvii) 4-E4-C2- (-phenyl-5-ethyl-4- oxazolyl) ethoxy 3-s.
benzylidene -3.5-isox zolidinodione »xxxíx) 4-C4-C2-Í 2-benzothienyl-5-methyl-4-oxazolyl) - ^ r ethoxy benzyl13-3» 5-isoxazolidinedione and xl) 4-E4-C2-C5- Methyl-E2- (2-pyridylthio) ethyl-4-5-oxazolyl) ethoxy-3-benzyl-3,5-isoxazolidinedione. xli 1 5- [4- (3-methylimidazoE4,5-b pyridin-2-ylmethoxy) -benzyl} thiazolidino-2 »4-dione» xlii) 5-C4- (5-chloro-3-methylimidazoE4 »5-b3pyridin-2-ylmethoxy) benzyl thiazolidino-2» 4-dione »^^ 10 xliii) 5-E4- ( 5- ethoxy-3-ethylimidazoE4> 5-b3pyridin-2-ylmethoxy) -benzyl 3-azozolidino-2 »4-dione» xliv) 5-C4- (5-hydroxy-3-methylimidazoC4 »5-b3pyridin-2-ylmethoxy ) benzyl thiazolidino-2 »4-ione» xlv) 5-C4- (5-ethoxy-methylimidazoC4 »5-b3pyridin-2-ylmethoxy) foenzylthiazolidino-2, -dione» xlvi) 5-C4- (5- Ieopropo i-3-methylimidazoC4 »5- b3pyridin-2-ylmethoxy) benzyl Itiazolidino-» -iona and fc xlvii) 5-C4- (1-methylindolin-2-ylmethoxy-1-benzyl-thiazolidino-2 »4-dione» xlviii ) 5-C4- (1- e -benzimidazol-2-ylmethoxy) benzyl-3-thiazolidino-2,4-dione; xli) 5-C4- (6-ethoxy-1-methylbenzimidazol-2-ylmethoxy-1-benzyl thiazolidino-, 4-ione (compound B) »1) 5-C4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy ) - benzyl thiazolidino-2,4-dione li) 5-C4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl 3-thiazolidino-2 »4-dione, lii) 5-C4-Í 5-hydroxy-1, 4 »6» 7-tetramethyltoencimidazol-2-ylmethoxy-1-benzyl-thiazolidino-2 »4-dione, liii) 5-C4- (5-acetoxy-1» 4 »6,7-tetramethylbenzylnidazol-2-ylmethoxy-1-benzyl-3-thiazolidino-» 4-dione »Liv) 5-. { 4-E3- (5-methyl-2-phenyloxazol-4-yl) propioni! 3benzyl} thiazolidino-2'-4-dione and Iv) 5-C6- (2-fluorobenzyloxy) -2-na-il-methy1-thiazolidin-2,4-dione or a pharmacologically acceptable salt thereof. The compounds of formulas (I) to (X) of the present invention very preferably include i) 5-C4- (6-hydroxy-2, 5,7, 8-tetramethylchroman-2-ylmethoxy) benzyl thiazole? 2,4-ione (troglitazon 1, ii) 5-C4- (6-acetoxy-2, 5 ', B-tetramethylchroman-2-ylmethoxy Ibenzyl Itiazolidino-, 4-dione, iii) 5-C4- (6-eto icarbonyl i-2 »5» 7,8-tetramethylchromanyl-lime-1-benzylthiazolidino-2-dione, iv) 5-. { 4-C2- (5-ethyl-2-pyridyl-letoxy-benzyl) -2,4-thiazolidinedione (pioglitazon 1, v) 5-C (2-benzyl-3,4-dihydro-2H-taenzopyran-6-yl) ) il-thiazolidino-2,4-dione (englitazone 1, vi) 5-. {4-C2- (N-methyl-N- (2-pyridyl) amino) ethoxy-3-benzyl}. iazolidino-2,4- dione (BRL-49653), vii) 5-E4-C2-ECEl- (2-pyridyl) phenyl3-ethylidene-3-aminooxy-3-ethoxy-3-benzyl-3-aiazolidino-, 4-dione (compound A), viii 1 4-C4-E2- (2-enyl-5) -methyl-4-oxazolyl) ethoxy-3-benzyl 3-3,5-iso-azolidinedione »i) 5-. { 4- (3-methylimidazoE4,5-b pyridin-2-ylmethyl) -benzyl.) Iazolidino- »4- ione» x 1 5-E4- (l-methylindolin-2-ylmethoxy) benzyl-3-thiazolidine -2 > 4-dione »xi) 5-E4-l-methyl-benzimidazol-2-ylmethoxy) benzyl-3-thiazolidino-2'-4-dione; xii) 5-C4- (6-methoxy-1-ethylbenzimidazol-1-ylmethoxy) -benzyl thiazolidino-4-dione (compound B), xiii) 5-C4- (5-hydroxy-1,4-6,7- rame ilbencimidazol-
2-ylmethoxy) benzyl iazolidino-2 »4-ione» xiv) 5-. { 4-C3- (5-methyl-2-phenyloxazol-4-yl) propionylbenzyl} thiazolidino-2,4-dione and xv) 5-C6- (2-luorobenzyloxy) 1-2- naph ilmethiiazolidin-2,4-ione or a pharmacologically acceptable salt thereof The compounds of the formulas (I) a ( X) of the present invention include more preferably i) 5-C4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl thiazolidino-2,4-ione (roglitazone), ii) -. { 4-E2- (5-ethyl-2-? Iridyl) ethoxy3-benzyl} -2,4-thiazolidinedione (ioglitazone) »iii) 5-- £ 4-C2- (N-methyl-N- (2-pyridyl-lamino-3-benzyl) -thiazolidin-2» 4-dione (BRL-49653 ), iv) 5-C4-C2-CCCl- (2-pyridyl) phenyl ethylidene-B5
aminoloxy-3-ethoxy-benzyl 3-thiazolidino-, 4-dione (compound A) and v) 5-E4- (-methoxy-1-ethyl-benzimidazol-2-ylmethoxy) -benzyl-thiazolidino-, 4-ione (compound B) or a pharmacologically acceptable salt of the same.
The way of carrying out the invention The improved insulin sensitivity compounds used in the present invention are administered in various ways. The form of administration is not particularly limited and is determined depending on various types of preparation methods: age and sex of patients, other conditions »the severity of the disease, etc. For example, the compound is administered orally in the form of tablets »pills» powders »granules» syrups »solutions» suspensions »emulsions and capsules. In addition »in the case of injections» the compound is administered intravenously individually or in one. mix with a common adjuvant solution »such as glucose and an amino acid, and further» if necessary, the compound is administered individually intramuscularly »intracutaneously, subcutaneously or intraperitoneally. In the case of suppositories, the compound is intrarectally administered. Oral administration is preferable. Various types of these preparations can be prepared by mixing the known adjuvant which is normally used in the known field of pharmaceutical preparation »such as excipients» binders »B6
disintegrants »lubricants, solubilizers» flavorings and coating agents with an active compound of the present invention according to the conventional method. When the present compound is molded into tablets, conventionally known substances can be used in this field, such as a vehicle. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water »Or ethanol, propanol» simple syrup »glucose solution» starch solution »solution of gelatin, carboxymethylcellulose, shellac, methylcellulose» potassium phosphate and polyvinylpyrrolidone; disintegrants, such as dry starch, sodium alginate, powdered agar, laminating powder, sodium hydrogencarbonate, sodium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid onoglyceride, starch and lactose: inhibiting agents of disintegration such as sucrose, stearic acid »cocoa butter and hydrogenated oil; absorption accelerating agents 0 such as quaternary ammonium base and sodium lauryl sulphite; humectants such as glycerin and starch »adsorbing agents such as starch» lactose »kaolin» bentonite and colloidal silicic acid; and lubricants such as purified talcum »stearate» boric acid powder and polyethylene glycol. In addition, the tablets 5 can be made »if necessary, - by applying a coating film to the tablets» for example a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated coated tablet, a film-coated tablet; a double-layer tablet or a multi-layer tablet. When the present compound is molded into pill form, substances conventionally known in the art such as a vehicle can be widely used in this field. Examples include tailing excipients such as glucose »lactose» starch »cocoa oil» hydrogenated vegetable oil »kaolin and k10 talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; and disintegrants such as agar laminarán. When the present compound is molded in the form of suppositories »known substances can be widely used
Conventionally in this field such as a vehicle.
Examples include polyethyleneglycol, cocoa butter, "higher alcohols," higher alcohol esters, gelatine, and semi-synthetic glyceride. In case the present compound is prepared 20 or an injection »it is preferable that the solution and suspension be sterilized and isotonic for the blood. When the present compound is formed as said solutions »emulsions} and suspensions, substances used conventionally in this field can be used
as a diluent. Examples include water »ethyl alcohol» propylene glycol »ethoxylated iso-ethereal alcohol» polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid ester. In this case »it is possible to include sodium chloride. glucose or glycerin in an amount sufficient to prepare an isotonic solution in a armaceutical formulation. In addition, common solubility enhancers can also be added to the same pH regulators softening agents. Furthermore, "preservative" coloring agents, perfumes, flavors, sweeteners and other medicines can be added »if necessary. The amount of the active ingredient contained in the above-mentioned pharmaceutical preparations is not particularly limited and suitably selected from a wide range, and it is suitable that the content is usually from 1 to 70% by weight in all compositions, preferably from 1 to 30. % in weigh. Furthermore, autoimmune diseases include those classified as systemic autoimmune diseases such as systemic lupus erythematosus, chronic rheumatoid arthritis, juvenile rheumatoid arthritis, Sjbgren's syndrome, and sclerotic erythematosus, mixed connective tissue disease and dermatoiositis; and diseases classified as or organ-specific autoimmune diseases such as Hashimoto's disease »primary myxedema» thyrotoxia »pernicious anemia» ulcerative colitis »autoimmune atrophic gastritis, Addison's idiopathic disease, male infertility, B9 syndrome
Goodpasture, acute progressive glomerular nephritis, severe iaetenia, multiple ioeitis, pemphigus vulgaris, pemphigoid bolus, sympathetic ophthalmia »multiple sclerosis» autoimmune olymetic anemia, idiopathic thrombocytopenic purpura, post-myocardial infarction syndrome »rheumatic fever» lupoid hepatitis, primary biliary cirrhosis »syndrome of Behset and Crest syndrome. In the present invention, the dose of the compound that improves insulin resistance may vary depending on the condition of the disease, the age of the patient, methods of administration, etc. In the case of oral administration »for example» it is desirable to administer a compound in an amount of 0.1 mg (preferably 1 mg) as a lower limit and 1000 mg (preferably 500 mg) or an upper limit »one or more times a day for an adult. In the case of intravenous administration, it is desirable to administer a compound in an amount of O.Ol mg (preferably 0.1 mg) as a lower limit and 500 mg (preferably 200 mg) as an upper limit of one a. several times a day for an adult, depending on the conditions of the disease. The present invention will be described in more detail below by means of examples »test examples and preparation.
CEJEMPLOS
EXAMPLE 1 Inhibitory effect of lymphocyte invasion
Streptozotocin was administered intraperitoneally for 5 days to two week old DBA / 2 mice at 40 mg / kg to induce autoimmunity to islet β cells. Troglitazone was orally administered by mixing in F2 powder feed at an O.2% concentration for 38 days from the initial day of administration of streptozotocin (240 mg / kg / day). Control mice were given only powdered food during the same period. Blood samples were taken from the tail vein before the start of streptozotocin administration during and the final day of drug administration. The blood samples were separated by centrifugation and the levels of the pooled plasma were measured with a glucose analyzer (Sino-Test Co., Ltd.). These results are shown in figure 1. In the figure »the glucose levels (mg / dl) are plotted on the vertical axis» while the time
(days) is recorded on the horizontal axis. The mice used in the study were sacrificed by measuring the glucose levels on the last day of troglitazone administration. The pancreas of each animal was excised and fixed with Bouin's solution. Thin slices of tissue from the pancreas were prepared and the degree of invasion of lymphocytes in the islet cell was observed with a light microscope. The percentage (%) of the number of islet cells that exhibited lymph node invasion in relation to the total number of islet cells was calculated as the degree of lymphocyte invasion. Furthermore, the degree of invasion of lymphocytes was classified as O at 40% or 40 to 60%. The number of mice classified in each scale is illustrated in Table 1 as a percentage (%) in relation to the total number of mice in the troglitazone administration group and the control group.
TABLE 1
Degree of lymphocyte invasion Study group 0 to 40% 40 to 60%
Control group 37.5 62.5
Troglitazone administration group 100
As shown in table 1 above »unlike the degree of invasion of lymphocytes in islet cells that reached 40 to 60% in 62.5% of mice in the control group» in the troglitazone group »the degree of invasion of lymphocytes in islet cells in all mice was 40% or menoe. Accordingly, troglitazone inhibited the invasion of the lymphocytes in the target cells. Furthermore, "based on the above-mentioned figure 1 and table 1, it was shown that troglitazone inhibits the S invasion of lymphocytes in the target cells" and also suppresses the onset of autoimmune disease.
EXAMPLE 2 Inhibitory effect of bone destruction induced by k10 adjuvant arthritis \ The inhibitory effect was determined in a manner similar to that of Winder et al. "(Arthritie Rheu.» Vol. 12, p.772 »1969). Using Levis rats »(female, 8 -10 weeks of age» weights
corporal: 160-200 g »Japan Charles River) in groups of 5 each, was injected adjuvant (Mycobacterium butyricum heat-removed) intradermally in the leg, right rear of each
^ rata at 100 μg / O.OS l / paw to induce arthritis. Troglitazone 0.2% was orally administered, pioglitazone 0.05%
and BRL-49653 to O.005% »respectively» mixing in powdered food until day 20 »taking the day of the adjuvant injection as day O. The ratae of an Aeolus control group were read to give food in dust during the same period. Lae rats were slaughtered on day 21. After extirpating the
In the right rear leg (the injected leg), soft X-rays were taken from each leg to observe and grade the state of bone destruction. The destruction of bone was evaluated by evaluating 5 scales consisting of O »1» 2 »3 and 4» assigning O points in the absence of bone destruction (normal) and increasing the graduations depending on the state of destruction of the joint »destruction of bone bone »deformation and osteophyte formation. The worst condition of these bone disorders was assigned a grade of 4. The bone disorders were graded in two places: the calcaneus and the place extending from the tarsal bone
# ° to the etatarsal bones. In this way »the graduation for each animal was determined by calculating the total graduation for the two places and the maximum graduation was B points. The results are shown in table 2.
TABLE 2
Degree of destruction of bone inhition bición destruction of
• > O bone (%) Study group
Control group 7.4 ± 0.4 Troglitazone administration group 5.4 ± 0. * 27.0 Pioglitazone administration group 4,411.0 40 .: Administration group of BRL-49653 4.811.2 53.1 30 *: P < 0.05 vs. control group As is clear from table 2, the troglitazone administration group exhibited significant inhibition of bone destruction as compared to the control group (ilcoxon test). The administration groups of pioglitazone and BRL-49653 also exhibited inhibition of bone destruction.
EXAMPLE 3 Inhibitory effect of lymphocyte invasion
Streptozotocin was administered intraperitoneally for 5 days to two week old DBA / 2 mice at 40 mg / kg to induce autoimmunity of islet β cells. Pioglitazone was orally administered by mixing in F2 powder feed at a concentration of 0.2% (236 mg / kg / day) for 3B days from the initial day of administration of eetreptozotocin. Only the powdered food was given to the mouse in the control group during the same period. Blood samples were collected from the tail vein before and during the last day of streptozotocin administration. The blood samples were centrifuged to obtain plasma and the plasma glucose levels obtained were measured with a glucose analyzer (Sino-Test Co., Ltd.). These results are shown in Figure 2. In the figure »the glucose levels (mg / dl) are plotted on the vertical axis» while the time (day) is plotted on the horizontal axis. The mice used in the experiment were sacrificed by measuring the glucose levels on the last day of the administration of pioglitazone. The pancreas of each animal was excised and fixed with Bouin's solution. Thin slices of tissue from the pancreas were prepared and the degree of invasion of lymphocytes in the islet cells was observed under a light microscope. The percentage (%) of the number of islet cells that exhibited lymphocyte invasion in k10 relative to the total number of islet cells was calculated as the degree of invasion of lymphocyte. Furthermore, the degree of invasion of lymphocytes was classified as O at 40% or 40 to 60%. The number of mice classified in each scale is illustrated in Table 3 as a percentage (%) in relation to the total number of 15 mice in the pioglitazone administration group and the control group.
I TABLE 3
JO Degree of lymphocyte invasion Study group O a. 40% 40 to 60%
Control group 37.5 62.5 Group of administration of pioglitazone IOO O Co or shown in table 3 above »unlike the degree of invasion of lymphocytes in islet cells that reached 40 to 60% in 62.5% of the mice in the group of control »in the pioglitazone group» the degree of invasion of lymphocytes in islet cells in all mice was 40% or less. In agreement with these results, pioglitazone inhibited the invasion of the lymphocyte in the target cells. Still more »on the basis of figure 2 and table 3 mentioned above» it was found that the. pioglitazone inhibits the invasion of lymphocytes in target cells, and also suppresses the onset of autoimmune disease.
EXAMPLE 4 Inhibitory effect of lymphocyte invasion
Streptozotocin was administered intraperitoneally for 5 days to 2-week old DBA / 2 mice at 40 mg / kg to induce autoimmunity of islet β cells. BRL-49653 or compound A was orally administered by mixing in powder feed F2 at a concentration of 0.1% (BRL-49653: 125 mg / kg / day, compound A: 94 mg / kg / day respectively) for 31 days from initial day of administration of streptozotocin. The mice in the control group were given only powdered feed during the same period. Blood samples were taken from the vein of the tail before the start »during and the last day of administration of streptozotocin. The blood samples were centrifuged to obtain plasma. and the glucose levels in the obtained plasma were measured with a glucose analyzer (Sinotest). These results are shown in Figure 3. In the figure, the glucose levels (mg / dl) are plotted on the vertical axis, while the time (days) is plotted on the horizontal axis. The mice used in the experiment were O sacrificed following the measurement of glucose levels on the last day of drug administration. The pancreas of each animal was excised and fixed with Bouin's solution. Thin slices of tissue from the pancreas were prepared and the degree of invasion of lymphocyte in the islet cells was observed under a light microscope. The percentage (%) of the number of islet cells exhibiting lymphocyte invasion in relation to the total number of islet cells observed was calculated, and this was evaluated as the degree of lymphocyte invasion. Furthermore, the degree of invasion of lymphocytes from each mouse was classified as 0 to 40% or 40 to 60%. The number of mice classified in each scale was represented as or shown in Table 4 co or a percentage (%) in relation to the total number of mice in the administration group of BRL-49653 or compound A and the control groups .
9B
TABLE 4
Degree of invasion of lymphocytes O at 40% 40 to 60%
Control group 55.6 44.4
Management group of BRL-49653 100 O Administration group of compound A 100
As shown in table 4 above, "unlike the control mice where it was observed that 40 to 60% of the islet cells were invaded by lymphocytes in 44.4% of the total mice" in the groups of BRL-49653 and compound A »islet cells that were invaded by lymphocytes were less than 40% in all mice. Namely, BRL-49653 and compound A inhibited the. invasion of the lymphocytes in the target cells. Still more »from the figure. 3 and Table 4 mentioned above, it was shown that BRL-49653 and Comet A inhibit the invasion of the lymphocyte in the target cells "and also suppress the onset of the autoimmune disease.
EXAMPLE 5 Inhibitory effect of bone destruction induced by adjuvant arthritis
The inhibitory effect was determined according to the methods of Winder and others "(Arthritis Rheu.» Vol. 12 »p. 472» 1969). Using Lewie rats »(female» 8-10 weeks of age, body weights: 160-200 g »Japan Charles River) in groups of 5 each. adjuvant (Mycobacterium butyricum heat-killed) was injected intradermally into the palm of the right hind paw of each rat at 100 μg / 0.05 ml / paw to induce arthritis. Compounds A, 0.1% and compound B, 0.1% were orally administered to the rats. respectively. mixing in powdered food until day 20, on the day of the adjuvant injection as day 0. Only powdered food was given to the rats in a control group during the same period. The rats were sacrificed on day 21. After the right hind paw (the injected paw) was removed, soft X-rays were taken from each paw to observe and grade the state of bone destruction. The destruction of bone was evaluated by evaluating 5 scales consisting of 0 »1, 2» 3 and 4, assigning O points in the absence of bone destruction (normal) and increasing the graduations depending on the state of destruction of the joint, destruction of bone. bone, deformation and osteophyte formation. The worst condition of bone destruction was assigned a grade of 4. The lOO
Bone destruction was graded in two places, the calcum and the site extending from the tarsal bones to the etatarsal bones. In this way, the graduation for each animal was determined by calculating the total graduation for the two places and the maximum graduation was 8 points. The results are shown in table 5.
TABLE 5
Destruction rate of bone inhi- bition index of bone destruction (%)
Study group
Control group B.O ± O.O Administration group of compound A 6.6 ± 0.7 * 17.5 Group administration of compound B 6.6 ± O.B 17.5
As is clear from table 5, bone destruction tended to be inhibited in the groups of administration of compound and compound B compared to the control groups (ilcoxon test).
LOL
EXAMPLE OF TEST 1 Acute toxicity
Acute toxicity was determined according to
conventional methods. Namely, after administering troglitazone orally at 300 mg / kg to three ddY (male) mice, the animals were observed for 5 days. All the animals survived during that time.
THE EXAMPLES OF FORMULATION
Formulations may be produced which contain as an active ingredient an insulin resistance enhancing substance or its archaeologically acceptable salt
of the present invention in accordance with »for example» the following and method.
Formulation Example 1 - Powder 5 g of troglitazone »895 g of lactose and 20 lOO g of corn starch are mixed in a mixer to obtain a powder.
Formulation Example 2 - Grains 5 g of troglitazone, 865 g of lactose and
lOO g of lower-substituted hydroxypropyl cellulose, followed by the addition of 300 g of 10% aqueous hydroxypropyl cellulose and kneaded. This mixture is then extruded and granules are formed using a granulating machine and then drying the granulated product.
Formulation Example 3 - Capsules 5 g of troglitazone are mixed. 115 g of lactose »58 g of corn starch and 2 g of magnesium stearate using a V-shaped blender» and then filling 1 g of the mixture into No. 3 capsules to obtain capsules.
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 then tablets are formed using a manufacture of tablets.
Formulation Example 5 - Powder 5 g of pioglitazone are mixed »895 g of lactose and
10Og of cornstarch with a mixer to obtain a powder.
Formulation Example 6 - Granules 5 g of BRL-49653 »865 g of lactose and 100 g of lower-substituted hydroxypropyl cellulose are mixed» followed by the addition of 300 g of 10% aqueous hydroxypropylcellulose and kneaded. This mixture is then extruded and granules are formed using a granulating machine and dried by drying the granulated product.
Formulation Example 7 - Capsules 5 g of compound A »115 g of lactose» 58 g of corn starch and 2 g of magnesium stearate are mixed using a V-shaped blender, and then filling 180 mg of the mixture into capsule of No. 3 to obtain capeulas.
Formulation Example B - Tablets 5 g of compound A, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, and then tablets are formed using a machine of making tablets. Industrial Applicability The insulin resistance compounds of the present invention are useful as a preventive or therapeutic agent for autoimmune diseases O (excluding type I diabetes).
Claims (23)
1. The use of an insulin resistance improving compound in the manufacture of a medicament for the prophylaxis or treatment of autoimmune diseases, with the exception of type I diabetes.
The use according to claim 1 further characterized because the OH-improving compound insulin resistance is selected from the group consisting of thiazolidinedione compounds »oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds.
3. The use according to claim 1, further characterized in that the resistance improving compound, a. the. Insulin is selected from thiazolidinedione compounds.
4. The use according to claim 1 » > further characterized in that the insulin resistance enhancing compound is a compound of the formula (I): where R3- »and R3? they may be the same or different and each represents a hydrogen atom or an alkyl group of C-CB; R ß represents a hydrogen atom, an aliphatic acyl group of Cx-Cß "a cycloalkylcartoonyl group of Ce-Cß" a benzoyl or naphthoyl group which may have a substituent (the substituent is an alkyl group of Cx-C ^ »alkoxy) of C -C. * or hydroxyl »a halogen atom or an amino group, C-1 monoalkylamino, dialkylamino of C -C ^ or a nitro group). a heterocyclic acyl group of 4 to 7 members containing 1 to 3 heterogeneous atoms selected from the group of heterogeneous atoms consisting of nitrogen, oxygen and sulfur atoms, a phenylacetyl group, a phenylpropionyl group, a phenylacetyl or phenylpropionyl group. substituted with at least one halogen atom, a cyano oyl group, a C2-C7 alkoxycarbonyl group or a group 15-benzyloxycarbonyl; R- * ß and RSa? they can be the same or different and each represents a hydrogen atom »an alkyl group of C-C3 or an alkoxy group of C-Cs, or R- * and R? ? k taken together represent an alkylenedioxy group of C -C ^ Yß and Z? they can be the same or different and each one represents 20 an oxygen atom or an imino group "and ß is an integer from 1 to 3; or an archaeologically acceptable salt thereof.
5. The use according to claim 1 »further characterized in that the insulin resistance improving compound is a compound of the formula (II): 25 or a pharmacologically salt thereof.
6. The use according to claim 1 »further characterized in that the insulin resistance improving compound is a compound of the formula (III): where the broken line represents a single link or a non-link; na is O, 1 or 2; X = is an O, S, S = 0 or S (= 0) (= 0); R = is an H, CH3 or C ^ H ^ R ^ a is independently H »cycloalkyl of Cs-C ^» methylcycloalkyl of Cs-Cß, pyridyl, thienyl, furyl, naphthyl, p-bi-enylyl »tetrahydrofuranyl, tetrahydrothienyl» tetrahydropyranyl , CeH4Waß (where w350 is H, OH, F, Cl, Br, Cx-C ^ alkyl, C ^ ^ alkoxy or C ^ C ^ thioalkyl) or alq-W3-0 (where alq is a C-C6-alkylene, ethylidene or isopropylidene, and W3-0 is H, OH, C-C7-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3-C3 !); SO is H or CH3; R3 < = is H, C -Cß alkyl, CeH ^ W30 or benzyl; and R- * ° is H; or R3-0 and R530 all together can form an alkylene of C ^ -Cβ and R3 < = and R "* a are each H; or R3 < = and R ** a taken together can form alkylene of C ^ -C6, and R3-0 and R20 are each H; or R520 and R3C taken together can forming alkylene of C -C ^, and 3- * 2 and R "* ° are each H; or a pharmaceutically acceptable salt thereof.
7. The use according to claim 1 »further characterized in that the insulin resistance enhancing compound is a compound of the formula (IV): wherein: Aa, a represents an optionally substituted heterocyclic aromatic group. "R a represents a hydrogen atom, an alkyl group" an acyl group "an aralkyl group wherein the aryl portion can be substituted or unsubstituted) or a group optionally substituted aryl; 3 ^ and R3, a each represent a hydrogen atom or R3 <a and R3 <all together form a bond; A32 ** represents a benzene ring having not more than 5 euetitutents in total and an "integer" from 2 to 6, or a "pharmceutically acceptable" thereof. OB
8. The use according to claim 1 »further characterized in that the insulin resistance enhancing compound is an oxime derivative of the formula (V): (V) wherein: R3- "represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms; R53 * represents a straight or branched chain alkylene group having from 2 to 6 carbon atoms; carbon; R3 * represents a hydrogen atom »a straight or branched chain alkyl group having from 1 to 6 carbon atoms» a straight or branched chain alkoxy group having from 1 to 4 carbon atoms »an alkylthio group of straight or branched chain having from 1 to 4 carbon atoms »a halogen atom, a nitro group» an amino group »a straight or branched chain monoalkylamino group having from 1 to 4 carbon atoms» a dialkylamino group of chain straight or branched in which the alkyls may be the same or different and each having from 1 to 4 carbon atoms "an aryl group having from 6 to 10 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms carbon; Xß represents an aryl group that It has 6 to 10 carbon atoms and may have 1 to 3 ex substituents, defined below, or an aromatic heterocyclic group which may have 1 to 3 cx constituents; the substituent ex represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms "(iii) a hydroxyl group »(iv) a straight or branched chain acyloxy group having from 1 to 4 carbon atoms» (v) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (vi) a group straight chain or branched alkylenedioxy having from 1 to 4 carbon atoms, (vii) an aralkyloxy group having from 7 to 12 carbon atoms, (viii) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (ix> a straight or branched chain alkylsul onyl group having 1 to 4 carbon atoms »(x) a halogen atom» (xi) a nitro group »(xii) an amino group» ( xiii) a straight or branched chain monoalkylamino group having from 1 to 4 carbon atoms "(xiv) a dialkylamino group of c straight or branched adena in which the alkyls may be the same or different and each have from 1 to 4 carbon atoms "(x) an aralkyl group having from 7 to 12 carbon atoms" (xvi) an aryl group which it has from 6 to 10 carbon atoms »which may have a substituent S, (xvii) an aryloxy group having from 6 to 10 carbon atoms» which may have a substituent β, defined below, (xviii) an arylthio group having from 6 to 10 carbon atoms "which can have a substituent β" defined below "(xix) an arylsulfonyl group having from 6 to 10 carbon atoms" which can have a substituent β "defined below" (xx) ) an arylsulfonylamine group having from 6 to 10 carbon atoms "which can have a substituent β" defined below "(the nitrogen atom of the amino moiety can be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) »(x? i) an aromatic heterocyclic group ico »(xxii) an aromatic heterocyclic group» (xxiii) an aromatic heterocyclicthio group »(xxiv) an aromatic heterocyclylsulfonyl group or (xxv) a heterocyclylsulphonylamino aromatic group (the nitrogen atom of the amino portion can be substituted with an alkyl group of straight or branched chain having 1 to 6 carbon atoms); the substituent ß represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms »a straight or branched chain halogenoalkyl group having from 1 to 4 carbon atoms» a straight or branched chain alkoxy group having from 1 to 4 carbon atoms »a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms» ß repreeenta an oxygen atom »a sulfur atom or a group of the formula >N-R- * ß (wherein R- * ß represents a hydrogen atom »a straight or branched chain alkyl group having from 1 to 6 caybon atoms or a straight or branched chain acyl group having from 1 to B carbon atoms); and Zß represents a 2,4-dioxothiazolidin-5-ylidenemethyl group »a 2,4-dioxothiazolidin-5-ylmethyl group» a 2'4-dioxooxazolidin-5-yl ethyl group or a 3,5-dioxo-oxazolidin-5-ylmethyl group; or a pharmacologically acceptable salt thereof.
9. The use according to claim 1, further characterized in that the insulin resistance enhancing compound is an isoxazolidinedione derivative of the formula (VI): wherein: R * represents an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group "an optionally substituted heterocyclic group", an optionally substituted condensed heterocyclic group or a group of the following formula: wherein: R3 - ** 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; R3 ** and R3 * 1 are the same or different and each represents a hydrogen atom or an inferior alkyl group and X * represents an oxygen atom, a sulfur atom or a secondary amino group; - ** 1 represents a hydrogen atom or a lower alkyl group; s # represents a lower alkyl group and 4 * and Q * - each represents a hydrogen atom or P * and Q < All together represent a link; or a pharmacologically acceptable salt thereof.
10. The use according to claim 1, further characterized in that the insulin resistance enhancing compound is a heterocyclic compound of the formula. (VINE: (VII) wherein: Xa represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindoline ring group, an imidazopyridine ring group or an imidazole i idine ring group, and these ring groups may have from 1 to 3 substituents (a) described below; Y9 represents an oxygen or sulfur atom; Z9 represents a 2'4-dioxothiazolidin-5-ylidenemethyl group »a 2'4-dioxothiazolidin-5-ylmethyl group» a 2'4-dioxo-oxazolidin-5-ylmethyl group, a 3,5-diooxadiazolidin-2-ylmethyl group or an N-hydroxyureidomethyl group; R "represents a hydrogen atom" a straight or branched chain alkyl group having from 1 to 4 carbon atoms "a straight or branched chain alkoxy group having from 1 to 4 carbon atoms" a.- halogen atom »A hydroxyl group» a nitro group »an amino group which may have a solvent (b) (the constituent (b) represents a straight or branched chain alkyl group having from 1 to 8 carbon atoms» a chain aralkyl group straight or branched having from 7 to 11 carbon atoms »an aryl group having from 6 to 10 carbon atoms» a straight or branched chain aliphatic acyl group having from 1 to 11 carbon atoms »an acyl group aro -aliphatic having from B to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms and m9 is an integer of 1 to 5, the substituent (a) represents a chain alkyl group straight or branched having 1 to 4 carbon atoms »a straight or branched chain alkoxy group having from 1 to 4 carbon atoms» a benzyloxy group »a halogen atom» a hydroxyl group »an acetoxy group» a group phenylthio, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, a tri-loromethyl group, a nitro group, an amino group which may have a substituent (b), as defined above, an aryl group which it has from 6 to 10 carbon atoms which can have a substituent (c) (the substituent (c) represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group which it has from 1 to 4 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a phenyl group. a trifluoromethyl group or an amino group which may have a substituent b), as defined above) or a straight or branched chain aralkyl group having from 7 to 11 carbon atoms which may have a substituent (c), co or defined above: or a pharmacologically acceptable salt thereof.
11. The use according to claim 1, further characterized in that the insulin resistance enhancing compound is a condensed heterocyclic compound of the formula (VIII): where: ? represents a benzimidazole ring group, and the group may have from 1 to 5 its assistants (a) as defined in claim I; * »Represents an oxygen or sulfur atom; Z * 1 represents a 2,4-dioxothiazolidin-5-ylidenyl ethyl group »a 2,4-dioxothiazolidin-5-ylmethyl group, a 2'4-dioxooxazolinyl-5-ylmethyl group» a 3,5-diooxadiazolidin-2-ylmethyl group or an N-hydroxyureidomethyl group; R? represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom, a hydro group "ilo" a nitro group, an amino group which may have a solvent (b) as defined in claim 10, or a straight chain, or branched aralkyl group having from 7 to 11 carbon atoms; m * -1 is an integer from 1 to 5; or an archaeologically acceptable salt thereof.
12. The use according to claim 1, characterized in that the insulin resistance improving composition is a compound of the formula (IX) - where: the broken line represents a link or a non-link; V1- is -CH = CH-, -N = CH-, -CH = N- or S; W * - is CHffi, CHOH, CO, C = N0R3- or CH = CH; X * - is S »O, NR3-5-» -CH = N- or -N = CH-; Y * - is CH or N »Z * - is hydrogen» Cx-C ^ alkyl, CgC ^ cycloalkyl, phenyl »naphthyl, pyridyl» furyl »thienyl or phenyl substituted with one or two substituents chosen from C-alkyl groups C3 »trifluoromethyl and Cx-C3 alkoxy and fluorine, chlorine or bromine atoms, which may be the same or different; Z3-3- is hydrogen or alkyl of C ^ -C ^ R3- and R3-5- each independently represent hydrogen or methyl and n * -ee 1 »2 or 3; or one JL.O pharmacologically acceptable salt thereof.
13. The procedure according to claim 1, further characterized in that the insulin resistance enhancing composition is a naphthalene derivative of the formula (X): *, ßd, Ras, -4S and Rsd each independently represent a hydrogen atom »a halogen atom» an alkyl group »aryl» alkoxy »alkoxyalkoxy, aryloxy, alkanoyloxy, arylsarbonyloxy, carboxyl» alkoxycarbonyl »aryloxycarbonyl» carbamoyl, alkylaminocartoonyl » arylaminocarbonyl »amino» > alkylamino »alkanoylamino, arylcarbonylamino, ethylenedioxymethyl» formyl »cyano» nitro or trihalogenomeyl; R6 = "represents a hydrogen atom" an optionally substituted alkyl group or an optionally substituted aryl group; nd is an integer from 0 to 3 and the broken line represents a link that can be a double bond; or a pharmacologically acceptable salt thereof.
14. The use according to claim 1 »further characterized in that the insulin resistance improving compound is selected from the group consisting of: 5-C4- (6-hydroxy-2» 5 »7, B -tetramethylchroman-2-ylmethoxy) benzyl 3-thiazolidino-2,4-dione-troglitazone), 5-C4- (6- 15 asetoxin-2 »5» 7, B-tetrame-ilchroman-2-ylmethoxy) benzyl iazoli ino- 2,4-dione, 5-E4-C6-ethoxycarbonyloxy-2, 5.7, S-tetramethyl-chroman- 2-ylmethoxy) benzyl 3-thiazolidino-2,4-dione, 5-. { 4-E2- (5-ethyl-2-pyridyl) ethoxy-3-benzyl} -2,4-thiazolidinedione (pioglitazone), 5- E (2-benzyl-3'-4-ylhydro-2H-toenzopyran-6-yl) methyl thiazolidino- 20 2,4-dione (englitazone) »5-. { 4-E2- (N-methyl-N- (2-pyridyl) amino) ethoxy 3-benzyl} iazolidino-2,4-dione (BRL-49653). 5-E4-C2-CCCl-C4- (2-pyridyl) enyl-lethylidene-amino-oxy-3-ethoxy-3-toencyl-thiazolidino-2 »4-dione» 4-E4-E2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy 3-benzyl 3-3 »5-isoxazolidinedione» 5-C4- (3- 25 me boundness C4 »5-b pyridin-2-ylethoxy) -benzyl} thiazolidino-2'-dione, 5-C4- (1-methy1indolin-2-ylmethoxy) benzyl-3-aiazolidino-2'-dione »5-C4- (l-methylbenzimidazol-2-ylmethoxy > benzyl 3-thiazolidino -2 »4-dione» 5-C4- (6-methoxy-1-ethylbenzimidazol-2-ylmethoxy) -benzyl-3-thiazolidino-2 »4-dione» 5-E4- (5-hydroxy-1 »4» 6 »7- tetramethylbenzimidazol-2-yl ethoxy) benzyl 3-thiazolidino-2, 4-dione, 5-. { 4-C3- (5-methyl-2-phenyloxazol-4-yl) propioni! 3-oxenyl} thiazolidino-2,4-dione and 5-C6- (2-luorobenzyloxy) -2-afthylmethylthiazolidin-2,4-ione and pharmacologically acceptable salts thereof.
15. The use according to claim 1 »further characterized in that the insulin resistance improving compound is selected from the group consisting of: 5-C4- (6-hydroxy-2,5,7,8-tetramethylchroman -2-ylmethoxy) benzylthiazolidino-2,4-dione (troglitazone), 5-. { 4-C2-> 5-ethyl-2-pyridyl-letoxy-benzyl} -2, 4- iazolidinedione (pioglitazone), 5-. { 4-E2- (N-ethyl-N ~ (2-pyridyl) amino) ethoxy3-benzyl} thiazolidino-2,4-dione (BRL-49653) »5-C4-C2-CCEl- (2-pyridyl) enyl3-ethylidene-3-amino-3-yl-3-ethoxy-3-benzyl-31-azolidine-2,4-dione and 5-C4- (-ethoxy-1-methylbenzimidazole- 2-ylmethoxy) -benzyl 3-thiazolidino-4-ione and pharmacologically acceptable salts thereof.
16. The use according to any of claims 1 to 15 »further characterized in that said autoimmune disease is one that is treatable by the inhibitory action of the invasion of tissue lymphocyte.
17. The use according to any of claims 1 to 15 »further characterized in that said autoimmune disease is a seven-way autoimmune disease.
18. The procedure according to any of claims 1 to 15, further characterized in that said autoimmune disease is an organ-specific autoimmune disease.
19. The use according to any of claims 1 to 15, further characterized in that said autoimmune disease is chronic rheumatoid arthritis.
20. The use according to any of claims 1 to 15 »further characterized in that said autoimmune disease is juvenile rheumatoid arthritis.
21. The use according to any of claims 1 to 15, further characterized in that said autoimmune disease is systemic lupus erythematosus.
22. The use according to any of claims 1 to 15 »further characterized in that said autoimmune disease is Hashi oto disease.
23. A composition for the prophylaxis or treatment of autoimmune diseases with the exception of type I diabetes, which comprises a pharmacologically effective amount of an anti-autoimmune disease agent and a pharmacologically acceptable diluent or carrier, further characterized in that said anti-inflammatory agent - autoimmune disease is an insulin resistance improving agent, as defined in any of claims 1 to 15.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8-138667 | 1996-05-31 | ||
JP8-181850 | 1996-07-11 | ||
JP8-319225 | 1996-11-29 |
Publications (1)
Publication Number | Publication Date |
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MXPA98009928A true MXPA98009928A (en) | 1999-04-27 |
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