MXPA97002058A - Treatment and profilaxis of pancreati - Google Patents

Abstract

The present invention relates to: insulin sensitizers, especially thiazolidinedione compounds, such as troglitazone, which are useful for the treatment and prevention of pancreatitis

Description

TREATMENT AND PROPHYLAXIS OF PANCREATITIS BACKGROUND OF THE INVENTION The present invention relates to a new use for a series of known compounds, including thiazolidinedione compounds, oxazolidinedione compounds. isoxazolidinedione compounds and oxadiazolidinedione compounds, in the treatment and prophylaxis of pancreatitis. Pancreatitis is commonly classified in a general way as acute pancreatitis or chronic pancreatitis, depending on whether the condition persists or not after the removal of the etiologic agent. Except "where the context re- fers otherwise, the term" pancreatitis ", as used herein, includes both acute pancreatitis and chronic pancreatitis. Probably, about 40% of cases of acute pancreatitis can be attributed to alcohol abuse.

Other causes include idiopathic origins, cholelithiasis, over-feeding and trauma. The first three causes represent 70 to 80% of this disease. The number of patients suffering from chronic pancreatitis has grown steadily in recent years, approximately linearly with an increase in alcohol intake, although it is also associated with an increase in the intake of protein and fat. Chronic pancreatitis is a pathological condition characterized by function decreased exocrine «due to pancreatic malfunction. In chronic pancreatitis, the destruction of the pancreatic parenchyma begins in the pancreatic acid cells and rapidly spreads to the islets of Langerhans. The main cause of chronic pancreatitis is alcohol abuse and other causes include cholelithiasis, acute pancreatitis and idiopathic origins (particularly frequent in females). Recently, the incidence of chronic pancreatitis due to alcohol abuse has been increasing. The preferred treatment for acute pancreatitis includes internal medicinal conservative treatments, such as elimination of the cause of the disease, protection of the pancreas, prevention of self-digestion in the pancreas, pain control, with r-means against infection and nutritional control. . On the other hand, to treat chronic pancreatitis, it would be convenient to inhibit "deterioration of the pathological state of the pancreas and regenerate and restore pancreatic tissue, but such treatment is not available. Therefore, symptomatic treatment generally occurs both for acute pancreatitis and for chronic pancreatitis. Different drugs have been used for the medical treatment of pancreatitis, of which the most widely used are protease inhibitors. It is thought that protease inhibitors inhibit the action of trypsin, which accelerates self-digestion in the pancreas. In addition, it has reports that "protease inhibitors promote regeneration" of exocrine tissue in the pancreas. However, this evaluation is controversial. It is known that many thiazolidinedione derivatives increase insulin activity and improve diabetic diet CFujiwara et al., Diabetes 3_7, 1549, (1988)]. In particular, it has been proved that a class of "two thiazolidinedione drift" included in the compounds known as "insulin sensitizers" are "of considerable value" CC.A. Hofrnann et al., Diabetes Care, JJ5, 1075, (1922)]. However, there has been no previous report that thiazolidinedione derivatives could be used to treat pancreatitis. Now he has "surprisingly discovered that the class" of compounds now known as "insulin sensitizers", and which include different thiazolidinedione compounds, "oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds, have the ability to treat and prevent pancreatitis.

BRIEF DESCRIPTION OF THE INVENTION Therefore, an object of the present invention is to provide a method for the treatment or prophylaxis of pancreatitis by administering to a mammal, which can be human, suffering from pancreatitis, or is susceptible to suffering from it, an effective dose of an insulin sensitizer. enough fortreat or inhibit pancreatitis. Other objects and advantages will become evident as the description continues.

DETAILED DESCRIPTION OF THE INVENTION At present, experimental evidence seems to suggest that the activity that inhibits or prevents prancreatitis derives from the mode of action of insulin sensitizers, and "in this way it is believed that the chemical structure of the compounds is" of less importance than their activities. Therefore, any compound having insulin sensitizing activity can be used in the present invention. The insulin sensitizer can also be referred to as an insulin resistance enhancing agent, and was originally used for the prevention and / or treatment of diabetes. The term encompasses a wide variety of compounds, typically thiazolidinedione compounds, oxazolidinedione compounds, isoxazole idynedione compounds and oxadiazolidinodone compounds. A class of preferred insulin sensitizers for use in the method of the present invention are those thiazolidinedione compounds of formula (T): wherein: R1 and R2 are the same or different from each other and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 3 represents a hydrogen atom, an aliphatic acyl group having from 1 to 6 carbon atoms, a cycloalkanecarbonyl group having from 5 to 7 carbon atoms in the cycloalkane part, a benzoyl group, a naphthoyl group, a group benzoyl or naphthoyl which is substituted by at least one s? bstit? ent selected from the group consisting of a-substituents, "defined below, a heterocyclic acyl group in which the heterocyclic part has from 4 to 7 ring atoms" "Of which" from 1 to 3 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, a phenylacetyl group, a phenylpropionyl group, a phenylacetyl or phenylpropionyl group which is substituted by at least one halogen substituent, a cinnamoyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxyl portion, or a benzyloxycarbonyl group; R * and R5 are the same or different from each other and each represents a hydrogen atom, an alkyl group having 5 carbon atoms or a carbonyl group having 1 to 5 carbon atoms, or R 1 and R 5 together represent an alkylenedioxy group having 1 to atoms of carbon; n is 1, 2 or 3; Y and Z are the same or different from each other and each represents an oxygen atom or an imino group; and the a-substituents are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, hydroxyl groups, amino groups, alkylamino groups, they have "from 1 to 4 carbon atoms, dialkyl groups having from 1 to 4 carbon atoms in each alkyl group, and nitro groups; and pharmaceutically acceptable salts thereof. In the compounds "of formula (I) used in the present invention, where" R * represents an alkyl group having from 1 to 5 carbon atoms, this may be a straight or branched chain alkyl group having 1 to 5 carbon atoms. at 5 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and isopentyl groups; of which methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups are preferred. Of these, those alkyl groups having 1 to 4 carbon atoms are preferred, and the methyl group is preferred.

Where R2 or RS represent an alkyl group having 5 carbon atoms, this may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and sopentyl, of which methyl, ethyl groups are preferred, propyl, isopropyl, butyl, isobutyl and pent lo. Of these, alkyl groups having 1 to 3 carbon atoms are preferred, and the methyl group is preferred. In "where R3 represents an aliphatic alkyl group, this may be a straight or branched chain group having from 1 to 6 carbon atoms, preferably an alkanoy group having from 1 to 6 carbon atoms, for example a forrnyl group, acetyl, ilo, butyl, isobutyryl, valep- lo, isovaleryl, pivaloyl, or hexanoyl, "of which the foryl, acetyl, propiomyl, butyl, butyl, oxalyl, and hexanoyl groups are preferred. Aliphatic acyl groups are preferred, particularly alkanoyl groups having 1 to 4 carbon atoms, and the acetyl group is preferred. In <wherein R3 represents an aromatic acyl group, this is a benzoyl or naphthoyl group in which the aromatic ring may be unsubstituted or may be substituted by at least one substituent selected from the group consisting of substituents a, defined above and exemplified below. Examples of said of-substituents include: alkyl groups having from 1 to 4 carbon atoms, which may be straight or branched chain groups such as the methyl, ethyl, propyl, isopropyl, butyl isobutyl, sec-butyl and t-butyl groups, of which prefer the methyl and t-butyl groups; -Alkoxyl groups having from 1 to 4 carbon atoms, which may be straight or branched chain groups, such as ethoxy, ethoxy, prooxo, isopropoxy, butoxy, and obutoxy, sec-butoxy and t-butoxy groups, of which the ethoxy group is preferred; - halogen atoms such as the fluorine, chlorine, bromine and iodine atoms, of which the fluorine and chlorine atoms are preferred, hydroxyl groups; -groups to i o; -Alkyl groups having from 1 to 4 carbon atoms, which may be straight chain or branched chain groups, such as the linear groups, ethylene, non-propyl, L-butylamino, butylated, isobutyl, sec. -butylate, and t ~ but., which are preferred by the metilarrimo group; - Jialkylaromine groups that have "1 to 4 carbon atoms in each part" of alkyl, which may be straight or branched chain groups such as the dimethylarmine, diethylane, d? pr * op? lam, dusopropyl groups inobutyl, dibutylamino, diisobutylammon, butyiamino, di-t-butylamino, N-methyl--ethylamino, N-methyl-N-propylamino, N-meth? N-? so? rop? lam? no, N-methyl-N-butyia ino, N- met? iN-? sobut? lam? no, N-methyl-N-sec-butylamino, N-met i 1 -Nt- ut i lamí no, N-et? iN-prop? lam? no, N-ethyl -N- 1 sopropilarnino, N-etil-N-butilamino, N-etil-N- ísobutila ino, N-etii-N-sec-butilarnmo, N-etil-Nt-butilammo, N-prop lNi soproμilammo, N-propil -N- butiiam.no, N-? Rop? L -N?? Ssbut? Larn? No, N-μropil -N-sec-butylannmo, N-propyl-Nt-butylamm, N-isopropyl-N-butiiarnino, N - isopropyl-N-isobutylammo, N-isopropyl-N-sec-butylannino, N-isopropyl-Nt-butyiamino, N-bu iJ-N- isobutylarnino, N-but-lN-sec-butylanin, N- butii-Nt-butilarmno, N-? sobut? iN-sec-but? lamino, N-? sobut? l-N ~ < -butylamm and N-sec-butyl-N-t-butylamine, where the dimethylamine group is preferred; and nitro groups. In the case of R3 represents a benzoyl or naphthoyl group, there is no particular restriction on the number of substituents, except that which may be imposed by the number of substitutable positions (5 in the case of benzoyl or 7 in the case «Je na toílo) and possibly by restrictions are cas. However, in general, 1 to 3 substituents are preferred. Where there is more than one substituent, the substituyent.es may be the same or different from each other. Examples of substituted or unsubstituted benzoyl or naphthoyl groups include benzoyl groups, 4- in mtrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl, 3,4-dichlorobenzoyl, 4-ammobenzoyl, 3-d? meth? laminobenzoyl, 2-rnetoxybenzoyl, 3,5-d? -t-but? l-4- H? drox? benzo? lo and 1- and 2-naphthoyl. Of these, benzoyl and unsubstituted 1-naphthoyl groups, preferably the benzoyl group, are preferred. In the form of R3 represents a cycloalkanecarbonyl group, this has from 5 to 7 carbon atoms in the cycloalkane ring, and thus a total of 6 to 8 carbon atoms in the whole group. Examples of such groups include the cyclopentanecarbomyl, cyclohexanecarbomyl and cycloheptanecarbonyl groups, of which the cyclohexanecarbonyl group is preferred. Where R3 represents a heterocyclic acyl group, this is a group in which a heterocyclic group is attached to a carbonyl group. The heterocyclic part has from 4 to 7 ring atoms, preferably 5 or 6 ring atoms, "of which of 3, preferably 1 or 2, and preferably 1, are heteroatoms selected from the group consisting of nitrogen atoms. , oxygen and sulfur. Where there are three heteroatoms in the heterocyclic group, these are preferably nitrogen atoms or one or "two atoms" of nitrogen and correspondingly, two or one atoms are oxygen and / or sulfur. The heterocyclic group is preferably aromatic. Examples "The groups of preferred heterocyclic acyl groups include the furoyl groups (preferably 2-furoyl), tenoyl (preferably 3-tenoyl), 3- priridmcarbonilo (nicotinoilo) and 4-pyridinecarbomlo (isonicotmoyl). In 'wherein R3 represents a fenilacetiio or phenylpropionyl group w is substit? I' do, preferably in the phenyl group, by at least one halo substituent "geno, the halogen substituent may be a fluorine, chlorine, bromine or iodine, and it may be from 1 to 5 such halogen substituents, preferably "from 1 to 3 halogen substituents, and preferably a halogen substituent. Fjemplos "he said groups include p_-chlorophen groups? Lacetílo, o_-f luorofenilacetilo, £ -bromofenilacetilo, £ -I" dofenilacetilo, o-chlorophenylacetyl, o-flurofenilacetilo, o-bromophenylacetyl, o-yodofenilacetüo, m-chlorophenylacetyl, m -flurofenilacetilo, rn-bromophenylacetyl, -yodofenilacetilo, 2, 4-d? chlorophenylacetyl, 2,4-difluorophenylacetyl, 2, 4-dibromofen? lacetiio, 2,4-diyodofenilacetüo, 3- (£ -clorofeml) propion? I, 3 - (£ luorofenil -f) propionyl, 3- (? £ -brornofen l) propionyl, 3- (£ ~ brornofeniDpropionilo, 3- (£ -chlorophenyl) propionyl, 3- (£ iodophenyl) propionyl, 3- (o- chlorophenyl) propionyl, 3- (o-fluoropheni 1) propionyl, 3- (o-romophenyl) propionyl, 3- (o-iodophenyl) propionyl, 3- (m-chlorophenyl) propionyl, 3- (m-fluoropheyl) pro-onyl, 3- (rn-bromo-phenyl-1) -propionyl, 3- (rn-iodo-phenyl) -propionyl, 3- (2,4-d-chlorophenyl) pro-on-lo, 3- (2, 4) ~ difluorofeniDpropiomlo, 3- (2,4-d? bromophenyl) prop? on? lo and 3 ~ (2, 4-diiodopheni.1) propionyl, of w the ref group erido e_s_j¿-clorofenilace + ilo.

Where R3 represents an alkoxycarbonyl group, it may be a straight or branched chain alkoxycarbonyl group having 6 carbon atoms in the alkoxyl part, ie, having a total of 2 to 7 carbon atoms. carbon such horn the etoxicarboni groups I, etoxicarbomlo, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxicarbomlo, t-butoxycarbonyl, pentiioxi carbonyl and yl hexiloxicarbo, "of w those groups coxicarbomlo having 2 to 4 carbon atoms prefer of carbon and the ethoxycarbonyl group is preferred. Where * represents an alkyl group, this may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms, such as the groups R, R, N, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. and pentium, of w alkyl groups having 1 to 4 carbon atoms, preferably a methyl or t-butyl group, and most preferably a methyl group are preferred. Where R * or 5 represent an alkoxy group, this may be a straight or branched chain alkoxy group having from 1 to 5 carbon atoms, such as the rnetoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy groups, t-butoxy and pentyloxy, of w alkoxy groups having 1 to 4 carbon atoms, preferably a methoxy or t-butoxy group, and most preferably a rnetoxy group are preferred. Where R * and R5 together represent an alkylenedioxy group, it has from 1 to 4 carbon atoms and the examples include the methylenedioxy, ethylenedioxy, propylenedium i, t rirnet i lendioxy and tetra ethylenedioxy groups, of w the methylenedioxy and ethylenedioxy groups are preferred. n is 1, 2 or 3, but is preferably 1. Y and Z are the same or different from each other and each represents an oxygen atom or an imam group; however, preferably both are "oxygen atoms". The preferred compounds used in the present invention are the compounds of formula la: wherein R1, R2, R4 and Rd are the same or different from each other and each represents a hydrogen atom or an alkyl group having "from 1 to 5 carbon atoms; and R3 represents a hydrogen atom, one alafático acyl group having one to six carbon atoms, a benzoyl group, a naphthoyl group, a benzoyl or naphthoyl group w is substituted by at least one substituent selected "read group" ie substituents or, defined above, or an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy portion. the a-substituents are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, groups alkoxy having 4 carbon atoms, halogen atoms, hydroxyl groups, arnino groups, alkylammon groups having from 1 to 4 carbon atoms, dialkylammon groups having from 1 to 4 carbon atoms in each alkyl part, and nitro groups; and pharmaceutically acceptable salts "thereof. Preferred classes of compounds used "two in the present invention are the compounds of formula I or the and pharmaceutically acceptable salts thereof in which: (fl) Ri represents an alkyl group having from 1 to 4 carbon atoms. (B) R2 represents a hydrogen atom or an alkyl group having "from 1 to 3 carbon atoms. (C) R3 represents a hydrogen atom, an aliphatic acyl group having from 1 to 4 carbon atoms, a non-substi tuted benzoyl or naphthoyl group, or an alkoxycarbombo group having from 2 to 4 carbon atoms. carbon. (D) * represents an alkyl group having from 1 to 4 carbon atoms. (E) R 5 represents a hydrogen atom or an alkyl group having "from 1 to 3 carbon atoms". In particular, of the above compounds are preferred compounds of formula I and that in which R * is as defined in (A) above, 2 is as defined in (B) above, R3 is as defined in (C) ) above, R * is as defined in (D) above, and RS is co or defined in (E) above.

The preferred compounds of compounds used in the present invention are the compounds of formula I and the pharmaceutically acceptable salts thereof, in which: (F) R 1 represents an alkyl group having from 1 to 4 carbon atoms. (G) R 2 represents a hydrogen atom or an alkyl group having "from 1 to 3 carbon atoms". (H) R3 represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group. (I) R4 represents an alkyl group having from 1 to 4 carbon atoms. (3) RS represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. In particular, of the above compounds the compounds of formula I and Ta in which R 1 is as defined in (F) above, R 2 is as defined in (G) above, R 3 is as defined in ( H) above, R * is co or defined in (I) above, and R5 is as defined in (3) above. The most preferred classes of compounds used in the present invention are the compounds of formula I and the pharmaceutically acceptable salts thereof in which: (K) R1 represents a me-Lio group. (L) R 2 represents a hydrogen atom or a methyl group. (M) R3 represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group.

(N) * represents a methyl group or? N t-butyium group. (0) RS represents a hydrogen atom or a methyl group. In particular, of the above compounds the compounds of formula I and that in which R 1 is as defined in (K) above, R 2 is as defined in (L) above, R 3 is as defined in (H) ) above, R * is co or defined in (N) above, and R5 is as defined in (0) above. When the compounds of formula I of the present invention contain at least one basic group in their molecules, they can form addition salts with acid. Examples of said acid addition salts include salts with mineral acids, especially halogenhydric acids (such as hydrofluoric acid, brornhydric acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkane-ionic acids, such as methanesulfonic acid, trifluorornetanosulphonic acid or ethanesulphonic acid; salts with phonic acids, such as benzylsulphonic acid or p-toluensulonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tart-rich acid, oxalic acid, aleic acid, rnic acid, succinic acid, benzoic acid, rnandhelic acid, ascorbic acid, lactic acid, glucomatic acid or citric acid; and salts with amino acids, such as glutarmic acid or aspartic acid.

Said acid addition salts can be easily prepared by conventional means. The compounds of the present invention can also form salts with cations, for example metals. Examples of such salts include salts with an alkali metal such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; salts with other metals, such as magnesium or aluminum; ammonia salts; salts of organic base, such as a salt with rnetiiarnma, dimet i lamina, trietiiamma, dusopropilamina, cyclohexilarnina, or diciclohexila ma; and salts with a basic amino acid such as lysine or arginine. Said salts, likewise, can easily be prepared by conventional means. The compounds of the present invention can exist in the form of several isomers. In this way, the carbon atom at position 2 of the annulus and at position 5 the thiazolidine ring, are both asymmetric carbon atoms. In each of the compounds of formula I and the stereoisomers due to these asymmetric carbon atoms, as well as equimolar and non-equi-ble mixtures thereof are all represented only by the single formula. Therefore, the scope of the present invention covers all these isomers separately, as well as mixtures thereof. In the compounds of formula I, in which Y and Z represent both í ino groups, in which Y and Z represent to oxygen atoms, and in which one of Y and Z represents a volume "Oxygen and the other represents an imam group, can exist in the form of vain tautomeros as explained in the Japanese patent application Kokai No. Sho 60-51189, US patent No., 572 912 and European Patent No. 139 421. In each of the compounds of the formula I and the, the tauomers and the equimolar and non-nolarlar mixtures thereof are all represented only by the formula I. Accordingly, the scope of the present invention covers all these tautoms and all mixtures thereof. The compounds of the present invention can also form solvates (for example hydrates), and the present invention encompasses all those solvates. The present invention additionally encompasses all so-called "prodrugs", which are to be converted by etabolic change into any of the compounds of formula T or salts thereof. The specific examples of the compounds of the formula I are those composed of the formula la: in which l, R2. R3, R «, and RS, are how they are defined following table I. The following abbreviations are used in the table: Oc: acetyl iBu: isobutyl tBu: t-butyl Byr: butyryl Bz: benzoyl Etc: ethoxycarbonyl Et: ethyl Me: methyl Pn: pentyl TABLE 1 Of the compounds listed above, the Preferred compounds are compounds No .: 1. 5-C4- (6-H? droxy-2,5,7,8-tetramethylcro-an-2-ylmethoxy) benzyl thiazolidino-2,4-dione; Four . 5- C 4- (6 ~ Hydrox i -2-mei il ~ 7-t-but? Lchroman -2- ilrnetox i) benzyl 1] thiazole idino ~ 2,4-dione; 5. 5-C4- (6-Hydrox? -2-et? L-5,7,8, -tr? Methylchroman-2-ylmethoxy) benzyl] -thiazolidino-2,4-dione; 6. 5-C4- (6-Hydrox? -2-isobutyl 1-5,7,8-trimethylchroman-2-ylmethoxy) benzyl-thiazolidino-2,4-dione; 8. 5-C4- (6-ftcetox? -2,5,7,8-tet amet? Lchroman-2-yltrnetoxy) benzyl] thiazole? Dino-2,4-dione; 10. 5-C - (6-Ethoxycarbonyloxy -2, 5,7, 8-tetramethylchroman-2-lmetoxy) benzyl] -thiazolidino-2,4-dione; and pharmaceutically acceptable salts thereof. The most preferred compounds are compounds No. 1.4 and 10, and the most preferred compound is compound No. 1 (commonly known as "troglitazone", by which name it will be referred to hereinafter). The compounds of formula I and the salts of the same of the present invention are known compounds, and are described in, for example, Japanese Patent Application Kokai No. Sho 60-51189, U.S. Pat. No. 4, .572 912 and European patent No. 0 139 421. These may be prepared as described in those documents or by other known methods. In addition to the thiazolidine derivatives of the formula I described above, it has been discovered that other sensitizers known insulin makers can also be used for the treatment or prevention of pancreatitis, although the mechanism by which this is obtained is not known. Examples of such other compounds include: i. MCC-555; 5-C6-Y 2-Fluorobenzyloxy) -2-naphthylmethyl thiazolidino-2,4-dione, which is described as an antilipemic and antidiabetic agent in Diabetes, 4J5, Suppl. 1141A (1996) and Example 4 «of EP 604 983A; ii. Pioglitazone: 5-. { 4-C2- (5-Etii? Iridin-2-yl) ethoxy] benzyl} -thiazolidin-2,4-dione, which is described as an insulin sensitizer in Japanese Patent Publication No. Sho 62-42903 and No. Hei 5-66956 and in the patents "of E.U.A. Nos. 4,287,200, 4,340,605, 4,438,141, 4,444,779 and 4,725,610; iii. Englitazone: 5 ~ (2-Benzyl-3, 4-dihydro-2H-benzopyran-6-ylmethi) -thiazolidino-2,4-dione; which is described as an insulin sensitizer in Japanese Patent Publication No. Hei 5-86953 and in the patent of E.U.A. No. 4 703 052; iv. BRL -49653: 5- -. { 2 ~ [N-Methyl ~ N- (? Iridin-2-yl) amino] ethoxy} benzyl] thiazolidino-2,4-dione, which is described as a sens.ibiza < of insulin in the application "of Japanese patent Kokai No. He.i-1-131169 and in the patents of E.U.A. Nos. 5 002 953, 5 194 443, 5 232 925 and 5 260 445; v. Compound A: 5- (4- { 2-Cl- (4-2'-pyridylphenyl) ethylidene-anninoxy] ethoxy} benzyl) thiazolidino-2,4-dione, which is described as an insulin sensitizer in European Patent No. 708 098A; saw. Compound B: 4-C4-C2- (5-Methyl-2-phenyloxazol-4-yl) ethoxy] benzyl} isoxazoli «Jino-3,5-dione, which is described as an antilipemic and antidiabetic agent in UO 95/18125; vii. Compound C: 5-. { 4- (5-Methoxy-3-methylimidazoC4,5-b] pyridin-2-yl-methoxy) benzyl} thiazolidino-2,4-dione (and its hydrochloride), which are "described as insulin sensitisers" in the application "Japanese Patent Kokai No. Hei 7-330728 and in European Patent No. 676 398A; viii. 5- [4- (6-Methoxy-l-methylbenzimidazol-2-ylmethoxy) benzyl] -thiazolidino-2,4-dione, which is described as an insulin sensitizer in European Patent No. 745 600A; ix. 5- E4- (l-Methoxybenzyl-midazol-2-ylmethoxy) benzyl] thiazolidino-2,4-dione, which is described as an insulin sensitizer in European Patent No. 745 600A; x. 5-C4- (5-Hydroxy-l, 4,6, 7-tetramethylbenzylnidazol-2-lrnetoxy) -benzyl] thiazoli «dino-2,4-dione, which is described as an insulin seneitizer in the European patent No. 745 600A; xi. 5-1.4- (l-Metiiindolin-2-ylmethoxy) benzyl] thiazolidino-2, -dione, which is "described as an insulin sensitizer in Japanese Patent No. Hei 7-330728 and in European Patent No. 676 398A; xii. Darglitazone: 5-. { 4- [3- (5-Rethyl-2-phenyloxazol-4-yl)? Rop-nyl] -benzyl} thiazolidino-2,4-dione, which is described as a hypoglycemic and hypocholesterolemic agent in the application "of Japanese Patent Kokai No. Hei 1-272574 and European Patent No. 332 332A. The compounds employed in the present invention can be administered by vain routes. The route of administration is not particularly critical to the present invention, and is determined in accordance with the form of drug preparation and the age, sex and condition of the patient, as well as the nature and extent of the disease. For example, for oral administration, the compounds may be administered in the form of tablets, pills, powders, granules, syrups, liquid preparations, suspensions, emulsions or capsules. Injections can be administered intravenously by themselves or mixed with normal fluid replacements, such as glucose and amino acids; or they may be, if necessary, administered intramuscularly, intracutaneously, subcutaneously or intrapeptoneally by themselves. When suppositories are used, they can be administered intrarectally. The compounds of the present invention can be administered alone or with any known additives commonly used in the field of the preparation of drugs such as vehicles, binders, disintegrators, lubricants, solubilizers, co-regulators, and coating agents. Such preparations can be obtained by known means. When you are going to prepare tablets, the vehicles that widely used in this field can be employed, for example: vehicles, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders, such as water, ethanol, propanol, simple syrup, glucose solution, almi'don solution, gelatinous solution, carboxymethyl cellulose, purified lacquer, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone; disintegrators, such as dry milk, sodium alginate, agar powder, laminating powder, sodium bicarbonate, calcium carbonate, polyethylene sorbitan fatty acid esters, sodium lauryl sulphate, stearic acid monoglyceride, starch and lactose; disintegration inhibitors, such as sucrose, stearin, cocoa oil and hydrogenated oil; absorption accelerators, such as quaternary ammonium bases and sodium lauryl sulfate; humectants, such as glycerin and starch; absorbers, such as starch, lactoea, l-aol na, bentomta and colloidal silicic acid; and lubricants, such as purified talcum, salts of stearic acid, boric acid powder and polyethylene glycol. In addition, the tablets may, if necessary, be prepared as normal coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or as "double-layer or multi-tablet" tablets. layers. When preparing pills, vehicles that are widely known in this field can be used "two, : * R for example: vehicles, such as glucose, lactose, starch, cocoa oil, hardened vegetable oil, kaolin and talc; binders, such as gum arabic, tragacanth powder, gelatin and ethanol; and disintegrators, such as "laminaran" agar. It is possible to use vehicles widely known in the field when preparing suppositories, for example: polyethylene glycol, cocoa oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycends. When injections are to be prepared, then they may be solutions, emulsions or suspensions that are preferably sterilized and isotonic to the blood. When these solutions, emulsions and suspensions are to be prepared, diluents conventionally used in this field can be employed; for example, water, ethyl alcohol, propylene glycol, ethoxy isostearyl alcohol, polyoxy-isosteanyl alcohol, and sorbent fatty esters of pol otylene. In this case, enough sodium chloride, glucose or glycepine to make it isotonic to the solution can be included in these preparations; or common solubilizers, pH regulators or pain suppressors can be added. In addition, coloring agents, preservatives, perfumes, flavoring agents, sweetening agents and any other drug may be added if necessary. The amount of active ingredient contained in these preparations is not particularly critical, and can be selected on a wide scale. In general, from 1 to 70%, by weight, preferably from 1 to 30% by weight of the active ingredient can be present throughout the composition. Although the dosage can vary depending on the symptoms, age and body weight of the patient, as well as the route of administration and the form of the drug, an upper limit of 5,000 mg (preferably 1,000 g, and rnuy preferably 500 rng ), and a lower limit of 0.5 mg (preferably 10 mg and preferably 50 mg), can preferably be administered daily to an adult human patient.

BIOLOGICAL ACTIVITY Since the decrease in the amount of pancreatic parenchyma resulting from chronic pancreatitis causes pancreatic weight loss, any suppression of the decrease in the amount of pancreatic parenchyma can be used as an index to evaluate any improvement in pancreatic parenchyma. pancreatitis Furthermore, since the egeneration and necrosis of pancreatic parenchyma and its replacement by connective tissue * occurs in chronic pancreatitis, the seriousness of pancreatitis can be estimated by measuring histopathologically the area over which the pancreatic parenchyma is replaced with tissue. connector (known as the "scarred area"). The measurement of pancreatic weight can be carried out by conventional procedures after the experimental animals have been sampled using phlebotomy. In the pancreatitis, the secretion of digestive enzymes is "damaged and the release of digestive enzymes to the duodenum is reduced. 0 «others, digestive enzymes are spilled in the blood and their level in the blood and urine increases. Consequently, the point of pancreatitis can be estimated by reducing the amount of digestive enzymes that have been spilled in the blood (Methods of Climcal Examination: Kmbara Publ isher).

EXAMPLES The invention is further illustrated by means of the following examples, which illustrate the biological activities of the compounds of the present invention and their subsequent preparation, which illustrates the preparation of the compositions of the present invention. The following general procedure can be used to test * a compound and determine if it is effective against pancreatitis. The effects of pancreatitis can be simulated, as is normally done, in experimental animals, by the administration of "streptozotocin C (N-rnetylnitroso-carbornoil) -D-glucosarnane: R.A. Beett et al. ^ Cancer Res., 41, 2786-2790, (1981); a product of Si grna Chemical Company], which is capable of specifically destroying the B cells of the "Je L ngerhans" and which induces "in this way a decrease in pancreatic weight. The streptozotocma is administered intravenously to the experimental animal, and then a powder feed mixed with a test compound is given to a group of animals that have been dosed with streptozotooi a. This group will henceforth be referred to as the "treated group". Meanwhile, only one powder food is given to another group of animals that have been dosed with streptozotocin. This group > or it is subsequently referred to as the "control group". Normal animals (not dosed) fed only with food are also used as a model group against experimental animals ("dosed with streptozotocin). After the test compounds have been administered to the animals for a predetermined period, each animal is sacrificed to measure its pancreatic weight. The measurement of the scarred area can also be carried out by conventional methods. More specifically, male UBN / Kob rats are used as co-spontaneous chronic pancreatitis models and are fed a powder feed mixed with a test compound. The pancreas of each animal is subsequently removed completely. Its weight is measured and also the area c? Catpza "da is measured relative to the total transverse area of tissue of the pancreas sliced by an image analyzer. The measurement of digestive enzymes can be also carried out by conventional procedures. For example, after the test drug mixed in the powder feed has been administered to the male UBN / Kob rats for a definite period, the blood can be collected and the lipase activity (one of the digestive enzymes) ) in the plasma can be measured.

EXAMPLE 1 Inhibitory effect of pancreatic weight loss (i) Effect of streptozotoci a The test animals were Uistar-Imarnichi rats each with a body weight of approximately 200 g and used in groups of rats each consisting of 5 animals. Each test animal was administered intravenously at a dose of 20 rnG / kg or 40 mg / l-g. After seven days, the rats were sacrificed and the pancreas of each animal was weighed. The results are summarized in table 2.

TABLE 2 As can clearly be seen from Table 2, the administration of streptozotocin caused the decrease in pancreatic weight. (ii) Inhibitory Effect The test animals were Uistar-Imamichi rats each with a body weight of approximately 200 g and used in groups of rats each consisting of 12 animals. Eetreptozotocin was administered intravenously at a dose of 25 mg / kg once to each animal. Seven days "after" the administration, a group of rats was fed a powder F2 (Funabashi Farms) powder mixed with 0.2% troglitazone. { 5-υ 4 - (6-hydroxy? -2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidino-2,4-dione} , and this was continued for 14 days. The average dose of the compound during this period was 170 rng / kg / day. This group will later be referred to as "the treated group". Meanwhile, another group of rats was fed only the F2 food powder. This group will be referred to later as "the control group". On the other hand, as a model group against the experimental animals to which streptozotocin was administered, rats not dosed with streptozotocin were fed the F2 food powder alone. This group will later be referred to herein as "the normal group. "After a predetermined period, the rats were sacrificed and the pancreatic weight of each animal was measured.The results are summarized in Table 3.

TABLE 3 * p < 0.05 vs. control group As can be clearly seen from table 3, trglitazone significantly inhibited pancreatic weight caused by the administration of streptozotocin. 97 to 98% of the pancreas consisted of exocrine pancreatic tissue, and no lesions such as edema were observed. Consequently, the increase in pancreatic weight is thought "} which is attributable to the increase in exocrine pancreatic tissue obtained by the administration of troglitazone.

EXAMPLE 2 Pancreatic weight increase The test animals were male WBN / Kob rats, which are commonly used as models of spontaneous chronic pancreatitis and suffer from pancreatic weight loss and exocrine pancreatic tissue dysfunction due to degeneration and necrosis of the pancreatic parenchyma and its replacement by CTsuchitani connector tissue and other Labratory Animáis, 19 (3), 200-207, (1985)]. Each group of test animals contained 4 animals, and the animals were used for the experiment when they reached 12 weeks of age. The animals were fed with powdered F2 feed mixed with 0.2% troglitazone for three months. This group will later be referred to as "the treated group". The average compound dose during this period was "140 rng / kg / day. Meanwhile, four other rats (control group) were fed the F2 food powder only. After the rats were fed with food for three months, the pancreas of each animal was completely excised and its weight was measured. The results are summarized in Table 4.

TABLE 4 ** p < 0.01 vs. "Control group It can be seen from the previous results that the pancreatic group of the treated group showed a significant increase compared to that of the control group. Since 97 to 98% of the pancreas consists of exogenous pancreatic tissue, it is considered that the increase in pancreatic weight results from an increase in exocrine pancreatic tissue.

EXAMPLE 3 Suppression of the decrease in pancreatic weight The procedure described in example 2 was repeated, except that the test compound was pioglitazone ("the pioglitazone group"), BRL-49653 ("the group BRL-49653"), or compound A ("the group of compound A"). The results are shown in the following table 5, which also shows the number of animals in each group and the dose of each test compound.

TABLE 5 + Rats Uistar < the same age. *** p < 0.001, ** p < 0.01 vs. control group EXAMPLE 4 Scarred Area of Pancreatic Tissue In order to evaluate the results of Example 2 hietopathologically, each pancreae used for the weight measurement in Example 2 was fixed in 10% neutral formalin. This was later divided into one half of the spleen side and one half of the side of the duodenum, and half of it was sliced at 3 mm intervals to provide transverse pieces of tissue. All these pieces of tissue were subjected to the paraffin preparation by conventional procedures and subsequently to hematoxylin staining. eosma and Maseon's trichromatic stain to prepare doe tissue preparations, which are used for histopathological examination. The total cross-sectional area of the piece of pancreatic tissue in each preparation was measured by an image analyzer (SPICCOII, manufactured by Olympus Optical Co., Ltd.). The results are summarized in Table 6. In addition, the surface area "of the area that has suffered" degeneration and necrosis in which the exogenous pancreatic tissue was replaced by connective tissue (the scarred area) was measured using an image analyzer. . The results are summarized in table 7. TABLE 6 Total cross-sectional area of a piece of pancreatic tissue (mm2) p < 0.05 vs. Control group From the above results it can be seen that the total cross-sectional area of the pancreatic tissue of the group > or treaty showed a remarkable increase compared to that of control group. In this measurement, since any change in tissue that could have caused an increase in pancreatic weight (such as edema) was not observed, it is thought that this result indicates an increase in exocrine pancreatic tissue (ie, simple hypertrophy). ) TABLE 7 Scarred area in the exocrine pancreatic tissue (mm2) * p < 0.05 vs. Control group In this case, the treated group showed significantly lower values compared to the control group. Consequently, it can be concluded that degeneration and necrosis in the exocrine pancreatic tissue are suppressed in the group. or treated.

EXAMPLE 5 Scarred area of pancreatic tissue In order to evaluate the results of histopathological example 3, the total cross-sectional area and the scarred area of each pancreas whose weight was measured in Example 3, was measured by the procedure described in Example 4. The results are summarized in Tables 8 and 9, respectively. TABLE 8 The cross-sectional area of pancreatic tissue piece (m 2) ** p < 0.0i, * p < 0.05 vs. Control group TABLE 9 SCARED AREA IN THE EXOCRINE PANCREATIC TISSUE (m? Ta2) ** p < 0.01, * p < 0.05 vs. Control group From the previous results (Table 8) it can be seen that the total cross-sectional area of the pancreatic tissue of each of the groups using a test compound showed a marked increase compared to that of the control group. In this measurement, since no tissue change was observed that could have caused an increase in pancreatic weight (such as edema), this result is thought to indicate an increase in exocrine pancreatic tissue (ie, simple hypertrophy. ). In addition, each of the groups "using a test compound showed a significantly lower value of the scarred area compared to the control group (Table 9).

Therefore, it can be concluded that "The incecrosis of exocrine pancreatic tissue is suppressed in These groups.

EXAMPLE 6 Effect of long-term troglitazone treatment on plasma lipase activity and increase in pancreatic weight The test animals were male UBN / Kob rats. Each group of test animals contained 6 animals, and the animals were used for the experiment when they had reached 12 weeks. The animals were fed with F2 powder feed mixed with 0.2% or 0.05% troglitazone for 9.5 months. Those groups from here on are known as "the 0.2% group" and "the 0.05% group," respectively. The average doses of the compound "during this period were" 120 rng / kg / day and 30 rng / g / i, respectively. Meanwhile, another 6 rats (gr? P »or« Je control) were fed with powder food F2 only. After lae rats had been fed with food for 9.5 months, each rat was decapitated and its blood was collected. The blood serum was separated and the level of lipase in the plasma was measured using an autoanalyzer (type 7250, reported by Hitachi Ltd.). The lipase activities in the plasma of both the "0.2% group" and the 0.05% group showed a significant decrease compared to the "group" control group.

After the blood had been collected, the pancreas of each animal was completely excised and weighed. The pancreatic weight of both the "0.2% group" and the "0.05% group" showed a significant increase compared to that of the control group. The results are summarized in table 10. TABLE 10 *** p < 0 001, *? < 0 05 vs. Group of role EXAMPLE 7 Scarred area of pancreatic tissue In order to evaluate the results of Example 6 histopathologically, the total cross-sectional area and the healed area of each pancreas whose weight was measured in Example 6, was measured by the procedure "described in Example 4. The results are summarized in tables 11 and 12, respectively.

TABLE 11 Total cross-sectional area of a portion of pancreatic tissue (mm2) p < 0.05, go. Control group TABLE 12 Scarred area in the exocrine pancreatic tissue ** p < 0.01, vs. Control group From the previous results (table 11) it can be seen that the total cross-sectional area of the pancreatic tissue of each of the groups that use a test compound showed a marked increase compared to the "group" control group. In this measurement, since no change in tissue that could have caused an increase in pancreatic weight (such as edema) was observed, it is thought that this result indicates an increase in exogenous pancreatic tissue (ie, simple hypertrophy). In addition, each of the groups using a test compound showed a value significantly "from the c? Catr? Za" area compared to the control group (Table 12). Therefore, it can be concluded that the "degeneration mcecrosis" of exogenous pancreatic tissue are suppressed in these groups.

EXAMPLE 8 Acute toxicity Acute toxicity was tested by conventional procedures. Very specifically, troglitazone was administered orally to 3 ddY mice (males) in a single dose of 300 rng / kg, and the mice were observed for 5 days. At the end of this time, the animals were all alive. When the acute toxicities of compounds No. 2, 3, 4 and 10 were measured in the same manner, the mice were all alive after an oral dose of 300 mg / kg or more.

PREPARATION 1 Capsules Troglitazone 100 mg lactose 168.3 mg corn starch 70 mg magnesium stearate 1.7 mg total volume 340.0 mg Powders of the above formulation were mixed and passed through a 20 mesh screen (Tyler's normal mesh), and the resulting mixed powder was packed into gelatin capsules to prepare capsules.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. The use of an insulin sensitizer p > for the manufacture of a medicament for the treatment of prophylaxis of pancreatitis.

2. The use of a sensitizer "Je insulin de conformi" Jad with claim 1, characterized by "Jernás because said insulin sensitizer is a thiazolidinedione compound, a compound" of oxazolidinodione, an isoxazolidinedione compound or a compound of Oxadiozolidinedione.

3. The use of an ineulin sensitizer according to claim 1, further characterized in that said insulin sensitizer is a thiazolidinedione compound or an isoxazolidinedione compound.

4. The use of an insulin sensitizer in accordance with claim 1. further characterized in that said insulin sensitizer is at least one compound of the formula (I): wherein R * and R2 are the same or different from each other and each represents a hydrogen atom or an alkyl group having "from 1 to 5 carbon atoms; R3 represents a hydrogen atom, an acyloaliphatic group having from 1 to 7 carbon atoms, a cycloalkanoyl group of 5 to 7 carbon atoms in the cycloalkane part, a benzoyl group, a naphthoyl group, a benzoyl or naphthoyl group which it is replaced by * at least one of substituents or, 'I defined' later on, an acyloheterocyclic group in which the heterocyclic part has from 4 to 7 ring atoms of which 'from 1 to 3 are heterogeneous atoms' of n? tró < geno and / or oxygen and / or sulfur, a iacetiio-faith group, a phenylpropionyl group, a phenylethyl or phenylpropiomyl group which is substituted by a halogen substituent, a cmarnoyl group, an alkoxycarbonyl group having from 1 to 6 carbon atoms, carbon in the alkoxy part or a benzyloxycarbonyl group; R * and R5 are the same or different from each other and each represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or an alkoxy group having 5 carbon atoms, or R * and RS together represent an alkylenedioxy group having 4 carbon atoms; n is 1, 2 0 3; Y and Z are the same or different from each other and each represents an oxygen atom or an ammo group; and the substituents or are selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, "halogen atoms, hydroxy groups, amino groups, alkylamino groups having" from 1 to 4 volumes of carbon, dialkyl groups having from 1 to 4 carbon atoms in each alkyl part and nitro groups; and pharmaceutically acceptable salts thereof.

5. The use of an insulin sensitizer according to claim 1, further characterized in that said insulin sensitizer is at least a compound of the formula (Ia): wherein R1, R2, R *, and R5 are the same or different from each other and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; and R3 represents an atom "Je hydrogen, an acyl allylic group having 1 to

6 carbon atoms, a benzoyl group, a naphthoyl group, a group > or benzoyl or naphthoyl which is substituted by at least one of substituents a, defined below, or an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy part; the a-substituents are selected from alkyl groups having "from 1 to 4 carbon atoms", alkoxy groups having from 4 carbon atoms, "halogen atoms, hydroxy groups, amino groups, alkoxy groups having the 4 carbon atom, dialkylamino groups that have «from 1 to 4 carbon atoms in each part alkyl and group > I nitro; Y pharmaceutically acceptable salts thereof. 6. The use of an insulin sensitizer according to claim 4, further characterized in that R1 represents an alkyl group having 1 to 4 carbon atoms.

7. The use of insulin sensitizer according to claim 4, further characterized in that R 2 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.

8. The use of an insulin sensitizer according to claim 4, further characterized in that R3 represents a hydrogen atom, an acyloaliphatic group having 1 to 4 carbon atoms, an unsubstituted benzoyl or naphthoyl group, or an alkoxycarbonyl group having from 2 to 4 carbon atoms.

9. The use of an insulin sensitizer according to claim 4, further characterized in that R * represents an alkyl group having 1 to 4 carbon atoms.

10. The use of an insulin sensitizer according to claim 4, further characterized in that RS represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

11. The use of an insulin sensitizer according to claim 4, further characterized in that l represents an alkyl group having 1 to 4 atoms e carbon; R2 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R3 represents a hydrogen atom, an acyloaliphatic group having 1 to 4 carbon atoms, or an unsubstituted benzoyl or naphthoyl group? or an alkoxycarbonyl group having from 2 to 4 carbon atoms; R * represents an alkyl group having from 1 to 4 carbon atoms; and R5 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

12. The use of an insulin sensitizer according to claim 4, further characterized in that R3 represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group.

13. The use of an insulin sensitizer according to claim 4, further characterized in that R1 represents an alkyl group having 1 to 4 carbon atoms; R 2 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R3 represents a hydrogen atom or an acetyl group, a benzoyl group or an ethoxycarbonyl group; R * represents an alkyl group having from 1 to 4 carbon atoms; and Rs represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atom.

14. The use of an insulin sensitizer "according to claim 4, further characterized in that R1 represents a methyl group.

15. The use of a sensitizer for ineulin according to claim 4, characterized "do a" demae because R2 represents a hydrogen atom or a methyl group.

16. The use of an insulin sensitizer according to claim 4, further characterized in that R3 represents a hydrogen atom, an acetyl group, or an ethoxycarbomyl group.

17. The use of an insulin sensitizer according to claim 4, further characterized in that * represents a methyl group or a -butyl group.

18. The use of an insulin sensitizer according to claim 4, further characterized in that RS represents a hydrogen atom or a methyl group.

19. The use of an insulin sensitizer according to claim 4, further characterized in that l represents a methyl group; R2 represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, an acetyl group, or an ethoxycarbonyl group; R * represents a methyl group or a t-butyl group; RS represents a hydrogen atom or a methyl group.

20. The use of an insulin sensitizer according to claim 5, characterized in that R represents an alkyl group having 1 to 4 carbon atoms.

21. The use of an insulin sensitizer according to claim 5, further characterized in that R2 represents a hydrogen atom or an alkyl group which has «1 to 3 carbon atoms».

22. The use of an insulin sensitizer according to claim 5 further characterizes "Jo" because R3 represents a hydrogen atom, an acyloaliphatic group having from 1 to 4 carbon atoms, an unsubstituted benzoiolo or naphthoyl group, or an alkoxycarbonyl group having from 2 to 4 carbon atoms.

23. The use of an insulin sensitizer according to claim 5, further characterized in that R represents an alkyl group having from 1 to 4 carbon atoms.

24. The use of an insulin sensitizer according to claim 5, further characterized in that R5 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

25. The use of an insulin sensitizer according to claim 5, further characterized in that R1 represents an alkyl group having 1 to 4 carbon atoms; R2 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R3 represents a hydrogen atom, an acyloaliphatic group having "from 1 to 4 carbon atoms, an unsubstituted benzoyl or naphthoyl group, or an alkoxycarbonyl group having" from 2 to 4 carbon atoms; R * represents an alkyl group having from 1 to 4 carbon atoms; and RS represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

26. The use of a "insulin" sensing element "according to claim 5, further characterized in that R3 represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbomyl group.

27. The use of an insulin sensitizer according to claim 5, further characterized in that R1 represents an alkyl group having from 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R3 represents a hydrogen atom, a group an acetyl group, a benzoyl group or an ethoxycarbonyl group; R * represents an alkyl group having "from 1 to 4 carbon atoms; and RS represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

28. The use of an insulin sensitizer according to claim 5, further characterized in that R1 represents a methyl group.

29. The use of a sensitizer "Je insulin according to claim 5, further characterized in that R2 represents a hydrogen atom or a methyl group.

30. The use of an insulin sensitizer according to claim 5, further characterized in that R3 represents a hydrogen atom, an acetyl group, or an ethoxycarbonyl group.

31. The use of an insulin sensitizer according to claim 5, further characterized because R * represents a methyl group or a t-butyl group.

32. The use of an insulin sensitizer according to claim 5, further characterized in that RS represents a hydrogen atom or a methyl group.

33. The use of a sensitizer "Je insulin according to claim 5, further characterized in that Rl represents a methyl group; R 2 represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, an acetyl group, or an ethoxycarbonyl group; R * represents a methyl group or a t-butyl group; RS represents a hydrogen atom or a methyl group.

34. The use of an insulin sensitizer according to claim 5, further characterized in that said insulin sensitizer is at least one of: 5-C4- (6-h? Drox? -2.5.7, 8-tet rame? T? Lchroman-2-? Lrneto?) Benzyl-thiazoli d? No-2,4-d? Ona: 5-114- (6-h? Drox? ~ 2-met? L-7- t-but? lcrornan-2-llynetoxy) benc? l] t.?azol? d? no-2-4-d? on; 5- [4- (6-H? Drox? -2-et? L-5, 7,8-tmetmet? Lchroman-2-? Lmethoxy?) Benzyltazole? D? No-2,4-ione; 5-C4- (6-h? Drox? -2-? Sobut? L-5,7,8-tr? Met? Lcrornan-2-yl-ethoxy) en-l? -t? Azol? Dmo-2,4- Mrs; 5-T4 - (6-acetox? -2, 5,7,8-tetramet? Lchroman-2? Lmethox?) Benzyl t? Azole? ? no-2, 4-dione; 5-r4- (6-ethoxy? Carbon? Lox? -2,5,7,8-tetrame? Lchroman-?? Methoxy?) Benc? L] -t? Azole? D? No-2,4-d? ona; 5-C6- (2-fluoroben-c? Lox?) -2-naphth? Lmet? L] t? Azol? Dmo-2,4-d? Ona; 5-. { 4-C2 ~ (5-et? L-pi r? D? N-2-? L) ethoxy? benc? l} t? aol? d? no-2,4-d? ona; 5- (2-benzyl-3, 4-d? -hydro-2H-benzop? Ran-6? Lmet? L) t? Aolol? D? No-2,4-dione; 5- E 4-. { 2- [N-methyl-N- (pyridin-2-yl) amino] ethoxy] benzyl] thiazolidino-2,4-dione, - 5 - (4 -. {2 - 1 - (4 - 2 '- pi ri di 1 f or 1) eti 1 denenoxynoxy] -ethoxy. benzyl) thiazolidino-2, -dione; 4-. { 4-C2- (5-Rethyl-2-phenyl-oxazo.l-4-yl) ethoxy] benzyl} ieoxazolid.ino-3,5-dione; 5-. { 4 ~ (5-methoxy-3 ~ methylimidazoC4, 5-b] pyrid.in-2-yl-methoxy) benzyl} -thiazoli-dino-2,4-dione; 5- Hydrochloride. { 4- (5-methoxy-3-methyl-imi "dazoC4? 5-b] pyridin-2-yl-methoxy-benzyl} -thiazolidino-2,4-dione: 5- C4- (6-methoxy-1-methylbenzimidazole- 2-ylmethoxy) encyl] thiazoli-di-2, 4-dione; 5-C4- (1-rnet.-ylbenzyrnidazol-2-ylne-toxy) -benzyl] -thiazolidino-2,4-dione; - C 4- (5- hydro-1, 4, 6, 7- tet ramet.il enzi-rnidazol-2-ylmethoxy) benzyl] -thiazolidino-2, -dione; 5-C4- (1-metiiin « dolin-2-ylmethoxy) benzyl] thiazolidino-2,4-dione; 5-. {4-C3- (5-rnethyl-2-phenyloxazol-4-yl) propionyl] benzyl} -thiazolidin-2, 4-dione, and pharmaceutically acceptable salts thereof.