RU2167656C2 - Use of insulin sensibilizing agent for treatment and prophylaxis of pancreatitis - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention proposes novel agent for treatment and prophylaxis of pancreatitis. Invention proposes the known insulin sensibilizing agents, especially thiazolidinedione compounds, for example, troglytazon, oxazolidinedione compounds or oxadiazolidinedione compounds. EFFECT: broadened arsenal of agents of indicated prescription. 34 cl, 12 tbl

Description

BACKGROUND OF THE INVENTION
The invention relates to a new method of using a series of known compounds, including thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds in the treatment and prevention of pancreatitis.

 Pancreatitis is usually roughly divided into acute pancreatitis or chronic pancreatitis, depending on whether or not the state of pancreatitis persists after the elimination of the etiological agent. Except where the context requires otherwise, the term “pancreatitis,” as used here, includes both acute pancreatitis and chronic pancreatitis.

 Perhaps approximately 40% of cases of acute pancreatitis may be due to alcohol abuse. Other causes include idiopathic, traumatic, cholelithiasis, and overeating. The first three reasons are responsible for 70-80% of this disease.

 The number of patients suffering from chronic pancreatitis has been steadily increasing in recent years, approximately linearly depending on the increase in alcohol consumption, although this is also associated with an increase in protein and fat intake. Chronic pancreatitis is a pathological condition characterized by decreased exocrine function associated with pancreatic dysfunction. In chronic pancreatitis, destruction of the pancreatic parenchyma begins with acinar cells and soon spreads to the islets of Langerhans. The main cause of chronic pancreatitis is alcohol abuse, and other causes include cholelithiasis, acute pancreatitis, and idiopathic origin (especially often in women). Recently, the incidence of chronic pancreatitis associated with alcohol abuse has begun to increase.

 The preferred treatment for acute pancreatitis includes prophylactic, therapeutic, drug treatment, such as eliminating the cause of the disease, protecting the pancreas, preventing self-digestion in the pancreas, relieving pain, anti-infection measures and regulating nutrition.

 On the other hand, for the treatment of chronic pancreatitis, it would be desirable to suppress the deterioration of the pathological condition of the pancreas and to regenerate and restore the pancreatic tissue, but such treatment does not exist.

 Accordingly, symptomatic treatment is mainly prescribed for both acute and chronic pancreatitis. For the treatment of pancreatitis, various drugs have been used, of which protease inhibitors are the most widely used. It is believed that protease inhibitors suppress the action of trypsin, which accelerates self-digestion in the pancreas. In addition, protease inhibitors have been reported to stimulate exocrine tissue regeneration in the pancreas. However, this assessment is contradictory. Many thiazolidinedione derivatives are known to increase insulin activity and improve diabetes status [Fujiwara et al., Diabetes, 37, 1549 (1988)]. In particular, the significant value of the class of thiazolidinedione derivatives included in the compound, known as “insulin sensitizing agents”, “insulin sensitizers” [C.A. Hofmann et al., Diabetes Care, 15, 1075 (1922)]. However, previously there were no reports that thiazolidinedione derivatives can be used to treat pancreatitis.

 And now we unexpectedly discovered that this class of compounds, now known as “insulin sensitizers,” and which includes various thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds, has the ability to treat and prevent pancreatitis.

SUMMARY OF THE INVENTION
Therefore, an object of the present invention is a method of treating or preventing pancreatitis by administering to a mammal, which may be a person suffering from pancreatitis or prone to pancreatitis, an effective dose of an insulin sensitizer sufficient to cure or suppress pancreatitis.

 Other objects and advantages will become apparent in the course of further description.

DETAILED DESCRIPTION OF THE INVENTION
Currently, experimental data suggest that the activity to suppress or prevent pancreatitis is the result of the mechanism of action of insulin sensitizers, and thus the chemical structure of these compounds is believed to be less important than their activity. Accordingly, having activity to increase insulin sensitivity can be used in this invention.

 An insulin sensitizer, which can also be called a substance that increases insulin resistance, was originally used to prevent and / or treat diabetes. The term encompasses a wide range of compounds, typically thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds.

где R¹ и R² являются одинаковыми или разными, и каждый представляет атом водорода или алкильную группу, имеющую от 1 до 5 атомов углерода;
R³ представляет собой атом водорода, алифатическую ацильную группу, имеющую от 1 до 6 атомов углерода, циклоалканкарбонильную группу, имеющую от 5 до 7 атомов углерода в циклоалкановой части, бензоильную группу, нафтоильную группу, бензоильную или нафтоильную группу, которая замещена по крайней мере одним заместителем, выбираемым из группы, состоящей из заместителей α, которым дано определение ниже, гетероциклическую ацильную группу, в которой гетероциклическая часть имеет от 4 до 7 атомов в кольце, из которых от 1 до 3 являются гетероатомами, выбираемыми из группы, состоящей из атомов азота, кислорода или серы, фенилацетильную группу, фенилпропионильную группу, фенилацетильную или фенилпропионильную группу, которые замещены по крайней мере одним галогеновым заместителем, циннамоильную группу, алкоксикарбонильную группу, имеющую от 1 до 6 атомов углерода в алкоксильной части или бензилоксикарбонильную группу;
R⁴ и R⁵ являются одинаковыми или разными, и каждый представляет собой атом водорода, алкильную группу, имеющую от 1 до 5 атомов углерода или алкоксильную группу, имеющую 1 - 5 атомов углерода, или R⁴ и R⁵ вместе представляют собой алкилендиокси-группу, имеющую от 1 до 4 атомов углерода;
n равно 1, 2 или 3;
Y и Z являются одинаковыми или разными, и каждый представляет собой кислородный атом или иминогруппу; и
заместители α выбираются из группы, состоящей из алкильных групп, имеющих от 1 до 4 углеродных атомов, галогеновых атомов, гидроксильных групп, аминогрупп, алкиламино-групп, имеющих от 1 до 4 углеродных атомов, диалкиламино-групп, имеющих от 1 до 4 углеродных атомов в каждой алкильной части, и нитрогрупп;
и их фармацевтически приемлемые соли.One of the classes of preferred insulin sensitizers for use in the method of this invention are thiazolidinedione compounds of the formula (I):

where R ¹ and R ² are the same or different, and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms;
R ³ represents a hydrogen atom, an aliphatic acyl group having from 1 to 6 carbon atoms, a cycloalkanecarbonyl group having 5 to 7 carbon atoms in the cycloalkane part, a benzoyl group, a naphthoyl group, a benzoyl or naphthoyl group which is substituted by at least one a substituent selected from the group consisting of substituents α, as defined below, a heterocyclic acyl group in which the heterocyclic part has from 4 to 7 atoms in the ring, of which 1 to 3 are heteroatoms, selected from the group consisting of nitrogen, oxygen or sulfur atoms, a phenylacetyl group, a phenylpropionyl group, a phenylacetyl or phenylpropionyl group which are substituted by at least one halogen substituent, a cinnamoyl group, an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy part or benzyloxycarbonyl group;
R ⁴ and R ⁵ are the same or different, and each represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or an alkoxyl group having 1 to 5 carbon atoms, or R ⁴ and R ⁵ together represent an alkylenedioxy group having from 1 to 4 carbon atoms;
n is 1, 2 or 3;
Y and Z are the same or different, and each represents an oxygen atom or an imino group; and
substituents α are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, hydroxyl groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups having from 1 to 4 carbon atoms in each alkyl part, and nitro groups;
and their pharmaceutically acceptable salts.

In the compounds of formula (I) used in this invention, where R ¹ represents an alkyl group having from 1 to 5 carbon atoms, it may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl and isopentyl groups, of which methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups are preferred. Of these groups, those alkyl groups which have from 1 to 4 carbon atoms are more preferred, and the methyl group is most preferred.

When R ² or R ³ represents an alkyl group having from 1 to 5 carbon atoms, it may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl , isobutyl, b-butyl, pentyl and isopentyl groups, of which methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups are preferred. Of these, those alkyl groups which have from 1 to 3 carbon atoms are more preferred, and the methyl group is most preferred.

When R ³ is an aliphatic acyl group, it may be a straight or branched chain group having from 1 to 6 carbon atoms, preferably an alkanoyl group having from 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl , valeryl, isovaleryl, pivaloyl, or hexanoyl groups, of which formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and hexanoyl groups are preferred. Those aliphatic acyl groups are preferred, especially those alkanoyl groups which have 1 to 4 carbon atoms, and the acetyl group is most preferred.

When R ³ is an aromatic acyl group, it 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 α as defined above, and examples of which are given below. Examples of such substituents α include:
alkyl groups having from 1 to 4 carbon atoms, which may be straight or branched chain groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and t-butyl groups, of which we prefer methyl and t-butyl group;
alkoxyl groups having from 1 to 4 carbon atoms, which may be straight or branched chain groups, such as methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, isobutoxyl, b-butoxyl and t-butoxyl groups, of which we prefer the methoxy group ;
halogen atoms such as fluorine, chlorine, bromine and iodine atoms, of which we prefer fluorine and chlorine atoms;
hydroxyl groups;
amino groups;
alkylamino groups having from 1 to 4 carbon atoms, which may be straight or branched chain groups, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, b-butylamino and t-butylamino groups of which we prefer a methylamino group;
dialkylamino groups having from 1 to 4 carbon atoms in each alkyl part, which may be straight or branched chain groups, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-w-butylamino , di-t-butylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-isopropylamino, N-methyl-N-butylamino, N-methyl-N- isobutylamino, N-methyl-N-v-butylamino, N-methyl-N-t-butylamino, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-ethyl-N-butylamino -, N-ethyl-N-isobutylamino, N-ethyl-N-w-butyl min-, N-ethyl-N-t-butylamino, N-propyl-N-isopropylamino, N-propyl-N-butylamino, N-propyl-N-isobutylamino, N-propyl-N-w-butylamino -, N-propyl-N-t-butylamino, N-isopropyl-N-butylamino, N-isopropyl-N-isobutylamino, N-isopropyl-N-b-butylamino, N-isopropyl-N-t- butylamino, N-butyl-N-isobutylamino, N-butyl-N-b-butylamino, N-butyl-N-t-butylamino, N-isobutyl-N-b-butylamino, N-isobutyl-N t-butylamino and N-vt-butyl-N-t-butylamino groups, of which we prefer the dimethylamino group; and
nitro groups.

When R ³ represents a substituted benzoyl or naphthoyl group, there is no particular limitation on the number of substituents, except that it can be determined by the number of substitutable positions (5 in the case of benzoyl or 7 in the case of naphthoyl) and possibly spatial restrictions. However, in general, we prefer 1 to 3 substituents. Where more than one substituent is present, the substituents may be the same or different.

 Examples of such substituted or unsubstituted benzoyl or naphthoyl groups include benzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl, 3,4-dichlorobenzoyl, 4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl, 3,5-di butyl 4-hydroxybenzoyl and 1- and 2-naphthoyl groups. Of these, we prefer the unsubstituted benzoyl and 1-naphthoyl groups and most prefer the benzoyl group.

When R ³ is a cyaloalkane carbonyl group, it has from 5 to 7 carbon atoms in the cycloalkane ring, and thus, generally from 6 to 8 carbon atoms in the whole group. Examples of such groups include cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl groups, of which a cyclohexanecarbonyl group is preferred.

When R ³ is a heterocyclic acyl group, it is a group in which a heterocyclic group is attached to a carbonyl group. The heterocyclic moiety has from 4 to 7 atoms in the ring, more preferably from 5 to 6 atoms in the ring, of which 1 to 3, more preferably 1 or 2, and most preferably 1, are heteroatoms selected from the group consisting of atoms nitrogen, oxygen and sulfur. When 3 heteroatoms are present in a heterocyclic group, preferably they are all nitrogen atoms, or one or two are nitrogen atoms and, accordingly, two or one are oxygen or sulfur atoms. The heterocyclic group is preferably aromatic. Examples of preferred heterocyclic acyl groups include a furoyl (more preferably 2-furoyl), tenoyl (more preferably 3-tenoyl), 3-pyridinecarbonyl (nicotinoyl) and 4-pyridinecarbonyl (isonicotinoyl) group.

When R ³ represents a phenylacetyl or phenylpropionyl group which has substituents, preferably at least one halogen substituent in the phenyl group, the halogen substituent may be a fluorine, chlorine, bromine or iodine atom, and from 1 to 5 such halogen substituents may be present, preferably 1 to 3 halogen substituents, and more preferably 1 halogen substituent. Examples of such groups include p-chlorophenylacetyl, p-fluorophenylacetyl, p-bromophenylacetyl, p-iodophenylacetyl, o-chlorophenylacetyl, o-fluorophenylacetyl, o-bromophenylacetyl, o-iodophenylacetyl, m-chlorophenylacetyl, m-fluorophenyl iodophenylacetyl, 2,4-dichlorophenylacetyl, 2,4-difluorophenylacetyl, 2,4-dibromophenylacetyl, 2,4-diiodophenylacetyl, 3- (p-chlorophenyl) propionyl, 3- (p-fluorophenyl) propionyl, 3- (p-bromophenyl ) propionyl, 3- (p-iodophenyl) propionyl, 3- (o-chlorophenyl) prop onyl, 3- (o-fluorophenyl) propionyl, 3- (o-bromophenyl) propionyl, 3- (o-iodophenyl) propionyl, 3- (m-chlorophenyl) propionyl, 3- (m-fluorophenyl) propionyl, 3- ( m-bromophenyl) propionyl, 3- (m-iodophenyl) propionyl, 3- (2,4-dichlorophenyl) propionyl, 3- (2,4-difluorophenyl) propionyl, 3- (2,4-dibromophenyl) propionyl and 3 - (2,4-diiodophenyl) propionyl groups, of which the p-chlorophenylacetyl group is most preferred.

When R ³ is an alkoxycarbonyl group, it may be a straight or branched chain alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy part, i.e. having a total of 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, b-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups, of which we prefer such alkoxycarbonyl 4 carbon atoms, and an ethoxycarbonyl group is most preferred.

When R ⁴ is an alkyl group, it may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl groups, of which we prefer those alkyl groups which have from 1 to 4 carbon atoms, the methyl or t-butyl group is more preferred, and the methyl group is most preferred.

When R ⁴ and R ⁵ represents an alkoxyl group, it may be a straight or branched chain alkoxyl group having from 1 to 5 carbon atoms, such as methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, isobutoxyl, t-butoxyl and pentyloxy groups, of which we prefer alkoxyl groups which have from 1 to 4 carbon atoms, methoxy or t-butoxyl groups are more preferred, and methoxy is most preferred.

When R ⁴ and R ⁵ together represent an alkylenedioxy group, it has from 1 to 4 carbon atoms, and examples include a methylenedioxy group, an ethylenedioxy group, a propylene dioxo group, a trimethylene dioxo group, and a tetramethylenedioxy group, of which methylenedioxy and ethylenedioxy are preferred.

 n is 1, 2 or 3, but preferably 1.

 Y and Z are the same or different and each represents an oxygen atom or an imino group, however, both are preferably oxygen atoms.

где R¹, R², R⁴ и R⁵ являются одинаковыми или разными и каждый представляет собой атом водорода или алкильную группу, имеющую от 1 до 5 атомов углерода; и
R³ представляет собой атом водорода, алифатическую ацильную группу, имеющую от 1 до 6 атомов углерода, бензоильную группу, нафтоильную группу, бензоильную или нафтоильную группу, которая является замещенной по крайней мере одним заместителем, выбираемым из группы, состоящей из заместителей α, которым дано определение ниже, или алкоксикарбонильную группу, имеющую от 1 до 6 атомов углерода в алкоксильной части;
заместители α выбираются из группы, состоящей из алкильных групп, имеющих от 1 до 4 атомов углерода, алкоксильных групп, имеющих от 1 до 4 атомов углерода, галогеновых атомов, гидроксильных групп, аминогрупп, алкиламиногрупп, имеющих от 1 до 4 углеродных атомов, диалкиламиногрупп, имеющих от 1 до 4 углеродных атомов в каждой алкильной части, и нитрогрупп;
и их фармацевтически приемлемые соли.Preferred compounds used in this invention are compounds of formula (1a):

where R ¹ , R ² , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; and
R ³ represents a hydrogen atom, an aliphatic acyl group having from 1 to 6 carbon atoms, a benzoyl group, a naphthoyl group, a benzoyl or naphthoyl group which is substituted by at least one substituent selected from the group consisting of substituents α to which the definition below, or alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy part;
substituents α are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxyl groups having from 1 to 4 carbon atoms, halogen atoms, hydroxyl groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups, having from 1 to 4 carbon atoms in each alkyl part, and nitro groups;
and their pharmaceutically acceptable salts.

Preferred classes of compounds used in this invention are compounds of formula (1) or (1a) and their pharmaceutically acceptable salts, in which:
(A) R ¹ represents an alkyl group having from 1 to 4 carbon atoms.

(B) R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

(B) R ³ represents a hydrogen atom, an aliphatic acyl 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.

(D) R ⁴ 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, we prefer compounds according to the formulas (1) and (1a), in which R ¹ represents what is defined in (A) above, R ² is what definition is given in (B) above, R ^{3 is} defined in (B) above, R ^{4 is} defined in (D) above, and R ^{5 is} defined in (D) above.

More preferred classes of compounds used in this invention are compounds of formula (1) and (1a) and their pharmaceutically acceptable salts, in which:
(E) 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) R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group.

(I) R ⁴ represents an alkyl group having from 1 to 4 carbon atoms.

(K) R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms.

In particular, of the above compounds, we prefer compounds according to the formula (1) and (1a), in which R ¹ is presented in (E) above, R ^{2 is} defined in (G), above, R ³ is presented in (3), above, R ⁴ is what is presented in (I) and R ^{5 is} defined in (K) above.

The most preferred classes of compounds used in this invention are compounds of the formula
(1) and (1a) and their pharmaceutically acceptable salts, in which:
(L) R ¹ represents a methyl group.

(M) R ² represents a hydrogen atom or a methyl group.

(H) R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group.

(O) R ⁴ represents a methyl or t-butyl group.

(P) R ⁵ represents a hydrogen atom or a methyl group.

In particular, of the above compounds, we prefer compounds according to the formula (1) and (1a), in which R ¹ is represented in (L), above, R ^{2 is} defined in (M), above, R ^{3 is} defined in (H) , above, R ^{4 is} defined in (O), above and R ^{5 is} defined in (P), above.

 When the compounds of formula (1) of the present invention contain at least one basic group in their molecules, they can thus form acid addition salts. Examples of such acid addition salts include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; salts with amino acids such as glutamic acid or aspartic acid. Such acid addition salts can be easily prepared by conventional methods.

 The compounds of this invention can also form salts with cations, for example metals. Examples of such salts include: salts with alkali metals such as sodium, potassium or lithium; salts with alkaline earth metals such as barium or calcium; salts with other metals, such as magnesium or aluminum; ammonium salts; salts with organic bases, such as a salt with methylamine, dimethylamine, triethylamine, diisopropylamine, cyclohexylamine; and salts with basic amino acids such as lysine or arginine. Such salts can also be easily obtained by conventional methods.

 The compounds of this invention may exist in the form of various isomers.

 So, the carbon atom in position 2 of the chroman ring and the carbon atom in position 5 of the thiazolidine ring are both asymmetric carbon atoms. For each of the compounds according to formulas (1) and (1a), the stereoisomers associated with these asymmetric carbon atoms, as well as their equimolar and non-equimolar mixtures, are all represented by only one formula. Accordingly, the scope of the invention includes all of these isomers separately, as well as all mixtures thereof.

 The compounds of formula (1) in which Y and Z both represent imino groups, in which Y and Z both represent oxygen atoms and in which one of Y and Z represents an oxygen atom and the other represents an imino group, can exist in as various tautomers, as explained in Japanese Patent Kokai Application Sho 60-51189, US Patent No. 4572912 and European Patent No. 139421.

 For each of the compounds according to formulas (1) and (1a), tautomers and their equimolar and non-equimolar mixtures are all represented by only one formula. Accordingly, the scope of the present invention covers all of these tautomers and all mixtures thereof.

 The compounds of this invention can also form solvates (e.g. hydrates), and the invention encompasses all such solvates.

 This invention further includes all so-called "prodrugs" that can be converted by in vivo metabolic changes into any of the compounds of formula (1) or a salt thereof.

в которой R¹, R², R³, R⁴ и R⁵ дано определение в следующей таблице 1. В таблице использованы следующие аббревиатуры:
Ac: - ацетил,
iBu: - изобутил,
tBu: - т-бутил,
Byr: - бутирил,
Bz: - бензоил,
Etc: - этоксикарбонил,
Et: - этил,
Me: - метил,
Pn: - пентил
Из соединений, перечисленных выше, предпочтительными соединениями являются соединения N:
1. 5-[4-(6-гидрокси-2,5,7,8, тетраметилхроман-2-илметокси)-бензил] тиазолидин-2,4-дион;
4. 5-[4-(6-гидрокси-2-метил-7-т-бутилхроман-2-илметокси)-бензил] тиазолидин-2,4-дион;
5. 5-[4-(6-гидрокси-2-этил-5,7,8-триметилхроман-2-илметокси)бензил] тиазолидин-2,4-дион;
6. 5-[4-(6-гидрокси-2-изобутил-5,7,8-триметилхроман-2-илметокси)бензил] тиазолидин-2,4-дион;
8. 5-[4-(6-ацетокси-2,5,7,8-тетраметилхроман-2-илметокси)-бензил] тиазолидин-2,4-дион;
10. 5-[4-(6-этоксикарбонилокси-2,5,7,8-тетраметилхроман-2-илметокси)бензил] тиазолидин-2,4-дион;
и их фармацевтически приемлемые соли.Specific examples of compounds of formula (1) are compounds of formula (1a):

in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} defined in the following table 1. The following abbreviations are used in the table:
Ac: - acetyl,
iBu: - isobutyl,
tBu: - t-butyl,
Byr: - butyryl,
Bz: - benzoyl,
Etc: - ethoxycarbonyl,
Et: - ethyl,
Me: methyl
Pn: - pentyl
Of the compounds listed above, preferred compounds are compounds N:
1. 5- [4- (6-hydroxy-2,5,7,8, tetramethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
4. 5- [4- (6-hydroxy-2-methyl-7-t-butylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5. 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
6. 5- [4- (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
8. 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione;
10. 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
and their pharmaceutically acceptable salts.

 More preferred compounds are compounds N 1,4 and 10, and the most preferred compound is compound N 1 (commonly known as "troglitazone", under this name it is referred to in the description below).

 The compounds of formula (I) and their salts of the present invention are known compounds and are described, for example, in Japanese Patent Kokai Application Sh 60-51189, US Patent No. 4,572,912 and European Patent No. 0139421. They can be prepared as described in these documents or other known methods.

 In addition to the thiazolidine derivatives of formula (1) described above, we found that other known insulin sensitizers can be used to treat and prevent pancreatitis, although the mechanism by which this is achieved is unknown.

Examples of such other compounds include:
I. MCC-555: 5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione, which is disclosed as an antilipemic and antidiabetic agent in Diabetes, 45, Suppl. 2, 141A (1996) and Example 4 of EP 604983A;
II. Pioglitazone: 5- {4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl} thiazolidin-2,4-dione, which is disclosed as an insulin sensitizer in Japanese Patent Publication N Sho 62-42903 and N Hei 5- 66956 and in US patent N 4287200, 4340605, 4438141, 4444779 and 4725610;
III. Englitazone: 5- (2-benzyl-3,4-dihydro-2H-benzopyran-6-ylmethyl) thiazolidine-2,4-dione, which is disclosed as an insulin sensitizer in Japanese Patent Publication N Hei 5-86953 and US patent N 4,730,052;
IV. BRL-49653: 5- [4- {2- [N-methyl-N- (pyridin-2-yl) amino] ethoxy} benzyl] thiazolidine-2,4-dione, which is disclosed as an insulin sensitizer in Japanese Patent Kokai Application N Hei 1-131169 and U.S. Patent Nos. 5002953, 5194443, 5232925 and 5260445;
V. Compound A: 5- (4- {2- [1- (4-2'-pyridylphenyl) ethylideneaminooxy] -ethoxy} benzyl] thiazolidine-2,4-dione, which is disclosed as an insulin sensitizer in European Patent No. 708098A;
VI. Compound B: 4- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl} isoxazolidin-3,5-dione, which is disclosed as an antilipemic and antidiabetic agent in WO 95/18125;
VII. Compound B: 5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-yl-methoxy) benzyl} thiazolidin-2,4-dione (and its hydrochloride), which are disclosed as insulin sensitizers in Japanese Patent Kokai Applucation N Hei 7-330728 and in European Patent No. 676398A;
Viii. 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione, which is disclosed as an insulin sensitizer in European Patent No. 745600A;
IX. 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione, which is disclosed as an insulin sensitizer in European Patent No. 745600A;
X. 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione, which is disclosed as an insulin sensitizer in European Patent No. 745600A;
Xi. 5- [4- (1-methylindolin-2-ylmethoxy) benzyl] thiazolidin-2,4-dione, which is disclosed as an insulin sensitizer in Japanese Patent Kokai Application No. Hei 7-330728 and European Patent No. 676398A;
XII. Darglitazone: 5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) -propionyl] benzyl] thiazolidine-2,4-dione, which is disclosed as a typeoglycemic and hyposolesterolemic agent in Japanese Patent Kokai Application N Hei 1-272574 and European patent N 332332A.

 The compounds used in this invention can be administered in various ways. The route of administration is not particularly important in this invention, and it is determined in accordance with the form of the drug, age, gender and condition of the patient, as well as the nature and stage of the disease. For example, when administered orally, 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 as a medicine on its own or in a mixture with conventional replacement fluids, such as glucose and amino acids; or they can be administered, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally, by themselves. When candles are used, they can be administered rectally.

 The compounds of this invention can be administered in pure form or in admixture with known additives commonly used in the manufacture of medicaments such as carriers, binders, disintegrants, lubricants, solubilizers, flavoring agents and coating agents. Such preparations can be made by known methods.

 When tablets are to be made, carriers that are widely known in the art can be used, for example, carriers 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, starch solution, gelatin solution, carboxymethyl cellulose, purified shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, fatty acid polyoxyethylene sorbitan esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil, absorption accelerators such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants, such as refined talc; stearic acid salts, boric acid powder and polyethylene glycol. In addition, tablets, if necessary, can be obtained in the form of conventional coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or as two-layer or multilayer tablets .

 When it is desired to make pills, carriers widely known in the art can be used, for example, carriers such as glucose, lactose, starch, cocoa butter, cured vegetable oil, kaolin and talc; binders such as gum arabic, tragacanth powder, gelatin and ethanol; and disintegrants such as laminar agar.

 When suppositories are desired, carriers that are widely known in the art can be used, for example, polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin and semi-synthetic glycerides.

 When injectable forms are desired, they may be solutions, emulsions or suspensions, which are preferably sterilized and isotonic with blood. When you need to prepare these solutions, emulsions and suspensions, you can use the usual solvents used in this area; for example, water, ethyl alcohol, propylene glycol, ethoxyisostearyl alcohol, polyoxyisostearyl alcohol and esters of fatty acids and polyoxyethylene sorbitan. In this case, a sufficient amount of sodium chloride, glucose or glycerol may be included in these preparations in order to make the solution isotonic; or conventional solubilizers, buffers, or pain suppressants.

 In addition, tinting agents, preservatives, flavoring agents, flavoring agents, sweeteners and other medicinal substances may be added, if necessary.

 The amount of active ingredient contained in these preparations is not critical and can be selected over a wide range. In general, the active ingredient may be present in an amount of 1 to 70% by weight, preferably 1 to 30% by weight of the total composition.

 Although the dosage may vary depending on the symptoms, age and body weight of the patient, as well as on the route of administration and dosage form, an adult may preferably receive a daily dose with an upper limit of 5000 mg (preferably 1000 mg and more preferably 500 mg), and a lower limit of 0.5 mg (preferably 10 mg, and more preferably 50 mg).

Biological activity
Since the decrease in pancreatic parenchyma resulting from chronic pancreatitis leads to pancreatic weight loss, any suppression of pancreatic parenchyma reduction can be used as an indicator to measure any improvement in pancreatitis. In addition, since pancreatic parenchyma degenerates and is replaced by connective tissue in chronic pancreatitis, the severity of pancreatitis can be assessed by histopathological measurement of the area in which the pancreatic parenchyma is replaced by connective tissue (known as the “scar area”).

 Pancreas weight can be measured using conventional techniques after experimental animals are killed by phlebotomy.

 With pancreatitis, the secretion of digestive enzymes is less and the secretion of digestive enzymes in the duodenum is reduced. In addition, digestive enzymes enter the bloodstream, and their levels in the blood and urine increase. Accordingly, the degree of development of pancreatitis can be assessed by determining the amount of digestive enzymes that have entered the bloodstream (Methods of Clinical Examination: Kinbara Publisher).

Examples
The invention is further illustrated by the following examples, which demonstrate the biological activity of the compounds of this invention and the subsequent preparation, which illustrates the manufacture of the compositions of this invention.

 The following basic procedure can be used to test the compound to determine whether it is effective in treating pancreatitis.

 The effects of pancreatitis can be mimicked, as is customary, in experimental animals by the administration of steptozotocin [(N-methylnitrosocarbamoyl) -D-glucosamine: R. A. Bennett et al. , Cancer Res., 41, 2786-2790 (1981); product of Sigma Chemical Company], which is capable of specifically destroying B cells of islets of Langerhans, and which, therefore, causes a decrease in pancreatic weight. Steptozotocin is administered intravenously to the experimental animal, and then a group of animals that have been given a dose of steptozotocin is given a powdered feed mixed with the test compound. This group is hereinafter referred to as the “treated group”. At the same time, another group of animals that were injected with steptozotocin is given only powdery food. This group is hereinafter referred to as the “control group”. Normal animals (which were not injected with streptozotocin) and which were fed only food were used as a pure group for comparison with experimental animals (which were injected with streptozotocin). After the test substances were administered to the animals for a certain period, each animal was killed to determine the weight of the pancreas.

 Measurement of the area of scar tissue can also be carried out using conventional methods. More specifically, male WBN / Kob rats are used as a model of spontaneous chronic pancreatitis and are fed with powdered food mixed with the test substance. The pancreas of each animal is then fully enucleated. Its weight is measured, and the region of scar tissue is also measured in relation to the total cross-sectional area of the pancreatic tissue, from which sections were made using an image analyzer.

 The determination of digestive enzymes can also be carried out using conventional techniques. For example, after male WBN / Kob rats are mixed with the test substance in a powdered food for a certain period, it is possible to collect blood and determine the lipase activity (of one of the digestive enzymes) in the plasma.

Example 1
Pancreatic Weight Loss Inhibitory Effect
(1) Effect of steptozotocin
The animals tested were Wistar-Imamichi rats, each having a body weight of about 200 g, and groups of rats were used, each of which consisted of 5 animals. Streptozotocin was intravenously administered to each test animal at a dose of 20 mg / kg or 40 mg / kg. Seven days later, the rats were sacrificed and the pancreas of each animal was weighed.

 The results are summarized in table 2.

 As can be clearly seen from table 2, the introduction of streptozotocin caused a decrease in pancreatic weight.

(II) Suppressive effect
The animals tested were Wistar-Imamichi rats, each weighing approximately 200 g, and groups of rats were used, each of which consisted of 12 animals. Streptozotocin was administered intravenously at a dose of 25 mg / kg once to each animal. 7 days after administration, a group of rats was fed F2 powder food (Funabashi Farms) mixed with 0.2% troglitazone {5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione}, and this continued for 14 days. The average dose of this substance during this period was 170 mg / kg / day. This group is hereinafter referred to as the “treated group”.

 At the same time, the other group of rats was fed only with powdered food F2. This group is hereinafter referred to as the “control group”. On the other hand, as a pure control group for experimental animals that were injected with streptozotocin, rats that were not injected with streptozotocin were fed only with F2 powdery food. This group is hereinafter referred to as the “normal group”. After a certain period of time, the rats were sacrificed and the weight of the pancreas in each animal was determined.

 The results are summarized in table 3.

 As can be clearly seen from Table 3, troglitazone significantly inhibited pancreatic weight loss caused by the administration of streptozotocin. 97-98% of the pancreas consisted of exocrine pancreatic tissue, and no damage such as edema was observed. Accordingly, an increase in pancreatic weight is believed to be associated with an increase in exocrine pancreatic tissue achieved through the administration of troglitazone.

Example 2
Pancreatic weight gain
The test animals were male WBN / Kob rats, which are commonly used as models of spontaneous chronic pancreatitis and suffer pancreatic weight loss and exocrine pancreatic tissue dysfunction associated with pancreatic parenchyma degeneration and necrosis and replacement of its connective tissue [Tsuchitani et al. Laboratory Animals, 19 (3), 200-207, (1985)]. Each group of test animals consisted of 4 animals, and these animals were used for the experiment when they reached the age of 12 weeks. The animals were fed with powdered feed F2 mixed with 0.2% troglitazone for three months. This group is hereinafter referred to as the “treated group”. The average dose of this compound for this period was 140 mg / kg / day. At the same time, the other four rats (control group) were fed only with F2 powder feed. After rats received this food for three months, the pancreas of each animal was fully enucleated and its weight was determined. The results are summarized in table 4.

 From the above results, it can be seen that a significant increase in the weight of the pancreas in the treated group compared with the weight in the control group was demonstrated. Since 97 - 98% of the pancreas consists of exocrine pancreatic tissue, it is believed that an increase in pancreatic weight occurs as a result of an increase in exocrine pancreatic tissue.

Example 3
Pancreatic Weight Loss Suppression
The procedure described in Example 2 was repeated except that the test compound was pioglitazone ("pioglitazone group"), BRL-49653 ("BRL-49653 group") or compound A (group "compound A"). The results are presented in the following table 5, which also shows the number of animals in each group and the dose of each test compound.

Example 4
Area of scar tissue in pancreatic tissue
To evaluate the results of Example 2 histopathologically, each pancreas used to determine the weight in Example 2 was fixed in 10% neutral formalin. It was then divided into the splenic half and duodenal half, and sections were cut from each half at 3 mm intervals to obtain pieces of tissue cross-section. All these pieces of tissue were prepared for paraffin sections by conventional methods and then stained with hematoxylin-eosin and three-chromic Masson staining to obtain two-tissue preparations, which were used for histopathological evaluation. The entire cross-sectional area of a piece of pancreatic tissue on each preparation was measured using an image analyzer (SPICCAII, manufactured by Olympus Optical Co., Ltd.). The results are summarized in table 6.

 In addition, using the image analyzer, we measured the surface area of the zone that underwent degeneration and necrosis, and in which the exocrine pancreatic tissue was replaced by connective tissue (the area of scar tissue). The results are summarized in table 7.

 From the above results, it can be seen that the total cross-sectional area of pancreatic tissue from the treated group, as shown, is significantly increased compared with this indicator in the control group. In this measurement, since there was no change in tissue that could cause an increase in pancreatic weight (such as edema), this result is believed to show an increase in exocrine pancreatic tissue (i.e., simple hypertrophy).

 In this case, as shown, the treated group had significantly lower values compared to the control group. Accordingly, we can conclude that degeneration and necrosis of exocrine pancreatic tissue are suppressed in the treated group.

Example 5
Area of scar tissue in pancreatic tissue
To evaluate the results of Example 3 histopathologically, the entire cross-sectional area and the area of scar tissue in each pancreas, the weight of which was determined in Example 3, was measured using the procedure described in Example 4. The results are summarized in Tables 8 and 9, respectively.

 From the above results (table 8), it can be seen that the total cross-sectional area of pancreatic tissue from each group with the test compound, as shown, is significantly increased compared with the control group. In this measurement, since no changes in tissue were observed that could cause an increase in pancreatic weight (such as edema), this result was believed to indicate an increase in exocrine pancreatic tissue (i.e., simple hypertrophy).

 In addition, in each of the groups taking the test compound, a significantly lower value of the area of scar tissue was shown in comparison with the control group (table 9). Accordingly, it can be concluded that degeneration and necrosis in the exocrine pancreatic tissue in these groups are suppressed.

Example 6
The effect of long-term treatment with troglitazone on plasma lipase activity and pancreatic weight gain
The test animals were male WBN / Kob rats. Each group of test animals consisted of 6 animals, and the animals were used for the experiment when they reached the age of 12 weeks. Animals were fed with powdered feed F2 mixed with 0.2% or 0.05% troglitazone for 9.5 months. These groups are hereinafter referred to as the “0.2% group” and the “0.05% group”, respectively. The average doses of this compound over this period were 120 mg / kg / day and 30 mg / kg / day, respectively. At the same time, the other six rats (control group) were fed only with F2 powder food. After the rats were fed this food for 9.5 months, each rat was beheaded and blood was collected. Blood serum was separated and the plasma lipase level was determined using an autoanalyzer (type 7250 manufactured by Hitachi Ltd.). A significant decrease in plasma lipase activity was shown both in the 0.2% group and in the 0.05% group compared with the activity in the control group.

 After the blood was collected, the pancreas of each animal was fully enucleated and weighed. It was shown that the weight of the pancreas both in the 0.2% group and in the 0.05% group increased significantly compared to the control group. The results are summarized in table 10.

Example 7
Area of scar tissue in pancreatic tissue
To evaluate the results of Example 6 histopathologically, the total cross-sectional area and the area of scar tissue of each pancreas, the weight of which was determined in Example 6, were measured using the procedure described in Example 4. The results are summarized in Table 11 and 12, respectively.

 From the above results it can be seen (table 11) that, as shown, the total cross-sectional area of the pancreatic tissue in each of the groups with the test compound was significantly increased compared with the control group. In this measurement, as there was no change in tissue that could cause an increase in pancreatic weight (such as edema), this result is believed to show an increase in exocrine pancreatic tissue (i.e., simple hypertrophy).

 In addition, in each of the groups with the test substance, a significantly reduced amount of scar tissue was shown compared with the control group (table 12). Accordingly, we can conclude that degeneration and necrosis in the exocrine pancreatic tissue in these groups are suppressed.

Example 8
Acute toxicity
Acute toxicity was investigated using conventional methods. More specifically, troglitazone was administered orally to three ddY mice (males) at a single dose of 300 mg / kg, and the mice were monitored for 5 days. At the end of this period, all animals were alive. When the acute toxicity of compounds N 2, 3, 4, and 10 was determined in the same way, the mice were alive after oral administration of a dose of 300 mg / kg or more.

Drug 1
Capsules
Troglitazone - 100 mg
Lactose - 168.3 mg
Corn Starch - 70 mg
Magnesium Stearate - 1.7 mg
Total volume - 340.0 mg
The powders from the above recipe were mixed and passed through a 20 mesh sieve (Tyler standard openings) and the resulting mixed powder was packaged in gelatin capsules to obtain a capsule dosage form.

Claims (34)

 1. The use of a pharmaceutically effective amount of an insulin sensitizer as an active ingredient in a medicament for the treatment and prevention of pancreatitis.  2. The use according to claim 1, characterized in that said insulin sensitizer is a thiazolidinedione compound, an oxazolidinedione compound or an oxadiazolidinedione compound.  3. The use according to claim 1, characterized in that said insulin sensitizer is a thiazolidinedione compound. 4. The use according to claim 1, characterized in that said insulin sensitizer is at least one compound of formula (I)

in which R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms;
R ³ represents a hydrogen atom, an aliphatic acyl group having from 1 to 6 carbon atoms, a cycloalkanecarbonyl group having 5 to 7 carbon atoms in the cycloalkane part, a benzoyl group, a naphthoyl group, a benzoyl or naphthoyl group which is substituted by at least one of substituents α, as defined below, are a heterocyclic acyl group in which the heterocyclic part has 4 to 7 atoms in the ring, of which 1 to 3 are heteroatoms of nitrogen and / or oxygen and / or sulfur, phenylacetyl uppa, phenylpropionyl group, phenylacetyl group or phenylpropionyl group which has at least one halogen substituent, cinnamoyl group, alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy part, or benzyloxycarbonyl group;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or an alkoxyl group having from 1 to 5 carbon atoms, or R ⁴ and R ⁵ together represent an alkylenedioxy group having from 1 to 4 carbon atoms;
n is 1, 2 or 3;
Y and Z are the same or different and each represents an oxygen atom or an imino group;
substituents α are selected from alkyl groups having from 1 to 4 carbon atoms, alkoxyl groups having from 1 to 4 carbon atoms, halogen atoms, hydroxyl groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups having from 1 to 4 carbon atoms in each alkyl part, and nitro groups,
or a pharmaceutically acceptable salt thereof. 5. The use according to claim 4, characterized in that said insulin sensitizer is at least one compound of formula (Ia)

in which R ¹ , R ² , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms;
R ³ represents a hydrogen atom, an aliphatic acyl group having from 1 to 6 carbon atoms, a benzoyl group, a naphthoyl group, a benzoyl group or a naphthoyl group which has at least one of the substituents α as defined below, an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxyl moiety;
substituents α are selected from alkyl groups having from 1 to 4 carbon atoms, alkoxyl groups having from 1 to 4 carbon atoms, halogen atoms, hydroxyl groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups having from 1 to 4 carbon atoms in each alkyl part, and nitro groups,
and its pharmaceutically acceptable salt. 6. The use according to claim 4, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms. 7. The use according to claim 4, characterized in that R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 8. The use according to claim 4, characterized in that R ³ represents a hydrogen atom, an aliphatic acyl 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. 9. The use according to claim 4, characterized in that R ⁴ represents an alkyl group having from 1 to 4 carbon atoms. 10. The use according to claim 4, characterized in that R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 11. The use according to claim 4, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms; R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R ³ represents a hydrogen atom, an aliphatic acyl 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 ⁴ represents an alkyl group having from 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 12. The use according to claim 4, characterized in that R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group. 13. The use according to claim 4, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms; R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group; R ⁴ represents an alkyl group having from 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 14. The use according to claim 4, characterized in that R ¹ represents a methyl group. 15. The use according to claim 4, characterized in that R ² represents a hydrogen atom or a methyl group. 16. The use according to claim 4, characterized in that R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group. 17. The use according to claim 4, characterized in that R ⁴ represents a methyl or t-butyl group. 18. The use according to claim 4, characterized in that R ⁵ represents a hydrogen atom or a methyl group. 19. The use according to claim 4, characterized in that R ¹ represents a methyl group; R ² represents a hydrogen atom or a methyl group; R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group; R ⁴ represents a methyl or t-butyl group and R ⁵ represents a hydrogen atom or a methyl group. 20. The use according to claim 5, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms. 21. The use according to claim 5, characterized in that R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 22. The use according to claim 5, characterized in that R ³ represents a hydrogen atom, an aliphatic acyl 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. 23. The use according to claim 5, characterized in that R ⁴ represents an alkyl group having from 1 to 4 carbon atoms. 24. The use according to claim 5, characterized in that R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 25. The use according to claim 5, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms; R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R ³ represents a carbon atom, an aliphatic acyl 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 ⁴ represents an alkyl group having from 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 26. The use according to claim 5, characterized in that R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group. 27. The use according to claim 5, characterized in that R ¹ represents an alkyl group having from 1 to 4 carbon atoms; R ² represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group; R ⁴ represents an alkyl group having from 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 28. The use according to claim 5, characterized in that R ¹ represents a methyl group. 29. The use according to claim 5, characterized in that R ² represents a hydrogen atom or a methyl group. 30. The use according to claim 5, characterized in that R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group. 31. The use according to claim 5, characterized in that R ⁴ represents a methyl or t-butyl group. 32. The use according to claim 5, characterized in that R ⁵ represents a hydrogen atom or a methyl group. 33. The use according to claim 5, characterized in that R ¹ represents a methyl group; R ² represents a hydrogen atom or a methyl group; R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group; R ⁴ represents a methyl or t-butyl group and R ⁵ represents a hydrogen atom or a methyl group. 34. The use of claim 1, wherein said insulin sensitizer is at least one of:
5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione;
5- [4- (6-hydroxy-2-methyl-7-t-butylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (6-hydroxy-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] thiazolidine-2,4-dione;
5- {4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl} thiazolidin-2,4-dione;
5- (2-benzyl-3,4-dihydro-2H-benzopyran-6-ylmethyl) thiazolidin-2,4-dione;
5- [4- {2- [N-methyl-N- (pyridin-2-yl) amino] ethoxy} benzyl] thiazolidine-2,4-dione;
5- [4- {2- [1- (4-2'-pyridylphenyl) ethylidene aminooxy] ethoxy} benzyl) thiazolidine-2,4-dione;
4- {4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl} -isoxazolidin-3,5-dione;
5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidin-2,4-dione;
5- {4- (5-methoxy-3-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl} thiazolidin-2,4-dione hydrochloride;
5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidin-2,4-dione;
5- [4- (1-methylindolin-2-ylmethoxy) benzyl thiazolidin-2,4-dione;
5- {4- [3- (5-methyl-2-phenyloxazol-4-yl) propionyl] benzyl} -thiazolidine-2,4-dione,
and their pharmaceutically acceptable salts. Priority on points and signs:
03/18/96 - according to claims 1 and 3 - 33 and on the basis of "thiazolidinedione" and according to the first six compounds of claims 2 and 34;
03/17/97 - according to paragraphs 2 and 34 and according to the signs of the remaining compounds.

Images