MXPA99008704A - Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome and gestational diabetes - Google Patents

Abstract

Novel methods of using thiazolidinone derivatives and related antihyperglycemic agents to treat populations at risk for developing noninsulin-dependent diabetes mellitus (NIDDM) and complications arising therefrom are disclosed. In one embodiment, the compounds of the invention are used to treat polycystic ovary syndrome in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus. In another embodiment, the compounds of the invention are used to treat gestational diabetes in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus.

Description

USE OF TIAZOLIDINEDIONA DERIVATIVES IN THE TREATMENT OF POLYSTIC OVARY SYNDROME AND GESTATIONAL DIABETES FIELD OF THE INVENTION The present invention relates to a number of compounds that can be used to treat certain disease states to prevent or delay the onset of non-insulin-dependent diabetes mellitus (NIDDM). More specifically, the present invention involves in one exemplary administration to a patient of certain known thiazolidinedione derivatives and antihyperglycemic agents that treat disease states such as polycystic ovary syndrome and gestational diabetes that are at greater risk in the development of NIDDM. , preventing or challenging the beginning of NIDDM or the complications that result from it.

BACKGROUND OF THE INVENTION Diabetes is one of the most prevalent chronic disorders in the world with personal and financial costs also significant for patients and their families, as well as for society. There are different types of diabetes with different etiologies and pathogenesis. For example, diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hypoglycaemia and glycosuria and resulting from inadequate production or utilization of insulin.

NIDDM or also referred to as Type P diabetes, is the form of diabetes mellitus that occurs predominantly in adults in whom adequate production of insulin is available for use, however there is a defect in utilization and metabolism mediated by insulin. glucose in peripheral tissues. NIDDM manifests is characterized by three main metabolic abnormalities: resistance to insulin-mediated glucose wasting, impaired insulin-stimulated insulin secretion, and overproduction of glucose by the liver. It has been shown that for some people with diabetes a genetic predisposition results in a mutation in genes coding for insulin and / or insulin receptor and / or insulin-mediated signal transduction factor, resulting in insufficient insulin and / or effects mediated by insulin thus disabling the use or metabolism of glucose.

Reports indicate that insulin secretion is often increased early, presumably as a compensation for insulin resistance. People who actually develop NIDDM seem to do so because their B cells eventually fail to maintain enough insulin secretion to compensate for insulin resistance. The mechanisms responsible for the failure of B cells have not been identified, but may be related to chronic demands placed on B cells by peripheral insulin resistance and / or the effects of hyperglycemia to disable B cell function B-cell failure could also occur as an independent and inherent defect in "prediab ethical" individuals.

NIDDM often develops from certain at-risk populations, one of such populations being individuals with polycystic ovarian syndrome (PCOS). PCOS is the most common endocrine disorder in women of reproductive age. This syndrome is characterized by hyperandrogenism and disorganized gonadotropin secretion which produces oligo - or anovulation. Recent prevailing estimates suggest that 5 to 10% of women between 18 and 44 years of age (about 5 million women, according to the 1990 census) have the fully developed syndrome of hyperandrogenism, chronic anovulation, and polycystic ovaries . No matter that for more than 50 years since its original description, the etiology of the syndrome remains a mystery. The biochemical profile, the ovarian morphology, and the clinical characteristics are not specific; therefore, the diagnosis remains as an exclusion of disorders, such as tumors that secrete androgen, Cushing's syndrome and congenital adrenal hyperplasia of late onset.

PCOS is related to deep insulin resistance that results in substantial hyperinsulinemia. As a result of their insulin resistance, women with PCOS are at a higher risk of developing NIDDM. Hirsutism, acne, and alopecia, which are commonly found in women with PCOS, are clinical manifestations of hyperandrogenism. Menstrual discomfort and infertility are the result of ovulatory dysfunction. Excess androgen, probably due to the eventual conversion of androgens to estrogen, also plays an important role in the interrupted release of gonadotropin in PCOS.

There are two main theses for the association between PCOS and insulin resistance: 1) androgens produce insulin resistance, or 2) hyperinsulinemia produces hyperandrogenism. In support of the first hypothesis, the administration of synthetic androgen can increase insulin levels in women. However, in women with PCOS with acanthosis nigricans (which is a marker for insulin resistance), oophorectomy lowers testosterone levels but does not alter insulin resistance. In addition, treatment with prolonged GnRH agonist in women with PCOS decreases the level of testosterone and androstenedione in the normal female range, but does not alter glucose tolerance, insulin levels or insulin action. Thus, although certain synthetic androgens may have a modest effect on insulin sensitivity, natural androgens do not produce insulin resistance of the magnitude found in PCOS.

In contrast, there are several lines of evidence that support the alternative hypothesis that hyperinsulinemia produces hyperandrogenism. First, extreme insulin resistance from a variety of etiologies, ranging from insulin receptor mutations to autoimmune insulin resistance, is related to the hyperandrogenism of the ovaries. Second, insulin can directly stimulate androgen secretion of the ovaries in vitro and in vivo in women with PCOS. Finally, decreasing insulin levels for 10 days with diazoxide results in a significant decrease in testosterone levels in women with PCOS. Insulin does not alter the release of gonadotropin but seems to act directly on the ovaries. However, these actions of insulin are not observed in women with normal ovulation, suggesting that changes in the polycystic ovaries are necessary for these effects of insulin to manifest.

Insulin resistance in PCOS is secondary to a marked decrease in signal transduction mediated by the insulin receptor and a modest, but significant, decrease in adipocyte GLUT4 content. In many women with PCOS, the decrease in insulin receptor signals is the result of intrinsic abnormalities in the phosphorylation of the insulin receptor. The magnitude of insulin resistance in PCOS is similar to that in NIDDM and in obesity. However, the cellular mechanisms of insulin resistance appear to differ in PCOS compared to those other common insulin-resistant states. The change to the right in the insulin dose response curve for adipocyte glucose intake is much more striking in PCOS than in obesity. In addition, decreases in adipocyte insulin sensitivity and response are significantly correlated with hyperinsulinemia, glycemia and / or obesity in individuals with NIDDM or obesity, whereas insulin resistance is dependent on these parameters in PCOS.

Finally, no persistent abnormalities have been identified in the autophosphorylation of the insulin receptor in NIDDM or in obesity.

NIDDM also develops from a population of at-risk individuals with gestational diabetes mellitus (GDM). Pregnancy is usually related to progressive resistance to insulin-mediated glucose disposal. In fact, insulin sensitivity is lower during the end of pregnancy than in almost all other physiological conditions. It is considered that insulin resistance is largely mediated by the effects of circulatory hormones such as placental lactogen, progesterone and cortisol, all of which are elevated during pregnancy. In view of insulin resistance, the responsiveness of the pancreatic B cell to glucose normally increases by almost three at the end of pregnancy, a response that serves to minimize the effect of insulin resistance on glucose levels circulatory Thus, pregnancy provides an important "stress test" of the ability of B cells to compensate for insulin resistance.

Studies of the action of insulin and B cell function during pregnancy indicate that, during the third trimester, women with moderate GDM have the same degree of insulin resistance as non-diabetic pregnant women. However, studies during the second trimester and after pregnancy indicate that women with GDM are a little resistant to insulin compared to women who maintain normal glucose tolerance during pregnancy. Taken together, the available data indicate that pancreatic B cells from women who develop GDM can find two types of insulin resistance: 1) mild, underlying, and perhaps moderate, moderate insulin resistance that is present even when women are not pregnant women; and 2) physiological insulin resistance marked (probably hormonally mediated) that occurs during pregnancy in all women. The data indicate that the main characteristic that distinguishes women with GDM from normal pregnant women is the function of pancreatic B cells. The majority of women develop GDM because their pancreatic B cells are unable to maintain improved insulin secretion in the face of insulin resistance. This disability is very similar to the defect of B cells that has been observed in longitudinal studies of patients who develop NIDDM, a fact that may explain why women with MDG are at a much higher risk of NIDDM: GDM identifies women whose B cells they will decompensate when faced with severe or conical insulin resistance.

Other populations that are considered at risk of developing NIDDM are people with syndrome X; people with concomitant hyperinsulinemia; people with insulin resistance characterized by hyperinsulinemia and failure to respond to exogenous insulin; and people with abnormal insulin and / or evidence of glucose disorders related to excess circulating glucocorticoids, growth hormones, catecholamines, glucagon, parathyroid hormone, and other insulin-resistant conditions.

Failure to treat NIDDM can result in mortality due to cardiovascular disease and other diabetic complications that include retinopathy, nephropathy, and peripheral neuropathy. For many years the NIDDM treatment has involved a program aimed at lowering blood sugar with a combination of diet and exercise. As an alternative, NIDDM treatment involved oral hypoglycemic agents, such as sulfonylureas alone or in combination with insulin injections. Recently, alpha-glucosidase inhibitors, such as a carboxy, have been shown to be effective in reducing postprandial elevations in blood glucose (Lefevre, et al., Drogas 1992; 44: 29-38). In Europe and Canada another treatment used primarily in obese diabetics is metformin, a biguanide.

In any case, what is required is a method to treat populations at risk such as those with PCOS or GDM to prevent or delay the onset of NIDDM in order to bring relief of symptoms, improve quality of life, prevent acute and lasting complications , reduce the mortality and treat the accompanying disorders of the populations in NTDDM irrigation. It is thought that the methods of using the compounds presented to treat populations at risk with conditions such as PCOS and GDM meet these objectives.

The compounds of the present invention, and the methods for making the compounds, are known and some are presented in U.S. Patents 5,223,522 issued June 29, 1993; 5,132,317 issued July 12, 1992; 5,120,754 issued June 9, 1992; 5,061,717 issued October 29, 1991; 4,897,405 issued January 30, 1990; 4,873,255 issued October 10, 1989; 4,687,777 issued August 18, 1987; 4,572,912 issued February 25, 1986; 4,287,200 issued September 1, 1981; 5,002,953 issued March 26, 1991; U.S. Patent Nos. 4,340,605; 4,444,779; 4,461,902; 4,703,052; 4,725,610; 4,897,393; 4,918,091; 4,948,900; 5,194,443; 5,232,925; and 5,260,445; WO 07/91/107; WO 92/02520; WO 94/01433; WO 89/08651; and JP Kokai 69383/92. The compounds presented in these issued patents are useful therapeutic agents for the treatment of diabetes, hyperglycemia, hypercholesterolemia and hyperlipidemia. The teachings of these issued patents are hereby incorporated by reference.

With respect to the prevention of NIDDM, there has been a discovery of this concept using a sulphonylurea as a treatment, but this concept is not considered large in the scientific community because prolonged treatment with sulfonylureas can reduce insulin secretion by destroying the cells pancreatic beta. Furthermore, sulfonylureas can cause clinically severe hypoglycemia. The concept of using a biguanide, such as metformin, has also been presented.

There is no discovery in the above-identified references suggesting the use of the compounds identified in this application in the treatment of at-risk populations such as those with PCOS or GDM to prevent or delay the onset of NIDDM and the complications that result from it. .

SUMMARY OF THE INVENTION In a copy of this invention, a method is presented for the treatment of PCOS to prevent or delay the start of NIDDM. Improvements in insulin sensitivity by treatment with the compounds of the following formulas will reduce insulin levels, which would result in lower androgen production and biological availability in women with PCOS. Decreased androgen levels will improve the clinical symptoms of androgen excess and anovulation commonly found in women with PCOS.

In another example of this invention, a method is presented for the treatment of GDM. The improvement in full body insulin sensitivity by treatment with the compounds of the following formulas will reduce the rate of B cell breakdown and delay the development of NIDDM in women with GDM. The compounds can also be applied to women who had gestational diabetes to delay or prevent NIDDM and its long-lasting complications. As agents having the above-mentioned effects, the compounds of the following formulas are useful in the treatment of individuals to prevent or delay the onset of NIDDM.

In another example of the present invention there is a method to treat population states, other than those with PCOS or GDM, who are at risk of developing NIDDM are people with syndrome X; people with concomitant hyperinsulinemia; people with insulin resistance characterized by hyperinsulinemia and by failing to respond to exogenous insulin; and people with abnormal insulin and / or evidence of glucose disorders related to excess circulatory glucocorticoids, growth hormone, catecholamines, glucagon, parathyroid hormone, and other insulin-resistant conditions. The treatment of the above populations with the compounds of the following formulas will prevent or delay the onset of NIDDM.

In accordance with the foregoing, the present invention is the use of the compounds of the Formula I here R1 and R2 are the same or different and each represents a hydrogen atom or a Ci-C5 alkyl group; R3 represents a hydrogen atom, a Ci-C6 aliphatic acyl group, an alicyclic acyl group, an acyl aromatic group, an acyl heterocyclic group, an araliphatic acyl group, a carbonyl group (Ci-C6 alkoxy) or an aralkyl-oxycarbonyl group; R4 and R5 are the same or different and each represents a hydrogen atom, a Ci-C5 alkyl group or a Ci-C5 alkoxy group or R4 and R5 together represent an alkylenedioxy Ci-C group; n is 1, 2 or 3; W represents the group - CH2 -, > CO, or CH-OR6 (in which R6 represents any of the atoms or groups defined for R3 and may be the same as or different from R3); and Y and Z are the same or different and each represents an oxygen atom or an imino group (= NH); and the pharmaceutically acceptable salts thereof. The present invention is also the use of the compounds of Formula II or wherein Ru is alkyl, alkoxy, cycloalkyl, phenylalkyl, phenyl, substituted or unsubstituted acyl group, a 5- or 6-membered heterocyclic group including 1 or 2 heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur, or a group of the formula where R? 3 and R? they are the same or different and each is lower alkyl or R 3 and Ri are combined with each other either directly or as they are interrupted by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur to form a chain of 5 - or 6 - members; wherein E_2 means a bond or a lower alkylene group; and wherein Li and L2 are the same or different and each is hydrogen or lower alkyl or Li and L2 combine to form an alkylene group; or a pharmaceutically acceptable salt thereof.

The present invention is also the use of the compounds of Formula III wherein R15 and R6 are independently hydrogen, lower alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms, halogen, ethinyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro, or benzyloxy substituted with halogen; n is from 0 to 4 and the pharmaceutically acceptable salts thereof.

The present invention is also directed to the use of the compounds of Formula IV where the dotted line represents a link or no link; V is - CH = CH -, - N = CH -, - CH = N - or S; D is CH2, CHOHO, CO = NOR17 or CH = CH; X is S, O, NR18, - CH = N or - N = CH; And it is CH or N; Z is hydrogen, (Ci-C7) alkyl, (C3-C7) cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl or phenyl mono- or disubstituted with the same or different groups which are alkyl (Ci-C3), fluoro, chlorine or bromine; Zi is hydrogen or (Ci-C3) alkyl; p and Ri8 are each independently hydrogen or methyl; and n is 1, 2 or 3; the pharmaceutically acceptable cationic salts thereof; and the pharmaceutically acceptable acid addition salts thereof when the compound contains a basic nitrogen.

The present invention is also directed to the use of compounds of Formula V where the dotted line represents a link or no link; A and B are each independently CH or N, provided that when A or B are N, the other is CH; Xi is S, SO, SO2, CH2, CHOH or CO; n is 0 or 1; Yi is CHR.20 or R2 ?, provided that when n is 1 and Yi is NR21, Xi is SO2 or CO: Z2 is CHR22, CH2CH2, CH = CH, CH-CH, OCH2, SCH2, SOCH2 or SO2CH2; Ripm R20, R21 and R22 are each independently hydrogen or methyl; and X2 and X3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromine, chlorine or fluoro; a pharmaceutically acceptable cationic salt thereof; or a pharmaceutically acceptable acid addition salt thereof when A or B is N.

The present invention also relates to the use of the compounds of Formula VI or a pharmaceutically acceptable salt thereof wherein R_3 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or phenyl mono- or disubstituted wherein said substitutes are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or trifluoromethyl.

The present invention also provides the use of a compound of the Formula vp OR or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, wherein: A2 represents an alkyl group, a substituted or unsubstituted aryl group or an aralkyl group in where the alkylene or aryl moiety can be substituted or not replaced; A3 represents a benzene chain that has a total of up to 3 optional substitutes; R2 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the alkyl or aryl moiety can be substituted or unsubstituted or a substituted or unsubstituted aryl group; or A2 together with R2 represents a substituted or unsubstituted C2-3 polymethylene group, optional substitutes for the methylene group are chosen from the alkyl or aryl substitutes or adjacent together with the methylene carbon atoms to which they are attached form a phenylene group replaced or unsubstituted; R25 and R26 each represent hydrogen, or R25 and R26 together represent a bond; X4 represents O u S; and n represents an integer in the range from 2 to 6.

The present invention also provides the use of a compound of the Formula VHI or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, wherein: R27 and R28 independently represent an alkyl group, an aryl group substituted or unsubstituted or an aralkyl group which is substituted or unsubstituted in the aryl or alkyl moiety; or R27 together with R28 represents a linking group, the linking group consists of an optionally substituted methylene group and either an optionally further substituted methylene group or an O or S atom, optional substitutes of said methylene groups are chosen from alkyl groups -, aryl - or aralkyl methylene or adjacent substitutes together with the carbon atoms to which they are attached form a substituted or unsubstituted phenylene group; R29 and R30 each represent hydrogen, or R29 and R30 together represent a bond; A4 represents a benzene chain that has a total of up to 3 optional substitutes; X5 represents O u S; and n represents an integer in the range of 2 to 6.

The present invention also provides the use of a compound of Formula IX or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or pharmaceutically acceptable solvate thereof, wherein: A5 represents a substituted or unsubstituted aromatic heterocyclic group; Ace represents a benzene chain that has a total of up to 5 substitutes; X represents O, S or NR32 wherein R32 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety can be substituted or unsubstituted, or a substituted or unsubstituted aryl group; Y2 represents O u S; R3? represents an alkyl, aralkyl or aryl group; and n represents an integer in the range from 2 to 6.

Aromatic heterocyclic groups include substituted or unsubstituted single chain or fused aromatic heterocyclic groups comprising up to 4 heteroatoms in each chosen chain of oxygen, sulfur or nitrogen.

Preferred aromatic heterocyclic groups include substituted or unsubstituted single chain heterocyclic groups having from 4 to 7 atoms per chain, preferably 5 or 6 atoms per chain.

In particular, the aromatic heterocyclic group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, chosen from oxygen, sulfur or nitrogen.

Suitable values for A5 when it represents a 5-membered aromatic heterocyclic group includes thiazolyl and oxazolyl, especially oxazolyl.

The appropriate values for A5 when it represents a 6-membered aromatic heterocyclic group includes pyridyl or pyrimidinyl.

R3? Suitable represents an alkyl group, in particular a Ci-Cß alkyl group, for example a methyl group. Preferably, A5 represents one half of formula (a), (b) or (c): (a) ib) (C R33 and R34 independently represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group or when R33 or R34 are each coupled to adjacent carbon atoms, then R33 and R3 together with the carbon atoms to which they are attached they form a benzene chain wherein each carbon atom represented by R33 and R34 together may be substituted or unsubstituted, and in the middle of Formula (a), X7 represents oxygen or sulfur.

In a favored aspect R33 and R34 together represent one half of Formula (d): wherein R 35 and R 36 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.

The present invention also provides the use of the compounds of Formula X A "7, Xfl 8- (CEU 2 O or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, wherein: A7 represents an aryl group substituted or unsubstituted substitute; Ag represents a benzene chain having in total up to 5 substitutes; Xg represents O, S or NR39 wherein NR39 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety can be substituted or unsubstituted, or a substituted or unsubstituted aryl group, Y3 represents O u S, R37 represents hydrogen, R38 represents hydrogen or an alkyl, aralkyl or aryl group or R37 together with R g represent a bond; the range from 2 to 6.

Still another example of the present invention is the use of a pharmaceutical composition for the administration of an effective amount of a compound of the formulas of the preceding I to X together with a pharmaceutically acceptable carrier in unit dosage form in the methods of treatment. aforementioned.

DETAILED DESCRIPTION OF THE PRE-EXAMPLES The compounds used in the treatment methods of the invention, which are derivatives of 5 - [4 - (cromoanalkoxy (benzyl] thiazolidene, can be represented by Formula (Ia), (Ib) and ) (in which R1, R2, R3, R4, R5, R6, n, Y and Z are as defined above) and include pharmaceutically acceptable salts thereof.

In the compounds of the invention, wherein R or R2 represent an alkyl group, this may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms and preferably is a primary or secondary alkyl group, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl group.

Where R3, R6, or R6 'represents an aliphatic acyl group, it preferably has from 1 to 6 carbon atoms and may include one or more double or triple carbon-carbon bonds. Examples of such groups include the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl, methacryloyl and crotonyl groups.

Where R3, R6 or R6 'represents an alicyclic acyl group, it is preferably a cyclopentanecarbonyl, cyclohexanecarbonyl or cyclopentanecarbonyl group.

Where R3, R6 or R6 'represents an aromatic acyl group, the aromatic moiety thereof may optionally have one or more substitutes (for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy substitutes); examples of said acyl aromatic groups include benzoyl, p-nitrobenzoyl, m-fluorobenzoyl, or -chlorobenzoyl, p-aminobenzoyl, m- (dimethylamino) benzoyl, o-methoxybenzoyl, 3,4-dichlorobezoyl, 3,5-di- 1-butyl-4-hydroxybenzoyl, and 1-naphthoyl.

Where R3, R6 or R6 'represents a heterocyclic acyl, the heterocyclic moiety thereof preferably has one or more, preferably one of oxygen, sulfur or nitrogen atoms and has from 4 to 7 chain atoms; Examples of such heterocyclic acyl groups include the 2-furoyl, 3-tenoyl, 3-pyridinecarbonyl (nicotinyl) and 4-pyridinecarbonyl groups.

Where R3, R6 or R6 'represents an acraliphatic acyl group, the araliphatic moiety thereof may optionally have one or more double or triple carbon-carbon bonds and the aryl moiety thereof may optionally have one or more substitutes (e.g., substitutes). nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy); Examples of such acyl araliphatic groups include the phenylacetyl, p-chlorophenylacetyl, phenylpropionyl and cinnamoyl groups.

Where R3, R6 or R6 'represents a carbonyl group (Ci-Ce alkoxy), the alkyl moiety thereof may be any of those alkyl groups as defined for R1 and R2, preferably it is a methyl or ethyl group, and the alkoxycarbonyl group represented by R3, R6 or R6 'is therefore preferably a methoxycarbonyl or ethoxycarbonyl group.

Where R3, R6 or R6 'represents an aralkyloxycarbonyl group, the aralkyl moiety thereof can be any of those included within the acraliphatic acyl group represented by R3, R6, or R6', but is preferably a benzyloxycarbonyl group.

Where R4 and R5 represent alkyl groups, they may be the same or different and may be straight or branched chain alkyl groups. Preferably they have from 1 to 5 carbon atoms and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and isopentyl groups.

Where R4 and R5 represent alkoxy groups, these may be the same or different and may be straight or branched chain groups, preferably having from 1 to 4 carbon atoms. Examples include the methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. As an alternative, R4 and R5 may together represent an alkylene dioxy group Ci-C4, more preferably a methylenedioxy or ethylenedioxy group.

Preferred classes of compounds of Formula I are as follows: (1) The compounds in which R 3 represents a hydrogen atom, an aliphatic acyl group Ci-C 6, an acyl aromatic group or a heterocyclic acyl group. (2) The compounds in which Y represents an oxygen atom; R1 and R2 are the same or different and each represents a hydrogen atom or a Ci-C5 alkyl group; R3 represents a hydrogen atom, an aliphatic Ci-C6 acyl group, an acyl aromatic group, an aliphatic acyl group Ci-C6, an acyl aromatic group or a pyridinecarbonyl group; and R4 and R5 are the same or different and each represents a hydrogen atom, a Ci-C5 alkyl group or an Ci or C2 alkoxy group. (3) The compounds as defined in (2) above, wherein: R1, R2, R4 and R5 are the same or different and each represents a hydrogen atom or an alkyl group Ci - C5; n is 1 or 2; and W represents the group - CH2 - or > CO. (4) The compounds as defined in (3) above, in which R3 represents a hydrogen atom, an aliphatic acyl group Ci-C5, a benzoyl group or a nicotinyl group. (5) The compounds as defined in (4) above, wherein: R1 and R4 are 9 S equal or different and each represents a Ci-C5 alkyl group; R and R are the same or different and each represents the hydrogen atom or the methyl group; and R3 represents a hydrogen atom or an aliphatic acyl group dC. (6) The compounds in which: W represents the group - CH2 - or > CO; Y and Z represent both oxygen atoms; n is 1 or 2; R1 and R4 are the same or different and each represents a Ci-C alkyl group; R2 and R5 are the same or different and each represents the hydrogen atom or the methyl group; and R3 represents a hydrogen atom or an aliphatic acyl group Ci-C. (7) The compounds as defined in (6), wherein n is 1. (8) The compounds as defined in (6) or (7) above, in which W represents the group -CH2-.

Preferred compounds among the compounds of Formula I are those wherein: R1 is a Ci-C4 alkyl group, more preferably a methyl or isobutyl group, more preferably a methyl group; R 2 is a hydrogen atom or a Ci-C alkyl group, preferably a hydrogen atom or a methyl or isopropyl group, more preferably a hydrogen atom, a methyl group, more preferably a methyl group; R3 is a hydrogen atom, an aliphatic acyl group Ci-C, an acyl aromatic group or a pyridinecarbonyl group, preferably a hydrogen atom, or an acetyl, butyryl, benzoyl or nicotinyl group, more preferably a hydrogen atom or an acetyl, butyryl or benzoyl group, more preferably a hydrogen atom or an acetyl group; R 4 is a hydrogen atom, a Ci-C alkyl group or a C 1 or C 2 alkoxy group, preferably a methyl, isopropyl, t-butyl or methoxy group, more preferably a methyl or t-butyl group and more preferably a methyl group; R5 is a hydrogen atom, a Ci-C alkyl group or a Ct or C2 alkoxy group, preferably a hydrogen atom or a methyl or methoxy group, more preferably a hydrogen atom or a methyl group and more preferably a group methyl; n is 1 or 2, preferably 1; And it's an oxygen atom; Z is an oxygen atom or an imino group, preferably an oxygen atom; and W is a group - CH_ - or > CO, preferably a group - CH2_.

With reference to the general Formula II, the substitutes can be any from 1 to 3 chosen from the group nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy, the acyl aromatic group can be benzoyl and naphthoyl. The alkyl group Rn can be a straight or branched chain alkyl of 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, 1-propyl, n-butyl, i-butyl, t-butyl, n-pentyl , i - pentyl, n - hexyl, n heptyl, n-octyl, n-nonyl and n-decyl; the cycloalkyl group Rp can be a cycloalkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl; and the phenylalkyl group Rn may be a phenylalkyl group of 7 to 11 carbon atoms such as benzyl or phenethyl. As examples of the heterocyclic group Rn, there may be mentioned groups of 5- or 6-members which each include 1 or 2 heteroatoms chosen from nitrogen, oxygen and sulfur, such as pyridyl, thienyl, füril, thiazolyl, etc.

When Rp is R 13 \ N- R 14 the R 3 and R 4 alkyls may each be an alkyl of less than 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and n-butyl. When R 3 and R 4 combine with each other to form a 5- or 6-membered heterocyclic group as they are taken together with the adjacent N atom, i.e. in the form of this heterocyclic group may further include a heteroatom chosen from nitrogen, oxygen and sulfur as exemplified by piperidino, morpholino, pyrrolidino and piperazino. The lower alkylene group R12 may contain from 1 to 3 carbon atoms and thus may be, for example, methylene, ethylene or trimethylene. The link R12 is equivalent to the symbol "-", "." or the like which are used in the chemical structural formulas, the compound of the general Formula JJ is represented by the following general Formula II (a) Thus, when R12 is a bond, atoms adjacent to it on both sides combine together directly. As examples of the lower alkyls Li and L2, they can be alkyl groups of less than 1 to 3 carbon atoms, such as methyl and ethyl. The alkylene group formed of Li and L2 are joined together is a group of the formula - (CH2.1 - [wherein n is an integer from 2 to 6] The cycloalkyl, phenylalkyl, phenyl and heterocyclic groups mentioned above, as well as said heterocyclic group may have from 1 to 3 substitutes at optimum positions in the respective chains, Examples of such substitutes are minor alkyls (eg, methyl, ethyl, etc.), lower alkoxy groups (eg, methoxy, ethoxy, etc.), halogens (for example, chlorine, bromine, etc.) and hydroxyl The case also falls within the scope of general Formula II that an alkylenedioxy group of the formula - O - (CH 2) m - O - ) is an integer from 1 to 3], as it is methylenedioxy, it is coupled to the two adjacent carbon atoms in the chain to form an additional chain.

Preferred compounds of Formula III are those in which R15 and RIÓ are independently hydrogen, lower alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms, halogen, ethinyl, nitrile, trifluoromethyl , vinyl or nitro; n is 1 or 2 and the pharmaceutically acceptable salts thereof.

Preferred in Formula IV are compounds wherein the dashed line represents no bond, particularly where D is CO or CHOH. Most preferred are compounds where V is - CH = CH -, - CH = N - or S and n is 2, particularly those compounds where X is O and Y is N, X is S and Y is N, X is S and Y is CH or X is - CH = N - and Y is CH. In the most preferred compounds X is O u S and Y is N forming an oxazol-4-yl, oxazol-5-yl, thiazol-4-yl or thiazol-5-yl group; more particularly a 2 - [(2-thienyl), (2-furyl), phenyl or phenyl-substituted] -5-methyl-4-oxazolyl group.

The preferred compounds in Formula V are: a) those where the dotted line represents no bonds, A and B are each CH, X? is CO, n is 0, R19 is hydrogen, Z2 is CH2CH2, or CH = CH and X3 is hydrogen, particularly when X2 is hydrogen, 2-methoxy, 4-benzyloxy or 4-phenyl; b) those where A and B are each CH, Xi is S or SO2, n is 0, R? 9 is hydrogen, Z2 is CH2CH2 and X3 is hydrogen, particularly when X2 is hydrogen or 4-chloro.

A preferred group of compounds is that of Formula VI wherein R_3 is alkyl (Ci-Cß), cycloalkyl (C3-C7), phenyl, halophenyl or alkylphenyl (Ci-C6). Especially within this group are the compounds wherein R23 is phenyl, methylphenyl, fluorophenyl, chlorophenyl or cyclohexyl.

When used herein with respect to the Formulas VII through X, the term "aryl" includes phenyl and naphthyl, phenyl, suitably substituted with up to 5, preferably up to 3 groups selected from the halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy or alkylcarbonyl.

The term "halogen" refers to fluorine, chlorine, bromine and iodine; preferably chlorine.

The terms "alkyl" and "alkoxy" refer to groups having straight or branched carbon chains, containing up to 12 carbon atoms.

The appropriate alkyl groups are Ci alkyl groups. 12 especially the Ci alkyl groups. 6, for example, the methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.

Suitable substitutes for any alkyl group include those indicated above in relation to the term "aryl".

Suitable substitutes for any heterocyclyl group include up to 4 substitutes selected from the group consisting of alkyl, alkoxy, aryl, and halogen or any 2 substitutes on adjacent carbon atoms, together with the carbon atoms to which they are coupled, can form a group aryl, preferably a benzene chain, and wherein the carbon atoms of the aryl group represented by said two substitutes may themselves be substituted or unsubstituted.

Specific examples of the compounds of the present invention are given in the following list: (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2-yl) methoxy] -phenyl] methyl] 2,4-thiazolidinedione; 4- (2-naphthylmethyl) -1,2,3,5-oxathiadiazole-2-oxide; 5 - [4 - [3 - [N - (benzoxasol-2-yl) - N -methylamino] -ethoxy] benzyl] -5-methylthiazolidone-2,4-dione; 5 - [4 - [2 - [2,4-dioxo-5-phenylthiazolidin-3-yl) -ethoxy] benzyl] thiazolidine-2,4-dione; 5 - [4 - [2 - [N-methyl-N (phenoxycarbonyl) amino] -ethoxy] benzyl] thiazolidine-2,4-dione; - . 5 - [4 - (2-phenoxyethoxy) benzyl] thiazolidine-2,4-dione; 5 - [4 - [3 - (5-Methyl-2-phenyloxazol-4-yl) -propionyl] benzyl] thiazolidine-2,4-dione; 5 - [4 - [2 - (4-chlorophenyl) ethylsulfonyl] benzyl] -thiazolidine-2,4-dione; 5 - [4 - [3 - (5-Methyl-2-phenyloxazol-4-yl) -propionyl] -benzyl] thiazolidine-2,4-dione; and 5 - (4 - [2 - (N - (2-pyridyl) amino) -ethoxy] benzyl) 2,4-thiazolidinedione.

As defined herein, "NIDDM complications" refers to cardiovascular complications or several of the metabolic and circulatory discomforts that are related to hyperglycemia, eg, insulin resistance, hyperinsulinemia and / or hyperproinsulinemia, delayed insulin release , dyslipidemia, retinopathy, peripheral neuropathy, nephropathy and hypertension.

The compounds of the Formulas from I to X are also capable of forming pharmaceutically acceptable basic bases.

The compounds of the Formulas from I to X are also capable of simultaneously forming pharmaceutically acceptable acid and / or basic addition salts. All these forms are within the scope of the present invention.

The pharmaceutically acceptable acid addition salts of the compounds of the Formulas I to X include salts derived from non-toxic inorganic acids such as hydrochloric, hydroiodic, hydrofluoric, phosphorous and the like, as well as salts derived from non-toxic organic acids, such as mono- and dicarboxylic aliphatic acids, acids alkane substituted with phenyl, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Said salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are amino acid salts such as arginate and the like and gluconate, galacturonate, n-methyl glucamine (see, for example, Berge S.M., et al., "Pharmaceutical Salts", Journal of Science Pharmaceutical 1977; 66: 1-19).

The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner or as stated above. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their free base for the purposes of the present invention.

The pharmaceutically acceptable basic addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of the appropriate amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, for example, Berge S.M., et al, "Pharmaceutical Sales", Journal of Science Pharmaceutical 1977; 66: 1-19).

The basic addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the base in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner or as stated above. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise they are equivalent to their respective free acids for the purposes of the present invention.

Certain of the compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain compounds of the present invention possess one or more chiral centers and each center can exist in different configurations. The compounds can, therefore, form stereoisomers. Although these are all represented in the present by a limited number of molecular formulas, the present invention includes the use of both individual and isolated isomers and mixtures, including the racemates thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials in the preparation of the compounds, the individual isomers can be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers can be obtained by conventional resolution techniques, or the mixture can be used as it is, without resolution.

In addition, the thiazolide part of the compound of the Formulas I to X may exist in the form of tautomeric isomers. All tautomers are represented by Formulas I through X, and are intended as a part of the present invention.

To prepare pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, lozenges, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, bonds, preservatives, tablet disintegrating agents or an encapsulating material.

In the powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in appropriate proportions and compacted in the desired shape and size.

The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyelulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier that provides a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, the pills are included. The tablets, powders, capsules, pills and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melts first and the active component disperses homogeneously there, stirring. The melted homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or glycol propylene solutions and water. For parenteral injection, liquid preparations can be formulated in solution with polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic goats, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, into liquid preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, natural or synthetic sweeteners, dispersants, thickeners, solubilizing agents and the like.

The pharmaceutical preparation is preferably in the form of doses per unit. In that form, the preparation is subdivided into doses per unit containing appropriate amounts of the active component. The dosage form per unit can be a packaged preparation, the package contains discrete quantities of the preparation, such as tablets, capsules and powders packed in vials or ampoules. Also, the dosage form per unit may be a capsule, tablet, pill itself, or it may be the appropriate number of any of these in packaged form.

The amount of the active component in a dose preparation per unit can be varied or adjusted from 0.1 mg to 100 mg, preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

In the therapeutic use in the treatment of at-risk populations such as those with impaired glucose tolerance, to prevent or delay the onset of NIDDM and the complications arising therefrom, the compounds used in the pharmaceutical methods of this invention are administered together with a pharmaceutically acceptable carrier at the initial dose of about 0.01 mg to about 20 mg per kilogram daily.

A daily dose range of about 0.01 to about 10 mg per kilogram is preferred. The doses, however, will vary depending on the requirements of the patient, the severity of the condition being treated and the compound used. The determination of the appropriate dose for a particular situation is within the knowledge of science. In general, treatment starts with smaller doses than with less than the optimal dose of the compound. From this, the dose is increased by small increments until the optimum effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired.

The following non-limiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention.

The compounds of Formulas I through X are valuable agents for the regression of an individual to a state of glucose tolerance and thus prevent or delay the onset of NIDDM. Tests were carried out which showed that the compounds of the Formulas I to X possess the activity presented. The tests employed in the compounds of the Formulas I to X were carried out in the following study.

EXAMPLE 1 A study will be conducted to determine the effect of troglitazone ((+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1 - benzopyran-2-yl) -methoxy] phenyl] methyl] -2,4-thiazolidinedione) on the levels of insulin and androgen resistance in women with PCOS. Since hyperandrogenism results in chronic anovulation and hirsutism, decreasing androgen levels can improve hirsutism and even restore normal ovulatory menstrual function in women with PCOS. The specific purpose of the study will be to determine the effects of improved insulin sensitivity and decreasing levels of insulin secondary to troglitazone treatment on circulating androgen levels and gonadotropin in women with PCOS.

I. SUBJECTS A. General Selection Criteria A total of 30 women will be studied. All subjects will be in excellent health, between the ages of 18 and 45 and eutiroiodes. They will not have a history of cardiorespiratory, hepatic or renal disability. No subject will be taking medications that are known to affect reproductive hormone levels or carbohydrate metabolism for at least 1 month before the study, with the exception of oral contraceptives, which will be discontinued 3 months before the study. Obesity will be defined as the body mass index (BMt: weight (kg.) / Hr2 (m) of> 27 kg / m2, non-obese patients will have an MBI of <25 kg / m2.

B. Selection Criteria for PCOS. The diagnosis of PCOS will require biochemically documented hyperandrogenism (serum testosterone levels, biologically available testosterone and / or two standard deviations of androstenedione or more over the control average), chronic anovulation (<6 months / year or dysfunctional uterine bleeding), and polycystic ovaries present in the vaginal ovarian ultrasound. These are the least controversial criteria for the diagnosis of PCOS. The LH: FSH ratio and hirsutism will not be used as selection criteria. Tumors of androgen secretion, Cushing's syndrome, and late-onset congenital adrenal hyperplasia will be excluded by appropriate tests in all women. Women with hyperprolactinemia will be excluded due to the possible effect of hyperprolacticemia on insulin sensitivity.

C. Disqualification criteria 1. Pregnancy 2. Intercurrent medical disease 3. Hepatic or renal dysfunction 4. Hemoglobin < 11 gm / dl 5. Weight < 50 kg.

H. STUDY PROTOCOL A. Subject Preparation for All Studies All tests were conducted during anovulation by plasma progesterone levels documented in women with PCOS. Subjects will consume a diet to maintain the weight of 55% carbohydrates, 30% fat, 15% protein for 3 days before testing and all tests will be done in the post-absorption state after 10-12 hours of fasting.

B. PROTOCOL 1. Visit 1 - Day 1. A complete history and physical examination will be performed and blood will be obtained for a complete blood count, electrolytes, thyroid function (thyroid profile with tHS level), kidney chemicals and liver function. Blood will be obtained for testosterone (T), biologically available T (uT), LH, FSH, dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), sex hormone binding globulin (SHBG), sterone (Ei), estradiol (E2) ), insulin and C-peptide levels. A load of 75g of glucose will be ingested in the morning after a fast of 10-12 hours and glucose and insulin levels will be obtained every 30 minutes for 2 hours.

All women with PCOS will have fasting insulin levels > 15 μU / ml and may have impaired glucose tolerance by WHO criteria. No subject, however, will have diabetes mellitus.

DIAGNOSTIC CRITERIA WHO 2. Visit 1 - Day 2. An intravenous glucose tolerance test with frequent samples (FSGIT) will be carried out. Basal blood samples will be collected at minute - 15, - 10, - 5 and - 1. Glucose (300 mg / kg) will be injected as in IV bolus at the time of 0 min and tolbutamide (500 mg) will be injected at the 20 minutes. Blood samples will be taken at 2, 3, 4, 5, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100 minutes and every 20 minutes thereafter until 240 minutes for glucose and insulin levels. 3. Therapy with Troglitazone. Troglitazone will begin after Visit 1, day 2, when a pregnancy test with urine will be documented negative. Troglitazone will be administered in a two-level double-bond randomized trial: 200 mg / day and 400 mg / day. Subjects will be randomly assigned to one of the daily doses of troglitazone. All women will take two pills: any two 200 mg pills or a 200 mg pill and a placebo pill. There will be 15 subjects in each of the two treatment groups. Troglitazone will be administered as a single daily dose with breakfast. 4. Visits 2 and 3. Subjects will return monthly. Blood will be obtained every 10 minutes x 3 and the plasma will be collected for T, μT, A, DHEAS, SHBG, E2, Ei, LH and FSH levels. Basal insulin and glucose levels and 2 hours after 75g of glucose will be determined.

. Visit 4. The studies carried out in Visit 1 will be repeated. Subjects will be instructed to return all unused supplies to ensure compliance. The details related to patient dosing and compliance will be recorded in the case report form.

HL STATISTICAL ANALYSIS Each subject will serve as their own control, and the data will be analyzed by t-tests in pairs. Differences in treatment against baseline hormone levels and parameters of insulin action will be compared between the two dose groups by t-tests in pairs. Repeated measurements of variation analysis will be carried out to determine changes over time. The transformation of the records of the data will be carried out when it is necessary to achieve homogeneity of variation. This is a pilot study and 15 women with PCOS will be examined at two dose levels of troglitazone.

IV. HUMAN SUBJECTS A. Risks 1. Blood Removal. All subjects will have a complete and normal blood count and hemoglobin levels of > 11 mg / dl. No subject will have > 500 ml of blood withdrawn in periods of 24 hours and > 1000 ml of blood withdrawn in a period of 12 weeks. 2. FSGIT. There is a small risk of hypoglycaemia during FSGIT, and the test will be terminated immediately by the administration of 50% dextrose if symptoms or signs of severe hypoglycemia develop. There is a small risk of allergy to tolbutamide; the drug will not be given to any subject with a history of drug allergy with sulfa or sulfonylureas. 3. Troglitazone. The main side effects of troglitazone are nausea, peripheral edema, and abnormal liver function. Other adverse events reported include dyspnea, headache, thirst, gastrointestinal discomfort, insomnia, dizziness, itching, incoordination, confusion, fatigue, pruritus, alterations in blood counts, changes in serum lipids, acute renal failure and dry mouth. Additional symptoms have been reported, for which the relationship with troglitazone is unknown, including palpitations, sensations of cold and heat, swelling of body parts, skin rash, attacks and hyperglycemia. 4. Disqualification Criteria Subjects will be disqualified if they develop one or more of the following: HB < 11 g dl, weight < 50kg, abnormal hepatic or renal chemistries, hypertension, pregnancy, significant disease or excessive bleeding. a Chemistry - Complete blood count with differential, electrolytes, liver function, renal function, thyroid profile with TSH level. b Hormones - Levels of T, μT, LH, FSH, DHEAS, SHBG, P, A, E2, EI, insulin, peptide C.

EXAMPLE 2 Thiazolidinediones have been shown to increase insulin sensitivity in non-diabetic and diabetic insulin resistant animals and humans with NIDDM. Several thiazolidinediones are being tested in the United States, including studies of proglitizone in rats fed fructose and obese rhesus monkeys. The drugs seem to improve insulin sensitivity in skeletal muscles and the liver, important sites of insulin resistance in DDM. In response to increased sensitivity to insulin, which has been in the range of 40-100% above treatment levels, pancreatic B cells appear to regulate insulin secretion, so hyperinsulinemia is reduced and hypoglycemia is not a risk. Of the possible pharmacological interventions, thiazolidinediones seem well suited for testing in the prevention of NIDDM in patients whose underlying insulin resistance is considered to lead to B-cell decompensation and diabetes. Therefore, it is proposed to test the effect of a thiazolidinedione that has been shown to increase insulin sensitivity in people with NIDDM, on insulin sensitivity and NIDDM ratios in our very high risk patients with recent GDM.

In particular, it is proposed to test the effects of the agent, troglitazone, which has been shown to improve insulin-mediated glucose disposal in humans. While not wishing to be subject to the theory, if the hypothesis is correct, troglitazone will maintain the action of insulin that is commensurate with the reserve of B cells in some, and perhaps many subjects, thus preventing or delaying the development of NIDDM.

The demonstration that treatment with troglitazone will reduce the proportion of NIDDM in patients with GDM will have an important clinical and biological significance. The clinical significance is the obvious potential for the treatment of patients with GDM to prevent or delay the diabetes exercised and its long-term complications. The option of an agent that improves the action of insulin may not only reduce the risk of diabetic complications that are clearly related to chronic metabolic decompensation (ie, retinopathy, hefropathy and neuropathy), but can also reduce the risk of cardiovascular complications such as hypertension and atherosclerosis, which have been linked to insulin resistance and hyperinsulinemia. The biological significance of a reduced proportion of diabetes during treatment with troglitazone will depend to some extent on the effects of the drug on the action of insulin.

To test the hypothesis that interventions to improve insulin sensitivity throughout the body will reduce the rate of B cell decompensation and delay or prevent the development of NIDDM, a placebo-controlled double-bind of troglitazone will take cape. The test will be carried out among individuals at high risk of NTDDM, such as women with a GDM history. In particular, due to the proportions of age-adjusted prevalence NIDDM among Hispanic women between the ages of 24 and 64, it has been reported to be from 8 to 11%, proportions that are 2-3 times those of non-Hispanic whites in the United States. Together, the test will be conducted among Hispanic women.

I. DESCRIPTION OF THE STUDY DESIGN Hypothesis: Troglitazone will improve insulin sensitivity and delay or prevent NIDDM in Latina women with a history of GDM who are at very high risk of NIDDM.

Patients: ~ 230 Hispanic women with recent GDM and a glucose tolerance test at 6 - 12 weeks after delivery indicating a very high risk of developing NDDDM within 3 to 5 years (ie, total glucose area > 16.3 gm «min / dl).

Procedures: 1. Measurement of insulin sensitivity in the whole body (minimum model) in the baseline. 2. Random selection to drug or placebo (double bond design). 3. Measurement of insulin sensitivity after 4 and 24 months of treatment. 4. Follow for the development of NIDDM: a. Glucose fasting at 4-month intervals. b. Oral glucose tolerance test annually, c. Real follow-up of 36 months.

Analysis: 1. Comparison between groups (drug and placebo) of cumulative NIDDM proportions using life table methods: a) by intention to treat; b) by response to therapy. 2. Comparison between groups of changes in 4 months in Si using test t of group 2; changes between groups in Si over time using repeated ANOVA measurements. 3. Analysis within and between groups of factors related to any reduction in the proportion of NIDDM using Cox proportional hazards regression analysis.

II. PROOF OF INTERVENTION: SELECTION AND RECRUITMENT OF SUBJECTS A. Inclusion and Exclusion Criteria. INCLUSION: Ages between 18 and 45 years, recent GDM using the criteria of the National Diabetes Data Group, Diabetes, 29: 1039-1057 (1979), singleton pregnancy, Mexican-American or Central American (self-declared ethnicity); both parents and grandparents of Mexican or Central American heritage, residence within 60 minutes of the LAC Medical Center, postpartum OGTT glucose area of 6 to 12 weeks > 16.3 gm «min / dl.

EXCLUSION: Pregnancy plans within 4 years, a medical illness that requires chronic medications that alter glucose tolerance or that will impede the follow-up of 3 - 4 years (for example, malignancy, HIV infection), illegal drug abuse, disability to give informed consent. m. SPECIFIC PROCEDURES A. OGTT 1. Procedure. An internal antecubital venous catheter will be placed in the selected subjects in the morning after a fast of 10 to 12 hours. At least 30 minutes later, they will be given dextrose (75 g) orally for 5 minutes. Blood will be drawn at 1 - 0, 30, 60, 90 and 120 minutes from the start of dextrose ingestion. 2. Interpretation: OGTT plasma glucose concentrations will be interpreted according to the criteria of the National Diabetes Data group. 3. Risks: Limited to those of an intravenous line (pain, infection, lacerations / bleeding at the site), nausea at the time of ingestion of dextrose and phlebotomy (15 ml of blood).

B. GVGTT 1. Procedure: After a one-night fast, the subjects will be placed in bed rest and bilateral antecubital venous catheters will be placed. At least 30 minutes later, a sample of basal blood will be removed and dextrose (300 mg / kg body weight) will be given intravenously for one minute. An intravenous injection of tolbutamide (3 mg / kg) will be given 20 minutes after the dextrose injection. The plasma samples will be obtained at 2, 4, 8, 14, 19, 22, 30, 40, 50, 70, 100 and 180 minutes after the glucose injection and will be tested by glucose and insulin. 2. Analysis: Insulin sensitivity will be calculated by computer analysis of glucose and insulin patterns during IVGTT. 3. Risks: Hypoglycemia is a potential complication after the injection of tolbutamide. However, tolbutamide is injected when the plasma glucose is high, so hypoglycemia is unusual. It has never been observed in more than 50 IVGTTs in Hispanic women who use the tolbutamide dose of 3 mg / kg. Even so, patients will be observed for symptoms of hypoglycemia and the test will be stopped if symptomatic hypoglycemia occurs (< 60 mg / dl). The risks of intravenous lines and phlebotomy (total = 30 ml) are minimal. People with a hematocrite < 33% will not be studied with the IVGTT.

C. Body Morphometry 1. Procedures: Body weight will be measured on a standard pole scale (subjects with light clothes, no shoes). The height will be measured with a statometer. The circumference of the waist between the thorax and the iliac crest. The circumference of the hip will be measured at the level of the maximum posterior protrusion of the buttocks. 2. Interpretation: The body mass index will be calculated as: [weight in kilos] / [height in meters] and will be used as a substitute for adiposity measurements. The ratio of the circumference of the waist to the hip circumference will be calculated as a measurement of the fat distribution. Each measurement will be tested as a feature of NIDDM and for any therapy effects on NIDDM risk. 3. Risks: None.

D. Blood Pressure Blood pressure will be measured in triplicate in seated patients (x 5 minutes) with an aeriode sphygmomanometer. The first and fourth Korotoff sounds will be used to determine the systolic and diastolic blood pressure. There are no risks associated with the procedure.

E. Assays 1. Insulin: Insulin is measured in the plasma with a carbon precipitation radioimmunoassay using human insulin standard, anti-guinea pig guinea pig insulin antibodies and tyrosine iodine A-19 purchased from Novo-Nordisk. The control of quantity will be maintained. RIA has an actual interassay coefficient of variation of 12% at 7 ± 3 μU / ml and 7% at 32 ± 6 μU / ml, based on the collected plasma samples stored at -70 ° C for a period of 12 months . 2. Glucose: Glucose will be measured in duplicate by glucose oxidase (Beckman II Glucose Analyzer).

The present invention can be exemplified in other specific forms without departing from its spirit or essential characteristics. The specimens described should be considered in all aspects only as illustrative and not restrictive. The scope of the invention, therefore, is indicated by the appended claims instead of the present description. All the changes that come within the meaning and range of equivalence of the claims must be within its scope.

Claims (3)

CLAIMS:

1. A method for preventing or delaying the onset of non-insulin-dependent diabetes mellitus comprising administering to a host suffering from polycystic ovary syndrome or having suffered from gestational diabetes a therapeutically effective amount of the compound 5 - ( 4 - (2 - (N-methyl-N- (2-pyridyl) amino) -ethoxy) benzyl) 2,4-thiazolidinedione, 5- [p- [1-methylcyclohexyl] methoxy] benzyl] -2,4-thiazolidinedione (Ciglitazone), 5- [p- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] 2,4-thiazolidinedione (Pioglitazone), 5 - [p- [3 - (5-methyl-2-phenyl-4-oxazoli?) Propionyl] benzyl] -2,4-thiazolidinedione (Darglitazone), or 5 - [[(2R) -2-benzyl-6-chromanyl] methyl] 2,4-thiazolidinedione (Englitazone).

2. A method for treating polycystic ovary syndrome, the method comprises administering to a host suffering from polycystic ovary syndrome a therapeutically effective amount of the compound 5 - (4 - (2 - (N-methyl-N- (2-pyridyl ) amino) -ethoxy) benzyl) 2,4-thiazolidinedione, 5- [p- [l-methylcyclohexyl) methoxy] benzyl] -2,4-thiazolidinedione (Ciglitazone), 5- [p- [2- (5-ethyl) -2-pyridyl) ethoxy] benzyl] 2,4-thiazolidinedione (Pioglitazone), 5- [p- [3- (5-methyl-2-phenyl-4-oxazolyl) propionyl] benzyl] -2,4-thiazolidinedione ( Darglitazone), or 5 - [[(2R) -2-benzyl-6-chromanyl] methyl] 2,4-thiazolidinedione (Englitazone).

3. A method for treating gestational diabetes, the method comprises administering to a host suffering from gestational diabetes a therapeutically effective amount of the compound 5 - (4 - (2 - (N-methyl-N- (2-pyridyl) amino) - ethoxy) benzyl) 2,4-thiazolidinedione, 5- [p- [l-methylcyclohexyl) methoxy] benzyl] -2,4-thiazolidinedione (Ciglitazone), 5- [p- [2- (5-ethyl-2-pyridyl ) ethoxy] benzyl] 2,4-thiazolidinedione (Pioglitazone), 5- [p- [3- (5-methyl-2-phenyl-4-oxazolyl) propionyl] benzyl] -2,4-thiazolidinedione (Darglitazone), or 5 - [[(2R) -2-benzyl-6-chromanyl] methyl] 2,4-thiazolidinedione (Englitazone). EXTRACT OF THE INVENTION Novel methods for the use of thiazolidinone derivatives and related antihyperglycemic agents to treat populations at risk of developing non-insulin dependent diabetes mellitus (NIDDM) and complications arising therefrom are presented. In one example, the compounds of the invention are used to treat polycystic ovary syndrome to prevent or delay the onset of non-insulin-dependent diabetes mellitus. In another example, the compounds of the invention are used to treat gestational diabetes to prevent or delay the onset of non-insulin-dependent diabetes mellitus.