Specification
Field of the Invention
The present invention relates to novel antidiabetic compounds, their tautomeric forms, their dervatives, their analogues, their stereoisomers, their polymorphs, their
pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione of the general formula (I), their derivativesj their analogues, their tautomeric fprms, .their stereoisomers, their polymorphs and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
The present invention also relates to a process for the preparation of the above said novel azolidinedione compounds, their analogues, their d«ivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and pharmaceutical compositions containing them.
_ This invention also relate to novel intermediates, processes for preparing the intehnediates and processes for using the intermediates.
The azolidinediones of the general fonnula (I) defined above of the present invention are useful for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes^ impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis. The azolidinediones of the fonnula (I) are useful for the treatoient of insulin resistance associated with obesity and psoriasis. The Azolidinediones of the fonnula (I) can also be used to treat diabetic complications and can be used for treatment and/or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome
(PCOS), cwtain renal diseases, including diabetic n^hropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage raial diseases and microalbuminuria as well as certain eating disorders, as aldose reductase Inhibitors and for improving cognitive functions in dementia.
Background of the Invention Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing whichj the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnonnalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl J. Med. (1987) 317: 350 - 357 ; J. Clin. Endocrinol. Metab., (1988) 66 :580 - 583; J. Clin. Invest, (1975) 68 : 957 - 969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being reco^iized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclCTOsis and type 2 diabetes mellitus. The association of insulin resistance wifli obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108), draientia (Behavioral Brain Research (1996) 75 : 1 - 1 1) etc. may also have insulin resistance as a central pathogenic feature. Recently, it has also been reported that thia2oHdinediones improve the bone mineral density and thus may be useful for the treatment of osteoporosis (EP-783888).
A number of molecular defects have been associated with insulin resistarifee. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis.
Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related implications, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compound^ which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref Chem. Pharm. Bull 1982, Jf?, 3580-3600). In the formula (II), V rq)resents substituted or unsubstituted divalent aromatic group, B represents a sulfur or an
groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R' and R^ may also together represent, along with carbon atoms to which they are attached an aromatic pyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR' where R' is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like wherein these groups are defined as for R'-R*; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group, R' represents hydrogen atom, hydroxy, alkoxy, halogen or lower alkyl such as (d - Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted aralkyl group or forms a bond together with the adjacent group R'; R* represents hydrogen, hydroxy, alkoxy, halogen or lower alkyl group such as (Ci-Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted suralkyl or R* forms a bond together with R'; B represents an oxygen atom or a sulfiir atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one. .
Suitable groups represented by R' - R^ include hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro; substituted or unsubstituted (Q-Ci2)alkyl group, especially, linear or branched yl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (0.68 g, 1.: mmol) obtained in example 25 by an analogous procedure to that described in example 2. mp : 6'
IH NMR (CDCI3, 200 MHz) : 8 3.1 (dd, J = 14.2 and 9.4 Hz. IH), 3.44 (dd, J = 14.2 and 4.0 Hz IH), 4.31 (s, 4H), 4.5 (dd, J = 9.4 and 4.0 Hz, IH), 6.7 - 7.3 (m, I IH)
Mutation in colonies of laboratory animals and different sensitivities to dietary
regimens have made the development of animal models with non-insulin dependent diabetes
associated with obesity and insulin resistance possible. Genetic models such as db/db and
ob/ob (See Diabetes, (1982) 31(1) : 1- 6) in mice and fa/fa and zucker rats have been
developed by the various laboratories for understanding the pathophysiology of disease and
testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838 ; Annu.
Rep. Sankyo Res. Lab. (1994). 46 : 1-57). The homozygous animals, C57 BL/KsJ-db/db
mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and
insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and
normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a
feature commonly observed in late stages of human type II diabetes when blood sugar levels
are insufficiently controlled. The state of pancreas and its course vary according to the
models. Since this model resembles that of type II diabetes meilitus, the compounds of the
present invention were tested for blood sugar and triglycerides lowering activities.
The compounds of the present inventions showed blood sugar and triglycerides lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments.
Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, procured from the Jackson Laboratory, USA, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition, Hyderabad, India) and
acidified water, ad libitum. The animals having more than 300 mg / dl blood sugar were used for testing. The number of animals in each group was 4.
The random blood sugar and triglyceride levels were measured by collecting blood (100 yil) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma. The plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase en2yme (Dr. Redd/s Lab. Diagnostic Division Kits, Hyderabad, hidia) methods respectively. On 6th day the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 10 mg to 200 mg / kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml / kg). Troglitazone (100 mg / kg, daily those) was used as a standard drug which showed 28 % reduction in random blood sugar level on 6th day.
The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula:
The experimental results from the db/db /nice suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for obesity, cardiovascular disorders such as hypertension, hyperlipidaemia and other diseases; as it is known from the literature that such diseases are interrelated to each other.
Blood glucose level and triglycerides are also lowered at doses greater than 30 mg/kg. Normally, the quantum of reduction is dose dependent.
its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates, wherein R',
are the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, aralkoxycarbonylamino, alkoxycarbonylamino, mercaptoalkyl groups, carboxylic acid or its esters or amides, or sulfonic acid or its esters or amides; or R and R together represent along with carbon atoms to which they are attached an aromatic cyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; Ar represents optionally substituted divalent single or fused aromatic or heterocyclic group, R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl group or forms a bond together with R*; R* represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl or R forms a bond together with R''; B represents an oxygen atom or a sulfur atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one.
2. The compound as claimed in claim 1, wherein R1 and R2 together with the
adjacent carbon atoms to which they are attached represent an optionally substituted 5 to 6 membered aromatic ring structure having 5 to 6 ring atoms wherein the aromatic ring structure is substituted, the substituents are selected from halogen, (Ci-C6)alkoxy, Gyclo(C3-C6)alkyl, cyclo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxyl, acyl, acyioxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, and aminocarbonyl.
7. The pharmaceutical composition which comprises, a compound according to claim 4, as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
8. The pharmaceutical composition as claimed in claim 7, in the form of tablet, capsule, powder, syrup, solution or suspension.