Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-12-02
2001-11-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230500, C544S050000, C544S073000, C544S092000, C544S093000
Reexamination Certificate
active
06313113
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, 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 azolidinediones of the general formula (I), their analogues, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, 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, derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates; and pharmaceutical compositions containing them.
This invention also relates to novel intermediates, processes for preparing the intermediate and processes for using the intermediates.
The azolidinediones of the general formula (I) defined above of the present invention are useful for the treatment and/or prophylaxis of hyperlipidemia, hypercholesterolemia, 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 formula (I) are useful for the treatment of insulin resistance associated with obesity and psoriasis. The azolidinediones of the formula (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), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal 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 which, 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 abnormalities 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 Ser. No. WO 95/21608). It is now increasingly being, recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with 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 Ser. No. WO 95/07697), psoriasis (patent application Ser. No. WO 95/35108), dementia (Behavioral Brain Research (1996) 75: 1-11) etc. may also have insulin resistance as a central pathogenic feature. Recently, it has also been reported that insulin sensitizers 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 resistance. 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 complications, 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 compounds which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref.
Chem. Pharm. Bull.
1982, 30, 3580-3600). In the formula (II), V represents substituted or unsubstituted divalent aromatic group B represents a sulfur atom or an oxygen atom and U represents various groups which have been reported in various patent documents.
By way of examples, U may represent the following groups:
(i) a group of the formula (IIa) where R
1
is hydrogen or hydrocarbon residue or heterocyclic residue which may each be substituted, R
2
is hydrogen or a lower alkyl which may be substituted by hydroxy group, X is an oxygen or sulphur atom, Z is a hydroxylated methylene or a carbonyl, m is 0 or 1, n is an integer of 1-3. These compounds have been disclosed in the European Patent Application No. 0 177 353
An example of these compounds is shown in formula (IIb)
(ii) a group of the formula (IIc) wherein R
1
and R
2
are the same or different and each represents hydrogen or C
1
-C
5
alkyl, R
3
represents hydrogen, acyl group, a (C
1
-C
6
) alkoxycarbonyl group or aralkyloxycarbonyl group, R
4
-R
5
are same or different and each represent hydrogen, C
1
-C
5
alkyl or C
1
-C
5
alkoxy or R
4
, R
5
together represent C
1
-C
4
alkenedioxy group, n is 1, 2, or 3, W represents CH
2
, CO, CHOR
6
group in which R
6
represents any one of the items or groups defined for R
3
and may be the same or different from R
3
. These compounds are disclosed in the European Patent Application No. 0 139 421.
An example of these compounds is shown in (IId)
iii) A group of formula (IIe) where A
1
represents substituted or unsubstituted aromatic heterocyclic group, R
1
represents a hydrogen atom, alkyl group, acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group, n represents an integer in the range from 2 to 6. These compounds are disclosed in European Patent No. 0 306 228.
An example of this compound is shown in formula (IIf)
iv) A group of formula (IIg) where Y represents N or CR
5
, R
1
, R
2
, R
3
, R
4
and R
5
represents hydrogen, halogen, alkyl and the like and R
6
represents hydrogen, alkyl, aryl and the like, n represents an integer of 0 to 3. These compounds are disclosed in European Patent Application No. 0 604 983.
An example of this compound is shown in formula (IIh)
v) a group of formula (IIi), where R is (C
1
-C
6
) alkyl groups, cycloalkyl group, furyl, thienyl, substituted or unsubstituted phenyl group, X is hydrogen, methyl, methoxy, chloro or fluoro. These compounds have been disclosed in the U.S. Pat. No. 5,037,842.
An example of these compounds is shown in formula (IIj).
(vi) a group of formula (IIk) wherein A
1
represents a substituted or unsubstituted aromatic heterocyclyl group; R
1
represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted or a substituted or unsubstituted aryl group, n represents an integer in the range of from 2 to 6. These compounds have been disclosed in the patent application Ser. No. WO 92/02520.
An example of these compounds is shown in formula (IIl).
Some of the above referenced hitherto known antidiabetic compounds seem to possess bone marrow depression, liver and cardiac toxicities and modest potency and consequently, their regular use for the treatment and control of diabetes is becoming limited and restricted.
SUMMARY OF THE INVENTION
With an objec
Chakrabarti Ranjan
Lohray Braj Bhushan
Lohray Vidya Bhushan
Paraselli Rao Bheema
Ramanujam Rajagopalan
Ladas & Parry
Raymond Richard L.
Reddy-Cheminor Inc.
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