FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
N- Biphenylacyl thiazolidine-2, 4-dione derivatives, their production and uses.
2. APPLICANT (S)
(a) NAME : ELDER PHARMACEUTICALS LTD.
(b) NATIONALITY : INDIAN
(c) ADDRESS : Elder House, Plot No. C/9, Dalia Indl. Estate,
Off. New Link Road, Andheri (W),
Mumbai - 400 058, India
3. PREAMBLE TO THE DESCRIPTION
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The following specification describes the invention. _^



4. DESCRIPTION:
FIELD OF THE INVENTION: The present invention relates to the certain novel compounds and its isomers and its enantiomers and its pharmaceutically acceptable salts, and its solvates, to a process for preparing such compounds, to pharmaceutical compositions containing compounds and to the use of such compounds and composition in medicines.
This invention particularly relates to novel compounds of the general formula I

R2 R3 O
and its pharmaceutically acceptable salts, and its solvates, to a process for preparing such compounds, to pharmaceutical compositions containing compounds and to the use of such compounds and composition in medicines. The invention also relates to isomers and enantiomers of novel compounds.
BACKGROUND OF THE INVENTION:
Diabetes mellitus is a chronic multifactorial metabolic disease characterized by insulin resistance, hyperglycemia, and often hyperlipidemia. The incidence of disease is estimated to reach more than 300 million by the year 2025. The disease is associated with obesity, dyslipidemia and hypertension, leading to increased cardiovascular risks. Untreated type 2 diabetes leads to several chronic diseases such as retinopathy, nephropathy and cardiovascular diseases, the latter leading to increased mortality. The ornstone of treatment of diabetes is lifestyle modification through increased physical activity and attention to food intake, particularly in obese in which weight loss is the principle goal. After this, pharmacological therapy with sulfonylureas, biguanides and / or nsulin is commenced. However current therapies to reduce plasma glucose levels have
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inherent problems, including poor compliance, ineffectiveness and occurrence of hypoglycemic episodes with insulin and the sulfonylureas (Porte, J. R. D.; Schwartz, M. W. Diabetes complications: Why glucose potentially toxic? Science 1996, 272, 699-700.) Biguanides are associated with increased incidence of lethal lactic acidosis (Sarges, R. Hypoglycemic Drugs. Prog. Med. Chem. 1981,18, 191).
Owing to the forecasted epidemic in diabetes mellitus type 2, the increasing financial and social costs, and the complicated pathology of the disease, new therapies are needed that address insulin resistance, dyslipidemia, hyperglycemia, and hypertension components of the disease.
Therefore there is a need for more effective, orally active agents, particularly ones that normalize both glucose and insulin levels. Thiazolidinediones (TZDs) are known to be insulin sensitizers and have been developed and clinically used as antidiabetic agents. The target of TZDs has been identified as the peroxisome proliferator-activated receptor y (PPARy) and the glucose-lowering action of the TZDs has been shown to be closely related to their PPARy agonist activity. Peroxisome proliferator-activated receptors (PPAR) can be subdivided into three sub types, namely: PPARa, PPAR8 and PPARy. These are encoded by different genes (Motojima, "Peroxisome proliferator-activated receptor (PPAR): Structure, mechanisms of activation and diverse functions,"Cell Structure and Function 1993, 18, 267-277). Moreover, two isoforms of PPARy also exist, PPARy1 and y2 These two proteins differ in their NH2-terminal-30 amino acids and are the result of alternative promoter usage and differential mRNA splicing (Vidal-Puig., et al., Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J. Clin. Invest. 1996, 37, 2553-2561). TZDs have been shown to reduce plasmatic glucose, lipid and insulin levels, and can be used for treatment of the diabetes mellitus type 2. The first in the class was Ciglitazone which was discontinued during early clinical trials. Since the pioneering discovery of Ciglitazone by a group of scientists at Takeda, (Sohda, T., et al., Studies on antidiabetic agents. II. synthesis of 5-[4-(l-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem. Pharm. Bull. 1982, 30, 3580-3600) which effectively reduces insulin resistance by potentiating insulin action
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in genetically diabetic and / or obese animals, several new thiazolidinediones (TZDs) have been developed. Pioglitazone, (Sohda, T., et al., Synthesis and hypoglycemic activity of 5-[4-(Pyfidylalkoxy)-benzyl]-2, 4-thiazolidinediones. Arzneim-Forsch./Drug Res. 1990,40, 37-42) Troglitazone, (Yoshioka, T., et al., Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. J. Med. Chem. 1989, 32, 421-428) and Englitazone, (Clark, D. A., et al., Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2, 4-diones as hypoglycemic agents. J. Med. Chem. 1991, 34, 319-325) are some marketed drugs and many others are still at variable stages of clinical development.
Fig: 1 Some existing Thiazolidinediones.
O




Ciglitazone (Takeda)
Troglitazone (Rezuline, Park-devis)
Pioglitazone (Actos - Takeda)

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Rosiglitazone (Avandia - GlaxoSmithKline)
Englitazone (Pfizer)



Darglitazone (Pfizer)
The exact mechanism of action of this class of compounds is not fully understood. A member of the nuclear receptor superfamily, PPARy, is proposed as a possible molecular target for this type of compounds. The PPARs form heterodimers with retinoid X receptor (RXR) and activate upon binding to a hormone response element located in the promoter region of target genes by their cognate ligands. The activation of PPAR/RXR heterodimers results in specific induction of subsets of genes in controlling lipids, carbohydrate and energy homeostasis, [(a) Lehman, J. M., et al., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor y (PPARy). J. Biol. Chem. 1995, 270, 12953-12956. (b) Willson. T. M. et. al, The structure-activity relationship
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between peroxisome proliferator-activated receptor y agonism and the antihyperglycemic activity of thiazolidinediones. J. Med. Chem. 1996, 39, 665-668.]
The PPARy also plays a critical role in the regulation of adipocyte differentiation (Rosen, E. D., et al., PPARy is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999, 4, 611-617.) i.e., induction of differentiation and proliferation from preadipocytes to mature adipocytes, thereby increasing number of small adipocytes that are more sensitive to insulin and decreasing the number of large adipocytes by inducing apoptosis. During the adipocyte maturation process, the uptake of glucose and fatty acids, storage of triglycerides (TG) and production of adiponectin were also found to be promoted via TZD induced activation of PPARy (Spiegelman, B. M., PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998, 47(4), 507-14). Generation of small insulin-sensitive adipocytes by TZDs lowers circulating serum FFA levels and downregulates the production and secretion of TNF-a (Hotamisligil, G. S., The role of TNF-alpha and TNF receptors in obesity and insulin resistance. J. Intern. Med. 1999, 245, 621-625) and resistin (Steppan, C. M., et al., The hormone resistin links obesity to diabetes. Nature 2001, 409, 307-312) subsequently ameliorates insulin resistance (Yamauchi, T., et al., The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J. Biol. Chem. 2001, 276, 41245-41254). Some TZDs have also been proved to be protein tyrosine phsophatase-lB (PTP1B) inhibitors (Maccari, R., et al., 5-Arylidene-2, 4-thiazolidinediones as inhibitors of protein tyrosine phosphatases Biorg. Med. Chem. 2007, 15, 5137-5149).
TZDs, though effective some of them have been reported with hepatotoxicity. The cause of the hepatotoxicity may be related to activation of gene expression in the liver, toxic metabolites or drug-drug interactions. (Malaisse, W. J., Mechanism of action of a new class of insulin secretagogues. Exp. Opin. Clin. Endocrinol. Diabetes 1999, 107 (Suppl. 4), S140). Troglitazone can activate pregnane X receptor (PXR), a newly isolated orphan nuclear receptor. The PXR receptor regulates transcription of cytochrome P450 3A4 (CYP3A4) which is responsible for the oxidative metabolism of the majority of
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xenobiotics in liver. Because of concern over related liver failure, troglitazone was withdrawn from the European market in 1998.
Combination of two active pharmacophores into one molecule is one of the novel drug designing techniques used in drug discovery. The present inventors have attempted to design some novel molecules as potential PPARy agonist and PTP-1B inhibitors as antidiabetics. The literature report on structure activity relationship studies of antihyperglycemic 2, 4-TZDs have established structural requirements for these type of compounds (Kulkarni, V. M., et al., Three dimensional quantitative structure activity relationships (3D-QSAR) of antihyperglycemic agents. Biorg. Med. Chem. 1999, 7, 1475-1485). Molecular modeling and 3D QSAR techniques showed structural requirements for PTP1B inhibitors [(a) Kulkarni, V. M., et al., Molecular modeling of Protein tyrosine phosphatase 1B (PTP 1B) inhibitors Bioorg. Med. Chem. 2002, 10, 897-906. (b) Kulkarni, V. M., et al., Human Protein tyrosine phosphatase 1B inhibitors: QSAR by genetic function approximation, J. Enz. Ink. Med. Chem. 2007, 22, 3, 267-276. (c) Kulkarni, V. M., et al., 3D-QSAR CoMFA and CoMSIA on Protein Tyrosine Phosphatase IB Inhibitors Bioorg. Med. Chem. 2002, 10, 2267-2282). It has long been thought that protein tyrosine phosphatases, such as PTP-1B, have played a major role in the negative regulation of insulin signaling and are involved in the insulin resistance associated with Type 2 diabetes [(a) Kennedy, B. P.,; Ramachandran, C, Protein tyrosine phosphatase-IB in diabetes, Biochem. Pharmacol. 2000, 60, 877. (b) Moller, N. Protein tyrosine phosphatase (PTPs) as drug targets: Inhibitors of PTP-1B for the treatment of diabetes, Curr. Opin. Drug Discovery Dev. 2000, 3(5), 527-540]
The present invented series is the combination of two active pharmacophores, namely
thiazolidinedione and biphenyl moiety, latter as constituents of PTP-IB. Hence the
present invented series of compounds and pharmaceutical compositions prepared
herewith is expected to overcome the cited problem and also discloses a number of
pharmaceutical uses associated therewith such as insulin resistance, dyslipidemia,
hyperglycemia, hypertension, anti-inflammatory activity, analgesic
activity, cyclooxygenasel and 2 (COX-1 and COX-2) inhibition, PTP-IB inhibition, angiotensin antagonists, anti-cancer activity, PDE-4 enzyme inhibitor.
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OBJECTIVE OF THE INVENTION
The object of the present invention is to prepare novel series of biphenyl
thiazolidinedione derivatives and pharmaceutical compositions thereof having
antidiabetic activities.
Another object of the present invention is to provide the method of preparation of
biphenyl thiazolidinedione derivatives and their intermediates.
Another object of the present invention is to provide pharmaceutical uses of biphenyl
thiazolidinedione derivatives.
SUMMARY OF THE INVENTION:
The present invention relates to novel derivatives of biphenyl - thiazolidinedione of the
generic formula I:

.

wherein,
Zl and Z2 represents H, or any substituted group or together forms a chemical bond;
Rl represents H, alkoxy, nitro, halo, hydroxy, optionally substituted amino


linear or branched alkyl group, substituted alkyl group, cycloalkyl

group, -S-Rll alkyl thio, acyl group, substituted or unsubstituted heterocyclic group,
alkoxy carbonyl, aryloxy , aryloxy carbonyl;
R2 represents H, halo, hydroxy, linear or branched alkyl group, substituted alkyl group;
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R3, R4 and R5 independently represents H, alkoxy, hydroxy, linear or branched alkyl group, substituted alkyl group;
COOH . CN so3
R6 represents H, , linear or branched alkyl group, , .
TT COOH . CN so3H
represents
linear or branched alkyl group,
R6 represents H, , linear or branched alkyl group,
optionally substituted amino group;
R7 represents H, linear or branched alkyl group, cyclo alkyl group, an acyl group, an
aralkyl group where in aryl moiety is substituted or unsubstituted, or an aryl group;
R8 represents a substituted or unsubstituted heterocyclic group, linear or branched alkyl,
substituted alkyl;
R9 represents a substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aromatic group, substituted or unsubstituted cycloalkyl group, fused
arylheterocyclyl;
When Rl represents alkoxy group, and Zl and Z2 together forms chemical bond then, R2
or R3 or R4 or R5 is other than H, and when Rl, R2, R3, R4, R5 are each independently
represents H , and Zl and Z2 together forms chemical bond, then R6 is not H.
And when Rl, R2, R3, R4, R5 represents independently or together halo group and Zl
and Z2 together forms chemical bond, then R6 is not H.
their salts or pharmaceutical solvates or isomers or enantiomers are novel compounds and
their pharmaceutical compositions containing such compounds and the use of such
compounds and compositions in medicines and process for preparing the same.
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5. CLAIMS We Claim:
1) Compounds of the formula I


in which, Zl and Z2 represents H, or any substituted group or together forms a chemical bond;
Rl represents H, alkoxy, nitro, halo, hydroxy, optionally substituted amino

group, -S-Rl 1 alkyl thio, acyl group, substituted or un substituted heterocyclic group, alkoxy carbonyl, aryloxy , aryloxy carbonyl;
R2 represents H, halo, hydroxy, linear or branched alkyl group, substituted alkyl group; R3, R4 and R5 independently represents H, alkoxy, hydroxy, linear or branched alkyl group, substituted alkyl group;

COOH —CN —S03H
R6 represents H, , linear or branched alkyl group, , ,
optionally substituted amino group;
R7 represents H, linear or branched alkyl group, cyclo alkyl group, an acyl group, an
aralkyl group where in aryl moiety is substituted or unsubstituted, or an aryl group;
R8 represents a substituted or unsubstituted heterocyclic group, linear or branched alkyl,
substituted alkyl;
R9 represents a substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aromatic group, substituted or unsubstituted cycloalkyl group, fused
arylheterocyclyl;
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When Rl represents alkoxy group, and Zl and Z2 together forms chemical bond then,R2 or R3 or R4 or R5 is other than H, and when R1,R2,R3,R4,R5 represents H , and Zl and Z2 together forms chemical bond then R6 is not H.
And when Rl, R2, R3, R4, R5 represents independently or together halo group and Zl and Z2 together forms chemical bond, then R6 is not H.
6. DATE AND SIGNATURE
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