WO2005100331A2

WO2005100331A2 - Antidiabetic agents

Info

Publication number: WO2005100331A2
Application number: PCT/IB2005/000998
Authority: WO
Inventors: Mohammad Salman; Jitendra Sattigeri; Dharam Vir; Vija Dattatraya Gangan
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-04-14
Filing date: 2005-04-14
Publication date: 2005-10-27
Anticipated expiration: 2006-10-14
Also published as: WO2005100331A3

Abstract

The present invention relates to alkynyl derivatives, which have PPAR agonist activity and hence can be used as antidiabetic compounds. Compounds disclosed herein can be used for the treatment of diabetes and diabetes-associated complications, for the treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism, for the treatment of diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndorme, hypertensive nephrosclerosis, polycystic ovarian syndrome, eating disorders, psoriasis, obesity, for improving cognitive functions in dementia and as aldose reductase inhibitors. Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are provided.

Description

ANTIDIABETIC AGENTS

Field of the Invention The present invention relates to alkynyl derivatives, which have PPAR agonist activity and hence can be used as antidiabetic compounds. Compounds disclosed herein can be used for the treatment of diabetes and diabetes-associated complications, for the treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism, for the treatment of diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndorme, hypertensive nephrosclerosis, polycystic ovarian syndrome, eating disorders, psoriasis, obesity, for improving cognitive functions in dementia and as aldose reductase inhibitors. Processes for the preparation of such compounds, pharmaceutical compositions containing such compounds, and the methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are provided. Background of the Invention

Type 2 insulin-resistant diabetes mellitus [also known as non-insulin dependent diabetes mellitus] afflicts an estimated 6% of the adult population in western society and is expected to continue to grow at a rate of 6% per annum worldwide. Type 2 diabetes is a complex metabolic disorder and is characterized by hyperglycemia. This results from contribution of impaired insulin secretion from pancreas and insulin resistance mainly in muscle and liver. Insulin resistant individuals in addition to being hyperglycemic, exhibit a constellation of closely related clinical indications, which include obesity, hypertension, dyslipidemia, and premature atherosclerosis. In fact, 80% of diabetic mortality arises from atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late stage complications such as nephropathy, neuropathy and retinopathy.

Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise. Presently, several pharmacological agents are also available as hypoglycemic agents including insulin secretagogues - sulphonyl ureas (glimeperide) and non sulphonyl ureas (repaglinide)- which increase insulin secretion from pancreatic cells; biguanides - metformin - which lower hepatic glucose production; and α- glucosidase inhibitors - acarbose - which delays intestinal absorption of carbohydrate.

PPAR (Peroxisome-Proliferator- Activated Receptor) are ligand activated transcription factors (members of nuclear receptor family), which are offering promising therapeutic approach to type 2 diabetes mellitus. PPAR exists in three subtype forms α, β, γ and δ. PPAR γ is abundantly expressed in adipose tissues. Direct activation of PPAR y leads to induction of adipocyte genes such as for fatty acid transporter 1 which in turn contributes to lowering of triglycerides and free fatty acid levels. As FFA is a potential mediator of insulin resistance, lowering of FFA levels contributes to efficacy of PPAR γ activation in increasing insulin sensitivity and consequently glucose uptake in skeletal muscle cell. Glitazones - rosiglitazone and pioglitazone - belongs to this class of drug and are now proven insulin sensitisers [Moller, D.E.; Nature, 2001, 414(6865), 821-827]

WO 03/018553 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as reported antidiabetic agents. WO 01/14351 and WO 01/14352 disclose substituted benzylthiazolidine-2,4-dione derivatives allegedly capable of serving as ligands of the human peroxisome proliferator- activated receptor (PPAR), enhancing the transcriptional activity of the receptor and showing effects of lowering blood sugar level and lowering lipid level. WO 01/14349 discloses benzylthiazolidine-2,4-dione derivatives which are described as binding as ligands to human peroxisome proliferator-activated receptor (PPAR), thereby activating the receptor and exerting antihyperglycemic and antihyperlipidemic effects. European Patent 684242 discloses isoxazolidinedione derivatives, which are described as having b-ypoglycemic action and hyperlipidemic action, and being useful as therapeutic agents for diabetes and the complication thereof. U.S. Patent No. 6,008,237 discloses substituted 5-aryl-2,4- thiazolidinedione which are described as being potent agonists of PPAR, and therefore useful in the treatment, control or prevention of diabetes, hyperglycemia, hyperlipidemia, atherosclerosis, obesity, vascular restenosis, and other PPAR α, δ and/or γ mediated diseases, disorders and conditions. U.S. Patent No. 5,260,445 discloses certain substituted thiazolidinedione derivatives and their use in medicine. U.S. Patent No. 5,965,589 discloses novel thiazolidinedione derivatives described as having hypoglycemic activity, blood lowering activity, and antidiabetic action. U.S. Patent No. 5,910,592 discloses substituted thaizolidinedione derivatives and their use in medicine. U.S Patent No. 5,885,997 discloses 5 novel azolidinedione derivatives, which are described as being useful for the treatment of diabetes and related diseases.

Summary of the Invention

The present invention relates to alkynyl derivatives, which have PPA-R agonist activity and hence can be used as antidiabetic compounds, and processes for the syntheses of these

10 compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, N-oxides or metabolites of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, can be used for the treatment of diabetes mellitus and the disease or condition mediated through insulin resistance. Other

15 aspects will be set forth in accompanying description which follows and in t e part will be apparent from the description or may be learnt by the practice of the invention.

In accordance with one aspect, there are provided compounds having the structure of

their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N- 25 oxides or polymorphs wherein

A can represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acylo-xy, aryl or heterocycle.

U-V can represent R₂C=C or R₂CH-CH, wherein R₂ can represent hydrogen, alkyl, or alkoxy. W can represent sulphur, oxygen, or NR₃, wherein R₃ can represent hydrogen or alkyl.

X can represent

wherein n is an integer 0 to 3, and Ri can represent hydrogen or alkyl, with the pro πso that when X is — (CH₂)rf

U-V can not be R₂CH-CH, unless A is acyloxy, such as acetyloxy, for example. B can represent aryl or heterocycle.

Y can represent (CH₂)_n wherein n represents an integer 0 to 3. R can represent hydrogen, alkyl, cycloalkyl, aryl or heterocycle.

In accordance with a second aspect, there are provided processes for preparing compounds disclosed herein.

As used herein, the term "alkyl" refers to straight or branched saturated hydrocarbon having one to six carbon atom(s). One or more hydrogen atom(s) of alkyl can optionally be replaced by halogen, hydroxy, cyano, or -NR₅Re, wherein R₅ and Re are selected from hydrogen and alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, p-ropyl, isopropyl and butyl, and the like. As used herein, the term "alkenyl" or "alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of sa-dd alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl and propynyl, and the like. As used hexein, the term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloakyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like. As used herein, the term "cycloalkenyl" refers to unsaturatecd carbocyclic ring having three to seven carbon atoms. Examples of cycloakenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like. The "cycloalkyl" or

"cycloalkenyl" may optionally be substituted with halogen, hydroxy, cyano, nitro or -LNER₅R₆, wherein R₅ and R₆ are selected from hydrogen and alkyl. As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "acyl and acyloxy" refers to COR₇ and OCOR₇ wherein R₇ represents alkyl or aryl. A-s used herein, the term "alkoxy" refers to O-R₇ wherein R₇ represents alkyl or aryl. As used herein, the term "thioalkyl" refers to -S-R₇ wherein R₇ refers to alkyl or aryl. As used herein, the term "cycloalkoxy" refers to 0-R₈ wherein R₈ represents cycloalkyl or cycloalkenyl. Λ-s used herein, the term "haloakyl" refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen.

As used herein, the term "aryl" stands for an aromatic radical having 6 to 14 carbon, atoms. Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphexiyl, and the like. As used herein, the term "heterocycle" refers to non-aromatic, aromatic or aromatic fused with aromatic or non-aromatic ring system having one or more heteroatom (s) in either the aromatic or the non-aromatic part wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic. One or more carbon atom (s) of non-aromatic fused with aromatic ring is/are replaced by carbonyl or sulfonyl group. Examples of heterocycles include, but not limited to, benzoxazinyl, benzthiazinyl, benzimidazolyl, carbazolyl, Indolyl, phenoxazinyl and phenothiazinyl, isoxazolyl and pyridinyl, and the like. The aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from the group comprising of halogen, hydroxy, nitro, mercapto, cyano, alkyl, aryl, haloalkyl, alkox-y, haloalkoxy, thioalkyl, cycloalkoxy, -NR₅R₆, -CONRsRe, -COOR₆, -OCOR₆, -COR₆, -

NHSO₂R₆ and -SO₂NHR₆ wherein R₅ and R₆ are independently selected from hydrogen, allcyl and aryl.

As used herein, the term "polymorphs" includes all crystalline forms for compounds described herein. In addition, some of the compounds described herein may form solvates with water (for example, hydrate, hemihydrate or sesquihydrate) or common organic solvents. Such solvates are also encompassed within the scope of this invention.

The phrase "pharmaceutically acceptable salts" denotes salts of the free base, whicra possess the desired pharmacological activity of the free base. Suitable pharmaceutically acceptable salts may be prepared from an inorganic or organic acid. Example of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric acid and the like. Appropriate organic acids include, but are not limited to, aliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, stearic, algenic, beta-hydroxybutyric, cyclohexylaminosulfonic, galactaric, galacturonic acid and the like.

Detailed Description of the Invention

The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme

^■*^■• Scheme I

Formula II Formula HI Formula IV

Compounds of Formula Nil can be prepared according to Scheme I. Thus, a compound of Formula II is reacted with a compound of Formula III to give a compound of Formula IN (wherein A and X are the same as defined earlier), which on condensation with the thiazolidinedione of Formula N gives a compound of Formula NI, which on reduction gives a compound of Formula NIL The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IN can be carried out in a solvent such as, for example, dimethylformamide, chloroform, tetrahydrofuran, acetonitrile or dimethylsulfoxide. The reaction of a compound of Formula II with a compound of Formula III can be carried out in the presence of an organic base such as, for example, triethylamine, diethylamine, tributylamine, 4-dimethylaminopyridme or pyridine. The reaction of a compound of Formula

II with a compound of Formula III can be carried out in the presence of a coupling agent such as, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, Ν-methyl morpholine or hydroxy benzotriazole. The condensation of a compound of Formula IN with thiazolidinedione of Formula N to give a compound of Formula VI can be carried out in a solvent such as, for example, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide or toluene. The condensation of a compound of Formula IN with thiazolidinedione of Formula N can be carried out in the presence of organic base such as, for example, pyridine, piperidine, triethylamine or diethylamine. The condensation of a compound of Formula IV with thiazolidinedione of Formula N can be carried out in the presence of an organic acid such as, for example, acetic acid, dichloroacetic acid or benzoic acid.

The reduction of a compound of Formula NI to give a compound of Formula VII can be carried out in a solvent such as, for example, methanol, ethanol, tetrahydrofuran or acetonitrile. The reduction of a compound of Formula VI can be carried out in the presence of a reducing agent such as, for example, sodium borohydrate, cyanoborohydride or sodium triaacetoxyborohydride.

In the above scheme, where the specific base, coupling agents, reducing agents, solvents, etc., are mentioned it is be understood that other bases, coupling agents, reducing agents, solvents, etc., known to those skilled in the art may be used. Similarly the reaction temperature and duration may be adjusted according to the desired needs. An illustrative list of compounds disclosed herein is given below (also shown in Table

I and II): 5-[4-{3-acetoxyprop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 1)

5-[4-{3-(indol-l-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 2)

5-[4-{3-([5-methyl-2-phenyl-4-oxazolyl]methoxy)prop-l-ynyl}benzylidene thiazolidine-2,4- dione (Compound No. 3) 5-[4-{3-(phenoxazin-10-yl)prop-l-yl}benzylidene]thiazolidin-2,4-dione (Compound No. 4)

5-[4-{3-(indolin-l-yl)prop-l-ynyl} benzylidene]thiazolidine-2,4-dione (Compound No. 5)

5-[4-{3-(2-chlorophenothiazin-10-yl)prop-l-ynyl] benzylidene]thiazolidine-2,4-dione (Compound No. 6)

5-[4-{3-(2-trifluoromethylphenothiazin-10-yl)prop-l-ynyl} benzylidene]thiazolidine-2,4- dione (Compound No. 7)

5-[4- {3-(phenothiazin- 10-yl)prop- 1 -ynyl} benzylidene]thiazolidine-2,4-dione (Compound No. 8)

5-[4-{3-(3,6-dibrom-carbozol-9-yl)prop-l-ynyl] benzylidene]thiazolidine-2,4-dione (Compound No. 9) 5-[4-{3-(carbazol-9-yl)prop-l-ynyl} benzylidene] thiazolidine-2,4-dione (Compound No. 10)

5-[4- {3-(dibenz [b,f]azopin-5-yl)prop- 1-ynyl} benzylidene] thiazolidine-2,4-dione (Compound No. 11)

5-[4- {3-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 12) 5-[4-{3-(4-methyl-2-phenylimidazol-l-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 13)

5 - [4- { 3 -(3 -OXO-2H- 1 ,4-b enzoxazin-4-yl)prop- 1 -ynyl} benzylidene] thiazolidine-2,4-dione (Compound No. 14)

5-[4-{3-(2,3-dihydro-l,4-benzothiazin-4-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 15)

5-[4-{3-(N-(2-benzoxazoeyl)-N-methylamino)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 16)

5-[4- {3-(4-(4-fluorophenyl)piperizin- 1 -yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 17) 5-[4- {3-acetoxy prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 18)

5-[4-{3-([5-methyl-2-phenyl-4-oxazolyl] methoxy)}benzyl]thiazolidene-2,4-dione (Compound No. 19)

5-[4-{3-(N-(2-benzthiazolyl)-N-methylamino)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 20)

5-[4- {3-(indol-l-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 21)

5-{4-{3-(phenoxin-10-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 22) 5-[4- {3-(indolin-l-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 23)

5-[4- {3-(2-trifluoro methyl phenothiazin-10-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 24) 5-[4- {3-(carbazol-9-yl)prop-l -ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 25)

5-[4- {3-(dibenzo[b,f,]azepin-5-yl)prop-l-ynyl} benzyl] thiazolidine-2,4-dione (Compound No. 26) 5-[4- {3-(2,3-dihydro-l,4-berιzoxazm-4-yl)prop-l-vnyl] benzyl]thiazolidine-2,4-dione (Compound No. 27)

5 - [4- { 3 -(4-methyl-2-phenylimidazol- 1 -yl)prop- 1 -ynyl } benzyl]thiazolidene-2,4-dione (Compound No. 28)

5-[4-{3-(4-(4-flurophenyl)piperizin-l-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 29)

5-[4-{3-(2-chlorobenzimidazol-l-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 30)

5-[4-{3-(N-(2-benzoxazolyl)-N-methylamino)prop-l-ynyl}benzylidene]thiazolidine-2,4- dione (Compound No. 31)

5-[4-{3-(N-(2-benzthiazolyl)-N-methylamino)prop-l-ynyl}benzylidene]thiazolidine-2,4- dione (Compound No. 32) 5-[4- {3-(3-oxo-2H-l,4-benzthiazin-4-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione (Compound No. 33)

5-[4-{3-(3-oxo-2F£-l,4-benzthiazin-4-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione (Compound No. 34) Table I

Further compounds according to the disclosure herein are exemplified in Table II. Table II

In another aspect, pharmaceutical compositions comprising, as an active ingredient, at least one of the disclosed compounds or a pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent are disclosed. Compounds disclosed herein may be administered to human or animal for treatment by any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intrauethral, intramascular, intranasal), preferred route is oral. The pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" is intended to included non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type.

Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, sachets and suppositories. For solid form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia; disintegrating agents such as agar-agar, calcium carbonate, alginic acid, certain silicates and sodium carbonate; absorption acceptors such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof. In the case of capsules, tablets, pills, the dosage form may also comprise buffering agents.

The solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.

Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrup and elixir. For liquid preparations, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (such as cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, and fatty acid esters of Sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvants such as wetting agents, emulsiying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents. Injectible preparations such as sterile injections or aqueous solutions may be formulated according to the art using suitable dispersing or wetting and suspending agent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solutions, and isotonic sodium chloride. The formulations disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.

Examples set forth below demonstrate general synthetic procedures for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples

Example 1: Preparation of compounds of Formula III

In a 3-neck round-bottomed flask fitted with nitrogen gas inlet, guard tube and septum was placed dimethylformamide and sodium hydride (1.2 equiv). The suspension was cooled to 0 °C and a solution of heterocycle in dimethylformamide was added slowly. Ice bath was removed and the stirring continued at an ambient temperature for 1 hour. The clear solution was cooled down to 0 °C again and propargyl bromide added slowly. The reaction mixture was allowed to warm to an ambient temperature. After completion of reaction, reaction mixture was diluted in water and organics extracted with ethyl acetate. Organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was purified on column (Silica gel, 100-200 mesh).

Example 2: Preparation of compound of Formula IN In a 3-neck round-bottomed flask fitted with Ν₂ inlet, septum and a guard tube were placed triflate of Formula II (1 eq), Et₃N (2 eq), Pdcl₂ (pph₃)₂, (0.05 eq), PPh₃ (0.1 eq), Cul (0.1 eq) and dimethylformamide. The reaction mixture was heated to 70°C and at this temperature was added the compound of Formula III (1.2 eq) as a solution in dimethyl formamide slowly over a period of about 30 min, and heated till completion of reaction. Reaction mixture was poured in water and extracted with dichloromethane. The organic layer was washed with H₂O, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was then purified on column (silica gel, 100-200 mesh) using hexane-ethyl acetate as solvent system. The following compounds were prepared following the above procedure

4-[3-{indolin-l-yl}prop-l-ynyl]benzaldehyde. Yield=90%. 1H NMR (CDC1₃, 300 MHz): δ 3.00 (t, J=9.0Hz, 2H), 3.49 (t, J=9.0Hz, 2H), 4.17 (s, 2H), 6.65 (d, J=6.0Hz, 1H), 6.75 (t, J=9.0Hz, 1H), 7.09-7.14 (m, 2H), 7.50 (d, J=9.0Hz, 2H), 7.78 (d, J=9.0Hz, 2H), 9.97 (s, 1H).

4-[3-{indol-l-yl}prop-l-vnyl]benzaldehyde. Yield = >95%. 1H NMR (CDCI3, 300 MHz): δ 5.15(s, 2H), 6.56(d, J=3.0Hz, 1H), 7.14-7.30 (m, 3H), 7.48 (d, J=8.1Hz, 1H), 7.56 (d, J=8.1Hz, 2H), 7.67 (d, J=8.1Hz, 1H), 7.82 (d, J=8.2Hz, 2H), 9.99(s, 1H).

4-[3- {carbazol-9-yl}prop- 1 -ynyl}benzaldehyde. Yield = 96%.

4-{3-{3,6-dibromocarbazol-9-yl}prop-l-ynyl]benzaldehyde. Yield = 92%. ^ NMR ^DC , 300 MHz): δ 5.26 (s, 2H), 7.30-7.54 (m, 5H), 7.63 (d, J=8.7Hz, 2H), 7.78 (d, J=7.8Hz, 2H), 8.17 (s, 2H), 9.98 (s, lH).

4-[3-{Dibenzo[b,f]azapin-5-yl}prop-l-ynyl]benzaldehyde. Yield = 99%. 1H NMR (CDCI₃, 300 MHz): δ 4.69 (s, 2H), 6.75 (s, 2H), 7.02-7.12 (m, 4H), 7.24-7.32 (m, 4H), 7.41 (d, J=6.0Hz, 2H), 7.76 (d, J = 9.0Hz, 2H), 9.97 (s, 1H).

4-{3-[2-trifluoromethyl phenothiazin-10-yl]prop-l-ynyl}benzaldehyde. Yield = 89%. 1H NMR (CDCI₃, 300 MHz): δ 4.77 (s, 2H), 6.99-7.57 (m, 7H), 7.81 (d, J=9.0Hz, 2H), 8.00 (d, J=9.0Hz, 2H), 9.99 (s, 1H).

4-[3-{3-oxo-2H-l,4-benzoxazin-4-yl]prop-l-ynyl]benzadehyde. 1H NMR (CDCI₃, 300 MHz): δ 4.68 (s, 2H), 4.96 (s, 2H), 6.83-7.44 (m, 4H), 7.54 (d, J=7.8Hz, 2H), 7.80 (d, J=8.1Hz, 2H), 9.99 (s, 1H).

4-[3-{phenoxazin-10-yl}prop-l-ynyl]benzaldehyde. Yield = 34%. ^!HNMR (CDC1₃, 300 MHz): δ 4.54(s, 2H), 6.75-6.94(m, 8H), 7.53(d, J=9.0Hz, 2H), 7.78(d, J=9.0Hz, 2H), 9.98(s, 1H). 4-[3-[phenothiazin-10-yl]prop-l-ynyl]benzaldehyde. Yield = 36%. ¹H NMR (CDC1₃, 300

MHz): δ 4.77(s, 2H), 6.96(t, J=7.5Hz, 2H), 7.14-7.25(m, 6H), 7.57(d, J=7.8Hz, 2H), 7.82(d,

J=7.8Hz, 2H), 9.99(s, 1H).

4-[3-{2,3-dihydro-l,4-benzoxazin-4-yl}prop-l-ynyl]benzaldehyde. Yield = 96%. 1H NMR (CDC1₃, 300 MHz): δ 3.42(t, J=4.4Hz, 2H), 4.28(s, 2H), 4.36(t, J=4.3Hz, 2H), 6.70-6.91(m, 4H), 7.50(d, J=8.0Hz, 2H), 7.78(d, J=8.1Hz, 2H), 9.97(s, 1H).

4-[3-{2,3-dihydro-l,4-benzothiazin-4-yl}prop-l-ynyl]benzoldehyde. Yield = 80%. 1H NMR (CDC1₃, 300 MHz): δ .16(t, J=5.4Hz, 2H), 3.69(t, J=5.4Hz, 2H), 4.3 l(s, 2H), 6.75(t, J=7.5Hz, 1H), 6.93(d, J=8.4Hz, 1H), 7.06-7.13(m, 2H), 7.54(d, J=8.1H, 2H), 7.81(J=8.1Hz, 2H), 10.00(s, 1H).

4-[3-{2-chlorobenzimidazol-l-yl}prop-l-ynyl]benzaldehyde. Yield = 88%. 1H NMR (CDC1₃, 300 MHz): δ 5.20(s, 2H), 7.32-7.37(m, 2H), 7.50-7.56(m, 3H), 7.72-7.83(m, 3H), 10.00(s, 1H).

4-[3- {(5-methyl-2-phenyloxazol-4-yl)methoxy}porp- 1 -ynyl}benzaldehyde.

Example 3: Preparation of compound of Formula VI

In a single-neck round-bottomed flask equipped with Dean-Stark water separator, condenser and guard tube was placed compound of Formula IN (1 eq), 2,4-thiazolidinedione of Formula N (1.2 eq), piperidine (0.15 eq), benzoic acid (0.15 eq) and toluene. The reaction mixture was heated on oil bath at reflux to azeotropically remove water. After no more water separated, reaction mixture was filtered hot and the residue washed successively with hot toluene and water and dried in air.

The following compounds were prepared following the above procedure.

Compound No. 1: 5-[4- { 3 -acetoxy prop- 1 -ynyl} benzylidene]thiazolidine-2,4-dione. Yield 20%, mp=203-7°C. 1H NMR (DMSO, 300 MHz):δ 2.09(s, 3H, CH₃), 4.96(s, 2H), 7.61(s, 4H), 7.80(s, 1H). Compound No. 2: 5-[4-{3-(indol-l-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione.

Yield=43% m.p: 187-191°C. 1H NMR (CDC1₃, 500 MHz):δ 5.16(s, 2H), 6.53(d, J=2.7 Hz,

IH), 7.11-7.50(m, 8H), 7.64(d, J=7.8 Hz, IH), 7.72(s, IH); MS (+ve ion mode): m/z

359^+1).

Compound No. 3: 5-[4- {3-([5-methyl-2-phenyl-4-oxazolyl]methoxy)prop- 1 -ynyl} benzylidene thiazolidine-2,4-dione. Yield=60%, m.p. =175-9 °C. 1H NMR (CDCI3, 300 MHz):δ 2.46(s, 3H), 4.50(s, 2H), 4.63 (s, 2H), 7.37(d, J=9Hz, 2H), 7.43-7.45(m, 3H), 7.5 l(d, J=9Hz, 2H), 7.72(s, IH), 8.01(m, 2H); MS(+ ve ion mode): 431 (m⁺+l).

Compound No. 4: 5-r4-{3-(phenoxazin-10-vl)prop-l-vl}benzylidene1thiazolidin-2,4-dione. Yield=70%, m.p=205-8 °C. 1H NMR (CDCI₃, 300 MHz):δ 4.54(s, 2H), 6.77-6.78(m, 6H), 6.90-6.94(m, 2H), 7.40(d, J=8.4Hz, 2H), 7.48(d, J=8.4 Hz, 2H), 7.78(s, IH). MS(+ve ion mode): 424(M⁺+1).

Compound No. 5: 5- [4- {3 -(indolin- 1 -yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione Yield=84%, m.p: 185-9 °C. 1HNMR (CDCI₃, 300 MHz):δ 3.01(t, J=7.8Hz, 2H), 3.50(t, J=7.8Hz, 2H), 4.18(s, 2H), 6.67(d, J=7.8Hz, IH), 6.76(t, J=7.2 Hz, IH), 7.13-7.15(m, 2H), 7.35-7.96(m, 4H), 7.79(s, IH). MS(+ve ion mode): m/z 361(M⁺+1).

Compound No. 6: 5-[4-{3-(2-chloro phenothiazin-10-yl)prop-l-ynyl}benzylidene] thiazolidine-2,4-dione. Yield=42%, m.p.= 240-7 °C. 1H NMR (CDC1₃, 300 MHz):δ 4.75(s, 2H), 6.93-7.06(m, 3H), 7.12(d, J=9Hz, IH), 7.19-7.29(m, 3H), 7.43-7.53(m, 5H), 7.72(s, IH). MS (+ve ion made): 475 (M+l).

Compound No. 7: 5-r4-|3-r2-trifluoromethvlphenothiazin-10-v prop-l- ynyl}benzylidene]thiazolidine-2,4-dione. Yield=44%, m.p=227-230°C. ^!HNMR (DMSO-d₆, 300 MHz):δ 5.03(s, 2H), 7.06(t, J=6Hz, IH), 7.22-7.62(m, 10H), 7.77(s, IH). MS(+ve ion mode): 509(M⁺+1). Compound No. 8: 5 - 4- { 3 -(phenothiazin- 10-yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4- dione. Yield=56%, m.p= 205-9°C. ¹H MR (DMSO-d₆, 300 MHz):δ 4.80(s, 2H), 6.99(t, J=6Hz, 2H), 7.16(d, J=6Hz, 2H), 7.21-7.3 l(m, 4H), 7.47(d, J=8.4Hz, 2H), 7.53(d, J=8.4Hz, 2H), 7.74(s, IH).

Compound No. 9: 5-[4-{3-(3,6-dibromo-carbazol-9-yl)prop-l-ynyl}benzylidene] thiazolidine- 2,4-dione. Yield=36%, m.p = 194-202 °C. ^!H NMR (DMSO-d₆, 300 MHz):δ 5.37(s, 2H), 7.41(s, 2H), 7.54 (d, J=9Hz, 2H), 7.60(d, J=9Hz, 2H), 7.67-7.71(m, 4H), 8.20(s, IH). MS(+ve ion mode): 567(M⁺+1).

Compound No. 10: 5 - [4 { 3 -(carbazol-9-yl)prop- 1 -ynyl } benzylidene] thiazolidine-2,4-dione. Yield = 53%, m.p = 260-9 °C. 1H NMR (DMSO-d₆, 300 MHz):δ 5.62(s, 2H), 7.26(t, J=6Hz, 2H), 7.46-7.55(m, 6H), 7.74-7.78(m, 3H), 8.18(d, J=9Hz, 2H).

Compound No. 11: 5 - [4- { 3 -(dibenzo [b,f] azepin-5-yl)prop- 1 -ynyl } benzylidene]thiazolidine- 2,4-dione. Yield = 27%, m.p. = 167-172 °C. 1H NMR (DMSO-d₆, 300 MHz):δ 4.73(s, 2H), 6.73(s, 2H), 7.03-7. l l(m, 4H), 7.22-7.33(m, 6H), 7.45(d, J=8.3Hz, 2H), 7.69(s, IH), 8.02(s, IH). MS(+ve ion mode): m/z 435(M⁺+1).

Compound No. 12: 5-[4- {3-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)prop- 1 - ynyl}benzylidene]thiazolidine-2,4-dione. Yield = 36%, m.p. 198-203 °C. H NMR (DMSO- d₆, 300 MHz):δ 4.27(brs, 2H), 4.4(brs, 2H), 6.61-6.71(m, 2H), 6.80(t, J=8.2 Hz, IH), 6.93(d, J=8.2Hz, IH), 7.48(d, J=8.3 Hz, 2H), 7.56(d, J=8.3H, 2H), 7.75(s, IH). MS(+ve ion mode): m/z 377(M⁺+1).

Compound No. 13: 5 - [4- { 3 -(4-methyl-2-phenylimidazol- 1 -yl)prop- 1 - ynyl}benzylidene]thiazolidine-2,4-dione. Yield = 50%, m.p = 207-213 °C. 1H NMR(DMSO- d₆, 300 MHz):δ 2.16(s, 3H), 5.18(s, 2H), 7.19(s, IH), 7.46-7.71(m, 9H), 7.75(s, IH). MS(+ve ion mode): m/z 400 (M⁺+l). Compound No. 14: 5-[4-{3-(3 -oxo-2H- 1 ,4-benzoxazin-4-yl)prop- 1 - ynyl}benzylidene]thiazolidine-2,4-dione. Yield = 48%, m.p.= 253-262 °C. 1H NMR (DMSO-d₆, 300 MHz):δ 4.74(s, 2H), 5.03(s, 2H), 7.05-7.14(m, 3H), 7.37(d, J = 8.1Hz, 2H), 7.55(q, J=8.7Hz, 4H), 7.74(s, IH). MS (+ve ion Mode): 391(M⁺+1).

Compound No. 15: 5-[4-[3-(2,3-dihydro benzothiazin-4-yl)prop-l- ynyl}benzylidene]thiazolidine-2,4-dione. Yield = 37%, m.p.= 200-209 °C. 1H NMR (CDC1₃+ DMSO-dg, 300 MHz):δ 3.15(t, J=5.4 Hz, 2H), 3.68(t, J=5.4 Hz, 2H), 4.31(s, 2H), 6.7(t, J=7.2Hz, IH), 6.2(d, J=8.4Hz, IH), 7.03-7.07(m. 2H), 7.41-7.48(m, 4H), 7.71(s, IH). MS (+ve ion mode): m/z 393 (MΗ-1).

Compound No. 16: 5-[4- {3-(N-(2-benzoxazolyl)-N-methylamino)prop- 1 - ynyl}benzylidene]thiazolidine-2,4-dione. Yield = 36%, m.p = 226-235 °C. 1H NMR (CDCI₃+DMSO, 300 MHz):δ 3.40(s, 3H), 4.71(s, 2H), 7.13(t, J=7.5Hz, IH), 7.26(t, J=7.8 Hz, IH), 7.39(d, J=7.8Hz, IH), 7.51(d, J=8.4Hz, 2H), 7.58(d, J=8.4Hz, 2H), 7.81(s,lH). MS (+ve ion mode): m/z 390(M⁺+1).

Compound No. 17: 5-[4- {3- {4-(4-fluorophenyl)piperizin- 1 -yl)prop- 1 -ynyl} benzylidene] thiazolidine-2,4-dione. Yield = 43%, m.p = 175-180 °C. 1HNMR (DMSO-d₆, 300 MHz):δ 2.71(brs, 4H), 3.13(brs, 4H), 3.65(s, 2H), 6.93-7.1(m, 4H), 7.59(brs, 4H), 7.77(s, IH). MS (+ve ion mode): m/z 422(M⁺+1).

Compound No. 30: 5 - [4- { 3 -(2-chlorobenzimidazol- 1 -yl)prop- 1 -ynyl} benzylidene]thiazo lidine-2,4-dione. Yield = 5%, m.p = 206-214 °C. 1H NMR (CDC1₃ and DMSO-d₆, 300 MHz): δ 5.27(s, 2H), 7.29-7.67(m, 8H), 7.71(s, IH), 12.26(brs, IH). MS (+ve ion mode): m/z 394 (M⁺+l) and 396 (M⁺+3). Compound No 31: 5-[4-{3-(N-(2-benzoxazolyl)-N-methylamino)prop-l-ynyl}benzylidene] thiazolidine-2,4-dionen. Yield = 36%, m.p = 226-235 °C. H NMR (CDC1₃ and DMSO-d₆,

300 MHz): δ 3.40(s, 3H), 4.71(s, 2H), 7.13(t, J=7.5Hz, IH), 7.26(t, J=7.8Hz, IH), 7.39 (d,

J=7.8Hz, IH), 7.51 (d, J=8.4Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.8 l(s, IH). MS (+ve ion mode): m/z 390 (M⁺+l).

Compound No. 32: 5-r4-{3-rN-(2-benzthiazolylVN-methylamino prop-l-ynyllbenzylidene] thiazolidine-2,4-dione. Yield = 92%, m.p = 202-206 °C. ^JH NMR (DMSO-d₆, 300 MHz): δ 3.23(s, 3H), 4.71(s, 2H), 7.08(t, J=9Hz, IH), 7.31(t, J=9Hz, IH), 7.51-7.58(m, 4H), 7.77- 7.82(m, 2H). MS (+ve ion mode): m/z 406 ( ⁺+1).

Compound No. 33: 5-[4- {3-(3-oxo-2H- 1 ,4-benzthiazin-4-yl)prop-l -ynyl} benzylidene] thiazolidine-2,4-dione. Yield =76%, m.p = 230-238 °C. 1H NMR (DMSO-d₆, 300 MHz): δ 3.61(s, 2H), 5.04(s, 2H), 7.1 l(t, J=7.5Hz, IH), 7.35-7.59(m, 6H), 7.57(s, IH). MS (+ve ion mode): m/z 407 (M⁺+l).

Example 4: Preparation of compound of Formula Nil In a 50 ml. round-bottomed flask was placed dimethyl glyoxime (0.16 mmol),

CoCl₂.6H₂0 (0.08 mmol) and water (4 ml). The mixture was cooled to about 5°C and to this was added IN NaOH solution (4 drops) followed by sodium borohydrate (3.1 mmol). To this at 0°-5°C was added compound of Formula VI (0.8 mmol) slowly over a period of about 30 min. as a solution in THF:DMF (2:1) (8 ml). The reaction mixture was stirred overnight at about 30 to 40° C. After the completion of reaction, the reaction mixture was acidified to pH 6 using acetic acid. The reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water, brine dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was purified on column (silica gel, 100-200 mesh) using hexane-ethylacetate as mobile system. The following compounds were prepared according to this procedure.

Compound No. 18: 5-[4-{3-acetoxyprop-l-ynyl}benzyl]thiazolidine-2,4-dione. Yield = 40%, m.p = 126-130 °C. 1H NMR (CDC1₃, 300MHz):δ 2.13(s, 3H), 3.13(dd, J=13.5 & 9.7 Hz, IH), 3.50(dd, J=13.6 & 3.6 Hz, IH), 4.50(dd, J=9.7 & 3.6 Hz, IH), 4.85(s, 2H), 7.17(d, J=9Hz, 2H), 7.41(d, J=9Hz, 2H).

Compound No. 19: 5-[4- {3-([5-methyl-2-phenyl-4-oxazolyl]methoxy)}benzyl] thiazolidne- 2,4-dione. Yield = 34%, Viscous Liquid. 1H NMR (CDC1₃, 300 MHz):δ 2.46(s, 3H), 3.14- 3.22(m, IH), 3.50-3.56(m, IH), 4.48(s, 2H), 4.51-4.56(m, IH), 4.62(s, 2H), 7.22-7.24(m, 2H), 7.42-7.48(m, 5H), 8.02-8.05(m, 2H). MS(+ve ion mode): m/z (M⁺+l).

Compound No. 20: 5-[4-{3-(N-(2-benzthiazolyl)-N-methylamino)prop-l-ynyl)benzylidene] thiazolidine-2,4-dione. Yield = 92%, m.p = 202-6 °C. 1H NMR (DMSD-d₆, 300 MHz):δ 3.23(s, 3H), 4.71(s, 2H), 7.08(t, J=9Hz, IH), 7.31(t, J=9H, IH), 7.51-7.58(m, 4H), 7.77- 7.82(m, 2H). MS (+ve ion mode): m/z 406 (M⁺+l).

Compound No. 21: 5-[4-{3-(indol-l-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione; MS (+ve ion mode): m/z 361(M⁺+1).

Compound No. 22: 5 - [4- { 3 -(phenoxin- 10-yl)prop- 1 -ynyl } benzyl} thiazolidine-2,4-dione; MS (+ve ion mode): m/z 427 (M^+l).

Compound No. 23: 5-[4- {3-(indolin- 1 -yl)prop- 1 -ynyl}benzyl]thiazolidine-2,4-dione; MS (+ve ion mode): m/z 369 (M^+l).

Compound No. 24: 5-[4-{3-(2-trifluoro methyl phenothiazin-10-yl)prop-l -ynyl} benzyl] thiazolidine-2,4-dione; MS(+ve ion mode): m/z 511 (M^+l).

Compound No. 25: 5-[4- {3-(carbazol)-9-yl)prop- l-ynyl}benzyl]thiazolidine-2,4-dione; MS (+ve ion mode): m/z 411 (M⁺+l).

Compound No. 26: 5-r4-{3-(dibenzorb.flazepin-5-vDprop-l-vnyljbenzvnthiazolidine-2,4- dione; MS (+ve ion mode): m/z 437 (M^+l). Compound No. 27: 5-[4-{3-(2,3-dihydro-l,4-benzoxazin-4-yl)prop-l-ynyl}benzyl] thiazolidine-2,4-dione; MS (+ve ion mode): m/z 379 (MT^+l).

Compound No. 28: 5-[4- {3-(4-methyl-2-phenylimdazole- 1 -yl)prop- 1 -ynyl}benzyl] thiazolidine-2,4-dione.

Compound No. 29: 5-[4-{3-(4-(4-fluoro phenyl)piperizin-l-yl)prop-l-ynyl}benzyl] thiazolidine-2,4-dione; MS (+ve ion mode): m/z 424 (M^+l).

Compound No. 34: 5-[4- {3-(3-oxo-2H- 1 ,4-benzthiazin-4-yl)prop- 1 -ynyl}benzyl]thiazolidine- 2,4-dione; MS (+ve ion mode): m/z 408 (M^+l).

Example 5: Coactivator-dependent receptor ligand assays (CARLA) for PPARα/δ/γ in a homogeneous time resolved-fluorescence resonance energy transfer (TR-FRET) format The functional and binding assays for the PPARα, PPARδ and PPARγ are a variation of the coactivator-dependent receptor ligand assay (CARLA) (Krey et al., (1997) Mol. Endocrinol., 11:779-791). The present CARLA assays used a TR-FRET detection method previously reviewed (Hemmila I. LANCE, (1999) J. Biomol. Screening, 4:303-307; Mathis G., (1999) J. Biomol. Screening, 4:309-313). All assays included 3 nM of the glutathione-S- transferase (GST) fusion proteins of either the hPPARα ligand binding domain (LBD) (amino acids 167-468) (GST- hPPARα LBD), GST-hPPARδ LBD (amino acids 139-442) or GST- hPPARγ LBD (amino acids 175-476); 3 nM Eu-labelled anti-GST antibody (Wallac); 30 nM biotinylated steroid receptor coactivator-1 (SRC-1) peptide (an N-terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS, derived from amino acids 676-700 of SRC- 1); and 10 nM streptavidin-labelled allophycocyanin (APC; Prozyme).

The biotinylated SRC-1 peptide was prepared by standard solid-phase peptide synthetic methods. The GST-PPAR LBDs were expressed in pGEX vectors (Amersham Pharmacia) in the E. cøli strain BL21(DE3) using standard expression conditions at 18 °C. In some cases, the GST-PPAR LBDs were co-expressed with groESL. The GST fusion proteins were purified on glutathione sepharose affinity columns (Amersham Pharmacia) using the method described by the manufacturer. The assay buffer contained 50 mM Tris pH 7.4, 50 mM KCl, 0.1%) BSA, and 1 mM DTT. The assay was carried out in black half area 96-well plates in a final volume of 25 μl. After mixing all components, the reaction mixture sat for 3 hours at room temperature before reading the TR-FRET signal on a Wallac Victor 2 plate reader (measuring the ratio of signals at 665 nm and 620 nm). EC₅₀ values were estimated with the Excel add-in program XLFit (ID Business Solutions, Guildford, Surrey, UK) utilizing a 4-parameter logistic equation.

EC50 values for PPAR , PPAR γ, and PPAR δ were determined with respect to compounds numbered 14, 18-23 and 26-29. For PPAR 04 the ED50 values ranged from about 30 μM to about 5 μM, for example from about 10 μM to about 5 μM. For PPAR γ, the ED50 values ranged from about 6 μM to about 0.06 μM, for example from about 1.0 M to about 0.06 μM, or from about 0.2 μM to about 0.06 μM.

For PPAR δ, the ED50 values ranged from about 30 μM to about 2.4 μM, for example from about 10 μM to about 2.4 μM.

Claims

We claim: 1. A compound having the structure of Formula I,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N- oxides or polymorphs wherein

A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl or heterocycle;

U-V represents R C=C or R₂CH-CH, wherein R₂ represents hydrogen, alkyl or alkoxy; W represents sulphur, oxygen, or NR₃, wherein R₃ represents hydrogen or alkyl; X represents

wherein n is an integer 0 to 3, and Ri represents hydrogen or alkyl, with the proviso that when X is — (CHΛi⁷

U-V can not be R₂CH-CH, unless A is acyloxy;

B represents aryl, or heterocycle;

Y represents (CH )_n wherein n represents an integer 0 to 3; and

R represents hydrogen, alkyl, cycloalkyl, aryl or heterocycle.

2. A compound according to claim 1 wherein A is acyloxy.

3. A compound according to claim 1 wherein A is CH₃COO.

4. A compound according to claim 1 wherein A is an optionally substituted monocyclic heterocycle wherein the optional substituent (s) is/are selected from alkyl, aryl and halogen.

5. A compound according to claim 1 wherein A is:

6. A compound according to

optionally substituted bicyclic heterocycle wherein the optional substituent (s) is/are selected from alkyl, aryl and halogen.

7. A compound according to claim 1 wherein A is:

8. A compound according to claim 1 wherein A is aromatic ring fused with non- aromatic ring wherein one or more carbon atom(s) of the non-aromatic ring is/are replaced by carbonyl or sulfonyl group.

9. A compound according to claim 1 wherein A is:

10. A compound according to claim 1 wherein A is an optionally substituted tricyclic heterocycle wherein optional substituent is/are selected from halogen and haloalkyl.

11. A compound according to claim 1 wherein A is:

12. A compound according to claim 1 wherein X is:

13. A compound according to claim 1 wherein U-V is CH=C or CH₂-CH.

14. A compound which is:

5-[4- 3-acetoxyprop-l-ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- 3-(indol- 1 -yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- 3-([5-methyl-2-phenyl-4-oxazolyl]methoxy)prop-l-ynyl}benzylidene thiazolidine-2,4- dione

5-[4- 3 -(phenoxazin- 10-yl)prop- 1 -yl} benzylidene]thiazolidin-2,4-dione

5-[4-< 3 -(indolin- 1 -yl)prop- 1 -ynyl} benzylidene]thiazolidine-2,4-dione

5-[4- 3 -(2-chlorophenothiazin- 10-yl)prop- 1 -ynyl] benzylidene]thiazolidine-2,4-dione

5-[4- 3 -(2-trifluoromethylphenothiazin- 10-yl)prop- 1 -ynyl} benzylidene]thiazolidine-2,4- dione

5-[4- 3 -(phenothiazin- 10-yl)prop- 1 -ynyl} benzylidene]thiazolidine-2,4-dione

5-[4- 3 -(3 ,6-dibrom-carbozol-9-yl)prop- 1 -ynyl] benzylidene]thiazolidine-2,4-dione

5-[4- 3-(carbazol-9-yl)prop-l-ynyl} benzylidene] thiazolidine-2,4-dione

5-[4- 3-(dibenzo[b,f]azopin-5-yl)prop-l-ynyl} benzylidene] thiazolidine-2,4-dione

5-[4- 3-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- 3 -(4-methyl-2-phenylimidazol- 1 -yl)prop- 1 -ynyl }benzylidene]thiazolidine-2,4-dione

5-[4- 3-(3-oxo-2H- 1 ,4-benzoxazin-4-yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- 3-(2,3-dihydro-l,4-benzothiazin-4-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- 3-(N-(2-benzoxazoeyl)-N-methylamino)prop-l-ynyl}benzyl]thiazolidine-2,4-dione 5-[4-{3-(4-(4-fluorophenyl)piperizin-l-yl)prop-l-ynyl}benzylidene]thiazolidine-2,4-dione

5-[4- {3-acetoxy prop- 1 -ynyl}benzyl]thiazolidine-2,4-dione

5-[4- {3-([5-methyl-2-phenyl-4-oxazolyl] methoxy)}benzyl]thiazolidene-2,4-dione

5-[4-{3-(N-(2-benzthiazolyl)-N-methylamino)prop-l-ynyl}benzyl]thiazolidine-2,4-dione

5-[4- {3-(indol- 1 -yl)prop- 1 -ynyl}benzyl]thiazolidine-2,4-dione

5- {4- {3 -(phenoxin- 10-yl)prop- 1 -ynyl}benzyl]thiazolidine-2,4-dione

5-[4-{3-(indolin-l-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione

5-[4-{3-(2-trifluoro methyl phenothiazin-10-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione

5-[4-{3-(carbazol-9-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione

5-[4-{3-(dibenzo[b,f,]azepin-5-yl)prop-l-ynyl} benzyl] thiazolidine-2,4-dione

5-[4-{3-(2,3-dihydro-l,4-benzoxazin-4-yl)prop-l-ynyl] benzyl]thiazolidine-2,4-dione

5-[4-{3-(4-methyl-2-phenylimidazol-l-yl)prop-l-ynyl} benzyl]thiazolidene-2,4-dione

5-[4- {3-(4-(4-flurophenyl)piperizin- l-yl)prop- l-ynyl}benzyl]thiazolidine-2,4-dione

5 - [4- { 3 -(2-chlorobenzimidazol- 1 -yl)prop- 1 -ynyl } benzylidene] thiazolidine-2,4-dione

5-[4-{3-(N-(2-benzoxazoeyl)-N-methylamino)prop-l-ynyl}benzylidene]thiazolidine-2,4- dione

5-[4-{3-(N-(2-benzthiazolyl)-N-methylamino)prop-l-ynyl}benzylidene]thiazolidine-2,4- dione

5-[4- { 3 -(3 -OXO-2H- 1 ,4-benzthiazin-4-yl)prop- 1 -ynyl}benzylidene]thiazolidine-2,4-dione

5-[4-{3-(3-oxo-2H-l,4-benzthiazin-4-yl)prop-l-ynyl}benzyl]thiazolidine-2,4-dione or the pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, N- oxides or polymorph thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the preceding claims together with pharmaceutically acceptable carriers, excipients or diluents.

16. A method of treating mammal suffering from diabetes or diabetes associated complications, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

17. A method of treating a mammal suffering from disease or conditions mediated through insulin resistance and impaired insulin secretion, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

18. A method of treating a mammal suffering from a disease or condition selected from Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndorme, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors, for improving cognitive functions in dementia, psoriasis and obesity, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

19. A method of treating a mammal suffering from diabetes or diabetes-associated complications, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition according to claim 15.

20. A method of treating a mammal suffering from disease or conditions mediated through insulin resistance or impaired insulin secretion, comprising administering to the mammal a therapeutically effective amount of^" a pharmaceutical composition according to claim 15.

21. A method of treating a mammal suffering from a disease or condition selected from Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndorme, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors, for improving cognitive functions in dementia, psoriasis and obesity, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition according to claim 15.

22. A process of preparing a compound of Formula VI,

its pharmaceutically acceptable acid addition salts, solvates, enantiomers, N-oxides, polymorphs, metabolites, wherein A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl or heterocycle; X represents

wherein n is an integer 0 to 3, and Ri represents hydrogen or alkyl, with the proviso that when

U-V can not be R₂CH-CH, unless A is acyloxy, which method comprises reacting a compound of Formula II with a compound of Formula III

to give a compound of Formula IV (wherein A and X are the same as defined earlier),

Formula IV which is finally condensed with thiazolidinone of Formula N

to give a compound of Formula VI.

23. The process according to claim 22 wherein the reaction of a compound of Formula II with a compound of Formula III to gi^ve a compound of Formula IN is carried out in a solvent selected from dimethylformamide, chloroform, tetrahydrofuran and acetonitrile.

24. The process according to claim 23 wherein the reaction is carried out in dimethylformamide.

25. The process according to claim 22 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of an organic base selected from triethylamine, diethylamine, pyridine, tributylamine and 4-dimethylaminopyridine.

26. The process according to claim 25 wherein the reaction is carried out in the presence of triethylamine.

27. The process according to claim 22 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of a coupling agent selected from Ν-methylmorphine, hydroxybenzotriazole, or l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DBU).

28. The process according to claim 22 wherein the reaction of a compound of Formula IV with thiazolidinedione of Formula N is carried out in a solvent selected from methanol, ethanol, tetrahydrofuran, acetonitrile, dimethyl formamide and toluene.

29. The process according to claim 28 wherein the reaction is carried out in toluene.

30. The process according to claim 22 wherein the reaction of a compound of Formula TV with thiazolidinedione of Formula V is carried out in the presence of an organic base selected from pyridine, piperidine, triethylamine and diethylamine.

31. The process according to claim 30 wherein the reaction is carried out in the presence ofpiperidine.

32. The process according to claim 22 wherein the reaction of a compound of Formula IN with thiazolidinedione of Formula N is carried out in the presence of organic acid selected from acetic acid, dichloroacetic acid and benzoic acid.

33. The process according to claim 32 wherein the reaction is carried out in the presence of benzoic acid.

34. A process of

its pharmaceutically acceptable acid addition salts, solvates, enantiomers, Ν-oxides, polymorphs, metabolites, wherein A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl or heterocycle; X represents _ _ , _u ^/(CH2)n > -k «X ^"~ or -<PHX ~"

, U-N can not be R₂CH-CH, unless A is acyloxy,

which method comprises reducing a compound of Formula NI

to give a compound of Formula Nil (wherein A and X are the same as defined earlier).

35. The process according to claim 34 wherein the reduction of a compound of Formula NI to give a compound of Formula Nil is carried out in a solvent selected from methanol, ethanol, tetrahydrofuran and acetonitrile.

36. The process according to claim 35 wherein the reduction is carried out in tetrahydrofuran.

37. The process according to claim 34 wherein the reduction of a compound of Formula NI to give a compound of Formula Nil is carried out in presence of a reducing agent selected from sodium borohydrate, cyanoborohydride and sodium triacetoxyborohydride.

38. The process according to claim 37 wherein the reduction is carried out in the presence of sodium borohydrate.