MXPA96003865A - Compounds of- [3-aril-prop-2-inii] -5- (arilsulfonil) triazolidin-2,4-diona as agentesanti-hyperglucemi - Google Patents

Abstract

The present invention relates to a 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-dione or 5- [3-aryl-prop-2-ynyl] -5 - (arylsulfonyl) -thiazolidin-2,4-dione of the formula: characterized in that Ar is phenyl, 2-naphthyl, phenyl substituted with alkyl, phenyl substituted with alkoxy or phenyl substituted with halogen, N is 0 or 2M and Ar'es phenyl, phenyl substituted with alkyl, phenyl substituted with perfluoroalkyl, phenyl substituted with halogen, phenyl substituted with alkoxy, phenyl substituted with perfluoroalkoxy or phenyl substituted with alkylthio, or a pharmaceutically acceptable salt thereof;

Description

NEW ANTI-HIPERGLÜCEMIC AGENTS The present invention provides novel compounds that possess antihyperglycemic activity. More particularly, the present invention provides the novel 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-diones and 5- [3-aryl-prop-2-yny] -5- (aryl-sulfañil) -thiazolidin-2,4-diones, and the derivatives thereof, which are useful for lowering the blood glucose level in hyperglycemic mammals, and are useful in the treatment of diabetes mellitus not -insulin dependent (type 2), preferably in humans.

BACKGROUND OF THE INVENTION The treatment for non-insulin-dependent diabetes mellitus (type 2 diabetes) usually consists of a diet and exercise regimen, oral hypoglycemic agents and, in more severe cases, insulin. The most commonly used oral agents are sulfonylureas and biguanides. While sulfonylureas are valuable for the treatment of Type 2 diabetes, they can give rise to hypoglycemic episodes and show other toxic manifestations that limit their use. These are also prone to a high incidence REF: 22013, .- 1 of primary and secondary efficacy failures. Similarly, the use of biguanides has decreased due to its association with incidents of toxic lactic acidosis. A continuous need for new hypoglycemic agents that can be less toxic and more effective is clearly evident. The 5 - [(1 - and 2-naphthalenyl) sulfonyl] -2,4-thiazolidinediones (Zask and Jirkovsky, US Pat. No. 4,997,948, 1991), 5 - [(1- and 2-naphthalenyl) thio] -10 2 , 4-thiazolidinediones (Zask and Jirkovsky, US Patent No. 5,068,342, 1991) and the 5- [arylsulfonyl] -2,4-thiazolidinediones (Zask et al., J. Med. Chem. 1990, 33, 1418-1423) were previously described as antidiabetic agents. The compounds of the first invention, (I), differ in that they also contain a 5- [3-aryl-prop-2-ynyl] group. This last portion increases the antidiabetic potency of the 5-arylsulfonyl-2,4-thiazolidinediones. 2 - [(4-methylphenyl) -sulfonyl] -5-phenylpent-4-ynoic acid (BM13907), (A) (Wolff et al., U.S. Patent No. 4,933,367, 1990; Freund et al.,? Rch Pharmacol., 1989, 340 (sup.R40) Excerpt 117; Obermaier-Kusser Biochem. J. 1989, 261, 699) It was also described as an antidiabetic agent. The compounds of the present (I) differ in that they contain a 2-thiazolidinedione ring instead of a carboxyl group of A.

Other descriptions claim compounds that contain a 2,4-thiazolidinedione ring and also show antidiabetic activity. These include ciglitazone (U.S. Patent No. 4,461,902; Sohda et al., Chem. Pharm. Bull. 1982, 30, 3580) and a number of more potent analogues; pioglitazone (Sohda et al. Arzneim, Forsch. / Drug, Res. 1990, 40, 37), englitazone (Stevenson et al. Metabolism 1991, 40, 1268); CS-045 (Metabolism 1991, 40, 1213) and others (Hulin et al collaborators J. Med. Chem. 1992, 35, 1853; Sohda et al. J. Med. Chem. 1992, 35, 2617). None of the 2,4-thiazolidinedione-containing compounds of the foregoing descriptions contain the group 5- (arylsulfonyl), 5- (arylsulfañyl) or 5- [3-aryl-prop-2-ynyl] possessed by the compounds of the invention. present invention. Compounds in which the sulfur is attached at the 5-position of a 2,4-thiazolidinedione ring have been described (Japanese Patent Kokai 78 40, 770; Japanese Patent Kokai 78 46, 973; Mikrobiol. Zh. (Kiev ) 1970, 32, 518-520 (Ukraine), German Patent DE 3,045,059) but differ from the compounds of the present invention in that the nitrogen of the 2,4-thiazolidinedione ring is substituted or the sulfur is in the form of an acid sulphonic In addition, these compounds are not sulfones and do not contain a naphthalene ring. Furthermore, these compounds are claimed as possessing only antiseptic or antibiotic properties.

DESCRIPTION OF THE INVENTION This invention relates to the new 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-diones and 5- [3-aryl-prop-2-ynyl] -5 - (arylsulfanyl) thiazolidin-2,4-diones of the formula (I). These compounds have antihyperglycemic activity, which has been demonstrated by their ability to decrease plasma glucose levels in db / db mice (C57BL / KsJ) and to decrease plasma glucose levels and insulin levels in mice ob / ob (C57B1 / 6J). Both are models of non-insulin-dependent diabetes mellitus, -, - • - 1 (type 2). The compounds of this invention are characterized by the general formula (I), shown below, wherein Ar is phenyl, 2-naphthyl, phenyl substituted by alkyl, phenyl substituted by alkoxy, phenyl substituted by halogen, 2-pyridinyl, 2- substituted pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo- [b] -furanyl, 2-10 thienyl, 2-benzo- [b] -thienyl; n is 0 or 2; and Ar 'is phenyl, phenyl substituted by alkyl, phenyl substituted by perfluoroalkyl, phenyl substituted by halogen, phenyl substituted by alkoxy, phenyl substituted by perfluoroalkoxy and phenyl substituted by alkyl.

(D Preferred compounds of this invention include the compounds of the formula (I) in which Ar is phenyl, phenyl substituted with alkyl, phenyl substituted with halogen or 2-pyridinyl, n is 2; and Ar 'is phenyl, phenyl substituted by halogen and phenyl substituted by perfluoroalkoxy. The most preferred compounds of this invention include: 5- [3- (4-chlorophenyl) prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione, 5- [3- ( 4-fluorophenyl) prop-2-ynyl] -5- (pyridine-2-sulfonyl) -thiazolidin-2,4-dione, 5- [3- (4-chlorophenyl) prop-2-ynyl] -5- (4 -fluoro-benzenesulfonyl) -thiazolidin-2,4-dione, 5- (4-fluorobenzenesulfonyl) -5- [3- (4-fluoro-phenyl) -prop-2-ynyl] -thiazolidin-2,4-dione, 5-Benzenesulfonyl-5- [3- (4-chlorophenyl) -prop-2-ynyl] -thiazolidin-2,4-dione, 5-benzenesulfonyl-5- [3- (3,5-bis-trifluoromethyl-phenyl) -prop-2-ynyl] -thiazolidin-2,4-dione, 5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (4-chloro-benzenesulfonyl) thiazolidin-2,4-dione , 5- [3- (4-bromophenyl) -prop-2-ynyl] -5- (toluene-4-sulfonyl) thiazolidin-2,4-dione, and 5- [3-phenyl-prop-2-yny] -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione. The compounds of this invention can be prepared according to the methods described in Schemes I to V, the first of which is presented below: Scheme I In Scheme I, the appropriate commercially available arylthiol of the formula (II) is reacted with a base and the subsequent complex is reacted with one or more equivalents of 5-bromo-thiazolidin-2,4-dione (Zask et al., J. Med. Chem. 1990, 33, 1418-1423) to produce a 5-aryl-sulfanyl-thiazolidin-2,4-dione of the formula (III). The reaction is conveniently carried out in an aprotic solvent such as tetrahydrofuran or hexane, using 2 or more equivalents of a strong metal amide base such as lithium diisopropyl amide or lithium bis (trimethylsilyl) amide at low temperatures (e.g. from 0 to -78 ° C) followed by heating at room temperatures or higher for 1 to 10 hours. Alternatively, the compound of the formula (III) can be prepared in a protic solvent, such as water or a low molecular weight alcohol solvent. When performed in this manner, the arylthiol of the formula (II) is reacted with 2 or more equivalents of an alkali metal carbonate or bicarbonate base such as sodium carbonate or potassium bicarbonate at 0 ° C at room temperature. One or more equivalents of 5-bromo-thiazolidin-2,4-dione are added and the reaction times vary from 1 hour to 2 days. The compound of the formula (III) can be oxidized to provide the 5-arylsulfonyl-thiazolidin-2,4-dione of the formula (V). Following the procedure of Zask et al. (J. Med. Chem. 1990, 33, 1418-1423), this oxidation is conveniently carried out using an excess of aqueous hydrogen peroxide (2 to 20 equivalents) in acetic acid at room temperature or higher (30 to 80 ° C) for 1 to 10 hours. Alternatively, potassium peroxymonosulfate will also achieve the required oxidation, effectively. Potassium peroxymonosulfate (OSO-) is sold commercially as a 2: 1: 1 complex with inert ingredients, potassium acid sulfate (KHSO) and potassium sulfate (K "S0). This complex is sold under the commercial name oxone. The compound of the formula (III) is dissolved in a low molecular weight alcohol solvent such as methanol, and added to an aqueous solution of oxone containing 2 or more equivalents of the active ingredient KHSO, -. The reaction temperature can vary from 0 ° C to 50 ° C, and the reaction time can vary from 30 minutes to 2 days. Still alternatively, a perbenzoic acid reagent such as metachloroperbenzoic acid can be used to convert the compound of the formula (III) to the compound of the formula (V). Two or more equivalents of the perbenzoic acid, preferably in a halocarbon solvent such as chloroform, are used at room temperatures for a period of 1 hour to several days. The compound of the formula (V) can also be prepared by the reaction of one or more equivalents of an alkali metal arylsulfinate of the formula (IV) with 5-bromo-thiazolidin-2,4-dione. Suitable solvents for this transformation include polar aprotic solvents such as dimethylformamide, tetrahydrofuran and protic solvents such as low molecular weight alcohols or water. Alternatively, the alkali metal arylsulfinate of the formula (IV) can be reacted with 5-bromo-thiazolidin-2,4-dione using the Aliquat 336 phase transfer catalyst (tricaprylmethylammonium chloride) according to the process of G. Baum et al. (Synthesis 1987, 56-59). The alkali metal sulfinate of the formula (IV) can be conveniently prepared by the oxidation of the arylthiol of the formula (II) with 2 equivalents of aqueous hydrogen peroxide in the presence of an alkali metal hydroxide such as sodium hydroxide, in water or in a low molecular weight aqueous alcohol solvent. The alkali metal arylsulfinate of the formula (IV) can also be prepared by reduction of an arylsulfonyl chloride of the formula (XI). This transformation is most conveniently achieved using the procedure of Chew Lee and Lamar Field (Synthesis 1990, 391-397) in which the sulfonyl chloride of the formula (XI) is reacted with two equivalents of p-thiocresol and two equivalents of triethylamine in dichloromethane at -78 ° C to room temperature. The arylsulfinic acid obtained after working with aqueous acid is subsequently treated with an alkali metal hydroxide to produce the alkali metal arylsulfinate of the formula (IV).

The compounds of the formula (V) have two primary sites that can be alkylated with alkylating agents in the presence of a base. These sites are the 5-carbon atom of the thiazolidinedione and the nitrogen atom of the thiazolidinedione. The desired alkylation point for the compounds of the present invention is the carbon atom 5 of (V). In order to prevent potential competition with alkylation at the nitrogen atom of (V), the nitrogen can be protected with an appropriate alkylation protecting group. The trityl group (triphenylmethane) performs this function. The trityl group is introduced by the reaction of the compound of the formula (V) with one molar equivalent of triphenylmethane chloride in the presence of one molar equivalent of a tertiary amine base, such as triethylamine, preferably in a hydrocarbon solvent at 0 ° C. or at ambient temperatures.

Scheme II propargyl alcohol Afl ^ Pd (ll) / Cu (l) Ar "(Vil) (VIII) (IX) base In Scheme II, the (3-arylprop-2-ynyl) bromides of the formula (IX) can be prepare via a two-step process from commercially available arylidenes of the formula (VII) In the first step, the compound of the formula (VIII) is prepared by reacting the compound of the formula (VII) with one or more equivalents of propargyl alcohol, in the presence of a catalytic amount of a palladium (II) reagent such as dichlorobis (triphenylphosphine) -palladium (II) and a catalytic amount of a copper (I) reagent such as copper iodide (I) This reaction is also carried out in the presence of one or more equivalents of a secondary or tertiary amine such as diethylamine or triethylamine The secondary or tertiary amine can be used as a solvent or a halocarbon solvent such as chloroform can be used. 80 ° C are commonly used as tempera Reaction times with reaction times ranging from 1 hour to 2 days. The compound of the formula (IX) is then more conveniently prepared from the compound of the formula (VIII) by the reaction of (VIII) with 0.5 to one molar equivalent of phosphorus tribromide in anhydrous ether solvent containing pyridine. This reaction is most conveniently carried out at 0 ° C to room temperature, for a period of 1 hour to 30 hours. The compounds of the formula (I) are then prepared by alkylation of the compounds of the formulas (III), (V) or (VI) with the compounds of the formula (IX).

With reference to Scheme III: It's burning I I I the hydrogen at the 5-position of the thiazolidinedione of (VI) is removed by the action of one or more equivalents of a base. Commonly used bases include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyllithium or alkali metal amides such as lithium diisopropylamide. Suitable solvents include tetrahydrofuran or dimethylformamide at temperatures in the range of -78 ° C to room temperature.

After deprotonation of the compound of the formula (VI), the bromide of the formula (IX) is introduced and the reaction is typically stirred at 0 ° C or at room temperature for 1 to 48 hours, to produce the compound of the formula (X) The compound of the formula (X) is then treated with an acid to remove the triphenylmethane protecting group. Typical acids include one or more equivalents of trifluoroacetic acid or formic acid. This acid can be used as a solvent, or a halocarbon solvent such as dichloromethane can be commonly employed. This reaction is conveniently carried out at 0 ° C or at room temperature, for periods of 10 minutes to 2 hours.

With reference to Scheme IV: Scheme IV IO The 5- [3-aryl-prop-2-ynyl] -5- (arylsulfanyl) -thiazolidin-2,4-diones of the formula (I) can be pre-stopped by the reaction of the 5- (arylsulfañil) - suitable thiazolidin-2, 4-diones of the formula (III) with 2 or more equivalents of a base. Two equivalents of base effect the deprotonation of the nitrogen atom of the thiazolidinedione and in the 5-position to form a dianion. Common bases for achieving this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis (trimethylsilyl) amide. Suitable solvents include tetrahydrofuran for the alkali metal amide bases, and tetrahydrofuran or dimethylformamide for the alkali metal hydride bases. The reaction temperatures range from -78 ° C to room temperature. Two minutes to 1 hour after the base is introduced, one or more equivalents of the appropriate (3-arylprop-2-ynyl) bromide of the formula (IX) are added to the reaction mixture, and the reaction is stirred at 0 ° C or at room temperature for a period of 1 hour to 3 days. The alkylation occurs exclusively on the carbon atom in the 5-position of the thiazolidinedione to provide the 5- [3-aryl-prop-2-ynyl] -5- (ar-ylsulfañyl) -thiazolidin-2, -dione of the formula ( I).

With reference to Scheme V: It is a V (l) The 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-diones of the formula (I) can be prepared by the reaction of the 5- (arylsulfonyl) -thiazolidin- 2, 4-diones appropriate, of the formula (V) with 2 or more equivalents of a base. Two equivalents of base effect the deprotonation of the nitrogen atom of the thiazolidinedione and in carbon 5 to form a dianion. Common bases for achieving this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyllithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis (trimethylsilyl) amide. Suitable solvents include tetrahydrofuran for the alkali metal amide bases, and tetrahydrofuran or dimethylformamide for the alkali metal hydride bases. The reaction temperatures range from -78 ° C to room temperature. Two minutes to 1 hour after the base is introduced, one or more equivalents of the appropriate (3-arylprop-2-ynyl) bromide of the formula (IX) are added to the reaction mixture, and the reaction is stirred at 0 ° C or at room temperature for a period of 1 hour to 3 days. The alkylation occurs exclusively on the carbon atom at the 5-position of the thiazolidinedione to provide the 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-dione of the formula ( I). The compounds of this invention can also be prepared by a process comprising the reaction of a compound having the formula B (O) (B) wherein Ar and n are as defined above, and R is hydrogen or a protective protective group, with a compound having the formula C R2-CH -CaCAr ^ C) wherein Ar1 is as defined above and R2 is a leaving group, in the presence of a base to introduce a 3-ar-ilprop-2-ynyl substituent at the carbon atom at position 5 of the thiazolidinedione and, where appropriate, the elimination of the deletable protecting group and, where desired, the recovery of the compound having the formula I in the form of a pharmaceutically acceptable salt thereof. In the case where R is hydrogen, the process can be carried out as described hereinafter in Scheme IV or V. In this case, it will be noted that the base used must be a strong base, for example, one strong enough to effect deprotonation at the 5-position of the thiazolidinedione ring, as well as at the nitrogen atom of the thiazolidinedione ring. Another method for carrying out the process of the invention comprises the reaction of a compound of the formula B wherein R is a protecting group with the compound having the formula C. This can be carried out in a manner described herein with reference to Scheme III later in the present. The preparation of the 5- (arylsulfonyl) -3- (triphenylmethyl) -thiazolidin-2,4-diones (VI) for use as described in Scheme III, can be carried out as described under the Scheme. I. Where the final compound will have the formula I where n is 0, then the process can be carried out by using a compound having the formula (III) instead of the compound having the formula (V) in the reaction with triphenylmethane chloride in the presence of one molar equivalent of the base, and using the resulting 5- (arylsulphenyl) -3-trityl-thiazolidin-2,4-dione, instead of the compound of the formula (VI). The present invention also comprises a method for lowering the blood glucose level in a hyperglycemic mammal, comprising administering to said mammal an effective amount of one or more compounds described herein, effective to lower blood glucose. This method can also be observed as a method of treating hyperglycemia in a mammal, which comprises administering to said mammal an effective amount of one or more of the compounds described herein., effective to lower blood glucose. The mammal treated thus is preferably a human. The compounds of the present invention can also be used as agents for the treatment of hyperlipidemia and diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataracts). The compounds of the present invention, in order to increase the efficacy, can also be used in combination with insulin, sulfonylureas, biguanides, aldose reductase inhibitors and hypolipidemic agents. The doses of the compounds presented herein will vary with the particular compound chosen and with the form of administration. In addition, this will vary with the particular host under treatment. In general, the compounds of this invention are administered at a concentration level that provides pro-active effects without any harmful side effects. For example, the effective amount of the compound can usually be in the range of about 10 to about 250 mg / kg of body weight per day, administered once a day or divided into two to four administrations per week. The optimal dose for the individual subject to be treated will be determined by the person responsible for the treatment, with smaller doses being initially administered, and after that, increases in the dose are made to determine the most appropriate dose. Also encompassed by the present invention are pharmaceutical compositions useful for lowering blood glucose. Among these are compositions comprising a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which can be used according to the same methods of administration as the compounds themselves. The compounds of the present invention can form salts with appropriate therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid, and are included within the scope of this invention. Suitable inorganic bases for forming these salts include, for example, the hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium and the like. Suitable organic bases include primary and secondary amines such as methylamine, benzathine (N, N -dibenzyl-ethi-lendiamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benetamine (N-benzyl-phenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l, 3-propanediol), procaine, etc. In addition, quaternary salts, for example, tetraalkyl (eg, tetramethyl), alkyl-alkanol (eg, methyl-triethanol) and cyclic (eg, N, N-dimethylmorpholine-ammonium) salts, can be mentioned. . In principle, however, all ammonium salts that are physiologically compatible can be used. Transformations to the corresponding salts are easily carried out by reacting the acid form of the compounds with an appropriate base, usually an equivalent, in a cosolvent. The salt is isolated by concentration to dryness or by the addition of a non-solvent. For example, in the case of inorganic salts, it is preferred to dissolve the acid or compound in water containing a hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. Evaporation of the solution or addition of a water-miscible solvent of more moderate polarity, for example, a lower alkanol such as butanol, or a lower alkanone such as ethyl methyl ketone, gives the solid inorganic salt. In the case of an amine salt, it is preferred to use a cosolvent of moderate or low polarity such as ethanol, ethyl acetate and benzene. The evaporation of the solvent or the addition of a miscible diluent of less polarity such as benzene or n-hexane, give the solid salt. The quaternary ammonium salts can be prepared by mixing the acid of the compound with a quaternary ammonium hydroxide in an aqueous solution, followed by evaporation of the water.

The compounds of the present invention can be clinically administered to mammals, including man, by the oral or parenteral route. The oral administration can be either alone or in combination with a solid or liquid pharmaceutically acceptable carrier or diluent, such as starch, milk, sugar, certain types of clay, water, vegetable or mineral oils, and so on to form tablets, capsules , powders, syrups, solutions, suspensions and the like. For parenteral administration, the active compounds can be used in combination with aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous solutions of water and pharmaceutically acceptable soluble salts of the compounds. Injectable solutions prepared in this manner can be administered intravenously, intraperitoneally, subcutaneously or intramuscularly. The compounds of this invention can also be administered in the form of suppositories. The following non-limiting examples further illustrate this invention.

EXAMPLE 1 - (toluene-4-sulfanyl) -thiazolidin-2 > 4-diona. (III) To a solution of 5-bromo-thiazolidin-2,4-dione (5.0 g, 25.5 mmol, Zask et al., J. Med. Chem. 1990, 33, 1418-1423) and p-thiocresol [(II), 3.17 g, 25.5 mmol] in anhydrous tetrahydrofuran (200 ral) a - At 78 ° C, lithium bis (trimethylsilyl) amide (1.0 M in hexanes, 56 mL, 56 mmol) was added dropwise. After 30 minutes, the reaction mixture was warmed to room temperature. After an additional hour, 2 N hydrochloric acid was added at pH = 1. The layers were separated and the aqueous phase was extracted with ethyl acetate (3 X 300 ml). The combined organic phase was dried (magnesium sulfate), concentrated and subjected to flash chromatography (petroleum ether: ethyl acetate 3: 2) to give the title compound as a white solid (4.4 g, 72%): mp 124-126 ° C; NMR (CDC13): d 8.08 (s, 1H, NH), 7.48 (d, J = 8.7 Hz, 2H, ArH). 7.18 (d, J = 8.7 Hz, 2H, ArH), 5.32 (s, 1H, CH); MS (EI): 239 (MI, 90%), 196 (18%), 123 (100%).

EXAMPLE 2 - (pyridin-2-sulfanyl) -thiazolidin-2,4-dione. (III) To a solution of 5-bromo-thiazolidin-2,4-dione (28.24 g, 0.144 mol) and 2-mercaptopyridine [(II), 16.0 g, 0.144 mol] in anhydrous tetrahydrofuran (200 ml) at -78 ° C, lithium bis (trimethylsilyl) amide (1.0 M in hexanes, 317 ml, 0.317 mol) dropwise in a period of 40 minutes. After 30 minutes, the reaction mixture was warmed to room temperature. After an additional period of 3 hours, 10% hydrochloric acid was added until pH = 1. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 X 500 ml). The combined organic phase was washed with water (500 ml), with brine (500 ml), dried (magnesium sulfate) and concentrated to give the title compound as a green solid (30.45 g, 93%): mp 118 -120 ° C; NMR (DMSO, d6): delta 12.35 (s, 1H, NH), 8.39 (d, J = 5.3 Hz, 1H, PirH), 7.69 (dd, J = 7.3, 8.3 Hz, 1 H, PirH), 7.42 (d, J = 8.3 Hz, 1 H, PirH), 7.19 (dd, J = 5.3, 7.3 Hz, 1 H, PirH), 6.31 (s, 1 H, CH), MS (EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (CgH6N202S2): C, H, N.

Using the procedure described in Example 1, the compounds of the formula (III), Examples 3 and 4 were prepared from the appropriate aryl mercaptan of the formula (II) and the 5-bromo-thiazolidin-2,4-dione.

EXAMPLE 3 - (quinoline-2-sulfanyl) -thiazolidin-2,4-dione. (III) From 2-quinolintiol: mp 227-229 ° C.

EXAMPLE 4 - (naphthalene-2-sulfanyl) -thiazolidin-2,4-dione. (III) (Known: Zask et al., J. Med. Chem. 1990, 33, 1418-1423).

EXAMPLE 5 - (fluorophenylsulfanyl) -thiazolidin-2-t4-dione. (III) -Bromo-thiazolidin-2, -dione (15.0 g, 76.5 mmol) was added to a mechanically stirred solution at 0 ° C of 4-fluorothiophenol [(II), 9.8 g, 76.5 mmol], sodium carbonate (27.75 g). , 262 mmol) and water (120 ml). After 16 hours, the reaction mixture was diluted with water (500 ml), acidified with concentrated hydrochloric acid until pH = 1, and filtered. The resulting solid was washed with water and petroleum ether, and dried under vacuum to provide the title compound as a white solid (14.05 g, 75%): mp 99-100 ° C; NMR (DMSO, d6): delta 12.14 (s, 1 H, NH), 7.66 (t, J = 8.0 Hz, 2H, ArH), 7.29 (t, J = 8.5 Hz, 2 H, ArH), 6.05 (s) , 1 H, CH); MS (El): 243 (MI, 100%), 200 (30%), 128 (60%), 127 (50%); Anal. (CgH6FN02S2): C, H, N. Using the procedure described in Example 5, the compounds of the formula (III), Examples 6-10, were prepared from the appropriate arylmercaptan of the formula (II) and from the -bromo-thiazolidin-2, -dione.

EXAMPLE 6 - (benzenesulfanyl) -thiazolidin-2,4-dione. (III) From thiophenol: mp 103-107.5 ° C.

EXAMPLE 7 - (4-chlorophenylsulfanyl) -thiazolidin-2 > 4-diona. (III) From 4-chlorothiophenol: mp 109-110 ° C, EXAMPLE 8 - (4-bromophenylsulfanyl) -thiazolidin-2,4-dione. (III) From 4-bromothiophenol: mp 115-117 ° C. EXAMPLE 9 - (4-methoxyphenylsulfanyl) -thiazolidin-2,4-dione, (III) From 4-methoxythiophenol: mp 89-91 ° C, EXAMPLE 10 5- (toluene-3-sulfanyl) -thiazolidin-2, 4-dione > (III) From m-thiocresol: mp 61.5-64 ° C EXAMPLE 11 5- (4-fluorophenylsulfohyl) -thiazolidin-2,4-dione, (V) 30% hydrogen peroxide was added dropwise (50.4 ml, 0.489 mol) over a period of 1 hour and 20 minutes to a mechanically stirred solution of 5- (4-fluorophenylsulphane) -thiazolidin-2,4-dione [(III), from Example 5, 11.9 g, 48.9 mmol) ] in glacial acetic acid (457 ml) at 60 ° C. After an additional period of 3 hours, the reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried (magnesium sulfate) and concentrated to give the title compound as a white solid (10.9 g, 81%): mp 190-196 ° C; NMR (DMSO, d6): delta 12.78 (broad s, 1 H, NH), 8.00 (m, 2 H, ArH), 7.58 (t, J = 8.9 Hz, 2 H, ArH), 6.70 (s, 1 H , CH); MS (CI): 276 (M + H, 100%); Anal. (CQH6FN04S2): C, H, N. By the procedure described in Example 11, the compounds of the formula (V), Examples 12-14, were prepared from the 5- (arylsulfañil) -thiazoli-din-2 , Appropriate 4-dione, of the formula (III).

EXAMPLE 12 - (toluene-4-sulfonyl) -thiazolidin-2-t4-dione, (V) Prepared from 5- (toluene-4-sulfañyl) -thiazolidin-2,4-dione, (III) of Example 1: mp 73-75 ° C.

EXAMPLE 13 - (naphthalene-2-sulfonyl) -thiazolidin-2,4-dione, (V) (Known: Zask et al., J. Med. Chem. 1990, 33, 1418-1423).

EXAMPLE 14 - (4-chlorophenylsulfonyl) -thiazolidin-2,4-dione, (V) Prepared from 5- (4-chlorophenylsulfañyl) -thiazolidin-2,4-dione (III) of Example 7: mp 143-144.5 ° C.

EXAMPLE 15 - (benzenesulfonyl) -thiazolidin-2,4-dione, (V) A solution of 5- (benzenesulfañil) -thiazolidin-2,4-dione, [(III), Example 6, 10.0 g, 41.8 mmol] in methanol (105 ml) was added to a mechanically stirred suspension of oxone (51.4 g, 83.6 mmol) in water (210 ml) at 0 ° C. The suspension was immediately heated to room temperature. After 3.5 hours, the reaction was diluted with water (1.5 liters) and the solid filtered. The solid was washed with water and dried under vacuum to provide the title compound as a white solid (8.31 g, 73%): mp 130-133 ° C; NMR (CDC1 »): delta 8.07 (s, 1 H, NH), 7.98 (d, J = 7.2 Hz, 2 H, ArH), 7.78 (t, J - 7.5 Hz, 1 H, ArH), 7.67 (t , J = 8.1 Hz, 2 H, Ar H), 5.44 (s, 1 H CH); MS (EI): 225 (MI, 24%), 182 (18%), 153 (12%), 110 (100%). By the procedure described in Example 15, the compounds of the formula (V), Examples 16-18, were prepared from the appropriate 5- (arylsulfaphyl) -thiazo-lidin-2,4-dione of the formula (III ).

EXAMPLE 16 - (4-bromophenylsulfonyl) -thiazolidin-2,4-dione, (V) Prepared from 5- (4-bromophenylsulphane) -thiazolidin-2,4-dione, (III), of Example 8: mp 156.5 at 158 ° C.

EXAMPLE 17 - (4-methoxyphenylsulfonyl) -thiazolidin-2,4-dione, (V) Prepared from 5- (4-methoxyphenyl-sulfanyl) -thiazolidin-2,4-dione, (III), of Example 9: mp 93 at 95 ° C.

EXAMPLE 18 - (toluene-3-sulfonyl) -thiazolidin-2,4-dione, (V) Prepared from 5- (toluene-3-sulfañyl) -thiazolidin-2,4-dione, (III), of Example 10: mp 96 at 100 ° C.

EXAMPLE 19 - (pyridine-2-sulfonyl) -thiazolidin-2,4-dione, (V) M-chloroperbenzoic acid (25.7 g, 146 mmol) was added dropwise over a period of 30 minutes to a stirred suspension of 5- (pyridin-2-sulfañyl) -thiazolidin-2,4-dione [(III), Example 2, 15.0 g, 66.3 mmol] in chloroform (600 ml) at room temperature. After 18 hours, more m-chloroperbenzoic acid (4.65 g, 26.4 mmol) was added and the reaction mixture was stirred an additional 6 hours. The reaction mixture was cooled in an ice bath and the resulting solid (18.7 g) was filtered. A 10 g portion of the resulting solid was purified by flash chromatography (methylene chloride: acetonitrile 9: 1) to give the title compound as a white solid (4.18 g, 46%): mp 129-131 ° C; NMR (DMSO, d6): delta 12.00 (broad s, 1 H, NH), 8.85 (d, J = 4.0 Hz, 1 H, PirH), 8.23 (dd, J = 6.1, 7.9 Hz, 1 H, PirH) , 8.12 (d, J - 7.9 Hz, 1 H, PirH), 7.85 (dd, J = 4.0, 6.1 Hz, 1 H, PirH), 6.79 (s, 1 H, CH); MS (EI): 258 (MI, 8%), 215 (55%), 123 (22%), 78 (100%).

EXAMPLE 20 - (quinoline-2-sulfonyl) -thiazolidin-2,4-dione, (V) % Aqueous hydrogen peroxide (10.7 mL, 104 mmol) was added dropwise to a stirred solution of 2-quinolintiol [(II), 8.0 g, 49.6 mmol] in 2.5% aqueous sodium hydroxide (229 mL) and ethanol (229 ml). After 1 hour the reaction mixture was concentrated to give a white solid (8.34 g) which contained mainly sodium 2-naphthalenesulfinate (formula IV). A 7.0 g portion of this compound (less than or equal to 32.5 mmol) was added to a solution of 5-bromo-thiazolidin-2, -dione (6.38 g, 32.5 mmol) in anhydrous dimethylformamide (53 ml) and the resulting solution it was stirred at room temperature for 4 hours. The dimethylformamide was removed in vacuo and water (400 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate (2 x 400 ml) and the combined ethyl acetate phase was dried (brine) and concentrated. The crude product was subjected to flash chromatography (gradient: 98: 2 to 97: 3 methylene chloride: isopropanol) to give the title compound as a yellow solid (1.1 g, 9%): mp 168-169 ° C; NMR (DMSO, d6): delta 12.9 (broad s, 1 H, NH), 8.85 (d, J = 8.8 Hz, 1 H, ArH), 8.24 (d, J = 8.1 Hz, 1 H, ArH), 8.16 (d, J = 8.7 Hz, 2 H, ArH), 8.02 (dd, J = 6.9, 8.3 Hz, 1 H, ArH), 7.89 (dd, J = 6.9, 8.1 Hz, 1 H, ArH), 6.95 ( s, 1 H, CH); MS (EI): 308 (MI, 10%), 265 (8%), 145 (18%), 129 (100%), 128 (75%); Anal. (C12HgN204S2): C, H, N.

EXAMPLE 21 [3- (4-Chlorophenyl) -prop-2-ynyl] bromide, (IX) A suspension of p-iodochlorobenzene [formula (VII), 7.15 g, 30.0 mmol], propargyl alcohol (1.75 ml, 30 mmol), dichlorobis (triphenylphosphine) palladium (II) (0.21 g, 0.3 mmol), copper (I) iodide (29 mg, 0.15 mmol) and diethylamine (50 ml) was stirred under a nitrogen atmosphere at room temperature and the solution occurred within 20 minutes. After 5 hours, the diethylamine was removed, and the crude product was partitioned between water and ether. The ether phase was dried (brine), concentrated and flash chromatographed (petroleum ether: ethyl acetate 4: 1) to give 3- (4-chlorophenyl) -prop-2-inol (compound of formula VIII , 4.09 g, 82%). This compound of formula (VIII) (3.47 g, 20.83 mmol) was suspended in anhydrous ether (12 mL) and pyridine (0.42 mL) was added. The reaction mixture was cooled in an ice bath and a solution of phosphorus tribromide (1.0 ml, 10.42 mmol) in anhydrous ether (6 ml) was added dropwise over a period of 15 minutes. The reaction mixture was then stirred at room temperature for 2.5 hours, cooled in an ice bath and crushed ice was added. The reaction mixture was added to water (200 ml) and extracted with ether (200 ml). The ether phase was washed with water, with saturated aqueous sodium hydrogen carbonate solution and with brine. The extract was concentrated and subjected to flash chromatography (petroleum ether: ethyl acetate 9: 1) to give the product as a white solid (3.38 g, 86%): mp 41-43 ° C; NMR (CDClg): delta 7.37 (d, J-8.7 Hz, 2 H, ArH), 7.27 (d, J-8.7 Hz, 2 H, ArH), 4.16 (s, 2 H, CH2).

By the procedure described in Example 21, the compounds of the formula (IX), Examples 22-33, were prepared from the commercially available arylidene, appropriate, according to the formula (VII) or the 3-arylprop-2-inol commercially available, of the formula (VIII).

EXAMPLE 22 [3-Benzene-prop-2-ynyl] bromide, (IX) Prepared from 3-benzene-prop-2-inol (VIII); oil, NMR (CDClg) delta 7.43 (m, 2 H, ArH), 7.33 (m, 3 H, ArH), 4.16 (s, 2 H, CH2).

EXAMPLE 23 [3- [4- (Fluorophenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-fluoroiodobenzene, (VII): oil; MS (EI): 212 (MI, 8%), 214 (MI, 8%), 133 (100%).

EXAMPLE 24 [3- [4- (Methylphenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-methylodobenzene, (VII): oil; MS (EI): 208 (MI, 8%), 210 (MI, 8%), 129 (100%).

EXAMPLE 25 [3- [4- (Trifluoromethylphenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-iodo (trifluoromethyl) -benzene, (VII): oil; NMR (CDC13): delta 7.57 (d, J = 8.6 Hz, 2 H, ArH), 7.52 (d, J = 8.6 Hz, 2 H, ArH), 4.13 (s, 2 H, CH2).

EXAMPLE 26 [3- [4- (Bromophenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-bromoiodobenzene, (VII): mp 50-51 ° C.

EXAMPLE 27 [3- [4- (Methoxyphenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-iodoanisole, (VII): oil; NMR (CDClg): delta 7.37 (d, J = 8.8 Hz, 2 H, ArH), 6.83 (d, J = 8.8 Hz, 2 H, ArH), 4.16 (s, 2 H, CH2), 3.80 (s, 3 H, CH 3).

EXAMPLE 28 [3- [4- (Trifluoromethoxy-phenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-trifluoromethoxy-benzene, (VII): oil; NMR (DMSO, d6): delta 7.58 (d, J = 8.8 Hz, 2 H, ArH), 7.37 (d, J = 8.8 Hz, 2 H, ArH), 4. 49 (s, 2 H, CH2).

EXAMPLE 29 Bromide of [3- [3- (chlorophenyl)] -prop-2-ynyl J, (IX) Prepared from m-chloroiodobenzene, (VII): oil; NMR (CDClg): delta 7.44 (s, 1 H, ArH), 7.32 (m, 2 H, 2 H, ArH), 7.28 (m, 2 H, ArH), 4.14 (s, 2 H, CH2).

EXAMPLE 30 Bromide of [3- [2- (chlorophenyl)] -prop-2-ynyl], (IX) Prepared from o-chloroiodobenzene, (VII): oil; NMR (CDClg): delta 7.48 (dd, J = 1.9, 7.3 Hz, 1 H, ArH), 7.40 (dd, J = 1.5, 8.1 Hz, 1 H, ArH), 7.25 (m, 2 H, ArH), 4.21 (s, 2 H, CH2).

EXAMPLE 31 Bromide of [3- (3,5-bis (rifluoromethyl) -phenyl) -prop-2-ynyl], (IX) Prepared from 3- [3,5-bis (trifluoromethyl) phenyl] -prop-2-inol, (VIII): mp 30-31 ° C.

EXAMPLE 32 [3- [- (Methylthiophenyl)] -prop-2-ynyl] bromide, (IX) Prepared from p-iodothioanisole, (VII) oil; NMR (DMSO, d6): delta 7.36 (d, J = 8.3 Hz, 2 H, ArH), 7.22 (d, J = 8.3 Hz, 2 H, ArH), 4.48 (s, 2 H, CI1 *,).

EXAMPLE 33 [3- (3,5-bis (fluoro) phenyl] -2-prop-2-ynyl] bromide, (IX) Prepared from 3, 4-difluoroiodobenzene, (VII): oil; MS (EI): 231 (MI, 16%), 233 (MI, 16%), 151 (100%).

EXAMPLE 34 N- (triphenylmethyl) -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione, (VI).

Trifenylmethyl chloride (2.67 g, 9.58 mmol) was added to a stirred solution, at room temperature, of 5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione [(V), from Example 12, 1.30. g, 4.79 mmol], triethylamine (0.67 ml, 4.79 mmol) and dichloromethane (6.5 ml). After 1 hour, water (300 ml) was added and the organic material was extracted with ethyl acetate (2 x 200 ml). The combined extracts were dried (brine, magnesium sulfate), concentrated and purified by flash chromatography (petroleum ether / ethyl acetate 4: 1) to give the title compound as a white solid (1.1 g, 45%). : mp 105-110 ° C; NMR (CDC13): delta 7.85 (d, J - 8.3 Hz, 2 H, ArH), 7.48 (d, J = 8.1 Hz, 6 H, CPh3H), 7.38 (d, J = 8.3 Hz, 2 H, ArH) , 7.23 (m, 9 H, CPh3H), 5.13 (s, 1 H, CH), 2.46 (s, 3 H, CH3).

EXAMPLE 35 N- (Triphenylmethyl) -5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (toluene-4-sulfonyl) thiazolidin-2,4-dione, (X).

Sodium hydride (80% dispersion - in mineral oil, 93 mg, 3.10 mmol) was added to a solution of N- (triphenylmethyl) -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione [( VI), from Example 34, 1.06 g, 2.07 mmol] in anhydrous dimethylformamide (9 ml) at 0 ° C under an atmosphere of anhydrous nitrogen. After 20 minutes, [3- (4-chlorophenyl) -prop-2-ynyl] bromide [(IX), from Example 21, 0.52 g, 2.27 mmol] was added and the reaction mixture was stirred an additional period of 20 minutes at 0 ° C. Saturated aqueous ammonium chloride solution (60 ml) was added, followed by water (60 ml). After stirring for 10 minutes, the solid was filtered, washed with water and triturated with petroleum ether to give the title compound as a gray solid (1.16 g, 90%): mp 221-223 ° C; NMR (CDClg): delta 7.8 (d, J = 8.2 Hz, 2 H, ArH), 7.45 (d, J = 7.5 Hz, 6 H, CPh3H), 7.35 (d, J = 8.2 Hz, 2 H, ArH) , 7.14 (m, 11 H, Ar'H, CPh3H), 6.98 (d, J - 8.5 Hz, 2 H, Ar »H), 3.29 (d, J = 16.7 Hz, 1 H, CH2), 3.12 (d , J = 16.7 Hz, 1 H, CH2), 2.46 (s, 3 H, CH3).

EXAMPLE 36 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (toluene-4-sulfonyl) thiazolidin-2,4-dione, (I).

Trifluoroacetic acid (0.32 ml, 4.07 mmol) was added to a stirred suspension, at room temperature, of N- (triphenylmethyl) -5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (toluene). 4-sulfonyl) -thiazolidin-2,4-dione [(X), from Example 35, 1.29 g, 1.94 mmol] in methylene chloride (2 ml). The dissolution occurred immediately. After 1 hour, the reaction mixture was added to water (200 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate phase was washed with water and with brine, and then concentrated. The crude product was purified by flash chromatography (methylene chloride / isopropanol, 95: 5) and then triturated in petroleum ether to give the title compound as an off-white solid (0.52 g, 64%): mp 172- 174CC; NMR (CDC13): delta 8.00 (s, 1 H, NH), 7.85 (d, J = 8.3 Hz, 2 H, ArH), 7.41 (d, J = 8.3 Hz, 2 H, ArH), 7.26 (s, 4 H, Ar'H), 3.65 (d, J = 17.1 Hz, 1 H, CH2), 3.33 (d, J = 17.1 Hz, 1 H, CH2), 2.49 (s, 3 H, CH3); MS (CI); 420 (M + H, 58%), 422 (M + H, 24%), 265 (40%), 267 (26%), 157 (100%); Analysis Calculated for C? GH14ClN04S2: C, 54.35; H, 3.36; N, 3.36; Found: C, 54.74; H, 3.54; N, 2.98.

EXAMPLE 37 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (toluene-4-sulfanyl) thiazolidin-2,4-dione, (I).

Sodium hydride (dispersion to the 80% in mineral oil, 0.63 g, 21.1 mmol) to a solution of 5- (toluene-4-sulfañyl) -thiazolidin-2,4-dione [(III), of Example 1, 1.75 g, 8.44 mmol] in tetrahydrofuran anhydrous (9 ml) at 0 ° C under an anhydrous nitrogen atmosphere. After 10 minutes, a solution of [3- (4-chlorophenyl) -prop-2-ynyl] [(IX) bromide, of Example 21, 1.94 g, 8.44 mmol] in tetrahydrofuran was added over a period of 30 minutes. anhydrous (9 ml). After 2.5 hours, the reaction mixture was concentrated and dilute aqueous hydrochloric acid (85 ml) was added. The organic materials were extracted with ethyl acetate (2 x 85 ml) and the extracts were dried (brine), concentrated, purified by flash chromatography (methylene chloride / isopropan-ol, 98: 2) and triturated with ether. of petroleum to provide the title compound as a white solid (1.25 g, 38%): mp 108-109 ° C; NMR (DMSO, d6): delta 12.27 (s, 1 H, NH), 7.46 (d, J = 8.5 Hz, 2 H, Ar H, Ar 'H), 7.39 (d, J = 8.7 Hz, 1 H, Ar 'H), 7.27 (d, J - 7.9 Hz, 1 H, ArH), 3.48 (d, J = 17.3 Hz, 1 H, CH2), 3.32 (d, J = 17.3 Hz, 1 H, CH2), 2.34 (s, 3 H, CH 3); MS (EI): 387 (MI, 5%), 389 (2%), 124 (85%), 91 (100%); Analysis Calculated for C19H14C1N02S2: C, 58.21; H, 3.53; N, 3.77; Found: C, 58.02; H, 3.58; N, 3.52. Using the procedure described in the Example 37, the compounds of the formula (I), Examples 38-41 were prepared from the appropriate 5-ar-ylsulfanyl-thiazolidin-2,4-dione of the formula (III), and the (3-ar-ilpropyl bromide -2-inyl) of the formula (IX).

EXAMPLE 38 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (benzenesulfanyl) thiazolidin-2,4-dione, (I).

Prepared from the 5- (benzenesulfañil) -thiazolidin-2,4-dione of the formula (III), Example 6 and [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX) ), from Example 21: mp 87-88 ° C; Analysis Calculated for ClgH] L 2C1N02S2: C, 57.83; H, 3.24; N, 3.75; Found: C, 58.05; H, 3.07; N, 3.62.

EXAMPLE 39 - . 5 - [3- (4-chloro-en-1) -prop-2-in i i] -5- 4- • fluoro-phenyl- • sulf indigo) - -thiazoli-din-2-dione, (i) .

Prepared from 5- (4-fluorophenylsulphanyl) -thiazolidin-2,4-dione of the formula (III), Example 5 and [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), of Example 21: mp 116-117 ° C; Analysis Calculated for C1QH1 jClFNO ^: C, 55.17; H, 2.83; N, 3.57; Found: C, 54.58; H, 2.65; N, 3.39.

EXAMPLE 40 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (pyridin-2-sulfanyl) -thiazolidin-2,4-dione, (I).

Prepared from the 5- (pyridin-2-sulfañyl) -thiazolidin-2,4-dione, (III) of Example 2 and [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), of Example 21: mp 124-125 ° C; Analysis Calculated for ClyH1 ^ ÍN ^ S, -: C, 54.47; H, 2.96; N, 7.47; Found: C, 54.49; H, 2.86; N, 7.14.

EXAMPLE 41 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (quinolin-2-sulfanyl) -thiazolidin-2,4-dione, (I).

Prepared from the 5- (quinoline-2-sulphanyl) -thiazolidin-2,4-dione, (III) of Example 3 and [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), of Example 21: mp 163-165 ° C; Analysis Calculated for C H13ClN202S2: C, 58.04; H, 3.06; N, 6.40; Found: C, 57.98; H, 2.84; N, 6.15.

EXAMPLE 42 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (4-fluorobenzenesulfonyl) -thiazolidin-2,4-dione, (I).

Sodium hydride (dispersion in mineral oil, 0.55 g, 18.2 mmol) was added to a solution of 5- (4-fluorophenylsulfonyl) -thiazolidin-2,4-dione [(V), from Example 11, 2.0 g, 7.27 mmol] in anhydrous tetrahydrofuran (12 ml) at 0 ° C under an atmosphere of anhydrous nitrogen. After 1.5 hours, a solution of [3- (4-chlorophenyl) -prop-2-ynyl] bromide [(IX), from Example 21, 1.67 g, 7.27 mmol] in anhydrous tetrahydrofuran (12 ml) was added. After 20 hours, the reaction mixture was concentrated and dilute aqueous hydrochloric acid (100 ml) was added. The organic materials were extracted with ethyl acetate (3 x 100 ml) and the extracts were dried (brine), concentrated, purified by flash chromatography (methylene chloride / methanol 97: 3) and triturated with petroleum ether for provide the title compound as a white solid (0.99 g, 32%). The solid was further purified by recrystallization from ethanol: water: mp 176-177 ° C; NMR (DMSO, d6): delta 13.0 (broad s, 1 H, NH), 8.02 (m, 1 H, ArH), 7.59 (t, J = 8.9 Hz, 1 H, ArH), 7.45 (d, J = 8.5 Hz, 1 H, Ar'H), 7.35 (d, J = 8.5 Hz, 1 H, Ar'H), 3.66 (d, J = 17.5 Hz, 1 H, CH2), 3.50 (d, J = 17.3 Hz, 1 H, CH2); MS (-DCI): 422 (M-H, 22%); 424 (M-H, 16%), 263 (100%); Analysis Calculated for CjgHj: C, 51.01; H, 2.62; N, 3.30; Found: C, 51.08; H, 2.55; N, 2.97.

EXAMPLE 43 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione, (I).

Sodium hydride (80% dispersion in mineral oil, 0.32 g, 10.8 mmol) was added to a solution of 5- (pyridine-2-sulfonyl) -thiazolidin-2,4-dione [(V), from Example 19, 1.1 g, 4.30 mmol] in anhydrous tetrahydrofuran (7.5 ml) at 0 ° C under an atmosphere of anhydrous nitrogen. After 10 mis, a solution of [3- (4-chloro-phenyl) -prop-2-ynyl] [(IX) bromide, of Example 21, 0.99 g, 4.30 mmol] was added over a period of 30 mis. in anhydrous tetrahydrofuran (7.5 ml). After 27 hours at room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride (20 ml), water (120 ml) was added and the organic materials were extracted with ethyl acetate (2 x 150 ml). . The extracts were dried (brine), concentrated and purified by flash chromatography (gradient: 97: 3 to 88:12 methylene chloride: methanol) to give the title compound as a yellow solid (0.63 g, 36% strength). ): mp 140-141 ° C; NMR (DMSO, d6): delta 13.2 (broad s, 1 H, NH), 8.82 (dd, J-0.6, 4.0 Hz, 1 H, PirH), 8.23 (td, J = 1.6, 7.8 Hz, 1 H, PirH), 8.15 (d, J = 7.9 Hz, 1 H, PirH), 7.87 (ddd, J = 1.1, 5.3, 7.7 Hz, 1 H, PirH), 7.45 (d, J - 8.5 Hz, 1 H, Ar 'H), 7.45 (d, J = 8.5 Hz, 1 H, Ar'H), 7.35 (d, J = 8.5 Hz, 1 H, Ar'H), 3.88 (d, J = 17.2 Hz, 1 H, CH2), 3.74 (d, J = 17.2 Hz, 1 H, CH2): MS (+ DCI): 407 (M + H, 50%); 409 (M + H, 24%), 264 (80%), 266 (36%), 144 (100%); Analysis Calculated for C? : C, 50.18; H, 2.72; N, 6.88; Found: C, 50.07; H, 2.67; N, 6.57. By the procedure described in Example 43, the compounds of the formula (I), Examples 44-85, were prepared from the appropriate 5-arylsulfonyl-thiazolidin-2,4-dione of the formula (V) and the bromide of (3-arylprop-2-ynyl) of the formula (IX). n Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 44 2-naphthyl 4-chloro- 13 and 21 C22H14C1N04S2 190-191 phenyl 57.95, 3.09, 3.07 57.70, 3.09.2.97 45 phenyl 4-chloro- 15 and 21 C18H12C1N0 S2 92-93 phenyl 53.27, 2.98, 3.45 52.99, 3.13, 3.31 46 phenyl phenyl 15 and 22 C18H13N04S2 130-131 58.21, 3.53, 3.77 58.02, 3.58, 3.52 47 4-methyl phenyl 12 and 22 C19H15N04S2 143-145 phenyl 59.20, 3.92, 3.63 59.01, 3.96, 3.30 48 4-chloro-phenyl 14 and 22 C18H12C1N04S2 144-146 phenyl 53.27, 2.98, 3.45 53.25, 2.87, 3.25 49 4-chloro-4-chloro- 14 and 21 C18HnCl2N04S2 172-173 phenyl phenyl 49.10, 2.52, 3.18 49.25, 2.40, 3.02 50 4-fluoro-phenyl 11 and 22 C18H12FN04S2 135-141 phenyl 55.52, 3.11, 3.60 55.37, 3.04, 3.32 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 51 4-bromo-4-chloro-16 and 21 C18HnBrClN04S2 171-175 phenyl phenyl 44.60, 2.29, 2.89 44.31, 2.20, 2.70 52 phenyl 4-fluoro-15 and 23 C18H12FN04S2 171-172 phenyl 55.52, 3.11, 3.60 55.14, 2.98 , 3.37 53 4-methyl-4-fluoro-12 and 23 C19H FN04S2 154-156 phenyl phenyl 56.56, 3.50, 3.47 55.83, 3.38, 3.17 54 phenyl 4-methyl-15 and 24 C ^ H ^ NO ^ 168-169 phenyl 59.20, 3.92, 3.63 58.85, 3.81, 3.56 55 4-methyl-4-methyl-12 and 24 C20H17N04S2 195-196 phenyl phenyl 60.13, 4.29, 3.51 60.07, 4.25, 3.47 56 4-bromo-phenyl 16 and 22 ClgH12BrN04S2 172- 176 phenyl 48.01, 2.?, 3.11 47.87, 2.55, 3.11 57 4-methoxy-4-chloro-17 and 21 C- .J. CINO-S- 134-136 19 14 5 2 phenyl phenyl 52.35, 3.24, 3.21 52.21, 3.17, 3.03 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 58 2-naphthyl phenyl 13 and 22 C22H15N04S2 174-177 62.69, 3.58, 3.32 62.40, 3.53, 3.37 59 4-methoxyphenyl 17 and 22 C19H15N05S2 142-143 phenyl 56.84, 3.77, 3.49 56.81, 3.68, 3.32 60 4-methyl - 4-trifluoro-12 and 25 C20H14F3N04S2 76-80 phenyl methyl-phenyl 52.98, 3.11, 3.09 52.60, 3.04, 2.94 61 phenyl 4-bromo-15 and 26 ClgH12BrN04S2 81-83 phenyl 48.01, 2.69, 3.11 47.72, 2.54, 2.72 62 4-methyl-4-methoxy- 12 and 27 C2 () H17N05S2 80- 2 phenyl phenyl 57.82, 4.12, 3.37 57.12, 4.05, 2.87 63 4-methyl-4-bromo-12 and 26 C19H14BrN04S2 161-162 phenyl phenyl 49.14 , 3.W, 3.02 49.10, 2.84, 2.72 64 3-methyl phenyl 18 and 22 C19H15N04S2 128-130 phenyl 54.35, 3.36, 3.34 54.27, 3.20, 3.02 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 65 phenyl 4-trifluoro-15 and 25 C19H12F3N04S2-80-81 methyl-phenyl 0.53 H20 51.93, 2.75, 3.18 50.62, 2.76, 3.06 66 4-fluoro-4-fluoro- 11 and 23 C18HnF2N04S2 177-181 phenyl phenyl 53.07, 2.72 , 3.44 53.05, 2.69, 3.27 67 4-chloro-4-fluoro-14 and 23 C18HUC1FN04S2 171-173 phenyl phenyl 51.00, 2.62, 3.30 50.83, 2.59, 3.07 68 3-methyl-4-chloro- 18 and 21 C19H14C1N04S2 136- 137.5 phenyl phenyl 54.27, 3.20, 3.02 69 4-methyl-3-chloro- 12 and 29 C19H14C1N04S2 70-72 phenyl phenyl 54.35, 3.36, 3.34 53.94, 3.20, 3.04 70 phenyl 4-methoxy- 15 and 27 C19H15N05S2- 161-162 phenyl 0.711 ^ 0 55.09, 4.00, 3.38 54.78, 3.73, 3.09 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 71 phenyl 2-chloro-15 and 30 C18H12C1N04S2 162-163 phenyl 53.27, 2.98, 3.45 53.09, 2.82, 3.32 72 4-methyl-2-chloro- 12 and 30 C19H C1N04S2 160-161 phenyl phenyl 54.00, 3.20, 3.32 73 phenyl 3, 5-bis- 15 and 31 226-229 C20H11F6N04S2 trifluoro- 47.34, 2.19, 2.76 methyl-phenyl 47.10, 2.02, 2.73 74 4-methyl-3, 5-bis- 12 and 31 C 1H1, F, NO, S 207-209 21 13 6 4 2 phenyl trifluoro- 48.37, 2.51, 2.69 methyl-phenyl 48.24, 2.29, 2.53 75 phenyl 3-chloro- 15 and 29 C18H12C1N04S2 107-108 phenyl 53.27, 2.98, 3.45 53.03, 2.81.3.37 76 4 -fluoro- 4-bromo-11 and 26 C18HnBrFN04S2 155-157 phenyl phenyl 46.16, 2.37, 2.99 46.26, 2.24, 2.75 77 4-chloro-4-bromo-14 and 26 ClgH11BrClN04S2 160-161 phenyl phenyl 44.59, 2.28, 2.89 44.27 , 2.17, 2.65 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 78 4-fluoro-4-trifluoro-11 and 25 C19HnF4N04S2 143-145 phenyl-methyl phenyl 49.89, 2.42, 3.06 49.90, 2.37, 3.04 79 4-chloro-4-trifluoro- 14 and 25 C19HUC1F3N04S2 144-145 phenyl-methyl-phenyl 48.16, 2.34, 2.95 47.91, 2.46, 2.85 80 4-bromo-4-fluoro-16 and 23 C18HnBrFN04S2 186-188 phenyl phenyl 46.16, 2.36, 3.00 45.13, 2.42, 2.81 81 2-pyridyl 4-fluoro- 19 and 23 C17HnFN204S2 92-94 phenyl 52.30, 2.84, 7.18 52.05, 2.71, 2.09 82 4-f luoro-4-trif luoro- 11 and 28 C19HnF4N05S2 133-135 phenyl methoxy-phenyl 48.20, 2.34, 2.96 48.40, 2.48, 2.90 83 4-f luoro- 3, 4-di- 11 and 33 130-133 C18H10F3N04S2 fluoro-phenyl phenyl 50.82, 2.37, 3.29 49.83, 2.39, 3.44 84 4-fluoro-4-methyl-11 and 32 C19H FN04S3 74-76 phenyl-thio-phenyl 52.40, 3.24, 3.22 52.41, 3.31, 2.82 Example Ar Ar 'Examples Analysis pf (° C) of Cale. C, H, N Materials Found Initial C, H, N 85 2-quinolyl 4-chloro- 20 and 21 C21H13C1N204S2 191-192 phenyl 55.20, 2.87, 6.13 55.08, 2.67, 6.28 EXAMPLE 86 - (6-methylpyridin-2-sulfañil) -thiazolidin-2,4-dione, (III).

This compound was prepared from 5-bromo-thiazolidin-2,4-dione and from 2-methyl-6-mercapto-pyridine (AD Dunn, R. Norrie, J. L'Hostis, and S. Marjot J Prak, Chem. -Chem.Zt. 1992, 334, 119-125) according to the method described in Example 1: mp 114-115 ° C.

EXAMPLE 87 - (pyrimidin-2-sulfanyl) -thiazolidin-2,4-dione, (III) This compound was prepared from 5-bromo-thiazolidin-2, -dione and 2-mercaptopyrimidine according to the procedure described in Example 1: MS (EI): 227 (MI, 5%), 184 (15%), 80 (100%).

EXAMPLE 88 - (5-chloro-benzothiazol-2-ylsulfanyl) -thiazolidin-2,4-dione, (III).

This compound was prepared from 5-bromo-thiazolidin-2,4-dione and from 2-mercaptobenzothiazole, according to the procedure described in Example 5: melting point 253-255 ° C (decomposed).

EXAMPLE 89 - (5-benzoxazol-2-ylsulfanyl) -thiazolidin-2,4-dione, (III).

This compound was prepared from 5-bromo-thiazolidin-2,4-dione and 2-mercaptobenzoxazole, according to the procedure described in Example 5: melting point 241-243 ° C (decomposed).

EXAMPLE 90 - (6-methyl-pyridin-2-sulfonyl) -thiazolidin-2,4-dione, (V).

This compound was prepared from 5-bromo-thiazolidin-2,4-dione and from 2-methyl-6-mercapto-pyridine, (AD Dunn, R. Norrie, J. L'Hostis, and Marjot J. Prak, Chem. -Chem.Zt. 1992, 334, 119-125), according to the procedure described in Example 20: melting point 129-130 ° C (decomposes).

EXAMPLE 91 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (4-chlorophenylsulfanyl) -thiazolidin-2,4-dione, (I) N-butyl lithium (2.5 M in hexanes, 12.3 ml, 30.8 mmol) was added to a solution of 5- (4-chlorophenyl-sulfanyl) -thiazolidin-2,4-dione [(III), from Example 7, 4.0 g, 15.4 mmol] in anhydrous tetrahydrofuran (195 ml) at -78 ° C under an atmosphere of anhydrous nitrogen over a period of 40 minutes. After an additional period of 30 minutes, a solution of [3- (4-chlorophenyl) -prop-2-ynyl] [(IX) bromide, of Example 21, 3.53 g, 15.4 g, was added over a period of 12 minutes. mmol] in anhydrous tetrahydrofuran (65 ml). After 10 minutes, the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was added to saturated ammonium chloride solution (1 liter) and extracted with ethyl acetate (800 ml). The extracts were dried (brine), concentrated and purified by flash chromatography (petroleum ether: ethyl acetate 4: 1) to give the title compound as a white solid (2.58 g, 41%): mp 144- 146 ° C; NMR (DMSO, d6): delta 12.37 (s, 1 H, NH), 7.59 (d, J = 8.5 Hz, 2 H, Ar H), 7.56 (d, J = 8.7 Hz, 2 H, Ar H), 7.46 ( d, J = 8.5 Hz, 2 H, Ar'H), 7.40 (d, J = 8.3 Hz, 2 H, Ar'H), 3.52 (d, J = 17.3 Hz, 1 H, CH2), 3.35 (d , J = 17.3 Hz, 1 H, CH2); MS (EI): 407, 409, 411 (MI, 5%), 364, 366 (8%), 264 (30%), 193 (40%), 149 (100%), 143 (20%); Calculated Analysis for C18H11C12N02S2: C '52-95; H '2-72' N »3.43; Found: C, 52.95; H, 2.87; N, 3.29. Using the procedure described in the Example 91, the compounds of the formula (I), Examples 92-95 were prepared from the 5-arylsulfanyl-thiazolidin-2,4-dione of the formula (III) and the bromide of [3- (4-chloro- phenyl) -prop-2-ynyl] of the formula (IX), Example 21.

EXAMPLE 92 - (5-Chlorobenzothiazol-2-ylsulfanyl) -5- [3- (4-chlorophenyl) -prop-2-ynyl] -thiazolidin-2,4-dione, (I) Prepared from 5-benzothiazol-2-ylsulfañyl) -thiazolidin-2,4-dione, (III), Example 88 and [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), Example 21: melting point 187-188 ° C; Analysis Calculated for ClgH1C) Cl2N202S3: C, 49.04; H, 2.17; N, 6.02; Found: C, 48.94; H, 2.31; N, 6.21.

EXAMPLE 93 - (Benzoxazol-2-ylsulfanyl) -5- [3- (4-chlorophenyl) -prop-2-ynyl] -thiazolidin-2,4-dione, (I) Prepared from 5- (benzoxazol-2-ylsulfañyl) -thiazolidin-2,4-dione, (III), Example 89 and from [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), Example 21: mp 137-139 ° C; Analysis Calculated for C-TQH, C, 55.80; H, 2.67; N, 6.75; Found: C, 54.92; H, 2.76; N, 6.82.

EXAMPLE 94 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (6-methyl-pyridin-2-sulfanyl) -thiazolidin-2,4-dione, (I) Prepared from 5- (6-methyl-pyridin-2-sulfañyl) -thiazolidin-2,4-dione, (III), Example 86 and [3- (4-chlorophenyl) -prop-2-bromide inyl] of the formula (IX), Example 21: melting point 147-148 ° C; Analysis Calculated for C18H13C1N202S2: C, 55.59; H, 3.37; N, 7.20; Found: C, 55.52; H, 3.31; N, 7.02. ' EXAMPLE 95 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (pyrimidin-2-sulfanyl) -thiazolidin-2,4-dione, (I) Prepared from 5- (pyrimidin-2-sulfañyl) -thiazolidin-2,4-dione, (III), Example 87 and from [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), Example 21: mp 118-120 ° C; Analysis Calculated for C., H- (-.ClN_02S2: C, 51.13; H, 2.68; N, 11.18; Found: C, 51.27; H, 2.93; N, 10.82.

EXAMPLE 96 - [3- (4-chlorophenyl) -prop-2-ynyl] -5- (6-methy1-pyridin-2-sulfonyl) -thiazolidin-2,4-dione, (I) N-butyl lithium (2.5 M in hexanes, 2.77 mL, 6.93 mmol) was added to a solution of 5- (6-methyl-pyridin-2-sulfonyl) -thiazolidin-2,4-dione [(V), Example 90, 0.92 g, 3.38 mmol] in anhydrous tetrahydrofuran (30 ml) at -78 ° C under an atmosphere of anhydrous nitrogen over a period of 20 minutes. A solution of [3- (4-chlorophenyl) -prop-2-ynyl] bromide [(IX), from Example 21, 3.53 g, 15.4 mmol] in anhydrous tetrahydrofuran (10 ml) was added over a period of 20 minutes. . The reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was added to saturated aqueous solution of ammonium chloride (80 ml) and extracted with ethyl acetate (2 x 300 ml). The extracts were washed with water, dried (brine), concentrated and purified by flash chromatography (97: 3 to 93: 7 gradient of methylene chloride: isopropanol) to give a sticky solid which was triturated with diethyl ether. petroleum (90 ml): benzene (2 ml) to give the title compound as an off-white solid (0.55 g, 39%): melting point 104-106 ° C; NMR (DMSO, d): delta 13.1 (s, broad, 1 H, NH), 8.10 (t, J = 7.8 Hz, 1 H, piH), 7.95 (d, J = 7.7 Hz, 1 H, piH), 7.71 (d, J - 7.7 Hz, 1 H, piH), 7.45 (d, J = 8.8 Hz, 2 H, ArH), 7.35 (d, J = 8.7 Hz, 2 H, ArH), 3.86 (d, J = 17.4 Hz, 1 H, CH2); 3.72 (d, J - 17.4 Hz, 1 H, CH2), 2.57 (s, 3 H, CH3); MS (EI): 420 (MI, 3%), 265 (12%), 263 (38%), 194 (25%), 192 (70%), 149 (40%), 93 (100%) Calculated Analysis for C18H13C1N204S2: C, 51.37; H, 3.11; N, 6.66; Found: C, 50.99; H, 3.05; N, 6.58, EXAMPLE 97 - [3- (3,5-bis- (trifluoromethyl) phenyl) -prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione, (I) By the procedure described in Example 43, this compound was prepared from the 5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione of the formula (V), Example 19 and the bromide of [3- ( 3, 5-bis- (trifluoromethyl) phenyl) -prop-2-ynyl] of formula (IX), Example 31: melting point 150-152 ° C; NMR (DMSO, d6): delta 8.79 (d, J = 4.4 Hz, 1 H, piH), 8.16 (dt, J = 1.6, 7.9 Hz, 1 H, piH), 8.11 (s, 1 H, ArH), 8.05 (d, J = 7.9 Hz, 1 H, piH), 7.94 (s, 2 H, ArH), 7.9 (dd, J = 4.9, 7.3 Hz, 1 H, ArH), 3.87 (d, J = 17.2 Hz , 1 HOUR, CH2), 3.71 (d, J = 17.2 Hz, 1 H, CH2); MS (CI): 509 (MI + 1, 100%), 367 (32%), 366 (352%), 287 (35%), 194 (25%), 194 (20%); Analysis Calculated for Ci. nyH, I nUF6, N o04. S ¿": C, 44.89; H, 1.98; N, 5.51; Found: C, 42.80; H, 2.09; N, 5.77.

EXAMPLE 98 - (2,3-dichlorothiophen-5-sulfonyl) -thiazolidin-2,4-dione, (V) A solution of p-thiocresol (4.94 g, 39.8 mmol), triethylamine (5.55 ml, 39.8 mmol) in dichloromethane (30 ml) was added dropwise over a period of 12 minutes to a 2-chloro solution., 3-dichlorothiophen-5-sulfonyl (5.0 g, 19.9 mmol) in dichloromethane (50 ml) at -78 ° C under an atmosphere of anhydrous nitrogen. An additional 10 ml of dichloromethane was added and the reaction mixture was stirred at -78 ° C for 2 hours, and then warmed to room temperature in 20 minutes. The reaction mixture was poured into water (400 ml) and the layers were separated. The dichloromethane phase was washed with water (2 x 200 ml) and the combined aqueous phase was acidified with concentrated hydrochloric acid. Solid sodium chloride was also added to the aqueous phase, which was then extracted with ether (4 x 200 ml). The extracts were combined and dried (sodium sulfate) and concentrated to give 2,3-dichloro-thiophene-5-sulfinic acid as a white solid (2.89 g, 67%): NMR (DMSO, d6): delta 9.1 (s broad, 1 H, OH), 7.54 (s, 1 H, thiophene H); MS (EI): 216, 218, 220 (70, 50, 10%, MI), 199, 201, 203 (60, 50, 10%, -OH), 169 (50%), 167 (70%), 154 (70%), 152 (100%). This sulfinic acid (2.33 g, 10.73 mmol) was dissolved in a solution of sodium hydroxide (0.42 g, 10.73 mmol) in methanol (25 ml) at room temperature. The methanol was removed and the residual water was removed by azeotropic distillation with benzene to provide 2,3-dichloro-thiophene-5-sulfinic acid, such as the sodium salt, of the formula (IV) as a white solid (2.57 g. , 100%); NMR (DMSO, d): delta 6.89 (s, 1 H, thiophene H); Analysis Calculated for C4HC1202S2: C, 20.09; H, 0.41; Found: C, 19.80; H, 0.52. This solid salt of sulfinic acid of formula (IV) (2.12 g, 8.87 mmol) was mixed with 5-bromo-thiazo-lidin-2,4-dione (1.58 g, 8.06 mmol) and with Aliquat 336 (tricaprylmethylammonium chloride, 0.45 ml) and left to rest overnight. Dilute aqueous hydrochloric acid (100 ml) was added and the aqueous reaction mixture was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with brine and concentrated. The crude product was purified by flash chromatography using acid washed silica gel (H "P0, 2% in methanol) and ethyl acetate: petroleum ether 82:18 as the eluent to provide the title compound of the formula ( V), as a white solid: melting point 176-177 ° C; NMR (DMSO, d6): delta 13.0 (s, broad, 1 H, NH), 8.10 (s, 1 H, thiophene H), 6.85 (s, 1 H, CH); MS (EI): 331, 333, 335 (30, 20, 5%, MI), 215, 217, 219 (100, 70, 15%); Analysis Calculated for C7H3C12N0 S3: C, 25.31; H, 0.91; N, 4.22; Found: C, 25.83; H, 1.00; N, 4.23.

EXAMPLE 99 - [- (4-chlorophenyl) -prop-2-ynyl] -5- (2,3-dichlorothiophen-5-sulfonyl) -thiazolidin-2,4-dione, (I) By the procedure described in Example 96, this compound was prepared from the 5- (2,3-dichlorothiophen-5-sulfonyl) -thiazolidin-2,4-dione of the formula (V), Example 98 and the [3- (4-chlorophenyl) -prop-2-ynyl] bromide of the formula (IX), of Example 21: melting point 160-161 ° C; NMR (DMSO, d6): delta 8.03 (s, 1 H, thiophene H), 7.44 (d, J = 8.4 Hz, 2 H, ArH), 7.33 (d, J = 8.3 Hz, 2 H, ArH), 3.69 (d, J = 17.4 Hz, 1 H, CH2), 3.52 (d, J = 17.4 Hz, 1 H, CH2); MS (-FAB): 478, 480 (10%, 10%, M-H), 297 (30%), 148 (100%); Analysis Calculated for C 16 HgCl 3 N0 4 S 3: C, 39.97; H, 1.68; N, 2.91; Found: C, 40.30; H, 1.97; N, 2.95.

PHARMACOLOGY The blood glucose lowering activity of the compounds of this invention was demonstrable in experiments using diabetic mice (db / db). The db / db mouse (C57BL / KsJ) shows many metabolic abnormalities that are associated with non-insulin-dependent diabetes mellitus (Type II). The animals are obese, glucose intolerant and have fasting hyperglycemia, which is sometimes accompanied by paradoxical hyperinsulinemia. In addition, the db / db mouse will eventually develop some of the long-term complications that have been associated with diabetes mellitus. [See Coleman Diabetes, 3 ^ (Suppl 1), 1_ (1982)]. Despite these common states, the acute administration of sulfonylureas (even at extremely high doses) will not reduce the hyperglycemia of the db / db mice. [See Tutwiler et al., Diabetes 2_7, 856 (1978)]. The ability of a few other hypoglycemic agents that are effective in this species suggests that the other agents have mechanisms of action that are different from that of the sulfonylureas [ibid; Lee et al., Diabetes 3_1_: 12 (1982); Chang et al., Diabetes 3_2, 830 (1983); Hosoka a et al., Diabetes 3_4, 267 (1985)]. It is more likely that such compounds are therefore more effective in the population of Type II diabetic patients who do not respond to sulfonylurea therapy. The experiments are exemplified hereinafter after the listing of the following general procedure belonging to these experiments. On the morning of Day 1, 35 mice [males db / db (C57BL / KsJ), Jackson Laboratories, 2 to 7 months of age and body weight of 35 to 60 grams] who were fasting for 4 hours, were weighed and a baseline blood sample was collected from the tip of the tail of each mouse without anesthesia, placed directly in a tube containing fluoride, mixed and kept on ice. The food was then returned to the mice. The plasma was separated and the plasma glucose levels were determined by the Abbott VP analyzer. Due to the variable plasma glucose levels of the db / db mice, 5 mice that had the most exaggerated plasma glucose levels (eg, higher or lower) were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent plasma glucose levels: Group A Control with vehicle N = 6 Group B Positive control (ciglitazone) N = 4 Group C ler. Test drug N = 4 Group D 2S Test drug N = 4 Group E 3rd. Test drug N = 4 Group F 4Q Test drug N = 4 Group H 5a Test drug N = 4 On the afternoon of Days 1, 2 and 3 the vehicle, the control or the test drugs were administered (p.o.), to the mice fed ad libitum. The positive control, ciglitazone [(+) - 5 - [4- [(1-methylcyclohexyl] -methoxy] benzyl] thiazolidin-2,4-dione, see Fujita and cola-boradores, Diabetes, 3_2, 804 (1983), was administered by priming at a dose of 100 mg / kg / day.The test compounds were administered by priming at a dose of 100 mg / kg / day unless otherwise noted in the Table. Day 4, mice were weighed and fasted, but the water was available ad libitum. Three hours later, a blood sample was collected and then the mice were given the fourth administration of the drug or vehicle. Blood samples were collected again from the non-anesthetized mice at 2 and 4 hours after drug administration. The plasma was separated and the plasma glucose levels were determined by the Abbott VP Analyzer. For each mouse, the percentage change in their plasma glucose level on Day 4 (mean of the samples at 2 and 4 hours) from their respective level before drug administration (Baseline sample from Day 1) It was determined as follows: Average of the Samples of 2 and 4 hours (Day 4), ._ i x 100 Sample of the Baseline (Day 1) The analysis of variance followed by Dunnett's multiple comparison (on one side) was used to estimate the degree of statistical significance of the difference between the vehicle control group and the groups treated with the individual drug. A drug was considered active, at the specific dose administered, if the difference in plasma glucose level has a p less than 0.05. The results tabulated in the Table show that 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazo-lidin-2, 4-diones and the 5- [3-aryl-prop-2] -inyl] -5- (aryl-sulfañyl) -thiazolidin-2,4-diones of this invention show the property of lowering blood glucose levels in postprandial diabetic mice (db / db). The effective difference between the average percentage change of the vehicle and the group treated with the drug is reported in the Table. Examination of the results tabulated in the following Table shows that the compounds of this invention are very suitable as antihyperglycemic agents, since these decrease the blood glucose levels in diabetic mice. For example, the compounds of Examples 42, 43 and 81 at a dose of only 20 mg / kg, give results comparable or superior to the ciglitazone at 100 mg / kg.

Biological Data / Mouse db / db Db / db mice 4 Days-Postprandial, Decrease%, Glucose Example at a dose of 100 mg / kg at a dose of 20 mg / kg 36 35 np Biological Data / Mouse db / db 4 db / db mice 4-Postprandial, Decrease%, Glucose Example at a dose of 100 mg / kg at a dose of 20 mg / kg 37 27 np 38 19 np 39 a np 40 a np 41 a np 42 79 31 43 55 38 44 20 np 45 52 21 46 a np 47 43 23 48 36 np 49 70 18 50 26 np 51 69 a 52 58 a 53 65 a 54 a np 55 28 np 56 43 a 57 45 a Biological Data / Mouse db / db Mice db / db 4 Days-Postprandial, Decrease%, Glucose Example at a dose of 100 mg / kg at a dose of 20 mg / kg 58 24 np 59 21 np 60 36 to 61 53 to 62 to np 63 51 23 64 48 to 65 59 to 66 57 25 67 54 to 68 33 np 69 30 np 70 25 np 71 to np 72 30 np 73 54 21 74 22 np 75 to np 76 70 to 77 68 to 78 52 a Biological Data / Mouse db / db Mice db / db 4 Days-Postprandial, Decrease%, Glucose Example at a dose of 100 mg / kg at a dose of 20 mg / kg 79 37 np 80 64 a 81 67 36 82 56 a 83 33 np 84 a np 85 np a 91 24 np 92 a np 93 a np 94 a np 95 a np 96 aa 97 np a 99 np np = not tested a = less than 15% decrease at the tested dose * = reference standard # = average of 38 experiments The blood glucose lowering activity of the compounds of this invention was also demonstrable in experiments using diabetic mice (ob / ob). The non-insulin-dependent diabetic syndrome (NIDDM) can be typically characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance. The genetically obese-hyperglycemic ob / ob mouse shows many of these metabolic abnormalities and is thought to be a useful model for investigating hypoglycemic agents to treat NIDDM [Coleman, D .: Diabetology 14: 141-148, 1978]. The experiments are exemplified right now in the present, after listing the following general procedure belonging to these experiments. In each study, mice [male or female ob / ob mice (C57B1 / 6J) and their skinny companions (ob / + or + / +, Jackson Laboratories), aged 2 to 5 months (from 10 to 65 grams)] of a similar age, were randomly assigned according to body weight in 4 groups of 10 mice. The mice were housed 5 per cage and kept with normal food for rodents, with water ad libitum. Mice received the compound daily by priming (suspended in 0.5 ml of 0.5% methylcellulose); dissolved in the water to drink; or mixed in the diet. The dose of the given compounds was in the range of 2.5 to 200 mg / kg body weight / day. The dose is calculated based on weekly body weight fed, and is expressed as the active portion. The positive control, ciglitazone (5- (4- (l-methylcyclohexylmethoxy) benzyl) -2,4-dione, see Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani, A. Diabetes 32: 830-838, 1983) was given at a dose of 100 mg / kg / day, which produces a significant decrease in plasma glucose. Control mice received vehicle only. On the morning of Days 4, 7 or 14, two drops of blood (approximately 50 microliters) were collected in tubes containing sodium fluoride, either from the tail vein or after decapitation. For those studies in which the compound is administered daily by priming, blood samples are collected two hours after administration of the compound. The plasma is isolated by centrifugation, and the glucose concentration is measured enzymatically in an Abbott V.P. Analyzer. For each mouse, the percentage change in plasma glucose on Day 4, 7 or 14 is calculated in relation to the mean plasma glucose of the mice- - li ¬ treated with vehicle. The analysis of variance followed by Dunnett's Comparison Test (one-tailed) is used to estimate the significant difference between the plasma glucose values of the control group and the groups treated with the individual compound (SAS CMS Reléase 5.18). A compound will be considered active if the difference has a p less than 0.05. Examination of the results tabulated in the following Table shows that the compounds of this invention are very suitable as antihyperglycemic agents, since they decrease glucose levels in blood in diabetic mice. For example, the compounds of Examples 49, 51 and 81 at a dose of only 50 mg / kg, give comparable or superior results to the ciglitazone at 100 mg / kg.

Biological Data / Mouse ob / ob Dosage Mouse ob / ob at 4 Days Example mg / kg / day% Decrease% Decrease 0 Insulin Glucose 45 100 40 65 49 50 47 56 51 50 36 69 53 50 30 30 5 81 50 44 57 ciglitazone * 100 43 39 * Reference standard It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from this description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (23)

1. A 5- [3-aryl-prop-2-ynyl] -5- (ar-ylsulfo-nyl) thiazolidin-2,4-dione or 5- [3-aryl-prop-2-ynyl] -5- (arylsulfañil) thiazolidin-2,4-dione of the formula: characterized in that Ar is phenyl, 2-naphthyl, phenyl substituted by alkyl, phenyl substituted by alkoxy, phenyl substituted by halogen, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2- pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl substituted with halogen, 2-benzothiazolyl, benzimide-zolyl, 2-furanyl, 2-benzo- [b] -furanyl, 2-thienyl, 2-thienyl substituted with halogen, 2-benzo- [b] -thienyl; n is 0 or 2; and Ar 'is phenyl, phenyl substituted by alkyl, phenyl substituted by perfluoroalkyl, phenyl substituted by halogen, phenyl substituted by alkoxy, phenyl substituted by perfluoroalkoxy or phenyl substituted by alkylthio; a pharmaceutically acceptable salt thereof

2. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that: Ar is phenyl, phenyl substituted with alkyl, substituted phenyl with halogen, or 2-pyridinyl; n is 2; and Ar 'is phenyl, phenyl substituted by halogen or phenyl substituted by perfluoroalkoxy; or a pharmaceutically acceptable salt thereof.

3. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3- (4-chlorophenyl) ) -prop-2-ynyl] -5- (pyridine-2-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof,

4. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3- (4-fluorophenyl) - prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof

5. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3- (4-chlorophenyl) - prop-2-ynyl] -5- (4-fluorobenzenesulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

6. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- (4-fluorobenzenesulfonyl) -5 - [3- (4-fluorophenyl) -prop-2-ynyl] -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof,

7. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5-benzenesulfonyl-5- [3- (4-chlorophenyl) -prop-2-ynyl] -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof,

8. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5-benzenesulfonyl-5- [3- (3 , 5-bis-trifluoromethyl-phenyl) -prop-2-ynyl] -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

9. A 5- [3-aryl-prop-2-ynyl] -5- (ar-ylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3- (4-chlorophenyl) ) -prop-2-ynyl] -5- (4-chlorobenzenesulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof,

10. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3- (4-bromophenyl) - prop-2-ynyl] -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof

11. A 5- [3-aryl-prop-2-ynyl] -5- (arylsulfo-nyl) thiazolidin-2,4-dione according to claim 1, characterized in that it is 5- [3-phenyl-propyl] 2-inyl] -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of hyperglycemia in a mammal, characterized in that the method comprises administering to a mammal in need thereof, a therapeutic dose of a compound of the formula: wherein Ar is phenyl, 2-naphthyl, phenyl substituted with alkyl, phenyl substituted with alkoxy, phenyl substituted with halogen, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2- pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo- [b] -furanyl, 2-thienyl, 2-benzo- [b] -thienyl; n is 0 or 2; and Ar 'is phenyl, phenyl substituted by alkyl, phenyl substituted by perfluoroalkyl, phenyl substituted by halogen, phenyl substituted by alkoxy, phenyl substituted by perfluoroalkoxy or phenyl substi tuted by alkylthio; or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, characterized in that: Ar is phenyl, phenyl substituted by alkyl, phenyl substituted by halogen, or 2-pyridinyl; n is 2; and Ar 1 is phenyl, phenyl substituted by halogen or phenyl substituted by perfluoroalkoxy; or a pharmaceutically acceptable salt thereof.

14. The method according to claim 12, characterized in that the compound is 5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

15. The method according to claim 12, characterized in that the compound is 5- [3- (4-fluorophenyl) -prop-2-ynyl] -5- (pyridin-2-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

16. The method according to claim 12, characterized in that the compound is 5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (4-fluorobenzenesulfonyl) -thiazolidin-2, 4- dione or a pharmaceutically acceptable salt thereof.

The method according to claim 12, characterized in that the compound is 5- (4-fluorobenzenesulfonyl) -5- [3- (4-fluorophenyl) -prop-2-ynyl] -thiazolidin-2, -dione or a pharmaceutically acceptable salt thereof.

18. The method according to claim 12, characterized in that the compound is 5-benzenesulfonyl-5- [3- (4-chlorophenyl) -prop-2-ynyl] -thiazo-lidin-2,4-dione or a pharmaceutically acceptable salt of the same.

19. The method according to claim 12, characterized in that the compound is 5-benzenesulfonyl-5- [3- (3,5-bis-trifluoromethyl-phenyl) -prop-2-ynyl] -thiazolidin-2,4-dione or a pharmaceutically acceptable salt thereof.

20. The method according to claim 12, characterized in that the compound is 5- [3- (4-chlorophenyl) -prop-2-ynyl] -5- (4-chlorobenzenesulfonyl) -thiazolidin-2,4-dione or a salt pharmaceutically acceptable thereof.

21. The method according to claim 12, characterized in that the compound is 5- [3- (4-bromophenyl) -prop-2-ynyl] -5- (toluene-4-sulfonyl) -thiazolidin-2, 4- dione or a pharmaceutically acceptable salt thereof.

22. The method according to claim 12, characterized in that the compound is 5- [3-phenyl-prop-2-ynyl] -5- (toluene-4-sulfonyl) -thiazolidin-2,4-dione or a pharmaceutically acceptable salt of the same .

23. A pharmaceutical composition for alleviating hyperglycemia in a mammal, characterized in that it comprises an amount that relieves hyperglycemia of a 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-dione or a 5- [3-aryl-prop-2-ynyl] -5- (arylsulfañyl) -thiazolidin-2,4-dione of the formula: wherein Ar is phenyl, 2-naphthyl, phenyl substituted with alkyl, phenyl substituted with alkoxy, phenyl substituted with halogen, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, -pyr imidinyl, 2-benzoxazolyl, 2-benzothiazolyl 2-benzimidazolyl, 2-furanyl, 2-benzo- [b] -furanyl, 2-thienyl, 2-benzo- [b] -thienyl; n is 0 or 2; and Ar 'is phenyl, phenyl substituted by alkyl, phenyl substituted by perfluoroalkyl, phenyl substituted by halogen, phenyl substituted by alkoxy, phenyl substituted by perfluoroalkoxy or phenyl substituted by alkylthio; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. SUMMARY OF THE INVENTION This invention relates to the new 5- [3-aryl-prop-2-ynyl] -5- (arylsulfonyl) -thiazolidin-2,4-diones and the 5- [3-aryl-prop-2-ynyl] - 5- (arylsulfañil) -tiazo-lidin-2, 4-diones, characterized by the general formula (I), wherein Ar is phenyl, 2-naphthyl, phenyl substituted with alkyl, phenyl substituted with alkoxy, phenyl substituted with halogen, 2-pyridinyl, 2-substituted pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl 2-benzimidazolyl, 2-furanyl, 2-benzo- [b] - furanyl, 2-thienyl, 2-benzo- [b] -thienyl; n is 0 or 2; and Ar 'is phenyl, phenyl substituted with alkyl, phenyl substi tuted with perfluoroalkyl, phenyl substituted by halogen, phenyl substituted by alkoxy, phenyl substituted by perfluoroalkoxy and phenyl substituted by alkylthio. (I) This invention also relates to the use of the aforementioned compounds for the decrease of blood glucose levels in hyperglycemic mammals and the pharmaceutical compositions containing them.