Derivative thiazolidinedione or their pharmaceutically acceptable salt, a method of treating hyperglycemia in a mammal, the pharmaceutical composition

 

(57) Abstract:

Derivative thiazolidinedione General formula I, where AG - phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy-substituted phenyl, galatarasay phenyl, 2-pyridinyl, methylseleninic 2-pyridinyl, 2-chinoline, 2-pyridinyl, 2-benzoxazolyl, halogen-substituted 2-benzothiazolyl; n = 0 or 2; AG' is phenyl, alkyl substituted phenyl, performancemanagement phenyl, halogen-substituted phenyl, alkoxysilanes phenyl, perftorgeksilsilanami phenyl or alkylthiomethyl phenyl; or their pharmaceutically acceptable salts possess protivogipergonichesky activity. Compounds according to this invention can be used as tools for the treatment of hyperlipidemia and complications of diabetes. 3 C. and 20 C.p. f-crystals, 3 tables.

This invention relates to new compounds with protivogipergonichesky activity. In particular, this invention relates to new 5-[3-allprop-2-inyl] -5-(arylsulfonyl) thiazolidine-2,4-dione and 5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-diones and their derivatives for lowering blood glucose in hyperglycemic mammals, which are used in the treatment of insulin-independent (type 2) diabetes mellitus, suppose the (type 2 diabetes) usually consists of a medical scheme nutrition and physical activity, taking oral hyperglycemic funds and, in more severe cases, insulin. Commonly used oral means are sulfonylureas and biguanides. Although sulfonylureas are valuable for the treatment of type 2 diabetes, which can cause bouts of hypoglycemia and demonstrate other toxic effects, which limit their application. They also have a tendency to high frequency of primary and secondary disorders of the effectiveness of their actions (failures compensation). Similarly, the use of biguanides is reduced because of their Association with incidents of toxic lactic acidosis. The continuous need for new hypoglycemic tools that could be less toxic and more effective, quite obvious.

5-[1 and 2-naphthalenyl)sulfonyl]-2,4-preparations of thiazolidinediones (Zask and Jirkovsky U.S. patent 4997948, 1991), 5-[1 and 2-naphthalenyl)thio]-2,4-preparations of thiazolidinediones (Zask and Jirkovsky U.S. patent 5068342, 1991) and 5-[arylsulfonyl]-2,4-preparations of thiazolidinediones (Zask et al, J. Med.Chem. 1990, 33, 1418-1423) were previously described as antidiabetics. Compounds according to this invention (1) are characterized in that they contain 5-[3-allprop-2-inyl] group. This last part enhances the antidiabetic efficacy of 5-ar the USA 4933367, 1990; Freund, et al. Arch. Pharmacol. 1989, 340 (suppl R40) Abstract 117; Obermaier-Kusser Biochem. J. 1989, 261, 699) was also described as an antidiabetic agent. Compounds according to this invention (1) are characterized in that they contain 2,4-thiazolidinedione ring instead of a carboxyl group A.

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Other publications claimed compounds that contain 2,4-thiazolidinedione ring and which also exhibit antidiabetic activity. These include ciglitazone (ciglitazone) (U.S. patent N 4461902; 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, J. Med.Chem. 1992, 35, 1853; Sohda, et al, J. Med.Chem. 1992, 35, 2671). None of 2,4-thiazolidinediones compounds of the above publications do not contain 5-(arylsulfonyl), 5-(arylsulfonyl) or 5-[3-allprop-2-inyl] group of compounds according to this invention.

Compounds in which the sulfur is attached at the 5-position of 2,4-thiazolidinedione rings, have been described (Japan Kokai 7840, 770; Japan Kokai 7846, 973; Microbiol. J. (Kyiv) 1970, 32, 518-520 (Ukr.); Ger.Offen.DE 3045059), but they differ from the compounds according to this invention that the nitrogen 2,4-thiazolidinedione ring substituted or a sulfur the new rings. In addition, these compounds are claimed as having only antiseptic properties, or as are antibiotics.

Description of the invention

This invention relates to new 5-[3-allprop-2-inyl]-5- (arylsulfonyl)thiazolidine-2,4-dione and 5-[3-allprop-2-inyl]-5- (arylsulfonyl)thiazolidine-2,4-diones of the formula (I). These compounds have protivogipergonichesky activity, which was demonstrated by their ability to lower the levels of plasma glucose in db/db (C57BLC/KsJ) mouse, and lower levels of plasma glucose and insulin levels in ob/ob (C57Bl/6J) mice. Both are models of insulin-independent (type 2) diabetes mellitus.

The compounds of this invention are characterized by the General formula (I) below, where Ar denotes phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, 2-pyridinyl substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-chinoline, 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; Ar' is phenyl, alkyl substituted phenyl, performancemanagement phenyl, halogen-substituted phenyl, alkoxy-substituted phenyl, perftorgeksilsilanami phenyl and albnia formula (I), where Ar denotes phenyl, alkyl substituted phenyl, halogen-substituted phenyl or 2-pyridinyl, n is equal to 2; and Ar' denotes phenyl, halogen-substituted phenyl and perftorgeksilsilanami phenyl.

The most preferred compounds of this invention include:

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(pyridine-2-sulfonyl)thiazolidine - 2,4-dione;

5-[3-(4-Forfinal)prop-2-inyl] -5-(pyridine-2-sulfonyl)thiazolidine - 2,4-dione;

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(4-permentantly)thiazolidin - 2,4-dione;

5-(4-Permentantly)-5-[3-(4-Forfinal)prop-2-inyl] thiazolidin - 2,4-dione;

5-Benzazolyl-5-[3-(4-chlorophenyl)prop-2-inyl]thiazolidin - 2,4-dione;

5-Benzazolyl-5-[3-(3,5-bis-triptoreline)prop - 2-inyl]thiazolidin-2,4-dione;

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(4-chlorobenzenesulfonyl)thiazolidin - 2,4-dione;

5-[3-(4-Bromophenyl)prop-2-inyl]-5-(toluene-4-sulfonyl)thiazolidine - 2,4-dione;

5-[3-Phenyl-prop-2-inyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione;

Compounds according to this invention can be obtained according to the methods described in the General schemes 1 through V, the first of which is presented below:

Scheme I

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In scheme I the corresponding commercially available arylthiol formula (II) is subjected to collaboration is alidin-2,4-dione (Zask et al. , J. Med.Chem., 1990, 33, 1418-1423), receiving 5-arylsulfonamides - 2,4-dione of the formula (III). The reaction is usually carried out in an aprotic solvent such as THF or hexane, using 2 or more equivalents of a strong base, metal amide, such as sitedisability or letibit(trimethylsilyl)amide at low temperatures (for example, from 0 to -78oC) followed by warming to ambient temperature or a higher temperature for 1 to 10 hours. Alternatively, the compound of formula (III) can be obtained in proton solvent such as water or a low molecular weight alcohol solvent. In those cases, when the reaction is carried out in such a way, arylthiol formula (I) is subjected to interaction with 2 or more equivalents of carbonate or bicarbonate of an alkali metal such as sodium carbonate or potassium bicarbonate, at 0oC to room temperature. Add one or more equivalents of 5-bromothiazole-2,4-dione and duration of response ranged from 1 to 2 days.

The compound of formula (III) can then be oxidized to obtain 5-arylsulfonamides-2,4-dione of formula (V). Following the methodology Zask et al., (J. Med.Chem. 1990, 33, 1418-1423), this oxidation is usually carried out using an excess (2 to the ment environment or higher (30oup to 80oC) for 1 to 10 hours. Alternatively, the desired oxidation can be effectively done by peroxymonosulfate potassium. Peroxymonosulfate potassium (KHSO5supplied commercially in the form of 2:1:1 complex with inert ingredients, potassium acid sulfate (KHSO4) and potassium sulfate (K2SO4). This complex supply under the trade name Oxon. The compound of formula (III) is dissolved in a low molecular weight alcohol solvent such as methanol, and added to aqueous solution Oksana that contains 2 or more equivalent active ingredient KHSO5. The reaction temperature can be varied from 0oC to 50oC and the duration of reaction can be varied from 30 minutes To 2 days. Another alternative, for the conversion of compounds of formula (III) in a compound of formula (V) can be used reagent adventurou acid, such as metalloregulatory acid. Two or more equivalent adventurou acid is used, preferably in halogenougljovodonika a solvent such as chloroform at ambient temperature over a period of time from 1 hour to several days.

The compound of formula (V) can also be obtained by vzaimodeistvie solvents for this transformation are polar aprotic solvents, such as DMF, THF and proton solvents such as low molecular weight alcohols or water. Alternatively, arylsulfonate alkali metal of the formula (IV) can be subjected to interaction with 5-bromothiazole-2,4-dione, using interphase catalyst Aliquat 336 (chloride of tricaprylate) according to the method of G. Baum, et al. (Synthesis 1987, 56-59).

Sulfinate alkali metal of the formula (IV) can be obtained by oxidation arylthiol formula (II) with 2 equivalents of aqueous hydrogen peroxide in the presence of alkali metal hydroxide such as sodium hydroxide, in water or in aqueous low molecular weight alcohol solvent. Arylsulfonate alkali metal of the formula (IV) can be obtained by recovery of arylsulfonamides formula (XI). This transformation is most conveniently done using the method Chew Lee and Lamar Field (Synthesis 1990, 391-397), according to which sulphonylchloride formula (XI) is subjected to interaction with two equivalents of p-thiocresol and two equivalents of triethylamine in dichloromethane at from -78oC to room temperature. Arylsulfonic acid obtained by treatment of aqueous acid, then subjected to the treatment with alkali metal hydroxide to obtain arylsulfonate alkaline metal forming agents in the presence of a base. These areas are the C-5 carbon atom of thiazolidinedione and the nitrogen atom of thiazolidinedione. The required area of the alkylation of the compounds of this invention is the C-5 carbon atom of the compound (V). In order to prevent potential competition alkylation at the nitrogen atom of the compound (V), the nitrogen atom can be protected with suitable protecting the alkylation group. Trail(triphenylmethane)the group performs the same function. Trailguru introduced by reacting the compounds of formula (V) with one molar equivalent of chloride triphenylmethane in the presence of one molar equivalent of a tertiary amine base, such as triethylamine, preferably in halogenosilanes solvent at 0oC or at ambient temperature.

Scheme II

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In scheme II (3-allprop-2-inyl) bromides of the formula (IX) can be obtained by using two-stage method from commercially available arisitide formula (VII). In the first stage, the compound of formula (VIII) are obtained by reacting the compounds of formula (VII) with one or more equivalents propargilovyh alcohol in the presence of catalytic amounts of palladium (II) reagent, such as dichlorobis(triphenylphosphine) palladium (II) and Colnago or more equivalents of a secondary or tertiary amine, such as diethylamine or triethylamine. Secondary or tertiary amine can be used as a solvent or may be used halogenosilanes solvent, such as chloroform. Usually use the reaction temperature in the range from ambient temperature up to 80oC; and the reaction times vary from 1 hour to 2 days. The compound of formula (IX) is most conveniently be obtained from the compounds of formula (VIII) by reacting (VIII) with 0.5 to one molar equivalent trichromate phosphorus in a dry ethereal solvent containing pyridine. This reaction is most conveniently carried out at a temperature in the range from 0oC to room during the period of time from 1 hour to 30 hours.

The compounds of formula (I) is then obtained by alkylation of compounds of formula (III), (V) or (VI) with compounds of the formula (IX).

With regard to scheme (III):

Scheme III

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Thiazolidindiones C-5 hydrogen compound (VI) is removed by the actions of one or more equivalents of base. Commonly used bases include alkali metal hydrides such as sodium hydride, alkali alkali metal, such as butyl lithium or amides of an alkali metal, such as sitedisability the room temperature. After deprotonization the compounds of formula (VI) impose a bromide of formula (IX) and the reaction mixture is typically stirred at 0oC or room temperature for from 1 to 48 hours, receiving compound of formula (X). Then the compound of formula (X) is treated with acid to remove triphenylmethanol protective group. Typical acids include one or more equivalents triperoxonane acid or formic acid. This acid can be used as solvent or usually used halogenosilanes solvent, such as dichloromethane. This reaction is conveniently carried out at 0oC or room temperature for periods of time ranging from 10 min to 2 hours.

In terms of scheme IV

Scheme IV

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5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-dione can be obtained by reacting the corresponding 5-(arylsulfonyl)thiazolidine-2,4-diones of the formula (III) with 2 or more equivalents of base. Two equivalent bases cause deprotonation of a nitrogen atom of thiazolidinedione, and at C-5 position with the formation of dianion. For the usual reason, which provide this deprotonation include alkali metal hydrides such as sodium hydride, alkali alkaline metals(trimethylsilyl)amide. Convenient solvents include THF to the base of the amides of the alkali metal and THF or DMF for reasons of alkali metal hydrides. Reaction temperatures range from -78oC to room temperature. After 2 minutes up to 1 hour after the introduction of base in the reaction mixture one or more equivalents of the appropriate (3-allprop-2-inyl) bromide of formula (IX) and the reaction mixture was stirred at 0oC or room temperature over a period of time from 1 hour to 3 days. Alkylation occurs exclusively on the C-5 carbon atom of thiazolidinedione to obtain 5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-dione of the formula (I).

In terms of scheme V:

Scheme V

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5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-dione can be obtained by reacting the corresponding 5-(arylsulfonyl)thiazolidine-2,4-diones of the formula (V) with 2 or more equivalents of base. Two equivalent bases cause deprotonation of a nitrogen atom of thiazolidinedione and C-5 position thiazolidinedione education dianion. The usual reason that perform this deprotonation are alkali metal hydrides such as sodium hydride, alkali alkali metal is bis(trimethylsilyl)amide. Convenient solvents include THF to the base of the amides of the alkali metal and THF or DMF for reasons of alkali metal hydrides. Reaction temperatures range from -78oC to room temperature. From 2 to 1 hour after the introduction of base in the reaction mixture one or more equivalents of the appropriate (3-allprop-2-inyl)bromide of formula (IX) and the reaction mixture was stirred at 0oC or room temperature over a period of time from 1 hour to 3 days. Alkylation occurs exclusively on the C-5 carbon atom of thiazolidinedione to obtain 5-[C-allprop-2-inyl]-5- (aryl-sulfonyl)thiazolidine-2,4-dione of the formula (I).

Compounds according to this invention can be obtained according to the method, which involves reacting a compound having the formula B

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where Ar and n are such as defined above, and R1denotes hydrogen or a removable protective group, with a compound having the formula C

R2-CH2-CCAr1(C)

where Ar is as defined above, and R2means tsepliaeva group in the presence of a base, to introduce the Deputy 3-allprop-2-inyl C-5 carbon atom of thiazolidinedione and when it is advisable to remove the specified deleted C is emnd salt. In the case when R1is hydrogen, the method can be performed, as described below in scheme IV or V. In this case, it should be noted that the base should be a strong base, i.e., strong enough to cause deprotonation at C-5 position thiazolidinedione ring, a nitrogen atom, thiazolidindiones rings. Another method of implementing the method of the invention involves reacting the compounds of formula B where R1denotes a protective group, with a compound having the formula C. This can be accomplished by the method described herein below, referring to scheme III. Getting 5-(arylsulfonyl)- 3-(triphenylmethyl)thiazolidin-2,4-diones (VI) used as described in scheme III can be carried out as described in scheme I. If the target compound must be of the formula I where n is 0, the method can be carried out using the compound having the formula (III) instead of the compound having the formula (V) in the reaction with triphenylmethylchloride in the presence of one molar equivalent of a base and using the obtained 5-(arylsulfonyl)-3-titillation-2,4-dione instead of the compounds of formula (VI).

The invention also includes a method of lowering blood glucose in hipel more compounds, described herein as effective for lowering blood glucose. This method can be considered as a method of treating hyperglycemia in a mammal, which includes an introduction to such mammal an effective amount of one or more compounds described herein as effective for lowering blood glucose. Mammal being treated, therefore, preferably is the man. Compounds according to this invention can also be used as a means for the treatment of hyperlipidemia and complications of diabetes (e.g., neuropathy, nephropathy, retinopathy, cataract). Compounds according to this invention, in order to improve efficiency, can also be used in combination with insulin, sulfonylureas, biguanides, inhibitors elderadostone and lipid-lowering drugs.

Doses of the compounds presented here will depend on the specific compounds and forms of administration. In addition, it will depend on the specific host to be treated. Usually the compounds according to this invention are introduced at the level of concentration, which provide a protective effect without any harmful side effects. For example, the effective amount is Ni or divided into two or four installments per week. The optimal dose for the individual subject to be treated, should be determined by the person responsible for treatment, and usually first designate smaller doses, and the subsequent increase in dosage are made to determine the most appropriate dosage.

This invention also covers pharmaceutical compositions, used for lowering blood glucose. Among them are compositions containing a mixture of one or more compounds described herein or pharmaceutically acceptable salts, and pharmaceutically acceptable carrier, the composition can be applied by the same techniques as connections.

Compounds according to this invention can form salts with suitable therapeutically acceptable inorganic and organic bases. These are obtained salts possess the same activity as related acid, and they are included in the scope of this invention. Suitable inorganic bases, forming salts include, for example, hydroxides, carbonates or bicarbonates therapeutically acceptable alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium, etc. To benzylideneamino), choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylpenicillin), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propandiol), procaine, etc. can also be mentioned Quaternary salts, for example, tetraalkyl (for example, tetramethyl), alkylamino (for example, methyltetra) and cyclic (for example, N,N'-dimethylmorpholine) ammonium salts. In principle, however, can be used all ammonium salts, if they are physiologically compatible.

Conversion into the corresponding salt is easily achieved by reacting the acid form of the compounds with an appropriate base, usually one equivalent, in a co-solvent. Salt produce by concentration to dryness or by adding not solvent. For example, in the case of the inorganic salts, it is preferable to dissolve the acid or the compound in water containing a hydroxide, carbonate, or bicarbonate corresponding to the desired inorganic salt. Evaporation of the solution or adding a miscible with water solvent more moderate polarity, for example, a lower alcohol, such as butanol, or lower Alcanena, such as ethylmethylketone, leads to the production of solid inorganic salts. In case the ethyl acetate or benzene. Evaporation of the solvent or adding a miscible solvent of lower polarity, such as benzene or n-hexane, yields a solid salt. Quaternary ammonium salts can be obtained by mixing acid compounds with a Quaternary ammonium hydroxide in aqueous solution with subsequent evaporation of the water.

Compounds according to this invention can clinically be introduced mammals, including humans, either oral or parenteral. In oral introduction may or introduction of one connection or in combination with solid or liquid pharmaceutically acceptable carrier or diluent such as starch, milk, sugar, certain types of clay, water, vegetable or mineral oils, and so forth, in the form of tablets, capsules, powders, syrups, solutions, suspensions, etc. For parenteral administration, the active compound can be used in combination with aqueous or organic media, with the formation of injectable solutions or suspensions. For example, solutions in sesame oil or oil of groundnuts, aqueous solutions and water-soluble pharmaceutically acceptable salts of the compounds. Injectable solutions obtained in this way can be introduced in the form of suppositories. The following non-limiting examples illustrate in more detail the invention.

Example 1

5-(Toluene-4-sulfonyl)thiazolidine-2,4-dione, (III)

To a solution of 5-bromothiazole-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 dry THF (200 ml) at -78oC is added dropwise letibit(trimethylsilyl)amide (1.0 M in hexane, 56 ml, 56 mmol). After 30 min the reaction mixture is heated to room temperature. An hour later added 2n HCl to pH 1. The layers separated, and the aqueous phase extracted with ethyl acetate (3 x 300 ml). The combined organic phase is dried (MgSO4), concentrated and subjected to flash chromatography (3:2 petroleum ether:ethyl acetate) to give the named compound as a white solid (4.4 g, 72%): so pl. 124-126oC; NMR (CDCl3): 8,08 (s, 1H, of 7.48 (d, J = 8.7 Hz, 2H, 7,18 (d, J = 8.7 Hz, 2H, 5,32 (s, 1H), MS (EI): 239 (MI, 90%), 196 (18%), 123 (100%).

Example 2

5-(Pyridine-2-sulfonyl)thiazolidine-2,4-dione, (III)

To a solution of 5-bromothiazole-2,4-dione (28,24 t, 0.144 mol) and 2-mercaptopyridine [(II) 16,00 g, 0.144 mol] in dry THF (200 ml) at -78oC is added dropwise letibit(trimethylsilyl)amide (1.0 M in hexane, 317 ml, MX 0.317 mol) over a period of about 40 minutes After 30 min the reaction mixture nagra with ethyl acetate (2 x 500 ml). The combined organic phase washed with water (500 ml), brine (500 ml), dried (MgSO4and concentrate, getting a named connection in the form of a green solid (30,45 g, 93%): so pl. 118-120oC; NMR (DMSO, d6): to 12.35 (s, 1H, 8,39 (d, J = 5.3 Hz, 1H, of 7.69 (DD, J = 7,3, 8,3 Hz, 1H, 7,42 (d, J = 8,3 Hz, 1H, 7,19 (DD, J = 5,3, 7,3 Hz, 1H, of 6.31 (s, 1H), MS (EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (C8H6N2O2S2): C, H, n

Using the procedure described in example 1, the compounds of formula (III), examples 3 and 4, is obtained from the corresponding arylmercury formula (II) and 5-bromothiazole-2,4-dione.

Example 3

5-(Quinoline-2-sulfonyl)thiazolidine-2,4-dione, (III)

2 hinokitiol: so pl. 227-229oC.

Example 4

5-(Naphthalene-2-sulfonyl)thiazolidine-2,4-dione, (III) (Known: Zask et al., J. Med.Chem. 1990, 33, 1418-1423).

Example 5

5-(4-Perpenicular)thiazolidin-2,4-dione, (III)

5-(Bromothiazole-2,4-dione (15.0 g, a 76.5 mmol) is added at 0oC to a mechanically stirred solution of 4-portifino [(II), 9,8 g, a 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 conc. HCl to pH 1 and filtered. The obtained solid is washed with water and petroleum APIs; NMR (DMSO,6): 12,14 (s, 1H, 7,66 (t, J = 8.0 Hz, 2H, 7,29 (t, J = 8.5 Hz, 2H, equal to 6.05 (s, 1H), MS (EI): 243 (MI, 100%), 200 (30%), 128 (60%), 127 (50%); Anal. (C9H6FNO2S2): C, H, n

Using the procedure described in example 5, the compounds of formula (III), examples 6-10, obtained from the corresponding arylmercury formula (II) and 5-bromothiazole-2,4-dione.

Example 6

5-(Benzazolyl)thiazolidin-2,4-dione, (III)

From thiophenol: so pl. 103-107,5oC.

Example 7

5-(4-Chlorophenylsulfonyl)thiazolidin-2,4-dione, (III)

4-chlorothiophenol: so pl. 109-110oC.

Example 8

5-(4-Brompheniramine)thiazolidin-2,4-dione, (III)

4-bromothiophene: so pl. 115-117oC.

Example 9

5-(4-Methoxybenzenesulfonyl)thiazolidin-2,4-dione, (III)

4-methoxythiophene: so pl. 89-91oC.

Example 10

5-(Toluene-3-sulfonyl)thiazolidine-2,4-dione, (III)

From m-thiocresol: so pl. is 61.5-64oC.

Example 11

5-(4-Perpenicular)thiazolidin-2,4-dione (V)

30% hydrogen peroxide (50,4 ml, 0,489 mol) is added dropwise within 1 hour and 20 min to a mechanically stirred solution of 5-(4-Perpenicular)thiazolidin-2,4-dione [(III) of example 5, 11.9 g, 48,9 mmol] in glacial acetic acid (457 ml) at 60oC. With the Ute between water and ethyl acetate. The ethyl acetate layer is dried (MgSO4and concentrate, getting a named connection in the form of a white solid (10,9 g, 81%): so pl. 190 - 196oC; NMR (DMSO, d6): 12,78 (sh.s, 1H, 8,00 (m, 2H, 7,58 (t, J = 8,9 Hz, 2H, 6,70 (s, 1H), MS (C): 276 (M+H, 100%); Anal. (C9H6FNO4S2): C, H, n

According to the method described in example 11, the compounds of formula (V), examples 12-14, obtained from the corresponding 5-(arylsulfonyl)thiazolidine-2,4-dione of the formula (III).

Example 12

5-(Toluene-4-sulfonyl)thiazolidine-2,4-dione (V)

Obtained from 5-(toluene-4 - sulfonyl)thiazolidine-2,4-dione, (III) example 1: so pl. 73-75oC.

Example 13

5-(Naphthalene-2-sulfonyl)thiazolidine-2,4-dione (V)

(Known: Zask et al., J. Med.Chem. 1990, 33, 1418-1423).

Example 14

5-(4-Chlorophenylsulfonyl)thiazolidin-2,4-dione (V)

Obtained from 5-(4-chlorophenylsulfonyl)thiazolidin-2,4-dione, (III) example 7: so pl. 143-144,5oC.

Example 15

5-(Benzazolyl)thiazolidin-2,4-dione (V)

A solution of 5-(benzazolyl)thiazolidin-2,4-dione, [(III), example 6, 10.0 g, 41,8 mmol] in methanol (105 ml) is added to a mechanically stirred suspension oxone (51,4 g, with 83.6 mmol) in water (210 ml) at 0oC. the Suspension is immediately warmed to room temperature. After 3.5 hours the reaction sauma, getting a named connection in the form of a white solid (8,31 g, 73%); so pl. 130-133oC; NMR (CDCl3): 8,07 (s, 1H, 7,98 (d, J = 7.2 Hz, 2H, 7,78 (t, J = 7.5 Hz, 1H, to 7.67 (t, J = 8,1 Hz, 2H, 5,44 (s, 1H), MS (EI): 225 (MI, 24%), 182 (18%), 153 (12%), 110 (100).

According to the method described in example 15, the compounds of formula (V), examples 16-18, obtained from the corresponding 5-(arylsulfonyl)thiazolidine-2,4-dione of the formula (III).

Example 16

5-(4-Brompheniramine)thiazolidin-2,4-dione (V)

Obtained from 5-(4-brompheniramine)thiazolidin-2,4-dione, (III) example 8: so pl. 156-158oC.

Example 17

5-(4-Methoxybenzenesulfonyl)thiazolidin-2,4-dione (V)

Obtained from 5-(4-methoxybenzenesulfonyl)thiazolidin-2,4-dione, (III) example 9: so pl. 93-95oC.

Example 18

5-(Toluene-3-sulfonyl)thiazolidine-2,4-dione (V)

Obtained from 5-(toluene)-3-sulfanyl)thiazolidin-2,4-dione, (III) example 10: so pl. 96-100oC.

Example 19

5-(Pyridine-2-sulfonyl)thiazolidine-2,4-dione (V)

m-Chlormadinone acid (25,7 g, 146 mmol) is added by portions over 30 min to a stirred suspension of 5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione [(III), example 2, 15.0 g, to 66.3 mmol] in chloroform (600 ml) at room temperature. After 18 hours, add another m-chlormadinone acid (4,65 t, 2 is Edom and the obtained solid (18.7 g) is filtered off. 10 tons, part of the obtained solid substance, purified using flash chromatography (9:1 CH2Cl2:acetonitrile) to give the named compound as a white solid (4,18 g, 46%): so pl. 129-131oC; NMR (DMSO, d6): 12,00 (sh.s, 1H, cent to 8.85 (d, J = 4.0 Hz, 1H, 8,23 (DD, J = 6,1, 7.9 Hz, 1H, 8,12 (d, J = 7.9 Hz, 1H, a 7.85 (DD, J = 4.0 a, 6,1 Hz, 1H, 6,79 (s, 1H), MS (Z): 258 (MI, 8%) 215 (55%), 123 (22%), 78 (100%).

Example 20

5-(Quinoline-2-sulfonyl)thiazolidine-2,4-dione (V)

30% aqueous hydrogen peroxide (to 10.7 ml, 104 mmol) is added dropwise to a stirred solution of 2-hinokitiol [(II), 8.0 g, 49,6 mmol] in 2.5% aqueous Paon (229 ml) and ethanol (229 ml). After 1 hour the reaction mixture was concentrated, obtaining a white, solid substance (a 8.34 g), which contains mainly sodium-2-naphthalenesulfonate (formula IV). 7,0 g portion of this compound (32.5 mmol), are added to a solution of 5-bromothiazole-2,4-dione (6,38 g, 32.5 mmol) in dry DMF (53 ml) and the resulting solution was stirred at room temperature for 4 hours. DMF is removed in vacuo and to the residue is added water (400 ml). The aqueous phase is extracted with ethyl acetate (2 x 400 ml) and the combined an ethyl acetate phase is dried (brine) and concentrated. The crude product subjected to flash chromatography (gradient 98:2 CH2Cl2: isopropanol), the,9 (Sch.with, 1H, cent to 8.85 (d, J = 8,8 Hz, 1H, 8,24 (d, J = 8,1 Hz, 1H, 8,16 (d, J = 8.7 Hz, 2H, 8,02 (DD, J = 6,9, 8,3 Hz, 1H, 7,89 (DD, J = 6,9, 8,1 Hz, 1H, to 6.95 (s, 1H), MS (EI): 308 (MI, 10%) 265 (8%), 145 (18%), 129 (100%), 128 (75%); Anal. C12H8N2O4S2: C, H, n

Example 21

[3-(4-chlorophenyl)prop-2-inyl]bromide, (IX)

A suspension of p-sadharana [formula (VII), 7,15 g, 30.0 mmol], propargilovyh alcohol (1.75 ml, 30 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.21 g, 0.3 mmol), copper iodide (I) (29 mg, 0.15 mmol) and diethylamine (50 ml) stirred in an atmosphere of N2at room temperature, and the dissolution occurs within 20 minutes After 5 hours, diethylamin removed and the crude product is distributed between water and ether. The ether phase is dried (brine), concentrated and subjected to flash chromatography (4:1 petroleum ether:ethyl acetate) to give 3-(4-chlorophenyl)prop-2-enal (compound of formula VIII, 4.09 g 82%). This compound of formula (VIII) (3,47 g, 20,83 mmol) is suspended in dry ether (12 ml) and added dropwise pyridine (0,42 ml). The reaction mixture is cooled in a bath of ice and added dropwise within 15 min add solution trichromate phosphorus (1.0 ml, 10,42 mmol) in dry ether (6 ml). The reaction mixture was then stirred at room temperature for 2.5 hours, cooled in a bath with ice and added to saturated aqueous NaHCO3and a salt solution. The extract was concentrated and subjected to flash chromatography (9:1 petroleum ether: ethyl acetate) to give product as a white solid (3,38 g, 86%): so pl. 41-43oC; NMR (CDCl3); 7,37 (d, J = 8.7 Hz, 2H, 7,27 (d, J = 8.7 Hz, 2H, 4,16 (s, 2H, CH2).

According to the method described in example 21, the compounds of formula (IX), examples 22-23, obtained from the corresponding commercially available arriagada formula (VII) or commercially available C-allprop-2-inala formula (VIII).

Example 22

[3-Bensultap-2-inyl]bromide, (IX)

Derived from C-bensultap-2-inola, (VIII): oil, NMR (CDCl3): the 7.43 (m, 2H, 7,33 (m, 3H, 4,16 (s, 3H, CH2).< / BR>
Example 23 [3-[4-(Forfinal)]prop-2-inyl]bromide, (IX)

Obtained from p-periodontol, (VII): oil, MS (EI): 2,12 (MI, 8%), 214 (MI, 8%), 133 (100%).

Example 24

[3-[4-(Were)]prop-2-inyl]bromide, (IX)

Obtained from p-metallobeta, (VII): oil, MS (EI): 208 (MI, 8%), 210 (MI, 8%), 129 (100%).

Example 25

[3-[4-(Triptoreline)]prop-2-inyl]bromide, (IX)

Obtained from p-iodine(trifluoromethyl)benzene, (VII): oil; NMR (CDCl3): EUR 7.57 (d, J = 8.6 Hz, 2H, 7,52 (d, J = 8.6 Hz, 2H, 4,13 (s, 3H,

Example 26

[3-[4-(Bromophenyl)]prop-2-inyl]bromide, (IX)

Obtained from p-bromobenzoyl, (VII): so pl. 50-51oC.

Example 27
Hz, 2H, 6,83 (d, J = 8,8 Hz, 2H, 4,16 (s, 3H, of 3.80 (s, 3H,

Example 28

[3-[4-(trifloromethyl)]prop-2-inyl]bromide, (IX)

Obtained from p-triftormetilfullerenov, (VII): oil; NMR (DMSO d6): 7,58 (d, J = 8,8 Hz, 2H, 7,37 (d, J = 8,8 Hz, 2H, 4,49 (s, 3H,

Example 29

[3-[3-(Chlorophenyl)]prop-2-inyl]bromide, (IX)

Obtained from m-chlorodibenzo, (VII): oil; NMR (CDCl3): 7,44 (s, 1H, 7,32 (m, 2H, 7,28 (m, 2H, 4,14 (s, 2H,

Example 30. [3-[2-(Chlorophenyl)]prop-2-inyl]bromide, (IX)

Derived from o-chlorodibenzo, (VII): oil; NMR (CDCl3): of 7.48 (DD, J = 1,9, 7,3 Hz, 1H, 7,40 (DD, J = 1.5 and 8.1 Hz, 1H, 7,25 (m, 2H, 4,21 (c, 2H,

Example 31 [3-(3,5-Bis(trifluoromethyl)phenyl)prop-2-inyl]bromide, (IX)

Obtained from 3-(3,5-bis(trifluoromethyl)phenyl)prop-2-inola, (VIII): so pl. 30-31oC.

Example 32

[3-[4- (Were)prop-2-inyl]bromide, (IX)

Obtained from p-attianese, (VII): oil; NMR (DMSO d6): of 7.36 (d, J = 8,3 Hz, 2H, 7,22 (d, J = 8,3 Hz, 2H, 4,48 (s, 2H,

Example 33

[3-(3,5-Bis(fluoro)phenyl)prop-2-inyl]bromide, (IX)

Obtained from 3,4-diversamente, (VII): oil; MS (EI): 231 (MI, 16%), 233 (MI, 16%), 151 (100%).

Example 34

N-(Triphenylmethyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione, (VI)

Triphenylmethylchloride (2.67 g, 9,58 mmol) are added to stir at room temperature solution of 5-(toluene-4-sulfonyl)thiazolidine-2,4-t water (300 ml) and the organics extracted with ethyl acetate (2 x 200 ml). The combined extracts are dried (brine, MgSO4), concentrated and purified using flash chromatography (4: 1 petroleum ether:ethyl acetate) to give the named compound as a white solid (1.1 g, 45%): so pl. 105-110oC; NMR (CDCl3): a 7.85 (d, J = 8,3 Hz, 2H, of 7.48 (d, J = 8,1 Hz, 6H, 7,38 (d, J = 8,3 Hz, 2H, of 7.23 (m, 9H, 5,13 (s, 1H, of 2.46 (s, 3H,

Example 35

N-(Triphenylmethyl)-5-[3-(4-chlorophenyl)prop-2-inyl] -5-(toluene-4 - sulfonyl)thiazolidine-2,4-dione, (X)

Sodium hydride (80% dispersion in mineral oil, 93 mg, 3.10 mmol) are added to a solution of N-(triphenylmethyl)-5-(toluene-4 - sulfonyl)thiazolidine-2,4-dione [(VI), from example 34, 1.06 g, 2,07 mmol] in dry DMF (9 ml) at 0oC in an atmosphere of dry N2. After 20 minutes add [3-(4-chlorophenyl)prop-2-inyl] bromide [(IX), from example 21, 0.52 g, and 2.27 mmol] and the reaction mixture stirred for further 20 min at 0oC. Add saturated NH4Cl (60 ml) and then water (60 ml). After stirring for 10 min, the solid is filtered off, washed with water and ground to powder with petroleum ether, obtaining a named connection in the form of dry gray solids (1,16 g, 90%): so pl. 221-223oC; NMR (CDCl3): 7,80 (d, J = 8,2 Hz, 2H, 7,45 (d, J = 7.5 Hz, 6H, to 7.35(d, J = 8,2 Hz, 2H, 7,14 (m, 11H, 6,98 (d, J = 8.5 Hz, 2H, 3,29 (d, J = 16,7 Hz, 1H, 3,12 (d, J = 16.7 G is everysunday acid (0,32 ml, 4.07 mmol) is added at room temperature to a stirred suspension of N-(triphenylmethyl)-5-[3-(4-chlorophenyl)prop-2-inyl]-5-(toluene - 4-sulfonyl)thiazolidine-2,4-dione [(X) from example 35, 1.29 g, 1.94 mmol] in CH2Cl2(2 ml). The dissolution occurs instantly. After 1 hour the reaction mixture was added to water (200 ml) and extracted with ethyl acetate (200 ml). An ethyl acetate phase is washed with water and brine and then concentrated. The crude product was then purified using flash chromatography (95: 5 CH2Cl2:isopropanol) and then ground to powder in petroleum ether, obtaining a named connection in the form of not-quite-white solid (0.52 g, 64%): so pl. 172-174oC; NMR (CDCl3): 8,00 (s, 1H, a 7.85 (d, J = 8,3 Hz, 2H, 7,41 (d, J = 8,3 Hz, 2H, 7,26 (s, 4H, of 3.65 (d, J = 17,1 Hz, 1H, of 3.33 (d, J = 17,1 Hz, 1H, 2.49 USD (C, MN, MS (CI); 420 (M+H, 58%), 422 (M+H, 24%), 265 (40%), 267 (26%), 157 (100%);

Anal. Est. For C19H14ClNO4S2: C, 54,35; H, TO 3.36; N, 3,36;

Found: C, 54,74; H, 3,54; N, 2,98.

Example 37

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(toluene-4-sulfonyl)-thiazolidine - 2,4-dione, (I)

Sodium hydride (80% dispersion in mineral oil, 0,63 g, 21.1 mmol) are added to a solution of 5-(toluene-4-sulfonyl)thiazolidine - 2,4-dione [(III), example 1, about 1.75 g, 8,44 mmol] in dry THF (9 ml) at 0oC in the atmosphere is eh] in dry THF for 30 minutes After 2.5 hours, the reaction mixture was concentrated and add dilute aqueous HCl (85 ml). The organics extracted with ethyl acetate (2 85 ml) and the extracts dried (brine), concentrated and purified using flash chromatography (98: 2 CH2Cl2: isopropanol and ground to powder in petroleum ether, obtaining a named connection (1,25 g, 38%): so pl. 108-109oC; NMR (DMSO, d6): 12,27 (c, 1H, 7,46 (d, J = 8.5 Hz, 2H, 7,39 (d, J = 8.7 Hz, 1H, 7,27 (d, J = 7.9 Hz, 1H, 3,48 (d, J = 17.3 Hz, 1H, 3,32 (d, J = 17.3 Hz, 1H, of 2.34 (s, 3H), MS (EI); 387 (MI, 5%), 389 (2%), 124 (85%), 91 (100%);

Anal. Est. for C19H14ClNO2S2: C, 58,21; H, OF 3.53; N, OF 3.77;

Found: C, 58,02; H, To 3.58; N, 3,52.

Using the procedure described in example 37, the compounds of formula (I), examples 38-41, obtained from the corresponding 5-arylsulfonamides-2,4-dione of the formula (III) and the corresponding (C-allprop-2-inyl)bromide of formula (IX).

Example 38

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-benzosulfimide - 2,4-dione, (I)

Puchen of 5-(benzazolyl)thiazolidin-2,4-dione of the formula (III), example 6 and [3-(4-chlorophenyl)prop-2-inyl] bromide of formula (IX), from example 21, pl. 87-88oC;

Anal. Est. for C18H12ClNO2S2: C, 57,83; H, 3,24; N, 3,75;

Found: C, 58,05; H, Of 3.07; N, 3,62.

Example 39

5-[3-(alidin-2,4-dione of the formula (III), example 5 [3-(4-chlorophenyl)prop-2-inyl]bromide of formula (IX), from example 21, pl. 116-117oC;

Anal. Est. for C18H11ClFNO2S2: C, 55,17; H, AND 2.83; N, 3,57;

Found: C, 54,58; H, To 2.65; N, 3,39.

Example 40

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(pyridine-2 - sulfonyl)thiazolidine-2,4-dione, (I)

Puchen of 5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione (III), example 2 [3-(4-chlorophenyl)prop-2-inyl] bromide of formula (IX), from example 21, pl. 124-125oC;

Anal. Est. for C17H11ClNO2S2: C, 54,47; H, 2,96; N, 7,47;

Found: C, 54,49; H, 2,86; N, 7,14.

Example 41

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(quinoline-2-sulfonyl)thiazolidine - 2,4-dione, (I)

Puchen of 5-(quinoline-2-sulfonyl)thiazolidine-2,4-dione (III), example 3 [3-(4 - chlorophenyl)prop-2-inyl] bromide of formula (IX), from example 21, pl. 163-165oC;

Anal. Est. for C21H13ClN2O2S2: C 58,04; H, A 3.06; N, 6,40;

Found: C, 57,98; H, 2,84; N, 6,15.

Example 42

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(4-permentantly)thiazolidin - 2,4-dione, (I)

Sodium hydride (80% dispersion in mineral oil, 0.55 g, 18.2 mmol) are added to a solution of 5-(4-perpenicular)thiazolidin-2,4-dione [(V), from example 11, 2.0 g, 7,27 mmol] in dry THF (12 ml) at 0oC in an atmosphere of dry N2 is billaut for 25 minutes. After 20 hours, the reaction mixture was concentrated and add dilute HCl solution (100 ml). The organics extracted with ethyl acetate (3 x 100 ml) and the extracts dried (brine), concentrated and purified using flash chromatography (97: 3 CH2Cl2:methanol) and ground to powder with petroleum ether, obtaining a named connection in the form of a white solid (0,99 g, 32%): so pl. 176-177oC; NMR (DMSO, d6): 13,0 (sh. s, 1H, 8,02 (m, 1H, ArH to 7.59 (t, J = 8,9 Hz, 1H, 7,45 (d, J = 8.5 Hz, 1H, 7,35 (d, J = 8.5 Hz, 1H, 3,66 (d, J = 17.5 Hz, 1H, 3,50 (d, J = 17.3 Hz, 1H), MS (-DCl); 422 (M-I, 22%), 424 (M-H, 16%), 263 (100%), 265 (40%);

Anal. Est. for C18H11ClFNO4S2: C 51,01; H, 2,62; N, 3,30;

Found: C, 51,08; H, To 2.55; N, 2,97.

Example 43

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(pyridine-2-sulfonyl)thiazolidine - 2,4-dione, (I)

Sodium hydride (80% dispersion in mineral oil, 0.32 g, the 10.8 mmol) are added to a solution of 5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione [(V) of example 19, 1.1 g, 4.30 mmol] in dry THF (7.5 ml) at 0oC in an atmosphere of dry N2. After 10 minutes add a solution of [3-(4-chlorophenyl)prop-2-inyl]bromide [(IX), from example 21, 0,99 g, 4.30 mmol] in dry THF (7.5 ml) for 30 minutes After 27 hours at room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl (20 ml), add purified using flash chromatography (gradient: 97:3 to 88: 12 CH2Cl2:methanol) to give the named compound as a yellow solid (0,63 g, 36%): so pl. 140-141oC; NMR (DMSO, d6): 13,2 (sh.s, 1H, 8,82 (DD, J = 0,6, 4.0 Hz, 1H, PyrH), 8,23 (TD, J = l,6, 7,8 Hz, 1H, 8,15 (d, J = 7.9 Hz, 1H, 7,87 (DDD, J = 1,1, 5,3, 7.7 Hz, 1H, 7,45 (d, J = 8.5 Hz, 1H, Ar H to 7.35 (d, J = 8.5 Hz, 1H, Ar H 3,88 (d, J = and 17.2 Hz, 1H, 3,74 (d, J = and 17.2 Hz, 1H, MC (+DCI); 407 (M+H, 50%), 409 (M+H, 24%), 264 (80%), 266 (36%), 144 (100%);

Anal. Est. for C17H11ClN2O4S2: C, 50,18; H, 2,72; N, 6,88;

Found: C, 50,07; H, To 2.67; N, 6,57.

According to the method described in example 43, a compound of formula (I), examples 44-85, obtained from the corresponding 5-arylsulfonamides-2,4-dione of formula (V) and the corresponding (3-allprop-2-inyl)bromide of formula (IX) (see tab. 1).

Example 86

5-(6-Methylpyridin-2-sulfane)thiazolidin-2,4-dione, (III)

This compound is obtained from 5-bromothiazole-2,4-dione and 2-methyl-6-mercaptopyridine (A. D. 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: so pl. 114-115oC.

Example 87

5-(Pyrimidine-2-sulfonyl)thiazolidine-2,4-dione, (III)

This compound is obtained from 5-bromothiazole-2,4-dione and 2-mercaptopyrimidine according to the method described in example 1: MS (EI): 227 (MI, 5%), 184 (15%), 80 (100%).

Example 88

5-(5-Chlorobenzotriazol-2-ilself is iatola according to the method described in example 5: so pl. 253-255 (decomp.).

Example 89

5-(Benzoxazol-2-ylsulphonyl)thiazolidin-2,4-dione, (III)

This compound is obtained from 5-bromothiazole-2,4-dione and 2 - mercaptobenzoxazole according to the method described in example 5: so pl. 241 to 243 (decomp.).

Example 90

5-(6-Methylpyridin-2-sulfonyl)thiazolidine-2,4-dione (V)

This compound is obtained from 5-bromothiazole-2,4-dione and 2-methyl-mercaptopyridine (A. D. 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 20, pl. 129-130 (decomp.).

Example 91

5-[3-(4-Chlorophenyl prop-2-inyl] -5-(4-chlorophenylsulfonyl)thiazolidin - 2,4-dione, (I)

N-Utility (2.5 M in hexane, to 12.3 ml, 30,8 mmol) are added to a solution of 5-(4-chlorophenylsulfonyl)thiazolidin-2,4-dione [(III) of example 7, 4.0 g, to 15.4 mmol] in dry THF (195 ml) at 78oC in an atmosphere of dry N2within 40 minutes. After 30 min, a solution of [3-(4-chlorophenyl)prop-2-inyl]bromide [(IX), from example 21, of 3.53 g of 15.5 mmol] in dry THF (65 ml) is added over 12 minutes After 10 min, reaction mixture was allow to warm to room temperature. After 2 hours, the reaction mixture is transferred into a saturated aqueous ammonium chloride (1 l) and extracted with ethyl acetate (800 ml). The extracts are dried (brine), the end of the s in the form of a white solid (2.58 g, 41%), pl. 144-146oC; NMR (DMSO, d6): 12,37 (s, 1H, to 7.59 (d, J = 8.5 Hz, 2H, ArH), 7,56 (d, J = 8.7 Hz, 2H, 7,46 (d, J = 8.5 Hz, 2H, 7,40 (d, J = 8,3 Hz, 2H, 3,52 (d, J = l7,3 Hz, 1H, 3,35 (d, J = 17.3 Hz, 1H), MS (EI): 407, 409, 411 (MI, 5%), 364, 366 (8%), 264 (30%), 193 (40%), 149 (100%), 143 (20%);

Anal. Est. for C18H11Cl2NO2S2: C 52,95; H, 2,72; N, 3.43 POINTS;

Found: C, 52,95; H, 2,87; N, 3,29.

Using the procedure described in example 91, the compounds of formula (I), examples 92-95, obtained from the corresponding 5-arylsulfonamides-2,4-dione of the formula (III) and [3-(4-chlorophenyl)prop-2-inyl]bromide of formula (IX), example 21.

Example 92

5-(5-Chlorobenzotriazol-2-ylsulphonyl)-5-[3-(4-chlorophenyl)prop-2 - inyl]thiazolidin-2,4-dione, (I)

Obtained from 5-(5-chlorobenzotriazol-2-ylsulphonyl)thiazolidin-2,4-dione, (III), example 88, and [3-(4-chlorophenyl)prop-2-inyl]bromide of formula (IX), example 21: so pl. 187-188oC;

Anal. Est. for C19H10Cl2N2O2S3: C 49,04; H, 2,17; N, 6,02;

Found: C, 48,94; H, 2,31; N, 6,21.

Example 93

5-(Benzoxazol-2-ylsulphonyl)-5-[3-(4-chlorophenyl)prop-2-inyl] thiazolidin - 2,4-dione, (I)

Obtained from 5-(benzoxazol-2-ylsulphonyl)thiazolidin-2,4-dione, (III), example 89, and [3-(4-chlorophenyl)prop-2-inyl]bromide of formula (IX), example 21: so pl. 137-139oC;

Anal. Est. for C19Hlorgeril)prop-2-inyl]-5-(6-methyl-pyridine-2 - sulfonyl)thiazolidine-2,4-dione, (I)

Obtained from 5-(6-methyl-pyridine-2-sulfonyl)thiazolidine-2,4-dione, (III), example 86, and [3-(4-chlorophenyl)prop-2-inyl]bromide of formula (IX), example 21: so pl. 147-148oC;

Anal. Est. for C18H13ClN2O2S2: C, 55,59; H, 3,37; N, 7,20;

Found: C, 55,52; H, And 3.31; N, 7,02.

Example 95

5-[3-(4-Chlorophenyl)prop-2-inyl] -5-(pyrimidine-2-sulfonyl)thiazolidine - 2,4-dione, (I)

Obtained from 5-(pyrimidine-2-sulfonyl)thiazolidine-2,4-dione, (III), example 87, and [3-(4-chlorophenyl)prop-2-inyl] bromide of formula (IX), example 21: so pl. 118-120oC;

Anal. Est. for C16H10ClN3O2S2: C, 51,13; H, 2,68; N, 11,18;

Found: C, 51,27; H, At 2.93; N, 10,82.

Example 96

5-[3-(4-Chlorophenyl)prop-2-inyl]-5-(6-methyl-pyridine-2 - sulfonyl)thiazolidine-2,4-dione, (I)

N-Utility (2.5 M in hexane, 2,77 ml, 6,93 mmol) are added to a solution of 5-(6-methyl-pyridine-sulfonyl)thiazolidine-2,4-dione [(V), from example 90, 0,92 g, to 3.38 mmol] in dry THF (30 ml) at 78oC in an atmosphere of dry N2within twenty minutes. A solution of [3-(4-chlorophenyl)prop-2-inyl]bromide [(IX), from example 21, of 3.53 g of 15.4 mmol] in dry THF (10 ml) added dropwise within 20 minutes. The reaction mixture allow to warm to room temperature. After 16 hours, the reaction mixture is transferred into saturated the solution), concentrated and purified using flash chromatography (gradient: 97:3 to 93:7 CH2Cl2:isopropanol) to give a sticky solid, which fray with petroleum ether (990 ml):benzene (2 ml) to give the named compound in the form of not-quite-white solid (0.55 g, 39%): so pl. 104-106oC; NMR (DMSO, d6): 13,1 (sh.s, 1H, 8,10 (t, J = 7.8 Hz, 1H, pyH), 7,95 (d, J = 7.7 Hz, 1H, 7,71 (d, J = 7.7 Hz, 1H, 7,45 (d, J = 8,8 Hz, 2H, 7,35 (d, J = 8.7 Hz, 2H, 3,86 (d, J = 17,4 Hz, 1H, and 3.72 (d, J = 17,4 Hz, 1H, to 2.57 (s, 3H), MS (EI): 420 (MI, 3%), 265 (12%), 263 (38%), 194 (25%), 192 (70%), 149 (40%), 93 (100%);

Anal. Est. for C18H13ClN2O4S2: C, 51,37; H, 3,11; N, 6,66;

Found: C, 50,99; H, Was 3.05; N, 6,58.

Example 97

5-[3-(3,5-Bis(trifluoromethyl)phenyl)prop-2-inyl] -5-(pyridine-2 - sulfonyl)thiazolidine-2,4-dione, (I)

According to the method described in example 43, this compound is obtained from 5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione of formula (V), example 19, and [3-(3,5-bis(trifluoromethyl)phenylprop-2-inyl] bromide of formula (IX), example 31: so pl. 150-152oC: NMR (DMSO, d6): 8,79 (d, J = 4.4 Hz, 1H, pyH), 8,16 (dt, J = 1,6, 7.9 Hz, 1H, 8,11 (s, 1H, with 8.05 (d, J = 7.9 Hz, 1H, 7,94 (s, 2H, 7,9 (DD, J = 4,9, 7,3 Hz, 1H, a 3.87 (d, J = and 17.2 Hz, 1H, 3,71 (d, J = and 17.2 Hz, 1H), MS (CI): 509 (MI+1, 100%) 367 (32%), 366 (352%), 287 (35%), 194 (25%), 194 (20%);

Anal. Est. for C19H10F6M2O4S2: C 44,98; H, 1,98; N )

A solution of p-thiocresol (4.94 g, 39.8 mmol), triethylamine (5,55 ml, 39.8 mmol) in dichloromethane (30 ml) is added dropwise over 12 minutes to a solution of 2,3-dichlorothiophene-5-sulfonyl chloride (5.0 g, to 19.9 mmol) in dichloromethane (50 ml) at -78oC in dry nitrogen atmosphere. Add another 10 ml of dichloromethane and the reaction mixture stirred at -78oC for 2 hours and then warmed to room temperature for 20 minutes. The reaction mixture was poured into water (400 ml) and the layers separated. The dichloromethane phase is washed with water (2 x 200 ml) and the combined phase acidified with concentrated HCl. Solid NaCl is added to the aqueous phase, which is then extracted with simple ether (4 x 200 ml). The extracts are combined and dried (Na2SO4and concentrate, receiving 2,3-dichlorothiophene-5-sulinowo acid as a white solid (2,89 g, 67%): NMR (DMSO, d6): 9,1 (sh.s, 1H, 7,54 (s, 1H, thiophene MS (EI): 216, 218, 220, (70, 50, 10%, MI), 199, 201, 203 (60, 50, 10%, -HE), 169 (50%), 167 (70%), 154 (70%), 152 (100%). This sulinowo acid (2,33 g of 10.73 mmol) dissolved in sodium hydroxide solution (0,42 g of 10.73 mmol) in methanol (25 ml) at room temperature. The methanol is removed and the residual water is removed by distillation in the form of an azeotrope with benzene, receiving 2,3-dichlorothiophene-5-sulinowo acid, nutrie the C4HCl2O2S2: C 20,09; H, 0,41; Found: C, 19,80; H, 0,52. This sulinowo acid, sodium salt of formula (IV), (2,12 g, 8,87 mmol) is mixed with 5-bromo-thiazolidine-2,4-dione (1,58 g of 8.06 mmol) and Aliquat 336 (chloride of tricaprylate, 0.45 ml) and incubated over night. Add dilute aqueous HCl (100 ml) and the aqueous reaction mixture is extracted with ethyl acetate (2 x 100 ml). The combined extracts washed with brine and concentrated. The crude product was then purified using flash chromatography, using acid washed (2% H3PO4in methanol) silica gel and as eluent a mixture of 82:18 ethyl acetate:petroleum ether, getting named the compound of formula (V) in the form of a white solid: so pl. 176-177oC: NMR (DMSO, d6): 13,0 (sh.s, 1H, 8,10 (s, 1H, thiophene 6,85 (s, 1H), MS (EI): 331, 333, 335, (30, 20, 5%, MI), 215, 217, 219 (100, 70, 15%).

Anal. Est. for C7H3Cl2NO4S3: C, 23,51; H, 0,91, N, 4,22;

Found: C, 25,83; H, 1.00 M, N, 4,23.

Example 99

5-[3-(4-Chlorophenyl)prop-2-inyl]-5-(2,3-dichlorothiophene-5 - sulfonyl)thiazolidine-2,4-dione, (I)

According to the method described in example 96, this compound is obtained from 5-(2,3-dichlorothiophene-5-sulfonyl)thiazolidine-2,4-dione of formula (V), example 98, and 3-(4-chlorophenyl)prop-2-inyl] bromide forms = of 17.4 Hz, 1H, 3,52 (d, J = 17,4 Hz, 1H), MS (-FAB): 478, 480 (10%, 10%, M-H, 297 (30%), 148 (100%);

Anal. Est. for C16H8Cl3NO4S3: C 39,97; H, 1,68; N, 2.91 IN;

Found: C, 40,30; H, 1,97; N, 2,95.

PHARMACOLOGY

The activity of compounds of this invention in lowering the level of glucose in the blood is demonstrated in experiments using diabetic (db/db) mice.

db/db (C57BL/KsJ) mouse exhibits many metabolicheskie abnormalities associated with insulin-independent diabetes (type II) in humans. Animals are obese, intolerant to glucose and hyperglycemia in the fasting, which is sometimes accompanied by a paradoxical hyperinsulinemia. In addition, db/db mice may develop some of the late complications associated with diabetes. [See Coleman Diabetes, 31 (Suppl. l), 1 (1992)]. Despite these similarities (commonalities), emergency introduction of the sulfonylureas (even in extremely high doses) may not reduce hyperglycemia in db/db mice [see Tutwiler et al, Diabetes 27, 856, (1978). The ability of some other hyperglycemic tools to be effective for this kind of confirms that these other tools have mechanisms of action that is different from the mechanism of action of the sulfonylureas [ibid; Lee et al is effective in a population of diabetic patients type II, who do not respond to sulfonylurea therapy. The following are the experiments, which is the illustration of the above, after the next General techniques relevant to these experiments. On the morning of day 1 of 35 mice [male db/db (C57BL/KsJ), Jackson Laboratories, age from 2 to 7 months and weighing from 35 to 60 g] were subjected to starvation for 4 hours, weighed and selected baseline blood sample from the tail of each mouse without anesthesia, were placed directly in fluoride containing test tube, mixed and placed on ice. Then the mouse was fed. Plasma was separated and determined the levels of glucose in plasma using the Abbott VP Analyzer. Because of the variability of the levels of plasma glucose in db/db mice, 5 mice with small extrema (i.e., highest or lowest) levels of glucose in the plasma was removed and the remaining 30 mice were randomly divided into 7 groups equivalent to the average levels of plasma glucose:

Group A - filler-control N=6

Group B - positive control (ciglitazone) - N = 4

Group C - 1st test drug - N=4

Group D - 2nd test drug - N=4

Group E - 7 3rd test drug - N=4

Group F - 4th test drug is the preserver or the test drug was administered (p. o.. R. O.) fattened up, desire (ad libitum), mice. The positive control, ciglitazone[()-5-[4-[(1-methylcyclohexyl]methoxy] benzyl] thiazolidin-2,4-dione] see Fujita et al. Diabetes, 32, 804 (1983), was administered via a stomach tube at a dose of 100 mg/kg/day. The test compounds were administered via a stomach tube at a dose of 100 mg/kg/day unless otherwise stated in the table.

On the morning of day 4, the mice were weighed and subjected to starvation, but water was available on request (ad libitum). Three hours later, took a blood sample and then mice were subjected to the fourth administration of a medicinal product or filler. Neinstitucionalnih mice were again collected blood samples after 2 or 4 hours after administration of the drug. Separated plasma and determined the levels of glucose in plasma using the Abbott VP Analyzer.

For each mouse the percentage change in the level of glucose in plasma on day 4 (mean of the samples for 2 - and 4-hours) from its corresponding level before the introduction of drugs (basic sample on day 1) was defined as follows:

< / BR>
Analysis of variance, following multiple comparison (one-way) Donate (Dunnett''s multiple comparison (one-side), is used to establish the degree of static values of differences between group nasledstvo considered active if you enter a specific dose, if the difference in the level of glucose in plasma is p<0,05.

Analysis of the results presented in table. 2 shows that the compounds of this invention are suitable as protivogipergonichesky funds because they lower the levels of blood glucose 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 ciglitazone at 100 mg/kg

The activity of compounds of this invention in lowering the blood glucose is demonstrated in trials on diabetic (ob/ob) mice.

Insulin-independent diabetes (NIDDM) syndrome can usually be features such as the STU. In genetically obese-hyperglycemic ob/ob mouse can manifest many of these metabolicheskikh anomalies and, as I believe, this mouse is a useful model for investigation of hypoglycemic agents that treat NIDDM. [Coleman, D.: Diabetologia 14: 141-148, 1978]. The following are the experiments, which is the illustration of the above, after bringing the following General techniques relevant to these experiments.

In each study mice [male or female ob/ob (C57BI/6J) mice and their lean litermates (ob/+ or +/+, Jackson Laboratories), aged 2 to 5 months (from 10 to 65 g)] of similar age are statistically distributed over the body weight into 4 groups of 10 mice. Mice are placed in a cage for 5 pieces and incubated with normal diet for rodents with water (ad libitum). Mice receive daily through a stomach tube connection (suspended in 0.5 ml of 0.5% methylcellulose); dissolved in drinking water or mixed into food. The dose given to compounds ranged from 2.5 to 200 mg/kg body weight/day. The dose is calculated taking into account the fatted weekly body weight and expressed as the active part. The positive control, ciglitazone (5-(4-(1-methylcyclohexyl-methoxy)benzyl-2,4-dione, see Chang, A. , Wyse, B. , Gilchrist, B. , Peyerson, T., and Diani, A. Diabetes 32: the Shi receive only filler.

On the morning of day 4, 7 or 14 take two drops of blood (approximately 50 l (ul) containing sodium fluoride tubes or from the tail vein or after decapitate. In these studies, in which the compound is administered daily by means of a gastric probe, blood samples taken two hours after the introduction of the connection.

Plasma is separated by centrifugation and the concentration of glucose determined enzymatically on the Abbott VP Analyzer.

For each mouse, the percentage change of glucose in plasma on days 4, 7 or 14 was calculated relative to the mean values of glucose in the plasma of mice treated filler. Analysis of variance, following test comparison (one-tail) Dunnet (Dunett''s Comparison Test (one-tailed) was used to establish meaningful (significant) differences between the values of plasma glucose for the control group and groups treated individual connection (CMS SAS Realease 5.18). The connection should be considered active if the difference is p<0,05.

Compounds according to the invention can be successfully enter animals in the form of a simple composition on the basis of 2% tween 80 (Polysorbate 80) in physiological solution.

Compounds according to the invention can be administered in the form of conventional tablets, capsules, syrup, etc.

Standard tablets 300 mg can be obtained as follows.

Ingredients - a tablet

Active connection 300 mg

Polyvinylpyrrolidone - 22,5 mg

Lactose - 61,75 mg

Alcohol 3D3A - 200 degrees - 4,5 ml

Stearic acid 9 mg

Talc - 13.5 mg

Corn starch - 43,25 mg

These tablets are produced by mixing the active compounds, polyvinylpyrrolidone, lactose and rubbing through a sieve of 40 mesh. Then add the alcohol and the mixture is kneaded until such time as the wet weight will not pass through the sieve 4 mesh. The wet mass is dried and the dried granules are rubbed through a sieve of 20 mesh. Stearic acid, talc and cornstarch rubbed through a sieve of 60 mesh and thoroughly mixed with the granulate. The final mixture is pressed into tablets using standard concave punch with pressure 7/16 pounds.

Similarly, you can use for the introduction and regular syrups for oral administration to onewingedangel.

Ingredients per 1000 ml

Cocoa 180 grams

Sucrose - 600 g

Liquid glucose is 180 g

Glycerol 50 ml

Sodium chloride 2 g

Vanilla - 0.2 g

Sodium benzoate - 1 g

Purified water to 1000 ml

This syrup is produced by mixing sucrose and cocoa and the gradual addition of a mixture of liquid glucose, glycerine, sodium chloride, vanillin and sodium benzoate in 325 ml of hot purified water. The whole mixture boil for 3 minutes, allow to cool to room temperature and mixed with water, taken in an amount necessary to achieve the volume of syrup in 1000 ml. In this basic syrup can be made active compound at the desired concentration.

1. Derivative thiazolidinedione General formula I

< / BR>
where Ar is phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, 2-pyridinyl, methylseleninic 2-pyridinyl, 2-chinoline, 2-pyrimidinyl, 2-benzoxazolyl, halogen-substituted 2-benzothiazolyl, 2-benzothiazolyl;

n = 0 or 2;

Ar' is phenyl, alkyl substituted phenyl, performancemanagement phenyl, halogen-substituted phenyl, alkoxy-substituted phenyl, perftorgeksilsilanami phenyl or alkylthiomethyl phenyl;

or their pharmaceutically acceptable salts is gensomaden phenyl or 2-pyridinyl;

n = 2;

Ar' represents phenyl, halogen-substituted phenyl or perftorgeksilsilanami phenyl;

or its pharmaceutically acceptable salt.

3. Derived thiazolidinedione under item 1, which is 5-[3-(4-chlorophenyl) prop-2-inyl] -5-(pyridine-2-sulfonyl) thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

4. Derived thiazolidinedione under item 1, which is 5-[3-(4-forfinal)prop-2-inyl]-5-(pyridine-2-sulfonyl) thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

5. Derived thiazolidinedione under item 1, which is 5-[3-(4-chlorophenyl) prop-2-inyl] -5-(4-permentantly)thiazoline-2,4-dione or its pharmaceutically acceptable salt.

6. Derived thiazolidinedione under item 1, which is 5-(4-permentantly)-5-[3-(4-forfinal) prop-2-inyl] thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

7. Derived thiazolidinedione under item 1, which is 5-[3-(4-chlorophenyl)prop-2-inyl] thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

8. Derived thiazolidinedione under item 1, which is 5-[3-(3,5-bistrifluormethylbenzene)prop-2-inyl]thiazolidin-2,4-dione or its FA-[3-(4-chlorophenyl)prop-2-inyl] -5-(4-chlorobenzenesulfonyl)thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

10. Derived thiazolidinedione under item 1, which is 5-[3-(4-bromophenyl) prop-2-inyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

11. Derived thiazolidinedione under item 1, which is 5-[3-phenylprop-2-inyl] -5-(toluene-4-sulfonyl)thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

12. A method of treating hyperglycemia in a mammal comprising administration to the mammal of a therapeutic dose of the compounds of formula

< / BR>
where Ar is phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, 2-pyridinyl, methylseleninic 2-pyridinyl, 2-chinoline, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl;

n = 0 or 2;

Ar' is phenyl, alkyl substituted phenyl, performancemanagement phenyl, halogen-substituted phenyl, alkoxy-substituted phenyl, perftorgeksilsilanami phenyl or alkylthiomethyl phenyl;

or its pharmaceutically acceptable salt.

13. The method according to p. 12,

where Ar is phenyl, alkyl substituted phenyl, halogen-substituted phenyl or 2-pyridinyl;

n = 2;

Ar' represents phenyl, halogen-substituted phenyl or perftorgeksilsilanami phenyl;

or farmaceuticas-5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

15. The method according to p. 12, where the compound is 5-[3-(4-forfinal)prop-2-inyl] -5-(pyridine-2-sulfonyl)thiazolidine-2,4-dione or its pharmaceutically acceptable salt.

16. The method according to p. 12, where the compound is 5-[3-(4-chlorophenyl) prop-2-inyl] -5-(4-permentantly) thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

17. The method according to p. 12, where the compound is 5-(4-permentantly) 5-[3-(4-forfinal) prop-2-inyl] -thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

18. The method according to p. 12, where the compound is a 5-benzazolyl-5-[3-(4-chlorophenyl)prop-2-inyl]-thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

19. The method according to p. 12, where the compound is a 5-benzazolyl-5-[3-(3,5-bis-triptoreline)prop-2-inyl] thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

20. The method according to p. 12, where the compound is 5-[3-(4-chlorophenyl)prop-2-inyl] -5-(4-chlorobenzenesulfonyl)thiazolidin-2,4-dione or its pharmaceutically acceptable salt.

21. The method according to p. 12, where the compound is 5-[3-(4-bromophenyl)prop-2-inyl] -5-(toluene-4-sulfonyl) thiazolidine-2,4-dione or its pharmaceutically acceptable salsolidine-2,4-dione or its pharmaceutically acceptable salt.

23. Pharmaceutical composition for the reduction of hyperglycemia in a mammal, characterized in that it comprises an effective amount of 5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-dione and 5-[3-allprop-2-inyl] -5-(arylsulfonyl)thiazolidine-2,4-dione under item 1 or their pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

 

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< / BR>
in which R1denotes a group R6-SO2-NR7-; R6-NR7-SO2-; R6-SO2-O-; R6-O-SO2-;

R2denotes a hydrogen atom or halogen, cyano, alkyl, CNS or halogenation group;

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R6denotes alkyl, cycloalkyl, aryl, heteroaryl, aracelio or heteroallyl group, with aryl or heteroaryl group with one or
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