The method of obtaining derivatives of thiazolidinone or its pharmaceutically acceptable salt

 

(57) Abstract:

Usage: in medicine as anti-inflammatory drugs. The inventive product f-ly 1, where R - C2-C6alkenyl, C2-C6- quinil or a group of f-crystals 2, where n is an integer of 0 to 3, including both extreme values; R2- H, C1-C6- alkyl, C1-C6- alkoxy, C2-C6alkenyl, C2-C6-alkyl - group, f-crystals, 3 or 4, where n is specified above. R3- N or C1-C6- alkyl; R4and R5- H or together form a bond; R6and R7each H or together form a group S, or one of the radicals R6and R7- N, and the other group HE or SCH; X - group, f-crystals 5, m is 0,1 or 2; and Q NR8where R8-H, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, -SO2CH3or -(CH2)n-Y, where n is specified above, and Y is cyano, OR9-C(O)R10-NR11R12C1-C4-alkyl or a group of f-crystals 6, where R9N or C1-C4- alkyl, or a group-C(O) C1-C4- alkyl, R10- C1-C4- alkyl, C1-C4- alkoxy, or-NH2R11and R12independently from each other - H, C2-C6alkenyl; C2-C6- alcu>)q-S(C1-C4) or group f-ly 7 described above, and an integer 1 to 6, including both extreme values: R11and R12together form morpholino, piperidine, piperazinilnom or N-methyl-piperazinilnom ring; or its pharmaceutically acceptable salt. Reagent 1: compound f-ly 8. Reagent 2: compound f-ly 9. Connection f-crystals 1 to 9, respectively. F-La 1 f-La 2: f-La 3: f-La 4: f-La 5: f-La 6: f-La 7: f-La 8: f-La 9: 1 table.

The invention relates to methods of producing derivatives of thiazolidinone formula II:

in which R1represents a C2-C6alkenyl,2-C6quinil or group (CH2)n-S, where n is an integer in the range 0-3, including extreme values of the interval;

R2represents hydrogen, C1-C6alkyl, C1-C6alkoxy,

WITH2-C6alkenyl,2-C6quinil,1-C4-alkyl-O-

-CC1-C alkyl or-CH-S where n is an integer in the range 0-3, including both extreme values;

R3represents hydrogen or C1-C6alkyl;

R4and R5represents hydrogen or together form a bond;

R<
R6and R7represents hydrogen and the other group-OH or SCH3;

X is a group where m is 0,1 or 2, and

Q represents NR8where R8represents hydrogen, C1-C6alkyl, C2-C6alkenyl,3-C8cycloalkyl, SO2CH3or -(CH2)n-Y; where n is an integer in the range 0-3, including both extreme values, and

Y represents cyano, OR9, -R10< / BR>
-NR11TO12S-(C1WITH4) alkyl or a group

O-C1-C4alkyl where R9represents hydrogen, C1-C4alkyl or the group --C1-C4-alkyl

R10represents a C1-C4alkyl, C1-C4alkoxy, or-NH2< / BR>
R11and R12independently of one another represent hydrogen, C2-C6alkenyl,2-C6quinil,1-C6alkyl, (CH2)qOH, -(CH2)q-N(C1-C4alkyl)2,

-(CH2)q-S(C1-C4alkyl) or

-(CH2in which n has the value; q is an integer in the range of 1-6, including both extreme values; or R11and R12summations acceptable salt, characterized in that exercise: the reaction of the compound of the formula

HO-R3with the compound of the formula

in which R1, R2, R3and X have the above values, Q represents N-R8(where R8has the specified values), and R6and R7together form a group S, with the aim of obtaining the compounds of formula

in which R1, R2, R3, R6, R7, X and Q have the above meanings;

(a) with subsequent optional recovery of the compounds of formula II in which R6and R7together form a group S in order to obtain the compound of formula II in which R6and R7represents hydrogen;

(C) recovering the compounds of formula II in which R4and R5together form a connection with the purpose of obtaining compounds of formula II in which R4and R5represent hydrogen;

(C) recovering the compounds of formula II in which R4and R5together form a bond, and R6and R7together form a group=S to obtain the compounds of formula II in which R4, R5, R6and R7represent hydrogen;

(d) alkylation of compounds of formula II in which R3predstavlyaeti, WITH2-C6alkenyl,3-C6cycloalkyl or -(CH2)n-Y (where n is an integer in the range 0-3, including extreme values, and Y represents cyano, OR9,-SH, -S(C1-C4alkyl)-NR11R12or

O-C1-C4alkyl, where R9,R11and R12have the listed meanings: (e) atilirovanie the compounds of formula II in which R8represents a hydrogen in order to obtain the compounds of formula II in which R8represents -(CH2)n-Y, where n is an integer in the range 0-3, including both extreme values of the interval, and Y represents-R10where R10has the specified values;

(f) oxidation of compounds of formula II in which X represents a group in which m is 0, to obtain the compounds of formula II in which X represents a group -, m is 1;

(K) the recovery of the compounds of formula II in which R3represents a group -(CH2)n-Y where n has values in the range 0-3, including extreme values of the interval, Y is a OR9where R9represents a group --C1-C4alkyl order to obtain the compounds of formula II, in which the is a OR9where R9represents hydrogen;

(l) the reaction of compounds of formula II in which R8represents a group -(CH2)n-Y, where n is 0-3, including both extreme values of the interval, Y is-OR9where R9represents hydrogen, tosylchloramide, with the aim of obtaining the compounds of formula II in which R8represents -(CH2)n-Y, where n is 0-3, including both extreme values of the interval, and Y is a OR9where R9is tosyl;

(m) the reaction of compounds of formula II in which R8represents -(CH2)n-Y-, in which n is 0-3, including both extreme values, and Y is-OR9where R9toil, with an amine of the formula HNR11R12(where R11and R12have the specified values), with the aim of obtaining the compounds of formula II in which R8represents a group -(CH2)n-Y, where n is 0-3, including both extreme values, and Y represents NR11, R12;

(n) heating the compounds of formula II in which R8represents -(CH2)n-Y, and Y represents NR11R12(R11, R12no water is>represents -(CH2)n-Y, Y represents NR11R12where R11, R12one hydrogen and the other is not hydrogen.

(a) reaction of compounds of formula II in which R6and R7represents hydrogen, with triperoxonane anhydride with obtaining the compounds of formula II in which one of the radicals R6and R7represents hydrogen and the other is a group-OH;

(b) the formation of salts of the compounds of formula II by reaction mesolevel norms in connection with a strong acid or a strong base.

Compounds according to the invention and the compounds used in the method according to the invention, in which R4and R5represent hydrogen contain an asymmetric center at the carbon atom in position 5 of rhodanine or its derivative. In this regard, such compounds can exist as racemic mixtures or as individual stereoisomers. The method and compounds of the invention encompass both the racemate and its individual stereoisomers. The method according to the invention provides a method of obtaining stereoisomers of some compounds of the invention, as well as some of the compounds used in the method of the invention.

Compounds and method of jinene formula I with a strong base, as sodium hydroxide or a strong acid like hydrochloric acid.

Compounds according to the invention includes the following substances: 5-[[3,5-bis(4-pentyl)-4-hydroxyphenyl] -methyl] -3-ethylamino-4-thiazolidinone; 5-[[3-ethylthiophene-4-hydroxy-5-were] methylene] -2-thioxo-4-thiazolidinone; 5-[[3-(2-butene)-4-hydroxy-5-isopropoxyphenyl] -methyl]-3-(2-propenyl)-4-hydro XI-5-[[3,5-(methylthiophenyl))-4-hydroxyphenyl] methylene] -3-propyl-2-thioxo-4-t solidin-[[3,5-diacetyl-4-hydroxyphenyl] methyl] -4-thiazolidinone; 5-[[3-(3-methyl-1-butene)-4-hydroxy-5-propylphenyl] -methylene] -3-atilano-4-thia zole-[[3-(2-propenyl)-4-hydroxy-5-methoxyphenyl] methyl] -3-ethoxy-4-thiazoline h; 5-[[3,5-di-2-propenyl)-4-hydroxyphenyl]methylene]-3-(methylamino-methyl)-2-TIX-4-

The following compounds in addition to these are examples of substances suitable for use in the method of the invention. 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-(3-methoxypropyl)-2 - thio-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methylene] -2-thioxo-4-thiazole Denon; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methylene] -4-thiazolidinone; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methyl] -4-thiazolidinone; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methyl] -2-thioxo-4-thiazolidinone 3-acetyl-5-[[3,5-bis(1,1-dimeler)AMI but] -5-[4-hydroxybenzyl] rodann; 5-(4-hydroxy-3-methoxybenzylidene)rodann,5-[(4-hydroxy-3,5-DIPROPYLENE)m ethene]-3-[2-(dimethylamino)ethyl] -4-thiazolidinone; 5-[[3,5-bis(1-methylpropyl)-4-hydroxyphenyl]methyl]-3-methyl-4-thiazolidone; 5-[[3,5-dimethyl-4-hydroxyphenyl]-methylene] -3-methyl-4-thiazolidinone; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl] -3-(methylsulphonyl)-4-Ty atomidine; 5-[[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl] methyl] -3-(propylamino)-4-thiazole, idine; 3-amino-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methylene] -2-thioxo-4-t Azol-[[3,5-bis(1-methylethyl)-4-hydroxyphenyl] -methyl] -3-methyl-4-thiazolidinone; 5-[(4-hydroxy-3,5-acid)methyl] -3-methyl-2-thioxo-4-thiazolidinone; 5-[(4-hydroxy-3,5-acid)methylene] -3-methyl-2-thioxo-4-thiazolidinone. 5-[[3,5-bis(1,1-Dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-thiazolidine n (which in the subsequent service referred to as compound A). This connection get the reaction of 3,5-di-tert-butyl-4-hydroxybenzaldehyde with Rodnina at the temperature of reflux distilled in ice to acetic acid using a catalyst of fused sodium acetate. 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-thiazolidinone-connec tion), 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone (connection) and 5-[[-3,5-bi is A.

So, for example, by subjecting compound And the catalytic hydrogenation can be obtained as the connection and the connection C. the resulting ratio depends on temperature, pressure and duration of the hydrogenation, the type of solvent and the nature of the used catalyst. For example, in the case where the compound a is treated with 5% palladium on coal in ethanol medium at 100aboutC for 18 h, the ratio between the compounds b and C is 60:40. On the other hand, such a transformation can be realized by heating the compound in a mixture of hydrochloric acid and alcohol, as ethanol in the presence of zinc. Restoring tion without affecting benzyl double bond can be carried out by heating thione in the presence of a reducing agent such as a hydride tri-n-butyl tin in the environment such as directionspanel solvent like toluene and preferably in the presence of a free radical initiator such as azobisisobutyronitrile. However, to implement such recovery should be used N-substituted Rodnikovy substrate (i.e., Q can be-NH).

Transformation connection And D can be done in different ways, investigate-3,5-pyridinecarboxylic in the presence of silica gel. The reaction is conveniently carried out in the presence of such directionspanel solvent, as benzene or toluene, preferably in an inert atmosphere. The reaction can be performed at a temperature in the range from 25aboutWith up to the temperature of reflux distilled mixture. When the preferred temperature is about 80aboutSince the reaction is finished after 12-18 hours

In a similar way, depending on the purpose of different substituents, can be obtained from other thiazolidinone. For example, the compounds of formula II in which Q represents NR8and R8represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl or -(CH2)n-Y, where n is an integer in the range 0-3, including extreme values, and Y represents a cyano or NR11and R12where R11and R12independently from each other represent hydrogen or C1-C6alkyl, can be obtained according to the method of Tuber with TCS. as described above, using the appropriate N-substituted of Rodnina and R1, R2-substituted-4-hydroxybenzaldehyde. On the other hand rodann can be used for condensation with the aldehyde with the formation of such compounds in which Q pushim R8containing halide, such as and Odin or bromide, to obtain the corresponding N-substituted derivatives of such compounds of formula II in which R8represents a C1-C6alkyl, C2-C6alkenyl,3-C8cycloalkyl, or -(CH2)n-Y, where Y represents cyano, OR9, S -)1-C4alkyl), -NR11R12or group O-C1-C4- alkyl and n, R9, R11and R12have the meanings specified for formula II. The alkylation is usually carried out in an environment of such inert solvent like tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of such strong bases like sodium hydride. Similarly, rodann can be used for condensation with the aldehyde to form compounds in which Q represents NR8and R8represents hydrogen, followed by acylation relevant R8containing a halide of obtaining N-substituted derivatives of the formula II in which R8represents (CH2)n-Y, and Y is-R10where n and R10have the meanings specified for formula I.

The compounds of formula II in which Q represents the Teal or tosyl; R11and R12have the meanings specified for formula (I) may be obtained according to the following reaction scheme

< / BR>
Hydroxyalkyl rodann III is obtained by condensation of carbon disulphide, Chloroacetic acid and the corresponding hydroxyethylamine standard ways. By condensation with the appropriate R1, R2-substituted 4-hydroxybenzaldehyde, as described above, the resulting product is a condensed 2-thioxo-4-thiazolidinone IV, which is transformed into acetyl derivative. Thioxo connection can be optionally converted into a methylene compound of the formula Y as described above. Acetyl group of the intermediate of Y can be removed as a result of processing an aqueous solution of ammonia in a solvent such as acetonitrile, to obtain compound VI (i.e., the compounds of formula II in which a represents NR8and R8represents -(CH2)n-Y, where Y is a OR9and R9hydrogen). Then hydroxy compound VI in turn derived Totila (VII) as a result of processing p-toluensulfonyl chloride in the environment of pyridine, preferably at a temperature of about 0aboutC. ZAT is key corresponding HNR11R12an amine, in which R11and R12have the values listed in the previous paragraph. The last transformation is conveniently made by the reaction of compound VII in the presence of molar excess of amine. And in this case, for the realization of this transformation use such a solvent as acetonitrile.

The compounds of formula II in which Q represents NR8, R8represents -(CH2)n-Y (n=0) and Y represents NR11R12where R11and R12have the meanings indicated in formula II can be obtained according to the following reaction scheme

< / BR>
R11substituted hydrazine treated with benzaldehyde in an alcohol (preferably methanol) solvent with formation of an intermediate of compound X, which, in turn, reacts with the corresponding R12the halide in the presence of triethylamine and acetonitrile with the formation of intermediate compounds XI. Then, compound XI is treated with hydrazine to obtain R11, R12hydrazine XII. On the other hand XII can be obtained by restoring the nitroso-R11R12-amine using zinc dust and acetic acid or aluminum and strong OS is otci with sodium nitrite in the environment Hcl. Then, compound XII is treated with carbon disulfide, Chloroacetic acid and triethylamine to obtain intermediate compound XIII. The condensation of compound XIII with the corresponding R1,R2substituted 4-hydroxybenzaldehyde (i.e. AgSnO) get the connection XIV. As noted previously tion can be recovered by processing such a regenerating agent, as the hydride is tri-n-butyl tin in this directionspanel solvent like toluene, preferably in the presence of such free-radical initiator, as azobis-isobutyronitrile. The formation of compounds in which the radicals R11and R12represents hydrogen, can be carried out before or after recovery thione as a result of heating disubstituted compounds in a mixture of ethanol-water in the presence of such a catalyst as rhodium.

The compound of formula II in which X is equal to I or 2 can be easily obtained from sulfide (i.e., m 0) by processing such an oxidizing agent as m-derbentina acid in the environment appropriate organic solvent, such as chloroform, in a period of time sufficient to allow the desired oxidation.

The compounds of formula I of the divide-Qualification relevant R1, R2-substituted phenol, followed by condensation with Rodnina or desired N-zameshannym Rodnina, as described above, or used in accordance with the specified in other reaction schemes described in the text.

The person skilled in the art should be understood that the aryl fragment compounds of the formula II is available from the substance or can be easily obtained with known methods from available starting materials. For example, p-hydroxybenzaldehyde can be preaccelerated in the conditions of the Friedel-obtaining alkylbenzenes, which in turn can be proaccelerin. Similarly, the source rodann or N-substituted rodann is an available connection or can be obtained by well known methods from commercially available starting materials.

The compounds of formula II in which one of the radicals R6or R7represents hydrogen and the other is OH and X is a group where m is 0, is usually produced from their precursors of the formula II in which R6and R7represent hydrogen and X represents a group in which m is 1, by processing predestiny is a) at low temperature. Similarly, the compounds of formula II, in which the definition of Q Y represents cyano, receive processing nationalaverage analogue of the desired halogen-substituted aliphatic nitrile. From cyanoderivatives get tetrazolyl by treatment with azide three-N. butyl tin in the environment, for example, dimethyl ether of ethylene glycol. Other compounds of formula II can be obtained, in accordance with a more complete explanation below of the compounds, the synthesis of which is described above.

The method and compounds of the invention encompass both the racemate and its individual stereoisomers. Typically, the stereoisomers can be obtained in accordance with methods well known from the literature. However, for compounds of formula II in which X is a-S-; R4and R5represents hydrogen; and R1, R2, R3, R6, R7and Q have the meanings specified for such formulas, individual stereoisomers can be isolated in almost pure isomeric form in accordance with the new method described below. The following method is preferred compounds, isomers which can be selected are those compounds of formula II in which X, not only is and Q have the values specified for the preferred somewhat preferred, more preferred, particularly preferred and most preferred compounds of the invention.Racemic sulfide compound of formula 11 is reacted with a reagent obtained by combining tartrate ligand, an alkoxide of titanium, hydroperoxide and, optionally, water. The alkoxides of titanium, held for use in the present method can serve as the titanium alkoxides of the formula Ti (C1-C4alkoxy)4. Particularly preferred titanium alkoxide is an alkoxide, in which1-C4alkoxy group represents isopropoxy. Similarly, suitable tartrate ligands for use in the present method include di(C1-C4alkyl) tartratami, and especially preferred are diethyltartrate or diisopropylate. Finally, suitable hydroperoxides, which can be used in this way include cumene hydroperoxide, tert-butylhydroperoxide, etc. are Particularly preferred hydroperoxide is tert-butylhydroperoxide.

This reaction is performed by mixing these chemicals in the environment and so Inal p. such halogenated alkanes as methylene chloride, 1,2-dichloroethane, chloroform, etc., such esters as tetrahydrofuran, diethyl ether, etc., ketones such as acetone, etc., Particularly preferred inert solvent is methylene chloride. Typically, the amount of solvent should be sufficient to ensure that all compounds remained in solution during the reaction. However, you should avoid using excessive amounts of solvent, since the selection of the product may be undesirable losses.

The amount of titanium alkoxide used in this reaction is not critical. The titanium alkoxide may be used in amounts of 0.4 to 2.0 equivalents relative to the original racemic sulfide. For the reasons explained in detail below, the titanium alkoxide is preferably used in quantities sufficient to achieve a ratio of the titanium alkoxide (sulfide substrate, lying in the interval 0,5/1,0-0,75/1,0. If the titanium alkoxide used in amounts lower than equimolar relative to the sulfide source material, if desirable, can be added molecular sieves 3 or 4 in order to avoid deactivation by Chichester alkoxide of titanium and also not decisive. Usually tartrate ligand is used in quantities sufficient to achieve a ratio tartrate ligand/titanium alkoxide, lying in the interval 1/1-5/1, preferably the ratio is 2/1. Similarly, the amount of hydroperoxide can be from one to two equimolar amounts relative to the titanium alkoxide. The used amount of water can vary in the range from anhydrous reaction conditions (i.e. no equivalentof water) to 5 equivalents of water relative to the amount present of the titanium alkoxide. When using anhydrous reaction conditions, tartrate ligand should be used in a quantity sufficient to achieve a ratio tartrate ligand/titanium alkoxide corresponding to the upper value of the above interval ratios tartrate ligand/titanium alkoxide. Stereochemistry tartrate ligand determines the nature of the stereoisomer that will be obtained from racemic sulfide substrate. For example, if in this reaction using (+) diisopropylate, it will be highlighted in almost pure isomeric form (-) enantiomer of the original sulphide material. Accordingly, if Ishii with this, tartrate ligand must be chosen so that its stereochemistry was the opposite stereochemistry of the desired isomeric form.

Racemic sulfide substrate of the present method is reacted with a reagent derived from the alkoxide of titanium, tartrate ligand, hydroperoxide and, optionally, water until virtually all of the unwanted enantiomer sulfide source material doesn't turn in his sulfoxides similar. The conversion of the sulfoxide is carried out at a temperature lying in the range of (-50)-(+50)aboutC, and the preferred temperature is -20aboutC. After virtually all unwanted enantiomer turned in his sulfoxides similar, the reaction being removed by rapid cooling VLSI in accordance with well known methods.

To ensure the transformation of almost all unwanted enantiomer in sulfoxide, while minimizing the conversion of the desired enantiomer, only 50-70% of the racemic substrate must react with a reagent containing a titanium alkoxide. Restriction reactions 50-70% can be carried out at least in two ways. First, the hydroperoxide may be used in quantities which provide aspect] is icestar above 0.75 equivalents relative to the sulfide substrate under the condition track the progress of the reaction using standard analytical techniques, for example, thin-layer chromatography (TLC) or liquid chromatography high resolution (NRS).

If such equipment is installed, which turned out 50-70% of the sulfide starting material, the reaction is stopped to prevent further conversion.

After termination of the reaction the unreacted portion of the sulfide substrate can be isolated from the cooled reaction mixture by methods well known in the art. Such unreacted part will consist of the desired enantiomer in almost pure enantiomeric form.

The following additional examples illustrate the formation of compounds according to the invention as well as compounds used in the method of the invention. These examples also illustrate how the selective extraction of enantiomers provided by the invention. These examples are merely illustrative and do not limit in any way the scope of the invention.

P R I m e R 1. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-thiazolidine n (compound A).

In nitrogen atmosphere 117-2 g of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde, 66.6 g of rhodanine and 143.5 grams of fused sodium acetate were heated was gladly in was poured into a mixture of 1 l of ethanol and 1 l of ice with stirring. Was added water (500 ml) and after stirring for 30 minutes the resulting precipitate was isolated by filtration. The solid is suspended with 500 ml of ethyl acetate and filtered. The precipitate was dissolved in 3 l of ethanol was heated to boiling and added water to maintain the turbidity of the solution (approximately 450 ml of water). During cooling to room temperature to 99.6 g of the target product was isolated by filtration, so pl. approximately 260aboutC.

Calculated With 61,86; N 6,83; N 4,01.

WITH18H23NO2S2:

Found, 62,13; N 6,55; N 4,15.

P R I m e R s 2-3. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene] -4-thiazolidinone (compound) and 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone (connection).

The solution 69,90 g of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene] -2-thioxo-4-thiazolidin it in 4 l of ethanol was first made at a pressure of 500 lb. /in2in the presence of 200 g of 5% palladium on coal during the night when 100aboutC. the Reaction mixture was filtered evaporated to dryness. The resulting material was sequentially dissolved in 1 volume of hot ethyl acetate, diluted with 2 volumes of hexane, filtered and loaded into a chromatographic column filled with silica gel. By elution with 35% of ETHYLACETYLENE. The chromatography was allocated to 4.6 g of compound C. the Fractions containing mainly compound, recrystallized from the ethyl acetate/hexane, receiving In connection with the common output 13,79, repeated chromatography fractions containing the contaminated compound With the silica, when the elution of 25% solution of ethyl acetate in hexane, got 9,82 g of compound C. 2,5-[[3,5-bis(1,1-Dimethylethyl)-4-hydroxyphenyl]-methylene]-4-thiazolidinone, so pl. 209-213aboutC.

Calculated, 67,67; N 7,89; N Of 4.38.

WITH18H25NO2S.

Found, 67,44; N 8,11; N 4,65. 3,5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone, so pl. 149-152aboutC.

Calculated With 67,25; N. Of 8.47; N 4,36.

WITH18H27NO2S.

Found, C 67,43; N 8,44; N 4,21.

P R I m e R 4. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl]-2-thioxo-4-thiazolidinone (compound D).

In nitrogen atmosphere 13,98 g of 5-[[3,5-bis(1,1-dimethyl-ethyl-4-hydroxyphenyl] -methylene] -2-thioxo-4-thiazolidin it, 13,17 g diethyl-2,6-dimethyl-1,4-dihydro-3,5-pyridinecarboxylic and 600 ml of toluene was stirred to obtain a solution. In the reaction mixture were added 40 g of silica gel 60 (particle size less than 230 mesh) pre-vysusene was filtered in hot condition. The filtrate is evaporated to dryness. The residue was dissolved in 500 ml ethyl acetate, washed 5 times with 400 ml portions of 1 N. hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuum to obtain a yellow solid. In the chromatographic purification on silica gel with elution with 2.5% ethyl acetate in toluene was obtained 8.0 g of the target product, so pl. 178-179aboutC.

Calculated With 61,50; N 7,17; N 3,98.

WITH18E25NO2S2.

Found, 61,28; N 7,19; N 3,94.

P R I m e R 5. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-methyl-2-thioxo-4-thia sols

The target compound was obtained with the yield 76% of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-methyladenine according to the method of example 1, so pl. > 230aboutC.

Calculated With 62,77; N 6,93; N 3,85; S 17,64.

WITH19H25NO2S2.

Found, 62,54; N 7,05; N 3, 66; S 17,82.

P R I m e R 6. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-methyl-4-thiazolidinone

The target compound was obtained with the yield 71% 10,31 g thione of example 5 during heating with 38,51 ml hydride three-BC-butyanova and of 1.16 g azobisisobutyronitrile (AIBN) in 142 ml of toluene at the temperature of reflux distilled for 1 h ª organic layer 1 N. hydrochloric acid and saturated sodium chloride solution, drying over magnesium sulfate, concentration in vacuo and purification of the residue by chromatographytandem on silica gel, conducting elution 10-50% hexane in an ethyl acetate gradient. The purified product had a melting point of 142-144aboutC.

Calculated With 68,43; N 8,16; N 4,20.

WITH19H27NO2S.

Found, 68,68; 8,00; N 3,97.

P R I m e R 7. 5-[[3,5-Bis(1,1-Dimethylethyl)-4-hydroxyphenyl]-methyl]-3-methyl-4-thiazolidinone.

To 100 ml of THF was added to 6.43 g of compound of example 3. Was added sodium hydride (0.9 g), which was allocated gas. Added iodomethane (1.25 ml, 1.0 EQ) and the resulting mixture was stirred at room temperature for 23 h after which it was diluted with a volume of diethyl ether 1 N. HCl. The organic layer was separated and dried over sodium sulfate, filtered and evaporated. The resulting solid was treated with chloroform with the formation of an orange foam. A sample of the material obtained in quantity to 5.93 g was dissolved in 14 ml of hot mixture of ethyl acetate, diluted with 225 ml of hexane, and the resulting mixture was allowed to cool overnight to room temperature. The solvent Vybornova 400 ml of hexane. This mixture was allowed to cool to room temperature overnight and the precipitate was collected by filtration, washed with hexane and dried in vacuum to education 3,98 g of target compound, so pl. 102-105aboutC.

Calculated With 68,02; N 8,71; N 4,17.

WITH19H29NO2S.

Found, 68,22; N 8,80; N 4,21.

P R I m e R 8. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-dimethyl - amine-2-thioxo-4-thiazolidinone.

The target compound was obtained with the yield 65% of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde and N-dimethyl-aminoadenine, following the method of example 1.

P R I m e R 9. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-dimethylamino- -4-g thiazolidine.

The compound of example 8 was restored using the method of example 6 to obtain the target compound with a yield of 41% of T. pl. 138-141aboutC.

Calculated, 66,26; N To 8.34; N 7,73.

WITH20H30N2O2S.

Found, With 66,56; N 8,59; N 7,47.

P R I m e R 10. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene] -3-(methylamino)- -4-thiazolidinone.

A. Obtaining benzamidopiperidine.

Benzaldehyde (50,8 ml, 500 mmole) and 26.5 ml (500 mmole) of methylhydrazine R is rival from the solvent with obtaining and 67.8 g of substituted intermediate.

C. Obtaining the benzaldehyde N-methyl, N-2-propenylidene.

The specified connection (67,8 g), of 60.5 g of methyl alkyl and 50.5 g of triethylamine were dissolved in 1 liter of acetonitrile. The resulting mixture was heated for 16 h under reflux and then cooled. Was added 45 g of allyl bromide and 38 g of triethylamine and the mixture was again heated for 7 h under reflux cooled and then otparyvali from the solvent with getting 268 g of residue. To this residue was added 500 ml of THF. The filtrate was otparyvali from solvent to obtain 67 g of the above intermediate compounds.

C. Obtaining N-methyl, N-2-propylpiperazine.

The specified connection (59,9 g), 44 g of hydrazine and 137 ml of ethanol was heated under reflux for 21.5 and the mixture was allowed to cool. The reflux condenser was replaced with a distillation head and the mixture was distilled at atmospheric pressure. The first three distillate were collected, combined and added to 100 ml of 1 N. Hcl. Was added 100 ml of concentrated 1 N. Hcl while cooling with ice and the resulting mixture was separated and washed with a small amount of ethyl acetate. The resulting layers were separated and kept the water prior to the deposition of solids is% NaOH solution. The resulting solid was filtered and discarded. Separated filtrate, containing two layers. The top layer contained the substituted intermediate, and the lower, aqueous layer was extracted with diethyl ether, after which steaming gave an additional amount of product.

D. Obtaining N-methyl, N-3-propenyl-5-carboxy-methyl-dithiocarbamate.

To 12,67 g specified connection in 23 ml of ethanol, cooled to 0aboutTo that solution was added 11,18 g of carbon disulfide in 26 ml of diethyl ether. The resulting mixture was removed from the bath with ice and stood at room temperature for 15,5 h, after which the solvent was removed with the formation of approximately 36.5 g of residue. To this residue was added to 13.9 g of Chloroacetic acid dissolved in 29.5 ml 5 n. NaOH (cooled in a bath with ice). The resulting solution was stood for 3 h at room temperature. the pH of the solution was lowered to 3 by adding 8 ml of concentrated hydrochloric acid. Then added diethyl ether (50 ml) which was a division on the ri phase. The aqueous phase was decanted and was extracted with 50 ml of chloroform, then otparyvali from solvent to obtain, approximately, of 40.4 g of the target of the is but]-4-thiazolidone.

3,5-di-tert-butyl-4-hydroxybenzaldehyde (29.3 g), to 38.8 g of the specified connection and 40,34 g of sodium acetate were mixed in 810 ml of acetic acid and the resulting solution was heated under reflux for 24 hours the Solution was allowed to cool and was otparyvali for 50 h at room temperature. Then the solution was poured into 2 l of ice water, separated and washed with additional amounts of water with the formation of 44 g of the above intermediate compounds.

F. Obtain 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-[methyl-2- -propylamino]-4-thiazolidinone.

Using the techniques described in example 6, 42.8 g of the specified thione was restored in the above intermediate (a 8.34 g).

G. Obtain 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]-3-(methylamino)- -4-thiazolidinone.

The specified connection (6,11) solvent in a mixture of 135 ml of ethanol and 15.3 ml of water and the resulting mixture was heated to 70aboutC. was Added Tris-triphenylphosphine-rhodium (I) chloride (50 mg) and the resulting mixture was heated under reflux for 50 min and then was added 550 mg of catalyst, followed by heating at the temperature of reflux distilled for 2.5 hours the Mixture was cooled and permiso product after further processing, so pl. 151-153; 5aboutC.

Calculated With 65,86; N 7,56; N 8,09.

WITH19H28N2O2.

Found, 65,67; N 7,81; N To 8.34.

P R I m e R s 11 and 12

5-[[3,5-Di-2-propenyl-4-hydroxyphenyl] -methylene] -4-thiazolidinone and 5-[[3,5-dis-2-propenyl-4-hydroxyphenyl]methyl]-4-thiazolidinone.

A. Obtain 3,5-bis-[2-propenyl]-4-hydroxybenzaldehyde.

In the atmosphere and with mechanical stirrer, 250 parahydroxybenzoate, 247,6 g of allyl bromide, 311,7 g of potassium bicarbonate and 650 ml of acetone was heated under reflux for 18 hours the Mixture was allowed to cool, after which was added 1 l of water, followed by extraction with two portions of 800 ml of diethyl ether. In the subsequent distillation of the organic phase was received 299 g of 4-[2-propenyl]-oxybenzaldehyde, which was then heated with 300 ml of diethylaniline and for 5.5 h at 195-205aboutC. the Mixture was cooled and was added 750 ml of ethyl acetate. The mixture is washed three times and added 750 ml of ethyl acetate. The mixture is washed three times three and portions of 500 ml of 1N. HCl and after subsequent processing received about 138 g of 3-(2-propenyl)-4-hydroxybenzaldehyde. Monosubstituted aldehyde (159 g) was again heated under reflux in prisutstvija water and then was extracted with two portions of 430 ml of diethyl ether to obtain 170 g of 3-(2-propenyl)-4-(2-propenyloxy)benzaldehyde. Then disubstituted aldehyde were heated in 500 ml of diethylaniline in nitrogen atmosphere to 195-205aboutC for 6.5 hours the mixture was cooled and dissolved in 800 ml ethyl acetate, washed with three 1 l portions of 1N. HCl and, after subsequent processing, received 121,9 g substituted intermediate compound.

C. Obtain 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-methylene]-2-thioxo-4-thiazolidinone.

The specified connection (50.5 g), 36,6 g Rodnina and 164 g of sodium acetate at a temperature of reflux distilled in 1.25 l of acetic acid in the course of 14.5 hours the resulting solution was cooled, poured into 2 l of ice water with the formation, after the separation, about 75 g of the substituted intermediate, so pl. 157-160aboutC.

Obtain 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]methylene]-4-thiazolidinone and 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-methyl]-4-thiazolidinone.

The specified connection (74,8 g) was subjected to a reductive treatment with zinc dust (62 g) and conc. hydrochloric acid (950 ml) 2.1 l of hot (approximately 82about(C) ethanol. After mixing of the reagent solution was allowed to cool to room temperature, was stirred for 1 h and then added to the 3.75 l of ice water. The resulting solution Asadullo in 560 ml of chloroform and the resulting solution was then washed with 75 ml saturated sodium carbonate solution, 75 ml of water and 75 ml of saturated solution of brine. Received the chloroform solutions were combined and then treated with 100 ml of methylene chloride. The target products were obtained using chromatography was carried out on silica gel. By elution with a gradient 25-60% ethyl acetate in hexane were treated with different fractions, which were treated as follows.

Fractions 13-15 concentrated and then washed with ethyl acetate to obtain only 2.91 g of 5-[[3,5-di-2-propenyl-4-hydroxyphenyl] -methyl]-4-thiazolidinone. Fractions 16-18 concentrated with the formation of a residue, which was treated with 30 ml of methylene chloride. Fractions 19-23 concentrated with the formation of a residue, which was treated with 35 ml of methylene chloride. After processing the remaining undissolved substances were isolated by filtration and was treated with 40 ml of ethyl acetate with the receipt of 3.85 g of 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-4-thiazolidinone.

An ethyl acetate wash liquid fractions 13-15, methylenechloride solution connecting fractions 16-18, and methylenchloride and an ethyl acetate solution obtained from fractions 19-23, were combined and loaded onto a column of silica gel for chromatographic separation. In the elution with a mixture of ethyl acetate-hexane in cootes. is racchi, mainly containing 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]methyl]-4-thiazolidinone, recrystallized from hot ethyl acetate to obtain 1.24 g of the indicated compound (total yield 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-methyl] -4-thiazolidinone to 4.14 g). The fractions containing predominantly 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-methylene]-4-thiazolidinone was treated with 30 ml of hot ethyl acetate to obtain 1.73 g of the specified substances (total yield 5-[[3,5-di-2-propenyl-4-hydroxyphenyl]-methylene]-4-thiazolidinone of 5.85 g).

11. 5-[[3,5-di-2-Propenyl-4-hydroxyphenyl] methylene] -4-thiazolidinone, so pl. 184-188aboutC.

Calculated WITH 66,87; N 5,96; N 4,87;

WITH16H17NO2S.

Found, 66,62; N. Of 5.92; N 4,89.

12. 5-[[3,5-di-2-Propenyl-4-hydroxyphenyl] methyl] -4-thiazolidinone etc., 142-144aboutC.

Calculated With 66,41; N 6,62; N 4,84.

WITH16H19NO2S

Found, 66,18; N 6,69; N 4,60.

In accordance with the methods described in examples 11 and 12 and in other parts of the description were obtained the following compounds.

P R I m e p 13. 5-[[3,5-di-2-Propenyl-4-hydroxyphenyl]-methylene]-3-methyl-4-thiazolidinone, so pl. 155-OS.

Calculated With 67,74; N 6.35mm; N 4,65.

WITH17H19NOIl-4 thiazolidinone, so pl. 162 to 165 of theaboutC.

Calculated, 66,85; N To 7.59; N 4,59.

WITH17H23NO2S

Found, 67,12; N 7,37; N To 4.52.

P R I m e R 15. 5-[[3,5-Dipropyl-4-hydroxyphenyl]-methylene]-4-t-atomidine, so pl. 202-205 areaboutC.

Calculated With 65,95; N 7,26; N 4,81.

WITH16H21NO2S.

Found, 66,16; N 7,49; N 4,79.

P R I m e R 16. 5-[[3,5-Dipropyl-4-hydroxyphenyl]methyl]-4-thiazolidinone, so pl. 155-157aboutC.

Calculated With 65,49; N. Of 7.90; N 4,77.

WITH16H23NO2S

Found, 65,71; N 7,73; N 4,99.

P R I m e R 17. 5-[[3-(1,1-Dimethylethyl)-4-hydroxy-5-were]methylene] -4-thiazolidinone.

A. Obtain 4-hydroxy-3-methyl-5-(1,1-dimethylethyl)benzaldehyde.

In nitrogen atmosphere 76,65 g 2-(1,1-dimethylethyl)-6-METHYLPHENOL(Aldrich), 65.42 per g of hexamethylenetetramine and 700 ml triperoxide acid was stirred at the temperature of reflux distilled within 24 hours the Reaction solution was allowed to cool and the liquid was removed by evaporation. The resulting precipitate was transferred to a 1500 ml of water and 1000 ml of chloroform and then neutralized to pH 7 with solid sodium carbonate. The resulting layers were separated and the aqueous layer washed with chloroform. The organic is dried overnight over sodium sulfate. After removal of sodium sulfate, the chloroform evaporated. The resulting residue was transferred into 375 ml of toluene, was heated on the steam bath and then allowed to cool to room temperature over night.

In the subsequent processing of the received 28,3 g substituted intermediate compound.

C. Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-were]-methylene] -2-thioxo- -4-thiazolidinone. The obtained intermediate compound (28,3 g), 24 g of N-aminoadenine, to 48.3 g of sodium acetate and 735 ml of acetic acid was heated to the temperature of reflux distilled for 7 h and then was allowed to cool to room temperature with continuous stirring over night. The resulting mixture was poured into 1500 ml of ice water with stirring and then filtered. The wet precipitate on the filter was transferred into a beaker and dissolved in a mixture of ethyl acetate and water. The resulting organic and aqueous layers were separated. The organic layer was dried over sodium sulfate and then filtered with the purpose of removal of the specified substances. In the subsequent processing, with subsequent distribution in hot chloroform and subsequent drying in vacuum was about 18 g of the target intermediate substance, so CLASS="ptx2">

The recovery obtained tion was carried out by methods described and after appropriate processing received 1.56 g of the target product, so pl. 162 to 165 of theaboutC.

Calculated From 64,95; N 6,90; N Of 5.05.

WITH15H19NO2S.

Found, 65,12; N 7,05; N 4,99.

Using the techniques described in example 17 and other parts of the descriptions received the following additional connections.

P R I m e R 18. 5-[[3,5-Bis(1-methylethyl)-4-hydroxyphenyl]-methylene]-3-methyl-4-thiazolidinone, so pl. 200-210aboutC.

Calculated, 66,85; N To 7.59; N 4,59.

WITH17H23NO2S

Found, With 67,03; N. Of 7.55; N 4,37.

P R I m e R 19. 5-[[3,5-Bis(1-methylethyl)-4-hydroxyphenyl]-methyl]-2-thioxo-4-thiazolidinone.

P R I m e R 20. 5-[[3-(1,1-Dimethylethyl)-4-hydroxy-5%were]methyl] -4-thiazolidinone.

A solution of 0.28 g of the compound of example 17 in 30 ml of tetrahydrofuran was first made at a pressure of 60 pounds/inch2in the presence of 1.12 g of 5% palladium on coal over night at 60aboutC. the Reaction mixture was filtered and evaporated to dryness. The resulting residue was dissolved in 3.5 ml of a mixture of ethyl acetate-hexane at a ratio of 1:1.5 and loaded into a chromatographic column with silica gel. Spending the first connection, so pl. 64-68aboutC.

Calculated With 64,48; N 7,58; N 5,01.

WITH15H21NO2S.

Found, 64,32; N 7,66; N 4,79.

P R I m e R 21. 5-[[3,5-Bis(1-methylethyl)-4-hydroxyphenyl]-methyl]-4-thiazolidinone.

Using the method described in example 20, to 4.73 g of compound of example 19 was turned into a 1.88-target connection, so pl. 136-139aboutC.

Calculated With 65,49; N. Of 7.90; N 4,77.

WITH16H23NO2S.

Found, 65,79; N. Of 7.90; N 4,81.

P R I m e R 22. 5-[[3-(1,1-Dimethylethyl)-4-hydroxy-5-propylphenyl]methyl] -4-thiazolidinone.

A. Obtaining 3-2-(1,1-dimethylethyl)-phenoxypropane.

Methyl allyl (69,2 ml), 2-tert-butylphenol (122,9 ml) and potassium carbonate (to 121.6 g) was stirred in 265 ml of acetone at a temperature of reflux distilled for 50 h and then cooled to 35aboutC. was Added water (600 ml) and the resulting layers were separated. The aqueous layer was extracted with 600 ml of diethyl ether. The organic layer was combined ether extract of the aqueous layer and the resulting solution was dried overnight over sodium sulfate. After removal of sodium sulfate the solvent evaporated and received, after additional processing, 147 g of intermediate target has oedipodinae rearrangement as described in examples 11A and 12A with getting to 100.8 g of the target intermediate compounds.

C. Obtaining 2-(1,1-dimethylethyl)-6-propylene.

A solution of 54.9 g of the compounds in 575 ml of toluene was first made at a pressure of 60 pounds/inch2in the presence of 55 g of Nickel Raney for 3 h at room temperature. The reaction mixture was filtered and evaporated to dryness to obtain a 59.2 g of the target intermediate.

D. Obtaining 3-(1,1-dimethylethyl)-4-hydroxy-5-propylbenzamide.

The specified connection (55,48 g) was converted into 23,33 g target intermediate compound using the method described in example 17A.

E. Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-propylphenyl]-methylene] -2-thioxo-4-thiazole one

Using the method described in example 17B, the 5.51 g of the indicated compounds were turned in of 6.26 g of the target intermediate compounds, so pl. to 190.5-192aboutC.

Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-propylphenyl] methyl]-2-thioxo-4-thiazoline Nona

Using the method described in example 4, to 4.73 g of the indicated compounds were made in 2.1 g of the target intermediate compounds.

C. Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-propylphenyl]-methyl]-4-thiazolidinone.

A solution of 2.1 g of the compounds in 185 ml of ethanol was first made Puu the mixture was filtered and evaporated to dryness. The obtained residue was dissolved in 25 ml of methylene chloride and loaded into a chromatographic column filled with silica gel. Conducting elution 2000 ml 10-50% ethyl acetate in hexane gradient, with subsequent elution 2000 ml of a mixture of acetate-hexane at a ratio of 1:1 was obtained fraction, which after evaporation to dryness gave 0.75 g of the target product, so pl. 50-55aboutC.

Calculated With 66,41; N 8,20; N 4,56.

WITH17H25NO2S

Found, 66,61; N By 8.22; N 4,55.

P R I m e R 23. 5-[[3-Methylthiophenyl-4-hydroxy-5-ethoxyphenyl]-methylene] -3-dimethylamino-4-enous of old

A. Obtain 5-[[3-ethoxy-4-hydroxyphenyl]methylene]-3-dimethylamino-2-thioxo-4-thiazolidinone A.

3 Ethoxy-4-hydroxybenzaldehyde (of 45.7 g), N-dimethylaminopropane (53,35 g) and fused sodium acetate (92,4) reacted with each other in accordance with the method described in example 1, obtaining 52,92 g target intermediate compounds, so pl. 194-198aboutC.

C. Obtain 5-[[3-ethoxy-4-hydroxyphenyl]methylene]-3-dimethylamino-4-thiazolidinone.

Using the method described in example 6, 47,66 g the specified connection was turned into 14,02 g target intermediate compounds.

C. Obtain 5-[[3-ethoxy-4-hydroxy-5- (METI the ora of formaldehyde was dissolved in 50 ml of 2-ethoxyethanol, added fenistil (2,62 g) and 7.0 g of the compounds and the resulting solution was heated under reflux for 4 h, then cooled. To the cooled reaction mixture was added ethyl acetate (50 ml) and water (25 ml) and the pH of the resulting biphasic solution was lowered to 5 with concentrated hydrochloric acid. The organic phase was separated from the double phase was washed with a saturated solution of brine and then was loaded into a chromatographic column filled with silica gel. In the elution of 4 l of methylene chloride and 4 l of a mixture of 3% methanol and 97% methylene chloride was obtained fraction containing the target product. These fractions were combined and again loaded into a chromatographic column with silica gel. In the elution of 4 l of methylene chloride, followed by elution 1 l 22,5% acetonitrile in methylene chloride was obtained fraction, which after evaporation of the solvent gave the desired product. This product was further purified by treating a hot solution of 50 ml of hexane and 30 ml of ethyl acetate to obtain 6.20 g of 5-[[3-methylthiophenyl-4-hydroxy-5-ethoxyphenyl] -methylene]-3-dimethylamino-4-thiazolidinone. So pl. 118-120aboutC.

Calculated, 60,55; N 5,81; S="ptx2">

P R I m e R 24. (+)-5-[[3,5-(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone.

In a three-neck round bottom flask with a capacity of 50 ml, containing 25 ml of methylene chloride was added 1.31 g of 4-a molecular sieves, of 0.56 ml (a 1.88 mmole) isopropylate titanium, 0,79 ml of (3.75 mmole) /+/-aminobutiramida tartrate and 34 μl (of 1.88 mmole) of deionized water. The resulting solution was stirred for 20 min and then was added 0.8 g (2.5 mmole) of racemic mixtures of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methyl] -4-thiazolidinone. The resulting solution was cooled to -20aboutWith and added to 0.73 ml (a 1.88 mmole) 2.57 M solution of tert-butylhydroperoxide in isooctane. Then the reaction solution was stirred for 6 h at -20aboutC. After 6 hours, the reaction solution was rapidly cooled, pouring it into 50 ml of a solution derived from 9,9 g of iron sulfate heptahydrate (II), and 3.3 g of citric acid and water. The resulting solution was stirred for 30 minutes and then the stirring was stopped, so that it was possible to separate the organic and aqueous layers. The aqueous layer was decantation and washed with methylene chloride. Wash methylenchloride liquid was combined with the specified organic layer and the resulting solution promyslovskoye liquid evaporated from the receipt of 1.81 g of residue.

This residue was dissolved in 25 ml of methylene chloride and the resulting solution was chromatographically on a column of silica gel. In the elution 6000 ml 10-51% ethyl acetate in hexane gradient has received various fractions containing the specified target connection. These fractions were combined and the liquid evaporated to obtain 0,19 g of target compound. ( )25-73,6about(1,0 Meon).

Calculated With 67,25; N. Of 8.47; N 4,36.

WITH18H27NO2S.

Found, With 67,50; N 8,53 N 4,48.

P R I m e R s 25, 26 and 27. (+)-5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl] -4-thiazolidinone, (-)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl]-4-thiazolidinone-1-ACS ID and(+)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl]-4-thiazolidinone-1 OK led.

According to the manner similar to that described in example 24, the reaction between 0,89 ml (3.0 mmole) of isopropylate titanium, of 1.27 ml (6.0 mmole) of (-)-aminobutiramida tartrate, 54 μl (3.0 mmole) of deionized water, of 1.61 g (5.0 mmole) of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl] -4-thiazolidinone and 2.4 ml (6.5 mmole) 2.57 M solution of tert-butylhydroperoxide in isooctane to obtain a residue. The residue was dissolved in 75 ml of methylene chloride and the obtained result is 00 ml 10-50% ethyl acetate in hexane gradient has received various factions, containing(+)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone. These fractions were combined and evaporated the liquid phase with the receipt of 0.43 g of the product. Further elution with 4000 ml of a 50% aqueous solution of isopropanol in hexane received a different faction. Fractions that contained(-)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone-1-ACS ID, were combined and evaporated liquid to obtain 0.87 g of the product. The fractions containing(+)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl]-4-thiazolidinone-1-ACS ID were combined and evaporated liquid to obtain 0.27 g of the product.

25. (+)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone.

[25+70,41about(C 1.0, The Meon).

Calculated With 67,25; N. Of 8.47; N 4,36.

WITH18H27NO2S.

Found, With 66,95; P By 8.22; N, 4.26 Deaths.

26. (-)-5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone-1-ACS ID, so pl. 182-184aboutC.

[25-21,84about(C 1.0, The Meon).

Calculated With 64,06; N. Of 8.06; N 4,15.

WITH18H27NO3S.

Found, 63,84; N. Of 8.09; N 4,12.

27. (+)-5-[3,5-[bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl]-4-thiazolidinone-1 OK led,t, pl. 177-181aboutC.

[

Found, 63,88; N 8,12; N 4,29.

P R I m e R 28. (-)-5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl] -3-methyl-4-thiazoline non.

According to the manner similar to that described in example 24, the reaction between 0,45 ml (1.5 mmole) of isopropylate titanium, 0.63 ml (3.0 mmole) of (+)-diisopropylaniline, 27 μl (1.5 mmole) of water, 0.84 g (2.5 mmole) of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -methyl]-3-methyl-4-thiazolidinone and of 0.58 ml (1.5 mmole) of 2.75 M solution of tert-butylhydroperoxide in isooctane to obtain a residue. This residue was dissolved in 25 ml of methylene chloride and the resulting solution was chromatographically on a column of silica gel. By elution with 1000 ml of methylene chloride and then with 6000 ml of 0-10% ethyl acetate with methylenchloride the gradient, then using a 4000 ml 20-50% isopropyl alcohol and hexane gradient and then with 2000 ml of a 50% aqueous solution of isopropyl alcohol in hexane, were treated with different fractions containing the target compound. These fractions were combined and evaporated liquid to obtain 0.35 g of the target compound.

Calculated With 68,02; N 8,71; N 4,17.

C19H29NO2S.

Found, 67,95; N 8,55; N 4,18.

NMR (300 MHz; Cl3) 1,4(sing the years,2H).

P R I m e R 29. 5-[[3-(1,1-Dimethylethyl)-4-hydroxyphenyl]-methyl]-4-thiazolidinone.

A. Obtaining 3-(1,1-dimethylethyl)-4-hydroxybenzaldehyde.

In 184,4 ml (1,494 mmole) of N-methylformamide when cooling was bury 130,9 ml (1,404 mole) chloride fosforito within 20 minutes the Mixture was allowed to warm to room temperature and was stirred for 1 h Then the reaction mixture was bury within 25 min of ortho-tert-butylphenol (138,2 ml of 0.9 mole). After adding phenol resulting reaction mixture was stirred for another 30 min at room temperature and then was heated to 60aboutC and was stirred for 5 h at this temperature. The reaction mixture was poured into a volume of crushed ice and was extracted. The aqueous layer was separated and again washed with chloroform. Chloroformate layers were combined and extracted with 2000 ml of a 5% solution of potassium hydroxide. Then an aqueous extract of potassium hydroxide was added to 1000 ml of chloroform. the pH of the resulting two-phase mixture was placed on the value of 2.0 with concentrated hydrochloric acid. Layers resulting mixture was separated and the aqueous layer was again extracted with chloroform. The organic layer two-phase mixture and chloro is and was removed at reduced pressure with the formation of residue. This residue was dissolved in 100 ml of hot toluene and the resulting solution was diluted with 100 ml of hexane. This solution was slowly cooled to room temperature, which was accompanied by the formation of sludge. This precipitate was isolated by filtration, washed with hexane and then dried in vacuum, obtaining of 20.0 g of the desired substituted intermediate compound.

C. Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxyphenyl] methylene] -3-amino-2-thioxo-4-thiazolidinone.

Benzaldehyde intermediate substance from example 29A (20,0 g; to 112.2 mmole), N-aminoadenine (18,29 g; 123,4 mmole) and sodium acetate (36,8 g; 338,8 mmole) suspended in 560 ml of acetic acid. The suspension was heated to the temperature of reflux distilled, stirred at this temperature for 7 h (there was observed the formation of a precipitate) and then cooled to room temperature under stirring. The precipitate was isolated by filtration and then washed with a mixture of ethyl acetate and diethyl ether in the ratio 1:1, then diethyl ether. Selected residue was dried in vacuum at 60aboutC for 2 h to obtain 14.5 g of the desired target intermediate, so pl. 225aboutC.

C. Obtain 5-[[3-(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]-4-thiazole the/SUP>C) toluene. To this suspension was added a three-BC-butyl hydride (62,4; 232 mmole) and AIBN (1,14 g; of 6.96 mmole). The resulting suspension was heated to the temperature of reflux distilled and suspended solids slowly dissolved. 30 and 55 min after the start of heating was added an additional amount of AIBN (two servings 1,14 g). After 80 min after the start of heating of the hot reaction solution was transferred into a separating funnel and was added 1N hydrochloric acid solution. The resulting biphasic mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was washed with ethyl acetate and the resulting wash liquid were combined with the organic layer of the biphasic mixture. The combined solution was washed with a saturated solution of sodium chloride and then dried over sodium sulfate. Volatile components of the solution was removed under reduced pressure while receiving 87,7 g yellow solid. This solid is suspended in 1000 ml of hexane, and the resulting suspension was stirred for 15 minutes After 15 min, the suspension was filtered and selected solid was dissolved in 500 ml of diethyl ether. The ether solution was chromatographically on a column of silica gel used with the dignity and forth 2000 Il gradient 30-30% isopropyl alcohol in hexane. Fractions in which it was determined that the product is evaporated and was treated with methylene chloride. The resulting residue was dissolved in ethyl acetate, dried to dryness under reduced pressure and then treated with ethanol to obtain or 4.31 g of the desired intermediate target connection, so pl. 110aboutC (decomposition).

Calculated With 63,85; N 7,51; N, 5,32.

WITH14H17NO2S.

Found, 64,15; N. Of 6.73; N The Ceiling Of 5.60.

D. Obtain 5-[[3-(1,1 dimethylethyl)-4-hydroxyphenyl]-methyl]-4-thiazolidinone. The intermediate part of the substance from example 29S (395,1 mg; 1.5 mmole) was dissolved in 9 ml of methanol. Then to the solution was added magnesium (72,9 mg, 3.0 mmole) and the resulting reaction mixture for 3 h and stirred at room temperature. After 3 h, it was found that a large part of the added magnesium was included in the reaction and added another 182,3 mg (7.5 mmole) of magnesium. Stirring the reaction mixture at room temperature was continued overnight. The next morning saw a yellow precipitate. This precipitate was dissolved by adding methanol, the reaction solution in a mixture of ethyl acetate with 1N. hydrochloric acid. The organic layer from the obtained results in the Lyali and the resulting residue was treated with methylene chloride. Then the residue was dissolved in 25 ml of methylene chloride and the resulting solution was chromatographically on a column of silica gel using 5-20% gradient of isopropyl alcohol in hexane. The fractions containing pure practical product, evaporated with the use of 0.29 g of target compound, so pl. 65-70aboutC.

Calculated With 63,37; N 7,22; N 5,28.

WITH14H19NO2S.

Found, With 63,08; N 7,30; N 4,39.

The invention provides a method of treating inflammatory bowel disease in mammals. This activity is demonstrated in the following test systems.

Rats Srague-Dawley lab Charles river, Portaged, MI (group of six animals weighing approximately 250 g) twice a day orally was administered the test compound (10 mg/kg) or vehicle (control) for three days. On the third day, the animals were put intracolonic enema with 2% solution of acetic acid, and the enema tip was placed 8 cm above the rim of the anus. This concentration of acetic acid provides severe inflammation of the colon, characterized by rectal bleeding, diarrhea, erosion of epithelial tissue and destruction of crypts and to the Yali and cut along the longitudinal axis. Violations of the tissues inside the remote open part of the colon was assessed by three independent observers in the scale of assessments 0-4 (0 normal, 4 the most severe inflammation). Each group used 5-7 rats. The results of these tests are presented below.

Inhibition of colitis, caused by the action of acetic acid.

The compound of example, the Evaluation of lesions of the Control 3,4 0,3 1 2,2 0,5 2 1,1 0,5 3 0,4 0,1 4 1,5 0,3 6 2,4 0,5

7 2,1 0,1 8 2,2 0,5 10 1,2 0,3

11 2,0 0,6 12 2,0 0,6 16 1,2 0,5 18 2,8 0,6 21 1,5 0,5 22 0,8 0,2 23 2,7 0,6 24 1,0 0,2 25 2,5 0,7 26 2,4 0,6 27 2,2 0,5 29 2,2 0,5

Rats, varieties Srague-Dawley from Charles river laboratories, Portage, MI (males weighing about 300 g), did not give food within 24 hours After 24 h the animals orally was administered at 3 ml/kg rat solvent (control substance) or the test compounds dissolved in such a solvent. After 30 min, each animal was given a solution consisting of 100% ethanol. After 60 min after application of all animals umertvlâl and their stomachs were removed and washed. Tissue damage inside the remote, open the stomach, were evaluated by three independent, active blind experiments in the rating scale 0-5 (where 0 is the normal condition; 5 serious tissue damage). The distance between Obedinenie, dissolved in the solvent, compared with the results obtained in animals that received only the solvent to determine the inhibition of tissue damage in percent, which can be attributed to the test compound. The results of each test are presented in table.

The data show that the compounds used in the method according to the invention, the methods to treat inflammatory diseases of the digestive tract. The term "inflammatory disease of the stomach", as used in the text of the invention, refers to any disorder of the digestive system, which is characterized by inflammation. Examples of such disorders include Crohn's disease, mucous colitis, pseudomembranous enterocolitis, nonspecific ulcers of the colon, collagen colitis, relaxation of the colon, ulcerative forgive, evolutionary enteritis and colitis, idiomaticheskii diffusion ulcerative agranulocytosis enteritis caused by non-steroidal anti-inflammatory medication inflammation, cell sprue, etc.

The compounds of formula II are also used in the treatment of inflammatory bowel disease. In this regard, the present invention also relates to farmee pharmaceutically applicable diluents, eccipienti or media.

In the preparation of pharmaceutical compositions of the invention one or more compounds of the formula II is mixed with a carrier, or diluted by a carrier or capsulebuy in the media, which may have the form of a capsule, sachet, paper or other container. In the case when the media acts as a diluent, it may be a solid, semi-solid, or liquid material which acts as a binder, excipient or medium for the active ingredient. For example, the composition can be in the form of tablets, pills, powders, pellets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid and in liquid medium), ointments containing for example up to 10 wt. active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, Arabic gum, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone cellulose, water, syrup, methyl cellulose, methyl - and pre lubricating agents, wetting agents, emulsifying and suspendresume agents, protecting agents, sweetening agents or perfumes. The composition of the invention can be formed in such a manner that a rapid, prolonged or delayed release of the active ingredient after use on the patient using techniques well known in the field.

Composition, form, preferably in unit dosage form, such that each dosage contains 5-500 mg, usually 25-300 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units intended for single dose when applied to humans and other mammals, each unit contains a certain amount of active material calculated to provide the desired therapeutic effect, in Association with one or more suitable pharmaceutical diluents, eccipienti or media.

In the following prescription examples as active ingredient can be any of the compounds of formula II.

P R I m e R 30. Hard gelatin capsules are prepared using the following incredibaly with each other and were filled hard gelatin capsules in the amount of 460 mg per capsule.

P R I m e R 31. Tablet formulation was prepared using the following ingredients mg/tablet: Compound of example 11 250 Microcrystalline Zell - vine 400 Fused silica 10 Stearic acid 5

These components were mixed with each other and pressed into tablets weighing 665 mg each.

P R I m e R 32. A spray solution was prepared from the following components, wt. The compound of example 12 0.25 Ethanol 29,75 Propellant 22 (hardier - methane) 70,00

The active compound was mixed with ethanol and the mixture added to a portion of propellant 22, cooled to -30aboutWith, and was transferred to a filling device. Then the required amount was applied to the stainless steel container and diluted by the remaining number of propellant. Then the container was installed valve device.

P R I m e R 33. Tablets, each containing 60 mg of active ingredient, were prepared as follows, mg Compound of example 12 60 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as 10% solution in water) 4 Sodium carboxymethyl starch 4.5 magnesium Stearate 0.5 Talc 1 150 mg

The active ingredient, starch and cellulose was passed through sieve No. 45 mesh U.S. and thoroughly PE the Kali through a sieve No. 14 mesh U.S. dollars. Thus obtained pellets were dried at 50-60aboutWith and was passed through sieve No. 18 mesh U.S. dollars. Natrocarbonatite, magnesium stearate and talc, previously passed through sieve # 60 mesh U.S., then added to the granules which, after mixing extruded using teletrauma machine to obtain tablets each weighing 150 mg

P R I m e R 34. Capsules containing 80 mg of the drug, was prepared as follows, mg Compound of example 12 80 Starch 59 Microcrystalline Zell - vine 59 magnesium Stearate 2 Total 200

The active ingredient, cellulose, starch and magnesium stearate were mixed with each other, passing through sieve No. 45 mesh U.S. and was filled with a mixture of gelatin capsules in the amount of 200 mg per capsule.

P R I m e R 35. Candles containing 225 mg of active ingredient was prepared as follows, mg Compound of example 13 225 Glycerides of saturated fatty acids Up to 2000

The active ingredient was passed through sieve # 60 mesh U.S. and suspended in the glycerides of saturated acids, which are pre-melted with the supply of a minimum amount of heat. The mixture is then poured into candle form with a nominal volume of 2 g and gave the contents to cool.

P R I m e is EPA 11 50 Sodium carboxymethyl cellulose 50 Syrup 1.25 ml Solution of benzoic acid 0.10 ml Perfume q.Y. Color agent q.Y. Purified water To 5 ml

The drug was passed through sieve No. 45 mesh U.S. and was mixed with the sodium carboxymethyl cellulose and syrup to obtain a homogenous paste. A solution of benzoic acid, flavoring and color agent is diluted with a certain quantity of water and with stirring was added into the system. Then add water in sufficient quantity to achieve the required volume.

P R I m e R 37. Capsules containing 150 mg of the drug, was prepared as follows, mg Compound of example 13 150 Starch 164 Microcrystalline Zell vine 164 Stearate 22 500 mg

The active ingredient, cellulose, starch and magnesium stearate were mixed with each other, was passed through sieve No. 45 mesh U.S. and was filled with the mixture of hard gelatin capsules, 500 mg per capsule.

P R I m e R 38. Hard gelatin capsules are prepared using the following ingredients mg/capsule: Compound of example 3 250 Dry starch 200 magnesium Stearate 10

These ingredients were mixed with each other and filled with a mixture of hard gelatin capsules in the amount of 460 mg per capsule.

P R I m e R 39. Tablets containing 60 mg of active ingredient was prepared in the following manner, mg: connection of the de) 4 Sodium carboxymethyl starch 4.5 magnesium Stearate 0.5 Talc 1 150

The active ingredient, starch and cellulose was passed through sieve No. 45 mesh U.S. and thoroughly mixed. The solution of polyvinylpyrrolidone were mixed with the resultant powders which are then passed through sieve No. 14 mesh U.S. dollars. Thus obtained pellets were dried at 50-60aboutWith and was passed through sieve No. 18 mesh U.S. dollars. Natrocarbonatite, magnesium stearate and talc, previously passed through sieve # 60 mesh U.S., then added to the granules which, after mixing extruded in teletrauma machine to obtain tablets each weighing 150 mg

P R I m e R 40. Candles containing 225 mg of active ingredient, were prepared as follows, mg Compound of example 3 225 Glycerides of saturated fatty acids 2000

The active ingredient was passed through sieve # 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, pre-melted with the supply of a minimum amount of heat. The mixture is then poured into candle form with a nominal amount of 2 g and gave the mixture to cool.

Below compares the percentage of inhibition of colitis induced by acetic acid in relation to the control sample, for connection 13 to the invention of (5-[[3,5-di-2-propenylidene ohms. (Known compound).

Comparison of inhibition of colitis induced by acetic acid

Connection example VI yesnoyes 13 37,4

Known 22

As is clear compounds according to the invention is significantly more active than the compounds described in EP 211670.

The method of obtaining derivatives of thiazolidinone General formula I

< / BR>
where R1WITH2-C6alkenyl,2-C6-quinil or

< / BR>
where n 0 3;

R2hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C2-C6alkenyl,2-C6-quinil,1-C4-alkyl O -,

< / BR>
where n 0 3,

R3hydrogen or C1-C6-alkyl;

R4and R5hydrogen or together form a bond;

R6and R7each hydrogen or together form a S, or one of the radicals;

R6and R7hydrogen, and the other group HE or S CH3;

< / BR>
where m is 0 or 1;

Q NR8,

where R8hydrogen, C1-C6-alkyl, C2-C6alkenyl,3-C8-cycloalkyl, SO2CH3or -(CH2)nY

where n 0 3,

Y is cyano, OR9, -NR11R12, -S(C1-C4)-alkyl or groups who>alkyl, C1-C4-alkoxy or-NH2;

R11and R12independently from each other hydrogen, C1-C6-alkyl, C2-C6alkenyl,2-C6-quinil, (CH2)qOH,

-(CH2)qN(C1-C4-alkyl)2- (CH2)qS-(C1-C4-alkyl)

< / BR>
where n is the specified value;

q 1 6,

or its pharmaceutically acceptable salts, characterized in that carry out the reaction of compounds of General formula

< / BR>
with a compound of General formula

< / BR>
where R1, R2, R3and X have the above meanings;

Q N R8where R8has the specified values;

R6and R7together form S,

with the aim of obtaining compounds of General formula II

< / BR>
where R1, R2, R3, R6, R7, X and Q have the above meanings;

(a) with subsequent optional recovery of the compounds of formula II, where R6and R7together form a group S in order to obtain the compound of formula II, where R6and R7hydrogen

(b) recovering the compounds of formula II, where R4and R5together form a bond, with the aim of obtaining the compounds of formula To form a bond, and R6and R7together form S, with the aim of obtaining the compounds of formula II, where R4, R5, R6and R7hydrogen;

(d) alkylation of compounds of formula II, where R8hydrogen, to obtain the compounds of formula II, where R8WITH1-C6-alkyl, C2-C6alkenyl,3-C8-cycloalkyl or -(CH2)nY, where n is 0 to 3 and Y is cyano, OR9, - S-(C1-C4)-alkyl, -NR11R12or where R9, R11and R12have the specified values,

(e) the acylation of compounds of formula II, where R8hydrogen, with the aim of obtaining the compounds of formula II, where R8(CH2)nY, where n is 0 to 3, where R10has the specified values,

(f) oxidation of compounds of formula II, where X is the group where m is 0, to obtain the compounds of formula II, where X is a group and m 1,

(k) the recovery of the compounds of formula II, where R8group - (CH2)nY, where n is 0 to 3 and Y OR9where R9group

order to obtain the compounds of formula II, where R8group - (CH2)nY, where n is 0 to 3 and Y OR9where R9is hydrogen;

(l) the reaction of compounds of formula II, where R8the group -(CH2)nY, where n is 0 to 3, and Y OR)nY, where n is 0 to 3 and Y OR9where R9toil;

(m) the reaction of compounds of formula II, where R8- (CH2)nY, where n is 0 to 3, and Y OR9where R9toil, with an amine of the formula-NR11R12where R11and R12have the specified values, with the aim of obtaining the compounds of formula II, where R8the group -(CH2)nY, where n 0 3, and the Y group N R11R12;

(n) heating the compounds of formula II, where R8-(CH2)nY, and Y Is N R11R12and R11and R12are not hydrogen, in a mixture of ethanol:water in the presence of the catalyst in order to obtain the compounds of formula II, where R8- -(CH2)nY, and Y Is N R11R12where one of the radicals R11or R12hydrogen and the other is not hydrogen;

(o) by reacting the compounds of formula II, where R6and R7hydrogen, with triperoxonane anhydride with obtaining the compounds of formula II where one of the radicals R6and R7hydrogen, and the other group-IT;

(p) the formation of salts of the compounds of formula II by reaction mesolevel norms compounds with a strong acid or strong base.

 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: Disclosed are compound of formula I wherein Het represents group of formula 2 (m = 0 or 1; X is hydrogen or C1-C12-alkyl or C1-C4-haloalkyl; Y is group of formula 3 and 4 wherein substitutes have meanings described in specification); A represents hydrogen, unsubstituted C1-C12-alkyl; C3-C8-cycloalkyl, or aryl; B represents hydrogen or C1-C6-alkyl; or A and B with carbon atom to which they are attached form saturated C3-C10-alkyl; A and Q1 together represent unsubstituted C3-C6-alkanediyl, wherein two non-adjacent carbon atoms optionally form further unsubstituted cycle; meanings of the rest substitutes are as described in specification.

EFFECT: new agents for controlling of agriculture pests.

4 cl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: chemistry; oxa-and thiazole derivatives.

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10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

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5 cl, 1 tbl, 25 ex

FIELD: chemistry.

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8 cl, 39 ex, 2 tbl

FIELD: chemistry.

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EFFECT: wider field of use of the compounds.

9 cl, 5 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: medicine.

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EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

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