The method of obtaining ()6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol

 

(57) Abstract:

Usage: in medicine as an anti-hypertensive means (cromakalim). The inventive product (+)-6 cyano-3,4-dihydro-2,2 - dimethyl-TRANS-4-(2-oxo-1-pyrrolidinyl) -2H-1-Ben supiran-3-ol:cromakalim. B. F. C16H18N2O2so pl. 229-230°C. Yield 90 Reagent 1: 4-cyano-phenol. Reagent: isoprene. Process conditions: at 30-120°C in the environment of a solvent in the presence of an alkali metal and/or catalyst. Reagent 3:6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran, which turned into 6-cyano-2,2-dimethyl-2H-1-benzopyran at 40-150°C in the environment of a solvent in the presence of a catalyst and/or oxalates or by synthesized in benzyl portion of the molecule and dehydrobrominated obtained 6-cyano-3,4-dihydro-2,2-dimethyl-4-bromo-2H-1-benzopyran. 6-cyano-2,2-dimethyl-2H-1-benzopyran receive one-stage 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran effect of nagkalat in the environment of the solvent and subsequent interaction of this compound with 2-pyrrolidone in the presence of alkali metal at 20-100°C and the selection of the target product. The method allows to increase the output cromakalim from 26 to 55-65% relative to 4-cianfanelli. 11 C.p. f-crystals.

The invention Wallpaper () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula VI

known as Cromakalim (DRL 34 915).

Cromakalim is an anti-hypertensive composition of the new existing mechanism. He belongs to the peripheral group of anti-hypertensive substances, it acts by opening potassium channels in smooth muscle cells, and it thereby prevents the accumulation of electric potential across the membrane. Thus, it belongs to the activators of potassium channels [Drugs of the Future, 11, 175 (186), 12, 284 (1987), 13, 269 (1088), 14, 276 (1989)]

According to EP 076 075 [1] describes the possibility of obtaining Cromakalim, 4-cyano-phenol of the formula I

reacts with 3-chloro-3-methyl-Butina that leads to propargilovyh ether of the formula IX

which is then subjected to a closing cycle to produce 6-cyano-2,2-dimethyl-2H-1-benzopyran formula III

< / BR>
The compound of formula III is converted then after 6-cyano-TRANS-3 - bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol 6-cyano-3,3-dihydro-3,4-epoxy-2,3-dimeth - yl-2H-1-benzopyran formula V

< / BR>
Of the compounds of formula V can be obtained in three independent ways the final reaction product of the formula VI.

1) Compound of formula V is subjected to reaction with ammonia to obtain 6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-amino - 2H - 1-benzopyran-3-ol, formula formula VIII

and this compound is then subjected to a circuit loop in the system sodium hydride-tetrahydrofuran.

2) the Compound of formula V is subjected to reaction with 4-aminobutyric acid in the system sodium bicarbonate-ethanol, and the closure of the cycle leads to the final reaction product of the formula VI.

3) the Compound of formula V is subjected to reaction with 2-pyrrolidone in the presence of sodium hydride and dimethyl sulfoxide and end product of the reaction of formula VI.

When playing the developed examples of EP 075 076 the inventors found the following facts:

4-cyano-phenol is reacted with 3-chloro-3-methyl-Butina in the presence of sodium hydroxide benzyl-trimethyl-ammonium hydroxide-water and dichlorobutane at room temperature for 5-6 days; according to the description of the patent propargilovyh ether of the formula IX can be obtained with a yield of 69%, the Reaction was repeated several times, however, can only be achieved 46-50% yield. The reaction was carried out in acetone, dimethylsulfoxide, N,N-dimethylformamide as a solvent in the presence of carbonate and potassium iodide at 50-150aboutWith, and after 30-40 hours of reaction can be achieved only 40-55% yield. Additional probe-buten can be obtained from this connection only with the release of 55-60% in the course of the complicated reactions. 3-Chloro-3-methyl-buten is little stable connection, it decomposes upon standing, and the same time he is polymerized during the alkylation reaction, or it decomposes at a higher temperature. The reaction of 4-cyano-phenol of formula I and 3-chloro-3-methyl-butyne leads to propargilovyh ether of the formula IX with only 45-55% and the ester then undergoes a cycle closing in ortho-dichlorobenzene to 6-cyano-2,2-dimethyl-2H - 1-benzo (a) pyrene formula III with yields of 80% according to EPO 0 075 076. According to their own experimental experiments, the reaction can be carried out with access to the best 70% purification of the reaction product of formula III is a complex procedure and can be carried out by vacuum distillation or column chromatography. This reaction can be obtained derivative chromene formula III with the release of 35% relative to 4-cyano-phenol of formula l and 23% relative to 3-chloro-3-methyl-butyne.

3-Bromo-4-hydroxy-derivatives of the formula IV

can be obtained from chromene formula III in the system of dimethyl sulfoxide and water with the release of 90% according to EPO 075 076. Similarly epoxide of formula V can be obtained with a yield of 90% by reaction between 3-bromo-4-auxiproizvodnykh formula IV with sodium hydroxide in prisa end of the reaction product of formula VI was carried out by a simple method, in which the epoxide of formula V was subjected to reaction with 3-pyrrolidone in the presence of sodium hydride and dimethyl sulfoxide. Suddenly there was obtained a rather complex reaction mixture, and by thin-layer chromatography it was possible to determine 6-8 components, the number of which was comparable Reaction was repeated several times and the final reaction product of formula IV can be obtained with the yield of 20-25% only using complicated column chromatography as opposed to output 60% according to the invention.

According to the method disclosed in EP 076 075 [1] the final reaction product of the formula VI can be obtained only with the release of 22-26% relative to 4-cyano-phenol of formula I, and methods, when played on their own experiments can be carried out with only 6-8%

Thus, the methods disclosed in EP 076 075 [1] are unsuitable for industrial production of Cromakalim formula VI.

The aim of the invention was to elaborate a new economical and industrial accessible way of obtaining Cromakalim formula VI. The invention relates to a new method get () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-1-pyrrolidinyl)- 2H-1-benzopyran-2-ol of formula VI from 4-qi is retenu differs 4-cyano-phenol of formula I is administered in cooperation with isoprene with obtaining 6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran formula II

which is then converted into 6-cyano-2,2-dimethyl-2H-1-benzopyran in the presence of a catalyst and/or oxidant or by synthesized in benzyl part of the molecule and dehydrobrominated the compounds of the formula X

obtaining one-stage 6-cyano-3,4 - dihydro-2,2-dimethyl-3,4-epoxy-2H-1-Ben-soberana using nakilat and the subsequent interaction of this compound with 2-pyrrolidone to obtain the final reaction product.

The interaction of 2-cyano-phenol of formula I with isoprene is carried out at 30-120aboutIn the environment of a solvent and in the presence of alkali metals and/or catalysts. As the alkali metal is preferably applied potassium. The reaction is carried out in the presence as catalyst of acid Lisowska type, preferably aluminum trichloride; the molar ratio of 4-cyano-phenol of formula I:isoprene:potassium: aluminum trichloride is(0,8-1,2):(0,9-2,0):(01-0,7):(0,9-3,0), preferably 1:1:0,5: 1.

As the solvent used aromatic solvents, preferably benzene.

Prodolzhaet through catalysis by acids in the water-immiscible solvent is used as the acid catalyst, hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, methanesulfonic acid, paratoluenesulfonyl acid, preferably sulfuric acid, and using as a solvent of aliphatic and aromatic hydrocarbons, haloalkanes, preferably chloroform, and carry out the reaction at 60-80aboutWith, preferably for 4-6 hours While the molar ratio of 4-cyano-phenol of formula I:isoprene is 0.5:10, preferably 1:4.

In these circumstances the reaction of 6-cyano-3,4-dihydro-2,2 - dimethyl-2H-1-benzopyran formula (II) was obtained with the yield of 90-95% of it is a new connection. The transformation of compounds of formula (II) 6-cyano-2,2-dimethyl-2H-1-benzopyran formula III can be carried out by several independent ways:

1) Compound of formula II pomeroys in the benzyl part of the molecule with N-bromo-succinimide in the presence of traces of peroxide and almost quantitative yield formed 6-cyano-3,4-dihydro-2,2-dimethyl-2-bromo-2H-1-banter-EN formula X.

The connection in this way can be almost quantitative yield dehydrobrominated using an alkali metal alcoholate to obtain 6-cyano-2,2-dimethyl-2H-1-benzopyran formula III.

tetraacetate lead in glacial acetic acid or with 2,3-dichloro-5,6-dicyano-benzoquinone in neposrednom solvent.

In addition, you can epoxidizing compound of formula III in one stage to a derivative of formula V by using nagkalat in the presence of a solvent haloalkanes type.

In the implementation described above for obtaining compounds of formula III by synthesized in benzyl part of the molecule of the compounds of formula II and dehydrobrominated the compounds of formula X are forming in the benzyl part of the molecule of the compounds of formula II with the help of 0.9 to 1.5 molar equivalents, preferably 1-1,1 molar equivalent of N-bromosuccinimide in the presence of benzoyl peroxide in haloalkane, preferably carbon tetrachloride at 40-100aboutWith, preferably 70-80aboutC for 3-15 hours, preferably 4-6 h, and perform dehydrobrominated the compounds of formula X in the presence of 0.7 to 1.5 molar equivalents, preferably 1-1,1 molar equivalent of an alcoholate of an alkali metal, preferably of ethylate of sodium or of potassium tert-butylate, in an aromatic solvent, preferably benzene, at 75-85aboutC for 2-10 hours, preferably 4-7 PM

If you carry out the reaction for obtaining compounds of formula III by dehydrogenation of compounds of formula II, the 2,3-dichloro-5,6-dicyanobenzoquinone in aromatic solvents, preferably benzene, preferably at 75-80aboutC for 20 to 60 hours, preferably for 35-40 hours

Or carry out the dehydrogenation using 0.5 to 10 molar equivalents, preferably 1-3 molar equivalent leads to compounds, which lead aliphatic carboxylic acid, preferably glacial acetic acid at 90-100aboutC for 0.5 h, preferably 1-2 hours

According to the invention the compound of formula V is obtained by oxidation of compounds of formula III using nagkalat, preferably using 1-1,2 molar aqueous equivalent of meta-chloro-adventurou acid, and carry out the reaction in a halogenated hydrocarbon, preferably chloroform, in the presence of an aqueous solution of bicarbonate of alkali metals, preferably sodium bicarbonate at 0-5aboutWith over 3-40 h, preferably 18-23 hours

The final reaction product of the formula Vl is produced by the interaction of the compounds of formula (V) with 2-pyrrolidino and carry out the reaction in the presence of 1-1 .2 molar equivalent of an alkali metal, preferably sodium or alkali metal alcoholate, preferably sodium methylate or trebuchet potassium, at 20-30aboutC for 2-8 hours, preferably 3-5 hours


the epoxide of formula V can be obtained according to the invention with a high purity crystalline form;

the final reaction product of the formula (Vl) can be obtained under mild reaction conditions ( no need to use expensive sodium hydride and dimethylsulfoxide, which are dangerous for the environment and create difficulties during processing;

purification of the reaction product, and treating the reaction mixture are simple;

used solvents can be regenerated by distillation and can be returned in re-cycle;

the reaction can easily be controlled, and the volume of the reaction mixture may be increased;

industrial production does not require special equipment, and the reaction can be shown in the usual industrial plants.

According to the new way of Cromakalim can be obtained with the yield 55-65% relative to 4-cyano-phenol of the formula l, in contrast to the plants.

P R I m e R 1. Getting 6-cyano-2,2-dimethyl-2H-1-benzopyran.

with 11.9 g (0.1 mol) 4-cyan-phenol is dissolved in 200 ml of anhydrous benzene and then add small portions of 1.95 g (0.05 mole) of metallic potassium in the atmosphere of nitrogen. The reaction mixture is stirred until cessation of hydrogen evolution. Then added under stirring to 13.3 g (0.1 mol) of aluminum trichloride. With vigorous stirring, added dropwise 10 ml of 0.1 mol) of isoprene and 50 ml of absolute benzene. The reaction mixture is boiled for 6 hours, the Reaction mixture is cooled and add a solution of 250 ml of saturated ammonium chloride. The layers are separated, the organic layer is washed until neutral, dried over sodium sulfate, and the solvent is removed under vacuum. Get 17,29 g (92%) of colorless oil.

nD241,5475.

Calculated C 76,98; H 6,99; N Of 7.48.

Found, C 76,80; H 7,07; N 7,40.

PMR (DCl3): 1,35 (6N, singlet, 2 CH3), of 1.93 (2H, triplet, J 7 Hz, 3-CH2), 2,80 (2H, triplet, J 7 Hz, 4-CH2), to 6.80 (1H, double doublet, J18 Hz, J21 Hz, 7-H), 7,34 (2H, multiplet, 5H and 8H).

Mass spectrum (Rel, int.): 187 (60% M+), 172 (79%), 158 (32%), 144 (12%), 132 (100%), 116 (15%).

P R I m m e R 2. Getting 4-bromo-6-qi is I) 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and add to 18.7 g (0,105 mole) of N-bromo-succinimide and 1 g of peroxide Dibenzoyl.

The reaction mixture is boiled for 5 hours It is cooled, and precipitated succinimide filtered, washed with carbon tetrachloride 2 x 200 ml) and the combined organic layer is washed until neutral and dried over sodium sulfate, the solvent is removed. Get 25 g (94%) of a crystalline substance.

T,pl. 78-79aboutC.

Calculated, C, 56.16; H, 4.54; Br 30,02; N 5,26

Found, C 56,00; H, 4.60; Br 30,10; N 5,20.

PMR (DMSO-d6): of 1.29 (3H, singlet, CH3), to 1.47 (3H, singlet, CH3), and 2.26-2,69 (2H, multiplet, 3-CH2), USD 5.76 (1H, multiplet, Br-CH), 6,93 (1H, doublet, J 10 Hz, 8-H), TO 7.64 (1H, double doublet, J110 Hz, J22 Hz, 7-H), OF 7.90 (1H, doublet, J 2 Hz, 5-H).

P R I m er 3. Getting 6-cyano-2,2-dimethyl-2H-1-benzopyran.

of 26.6 g (0.1 mole) 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H - 1-benzopyran dissolved in 300 ml of benzene and added to 11.2 g (0.1 mol) of potassium tert-butylate. The reaction mixture is boiled for 4 hours It is cooled and washed with water 3 x 200 ml) and dried over sodium sulfate. After evaporation receive 17,05 g (95%) of a crystalline substance.

So pl. 45-47aboutC.

MICK (KBr): 2230 cm-1(literature data on so pl. 36-37aboutC).

P R I m e R 4. Getting 6-cyan-2,2-dim benzopyrene and type of 75.5 g (0.1 mole) of 90% ethylate sodium and the reaction mixture is boiled for 6 hours The following method similar to the method of example 3. Get 17 g (92%) of a solid substance, melting at 45-46aboutC.

P R I m e R 5. Getting 6-cyano-3,4-dihydro-2,2-dimethyl-2H - 1-benzopyran.

To stir a mixture of 220 g of 48% sulfuric acid and 200 g of chloroform added to 11.9 g (0.1 mole) of 4-cyano-phenol. Add at room temperature for 14 g (0.2 mole) of isoprene and the reaction mixture is vigorously stirred at 60aboutC for 5 hours the Mixture is cooled, the layers separated, and the organic layer washed with water 2 × 100 ml 5% sodium bicarbonate solution 2 x 150 ml water 2 x 100 ml, and the mixture is then dried over sodium sulfate. The solvent is removed under vacuum. Get to 17.7 g (95%) of colorless oil, physical constants and spectral data identical with the data disclosed in example 1.

P R I m e R 6. Getting 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran.

To a stirred mixture of 25 g (85% solution of phosphoric acid and 250 g of chloroform added to 11.9 g (0.1 mole) of 4-cyano-phenol. At room temperature add to 10.5 grams (0.15 mole) of isoprene, and the mixture is vigorously stirred at 60aboutC for 4 h, the Mixture can be further processed as described in example 5. Get 17,5 g (93%) bestwe achiveve a mixture of 40 g of 30% hydrochloric acid and 200 g of chloroform added to 11.9 g (0.1 mole) of 4-cyano-phenol. At room temperature add 21 grams (0,3 mol) of isoprene, and the mixture is vigorously stirred at 60aboutC for 5 h, the Mixture can be further processed as described in example 5. Get 16,8 g (90%) of colorless oil.

P R I m e R 8. Getting 6-cyano-2,2-dimethyl-2H-1-benzopyran.

In 300 ml of absolute benzene is boiled for 33 hours of 18.7 g (0.1 mol) of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and an increase of 22.7 g (0.1 mole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The solution is cooled, filtered, and mother liquor, washed with 5% sodium bicarbonate solution 3 x 100 ml), water (3 x 100 ml) and then dried over sodium sulfate, and the solvent is removed. Get 17 g (92%) of a crystalline substance, melting at 45-47aboutC.

P R I m e R 9. Getting 6-cyano-2,2-dimethyl-2H-1-benzopyran.

In 150 ml of glacial acetic acid in the presence of 41.5 g leads to compounds, which lead boiled for 2 h to 18.7 g (0,01 mol) of (6-cyano-3,4-hydro-2,2-dimethyl-2H-1-benzopyran). The mixture is cooled and poured onto 200 g of crushed ice, extracted with three times 100 ml of chloroform, and the organic layer washed with 5% sodium bicarbonate solution 3 x 100 ml) and water 3 x 100 ml. of the Mixture is dried over sodium sulfate, and after removal of the solvent receive 12,2-dimethyl-3,4-epoxy-2H-1-benzopyran.

In 300 ml of chloroform at room temperature dissolve of 18.5 g (0.1 mol) of 6-cyano-2,2-dimethyl-2H-1-benzopyran, after which the mixture is cooled with ice to 0 to 5aboutWith and add 37,74 g (to 0.011 mole) of a 50% meta-chloro-adventurou acid. The mixture is then stirred for 3 h, and after termination of cooling the reaction continued for 20 hours the Chloroform layer is then washed with 5% sodium hydroxide solution and water. The organic layer is dried over anhydrous sodium sulfate and evaporated. When cooled slowly get crystallizing yellow oil.

Output: 19,10 g (95%).

Etc., 104-105aboutC.

P R I m e R 11. Receive ()-6-cyano-3,4-dihydro-2,2-dimethyl - 3,4-epoxy-2H-1-benzopyran.

In 200 ml of water is dissolved 12,50 grams (0.15 mole) of sodium bicarbonate and the solution is then vigorously stirred together with a solution holds 18.52 g (0.1 mole) of 6-cyano-2,2-dimethyl-2H-1-benzopyran in 300 ml of chloroform. The reaction mixture is cooled to 0-5aboutWith and add 37,74 g (of 0.11 mole) of a 50% meta-chlormadinone acid. The mixture is then stirred for 3 h, and then after cessation of cooling the reaction continued for 20 hours, the Layers separated, the chloroform layer washed with 5% sodium hydroxide solution and water. Body is a pale yellow substance.

Output: 18,50 g (92%).

So pl. 103-104aboutC.

P R I m e R 12. Receive () -6-cyano-3,4-dihydro-2,2-dimethyl - TRANS-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-3-ol.

60 ml of 2-pyrrolidone is heated to 70aboutWith, and under inert atmospheric type of 2.53 g (0.11 g-atom) of metallic sodium. After complete addition, the solution is cooled to room temperature, add 20,12 g (0.1 mol () -6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran, and the reaction continued for 4 h Then the reaction mixture was poured onto 200 g of ice and vigorously stirred. Get a grayish-white precipitate, which is filtered, washed with ice water and dried. Raw the raw reaction product is recrystallized from a 3:2 mixture of chloroform and carbon tetrachloride.

Get a white, crystal substance in the form of small needles.

The output of 25.7 g (90%).

So pl. 229-230aboutC.

P R I m e R 1 3. Receive () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzop Iran-3-ol.

60 ml of pyrrolidone is heated to 40aboutWith, and in an inert atmosphere add 4,30 g (0.11 g-atom) of metallic potassium. After complete addition, the solution is cooled to room temperature, 4 h Then the reaction mixture was poured onto 200 g of ice and vigorously stirred. Get a grayish-white precipitate. It can be further processed as described in example 12, and the Output of 27.2 g (95%). So pl. 229-230aboutC.

P R I m e R 14. Receive () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzop Iran-3-ol.

60 ml of 2-pyrrolidone is dissolved at room temperature 20,12 g (0.1 mole) () -6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 - benzopyran and add to 12.35 g (of 0.11 mol) of potassium tert-butylate. The reaction mixture is supported at room temperature for 1.5 h, after which it was poured onto 200 g of ice. Then get a pale yellow precipitate. It can be processed further as described in example 12. Get a white, crystal substance in the form of small needles. The output of 25.5 g (85%).

So pl. 230-231aboutC.

1. METHOD GET ( )6-CYANO-3,4-DIHYDRO-2,2-DIMETHYL-TRANS-4-(2-OXO-1-PYRROLIDINYL)-2H-1-BENZOPYRAN-3-ol, including the interaction of 4-cyanophora with unsaturated hydrocarbon, characterized in that 4-cyanoprop subjected to interaction with isoprene at 30 120oIn the environment of a solvent in the presence of an alkali metal and/or catalyst and the resulting 6-cyan is storytale in the presence of a catalyst and/or oxidant or by synthesized in benzyl portion of the molecule and dehydrobrominated obtained 6-cyano-3,4-dihydro-2,2-dimethyl-4-bromo-2H-1-benzopyrane with production of 6-cyano-2,2-dimethyl-2H-benzopyran one-stage 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 -benzopyran effect of nagkalat in the environment of the solvent at 0, 20oWith and the subsequent interaction of this compound with 2-pyrrolidone in the presence of an alkali metal at 20 100oWith and release of the target product.

2. The method according to p. 1, characterized in that carry out the reaction of 4-cyano-phenol with isoprene in the presence of an alkali metal, preferably potassium, in the presence of catalysts Lisowska type at, preferably aluminum trichloride, in the environment of aromatic solvent, preferably benzene, at 60 to 80oC for 2 to 10 h, preferably 5 to 8 o'clock

3. The method according to p. 2, characterized in that the process is carried out at a molar ratio of 4-cyano-phenol of the formula isoprene potassium aluminum trichloride, is equal to 0,8 1,2 0,9 2,0 0,1 0,7 0,9 3,0 preferably 1 to 1 0.5 to 1.

4. The method according to p. 1, characterized in that carry out the reaction of interaction of 4-cyano-phenol of formula isoprene by acid catalysis in the environment of water-immiscible solvent and using as the acid catalyst, hydrochloric, sulfuric, phosphoric, perchloric, methansulfonate, paratoluenesulfonyl acids, preferably sulfuric acid, and using as a solvent of aliphatic and aromatic hydrocarbons, haloalkane the>

5. The method according to p. 4, characterized in that the process is carried out at a molar ratio of 4-cyano-phenol of the formula of isoprene 0.5 to 10.0, preferably 1 to 4.

6. The method according to p. 1, wherein 6-cyano-2,2-dimethyl-2H-1-benzopyran obtained by forming in the benzyl portion of the molecule 6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran and dehydrobrominated obtained 6-cyano-3,4-dihydro-2,2-dimethyl-4-bromo-2H - 1-benzopyran.

7. The method according to p. 6, characterized in that exercise bromination in the benzyl portion of the molecule 6-cyano-2,2-dimethyl-3,4-dihydro-2H-1 benzopyran with the help of 0.9 to 1.5 mol, preferably 1 to 1.1 mol, N-bromo-succinimide of carbon tetrachloride at 40 100oWith, preferably 70 to 80oC, for 3 to 15 hours, preferably 4 to 6 hours, and perform dehydrobrominated 6-cyano-3,4-dihydro-2,2-dimethyl-4-bromo-2H-1-benzopyran in the presence of 0.7 to 1.5 mol, preferably 1 to 1.1 mol, of an alcoholate of an alkali metal, preferably of ethylate of sodium or of potassium tert-butylate, in an environment of aromatic solvent, preferably benzene, at 75 85oC for 2 to 10 h, preferably 4 to 7 o'clock

8. The method according to p. 1, characterized in that carry out the reaction of obtaining 6-cyano-2,2-dimethyl-2H-1-benzopyran by d is Westley dehydrogenation using 0.5 to 10.0 mol, preferably 1 to 3 mol, 2,3-dichloro-5, 6-dicyanobenzoquinone in the environment of aromatic solvent, preferably benzene, preferably at 75 to 85oC for 20 to 60 hours, preferably 35 40 am

10. The method according to p. 8, characterized in that carry out the dehydrogenation using 0.5 to 10.0 mol, preferably 1 to 3 mol, leads to compounds, which lead aliphatic carboxylic acid, preferably glacial acetic acid at 90 100oC for 0.5 h, preferably 1 to 2 hours

11. The method according to p. 1, wherein 6-cyano-3,4-dihydro-2,2-dimethyl-3,4 epoxy-2H-1-benzopyran obtained by oxidation of 6-cyano-2,2-dimethyl-2H-1-benzopyrane with nagkalat, preferably 1 to 1.2 mole metacompetencies acid, and carry out the reaction in a halogenated hydrocarbon, preferably chloroform, in the presence of an aqueous solution of bicarbonate of an alkali metal, preferably sodium bicarbonate, at 0, 5oWith over 3 40 h, preferably 18 23 PM

12. The method according to p. 1, wherein 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran 2-pyrrolidone is carried out in the presence of 1 to 1.2 mol of an alkali metal, preferably sodium, or alkali metal alcoholate, predpochtitelnei product.

 

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The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to new cyclic imino-derivatives of General formula

In X And Y E (I) where a 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1means phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetaminophe, alkyl with 1-4 carbon atoms, substituted by two phenyl groups, cyclohexyl, naptalam or phenyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, moreover, these substituents are not in the position I, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, benzylaminocarbonyl, pyrrolidinecarbonyl, piperidyl, methylaminopropane, arylaminopoly, AMI - nomation, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of the cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A, R2alkyl with 1-4 carbon atoms, unsubstituted or substituted phenyl;

In amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano, one or two alkyl groups with 1-4 carbon atoms, alkoxycarbonyl with the total number of carbon atoms 2-5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y-E nonbranched alkyl with 2-5 carbon atoms, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1,2-Diocletian, carboxyla, phosphonopropyl, 0-methylphosphono, 0,0-dimethylphosphoric, oximation, alkoxycarbonyl with the total number of 2-7 carbon atoms, dimethylaminocarbonylmethyl is 1-3 carbon atoms in the CNS group, whereby phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted by alkyl with 1-4 carbon atoms, biphenyloxy, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

-X1X2X3X4X5where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -СОNH-, -NH-CO - or-NH-SO2- or between methylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of a, And X5with the rest IN;

X2nonbranched alkylen with 2-4 carbon atoms, albaniles with 2 or 3 carbon atoms and the double bond must not be adjacent to the heteroatom, phenylene, unsubstituted or substituted by fluorine, chlorine, bromine, stands, ethyl, trifluoromethyl, nitro-group, acetaminophe, meansville with 4-7 carbon atoms or bicycloalkyl to 7 carbon atoms;

X3bond, -CO-, -CO-NH -, or-NHCO-, if X3not directly followed by a heteroatom or a triple bond balance, and CO -,- CONH - and-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, the unbranched alkylene with 1-5 carbon atoms, phenylene, unsubstituted or substituted by fluorine, chlorine or stands, cycloalkyl with 4-7 carbon atoms;

X2together with X3and X4forms the unbranched alkylene with 3-6 carbon atoms, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or serialkiller from 8 to 11 carbon atoms;

X5link

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to the field of production of new derivatives pyrrolidine General formula

Y-Rwhere Y represents - (CH2)n-, whereby n = 0;

X is a hydrogen atom, halogen or lower alkyl group;

R is a phenyl group, phenyl group involved halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naftalina group, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl when n = 1;

X is H or halogen,

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y represents S(O)pwhere p = 0 or 2, -O - or-NH; X is hydrogen,

R-phenyl;

having anti-hypertensive activity

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-methyl-N-{(1S)-1-phenyl-1-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-2,2-diphenylacetamide. Method involves the following steps: (a) interaction of N-substituted derivative of phenylglycine of the formula (I): , wherein R means -OR1, -SR1; R1 means A, benzyl, unsubstituted phenyl or phenyl, biphenyl or naphthyl mono- or disubstituted with halogen atom, -OA or (C1-C6)-alkyl; A means linear or branched (C1-C6)-alkyl; M means hydrogen atom (H) or a cation chosen from group comprising alkaline metals, earth-alkaline metals, ammonium or alkylammonium with compound of the formula (II): , wherein R2 means H, A, or with acid-additive salt of compound of the formula (II) of acids HCl, HBr, HJ, H2SO4, H3PO4, or with organic carboxylic acid to obtain compound of the formula (III): , wherein R and R2 have above given values; (b) synthesized compound is converted to compound of the formula (IV): , by reduction reaction that is converted optionally to acid-additive salt of acids HCl, HBr, HJ, H2SO4, H3PO4, or to salt of organic carboxylic acid, and (c) synthesized compound of the formula (IV) is subjected for interaction with activated carboxylic acid of the formula (V): , wherein R4 means F, Cl, Br, J, -OA or -O-CO-A to yield compound of the formula (VI): , that is converted to a corresponding acid-additive salt using inorganic acid chosen from group comprising HCl, HBr, HJ, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, ortho-phosphoric acid or using organic acid.

EFFECT: improved method of synthesis.

7 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (IE) or of its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, including its chosen enantiomeric, diastereomeric and geometric isomers and their mixtures, where R4 and R5 are independently selected from C1-C6 alkoxy.

EFFECT: it makes it possible to use them in the pharmaceutical compositions and the methods of blocking Na channels in warm-blooded animals.

18 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tocopherol, tocotrienol and other derivatives of chroman of the general formula (1): wherein X is taken among the group comprising oxygen and nitrogen atoms; Y is taken among the group comprising oxygen, nitrogen and sulfur atoms wherein if Y represents oxygen or nitrogen atom then n = 1 and if Y represents sulfur atom then n = 0; R1 represents residue of carboxylic acid, carboxamide, ester, alcohol, amine or sulfate; R2 represents methyl; R3 represents methyl; R4 represents methyl; R5 is taken among the group comprising alkyl, alkenyl, alkynyl, carboxyl and ester residue wherein if Y represents nitrogen atom then indicated nitrogen atom is replaced with group R6 wherein R6 represents hydrogen atom or methyl wherein if X represents oxygen atom, Y represents oxygen atom and R5 represents phytyl then R1 doesn't mean butanoic acid. Also, invention relates to a pharmaceutical composition based on these compounds, a method for treatment of cellular-proliferative disease and a method for induction of cells apoptosis. Invention provides preparing new compounds possessing the proliferative effect.

EFFECT: valuable medicinal properties of compounds.

36 cl, 4 tbl, 19 dwg, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

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