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

 

(57) Abstract:

Usage: in medicine as an antihypertensive. The inventive product () -6-cyano-3, 4-dihydro-2,2 - dietitans-4-(2-oxo-1 - pyrrolidinyl)- 2H-1 - benzopyran-3-ol (cromakalim). Reagent 1: 4-cyanoprop. Reagent 2: 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 at 40-150°C bromilow in the 4-position benzoylpyrazoles rings. Reagent 4: (a) 4 - bromo - cyano - 3,4-dihydro - 2,2-dimethyl-2H-1 - benzopyran are dihydrobromide. Reagent 5: 6-cyano-3,4-dihydro-2,2 - dimethyl-2H-1 - benzopyran. Reagent 6: N-bromosuccinimide. Process conditions: in the midst of the solvent at 20-120°C. the Reagent 7: 6-cyano-3,4 - dihydro-2,2 - dimethyl - TRANS-3 - bromo-4-hydroxy-2H - benzopyran. Reagent 8: 2-pyrrolidon. Process conditions: in the presence of an alkali metal or an alcoholate of an alkali metal at 20-100°C. the Yield of the target product to 55-65%. 10 C.p. f-crystals.

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.

Of cromac the group of antihypertensive substances, works by opening potassium channels in smooth muscle cells and prevents the accumulation of electric potential across the membrane. Thus, it belongs to the activators potassium channels.

When receiving Cromakalim 4-cyano-phenol of the formula

(II) is reacted with 3-chloro-3-methyl-bootrom, resulting in propargilovyh ether of the formula H3(III) which is then subjected to a closing cycle to produce 6-cyano-2,2-dimethyl-2H-1-benzo (a) pyrene formula H3(IV)

The compound of formula (IV) is converted then after 6-Sinotrans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzo (a) pyrene-4-ol 6-cyano-3,4-dihydro-3,4-epoxy-2,2-dime-Teal-2H-1 - benzopyran formula

H3(V)

Of the compounds of formula (V) may be obtained from the final reaction product of the formula (I) in three ways.

1). The 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 of the formula

(VI) which is then subjected to reaction with the acid chloride of 4-harpalani acid to obtain the compounds of formula (VII) This compound is then subjected circuit loop to the system sodium hydride tetrahydrofuran.

2). The compound of formula (V) is subjected to reaction with 4-Amii formula (I).

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 the formula (I).

If these methods revealed the following shortcomings:

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; propargilovyh ether of the formula (III) 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 potassium carbonate and potassium iodide at 50-150aboutWith; after 30-40 hours of reaction can be achieved only 40-55% yield. An additional problem is that only 3-hydroxy-3-methyl-butyl is commercially available and according to the experiments of 3-chloro-3-methyl-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 an unstable compound, it decomposes upon standing and at the same time he is polymerized during the alkylation reaction, or he ruslanio propargilovyh ether of the formula (III) with access only 45-55% of this ester is then subjected to the cycle closing in orthodichlorobenzene to 6-cyano-2,2-dimethyl-2H-1-benzopyran formula (IV) with yields of 80% When playing back a response was received output at best 70% purification of the reaction product of the formula (IV) is a complex procedure and can be carried out by vacuum distillation or column chromatography. This reaction can be obtained derivative chromene formula (IV) with the release of 35% relative to 4-cyano-phenol of formula (II) and 23% relative to 3-chloro-3-methyl-butyne.

3-Bromo-4-auxiproizvodnykh formula

(VIII) can be obtained from chromene formula (IV) in dimethyl sulfoxide and water with the release of 90% in a Similar manner epoxide of formula (V) can be obtained with a yield of 90% by reaction between 3-bromo-4-auxiproizvodnykh formula (VIII) with sodium hydroxide in the presence of a solvent mixture of dioxane and water, i.e., can be carried out the conversion of (IV) ->> (VIII) >> (V);

The final reaction product of the formula (VI) was carried out by the most simple method, i.e., the epoxide of formula (V) was subjected to reaction with 3-pyrrolidone in the presence of sodium hydride and dimethyl sulfoxide. Was received quite a complex reaction mixture by thin-layer chromatography it was possible to determine 6-8 components, the number of which was comparable. The reaction was repeated several times and the final reaction product of the formula (I) was obtained with the yield of 20-25% only using complicated column chromatography as opposed to output 60% according to the invention.

According to known technique, the end ol the dick, when played on their own experiments can be carried out with only 6-8% Thus, these techniques are unsuitable for industrial production of Cromakalim formula (I).

The purpose of the invention to carefully develop a new economical and industrial accessible way of obtaining Cromakalim.

This invention relates to a new method get ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-1-Pirro - leinil) -2H-1-benzopyran-3-ol of the formula (I) from 4-cyano-phenol of formula (II) by reacting 4-cyano-phenol of formula (II) with isoprene at 30-120aboutWith in a solvent in the presence of alkali metals and/or catalysts with obtaining 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran formula (IX),

H3(IX) which is then bromilow in the 4-position benzopyrrole ring at 40-150aboutWith subsequent dehydrobrominated received () 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran obtaining 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran, which is subjected to reaction with N-bramucci - nimid in a solvent at from 20 to 100aboutWith obtaining 6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-3-bromo-4-hydroxy-2H-1-benzopyran formula (VIII), which then undergoes reaction with 2-pyrrolidone is the reaction product of the formula (I).

The present invention has the following advantages:

4-cyano-phenol of formula (II) reacts with isoprene with almost quantitative yield;

isoprene is inexpensive, readily available industrial intermediate product;

chromen formula (IV) can be obtained by selective reaction with good yield, therefore, is cleared only by crystallization in contrast to vacuum distillation;

the epoxide of formula (V) may be obtained according to the invention with a high frequency in crystalline form;

the final reaction product of the formula (I) can be obtained under mild reaction conditions, there is no need to use expensive sodium hydride dimethyl sulfoxide, 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 in the volume of the reaction mixture may be increased;

industrial production does not require special equipment and the reaction can be carried out on normal commercial installations.

The present invention is illustrated by the following examples.

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

In 200 ml of anhydrous benzene is dissolved 5,95 g (0.05 mol) of 4-cyano-phenol 13.3 g (0.1 mol) of aluminum trichloride. With vigorous stirring, added dropwise 10 ml (0.1 mol) of isoprene and 50 ml of absolute benzene. The reaction mixture is boiled for 6 h, then cooled and added dropwise 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, nD24: 1,5475. Analysis N N Calculated, 76,98 6,99 Of 7.48 Found, 76,80 7,07 7,40

PMR (CDCl3): 1,35 (6N, singlet, 2 CH3) to 1.83 (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. Receive () 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran.

In 200 ml of carbon tetrachloride is dissolved to 19.7 g (0.1 mol) of 6-cyan-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and add to 18.7 g (0,105 mol) of N-bromo-succinimide and 1 g of peroxide dibenzyl.

R is rechlorinated carbon h ml. The combined organic layer is washed until neutral, dried over sodium sulfate and the solvent is removed. Get 25 g (94%) of a crystalline substance.

So pl. 78-79aboutC. Analysis With N Br N Calculated, 56,16 4,54 30,02 5,26 Found 56,00 4,60 30,10 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, 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 e R 3. Getting 6-cyano-2,2-dimethyl-2H-2-benzopyran.

of 26.6 g (0.1 mol) () 4-bromo-6-cyan-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran dissolved in 300 ml of benzene and added 11.2 g (0.1 mol) of trebuchet potassium. The reaction mixture is boiled for 4 hours It is cooled and washed with water h ml) and dried over sodium sulfate. After evaporation gain of 17.5 g (95%) of a crystalline substance.

So pl. 45-47aboutC.

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

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

In 250 ml of benzene are dissolved to 26.6 g (0.1 mol) () 4-bromo-6-cyan-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran add, and 75.5 g (0.1 mol) of 90% ethylate sodium and the reaction mixture xtva, melting at 45-46aboutC.

P R I m e R 5. Getting 6-cyan-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 11.9 g (0.1 mol) of 4-cyano-phenol. Add at room temperature for 14 g (0.2 mol) of isoprene and the reaction mixture is vigorously stirred at 60aboutC for 5 hours the Mixture is cooled, the layers separated, the organic layer washed with water h ml, 5% sodium bicarbonate solution x ml and water h 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 to the data of example 1.

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

To a stirred mixture of 25 g of a 85% aqueous solution of orthophosphoric acid and 250 g of chloroform added 11.9 g (0.1 mol) of 4-cyanophora. At room temperature add 10.6 g (0.15 mol) 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 (98%) of colorless oil.

P R I m e R 7. Getting 6-cyan-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran.

To re the ri 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 according to example 5. Get 16,8 g (90%) of colorless oil.

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

In 300 ml of absolute benzene is boiled for 38 h at 18.7 g (0.1 mol) of 6-cyan-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and an increase of 22.7 g (0.1 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The solution is cooled, filtered off and mother liquor was washed with 5% sodium bicarbonate solution h ml water h 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-2-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-cyan-3,4-dihydro-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 x ml and water h ml. of the Mixture is dried over sodium sulfate and after removal of the solvent gain of 17.4 g (94%) of a solid substance, melting at 46-47aboutC.

P R I m e R 10. Receive (1)-TRANS-3-bromo-6-cyan-3,4-dihydro-2,2-Dec) 6-cyan-2,2-dimethyl-2H-2-benzopyran, to the solution are added dropwise at 32-35aboutWith 35,59 g (0.2 mol) of N-bromosuccinimide and 100 ml of 90% tertrahydrofuran ring solution. The mixture is further subjected to reaction at room temperature for 7 h and then evaporated. When cooled, the precipitated yellow crystalline substance, which is dissolved in hot carbon tetrachloride, insoluble succinimide filtered off and the filtrate is evaporated. Get slowly crystallizing yellow oil.

Output: 26,8 (95%).

So pl. 128,5-129,5about(Literature is so pl. 128-128,5aboutC).

P R I m e R 11. Receive ()-6-cyan-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-3-ol.

90 ml of 2-pyrrolidone is heated to 70aboutWith and under inert atmospheric type 4.83 g (0.21 g atom) of metallic sodium. After complete addition, the solution is cooled to room temperature and add 28,21 g (0.1 mol) (1)-TRANS-3-bromo-6-cyan-3,4-dihydro - 2,2-dimethyl-2H-1-benzopyran-4-ol. After 4 h reaction time the reaction mixture is poured onto 200 g of ice and vigorously stirred. The mixture can be further processed according to example 10. Get a white, crystal substance in the form of small needles.

Yield: 27 g (94%), so PL-1-benzopyran-3-ol.

In 90 ml of 2-pyrrolidone is dissolved at room temperature 28,21 g (0.1 mol) (1)-TRANS-3-bromo-6-cyan-3,4-dihydro-2,2-di - methyl-2H-1-benzopyran-4-ol and while cooling with ice water add 23,56 g (0.21 mol) of trebuchet potassium. After that, the mixture is stirred for 1.5 h at room temperature and poured onto 200 g of ice. Get a pale yellow precipitate. It can be further processed as shown in example 11.

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

Yield: 26 g (91%).

So pl. 230-231aboutC.

1. The WAY to OBTAIN 6-CYANO-3,4-DIHYDRO-2,2-DIMETHYL-TRANS-4-(2-HYDROXY-1-PYRROLIDINYL)-2H-1-BENZOPYRAN-3-ol, including the interaction of 4-cyanophora with unsaturated hydrocarbon, characterized in that, to increase output, as the unsaturated hydrocarbon used isoprene and the process is carried out at 30 120oIn the environment of a solvent in the presence of an alkali metal and/or catalyst and the resulting 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran bromilow in the 4-position benzopyrrole ring with subsequent dehydrobrominated received () 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and interaction obtained 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-banter-3-bromo-4-hydroxy-2H-1-benzopyran subjected to interaction with 2-pyrrolidone in the presence of an alkali metal or an alcoholate of an alkali metal at 20 100oC.

2. The method according to p. 1, characterized in that carry out the reaction of 4-cyano-phenol with isoprene in the presence of alkali metals, preferably of potassium, in the presence of catalysts Lisowska type, preferably aluminum trichloride, in an 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 molar ratio of 4-cyano-phenol: isoprene potassium aluminum trichloride is 0,8 1,2 0,9 2,0 1,7 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 4-cyano-phenol with isoprene by catalysis of acids in water-immiscible solvent and using 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 to 80oWith preferably for 4 to 6 hours

5. The method according to p. 4, characterized in that the molar ratio of 4-the Ute bromination in the benzyl portion of the molecule 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrane with the help of 0.9 to 1.5 molar equivalent, preferably of 1.0 to 1.1 molar equivalents of N-bromosuccinimide, in the presence of benzoyl peroxide in haloalkane, preferably carbon tetrachloride, at 40 100owith, preferably 70 80oC, for 3 to 15 hours, preferably 4 to 6 hours, and perform dehydrophenylalanine () 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran in the presence of 0.7 to 1.5 molar equivalent, preferably 1 to 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 85oC for 2 to 10 h, preferably 4 to 7 o'clock

7. The method according to p. 1, characterized in that carry out the reaction of obtaining 6-cyano-2,2-dimethyl-2H-1-benzopyran by dehydrogenation of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran.

8. The method according to p. 7, characterized in that carry out the dehydrogenation using a 0.5 to 10.0 molar equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone (CRS) in an aromatic solvent, preferably benzene, preferably at 75 to 80oC for 20 to 60 hours, preferably within 35 40 am

9. The method according to p. 7, characterized in that carry out the dehydrogenation using 0.5 to 10 molar equivalent, predpechatnoy acid, when 90 100oC for 0.5 h, preferably within 1 to 2 hours

10. The method according to p. 1, characterized in that the receive 6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-3-bromo-4-hydroxy-2H-1-benzopyran by reacting 6-cyano-2,2-dimethyl-2H-1-benzopyrane with preferably from 1.0 to 1.2 molar equivalent of N-bromosuccinimide and carry out the reaction, preferably in a mixture of tetrahydrofuran and water at 30 to 40oWith preferably for 1.5 to 2.5 hours

11. The method according to p. 1, characterized in that the interaction of 6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-3-bromo-4-hydroxy-2H-1-benzopyran 2-pyrrolidone is carried out in the presence of 1.0 to 2.1 molar equivalent of alkali metals, preferably sodium, or alkali metal alcoholate, preferably of Metelev or sodium tert-butylated potassium at 20 to 30°C for 2 to 8 hours, preferably 3 to 5 hours

 

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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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing methyl 1 -[3-(cyclohexylcarbamoyl)-2-oxochroman-4-yl]cyclopentanecarboxylate of formula (1) which consists in boiling 1-bromcyclopentanecarboxylic acid methyl ester with zinc and 2-oxo-2H-chromen-3-carboxylic acid cyclohexylamide in the medium of benzol - ethylacetate - hexamethylphosphorotriamide (10:5:1) for 4 hours.

EFFECT: produced compound is novel and possesses analgesic action.

1 tbl, 2 ex

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