Derivatives of 1,4-dihydropyridines and pharmaceutical composition based on them having vasoactive action

 

(57) Abstract:

The invention relates to new derivatives of 1,4-dihydropyridines with the General formula (I) listed in the description, where R1- nitro or trifluoromethyl, chlorine or chlorine atoms in positions 2 and 3, R2- rich C1-C8-alkyl straight or branched chain, or a group of the formula W-OZ, where W is a direct C1-C3-alkylen, Z-n-C1-C3-alkyl, R3is methyl or ethyl, n = 1 to 3. The proposed compounds have a vasodilator effect, and therefore can be used in the treatment of hypertension. Some of these compounds show vasoconstrictor activity and, thus, can be used to treat low blood pressure. Pharmaceutical composition based on them has vasoactive effect. 2 S. and 2 C.p. f-crystals, 4 PL.

The invention relates to new derivatives of 1,4-dihydropyridines and their use as pharmaceutical drugs with vasoactive effect.

It is known that some derivatives of 1,4-dihydropyridines have valuable pharmacological properties, affecting the blood flow in coronary vessels and reducing blood pressure. They cause the extension of the R. 578). On the other hand, through structural modification of such 1,4-dihydropyridines you can get a connection, providing vasoconstrictor and antihypotensive action (see German patent N A-2752820).

Currently, the search continues for new 1,4-dihydropyridines with increased efficacy and duration of action, devoid of unwanted side effects and is suitable for new ways therapeutic applications. The changes in the chemical structure can lead to changes in the physico-chemical properties of dihydropyridine system and at the same time affects such properties as the duration of action and selectivity.

For the treatment of angina or arrhythmias and changes in blood pressure in many patients successfully used diuretics and/or beta-blockers. However, these medicines do not provide full correction of severe hemodynamic disturbances, in particular the increase in peripheral resistance vessels. At the same time modern derivatives of 1,4-dihydropyridines, being a powerful vasodilator means, reduce the increased peripheral vascular resistance.

In addition, there is a problem predator, for example angina, developing due to an increase in heart rate.

In this connection, the new connection as the basis of pharmaceutical products should not cause too strong suppression of cardiac activity, and when tested in vivo or in vitro should give negative isotropically effect.

Available reports suggest wider use of these medicines for the treatment of hypertension due to the increased selectivity of their action on the cardiovascular system and the relatively small number of side effects. Their use in young patients with hypertension with high renin activity in plasma is limited, as they cause headaches, edema, reflex tachycardia and cardiodepression (see J. G. Lewis //Adverse, reactions to Calcium antagonists, Drugs, vol. 25, 1983, p. 196).

In addition, chronic treatment of hypertension, especially in elderly patients is difficult due to poor compliance of patients to the physician's orders, which largely contributes to the necessity of taking existing drugs several times a day.

The present invention is to develop) when you save it for possible period, reducing the frequency of drug application to once a day.

The present invention is the development of new derivatives of 1,4-dihydropyridines of General formula I:

,

where R1nitro or trifluoromethyl, chlorine or chlorine atoms in positions 2 and 3;

R2unsaturated C1-C8-alkyl straight or branched chain, or a group of the formula W-OZ, where W is a direct C1-C3-alkylene, and Z is H, C1-C3-alkyl;

R3methyl or ethyl;

n 1-3

or if R2-2-methyltetrahydrofuran, R1- 3-nitro, R3methyl, and n is 2.

Most preferred are the following compounds:

2-[N-(1,2-benzisothiazolin-3-(2H)- one-1,1-dioxide)] -ethyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid, or

2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] -1-ethyl ester of 2,6-dimethyl-5-isoproterenol-4-(2-triptoreline)-1,1-dihydropyridines-3-carboxylic acid, or

3-[N-(1,2-benzisothiazolin-3-((2H)-one-1,1-dioxide)] -propyl ester 4-(2,3-dichlorophenyl)-2,6-dimethyl-5 - methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid, or

3-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] -propyl ester 4-(2 the Lil-3(2H)-one-1,1-dioxide)] -ethyl ester of 2,6-dimethyl-4-(3-nitrophenyl)-5-[(2-tetrahydropyranyl)methoxycarbonyl]-1,4-dinitrophenyl-3-carboxylic acid, or

2-[N-(1,2-benzisothiazolin-3(2H)-one-1-oxide)]-ethyl ester 5-tert-butoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid, or

2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] -ethyl ester 5-tert-butoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dinitropyridine-3-carboxylic acid.

The compounds forming the subject of the present invention can be obtained by existing methods, for example by reaction:

a) compounds with the General formula (II):

,

in which R1and n as above,

and compounds with the General formula (III):

(III)

in which R2and R3as mentioned above,

with the formation of compounds with the General formula (I) or

b) compounds with the General formula (IV):

,

in which n is as defined above,

and compounds with the General formula (V):

,

in which R1, R2and R3as mentioned above,

with the formation of compounds with the General formula (I) or

in connection with General formula (VI):

R3CO, CH2COOR2,

in which

R2and R3as mentioned above,

compounds with the General formula (IV) in which n is as defined above, and compounds with the General formula (VII):

< / BR>
in which R1VIII):

,

in which as indicated above, the compounds with the General formula (III) in which R2and R3as described above, and compounds with the General formula (VII) in which R1as mentioned above,

with the formation of compounds with the General formula I or

d) compounds with the General formula (VI) in which R2and R3as mentioned above, the compounds with the General formula (VIII), in which as indicated above, and compounds with the General formula (VII) in which R1as described above, in the presence of ammonia, with the formation of compounds with the General formula (I).

The starting compounds are known substances or new connections that get existing methods.

Dosage forms on the basis of the proposed compounds intended for oral or rectal use. For the manufacture of compounds with the General formula (I) is combined with physiologically acceptable carriers, inactive ingredients and other additives. In connection with this object of the present invention are also medicines. Examples of such medicines are pills, coated tablet, capsules and suppositories, as well as liquid forms such as syrups and juices. The content of active ingredient the/P> Daily dose of active ingredient depends on the method of use of the medicinal product and in case of oral administration are usually 56-100 mg/day.

Example 1. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) Of 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester acetyloxy acid, of 5.55 g (0.05 M) of methyl ester of 3-aminocrotonic acid and 7,28 g (0.05 M) nitrobenzaldehyde is heated under conditions of flow and mixing in 50 ml of absolute ethanol for 10 hours. Cooling the resulting solution at room temperature is accompanied by the formation of a hard yellow substance with a melting point 179-182oC /after recrystallization from ethanol/. The yield of the final product is 67%

Example 2. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (005 M) 2-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide] ethyl ester acetyloxy acid, to 6.22 g (0.05 M) of methyl ester of 3-aminocrotonic acid and 7,28 g (0.05 M) of 3-nitrobenzaldehyde is heated in counter is once under reduced pressure is accompanied by the formation of a hard yellow substance with a melting point after recrystallization 89 - 91oC at exit 87%

Example 3. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3-carboxylic acid

A) 2-[N-(1,2-benzisothiazolin-3- (2H)-one-1,2-dioxide] ethyl ester 2-(3-nitrobenzylidene)acetyloxy acid

A mixture of 500 g (1,61 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester acutiloba acid 242,72 g (1,61 M) of 3-nitrobenzaldehyde, 7.3 ml of piperidine and 19.5 ml of glacial acetic acid are placed in 1.5 l of anhydrous isopropanol at 40oC and continuous stirring for 1 hour, then incubated for 16 hours at room temperature and, finally, two hours at 0oC. the resulting suspension is cooled to -10oC during the night, getting a solid yellow color with a melting point 145-147oC (after recrystallization from ethyl acetate). The yield of the final product is 85%

B) 2-[N-(1,2-benzisothiazolin-3- (2H)-one-1,1-dioxide]ethyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] ethyl ester 2-(3-nitrobenzylidene)acetyloxy acid and 4,85 g (0.03 M) 3-aminocrotonic acid in the form isop for 10 hours. The resulting solution is cooled to 0oC. the Solvent is drained. Get the product, which is dissolved in 10 ml of boiling ethyl acetate and leave at room temperature, stirring until complete solidification with the formation of a crystalline solid yellow color. Crystals are prismatic form with a melting point after recrystallization from methanol from 121 to 123oC. the Yield of the final product - 70%

Example 4. [N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide]methyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) of methyl ester of N-[1,2-benzisothiazolin-3(2H)-one-1,1-dioxide] acetyloxy acid, 6,52 (0.05 M) ethyl ester of 3-aminocrotonic acid and 7.69 g (0.05 M) of 3-nitrobenzaldehyde heated in 50 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 8 hours. The resulting liquid is cooled to -10oC for 12 hours, followed by stirring at room temperature, obtaining a solid yellow color with a melting point after recrystallization from ethanol 186-188oC. Yield 40%

Example 5. N-[1,2-benzisothiazolin-3-(2H)-one-1,2-dioxide] methyl ester of 2,6-DIN)-one-1,1-dioxide] methyl ether 2-(2-nitrobenzylidene)acetyloxy acid

A mixture of 50 g (0.33 M) of 2-nitrobenzaldehyde, 98,36 g (0.33 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester acetyloxy acid, 1.5 ml of piperidine and 4 ml of glacial acetic acid are heated in 620 ml of anhydrous isopropanol for 10 hours under vigorous stirring. After that, the resulting suspension is cooled during the night to -10oWith getting a solid yellow color with a melting point 140-141oC (after recrystallization from ethyl acetate). The yield of the final product -65%

B) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester of 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester 2-(2-nitrobenzylidene)acetyloxy acid and obtained as described in paragraph a, and 4,91 g (0.03 M) of methyl ester of 3-aminocrotonic acid are heated in 40 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 10 hours. After that, the solvent is removed by distillation under reduced pressure, and the residue is diluted with 20 ml of boiling ethyl acetate and allowed to cool (slow), thus obtaining a solid yellow color with a melting point 242-244o
A mixture of 15 g (0.03 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester 2-(2-nitrobenzylidene)-acetyloxy acid, obtained as described in example 5, and 5.55 g (0.03 M) of methoxyamine-3-aminocrotonic acid are heated in 40 ml of absolute ethanol under conditions of countercurrent and stirring for 10 hours. After that, the reaction mixture is slowly cooled at room temperature before the formation of solid yellow color with a melting point (after recrystallization from ethyl acetate) 180 to 182oC. the Yield of the final product 67%

Example 7. N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester of 2,6-dimethyl-5-(2-methoxyethoxymethyl)-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester acetyloxy acid, 8,03 g (0.05 M) 2-methoxyethanol ester 3-aminocrotonic acid and 7.62 g (0.05 M) of 3-nitrobenzaldehyde is heated under conditions of flow and mixing in 50 ml of isopropanol for 16 hours. After that the reaction mixture is cooled to room temperature with the formation of a solid yellow color, having a melting point at 164-165oC (after recrystallization from ethyl acetate). Output codemeter-5-methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) Of 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester acetyloxy acid, of 5.55 g (0.05 M) of methyl ester of 3-aminocrotonic acid and 8.43 g (0.05 M) of 2,3-dichlorobenzaldehyde heated in 50 ml of absolute ethanol under conditions of countercurrent and stirring for 10 hours. After that, the mixture is cooled to 0oC and left at this temperature for 5 hours. A solid yellow substance with a melting point 172-175oC (after recrystallization from ethanol). Yield 66%

Example 9. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 2,6-dimethyl-5-2-methoxyethoxymethyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] ethyl ester 2-(3-nitrobenzylidene)acetyloxy acid, obtained as described in example 3, and lower than the 5.37 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid are heated in 40 ml of absolute ethanol under conditions of countercurrent and stirring for 10 hours. After that the reaction mixture is cooled to -10oC, the solution is drained, and formed in the form of oil residue is first heated with 200 ml of a mixture of ethyl acetate and n-hexane (1:1), then stirred at room temp the Yield of the final product 51%

Example 10. N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide]methyl ester of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) of N-(1,2-benzisothiazolin)-3(2H)-one-1,1-dioxide methyl ester acetyloxy acid, of 5.81 g (0.05 M) of methyl ether-3-aminocrotonic acid and 7.62 g (0.05 M) of 3-nitrobenzaldehyde heated in 50 ml of absolute ethanol under conditions of countercurrent and stirring for 10 hours. After that the reaction mixture is stirred for 4 hours at room temperature and the resulting solid is dissolved in 600 ml of boiling ethanol. The resulting solution is cooled to room temperature, the solid precipitate is filtered off and the filtrate is concentrated to 1/3 of its volume and formation of solid yellow color with a melting point after recrystallization from ethanol from 187 to 188oC. the Yield of the final product - 43%

Example 11. N-91,2-benzisothiazolin-3-(2H)-one-1,1-dioxide]methyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-(2-methoxyethoxymethyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) N-[1,2-benzisothiazolin)-3(2H)-one-1,1-dioxide] methyl ester acetyloxy acid, 8,03 g (0.05 M) 2-methoxyethanol ester 3-aminocrotonic acid of 10 hours. After that the reaction mixture is cooled to -10oC, the supernatant liquid is drained and the sediment in the form of oil is dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete hardening and the formation of a yellow substance with a melting point (after recrystallization from ethyl acetate) 166-167oC. the Yield of the final product is 68%

Example 12. N-[1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide]methyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) N-[1,2-benzisothiazolin)-3(2H)-one-1,1-dioxide] methyl ester 2-(2-nitrobenzylidene)acetyloxy acid, obtained as described in example 5, 4.99 g (0.03 M) of isopropyl ester 3-aminocrotonic acid are heated in 40 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 10 hours. After that, the reaction mixture is slowly cooled down to room temperature with the formation of a solid yellow color, having a melting point 176-178oC (after recrystallization from ethanol). The yield of the final product in these conditions -79%

Example 13. N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioc the BR> A mixture of 15 g (0.05 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1]-dioxide methyl ester acetyloxy acid, of 5.81 g (0.05 M) of methyl ester of 3-aminocrotonic acid and 8,83 g (0.05 M) of 2,3-dichlorobenzaldehyde heated in 50 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 12 hours. After that the reaction mixture is cooled to -10oC, the supernatant discarded, and the residue is dissolved in 10 ml of boiling methanol. Then the resulting solution was stirred at room temperature until complete solidification, receiving a substance with a melting point 204-206oC, which on recrystallization from ethanol crystallizes and a half molecules of the latter. The yield of the final product is in these conditions 70%

Example 14. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 2,6-dimethyl-5-(2-methoxyethoxymethyl)-4-(2-triptoreline)-1,4-digitalorigin-3-carboxylic acid

A) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-triphtalocyaninine)-acetyloxy acid

A mixture of 50 ml (66 g, 0.38 M) 2-triftormetilfullerenov, 118 g (0.38 M) 2-N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester acetyloxy acid, 1.7 ml of piperidine and 4.6 ml of glacial acetic acid is within 16 hours stand at room temperature, then for a further 2 hours at 0oC. the resulting slurry is at -10oC during the night, which leads to the formation of a solid yellow color, having a melting point of from 135 to 137oC (after recrystallization from ethanol). The yield of the final product 87%

B) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 2,2-dimethyl-5-(2-methoxyethoxymethyl)-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-triphtalocyaninine)-acetyloxy acid and at 5.27 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 4 hours. After that the reaction mixture is cooled to 0oWith getting a solid yellow color with a melting point after recrystallization from ethanol 140-142oC. the Yield of the final product 81%

Example 15. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3 - carboxylic acid

A) 2-[N-(1,2-benzisothiazolin-3(2H)- one-1,1-dioxide)] ethyl ester 2-(2,3-dichlorobenzamide)-acetyloxy to ether acetyloxy acid, 1.3 ml of piperidine and 3.5 ml of glacial acetic acid were placed in a 270 ml of anhydrous isopropanol at 40oC for one hour with continuous stirring, and then was kept at room temperature for 16 hours and finally at 0oC for 2 hours. After that, the resulting suspension was left at -10oWith during the night, which led to the formation of a hard yellow substance with a melting point of 114 to 116oC. the Yield of the final product 95%

B) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5 - etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2,3-dichlorobenzamide)-acetyloxy acid and to 4.14 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 24 hours. After that, the reaction mixture is slowly cooled at room temperature until a solid yellow color, having a melting point (after recrystallization from ethanol) from 177 to 178oC. the Yield of the final product - 79%

Example 16. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]this is camping out 7,9 (0.02 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2,3-dichlorobenzamide)-acetyloxy acid, obtained as described in example 15, and 2,42 g (0.02 M) of isopropyl ester 3-aminocrotonic acid is heated under the conditions of distillation and mixing in 20 ml of absolute ethanol for 20 minutes. After that, the reaction mixture is slowly cooled to room temperature, receiving solid light yellow color with a melting point after recrystallization from ethanol 194-195oC. the Yield of the final product 79%

Example 17. 2-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide)] ethyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)ethyl ester 2-(2-triphtalocyaninine)-acetyloxy acid, obtained as described in example 14, and to 4.14 g (0.03 M) ethyl ester of 3-aminocrotonic acid are heated in 70 ml of anhydrous isopropanol in terms of flow and mixing for 20 minutes. After that the reaction mixture is cooled to -10oC. the Supernatant discarded, and the remainder is in the form of oil is dissolved in 15 ml of boiling ethyl acetate. The final solution is stirred at room temperature until complete solidification of getting the substance of light-yellow color, having a temperature of the melt(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-triphtalocyaninine)acetyloxy acid, obtained as described in example 14, and 4.6 g (0.03 M) of isopropyl ester 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 20 hours. After that, 15 ml of solvent is removed by distillation under reduced pressure, and the obtained solution is cooled during the night to -10oWith getting a solid white color with a melting point of 146-147oC (after recrystallization from ethyl acetate). The yield of the final product under these conditions is 77%

Example 19. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A) 2-[N-(31,2-benzisothiazolin-3- (2H)-one-1,1-dioxide)]ethyl ester 2-(2-chlorobenzylidene)acetyloxy acid

A mixture of 60 ml (74,88 g, 0,53 M) 2-chlorobenzaldehyde, 165,83 g (0,053 M) 2-[N - (1,2-benzothiazolin-3-(2H)-one-1,1-dioxide)]ethyl ester acetyloxy acid, 2.4 ml of piperidine and 6.4 ml of glacial acetic acid is stirred in 500 ml of anhydrous isopropyl alcohol at 40oWith over an hour, after which the judges, the suspension is cooled to -10oC during the night, and thus, the solid light-yellow color, having a melting point 163-165oC. the Yield of the final product is 92%

B) 2-[N-1,2-benzisothiazolin-3- (2H)-one-1,1-dioxide]ethyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-2H)-one-1,1-dioxide] -2-(2-chlorobenzylidene)-acetyloxy acid and 4,47 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated under conditions of countercurrent and continuous mixing in 35 ml of anhydrous isopropanol for 224 hours. After that the reaction mixture is cooled to room temperature, resulting in a solid yellow color with a melting point of 160-170oC (after recrystallization from ethanol). The yield of the final product 65%

Example 20.2 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 2,6-dimethyl-5-methoxycarbonyl-4-(2-triptoreline)- 1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-triphtalocyaninine)acetyloxy acid, obtained as described in example 14, and of 3.69 g (0.03 M) of methyl ester of 3-aminocrotonic acid is heated is in the reaction mixture is slowly cooled to room temperature, and thus receive the solid yellow color with a melting point 195-197oC (after recrystallization from ethanol). The yield of the final product under these conditions is 78%

Example 21. 2-[N-(1,2-benzothiazolyl)-3-(2H)-one-1,1-dioxide)]ethyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-(2-methoxycarbonyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-chlorobenzylidene)acetyloxy acid, obtained as described in example 19, and 5.5 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid are heated in 40 ml of absolute ethanol under conditions of countercurrent and constant stirring for 24 hours. Then remove the solvent by distilling the mixture under reduced pressure and the remaining material was diluted in 10 ml of boiling ethyl acetate. The final solution is stirred at room temperature until complete solidification, thus obtaining a solid yellow color with after recrystallization from ethanol the melting point of 128 to 130oC. the Yield of the final product 60%

Example 22. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-(2-methoxyethoxymethyl)-1,on ether 2-(2-dichlorobenzamide)acetyloxy acid, obtained as described in example 15, and 3.4 g (0.02 M) 2-methoxyethanol ester 3-aminocrotonic acid are heated in 25 ml of absolute ethanol under conditions of countercurrent and constant stirring for 20 hours. After that the reaction mixture is cooled to -10oC, discard supernatant liquid, and the residue is dissolved in 15 ml of boiling ethyl acetate. Finally, the resulting solution is cooled to 5oWith getting a solid substance with a melting point of 153 to 156oC (after recrystallization from ethanol). The yield of the final product 46%

Example 23. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-isopropoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0,03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] ethyl ester 2-(2-chlorobenzylidene)acetyloxy acid, obtained as described in example 19, and 4.95 g (0,03 M) isopropyl ester 3-aminocrotonic acid is heated in 160 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 24 hours. Then the reaction mixture was cooled to room temperature, obtaining a solid yellow color with a melting point (after recrystallization from ethyl acetate) 186-187o
A mixture of 15 g (0,03 M) 2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] ethyl ester 2-(2-hlorofenilpiperazin)acetyloxy acid, obtained as described in example 19, and 3.98 g (0,03 M) methyl ester 3-aminocrotonic acid are heated in 80 ml of absolute ethanol under conditions of countercurrent and continuous stirring during 24 hours. After that the reaction mixture is first cooled to -10oWith during the night, and then stirred at room temperature until complete solidification, and thus, solid substance with a melting point of from 160 to 162oC (after recrystallization from ethyl acetate). The yield of the final product -67%

Example 25. 3-[N-1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester acetyloxy acid, 6,97 g (0.05 M) of 3-nitrobenzaldehyde and 6.6 g (80,05 M) isopropyl ester 3-aminocrotonic acid are heated in 50 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 6 hours. After that the reaction mixture is cooled to room temperature, receiving solid yellow is the first product 64%

Example 26. 3[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester acetic acid, 6,97 g (0.05 M) of 3-nitrobenzaldehyde and 6 g (0.05 M) ethyl ester of 3-aminocrotonic acid are heated in 50 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 8 hours. After the reaction mixture was cooled to 0oC and stirred at this temperature until complete solidification in a yellow substance with a melting point 143-145oC (after recrystallization from ethanol). The yield of the final product under these conditions is 55%

Example 27. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester of 2,6-dimethyl-5 - methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzodiazepin-3-(2H)-one-1,1 - dioxide)] propyl ester acetyloxy acid, 6,97 (0,05 M) of 3-nitrobenzaldehyde and 5,31 g (0.05 M) of methyl ester of 3-aminocrotonic acid are heated in 50 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 8 hours. Then implement the compliance 185-188oWith that, if recrystallization from ethanol crystallizes and a half molecules of the latter. The yield of the final product is 70%

Example 28. 3-[N-(1,2-benzisothiazolin-(2H)-one-1,1-dioxide)]propyl ester of 2,6-dimethyl-5-(2-methoxyethoxymethyl)-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-1,1-dioxide)] propyl ester acetyloxy acid, 6,97 g (0.05 M) of 3-nitrobenzaldehyde and 7,34 g (0.05 M) 2-methoxyethanol ester 3-aminocrotonic acid are heated in 50 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 8 hours. After that the reaction mixture is cooled to -10oC, the supernatant fluid is drained off, and the residue is dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete solidification, receiving a yellow substance with a melting point after recrystallization from ethyl acetate 133-135oC. the Yield of the final product 64%

Example 29. 3-[N-(1,2-benzisothiazolin-3-(2H)-n-1,1-dioxide)]propyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-he-is about ether 3-aminocrotonic acid is heated under continuous stirring for 18 hours. After that the reaction mixture is cooled to -10oC, the supernatant discarded, and the residue is dissolved in 15 ml of boiling ethyl acetate. After dissolving the oily residue obtained liquid was stirred at room temperature until complete solidification, getting a white substance with a melting point after recrystallization from ethanol 173-177oC. the Yield of the final product under these conditions was 66%

Example 30. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 6-ethyl-2-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-(3-nitrobenzylidene)ethyl-2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] ethyl ester, obtained as described in example 3, and 4,36 g (0.03 M) of methyl ester of 3-amino-4-methylcrotonate acid is heated in 35 ml of absolute ethanol under conditions of protomoteca and continuous stirring for 8 hours. After that the reaction mixture is cooled to -10oC, the supernatant discarded and the oily residue is dissolved in 10 ml of boiling ethyl acetate. The final solution was stirred at room temperature until complete solidification, receiving a yellow substance with a melting point after perakis,1-dioxide)]ethyl ester 6-ethyl-2-methyl-5-methoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-triphtalocyaninine)-acetyloxy acid, obtained as described in example 14, and to 4.14 g (0.03 M) of methyl ester of 3-amino-4-methylcrotonate acid is heated under conditions of countercurrent with continuous stirring in 35 ml of absolute ethanol for 14 hours. After that the reaction mixture is cooled to -10oC, and thus, the solid yellow color with a melting point after recrystallization from ethyl acetate 137-138oC. the Yield of the final product 49%

Example 32. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester 4-(2-chlorophenyl-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester 2-(2-chlorobenzylidene)acetyloxy acid

A mixture of 25 g (0.08 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] propyl ester acetyloxy acid, and 8.7 ml (0.08 M), 10.8 g of 2-chlorobenzaldehyde, with 0.27 ml of glacial acetic acid and 0.44 ml of piperidine in 50 ml of anhydrous isopropanol for one hour stirred at 44oC, then continue stirring at room temperature for 16 hours and finally another 2 hours at 0oC. follow-up to the LTO blocks-orange color with a melting point 66-68oC. the Yield of the final product 77%

B) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 12 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester 2-(2-chlorobenzylidene)-acetyloxy acid and 3.5 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated in 90 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 24 hours. After that the reaction mixture is cooled to room temperature, which leads to the formation of a solid yellow color, having a melting point of 171 to 172oC (after recrystallization from ethanol). The yield of the final product 65%

Example 33. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A) 3-[N-(1,2-benzisothiazolin-3- (2H)-one-1,1-dioxide)] propyl ester 2-(2-triphtalocyaninine)acetyloxy acid

A mixture of 25 g (0,08 M) propyl ether acetyloxy acid 3-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1 - dioxide] 10.1 ml (13,38 g of 0.08 M) 2-triftormetilfullerenov, with 0.27 ml of glacial acetic acid and 0.44 ml piperine wee room temperature for 16 hours and another 2 hours at 0oC. After the reaction, the mixture is left at -10oWith during the night, which leads to the formation of a very dense oily residue, which is separated, drain the supernatant and diluted in 15 ml of boiling ethyl acetate. The final solution was stirred at room temperature until complete solidification to the substance of white color, having a melting point of 104 to 105oC. the Yield of the final product under these conditions is 76%

B) 3-[N-(1,2-benzisothiazolin-3- (2H)-one-1,1-dioxide)]propylether 2,6-dimethyl-5-isopropoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid and 4.5 g (0,03 M) isopropyl ester 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 18 hours. After that the reaction mixture is cooled to -10oC, receiving solid light yellow color with a melting point 175-176oC /after recrystallization from ethanol). The yield of the final product 80%

Example 34. 3-[N-(1,2-benzisothiazolin-(2H)-one-1,1-dioxide]propyl ester 4-(2-chlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 12 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)one-1,1-dioxide)] praelonga ester 3-aminocrotonic acid are heated in 60 ml of absolute benchmark in terms of flow and continuous stirring for 24 hours. After that the reaction mixture is cooled to room temperature, resulting in formation of a hard yellow substance with a melting point 170-171oC (after recrystallization from standard). The yield of the final product under these conditions is 66%

Example 35. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 4-(2,3-dichlorophenyl)-6-ethyl-2-methyl-5-methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0,03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester of 2,3-(dichlorobenzamide)acetyloxy acid, obtained as described in example 15, and 4.1 g (0,03 M) methyl ester 3-aminocrotonic acid is heated in 35 ml of absolute benchmark in terms of counter-current with continuous stirring for 18 hours. After that the reaction mixture is cooled to -10oC. this forms a very dense precipitate in the form of oil, which is separated, merging nadosadocnuu liquid. Then the precipitate is dissolved in 15 ml of boiling ethyl acetate. Finally, the thus obtained solution was subjected to stirring at room temperature, which leads to the formation of solid crystalline substances of yellow color in the form of needles, which has a melting point at 173-175oC (after percectly ester 4-(2-chlorophenyl)-6-ethyl-5-methoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0,03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] ethyl ester 2-(2-chlorobenzylidene)acetyloxy acid, obtained as described in example 19, and 4,47 g (0,03 M) methyl ester 3-aminocrotonic acid is heated under conditions of countercurrent and continuous mixing in 70 ml of absolute ethanol for 24 hours. After that, the solvent is removed by distillation under reduced pressure, and the remaining oily residue is dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete solidification with the formation of the substance of white color, having a melting point after recrystallization from ethanol 195-196oC. the Yield of the final product 68%

Example 37.

A) 3-[N-(1,2-benzisothiazolin-3- (2H)-one-1,1-dioxide)] propyl ester 2-(2-nitrobenzylidene)acetyloxy acid

A mixture of 50 grams (0.15 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester acetyloxy acid, 23, 22 g (0.15 M) 2-nitrobenzaldehyde, 0.8 ml of piperidine and 0.5 ml of glacial acetic acid in 100 ml of anhydrous isopropanol was stirred at 60oC for 3 hours, then continue stirring at room temperature for 20 chemparathi before the formation of solids yellowish color with a melting point (after recrystallization from ethanol) 112-113oC. the Yield of the final product 75%

B) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] -propyl ester of 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0,03 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-(2-nitrobenzylidene)acetyloxy acid and 3.77 g (0,03 M) methyl ester 3-aminocrotonic acid is heated under conditions of countercurrent and continuous mixing in 35 ml of anhydrous isopropanol for 10 hours. After that the reaction mixture is cooled to room temperature, resulting in formation of a hard yellow substance with a melting point (after recrystallization from ethanol) from 191 to 193oC. the Yield of the final product 62%

Example 38. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester of 2,6-dimethyl-5-(2-methoxyethoxymethyl)-4-(2-nitrophenyl)-1,4-dinitropyridine-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-(2-nitrobenzylidene)acetyloxy acid, obtained as described in example 37, and a total of 5.21 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent and continuous stirring for 18 is a very thick oil, which separate, decant the supernatant liquid. The residue is dissolved in 10 ml of boiling ethyl acetate. The final solution was stirred at room temperature until complete solidification and get a yellow substance with a melting point 146-150oC (after recrystallization from ethanol and ethyl acetate). The yield of the final product under these conditions is 22%

Example 39. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-1,1 - dioxide)]propyl ester 2-(2-nitrobenzylidene)acetyloxy acid, obtained as described in example 37, and 4,69 g (0.03 M) of isopropyl ester 3-aminocrotonic acid are heated in 70 ml of isopropanol under conditions of countercurrent with continuous stirring for 12 hours. After that the reaction mixture is cooled to room temperature, thus obtaining a solid yellow color with a melting point of 177-179oC (after recrystallization from ethyl acetate). The yield of the final product 60%

Example 40. 3-[N-1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyrido is n)acetyloxy acid

A mixture of 100 g (0,31 M) ethyl-3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester, 53,8 g (0,31 M) of 2,3-dichlorobenzaldehyde, 1,76 ml of piperidine and 1.1 ml of glacial acetic acid in 200 ml of isopropanol was stirred at 60oC for 2 hours, then continue stirring at room temperature for 24 hours and finally at 0oC for 2 hours. After that, the resulting suspension is kept over night at -10oWith, thus obtaining a solid yellow color, having a melting point of between 116 and 118oC (after recrystallization from ethanol). The yield of the final product 89%

C) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-DIACID)]propyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.05 M) 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester of 2-(2,3-dichlorobenzamide)acetyloxy acid and 4.15 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated under conditions of countercurrent and continuous mixing in 35 ml of anhydrous ethanol for 24 hours. After that the reaction mixture is cooled to -10oWith that leads to the formation of very dense oily residue, which is separated, while the supernatant liquid is atoi temperature for 3 hours prior to the formation of a solid yellow substance with a melting point of 172-174oC (after recrystallization from ethyl acetate). The yield of the final product 41%

Example 41. 3[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester of 2,6-dimetyl-5-etoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)one-1,1 - dioxide)] propyl ester 2-(2-nitrobenzylidene)acetyloxy acid, obtained as described in example 37, and to 4.23 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated in 35 ml of anhydrous isopropanol for 16 hours. After that the reaction mixture is cooled to room temperature, which leads to the formation of solid crystalline yellow substance with a melting point (after recrystallization from ethanol) between 166 and 168oC. the Yield of the final product 60%

Example 42. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-isopropoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-(2-dichlorobenzamide)acetyloxy acid, obtained as described in example 40, and 4.61 in (0.03 M) of isopropyl ester 3-aminocrotonic acid is heated in 35 ml of anhydrous isopropanol in terms P10oWith that leads to the formation of a very thick oil, which is drained and dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete solidification and obtaining the substance of light-yellow color in the form of crystalline particles with a melting point of at 165-167oC (after recrystallization from ethanol). The yield of the final product 70%

Example 43. 3-[N-(1,2-benzisothiazolin-3(2H)-one-1,1 - dioxide)]propyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carbonyl acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3(2H) he 1,1-dioxide)] propyl ester 2-(2-triphtalocyaninine)acetyloxy acid, obtained as described in example 33, and was 4.02 g (0.03 M) ethyl ester of 3-aminocrotonic acid is heated in 35 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 20 hours. After that the reaction mixture is cooled to room temperature, resulting in formation of a hard yellow substance with a melting point at 153 to 155oC (after recrystallization from ethanol). The yield of the final product 78%

Example 44. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester of 2,6-DIMET of 30 g (0,07 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 2-(3-nitrobenzylidene)acetyloxy acid, obtained as described in example 3, and 13,45 g (0,07 M) 3-aminocrotonic acid in the form of 2-tetrahydropyranyl ether is heated under conditions of countercurrent with continuous stirring in 70 ml of absolute ethanol for 8 hours. After that, the reaction mixture is left overnight at room temperature, and the solid yellow color, having a melting point between 189 and 191oC (after recrystallization from ethyl acetate). The yield of the final product 79%

Example 45. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester of 2,6-dimethyl-5-(2-methoxycarbonyl)-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 51 g (0.03 M) Of 3-[N-(2,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester 2-(2-triphtalocyaninine)acetic acid obtained as described in example 33, and 4,96 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 35 ml of absolute ethanol for 20 hours. After that the reaction mixture is cooled to -10oC, the supernatant discarded, and the residue is dissolved in 10 ml of boiling ethyl acetate. Thus obtained solution is cooled to 5oC, receiving solid yellow
Example 46. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester 6-ethyl-2-methyl-5-methoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-(2-triphtalocyaninine)acetyloxy acid, obtained as described in example 33, and was 4.02 g (0.03 M) of methyl ester of 3-amino-4-methylcrotonate acid is heated in 35 ml of absolute ethanol under conditions of countercurrent with continuous stirring for 20 hours. After that, the solvent is removed by distillation under reduced pressure and the resulting residue is dissolved in 10 ml of boiling ethyl acetate. Thus obtained solution is cooled to 5oC, which leads to the formation of a hard yellow substance with a melting point 144-147oC (after recrystallization from ethyl acetate). The yield of the final product 35%

Example 47. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]methyl ester 6-ethyl-2-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester of 2-(3-nitrobenzylidene)acetyloxy acid

A mixture of 50 g (0.33 M) of 3-nitrobenzaldehyde, 98,36 g (0.03 M) mechilovsky acid in 215 ml of anhydrous isopropanol was stirred at 60oC for 4 hours, then continue stirring at room temperature for 24 hours and finally at 0oC for a further 3 hours. After that, the resulting suspension is drained, and the remaining residue is dissolved in 20 ml of boiling ethyl acetate. After that, the resulting solution was stirred at room temperature until complete solidification of the substance of light-yellow color with a melting point of at 175-177oC, which is used in the next stage without additional purification. The yield of the final product 65%

B) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide]methyl ester 6-ethyl-2-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0,035 M) N-[1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide] methyl ester of 2-(3-nitrobenzylidene)acetyloxy acid and 4.5 g (0,035 M) 3-amino-4-methylcrotonate acid in the form of methyl ester is heated under conditions of countercurrent with continuous stirring in 35 ml of absolute ethanol for 12 hours. After that the reaction mixture is cooled to 5oC, which leads to the formation of a solid yellow color, having a melting point between 176 and 178oC (after recrystallization from ethanol). The yield of the final product 47%

Example 48. 3-[N-(hydropyridine-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-(2-chlorobenzylidene)acetyloxy acid - 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)]propyl ester, obtained as described in example 32, and 5.32 g (0.03 M) 2-methoxyethanol ester 3-aminocrotonic acid is heated under conditions of countercurrent and continuous mixing in 35 ml of absolute ethanol for 24 hours. Then by distillation under reduced pressure to remove the solvent, and the residue is dissolved in 15 ml of boiling Diisopropylamine. Thus obtained solution during the night cooled to -10oC, which leads to the formation of a solid yellow color, having a melting point of from 55 to 101oC (after recrystallization from ethanol). The yield of the final product - 63%

Example 49. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 5-tert-butoxycarbonyl-4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 13,47 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1 - dioxide)] ethyl ester 2-(2-chlorobenzylidene)acetyloxy acid, obtained as described in example 19, and 4,88 g (0.03 M) of tert-butyl methyl ether 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 40 ml of absolute ethanol for about 15 colors having a melting point between 173 and 175oC (after recrystallization from ethanol). The yield of the final product 66%

Example 50. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester 5-tert-butoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-2,3-dichlorobenzimidazole acid, obtained as described in example 40, and of 5.06 g (0.03 M) butyl ether 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 40 ml of absolute ethanol for 20 hours. After that the reaction mixture is cooled to room temperature, resulting in formation of a hard yellow substance with a melting point of between 201 and 203oC (after recrystallization from ethanol). The yield of the final product - 58%

Example 51. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 5-tert-butoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] ethyl ester 2-(3-nitrobenzimidazole acid, obtained as described in example 3, and 5.31g (0.03 M) of tert-butyl E. the aqueous ethanol for 12 hours. After that, the solvent is removed by distillation under reduced pressure, and the residue is dissolved in 10 ml of boiling methanol. Thus obtained solution was stirred at room temperature until complete curing in yellow prismatic crystals having a melting point of 153 to 155oC (after recrystallization from ethanol). The yield of the final product 74%

Example 52. 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]propyl ester 4-(2-chlorophenol)-2,6-dimethyl-5-isopropoxycarbonyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) Of 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] propyl ester 2-(2-chlorobenzylidene)acetyloxy acid, obtained as described in example 32, and 4.8 g (0.03 M) of isopropyl ester 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 35 ml of absolute ethanol for 24 hours. After that, 20 ml of solvent is removed by distillation under reduced pressure and the remaining solution is cooled to -10oWith, resulting in a solid yellow color, having a melting point of between 142 and 145oC (after recrystallization from ethanol). The yield of the final product 87%

Example 53. N-[(1,2-benzisothiazolin)-3-(2H)-it-1, is s

A mixture of 15 g (0.03 M) N-[1,2-benzisothiazolin-(2H)-one-1,1-dioxide]methyl ester of 2-(3-nitrobenzylidene)acetyloxy acid, obtained as described in example 47, and of 5.48 g (0.03 M) of tert-butyl methyl ether 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 80 ml of anhydrous ethanol for 12 hours. After that the reaction mixture is cooled to room temperature, resulting in formation of a hard yellow substance in the form of prismatic crystals, which has a melting point of 207 to 209oC (after recrystallization from ethanol). The yield of the final product 70%

Example 54. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 5-tert-butoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 2-(2-nitrobenzylidene)acetyloxy acid

A mixture of 100 g (0.66 M) 2-nitrobenzaldehyde, 206 g (0.66 M) 2-[N-(1,2-benzisothiazolin)-3-(2H)-one-1,1-dioxide)] ethyl ester acetyloxy acid, 3 ml of piperidine and 8 ml of glacial acetic acid in 620 ml of anhydrous isopropanol leave for 0.5 hour at 40oWith continuously stirring it, and then continue stirring at komnatnogo filtered and washed with boiling methanol, what gives the material a light yellow color with a melting point between 161 and 163oC. the Yield of the final product 85%

B) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester 5-tert-butoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)] ethyl ester 2-(2-nitrobenzylidene)acetyloxy acid and 5.31g (0.03 M) of tert-butyl methyl ether 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 40 ml of absolute ethanol for 12 hours. After that the reaction mixture during the night cooled to -10oC, the supernatant discarded, and the remaining residue is dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete solidification, resulting in the formation of the yellow substance with a melting point of 164 to 165oC (after recrystallization from ethanol). The yield of the final product

57%

Example 55. 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1 - dioxide)]ethyl ester 5-tert-butoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridines-3-carboxylic acid

A mixture of 15 g (0.03 M) 2-[N - (1,2-benzis is isano in example 15, and 5,04 g (0.03 M) of tert-butyl methyl ether 3-aminocrotonic acid is heated under conditions of countercurrent with continuous stirring in 40 ml of absolute ethanol for 14 hours. After that, the solvent is evaporated by distillation under reduced pressure and the remaining residue is dissolved in 15 ml of boiling ethyl acetate. Thus obtained solution was stirred at room temperature until complete solidification and formation of a yellow substance with a melting point after recrystallization from ethyl acetate 160-163oC. the Yield of the final product - 80%

Biological tests

The vasodilator action of the tested preparations was determined as follows. Isolated thoracic aorta of new Zealand rabbits were placed in a container for culturing organs. Contractile activity spiral strips of the wall of the aorta was evaluated after depolarization Krebs solution in the absence of calcium (35 mm potassium) and after adding individual portions of exogenous calcium (1,55 mm). The tested compounds were introduced into the system in increasing concentrations prior to the introduction of calcium. Figures IC50(the negative logarithm of the molar concentration causing 50% inhibition induced their curves.

Selective effect of test compounds on certain fabrics were evaluated against indicators IC50(molar concentration causing 50% inhibition of contraction in the isolated left atrium of rabbits under conditions of stimulation to the indicators IC50when depolarization rabbit aortic K+.

The left atrium was placed in a container for the cultivation of bodies in the presence of 1 g of Krebs solution saturated with 95% O2and 5% CO2when 30-32oC. electrical Stimulation was carried out at 1 Hz. After equilibration of the system during the hours of initial airway took over 100% Then every 15 minutes was added to the test compounds at increasing concentrations and recorded the changes in the force of contraction of the tissue. Figures IC50was calculated on the basis of the dependence of the effect on the dose, which was determined separately from each experiment (table. 1).

Antihypertensive activity of test compounds was evaluated in rats Okamoto with spontaneous hypertension. Systolic blood pressure was determined in the blood vessels of the tail using plethysmographic method. On the day of experiment, rats were placed for 2 hours in a thermostat at 311oWith and made sapsprint. Hypertensive thought only animals in which the basal values of systolic blood pressure exceeded 170 mm RT.article The test compound at a dose of 20 mg/kg or vehicle (20% PEG in a 0.5% aqueous solution of methylcellulose) at a dose of 10 ml/kg was administered orally using a stomach probe 24 hours after cessation of feeding animals. The results were expressed in percent of initial value 2 hours after the injection. The data obtained are presented in table. 2.

The duration of action of the tested compounds was evaluated on isolated thoracic aorta of rabbits. After the reduction depolarized fragments of rabbit aorta induced by adding calcium blocked test compound in a concentration of 10-7M, fabric every 30 minutes re-laundered sequential introduction of individual servings of calcium for a total of 4 hours. Registered recovery (%) normal contractility of the aorta (table. 3).

The control connection is used nifedipine is 3,5-dimethyl ether of 2,2-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3,5-dicarboxylic acid.

Vasoconstrictor . the touch, the concentration of K+was 10 mm. To enhance the contractile activity was added to increasing concentrations of test compounds.

Indicators EC50(the negative logarithm of the molar concentration causing strengthening stimulating action of calcium on the contractile activity in the conditions of weak depolarization rabbit aortic K+50%) was determined using the corresponding dose-dependent curves (table. 4).

1. Derivatives of 1,4-dihydropyridines of General formula I

< / BR>
where R1nitro or trifluoromethyl, chlorine or chlorine atoms in positions 2 and 3;

R2rich C1-C8-alkyl straight or branched chain, or a group of the formula W-OZ, where W is a direct C1-C3-alkylene, and Z is H, C1-C3-alkyl;

R3methyl or ethyl;

n 1 3,

or if R2methyltetrahydrofuran, R1- 3-nitro-, R3methyl, and n is 2.

2. Connection on p. 1 representing 2-[N-(1,2-benzisothiazolin-3 (2H)-one-1,1-dioxide)] -ethyl ester of 2,6-dimethyl-5-etoxycarbonyl-4-(2-triptoreline)-1,4-dihydropyridines-3-carboxylic acid or 2-[N-(1,2-benzisothiazolin-3 (2H)-one-1,1-dioxy)] 1-ethyl ester of 2,6-dimethyl-5-isopropoxycarbonyl-4-(Lowy ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4 - dihydropyridines-3-carboxylic acid, or 3-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] propyl ester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-5-etoxycarbonyl-1,4-dihydropyridines-3 - carboxylic acid, or 2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] ethyl ester of 2,6-dimethyl-4-(3-nitrophenyl)-5- [2-tetrahydropyranyl)-methoxycarbonyl] 1,4-dinitrophenyl-3-carboxylic acid, or 2-[N-(1,2-benzisothiazolin-3(2H)-one-1,1-dioxide)] ethyl ester 5-tert.butoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridines-3-carboxylic acid, or 2-[N-(1,2-benzisothiazolin-3 (2H)-one-1,1-dioxide)] ethyl ester 5-tert. butoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridines-3-carboxylic acid.

3. Pharmaceutical composition having vasoactive action, including an active ingredient and a carrier, characterized in that as the active ingredient it contains a derivative of 1,4-dihydropyridines of General formula I in an effective amount.

4. The composition according to p. 3, characterized in that as the active ingredient it contains 2,6-dimethyl-4-(3-nitrophenyl)-5-[(2-tetrahydropyranyl)-methoxycarbonyl] -1,4-dihydropyridines-3-carboxylic acid, or 2-[N-(1,2-benzisothiazolin-3-(2H)-one-1,1-dioxide)] ethyl ester and has vasoconstrictive activity.

 

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IB R=CHF2O-, R'=CH3O-, Alk=C2H5(K-3);

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< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

< / BR>
Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

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The invention relates to agriculture, particularly livestock, and can be used to reduce losses of meat production and maintaining (improving) its qualitative characteristics of young cattle, due to technological stress factors when growing, fattening and implementation

FIELD: medicine, endocrinology, pharmacology, pharmacy.

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10 cl, 3 tbl

FIELD: medicine, toxicology.

SUBSTANCE: invention proposes applying 15% aqueous solution of 1-methyl-5-[2'-(benzyldimethylammonio)ethyl]carbamoyl pyridinium-2-aldoxime dichloride that exceeds the 15% solution of dipiroxime (TMB-4, trimedoxime bromide) used in native medicinal practice by the curative effectiveness. Invention can be used in urgent treatment of acute poisoning with organophosphorus poisonous substances eliciting neuroparalytic effect.

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EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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13 cl, 1 tbl, 30 ex

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25 cl, 29 ex

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

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EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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