SU1435152A3 - Method of producing derivatives of 1,5-benzothiazepin or pharmaceutically acceptable salts thereof - Google Patents

Abstract

Novel fused 7-membered ring compounds represented by formula (I), (wherein R<1> and R<2> each represents hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy or, when bound to each other, they represent tri- or tetra- methylene, R<3> and R<5> each represents hydrogen, lower alkyl or aralkyl, R<4> represents hydrogen or lower alkyl, R<6> represents a fused or non-fused hetero-alicyclic group containing at least one N, O or S as ring atom, A represents an alkylene chain, and n represents 1 or 2) and the salts thereof. These compounds are effective in inhibiting angiotensin converting enzyme, and are useful as agents for diagnosis, prophylaxis and treatment of circulatory organ diseases including hypertension, heart diseases, and apoplexy.

Description

s

 This invention relates to a process for the preparation of new 1,5-benzothiazepine derivatives of the formula

0

CSNOp Soon

where

or their pharmaceutically acceptable salts, which have the activity of an inhibitor of the enzyme that converts angiotensin, and can be used in medicine in the treatment of hypertension, cardiopathy and cerebral apoplexy.

The aim of the invention is to obtain derivatives of 1,5-benzothiazepine with the activity of an angiotensin-converting enzyme inhibitor.

Example 1. A mixture of tert-butyl ester 3 (Juamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (3 g), 100 ml of acetonitrile, 4, 0 g of 6- (1-benzyloxycarbonyl-4-piperidyl) -2-: chlorhexanoic acid ethyl ester, 1.0 g of triethylamine and 1.6 g of potassium iodide are transferred at 80 ° C for 3 days. Ethyl ether is added 6- (1-bevsyl-hydroxycarbonyl-4-piperidyl) -2-chloro-hexanoic acid (2.0 g) and 0.8 g of potassium iodide and stirring is continued at 80 ° C. for an additional day. The mixture is concentrated in vacuo , diluted with 100 ml of water and extracted with ethyl acetate. atom (300 ml). The extract is washed with water, dried with anhydrous magnesium sulfate and evaporated in vacuo. When chromatographic purification of the residue (oil) on a column of silica gel (hexane: ethyl acetate 2: 1), tert-butyl ether 3 (R) - 3– (1 -benzyloxycarbonyl-4-piperidyl) -1 (K) -ethoxycarbonylpentyl amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (3.1 g) as colorless oil and tert-butyl ether 3 (R) (1-benzyl oxycarbonate-4-pipovidil) -1- (S) -etoc cicarbonone JI-pentilyl amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine- 5-acetic acid (2.1 g) as colorless oils.

five

0

five

0

five

0

five

0

five

Example 2, A mixture of 3 (K) -amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester (2.05 g) and 1.5 g 6- (1-benzine 1 -carbonyl-4-piperidyl) -2-meta-sulfonyl-hydroxyhexanoic acid ethyl ester is heated at 90 ° C for 24 hours. After cooling, 300 ml of ethyl acetate are added to the mixture and the resulting solution is washed with two portions (30 ml) of a 5% phosphoric acid solution and then with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oily residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to give 0.7 g of tert-butyl ether 3 (R) (1-benzyloxycarbonyl-4 -piperidyl) -1 (R) -ethoxycarbonylpentyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless oil. From the subsequent fraction, 0.55 g of 3 (R) -t-butyl ether (1-benzyl-hydroxycarbonyl-4-piperidyl) -1 (S) -ethoxy-carbonyl-pentyl 3 amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetic acid as a colorless oil.

Example 3. 3.7 g of 6- (1-benz1-hydroxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid and 4.4 g of quinine are dissolved in hot acetone in B1501-III. After removal of the insoluble material by filtration, the solution is placed in a refrigerator. The crystals that separated were collected by filtration and recrystallized three times from acetone to give 1.9 g of quinine salt as colorless crystals. This salt (1.2 g) is added to a mixture of 200 ml of ethyl acetate and 50 ml of 1 and. hydrochloric acid and the resulting mixture is thoroughly mixed. An ethyl acetate layer is washed with 1N. hydrochloric acid (30, 20 ml) and then with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 50 ml of toluene, 10 ml of ethyl alcohol and 0.05 g of para-toluenesulfonic acid are added to the oily residue (0.6 g). The resulting mixture was stirred for 3 hours, cooled, diluted with ethyl acetate, washed twice with water (50 ml each time) and dried over anhydrous magnesium sulphate. Evaporation of the solvent gives 0.6 g.

31

ethyl ester as a colorless oil, which is dissolved in 5 ml of pyridine. To the stirred solution is added dropwise 0.5 ml of methanesulfonyl chloride at ice bath temperature. After stirring for 2 hours at ice bath temperature, the mixture is stirred at room temperature for 30 minutes and cooled again in an ice bath. Then 0.5 ml of water is added and the mixture is stirred at an ice-bath temperature for 30 minutes and at room temperature also for 30 minutes. The mixture is diluted with water (20 ml) and extracted with ethyl acetate (.50 ml). The extract is washed successively with 10% hydrochloric acid, water, 1N sodium hydroxide solution and water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 0.6 g of 6-C1-benzyl-cicarbonyl-4-piperidyl ethyl ether ) -2-Methyl-naphthoxyhexanoic acid in the form of a colorless oil, oi. -12.8 ° (in methanol). A mixture of this sulfonate (0.5 g) and 0.1 g of 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is heated at 80-100 ° C during the day. After cooling, 200 ml of ethyl acetate is added, and the resulting solution is successively washed with 5% phosphoric acid solution (30, 20 ml) and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a yellow oil, which is purified by chromatography on a silica gel column (hexane: ethyl acetate 2: 1). From the first fraction, 0.45 g of 3 (.R) -5- (. 1-benzyloxycarbonyl-4-piperidyl-1 (K) -ethoxycarbonyl-M-amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless oil. From the second fraction, 0.09 g of tert-butyl 3 (K) -G5- (1-benzyloxycarbonyl-4-piperidyl) -1- (3 ) -ethoxycarbonylpentyl amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless oil.

Example 4. In 50 ml of hot acetone, 5 g of 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid and 4.2 g of cinchonidine are dissolved. After cooling, the solution is once

Q 5 n 5 n

0

52

Add 50 ml of diethyl ether and expose to refrigerate. The precipitated crystals are removed by filtration, and the filtrate is concentrated in vacuo. The residue is dissolved in 5 ml of acetone and the resulting solution is diluted with 35 ml of diethyl ether. After refrigerating, the crystals formed are collected by filtration to obtain 1.4 g of cinchonidine salt. This salt (1.3 g) is added to a mixture of 200 ml of ethyl acetate and 50 ml of 1N. hydrochloric acid and the resulting mixture is thoroughly mixed. An ethyl acetate layer is washed with 1N. hydrochloric acid (50 ml) and water (50 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo, an oily precipitate is obtained, which is dissolved in a mixture of 30 ml of toluene, 3 ml of ethyl spirit and 0.05 g of paratoluenesulfonic acid . This solution is stirred for 1 hour at 90-100 ° C, cooled, diluted with ethyl acetate (200 ml) and washed twice with water (50 ml each time). The organic layer was dried over anhydrous magnesium sulphate and evaporated in vacuo to give the ethyl ester as a colorless oil, which was dissolved in 5 ml of pyridine. To the stirred solution is added dropwise 0.4 ml of methanesulfonyl chloride at the temperature of the ice bath. After stirring for 30 minutes, 1 ml of water was added to the mixture, and the resulting mixture was stirred for 30 minutes at an ice-bath temperature and diluted with 150 ml of ethyl acetate. The organic layer is washed successively with 1N. hydrochloric acid (2 times 50 ml), sodium bicarbonate solution (50 ml) and water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 6- (1-benzyloxycarbonyl-4-piperidyl) ethyl ester -2- methanesulfonyloxyhexanoic acid (0.8 g) as a colorless oil., 7 ° (in methanol). A mixture of this mesylate (0.72 g) and 1.46-g of 3 (K) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester stirred overnight at 90-100 ° C. After cooling, the reaction mixture is dissolved in 200 ml of ethyl acetate and the solution is washed successively with a 5% phosphorus acid solution (twice but 30 ml) and dried, dried over anhydrous magnesium sulfate and evaporated in vacuo, a yellow oil is obtained, which is purified Chromatographically on a column of silica gel (hexane: ethyl acetate 2: 1). From the first fraction, 0.12 g of 3 (R) -5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl / amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine 5-acetic acid as a colorless oil. From the second fraction, 0.52 g of 3 (R) -5- (1-benzox 1oxycarbonyl-4-piperidyl) 1 (5) -ethoxycarbonylpentyl amino-4-QKCO-2,3,4,5-tetrahydro-1 tert-butyl ether is obtained; 5 Benzothiazepine-5-acetic acid as a colorless oil.

Example 5. B2 ml of acetic acid dissolve 0.6 g of tert-butyl-3 (R) -3- (1-benzyloxycarbonyl-4-piperidyl-1CR) ethoxycarbonyl-propyl-3-amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetate, 2 ml of 30% aqueous solution of hydrogen bromide in ethyl acetate are added to the solution and the mixture is left to stand at room temperature for 1 hour. 150 ml of diethyl ether are added to the reaction solution and the mixture is allowed to settle. After that, the solvent is decanted, the precipitate is washed with diethyl ether, dried, and 0.5 g of dihydrobromide is obtained; 3 (R) - 1 (R) -ethoxy-parboxylic acid, p-3- (4-pipe-rydyl) propyl amino-4-oxo- -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder. - 106 ° (from 0.6 in methanol).

Found,%: C 41.43, H 5.39, N 6.30

C, jHj,. 2NVG.N20.

Calculated,%: C 41.96; H 5.60; N 6.68.

Example 6, analogously to example 5, 0.4 g of tertiary-3 (R) (1-benzyloxycarbonyl-4-piperidyl) - (S) -ethoxycarbonylpropyl amino-4-oxo-2, 3,4,5-tetrahydro-1, 5-Benzotkazepin 5-acetate is treated with hydrogen bromide, 0.35 g of dihydrobromide 3 (K) - 1 - (S) -ethoxycarbonyl-3- (4-piperidyl) propyl amino-4-oxo-2,3,4,5 - tetrahydro-1,5-benzothiazepic-5-acetic acid as a colorless powder .. fixLln methanol

3SI326

Found, Z: C 40.47; H 5.32; N 6.28.

C2, H. ,, N, 05.S 2 HBr-HjO. Calculated,%: C 40.81-, H 5.76;

N 6.49.

Example 7. B4 ml of 1N aqueous solution of sodium hydroxide dissolved 0.15 g of 3 (R) D (5) -ethoxycarbonyl-3- (4-piperidyl) propyl amino 4-oxo-2,3,4,5- the tetrahydro-1,5-benzothiazepine-5-acetic acid prepared in Example 6 and the solution was left to stand at room temperature.

temperature for 2 hours. The solution is weakly acidified with 1 ml of acetic acid and purified by column chromatography on Amberliti XAD-2 (methanol: water 1: 1). The eluate is concentrated under reduced pressure, the residue is lyophilized, and 0.06 g of 3 (R) (S) -carboxy-3- (4-pyperidyl) propyl amino-4-oxo-2,3,4,5-tetrahydro is obtained. -1,5-benzothiazepine-acetic acid as a colorless powder. . - 128 ° (with 0.1 in a mixture of methanol-water). Mass Spectrum (m / fe): 422 CMH); with the addition of KJ: 450 CM + K).

Found %: C 54.05, H 6.17; S 9.21

C.H.N.O.S.

Calculated,%: C, $ 54.65; H, 6.65; N, 9.56. PRI me R 8. A mixture of 0.4 g of tert-butyl 3 (R) -aMHHo-4-pKco-2,3,4,5-tetrahydro-1,5-benzothiazepine 5-acetic acid, 1 g of ethyl ester 4 - (1-benzyloxycarbonyl-4-pyperidyl) -2-x-butyric acid, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile are heated

under reflux for 2 days. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by chromatography on a column of sipicagel (hexane: ethyl acetate 2: 1) to give 0.15 g of tert-butyl 3 (R) ether (1-benztoxycarbonyl-4-peridyl) -1 (R ) -ethoxycarbonyl-I-amino-4-oxo-2,3,4,5-tetrahydro-1,5benzothiazepine-5-acetic acid and 0.25 g of 3 (R) -3 1 -benzyloxycarbonyl-4-piperidyl tert-butyl ester -1 (8) -ethoxycarbonyl1Propyl / amino-4-oxo-2,3,4,5-tetrahydro-1,5benzothiazepine-5-acetic acid

in the form of colorless oily products.

Example 9. Acetic acid-B1ML is dissolved in 0.5 g of t-butyl 7

3 (R) (1-benzyloxycarbonyl-4-piperidyl) -1- (R) -ethoxycarbonylhexyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5 ester α-acetic acid and to this solution 2 ml of 30% hydrogen bromide in acetic acid was added, the mixture was kept at room temperature for 1 hour. 200 ml of diethyl ether was added to the reaction solution and the mixture was allowed to stand. The supernatant is decanted and the precipitate is dissolved in 20 ml of 1N. an aqueous solution of sodium hydroxide, after which

allow the solution to stand at room temperature for 30 minutes. This solution is neutralized by adding 2 ml of acetic acid, and purified on a column by the method of MS1 gel chromatography (water: methanol 1: 2). The eluent is concentrated under reduced pressure, and the residue is lyophilized, 0.23 g of 3 (R) (R) -Kap6oKCH-6- (4-piperidyl) hexyl amino-4-oxo-2,3 4,5-tetrahydro-1 is obtained, 5-benzothiazepine-5-acetic acid in the form of a colorless powder, 144 ° (in water).

EXAMPLE 10 B1 ml of acetic acid dissolves 3 (K) tert-butyl ester 3 (K) (1-benzyloxycarbonyl-4-piperidyl) -1- (S) ethoxycarbonyl hexylJ amino-4-oxo-2,3,4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid and to this solution add 2 ml of a 30% aqueous solution of hydrogen bromide in acetic acid, react the reaction mixture at room temperature for 1.5 hours. B the solution is added with 200 ml of diethyl ether and allowed to stand. The supernatant is decanted and the precipitate is dissolved in 30 ml of 1N. sodium hydroxide aqueous solution, then leave the solution to stand at room temperature for 30 minutes. 3 ml of acetic acid and i are added to the solution; purified by the method of MC1 gel chromatography (water and methanol 1: 2). The eluent is concentrated under reduced pressure and the residue is lyophilized, yielding 0.43 g of 3 (K) (8) -carboxy-6- (4-periperidyl) hexyl amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetic acid as a colorless powder. oi} j3 - 121 ° (in water), mass spectrum of secondary ions (m / e): 464 (MH).

Example 11 0.3 g of tert is dissolved in 1.5 ml of acetic acid

20

- - s -,

ib

y, "with

- 35 45 50 - 55

528

butyl ester 3 (R) (1-benyl-hydroxycarbonyl-4-1Shleridyl) -1 (5) -ethoxycarbonylheptyl amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine-5- acetic acid and to this solution 1 ml of 30% hydrogen bromide in acetic acid was added, the mixture was kept at room temperature for 0.5 h. 80 ml of diethyl ether was added to the reaction solution, and the solution was allowed to stand. the precipitate is decanted off, the precipitate is dissolved in 10 ml of 1N. aqueous solution of sodium hydroxide, maintain the solution at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid and purified by chromatography on an HRD-2 column (water: methyl alcohol 1: 1). The eluent is concentrated under reduced pressure and the residue is lyophilized, yielding 0.1 g of 3 (R) -fl (S) -carboxyl-7 (4-piperidyl) -heptyl3-amine-4-oco-2,3,4,5 - tetrahydro-1, 5-benzothiazepine-5-acetic acid as a colorless powder. (in water). Mass spectrum of secondary ions (t / e): 478 (MN).

EXAMPLE 12 Vyum acetic acid dissolve 5.2 g of 3 (K) tert-butyl ester (1) (1-benzylcarbonylpiperidine) -1 (S) -ethoxycarbonylpentyl amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid and add 10 ml of 30% aqueous solution of hydrogen bromide in acetic acid. The mixture was kept at room temperature for 1.5 hours and then 200 ml of diethyl ether were added to the mixture. After settling, the supernatant is removed by decantation, the precipitate is dissolved in 90 ml of 1N. an aqueous solution of sodium hydroxide. After keeping the mixture at room temperature for 1.5 hours, the mixture is neutralized with acetic acid (10 ml), purified by chromatography on a column with MC1 gel (water: methanol 1: 1). The eluate is concentrated under reduced pressure to approximately 10 ml and the crystallized crystals are collected by filtration and dried, yielding 2.1 g of 3 (R) -fl (S) -carboxy-5- (4-piperidyl) -pentyl amno-4 -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless crystalline powder, melting at a temperature of

hpppuric acid produced by PPA by adding a compound. A solution of compound I in a buffer solution of 5% dimethyl sulfoxide 100 mM reverse hydrochloric acid (H 8.3 5. containing 300 mM sodium chloride) is added to 100 ml of PPA (protein concentration 200 mg / ml) and 100 μl of 1.25 mm GGL. In this experiment

A batch solution containing dimethyl sulfoxide at a concentration of 5 equal to the concentration in the test solution was used as a control. After the solution was heated for 1 hour, 1150 µl 1 and were added to it. hydrochloric acid, for 10GO, to terminate the reaction. After adding 0.8 µl of ethyl acetate, the solution is centrifuged at a speed of 1 ~ 1500 rpm for 2 minutes. From this 4 acetate layer, an aliquot of 0.5 ml is taken and dried at a temperature not higher than 40 ° C in a stream of gaseous chlorine. The residue is thoroughly mixed with e, 4.5 ml of distilled water, and the mixture is subjected to colorimetric g at a wavelength of 223 nm.

The test results obtained for compound i 5 are presented in abl. one .

Experimental example 2.

The effect of compounds 1 on the hypertrophic activity of angiotensin 1

(Experimental technique).

As experimental animals, males, SSpra-i ye-Aulei rats, weighing from 300 to 400 g, were used as yorks, and they were fed with sufficient free nutrition to measure hypertonic activity. Then 300 µg / kg of compound are administered intravenously.

1 as an isotonic saline and after 5, 10, 30, 60, .90 and 120 minutes after this administration, angiotensin I and II are re-injected to follow the hypertonic reactions. When calculating the percentage inhibition of the angiotensin I hypertonic activity, the percentage of inhibition was corrected for the basis of the time variation of the hypertonic reaction caused by angiotensin II.

The test results obtained for the compound; 1, are presented in table. 2

Compounds 1 are low toxic compounds and can be found in medicine.

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Claims (1)

Invention Formula The method of obtaining derivatives, 5-benzothiazepine formula / - (CH2) Do-: MNSI-Soon N i 0 sn.soon where n 2-6, or their pharmaceutically acceptable salts, otkkch-yaetsya the fact that the compound of General formula l I o CHjCOORi where R is a branched lower alkyl, is reacted with a compound of the general formula , 1435152 The CD is benzyloxycarbonyl, the compound obtained is subjected to hydrolysis and the desired product is isolated as a pharmaceutically acceptable salt or in free form. Table 1 (CH2) I, R 7 - CH SOOK 2 Rj lower alkylJ Rj is a halogen or lower alkylsulfonyloxy group; ten 300 100 100 table 2 100 100 95 79