SU1246893A3 - Method of producing substituted octahydro-1-(w-mercaptoalkanoyl)-1h-indole-2-carboxylic acid or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The method of obtaining the substituted octahydro-1 (Y-mercaptoalkanoyl) -1H-α-indole-2-carboxylic acid of the general formula I g COORi Rj-S-CHj-CH-C-N, where R is hydrogen or lower C. - C. - - - alkyl, R is methyl; R is hydrogen or R, where R is lower C - C, alkyl, or pharmaceutically acceptable salts thereof, characterized in that octahydro-1H-indole-2-carboxylic acid ethyl or trimethylsilyl ester is acylated with an acid halide of general formula II RrQ-S-CH -CH-CX D 1 II O RO O R2 g O) with where R has the indicated meanings; X is chlorine or bromine, the resulting product is either substituted or hydrolyzed with a base to produce compounds of general formula I, where R and Rj are hydrogen, and the target product is isolated in free form or in the form of pharmaceutically acceptable salts. no O5 00) with

Description

s

I

The invention relates to the field of the preparation of new substituted octahydro-1 - (W-repcaptoalkoalkoyl) -1 H-indole-2-carboxylic acid of the general formula

2 9

COORi

S -CH-CH-C --4

I

R. R, hydrogen or lower: C

- alkyl;

methyl;

ABOUT

Sr.

Where

R,

- hydrogen or R - s - 5 lower s ,, - C, - alkyl.

HJiPi Pharmaceuticals have physically useful salts that have anti-hypertoxic effect.

The aim of the invention is to develop, on the basis of a known method, a method of producing new compounds with similar pharmacological properties.

Example 1. Ethyl (2 (, 3 sC-JJ, 7 (x:) - octagidro-1 - s- (acetylthio) -propanoyl j -1 H-indole-2-carboxylate.

A solution of 4.2 g (0.025 mol) of 3- (adylthylthio) -propaioyl chloride in 10 ml of dichloromethane is introduced over 20 mi into a stirred mixture of 4.9 g (0.025 mol) of paneMpi4ecKoro ethyl- (2 (1 (5 3; (., 7 () -octagidro-1H-indole-2-carboxyplate and 4.0 g of sodium bicarbonate in 40 ml of water and 90 ml of dichloromethane at ла: lacinium up to 5-10 ° C. After 40--1H, two phases The aqueous phase is extracted with 50 Pg of dichloromethane. The combined organic extracts are washed first with dilute 0.01 p sulfuric acid, then sodium bicarbonate (0.01 N ,.) and then with water. The organic layer is separated and dried over sodium sulfate. The solvent is removed in vacuo, whereby 5.8 g of product is obtained in the form of a viscous colorless liquid, mint, 245 (at 753 mm Hg, g).

IR spectrum (film), cm

-one

745

(ester), 1690 (S-acetyl) 5 1643 (amide) ,. Thin layer chromatography (using 2: 1 acetonitrile-methanol for elution, use of SiO adsorbent.): Single point Rf 0.3.

46893

Calculated €, at, 7 ,: С 58.70; H 7.70; M.

CuH, NO, S

Found,% C 58,17; H 7.69; ;; N 4.00

Egil (2l., Zl., 7/1) -octagidro-1 Nnn

dol - 2 - carboxylate5 used in

As the initial product in dkmer 1 ", it is pressed as follows in obra-10 zones. A solution of 100 g (Oz53 mol) ethyl5

0

five

thirty

35

40

AS

indole-2-carboxylate in 100 ppm of absolute ethanol and 32 ml of concentrated sulfuric acid are hydrogenated by passing over rhodium deposited on charcoal (4jO g; 10%), using Paar hydrogenation equipment, until hydrogen absorption ceases (22.3 h). The catalyst is removed by filtration, the filtrate is evaporated in vacuo. The residual syrupy evaporation product is dissolved in ice water, the solution is neutralized first with potassium carbonate and then alkalized with potassium bicarbonate. The oily residue is extracted with 300 ml of diethyl ether, and the aqueous layer is extracted with another 300 ml portion of diethyl ether. The combined ethereal extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated in vacuo, resulting in 78.5 g of ethyl (, 2 ° C ,,,) octagidro 1 H-indol-2-carboxylate in As a post center colorless oil of high purity. The initial aqueous layer is 1 saturated with solid sodium chloride and extracted twice with 150 ml of ethyl acetate. The combined extracts are washed with a small amount of water, dried over sodium sulfate and evaporated in vacuo, resulting in an additional 6.5 g of product,

IR spectrum (film) 5 3450, 3300 (W), 1732 (ester).

J5

p-1.4767.

The dns material is sufficiently limited so that it cannot immediately be used for the implementation of the u.eccs. according to example 1.

Example 2. (2 (i, 3i / | i-5 7 /) - Octagidro-1 - (3-mercaptopropanoyl) dol-2-carbolic acid,

Suspension 2.0 g of ethyl (2 &, Zy-p, 7i) -octagidro-1- 3- (adethylthio) -propano-1H-and N of d o l - 2 - k a rb about with and l and t and in 10 NLT

A 10% aqueous solution of sodium hydroxide is held at room temperature overnight under a nitrogen atmosphere. The resulting solution is acidified by adding glacial acetic acid to a pH of 6.0. The gummy residue is extracted twice with 100 ml of diethyl ether. The combined ether extracts are washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under a nitrogen atmosphere. After stirring the residual evaporation product with warm acetonitrile and cooling, 1.6 products are obtained, m.p. 143-144 ° C. By recrystallizing this product from acetonitrile, a highly pure sample is obtained, m.p. MZ-MB C. IR spectrum (KB g), 2615 (SH), 1735 (COOH), 1597 (amide).

Calculated,%: C 56.02; H 7.44; N 5.44.

 ,

Found,%: C 56.33; H 7.46; N 5.43.

Example 3. (2 (/, 3 (1,) -0kta hydro-1- 3- (acetylthio) propanoylJ - -1H-indole-2-carboxylic acid.

A. C- (Acetylthio) -propanoyl chloride (4.2 g, 0.025 mol) is added dropwise at a temperature of from -5 to 0 ° C to a thoroughly mixed solution of 4.2 g (0.025 mol) (2y: 3c, 7fti ) -octa hydro-1H-indol-2-carboxylic acid and 6.0 g of potassium bicarbonate in 30 ml of water. The resulting solution was stirred for another 45 minutes at 0 ° C and then 2N was added. sulfuric acid to pH 3.5. The oily product is dissolved in 150 ml of diethyl ether, the aqueous layer is extracted with an additional 150 ml of ether. The combined ether extracts are washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated to a residual volume of about 40 ml, after cooling of which 2.4 g of high-purity white crystals are obtained, m.p. 103-104 ° C. After concentration of the filtrate followed by dilution of the heat with isopropyl ether, an additional 2.9 g of this product is obtained, m.p. 103-104 ° C. After recrystallization from ethyl acetate, another crystalline form of the product is obtained, m.p. 131-133 C.

JK-spectrum (KB g), 1742 (CO., 1689 (C 08 acetyl); 1648, 1592 (0 amide).

: Calculated,%: C 56.17; H 7.07; N 4.68.

C "2 N0 S

Found,%; C 56.41; H 6.94; N 4.60.

The starting material (2i, 3, 7o) -octahydro-1H-indole-2-carboxylic acid can be obtained by hydrolysis of the ethyl ether obtained in Example 1.

A solution of 2.0 g {0.01 mol) ethyl (2 (1 Sobr, loL) -octagidro-1H-indole-2-carboxylate in 25 ml of 15% hydrochloric acid is heated under reflux for 4 h and then evaporated to dryness in vacuum.

The whitish precipitate is recrystallized from acetonitrile-ethyl acetate (3: 1), resulting in 1.7 g of analytically pure product as the hydrochloride salt, m.p. 186-187 C (melting with decomposition). By concentrating the filtrate to a small residual volume and subsequent cooling, an additional 0.2 g of product is obtained, i.e. pieces.184-186 C.

The free acid is obtained by dissolving 1.2 g of the hydrochloride salt in 10 ml of water and adding 2N. Hydrochloride salt to 6.5. The resulting solution is evaporated to dryness under reduced pressure in a rotating rotary apparatus at a bath temperature of 35 s. The residual product is heated under reflux with 50 ml of acetonitrile and filtered while hot. The solution is concentrated to a residual volume of about 10 ml and cooled, resulting in 0.5 g of product, m.p. 239-240 ° C (melting with decomposition). TLC (using methanol CHjCN for elution and SiO as the adsorbent shows a single point: Rf 0.4).

Calculated,%: C 63.88; H 8.94; N 8.28.

C, H N0,

Found,%: C 64.13; H 8.83; N 6.17.

B. (2c, 3 ((,) - Octagndro-1-3- - (acetylthio) propanoyl - 11 -indole-2-carboxylic acid can also be obtained as follows. Mixture (2nd., 3 ((., a) octagidro-1H-indole-2-carboxylic acid (3.0 g, 0.0177 mol), hexamethyldielazan (3.0 g, 0.0186 mol) and one drop of chloromethylsilane in 10 ml of acetonitrile is heated under reflux in a for 3 hours. The resulting solution is cooled in an ice bath and a solution of 2.9 g (0.0777 mol) H- (acetylthio-propanoyl chloride in 5 ml of acetonitrile) is added dropwise to it. 15 ml of the sample containing acetonitrile and volatile, distilled and atmospheric pressure. The solution is cooled and filtered, and then concentrated under reduced pressure, removing the remaining solvent. As a result, the oil is obtained, which hardens when removed. The residue is dissolved in 60 ml of boiling ethyl acetate. The solution is filtered and cooled. resulting in 3.0 g of the desired product, mp 131-133 ° C.

Example 4, Ethyl (2c., 3 |, 7a) - octahydro-1 3- (acetylthio) -2-methyl propanol j-u1-indole-2-carboxylate.

In Example 1, using ethyl (2 (U, CcS 5 Tul.) -Octahydro-111-indole-2-carboxylate and 3- (acetylthio) -2-methylpropanoyl chloride) as starting materials, ethyl ((, 3 (|, 7c) -Octahydro-1- 3 (acetylthio) -2-methyl propanoyl, 1H-icdol-2-carboxylate 5 is a viscous oil, b.p. (at 748 mm Hg).

IR spectrum (film), cm: 1742 (ester), 1690 (S-acetyl), 1640 (amide). Fine-chromatography (using apetonitrile as the eluent and SiO as the adsorbent) shows one point; Rf 0.6.

Calculated,%: C 59.81; H 7.97; N 4,10

,, N0 S

Found,%: C 59.55; H 7.86; N 4.04.

PRI m a p 5A, (2 :: i, 3 (ip, 7s: p-OKTa hydro-1 H- (acetylthio) -2-methylpropanoyl -1 H-indole-2-carboxylic acid, diastereoisomer A,

A solution of 2.05 g (0.01 mol) of chloro-, hydrate (2ot, 3ii (: | 5, 7 i} -octa-gid, po 1H-in is the proportion of 2-carboxylic acid in 15 ml without aqueous pyridine. Stirred while add drop by drop for 10 minutes 1.81 g

(0.01 mol) 3- (acetylthio) -2-methylpropanoyl chloride. Stirring is continued for 2 hours, then the pH of the solution is adjusted to 3.5. by slowly adding 15% sulfuric acid. The resulting precipitate is dissolved in 100 ml of diethyl ether, the aqueous phase is extracted with an additional 100 ml of ether. The combined extracts were washed with a saturated solution of sodium chloride, dried over sodium sulphate, then centrifuged to a residual volume of 15 ml. After overnight and after filtration, 1.4 g of white crystals are obtained, m.p. 165-167 ° C. After recrystallization from cyclohexane-ethyl acetate (1: 1), 0.9 g of high-purity diastereoisomer A is obtained, m.p. 168.5-170 0.

IR spectrum (KB g), 1742 (COOP 1689 (S-acetyl), 1648, 1592 (amide),

Calculated,%: C 57.49: H 7.40; N 4.47.

C, jH ... NO, S

Found, Zi C 57.33; P 7.15; N 4.36.

PRI me R 5 V. (2oi, 3ot, S,) —OK-tagidro — 3- (acetylthio) -2-methyl-propaiio) -1H-indole-2-carboxylic acid, diastereisomer B.

After obtaining diastereomer A by filtration, 20 ml of isopropyl ether are introduced into the initial filtrate, the solution is concentrated to a residual volume of 15 ml. Upon cooling, an additional 0.7 g of the desired product is obtained, m.p. 135-137 ° C. As a result of fractional ionization crystallization alternately from hexane and ethyl acetate, a pure sample of diastereomer isomer B is obtained in the form of a white solid: . 1 51-1 53 55 С.

PRI me R 6A. (2 () (, 3k; th,) - 0k-tagidro-1 - (3-mercapto-2-iethylpropanoyl) - 1 H-indole-2 carboxylic acid, diastereomer A.

(2f6, 3i (|, 711) -Oct-1-h-3 (acetylthio) -2-methylpropanoyl -1H-indole-2-carboxylic acid (diastereoisomer A) in an amount of 1.0 g was dissolved in 5N solution ammonia in methanol at room temperature under t3OTa. The solution is stirred for 2.5 h and then the solvent is removed under reduced pressure. The residual product is dissolved in water.

acidified with 10% potassium bisulfite solution and extracted with ethyl acetate. After drying (using magnesium sulfate) and evaporation of the topographic layer, the diastereomer A of the desired product is obtained, which is purified by crystallization from ethyl acetate. Pure isomer A has

m.p. iss-ise c.

PRI me R 6B. (2 (1 ,, 7 ";) - OK-tagidro-1- (Z-mercapto-2-methylpropanoyl) -1H-indole-2-carboxylic acid, diastereoisomer B.

Carrying out the process of Example 5B, the diastereoisomer B (2rt, 3ci, 7iip) -octagidro-1 - (3-mercapto -2- -methylpropanoyl) -1H-indole-2-carboxylic acid is obtained in the form of a white solid, t. square 141-142 with,

(2L, 3 / i $. Id}) -Oct-hydro-1 - (3-mercapto-2-methylpropanoyl) -1H-indole-2-carboxylic acid (5 mg) is dissolved in a solution of water (2.5 ml) and an equivalent amount of 1 n. sodium hydroxide. The solution is dried at a temperature below, sodium salt is obtained.

(2ot, 3at, 7ei |) -Oct-hydro-1- (3-mer-KartTo-2-methylpropanoyl) -1 H-indole-2-carboxylic acid (5 mg), magnesium oxide (49.5 mg) and water (10 ml) perz stir under mild heating until complete dissolution. The solvent is then removed by drying at a temperature below OC. Magnesium salt is obtained.

(2l ;, 3ot |, 7al) -Oct-hydro-1- (3-mercapto-2-methylpropanoyl) -1H-indole-2-carboxylic acid (5 mg) is dissolved in a mixture of calcium hydroxide (91 mg) and water (10 ml) and the solution dried at a temperature, resulting in a calcium salt.

(2 (i;, 3K., 7 (1) -Oct-hydro-1- (3-mercapto-2-methylpropanoyl) -1H-INDOL-2-carboxylic acid (5 mg) is dissolved in a mixture of an equivalent amount of bicarbonate potassium and water (10 ml) and dried at a lower temperature, resulting in a potassium salt.

; Example 7 (L) (2i) i, 3ft:, 7 ((p) - -Oct-1-3- (acetylthio) -propenoyl -1H-indole-2-carboxylic acid

Carried out the process according to example 3, (L) - (, ZOC |,) -octagidro-1 H-indol-2-carboxylic acid is converted

in (L) (,, 7c) -octahydro-1- 3 - (acetylthio) -propanoyl -1H-indole-2 -carboxylic acid, having so pl. 110-1124, m- 51 (, methane). 5 Example 8. (L) (2t, 3, -Octagidro-1- (3-mercaptopropanoyl) -1 -1H-indole-2-carboxylic acid. The process was performed as in Example 6A, (b) - (2, .7 (17 a) -octahydro-1-W - (acetylthio) -propanoyl J-1H-indole-2-carboxylic acid is converted into (L) - (2ft, 3 (, lii}) -oct-hydro-1- (3-mercaptopropanoyl) -1H α-indole-2-carboxylic acid, having a mp of 168.5-170 ° C., - 68.5 ° (, methanol).

Example 9. (L} - (2ci ,, d, -Octagidro-1- 3- (benzoylthio) -2-methylpropanoyl-1H-indole-2-carboxylic acid, diastereoisomer A.

A solution of 1.8 g (L) - (2ft:, 3 ";, 7": |) - octahydro-1H-indole-2-carboxylic acid and 2.5 g of pyridine in 20 ml of tetrahydrofuran is cooled; at 0-5 ° C and (L) -3- (benzoylthio) -2 -2-methylpropionyl chloride is added dropwise. The mixture is stirred for 2 hours at 0-5 ° C., then concentrated, removing the solvent. The residue was treated with water, acidified with 6N. sulfuric acid and extracted with ethyl acetate i. The organic layer is washed with a saturated solution of sodium chloride, dried (using magnesium sulfate) and concentrated to dryness. The residue concentrate, which partially crystallizes, is stirred with ethyl acetate and filtered, and the desired product is separated. This product is purified by recrystallization from ethyl acetate, it has so pl. 184.5 - 185,} 1 - 135.6 (C 1, methanol). .

Example 10. lTiciclohexyl-amino salt, (L) - (2 (x, lei}) -octahydro-1 - (3-mercapto-2-methylpropanoyl) -1H-2-carboxylic acid (diastereoisomer A) .

Carried out the process according to Example 6A, but using (L) - (2d, 2, iL, lcL) - -octa-hydro-1-3- (benzoylthio) -2-methylpropano.yl 1 - 1 H-2-carbonic acid that (diastereoisomer A) instead of (2 - d, 7rfj) -octagidro-1-h- (acetylptio) - -2-methylpropanoyl -1H-indole-2-carboxylic acid, get (L) - (2 ( if, 7o (.) -octagidro-1 - (3-mercapto-2-methylpropanoyl) -111-2-carboxylic acid o This product is purified to give dicyclohexylamine salt, t, pl. 145-1484, niYl - 53.5 (, methanol),

The proposed compounds can be used to lower blood pressure.

The action of the enzyme renin on the angiotensinogen, pseudoglobulin in the blood plasma, leads to the formation of de. sapeptide angiotensin I. Angi. - Ovens I is converted by the action of the enzyme Angiotensin Conversion (ACE) to the octapeptide angiotensin II. The latter is an active substance that increases blood pressure and is the cause of various forms of hypertomy in various mammals, such as rats and dogs.

The proposed compounds take part in the sequence of rhenium processes — angiotensin 1 angiotensin II, inhibit the enzyme converting angiotensin I and eliminate the formation of angiotensin II, a substance that causes a rise in blood pressure, and therefore, these compounds are valuable substances, lower CHF,

CH

note LC, jj, is molar

a concentration that inhibits 50% of the converse of angiotensin I to angiotensin II, and for the compounds obtained is much better than for captril, for which it is equal to 2 x 10.

VNIIPY Order 4029/59

, zzh 379 Subscription

Random polygons , Uzhgorod, st. Project, 4

retaining or completely relieving hypertension.

The table shows the activity of compounds of formula (1) in vitro

or testing for inhibitory action with |) enzyme conversion of anti-stress. ACE test in vitro. The inhibitory effect of the angiotensin converting enzyme (ACE) is determined by testing ACE of guinea pig serum in the presence and absence of the test compound. ACE, from guinea pig serum and test compounds, was incubated for 10 minutes in a thermostat, after which the labeled substrate 3-hippuryl-glycylglycine was injected. After holding 1: and in a thermostat for 60: min, the reaction is stopped by entering 0.1 and. HC1. ACE cleaves the hippuryl-glycine bond, resulting in That is, glycylglycine and 3N-hippuric acid are formed. The HH-hippuric acid is then extracted with ethyl acetate, and the ACE inhibition of this sample is calculated based on the amount of the HH-hippuric acid produced.

s6 x 10

- 7

1.6 X 10

1.1 X 10

7.0 to 10 5.2 X 10

-9

- and

-7

1.7 X 10 5.2 X

Claims (1)

<claim-text> Method for producing substituted octahydro-1 (I-mercaptoalkanoyl) -1H-indole-2-carboxylic acid of general formula I </ claim-text> <claim-text> <a name="caption2"> </ a > ° ςθοΒι </ claim-text> <claim-text> n <sub> 3 </ sub> -8-sn <sub> g </ sub> -sn-c- ^ A <sub> l </ sub> </ claim-text> <table border = "1"> <tr> <td> where </ td> <td> </ td> <td> - </ td> <td> hydrogen or </ td> <td> the lowest is </ td> </ tr> <tr> <td> </ td> <td> </ td> <td> </ td> <td> - alkyl; </ td> <td> </ td> </ tr> <tr> <td> </ td> <td> <sup> K </ sup> 2 </ td> <td> - </ td> <td> methyl; </ td> <td> </ td> </ tr> <tr> <td> </ td> <td> <sup> to <sub> </ sup> 5 </ sub> </ td> <td> - </ td> <td> hydrogen or </ td> <td> K <sub> 4 </ sub> ~ C = 0, where - </ td> </ tr> <tr> <td> </ td> <td> </ td> <td> </ td> <td> lower C - </ td> <td> C, = alkyl, </ td> </ tr> <tr> <td> or </ td> <td> THEM </ td> <td colspan = "3"> pharmaceutically suitable co - </ td> </ tr> <tr> <td> lei, </ td> <td> about </ td> <td> t </ td> <td> l and h yu </ td> <td> and so with </ td> </ tr> </ table> <claim-text> that octahydro-1H-indole-2-carboxylic acid ethyl or trimethylsilyl ester is acylated with an acid halide of the general formula II </ claim-text> <claim-text> VgS-3-SNo-CH-C-XA | and </ claim-text> <claim-text> o to <sub> g </ sub> o </ claim-text> <claim-text> where K <sub> 2 </ sub> and have the indicated meanings; </ claim-text> <claim-text> X - chlorine or bromine, </ claim-text> <claim-text> the resulting product is either isolated, or subjected to hydrolysis with a base to obtain compounds of general formula I, where K, and P <sub> e </ sub> is hydrogen, and the target product is introduced in free form or in the form of pharmaceutically acceptable salts . </ claim-text> <claim-text> 31), „, 1246893 </ claim-text> <claim-text> 1246893 </ claim-text>