SU1639427A3 - Method for preparation of indole derivatives or theirs pharmaceutically suitable salts - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of indole derivatives of the total f-ly I

Description

 where Ri-C1 or methoxy-, HtN-C (0) -, HaN-C (0) CHz-, CH3-NH-C (0) -CHa-, (CH3) ZN-C (0) -CH2-, CH5-C (0) -NH-, CH, -C (0) -NH-CH2-, H2N-S (0) z -, CH jS (0) z -Nil-, CH3-S (0) 2 - NH-CH2-rpynpa; Kg, -C3-alkyl or H; A-C (0) - or -S (0) 2-; , or their pharmaceutically acceptable salts,

Rz№i (CH2)

(CH2) 2N

.

r

or its reactive derivative, at a temperature from room temperature to the boiling point of the reaction mass, followed by isolation of the target product in free form or

affecting the rapid and selective narrowing of blood vessels, which can be used in medicine. Rel - the creation of new, more active and less toxic petties of the specified class. Synthesis is carried out by acylation of the compound f-ly IT with acid fl III

3

-

./ X

CH3 CL

the desired salt. The novel compounds very tightly and selectively narrow the bundle of the carotid artery without affecting the arterial pressure and side effects. 1 tab.

05

oh

CO 4

to

och

The invention relates to methods for producing new indole derivatives of the general formula:

; cH1V-A-M-fo i)) Jx:

, CH3

sn,

where RJ, - is an xlrra atom. or methoxy-, HjNCO-,% NCOCH2-, CH5NHCOCH-, ((; H3) 2: KSOHN2-, CH CONH-, SNHSSCHSN2H NSO-, CH5802Sch-yl1 CH380HSHSNgrpymta;

R2 hydrogen or C-C5 alkyl |

R3, hydrogen or C -C alkyl;

And WITH- or -S02-;

m is an integer from 1 to 4, or - their pharmaceutically acceptable salts with strong and selective activity on the narrowing of blood vessels.

The purpose of the invention is to develop, on the basis of known methods, a method of producing new compounds with high pharmacological activity with low toxicity,

Example 1 Oxalate Н-Г2- 3- (2- (dimethylamino) ethyl) -1H-indol-5-yl} ethyl-4-methoxybeneol acetamide, Rf - CF30-; R3-H, R4 and R5 - CH3; ,,

N, N -carbonyldiimidazole (195 mg) was added to a stirred solution of 4-methoxyphenylacetic acid (166 g) in dry CH2Cl (10 ml) at room temperature under nitrogen atmosphere and stirring was continued for 1 hour. In CHgCl. O0 ml) N, N-dimethyl-1H-indole-3,5-diethanamine dioxalate (231 mg) was added and stirring was continued for 1 h. The reaction mixture was combined with a similarly prepared mixture, washed with an 8% aqueous solution NaHCO3 (20 ml) and water (2 x 20 ml) were mixed (sodium sulfate) and evaporated to give an oil (0.723 g). After purification using flash chromatography, an oil (214 mg, first exit) and a material containing impurities (119 mg, second exit) were obtained. The first yield was dissolved in methanol (2 ml) and oxalic acid (56 mg) in methanol (1 ml) was added. After adding dry ether (ER), a precipitate was formed, which was separated by filtration, washed with dry ER and dried, resulting in a product in the form of a solid (0.724 g), m.p. (calculated) 96-103 ° C (foam).

Example 2. Oxalate 4- (acetyl amino) -N-. (2- (dimethylamino) ethyl 1H-indole-5-yl | ethyl | benzene1, etamide, R, - HtNCOCHz-.

A mixture of carbonyldiimidazole (0.81 g) and 4- (acetylamino) -benzeneacetic acid (0.97 g) in dry DHF (75 ml)

stirred under nitrogen at reflux for 1.5 h, and then dioxalate M, n-dimethyl-1H-indol-3,5-diethanamine (1.2 g) was added, deflagration was continued for 5 h

0 and the mixture was cooled to room temperature and then concentrated under vacuum, resulting in the obtained resin, which was subjected to purification using instant chromatography,

5 The appropriate fractions were combined and evaporated. The resulting resin (0.7 g) was dissolved in absolute ethanol (70 ml) and treated with a solution of hydrogen chloride in

0 ether until the solution became acidic. The resulting solution was diluted with a dry ER (120 ml) in order to precipitate a solid, which was diluted with fresh dry ER (1 2.0 ml x 2), whereby the hydrochloride salt of the proposed compound (0.4 g) was obtained as a white solid. This salt was converted to the free base of said compound on a silica column. The resulting free base (0.33 g) was dissolved in absolute ethanol (35 ml) and treated with a solution of oxalic acid (0.07 g) in ethanol (15 ml). The resulting solution was diluted with a dry ER (120 ml), and The above proposed compound (0.33 g) precipitated as a solid, m.p., (softening) 75-80 ° C, foaming 115-120 ° C.

Example 3, g, 1-Tartrate N (2- (2- (dimethylamino) ethyl) -1H-indole-55, 4-benzenediacetamide,

A mixture of NN -carbonyldiimidazole (0.37 g) and 4- (aminocarbonylmethyl) benzeneacetic acid (0.45 g) in dry distilled DGF (150 ml) was stirred under nitrogen at reflux for 1.5 hours and then added whether dioxlide K, n-dnmethyl-1H-indole-3,5-diethanamine (0.54 g). Reflux was continued for 3 hours and the mixture was cooled to room temperature. The cooled mixture was evaporated under vacuum to give a gum- (calc, 2 g), which was adsorbed onto creme dioxide

five

0

0

nor, and subjected to purification using instant chromatography. The appropriate fractions were combined and evaporated to give a solid (0.43 g), which was adsorbed onto alumina (Fima Merck 1077) and subjected to alumina chromatography for further purification. The appropriate fractions were combined and evaporated, whereby a solid was obtained (0.8 g), which was dissolved in hot absolute ethanol (3 ml) and treated with a tartaric acid solution (0.1 g). The resulting solution was diluted with a dry ER (50 ml) for sedimentation

Day solid swarm was stirred for 24 hours and filtered, in

substances, H at 20 ° C

Cats te resulttempera- (shrinkage) foam

those that received the proposed compound of this example (b, 38 g) in the form of a solid with a tour t, mp, 80-82Y,

Example 4. 4-chloro- (dimethitamino) ethyl) -1 -H-indole-5-yl hydrochloride | -ethylCHbenzeneacetamide, i j

A mixture of N, N - arbonyldimidazole (0.58 g) and 4-chlorobenzene-acetic acid (0.6) g) in dry THF (75 ml) was stirred under nitrogen at reflux for 2 hours and then dioxalate M, M was added -dimethyl-1H-indol-3,5-diethanamine (0.7 g), deAlgation continued for 3 hours and the mixture was cooled to room temperature. The cooled mixture was evaporated in vacuo to give a semi-solid (20 g), which was purified using flash chromatography. The appropriate fractions were combined and evaporated to give a solid, T, 1 g), which was divided between (3 x 100 ml) and water (O 00 ml). The organic extracts were combined, washed with water (100 ml), dried (sodium sulfate) and evaporated. The resulting resin (0.7 g) was dissolved in absolute zero (15 ml) and treated with a solution in simple hydrogen chloride ester (ml), after which a turbid solution was prepared, which was diluted with a dry ER (50 ml) to precipitate solid. The top layer of liquid was decanted and the solid was ground with

five

0

five

fresh ER (100 ml), as a result of which the proposed compound of this example was obtained (0.63 g) as a solid with a temperature of mp, (softening) 65-70 ° C, melting point 5-100 ° C.

Example 5. 4- (aminocarbonyl) -N- j - (- (- (dimethylamino)) ethyl) -1L-indol-5-yl chlnl1-enzolacetate-amide hydrochloride.

Suspension of K, K-carbonyldiimidachol (0.58 g) and 4- (aminocarbonyl) benzene-acetic acid (0.5 e} g) in dry TTF (20 ml) under nitrogen atmosphere de (Kegmized for 2 h , and dioxalate M, K-dimethyl-1H-indole-3,5-diethanamine (0.7 g) was added. The reflux was continued for 7 hours and the mixture was cooled by fleHHvso and evaporated under vacuum, resulting in a brown gum, This was purified by flash chromatography.The second fraction (100 ml) was collected (the first 300 ml) and evaporated to give a light brown, which crystallized and from a mixture of ethanol (20 ml) and IP (20 ml), after which a white solid was obtained, which was dissolved in warm ethanol (30 ml) and treated with a solution of simple hydrogen ester (ml). The resulting solution was stirred under nitrogen for 0.5 h, then the ER (100 ml) was diluted to precipitate a white solid. The upper layer was decanted, and the solid was triturated with ER (100 ml), after which the proposed compound of this example was obtained (0, 26 g) as a white solid with TeMnepaTvpou m.p. (softening) 65-70V, melting 170-12i ° C.

Example N-J - (3- (- (dimethylamino1-ethyl1-1H-indole-I-schuctil) -4- (methylsulfonyl) amino-benzenemethanoglLonamide hydrochloride.

A solution of phenyl-4-G1 methylsuldunyl) -

0 amino 1benzenemethansullate (0.68 g) and dioxalate M, M-dimethyl-1H-indol-3,5-diethanamine (1.4 g) in pyridine (6 ml) was heated to a temperature of 100 G which was maintained for 2 hours. Obtained in As a result, the mixture was evaporated, t after which a brown gum remained, which was adsorbed onto flBvoKHCH silicon and purified by flash chromatography, collected

0

five

five

50 ml fractions. Fractions 28-32 were combined and evaporated, resulting in a pale brown foam, which was dissolved in absolute ethanol (26 ml) and treated with a solution of hydrogen chloride ether and ether (30 ml) to precipitate the proposed compound of this example ( 0.24 g) in the form of an off-white solid with a temperature of mp. (shrinkage) 120-125 C, the formation of foam 135-140 ° C.

Example 7. Oxalate, 310

stirring slurry 4g (benzene acetic acid acetylum (1.6 g) in CHOMCl j, (80 ml) in an atmosphere. A The resulting mixture was brought to room temperature and p stirred for 3 h, then oxalyl chloride (1 and the mixture was stirred at 20 ° C for 3 hours. The mixture was then evaporated under vacuum at a temperature below 30 ° C, leaving a yellow solid that was dissolved in dry DHF (80 ml) and

(2- (dimethylamino) ethyl) -1H-indol-5-yl -15 bavly in a stirred solution Ј (methylsulfonyl) amineG benzenecetamide.

A mixture of NSN -carbonyldiimidazole (1.62 g) and 4-Ј (methylsulfonyl) amino 1-benzeneacetic acid (2.3 g) in dry distilled THF (100 ml) was stirred under nitrogen at reflux for 2.5 h, and then dioxalate K, M-dimethyl-III-indole-3,5-diethanamine (1.2 g) was added. Reflux was continued for 4 hours and the mixture was cooled to 20 ° C overnight. The cooled mixture was evaporated in vacuo, after which a brown gum remained, which was partitioned between ethyl acetate (3A) (3x100 ml) and 2M hydrochloric acid solution (100 ml). The acidic aqueous layer was made basic (pH = 8) and extracted with EA (3x150 ml) The EA extracts were combined and washed with brine (3 x 150 ml / l), dried (sodium sulfate) and evaporated, then a brown gum was left, which was purified by flash chromatography, collecting 25 ml fractions. Fractions 26-32 combined and evaporated, followed by a white foam, which was dissolved in hot ethanol (150 ml) and treated with a hot solution of oxalic acid (0.25 g) in ethanol (65 ml) to precipitate upon cooling (0 ° C) of the proposed compound of this example 0.17 g) as a white solid, temp Atur mp 165-166 ° C.

Example 8. Oxalate - (acetyl-amino) -M- {2- 3- (2- (dimethylamino) 1H-indole-5-yl ethyl 1b enzolietamid.

Oxalyl chloride (1.1 ml) was added dropwise to a cold (0 ° C) re-20

25

thirty

35

40

50

55

triethylamine (2.5 ml) and intermediate (1.27 g) in dry DHF (80 ml). The resulting (-lt) mixture was stirred at 20 ° C for about 19 hours, diluted with methanol (20 ml) and evaporated in vacuo, after which a brown solid remained (approximately 3.0 g). He was subjected to purification using flash chromatography, after which he received a coke resin, which was then subjected to purification using colo for chromatography, eluting it with methanol-ammonia (100: 1), resulting in free expression of the proposed compound. For example, in the form of a colorless p. A part of the foam (0.21 g) was dissolved in warm ethanol (5 ml) and treated with oxalic acid (47 mg) in zero (2 ml) to precipitate the proposed precipitation (0.18 g) the form of a white solid; temperature, m.p. 201-202 ° C (foam).

Example 9. Oxalate 4- (ace amino) -N- | 2-p- (2- (dimethylamino) 1H-indol-5-yl benzene-acetamide

A suspension of 4- (acetylamino) benzo 45 acetic acid (0.083 g) in dry CHjC 2. (20 ml) was treated with trimethylacetyl chloride (0.06 ml), then triethylamine (ml). The working mixture was stirred at 2 hours for 2 hours to obtain a prosthetic solution, to which was added a solution of dioxalate M, n-dimethyl-1 dol-3,5-diethanamine (0.1 g) in chrome (20 ml).

The resulting mixture was stirred at 0 ° C for 20 h and evaporated under vacuum, after which a brown gum remained, which was purified using XP

mixed suspension of 4g (acetylamino) - benzene acetic acid (1.6 g) in dry CHgClj, (80 ml) in a nitrogen atmosphere. The resulting mixture was heated to room temperature and stirred for 3 hours, then oxalyl chloride (1.1 ml) was added again and the mixture was stirred at 20 ° C for 3 hours. The mixture was then evaporated under vacuum at a temperature below 30 ° C, resulting in a yellow solid that was dissolved in dry DHF (80 ml) and up to 5 bavlly in the stirred solution

5 bavli in the stirred solution

0

five

0

35

0

0

five

triethylamine (2.5 ml) and intermediate (1.27 g) in dry DHF (80 ml). The resulting i-ryl mixture was stirred at 20 ° C for approximately 19 hours, diluted with methanol (20 ml) and evaporated in vacuo, after which the brown solid remained (approximately 3.0 g). It was subjected to purification using flash chromatography, after which a brown resin was obtained, which was then subjected to purification using a chromatography column, eluting with methanol-ammonia (100: 1), resulting in a free base of the proposed compound of this example as colorless foam. A portion of the foam (0.21 g) was dissolved in warm ethanol (5 ml) and treated with oxalic acid (47 mg) in ethanol (2 ml) to precipitate the proposed compound (0.18 g) as a white solid, temperature so pl. 201-202 ° C (foam).

Example 9. 4- (acetyl-amino) -N- | 2-p- (2- (dimethylamino) ethyl) -1H-indole-5-yl benzene-acetamide oxalate.

A suspension of 4- (acetylamino) benzene-45 acetic acid (0.083 g) in dry CHjC 2 (20 ml) was treated with trimethylacetyl chloride (0.06 ml) and then with triethylamine (ml). The reaction mixture was stirred at 20 ° C for 2 hours to obtain a clear solution, to which was added a solution of dioxalate M, n-dimethyl-1H-ind-3,5-diethanamine (0.1 g) in dry (20 ml ).

The resulting mixture was stirred at 0 ° C for 20 hours and evaporated in vacuo, after which a brown resin remained, which was purified using chromatographic columns, resulting in an off-white foam which was dissolved in absolute ethanol (5 ml) for precipitating a compound according to this example (80 mg) as a white solid, temperature so-called. 201-202 ° C (pen).

Example 10. 4- (acetyl-amino) -N-J2- 3- (2- (dimethylamino) ethyl) -1H-indol-5-yl ethyl 1 benzene-acetamide oxalate.

A suspension of 4- (acetylamino) benzeneacetic acid (0.083 g) and 4- (aminocarbonyl) benzeneacetic acid (0.1 g) in dry CH2Cl2 (40 ml) at 5 ° C was treated with triethylamine (0.12 ml), and then diphenylphosphoryl azide (0.185 ml). The resulting suspension was stirred at room temperature for 21 hours and evaporated in vacuo, leaving a yellow gum, which was divided between FOR (3x35 ml) and 0.2 M hydrochloric acid (35 ml). The organic phase was decanted and the acidic aqueous phase was basified (pK 8) with KZC03 and extracted BY (3x35 ml). This organic extract was dried (sodium sulfate) and evaporated, after which the off-white foam remained, which was purified using a chromatographic column, resulting in a white foam, which was dissolved in absolute ethanol (5 ml) and treated with oxalic acid (27 mg) in ethanol (5 ml) to precipitate the proposed compound, i, of this example (80 mg) as a white solid with a temperature of mp. 200.5-202 ° C (foam).

Example II Oxalate (2- (dimethylamino) ethyl) -1H-indol-5-ylTlL, the organic phase was decanted, and the acidic aqueous layer was then washed with (75 ml). The acidic aqueous layer was basified (pH 8) with KgCOj and extracted with an EA – isopropanol mixture (20: 1, 3x100 ml). These organic extracts were combined, washed with brine (100 ml), dried (sodium sulfate) and evaporated, after which the white foam remained, which was purified by flash chromatography, resulting in a white ne) 5 which was dissolved in absolute ethanol (70 ml) and treated with oxalic acid (0.138 g) in ethanol (5 ml) to precipitate the proposed compound of this example —.

20 (0.58 g) as a white solid, temperature so pl. 168-169 C.

Example 12. Oxalate 4- (aminosulfonyl) -M-H2-Ј3- (2- (dimethylamino-ethyl) -1H-indole-5-shLettSbeneolacet25 amide.

A mixture of 4- (aminosulfonyl) benzeneacetic acid (0.58 g) and dioxalate K-dimethyl-III-indole-3 -diethanamine (0.56 g) in dry CH2Cl2 (150 ml)

30 in nitrogen atmosphere at 5 ° C was treated with triethylamine (0.7 ml), and then diphenylphosphoryl azide (1 ml). The resulting suspension was stirred at room temperature.

during 24 h and quickly cooled using 1 M hydrochloric acid solution (2x60 ml). The organic phase was decanted, and the aqueous layer was washed with EA (60 ml), then basified (pH 8) with use and extracted with a mixture of WA – propanol (20: 1, 3x100 ml). The organic extracts were combined, washed with brine (100 ml), dried (sulethyl | -4-Ј (methylsulphonyl) aminrD methyl-d fate soda) ft, evaporated, after which benzenecetamide was not completely white foam,

which was purified using a chromatographic column, resulting in a white foam, 50 which was dissolved in hot ethanol

Suspension of 4- (aminocarbonyl) benzene-acetic acid (0.73 g) and N, N-dimethyl-1K-indole-3,5-diethanamine dioxalate (0.7 g) in dry CH2Cl (240 ml) in a nitrogen atmosphere at 5 ° C was treated with triethylamine (0.9 ml), and then diphenylphosphoryl azide (l, 29 ml). The resulting suspension was stirred at room temperature for 21 hours. It was rapidly cooled with 1 M hydrochloric acid (2x75 ml), Two phases (25 ml) and treated with oxalic acid (0.1 A g) in ethanol (10 ml ). The resulting solution was cooled to 20 ° C and diluted with dry 55 EA (approximately 100 ml) to precipitate the compound according to: this example to precipitate (0.56 g) as an off-white solid with a temperature of m.p. ) 123-125 С,

were added, the organic phase was decanted, and the acidic aqueous layer was then washed with 3A (75 ml). The acidic aqueous layer was basified (pH 8) with KgCOj and extracted with an EA – isopropanol mixture (20: 1, 3x100 ml). These organic extracts were combined, washed with brine (100 ml), dried (sodium sulfate) and evaporated, after which the white foam remained, which was purified by flash chromatography, resulting in a white pepper, which was dissolved in absolute ethanol (70 ml) and treated with oxalic acid (0.138 g) in ethanol (5 ml), in order to precipitate the proposed compound of this example -.

(0.58 g) as a white solid, temperature so pl. 168-169 C.

Example 12. Oxalate 4- (aminosulfonyl) -M-H2-Ј3- (2- (dimethylamino-ethyl) -1H-indole-5-shLettSbeneolace5 amide.

A mixture of 4- (aminosulfonyl) benzeneacetic acid (0.58 g) and dioxalate K-dimethyl-III-indole-3 -diethanamine (0.56 g) in dry CH2Cl2 (150 ml)

0 in nitrogen atmosphere at 5 ° C was treated with triethylamine (0.7 ml), and then diphenylphosphoryl azide (1 ml). The resulting suspension was stirred at room temperature.

g for 24 h and quickly cooled using 1 M hydrochloric acid solution (2x60 ml). The organic phase was decanted, and the aqueous layer was washed with EA (60 ml), then basified (pH 8) with use and extracted with a mixture of behind-i-propanol (20: 1, 3x100 ml). The organic extracts were combined, washed with brine (25 ml), and treated with oxalic acid (0.1 g) in ethanol (10 ml). The resulting solution was cooled to 20 ° C and diluted with dry EA (approximately 100 ml) to precipitate the compound according to: this example to precipitate (0.56 g) as an off-white solid with a temperature of mp. (wrinkling) 123-125 С,

Example

ten

13. d.l-Tartrate 4Ј (acetylamino) methyl -N-G2-Ј3- (2- (dimethylamino) ethyl) -1H-indole-5-shl ethylS of benzene-acetamide.

Suspension of 4- Ј (acetylamino) methyl 1-benzeneacetic acid (0.62 g) and dioxalate K, N-dimethyl-1H-indole-3,5-diethanamine (0.7 g) in Suom CPgC1g (240 ml) in an atmosphere nitrogen at 5 ° C was treated with triethylamine (0.9 ml), then with diphenylphosphoryl aeid (1.29 ml), the resulting suspension was stirred at room temperature for 64 h and cooled quickly with a 1 M solution of hydrochloride lot (2x75 ml) .- Two phases they were separated, the organic phase was decanted, and the aqueous layer was washed with 3A (75 ml). The EA extract was decanted and the acidic aqueous layer was basified (pH 8) with use and extracted with the mixture FOR — isopropanol (20: 1, 3x100 ml). The organic extracts were combined, washed with brine (100 ml), 25 dried (sodium sulfate) and evaporated, after which the brown resin remained, which was purified using a chromatographic column. As a result, a pale brown foam remained, which was dissolved in absolute ethanol (15 ml) and treated with oxalic acid (90 mg) in ethanol (10 ml). The resulting solution was diluted with a dry ER (approximately 100 ml), 35 grams, resulting in a

the impression in this example (0.29 g) as a pale brown solid with a temperature of m.p. (shrinkage of 90-93 ° C, foam 95-100 ° C.

Example 14. s, 1-Tartrate tf- J 2-JJ3- (.- (dimethylamino) ethyl) -1H-nndol-5-yl3-ethyl | -H, M -dimethyl-}, benzenediacetamide.

A suspension of (dimethylamino) -2 oxoethyl benzene acetic acid (0.74 g) and dioxalate M, H-dimethyl-1H-indole-3,5-diethanamine in dry (300 ml) was treated with triethylamine (1 ml), and then diphenylphosphorylase (1.7.9 ml). The resulting suspension was stirred at room temperature for 60 h and quickly cooled with a 1 M hydrochloric acid solution (2x75 ml). The two phases were separated, the organic phase was decanted, and the acidic aqueous layer was then washed behind (75 ml). The organic extract was mixed, and the aqueous fractions were basified (pH 8) using an id-CO and extracted with a mixture of behind isopropanol (20: 1, 3x100 ml).

The organic extracts were combined, washed with brine (dried with 100 m (sodium sulfate) and evaporated to give a white gel

20

thirty

whether

foam that has been cleaned with

using chromatographic

To precipitate an off-white solid which gave the resin upon filtration, this resin was dissolved in water (20 ml) and diluted with hydrochloric acid (2N, 2 ml), the aqueous solution was washed with 3 × (2x20 ml), organic washing liquids was decanted, and the aqueous layer was basified with use and extracted with 3A – isopropanol (20: 1, 3x50 ml), the organic extracts were combined, dried (sodium sulfate) and evaporated in vacuo, leaving a pale brown gum (0.35 g) which is dissolved in absolute ethanol (20 ml) was treated with a hot solution (3,1-tartaric acid (125 mg) in ethanol (10 ml). The resulting solution was diluted with a dry ER to precipitate an off-white solid. This solid was filtered and dried, resulting in received the proposed unified tempera (shrinkage) 85-90 ° C, foam

white foam, which was dissolved in absolute absolute ethanol (65 ml) and treated with tartaric acid (215 in ethanol (15 ml). The resulting solution

40 The thief was cooled to 20 ° C and diluted with a dry SO (about 200 ppm) to precipitate the proposed compound of this example (0.65 g) as a white solid.

45 pounds so pl, 100-110 ° C.

Example 15, a) Oksalat N-p. (- (dimethylamino) ethyl) -1H-indol-5-yl ethyl-4-methoxybenzene

50 panamida,

Diphenylphosphoryl azide (1.5 ml) was added to a solution of dioxalate M, N-d methyl-1H-indole-3,5-diethanamine 55 (0.8 g) and 3- (4-methoxyphenyl) propanoic acid (0 , 62 g) in THF (100 and triethylamine (0.96 ml) and stirred at 5 ° C for 1.5 hours. Growing thaw at room temperature

5 5 longs, resulting in received

the impression in this example (0.29 g) as a pale brown solid with a temperature of mp. (shrinkage) 90-93 ° C, foam 95-100 ° C.

Example 14. s, 1-Tartrate tf-J 2-JJ3- (.- (dimethylamino) ethyl) -1H-nndol-5-yl3-ethyl | -H, M-dimethyl -}, 4-benzene diacetamide.

A suspension of (dimethylamino) -2-oxoethyl benzene acetic acid (0.74 g) and dioxalate M, H-dimethyl-1H-indole-3,5-diethanamine in dry (300 ml) in nitrogen atmosphere 5 at 5 ° C was treated with triethylamine ( 1 ml), and then diphenylphosphoryl azide (1.7.9 ml). The resulting suspension was stirred at room temperature for 60 hours and rapidly cooled. . They gave 1 M solution of hydrochloric acid (2x75 ml). The two phases were separated, the organic phase was decanted, and the acidic aqueous layer was then washed behind (75 ml). The organic extract was mixed, and the aqueous fractions were basified (pH 8) using annelid-CO and extracted with the mixture FOR — isopropanol (20: 1, 3 × 100 ml).

The organic extracts were combined washed with brine (100 ml). dried (sodium sulfate) and evaporated, resulting in a white

0

whether

foam that has been cleaned with,

using a chromatographic column, resulting in a

temperature- (shrinkage) 85-90 ° C, foam

white foam, which was dissolved in hot absolute ethanol (65 ml) and treated with tartaric acid (215 mg) in ethanol (15 ml). The resulting solution was cooled to 20 ° C and diluted with a dry 3A (about 200 ppm) to precipitate the proposed compound of this example (0.65 g) as a white solid.

swarm mp, 100-110 ° C.

Example 15, a) Oksalat N-p. (- (dimethylamino) ethyl) -1H-indol-5-yl ethyl-4-methoxybenzenepropanamide,

Diphenylphosphoryl azide (1.5 ml) was added to a solution of dioxalate M, N-dimethyl-1H-indole-3,5-diethanamine (0.8 g) and 3- (4-methoxyphenyl) propanoic acid (0, 62 g) in THF (100 ml) and triethylamine (0.96 ml) and stirred at 5 ° C for 1.5 hours. The solution was heated to room temperature and stirred for an additional 16 hours. The resulting solution was added to a saturated solution of W "(X-3. (100 ml) and extracted with EA (3 x 50 ml). The combined organic extracts were dried (sodium sulfate) and evaporated under vacuum, resulting in a crude product as transparent After purification using flash chromatography, the pure free base of the proposed syngene of this example was obtained as a clear oil (1.0 g). The free base was dissolved in hot ethanol (10 ml) and oxalic acid (0.25 g ) in ethanol (2 ml), pa the creature was evaporated to dryness, and the resulting solid was subjected to recrystallization from CHC1} (20 ml) -and ethanol (3 ml), after which the proposed compound of this example was obtained as a white solid (0.6 g) , temperature mp 112-114 ° C

The following compounds were prepared using the same procedure again:

b) Oxalate | 2-p3- (2- (dimethyl-amino) ethyl) -1H-indol-5-ylC ethyl} -3- | 4- cmethylsulfonyl) aminoKbenzenepropanamide, (0.36 g) with a temperature of m.p. 83-85 ° G, from N.N-d and methyl-1H-indole-3,5-diethanamine dioxalate (0.8 g and 4- (methylsulfonyl) amino | benzene-propanoic acid (0.72 g),

c) Oxalate 4- (acetylamino) -M-Ј2- 3- (2- (dimethylamino) ethyl) -1 H-indol-5-yl ethyl | benzenepropanamide (0.35 g) temperature m.p. 161-162 ° C, from N.N-dimethyl1 K-indole-3,5-dietary dioxalate intermediate; 1 namin (0.8 g) and 4- (acetylamino) ba :: zolpropanoic acid (0.72 g).

d) Oxalate K- | 2-Ј3- (2- (dimethyl-amino) ethyl) -1H-indol-5-yl1-ethyl-4- (methylsulphonyl) amine benzenebutanamide, (d) with a temperature of mp. 70-75 ° C from intermediate dioxalate N, N-dimethyl-1K-indole-3,5-diethanamine (0.8 g) and 4- (1-methylsulfonyl) aminoP benzenebutanoic acid (0.8 g).

Example 16. djl-Tartrate N-J2-д3- (2- (dimethylamino) ethyl) -1H-indole-5-yp ethyl_-N-methyl-I, 4-benzene-dianethamide.

Suspension. 4- Ј (2-methylamino) -2-oxaethyl benzeneacetic acid (0.21 g

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0

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0

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and dioxalate K, 3-dimethyl-H indol-3,5-diethanamine (0.23 g) in dry (80 ml) under nitrogen atmosphere at 5 ° C was treated with triethylamine (0.3 ml), then diphenyl phosphoryl azide (0 43 ml). The resulting suspension was stirred at room temperature for 23 hours and extracted into 1N. hydrochloric acid solution (2x320 ml). The acidic aqueous layers were combined and washed with EA (40 ml), basified (pH 8) with help and extracted with a mixture of EA - isopropanol (20: 1, 3x30 ml), the organic extracts were combined, washed with brine (30 ml), dried (sodium sulfate) and evaporated, leaving a brown gum, which was purified using flash chromatography. The resulting white foam was dissolved in hot absolute ethanol. (20 ml) and treated with d, l-BHH-acid (0.068 g) in hot ethanol (5 ml). The resulting solution was cooled (20 ° C) and diluted with dry EA (approximately 150 ml) to precipitate the proposed compound of this example (0.2 g) as an off-white solid, mp. 85-90 ° C (foam).

Example 17. Succinate 4- (acetylamino) (2- (dimethylamino) ethyl) -1K-indol-5-iguetil1benzenebutane-amide.

Diphenylphosphoryl azide (1.5 ml) was added to a cooled (ice on n-na) solution of dioxalate M, M-d tmethyl-IH-indole-3,5-diethanamine (0.8 g) and 4- (acetylamino) benzenebutane acids (0.76 g) in TG (100 ml) and triethylamine (1 ml). After 1 h, the solution was heated to room temperature and stirring continued overnight. A saturated solution of KgCOj (100 ml) was added and the solution was extracted with ethanol (2 x 50 ml), the combined organic extracts were evaporated to dryness under vacuum to obtain a brown oil, which was purified using chromatography. As a result, the free base of the proposed compound of this example was obtained as a brown oil (0.6 g). The free base (0.6 g) was dissolved in the hot mixture.

ten

CHC C — ethanol (10: 1) (20 ml) and added succinic acid (0.17 g) in ethanol (2 ml). Upon cooling, the proposed compound crystallized in the form of a light brown solid (0.3 g) with a temperature of m.p. 68-70 ° C

Example 18, N- (acetyl-amino) -K-C2-Ј3- (2- (dimethyl-amino) -ethyl) -1H-indol-5-yl-1-ethylTmethylamino-benzeneacetamide Oxalate

4- (Acetylamino) benzene acetic acid (696 mg) was dissolved in dry dimethylformamide (30 ml) containing triethylamine (0.56 ml) under nitrogen atmosphere. The solution was cooled in an ice bath and pivaloyl chloride (0.50 ml) was added. The mixture was stirred in an ice bath for 1 hour to obtain a white precipitate, and then a solution of the free base of di-p-toluoyl-L-tartrate-2 Јz- (2- (dimethylamino ) ethyl) | -1Nindol-5-yl | -M-methylethanamine (868 mg) 25 by a thief 4-acetylaminobenol-acetic acid in dimethylformamide (20 ml). Received 6% acetic acid, the volumetric rate of 3 ml / min (yields are given in% of theory.)

Example 19 A solution of triphene phosphate (1.6 g) and triethylamine (0.72 ml) in dry dimethylformamide (40 ml) was stirred for 5 minutes. A solution of 4thylaminobenzeneacetic acid (in dry dimethylformamide (10 ml) was added and stirring was continued for 15 minutes. The resulting mixture was treated with a suspension of dioxalate H, M-dime 15 1H-indole-3,5-diethanamine (1.32 g) of triethylamine ( 1.2 ml) in dry dimsilformamide (0 ml) and the solution was stirred at 40 ° C in an atmosphere of azo for 20 h, as a result of which the proposed compound radiated (x.h.d. 68%),

Example 20 A solution of 1,3-di cyclohexyl-carbodiimide (1.34 g) in (10 ml) was treated with a solution of

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acids (1.25 g) in dimethylformamide (5 ml) and dichloromethane (5 ml) for 5 minutes at 0-5 ° C. The resulting suspension was stirred for 10 minutes at 0 ° C and processed

The resulting suspension was stirred at room temperature for 72 hours. The solvent was evaporated under vacuum to obtain an oil, which was suspended and subjected to flash chromatography, whereby the free base of the proposed compound of this example (1.11 g) was obtained as a transparent resin . A sample (892 mg) was dissolved in methanol (3 ml) and oxalic acid (182 mg) was added. The resulting solution was treated with an ER (80 ml) and the mixture was stirred for 6 hours until the proposed compound of this Example (1.01 g) in the form of a white solid with a temperature t, pl. (foam) 100-1 10 ° G.

Examples 19-23. These examples illustrate the preparation of 4- (acetylamino) -N- {2- p- (2- (dimethylamino) ethyl 1H-indole-5-yl | benzeneacetate).

In each case, when the presence of two compounds was determined using high pressure liquid chromatography (g.h.c.d.), this procedure was carried out with relatively reliable samples using columns 5 (C-O DS1, carried out using a mixture of CH3CN (68) - НгО (20) - O.OSM solution of sodium acetate, the pH of which was provided by level 5 using

5 thief 4-acetylaminobene-acetic

6% acetic acid, volumetric rate of 3 ml / min (yields are given in% of theory.),

Example 19 A solution of triphenyl phosphate (1.6 g) and triethylamine - (0.72 ml) in dry dimethylformamide (40 ml) was stirred for 5 minutes. A solution of 4 acetylaminobenzeneacetic acid (g) in dry dimethylformamide (10 ml) was added and stirring continued for 15 minutes. The resulting mixture was treated with a suspension of dioxalate H, M-dimethyl-5 1H-indole-3,5-diethanamine (1.32 d) and triethylamine (1.2 ml) in dry dimethylformamide (0 ml) and the solution was stirred at 40 ° C under nitrogen atmosphere for 20 hours, resulting in sweating of the proposed compound (x.h.d. 68% ),

Example 20 A solution of 1,3-dicyclohexyl-carbodiimide (1.34 g) in (10 ml) was treated with a plant.

thief 4-acetylaminobene-acetic

acids (1.25 g) in dimethylformamide (5 ml) and dichloromethane (5 ml) for 5 minutes at 0-5 ° C. The resulting suspension was stirred for 10 minutes at 0 ° C and processed

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whether the suspension of dioxalate NjN-dimethyl-1H-indole-3,5-diethanamine (1, 32 g) and triethylamine (1.25 ml) in dry dimethylformamide (05 ml) for c 5 min at 0-5 ° С, The solution was heated to room temperature, stirred under nitrogen for 18 hours, and the proposed compound was prepared according to the examples (x.h.d.d. 62%),

Example 21. A solution of oxalyl chloride (0.471 ml) in (10 ml) was added to a mixture of dimethylformamide (10 ml) and CH2Cl1 (10 ml) at - (10-15) ° C. After this stirring for a further 20 minutes at - (6-10) ° C, a solution of 4-acetylaminobenzoacetic acid (958 g) in dimethylformamide (10 ml) was added, while the temperature of the reaction mixture was maintained below -2 ° C. as a result, the suspension was stirred at 0 ° C for 30 minutes, cooled to -15 ° C, and then treated with a solution of dioxalate K, M-dimethyl-IH-indole-3, 5-diethanamine (1.2 g) and triethylamine (2 , 23 ml) in dry dimetipformamido (10 ml) for 5 min. By chatting, the mixture is slowly heated.

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dried to 20 ° C and stirred for 1 h, after which the proposed compound was obtained according to the examples (f.h.d.d., 71%).

Example 22. A solution of 4-acetylaminobenzeneacetic acid (1.00 g), dioxalate M, H-dimethyl-1H-indole-3,5-diethanamine (1.32 g), triphenylphosphine (2.02 g) and triethylamine (3.29 ml) in a mixture of dimethylformamide (32 ml) and CH.C. (22 ml) was treated dropwise at 0-5 G with a solution of CC1 (7.26 ml) in (10 ml) for about 20 min. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours, resulting in the preparation of the proposed compound according to the examples (LC x 59.6%).

Example 3, Suspension of 4- (acetylamino) benoleic acid (1.00 g) in dry (50 ml) was treated with trimethylacetyl chloride (0.72 ml) and then triethylamine (1.44 ml), then the mixture was stirred at room temperature nitrogen atmospheres for 2.3 hours, resulting in a yellow solution. A solution of dioxalate M, M-dimethyl-1H-indole-3,5-diethanamine (1.32 g) and triethylamine (1.20 ml) in dry dimethylformamide (50 ml) was added and the solution was stirred at room temperature in an atmosphere nitrogen for 20.7 h as a result of which the proposed compound was obtained according to the examples (f.h.d., 43.7%).

The compounds obtained very tightly and selectively narrow the bundle of the carotid artery in an anesthetized dog, with almost no effect on blood pressure. This action was confirmed in laboratory tests.

Beagle dogs of any sex weighing 7–12 kg were anaesthetized with veronal sodium (30 mg / kg) after induction with thiopentone (25 mg / kg, intravenously) and pentoperonal (60 mg, intravenously). The vessels were then removed and prepared to measure the stretch.

Preparation of the drug.

The vascular strips of the saphenous vein of the leg and thigh, as well as the carotid and laryar arteries were cut in a spiral in the vascular band. Each strip was hung using cotton thread in a bath for dissecting organ

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new (20 ml) containing modified Krebs solution. Contractions were recorded isometrically using an auxiliary device with a Stuthum micro-scale (model UL5). attached to the Stuthum universal converter (UC3 model). The strips had a length of 1-2 cm, and the residual tension effect was 400-500 mg.

The tests compared nine compounds of the invention with 5-hydroxytryptamine (5 NT) relative to the reduction of the isolated saphenous vein in a dog's leg, the response of compound 5HT was defined as 1 and the evaluation of other compounds was carried out by comparing their reactions with the reaction of this compound.

The test results are shown in the table.

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The proposed compounds do not have an adverse effect at therapeutic doses and even at significantly higher doses (tests were performed on various animals).

Thus, for example, the compound of Example 2 does not have an undesirable effect when injected into the organism of rats or monkeys in doses up to 3 mg / kg and —in dogs in up to 1 mg / kg (orally),

Claims (1)

Invention Formula The method of producing indole derivatives of the general formula CH3 CH3 (CH-AI-CCH W (CIS) 2x: i Yal nineteen  one where Rj is chlorine or methoxy-, HgNCO-, HeNCOCHz-, CH3ftHCOCH2-t (CK3) 2NCOCHZ-, CH3CONH-, CH2СШСН2-, HzNSOe-, СН3ЙОГЩ- or CH3POeNHCH2- group; R, is hydrogen or C-Cd-alkyl; Ra is hydrogen or C -C alkyl; A - -CO- or -S02-j m is an integer from up to 4, or their pharmaceutically acceptable friends, characterized in that the compound of the general formula and Msna) 3 639427 20 where R and RJ have the indicated meanings, or its salt is acylated with an acid of the general Formula 15 l 5H2) W-A-OH where R /, Ait has the indicated meanings, or its reactive derivative at a temperature from room temperature to the boiling point of the reaction medium, followed by isolation of the target product in free form or in the form of a pharmaceutically acceptable salt.