SU1438609A3 - Method of producing derivatives of indosulfonamide of alkali metal salts thereof - Google Patents

Abstract

The invention relates to indole derivatives, in particular indolsulfonamide of the general formula, .. -dcj -) where K is —CHH — CH2 — C olOH; R - H. Halogen; R is CbH5 (it can be para-substituted by lower alkyl or halogen); RJ and R4 - And together or - connection, X - 1 or 2; Y-0 or I, or their alkaline salts, possess anti-asthma or antiallergic action, which can be used in medicine. The purpose of the invention is the creation of new active and low-toxic substances of the specified class. Their synthesis is carried out by treating unsubstituted indolic nitrogen with acrylonitrile in an inert solvent medium, followed by saponification and isolation of the target product containing a simple bond at (Rj + R4), or hydrogenating it in the presence of an acid and a reducing agent to isolate the product, where. The target product exudes sweat in free form or as an alkali metal salt, or mixture of isomers, or individual isomers. New substances delayed platelet aggregation and have low toxicity. 3 tab. § CO with co 00 O) o co

Description

cm

t1438609

This invention relates to the preparation of new derivatives of the indolesulfonamide formula

4- (ind nol 10% of the water of the river, the water of the b eb ex exe Sésiv Mas à r y lu nne (69b; rf

R

Rar a - NH-SOj-R ..) x

where Rf is hydrogen or halogen

Rj is phenyl, unsubstituted or

substituted in para-position by scientific research institutes with halogen or lower alkyl;

Rj and Cd together form a simple chemical bond, or both mean. Hydrogen5 20 X - 1 or 2 | Y - O or 1,

or their alkaline salts: metals with anti-asthma or antiallergic action.,, 25

The purpose of the invention is to develop, on the basis of known methods, a method for the elimination of new compounds j possessing valuable pharmacological properties with a low toxicity. thirty

Example 1- (Benzenesulfonamide-dimethyl) -4- (2-carboxyethyl) cyclopentano-p, indole,

A. (Benzenesulfonyl) H- {2-cyano-ethyl) aminomethyl-4- (2-cnanoethyl) 35 cyclopentano-D52-LJindole,

1.9 g (0.0058 mol) of 1 (benzenesul fonamidomethyl) cyclopentano-fl 2-bj indole together with 1.83 g (2.3 Mjij 0.0346 Mole) of acryl nitrile and 0.24 i- 40 (0, 00058 mol) of a 40% aqueous solution of hydroxy oxenzoyl trimethylamine-in methanol is stirred for 2 hours at 60-70 ° C in 60 ml of dioxac. Then, the reaction mixture is evaporated in vacuo, 45 the residue is taken up in methylene chloride and extracted twice with dilute sulfuric acid. The organic phase is washed with a saturated solution of bicarbonate, sodium sulfate, dried and evaporated. 2.4 g (95% of theory) of the product are thus obtained in the form of a solid foam. , 45: SNZON 99: 1.

B, 1 (Benzenesulfonamidomethyl) -4- 1 {2-carboxyethyl) cyclopentano-l, 55 indole.

2.4 g (0.0055 mol) (SeH3on-sulfonyl) -N- (2 ianoet1-sh) aminoethyl1-

0

five

0

five

0

five

0 5 0

five

4- (2-cyanostil) cyclopentano-l, 2-bj indole is dissolved in 35 ml of isopropanol and 55 ml of 10% potassium hydroxide solution is added to the solution. The reaction mixture is stirred for 4 hours at, diluted with 100 ml of water and extracted with 100 ml of methylene chloride. The aqueous phase is acidified with dilute sulfuric acid and extracted three times with 100 ml of methylene chloride. The combined organic phases are dried with sodium sulfate and evaporated. The oily residue (1: 9 g) is dissolved in methanol and 0.26 g of sodium methoxide is added to the solution. a solution of 2.0 g (69.2% of theory) of the product is obtained as bc; crocrystalline sodium salt,, 37 СН5.С12: СНЗОН 95: 5

The i- (benzenesulfon-aminomethyl) cyclopentano-1,2-b1indole used as the starting compound is obtained by the following method

3- (Nitromethyl) cyclopentanone,

100 g of 2-cyclopentanone, together with 666 ml of nitometane and 5 g of 1,5-diazo-bidiclos (4.3.0) non-5-ene, is dissolved in 1J1 l of isopropanol and left to stand for 5 hours at room temperature. temperature Isopropanol is generally distilled off under vacuum, the residue is dissolved in ethyl acetate and washed twice with 0.5 l of dilute sulfuric acid. Then the organic phase is dried with sodium sulfate and evaporated. 54 g (88% of theory) of 3- (nitromethyl) cyclopentanone are obtained, the purity of which is sufficient for its use in the next stage, 52 CHgClfj: CHjOH 99: 1.

57.2 g (0.4 mol) of 3- (nitromethyl) cyclopentanone are dissolved in 573 ml of absolute tetrahydrofuran in a nitrogen atmosphere. At 0 ° C, 800 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran is added dropwise to this solution. At the end of the addition, the droplets are further stirred for 1 h at. Then the cooling is stopped, as a result of which the temperature of the reaction solution rises to 40 ° C. After the temperature is lowered, the mixture is further stirred for 1 hour at this temperature. To the cooled reaction mixture, 100 ml-45% sodium hydroxide are carefully added dropwise.

liquor. At the end of the addition to & p- l, the mixture is additionally stirred for 60 minutes at room temperature. The reaction mixture is filtered through Kieselgur, which is then washed with 1.5 l of tetrahydrofuran. The combined filtrates in vacuo are carefully evaporated. . 22.5 g (49% of theory) of a viscous, oily product, P 0.0 CHgCla: CHgGH 9: 1 are obtained.

3- (Benzenesulfonamidomethyl) cyclo pentanol.

9 g (0.078 mol) of 3- (am1 {nomethyl) cyclspentanol together with 13.8 g (10 ml, 0.078 mol) of triethylamine is dissolved in 200 ml of tetrahydrofuran. At a temperature, 7.9 g (10 p8 ml, 0.078 mol) of benzenesulfonic acid chloride are added dropwise. At the end of the addition, the droplets are additionally stirred for 1 hour at 0 s. The reaction mixture is then diluted with 200 ml of methylene chloride and washed twice with 150 ml of dilute sulfuric acid. The organic phase is extracted twice with 150 ml of 2N sodium hydroxide, the combined extracts are acidified by the addition of concentrated hydrochloric acid and extracted twice with 150 ml of methylene chloride. The combined methylene chloride phases are dried with sodium sulfate and evaporated in vacuo. 9.1 g are thus obtained (39% of theory)

ten

15

kume are evaporated. Thus, 4.4 g (59% of theory) of a viscous oily product are obtained, 51 CHjCl J CH3 95: 5.

1- (Benzenesulfonamidomethyl) cyclopentano- |; 1, 2-indol.

21 g (0.0826 mol) of 3- (benzenesulfonamidomethyl) cyclopentanone, together with 9 g (0.0826 mol) of phenylhydrazine, are dissolved in 200 ml of glacial acetic acid and heated with an o6paTHbtM fridge for 4 hours. The reaction solution is then diluted with 1.3 liters of ether and 300 ml of water is added to this solution. Cooling and stirring is alkalized by the addition of 45% sodium hydroxide and the organic phase is separated.

20 The aqueous phase is extracted once more with 500 ml of ether, the combined organic phases are dried with sodium sulfate and evaporated. The residue is subjected to chromatography on a column containing 25 kg of silica gel (0.04-- 0.063 mm) using a mixture of toluene and ethyl acetate in the ratio 85:15 as eluent. The resulting fraction is evaporated and 9 g are obtained (7% of theory) crystalline product, So pl. 161-164 seconds , 92 CHpClft CHjOH 95: 5.

Example2. 4- (2-carboxy-ethyl) -1- (4-fluorophenylsulfonamidomeso

viscous, oily product in the form of gg tyl) cyclopentano-l, 2-blindol,

mixtures of isomers, 51 and 0.45 CHgCla: 4- (2-Cyanoethyl) (4-fluorophenylCH,.,. sulfonyl) -K- (2-cyanoethyl) aminome3- (Bexzolsulfonamidomethyl) cycloyl methyl, cyclopentano- 1,2 -1 indol. pentanone. Example 1A was repeated with that difference, 5 g (0.0294 mol) of 3- (benzenesulfate that 0.67 g of fonamidomethyl) cyclopentanol was used with solution- (0.00195 mol) - (4-fluorophenylsulfonamidomethyl) diclopentano ft , 2indol.

rinse in 60 ml of glacial acetic acid. 2.79 g (0.0279 mol) of chromium trioxide dissolved in. 2 ml of water and 8.8 ml of glacial acetic acid. Then the temperature of the reaction mixture is raised to room temperature and stirred at this temperature for 1 hour. The reaction mixture is diluted by adding 200 ml of ether and washing twice with 150 ml of water. The organic phase is extracted twice with 200 ml of 2N. In caustic soda, the combined alkaline phases are acidified by the addition of concentrated hydrochloric acid and extracted twice with 200 ml of methylene chloride. The combined methylene chloride phases are dried with sodium sulfate and in ba50

. Thus obtained 0.83 g (95%

theory) of the product as a solid 45 foam. , 39, toluene: ethyl acetate with acetic acid 8: 2.

B. 4- (2-Carboxyethyl) -1- (4-fluorophenylsulfonamidomethyl) cyclopentano-1,2-h1indole.

Example 1B is repeated with the difference that the hydrolysis is subjected to 0.83 g (0.00184 mol) of 4- (2-cyanoeth1) (4-fluorophenylsulfonyl) -N- (2-cyanoethyl) aminomethyl cyclopentano-1, 2 gb indole. 0.67 g (87% of theory) of a crystalline product is thus obtained as the sodium salt. . M.p. 150-160 S., 59 CHcCli:. .

0

five

kume are evaporated. Thus, 4.4 g (59% of theory) of a viscous oily product are obtained, 51 CHjCl J CH3 95: 5.

1- (Benzenesulfonamidomethyl) cyclopentano- |; 1, 2-indol.

21 g (0.0826 mol) of 3- (benzenesulfonamidomethyl) cyclopentanone, together with 9 g (0.0826 mol) of phenylhydrazine, are dissolved in 200 ml of glacial acetic acid and heated with an o6paTHbtM fridge for 4 hours. The reaction solution is then diluted with 1.3 liters of ether and 300 ml of water is added to this solution. Cooling and stirring is alkalized by the addition of 45% sodium hydroxide and the organic phase is separated.

0 The aqueous phase is extracted once more with 500 ml of ether, the combined organic phases are dried with sodium sulfate and evaporated. The residue is subjected to chromatography on a column containing 25 kg of silica gel (0.04-- 0.063 mm) using a mixture of toluene and ethyl acetate in the ratio 85:15 as eluent. The resulting fraction is evaporated and 9 g are obtained (7% of theory) crystalline product, So pl. 161-164 seconds , 92 CHpClft CHjOH 95: 5.

Example2. 4- (2-carboxy-ethyl) -1- (4-fluorophenylsulfonamidomeso

gg til) cyclopentano-l, 2-blindol,

50

. Thus obtained 0.83 g (95%

theory) of the product as a solid 45 foam. , 39, toluene: ethyl acetate with acetic acid 8: 2.

B. 4- (2-Carboxyethyl) -1- (4-fluorophenylsulfonamidomethyl) cyclopentano-1,2-h1indole.

Example 1B is repeated with the difference that the hydrolysis is subjected to 0.83 g (0.00184 mol) of 4- (2-cyanoeth1) (4-fluorophenylsulfonyl) -N- (2-cyanoethyl) aminomethyl cyclopentano-1, 2 gb indole. 0.67 g (87% of theory) of a crystalline product is thus obtained as the sodium salt. . M.p. 150-160 S., 59 CHcCli:. .

C1

47

0.35 toluene: ethyl 204-206 (from ethyl ether of ethyl acetate / isopropyl acid 8: 2 panol)

53

0.29 toluene: acetic acid ethyl ester 8: 2

7A CH "

85

0.37

206-208 (from ether / isopropanol)

180-190

(from simple

ether)

5B C1 89.5 0.61 CHgCl2: CHi, OH 9: l150

(sodium salt)

6B F98.5 0.57 CHaClij: CHjOH 9: 1 160-170

(sodium salt)

7B CHj 95

0.53: CH, 150-60

(sodium salt)

PRI me R 8. Z-CA-Fluorophenylsulfonamido) -9- (2-carboxyethyl) -1,2, 3,4-4a-t, 9a-t-hexahydrocarbazole (isomer A) and 3- y- (4-fluorophenylsulfonamido-) -9- (2-carboxyethyl) -1,2,3,4,4a-c, 9a-c-hexahydrocarbazole (isomer B)

 BN50, -O-G

isomer A

isomer B

soon

5 g (0.0144 mol) of 3- (4-fluorofansh1Sulphonamido) -9- (2-carboxyethyl) -1,2,3,4-tetrahydrocarbazole sodium salt are dissolved in 50 ml of trifluoroacetic acid and to this solution With portions, 5.01 g (0.08 mol) of cyanoborane sodium is added. The temperature of the reaction mixture was raised to room temperature, diluted with water and extracted with 200 ml of ethyl acetate. The acetic phase is extracted twice with 100 ml of 2N sodium Table 2 ISHSO —O-X

The alkaline liquor, the pH of the combined sodium hydroxide phases is adjusted to 5 and thirds are extracted with 150 ml of methylene chloride, dried with sodium sulfate and carefully evaporated in vacuo. The residue is subjected to chromatography on a column containing 500 g of silica gel (0.040-0.063) using methylene chloride / glacial acetic acid as an eluent in a ratio of 100: 1. Two fractions are obtained, of which, after evaporation, 2.87 g (60.2% of theory) of isomer A and 0.7 g (14.9% of theoretical) of isomer B are obtained as solid foam, Rf isomer (A): 0, 24

CH 2 S 12: CH 2 100: 2

Rf isomer (B): 0.14.

EXAMPLE 9 (Benzenesulfonamido) -9- (2-to arboxyethyl) -1,2,3,4, 4a-t, 9a-t-hexahydrocarbazole (isomer A) and (benzenesulfonamido) -9 - (2-carboxyethyl) -1,2,3,4-4a-c, 9a-c-hexahydrocarbazole (isomer B)

(isomer A)

c

..4NS02HQ

(isomer B)

Analogously to Example 8, 1.18 g (0.0028 mol) of sodium salt of 3- (benzenesulfonamido) -9- (2-carboxymethyl) -1,2,3,4-tetrahydrocarbazole “was reconstituted after chromatography get - two fractions, of which 0.45 g (40% of theory) of isomer A and g (18% of theory) of isomer B are obtained in the form of solid foam by evaporation. Rf isomer A50,

 CH2C12: CH 100: A Rf Isomer B: 0.22

Example 10, 3-2- (4-Methylfexylsulfonamido) -9- (2-carboxyethyl) - 1,2,3,4j4a-t, 9a-t-hexahydrocarbazole (isomers A)

  n

NHS02,

(isomer A)

n soon

and

(4-methylphenylsulfonylamido) -9- (2-carboxyethyl) -1-293,4,4a-c, 9a-c-hexahydrocarbazole (isomer B)

n n

  -Snz

.WS02, -t3

isomer B

Analogously to Example 8, 18.06 g of sodium salt of 3- (4-methylphenylsulfonamido) -9- (2-carboxy ethyl) -1,2,3,4-tetrahydrocarbazole are dissolved. After chromatography, two are obtained. fractions from which 3.65 g (20% of theory) of isomer A are obtained by evaporation as crystalline residue (mp) and 1, P g (6% of theory) of isomer B in the form of solid polystyrene. Rf isomer A: 0.39

CHgCli: CHi, COOH "lOO; i2

Rf isomer B: 0,20

five

Example P. 3- (4-Chlorophenylsulfonamido) -9- (2-carboxyethyl) -6- fluoro-1.2eZ, 4-tetrahydrocarbazole, A. (4-Chlorophenylsulfonyl) -H- (2-cyanoethyl) amino1- 9- (2-cyanoethyl) -6-fluoro-1,2,35 4 tetrahydrocarbazole.

Example 1A is repeated, with the difference that 3.4 g of 4- (4-chlorophenylsulfonamido) -6-fluoro-1,2,3,4-tetrahydrocarbazole is used. 27.6 g (61% of theory) of the product are thus obtained in the form of a solid foam.

Rf 0.25 toluene: ethyl acetate 8: 2.

B, 3- (4-Chlorophenylsulfonamido) -9- (2-carboxyethyl) -6-fluoro, 2,3,4-tetrahydrocarbazole

Example 1B is repeated, with the difference that 27.6 g of 3- IN- (chlorophenylsulfonyl) (2-cyanoethyl) -amino 1 9- (2-cyanostil-6-fluoro, 2,3,4- tetrahydrocarbazole, - 5 thus 5–6 g (100% of theory) of crystalline sodium salt are obtained, t, mp M8-130 C, 52 CH2Cl: CH3OH 9: 1.

Example 12. 9- (2-Carboxyethyl) - 4- (4 Fluorophenylsulfonamidom1) - |, 2, 0, 3,4-tetrahydrocarbazole,

A. 9- (2-Cyanoethyl) (4-fluorophenylsulfonyl) -N- (2-cyanoethyl) amino; methyl} -J, 2,3,4 tetrahydrocarbazole.

Example 1A is repeated, with the difference that 4- (4-fluorophenylsulfonamidomethyl) -1,2,3,4-tetrahydrocarbolol is reacted with acrylonitrile. 0.91 g (88% of theory) is obtained, the prod as oil, Rf 0.37 toluene: acetic acid ethyl ester 8: 2.

B. 9- (2-Carboxyethyl) -4- (4-fluorophenylsulfonamidomethyl) -1,2,3,4-tetrahydrocarbazole,

Example 1B is repeated, with the difference that 0.91 g of 9 (2-cyanoethyl) (4-fluorofensh1-sulfonyl) -N- (2-cyanoethyl) aminomethyl Z-1, 2, 3,4-tetrahydrocarbazole is subjected to the purification. Thus obtained 0.77 g (89% of theory)

and

crystalline product in the form of sodium salt. M.p. 160 s. Rf 0,57 СК С15: СНЗОН 9 :.

Example 13. (+) - 3- (4-Fluoro-1-slsulfonamido) -9- (2-carboxyethyl) -, 2,3,4-tetrahydrocarbazole.

5.16 g (0.015 mol). (4 -) - 3- (4-fluorophenylGylfloflamido) -1, 2,3,4 tetrahydrocarbazolium is dissolved in 200 ml

five

five

dry dimethylformamide in a nitrogen atmosphere and to this solution 0.5 g (0,0165 mol) of sodium hydride with 20% spun oil was added in portions. But when the formation of hydrogen was complete, 2 mil (0.03 mol) acrylonitrile was added to the reaction mixture. Stir during 1 h at room temperature, then 0.5 ml of acrylonitrile is added again and stirred for 1 h at room temperature. The mixture is diluted with 1 L of ethyl acetate and water is extracted three times. The vinegar ester phase is dried with sodium sulfate and evaporated. 7.8 g of crude product are thus obtained, which is subjected to chromatography on a column of silica.

using a gel (0.063–0.2 mm) with the use of a mixture of toluene and aggregation of tromo ethyl ester of acetic acid in a 1: 1 ratio as a mixture solvent. A fraction is obtained.

bocytes. For this, to the preincubated sample, as an aggre- gating aggregating agent, added from which 5.8 g is obtained by evaporation.

(86% of theory) of monocyanoethyl was 25 or 0.1 ml of collagen. For a period of 6 minutes

Dinene in the form of a solid foam, which, according to Example 1A, is converted into a bis-cyanoethyl compound.

B. (+) - 3- (4-Fluorophenmsulfonamido-) -9- (2-carboxyethyl) -1,2,3,4-tetrahydrocarbazole.

5.8 g (0.0128 stranded) of the product according to stage A is dissolved in 60 ml of isopropanol. 130 ml of a 10% potassium hydroxide solution was added to this solution, heated under reflux for 16 hours, cooled, diluted with water and extracted with ethyl acetate. The aqueous phase is concentrated in vacuo and, with vigorous stirring, acidified by the addition of conical nitrile hydrochloric acid. It is washed with water and etched off under vacuum. 4.4 g (86.6% of theory) of the desired product are obtained. M.p. 85-95 s, rotation index: wjj 42.55 (cHCl).

Example 14. (-) - 3- (4-Fluorophene-1-sulfonamido) -9- (2-carboxyethyl) -1,2,3,4-tetrahydrocarbazole.

A. C -) - 3-1K- (4-fluorophenylsulfonyl) -N- (2-cyanoethyl) amino-9- (2-cyanoethyl) -, 2,3,4-tetrahydrocarbazole.

The preparation was carried out analogously to example 13A.

B. (-) - 3- (4-Fluorophenylsulfonamido-) -9- (2-carboxyethyl) -1,2,3,4-tetra hydrocarbazole.

The preparation of the target product is carried out analogously to example 13B. Output 86.2% of theory, so pl. 85-95 C, I 0

Kazatesh, rotations: about -37.83 (CHCl,).

Pharmacological experience

Blood was used to determine the inhibitory platelet aggregation effect of healthy male and female proban, cox. As an anticoagulant, a 3.8% vodka solution of sodium citrate was mixed with blood in a 1: 9 ratio. From this blood by centrifuging platelet-rich citrate plasma.

0.8 ml of this plasma and O, 1 ml of the active substance solution was subjected to pre-incubation.

Then gurbidimetry in the aggregometer when the aggregation was determined by

bocytes. To this end, changes in optical density were recorded to the preincubated sample as aggregating agent that was added, and after 6 minutes, the degree of delay in% was compared with the control. 30 The results of the experiment are summarized in table 3.

 T b b face 3.

Delay concentration limit (mg / L)

55

Zulotrobai trade product that has

S) -S02NH-CH2-CHi {oVoCH2COOH

Compounds I are classified as little toxic substances.

Claims (1)

Invention Formula The method of obtaining derivatives of indolsulfonamido General formula I R3: JpHjV H-S02-R; j : (cH-, v R is hydrogen or halogen; Riji is phenyl, unsubstituted or substituted by steam, with halogen or lower alkyl; R - together form a simple chemical bond, or both are hydrogen, X is 1 or 2; Y - O or 1, Editor N.Kishtulinets Tehred M.Hodannch Order 5972/58 Circulation 370. Subscription VNIIPI USSR State Committee for inventions and discoveries 113035, MoskvaJ Zh-33, Raushsk nab., 4/5 or their alkali metal salts, i.e. in that the compound of the general formula II (CH2,) y - NH-502-R :( where R}, R2 X and Y have the indicated values, is reacted with acrylstrike in an inert solvent, the compound thus obtained is washed and compound I is isolated, where R and R4 together form a simple chemical bond, or it is subjected to hydrogenation in the presence of an acid and a reducing agent to produce compound I, where Rj and R4 together represent hydrogen, and the desired product is isolated in free form or as an alkali metal salt, or mixture of isomers, or individual isomers. Proofreader S. Shekmar