CN87100773A - Cycloalkano[1,2-b]indole-sulfonamide compounds - Google Patents

Abstract

Novel cycloalkano[1,2-b]indole-sulfonamide compounds and their salts can be reacted by [benzenesulfonamidoalkyl]cycloalk[1,2-b]indole with acrylonitrile , followed by hydrolysis, where appropriate, hydrogenation and reaction with a base. [Benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole is an intermediate which can be prepared from the corresponding phenylhydrazine and cycloalkanone. The cycloalkano[1,2-b]indole-sulfonamide compounds and their salts can be used to treat diseases.

Description

Cyclobenzo [1,2-b ] indole-sulfonamides

The present invention relates to new cycloalkano [1, 2-b ] indole-sulfonamides, to a process for their preparation and to their use in medicine. [ benzenesulfonylaminoalkyl ] -cycloalkano [1, 2-b ] indoles are also novel and useful as intermediates in the preparation of the novel compounds.

Novel cycloalkano [1, 2-b ] indole-sulfonamides of the general formula (I) or salts thereof have been found and, if appropriate, also isomeric forms thereof,

Wherein R ¹ represents hydrogen-halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula-S (O) mR ³,

Wherein R ³ denotes an alkyl or aryl group, m denotes one of 0,1 or 2, and R ³ may representIs a group of (a) and (b),

Wherein R ⁴ and R ⁵ are identical OR different and represent hydrogen, alkyl, aryl, aralkyl OR acetyl, R ⁴ and R ⁵ may represent a group of the formula-OR ⁶,

Wherein R ⁶ is hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ -or trifluoromethyl, or represents alkyl, alkenyl or cycloalkyl, each of which may also be substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyanoOptionally substituted;

R ² represents aryl which may be sub-optionally substituted by up to 5 radicals from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxy, carboxyl, phenyl, phenoxy, benzyloxy, benzylthio, or by the formula

An aryl group substituted by a group of (a),

Wherein R ⁴ and R ⁵ have the meanings given above;

x represents 1,2 or 3;

y represents 0 or 1.

The cycloalkano [1,2-b ] indole-sulfonamides of the invention have several asymmetric carbon atoms and may thus have different stereochemical forms. The present invention relates to individual isomers and also to mixtures thereof.

The following isomers of the cycloalkano [1, 2-b ] indole-sulfonamide compounds are described in the examples:

a) Cyclobenzo [1, 2-b ] indole-sulfonamides

The meanings of R ¹、R², x and y are as described above.

The cycloalkano [1, 2-b ] indole-sulfonamide compounds of the invention may also be in the form of salts thereof. In general, the salts recited herein are salts thereof with organic or inorganic bases.

In the context of the present invention, preference is given to physiologically acceptable salts, and physiologically preferred salts of the cycloalkano [1, 2-b ] indole-sulfonamide compounds are metal salts or ammonium salts of the substances according to the invention having free carboxyl groups. Examples of particularly preferred salts are sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine or 1, 2-ethylenediamine.

The substances according to the invention have a surprising platelet aggregation-inhibiting effect and are therefore useful for the treatment of humans and animals.

Alkyl generally represents a straight-chain or branched hydrocarbon group having 1 to 12 carbon atoms, and lower alkyl groups having 1 to 6 carbon atoms are preferable, examples of which are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 12 carbon atoms and having one or more (preferably one or two) double bonds, preference being given to lower alkyl radicals having 2 to 6 carbon atoms and one double bond, alkenyl radicals having 2 to 4 carbon atoms and one double bond being particularly preferred, examples being vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, cyclohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

Cycloalkyl generally represents a cyclic hydrocarbon group having 3 to 8 carbon atoms, with cyclopentane and cyclohexane being preferred, examples being cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon group having 1 to 12 carbon atoms and linked through an oxygen atom, preferably a lower alkoxy group having 1 to 6 carbon atoms, particularly preferably a lower alkoxy group having 1 to 4 carbon atoms, examples of which are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, heptyloxy, isoheptyloxy, octyloxy or isooctyloxy.

Alkylthio generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms and linked by sulfur atoms, lower alkylthio having 1 to 6 carbon atoms being preferred, alkylthio having 1 to 4 carbon atoms being particularly preferred, examples being methylthio, ethylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio,Hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio and isooctylthio.

Aryl generally represents an aromatic group having 6 to 12 carbon atoms, with preference being given to phenyl, naphthyl and diphenyl.

Aralkyl generally represents an aryl group having 7 to 14 carbon atoms and linked through an alkylene chain, and aralkyl groups having an aliphatic moiety of 1 to 6 carbon atoms and an aromatic moiety of 6 to 12 carbon atoms are preferable, with aralkyl groups such as benzyl, naphthylmethyl, phenethyl and phenylpropyl being examples.

Alkoxycarbonyl groups of the formula

Alkyl group

The alkyl group of the formula represents a straight-chain or branched hydrocarbon group having 1 to 8 carbon atoms, preferably a lower alkoxycarbonyl group having an alkyl moiety of 1 to 6 carbon atoms, particularly preferably an alkoxycarbonyl group having an alkyl moiety of 1 to 4 carbon atoms. Alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl are examples.

Carboxyalkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms and substituted by a carboxyl group, preferably a carboxyl-lower alkyl radical having 1 to 6 carbon atoms. Examples of carbonylalkyl groups are carboxymethyl, 1-carboxyethyl, 1-carboxypropyl, 1-carboxybutyl, 1-carboxypentyl, 1-carboxyhexyl, 2-carboxyethyl, 2-carboxypropyl, 2-carboxybutyl, 3-carboxypropyl, 3-carboxybutyl, 4-carboxybutyl, 2-carboxy-1-propyl, 1-carboxy-1-propyl.

Alkoxycarbonylalkyl generally represents a straight-chain or branched hydrocarbon radical having from 1 to 12 carbon atoms and substituted by an alkoxycarbonyl group, the alkoxycarbonyl group having the meaning indicated above, preferably being a lower alkoxycarbonyl-lower alkyl radical having from 1 to 6 carbon atoms in the respective alkyl moiety,Examples thereof are methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, isopropoxycarbonylmethyl, isobutoxycarbonyl methyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonylethyl, 1-butoxycarbonylethyl, 1-isopropoxycarbonylethyl, 1-isobutoxycarbonyl ethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-propoxycarbonylethyl, 2-butoxycarbonylethyl, 2-isopropoxycarbonylethyl, 2-isobutoxycarbonyl ethyl, 2-methoxycarbonyl-2-propyl, 2-ethoxycarbonyl-2-propyl, 2-propoxycarbonyl-2-propyl, 2-butoxycarbonyl-2-propyl, 2-isopropoxycarbonyl-2-propyl, 2-isobutoxycarbonyl-2-propyl, 2-methoxycarbonyl-2-propyl, 1-ethoxycarbonyl-2-propyl, 2-propoxycarbonyl-2-propyl, 1-butoxycarbonyl-2-propyl, 1-isopropoxycarbonyl-2-propyl, 1-isobutoxycarbonyl-2-butoxycarbonyl-3-methoxycarbonyl-3-isopropoxycarbonyl-3-isopropyl and 3-ethoxycarbonyl-3-isopropyl.

Halogen generally represents fluorine, chlorine, bromine or iodine, preference being given to fluorine, chlorine or bromine, particular preference being given to halogen being fluorine or chlorine.

Preferred compounds of the formula (I) are those in which, if appropriate, they are in the form of their isomers or their salts

R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl, or lower alkoxycarbonyl, and represents formula

The group of S (O) mR ³,

Wherein R ³ denotes lower alkyl or phenyl,

M denotes 0 or2, and R ³ may represent formula

Is a group of (a) and (b),

Wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, lower alkyl, phenyl, benzyl or acetyl, or represent formula

The group-OR ⁶ -is a radical,

Wherein R ⁶ is hydrogen, lower alkyl, phenyl-SO ₂ -, methyl-SO ₂ -, ethyl-SO ₂ -, or trifluoromethyl, or represents lower alkyl, lower alkenyl, cyclopentyl, or cyclohexyl, each of which may also be optionally substituted with carboxy, methoxycarbonyl, ethoxycarbonyl, fluoro, chloro, bromo, hydroxy, lower alkoxy, or cyano;

R ² represents phenyl which may be optionally substituted by up to 3 groups from fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkyl, carboxymethyl, carboxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, lower alkoxy, lower alkylthio, hydroxy, carboxy, lower alkoxycarbonyl, phenyl, phenoxy, benzylthio, or by

A phenyl group substituted by a group of (a),

Wherein the meanings of R ⁴ and R ⁵ have already been indicated,

X represents 1,2 or 3,

Y represents 0 or 1.

Particularly preferred compounds of the formula (I) are those in which, if appropriate, they are in the form of their isomers or their salts

R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amino, dimethylamino, diethylamino or acetamido, or represents a group of the formula

The group-OR ⁶ -is a radical,

Wherein R ⁶ denotes hydrogen, C ₁-C₄ alkyl, phenyl or benzyl, or represents C ₁-C₄ alkyl;

R ² represents phenyl substituted by up to 3 identical or different groups from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C ₁-C₄ alkyl, C ₁-C₄ alkoxy, methylthio, hydroxy, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetamido or diethylamino;

x represents 1 or 2;

y represents 0 or 1.

The most particularly preferred compounds of the formula (I) are those in which, if appropriate, isomers or salts thereof, in which

R ¹ represents hydrogen, fluoro, methyl, methoxy, benzyloxy or hydroxy;

r ² represents phenyl substituted by fluoro, chloro, trifluoromethyl, methyl, ethyl, propyl, isopropyl or methoxy;

x represents 1 or 2;

y represents either 0 or 1 and is preferably chosen,

Particularly preferred are (+) -or (-) -isomerised cycloalkano [1,2-b ] indole-sulphonamides of formula (XII) or salts thereof,

Wherein R ¹ represents hydrogen, fluoro, methyl, methoxy, benzyloxy or hydroxy;

R ² represents phenyl substituted by fluorine, chlorine, trifluoromethyl, methyl, propyl, isopropyl or methoxy;

y represents 0 or 1.

The following cycloalkano [1,2-b ] indole-sulfonamides are described by way of exampleThe method comprises the following steps:

1- (benzenesulfonamidomethyl) -4- (2-carboxyethyl) cyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamidomethyl) -cyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamidomethyl) -cyclopenta [1, 2-b ] indole

1- (Benzenesulfonamidomethyl) -4- (2-carboxyethyl) -7-methoxy-cyclopenta [ 1,2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamidomethyl) -7-methoxycyclopenta [ 1,2-b ] indole

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamidomethyl) -7-methoxycyclopenta [ 1,2-b ] indole

1- (Benzenesulfonamido) -4- (2-carboxyethyl) cyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamido) cyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamido) cyclopenta [1, 2-b ] indole

1- (Benzenesulfonamido) -4- (2-carboxyethyl) -7-methoxycyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamido) -7-methoxycyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamido) -7-methoxy ringPentano [1,2-b ] indoles

1- (Benzenesulfonamidomethyl) -4- (2-carboxyethyl) -7-methylcyclopentano [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamidomethyl) -7-methylcyclopentano [ 1,2-b ] indole

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamidomethyl) -7-methylcyclopentano [ 1,2-b ] indole

1- (Benzenesulfonamido) -4- (2-carboxyethyl) -7-methylcyclopentano [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamido) -7-methyl-cyclopenta [ 1,2-b ] indole

4- (2-Carboxyethyl) -1- (4-toluenesulfonamidomethyl) cyclopenta [1, 2-b ] indole

4- (2-Carboxyethyl) -1- (4-toluenesulfonamido) -cyclopenta [1, 2-b ] indole

3- (Benzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a,9 a-hexahydrocarbazole

3- (Benzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a,9 a-hexahydrocarbazole

3-R- (benzenesulfonamido) -9- (2-carboxyethyl) -6-methoxy-1, 2,3, 4a-t,9 a-t-hexahydrocarbazole

3-R- (benzenesulfonamido) -9- (3-carboxyethyl) -6-methoxy-1,2,3, 4A-c,9 a-c-hexahydrocarbazole

3-R- (benzenesulfonamidomethyl) -9- (2-carboxyethyl) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole

3-R- (benzenesulfonamidomethyl) -9- (2-carboxyethyl) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole

3-R- (benzenesulfonamidomethyl) -9- (2-carboxyethyl) -6-methoxy-1, 2,3, 4a-t,9 a-t-hexahydrocarbazole

3-R- (benzenesulfonamidomethyl) -9- (2-carboxyethyl) -6-methoxy-1, 2,3, 4a-c,9 a-c-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-toluenesulfonamido) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-toluenesulfonamido) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -6-methoxy-1, 2,3, 4a-t,9 a-t-hexahydrocarbazole

9- (2-Carboxyethyl) -3-r- (4-fluorobenzenesulfonamido) -6-methylOxy-1, 2,3, 4a-c,9 a-c-hexahydrocarbazole

(+) -3- (4-Chlorenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

(+) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

(-) -3- (4-Chlorenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

(-) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

(±) -3- (4-Chlorobenzenesulfonamido) -9- (2-carboxyethyl) 1,2,3, 4-tetrahydrocarbazole

(±) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

Particularly preferred are:

(+) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) 1,2,3, 4-tetrahydrocarbazole and

(-) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) 1,2,3, 4-tetrahydrocarbazole

Furthermore, the present invention provides a process for preparing a cycloalkano [1,2-b ] indole-sulfonamide compound and a salt thereof, characterized by reacting a [ benzenesulfonylaminoalkyl ] cycloalkano [1,2-b ] indole of the general formula (XIII)

In an inert solvent, if appropriate in the presence of an acid and a reducing agent, the isomers are separated, if appropriate by customary methods, the salts thereof are prepared, if appropriate by reacting with acrylonitrile in the presence of an acid and a reducing agent, and then, if appropriate, reacting with a suitable base,

In the formula (XIII)

R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a radical of the formula-S (O) mR ³,

Wherein R ³ is an alkyl group or an aryl group,

M is a number of 0,1 or 2,

R ³ represents

Is a group of (a) and (b),

Wherein R ⁴ and R ⁵ are identical OR different and represent hydrogen, alkyl, aryl, aralkyl OR acetyl, represent a group of the formula-OR ⁶,

Wherein R ⁶ is hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ -, or trifluoromethyl, or represents alkyl, alkenyl, or cycloalkyl, each of which may be optionally substituted with carboxy, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio, or cyano;

R ² represents aryl optionally substituted by up to 5 groups halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or by

Aryl substituted by groups of (2)

Wherein R ⁴ and R ⁵ have the meanings given above;

x represents 1,2 or 3,

Y represents 0 or 1.

The method of the present invention may be illustrated as follows:

Cycloalkano [1, 2-b ] indoline-sulphonamides of the type of formula (I) correspond to formula (Ia),

Wherein R ¹、R², x and y have the meanings given above.

In practicing the process of the invention, the intermediates produced are typically isolated, and thus the process of the invention may be practiced in several steps, although several steps may be combined.

Solvents used in the process of the invention are water and organic solvents which remain unchanged under the reaction conditions, preferred solvents include alcohols (such as methanol, ethanol, propanol or isopropanol), ethers (such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether or ethylene glycol dimethyl ether), hydrocarbons (such as benzene, toluene, xylene, cyclohexane, hexane or petroleum fractions), dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, acetonitrile or pyridine. Mixtures of the above solvents may also be used.

The base used in the process of the present invention is a usual basic compound, and preferred bases include alkali metal and alkaline earth metal hydroxides (such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide), alkali metal hydrides (such as sodium hydride), alkali metal or alkaline earth metal carbonates (such as sodium carbonate, potassium carbonate), or alkali metal alkoxides (such as sodium methoxide or sodium ethoxide, potassium methoxide or potassium ethoxide, or potassium tert-butoxide), or amides (such as sodium amide or lithium diisopropylamide), or organic amines (such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine).

The process of the invention is generally carried out at a temperature in the range from 0℃to 150℃and preferably at a temperature in the range from 20℃to 100 ℃.

The process of the invention is generally carried out at atmospheric pressure, but may also be carried out under reduced or increased pressure (for example in the range from 0.5 to 5 bar).

In general, 1 to 20 moles of acrylonitrile, preferably 1 to 10 moles, are used per mole of [ benzenesulfonaminoalkyl ] cycloalkano [1, 2-b ] indole.

The N, N' -dicyanoethyl compound may be hydrolyzed in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, or an alkoxide thereof, in an inert solvent such as water or an alcohol by a method known per se. The preferred base is sodium hydroxide, potassium hydroxide or barium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide, preferably in water, methanol, ethanol, propanol or isopropanol, or mixtures of these solvents.

Generally, 1 to 100 moles of the base, preferably 2 to 50 moles, are used per mole of the N, N' -dicyanoethyl compound.

The hydrolysis is carried out at a temperature of 0℃to 100℃and preferably 20℃to 80 ℃.

The hydrogenation is carried out by methods known per se. An acid may be used as a solvent for the hydrogenation reaction.

Suitable solvents for the hydrogenation reaction are inert organic solvents which do not change under the reaction conditions, the preferred solvents comprising ethers such as diethyl ether, dioxane or tetrahydrofuran, or glacial acetic acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.

Acids useful in all steps of the present invention are organic acids. Preferred organic acids include carboxylic acids (e.g., acetic acid, propionic acid, chloroacetic acid, dichloroacetic acid, or trifluoroacetic acid), all sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, or benzenesulfonic acid or trifluoromethanesulfonic acid).

Suitable reducing agents for the hydrogenation according to the invention are the customary reducing agents, preference being given to hydrides (for example sodium borohydride, sodium cyanoborohydride, tetrabutylammonium borohydride, tetrabutylammonium cyanoborohydride, tributyltin hydride), triethylsilane, dimethylphenylsilane or triphenylsilane.

The hydrogenation is generally carried out at a temperature in the range of-40℃to +80℃, preferably-20℃to +60℃.

The [ benzenesulfonylalkyl ] cycloalkano [1,2-b ] indole (formula XIII) used is novel and the process for preparing [ benzenesulfonylalkyl ] cycloalkano [1,2-b ] indole is likewise found, characterized in that phenylhydrazine of the formula (XIV) (in which R ¹ has the meaning given above) is reacted with a catalyst of the formula

Reacting with cycloalkanone sulfonamide compound (represented by general formula (XV), wherein R ², x and y are as defined above),

The reaction is carried out in an inert solvent, if appropriate in the presence of a catalyst.

The process for the preparation of [ benzenesulfonylalkyl ] -cycloalkano [ 1,2-b ] indoles of the invention can be illustrated by the following scheme:

Suitable solvents for the process according to the invention are inert organic solvents which do not change under the reaction conditions, preference being given to alcohols (e.g.methanol, ethanol, n-propanol, isopropanol and ethylene glycol), ethers (e.g.diethyl ether, dioxane, tetrahydrofuran, ethylene glycol-methyl ether or ethylene glycol-dimethyl ether), halogenated hydrocarbons (e.g.dichloromethane, trichloromethane or tetrachloromethane, dichloroethylene and trichloroethylene), ethyl acetate, toluene, acetonitrile, glacial acetic acid, hexamethylphosphoric triamide, pyridine and acetone. Of course, mixtures thereof may also be used.

Suitable catalysts for the process according to the invention are the usual acids or Lewis acids, preferably inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid, or organic acids such as carboxylic acids or sulfonic acids, for example acetic acid, methanesulfonic acid and toluenesulfonic acid, or Lewis acids such as zinc chloride, zinc bromide or boron trifluoride etherate.

The process according to the invention is generally carried out at a temperature in the range from 0℃to 200℃and preferably from 20℃to 150 ℃.

The process according to the invention is usually carried out at atmospheric pressure, but also under elevated or reduced pressure (for example 0.5 to 5 bar).

The amount of hydrazine used is generally from 1 to 3 moles, preferably from 1 to 1.5 moles, relative to the ketone.

As the hydrazine used in the method of the present invention, phenylhydrazine, 4-methoxyphenylhydrazine, 4-chlorophenylhydrazine and 4-methylphenylhydrazine are mentioned.

The ketones used in the process of the invention are:

3- (benzenesulfonamidomethyl) cyclopentanone

3- (Benzenesulfonamidomethyl) cyclohexanone

4- (Benzenesulfonamidomethyl) cyclohexanone

3- (Benzenesulfonamido) cyclopentanone

3- (Benzenesulfonamido) cyclohexanone

4- (Benzenesulfonamido) cyclohexanone

3- (4-Chlorosulfonamidomethyl) cyclopentanone

3- (4-Fluorobenzenesulfonamidomethyl) cyclopentanone

3- (4-Methylbenzenesulfonamidomethyl) cyclopentanone

3- (4-Chlorosulfonamidomethyl) cyclohexanone

3- (4-Fluorobenzenesulfonamidomethyl) cyclohexanone

3- (4-Methylbenzenesulfonamidomethyl) cyclohexanone

4- (4-Chlorosulfonamidomethyl) cyclohexanone

4- (4-Fluorobenzenesulfonamidomethyl) cyclohexanone

4- (Methylsulfonylmethyl) cyclohexanone

3- (4-Chlorosulfonamido) cyclopentanone

3- (4-Fluorobenzenesulfonamido) cyclopentanone

3- (4-Methylbenzenesulfonamido) cyclopentanone

3- (4-Chlorosulfonamido) cyclohexanone

3- (4-Fluorobenzenesulfonamido) cyclohexanone

3- (4-Methylbenzenesulfonamide) cyclohexanone

4- (4-Chlorosulfonamido) cyclohexanone

4- (4-Fluorobenzenesulfonamido) cyclohexanone

4- (4-Methylbenzenesulfonamido) cyclohexanone

The hydrazine (XIV) used as starting material is known and can be prepared by known methods (cf. Houben-Weyl, "Methoden der organischen chemie" X/2, page 1, total 123 (693).

Some cycloalkanone sulfonamide compounds of the general formula (XVa) in which y and R ² have the meanings given above are known compounds,

They can be prepared by known methods (cf. Houben-Weyl, "Methoden der organischen Chemie", IX,605;A.Mooradian et al, "J.Med. Chem.20 (4), 487 (1977)).

Cyclopentanone sulfonamides (formula Xvb, where x, y and R ² have the meanings given above) are novel compounds as starting materials.

A process for preparing novel compounds of the cycloalkanone sulfonamide type, characterized in that a cycloalkanol of the general formula (XVI) (in which x and y have the meanings given above) is reacted with a cycloalkanol of the general formula

With a sulfonyl halide of the formula (XVII) (in which R ² has the meaning given above and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine),

The reaction is carried out in an inert organic solvent, if appropriate in the presence of a base, and then the oxidation is carried out in an inert solvent.

Preparation of cycloalkanol cycloalkanone (XVIII)

The reaction with nitromethane in an inert organic solvent, if appropriate in the presence of a base, and then the reduction of the compound (XIX) (CA 92,89 849 and CA 87,22191).

The sulfonyl halides can be prepared by methods known per se (cf. Houben-Weyl, "Methoden der organischen Chemie" IX, 564).

The preparation of the cycloalkano [1, 2-b ] indole sulfonamide compounds of the present invention can be illustrated by the following scheme:

according to the reaction scheme, in a first step a), cyclopentanone is reacted in an inert solvent, such as an alcohol (e.g. methanol, ethanol or propanol) or an ether (e.g. diethyl ether, tetrahydrofuran or dioxane) or a chlorinated hydrocarbon (e.g. dichloromethane, chloroform or carbon tetrachloride), in a base (e.g. sodium hydride, sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, potassium tert-butoxide, 1, 5-diaza Reacting a bicyclo [ 4.3.0 ] non-5-ene, 1, 5-diazabicyclo [ 5.4.0 ] -carbon-5-ene, pyridine or triethylamine with a nitro compound (such as nitromethane) at a temperature of from 0 ℃ to 100 ℃ to produce the nitro compound.

In step b), the nitro compound is reduced in an inert solvent such as an ether (e.g., tetrahydrofuran, dioxane or diethyl ether) in the presence of a reducing agent such as a hydride (e.g., liAlH ₄、Na〔Al（OCH₂-CH₂OCH₃）₂H₂) or diisobutylaluminum hydride at-20 ℃ to +60 ℃ to produce a cycloalkanol.

In step c), the cycloalkanol is reacted with a sulfonyl halide in an inert solvent such as an ether (e.g., dioxane, tetrahydrofuran or diethyl ether), a chlorinated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride) or ethyl acetate or pyridine to convert to a sulfonamide. Where appropriate, this can be carried out in the presence of a base, such as 1, 5-diaza-bicyclo [ 4.3.0 ] -non-5-ene, 1, 5-diaza-bicyclo [ 5.4.0 ], pyridine or triethylamine, at a temperature of from-20℃to +60℃.

In step d), the sulfonamide is oxidized in an inert solvent (e.g., water, glacial acetic acid, acetone, pyridine, or mixtures thereof) at-20 ℃ to +100 ℃ with an oxidizing agent (e.g., a chromium (VI) compound, such as CrO ₃、K₂Cr₂O₇ or Na ₂Cr₂O₇) to produce a cycloalkanone sulfonamide compound.

In step e), the cycloalkanone sulfonamide compound (Xvb) is reacted with hydrazine (XIV) (as described above) to give the corresponding [ benzenesulfonylalkylcycloalkano [1,2-b ] indole of the formula XIII

Wherein R ¹、R², x and y have the meanings given above.

The pure enantiomers of the [ benzenesulfonamido ] cycloalkano [1, 2-b ] indoles (formula XIIIa, wherein R ¹ and R ² have the meaning given above) are likewise novel.

It has been found that a process for the preparation of the pure [ benzenesulfonamido ] cycloalkano [ 1,2-b ] indole enantiomer, characterized in that the pure cycloalkano [ 1,2-b ] indole amine enantiomer (formula XX, wherein R ¹ is as defined above) is prepared by reacting a compound of formula (I) with a compound of formula (II) wherein R ¹ is as defined above

With sulfonyl halides (of the formula XVII, in which R ² has the meaning given above; hal represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine)

The reaction is carried out in an inert solvent, if appropriate in the presence of a base.

Suitable solvents for this process include the usual organic solvents which do not change under the reaction conditions, among which ethers (e.g. diethyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether) or hydrocarbons (e.g. benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions) or halogenated hydrocarbons (e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene) or ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane are preferably selected. Mixtures thereof may also be used.

The bases used in this process are generally basic compounds, preference being given to alkali metal or alkaline earth metal hydroxides (for example lithium, sodium, potassium or barium hydroxide) or alkali metal hydrides (for example sodium hydride) or alkali metal or alkaline earth metal carbonates (for example sodium carbonate, sodium hydrogencarbonate, potassium carbonate or calcium carbonate) or alkali metal alkoxides (for example sodium methoxide,Sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide) or alkali metal amides (e.g. lithium diisopropylamide or sodium amide) or organic amines (e.g. ethyldiisopropylamine, benzyltrimethylamine hydroxide, tetrabutylammonium hydroxide), pyridine, dimethylaminopyridine, triethylamine, N-methylpiperidine, 1, 5-diazabicyclo [ 4.3.0 ] non-5-ene, 1, 5-diazabicyclo [ 5.4.0 ] non-carbon-5-ene.

According to the process of the present invention, the reaction is generally carried out at a temperature of from-30℃to +150℃, preferably from-20℃to +80℃.

The process according to the invention is generally carried out at atmospheric pressure, but also under reduced or increased pressure (for example in the range from 0.5 to 200 bar).

The pure cycloalkano [1, 2-b ] indoleamine enantiomers of the general formula (XX) of the invention are novel compounds, which can be prepared by the following synthetic methods A, B or C:

Synthesis method A

R ¹ is as defined above,

R ^＊ represents enantiomerically pure D-or L-amino acid groups, preferably 2S- (chloroacetamido) -3-phenylpropionyl

Synthesis method B

R ¹ has the meaning given above

Synthesis method A

According to the process, in step 1, 4-acetaminophen (XXI) is hydrogenated with Raney nickel,A cis/trans mixture of 4-acetamidocyclohexanol (XXII) as described in Billman, J.H., buhler, J.A. in J.am.chem.Soc.75,1345 (1953) is obtained. In step 2, 4-acetaminocyclohexanol (XXII) is further subjected to Fischer indole synthesis with an oxidant such as phenylhydrazine (XIV), followed by removal of the acetyl groups by acid hydrolysis.

This step is carried out in a solvent such as water, acetic acid and/or propionic acid at 0℃to +150℃ (preferably 0℃to +110 ℃).

In step 3, the readily available racemic 3-amino-1, 2,3, 4-tetrahydrocarbazole (XXIII) is coupled with the pure amino acid enantiomer (suitably in its activated form) to give the corresponding diastereomeric mixture, which can be separated into the individual diastereomers by conventional methods, such as crystallization or column chromatography.

Suitable and preferred pure enantiomers of amino acid derivatives are acetylphenylalanine, N-tert-butoxycarbonylphenylalanine, chloroacetylphenylalanine, benzyloxycarbonylphenylalanine, methoxyphenylacetic acid or acetoxyphenylacetic acid, N-chloro-acetyl-N-phenylalanine being preferred.

Commonly used activators are the usual peptide coupling reagents, of which preference is given to those comprising carbodiimides (for example diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminoisopropyl) -N' -ethylcarbodiimide hydrochloride) or carbonyl compounds (for example carbonyldiimidazole) or 1, 2-oxazolium compounds (for example 2-ethyl-5-phenyl-1, 2-oxazolium 3-sulphonate) or propanephosphonic anhydride, isobutyl chloroformate, benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, methanesulfonyl chloride, where appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine, or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The coupling is generally carried out in an inert organic solvent at a temperature of from-80 ℃ to +50 ℃.Preferred organic solvents are chlorinated hydrocarbons (e.g. dichloromethane or chloroform) or hydrocarbons (e.g. benzene, toluene, xylene or petroleum fractions) or ethers (e.g. dioxane, tetrahydrofuran or diethyl ether) or ethyl acetate, dimethylformamide, dimethyl sulfoxide or acetone, acetonitrile or nitromethane, the preferred temperatures being from-40 ℃ to +30 ℃.

After separation of the diastereomeric mixture (XXIV), the individual diastereomers are hydrolyzed with acid in step 4 to give the pure amine enantiomer (XX).

The hydrolysis is generally carried out using inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, methanesulfonic acid or trifluoroacetic acid, or mixtures thereof.

The solvent used for the hydrolysis is generally water or an aqueous solution of the corresponding acid or a mixture of the acids used.

The hydrolysis is carried out at a temperature of generally +20℃ to +150℃ and preferably +20℃ to +120℃.

The process of the invention is generally carried out under atmospheric pressure, but may also be carried out under reduced pressure or under elevated pressure, for example in an autoclave or in a pressurized tube. It has proven advantageous to add thioglycollic acid to the reaction mixture as an oxidation inhibitor.

Synthesis method B

According to the present method, 1, 4-cyclohexanedione monoethylene ketal (XXV) is reacted with phenylhydrazine (XIV) to perform Fischer indole synthesis to give ketal (XXVI) as described in A.Britten and G.lockwood in J.chem.Soc., perkin Trans.1, (1974), 1824-1827.

The ketal (XXVI) is hydrolyzed in step 2 to give the ketone (XXVII), which is then subjected to reductive amination with S-phenethylamine in step 3 to convert to diastereomeric mixture (XXVIII).

The reductive amination is generally carried out with reducing agents such as hydrogen, suitably palladium, platinum or palladium/animal bone charcoal as catalyst, or complex hydrides, preferably sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium aluminum borohydride, aluminum hydride, diisobutylhydrogenAluminum oxide, lithium triethylborohydride, sodium cyanoborohydride, tetrabutylammonium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) dihydride aluminate or lithium tris (1-methylpropyl) borate, in an inert solvent at-80 ℃ to +100 ℃. The inert solvent used is a hydrocarbon (preferably benzene, toluene or xylene) or chlorinated hydrocarbon (such as methylene chloride or chloroform) or an ether (such as diethyl ether, tetrahydrofuran, dioxane or 1, 2-dimethoxymethane) or acetonitrile, dimethylformamide, dimethyl sulfoxide or an alcohol (such as methanol, ethanol, propanol or isopropanol), preferably at a temperature of-80 ℃ to +50 ℃.

The diastereomeric mixture (XXVIII) may be separated into the individual diastereomers by conventional methods such as chromatography or crystallization, with crystallization being preferred. Where appropriate, the product is in the form of a suitable acid addition salt.

Suitable acid addition products are addition products of the enantiomers of the invention with inorganic or organic acids, wherein the preferred acids include hydrochloric, sulfuric, phosphoric or methanesulfonic acid, benzenesulfonic, naphthalenedisulfonic or acetic acid, maleic, fumaric, citric or lactic acid.

The method for removing the phenethyl group of the separated diastereomer (XXVIII) is the catalytic transfer hydrogenation process in step 4, giving the pure amine enantiomer (XX).

Step 4 is generally carried out using a reducing agent such as hydrogen, suitably in the presence of palladium, palladium/animal bone charcoal, or platinum, or ammonium formate, using a solvent such as an alcohol (e.g. methanol, ethanol, propanol or isopropanol) or dimethylformamide or dimethyl sulfoxide, at a temperature in the range of 0 ℃ to +200 ℃, preferably +20 ℃ to +150 ℃ (l.e. overman and S.Sugai, J.Org.Chem.50,4154-4155 (1985)).

Synthesis method C

According to this method, the racemic compound (XXIII) is resolved by forming a salt with an acid having optical activity, and then crystallizing the salt in an appropriate solvent one or several times. Treatment with alkaliThe pure enantiomer compound (XXIII) is then free from the salt obtained.

Suitable optically active acids are:

(+) -camphorsulfonic acid, (-) -camphorsulfonic acid, (+) -camphorsulfonic acid, (-) -camphor-3-carboxylic acid, (+) -camphoric acid, (-) -maleic acid, (+) -mandelic acid, (-) -mandelic acid, (+) -lactic acid, (-) -2- [ (phenylamino) carbonyloxy ] propionic acid, (-) -2-methoxyphenylacetic acid, (-) -2, 3-dioxybenzoyl succinic acid, (-) -2, 3-dioxo-4-toluoyl succinic acid, (-) -methoxyacetic acid, (-) -1,1 '-binaphthyl-2, 2' -diyl hydrogen phosphate.

Suitable solvents for crystallization are:

water, alcohols (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, or tert-butanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, or ethylene glycol dimethyl ether), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), hydrocarbons (e.g., benzene, toluene, xylene, hexane, or cyclohexane), chlorinated hydrocarbons (e.g., methylene chloride or chloroform), or ethyl acetate, acetonitrile, nitromethane, dimethylsulfoxide, dimethylformamide, or sulfolane, and mixtures of the above solvents may also be used.

The bases usable in this process are the usual basic compounds, with preference being given to the hydroxides of the alkali metals or alkaline earth metals. (such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide), or an alkali metal hydride (such as sodium hydride), or an alkali metal or alkaline earth metal carbonate (such as sodium carbonate, sodium bicarbonate, potassium carbonate or calcium carbonate), or an alkali metal alkoxide (such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide).

Novel cycloalkano [1, 2-b ] indole-sulfonamides and their salts are useful as compounds in pharmaceutical agents which have platelet aggregation inhibiting and thromboxane A ₂ antagonizing effects. They are preferably used for the treatment of thrombosis, thromboembolism and ischemiaCan be used as antiasthmatic and antiallergic. Such novel effective compounds can be formulated into conventional dosage forms such as tablets, capsules, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using pharmaceutically suitable inert non-toxic excipients or solvents by known methods. The therapeutically effective compounds are required in the indicated dosage ranges, in each case at concentrations of from 0.5 to 90% by weight, preferably from 5 to 70% by weight.

The formulations are prepared, for example, by dispersing the active compounds in solvents and/or excipients, optionally with the use of emulsifiers and/or dispersants, and optionally with the use of organic solvents as auxiliaries when water is used as diluent.

Adjuvants are water, nontoxic organic solvents [ such as paraffins (e.g. petroleum fractions) ], vegetable oils (e.g. peanut oil/sesame oil), alcohols (e.g. ethanol and glycerol) and glycols (e.g. propylene glycol and polyethylene glycol), solid excipients such as natural rock powders (e.g. kaolin, bauxite, talc, chalk powder) and synthetic rock powders (e.g. highly disperse silica and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates), dispersants (e.g. wood ropes, sulfite waste streams, methylcellulose, starch and polyvinylpyrrolidone), lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The administration method may be a usual method, preferably oral or parenteral administration, particularly lingual administration or intravenous injection. For oral administration, the tablets may naturally contain, in addition to the above excipients, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, and various other substances such as starch (preferably Mashu starch), gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may also be used in tableting. Such as aqueous suspensions and/or elixirs for oral administration, the active compounds may be combined with various flavoring or coloring agents in addition to the adjuvants described above.

For parenteral administration, the effective compounds may be formulated using suitable liquid excipientsThe solution is applied.

Generally, intravenous administration is used in an amount of about 0.001 to about 1 mg/kg body weight, preferably about 0.01 to about 0.5 mg/kg body weight, and oral administration is used in an amount of about 0.01 to about 20 mg/kg body weight, preferably about 0.1 to about 10 mg/kg body weight, for effective results.

However, deviations from the above-described dosages may be advantageous at times, particularly when acting as a feature of body weight or method of use. But this is also a function of individual differences in the agent or the nature of the agent formulation and the time interval of use. Thus, in some cases less than the minimum dose indicated above may be used, and in other cases more than the upper limit indicated above may be used. In the case of larger doses, it is recommended to divide the medication into several uses during the course of a day.

The cycloalkano [1, 2-b ] indole-sulfonamide compounds of the present invention are useful as human and veterinary drugs.

Preparation example

Example 1

3- (Nitromethyl) cyclopentanone

100 G of 2-cyclopentenone are dissolved in 1.1 l of isopropanol together with 666 ml of nitromethane and 5g of 1, 5-diazabicyclo [ 4.3.0 ] keto-5-ene (DBN), and the solution is left at room temperature for 5 hours. The isopropanol was then substantially distilled off in vacuo, the residue was dissolved in ethyl acetate and the solution was washed twice with 0.5 l each time with dilute sulfuric acid. The organic layer was dried over sodium sulfate and the solvent was distilled off to give 154 g (88% of theory) of 3-(Nitromethyl) cyclopentanone, which is sufficiently pure for the next reaction.

Rf=0.52 CH₂Cl₂∶CH₃OH=99∶1

Example 2

3- (Aminomethyl) cyclopentanol

57.2 G (0.4 mol) of 3- (nitromethyl) cyclopentanone are dissolved in 573 ml of anhydrous tetrahydrofuran under nitrogen, and 800 ml of a solution of 1mol of lithium aluminum hydride in tetrahydrofuran are added dropwise at 0 ℃. After the completion of the dropwise addition, the mixture was stirred at 0℃for 1 hour. The cold bath was removed and the temperature of the reaction solution was raised to 40 ℃. After the temperature had dropped to 20 ℃, the mixture was stirred at this temperature for 1 hour. The reaction mixture was cooled to 0 ℃, 100 ml of 45% strength sodium hydroxide solution was carefully added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 1 hour, filtered with celite and the celite was washed with 1.5 l tetrahydrofuran. The filtrates were combined and evaporated to dryness in vacuo to give 22.5 g (49% of theory) of a viscous oily product.

Rf=0.01 CH₂Cl₂∶CH₃OH=9∶1

Example 3

3- (Benzenesulfonamidomethyl) cyclopentanol

9 G (0.078 mol) of 3- (aminomethyl) cyclopentanol and 13.8 g (=10 ml) (0.078 mol) of triethylamine are dissolved in 200ml of tetrahydrofuran, and 7.9 g (=10.8 ml) (0.078 mol) of benzenesulfonyl chloride are then added dropwise at 0 to 5 ℃. After the completion of the dropwise addition, the mixture was stirred at 0℃for 1 hour. 200ml of twoThe reaction mixture was diluted with methyl chloride and washed twice with 150 ml of dilute sulfuric acid each time. The organic phase is extracted twice with 150 ml of 2N sodium hydroxide solution each time. The extracts were combined, acidified with concentrated hydrochloric acid and extracted twice with 150 ml of dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo to give 9.1 g (39% of theory) of a viscous oily isomer mixture.

Rf=9.51 and 0.45 3830OH=95:5

Example 4

3- (Benzenesulfonamidomethyl) cyclopentanone

7.5 G (0.0294 mol) of 3- (phenylsulfonylaminomethyl) cyclopentanol are dissolved in 60 ml of glacial acetic acid, 2.79 g (0.0279 mol) of chromium trioxide in 2ml of water and 8.8 ml of glacial acetic acid are added dropwise at 0-5℃and the temperature of the reaction mixture is allowed to rise to room temperature. After stirring the reaction mixture at room temperature for 1 hour, it was diluted with 200ml of diethyl ether and washed twice with 150 ml of water. The organic phase is extracted twice with 200ml of 2N sodium hydroxide solution each time. The sodium hydroxide phases are combined, acidified with concentrated hydrochloric acid and extracted twice with 200ml of dichloromethane. The dichloromethane phases are combined, dried over sodium sulfate and evaporated in vacuo to give 4.4 g (59% of theory) of the product as a viscous oil.

Rf=0.51 CH₂Cl₂∶CH₃OH=95∶5

Example 5

1- (Benzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole

21 G (0.0826 mol) of 3- (benzenesulfonamidomethyl) cyclopentanone and 9 g (0.0826 mol) of phenylhydrazine were dissolved in 200 ml of glacial acetic acid, heated at reflux for 4 hours, and the reaction solution was diluted with 1.3 l of diethyl ether and 500 ml of water were added. The mixture was made basic with 45% strength sodium hydroxide solution under cooling and stirring, and the organic phase was separated off. The aqueous phase was extracted once more with 500 ml of diethyl ether, the organic phases were combined, dried over sodium sulphate and evaporated to dryness. The residue obtained is chromatographed on a column of 2 kg of silica gel (Merck 0.04-0.063 mm), eluting with toluene and ethyl acetate (85:15), one of the fractions being evaporated to give 1.9 g (7% of theory) of the crystalline product, melting point 161-164 ℃.

Rf=0.92 CH₂Cl₂∶CH₃OH=95∶5

Example 6

1- [ N- (benzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] -4- (2-cyanoethyl) cyclopenta [1,2-b ] indole

1.9 G (0.0058 mol) of 1- (benzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole, 1.83 g (=2.3 ml) (0.0346 mol) acrylonitrile and 0.24 g (0.00058 mol) of a 40% strength methanolic solution of benzyltrimethylammonium hydroxide were placed in 60ml of dioxane and stirred at 60-70℃for 2 hours, then the reaction mixture was evaporated in vacuo, the residue was dissolved in dichloromethane and the solution was extracted twice with dilute sulfuric acid. The organic phase is washed with saturated bicarbonate solution, dried over sodium sulfate and the solvent is evaporated, yielding 2.4 g (95% of theory) of a foamy solid product.

Rf=0.45 CH₂Cl₂∶CH₃OH=99∶1

Example 7

1- (Benzenesulfonamidomethyl) -4- (2-carboxyethyl) cyclopenta [1, 2-b ] indole

2.4 G (0.0055 mol) of 1- [ N- (benzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] -4- (2-cyanoethyl) cyclopenta [1, 2-b ] indole are dissolved in 35 ml of isopropanol and 55 ml of 10% strength sodium hydroxide solution are added. The reaction mixture was stirred at 70 ℃ for 4 hours, then diluted with 100ml of water and extracted with 100ml of dichloromethane. The aqueous phase is acidified with dilute sulfuric acid and extracted three times with 100ml of dichloromethane each time. The organic phases were combined, dried over sodium sulfate and the solvent was distilled off. The oily residue (1.9 g) was dissolved in methanol, 0.26 g of sodium methoxide was added and the solution evaporated to give 2.0g (69.2% of theory) of the microcrystalline sodium salt product.

Rf=0.37 CH₂Cl₂∶CH₃OH=95∶5

Example 8

3- (4-Fluorobenzenesulfonamidomethyl) cyclopentanol

19.8 G (0.172 mol) of 3- (aminomethyl) cyclopentanol are reacted with 28.3 g (0.172 mol) of 4-fluorobenzenesulfonamide in a manner analogous to example 3, giving 17.3 g (36% of theory) of a viscous oily isomer mixture.

Rf=0.53 and 0.46 3830OH=95:5

Example 9

3- (4-Fluorobenzenesulfonamidomethyl) cyclopentanone

17.3 G (0.0638 mol) of 3- (4-fluorobenzenesulfonamidomethyl) cyclopentanol were oxidized in analogy to example 4, giving 14.3 g (83% of theory) of the product as a viscous oil.

Rf=0.76 CH₂Cl₂∶CH₃OH=9∶1

Example 10

1- (4-Fluorobenzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole

14.3 G (0.0527 mol) of 3- (4) are introduced in a manner analogous to example 5Reaction of fluorobenzenesulfonamidomethyl) cyclopentanone with phenylhydrazine gives, after chromatography on silica gel, 0.67 g (3.7% of theory) of microcrystalline product.

Rf=0.47 CH₂Cl₂∶CH₃OH=99∶1

Example 11

4- (2-Cyanoethyl) -1- [ N- (4-fluorobenzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] cyclopenta [1, 2-b ] indole

In analogy to example 6, 0.67 g (0.00195 mol) of 1- (4-fluorobenzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole are reacted to give 0.83 g (95% of theory) of a foamed solid product.

Rf=0.39 toluene: ethyl acetate=8:2

Example 12

4- (2-Carboxyethyl) -1- (4-fluorobenzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole

Hydrolysis of 0.83 g (0.00184 moles) of 4- (2-cyanoethyl) -1- [ N- (4-fluorobenzenesulfonyl) -N- (2-cyanoethyl) aminoethyl ] cyclopenta [1, 2-b ] indole afforded 0.67 g (87% of theory) of the crystalline product sodium salt with a melting point of 150-160 ℃.

Rf=0.59 CH₂Cl₂∶CH₃OH=9∶1

Example 13

3- (4-Chlorosulfonamidomethyl) cyclopentanol

16.8 G (0.146 mol) of 3- (aminomethyl) cyclopentanol are reacted with 4-chlorobenzenesulfonyl chloride in a manner analogous to that of example 3, giving 16.6 g (39% of theory) of the product as a viscous oily isomer mixture.

Rf=0.46 and 0.44 CH ₂Cl₂∶CH₃ oh=95:5

Example 14

3- (4-Chlorosulfonamidomethyl) cyclopentanone

16.6 G (0.0573 mol) of 3- (4-chlorobenzenesulfonamidomethyl) cyclopentanol are oxidized in analogy to example 4, giving 13.8 g (83.7% of theory) of the product as a viscous oil.

Rf=0.7 CH₂Cl₂∶CH₃OH=95∶5

Example 15

1- (4-Chlorenesulfonamidomethyl) cyclopenta [1, 2-b ] indole

13.8G (0.048 mol) of 3- (4-chlorobenzenesulfonamidomethyl) cyclopentanone were reacted with phenylhydrazine in a similar manner to example 5. After chromatography on silica gel, 1.65 g (9.5% of theory) of a foamy solid product are obtained.

Rf=0.46 CH₂Cl₂∶CH₃OH=99∶1

Example 16

1- [ N- (2-Chlorosulfonyl) -N- (2-cyanoethyl) aminomethyl ] -4- (2-cyanoethyl) cyclopenta [1, 2-b ] indole

1.65 G (0.0046 mol) of 1- (4-chlorobenzenesulfonamidomethyl) cyclopenta [1, 2-b ] indole are reacted in analogy to example 6 to give 1.8 g (84% of theory) of the product as a foamy solid.

Rf=0.38 toluene: ethyl acetate=8:2

Example 17

4- (2-Carboxyethyl) -1- (4-chlorobenzenesulfonamidomethyl) cyclopenta[ 1,2-B ] indoles

1.9 G (0.0038 mol) of 1- [ N- (4-chlorobenzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] -4- (2-cyanoethyl) cyclopenta [1, 2-b ] indole are hydrolyzed in analogy to example 7 to give 1.33 g (81.3% of theory) of the sodium salt microcrystalline product having a melting point of 160 ℃.

Rf=0.55 CH₂Cl₂∶CH₃OH=9∶1

Example 18

4- (Benzenesulfonamido) cyclohexanol

69 G (0.6 mol) of 4-aminocyclohexanol were reacted with 107 g (0.6 mol) of benzenesulfonyl chloride in a similar manner to example 3 to give 72.8 g (47% of theory) of crystalline product with a melting point of 106-108 ℃.

Rf=0.38 CH₂Cl₂∶CH₃OH=95∶5

Example 19

4- (Benzenesulfonamido) cyclohexanone

In a similar manner to example 4, 72.8 g (0.285 mol) of 4- (benzenesulfonamide) cyclohexanol were oxidized and crystallized from petroleum ether to give 57.5 g (80% of theory) of the product with a melting point of 80-82 ℃.

Rf=0.66 CH₂Cl₂∶CH₃OH=95∶5

Example 20

3- (Benzenesulfonamido) -1,2,3, 4-tetrahydrocarbazole

57.5 G (0.227 mol) of 4- (phenylsulfonamide) cyclohexanone are reacted with phenylhydrazine in analogy to example 5 to give 41.5 g (56% of theory) of the product crystallized from isopropanol and having a melting point of 155 ℃.

Rf=0.82 CH₂Cl₂∶CH₃OH=95∶5

Example 21

3- [ N- (benzenesulfonyl) -N- (2-cyanoethyl) amino ] -9- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazole

10 G (0.0306 mol) of 3- (benzenesulfonamido) -1,2,3, 4-tetrahydrocarbazole were reacted analogously to example 6 to give crystals from diethyl ether10 G (75% of theory) of the product, melting point 180-190 ℃.

Rf=0.29 toluene: ethyl acetate=8:2

Example 22

3- (Benzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

10 G (0.0263 mol) of 3- [ N- (benzenesulfonyl) -N- (2-cyanoethyl) amino ] -9- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazole were hydrolyzed in analogy to example 7 to give 7.57 g (68% of theory) of the sodium salt as crystalline product having a melting point of 160-165 ℃

Rf=0.44 CH₂Cl₂∶CH₃OH=95∶5

The compounds in table 1 below were prepared in analogy to example 18:

TABLE 1

EXAMPLE number X yield Rf

23 Cl 80% 0,37 CH₂Cl₂∶CH₃OH=95∶5

28 F 75% 0,4 CH₂Cl₂∶CH₃OH=95∶5

33 CH₃48,7% 0,5 CH₂Cl₂∶CH₃OH=95∶5

The compounds in table 2 below were prepared in analogy to example 19:

TABLE 2

Example number X yield Rf melting point:

24 Cl 86% 0,77 CH₂Cl₂∶CH₃OH=9∶1 103-4°C

Self petroleum ether

Middle crystallization

29 F 94% 0,7 CH₂Cl₂∶CH₃OH=9∶1 104-8°C

Self petroleum ether

Middle crystallization

34 CH₃90,7% 0,57 CH₂Cl₂∶CH₃OH=95∶5

The compounds in table 3 below were prepared in analogy to example 20:

TABLE 3 Table 3

EXAMPLE number X yield Rf

Melting point:

Toluene/ethyl acetate 8:2:163 DEG C

25 Crystallization of Cl 75,4% 0,52 from diethyl ether

146-9°C

30 F73% 0,39 CH ₂Cl₂∶CH₃ OH=99:1 from diethyl ether

136-8°C

35 Ch3830oh=8:2 from the isopropanol mesoknot

Crystal

The compounds in the following table 4 were prepared in analogy to example 21:

TABLE 4 Table 4

EXAMPLE number X yield Rf

Melting point:

26 Cl 47% 0.35 toluene ethyl acetate 8:2 204-6 ℃ C

From diethyl ether/isopropyl

Crystallization in alcohol

31 F53% 0.29 toluene/ethyl acetate 8:2:206-8 DEG C

From diethyl ether/isopropyl

Crystallization in alcohol

36 CH ₃% 0.37 toluene to ethyl acetate 8:2 180-90 DEG C

Crystallization from diethyl ether

The compounds in the following table 5 were prepared in analogy to example 22:

TABLE 5

EXAMPLE number X yield Rf

Melting point:

27 Cl 89,5% 0,61 CH₂Cl₂∶CH₃OH=9∶1 150°C

Sodium salt

32 F 98,5% 0,57 CH₂Cl₂∶CH₃OH=9∶1 160-70°C

Sodium salt

37 CH₃95% 0,53 CH₂Cl₂∶CH₃OH=9∶1 150-60°C

Sodium salt

Examples 38 and 39

3-R- (4-fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole (isomer A) and 3-r- (4-fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole (isomer B)

5 G (0.0114 mol) of 3- (4-fluorobenzenesulfonamido) -9- (2-)The sodium salt of carboxyethyl) -1,2,3, 4-tetrahydrocarbazole was dissolved in 50ml of trifluoroacetic acid and 5.01 g (0.08 mol) of sodium cyanoborohydride were added in portions at 0 ℃. The reaction mixture was allowed to warm to room temperature, diluted with water and extracted with 200 ml of ethyl acetate, the ethyl acetate phase extracted twice with 100ml of 2N sodium hydroxide solution each time. The sodium hydroxide solutions were combined, brought to pH5 and extracted three times with 150ml of dichloromethane. The extract was dried over sodium sulfate, evaporated thoroughly in vacuo and the residue was chromatographed on 500 g of silica gel (Merck, 0.040-0.063 mm), eluting with a mixture of dichloromethane and glacial acetic acid (100:1) to give two fractions, which after evaporation gave 2.87 g (60.2% of theory) of isomer (A) and 0.7 g (14.9% of theory) of isomer (B) as foamy solids, respectively.

Rf (isomer a) =0.24 CH ₂Cl₂∶CH₃ oh=100:2

Rf (isomer B) =0.14 CH ₂Cl₂∶CH₃ oh=100:2

Examples 40 and 41

3-R- (benzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole (isomer A) and 3-r- (benzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole (isomer B)

1.18 G (0.0028 mol) of the sodium salt of 3- (benzenesulfonamido) -9- (2-carboxymethyl) -1,2,3, 4-tetrahydrocarbazole were reduced in analogy to example 38. Chromatography gave two fractions which, after evaporation to dryness, gave 0.45 g (40% of theory) of isomer A and 0.2 g (18% of theory) of isomer B as foamy solids.

Rf (isomer a) =0.4 CH ₂Cl₂∶CH₃ cooh=100:4

Rf (isomer B) =0.22 CH ₂Cl₂∶CH₃ cooh=100:4

Examples 42 and 43

3-R- (4-methylbenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-t,9 a-t-hexahydrocarbazole (isomer A) and

3-R- (4-methylbenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4a-c,9 a-c-hexahydrocarbazole (isomer B)

18.06 G of 3- (4-methylbenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole sodium salt was reduced in analogy to example 38. Chromatography gave two fractions which, after evaporation to dryness, gave 3.65 g (20% of theory) of isomer A as crystalline residue with a melting point of 156-62℃and 1.11 g (6% of theory) of isomer B as a foamy solid.

Rf (isomer A) 0.39

Rf (isomer B) 0.20

CH₂Cl₂∶CH₃COOH=100∶2

Example 44

3- (4-Chlorosulfonamido) -6-fluoro-1, 2,3, 4-tetrahydrocarbazole

26.5 G of 4- (4-chlorobenzenesulfonamido) cyclohexanone are reacted with 4-fluorobenzenehydrazine in analogy to example 5 to give 35.4 g (100% of theory) of the product as a foamy solid.

Rf=0.53 toluene: ethyl acetate=8:2

Example 45

3- [ N- (4-Chlorosulfonyl) -N- (2-cyanoethyl) amino-9- (2-cyanoethyl) -6-fluoro-1, 2,3, 4-tetrahydrocarbazole

In analogy to example 6, 3.4 g of 4- (4-chlorobenzenesulfonamido) -6-fluoro-1, 2,3, 4-tetrahydrocarbazole were reacted to give 27.6 g (61% of theory) of the product as a foamy solid.

Rf=0.25 toluene: ethyl acetate=8:2

Example 46

3- (4-Chlorosulfonamido) -9- (2-carboxyethyl) -6-fluoro-1, 2,3, 4-tetrahydrocarbazole

27.6 G of 3- [ N- (chlorobenzenesulfonyl) -N- (2-cyanoethyl) amino ] -9- (2-cyanoethyl) -6-fluoro-1, 2,3, 4-tetrahydrocarbazole were hydrolyzed in analogy to example 7 to give 25.6 g (100% of theory) of crystalline product having a melting point of 118-130 ℃.

Rf=0.52 CH₂Cl₂∶CH₃OH=9∶1

Example 47

3- (Nitromethyl) cyclohexanone

21.9 G of cyclohexanone and 175 ml of nitromethane, 2.1 g of 5-diazabicyclo [ 4.3.0 ] non-5-ene (DBN) were placed together in 250 ml of isopropanol at room temperature for 2 days. The procedure of example 1 was followed to give 37.2 g (100% of theory) of 3- (nitromethane) cyclohexanone, which was pure for the next reaction.

Rf=0.62 CH₂Cl₂∶CH₃OH=99∶1

Example 48

3- (Aminomethyl) cyclohexanol

In a similar manner to example 2, 37.2 g of 3- (nitromethyl) cyclohexanone was reduced with lithium aluminum hydride to give 7.5 g (24.5% of theory) of 3- (aminomethyl) cyclohexanol as a viscous oily product.

Rf=0.04 CH₂Cl₂∶CH₃OH=9∶1

Example 49

3- (4-Fluorobenzenesulfonamidomethyl) cyclohexanol

In a similar manner to example 3, 7.5 g of 3- (aminomethyl) cyclohexanol were reacted with 11.3 g of 4-fluorobenzenesulfonamide to give 11.05 g (66% of theory) of a viscous oily isomer mixture

Rf=0.41 and 0.38 CH ₂Cl₂∶CH₃ oh=95:5

Example 50

3- (4-Fluorobenzenesulfonamidomethyl) cyclohexanone

11 G of 3- (4-fluorobenzenesulfonamidomethyl) cyclohexanol were oxidized with chromium trioxide in analogy to example 4 to give 9.3 g (86% of theory) of the product as a foamy solid.

Rf=0.86 CH₂Cl₂∶CH₃OH=9∶1

Example 51

4- (4-Fluorobenzenesulfonamidomethyl) -1,2,3, 4-tetrahydrocarbazole

9G of 3- (4-fluorobenzenesulfonamidomethyl) cyclohexanone are reacted with phenylhydrazine in analogy to example 5 to give 9g of crude product, which is chromatographed on 1 kg of silica gel (Merck 0.04-0.063 mm) eluting with a mixture of toluene and ethyl acetate (8:2), one of the fractions being evaporated to dryness to give 0.8 g (7.2% of theory) of product as a foamy solid.

Rf=0.44 toluene: ethyl acetate=8:2

Example 52

9- (2-Cyanoethyl) -4- [ N- (4-fluorobenzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] -1,2,3, 4-tetrahydrocarbazole

In analogy to example 6, 0.8 g of 4- (4-fluorobenzenesulfonamidomethyl) -1,2,3, 4-tetrahydrocarbazole was reacted with acrylonitrile to give 0.91 g (88% of theory) of the product as an oil.

Rf=0.37 toluene: ethyl acetate=8:2

Example 53

9- (2-Carboxyethyl) -4- (4-fluorobenzenesulfonamidomethyl) -1,2,3, 4-tetrahydrocarbazole

Hydrolysis of 0.91 g of 9- (2-cyanoethyl) -4- [ N- (4-fluorobenzenesulfonyl) -N- (2-cyanoethyl) aminomethyl ] -1,2,3, 4-tetrahydrocarbazole was carried out in analogy to example 7, giving 0.77 g (89% of theory) of the sodium salt as crystalline product having a melting point of 160 ℃.

Rf=0.57 CH₂Cl₂∶CH₃OH=9∶1

Example 54

4-N-acetamido cyclohexanol

300 G of p-acetaminophen are dissolved in 750 ml of ethanol, hydrogenated with 30 g of Raney nickel at 180℃and 100 bar, and the catalyst filtered off after the hydrogen absorption. Then, 30 g of Raney nickel are added, the hydrogenation is repeated at 180℃and 100 bar overpressure, the catalyst is filtered off, the filtrate is evaporated in vacuo, 200 ml of acetone are added and stirring is carried out while the residue is still moist. After the crystallization is filtered out by suction, the mother liquor is further concentrated, the precipitated crystallization is filtered out by suction, the mother liquor is concentrated again, and the crystallization collected for three times obtains 342.4 g (80.8% of theoretical value) of product with the melting point of 100-103 DEG C

Example 55

3-Amino-1, 2,3, 4-tetrahydrocarbazole (racemate)

50 G (0.318 mol) of 4-N-acetaminocyclohexanol were dissolved in 400 ml of glacial acetic acid and stirred at room temperature, while a solution of 31.8 g (0.318 mol) of chromium trioxide in a mixture of 26 ml of water and 105 ml of glacial acetic acid was added, and the temperature of the reaction solution was raised to 60 ℃. The reaction mixture was stirred for 3 hours, then 45.7 g (0.423 mol) phenylhydrazine was added, the temperature of the reaction solution was raised to 80 ℃ and nitrogen evolution was started. The reaction mixture was heated at reflux for 2.5 hours, and after the reaction mixture was cooled, 500 ml of concentrated hydrochloric acid and 59 ml of thioglycolic acid were added, followed by heating at reflux under a nitrogen stream for 16 hours. After cooling the mixture was diluted with 500 ml of ethyl acetate and made basic during cooling with 45% strength sodium hydroxide solution. The precipitated chromium hydroxide was removed by suction filtration through a layer of celite and washed with a dichloromethane/methanol (9:1) mixture. The organic phase was separated from the filtrate and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases are washed twice with 2N sodium hydroxide solution and then extracted twice with 2N sulfuric acid, 1 liter each. The acidic aqueous phase was basified with 45% strength sodium hydroxide solution and extracted three times with 1 liter of dichloromethane, the dichloromethane phases were combined, dried over sodium phosphate and evaporated to dryness. To the residue was added 300 ml of diethyl ether and 50ml of isopropanol, and stirred. The precipitated product is filtered off with suction, washed with diethyl ether and dried in vacuo to give 28.6 g (48.3% of theory) of the product, melting point 174-176 ℃.

Example 56

3- [ 2S- (chloroacetamido) -3-phenylpropionamido ] -1,2,3, 4-tetrahydrocarbazole (diastereomeric mixture)

43G (0.231 mol) of 3-amino-1, 2,3, 4-tetrahydrocarbazole and 55.87 g (0.231 mol) of N-chloroacetyl-L-phenylalanine are suspended in 1.5L of dichloromethane in a nitrogen stream, 115.2 ml (0.832 mol) of triethylamine are added at 0℃and a solution of 50% strength of procarbamate in dichloromethane is then added dropwise to the reaction mixture at-20℃and stirred for 30 minutes at-20℃and then for 1.5 hours at 0 ℃. The reaction mixture was washed with 1 liter of 2N sulfuric acid, then with 1 liter of water, and finally with 1 liter of saturated bicarbonate solution twice. Drying over sodium sulfate and evaporation gave 100 g of a solid residue.

Examples 57 and 58

3- [ 2S- (Chloroacetamido) -3-phenylpropionamido ] -1,2,3, 4-tetrahydrocarbazole (diastereomers A and B)

A) Separation of diastereomers by column chromatography

100 G of the crude product from example 56 are chromatographed on 2.5 kg of silica gel (0.063-0.2 mm, merck) with a toluene/ethyl acetate (6:4) mixture as mobile phase, giving two fractions, after evaporation, the 1 st fraction giving 34 g (35.9% of theory) of diastereomer A (example 57), melting point 217-220 ℃.

Evaporation of fraction 2 gives 24.3 g (25.7% of theory) of diastereomer B (example 58), melting point 193-195 ℃.

The optical rotation of diastereomer A, [ alpha ] ²⁰＝32.59°（CH₃ OH) (example 57)

The optical rotation of diastereomer B, [ alpha ] ²⁰＝5.09°（CH₃ OH) (example 58)

B) Separation of diastereomers by crystallization

11.5 G of the crude product from example 56 are stirred in an ether/isopropanol mixture. The crystals were filtered off with a suction filter and heated under reflux in 40 ml of acetone for 3 hours. Cooled, left overnight, the product is filtered off with suction and washed with acetone to give 1.2 g (5.5% of theory) of pure diastereomer A (example 57).

Example 59

3-Amino-1, 2,3, 4-tetrahydrocarbazole (enantiomer A)

24.1 G (0.059 mol) of the diastereomer from example 57 are dissolved in 460 ml of glacial acetic acid, 460 ml of concentrated hydrochloric acid and 24 ml of thioglycolic acid are added and heated under reflux for 3 days under nitrogen. The reaction mixture was diluted with 200ml of water, cooled and brought to pH5 with 45% strength sodium hydroxide solution. Extraction was performed twice with 1.5L each time of ethyl acetate. The aqueous phase was basified with 45% strength sodium hydroxide solution and extracted three times with ethyl acetate, 1.5 l each. The extracts were combined, dried over sodium sulfate and evaporated. The residue was added to 150ml of diethyl ether and stirred. The precipitated product is filtered off with suction and dried in vacuo to give 7.8 g (71.3% of theory) of enantiomer A, melting point 160-166 ℃.

Optical rotation [ α ] ²⁰ =78.38° (dmso+10% water)

Example 60

3-Amino-1, 2,3, 4-tetrahydrocarbazole (enantiomer B)

In a similar manner to the preparation of example 59 from the product of example 57, the product of example 58 was hydrolyzed to give enantiomer B having a melting point of 162-167 ℃. Optical rotation [ alpha ] ²⁰ = -78.11 ° (dmso+10% water).

Example 61

3, 3-Ethylenedioxy-1, 2,3, 4-tetrahydrocarbazole

77.2 G (0.5 mol) of 1, 4-cyclohexanedione monoethylene ketal and 48.4 ml (0.5 mol) of phenylhydrazine are dissolved in 2 l of dichloromethane, 300 g of magnesium sulfate are added and stirred for 30 minutes. Then, magnesium sulfate was filtered off with suction, washed with methylene chloride and the filtrate was evaporated to dryness. The residue was dissolved in 1.5 l of benzene, 62.1 g (0.46 mol) of anhydrous zinc chloride was added, and the mixture was heated under reflux (with a water separator) for 3 hours. The reaction solution was concentrated, 2N sodium hydroxide solution was added, and the mixture was extracted three times with ethyl acetate. The ethyl acetate phases were combined, dried over sodium sulfate and evaporated to dryness. The residue is crystallized from a small amount of diethyl ether to give 3.5 g (72.9% of theory) of the product with a melting point of 145-146 ℃.

Example 62

1,2,4,9-Tetrahydrocarbazol-3-one

165 G (0.72 mol) of 3, 3-ethylenedioxy-1, 2,3, 4-tetrahydrocarbazole were dissolved in 2 l of acetone and 3g of p-toluenesulfonic acid were added. After refluxing for 4 hours under heating, the reaction mixture was concentrated, 2 liters of ethyl acetate was added, and the mixture was extracted three times with 1 liter of saturated bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated to dryness. Crystallization of the residue in diethyl ether gives 118.7 g (89.1% of theory) of the product, meltPoints 145-148 ℃.

Example 63

3- (1S-Phenylethylamino) -1,2,3, 4-tetrahydrocarbazole

11.06 G (0.0595 mol) of 1,2,4,9-tetrahydrocarbazol-3-one are heated under reflux (with a water separator) for 1 hour with 7.78 g (0.065 mol) of 1S-phenylethylamine and 300ml of benzene. After removal of the benzene by evaporation, the residue was dissolved in 50ml of dichloromethane and the solution was dropped at-50℃into a solution of 15.3 g (0.0595 mol) of tetrabutylammonium borohydride in 120 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature over 1 hour, 6ml of methanol was added, and 120 ml of 2N sulfuric acid (evolution of hydrogen) was carefully added. After stirring at room temperature for 1 hour, the precipitated crystals were suction-filtered and washed twice with water and once with dichloromethane. After drying under high vacuum, 0.16g (39.7% of theory) of bisulfate product is obtained, melting point 160-170 ℃.

Optical rotation [. Alpha. ] ²⁰＝26.36°（CH₃OH/H₂ O=80:20

Example 64

3-Amino-1, 2,3, 4-tetrahydrocarbazole (enantiomer A)

[ Example 64 was prepared according to the procedure B, with results consistent with example 59 ]

To convert the bisulphate salt to the hydrochloride salt, 10 g of the bisulphate salt from example 53 was suspended in 50 ml of methanol, 30 ml of 2N sodium hydroxide solution was added, the mixtureExtracting with ethyl acetate. The organic phase is evaporated off and the residue is taken up in 50ml of methanol and 20ml of concentrated hydrochloric acid are added. The hydrochloride precipitated out upon concentration in vacuo, after suction filtration, washed with water and dried in vacuo to give 7.6 g of hydrochloride. This 7.6 g (0.023 mol) of hydrochloride was heated to reflux with 7.17 g (0.115 mol) of ammonium formate and 7.2 g of 10% palladium on activated carbon in 80ml of anhydrous dimethylformamide for 20 minutes. The mixture was cooled, diluted with water, the catalyst was filtered off with suction and washed with water. The combined filtrates were acidified with 2N sulfuric acid and extracted twice with ethyl acetate. The aqueous phase was made basic with 2N sodium hydroxide solution and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was further evaporated under high vacuum to remove dimethylformamide. Crystallization in diethyl ether gives 3g (70% of theory) of enantiomer A, melting point 160-166 ℃.

Optical rotation [. Alpha. ] ²⁰ =78.38° (DMSO+10% water)

Example 65

3- (4-Fluorobenzenesulfonamido) -1,2,3, 4-tetrahydrocarbazole (enantiomer A)

3.72 G (0.02 mol) of the product of example 59 were suspended in 30 ml of dichloromethane together with 3ml (0.022 mol) of triethylamine, and when cooled, 3.9 g (0.02 mol) of 4-fluorobenzenesulfonyl chloride was added. The reaction mixture was dissolved at room temperature for 1 hour, then stirred with 200ml of ethyl acetate, and extracted twice with 2N sulfuric acid and twice with 2N sodium hydroxide solution. The organic phase is dried over sodium sulfate, evaporated to dryness and the solid residue is crystallized by addition of diethyl ether to give 5.8g (84% of theory) of the product with a melting point of 150-152 ℃.

Optical rotation [. Alpha. ] ²⁰＝50.43°（CHCl₃

Example 66

3- (4-Fluorobenzenesulfonamido) -1,2,3, 4-tetrahydrocarbazole (enantiomer B)

In a similar manner to the preparation of the product of example 65 from the product of example 59, enantiomer B was prepared from the product of example 60. Melting point 150-152 deg.C.

Optical rotation [ alpha ] ²⁰＝-48.99°（CHCl₃).

Example 67

3- [ N- (4-Fluorobenzenesulfonyl) amino ] -9- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazole (enantiomer A)

5.16 G (0.015 mol) of the product from example 65 are dissolved in 200ml of anhydrous dimethylformamide under nitrogen, and 0.5 g (0.0165 mol) of sodium hydride and a dispersant of 20% spindle oil are added in portions. Once the hydrogen evolution was complete, 2ml (0.03 mol) of acrylonitrile was added to the reaction mixture, after stirring at room temperature for 1 hour, 0.5ml of acrylonitrile was added, and the mixture was stirred at room temperature for 1 hour. Dilution with 1 liter of ethyl acetate and extraction with water three times, the ethyl acetate phase was dried over sodium sulfate and evaporated to dryness to give 7.8 g of crude product. The crude product was taken up in 150 g of silica gel (0.063-0.2 mm, merck)Chromatography, using toluene/ethyl acetate (1:1) mixture as mobile phase. After evaporation of one fraction, 5.8 g (86% of theory) of the product are obtained as a foamy solid.

The preparation of the dicyanoethyl adduct (3- [ N- (4-fluorobenzenesulfonyl) -N- (2-cyanoethyl) amino ] -9- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazole) was carried out under the conditions shown in example 6.

Example 68

3- [ N- (4-Fluorobenzenesulfonyl) -N- (2-cyanoethyl) amino ] -9- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazole (enantiomer B)

The product of example 68 was prepared from the product of example 66 in a similar manner to the product of example 67.

Example 69

(+) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

5.8 G (0.0128 mol) of the product of example 67 are dissolved in 60 ml of isopropyl alcohol130 Ml of 10% potassium hydroxide solution was added to the mixture, the mixture was heated under reflux for 16 hours, and the mixture was cooled, diluted with water, and extracted with ethyl acetate. The aqueous phase is concentrated in vacuo and then acidified by dropwise addition of concentrated hydrochloric acid with vigorous stirring, the acid evolved in the process is filtered off with suction, washed with water and dried thoroughly in vacuo to give 4.4 g (86.6% of theory) of product. Melting point of 85-95 DEG C

Optical rotation [. Alpha. ] ²⁰＝42.55°（CHCl₃

Example 70

(-) -3- (4-Fluorobenzenesulfonamido) -9- (2-carboxyethyl) -1,2,3, 4-tetrahydrocarbazole

Example 70 was prepared from example 68 in a similar manner as example 69 was prepared from example 67.

Melting point of 85-95 DEG C

Optical rotation [. Alpha. ] ²⁰＝-37.83°（CHCl₃

Example 71

(+) -3-Amino-1, 2,3, 4-tetrahydrocarbazole

18.6 G (0.1 mol) of racemic 3-amino-1, 2,3, 4-tetrahydrocarbazole are heated to reflux with 15.2 g (0.1 mol) (+) -mandelic acid in 100 ml of tetrahydrofuran, and once the solution is clear, it is allowed to cool and a small amount is added with a spatula head(+) -Mandelate salt of (+) -3-amino-1, 2,3, 4-tetrahydrocarbazole (enantiomer A, example 59) was used as seed. The mixture was stirred overnight and the precipitated crystals were suction filtered to give an enantiomerically enriched material. Crystalline 4.7 g was dissolved in 330 ml boiling toluene isobutyl ketone, and after slightly cooling, seed crystals were added and cooling was continued while stirring. After suction filtration, the product was washed with methyl isobutyl ketone to give 3.4 g of (+) -mandelate salt of (+) -3-amino-1, 2,3, 4-tetrahydrocarbazole.

Example 72

Blood from healthy female and male amphoteric subjects was assayed to inhibit platelet aggregation. 1 part of an aqueous sodium citrate solution having a concentration of 3.8% was mixed with 9 parts of blood as an anticoagulant. Platelet rich plasma citrate (PRP) was obtained from blood after centrifugation (Jurgens/Beller, KLINISCHE METHODEN DER BLUTGERINNUNGSANALYSE (clinical hemagglutination analysis), thieme Press, stuttgart, 1959).

0.8 Ml of PRP and 0.1 ml of the active compound solution were pre-incubated in a 37℃water bath. Platelet aggregation was then determined by nephelometry on an agglutinometer [ aggregometer ] at 37 ℃ [ Bern, G.V.R., J.Physiol., (London) 162,1962 and Therapeutische Berichte 47,80-86,1975 ]. For this purpose, a seeding agent, 0.1 ml collagen, was added to the pre-incubated samples, and the change in optical density of the PRP samples over the course of 6 minutes and the deviation after 6 minutes were recorded. Percent inhibition was calculated compared to the control group.

Range of Cyclobenzo [1,2-b ] indole inhibition concentrations

Sulfonamide example number (mg/kg)

6 10-3

12 0.03-0.01

17 0.03-0.01

22 3-1

27 0.1-0.03

32 0.1-0.03

38 1.0-0.3

39 0.3-0.1

40 1.0-0.3

41 0.3-0.1

46 0.1-0.01

52 0.3-0.1

Claims (20)

1. Cycloalkano[1,2-b]indole-sulfonamide compounds of the formula, and, if appropriate, their isomeric forms or their salts, wherein R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group or an aryl group, m is a number 0, 1 or 2, R ³ can be represented by

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl; and may each represent a group of formula -OR ⁶ , wherein R ⁶ represents hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ - or trifluoromethyl; or represents alkyl, alkenyl or cycloalkyl, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

an aryl group substituted with a group wherein R ⁴ and R ⁵ have the same meanings as described above; X represents 1, 2 or 3; y represents 0 or 1. 2. Cycloalkano[1,2-b]indole-sulfonamide compounds according to claim 1, where appropriate, their isomers or their salts, wherein R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or lower alkoxycarbonyl, and represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to a lower alkyl group or a phenyl group, m refers to a number of 0 or 2, R ³ also represents the formula

The group, wherein R ⁴ and R ⁵ are the same or different and are hydrogen, lower alkyl, phenyl, benzyl or acetyl, or represent a group of formula -OR ⁶ , Wherein R ⁶ represents hydrogen, lower alkyl, phenyl, phenyl-SO ₂ -, methyl-SO ₂ -, ethyl-SO ₂ - or trifluoromethyl; or represents lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted by carboxyl, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, hydroxy, lower alkoxy or cyano; ^R2 represents a phenyl group which may be selectively substituted by up to three groups selected from fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkyl, carboxymethyl, carboxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, lower alkoxy, lower alkylthio, hydroxy, carboxyl, lower alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio; or

Substituted phenyl Wherein ^R4 and ^R5 have the meanings indicated above, x represents 1, 2 or 3, y represents 0 or 1. 3. Cycloalkano[1,2-b]indole-sulfonamides according to claim 1 or 2, where appropriate, their isomers or their salts, wherein R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amino, dimethylamino, diethylamino or acetylamino; or represents a group of the formula -OR ⁶ -, Wherein R ⁶ refers to hydrogen, C ₁ -C ₄ alkyl, phenyl or benzyl, or represents C ₁ -C ₄ alkyl; R ² represents a phenyl group which may be substituted by up to 3 identical or different fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, methylthio, hydroxy, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetylamino or diethylamino groups; x represents 1 or 2; y represents 0 or 1 4. The (+) or (-) isomer of the cycloalkano[1,2-b]indole-sulfonamide compound according to claims 1 to 3 having the following formula:

Wherein R ¹ represents hydrogen, fluorine, methyl, methoxy, benzyloxy or hydroxy; ^R2 represents a phenyl group substituted by fluorine, chlorine, trifluoromethyl, methyl, ethyl, propyl, isopropyl or methoxy, y represents 0 or 1. 5. (+)-3-(4-Fluorobenzenesulfonylamino)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole. 6. (-)-3-(4-Fluorobenzenesulfonyl)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole. 7. Cycloalkano[1,2-b]indole-sulfonamide compounds of the formula, in isomeric form or salts thereof, as appropriate, for use in therapy.

wherein R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl; represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group or an aryl group, m is a number among 0, 1 or 2. R ³ can represent the formula

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl; each represents a group of formula -OR ⁶ , Wherein R ⁶ refers to hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ - or trifluoromethyl, or represents an alkyl, alkenyl or cycloalkyl group, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

an aryl group substituted with Wherein R ⁴ and R ⁵ have the same meanings as described above; x represents 1, 2 or 3; y represents 0 or 1. 8. A process for the preparation of cycloalkano[1,2-b]indole-sulfonamides of the formula I, where appropriate in their isomeric forms or their salts.

The invention is characterized in that a [benzenesulfonylaminoalkyl]cycloalkano[1,2-b]indole

In an inert solvent, if appropriate, react with acrylonitrile in the presence of a base, and then hydrolyze the N,N'-biscyanoethyl compound. If a cycloalkylo[1,2-b]indole-sulfonamide compound is to be prepared, the cycloalkylo[1,2-b]indole-sulfonamide compound is hydrogenated. The hydrogenation is carried out in an inert solvent in the presence of an acid and a reducing agent. If appropriate, isomers are separated by a conventional method. If a salt is to be prepared, the reaction is carried out with a suitable base. In formula I, R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group or an aryl group, m is a number 0, 1 or 2, R ₃ can also represent the formula

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl, each representing a group of formula -OR ⁶ , Wherein R ⁶ refers to hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ - or trifluoromethyl, or represents an alkyl, alkenyl or cycloalkyl group, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents a halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio or a group of the formula

an alkyl group optionally substituted with up to 5 groups, Wherein R ⁴ and R ⁵ have the same meanings as described above; x represents 1, 2 or 3; y represents 0 or 1, In formula XII, R ¹ , R ² , X and Y are as defined above. 9. A process for preparing cycloalkylo[1,2-b]indole-sulfonamides or their isomeric forms according to claim 8, characterized in that [benzenesulfonamidoalkyl]cycloalkylo[1,2-b]indole is used. R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or lower alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , wherein R ³ is a lower alkyl group or a phenyl group, m refers to 0 or 2, R ³ can also represent the formula

The group, wherein ^R4 and ^R5 are the same or different and represent hydrogen, lower alkyl, phenyl, benzyl or acetyl, or a group representing ^-OR6 , Wherein R ⁶ refers to hydrogen, lower alkyl, phenyl, phenyl-SO ₂ -, methyl-SO ₂ -, ethyl-SO ₂ - or trifluoromethyl, or represents a lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted by carboxyl, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, hydroxy, lower alkoxy or cyano; R represents ^{a phenyl group} which may be selectively substituted by up to three groups selected from fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkyl, carboxymethyl, carboxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, lower alkoxy, lower alkylthio, hydroxy, carboxyl, lower alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or by

Substituted phenyl, Wherein R ⁴ and R ⁵ have the meanings indicated; x represents 1, 2 or 3; y represents 0 or 1. 10. A process for the preparation of cycloalkylo[1,2-b]indolesulfonamides or isomeric forms thereof according to claims 8 and 9, characterized in that [benzenesulfonamidoalkyl]cycloalkylo[1,2-b]indole is used: R ¹ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amino, dimethylamino, diethylamino, acetylamino, or represents a group of formula -OR ⁶ , Wherein R ⁶ represents hydrogen, C ₁ -C ₄ alkyl, phenyl or benzyl, or represents C ₁ -C ₄ alkyl; R ² represents a phenyl group which may be substituted by up to 3 identical or different fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, methylthio, hydroxy, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetylamino or diethylamino groups; x represents 1 or 2; y represents 0 or 1. 11. A process according to claims 8-10, characterised in that the reaction of [phenylsulfonylaminoalkyl]cycloalkano[1,2-b]indole with acrylonitrile is carried out at a temperature within the range of 0-150°C. 12. A process according to claims 8-11, characterised in that the ratio of acrylonitrile to [phenylsulfonylaminoalkyl]cycloalkano[1,2-b]indole used is 1-20 mol:1 mol. 13. [Benzenesulfonylaminoalkyl]cycloalkano[1,2-b]indole having the formula wherein R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ represents an alkyl group or an aryl group, m is a number 0, 1 or 2, R ³ can represent the formula

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl, and represent a group of formula -OR ⁶ , Wherein R ⁶ refers to hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, aralkyl-SO ₂ - or trifluoromethyl, or represents an alkyl, alkenyl or cycloalkyl group, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, arylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

an aryl group substituted with a group wherein ^R4 and ^R5 have the same meanings as above, X represents 1, 2 or 3; y represents 0 or 1. 14. A process for the preparation of [benzenesulfonamidoalkyl]cycloalkano[1,2-b]indoles of formula XII.

The invention is characterized in that phenylhydrazine of general formula XIV is

reacting with a cycloalkanone sulfonamide compound of the general formula XV in an inert solvent, optionally in the presence of a catalyst,

In formula XII, R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group or an aryl group, m is a number 0, 1 or 2, R ₃ can represent the formula

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl, and represent a group of formula -OR ⁶ , Wherein R ⁶ refers to hydrogen, alkyl, aryl, aralkyl, alkyl-SO ₂ -, aryl-SO ₂ -, arylalkyl-SO ₂ -, trifluoromethyl, or represents an alkyl, alkenyl or cycloalkyl group, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, arylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

Group-substituted aryl groups; Wherein ^R4 and ^R5 are as defined above, X represents 1, 2 or 3; y represents 0 or 1; In formula XIV, ^R1 is as defined above, In formula XV, R ² , x and y are as defined above. 15. Ketones having the formula

wherein ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

an aryl group substituted with Wherein R ⁴ and R ⁵ have the same meaning as above; X represents 1, 2 or 3; y represents 0 or 1. 16. A method for preparing a cycloalkanone sulfonamide compound of the formula:

The method is characterized in that a cycloalkanol of the following formula is reacted with a sulfonyl halide of the formula XVII in an inert organic solvent, if appropriate in the presence of a base, and then oxidized in an inert solvent.

In formula I, ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio; or

an aryl group substituted with Wherein R ⁴ and R ⁵ have the same meanings as described above; X represents 1, 2 or 3; y represents 0 or 1; In formula XVI, X and Y are defined as above. In formula XVII, ^R2 is defined as above, Hal represents fluorine, chlorine, bromine, and iodine. 17. A medicament containing a cycloalkano[1,2-b]indole-sulfonamide compound of the formula, where appropriate, an isomer thereof or a salt thereof:

wherein R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group, an aryl group; m is a number 0, 1 or 2, R ₃ can represent the formula

The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, arylalkyl or acetyl, each representing a group of formula -OR ⁶ , Wherein R ⁶ represents hydrogen, alkyl, aryl, arylalkyl, alkyl-SO ₂ -, aryl-SO ₂ -, arylalkyl-SO ₂ - or trifluoromethyl, or represents an alkyl, alkenyl or cycloalkyl group, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

Group-substituted aryl groups; Wherein ^R4 and ^R5 are as defined above, X represents 1, 2 or 3; y represents 0 or 1. 18. The pharmaceutical preparation according to claim 14, which contains 0.5-50% by weight of cycloalkano[1,2-b]indolesulfonamide compounds and/or their salts. 19. Use of the cycloalkano[1,2-b]indole-sulfonamide compounds of the formula, in the form of their isomers or salts, as appropriate, in the preparation of medicaments for the treatment of diseases.

wherein R ¹ represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formula -S(O)mR ³ , Wherein R ³ refers to an alkyl group or an aryl group, m is a number 0, 1 or 2, R ³ can represent the formula The group, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aryl, arylalkyl or acetyl, each representing a group of formula -OR ⁶ , Wherein R ⁶ represents hydrogen, alkyl, aryl, arylalkyl, alkyl-SO ₂ -, aryl-SO ₂ -, arylalkyl-SO ₂ - or trifluoromethyl, or represents alkyl, alkenyl, cycloalkyl, each of which may be optionally substituted by carboxyl, alkoxycarbonyl, halogen, hydroxy, alkoxy, alkylthio or cyano; ^R2 represents an aryl group which may be selectively substituted by up to five groups selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzylthio, or a group of the formula

substituted aryl groups, Wherein R ⁴ and R ⁵ have the same meanings as described above; X represents 1, 2 or 3; y represents 0 or 1. 20. Use of the platelet aggregation inhibitor or thromboxane _A2 antagonist formulated according to claim 19.