JPH0450301B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel cycloalkano[1,2-b]
Indole sulfonamide, its manufacturing method,
and its use in medicine. Similarly, a new compound [benzenesulfonamidoalkyl]-cycloalkano[1,2-
b] Indoles can be used as intermediates for the preparation of this new compound. General formula () In the formula, R ¹ represents hydrogen, halogen or C ₁ -C ₄ -alkyl, and R ² can also be mono- or di-substituted by halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl. represents a certain phenyl, x represents the number 1 or 2, y represents the number 0 or 1, a novel cycloalkano[1,2-b]indole sulfonamide, or a salt thereof, in the form of an isomer as appropriate; Found. The cycloalkano[1,2-b]indole sulfonamides according to the invention have several asymmetric carbon atoms and therefore can exist in various stereochemical forms. The present invention relates both to individual isomers and to mixtures thereof. Cycloalkano[1,2-
b] Indole sulfonamides may be mentioned by way of example. acycloalkano[1,2-b]indole sulfonamide bcycloalkano[1,2-b]dihydroindole sulfonamide R ¹ , R ² , x and y have the meanings given above. The cycloalkano[1,2-b]indole sulfonamide according to the present invention may be in the form of its salt. Generally, salts that may be mentioned in this connection are salts with organic or inorganic bases. Physiologically acceptable salts are preferred within the scope of the invention. Cycloalkano[1,2-
b] Physiologically acceptable salts of indole sulfonamides can be metal or ammonium salts of the substances according to the invention having free carboxyl groups. Examples of particularly preferred are sodium, potassium, magnesium or calcium salts and ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol,
It is an ammonium salt derived from arginine or ethylenediamine. Surprisingly, the substances according to the invention exhibit an inhibitory effect on platelet aggregation and can be used in therapeutic treatments for humans and animals. The following cycloalkano[1,2-b]indole sulfonamides may be mentioned by way of example. 1-(Benzenesulfonamidomethyl)-4-
(2-carboxyethyl)cyclopentano[1,
2-b]indole, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamidomethyl)-cyclopentano[1,2-b]indole, 4-(2-carboxyethyl)-1-( 4-chlorophenylsulfonamidomethyl)-cyclopentano[1,2-b]indole, 1-(benzenesulfonamido)-4-(2-carboxyethyl)cyclopentano[1,2-b]
Indole, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamide)cyclopentano[1,2-b]indole, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamide) ) cyclopentano[1,2-b]indole, 1-(benzenesulfonamidomethyl)-4-
(2-carboxyethyl)-7-methylcyclopentano[1,2-b]indole, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamidomethyl)-7-methylcyclopentano [1,2-b]indole, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamidomethyl)-7-methylcyclopentano[1,2-b]indole, 1-(benzenesulfone amido)-4-(2-carboxyethyl)-7-methylcyclopentano[1,2-b]indole, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamide)-7- Methylcyclopentano[1,2-b]indole, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamido)-7-methylcyclopentano[1,2-b]indole, 4- (2-carboxyethyl)-1-(4-tolylsulfonamidomethyl)-cyclopentano[1,
2-b] indole, 4-(2-carboxyethyl)-1-(4-tolylsulfonamido)-cyclopentano[1,2-
b] Indole, 3-(benzenesulfonamide)-9-(2-carboxyethyl)-1,2,3,4,4a,9a-hexahydrocarbazole, 3-(benzenesulfonamide)-9-(2- carboxyethyl)-1,2,3,4,4a,9a-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9
-(2-carboxyethyl)-1,2,3,4,
4a-t,9a-t-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9
-(2-carboxyethyl)-1,2,3,4,
4a-c,9a-c-hexahydrocarbazole, 9-(2-carboxyethyl)-3-r-(4-
Chlorophenylsulfonamide)-1,2,3,
4,4a-t,9a-t-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-
Chlorophenylsulfonamide)-1,2,3,
4,4a-c,9a-c-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-
Fluorophenyl sulfonamide)-1,2,3,
4,4a-t,9a-t-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-
Fluorophenyl sulfonamide)-1,2,3,
4,4a-c,9a-c-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-
tolylsulfonamide)-1,2,3,4,4a-
t,9a-t-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-
tolylsulfonamide)-1,2,3,4,4a-
c,9a-c-hexahydrocarbazole (+)-3-(4-chlorophenylsulfonamide-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole (+)-3-(4-fluorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole (-)-3-(4-chlorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole (-)-3-(4-fluorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole (±)-3-(4-chlorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole (±)-3-(4-fluorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole Particularly preferred are: (+)-3-(4-fluorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole and (-)-3-(4-fluorophenylsulfonamido-)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole. Furthermore, the general formula () In the formula, R ¹ represents hydrogen, halogen or C ₁ -C ₄ -alkyl, and R ² can also be mono- or di-substituted by halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl. [benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole representing a certain phenyl, x represents the number 1 or 2, and y represents the number 0 or 1, in the presence of an inert solvent, as appropriate is reacted with acrylonitrile in the presence of a base, and then this N,N'-biscyanoethyl compound is hydrolyzed to produce a cycloalkano[1,2-b]dihydroindolesulfonamide. The cycloalkano[1,2-b]indole sulfonamide is hydrogenated in the presence of an acid and a reducing agent, optionally in the presence of an inert solvent, the isomers resolved by conventional means, and the salts A method for producing cycloalkano[1,2-b]indol sulfonamides and salts thereof according to the present invention has been found, which is characterized by reacting with a suitable base. The manufacturing method described in the present invention can be expressed by the following formula. Cycloalkano[1,2-b]dihydroindole sulfonamides falling within the scope of formula (a) are where R ¹ , R ² , x and y correspond as defined above. When carrying out the process according to the invention, it is generally possible to isolate the intermediate produced. The process according to the invention can therefore be carried out in several stages. It is also possible to combine several stages. Possible solvents when carrying out the process according to the invention are water and organic solvents that do not change under the reaction conditions. Preferred for this are: alcohols such as methanol, ethanol, propanol or isopropanol; ethers,
For example diethyl ether, tetrahydrofuran, dioxane, glycol monomethyl or dimethyl ether; hydrocarbons such as benzene,
Includes toluene, xylene, cyclohexane, hexane or petroleum fractions; dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, acrylonitrile or pyridine. It is likewise possible to use mixtures of these solvents. Possible bases for the process according to the invention are the customary basic compounds. This preferably includes:
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 or potassium carbonate, or alkali metal alcoholates, such as sodium methanolate or ethanolate, potassium methanolate, ethanolate or tertiary butyrate, or amides, such as sodium amide or lithium. diisopropylamide; or organic amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine. The manufacturing method described in the present invention is generally carried out between 0°C and 0°C.
It is carried out at a temperature range of 150°C, preferably 20°C to 100°C. The process according to the invention is generally carried out under atmospheric pressure, but it is also possible to carry out under reduced or elevated pressure (for example in the range from 0.5 to 5 bar). Generally, [benzenesulfonamidoalkyl]
1 to 20 mol, preferably 1 to 10 mol, of acrylonitrile are used per mole of cycloalkano[1,2-b]indole. The above N,N'-bicyanoethyl compound is
Hydrolysis is carried out in a manner known per se in the presence of a base, for example an alkali metal or alkaline earth metal hydroxide or alkanolate, in an inert solvent, for example water or an alcohol. Preferred bases used are sodium, potassium or barium hydroxides, or sodium methanolate, potassium methanolate, sodium ethanolate or potassium ethanolate;
Preferably it is carried out in water or methanol, ethanol, propanol or isopropanol or in a mixture of these solvents. Generally, N,N'-biscyanoethyl compound 1
1 to 100 mol per mole, preferably 2 to 50 mol of base are used. The hydrolysis is carried out at a temperature range of 0°C to 100°C, preferably 20°C to 80°C. The hydrogenation is carried out in a manner known per se. It is also possible to use the acid used as a solvent for this reaction. Suitable solvents for hydrogenation are inert organic solvents that do not change under the reaction conditions. This preferably includes ethers such as diethyl ether, dioxane or tetrahydrofuran,
Alternatively, glacial acetic acid, trifluoroacetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid is included. Acids that can be used in all of the manufacturing steps described in this invention are organic acids. Preference is given here to: carboxylic acids, such as acetic acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid; or all sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid or benzenesulfonic acid, or trifluoromethane. Contains sulfonic acid. Suitable reducing agents for the hydrogenation according to the invention are customary reducing agents. Preference is given here to hydrides such as sodium borohydride, sodium cyanoborohydride, tetrabutylammonium borohydride, tetrabutylammonium cyanoborohydride, tributyltin hydride, triethylsilane, dimethylphenylsilane or triphenylsilane. included. This hydrogenation is generally carried out at -40℃ to +80℃,
It is preferably carried out at a temperature range of -20°C to +60°C. [Benzenesulfonamidoalkyl]cycloalkano[1,2-b] of general formula () to be used
Indole is a new substance. General formula () In the formula, R ¹ has the above meaning. The phenylhydrazine has the general formula () In the formula, R ² , x and y are characterized by reacting with a cycloalkanone sulfonamide having the above meanings in the presence of an inert solvent and optionally a catalyst [benzenesulfone] A method for producing amidoalkyl]cycloalkano[1,2-b]indoles has also been found. The production of [benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole according to the present invention can be represented by the following formula. Possible solvents for the process according to the invention are inert organic solvents that do not change under the reaction conditions. Preference is given for this: alcohols, such as methanol, ethanol, n-propanol, isopropanol and glycols; ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl or dimethyl ether; halogenated hydrocarbons, such as di-, tri- or tetrachloromethane, dichloroethylene and trichloroethylene; ethyl acetate, toluene, acetonitrile, glacial acetic acid, hexamethylphosphoric triamide, pyridine and acetone. It is of course also possible to use mixtures of these solvents. Catalysts suitable for the process disclosed by the present invention are conventional acids and Lewis acids. Preference is given here to inorganic acids such as hydrochloric, hydrobromic or sulfuric acid, or organic acids such as carboxylic or sulfonic acids, such as acetic acid, methanesulfonic acid and toluenesulfonic acid, or Lewis acids such as zinc chloride, odorous, etc. Includes zinc chloride or boron trifluoride etherate. The process disclosed by the present invention is generally carried out at temperatures between 0°C and 200°C, preferably between 20°C and 200°C.
Perform at a temperature range of 150℃. The process disclosed by the invention is generally carried out under atmospheric pressure, but it is equally possible to carry out under elevated or reduced pressure (eg 0.5 to 5 bar). The hydrazine is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mol of the ketone. Examples of hydrazines used in the process according to the invention are:
Phenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine and 4
- methylphenylhydrazine. Examples of ketones used according to the description of the invention are: 3-(benzenesulfonamidomethyl)cyclopentanone 3-(benzenesulfonamidomethyl)cyclohexanone 4-(benzenesulfonamidomethyl)cyclohexanone 3-(benzenesulfonamide) Cyclopentanone 3-(benzenesulfonamido)cyclohexanone 4-(benzenesulfonamido)cyclohexanone 3-(4-chlorophenylsulfonamidomethyl)cyclopentanone 3-(4-fluorophenylsulfonamidomethyl)cyclopentanone 3- (4-Methylphenylsulfonamidomethyl)cyclopentanone 3-(4-chlorophenylsulfonamidomethyl)cyclohexanone 3-(4-fluorophenylsulfonamidomethyl)cyclohexanone 3-(4-methylphenylsulfonamidomethyl) Cyclohexanone 4-(4-chlorophenylsulfonamidomethyl)cyclohexanone 4-(4-fluorophenylsulfonamidomethyl)cyclohexanone 4-(4-methylphenylsulfonamidomethyl)cyclohexanone 3-(4-chlorophenylsulfonamido)cyclo Pentanone 3-(4-fluorophenylsulfonamide)
Cyclopentanone 3-(4-methylphenylsulfonamide) Cyclopentanone 3-(4-chlorophenylsulfonamide) cyclohexanone 3-(4-fluorophenylsulfonamide)
Cyclohexanone 3-(4-methylphenylsulfonamide) cyclohexanone 4-(4-chlorophenylsulfonamide) cyclohexanone 4-(4-fluorophenylsulfonamide)
Cyclohexanone 4-(4-methylphenylsulfonamido)cyclohexanone. Hydrazine () used as starting material
is a known substance or a known method (Houben-Weyl "Method of Organic Chemistry"),
X/2, p. 1, 123, (693)). General formula (a) used as starting material Some of the cyclohexanone sulfonamides in which y and R ² have the above-mentioned meanings are known substances and are themselves known methods (Houben-Weyl, "Methods of Organic Chemistry"). Chemie）”，，
605; A. Mooradian et al.
(See J.Med.Chem. 20 (4), 487 (1977)). General formula (b) used as starting material Cyclopentanone sulfonamide in which x, y and R ² have the above meanings is a new substance. General formula () In the formula, x and y are cycloalkanols having the above meanings, and are represented by the general formula () Hal−SO ₂ −R ² (), where R ² has the above meanings, and Hal is fluorine, chlorine, bromine. or a sulfonyl halide representing iodine, preferably chlorine or bromine, in an inert organic solvent, optionally in the presence of a base, and then oxidized in an inert solvent. A method for producing cycloalkanone sulfonamides has also been discovered. The above cycloalkanols are cycloalkanones () is reacted with nitromethane in an inert organic solvent, optionally in the presence of a base, and then the compound () (Chemical Abstracts (CA) 92, 89 849 and Chemical Abstracts (CA) 87, 22 191). The above-mentioned sulfonyl halides can be prepared by a method known per se (Houben-Weyl).
“Methods of Organic Chemistry”
Chem.)", 564). The production of the cycloalkano[1,2-b]indole sulfonamide according to the present invention can be represented by the following reaction. According to this, in the first step a), the cycloalkanone is combined with an alcohol, such as methanol, ethanol or propanol, or with an ether, such as diethyl ether, tetrahydrofuran or dioxane, or with a chlorinated hydrocarbon, such as methylene chloride, chloroform. or a base such as sodium hydride, sodium or potassium methanolate, sodium or potassium ethanolate, potassium tert-butanolate, 1,5-diazabicyclo[4.3.0]nona-5, in an inert solvent such as carbon tetrachloride.
-ene, 1,5-diazabicyclo[5.4.0]undec-5-ene, 1,5-diazabicyclo[5.4.0]undec-5-ene, by reacting with a nitro compound, such as nitromethane, in the presence of pyridine or triethylamine at a temperature in the range of 0°C to 100°C. shall be. In step b), a hydride such as _LiAlH4 , Na[Al( _{OCH2CH2 - OCH3} ) _{2H2 ]} in an inert solvent such as an ether such as tetrahydrofuran, dioxane or diethyl ether is used.
Alternatively, the above nitro compounds are reduced to cycloalkanols in the presence of a reducing agent such as diisobutylaluminum hydride at temperatures within the range of -20°C to +60°C. In step c), optionally a base is added in an inert solvent such as an ether, such as dioxane, tetrahydrofuran or diethyl ether, or a chlorinated hydrocarbon, such as methylene chloride, chloroform or carbon tetrachloride, or ethyl acetate or pyridine. , for example 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo[5.4.0]undec-5-ene, -20 in the presence of pyridine or triethylamine.
The cycloalkanols described above are converted to sulfonamides by reacting with sulfonyl halides at temperatures between .degree. C. and +60.degree. In step d), the above sulfonamide is treated with chromium() in an inert solvent such as water, glacial acetic acid, acetone, pyridine or mixtures thereof.
Compounds such as CrO ₃ , K ₂ Cr ₂ O ₇ or Na ₂ Cr ₂ O ₇
The cycloalkanone sulfonamide is oxidized using an oxidizing agent such as at a temperature of -20°C to +100°C. In step e), the cycloalkanone sulfonamide (b) and hydrazine () are reacted as described above to give the formula () In the formula, R ¹ , R ² , x and y are the corresponding [benzenesulfonamide alkyl] having the above meanings.
Cycloalkano[1,2-b]indole. General formula (a) Enantiomerically pure [benzenesulfonamido]cyclohexanone[1,2-b]indole in which R ¹ and R ² have the meanings given above is likewise a new substance. General formula () In the formula, R ¹ has the above meaning, and enantiomerically pure cyclohexano[1,2-b]indoleamine is represented by the general formula () Hal−SO ₂ −R ² (), where R ² has the above meaning. Hal means the reaction of fluorine, chlorine, bromine or iodine with a sulfonyl halide, preferably representing chlorine or bromine, in the presence of an inert solvent and optionally in the presence of a base. enantiomerically pure [benzenesulfonamido]cyclohexanone [1,2
-b] A method for producing indole was also discovered. Solvents suitable for this process are customary organic solvents that do not change under the reaction conditions. This preferably includes ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons,
for example benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine,
Includes pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is likewise possible to use mixtures of the abovementioned solvents. The base for this step can be any conventional basic compound. This preferably includes alkali metal and alkaline earth metal hydroxides,
for example lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal hydrides such as sodium hydride,
or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, sodium bicarbonate, potassium carbonate or calcium carbonate;
or alkali metal alcoholates, such as sodium methanolate, sodium ethanolate,
potassium methanolate, potassium ethanolate or potassium tert-butyrate, or alkali metal amides such as lithium diisopropylamide or sodium amide; or organic amines such as ethyldiisopropylamine, benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, Included are dimethylaminopyridine, triethylamine, N-methylpiperidine, 1,5-diazabicyclo[4.3.0]non-5-ene or 1,5-diazabicyclo[5.4.0]undec-5-ene. This process disclosed by the present invention generally comprises:
It is carried out in a temperature range of -30°C to +150°C, preferably -20°C to +80°C. The process disclosed by the present invention is generally carried out under atmospheric pressure, but it is equally possible to carry out under reduced or elevated pressure (for example in the range from 0.5 to 200 bar). The enantiomerically pure cyclohexano[1,2-b]indoleamine of general formula () described in the present invention is a new material and can be prepared according to synthetic principles A, B or C below. R ¹ has the above meaning; R* represents an enantiomerically pure D- or L-amino acid residue, preferably a 2s-(chloroacetamido)-3-phenylpropionyl group; R ¹ is the synthetic principle with the above meaning A According to this, in step 1, paracetamol ( ) is hydrogenated over Raney-Nickel, and is published by JHBillman and JABuhler in the American Journal of Chemistry (J. Am.
4-acetamidocyclohexanol () as described in Chem.Soc.) 75 , 1345 (1953)
A cis/trans mixture of In step 2, 4-acetamidocyclohexanol (
) is applied in a one-bath method using Fischer's indole synthesis method using an oxidizing agent such as phenylhydrazine (), and then by acid hydrolysis,
Remove acetyl group. The manufacturing process is carried out in a solvent such as water, acetic acid and/or propionic acid at temperatures ranging from 0°C to +150°C.
It is carried out at a temperature of 0.degree. C., preferably 0.degree. C. to 110.degree. The racemic 3-amino-1,2,3,4-tetrahydrocarbazole () easily obtained in this way is obtained in step 3 by coupling with an enantiomerically pure amino acid in suitably activated form. , converted into the corresponding diastereomeric mixture, which can be resolved into the individual diastereomers by conventional methods, such as crystallization or column chromatography. Suitable enantiomerically pure amino acid derivatives include acetylphenylphenylalanine,
N-tert-butoxycarbonylphenylalanine,
Chloroacetylphenylalanine, carbobenzoylphenylalanine, methoxyphenylacetic acid or acetoxyphenylacetic acid, preferably N-chloro-N-phenylalanine. Commonly used activating agents are conventional peptide coupling agents. Preferred for this are carbodiimides, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminoisopropyl)
-N'-ethylcarbodiimide hydrochloride, or
carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate, or propanephosphonic anhydride, or isobutyl chloroformate,
or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or methanesulfonyl chloride, optionally with a base such as triethylamine, or N-
Used in the presence of ethylmorpholine or N-methylpiperidine, or dicyclohexylcarbodiimide and N-hydroxysuccinimide. Coupling generally takes place in an inert organic solvent, preferably with a chlorinated hydrocarbon, such as methylene chloride or chloroform;
for example in benzene, toluene, xylene or petroleum distillates, or in ethers such as dioxane, tetrahydrofuran or diethyl ether, or in ethyl acetate, dimethylformamide, dimethylsulfoxide or acetone,
- in acrylonitrile or nitromethane
80℃ to +50℃, preferably -40℃ to 30℃
Carry out at a temperature of °C. After the diastereomeric mixture () has been resolved, the individual diastereomers are subjected to acid hydrolysis in step 4 to give the enantiomerically pure amine (). This hydrolysis generally involves inorganic or organic acids,
For example, hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, formic acid,
It is carried out using acetic acid, propionic acid, methanesulfonic acid or fluoroacetic acid or a mixture of these acids. The solvent commonly used for this reaction is water or an aqueous solution of the corresponding acid or the mixture of acids used. This hydrolysis typically occurs at temperatures between +20°C and +150°C.
, preferably in the temperature range of +20°C to +120°C. The process disclosed by the invention is generally carried out under atmospheric pressure, but it is equally possible to carry out it under reduced pressure or under pressure, for example in an autoclave or a pressurized tube. It is advantageous here to add thioglycolic acid as an oxidation inhibitor to the reaction mixture. Synthesis Principle B According to this method, A.Britten and G.Lockwood reacted 1,4-cyclohexanedione monoethylene ketal () with phenylhydrazine () using Fischer's indole synthesis method. Ketal () as described in J.Chem.Soc., PerKin Trans. 1 , 1974 , 1824-1827. The ketal ( ) is hydrolyzed in step 2 to give the ketone ( ), which is converted in step 3 to the diastereomeric mixture ( ) by reductive amination using s-phenethylamine. This reductive amination generally involves hydrogen in the presence of a reducing agent, such as palladium, platinum or palladium on animal charcoal, optionally as a catalyst.
or complex hydrides, preferably sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium aluminum borohydride, aluminum hydride; diisobutylaluminum hydride, lithium triethylhydride borate, cyanotrihydride Sodium borate, tetrabutylammonium cyanotrihydroborate, tetrabutylammonium hydridoborate,
using lithium aluminum hydride, sodium bis[2-methoxyethoxy]dihydridoaluminate or lithium hydridotris[1-methylpropyl]borate in an inert solvent, such as a hydrocarbon, preferably benzene, toluene, or xylene, or Chlorinated hydrocarbons, such as methylene chloride or chloroform, or ethers, such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxymethane, or acetonitrile, dimethylformamide, dimethyl sulfoxide, or alcohols, such as methanol, ethanol, propanol. Alternatively, it is carried out in isopropanol at a temperature range of -80°C to +100°C, preferably -80°C to +50°C. The diastereomeric mixture () is separated into the individual diastereomers by customary methods, such as chromatography or crystallization, preferably by crystallization, if appropriate in the form of the appropriate acid adduct. Suitable acid adducts in this connection are adducts of the enantiomers according to the invention with inorganic or organic acids. This preferably includes hydrochloric acid,
Includes sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, maleic acid, fumaric acid, citric acid, or lactic acid. Removal of the phenylethyl group of the resolved diastereomer () is carried out in step 4 by catalytic transfer hydrogenation to yield the enantiomerically pure amine (). Step 4 generally involves reducing alcohols such as methanol, ethanol, propanol or isopropanol, or dimethylformamide or dimethyl using a reducing agent, such as hydrogen, or ammonium formate, optionally in the presence of palladium, palladium on animal charcoal or platinum. 0°C to +200°C, preferably +20°C to +150°C in an inert solvent such as a sulfoxide.
(Overman (LE)
J.Org.Chem. 50 , 4154-4155 (1985)). Synthesis Principle C According to this, racemic resolution of compound () is carried out by forming a salt with an optically active acid and crystallizing this salt once or several times in an appropriate solvent. By treating the salt thus obtained with a base, the enantiomerically pure compound (
) is released. Suitable optically active acids are: (+)-sulfonic acid, (-)-sulfonic acid, (+)-sulfonic acid, (+)-sulfonic acid, (-)-sulfonic acid, (-)-sulfonic acid-3
-carboxylic acid, (+)-alcoholic acid, (-)-alcoholic acid, (-)-malic acid, (+)-mandelic acid,
(-)-mandelic acid, (+)-lactic acid, (-)-lactic acid,
(-)-2-[(phenylamino)carbonyloxy]-propionic acid, (-)-α-methoxyphenylacetic acid, (-)-di-0-benzoyltartaric acid, (-)
-di-0-4-toluoyltartaric acid, (-)-methoxyacetic acid, and (-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. Suitable solvents for crystallization are: water; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol or tertiary-butanol; ethers,
For example diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone; hydrocarbons such as benzene, toluene, xylene,
hexane or cyclohexane; chlorinated hydrocarbons such as dichloromethane or chloroform; or such as ethyl acetate, acetonitrile, nitromethane, dimethylsulfoxide, dimethylformamide or sulfolane.
It is likewise possible to use mixtures of the abovementioned solvents. Possible bases for this method are the customary basic compounds. This includes preference for: hydroxides of alkali metals or alkaline earth metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide; or hydrides of alkali metals, such as sodium hydride; or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, sodium bicarbonate, potassium carbonate or calcium carbonate; or alkali metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate or Contains potassium tertiary butyrate. The novel cycloalkano[1,2-b]indole sulfonamides and their salts can be used as active compounds in medicine. The active compound has a platelet aggregation inhibitory effect and thromboxane _A2 antagonizing effect.
Shows thromboxane A ₂ ) action. These can be suitably used for the treatment of thrombosis, thromboembolism, and ischemia, and as anti-asthmatic agents and anti-allergic agents. The novel active compounds can be prepared in a known manner using inert, non-toxic, pharmaceutically suitable vehicles or solvents in conventional formulations such as tablets, capsules, dragees, pills, granules, aerosols, etc. Can be converted into syrups, emulsions, suspensions and solutions. In each case, the therapeutically active compound is administered in a dosage range sufficient to achieve a dosage range of about
It should be present in a concentration of 0.5 to 90% by weight, preferably 5 to 70%. The above formulations are prepared, for example, by bulking up the active compound with a solvent and/or vehicle, optionally with emulsifiers and/or dispersants, and, for example, when water is used as diluent, an organic solvent. can optionally be used as a co-solvent. Examples of auxiliaries that may be mentioned are: water; non-toxic organic solvents such as paraffins (e.g. petroleum distillates), vegetable oils (e.g. peanut oil/sesame oil), alcohols (e.g. ethyl alcohol and glycerol) and glycols (e.g. solid vehicles such as natural rock powders (such as kaolin, alumina, talc and chalk);
Synthetic rock powders (e.g. highly dispersed silica and silicates), as well as sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryls) sulfonates), dispersants (e.g. lignin sulfite waste liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,
stearic acid, and sodium lauryl sulfate)
It is. Administration is by conventional means, preferably orally or parenterally, especially perlingually,
or intravenously. In the case of oral administration, the tablets, of course, contain no additives in addition to the vehicle mentioned above.
For example, sodium citrate, calcium carbonate and dicalcium phosphate may be included together with various additives such as starch, preferably potato starch, gelatin, etc. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used in making tablets. In the case of aqueous suspensions and/or elixirs intended for oral use, the active compounds can be mixed, in addition to the adjuvants mentioned above, with various flavor modifiers or colorings. For parenteral administration, solutions of the active compounds in suitable liquid vehicles may be employed. Generally, in the case of intravenous administration, a dosage of about 0.001 to 1 mg, preferably about 0.01 to 0.5 mg per kg of body weight is advantageous to achieve an effective result, and in the case of oral administration Generally about 0.01 to 1 mg/kg body weight, preferably about
Dosage ranges from 0.01 to 10 mg. However, it may sometimes be advantageous to deviate from the above amounts, in particular depending on the body weight or the nature of the method of administration, and also depending on the behavior of the solid towards the medicament or the nature of the pharmaceutical formulation and the time and duration of administration. There are possibilities depending on the interval. Therefore, in some cases it may be sufficient to treat with less than the abovementioned minimum amount, while in other cases it may be necessary to exceed the abovementioned upper limit. When administering a relatively large amount, divide it into several doses,
Administration over one day may be recommended. The cycloalkano[1,2-b]indole sulfonamides according to the invention can be used in both human and veterinary medicine. Production Examples Example 1 3-(nitromethyl)cyclopentanone 100g of 2-cyclopentenone, nitromethane
666 ml and 5 g of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) were dissolved in 1.1 isopropanol and the solution was heated to room temperature for 5 g.
Leave it for a while. The isopropanol is then substantially distilled off in vacuo, the residue is dissolved in ethyl acetate, and this solution is washed twice with 0.5 portions of dilute sulfuric acid. The organic phase is dried over sodium sulphate and evaporated. In this way, 154 g (88% of theory) of 3-(nitromethyl)cyclopentanone are obtained in sufficient purity for the subsequent reaction. Rf=0.52 CH ₂ Cl ₂ :CH ₃ OH=99:1 Example 2 3-(aminomethyl)cyclopentanol 3-(nitromethyl)cyclopentano 57.2g
(0.4 mol) is dissolved in 573 ml absolute tetrahydrofuran under nitrogen. To this solution, at 0° C., 800 ml of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran are added dropwise. After the dropwise addition is complete, the mixture is stirred at 0° C. for 1 hour. The cooling bath is then removed and the temperature of the reaction solution rises to 40°C. After the temperature has fallen to 20° C., the mixture is stirred at this temperature for 1 hour.
The reaction mixture is cooled to 0° C. and then 100 ml of a 45% strength solution of sodium hydroxide are carefully added dropwise. After the dropwise addition is complete, the reaction mixture is stirred for 1 hour at room temperature, filtered through diatomaceous earth, and the diatomaceous earth is washed with 1.5 portions of tetrahydrofuran. The filtrates are collected and thoroughly evaporated in vacuo. In this way, 22.5 g (49% of theory) of a viscous oily product are obtained. Rf=0.01 CH ₂ Cl ₂ :CH ₃ OH=9:1 Example 3 3-(benzenesulfonamidomethyl)cyclopentanol 3-(aminomethyl)cyclopentanol 9g
(0.078 mol) of triethylamine 13.8g = 10ml
(0.078 mol) in 200 ml of tetrahydrofuran. Then, at 0-5 DEG C., 7.9 g=10.8 ml (0.078 mol) of benzenesulfonyl chloride are added dropwise. After the dropwise addition is complete, the reaction mixture is stirred at 0° C. for 1 hour. The mixture is then diluted with 200 ml of methylene chloride and washed twice with 150 ml portions of dilute sulfuric acid. Then, the organic phase
Extract twice with 150 ml portions of 2N sodium hydroxide solution, collect the extracts, acidify with concentrated hydrochloric acid, and extract twice with 150 ml portions of methylene chloride. The methylene chloride phases are combined, dried over sodium sulfate and evaporated in vacuo. In this method, a viscous oily isomer mixture
9.1 g (39% of theory) are obtained as product. Rf = 9.51 and 0.45 CH ₂ Cl ₂ :CH ₃ OH = 95.5 Example 4 3-(benzenesulfonamidomethyl)cyclopentano 7.5 g (0.0294 mol) of 3-(benzenesulfonamidomethyl)cyclopentanol are dissolved in 60 ml of glacial acetic acid. Chromium trioxide 2.79g
(0.0279 mol) dissolved in 2 ml of water and 8.8 ml of glacial acetic acid is added dropwise at 0-5 DEG C. and the temperature of the reaction mixture is then raised to room temperature.
After stirring the reaction mixture at room temperature for 1 hour,
Dilute with 200 ml of ether and wash twice with 150 ml of water. The organic phase is then extracted twice with 200 ml portions of 2N sodium hydroxide solution, the combined sodium hydroxide phase acidified with concentrated hydrochloric acid and extracted twice with 200 ml portions of methylene chloride. The methylene chloride phases are combined, dried over sodium sulfate and evaporated in vacuo. In this way, 4.4 g (59% of theory) of a viscous oil product are obtained. Rf=0.51 _CH2Cl2 : _CH3OH =95:5 Example 5 1-(benzenesulfonamidomethyl ₎ cyclopentano[1,2-b]indole 21 g (0.0826 mol) of 3-(benzenesulfonamidomethyl)cyclopentanone are dissolved in 200 ml of glacial acetic acid with 9 g (0.0826 mol) of phenylhydrazine and the solution is heated under reflux for 4 hours. The reaction solution is then diluted with 1.3 parts of ether and 500 ml of water are added. While cooling and stirring, the mixture is made alkaline by adding 45% strength sodium hydroxide solution and the organic phase is then separated off. The aqueous phase was extracted once again with 500 ml of ether, the organic phase was collected and dried over sodium sulfate,
Evaporate. The residue obtained in this way is
Chromatography is performed using 2 Kg of silica gel (Merck, 0.04-0.063 mm), eluting with a mixture of toluene and ethyl acetate in a ratio of 85:15. In this way a fraction is obtained which, after evaporation, gives 1.9 g (7% of theory) of a crystalline product with a melting point of 161 DEG -164 DEG C. Rf=0.92 _CH2Cl2 : _CH3OH =95:5 Example 6 _1- [N-(benzenesulfonyl)-N-(2-cyanoethyl)aminomethyl]-4-2-cyanoethyl)cyclopentano[1,2 -b] indole 1-(benzenesulfonamidomethyl)cyclopentano[1,2-b]indole 1.9g
(0.0058 mol), 1.83 g of acrylonitrile = 2.3
ml (0.0346 mol) and 0.24 g of a 40% strength methanol solution of benzyltrimethylammonium hydroxide
(0.00058 mol) in 60 ml of dioxane and stirred at 60-70°C for 2 hours. The reaction mixture was then evaporated in vacuo, the residue taken up in methylene chloride and the solution diluted with dilute sulfuric acid.
Extract times. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated. In this way, 2.4 g (95% of theory) of product are obtained as a solid foam. Rf=0.45 CH ₂ Cl ₂ :CH ₃ OH=99:1 Example 7 1-(benzenesulfonamidomethyl)-4-
(2-carboxyethyl)cyclopentano[1,
2-b] Indole 1-[N-(benzenesulfonyl)-N-(2-cyanoethyl)aminomethyl]-4-(2-cyanoethyl)cyclopentano[1,2-b]indole
2.4 g (0.0055 mol) dissolved in 35 ml of isopropanol and 55 ml of a 10% strength solution of potassium hydroxide
Add. The reaction mixture is stirred at 70° C. for 4 hours, then diluted with 100 ml of water and extracted with 100 ml of methylene chloride. The aqueous phase is made acidic with dilute sulfuric acid,
Extract three times with 100 ml portions of methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated. The oily residue (1.9 g) is dissolved in methanol and 0.26 g of sodium methylate is added.
Evaporating this solution yields 2.0 g (69.2 of the theoretical amount).
%) of product as microcrystalline sodium salt. Rf=0.37 _CH2Cl2 : _CH3OH =95:5 _Example 8 3-(4-fluorophenylsulfonamidomethyl)cyclopentanol Similar to the procedure of Example 3, 19.8 g (0.172 mol) of 3-(aminomethyl)cyclopentanol
is reacted with 28.3 g (0.172 mol) of 4-fluorophenylsulfonamide. This results in 17.3 g (36% of theory) of a viscous oily isomer mixture as product. Rf = 0.53 and _{0.46 CH2Cl2} : _CH3OH = 95:5 Example 9 3-(4-fluorophenylsulfonamidomethyl)cyclopentanone Analogous to the procedure of Example 4, 17.3 g (0.0638 mol) of 3-(4-fluorophenylsulfonamidomethyl)cyclopentanol was oxidized. This resulted in 14.3 g (83% of theory) of a viscous oily product.
is obtained. Rf=0.76 _CH2Cl2 : _CH3OH =9:1 _Example 10 1-(4-fluorophenylsulfonamidomethyl)cyclopentano[1,2-b]indole 3-(4-fluorophenylsulfonamidomethyl)cyclopentanone 14.3g (0.0527mol)
is reacted with phenylhydrazine in the same manner as in Example 5. This method produces a microcrystalline product after chromatography on silica gel.
0.67 g (3.7% of theory) is obtained. Rf=0.47 _CH2Cl2 : _CH3OH =99:1 Example 11 4-(2-cyanoethyl)-1-[N-( ₄ -fluorophenylsulfonyl)-N-(2-cyanoethyl)aminomethyl] cyclopentano[1,2
-b] indole 1-(4-fluorophenylsulfonamidomethy)cyclopentano[1,2-b]indole
0.67 g (0.00195 mol) is reacted in the same manner as in Example 6. This method gives 0.83 g (95% of theory) of product as a solid foam. Rf=0.39 Toluene:Ethyl acetate=8:2 Example 12 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamidomethyl)cyclopentano[1,2-b]indole 4-(2-cyanoethyl)-1-[N-(4-fluorophenylsulfonyl)-N-(2-cyanoethyl)aminomethyl]cyclopentano[1,2-
b] Hydrolyze 0.83 g (0.00184 mol) of indole in the same manner as in Example 7. In this way, 0.67 g (87% of theory) of a crystalline product with a melting point of 150-160
Obtained as sodium salt at °C. Rf=0.59 _CH2Cl2 : _CH3OH =9:1 Example ₁₃ 3-(4-chlorophenylsulfonamidomethyl)cyclopentanol 3-(aminomethyl)cyclopentanol 16.8
g (0.146 mol) are reacted analogously to Example 3 with 4-chlorophenylsulfonyl chloride.
In this way, 16.6 g of a viscous oil product (39
%) are obtained as a mixture of isomers. Rf=0.46 and _0.44CH2Cl2 : _CH3OH =95:5 Example ₁₄ 3-(4-chlorophenylsulfonamidomethyl)cyclopentanone 3-(4-chlorophenylsulfonamidomethyl)cyclopentanol 16.6g (0.0573mol)
is oxidized in the same manner as in Example 4. In this way, 13.8 g (83.7% of theory) of viscous oil product
is obtained. Rf=0.7 _CH2Cl2 : _CH3OH =95:5 Example ₁₅ 1-(4-chlorophenylsulfonamidomethyl)cyclopentano[1,2-b]indole 13.8 g (0.048 mol) of 3-(4-chlorophenylsulfonamidomethyl)cyclopentanone,
It is reacted with phenylhydrazine in the same manner as in Example 5. In this way, after chromatography on silica gel, 1.65 g (9.5% of theory) of product are obtained as a solid foam. Rf=0.46 _{CH2Cl2 : CH3OH} =99:1 Example 16 1-[N-(2-chlorophenylsulfonyl)-
N-(2-cyanoethyl)aminomethyl]-4-
(2-cyanoethyl)cyclopentano[1,2
-b] indole 1-(4-chlorophenylsulfonamidomethyl)cyclopentano[1,2-b]indole
1.65 g (0.0046 mol) is reacted in the same manner as in Example 6. In this way, 1.8g (84% of the theoretical amount)
The product is obtained as a solid foam. Rf=0.38 Toluene:Ethyl acetate=8:2 Example 17 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamidomethyl)cyclopentano[1,2-b]indole 1-[N-(4-chlorophenylsulfonyl)-
N-(2-cyanoethyl)amidomethyl]-4-
(2-cyanoethyl)cyclopentano[1,2-
b] 1.9 g (0.0038 mol) of indole is hydrolyzed in the same manner as in Example 7. In this way, 1.33
g (81.3% of theory) of product are obtained as a crystalline sodium salt with a melting point of 160°C. Rf=0.55 CH ₂ Cl ₂ :CH ₃ OH=9:1 Example 18 4-(benzenesulfonamido)cyclohexanol 4-Aminocyclohexanol 69g (0.6mol)
with 107 g (0.6 mol) of benzenesulfonyl chloride,
The reaction is carried out in the same manner as in Example 3. using this method,
72.8 g (theoretical amount) of crystalline product with melting point 106-108 °C
47%). Rf=0.38 CH ₂ Cl ₂ :CH ₃ OH=95:5 Example 19 4-(benzenesulfonamido)cyclohexanone 72.8 g (0.285 mol) of 4-(benzenesulfonamido)cyclohexanol are oxidized as in Example 4. Crystallization with petroleum ether gives 57.5 g (80% of theory) of product with a melting point of 80-82°C. Rf=0.66 CH ₂ Cl ₂ :CH ₃ OH=95:5 Example 20 3-(benzenesulfonamide)-1,2,3,
4-tetrahydrocarbazole 57.5 g (0.227 mol) of 4-(benzenesulfonamido)cyclohexanone are reacted with phenylhydrazine analogously to Example 5. In this way, crystallized with isopropanol, melting point 155
41.5 g (56% of theory) of product are obtained. Rf=0.82 CH ₂ Cl ₂ :CH ₃ OH=95:5 Example 21 3-[N-(benzenesulfonyl)-N-(2-cyanoethyl)amino]-9-(2-cyanoethyl)-1,2, 3,4-tetrahydrocarbazole 3-(benzenesulfonamide)-1,2,3,
10 g (0.0306 mol) of 4-tetrahydrocarbazole are reacted in the same manner as in Example 6. In this way, 10 g (75% of theory) of a product crystallized from ether and having a melting point of 180-190 DEG C. are obtained. Rf=0.29 Toluene:Ethyl acetate=8:2 Example 22 3-(benzenesulfonamide)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole 3-[N-(benzenesulfonyl)-N-(2-cyanoethyl)amino]-9-(2-cyanoethyl)
-1,2,3,4-tetrahydrocarbazole 10
g (0.0263 mol) is hydrolyzed analogously to Example 7. In this way, 7.57 g (68% of theory) of a crystalline product with a melting point of 160-165 DEG C. are obtained as the sodium salt. Rf=0.44 CH ₂ Cl ₂ :CH ₃ OH=95:5 In the same manner as in Example 18, the following compounds listed in Table 1 were produced.

[Table] In the same manner as in Example 19, the following compounds listed in Table 2 were produced.

[Table] In the same manner as in Example 20, the following compounds listed in Table 3 were produced.

[Table] From propanol
The following compounds listed in Table 4 were prepared in the same manner as in Example 21.

[Table] From Tel
The following compounds listed in Table 5 were prepared in the same manner as in Example 22.

[Table] Examples 38 and 39 3-r-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,3,
4,4a-t,9a-t-hexahydrocarbazole (isomer A) and 3-r-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,3,
4,4a-c,9a-c-hexahydrocarbazole (isomer B) 3-(4-fluorophenylsulfonamide)-
9-(2-carboxyethyl)-1,2,3,4-
5g sodium salt of tetrahydrocarbazole
Sodium cyanoborohydride (0.0114 mol) was dissolved in 50 ml of trifluoroacetic acid at 0°C.
g (0.08 mol) in small portions. The reaction mixture is allowed to reach room temperature, diluted with water and extracted with 200 ml of ethyl acetate. The ethyl acetate phase was extracted twice with 100 ml portions of 2N sodium hydroxide solution, the sodium hydroxide phase was collected and adjusted to pH 5, extracted three times with 150 ml portions of methylene chloride, dried over sodium sulfate, and extracted in vacuo. Evaporate thoroughly. The residue is chromatographed on 500 g of silica gel (Merck, 0.040-0.063 mm) and dissolved in a 100:1 mixture of methylene chloride and glacial acetic acid. In this way two fractions are obtained, each containing an isomer after evaporation.
2.87 g (60.2% of theory) of A and 0.7 g (14.9% of theory) of isomer B are obtained as a solid foam. Rf of isomer A: 0.24 CH ₂ Cl ₂ :CH ₃ COOH = 100:2 Rf of isomer B: 0.14 Examples 40 and 41 3-r-(benzenesulfonamide)-9-(2
-carboxyethyl)-1,2,3,4,4a-
t,9a-t-hexahydrocarbazole (isomer A) and 3-r-(benzenesulfonamide)-9-(2
-carboxyethyl)-1,2,3,4,4a-
c,9a-c-hexahydrocarbazole (isomer B) 1.18 g (0.0028 mol) of the sodium salt of 3-(benzenesulfonamido)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole is reduced as in Example 38. The chromatography yielded two fractions which, when evaporated, gave 0.45 g of isomer A (40% of theory) and 0.2 g of isomer B (18% of theory) as a solid foam. can get. Rf of isomer A: 0.4 CH ₂ Cl ₂ :CH ₃ COOH = 100:4 Rf of isomer B: 0.22 Examples 42 and 43 3-r-(4-methylphenylsulfonamide)
-9-(2-carboxyethyl)-1,2,3,
4,4a-t,9a-t-hexahydrocarbazole (isomer A) and 3-r-(4-methylphenylsulfonamide)
-9-(2-carboxyethyl)-1,2,3,
4,4a-c,9a-c-hexahydrocarbazole (isomer B) 3-(4-methylphenylsulfonamide)-9
-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole sodium salt 18.6g
is reduced in the same manner as in Example 38. Chromatography gave two fractions which, on evaporation, gave 3.65 g (20% of theory) of isomer A with a melting point of 156-62°C as a crystalline residue; 1.11 g (6% of theory) of B are obtained as a solid foam. Rf of isomer A: 0.39 Rf of isomer B: 0.20 _CH2Cl2 : _CH3COOH =100:2 Example 44 3-(4-chlorophenylsulfonamidomethyl)-6 _- fluoro-1,2,3 ,4-tetrahydrocarbazole 26.5 g of 4-(4-chlorophenylsulfonamido)cyclohexanone are reacted with 4-fluorophenylhydrazine analogously to Example 5. This results in 35.4 g (100% of theory) of product as a solid foam. Rf=0.53 Toluene:Ethyl acetate=8:2 Example 45 3-[N-(4-chlorophenylsulfone)-N
-(2-cyanoethyl)amino]-9-(2-cyanoethyl)-6-fluoro-1,2,3,4
-tetrahydrocarbazole 4-(4-chlorophenylsulfonamide)-6
3.4 g of -fluoro-1,2,3,4-tetrahydrocarbazole are reacted as in Example 6. In this way, 27.6 g (61% of theory) of product are obtained as a solid foam. Rf=0.25 Toluene:Ethyl acetate=8:2 Example 46 3-(4-chlorophenylsulfonamide)-9
-(2-carboxyethyl)-6-fluoro-
1,2,3,4-tetrahydrocarbazole 3-[N-(4-chlorophenylsulfonyl)-
N-(2-cyanoethyl)amino]-9-(2-cyanoethyl)-6-fluoro-1,2,3,4-
27.6 g of tetrahydrocarbazole are hydrolyzed in the same manner as in Example 7. In this way, melting point 118−
25.6 g (100% of theory) of crystalline product at 130° C. are obtained. Rf=0.52 _CH2Cl2 : _{CH3OH =} 9:1 Example 47 3-(nitromethyl)cyclohexanone 21.9g of cyclohexanone, 175g of nitromethane
ml and 5-diazabicyclo-[4.3.0]-nona-
Add 2.1 g of 5-ene (DBN) to 250 ml of isopropanol and leave at room temperature for 2 days. Work-up similar to the procedure of Example 1 provides 3-(nitromethyl) of sufficient purity for use in the next reaction.
37.2 g (100% of theory) of cyclohexanone are obtained. Rf=0.62 CH ₂ Cl ₂ :CH ₃ OH=99:1 Example 48 3-(aminomethyl)cyclohexanol 3-(nitromethyl)cyclohexanone 37.2g
is reduced with lithium aluminum hydride in the same manner as in Example 2. In this method, viscous oily 3
-(aminomethyl)cyclohexanol 7.5g
(24.5%) is obtained. Rf=0.04 _CH2Cl2 : _CH3OH =9:1 _Example 49 3-(4-fluorophenylsulfonamidomethyl)cyclohexanol In a similar manner to the procedure of Example 3, 7.5 g of 3-(aminomethyl)cyclohexanol was dissolved in 11.3 g of 4-
React with fluorophenyl sulfonamide.
As a result, 11.05 g (theoretical amount of 66
%) of a viscous oily isomer mixture is obtained. Rf = 0.41 and _{0.38 CH2Cl2} : _CH3OH = 95:5 Example 50 3-(4-fluorophenylsulfonamidomethyl)cyclohexanone Analogous to the procedure of Example 4, 11 g of 3-(4-fluorophenylsulfonamidomethyl)cyclohexanol are oxidized with chromium trioxide. This gives 9.3 g (86% of theory) of product as a solid foam. Rf=0.86 _CH2Cl2 : _CH3OH =9:1 Example 51 4-( ₄ -fluorophenylsulfonamidomethyl)-1,2,3,4-tetrahydrocarbazole Analogous to the procedure of Example 5, 9 g of 3-(4-fluorophenylsulfonamidomethyl)cyclohexanone are reacted with phenylhydrazine.
This results in 9 g of crude product. this,
Chromatograph using 1 Kg of silica gel (Merck, 0.04-0.063 mm) and elute with a mixture of toluene and ethyl acetate in a ratio of 8:2. As a result, evaporation of one fraction gives 0.8 g (7.2% of theory) of product as a solid foam. Rf=0.44 Toluene:Ethyl acetate=8:2 Example 52 9-(2-cyanoethyl)-4-[N-(4-fluorophenylsulfonyl)-N-(2-cyanoethyl)aminomethyl]-1,2 ,3,4-tetrahydrocarbazole Similar to the procedure of Example 6, 4-(4-fluorophenylsulfonamidomethyl)-1,2,
0.8 g of 3,4-tetrahydrocarbazole is reacted with acrylonitrile. As a result, 0.91g
(88% of theory) of product is obtained as an oil. Rf=0.37 Toluene:Ethyl acetate=8:2 Example 53 9-(2-carboxyethyl)-4-(4-fluorophenylsulfonamide)-1,2,3,
4-tetrahydrocarbazole Example 7 and 0.91 g of 9-(2-cyanoethyl)-4-[N-(4-fluorophenylsulfonyl)-N-(2-cyanoethyl)aminomethyl]-1,2,3,4-tetrahydrocarbazole were added. Hydrolyze in the same way. In this method, 0.77 g of crystalline product
(89% of theory) is obtained as the sodium salt. Melting point: 160°C Rf=0.57 _CH2Cl2 : _CH3OH =9:1 Example ₅₄ 4-N-acetamidocyclohexanol 300 g of paracetamol are hydrogenated in 750 ml of ethanol with 30 g of Raney nickel at 180° C. and 100 bar. Once the hydrogen absorption is complete, the catalyst is removed by filtration, 30 g of Raney nickel is added and the hydrogenation is repeated at 180° C. and 100 bar overpressure. The catalyst is then removed by filtration,
The filtrate is evaporated in vacuo and 200 ml of acetone are added to the still wet residue and stirred. After the crystals are filtered off with suction, the mother liquor is further concentrated, the precipitated crystals are filtered off with suction again, and the mother liquor is concentrated again.
By the third batch, the total amount was 342.4g (theoretical amount)
80.8%) of the product is obtained. Melting point: 100-103°C Example 55 3-amino-1,2,3,4-tetrahydrocarbazole (racemic form) Dissolve 50 g (0.318 mol) of 4-N-acetamidocyclohexanol in 400 ml of glacial acetic acid, and dissolve 31.8 g (0.318 mol) of chromium trioxide in 26 ml of water.
The solution was dissolved in a mixture with 105 ml of glacial acetic acid,
Add with stirring at room temperature. As a result, the temperature of the reaction solution rises to 60°C. This reaction mixture was
Stir for an hour, then add 45.7g of phenylhydrazine.
(0.423 mol) is added. As a result, the reaction solution is
It is heated to 80°C and the first nitrogen evolution is observed.
The reaction mixture is then heated under reflux for 2.5 hours. After the reaction mixture has cooled, 500 ml of concentrated hydrochloric acid and 59 ml of thioglycolic acid are added and the mixture is heated under reflux and nitrogen for 16 hours. After the mixture has cooled, 500 ml of ethyl acetate are added with cooling and made alkaline with 45% strength sodium hydroxide. The precipitated chromium hydroxide is removed by suction filtration through a layer of diatomaceous earth and washed with a methylene chloride/methanol mixture in a ratio of 9:1. The organic phase is separated from the filtrate and the aqueous phase is extracted three more times with ethyl acetate. The organic phases are combined and washed twice with 2N sodium hydroxide solution and then extracted twice with 2N sulfuric acid each time. The acidic aqueous phase is made alkaline with 45% strength sodium hydroxide solution and extracted three times with one portion of methylene chloride. The methylene chloride phases are combined, dried over sodium phosphate and evaporated. 300ml ether and 50ml
of isopropanol is added to the residue and the mixture is stirred. The precipitated product is filtered off with suction,
Wash with ether and dry in vacuo. product
28.6 g (48.3% of theory) are obtained. Melting point: 174-176°C Example 56 3[2s-(chloroacetamide)-3-phenylpropionamide]-1,2,3,4-tetrahydrocarbazole (diastereomer mixture) 43 g (0.231 mol) of 3-amino-1,2,3,4-tetrahydrocarbazole and 55.87 g (0.231 mol) of N-chloroacetyl-L-phenylalanine were suspended in 1.5 methylene chloride at 0°C under nitrogen. Let it become cloudy and add 115.2 ml (0.832 mol) of triethylamine. Then, at -20 DEG C., 150 ml (0.231 mol) of a 50% strength methylene chloride solution of propanephosphonic anhydride are added dropwise to the reaction mixture. This was stirred at -20°C for 30 minutes, then at 0°C.
Stir for 1.5 hours. For work-up, the reaction mixture was treated with 1 part of 2N sulfuric acid, 1 part of water, and 1 part of water.
Wash twice with saturated bicarbonate solution. Drying over sodium sulfate and evaporation gives 100 g of a solid residue. Examples 57 and 58 3-[2s-(chloroacetamide)-3-phenylpropionamide]-1,2,3,4-tetrahydrocarbazole (diastereomer A and diastereomer B) a Dialysis by column chromatography Resolution of Stereomers 100 g of the crude product of Example 56 was purified using 2.5 Kg of silica gel (0.063 to 0.2 mm, Merck) using a toluene/ethyl acetate mixture in a ratio of 6:4 as the fluid phase.
chromatograph. Two fractions are obtained in this way, the first of which, on evaporation, gives 34 g (35.9% of theory) of diastereomer A (Example 57). Melting point: 217-220° C. Evaporation of the second fraction gives 24.3 g (25.7% of theory) of the other diastereomer B (Example 58). Melting point: 193-195°C Optical rotation of diastereomer A: [α] ²⁰ = 32.59° (CH ₃ OH) (Example 57) Optical rotation of diastereomer B: [α] ²⁰ = 5.09° (CH ₃ OH ) (Example 58) b Resolution of the diastereomers by crystallization 11.5 g of the crude product of Example 56 are stirred in a mixture of ether and isopropanol. The crystals are filtered off with suction and heated under reflux for 3 hours in 40 ml of acetone. After cooling and standing overnight, the product is filtered off with suction and washed with acetone. using this method,
1.2 g of pure diastereomer A (5.5% of theory)
is obtained (Example 57). Example 59 3-amino-1,2,3,4-tetrahydrocarbazole (enantiomer A) Diastereomer (57) 24.1g (0.059mol)
Dissolve in 460 ml of glacial acetic acid. Added 460 ml of concentrated hydrochloric acid and 24 ml of thioglycolic acid, and incubated under nitrogen for 3 days.
Heat to reflux temperature. This reaction mixture is then
Dilute with 200 ml of water and adjust to pH 5 by adding 45% strength sodium hydroxide solution while cooling. It was then extracted twice with 1.5 parts of ethyl acetate, and 45
The aqueous phase is made alkaline using 1.5% strength sodium hydroxide solution and extracted three times with 1.5 parts of ethyl acetate. The ethyl acetate extracts are combined, dried over sodium sulfate and evaporated. The residue is stirred in 150 ml of ether. The precipitated product is filtered off with suction and dried in vacuo. 7.8g (71.3% of theoretical amount)
enantiomer A is obtained. Melting point: 160-166°C Optical rotation [α] ²⁰ = 78.38° (DMSO + 10% water) Example 60 3-Amino-1,2,3,4-tetrahydrocarbazole (enantiomer B) Enantiomer B was prepared by hydrolysis of (58) in a similar manner to (57) to (59). Melting point: 162-167℃ Optical rotation [α] 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 is dissolved in methylene chloride (2) along with 48.4 ml (0.5 mol) of phenylhydrazine, 300 g of magnesium sulfate is added, and the mixture is stirred for 30 minutes. . The magnesium sulphate is then filtered off with suction, washed with methylene chloride and the filtrate is evaporated. The residue is taken up in 1.5 g of benzene, 62.1 g (0.46 mol) of anhydrous zinc chloride are added and the mixture is heated under reflux for 3 hours with a water separator. The reaction solution is then concentrated, 2N sodium hydroxide solution is added and the mixture is extracted three times with ethyl acetate. The ethyl acetate phases are combined, dried over sodium sulfate and evaporated. The residue is crystallized from a small amount of ether.
In this way, 3.5 g (72.9% of theory) of product are obtained. Melting point: 145-146°C Example 62 1,2,4,9-tetrahydrocarbazole-
3-on 3,3-ethylenedioxy-1,2,3,4-
165 g (0.72 mol) of tetrahydrocarbazole are dissolved in 2 acetone and 3 g of p-toluenesulfonic acid are added. This reaction solution was refluxed for 4 hours.
After heating for an hour and concentrating, 2 portions of ethyl acetate are added and the mixture is extracted 3 times with 1 portion of saturated bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallized from ether. In this way, 118.7g (89.1% of the theoretical amount)
of product is obtained. Melting point: 145-148℃ Example 63 3-(1s-phenylethylamino)-1,2,
3,4-tetrahydrocarbazole 1,2,4,9-tetrahydrocarbazole-
11.06 g (0.0595 mol) of 3-one with 7.78 g (0.065 mol) of 1s-phenylethylamine in 300 ml
of benzene with a water separator under reflux.
Heat for an hour. After removing the benzene by evaporation, the residue was dissolved in 50 ml of methylene chloride and the solution was dissolved in tetrabutylammonium borohydride.
Add dropwise to a solution of 15.3 g (0.0595 mol) in 120 ml of methylene chloride at -50°C. The reaction mixture is brought to room temperature within 1 hour, 6 ml of methanol are added and 120 ml of 2N sulfuric acid are carefully added (evolution of hydrogen). After stirring for 1 hour at room temperature, the precipitated crystals are filtered off with suction and washed twice with water and once with methylene chloride. Drying under high vacuum gives 0.16 g (39.7% of theory) of product as hydrogen sulphate. Melting point: 160-170℃ Optical rotation: [α] ²⁰ = 26.36° (CH ₃ OH/H ₂ 0 = 80:
20) Example 64 3-amino-1,2,3,4-tetrahydrocarbazole (enantiomer A) [The compound of Example 64 prepared by Method B is
Same as Example 59. ] 10 g of hydrogen sulfate obtained in Example 53 was suspended in 50 ml of methanol to convert it to hydrochloride.
30 ml of 2N sodium hydroxide solution are added and the mixture is extracted with ethyl acetate. The organic phase was evaporated and the residue was dissolved in 50 ml methanol and 20 ml
of concentrated hydrochloric acid. Upon concentration under vacuum, the hydrochloride salt precipitates out. After suction filtration, wash with water,
Drying in vacuo gives 7.6 g of hydrochloride.
7.6 g (0.023 mol) of this hydrochloride was added to 7.17 g (0.115 mol) of ammonium formate and activated carbon for 10 min.
% supported palladium in 80 ml of dry dimethylformamide and heated under reflux (under nitrogen) for 20 minutes. After cooling, the mixture is diluted with water and the catalyst is filtered off with suction and washed with water.
The filtrates are collected, acidified with 2N sulfuric acid, and extracted twice with ethyl acetate. The aqueous phase is made alkaline with 2N sodium hydroxide solution and extracted three times with ethyl sulfate.
The organic phase is dried over sodium sulphate and evaporated.
The residue is further evaporated under high vacuum to remove dimethylformamide. 3g (70% of theoretical amount)
The crystalline enantiomer A of is obtained from ether. Melting point: 160-168℃ Optical rotation [α] ²⁰ = 78.38° (DMSO + 10% water) Example 65 3-(4-fluorophenylsulfonamide)-
1,2,3,4-tetrahydrocarbazole (enantiomer A) 3.72 g (0.02 mol) of the product of Example 59 was added to 30 ml with 3 ml (0.022 mol) of triethylamine.
of methylene chloride, and while cooling, add 3.9 g (0.02 g) of 4-fluorobenzenesulfonyl chloride.
mol) is added. The reaction mixture is stirred for 1 hour at room temperature, then stirred with 200 ml of ethyl acetate and extracted twice with 2N sulfuric acid and twice with 2N sodium hydroxide solution. The organic phase is dried over sodium sulphate and evaporated. The solid residue is crystallized by adding ether. 5.8 g (84% of theory) of product are obtained. Melting point: 150-152°C Optical rotation: [α] ²⁰ = 50.43° (CHCl ₃ ) Example 66 3-(4-fluorophenylsulfonamide)-
1,2,3,4-tetrahydrocarbazole (enantiomer B) Enantiomer B is prepared from the product of Example 60 in a manner analogous to the preparation of Example 65 from the compound of Example 59. Melting point: 150-152°C Optical rotation: [α] ²⁰ = -48.99° (CHCl ₃ ) Example 67 3-[N-(4-fluorophenylsulfonyl)
amino]-9-(2-cyanoethyl)-1,2,
3,4-tetrahydrocarbazole (enantiomer A) 5.16 g (0.015 mol) of the product of Example 65 were dissolved in 200 ml of dimethylformamide under nitrogen,
0.5g (0.0165mol) of sodium hydride at 20%
Add little by little along with spindle oil. Once hydrogen evolution is complete, 2 ml (0.03 moles) of acrylonitrile are added to the reaction mixture. After stirring at room temperature for 1 hour, acrylonitrile 0.5
ml is added again and the mixture is stirred at room temperature for 1 hour. Dilute with 1 part of ethyl acetate and extract three times with water. The ethyl acetate phase was dried with sodium sulfate,
Evaporate. In this way 7.8 g of crude product are obtained. Add this to 150g of silica gel (0.063~
0.2 mm) and 1:1
Elute with a toluene/ethyl acetate mixture in a ratio of .
A fraction is obtained which, after evaporation, gives 5.8 g (86% of theory) of product as a solid foam. Biscyanoethyl adduct (3-[N-(4-fluorophenylsulfonyl)-N-(2-cyanoethyl)amino]-9-(2-cyanoethyl)-1,
2,3,4-tetrahydrocarbazole) is prepared under the conditions shown in Example 6. Example 68 3-[N-(4-fluorophenylsulfonyl)
-N-(2-cyanoethyl)amide]-9-(2
-cyanoethyl)-1,2,3,4-tetrahydrocarbazole (enantiomer B) The compound of Example 68 is prepared from the product of Example 66 in a manner analogous to the preparation of Example 67 from the compound of Example 65. Example 69 (+)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,
3,4-tetrahydrocarbazole 5.8 g (0.0128 mol) of the product of Example 67 was added to 60
ml of isopropanol, 130 ml of 10% strength potassium hydroxide solution are added and, after heating under reflux for 16 hours, the mixture is cooled, diluted with water and extracted with ethyl acetate. The aqueous phase is concentrated in vacuo and then acidified by dropwise addition of concentrated sulfuric acid with vigorous stirring. The acid precipitated during this time is filtered off with suction, washed with water and thoroughly dried in vacuo.
4.4 g (86.6% of theory) of product are obtained. Melting point: 85-95°C Optical rotation: [α] ² = 42.55° (CHCl ₃ ) Example 70 (-)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1, 2,
3,4-tetrahydrocarbazole The compound of Example 70 is prepared from the product of Example 68 in a manner analogous to the preparation of Example 69 from the compound of Example 67. Melting point: 85-95°C Optical rotation: [α] ²⁰ = -37.83° (CHCl ₃ ) Example 71 (+)-3-Amino-1,2,3,4-tetrahydrocarbazole 18.6 g (0.1 mol) of racemic 3-amino-1,2,3,4-tetrahydrocarbazole (+)-
Heat under reflux with 15.2 g (0.1 mol) of mandelic acid in 100 ml of tetrahydrofuran. Once a clear solution was obtained, it was cooled and a spatula full of (+)-mandelate of (+)-3-amino-1,2,3,4-tetrahydrocarbazole (enantiomer A, Example 59) was added. Add as seed crystals. The mixture is stirred overnight and the precipitated crystals are filtered off with suction. In this way 6.05 g of enantiomerically enriched material are obtained. this crystal
Dissolve 4.7 g in 330 ml of boiling methyl isobutyl ketone, and after cooling slightly add seeds to this solution and stir while continuing to cool. After filtering off with suction and washing with methyl isobutyl ketone, 3.4 g of (+)-3-amino-1,2,3,4-tetrahydrocarbazole are obtained as the (+)-mandelate salt. Example 72 Blood from healthy individuals of both sexes was used to measure the platelet aggregation inhibitory effect. One part of a 3.8% strength aqueous solution of sodium citrate to nine parts of blood is mixed as an anticoagulant. This blood is centrifuged to obtain platelet-rich citric blood plasma (PRP) (Jurgens/Beller, Clinical Assay for Blood Coagulation (Klinische Methoden).
der Blutgerinnungsanalyse); Thieme, Stuttgart, 1959). For this study, 0.8 ml of PRP and 0.1 ml of active compound solution are prewarmed in a water bath at 37°C. Subsequently, platelet aggregation was measured at 37°C by the turbidity method using an aggregometer (GVR Born, J. Physiol.
(London)), 162 , 1962 and Therapeutische Berichte 47 , 80-86,
1975). For this purpose, the aggregation inhibitor collagen 0.1
ml to the prewarmed sample. The change in optical density of the PRP sample is recorded for 6 minutes and the change is measured after 6 minutes. For this purpose, the percentage inhibition is calculated in comparison with the control example. Cycloalkano[1,2-b] Limit Inhibition Indole Sulfonamide Limit Concentration Example No. (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 The results of the acute toxicity test are shown below. LD ₅₀ value (mouse) [mg/Kg] Oral 1 R ¹ = H LD ₅₀ = 1000-1250 R ² = 4-F-phenyl X = 2 Y = 0 2 R ¹ = H LD ₅₀ = 1200 R ² = 4 -F ₃ C-phenyl X=2 Y=0 3 ^{R 1} =H LD ₅₀ = 1000 ^{R 2} = 4-F _- phenyl =4-F-phenyl X=2 Y=0

Claims (1)

[Claims] 1 formula In the formula, R ¹ represents hydrogen, halogen or C ₁ -C ₄ -alkyl, and R ² can also be mono- or di-substituted by halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl. represents a certain phenyl, x represents the number 1 or 2, y represents the number 0 or 1, and cycloalkano [1,2
-b] Indole sulfonamide or a salt thereof. 2 formulas In the formula, R ¹ represents hydrogen, fluorine or methyl, R ² represents phenyl substituted with fluorine, chlorine, trifluoromethyl, methyl, ethyl, propyl or isopropyl, and y represents the number 0 or 1 (+) of the cycloalkano[1,2-b]indole sulfonamide according to claim 1 of
or (-) isomer or salt thereof. 3 (+)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,
The cycloalkano[1,2-
b] Indole sulfonamide. 4 (-)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,
The cycloalkano[1,2-
b] Indole sulfonamide. 5 formula In the formula, R ¹ represents hydrogen, halogen or C ₁ -C ₄ -alkyl, and R ² can also be mono- or di-substituted by halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl. [benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole representing a certain phenyl, x represents the number 1 or 2, and y represents the number 0 or 1, in the presence of an inert solvent, as appropriate is reacted with acrylonitrile in the presence of a base, and then this N,N'-biscyanoethyl compound is hydrolyzed to produce a cycloalkano[1,2-b]dihydroindolesulfonamide. The cycloalkano[1,2-b]indole sulfonamide is hydrogenated in the presence of an acid and a reducing agent, optionally in the presence of an inert solvent, the isomers separated by conventional means, and then the salt When producing a formula characterized by carrying out a reaction with a suitable base In the formula, R ¹ , R ² , x and y are cycloalkano[1,2
-b] A method for producing indole sulfonamide or a salt thereof. 6. The process according to claim 5, characterized in that the reaction between [benzenesulfonamidoalkyl]-cycloalkano[1,2-b]indole and acrylonitrile is carried out at a temperature in the range of 0 to 150°C. . 7. Claims 5 and 6, characterized in that acrylonitrile and [benzenesulfonamidoalkyl]-cycloalkano[1,2-b]indole are used in a ratio of 1 to 20 moles to 1 mole. Any method described. 8 formula In the formula, R ¹ represents hydrogen, halogen or C ₁ -C ₄ -alkyl, and R ² can also be mono- or di-substituted by halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl. represents a certain phenyl, x represents the number 1 or 2, y represents the number 0 or 1, and cycloalkano [1,2
-b] A platelet aggregation inhibitor containing indole sulfonamide or a salt thereof as an active ingredient. 9. Claim 8 containing 0.5 to 50% by weight of the above cycloalkano[1,2-b]indole sulfonamide and/or its salt.
Drugs listed in section.