CS276468B6 - Method of production of new (phenylsulfonamidoalkyl)- and (phenylsulfonamidocycloalkano)-|1,2-b¨-indoles - Google Patents

Abstract

New compounds of formula XIII wherein R 1 is hydrogen, fluoro, chloro or methyl, R 1 is phenyl which is optionally once or twice substituted with halogen or trifluoromethyl, x is the number I or 2 and y is the number 0 or 1 are being prepared by getting on phenylhydrazines of formula XIV act with cycloalkane sulfonamides of formula XV in the presence inert solvents, optionally in the presence catalyst. Produced compounds serve as intermediates for production pharmacology of active cycloalkanophils, 2- -bj indoleulfonamides.

Description

in which

R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, p

R represents a phenyl group which is optionally substituted once or twice by a halogen atom or a trifluoromethyl group, x represents the number 1 or 2 and y represents the number 0 or 1, which may exist in isomeric form or in the form of the corresponding salts.

The novel [phenylsulfonamidoalkyl] and are carried out according to the process of the invention, E-phenylsulfonamido [1,2-b] indoles, which correspond to the general formula ΣΙΙΙ

(XIII), in which

R · * · represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group,

R 1 represents a phenyl group which is optionally substituted once or twice by a halogen atom or a trifluoromethyl group, x represents the number 1 or 2a.

y is the number 0 or 1,

CS 276468 B6 2 and optionally in isomeric form serve as intermediates for the preparation of the above-mentioned cycloalkano [1,2-b] indolesulfonamides of the general formula I.

The novel [phenylsulfonamidoalkyl} - and phenylsulfonamido cycloalkano, 2-bJ indoles of formula XIII have several asymmetric carbon atoms and can therefore exist in different stereochemical forms. The scope of the present invention includes both the process for the preparation of the individual isomers and the process for the preparation of their mixtures.

Examples of enantiomerically pure (phenylsulfonamidoalkyl) and (phenylsulfonamido) cyclohexano [1,2-b] indoles are the compounds of formula XIIIa below.

(XHIa), 'in which 12,,,

R and R are as defined above.

These compounds are also novel and their preparation is within the scope of this invention.

Halogen is generally understood to mean fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Particularly preferably, the halogen atom represents a fluorine atom or a chlorine atom.

The present invention relates to a process for the preparation of novel phenylsulfonamidoalkyl] - and / or phenyleulfonamido] cycloalkano [1,2-b] indoles of the general formula XIII, which comprises applying to the phenylhydrazines of the general formula XIV

(XIV), in which,

R 5 has the meaning given above, it acts cycloalkanonesulfonamides of the general formula XV

(XV), in which p,, ‘

R, x and Y are as defined above, in the presence of inert solvents, optionally in the presence of a catalyst.

The preparation of {phenylsulfonamidoalkyl] - and (phenylsulfonaminocycloalkanof1,2-b] indoles of formula XIII by the process of this invention can be illustrated by the following reaction scheme

Here, the solvents for the process according to the invention can be inert organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, n-propanol, isopropyl alcohol, glycol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol mono- or dimethyl ether, halogenated hydrocarbons, such as di-, tri- or carbon tetrachloride, dichloroethylene, trichloromethylene, ethyl acetate, toluene, acetonitrile, glacial acetic acid, phosphorus hexamethyltriamide η »

CS 276468 Β6 4 acids, pyridine and acetone. Of course, it is also possible to use mixtures of these solvents.

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

The process according to the invention is generally carried out in the temperature range from 0 ° C to 200 ° C, preferably from 20 ° C to 150 ° C. The process according to the invention is generally carried out at atmospheric pressure. It is also possible to work under reduced pressure or at elevated pressure (for example in the range from 0.05 to 0.5 MPa).

In general, hydrazine is used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on the ketone.

The following compounds are used, for example, as phenylhydrazines of the formula XIV, which serve as starting materials for the process according to the invention:

phenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-methylphenylhydrazine.

Suitable ketones of the formula XV, which are also used as starting materials for the process according to the invention, are, for example, the following compounds:

3- (phenylsulfonamidomethyl) cyclopentanone,

3- (phenylsulfonamidomethyl) cyclohexanone,

4- (phenylsulfonamidomethyl) cyclohexanone,

3- (phenylsulfonamido) cyclopentanone,

3-phenylsulfonamido) cyclohexanone,

4- (phenylsulfonamido) cyclohexanone,

3- (4-chlorophenylsulfonamidomethyl) cyclopentanone, 3- (4-fluorophenylsulfonamidomethyl) cyclopentanone, 3- (phenylsulfonamidomethyl) cyclopentanone, 3- (4-chlorophenylsulfonamidomethyl) cyclohexanone, 3- (4-fluorophenylsulfonamidomethyl) cyclohexanone, 4- (4-chlorophenylsulfonamidomethyl ) cyclohexanone, 4- (4-fluorophenylsulfonamidomethyl) cyclohexanone, 3- (4-chlorophenylsulfonamido) cyclopentanone, 3- (4-fluorophenylsulfonamido) cyclopentanone, 3- (4-chlorophenylsulfonamido) cyclohexanone, 3- (4-fluorophenylsulfonamido) cyclohexanone , 4- (4-chlorophenylsulfonamido) cyclohexanone and 4- (4-fluorophenylsulfonamido) cyclohexanone.

The phenylhydrazines of the formula XIV which are used as starting materials are known or can be prepared by known methods (cf. Houben-Weyl, Methoden der organischen Chemie, X / 2, pp. 1, 123, 693).

Cycloalkanone sulfonamides of the general formula XV

(CH ₂ ) _y -NH-SO ₂ -R ² (XV), in which, x, y and R have the meanings given above, which are also used as starting materials for the process according to the invention, are novel compounds. A process for the preparation of these compounds is described in the description of the invention for Czechoslovakia. No. 276,469.

The preparation of phenylsulfonamidoalkyl] - and / or phenylsulfonaminocycloalkanoyl-1,2-bindoles can be illustrated by the following reaction scheme:

+ h ₃ cno ₂ degree a)

degree b)

HalSO ₂ -R ² degree c)

CS 276468 Β6

In the first step a) the cycloalkenones are reacted in inert solvents such as alcohols, for example methanol, ethanol, propanol or ethers, for example diethyl ether, tetrahydrofuran or dioxane, or in chlorinated hydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride. in the presence of bases such as sodium hydride, sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, tert-potassium butoxide, 1,5-diazabicyclo {4,3,5-one-5-ene, 1,5-diazabicyclo [5, 4, o] undec-5-ene, pyridine or triethylamine with nitro derivatives, such as nitromethane, at temperatures ranging from 0 ° C to 100 ° C to give the corresponding nitro derivatives.

In step b) the nitro derivatives are reduced in an inert solvent such as ethers, for example tetrahydrofuran, dioxane or diethyl ether, in the presence of a reducing agent such as hydrides, for example lithium aluminum hydride, Na 2 CO 2 CH 2 CH 2 O 2 / HCl or diisobutylaluminum hydride at temperatures ranging from -20 ° C. to +60 ° C to form cycloalkanols.

In step c), the cycloalkanols are converted by treatment with sulfonic acid halides in inert solvents such as ethers, for example dioxane, tetrahydrofuran or diethyl ether, or in chlorinated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride or ethyl acetate or pyridine, optionally in the presence of bases. as 1,5-diazabicyclo [4.3.0] non-5-ene, 1,5-diazabicyclo [5.4.0] undec-5-ene, pyridine or triethylamine at temperatures from -20 ° C to +60 ° C to sulfonamides. .

In step d) the sulfonamides are oxidized in inert solvents such as water, glacial acetic acid, acetone, pyridine or mixtures thereof by the action of oxidizing agents such as chromium compounds, for example chromium oxide, potassium dichromate, sodium dichromate, at temperatures from -20 ° C to +100 ° C to form cycloalkanonesulfonamides.

In step e), the cycloalkanonesulfonamides (XV) and the hydrazines of formula XIV are reacted as described above to give the corresponding benzenesulfonamidoalkyl-cycloalkanof1,2-bj indoles of formula XIII.

in which 12 ',,

R, R, X and y are as defined above.

Ehantiomerically pure benzenesulfonamido} cyclohexano [1,2-b] indoles of formula XIIIa

in which 12 * *,

R and R are as defined above, they are also novel compounds.

The enantiomerically pure benzenesulfonamide cyclohexano [1,2-b] indoles of formula XIIIa and e according to the invention are prepared by reacting the enantiomerically pure cyclohexano [1,2-b] indolines of formula XX

H in which

R · ¹ is as defined above, b is sulfonic acid halides of formula XVII

Hal - S0 ₂ - R ² (XVII), vs in which o

R is as defined above and

Hal means fluorine, chlorine, bromine, iodine, preferably chlorine or bromine, in the presence of inert solvents, optionally in the presence of a base.

Suitable solvents for this process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane, or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene, , or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, phosphoric acid hexamethyltriamide, acetonitrile, acetone or nitromethane.

It is also possible to use mixtures of these solvents.

The bases for this process can be the customary basic compounds. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal hydrides, such as sodium hydride, or alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate. sodium bicarbonate, potassium carbonate or calcium carbonate, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide or target, potassium butoxide, or alkali metal amides such as lithium diisopropylamide or lithium amide, or organic amines such as ethyldiisopropylamine , benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, dimethylaminopyridine, triethylamine, N-methylpiperidine, 1,5-diazabicyclo {4.3, one-5-ene or 1,5-diazabicyclop, 4,0-unec-5-ene.

The process described above is generally carried out in the temperature range from -30 ° C to + 150 ° C, preferably in the temperature range from -20 ° C to + 80 ° C.

Furthermore, the above procedure is generally carried out at atmospheric pressure. It is also possible to operate at reduced pressure or at elevated pressure, for example in the range from 0.05 to 20.0 MPa.

Enantiomerically pure cyclohexano [1,2-b] indollamines of formula XX are novel compounds and can be prepared according to the following basic syntheses A, B or C.

Synthesis A

(XXI) level 1

separation of individual diastereomers step 4 (XXIV) mixture of diastereomers

whereas

R ¹ is as defined above and p

R represents an enantiomerically pure D- or L-amino acid residue, preferably a 2S- (chloroacetamido) -3-phenylpropionyl residue.

Synthesis B

where r! has the meaning given above.

Synthesis A

According to this method, paracetamol of formula XXI is hydrogenated in the presence of Raney nickel to a cis / trans mixture of 4-acetamidocyclohexanol of formula XXII as described by Billman, J. H., Biihler, J. A., in J. Am. Chem. Soc. 75. 1345 (1953) In step 2), the 4-acetamidocyclohexanol of formula XXII is subjected to a Fischer indole synthesis in a one-step procedure by the action of oxidizing agents such as phenylhydrazines of formula XIV and then the acetyl group is removed by hydrolysis under acidic conditions.

This step of the process is carried out in a solvent, such as water, acetic acid and / or propionic acid, at temperatures from 0 ° C to + 150 ° C, preferably at temperatures from 0 ° C to 110 ° C. The racemic 3-amino-1,2,3,4-tetrahydrocarbazoles of the formula dobře which are readily available in this way are converted in step 3) by coupling with enantiomerically pure amino acids, optionally in their activated form, into the corresponding diastereomeric mixtures, which can be converted by customary methods such as crystallization. or by column chromatography to separate the individual diastereomers. .

Suitable enantiomerically pure amino acid derivatives are preferably acetylenenylalanine, N-tert-butoxycarbonylphenylalanine, chloroacetylphenylalanine, benzoxycarbonylphenylalanine, methoxyphenylacetic acid or acetoxyphenylacetic acid, preferably N-chloroacetyl-N-phenylalenine.

As activating agents, generally customary peptide coupling agents are used. These preferably include carbodiimides, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, or N- (N-dimethylaminoisopropyl-N, 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 acid anhydride, or isobutyl chloroformate or benzotriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate or methanesulfonic acid chloride, optionally in the presence of a base such as triethylamine or N-ethylmorpholine , or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The coupling is generally carried out in inert organic solvents, preferably in chlorinated hydrocarbons, such as methylene chloride or chloroform, or in hydrocarbons, such as benzene, toluene, xylene or petroleum fractions, or in ethers such as dioxane, tetrahydrofuran or diethyl ether, or ethyl acetate, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile or nitromethane at temperatures from -80 ° C to + 50 ° C, preferably from -40 ° C to + 30 ° C.

After separation of the mixtures of diastereomers of the formula XXIV, in step 4) the individual diastereomers are hydrolyzed under acidic conditions to the enantiomerically pure amines of the formula XX.

This hydrolysis is generally carried out by the action of 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 of said acids.

The solvents used are generally water or an aqueous solution of the acid or mixture of acids used.

The hydrolysis is generally carried out in the temperature range from + 20 ° C to + 150 ° C, preferably from + 20 ° C to + 120 ° C.

The process according to the invention is generally carried out at atmospheric pressure. It is also possible to operate at reduced or elevated pressure, for example in an autoclave or in a sealed tube.

It has proven advantageous to use thioglycolic acids as an additive to the reaction mixture as an oxidation inhibitor.

Synthesis B:

According to the principle of said synthesis, a 1,4-cyclohexanedione monoethylene ketal of formula XXV is reacted with phenylhydrazines of formula XIV in a Fischer indole synthesis to give ketals of formula XXVI as described by A. Britten and G. Lockwood in J. Chem. Soc., Perkin. Trance. 1, 1274, 1824-1827.

Hydrolysis of the ketals of formula XXVI in step 2 yields ketones of formula XXVII, which in step 3 are converted by reductive amination with S-phenethylamine to a mixture of diastereomers of formula XXVIII.

The reductive amination is generally carried out by the action of reducing agents such as hydrogen, optionally in the presence of palladium, platinum or palladium on activated carbon as catalyst, or complex hydrides, preferably sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium aluminum borohydride, aluminum hydride; diisobutylaluminum hydride, lithium triethyl hydride borohydride, sodium cyanobrihydroborate, tetrabutylammonium cyanobrihydroborate, tetrabutylammonium borohydride, lithium aluminum hydride, sodium bis- (2-methoxyethoxy] dihydroaluminate or lithium hydrodicitrile solvents such as , 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 or isopropyl alcohol, at temperatures in range from -80 ° C to +100 ° C, preferably at temperatures from -80 ° C to +50 ° C.

The mixture of diastereomers of the formula XXVIII is separated into the individual diastereomers by customary methods, such as chromatography or crystallization, preferably crystallization, optionally in the form of suitable acid addition products. '

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

Removal of phenylethyl groups in the separated distereomers of formula XXVIII is performed in step 4 by catalytic hydrogenation to give enantiomerically pure amines of formula XX.

Step 4 is generally carried out using reducing agents such as hydrogen, optionally in the presence of palladium on carbon or platinum, or ammonium formate in inert solvents such as alcohols, for example methanol, ethanol, propanol or isopropyl alcohol, or dimethylformamide or dimethylsulfoxide at temperatures in range from 0 ° C to + 200 ° C, preferably at temperatures from + 20 ° C to + 150 ° C (cf. LE Overmann and S. Sugai, J. Org. Ohem. 50. 4154-4155 (1985)).

Synthesis 0:

According to the principle of this synthesis, the racemate of the compounds of formula XXIII is resolved by forming salts with optically active acids and crystallizing these salts once or several times from suitable solvents. The enantiomerically pure compounds of formula XXIII are liberated from the salts thus obtained by treatment with base.

Suitable optically active acids are:

(+) - camphorsulphonic acid, (-) - camphorsulphonic acid, (+) - camphor-3-carboxylic acid, (-) - camphor-3-carboxylic acid, (+) - camphoric acid, (-) - camphoric acid, - (-) - malic acid, (+) - mandelic acid, (-) - mandelic acid, (+) - lactic acid, (-) - lactic acid, (-) - 2 - f (phenylamino) carbonyloxy] propionic acid, ( _) - <2-Niethoxyphenylacetic acid, (-) - di-O-benzoyltartaric acid, (-) - di-O-4-toluoyltartaric acid, (-) - methoxyacetic acid, (-) - 1,1-binaphthyl- 2,2-dihydrogen phosphate.

Suitable solvents for the crystallization are solvents such as water, alcohols, such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, sec-butanol, tert, butanol, ethers, such as diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform, or ethyl acetate, acetonitrile, nitromethane, dimethyl sulfoxide, dimethylformamide, sulfolane. It is also possible to use mixtures of these solvents.

The bases for this process can be the customary basic compounds. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as 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 alkoxides, such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or a target, potassium butoxide.

The process according to the invention is further illustrated in the following section. However, the examples do not limit the scope of the invention in any way.

Examples of design:

Example 1

3- (nitromethyl) cyclopentanone

100 g of 2-cyclopentenone ae together with 666 ml of nitromethane and 5 g of 1,5-diazabicyclo [4.3, θ] non-5-ene (DBN) are dissolved in 1.1 liters of isopropyl alcohol and the solution is allowed to stand at room temperature. for 5 hours. The isopropyl alcohol is then distilled off as far as possible under reduced pressure, the residue is dissolved in ethyl acetate and the solution obtained is washed twice with 0.5 liter of dilute sulfuric acid each time. The organic phase is dried over sodium sulfate and evaporated. 154 g (88% of theory) of 3- (nitromethyl) cyclopentanone are thus obtained, which is sufficiently pure for the next reaction.

Rf = 0.52 (99: 1 mixture of methylene chloride and methanol).

Example 2

3- (aminomethyl) cyclopentanol

HIM

NHj

57.2 g (0.4 mol) of 3- (nitromethyl) cyclopentanol are dissolved in 573 ml of absolute tetrahydrofuran under a nitrogen atmosphere. A solution of 800 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran is added dropwise to this solution at 0 ° C. After completion of the dropwise addition, the reaction mixture was further stirred at 0 ° C for 1 hour. Then, the cooling bath was removed, and the temperature of the reaction solution was raised to 40 ° C. After the temperature dropped to 20 ° C, the reaction mixture was further stirred at this temperature for 1 hour. To the reaction mixture cooled to 0 ° C was then carefully added dropwise 100 ml of 45% sodium hydroxide solution. After completion of the dropwise addition, the reaction mixture was further stirred at room temperature for 1 hour, then the reaction mixture was filtered through celite and the celite was washed with 1.5 liters of tetrahydrofuran. The combined filtrates were evaporated thoroughly under reduced pressure. 22.5 g (49% of theory) of a viscous, oily product are thus obtained.

= 0.01 (solvent system; mixture of methylene chloride and methanol in a ratio of 9: 1).

Example. 3

3- (benzenesulfonamidomethyl) cyclopentanol

g (0.078 mol) of 3- (aminomethyl) cyclopentanol are dissolved together with 13.8 g = 10 ml (0.078 mol) of triethylamine in 200 ml of tetrahydrofuran. 7.9 g = 10.8 ml (0.078 mol) of benzenesulfonic acid chloride are then added dropwise at 0-5 [deg.] C. After completion of the dropwise addition, the reaction mixture was further stirred at 0 ° C for 1 hour. The reaction mixture is then diluted with 200 ml of methylene chloride and washed twice with 150 ml of dilute sulfuric acid each time. The organic phase is then extracted twice with 150 ml of 2N sodium hydroxide solution each time, the combined extracts are acidified with concentrated hydrochloric acid and extracted twice with 150 .mu.l of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under reduced pressure. 9.1 g (39% of theory) of a viscous, oily mixture of isomers are thus obtained as product.

Rf = 9-51 and 0.45 (solvent system: mixture of methylene chloride and methanol in a ratio of 95-5).

Example 4

3- (benzenesulfonamidomethyl) cyclopentanone

7.5 g (0.0294 mol) of 3- (benzenesulfonamidomethyl) cyclopentanol are dissolved in 60 ml of glacial acetic acid. A solution of 2.79 g (0.0279 mol) of chromium oxide in 2 ml of water and 8.8 ml of glacial acetic acid is added dropwise at 0 DEG to 5 DEG C. and then the temperature of the reaction mixture is allowed to rise to room temperature. After stirring for 1 hour at room temperature, the reaction mixture is diluted with 200 ml of ether and washed twice with 150 ml of water each time. The organic phase is then extracted twice with 200 ml of 2N sodium hydroxide solution each time, the combined phases in sodium hydroxide solution are acidified with concentrated hydrochloric acid and extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under reduced pressure. 4.4 g (59% of theory) of a viscous, oily product are thus obtained.

and 0.51 (solvent system: mixture of methylene chloride and methanol in the ratio, 95: 5).

Example 5 1- (Benzenesulfonamidomethyl) cyclopentano [1,2-b] indole

g (0.0826 mol) of 3- (benzenesulfonamidomethyl) cyclopentanone are dissolved together with 9 g (0.0826 mol) of phenylhydrazine in 200 ml of glacial acetic acid and the solution obtained is heated to reflux for 4 hours. dilute 1.3 liters of ether and add 500 ml of water. With cooling and stirring, the reaction solution was basified by adding 45% sodium hydroxide solution, after which the organic phase was separated. The aqueous phase is extracted once more with 500 ml of ether, the combined organic phases are dried over sodium sulfate and evaporated. The residue thus obtained is chromatographed on 2 kg of silica gel (Merck, particle size 0.04 to 0.063 mm) using a mixture of toluene and ethyl acetate in a ratio of 85:15 as eluent. This gives a fraction which, after evaporation, gives 1.9 g (7% of theory) of crystalline product. Melting point 161-164 ° C. ·

Rf = 0.92 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 6

3- (4-fluorophenylsulfonamidomethyl) cyclopentano

In a manner analogous to that described in Example 3, 19.8 g (0.172 mol) of 3- (aminomethyl) cyclopentanol were reacted with 28.3 g (0.172 mol) of 4-fluorophenylsulfonamide. 17.3 g (36% of theory) of a viscous, oily mixture of isomers are obtained as the reaction product.

Values of 0.53 and 0.46 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 7

3- (4-fluorophenylsulfonamidomethyl) cyclopentone

OS 276463 B6

In a manner analogous to that described in Example 4, 17.3 g (0.0638 mol) of 3- (4-fluorophenylsulfonamidomethyl) cyclopentanol were oxidized. 14.3 g (83% of theory) of a viscous, oily product are obtained.

Value = 0.76 (solvent system: 9: 1 mixture of methylene chloride and methyl alcohol).

Example 8

1- (4-fluorophenylsulfonamidomethyl) cyclopentano [1,2-b] indole

In a manner analogous to that described in Example 5, 14.3 g (0.0527 mol) of 3- (4-fluorophenylsulfonamidomethyl) cyclopentanone were reacted with phenylhydrazine. 0.67 g (3.7% of theory) of microcrystalline product is thus obtained after chromatography on silica gel.

Rf value 0.47 (solvent system: 99: 1 mixture of methylene chloride and methanol).

Example 9

3- (4-chlorophenylsulfonamidomethyl) cyclopentanol

CS 276463 N6

16.8 g (0.146 mol) of 3- (aminomethyl) cyclopentanol are reacted in a manner analogous to that described in Example 3 with 4-chlorophenylsulfonic acid chloride. 16.6 g (39% of theory) of a viscous, oily product are thus obtained in the form of a mixture of isomers.

Value a 0.46 and 0.44 (solvent system: 95: 5 mixture of methylene chloride and methyl alcohol).

Example 10 '

3- (4-chlorophenylsulfonamidomethyl) cyclopentanone

In a manner analogous to that described in Example 4, 16.6 g (0.0573 mol) of 3- (4-chlorophenylsulfonamidomethyl) cyclopentanol were oxidized. 13.8 g (83.7% of theory) of a viscous, oily product are thus obtained.

R value _f = 0.7 (solvent system: 95: 5 mixture of methylene chloride and methyl alcohol)

Example 11 1- (4-Chlorophenylsulfonamidomethyl) cyclopentano-1,2-bJ-indole

13.8 g (0.048 mol) of 3- (4-chlorophenylsulfonamidomethyl) cyclopentanone are reacted with phenylhydrazine in a manner analogous to that described in Example 5. 1.65 g (9.5% of theory) of product are obtained after chromatography on silica gel. in the form of a solid foam.

Rf value 0.46 (solvent system: 99: T mixture of methylene chloride and methanol).

Example 12

4- (benzenesulfonamido) cyclohexanol

g (0.6 mol) of 4-aminocyclohexanol are reacted with 107 g (0.6 mol) of benzenesulfonic acid chloride in a manner analogous to that described in Example 3. 72.8 g (47% of theory) of crystalline product are thus obtained. Melting point 106-108 ° C.

Es _Rf value of 0.38 (solvent system: methylene chloride-methanol 95: 5).

Example 13

4- (benzenesulfonamido) cyclohexanone

CS 276468 B6 20

72.8 g (0.285 mol) of 4- (benzenesulfonamido) cyclohexanol are oxidized in a manner analogous to that described in Example 4- After crystallization from petroleum ether, 57.5 g (80% of theory) of product are obtained, m.p. 80-82 ° C.

Value = 0.66 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 14

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

57.5 g (0.227 mol) of 4- (benzenesulfonamido) cyclohexanone are reacted in an analogous manner to that described in Example 5 with phenylhydrazine. 41.5 g (56% of theory) of product are thus obtained, which crystallizes from isopropyl alcohol. Melting point 155 ° C.

Rf = 0.82 (solvent system: 95: 5 mixture of methylene chloride and methanol) ·

In a manner analogous to that described in Example 12, the compounds listed in Table 1 were prepared:

Table 1

example number X yield value of R _f 15 Cl 80% 0.37 (solvent system: CH ₂ Cl ₂ : CH 2 OH and 95: 5) 18 P 75% 0.4 (solvent system: CH ₂ Cl ₂ : CH ₃ OH = 95 ί 5) 21 CH ₃ 48.7% 0.5 (solvent system: CH ₂ Cl ₂ : CH ₃ OH = 95: 5)

In a manner analogous to that described in Example 13, the compounds listed in Table 2 below were prepared:

Table 2

example number X yield value R ^. (solvent system) melting point (° C) 16 01 86% 0.77 103 to 104 _{CH 2} Cl 2: CH 2 OH = 9: 1 (from petroleum ether) 19 F 94% 0.7 104 to 108 C ₁₂ : CH ₃ OH = 9: 1 (from petroleum ether) 22 OH, 90.7% 0.57 CH ₂ Cl ₂ : CH ₃ OH = 95: 5

In a manner analogous to that described in Example 14, the compounds in Table 3 were prepared:

H

Table 3

example number X yield value R ^ (solvent system) melting point (° C) 17 Cl 75.4% 0.52 (mixture of toluene and ethyl acetate 8: 2) 163 (from ether) 20 F 73% 0.39 (mixture of methylene chloride and methanol 99: 1) 146 to 149 (from ether) 23 CH ₃ 55% 0.42 (mixture of methylene chloride and methanol 8: 2) 136 to 138 (from isopropyl alcohol)

OS 276468 B6

Example 24

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

26.5 g of 4- (4-chlorophenylsulfonamido) cyclohexanone are reacted analogously to Example 5 with 4-fluorophenylhydrazine. 35.4 g (100% of theory) of product are obtained in the form of a solid foam.

_Rf value = 0.53 (solvent system: ethyl roluenu ethyl acetate 8: 2).

Example 25

3- (nitromethyl) cyclohexanone

21.9 g of cyclohexanone are kept at rest together with 175 ml of nitromethane and 2.1 g of 5-diazabicyclo [4.3.0] non-5-ene (DBN) in 250 ml of isopropyl alcohol for 2 days at room temperature. The work-up is carried out analogously to the procedure given in Example 1 and gives 37.2 g (100% of theory) of 3- (nitromethyl) cyclohexanone which is sufficiently pure for the next reaction. .

_Rf value = 0.62 (solvent system: methylene chloride: methanol = 99: 1).

Example 26

3- (aminomethyl) cyclohexanol

37.2 g of 3- (nitromethyl) cyclohexanone ee are reduced in a manner analogous to that described in Example 2 using lithium aluminum hydride as reducing agent. 7.5 g (24.5% of theory) of viscous, oily 3- (aminomethyl) cyclohexanol are thus obtained.

Rf = 0.04 (solvent system: 9: 1 mixture of methylene chloride and methanol).

Example 27

3- (4-fluorophenylsulfonamidomethyl) cyclohexanol

In a manner analogous to that described in Example 3, 7.5 g of 3- (aminomethyl) cyclohexanol are reacted with 11.3 g of 4-fluorophenylsulfonamide. 11.05 g (66% of theory) of product are thus obtained in the form of a viscous, oily mixture of isomers.

Rf value 0.41 and 0.38 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 28

3- (4-fluorophenylsulfonamidomethyl) cyclohexanone

In a manner analogous to that described in Example 4, 11 g of 3- (4-fluorophenylsulfonamidomethyl) cyclohexanol are oxidized with chromium oxide. 9.3 g (86% of theory) of product are obtained in the form of a solid foam.

_Rf and 0.86 values (solvent system: 9: 1 mixture of methylene chloride and methanol).

Example 29

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

In a manner analogous to that described in Example 5, 9 g of 3- (4-fluorophenylsulfonamidomethyl) cyclohexanone were reacted with phenylhydrazine. 9 g of crude product are obtained, which product is chromatographed on 1 kg of silica gel (Merck, particle size 0.04-0.063 mm) using a mixture of toluene and ethyl acetate in a ratio of 8: 2 as eluent. One fraction yields 0.8 g (7.2% of theory) of product in the form of a solid foam after evaporation.

R _B value of 0.44 (solvent system: toluene-ethyl acetate 8: 2).

Example 30

4-N-ac etamidocyclohexanol

300 g of paracetamol are hydrogenated in 750 ml of ethanol in the presence of 30 g of Raney nickel at a temperature of 180 DEG C. and a pressure of 10.0 MPa. After uptake of hydrogen, the catalyst was filtered off and, after the addition of 3θ g of Raney nickel, the hydrogenation was carried out again at 180 DEG C. and 10.0 MPa. The catalyst is then filtered off, the filtrate is evaporated under reduced pressure and the still wet residue is mixed with 200 ml of acetone and stirred thoroughly. After filtering off the crystals, the mother liquor is further concentrated, separated again from the precipitated crystals and the mother liquor is concentrated again. Together with this 3rd batch, a total of 342.4 g (80.8% of theory) of product is obtained.

Melting point: 100 to 103 ° C. >

Example 31

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

g (0.318 mol) of 4-N-acetamidocyclohexanol are dissolved in 400 ml of glacial acetic acid and a solution of 31.8 g (0.318 mol) of chromium oxide in a mixture of 26 ml of water and 105 ml of glacial acetic acid is added to the solution obtained with stirring at room temperature. . The temperature of the reaction solution rises to 60 [deg.] C. The reaction mixture was further stirred for 3 hours, and then 45.7 g (0.423 mol) of phenylhydrazine was added thereto. The reaction solution is heated to 80 [deg.] C. and nitrogen is initially evolved. The reaction mixture was then heated to reflux for 2.5 hours. After cooling, 500 ml of concentrated hydrochloric acid and 59 ml of thioglycolic acid were added to the reaction mixture, and the reaction mixture was heated under reflux for 16 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with 500 ml of ethyl acetate and basified with 45% sodium hydroxide solution while cooling. Excluded chromium hydroxide

CS 276468 Βδ is filtered off through a pad of celite and washed with a 9: 1 mixture of methylene chloride and methanol. The organic phase is separated from the filtrate and the aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are washed twice with 2N sodium hydroxide solution and then extracted twice with 1 liter of 2N sulfuric acid solution twice in succession. The acidic aqueous phase is basified with 45% sodium hydroxide solution and then extracted three times with 1 liter of methylene chloride each time. The combined methylene chloride phases are dried over sodium phosphate and evaporated. 300 ml of ether and 50 ml of isopropyl alcohol are added to the residue and the mixture is stirred. ^'1 precipitated product was filtered, washed with ether and dried in vacuo. 28.6 g (48.3% of theory) of product are obtained.

Melting point: 174-176 ° C.

Example 32

3- (2S- (chloroacetamido) -3-phenylpropionamido] -1,2,3,4-tetrahydrocarbazole (mixture of diastereomers)

g (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 1.5 liters of methylene chloride under a nitrogen atmosphere and then at room temperature. At 0 DEG C., 115.2 ml (0.832 mol) of triethylamine are added. 150 ml (0.231 mol) of a 50% solution of propanephosphonic acid anhydride in methylene chloride are then added dropwise to the reaction mixture at -20 ° C. The reaction mixture was further stirred at -20 ° C for 30 minutes and then stirred at 0 ° C for 1.5 hours. For working up, the reaction mixture is washed with 1 liter of 2N sulfuric acid solution, 1 liter of water and twice with 1 liter of saturated sodium bicarbonate solution each time. After drying over sodium sulfate and evaporation, 100 g of a solid residue are obtained.

CS 276468 Βδ

Examples 33 and 34

3- [2S- (chloroacetamido) -3-phenylpropionamidol-1,2,3,4-tetrahydrocarbazole (diastereomer A and diastereomer B)

a) Separation of diastereomers by column chromatography

100 g of the crude product from Example 32 are chromatographed on 2.5 kg of silica gel (particle size 0.063 to 0.2 mm, Merck) using a 6: 4 mixture of toluene and ethyl acetate as eluent. Thus, two fractions are obtained, the first of which, after evaporation, gives 34 g (35.9% of theory) of diastereomers A (Example 33). Melting point 217-220 ° C.

The second fraction gives, after evaporation, 24.3 g (25.7% of theory) of the second diastereomer B (Example 34). Melting point 193-195 ° C.

Optical rotation of diastereomers A: (Example 33)

M ²⁰ _to 32.59 ° (methanol)

Optical rotation of diastereomers B: (Example 34) = 5.09 ^° (methanol)

b) Separation of diastereomers by crystallization:

11.5 g of the crude product from Example 32 are stirred in a mixture of ether and isopropyl alcohol. The filtered crystals are heated to reflux in 40 ml of acetone for 3 hours. After cooling and standing overnight, the crystals were filtered off and washed with acetone. 1.2 g (5.5% of theory) of pure diastereomers A (Example 33) are thus obtained.

Example 35

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

nh ₂

CS 276468 Bé

24.1 g (0.059 mol) of the diastereomer from Example 33 are dissolved in 46 ml of glacial acetic acid, 460 ml of concentrated hydrochloric acid and 24 ml of thioglycolic acid are added to the solution obtained and the reaction mixture is heated under reflux for 3 days under nitrogen. cooler. The reaction mixture is then diluted with 200 ml of water and adjusted to pH 5 by adding 45% sodium hydroxide solution while cooling. The mixture is then extracted twice with 1.5 liters of ethyl acetate each time, the aqueous phase is then basified with 45% sodium hydroxide solution and extracted three times with 1 »5 liters of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated. The residue is taken up in 150 ml of ether. The precipitated product is filtered off and dried in vacuo. 7.8 g (71.3% of theory) of enantiomer A are obtained. Melting point 160-166 ° C.

Optical rotation = 78.38 ^° (dimethyl sulfoxide + 10% water).

Example 36

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

Enantiomer B is prepared by hydrolysis of the diastereomer of Example 34 in analogy to the procedure for the preparation of the enantiomer of Example 35 from the diastereomer of Example 33. m.p. 162-167 ° C.

Optical rotation = -78.11 ^° (dimethyl sulfoxide + 10% water).

Example 37

3,3-ethylenedioxy-1,2,3,4-tetrahydrocarbazole

0 ---

H

77.2 g (0.5 mol) of 1,4-cyclohexanedione monoethyl ketal are dissolved together with 48.4 ml (0.5 mol) of phenylhydrazine in 2 liters of methylene chloride, 300 g of magnesium sulphate are added to the solution obtained and the mixture is stirred. for 30 minutes. The magnesium sulfate is then filtered off, washed with methylene chloride and the filtrate is evaporated. The residue is taken up in 1.5 liters of benzene, 62.1 g (0.46 mol) of anhydrous zinc chloride are added and the mixture is heated for 3 hours using a water separator to reflux. The reaction solution was concentrated, 2N sodium hydroxide solution was added to the residue, and extraction was performed three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The residue crystallizes from a small amount of ether. 3.5 g (72.9 theory) of product are thus obtained. Melting point 145-146 ° C.

Example 3θ

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

H

165 g (0.72 mol) of 3,3-ethylenedioxy-1,2,3,4-tetracarbazole are dissolved in 2 liters of acetone and 3 g of p-toluenesulfonic acid are added to the solution obtained. After refluxing for 4 hours, the reaction solution is concentrated, 2 liters of ethyl acetate are added and the extraction is carried out three times with 1 liter of saturated sodium bicarbonate solution each time. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from ether. 118.7 g (89.1% of theory) of product are thus obtained. Melting point 145-148 ° C.

Example 39

3- (1H-phenylethylamino) -1,2,3,4-tetrahydrocarbazole

11.06 g (0.0599 mol) of 1,2,4,9-tetrahydrocarbazol-3-one are heated together with 7.78 g (0.065 mol) of IS-phenylethylamine in 300 ml of benzene for 1 hour using a boiling water separator. under reflux. After evaporating the benzene, the residue was dissolved in 50 ml of methylene chloride, and a solution of 15.3 g (0.0595 mol) of tetrabutylammonium borohydride in 120 ml of methylene chloride was added dropwise to the obtained solution at -50 ° C. The temperature of the reaction mixture is allowed to rise again to room temperature over the course of 1 hour, after which 6 ml of methanol are added and then 120 ml of 2N sulfuric acid solution are carefully added (hydrogen evolution). After stirring for 1 hour at room temperature, the precipitated crystals are filtered off, washed twice with water and once with methylene chloride. After drying under high vacuum, 0.16 g (39% of theory) of product are obtained in the form of the bisulfate.

Melting point 160-170 ° C. . ,

[420 ₌ 26.36 ⁰ (80:20 mixture of methanol and water).

Example 4Q

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

[Example 40, prepared according to Procedure B, is identical to Example 35] The hydrogen sulphate obtained from Example 39 was suspended in 50 ml of methanol to convert it to the hydrochloride, then 30 ml of 2N sodium hydroxide solution were added and extracted with ethyl acetate. The organic phase is evaporated, the residue is dissolved in 50 ml of methanol and 20 ml of concentrated hydrochloric acid are added. Concentration under reduced pressure precipitates the hydrochloride. After filtration, washing with water and drying under reduced pressure, 7.6 g of hydrochloride are obtained. This 7.6 g (0.023 mol) of hydrochloride, together with 7.17 g (0.115 mol) of ammonium formate and 7.2 g of 10% palladium on activated carbon, are heated in 80 ml of absolute dimethylformamide for 20 minutes to reflux ( under a nitrogen atmosphere). After cooling, the reaction mixture is diluted with water, the catalyst is filtered off and washed with water. The combined filtrates were acidified with 2N sulfuric acid solution and extracted twice with ethyl acetate. The aqueous phase was basified with 2N sodium hydroxide solution and extracted three times with ethyl acetate. Organic. the phases are dried over sodium sulphate and evaporated. The residue was further evaporated under high vacuum to remove dimethylformamide. 3 g (70% of theory) of crystalline enantiomer A are obtained from ether.

Melting point 160-166 ° C.

= 78.38 ⁰ (dimethyl sulfoxide + 10% water) i

Example 41

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

3.12 g (0.02 mol) of the product from Example 35 are suspended together with 3 ml (0.022 mol) of triethylamine in 30 ml of methylene chloride and then 3.9 g (0.02 mol) of 4-fluorobenzenesulfonic acid chloride are added while cooling. . The reaction mixture is dissolved at room temperature over 1 hour, then stirred with 200 ml of ethyl acetate and extracted twice with 2N sulfuric acid solution and twice with 2N sodium hydroxide solution. The organic phase is dried over sodium sulfate and evaporated. Ether was added to the solid residue and allowed to crystallize. 5.8 g (84% of theory) of product are obtained. Melting point 150-152 ° C.

^ 20 _{and 50> 43} o _(CHCl3 ,

Example 42

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

The preparation of enantiomer B is carried out using the product of Example 36 in a manner analogous to that described in Example 41 in the preparation of the product using the compound of Example 35.

CS 276468 Βδ

Melting point 150-152 ° C.

= -48.99 ° (CHCl ₃ ).

Example (+) - 3-amino-1,2,3,4-tetrahydrocarbazole

18.6 g (0.1 mol) of racemic 3-amino-1,2,3,4-tetrahydrocarbazole are heated together with 15.2 g (0.1 mol) of (+) - mandelic acid in 100 ml of tetrahydrofuran to boiling under reflux. After obtaining a clear solution, the reaction mixture is allowed to cool and (+) - 3-amino-1,2,3,4-tetrahydrocarbazole mandelic acid salt (enantiomer A, Example 35) is added as seed crystals at the tip of a spatula. The reaction mixture was stirred overnight, and the precipitated crystals were filtered off. This is how it is obtained. 6.05 g of enantiomerically enriched material. 4.7 g of these crystals are dissolved in 330 ml of methyl isobutyl ketone under heating to boiling, after gentle cooling the solution is seeded and stirred during further cooling. After filtration and washing with methyl isobutyl ketone, 3.4 g of (+) - 3-amino-1,2,3,4-tetrahydrocarbazole salt with (+) - mandelic acid are obtained.

In a manner analogous to that described in the above examples, the following compounds of formula XIII are also prepared

(XIII) Example “1 number ^K

R ² ent / rac physical constants

0 2 rac R _f = 0.73 (ether) 0 2 (+) ent R _f = 0.73 (ether) 0 '2 (+) ent ^R f = 0.82 (ether) 0 2 (-) ent R _f = 0.82 (ether)

(+) ent R _f = 0.80 (ether) rac R _f = 0.64 (CH ₂ Cl ₂ : MeOH = 50: 1)

G 85?

H 8-r

make rac

I 6-C1

J 8-C1

K 6-CH ₃

H _f = 0.56 (CH ₂ Cl ₂ : MeOH = 50: 1)

R _f = 0.58 (CH ₂ Cl ₂ : MeOH = 50: 1)

R _f = 0.59 (CH ₂ Cl ₂ : MeOH = 5O: 1) rac R _f = 0.75 (CH ₂ Cl ₂ : MeOH = 5O: 1) rac R _f = 0.32 (CH ₂ Cl ₂ : MeOH = 50: 1) Example ₂ Physical number R ^R yx ent / rac constant

rac R _f = 0.61 (CH ₂ Cl ₂ : MeOH = 5O:

rac R _f = 0.54 (CH ₂ Cl 2: MeOH = 5O: 1) rac R _f = 0.21 (CH ₂ Cl ₂ : MeOH = 99: 1) rac R _f = 0.63 (Tol: EE = l) rac R- = 0.49 (Tol: EE = 4: l)

Explanations to the table:

R _f = migration rate in the chromatogram ent = enantiomer rac = racemate

MeOH = methanol

Tol = toluene

EE ethyl acetate

The residue - (CH 2 -BH-SO 2 R 2 in the general formula ΣΙΙΙ occupies position 3 in Examples A to M, position 2 in Examples N to O and position 4 in Example P).

Claims (2)

A process for the preparation of novel {phenylsulfonamidoalkyl] - and / or phenylsulfonamide cycloalkanop., 2-bJ indoles of the general formula XIII in which R · * · represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, 2 -, „, ~, R represents a phenyl group which is optionally substituted one or two times by a halogen atom or a trifluoromethyl group, X is the number 1 or 2 and y is the number 0 or 1, characterized in that the phenylhydrazines of the general formula XIV (XIV), NH - NH ₂ in which R ⁷ · has the meaning given above, it acts cycloalkanonesulfonamides of the general formula XV in which o,,, R, x and y are as defined above, in the presence of inert solvents or in the presence of a catalyst. t. 2. A process according to claim 1, wherein the corresponding compounds of formula XIV and XV are used as starting materials to give compounds of formula XIII, wherein R is a phenyl group which is monosubstituted by a fluorine atom chlorine or a trifluoromethyl group and R 1, x and y have the meanings given in point 1.