JPS62198659A - Cycloalkano(1,2-b)indolesulfonamide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cycloalkano[1,2-b]indole sulponamides, to a process for their preparation, and to their use in medicine. The likewise novel compound [benzenesulfonamidoal,l]-cycloalkano[1,2-b]indole can be used as an intermediate for the preparation of this new compound.

General formula (I) OOH where R1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or
(Formula %Formula %) (In this formula, R'' represents alkyl or aryl, m is the number 0.1,
or 2) or a group of the formula (in this formula, R4 and Rs may be the same or different,
(represents hydrogen, alkyl, aryl, aralkyl or acetyl) or represents a group of the formula (in this formula, R6 is hydrogen, alkyl, aryl, aralkyl, alkyl-802-, aryl-8O□-, aralkyl-
802- or trifluoromethyl) or represents alkyl, alkenyl or cycloalkyl, each of which may be substituted by carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano, R2 is halogen, cyan, trifluoromethyl, I-lifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy,
represents aryl which may be substituted up to 5 by benzyloxy or benzylthio or by groups of the formula (in which R4 and R'' have the meanings given above), X represents the number 1.2 or 3; , y represents the number 0 or 1, a novel cycloalkane [1,2
-b] Indole sulfonamide or a salt thereof was found.

The cycloalkano[1,2-b]indole sulfonamides according to the invention have several asymmetric carbon atoms and therefore can exist in a variety of stereochemical forms.The invention relates to the individual isomers. It is also about a mixture of both.

The following isomeric forms of cycloalkano[1,2-b]indole sulponamides may be mentioned by way of example.

a) Cycloalkano[1,2-b]indole sulfonamide (CH2) y N HS O2R”C○○H (CH2) 2NH-8o2-R”0OH (CH2) y N HS Oz R” (CH2)
yNHSO2R" (C)12) yNHSO2R2b) Cycloalkano[1,2-bl dihydroindolesulfonamide 0OH R1, R2, X and y have the above meanings.

The cycloalkano[1,2-b]indole sulfonamides according to the invention may also be in the form of their salts - salts which may be mentioned in this connection are also salts with organic or inorganic bases. It is.

Physiologically acceptable salts are preferred within the scope of the invention. Physiologically acceptable salts of cycloalkano[1,2-b]indole sulfonamides can be metal or ammonium salts of the substances according to the invention having a free carboxyl group. Particularly preferred examples are sodium, potassium, magnesium or calcium salts and those derived from ammonia or organic amines such as ethylamine, di- or I-liethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine or ethylenediamine. It is an ammonium salt.

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.

Lkl generally represents a straight or branched hydrocarbon radical having 1 to 12 carbon atoms. Preference is given to lower alkyl having, for example, 6 carbon atoms; examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Generally, 2 to 12 carbon atoms and 1
represents a straight-chain or branched hydrocarbon group having one or more double bonds, preferably one or two double bonds. Preference is given to lower alkenyl groups having 2 to, for example, 6 carbon atoms and one double bond. 2
Particular preference is given to alkenyl radicals having from 4 carbon atoms to 1 double bond; examples which may be mentioned are vinyl, allyl, propenyl, impropenyl, butenyl, imbutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl. , heptenyl, isohebutenyl, octenyl and inoctenyl.

Preference is given to cyclopentane and cyclohexane rings, which generally represent cyclic hydrocarbon radicals having 3 to 8 carbon atoms. Examples that may be mentioned are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkoxy generally has 1 to 12 carbon atoms and represents a straight-chain or branched hydrocarbon group bonded via an oxygen atom; Particular preference is given to alkoxy radicals having 1 to 4 carbon atoms, examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isohebutoxy, octoxy and It is isooctoxy.

LH generally has 1 to 12 carbon atoms and represents a straight-chain or branched hydrocarbon radical linked via a sulfur atom. Preference is given to lower alkylthio having, for example, 6 carbon atoms. Particular preference is given to alkylthio groups having 4 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, penalthiohexylthio-isohexylthio, heptylthio, isoheptylthio, octylthio and isooctylthio.

Otsu92 generally represents an aromatic group having 6 to, for example, 12 carbon atoms. Preferred aryl groups are phenyl, naphthyl and diphenyl.

Okujiki 1 generally has from 1 to 14 carbon atoms, and 1 to 6 carbon atoms in the 6 aliphatic moieties representing the aryl group bonded through an alkylene chain, and 1 to 6 carbon atoms in the aromatic moiety. Aralkyl groups having 6 to 12 carbon atoms are preferred.

Examples that may be mentioned are the following aralkyl groups: benzyl,
Naphthylmethyl, phenethyl and phenylpropyl.

It can be expressed as

In this formula, alkyl represents a straight-chain or branched hydrocarbon group having 1 to 8 carbon atoms. Lower alkoxycarbonyl having 1 to, for example, 6 carbon atoms in the alkyl moiety is preferred. Particular preference is given to alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. Examples that may be mentioned are the following alkoxycarbonyl groups: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl.

Luposiale is a straight chain, generally having from 1 to 12 carbon atoms and substituted with a carboxyl group.
Or represents a branched hydrocarbon group. Carboxy-lower alkyl having 1 to, for example, 6 carbon atoms is preferred.

Examples that may be mentioned are: carboxymethyl, 1-carboxyethyl, 1-carboxypropyl, 1-carboxybutyl,
1-carboxypentyl, 1-carboxyhexyl, 2
-Carboxyethyl, 2-carboxypropyl, 2-carboxybutyl, 3-carboxypropyl, 3-carboxybutyl, 4-carboxybutyl, 2-carboxy-
1...propyl and 1-carboxy-1-propyl.

Generally speaking, the length of the ground is 1 to 12.
represents a straight-chain or branched hydrocarbon group having 5 carbon atoms and substituted by an alkoxycarbonyl group having the abovementioned meaning.

Lower alkoxycarbonyl-lower alkyl having 1 to, for example, 6 carbon atoms in each alkyl moiety is preferred, examples which may be mentioned are: methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,
Butoxycarbonylmethyl, isopropoxycarbonylmethyl, isobutoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1
-Propoxycarbonylethyl, nee-butoxycarbonylethyl, 1-isopropoxycarbonylethyl, 1-
Isobutoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-propoxycarbonylethyl, 2-butoxycarbonylethyl, 2-impropoxycarbonylethyl, Z-imbutoxycarbonylethyl, 2-methoxycarbonyl-2-
Propyl, 2-ethoxycarbonyl-2-propyl, 2
-propoxycarbonyl-2-70pyl, 2-butoxycarbonyl-2-propyl, 2-isopropoxycarbonyl-2-propyl, 2-imbutoxycarbonyl-
2-propyl, 1-methoxycarbonyl-2-propyl, 1-ethoxycarbonyl-2-propyl, 1-propoxycarbonyl-2-propyl, 1-butoxycarbonyl-2-propyl, 1-iso10boxycarbonyl-2
-propyl, 1-isobutoxycarbonyl-2-propyl, 3-methoxycarbonyl-10vir, 3-ethoxycarbonylpropyl, 3-isopropoxycarbonylpropyl and 3-imbutoxycarbonylpropyl.

Halogen generally represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Particularly preferably represents fluorine or chlorine.

The compound of general formula ('I) is preferably a compound of formula ('I) in which 1 (+ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or lower alkoxycarbonyl, or formula % formula %) (this formula , R3 represents lower alkyl or phenyl, and in is the number 0
or 2) or a group of the formula (in this formula, R4 and R4 may be the same or different,
represents hydrogen, lower alkyl, phenyl, benzyl or acetyl) or represents a group of the formula (in which R6 represents hydrogen, lower alkyl, phenyl, phenyl-5O
2~, Mae J-Lou 50. -1mthyl-5O2- or trifluoromethyl), or both may be substituted by carboxyl, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, lower alkoxy or cyanide. represents a certain lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl, and R2 is fluorine, chlorine, bromine, cyanide, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,
lower alkyl, carboxymethyl, carboxyethyl,
or by the formula (in which R4 and R' are as defined above) represents phenyl, which may be substituted up to 3 by groups of It's salt.

Particularly preferred compounds of general formula (I) are those in which R1 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amine, dimethylamino, diethylamino or acetylamino. or represents a group of the formula (in this formula, R6 represents hydrogen, Cl-04-alkyl, phenyl or benzyl), or represents Cl-C<-alkyl, and R2 is fluorine, chlorine, Bromine, cyano, trifluoromethyl, trifluoromethoxy, CbiC1-alkyl, CI
-C, - represents phenyl substituted with up to 3 substituents selected from methylthio, hydroxyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetylamino or diethylamino, and X is the number 1 or 2, and y represents the number 0 or 1, as appropriate, in the form of an isomer or a salt thereof.

Particularly preferred compounds of general formula (1) are those in which R1 represents hydrogen, fluorine, methyl, methoxy, benzyloxy or hydroxyl, and R2 represents fluorine, chlorine, trifluoromethyl, methyl, ethyl, propyl, isopropyl or It represents phenyl substituted with methoxy, X represents the number 1 or 2, and y represents the number 0 or 1, appropriately in the form of an isomer or a salt thereof.

Particularly preferred are the formulas in which R1 represents hydrogen, fluorine, methyl, methoxy, benzyloxy or hydroxyl and R2 represents phenyl substituted by fluorine, chlorine, trifluoromethyl, methyl, propyl, isopropyl or methoxy; y represents the number 0 or 1 and is a (+) or (-) isomer of cycloalkano-[1,2-b]-indole sulfonamide or a salt thereof.

The following cycloalkano[1,2-b]indole sulfonamides may be mentioned by way of example.

1-(benzenesulfonamidomethyl)-4-(2-carboxyethyl)cyclopentano[1,2-b]zeynol, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamidomethyl)-cyclopentano[ 1,z-b]zeynol, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamitomethyltocyclopentano[1,2-
b] Zeynol, 1-(benzenesulfonamidomethyl)-4-(2-carboxyethyl)-7-medoxycyclopentano[1,
z-b: +indole, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamidomethyl)-7methoxycyclobentano['l,2-b]indole, 4-(2-carboxyethyl) )-1-(4-chlorophenylsulponamidomethyl)-7-medoxycyclobentano[1,Z-b]zeynol, 1-(benzenesulfonamido)-4-(2-carboxyethyl)cyclopentano[1, 2-bl indole,
4-(2-carboxyethyl)-1-(4-)fluorophenylsulfonamido)cyclopentano[1,2-b
]zeinol, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamido)cyclopentano[1,2-bl indole, 1-(benzenesulfonamide)-4-(2-carboxyethyl)-7-med oxycyclopentano[1,2-b
] Zeinol, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamide)-7-medoxycyclobentano[1,2-b]zeinol, 4-(2-carboxyethyl)-1- (4-chlorophenylsulfonamide)-twomethoxycyclopentano[
1,2-b]zeynol, 1-(benzenesulfonamidomethyl)-4-(2-carboxyethyl)-7-methylcyclopentano[1,2
-b] Zeinol, 4-(2-carboxyethyl>(-(4-fluorophenylsulfonamidomethyl) [1.2-bl indole, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamidomethyl) -7-Methylcyclopentano[1.

2-b] Zeynol, 1-(benzenesulfonamido)-4-(2-carboxyethyl)-7-methylcyclopentano[1.2-b]
Zeynol, 4-(2-carboxyethyl)-1-(4-fluorophenylsulfonamide indole, 4-(2-carboxyethyl)-1-(4-chlorophenylsulfonamide)-7-methylcyclopentano[1
．． 2-b]zeinol, 4-(2-carboxyethyl)-1-(4-)lylsulfonamidomethyl)-cyclopentano[1.2-b]zeinol, 4-(2-carboxyethyl)-1-(4 -tolylsulfonamide)-cyclopentano[1.2-b]zeynol, 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-(benzenesulfonamide)-9 -(Z-carboxyethyl)-6-medoxy 1.2,3,4,4a
-t,9a-t-hexahydrocarbazole, 3-r- (benzenesulfonamido)-9-(2-carboxyethyl)-6-medoxy 1.2,3,4,4
a-c,9a-c-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9-(2
-carboxyethyl)-1.2,3,4,4a-t,9
at-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9-(2
-carboxyethyl)-1.2,3,4,4a-c,9
a-c-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9-(2
-carboxyethyl)-6-medoxy1.2,3,4
, 4a-t, 9a-t-hexahydrocarbazole, 3-r-(benzenesulfonamidomethyl)-9-(2
-carboxyethyl)-6-medoxy1.2,3,4
, 4a-c, 9a-c-hexahydrocarbazole, 9-(2-carboxyethyl)-3-r-(4-chlorophenylsulfonamide>4.Z, 3,4,4a-t,
9a-t-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-chlorophenylsulfonamide)-1,2,3,4,4a-a
, 9a-e-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-fluorophenylsulfonamide)-1,2,3,4,4a-
t,9a-t-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-fluorophenylsulfonamide)-1,2,3,4,4a-
e, 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-)lylsulfonamide)(,2,3,4,4a-c,9a-c
-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-fluorophenylsulfonamide)-6-medoxy 1.2,
3,4,4a-t, 9g-1-hexahydrocarbazole 9-(2-carboxyethyl)-3-r-(4-fluorophenylsulfonamide)-6-medoxy 1.2,
3,4.4a-c,9a-C-hexahydrocarbazole(+)-3-(4-chlorophenylsulfonamide-)
-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole(+)-3-(4-fluorophenylsulfonamide-
)-9-(2-carboxyethyl)-1,2,3,4-
Tetrahydrocarbazole (-)-3-(4-chlorophenylsulfonamide-)
-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole(-)-3-(4-fluorophenylsulfonamide-
)-9-(2-carboxyethyl)-1,2,3,4-
Tetrahydrocarbazole (±)-3-(4-chlorophenylsulfonamide-)
-9-(Z-carboxyethyl)-1,2,3,4-tetrahydrocarbazole (±)-3-(4-fluorophenylsulfonamide-
)-9-(2-carboxyethyl)-1,2,3,4-
Particularly preferred tetrahydrocarbazoles are: (+)-3-(4-fluorophenylsulfonamide-
)-9-(2-carboxyethyl)-1,2,3,4-
Tetrahydrocarbazole and (-)-3-(4-fluorophenylsulfonamide-
)-9-(2-carboxyethyl)-1,2,3,4-
6 which is tetrahydrocarbazole Furthermore, general formula (XIII) wherein R1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or
(Formula%Formula%) (In this formula, R3 represents alkyl or aryl, m is the number 0.1,
or 2) or a group of the formula (in this formula, R4 and Rs may be the same or different,
(represents hydrogen, alkyl, aryl, aralkyl or acetyl) or represents a group of the formula (in this formula, R6 is hydrogen, alkyl, aryl, aralkyl, alkyl-8O!-, aryl-8O□-, aralkyl-
502- or trifluoromethyl) or alkyl, alkenyl or cycloalkyl, each of which may be substituted by carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano, R2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl,
carboxyalkyl, alkoxycarbonylalkyl,
may be substituted up to 5 by alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio or by groups of the formula in which R4 and R5 have the meanings given above. represents aryl, X represents the number 1.2 or 3, and y represents the number O or 1.
React with acrylonitrile, optionally in the presence of a base,
Next, this N,N'-bicyanoethyl compound is hydrolyzed, and then, in the case of producing cycloalkano-1,2-bl dihydroindol sulfonamide, this cycloalkano[1,2-b]indole sulfonamide is , hydrogenation in the presence of an acid and a reducing agent, optionally in the presence of an inert solvent, and resolution of the isomers, optionally by conventional means,
Then, a process for producing cycloalkano[1<2-b]indole sulfonamides and salts thereof according to the present invention was found, which is characterized in that when producing a salt, the reaction is carried out with an appropriate base.

The manufacturing method described in the present invention can be expressed by the following formula.

Cycloalkano [1,2°-
b] Dihydroitol sulfonamide has the formula (Ia)C
OOH where R1, R2, X and y correspond to 0 having the meanings given above. When carrying out the process according to the invention, it is generally possible to isolate the intermediates 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. Preference is given for this: alcohols, such as methanol, ethanol, propatool or isopropyl; ethers, such as diethyl ether, tetrahydrofuran, dioxa〉', guttukol 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 includes preferably alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides, such as sodium hydride, alkali Carbonates of metals or alkaline earth metals, such as thorium carbonate or potassium carbonate, or alkali metal alcolades, such as sodium methanolade or ethanolade, potassium methanolade, ethanolade or tertiary butyralide, or amides, such as sodium amide or lithium. diisopropylamide; or organic amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiveridine.

The manufacturing method described in the present invention is suitable for -1k at temperatures ranging from 0°C to 150°C.
°C, preferably in the temperature range from 20°C to 100°C.

Although the manufacturing method described in the present invention is generally carried out under atmospheric pressure,
It is also possible to carry out under reduced pressure or under increased pressure (for example in the range from 0.5 to 5 bar).

Generally, from 1 to 20 moles, preferably from 1 to 10 moles of acrylonitrile are used per mole of [benzenesulfonamidoalkylcocycloalkano[1,2-b]indole.

The N,N"-bicyanoethyl compounds mentioned above are prepared in a manner known per se in the presence of a base, such as an alkali metal or alkaline earth metal hydroxide or an alkanolade, in an inert solvent, such as water or an alcohol. The preferred base used is thorium, potassium is also the hydroxide of barium, and also the hydroxide of barium.
Lium methanolate, potassium methanolade, sodium ethanolade or potassium ethanolade,
It is preferably carried out in water or methanol, ethanol, brobanol or isopropanol or in a mixture of these solvents.

In general, 1 to 100 mol, preferably 2 to 50 mol, of base are used per mole of N,N'-bicyanoethyl compound.

The hydrolysis is carried out in the temperature range from 0'C to 100°C, preferably from 20°C to so'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. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or glacial acetic acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.

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, I-luenesulfonic acid or benzenesulfonic acid, or Contains triple ormethane 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 cyanoborohydride, tributyltin hydride, triethylsilane, dimethylphenylsilane or l-liphenylsilane. is included.

This hydrogenation is generally carried out between -40'C and +800C.
0°C, preferably -20°C to ÷60°C.

The [benzenesulfonamidoalkylcocycloalkano[1,2-b]indole of general formula (XIII) used is a new substance. General formula (XIV) H-NO3 In the formula, R1 has the above meaning.

of phenylhydrazine in the presence of a cycloalkanone sulfonamide of the general formula (XV), in which R2, X and y have the above meanings, and an inert solvent, and
[benzenesulfonamidoalkylcocycloalkano[1,
2-b] A method for producing indole was also found in a similar manner.

[Benzenesulfonamide alkyl] according to the present invention:/
It can be expressed 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 or tetrachloromethane, dichloroethylene and trichloroethylene; ethyl acetate, toluene,
Includes 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 generally requires 0°C
from 20°C to 200°C, preferably from 20°C to 150°C
It is carried out in the temperature range of °C.

The process disclosed by the present invention is carried out under atmospheric pressure, but also under elevated pressure or under reduced pressure (e.g.
5 to 5 bar) is likewise possible.

For 1 mole of the above ketone, the above hydrazine is -m
It is used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol.

Examples of hydrazines used in the process according to the invention are: phenylhydrazine, 4-methoxyphenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine and 4-methylphenylhydrazine0 Examples of ketones used according to the invention is: 3-(benzenesulfonamidomethyl)cyclopentanone 3-(benzenesulfonamidomethyl)cyclohexanone 4-(benzenesulfonamidomethyl)cyclohexanone 3-(benzenesulfonamido)cyclopentanone 3-
(benzenesulfonamide)cyclohexanone 4-(benzenesulfonamide)cyclohexanone 3-(4-chlorophenylsulfonamidomethyl)cyclopentanone 3-(4-fluorophenylsulfonamidomethyl)cyclopentanone 3-(4- Methylphenylsulfonamidomethyl)shi.

Clopentanone 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)cyclopentanone 3-(4-fluorophenylsulfonamido)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-methylphenylsulfonamide) cyclohexanone.

The hydrazine (XIV) used as a starting material is either a known substance or a known method (Houben-Weyl "Methods of Organic Chemistry").
Methoden der Organischen
Chemie)”, X/2.

1 page, 123. (693)).

In the general formula (XVa) used as a starting material, y and R2 have the above-mentioned meanings. Some of the cyclohexanone sulfonamides are known substances, and can be prepared by known methods (Zuben-Weyl (
Houben-Weyl) 'Methods of Organic Chemistry (Me
thodcn der Organischen Ch.
emie), IX, 605; Mooradian et al. (^
, Mooradian et al.), Journal of Medical Chemistry (J, Wed, Chew,) 2G (4),
487 (1977)).

The cyclopentanone sulfonamide of the general formula (XVb) (xvb) used as a starting material, where x, y and R2 have the above meanings, is a new substance.

General formula (XVI) (XVI) In the formula, X and y represent a cycloalkanol having the above meanings.
x-R' (XVT! > where R2 has the above meaning and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine, in an inert organic solvent, A novel method for producing the above-mentioned cycloalkanone sulfonamides has also been found, which is characterized by reaction in the presence of an appropriate base and subsequent oxidation in an inert solvent.

The above cycloalkanol is a cycloalkanone (XV
III) in an inert organic solvent, optionally in the presence of a base, with nitromethane, followed by reduction of compound (XIX) (Chemical Abstracts (C8) 92.89849 and chemical anth 1
- Rakutsu (C^)8fu, 22191).

The above-mentioned sulfonyl halide can be prepared by a method known per se (
1louben-, 11eyl
“Methods of Organic Chemistry”
anischen CheIll, )"IX, 564
).

The production of the cycloalkano[1,2-b]indole sulfonamide according to the present invention can be represented by the following reaction formula.

According to this, in the first step a), the cycloalkanone is converted into an alcohol, such as methanol, ethanol or propatool, or an ether, such as diethyl ether, tetrahydrofuran or dioxane, or a chlorinated hydrocarbon, such as methylene chloride.
In an inert solvent such as chloroform or carbon tetrachloride, bases such as sodium hydride, sodium or potassium methanolade, sodium or potassium ethanolade, potassium tert-butanolade, 1,5-diazabicyclo[4,3,0]nona -5-ene, 1,5-
The nitro compound is reacted with a nitro compound, such as nitromethane, in the presence of diazabicyclo[5,4,0]undec-5-ene, pyridine or triethylamine at a temperature in the range from 0°C to 100°C.

In stage 111b) the hydride, for example Li^In, is dissolved in an inert solvent such as an ether, for example tetrahydrofuran, dioxane or diethyl ether.
,,Na[^! (OCHzCH2-OCH*)J-1 or in the presence of a reducing agent such as diisobutylaluminum hydride at a temperature in the range of -20°C to 60oC to reduce the cyclo Alkanol.

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,O]non-5-ene,
1,5-diazabicyclo[5,4,O]launcher-5-
In the presence of ene, pyridine or triethylamine, -
The cycloalkanols described above are converted to sulfonamides by reacting with sulfonyl halides at temperatures between 20°C and +60°C.

In step d), the above sulfonamide is dissolved in an inert solvent such as water, glacial acetic acid, acetone, pyridine or mixtures thereof with a chromium(VI) compound such as Cr.
ys, KtCrzOy or NatCrzO- at a temperature of -20°C to +100°C to give the cycloalkanone sulfonamide.

Step 11? In #e), cycloalkanone sulfonamide (xvb) and hydrazine (XIV) are reacted as described above to form the formula (XIII) (XIII), where R1, R2, X and y are The corresponding [benzenesulfonamidoalkylcocycloalkano[1,2-b]indole has meaning.

The enantiomerically pure benzenesulfonamide cyclohexano[1,2-bl i]-dole of the general formula (XIIIa) in which R1 and R2 have the above meanings is likewise a new substance.

General formula (XX) <XX> In the formula, R1 has the above meaning, enantiomerically pure cyclohexano[1,
2-bl-in F-Ruami 7 O-R type (XVII)
Hal-5Ox-R2 (XVII) in which R2 has the above meaning and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine, and a sulfonyl halide in the presence of an inert solvent. A method for producing enantiomerically pure [benzenesulfonamidococyclohexano[1,2-b]indole, which is characterized by carrying out the reaction in the presence of an appropriate base, has also been found.

Solvents suitable for this process are customary organic solvents that do not change under the reaction conditions. These include preferably ethers, such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, Included are trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, 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 includes preferably alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sulfur hydroxide, potassium hydroxide or barium hydroxide, or alkali metal hydrides, such as sodium hydride, or an alkali metal or alkaline earth metal carbonate, such as sodium carbonate, sodium bicarbonate, potassium carbonate or calcium carbonate, or an alkali metal alcoholade, such as sodium methanolade, sodium ethanolade, potassium methanolade, potassium ethanolade or potassium carbonate. 3-butyrad, or alkali metal amides such as lithium diisopropylamide or sodium amide; or organic amines such as ethyldiisopropylamine, benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, dimethylaminopyridine, triethylamine, N-methylpiperidine ,1,
5-diazabicyclo[4,3,0]non-5-ene or 1,5-diazabicyclo[5,4,O]launcher
Contains 5-ene.

This process disclosed by the present invention involves -m to -30'
The process is carried out in a temperature range of from -150'C to 150'C, preferably from -20'C to +80'C.

The process disclosed by the present invention is generally carried out under atmospheric pressure, but under reduced or elevated pressure (e.g. 0.5
to 200 bar) is likewise possible.

The enantiomerically pure cyclohexano[1,2-b]indoleamine of the -a formula (XX) according to the present invention is a new substance and can be prepared according to the synthetic principles A, B or C below.

``Kin''Shiho''L'' ``XXIV diastereomeric mixture R+ has the above meaning, R is enanteomerically pure -1 or L-
Amino acid residue, preferably 2s-(chloroacetamide)
-3-phenylpropionyl group IB- ■ xxvn R1 has the above meaning.

According to this, in stage 1, paracetamol (X
XI) over Raney nickel to give Birman (
J., H. Billman) and Biehler (J.

^, Btlhler) in the American Journal of Chemistry (J, ^m
, Chew.

4-7 cetamide cyclohexanol (XXII) as described in Soc, ) Mutual, 1345 (1953).
In step 2, a cis/trans mixture of 4
- Fischer's indole synthesis method using an oxidizing agent such as phenylhydrazine (Xm) is applied to acetamidocyclohexanol (xxii) in a one-pot method, and then
Acid hydrolysis removes the acetyl group.

The manufacturing process is carried out in a solvent such as water, acetic acid and/or propionic acid at temperatures of 0°C to +150°C, preferably 0°C to 110°C.

Racemic 3-ami/-L2 easily obtained by this method
,3t4-tet? Hi)' On & Hazor (XXI)
The I is converted in step 3 into the corresponding noastereomeric mixture by coupling with the enantiomerically pure, suitably activated form of the amino acid, which is processed by conventional methods, e.g. crystallization or column chromatography. It can be separated into individual diastereomers by photography.

The 94 preferred enantiomerically pure amino acids are acetyl 7-aryl phenylalanine, N-tertiary hydroxyl phenyl aphnin, chloroacetylphenyl afnin, carbobenzoyl 7-enyl alanine, methoxyphenylacetic acid or acetoxyphenylacetic acid. , preferably N-chloro-N-phenylalanine.

Commonly used activators are conventional peptide coupling agents. Preference is given here to carbimides, such as diisopropylcarboximide, dicyclohexylcarboximide or N-(3-trimethylaminoisopropyl)-N-ethylcarbodiimide hydrochloride, or carbonyl compounds, such as carbonyldiimidazole, or , 2-oxacillium compound,
For example, 2-ethyl-5-phenyl-1,2-year-old xazolium 3-sulfonate, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tris (tumethyl ) phosphonium, methanesulfonyl, and optionally a base such as triethylamine,
or N-ethylmorpholine in the presence of N-methylpiperidine, or dicyclohexylcarboximide and (/N-hydroxysuccinimide).

The coupling is generally carried out in an inert organic solvent, preferably in chlorinated hydrocarbons, such as methylene chloride or chloroform, or hydrocarbons, such as benzene, toluene, xylene or petroleum distillates, or in ethers, such as Carry out in nooxane, tetrahydro7rane or diethyl ether or in ethyl acetate, dimethylformamide, dimethyl sulfoxide or acetone, acrylonitrile or nitromethane at temperatures of -80°C to +50°C, preferably -40°C to 30°C. .

)7 stereomer mixture (XXIV), the individual diastereomers are subjected to acid hydrolysis in step 4 to yield the enantiomerically pure amine (XXIV).
).

This hydrolysis is generally carried out using an inorganic or organic acid, such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, methanesulfonic acid or fluoroacetic acid, or
A mixture of these acids is prepared.

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 is generally carried out at temperatures between +20°C and +150°C.
It is preferably carried out at a 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.

According to this method, by Fischer's indole synthesis method,
1,4-cyclohexanedione monoethylene ketal (
XXV) was reacted with phenylhydrazine (XIV), and Brittten (^, Br1tten) and Lockwood (G, Lockwood) published the results in the Journal of Chemical Society (J, Cb).
ea+.

Soc, ), Perkin transaxle polishing (Per
kinTrans, ) 1.1974.1824-18
ketal (XXVI) as described in 27.

Ketal (XXVI) is hydrolyzed in step 2 to produce ketone (
XXVII), which is converted in step 3 to the noastereomeric mixture (XXVIII) by reductive amination using 3-7 enethylamine.

This reductive amination is generally carried out using hydrogen in the presence of a reducing agent, such as palladium, platinum or pads on animal charcoal, optionally as a catalyst, or complex hydrides, preferably sodium borohydride, potassium borohydride. , Lithium borohydride, Zinc borohydride, Lithium aluminum borohydride, Aluminum hydride; Quibutylaluminum hydride, Lithium triethylhydridoborate, Sodium cyanotrihydroborate, Tetrabutylammonium cyanotrihydroborate , tetrabutylammonium hydridoborate, lithium aluminum hydride, sodium bis[2-methoxyethoxy]dihydridoaluminate or hydridotris[1-
using lithium methylpropyl borate, an inert solvent,
For example, hydrocarbons, preferably benzene, toluene or xylene, or chlorinated hydrocarbons, such as methylene chloride or chloroform, or ethers, such as quetyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxymethane, or acetonitrile, dimethylform. -8 in amide, dimethyl sulfoxide, or alcohols such as methanol, ethanol, prop/-ol or impropanol.
0°C to +100°C, preferably -80°C to +5°C
It is carried out in a temperature range of 0°C.

The noastereomeric mixture (XXVIII) can be prepared by customary methods, such as chromatography or crystallization, preferably by crystallization, so that the mixture of noastereomers (XXVIII) can be prepared as appropriate by a suitable acid size axis + hr fit? -4 Al/J female 71,000 t merge → split.

Suitable acid adducts in this connection are adducts of the enantiomers according to the invention with inorganic or organic acids. This 4
Preferred examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, maleic acid, hexamaric acid, citric acid, or lactic acid.

Removal of the 7 enyl ethyl group of the resolved norastereomer (XXVIII) is carried out in step 4 by catalytic transfer hydrogenation to yield the enantiomerically pure amine (XX
).

Step 4 generally involves reducing alcohols, using hydrogen, or ammonium formate, optionally in the presence of a reducing agent such as palladium, palladium on animal charcoal or platinum.
in an inert solvent such as methanol, ethanol, propatool or isopropanol, or trimethylformamide or dimethyl sulfoxide.
℃ to +200℃, preferably +20℃ to +1
Performed in a temperature range of 50 °C (Overman (L, I
E.

Ove, rman) and Sugai (S, Sugai)
sOrganic Chemistry Magazine (J, Org, CheI6.) 5
0.4154-4155 (1985)).

According to this, racemic resolution of compound (XXIII) 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 resulting salt with a base, enantiomerically pure compound (XXIII) is liberated.

Suitable optically active acids are: (+)-cyanosulfonic acid,
(-)-Camhorsulfonic acid, (+)-Camhor-
3-carboxylic acid, (-)-cyano-3-carboxylic acid, (+)-cyanoic acid, (-)-cyanoic acid, (-
)-malic acid, (+)-mandelic acid, (-)-mandelic acid, (+)-lactic acid, (-)-lactic acid, (-)-2-[(phenyl 7/)carbonyloxy J-propionyl ,<
->-a-Methoxyphenylacetic acid, (-)-norlowbenzoyltartaric acid, (-)-norlow-4-)luoyltartaric acid, (-)-methoxyacetic acid, hydrogen phosphate (-)-1,1
'-vina7thi-2,2°-diyl.

Suitable solvents for crystallization are: water; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol or tertiary-butanol.
1/-le; ethers, such as noethyl ether,
ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; hydrocarbons, such as benzene, toluene, quinolene, hexane or cyclohexane; chlorinated hydrocarbons, such as nochloromethane or peraloform; or #acids Such as ethyl, acetonitrile, nitromethane, trimethylsulfoxide, trimethylformamide 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 an alkali metal or alkaline earth metal carbonate, such as sodium carbonate,
Sodium bicarbonate, potassium carbonate or calcium carbonate; or alkali metal alcoholades such as sodium methanolade, sodium ethanolade, potassium methanofoot, potassium ethanolade or potassium tert-butylade.

The present novel cycloalkaline 7[1,2-bl indole sulfonamide and its salts can be used as active compounds in medicine.
ateleL aggrcHation) inhibitory effect and thromboxane^2 antagonism (antagonizing
tbrosboxane^2) These are the ones that show the effect.
It can be suitably used for the treatment of thrombosis, thromboembolism, and ischemia, and as an anti-asthmatic agent and an anti-allergic agent.

In this case, the product is Ikko Tsukuda's sheep 9μ, inert,
Can be converted into conventional formulations such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using X-toxic, pharmaceutically suitable vehicles or solvents. 0 Therapeutically active compound is in each case sufficient to achieve the dosage range of about 0
．． 5 to 90% by weight, preferably not 70% by weight
should be present at a concentration of

The above formulation is prepared, for example, by using the active compound F8 medium and/or vehicle, optionally increasing the amount using an emulsifier and/or dispersant, and
For example, when using water as diluent, organic solvents can optionally be used as cosolvents.

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), furfurs (e.g. ethyl alcohol and glycerol) and glycols. solid vehicles such as natural rock powders (such as kaolin, alumina, talc and 1, chalk), synthetic rock powders (such as dispersed silica and silicates), and sugars (such as silica and silicates); sugars, lactose and glucose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates)
, dispersants (e.g. lignin sulfite waste liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,
stearic acid, and sodium lauryl sulfate).

Administration is in the conventional manner, preferably orally or parenterally, in particular perlingually,
or intravenously, in the case of oral administration, the tablets are
Of course, the vehicle may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably java starch, gelatin, etc. Agents 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 commercial use, the active compounds can be mixed, in addition to the auxiliaries mentioned above, with various flavor improvers or colorants.

For parenteral administration, solutions of the active compounds in suitable liquid vehicles may be employed.

Generally, for intravenous administration, about 0,00 to 1 mH, preferably about 0.01 to 0.5 vsg per 11 kg of body'ff, to achieve effective results.
Advantageously, in the case of oral administration, the dosage is generally from about 0.01 to 10 g, preferably from 0.1 to 10 g per kg of body weight.

However, it may sometimes be advantageous to deviate from the above amounts, depending in particular on the body weight or the nature of the method of administration.
Also, depending on the individual's behavior towards the drug, or depending on the nature of the drug combination and the time and interval of administration, its nj' potential. Therefore, in some cases it may be sufficient to treat the above-mentioned minimum wrinkles, while in other cases it may be necessary to exceed the above-mentioned upper limit. When administering a relatively large amount, divide it into several doses and administer 1
Administration over several days may be recommended.

The cycloalkano[1,2-bl indole sulfonamides according to the invention can be used in both human and veterinary medicine.

3-nitromethyl cyclopentanone 100 g of 2-cyclobentenone was mixed with 86 g of nitromethane.
6 ml and 1,5-)7 Zabishikell 4,3.
With 5g of OJ/Qi-5-ene (DBN), 1
．． The isopropanol was dissolved in ethyl acetate and the solution was brought to room temperature for 5 hours. Wash twice with 0.51 dilute sulfuric acid. The organic phase was dried with 17 um of sulfuric acid,
Evaporate. In this way, 154 g (88% of theory) of 3-(nitromethyl)cyclopentanone are obtained in sufficient purity for the subsequent reaction.

Rf = 0.52 CIl□C1□: cll+
01 (= 99: 13-7 tanomel cyclopentanol 3- Tromethyl (0.4 mol) is dissolved in 573 ml of absolute tetrahydro 7 run under nitrogen gas. Lithium hydride is added to this solution at 0°C. 800 ml of a 1 molar solution of aluminum in tetrahydro7 run is added in full. After the full addition is complete, the mixture is stirred at 0° C. for 1 hour. Then,
When the cooling bath is removed, the temperature of this reaction ffja is 40°C.
"Yu rises." After the temperature has fallen to 20° C., the mixture is stirred at this temperature for 1 hour. This reaction mixture was heated to 0°C.
1001 of a 45% strength solution of +7 um (hydroxide) is added in full with stirring. After the full addition is complete, the reaction mixture is stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the diatomaceous earth is washed with 1.5 f of tetrahydro7 run. mat-i and thoroughly evaporate in vacuo. In this way, a viscous oily product 22.
5 g<49% of theory) are obtained.

11f” 0.01 CHzClx: C1b
011'' 9: 17nol 3-(aminomethyl)cyclopentanol 9g (0,0
78 mol) and 13.8 g of triethylamine, IQp
1 (0,078 mol) in 2001 tetrahydro7ran. Then, at 0-5°C, benzenesulfonylph chloride, 9 g = 10.8 ml (0
, O'78 mol). After the full addition is complete, the reaction mixture is stirred at 0° C. for 1 hour. This mixture was then diluted with 200 parts methylene chloride and 1 part
Wash twice with 501 parts of dilute sulfuric acid. The organic phase is then extracted twice with 1501 portions of 2N sodium hydroxide f# solution, the combined extracts are acidified with concentrated hydrochloric acid, and extracted twice with 1501 portions of methylene chloride. The methylene chloride phases are combined, dried over sodium sulfate and evaporated in vacuo. In this way, a viscous oily isomer mixture 9.1% (39% of total weight) is obtained as product.

1 (f = 9.51 and 0.45 C112C1□
: (:113011 ” 95.5 Tanone 7.5 g (0,0294 mol) of 3-(benzenesulfonamidomethyl)cyclopentanol are dissolved in 60-1 glacial acetic acid. Chromium dioxide 2.79° (0,
0279 mol) dissolved in 21 parts of water and 8.8 ml of glacial acetic acid was added at 0-5°C, and then
The temperature of the reaction mixture is raised to room temperature. The reaction mixture is stirred for 1 hour at room temperature, then diluted with 200 ml of ether and washed twice with 150 ml of water.

Then, the organic phase was hydrated with 2N hydroxide in 200 ml portions).
Extract for 21 d with IJum solution, collect the sodium hydroxide phase, acidify with concentrated hydrochloric acid and extract twice with Zoo 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 the total weight) of a viscous oil is obtained.

Rf ='0.51 CIl, CL: C11,
011 = 95: 5th Anniversary Method: 21 g (0,0826 mol) of 2-enthol 3-(benzenesulfonamidomethyl)cyclobentanone and 9 g (0,0826 mol) of phenylhydracone were mixed with 200 liters of glacial acetic acid. This S solution is heated under reflux for 4 hours.

The reaction WI solution is then diluted with 1.31 parts of ether and 5001 parts of water is 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 is extracted once more with '500 constant 1 ether and the organic phases are combined, dried over sodium sulfate and evaporated. The residue thus obtained was chromatographed using a 2k, silica sol (Merck, 0.04-0.063 m1I) and 85:1 of toluene and #ethyl acid.
Elute with a mixture of ratios of 5 to 5. In this way, after evaporation, a crystalline product 1,9 with a melting point of 161-164 °C (R.
A fraction is obtained giving 7% of

1(f = 0.92 Cll2(:l□: C1
l, OH = 95: 5 pentano 12-b in 1
-M M 1-(benzenesulfonamidomethyltanol 1.2-bJ veinol 1.9 g (0.
0058 mol), acrylonitrile 1.8:d g
=2.3 ml (0.0346 mol) and benzyltrimethylammonium hydroxide.

40% strength methanol solution MO. 24 g (0.0
0058 mol) in dioxane 601 and stirred at 60-70°C for 2 hours. Then,
The reaction mixture is evaporated in vacuo, the residue is taken up in methylene chloride and the solution is extracted twice with dilute sulfuric acid. The organic phase is washed with a saturated solution of hydrogen carbonate, dried over sodium sulfate and evaporated.

By this method, 2.4 g (8! MiI rough f) 95
%) f) The product is obtained as a solid foam.

Rf=0.45 CLCI□: Cll,011
= 99: Nitooon 1-(N-(benzenesulfonyl)-N-(2-cyanoethyl)aminomethyl J-4-(2-cyanoethyl)
Cyclopenta/l 1,2-bJ indole 2.4 g
(0.0055 mol) is dissolved in 35 parts of Improper Tool and 55 parts of a 10% strength solution of potassium hydroxide is added. The reaction mixture is stirred at 70° C. for 4 hours, then diluted with 100 ml of water and extracted with 100 all of methylene chloride. The aqueous phase is acidified with dilute sulfuric acid and extracted three times with 1001 portions of methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated. Oily residue (1
．． 9 g) in methanol and add 0.26 g of sodium methylate.

When this solution is evaporated, 2.0 g (Rim's 6
9.2%) of the product is obtained as microcrystalline sodium salt.

+<r = 0.37 CIl□C1. :
C11.0■ = 95:5 cyclopentanol 3-(aminomethyl)cyclopentanol 19. tl gC O. 172 moles]
, 28.3B (0.172 mol) of 4-fluoro7
React with enylsulfonamide. This results in 17.3 g (36% of theory) of a viscous oily isomer mixture as product.

Rr= 0.53) fyoC/ 0.46 Cl12C
It: CIIsoll” 95: 5-cyclobentam B In the same manner as in Example 4, 3-(4-fluorophenylsulfone 7-t-methyl)cyclopentanol 17
．． 3 g (0.0638 mol) was oxidized. This resulted in 14.3 g (83% of theory) of a viscous oily product.
is obtained.

Old = 0.78 CIl□C1□: Cll. 01
1 = 9: 1 cyclobe otori/l, 2-b indore]! 14.3 g (0,0527 mol) of 3-(4-fluorophenylsulfonomidomethyl)cyclopentanone are reacted analogously to Example 5 with phenylhydranone. In this way, after chromatography on silica sol, 0.67 g of microcrystalline product (j!li
3.7% of theory) is obtained.

Rf = 0.47 CIl, CI□: CH30
) 1 = 99: 1 cyclopentano 1, 2-b
Indole N 1-(4-7fluorophenylsulfonamidomethylcyclopenta/l 1,2-bl indole 0.67 g(
0.00195 mol) was reacted in the same manner as in Example 6. This method gives 0.83 ml of product (95% of the volume) as a solid foam.

Rf=0.39) Luene:Ethyl acetate=8:2 IndoleOOII 4-(2-cyanoethyl)-1-[N-(4-fluoro7enylsulfonyl)-N-(2-Schiff/ethyl)amino methyl] cyclopentano[1, Z-bl indole 0
．． 83 g (0.00184 mol) was hydrolyzed in the same manner as in Example 7. In this way, a crystalline product of 0.87
g (87% of theory) has a melting point of 150-160℃
Obtained as the sodium salt of

Rf = 0.59 CIl. CI2: CIl.
Oll = 9: 1'A-(7:, No Kill S:
t '7 n Hen 4') - 11- 1 (4 Q a
(0.146 mol) is reacted with 4-chloro7enylsulfonyl chloride analogously to Example 3. In this way, 1 tl, 6 g of a viscous oil product (39% of theory)
) is obtained as a mixture of isomers.

Rf = 0.46 and 0,44 HzClz:
CIltoll” 95: 53-(4-chlorophenylsulfonamidomethyl)cyclopentanol 16,
! 5 g (0.05'73 mol) are oxidized analogously to Example 4. In this way, a viscous oily product of 13.8
g (83.7% of theory) is obtained.

Rf = 0.7 CII□CI2: CILO
13.8 g (0,048 mol) of 3-(4-20 lophenylsulfonamidomethyl)cyclopentanone was prepared in the same manner as in Example 5. , react with phenylhydracun. In this way, after chromatography on silica gel, 1.65% of the product (9.5% of theory) was obtained.
is obtained as a solid foam.

11f = 0.48 C11, C1□: CLO
[I = 99: 1 cyclopenta/1,2-bLL
and L1 ML L-(4-chlorophenylsulfonamidomethyl)cyclopentano[1,2-bl indole 1.85 g (0
,0046 mol) are reacted in the same manner as in Example 6.

In this way, 1.8 g (84% of theory) of product are obtained as a solid foam.

Rf=0.38) Luene:ethyl acetate=8:2
1 and L dichromatic C00I (1-[N-(4-chloro7enylsulfonyl)-to(2
-cyanoethyl)amidomethyl]-4-(2-cyanoethyl)cyclopenta/l 1,2-bl indole 1.
9 g (0,0038-1 l) are hydrolyzed analogously to Example 7. In this way, 1,3:(g (81.3% of theory) of product is obtained as a crystalline sodium salt with a melting point of 160° C.

Rf = 0.55 CI, C1,: C11,O
Il = 9: 14-(benzenesulfonamide
Cyclohexano-stop-A-bu F) F-hM +4-11-j
+l-IJII, -/8 (J Y+l-S with 107 g (0.6 mol) of benzenesulfonyl chloride,
The reaction is carried out in the same manner as in Example 3. In this way, Rongjia 1
72.8 g (47% of theory) of crystalline product having a temperature of 06-108 DEG C. are obtained.

Iff = 0.38 CIl, CI□: Cl1
1011 = 95: 54-(benzenesulfonamido)cyclohexanol 72.8 H (0,285 mol) is oxidized analogously to Example 4. Crystallization with petroleum ether gives a product of molten K2O - 82°C57.5
g (80% of theory) is obtained.

10=0.86CIl□C1,:C113011=95
57.5 g (0,227 mol) of cyclohexanone are reacted analogously to Example 5 with phenylhydrazine. In this way, 41.5 g (56% of theory) of a product with a melting point of 155° C. crystallized with impropatur are obtained.

Rf = 0.82 ClllCl□:C)130
■=95: 53-(benzenesulfone 7mide)-
1,2,3,4-tetrahydrocarbazole 10 g
C00O', 108 mol) is reacted in the same manner as in Example 6. In this way, crystallized with ether, melting point 18
10 g (75% of theory) of product at 0-190° C. are obtained.

Rf=0.29) Toluene:ethyl acetate=8:20
Of1 3-18-(benzenesulfonyl)amino]-9-(2-cyanoethyl)-1.
2,3,4-tetrahydrocarbazole 10 g (0
．． 0263 mol) was hydrolyzed in the same manner as in Example 7. In this way, 7.57 g (68% of theory) of a crystalline product with a melting point of 100 DEG -185 DEG C. are obtained as the sodium salt.

11f = 0.44 CIl. CI:
CH, ton = 95: 5 In the same manner as in Example 18, the following compounds listed in Table 1 were produced.

Example X Yield itr Shi23 C1 80% 0.37
CIl□CL:Cllzoll = 95:528
F 75% 0.4 ClltClt:CI
IsOH” 95:533 Clls 48.
7%0.5 ClltClt:CIlaOfl”
95:5 Similarly to Example 19, the following compounds listed in Table 2 were prepared.

Length a
113011=9:1 103-4℃ petroleum ether to 29F 94% 0.7 C11zC12
:CHiOII"9:1 104-8℃ from petroleum ether 34 C11. 90.7% 0.57 CH2
Cl□: C11.011=95=5 The following compounds listed in Table 3 were prepared in the same manner as in Example ZO.

Actual mX yield Rf Melting point example l. −
□ 25 Cl 75.4% 0.52) Luene: Ethyl acetate 8: Z 1B3°C Ether to 30F 73% 0.39 C11. C12: CIl. O
H=99:1 148-9°C from ether: J5 C11. 55% 0.42 CH2Cl□
:C11.011=8:2 138-8℃ From in-proper tool, the following compounds listed in ii4 were prepared in the same manner as in Example 21! ! ! I left it behind.

Execution X Yield Rf Melting point example - Isao,
-2B CI 47% 0.35) Toluene: Ethyl acetate 8:2 204-6°C Ether/isopropanol to 31F 53% 0.29) Toluene: Ethyl acetate 8:2 206-8°C Ether/isopropanol 38C11385% 0.3'7) toluene:ethyl acetate 8:2 180-90°C From ether, the compound F listed in Table 5 was produced in the same manner as in Example 22.

Execution X Yield Rr Melting point No.
□□27
CI 89.5% 0.61 C112CI2:C
H3011=9:1 150℃Ha salt 32F 98.5% 0.57 C11□C
1z:CII*011”9:1 180-F ℃Na
Salt 37 C11,95% 0.53 C112C1,:
C11,011=9:l 150-60°C Ha salt-38 and 39 3-r-(4-fluorophenylsulfonamide)-9
-(2-carboxyethyl)-1eL3eL4a-te
9a-L-hexahydrocarbazole (isomer A),
3-r -(4-fluorophenylsulfonamido)-9-(2-carboxyethyl)-1,2,3,4,
4a-c,9diC-hexahydrocarbazole (isomer B) 5 g (0.0114 5.01 g (0.08 mol) of sodium cyanofluoride hydride are added in small portions at 0°C. The reaction mixture is allowed to reach room temperature, diluted with water and extracted with 2001 ethyl acetate. Hydroxide the ethyl acetate phase with 2N hydroxide in 1001 increments)
The sodium hydroxide phase is collected and adjusted to pH 5, extracted three times with 150 ml portions of methylene chloride, dried over sodium sulfate and thoroughly evaporated in vacuo. The residue was dissolved in silica sol (melting, 0.040 - 0.083
Chromatography on 500 g of the solution was eluted with a 100:1 mixture of methylene chloride and glacial acetic acid. In this way two fractions were obtained, each containing 2.87 g of isomer (A) (buried #jEt)tjO, 2% after evaporation.
),! =lt. Body (B) 0,7 g (bury wj1McF
) 14.9%) is obtained as a solid foam.

Rf of isomer (A): 0.24 CI1. CL: CH, COO11 = 100:
Rf of 2 isomer (B): 0.14 Residue ILj'υ and 41 3 -r-(benzenesulfonamide)-9-(2-carboxyethyl)-LLL'L4il-ty9a-t-
hexahydrocarbazole (isomer A) and 3 -r-(benzenesulfone 7mido) -9 -(
2-carboxyethyl)-1.2.3,4,4a-c,
9a-c-hexahydrocarbazole (isomer B) 1.18 g (0 ,0028 mol)
is reduced in the same manner as in Example 38. The chromatography yielded two fractions, which were evaporated to give isomer A O, 45 g (40% of the buried I!!i amount) and isomer Bo, z gD! I! 18% of theory) is obtained as a solid foam. Rf of isomer (A): 0.4C11
2C1! : C11, COO11= 100 : 4
Rf of isomer (B): 0.22 1, 1 3-r -(4-methylphenylsulfonamide) -
9-(2-carboxyethyl)-1y2J@414a-
ty9a-t-hexahydrocarbazole (isomer A) I and 3-r-(4-methylphenylsulfonamide)-
9-(2-carboxyethyl)(, L3,4,4a-c
, 9a-c''-xahydrocarbazole (isomer B) 18.6 g of the sodium salt of 3-(4-/tylphenylsulfonamylboxyethyl)-1,2,3,4-tetrahydrocarbazole were carried out. Reduction is carried out analogously to Example 38. Chromatography gives two fractions which, on evaporation, yield 3.65 g (20% of theory) of isomer A with a melting point of 156-62° C. in crystalline form. 11 g (6% of theory) of isomer B1 are obtained as a solid foam.

Rf of isomer A: 0.39 Rf of isomer B: 0.20 CI(, Cl□: CHsCOOII ” 100:
2 times 1 month - 3-(4-chlorophenylsulfone 7mide) -6 -
Fluoro-1,2,3,4-tetrahydrocarbazole! ! 4-(4-chlorophenylsulfone 7 mitohexanone 2
6.5 g are reacted analogously to Example 5 with 4-fluorophenylhydrazine. As a result, 35.4
g (100% of theory) of product are obtained as a solid foam.

Rf=0.53) Luene: Ethyl acetate: 8:2m
and 3-[N, (4-chlorophenylsulfonyl)-
(2-cyanoethyl)amino]-9-(2-cyanoethyl)-(!l-fluoro1,Z,:(,4-te)lahydrocarpazole M N 4-<4-90lophenylsulfonami)' )-6-fluoro-1.2,3.4-tetrahydrocarbazole 3
．． 4g was reacted in the same manner as in Example 6. In this way, 27.6 g (61% of theory) of product are obtained as a solid foam.

Rf = 0.25)
8: 2 dogs around 1 3-(4-chlorophenylsulfone 7mido)-9-(2
-carboxyethyl)-8-fluoro-1,2,C4-
Tetrahydrocarbazole 0OII 3-[N -(4-chlorophenylsulfonyl) -N
-(2-cyanoethyl)amino] -27.6 g of -9-(2-cyanoethyl)-6-fluoro-1,2,3,4-tetrahydrocarbazole is hydrolyzed in the same manner as in Example 7. In this way, 25.6 g (100% of fill) of a crystalline product with a melting point of 118-130 DEG C. are obtained.

Elf” 0.52 CH2Cl2 : CH3
011=9': IK (9-light 3- to tromethylcyclohexane 21.9, to nitromethane 175
ml and V5-no7zabicyclo[4,3,OJ-non-5-ene (DBN > 2.1 g with 250
ml of Improper Tool and leave at room temperature for Z days. Working up analogously to the procedure of Example 1 gives 37.2 g (100% of theory) of 3-(nitromethyl)cyclohexanone of sufficient purity to be used in the next reaction.

Rf =0,62 ClbC12: CH3011
"99: 1#promoted 3-(aminomethyl)cyclohexanol 3- is reduced with tromethyl using lithium aluminum hydride in the same manner as in Example 2. In this way, 3-(aminomethyl)cyclohexanol in the form of a viscous oil is reduced. Hexanolf, 5, (24.

5%) is obtained.

Rf = 0,04 CHsOH2: CH
3-(4-fluorophenylsulfonamidomethyl)cyclohexanol In the same manner as in Example 3, 5 g of 3-(aminomethyl)cyclohexanol was added to 11.3 , with 4-fluorophenylsulfonamide.

As a result, 11.05 g (theoretical amount of 6
6%) of a viscous oily isomer mixture is obtained.

Rf = 0.41 and 0.38 CHsOH2:
3-(4-Fluorophenylsulfonamidomethyl)cyclohexanone Oxidize 3-(4-fluorophenylsulfonamidomethyl) cyclohexanone with chromium dioxide in a similar manner to the procedure of Example 4. do.

This results in 9.3 g (J!!!86% of theory) of product as a solid foam.

1 (f = 0.86 CH.CI2: C113
0H = 9: 1ゑm-shadow.

4-(4-fluorophenylsulfone-7midomethyl)-
i.

2, t 3 t 4-Tetrahydrocarbazole Analogously 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. Add this to 1kfr of silica sol (merry, 0
．． 04-0.063 am) and eluted with a mixture of toluene and ethyl acetate in a ratio of 8:2. As a result, when one fraction is evaporated, 0.
8 g (7.2% of theory) of product are obtained as a solid foam.

Rf = 0.44) Luene: Acetic acid ]-1,2,3,4-tetrahydrocarbazole N? N Analogous to the procedure of Example 6, 0.8 g of 4-(4-7-tetraphenylsulfonamidomethyl)-1,2,3,4-tetrahydrocarbazole is reacted with 7-crylonitrile. As a result, 0.91 g (111iiF1
88% of the product is obtained as an oil.

Rf = 0.37) Luene: Ethyl acetate = 8:2 3,4-tetrahydrocarbazole L(2-7/ethyl)-4-[N-(4-7LuoU7zWrusulfonyl)-N-(2-cyanoethyl)aminomethyl](t2tL4-tetrahydrocarbazole0 .91 g are hydrolyzed analogously to Example 7. In this way, 0.77 g of crystalline product (at
89%) is obtained as the sodium salt.

Melt #%: 160 G Rf = 0.57 C112C1□: Cal,
300 g of paracetamol are hydrogenated in 7501 ethanol with 30 g of Raney nickel at 18 G'C1100 bar. When the absorption of hydrogen was completed, the catalyst was removed by filtration, 30 g of 2N was added, and the temperature was heated to 180°C.
, repeat the hydrogenation at an excess pressure of 100 bar I), then remove the catalyst by filtration and evaporate the filtrate in vacuo,
Add Zoo Theory 1 acetone to the still wet residue and stir. 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. Up to the third patch, total amount 342.4 g
(80.8% of theory) of product is obtained.

Melting point: 100-103℃ Dog [Omi 3-7 Minnow 1.2,3.4-tetrahydrocarbazole (racemic) ■ 50 g of 4-N-7 cetamide cyclohexanol in 1 part of 400 carbon dioxide glacial acetic acid (0,318 31.8 g (0,318 mol) of chromium trioxide was dissolved in 26
A solution of Theory 1 in a mixture of water and 105 ml of glacial acetic acid is added with stirring at room temperature. As a result, the temperature of the reaction solution rises to 60°C. This reaction mixture was
Time Ill! Added, then phenylhydranone 45.7
g (0,423 mol) is added. As a result, the reaction solution is heated to 80° C. and the first evolution of nitrogen 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 for 16 hours under nitrogen. Heat for an hour. 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 was removed by suction filtration through a bed of diatomaceous earth and diluted with methylene chloride/chloride in a ratio of 9:1.
Wash with methanol mixture. 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 11 portions of 2N sulfuric acid. The filtrate aqueous phase is made alkaline with 45% strength sodium hydroxide solution and extracted three times with 1 liter portions of methylene chloride. The methylene chloride phases are combined, dried over sodium phosphate and evaporated.

Add 300 parts of ether and 50 parts of Improper Tool to the residue and stir the mixture. The precipitated product is filtered off with suction, washed with ether and dried in vacuo. 28.6 g (48.3% of the amount of 11 u) of product are obtained.

Melting point: 174-176°C 3-t2s-(chloro7cetamide)-3-phenylpropionamide]-1,2,3,4-tetrahydrocarbazole (noastereomer mixture) 3-ami/-1, 43 g (0,231 mol) of 2,3,4-tetrahydrocarbazole and 55.87 g (0,231 mol) of tochloroacetyl-L-phenylalanine were suspended in 1.51 methylene chloride with OC under nitrogen. , 115.2 ml (0,832 mol) of triethylamine are added.

Then, at -20°C, 150 ml of a 505 strength methylene chloride solution of propanephosphonic anhydride was added to the reaction mixture.
(0,231 mol) is added completely. This at -20℃
Stir for 30 minutes at 0.degree. C. and then for 1.5 hours at 0.degree. For work-up, the reaction mixture was heated with 1fNO2N 111
tate, 11. Wash twice with saturated solution of bicarbonate, 1:1 and 1:1. Drying over IJ sulfuric acid and evaporation gives 100 g of a solid residue.

'57 and 58 3 (2s-(chloroacetamide)-3-phenylpropionamide]-1,2,3,4-tetrahydrocarbazole (noastereomer-A and diastereomer-B
a) Resolution of noastereomers by column chromatography 100% of the crude product of Example 56 as a fluid phase:
Silica sol (0,063 to 0.2 mm, Merck) using a toluene/ethyl acetate mixture in a ratio of 4 to 2.5
chromatograph. In this way two divisions are obtained, the first of which is evaporated into 34 g (35.9 g of Jlfl!rftt).
%) is obtained (Example 57).

Melting point: 217-220°C Evaporation of the second fraction yields other noastereomer-82
4.3g (J!f!25.7% of theory) is obtained (
Example 58).

Melting point: 193-195°C Optical rotation of norstereomer-A 2 [αJ ” = 32.5
9° (CH, 011> (Example 57) 97
1] ” = 5.09' (C113011) (Example 58) b) Resolution of diastereomers by crystallization 11.5 g of the crude product of Example 5B are stirred in a mixture of ether and Impropatol. The crystals were separated by suction filtration, and
Heat under reflux for 3 hours in 1 of acetone. After cooling and standing overnight, the product is filtered off with suction and washed with acetone. In this way, pure norastereomer-A 1.
2 g (5.5% of buried il!rm) is obtained (Example 57).

and (9-tan 3-7 minnow i, z, a, +-tetrahydrocarnoizole (enantiomer A) noastereomer (5)) 24.1 g (0,059
mol) in 460 all glacial acetic acid. Dark j!
Add 1 part of M 460 Tsuru and 241 parts of thioglycolic acid,
Heat to reflux temperature for 3 days under nitrogen. The reaction mixture was then diluted with 200 ml of water and 45 ml of water was added while cooling.
% strength sodium hydroxide S solution is added to adjust the pH to 5. Then extracted twice with 1.51 parts of ethyl acetate,
The aqueous phase is made alkaline using 45% strength sodium hydroxide solution and extracted three times with 1.51 portions of ethyl acetate. The ethyl acetate extracts were collected and dried with sodium sulfate;
Evaporate.

The residue is stirred in 150 ml of ether. The precipitated product is filtered off with suction and dried in vacuo.

7.1 (g (71.3% of theory) of enantiomer
A is obtained.

Melting point: 160-166°C Optical rotation tαJ ” = 78.38° (DNSO + 10% water) 3-7my-1,2,3,4-tetrahydrocarbazole (enantiomer B) Enantiomer B can be obtained from (57) to ( It was produced by hydrolysis of (58) in the same manner as in the procedure for (59).

Melting point: 162-167°C Optical rotation [a J ” = -78,11” (0850+
10% water) [3,3-ethylenenooxy-1. Z, 3,4-tetrahydrocarbazole 1,4-cyclohemol/ethylene ketal 7
), 2 g (0.5 mol) of phenylhydranone 48
．． 41 (0.5 mol), 2Z is dissolved in methylene chloride, magnesium sulfate aOO is added, and the mixture is stirred for 30 questions. The magnesium sulfate is then filtered off with suction, washed with methylene chloride and the filtrate is evaporated. The residue is taken up in 1.51 g of benzene, 62.1 g of anhydrous zinc chloride (0.46 mol) is 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 (72.9% of theory) of product is obtained.

Melting point: 145-148° C. 1.2,4.9-Tetrahydrocarbazol-3-one I 165 g (0.72 mol) of 3.3-ethylenenooxy-LLL4-tetrahydrocarbazole in 21 mol of acetone Dissolve and add all 3 g of p-)luenesulfonic acid. After heating the reaction solution under reflux for 4 hours, it is concentrated, 21 parts of ethyl acetate are added, and the mixture is extracted three times with 11 parts of saturated carbonate solution. gM of organic phase
Dry with W1 sodium and evaporate. The residue is crystallized from ether. In this way, 118.7 g (89.1% of the weight) of product are obtained.

Melting point: 145-148°C
4-Tetrahydrocarbazole 1! 1.2.4.9-Tetrahydrocarbazol-3-one (11.06 g < 0.0595 mol) with 7.78 g (0,065 mol) of 13-phenylethyl 7mine in 300 so l benzene. , attach a water separator and heat under reflux for 1 hour. After removing the benzene by evaporation, the residue was dissolved in 50111 methylene chloride,
This solution was mixed with horahydride tetrabutylammonium 15
．． 3 g (0,0595 mol) is added neatly to a solution of 1201 in methylene chloride at -50°C.

The reaction mixture was returned to room temperature within 1 hour, 6 ml of methanol was added, and 1201 2N sulfuric acid was carefully added (hydrogen generation). After stirring at room temperature for 1 hour, the precipitated crystals were filtered off with suction. and diluted twice with water and once with methylene chloride.
Wash twice. When dried under high vacuum, 0.18 g (
39.7% of theory) of product is obtained as hydrogen sulphate.

Melting point: 160-170°C Optical rotation: [al”°=28.36° (C1130H/
l+, 0 = 80: 20) ILL-3-amino/-1,2,3,4-tetrahydrocarbazole (enantiomer A) 1 Compound of Example 64 prepared by method B is identical to that of Example 59 It is. ] To convert 10 g of the hydrogen sulfate obtained in Example 53 into the hydrochloride, suspend it in 5011 methanol, 2N hydroxide, add 30 111 of a +7um solution, and extract the mixture with ethyl acetate. do. evaporate the organic phase;
The residue is dissolved in 50-1 methanol and 20 ml of concentrated hydrochloric acid are added. Upon concentration in vacuo, the hydrochloride salt precipitates out. After filtering off with suction, washing with water and drying in vacuo, 7.6 g of the hydrochloride are obtained. This 7.6 g (
0,023 mol) of hydrochloride, 7.1 mol of ammonium formate
7 g (0,115 mol) and 7.2 g of palladium on activated carbon at 10% in 80 ml of dry dimethylformamide under reflux (under nitrogen).
Heat for 20 minutes. After cooling, the mixture is diluted with water,
The catalyst is filtered off with suction and washed with water. The ma was collected, acidified with 2N sulfuric acid, and extracted twice with ethyl acetate. water phase to 2N
Make alkaline with +7um solution and extract three times with ethyl sulfate. The organic phase was dried with sodium sulfate and
Evaporate. The residue is further evaporated under vacuum to remove dimethylformamide. 3g (70% of the theoretical amount
) is obtained from ether.

Melting point: 16o -186℃ Optical rotation [a] ”=78.38” (DHSO+10
% of water)
,3,4-tetofhydrorubazole (enantiomer A) 3.72 g (0.02 mol) of the product of Example 59 are suspended in 30 ml of methylene chloride with triethylamine 3 all (0.022 mol). , while cooling, add 3.9 g (0.02 mol) of 4-fluorobenzenesulfonyl chloride. 11 liters of this reaction mixture at room temperature. Ii agitation, then 200 m
1 of ethyl acetate, and then diluted twice with 2N sulfuric acid and 2N sulfuric acid.
Extract twice with sodium hydroxide solution. organic phase in vAt
Il! ! Dry with sodium and evaporate. Ether to solid residue? Crystallize at 67 Jl. 5.8g
(84% of theoretical) product is obtained.

Melting point: 150-152°C Optical rotation: [α12° = 50.43° (CIICI,)
The product of Example 60 was prepared in a similar manner to the preparation of Example 65 from the compound of Example 59. Create enantiomer B!!

Melting point: 150-152'C Optical rotation: [(21°=-4(t.99''(CllCl
*) Aitake-wang 3-(N-(4-fluorophenylsulfonyl)ami/
]-9-(2-cyanoethyl)-1,2,3,4-tetrahydrocarbazole (enantiomer A) N 5.18 g (0,015 mol) of the product of Example 65
is dissolved in 200 ml of trimethylformamide under nitrogen and 0.5 g (Q, 0165 ml) of sodium hydride is added in portions with 20% spindle oil. When the evolution of hydrogen is complete, 1 part (0.03 mol) of 7-acrylonitrile is added to the reaction mixture. After stirring at room temperature for 1 hour, 7crylonitrile 0.5
ul is added again and the mixture is stirred at room temperature for 1 hour. Dilute with 1N ethyl acetate and extract three times with water. The ethyl acetate phase is dried over sodium sulfate and evaporated. In this way 7.8 g of the product are obtained. Chromatograph using silica sol (o, oaa to 0.2 so-) and elute with a toluene/ethyl acetate mixture in a ratio of 1:1. After evaporation, 5.8
A fraction is obtained giving g (86% of theory) of product as a solid foam.

Biscyanoethyl adduct (3(N-(4-fluorophenylsulfonyl) -N -(2-cyanoethyl)amino J-9-(2-cyanoethyl)-1,2,3,4-
Tetrahydrocarbazole) is prepared under the conditions shown in Example 6.

Kakai 1-3-IN-(4-fluorophenylsulfonyl) -N
-(2-cyanoethyl)amide J -9-(2-cyanoethyl)-1,2,3゜4-tetrahydrocarbazole (enantiomer-B) (mN Vin) Manufactured from Example 6 from the compound of Example 65 The compound of Example 68 is prepared from the product of Example 66 in a manner analogous to that of Example 68.

K 凰迩”夛(10)-3-(4-fluorophenylsulfonamide)
-9-(2-carboxyethyl)-1t2tL4-tetrahydrocarbazole 0OII 5.8 g (Q, 0128 mol) of the product of Example 67 are dissolved in 60 ml of Impropatul and 130 ml of 10% strength potassium hydroxide solution ml 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 the gradual addition of concentrated hydrochloric acid with vigorous stirring. During this time, the precipitated acid was filtered off with suction and washed with water.
Dry thoroughly in vacuum. 4.4 g (physical weight 86
．． 6%) of product is obtained.

Melting point: 85 -95 °C Optical rotation 2 [α] ” = 42,55 ° (ClIC1a)
K-jLj-(-)-3-(4-fluorophenylsulfonyl/
)-9-(2-carboxyethyl)-LtL3t4-tetrahydrocarbazole0OII The compound of Example 70 was prepared from the product of Example 68 in a manner similar to the method used to prepare Example 69 from the compound of Example 6F. Manufacture.

Melting point: 85-95°C Optical rotation "t, a12° = -3f, 83' (Cl1C13
)(+)-3-Amino-L2t3t4-tetrahydrocarbazole racemate 3-7 minnow 18.8 g (0.1 mol) of (+)-mandelic acid 15.2 g (0,1 mol) and 100
Heat under reflux in a 7 ml run of tetrahydro. Once a clear solution was obtained, it was cooled and a spatula full of (+)-3-amino-1゜2.3.4-tetrahydrocarbazole (enantiomer A, Example 59) (+)-mandelate salt was added. Add as seed crystals. The mixture is stirred overnight and the precipitated crystals are filtered off with suction.

In this way, substances enriched as enantiomers6.
05 g is obtained. 4.7 g of these crystals are dissolved in 330-1 boiling methyl in butyl ketone, and after cooling slightly, seeds are added to the solution and stirred while continuing to cool. After filtering off with suction and washing with methyl imbutyl ketone, 3.4 g of (+)-a-ami/-1,2,3,4-tetrahydrocarbazole are obtained as the (+)-mandelate salt.

X1 Sat L Col Blood from healthy subjects of both sexes was used to measure the platelet aggregation inhibitory effect. 1 part of a 3.8% strength aqueous solution of sodium citrate to 9 parts of blood is mixed as an anticoagulant. This blood is centrifuged to obtain platelet-rich citric plasma (PRP) (Nildens/Bella (Jurg)
er+9/1ler) *Clinical analysis method of blood coagulation (K11nische Methoden der
Old uLgerinnnung? ! analysis); Chieme Publishing (°1°hieme, Stuttgart)
, 1959).

For this study, 0.8 so 1 PRP and 0.1 ml
of active compound S in a water bath at 37°C.

Subsequently, at 37°C, an aggregometer
Platelet aggregation was measured by turbidity method using
, Pbysiol.

(London) = 162-19 (52 and medical telegram (1° herapeutische Berich
t, e) 47.80-88.1975), for this purpose, 0.1 liter of aggregation inhibitor collagen is added to the prewarmed sample. 1) Optical density (opti) of RP sample
changes in cal denxity) were recorded for 6 minutes, and
Measure the transition after minutes. For this purpose, the percentage inhibition is calculated in comparison with the control example.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O) __mR^3 (In this formula, R^3 represents alkyl or aryl, and m represents the number 0, 1, or 2), or the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (this formula R^4 and R^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in which R ^6 represents hydrogen, alkyl, aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2-, or trifluoromethyl), or all of them represent carboxyl, alkoxycarbonyl, halogen, hydroxyl , alkyl, alkenyl or cycloalkyl which may be substituted by alkoxy, alkylthio or cyano, R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonyl Alkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In this formula, R^4 and R^5 are the above cycloalkanoyl, optionally in isomeric form, wherein x represents the number 1, 2 or 3 and y represents the number 0 or 1; [1,2-b]
Indole sulfonamide or its salt. 2. In the above formula, R^1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl, or lower alkoxycarbonyl, or the formula -S(O)_mR^3 (in this formula, R^3 represents lower alkyl or phenyl, m is the number 0
or 2), or the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (In this formula, R^4 and R^5 may be the same or different, hydrogen, lower alkyl , phenyl, benzyl or acetyl) or a group of the formula -OR^6 in which R^6 is hydrogen, lower alkyl, phenyl, phenyl-S
O_2-, methyl-SO_2-, ethyl-SO_2-, or trifluoromethyl), or each represents a group of carboxyl, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, lower alkyloxy or cyano represents lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl, which may be substituted with Carboxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, lower alkoxy, lower alkylthio, hydroxyl, carboxyl, lower alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by the formula ▲ mathematical formula, chemical formula, table, etc. ▼ represents phenyl, which may be substituted up to 3 by the groups (in this formula, R^4 and R^5 have the above meanings), x represents the number 1, 2 or 3, and y represents the number Cycloalkano[1,2-b]indole sulfonamide or a salt thereof, as appropriate in the isomeric form, according to claim 1, characterized in that it represents 0 or 1. 3. In the above formula, R^1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amino, dimethylamino, diethylamino, or acetylamino;
or represents a group of the formula -OR^6 (in this formula, R^6 represents hydrogen, C_1-C_4-alkyl, phenyl or benzyl), or represents C_1-C_4-alkyl, and R^2 is the same selected from fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C_1-C_4-alkyl, C_1-C_4-alkoxy, methylthio, hydroxyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetylamino or diethylamino or phenyl substituted up to 3 with different substituents, x represents the number 1 or 2, and y represents the number 0 or 1, claim 1 or 2, characterized in that: The cycloalkano[1,2-b
] Indole sulfonamide or its salt. 4. Formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R^1 represents hydrogen, fluorine, methyl, methoxy, benzyloxy, or hydroxyl, R^2 represents fluorine, chlorine, trifluoromethyl, methyl,
Cycloalkano-[1,2-b] according to any one of claims 1 to 3, wherein cycloalkano-[1,2-b] represents phenyl substituted with ethyl, propyl, isopropyl or methoxy, and y represents the number 0 or 1. - (+) or (-) isomer of indole sulfonamide or a salt thereof. 5, (+)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,3,4
-Tetrahydrocarbazole. 6, (-)-3-(4-fluorophenylsulfonamide)-9-(2-carboxyethyl)-1,2,3,4
-Tetrahydrocarbazole. 7. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this formula (in which R^3 represents alkyl or aryl, m represents the number 0, 1, or 2), or there is a formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in this formula, R^4 and R ^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in this formula, R^6 represents hydrogen, alkyl , aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano represents alkyl, alkenyl or cycloalkyl, which may be substituted by , R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, by hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by a group of the formula ▲a mathematical formula, a chemical formula, a table, etc.▼ (in which R^4 and R^5 have the meanings given above) represents aryl which may be substituted up to 5 by cycloalkano[1,2-b ]
Indole sulfonamide or its salts for therapeutic treatment. 8. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this In the formula, R^3 represents alkyl or aryl, and m represents the number 0, 1, or 2), or the formula ▲ is a mathematical formula, chemical formula, table, etc. R^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in this formula, R^6 is hydrogen, alkyl, aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or represents alkyl, alkenyl or cycloalkyl, which may be substituted by cyano, R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio , hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy,
Aryl which may be substituted up to 5 by benzyloxy or benzylthio or by a group of the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in which R^4 and R^5 have the meanings given above) , x represents the number 1, 2 or 3, and y represents the number 0 or 1 [benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole in the presence of an inert solvent,
React with acrylonitrile, optionally in the presence of a base,
Next, this N,N'-biscyanoethyl compound is hydrolyzed, and then, in the case of producing cycloalkano[1,2-b]dihydroindolesulfonamide, this cycloalkano[1,2-b]indole sulfonamide is is hydrogenated in the presence of an acid and a reducing agent, optionally in the presence of an inert solvent, and the isomers are separated, optionally by conventional means,
Then, when producing a salt, there are formulas that are characterized by reaction with an appropriate base ▲ Numerical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1, R^2, x and y are cycloalkano[1,2-b] with the above meaning, optionally in isomeric form
A method for producing indole sulfonamide or a salt thereof. 9. R^1 in the above formula represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or lower alkoxycarbonyl, or the formula -S(O)_mR^3 (in this formula, R^3 is Represents lower alkyl or phenyl, m is number 0
or 2) or of the formula (in which R^4 and R^5 may be the same or different and represent hydrogen, lower alkyl, phenyl, benzyl or acetyl) represents a group or has the formula -OR^6 (in this formula, R^6 is hydrogen, lower alkyl, phenyl, phenyl-S
O_2-, methyl-SO_2-, ethyl-SO_2-, or trifluoromethyl), or each represents a group of carboxyl, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, lower alkyloxy or cyano represents lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl, which may be substituted with Carboxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, lower alkoxy, lower alkylthio,
It may also be substituted up to 3 by hydroxyl, carboxyl, lower alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio or by groups of the formula in which R^4 and R^5 have the meanings given above. represents a certain phenyl, x represents the number 1, 2 or 3, y represents the number 0 or 1 [benzenesulfonamidoalkyl]cycloalkano[
1,2-b] characterized by using indole,
A process for producing cycloalkano[1,2-b]indole sulfonamides, optionally in isomeric form, as claimed in claim 8. 10. R^1 in the above formula represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methylthio, ethylthio, methylsulfonyl, phenylthio, phenylsulfonyl, amino, dimethylamino, diethylamino, or acetylamino;
or represents a group of the formula -OR^6 (in this formula, R^6 represents hydrogen, C_1-C_4-alkyl, phenyl or benzyl), or represents C_1-C_4-alkyl, and R^2 is the same selected from fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C_1-C_4-brukyl, C_1-C_4-alkoxy, methylthio, hydroxyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, acetylamino or diethylamino or phenyl substituted up to 3 with different substituents, x represents the number 1 or 2, and y represents the number 0 or 1 [benzenesulfonamidoalkyl]cycloalkano[
1,2-b] characterized by using indole,
A process for producing cycloalkano[1,2-b]-indolsulfonamides, appropriately in isomeric form, as claimed in claim 8 or 9. 11. Claims 8 to 10, 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. The method described in any of the above. 12. Claims 8 to 11, characterized in that acrylonitrile and [benzenesulfonamidoalkyl]-cycloalkano[1,2-b]indole are used in a ratio of 1 to 20 moles to 1 mole. The method described in any of the above. 13. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this formula (in which R^3 represents alkyl or aryl, m represents the number 0, 1, or 2), or there is a formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in this formula, R^4 and R ^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or a group of the formula -OR^2 (in which R^2 represents hydrogen, alkyl , aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano represents alkyl, alkenyl or cycloalkyl, which may be substituted by , R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, by hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by a group of the formula ▲a mathematical formula, a chemical formula, a table, etc.▼ (in which R^4 and R^5 have the meanings given above) [Benzenesulfonamidoalkyl]cycloalkano[1,2-b]indole represents aryl which may be substituted up to 5 by . 14. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this In the formula, R^3 represents alkyl or aryl, and m represents the number 0, 1, or 2), or the formula ▲ is a mathematical formula, chemical formula, table, etc. R^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in this formula, R^6 is hydrogen, alkyl, aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or Phenylhydrazine, which represents alkyl, alkenyl or cycloalkyl, which may be substituted by cyano, is expressed by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R^2 is halogen, cyano, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy,
Aryl which may be substituted up to 5 by benzyloxy or benzylthio or by a group of the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in which R^4 and R^5 have the meanings given above) , x represents the number 1, 2 or 3, and y represents the number 0 or 1 is reacted with a cycloalkanone sulfonamide in the presence of an inert solvent and optionally in the presence of a catalyst. There are formulas, mathematical formulas, chemical formulas, tables, etc., which are characterized by: [benzenesulfonamidoalkyl]cycloalkano[1, 2-b] Method for producing indole. 15. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxyl , by carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by a group of the formula ▲ which is a mathematical formula, chemical formula, table etc. ▼ (in which R^4 and R^5 have the meanings given above) represents an aryl which may be substituted up to 5; x represents the number 1, 2 or 3; y represents the number 0 or 1; a ketone; 16.Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼In the formula, x represents the number 1, 2 or 3, and y represents the number 0 or 1.The cycloalkanol is represented by the formula Hal-SO_2-R^2. R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio; or formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In this formula, R^4 and R^5 have the above meanings) represents aryl which may be substituted up to 5 times, and Hal is fluorine. , a sulfonyl halide representing chlorine, bromine or iodine in an inert organic solvent, optionally in the presence of a base, and then oxidized in an inert solvent▲Mathematical formula, chemical formula , tables, etc. ▼ Method for producing cycloalkanone sulfonamide where R^2, x and y have the above meanings. 17. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this formula (in which R^3 represents alkyl or aryl, m represents the number 0, 1, or 2), or there is a formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in this formula, R^4 and R ^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in this formula, R^6 represents hydrogen, alkyl , aryl, aralkyl, alkyl-SO_2, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano represents optionally substituted alkyl, alkenyl or cycloalkyl, R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, hydroxyl , by carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by a group of the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in which R^4 and R^5 have the above meanings) cycloalkano[1,2-b], optionally in isomeric form, represents aryl which may be substituted up to 5, x represents the number 1, 2 or 3, y represents the number 0 or 1;
A pharmaceutical containing indole sulfonamide or a salt thereof. 18, 0.5 to 50% by weight of the above cycloalkano[
1,2-b] Indole sulfonamide and/or a salt thereof. 19. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, or the formula -S(O)_mR^3 (this formula (in which R^3 represents alkyl or aryl, m represents the number 0, 1, or 2), or there is a formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in this formula, R^4 and R ^5 may be the same or different and represent hydrogen, alkyl, aryl, aralkyl or acetyl) or -OR^6 (in this formula, R^6 represents hydrogen, alkyl , aryl, aralkyl, alkyl-SO_2-, aryl-SO_2-, aralkyl-SO_2- or trifluoromethyl), or each represents a group of carboxyl, alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyano represents alkyl, alkenyl or cycloalkyl, which may be substituted by , R^2 is halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxy, alkylthio, by hydroxyl, carboxyl, alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzylthio, or by a group of the formula ▲a mathematical formula, a chemical formula, a table, etc.▼ (in which R^4 and R^5 have the meanings given above) represents aryl which may be substituted up to 5 by cycloalkano[1,2-b ]
Use of indole sulfonamide or a salt thereof for the manufacture of a medicament for the treatment of diseases. 20, platelet aggregation inhibitor or thromboxane A_
2. The method for producing a 2-antagonist according to claim 19.