Title of Invention	"1H-PYRIDO (3,4-B) INDOLE-4-CARBOXAMIDE DERIVATIVES,"
Abstract	Compounds of general formula (I) in which X represents hydrogen or a halogen or an alkyl, alkoxy, trifluoromethyl or phenylmethoxy group, R1 represents hydrogen or an alkyl, cyclopropyl or phenylmethyl group, R2 represents either an optionally substituted alkyl group or an optionally substituted phenylalkyl group or a cyclohexylmethyl group or a thienylmethyl group or a pyridinylmethyl group or an optionally substituted phenyl group or a pyridinyl group or a 5-methyl-1,2-oxazolyl group or a 5-methyl-1,3,4-thiadiazolyl group or a naphthyl group, R1 and R4 each represent hydrogen or an alkyl, 2-methoxyethyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl or phenylalkyl group or else together form, with the nitrogen atom which carries them, either an optionally substituted pyrrolidinyl group or a piperidinyl group or a morpholinyl group or a 4-methylpiperazinyl group or an azetidinyl group or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is single or double. Application in therapeutics. S

Title of Invention

"1H-PYRIDO (3,4-B) INDOLE-4-CARBOXAMIDE DERIVATIVES,"

Abstract

Compounds of general formula (I) in which X represents hydrogen or a halogen or an alkyl, alkoxy, trifluoromethyl or phenylmethoxy group, R1 represents hydrogen or an alkyl, cyclopropyl or phenylmethyl group, R2 represents either an optionally substituted alkyl group or an optionally substituted phenylalkyl group or a cyclohexylmethyl group or a thienylmethyl group or a pyridinylmethyl group or an optionally substituted phenyl group or a pyridinyl group or a 5-methyl-1,2-oxazolyl group or a 5-methyl-1,3,4-thiadiazolyl group or a naphthyl group, R1 and R4 each represent hydrogen or an alkyl, 2-methoxyethyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl or phenylalkyl group or else together form, with the nitrogen atom which carries them, either an optionally substituted pyrrolidinyl group or a piperidinyl group or a morpholinyl group or a 4-methylpiperazinyl group or an azetidinyl group or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is single or double. Application in therapeutics. S

Full Text	The subject of the present invention is 1H-pyrido[3,4-b]indole-4-carboxamide derivatives, their preparation and their application in therapeutics. The compounds of the invention correspond to the general formula (I) in which X represents a hydrogen or halogen atom or a (C1-C3) alkyl, (C1-C3) alkoxy, trifluoromethyl or phenylmethoxy group, R1 represents a hydrogen atom or a (C1-C3) alkyl, cyclopropyl or phenylmethyl group, R2 represents either a (C1-C3) alkyl group optionally substituted by a methoxy group, or a phenyl(C1-C3)alkyl group optionally substituted on the phenyl ring by a halogen atom or a methyl or methoxy group, or a cyclohexylmethyl group, or a thienylmethyl group, or a pyridinylmethyl group, or a phenyl group optionally substituted by one or more halogen atoms or a (C1-C3)alkyl or (C1-C3) alkoxy group, or a pyridinyl group, or a 5-methyl-l,2-oxazolyl group, or a 5-methyl- 1,3,4-thiadiazolyl group, or a naphthyl group, R3 and R4, independently of one another, each represent a hydrogen atom, a (C1-C3)alkyl group, a 2-methoxyethyl group, a hydroxy (C2-C4) alkyl group, a carboxy- (C1-C3)alkyl group, a (C1-C3) alkoxycarbonyl (C1-C3) alkyl group or a phenyl (C1-C3) alkyl group, or else together form, with the nitrogen atom which carries them, either a pyrrolidinyl group optionally substituted by a hydroxyl, ethoxy, methoxycarbonyl or methoxymethyl group, or a piperidinyl group, or a morpholinyl group, or a 4-methylpiperazinyl group, or an azetidinyl group, or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is single or double. Depending on the nature of this bond, a compound according to the invention can optionally exist in the form of a pure optical isomer or of a mixture of such isoxners. The preferred compounds are those in the general formula of which X is in the 6 position and represents a fluorine atom, R1 represents a methyl group, R2 represents a phenyl group, R3 represents a methyl group and R4 represents an ethyl group or else R3 and R4 form, with the nitrogen atom which carries them, a pyrrolidinyl ring. The compounds of general formula (I) can be prepared by processes illustrated in the following schemes. According to Scheme 1, the starting compound corresponds to the general formula (II), in which X is as defined above and R1 is as defined above; when R1 represents hydrogen, it is possible, if desired, to carry out an alkylation in order to produce a compound of general formula (II) in which R1 represents a (C1-C3)alkyl group. The compound of general formula (II) is thus reacted with ethyl pyruvate of formula (III), in acidic medium, for example in the presence of gaseous hydrochloric acid in ethanol or in the presence of sulphuric acid or of boron trifluoride etherate in acetic acid, between room temperature and the reflux temperature, in order to obtain the diester of general formula (IV). The latter is then treated in ethanol at the reflux temperature with an amine of general formula R2NH2, in which R2 is as defined above. An ester of general formula (V) is obtained, which is converted to the corresponding acid, of general formula (VI), by hydrolysis in basic medium. This acid is then converted to the primary, secondary or tertiary amide of general formula (I") by reaction with an amine of general formula HNR3R4, in which R3 and R4 are as defined above, either through the imidazolide obtained by reaction with N,N"-carbonyldiimidazole or through the acid chloride. In the compound of general formula (I") thus obtained, the bond between the 3 and 4 positions is a single bond. If it is desired to prepare a compound in which this bond is a double bond, a compound of general formula (I") is oxidized by means of 2,3-dichloro- 5,6-dicyanocyclohexa-2,5-diene-l,4-dione or of 3,4,5,6-tetrachlorocyclohexa-3,5-diene-l,2-dione, in a solvent such as toluene or dichloromethane, between room temperature and the reflux temperature, in order to obtain the corresponding compound, in the structure of which the bond between the carbon atoms in the 3 and 4 positions is double, which respectively has the general formula (I""): Finally, and if it takes place, the enantiomers can be prepared from the racemates according to any known method; thus, for example, an acid of general formula (VI) can be reacted with an optically pure chiral amine, such as a-methylbenzylamine, and the diastereoisomers can be separated by fractional crystallization in order to arrive at an optically pure acid and then at the esters and amides which derive therefrom. In the case of an optically pure acid of general formula (VI), the non-racemizing coupling reaction can be carried out by any known method, for example with use of (benzotriazol-1-yloxy)tris- (pyrrolidin-1-yl)phosphonium hexafluorophosphate. In the case where R2 is an aromatic ring, it is possible, if desired, to convert the diester (IV) to the amide (VII) by heating the reaction mixture at a temperature of 100 to 200°C, in an inert solvent or without solvent, for example at reflux of the corresponding amine of general formula R2NH2. It is then possible to convert the compound of general formula (VII) either to the ester of general formula (V), in refluxing ethanol, in acidic medium, for example in the presence of concentrated hydrochloric acid, or to the acid of general formula (VI), by hydrolysis in basic medium. The starting compounds of general formula (II) , mainly with R1=H, are described in the literature; the pyruvate of formula (III) is commercially available. According to Scheme 2, the starting compound corresponds to the general formula (VIII), in which X is as defined above. This compound is reacted with 2-ketoglutaric acid and is then treated in an acidic alcoholic medium, for example in ethanol saturated with gaseous hydrochloric acid, at the reflux temperature, in order to obtain the diester of general formula (IX), in which R represents a (C1-C3)alkyl group. If desired, an alkylation reaction of this compound is then carried out, in order to obtain the compound of general formula (X), in which R1 represents a (C1-C3)alkyl group, and then the latter is converted, in a protic solvent, for example N,N-dimethylformamide, in the presence of dimethylformamide dimethyl acetal, at the reflux temperature, in order to obtain the compound of formula (XI). If desired, the compound of general formula (IX) can be directly converted to the compound of general formula (XI), in which R1 represents a methyl group, under the conditions described above. The compound of general formula (XI) is then treated with an amine of general formula H2NR2, in which R2 is as defined above, in a protic solvent, for example N,N-dimethylformamide, optionally in the presence of an acid, for example 4-methylbenzenesulphonic acid, at the reflux temperature, in order to obtain the ester of general formula (V"). The latter is converted to the corresponding acid of general formula (VI") by hydrolysis in basic medium. Finally, this acid is converted to the primary, secondary or tertiary amide of general formula (I""), either through the imidazolide obtained by reaction with N,N"-carbonyldiimidazole or through the acid chloride. The starting compounds of general formula (VIII) are commercially available. Some compounds of general formulae (IX) and (X) are described in the literature According to Scheme 3, the starting material is the diester of general formula (X), described with respect to the process of Scheme 2. This diester is hydrolysed in acidic medium in order to obtain the diacid of general formula (XII), which is converted to the anhydride, for example by using acetyl chloride at the reflux temperature, in order to obtain the compound of general formula (XIII). The latter is converted, by reaction with an, amine of general formula HNR3R4, in which R3 and R4 are as defined above, in a chlorinated solvent, for example dichloromethane, in order to obtain the compound of general formula (XIV), which is converted to the ester of general formula (XV), the latter is then treated in a protic solvent, for example N/N-dimethylformamide, in the presence of dimethylformamide dimethyl acetal, at the reflux temperature, in order to obtain the compound of general formula (XVI), and, finally, the latter is reacted with an amine of general formula R2NH2, in which R2 is as defined above, in a protic solvent, for example N,N-dimethylformamide, optionally in, the presence of an acid, for example 4-methylbenzenesulphonic acid, at the reflux temperature, in order to obtain the compound of general formula (I""). Finally, if desired, a secondary amide of general formula (I""), in which R3 or R4 represents hydrogen, can be converted to the tertiary amide by an alkylation reaction known to a person skilled in the art, by means of an alkylating agent, for example an alkyl halide. Likewise, a compound of general formula (I") or (I""), in which R1 represents a hydrogen atom, can be converted to a compound, in the formula of which R1 represents an alkyl group, by an alkylation reaction of known type. Compounds with chemical structures analogous to that of the compounds of the invention are described in CA 83(13) 114712c, CA 94(9) 64698g and CA 96(9) 68779y. Some cpmpounds of general formulae (XII), (XIII), (XIV) and (XV) are described in the literature. A compound of general formula (I) in which R3 and/or R4 represent a hydroxy (C2-C4)alkyl group can be obtained by reaction of the corresponding acid of general formula (VI) or (VI") with an alcohol protected by a conventional protective group, followed by deprotection. A compound of general formula (I) in which R3 and/or R4 represent a carboxy(C2-C4)alkyl group can be obtained by hydrolysis of a corresponding ester. A compound of general formula (I) in which X represents a phenylmethoxy group can be obtained in two stages, known to a person skilled in the art, from a compound of general formula (I) in which X represents a methoxy group. The following examples illustrate in detail the preparation of a few compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained The numbers of the compounds shown between brackets in the titles correspond to those in the table given below. Example 1 (Compound No. 20) (±)-6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)- 2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-4-carboxamide 1.1. Ethyl 5-fluoro-l-methyl-lH-indole-2- carboxylate. 1.1.1. Ethyl 5-fluoro-lH-indole-2-carboxylate. 150 g (0.92 mol) of 4-fluorophenylhydrazine hydrochloride are added, while cooling the mixture, to a preprepared solution of 23 g (1 mol) of sodium in 1.5 1 of methanol and the mixture is stirred at room temperature for 3 0 min. The solution is concentrated under reduced pressure, the residue is taken up in dichloromethane and the sodium chloride is separated by filtration. The solvent is evaporated under reduced pressure, the residue is dissolved in 830 ml of ethanol containing 4.4 ml of acetic acid and 102 ml (0.91 mol) of ethyl pyruvate, and the mixture is heated at reflux for 2 h. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate, the solution is washed with water and dried over sodium sulphate, and the solvent is evaporated under reduced pressure. 181.6 g (0.83 mol) of hydrazone are obtained. 214 g (1.12 mol) of 4-methylbenzenesulphonic acid monohydrate, in solution of 2.5 1 of toluene, are dehydrated by heating the reaction mixture for 2 h at reflux in a Dean and Stark apparatus. 181.6 g (0.83 mol) of the hydrazone obtained above are added while cold and the mixture is heated at reflux for 3 h. The mixture is cooled, ethyl acetate and water are added, the organic phase is separated and dried, and the solvent is evaporated under reduced pressure. The residue is recrystallized from propan-2-ol and the mother liquors are purified by chromatography on a column of silica gel, elution being carried out with dichloromethane. 144 g (0.7 mol) of product are obtained, which product is used as is in the following stage. 1.1.2. Ethyl 5-fluoro-l-methyl-1H-indole-2- carboxylate. 11.7 g (0.39 mol) of sodium hydride, as an 80% suspension in oil, are washed with petroleum ether and then a solution of 62.1 g (0.3 mol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 600 ml of dimethylformamide is added. The mixture is stirred for 2 h at room temperature and then 24.3 ml (0.39 mol) of methyl iodide, in solution in 50 ml of dimethylformamide, are added. The mixture is stirred for 20 h at room temperature and is then poured onto ice-cold water. The reaction mixture is extracted with ethyl acetate, the organic phase is washed and dried over sodium sulphate, the solvent is evaporated under reduced pressure and 62.5 g (0.28 mol) of solid product are obtained, which product is used as is in the following stage. 1.2. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-a- methylene-1H-indole-3-acetate. A solution of 10.5 g (48 mmol) of ethyl 5-fluoro-l-methyl-1H-indole-2-carboxylate, 18 g (155 mmol) of ethyl pyruvate and 7.8 ml of concentrated sulphuric acid in 100 ml of acetic acid is stirred at room temperature for 1 h 30. The mixture is concentrated under reduced pressure, hydrolysis is carried out with ice-cold water, aqueous ammonia is added until the pH is alkaline and extraction is carried out with dichloromethane. The organic phase is washed with water and dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is recrystallized from a mixture of pentane and diethyl ether. 13 g (42 mmol) of solid are obtained. Melting point: 86-88°C. 1.3. Ethyl (±)-6-fluoro-9-methyl-l-oxo-2- (phenylmethyl)-2,3,4,9 -tetrahydro-1H- pyrido [3,4-b] indole-4 -carboxylate. A solution of 7 g (23 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-a-methylene-1H- indole-3-acetate and 15 ml (140 mmol) of benzylamine in 200 ml of ethanol is heated at reflux for 8 h. The solvent is evaporated under reduced pressure and the residue is taken up in dichloromethane and 1N hydrochloric acid. The organic phase is washed with water and is dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. 7 g (18 mmol) of solid product are obtained, which product is used as is in the following stage. 1.4. (±)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4- carboxylic acid. 6 g (16 mmol) of ethyl (±)-6-fluoro-9-methyl- l-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-4-carboxylate are hydrolysed with 2.5 g of sodium hydroxide in a mixture of water and ethanol, the mixture is concentrated under reduced pressure, water and acetic acid are added, extraction is carried out with ethyl acetate, the organic phase is washed with water and dried over sodium sulphate, and the solvent is evaporated under reduced pressure. 4 g (11 mmol) of solid are obtained, which solid is used as is in the following stage. Melting point: 264-265°C. 1.5. (±)-6-Fluoro-N,N,9-trimethyl-l-oxo-2- (phenylmethyl)-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole-4-carboxamide. A solution of 4 g (11 mmol) of (±)-6-fluoro- 9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H- pyrido [3 , 4-b] indole-4-carboxylic acid and 2.2 g (30 mmol) of 1,1"-carbonyldiimidazole in 200 ml of tetrahydrofuran is heated at 40°C for 2 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added and the mixture is allowed to stir for a few hours. The solvent is evaporated under reduced pressure, the residue is taken up in dichloromethane and water, the organic phase is separated, washed with water and dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and methanol. The product is recrystallized from ethyl acetate. 1.2 g (3 mmol) of product are obtained. Melting point: 185-186°C. Example 2 (Compound No. 59) 6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)- 2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide. A solution of 2 g (5 mmol) of (±)-6-fluoro- N,N, 9-trimethyl-l-oxo-2-(phenylmethyl)-2,3,4,9- tetrahydro-1H-pyrido [3 , 4-b] indole-4-carboxamide and of 1.6 g (7 mmol) of 2,3-dichloro-5,6-dicyano- 1,4-benzoguinone in 2 50 ml of dichloromethane is stirred for 1 h. The organic phase is washed and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is crystallized from diethyl ether. 1 g (2.6 mmol) of product is obtained. Melting point: 192-193°C. Example 3 (Compound No. 3 6) 6-Chloro-2-(2-methoxyethyl)-N,N,9-trimethyl-1-oxo- 2,3,4,9- tetrahydro-1H-pyrido [3,4 -b] indole- 4-carboxamide. 3.1. Ethyl 5-chloro-1-methyl-1H-indole- 2-carboxylate. The preparation is carried out as in Example 1.1.2, from 8.95 g (40 mmol) of ethyl 5-chloro- 1H-indole-2-carboxylate, 1.6 g (52 mmol) of sodium hydride, as an 80% suspension in oil, and 11.35 g (80 mmol) of methyl iodide. 9.5 g (40 mmol) of solid product are obtained, which product is used as is in the following stage. 3.2. Ethyl 5-chloro-2-(ethoxycarbonyl)-1-methyl-a- methylene-1H-indole-3-acetate. A solution saturated with hydrochloric acid and containing 9.5 g (40 mmol) of ethyl 5-chloro-1- methyl-1H-indole-2-carboxylate and 8.8 ml (80 mmol) of ethyl pyruvate is heated at reflux for 4 h. The solvent is evaporated under reduced pressure, the residue is taken up in ethyl acetate, which is washed to neutrality, the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. The product is purified by chromatography on a column of silica gel, elution being carried out with dichloromethane. 9.6 g (32 mmol) of solid product are obtained, which product is used as is in the following stage. 3.3. Ethyl (±)-6-chloro-2-(2-methoxyethyl)- 9-methyl-l-oxo-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indole-4-carboxylate. A solution of 9.5 g (31 mmol) of ethyl 5-chloro-2-(ethoxycarbonyl)-1-methyl-a-methylene- 1H-indole-3-acetate and 8.1 g (93 mmol) of 2- methoxyethylamine in 2 0 ml of ethanol is heated at reflux for 3 h. The solvent is evaporated under reduced pressure and the residue is taken up in ethyl acetate, which is washed with water and dried over sodium sulphate. 9.7 g (27 mmol) of solid product are obtained, which product is used as is in the following stage. 3.4. (±)-6-Chloro-2-(2-methoxyethyl)-9-methyl- 1-oxo-2,3,4,9 -tetrahydro-1H-pyrido[3,4- b] indole-4-carboxylic acid. 9.6 g (26 mmol) of ethyl (±)-6-chloro-2- (2-methoxyethyl)-9-methyl-l-oxo-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole-4-carboxylate are hydrolysed with a solution of 3.1 g (80 mmol) of sodium hydroxide in 260 ml of ethanol and 50 ml of water. The reaction mixture is concentrated, the residue is taken up in water and the aqueous phase is washed with ethyl acetate and acidified to pH=l with concentrated hydrochloric acid. Extraction is carried out with ethyl acetate. The organic phase is washed with water and dried with sodium sulphate. The solvent is evaporated under reduced pressure and 8.3 g (26 mmol) of solid product are obtained, which product is used as is in the following stage. 3.5. (±)-6-Chloro-2-(2-methoxyethyl)- N,N, 9-trimethyl-l-oxo-2,3,4,9-tetrahydro- 1H-pyrido [3,4-.b] indole-4-carboxamide. The preparation is carried out as in Example 1.5, from 8.3 g (26 mmol) of (±)-6-chloro-2-(2- methoxyethyl)-9-methyl-l-oxo-2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b] indole-4-carboxylic acid and from dimethylamine. 8.6 g of product are isolated, which product is recrystallized from propan-2-ol. 6.9 g (19 mmol) of product are obtained. Melting point: 217-219°C. Example 4 (Compound No. 77) (+)-6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)- 2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b] indole- 4-carboxamide. 4.1. (+)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)- 2,3,4, 9-tetrahydro-1H-pyrido [3,4-b] indole- 4-carboxylic acid. A solution of 20.5 g (58 mmol) of (±)-6- fluoro-9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 7.5 ml (58 mmol) of (R)-(+)-a-methylbenzylamine in 1000 ml of methanol is stirred. The mixture is concentrated under reduced pressure, the residue is taken up in 50 ml of ethyl acetate and 400 ml of diethyl ether, and the precipitate is separated by filtration and recrystallized three times from propan- 2-ol. 7.3 g (15 mmol) of diastereoisomer salt are isolated, which salt is redissolved in 100 ml of methanol, 16 ml of 1N hydrochloric acid and 200 ml of water are added, and the precipitate is separated by filtration and dried under reduced pressure at room temperature. 5.1 g (15 mmol) of dextrorotatory acid are obtained. Melting point: 264-269°C. [a] 20D = +41.6° (c = 0.5, CH3OH) ee > 99% (HPLC). 4.2. (+)-6-Fluoro-N,N,9-trimethyl-1-oxo-2- (phenylmethyl)-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole-4-carboxamide. A solution of 0.5 g (1.3 mmol) of (+)-6- fluoro-9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid, 0.11 g (1.3 mmol) of dimethylamine hydrochloride, dried beforehand under reduced pressure, and 0.68 g (13 mmol) of (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate in 10 ml of dichloromethane, passed beforehand through an alumina column, is cooled to -30°C and 0.68 ml (3.9 mmol) of N,N-di(l- methylethyl)ethylamine, in solution in 5 ml of dichloromethane, is added dropwise. The mixture is stirred for 6 h at between -3 0°C and -2 0°C, hydrolysis is carried out with 10 ml of 5% aqueous potassium hydrogensulphate solution, the mixture is extracted with dichloromethane, the organic phase is washed and dried, the solvent is evaporated under reduced pressure, the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate, and the product obtained is recrystallized from propan-2-ol. 0.37 g (1 mmol) of dextrorotatory amide is obtained. Melting point: 199-202°C. [a]20D = +6.3° (c = 1, CHC13) ee > 94% (HPLC) . Example 5 (Compound No. 76) (-) -6-Fluoro-N,N, 9-trimethyl-1-oxo-2- (phenylmethyl) - 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole- 4-carboxamide. 5.1. (-)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)- 2,3,4, 9-tetrahydro-1H-pyrido[3,4-b] indole- 4-carboxylic acid. The solvent from the various mother liquors from the recrystallization of the diastereoisomer salt of Example 4.1 is evaporated under reduced pressure, water and concentrated hydrochloric acid are added, and the precipitate is separated by filtration and dried under reduced pressure at room temperature. 13.6 g (3 8 mmol) of impure laevorotatory acid are obtained, to which are added 250 ml of methanol and 4.97 ml (38 mmol) of (S)-(-)-a-methylbenzylamine. The mixture is stirred and concentrated under reduced pressure and the precipitate is collected by filtration and recrystallized three times from propan-2-ol. 7 g (15 mmol) of diastereoisomer salt are obtained, which salt is redissolved in the minimum amount of methanol, 15 ml of 1N hydrochloric acid are added and the volume of the solution is doubled with water. The precipitate is separated by filtration, washed with water, superficially dried, and dried at room temperature under reduced pressure. 5 g (14 mmol) of laevorotatory acid are obtained. Melting point: 264-269°C. [a]20D = -42.2° (c = 0.5, CH3OH) ee > 99% (HPLC) . 5.2 . (-) -6-Fluoro-N,N, 9-trimethyl-1-oxo-2- (phenylmethyl)-2,3,4,9-tetrahydro-1H- pyrido [3 , 4-b] indole-4-carboxamide. By carrying out the preparation as described in Example 4.2, from (-)-6-fluoro-9-methyl-l-oxo-2- (phenylmethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole-4-carboxylic acid and from dimethylamine, 0.3 g (0.8 mmol) of laevorotatory amide is obtained after final recrystallization from ethyl acetate. Melting point: 204-205°C. [a]20D = -7.5° (c = 1, CHC13) ee > 98% (HPLC). Example 6 (Compound No. 101) 6-Fluoro-N,N,9-trimethyl-l-oxo-2-phenyl-2,9-dihydro-1H- pyrido [3 , 4-b] indole-4-carboxamide . 6.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-a- methylene-1H-indole-3-acetate. A solution of 37.2 g (180 mmol) of ethyl 5- fluoro-1H-indole-2-carboxylate, 25.8 g (222 mmol) of ethyl pyruvate and 31 ml of concentrated sulphuric acid in 400 ml of acetic acid is stirred for 20 h. The solvent is evaporated under reduced pressure, the residue is taken up in water and ethyl acetate, the organic phase is separated, washed with a dilute aqueous ammonia solution and then with a saturated aqueous sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated under reduced pressure. 37.1 g (122 mmol) of solid product are obtained, which product is used as is in the following stage. 6.2. 6-Fluoro-l-oxo-2-phenyl-2,3,4,9-tetrahydro- 1H-pyrido [3, 4-b] indole-4-carboxylic acid. A mixture of 25 g (82 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-a-methylene-1H-indole-3- acetate and 31.8 g (342 mmol) of aniline is heated at reflux for 17 h. A dilute hydrochloric acid solution and ethyl acetate are added, the organic phase is separated, washed with water and dried with sodium sulphate, and the solvent is evaporated under reduced pressure. 3 0 g of residue are obtained, which residue is hydrolysed with a solution of 43 ml of 3 0% sodium hydroxide in 400 ml of ethanol at reflux for 1 h. The mixture is concentrated under reduced pressure, water is added, the mixture is washed with ethyl acetate and dichloromethane, the aqueous phase is acidified with concentrated hydrochloric acid, and the precipitate is collected by filtration and dried under reduced pressure. 18.5 g (57 mmol) of solid compound are obtained, which compound is used as is in the following stage. 6.3. 6-Fluoro-N,N,9-trimethyl-l-oxo-2-phenyl-2,9- dihydro-1H-pyrido[3,4-b]indole-4-carboxamide. 5 g (15 mmol) of 6-fluoro-1-oxo-2-phenyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid in 40 ml of thionyl chloride are heated at reflux for 1 h. The solvent is evaporated under reduced pressure, the residue is taken up in dichloromethane, a large excess of liquefied dimethylamine is added, the mixture is stirred for a few hours, water is added, and the precipitate is separated by filtration and dried under reduced pressure. 3.4 g (9 mmol) of compound are obtained. 2.5 g thereof are dissolved in 50 ml of dimethyl sulphoxide, 0.6 g of powdered potassium hydroxide and 1.2 ml of iodomethane are added, and the mixture is stirred for 5 h at 50°C and then for 20 h at room temperature. Dilute hydrochloric acid is added, extraction is carried out with ethyl acetate, the organic phase is dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate. 2.2 g of a mixture containing 6-fluoro-N,N,9-trimethyl- l-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole- 4-carboxamide and 6-fluoro-N,N,9-trimethyl-1-oxo-2- phenyl-2,3,4, 9 - tetrahydro-1H-pyrido [3,4-b] indole- 4-carboxamide are obtained. This mixture is stirred with 1 g of 2,3-dichloro-5,6- dicyano-l,4-benzoquinone for 20 h and is washed with a saturated aqueous sodium hydrogencarbonate solution, the organic phase is separated and dried over sodium sulphate, the solvent is evaporated under reduced pressure, the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate, and the product is recrystallized from ethyl acetate. 0.5 g (1.5 mmol) of compound is obtained. Melting point: 195-197°C. Example 7 (Compound No. 97) N,N, 9-Trimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole-4-carboxamide. 7.1. Ethyl 2-(ethoxycarbonyl)-a-methylene-1H- indole-3-acetate An ethanol solution saturated with gaseous hydrochloric acid containing 39.1 g (207 mmol) of ethyl 1H-indole-2-carboxylate and 45.3 ml (410 mmol) of ethyl pyruvate is brought to approximately 60°C for 3 h. The mixture is concentrated under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with water and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is crystallized from cyclohexane. 45.4 g (158 mmol) of solid product are obtained, which product is used as is in the following stage. 7.2. l-Oxo-N,2-diphenyl-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole-4-carboxamide. A mixture of 32 g (111-mmol) of ethyl 2-(ethoxycarbonyl)-a-methylene-1H-indole-3-acetate and of 47.5 g (511 mmol) of aniline is heated at reflux for 13 h. Dichloromethane is added and the organic phase is washed with 1N hydrochloric acid. It is dried over sodium sulphate and the solvent is evaporated under reduced pressure. 38.8 g of impure product are obtained, which product is used as is in the following stage. 7.3. Ethyl l-oxo-2-phenyl-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole-4-carboxylate. A solution of 3 8.8 g of impure 1-oxo-N,2- dipheny1-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4- carboxamide in a mixture of ethanol, water and 37% hydrochloric acid is heated at reflux for 8 h. The reaction mixture is neutralized with concentrated sodium hydroxide and extraction is carried out with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. 22.6 g (68 mmol) of product are obtained, which product is used as is in the following stage. 7.4. 1-Oxo-2-phenyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-4-carboxylic acid. 22.6 g (68 mmol) of ethyl l-oxo-2-phenyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate are hydrolysed with 200 ml of 1N sodium hydroxide in 500 ml of methanol. The reaction mixture is acidified with 1N hydrochloric acid and the precipitate is filtered off. It is dried under reduced pressure. 18.1 g (59 mmol) of solid product are obtained, which product is used as is in the following stage. 7.5. N,N-Dimethyl-l-oxo-2-phenyl-2,3,4,9- tetrahydro-1H-pyrido [3,4-b] indole- 4-carboxamide. A solution of 10 g (33 mmol) of 1-oxo- 2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole- 4-carboxylic acid in 3 0 ml of thionyl chloride is heated at reflux for 4 h. The solvent is evaporated under reduced pressure, the residue is taken up in dichloromethane and a large excess of liquefied dimethylamine is added. The mixture is stirred for several hours and the solvent is evaporated under reduced pressure. Water and ethyl acetate are added. The precipitate is filtered off and dried under reduced pressure. 8.2 g of impure product are obtained, which product is used as is in the following stage. 7.6. N,N,9-Trimethyl-l-oxo-2-phenyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-4- carboxamide A mixture of 1.3 g (23 mmol) of powdered potassium hydroxide and of 6 g of impure N,N-dimethy1- 1-oxo-2 -phenyl-2,3,4,9- tetrahydro-1H-pyrido [3,4- b]indole-4-carboxamide in 60 ml of dimethyl sulphoxide is heated at 40°C for 30 min. 2.5 ml (40 mmol) of iodomethane are added and the reaction mixture is stirred for 5 h at room temperature. Water and dichloromethane are then added. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from ethyl acetate. 1.9 g (5.5 mmol) of product are obtained. Melting point: 196-197°C. Example 8 (Compound No. 123) N-Ethyl-6-fluoro-N,9-dimethyl-l-oxo-2-phenyl-2,9- dihydro-1H-pyrido [3,4-b] indole-4-carboxamide . 8.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1H-indole- 3-acetate A solution of 7.4 g (185 mmol) of sodium hydroxide £n 75 ml of water is added to a solution of 3 0 g (185 mmol) of 4-fluorophenylhydrazine hydrochloride in 3 00 ml of water, the mixture is stirred for 15 min and then a solution of 29 g (198 mmol) of ketoglutaric acid in 60 ml of water is added. The reaction mixture is stirred at room temperature for 3 h and is extracted with ethyl acetate, and the organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. 42 g (144 mmol) of product are obtained, which product is dissolved in 42 0 ml of ethanol saturated with gaseous hydrochloric acid and heated at reflux for 4 h. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate, and the organic phase is washed with normal sodium hydroxide and then with water, dried over magnesium sulphate and evaporated under reduced pressure. 42 g (143 mmol) of solid product are obtained, which product is used as is in the following stage. 8.2. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl- 1H-indole-3-acetate. A solution of 7.36 g (184 mmol) of 60% sodium hydride, washed beforehand with petroleum ether, and 45 g (153 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro- 1H-indole-3-acetate in 450 ml of N,N-dimethylformamide is stirred for 2 h at room temperature and then a solution of 19 ml (306 mmol) of iodomethane in 100 ml of N,N-dimethylformamide is added. After stirring for 20 h, the reaction mixture is poured onto ice-cold water, extraction is carried out with diethyl ether, the organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. 44.3 g (144 mmol) of product are obtained, which product is used as is in the following stage. 8.3. Ethyl a-(dimethylaminomethylidene)- 2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H- indole-3-acetate. A solution of 44.3 g (144 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole- 3-acetate and 57.4 ml of dimethylformamide dimethyl acetal in 450 ml of N,N-dimethylformamide is heated at reflux for 50 h. The solvent is evaporated under reduced pressure and the residue is taken up in diethyl ether. The insoluble material is removed by filtration and the solvent is concentrated under reduced pressure. 49.3 g (13 6 mmol) of solid product are obtained, which product is used as is in the following stage. 8.4. Ethyl 6-fluoro-9-methyl-l-oxo-2-phenyl- 2 , 9-dihydro-1H-pyrido [3,4-b] indole- 4-carboxylate. A solution of 16.3 g (45 mmol) of ethyl a-(dimethylaminomethylidene)-2-(ethoxycarbonyl)-5- fluoro-1-methyl-1H-indole-3-acetate, 4.64 ml (50 mmol) of aniline and 1.6 g (8 mmol) of 4-methylbenzene- sulphonic acid monohydrate in 160 ml of N,N- dimethylformamide is heated at reflux for 24 h. 3.3 g (31 mmol) of sodium carbonate are added in small portions and reflux is continued for 2 h. The solution is cooled and poured onto ice-cold water. Extraction is carried out with ethyl acetate and the organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. 10.9 g (30 mmol) of product are obtained, which product is used as is in the following stage. 8.5. 6-Fluoro-9-methyl-l-oxo-2-phenyl-2,9-dihydro- 1H-pyrido[3,4-b]indole-4-carboxylic acid. A solution of 22.8 g (65 mmol) of ethyl 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H- pyrido [3,4-b] indole-4-carboxylate and of 7.46 g (186 mmol) of sodium hydroxide in a mixture of 1 1 of ethanol and 100 ml of water is heated at reflux for 3 h. The mixture is concentrated under reduced pressure, the residue is taken up in water and the aqueous phase is washed with ethyl acetate. Acidification is carried out with concentrated hydrochloric acid to pH = 1 and the product is filtered off, which product is rinsed several times with water. It is dried under reduced pressure. 20.4 g (64 mmol) of solid compound are obtained, which compound is used as is in the following stage. 8.6. 6-Fluoro-N,9-dimethyl-l-oxo-2-phenyl-2,9- dihydro-1H-pyrido [3,4-b] indole-4-carboxamide . A solution of 5 g (15.6 mmol) of 6-fluoro-9- methyl-1-oxo-2-pheny1-2,9-dihydro-1H-pyrido[3,4-b]- indole-4-carboxylic acid and of 4.8 g (30 mmol) of N,N"-carbonyldiimidazole in 100 ml of N,N- dimethylformamide is stirred at 60°C for 4 h. A large excess of liquefied methylamine is added at room temperature and the reaction mixture is stirred for 20 h. The solution is poured onto ice-cold water and the precipitate is collected by filtration, washed with a saturated sodium hydrogencarbonate solution, with water and then with ethyl acetate, and dried under reduced pressure. 3.5 g of crude product are isolated. The filtrates are combined and extracted with dichloromethane. The organic phase is washed with a sodium hydrogencarbonate solution and then with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. 1.5 g of additional product are isolated. The two batches are combined and purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. 4.7 g (13.5 mmol) of solid product are obtained. 8.7. N-Ethyl-6-fluoro-N,9-dimethyl-1-oxo-2-phenyl- 2,9-dihydro-1H-pyrido[3,4-b] indole-4- carboxamide. A solution of 2.5 g (7.1 mmol) of 6-fluoro- N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4- b]indole-4-carboxamide and of 0.3 6 g (9 mmol) of 60% sodium hydride, washed beforehand with petroleum ether, is stirred for 3 h at 50°C. 1.67 ml (21 mmol) of iodoethane are added, stirring is maintained for 2 0 h, and the solution is poured onto ice-cold water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is purified by chromatography on silica, the elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from propan- 2-ol. 2.3 g of solid are obtained. Melting point: 181-182°C. Example 9 (Compound No. 98) 6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-ylcarbonyl)- 2,9-dihydro-1H-pyrido[3,4-b]indol-1-one. A solution of 3.2 g (10 mmol) of 6-fluoro- 9-methyl-1-oxo-2 -pheny1-2,9-dihydro-1H- pyrido [3,4-b] indole-4-carboxylic acid and of 3.2 g (20 mmol) of N,N"-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h at 60°C. 2.5 ml (3 0 mmol) of pyrrolidine are added at room temperature and the reaction mixture is stirred for 20 h. The solution is poured onto ice-cold water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from propan-2-ol. 3 g (7.7 mmol) of solid are obtained. Melting point: 203-205°C Example 10 (Compound No. 122) 6-Fluoro-N,N,9-trimethyl-l-oxo-2-(pyridin-2-yl)- 2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide. 10.1. Methyl 6-fluoro-9-methyl-l-oxo-2-(pyridin- 2-yl) -2,9-dihydro-1H-pyrido [3,4-b] indole- 4-carboxylate. A mixture of 4.1 g (12.2 mmol) of methyl a-(dimethylaminomethylidene)-5-fluoro-2- (methoxycarbonyl)-1-methyl-1H-indole-3-acetate and of 1.73 g (18.4 mmol) of 2-aminopyridine is heated at 180°C for 30 min. 7 ml of N,N-dimethylformamide are added and heating is continued for 4 h. The reaction mixture is cooled and poured onto a mixture of water and ethyl acetate, and the insoluble material is collected by filtration and dried under reduced pressure. 1.8 g (5.1 mmol) of solid are obtained, which solid is used as is in the following stage. 10.2. 6-Fluoro-9-methyl-l-oxo-2-(pyridin-2-yl)- 2, 9-dihydro-lff-pyrido [3,4-b] indole-4- carboxylic acid. A solution of 3.3 g (9.4 mmol) of methyl 6-fluoro-9-methyl-l-oxo-2-(pyridin-2-yl)-2,9-dihydro- 1H-pyrido[3,4-b]indole-4-carboxylate in a mixture of 100 ml of ethanol and of 28 ml of 1N sodium hydroxide is heated at reflux for 4 h. The mixture is concentrated under reduced pressure, water is added, acidification is carried out with concentrated hydrochloric acid and the precipitate is collected by filtration. It is washed with water and dried under reduced pressure. 2.8 g (8.3 mmol) of solid product are obtained, which product is used as is in the following stage. 10.3. 6-Fluoro-N,N,9-trimethyl-l-oxo-2-(pyridin- 2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole- 4-carboxamide. A solution of 2.5 g (7.4 mmol) of 6-fluoro- 9-methyl-l-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H- pyrido[3,4-b]indole-4-carboxylic acid and of 2.4 g (14.8 mmol) of N,N"-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added. The mixture is stirred for 48 h at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from ethyl acetate. 1.6 g (4.4 mmol) of solid are obtained. Melting point: 220-221°C Example 11 (Compound No. 125) 6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)- 4-(pyrrolidin-1-ylcarbonyl)-2,9-dihydro-1H- pyrido [3,4-b] indol-1-one 11.1. 2-Carboxy-5-fluoro-1H-indole-3-acetic acid. A solution of 26.5 g (103 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-1H-indole-3-acetate and 24 g of sodium hydroxide in a mixture of 530 ml of ethanol and of 100 ml of water is heated at reflux. The mixture is concentrated under reduced pressure, water is added, and the aqueous phase is washed with ethyl acetate and acidified with concentrated hydrochloric acid. The precipitate is filtered off, rinsed with water and dried under reduced pressure. 23.4 g (98.7 mmol) of product are obtained, which product is used as is in the following stage. 11.2 . 6-Fluoro-1,3,4,9-tetrahydropyrano [3,4-b] - indole-1,3-dione. A solution of 4.7 g (19.8 mmol) of 2-carboxy- 5-fluoro-1H-indole-3-acetic acid in 94 ml of acetyl chloride is heated at reflux for 5 h. The mixture is concentrated under reduced pressure, toluene is added and the solVents are evaporated under reduced pressure. 4.5 g of solid product are obtained, which product is used as in the following stage. 11.3. 5-Pluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- 1H-indole-2-carboxylic acid. A solution of 4.4 g (20 mmol) of 6-fluoro- 1,3,4,9-tetrahydropyrano[3,4-b]indole-1,3-dione and of 8.3 ml (100 mmol) of pyrrolidine in 100 ml of dichloromethane is stirred for 24 h at room temperature. The mixture is concentrated under reduced pressure, water is added and the aqueous phase is washed with ethyl acetate. Acidification is carried out with concentrated hydrochloric acid and ethyl acetate is added. The precipitate is collected by filtration, washed with water and dried under reduced pressure. 5 g (17.2 mmol) of solid product are obtained, which product is used as is in the following stage. 11.4. Methyl 5-fluoro-3-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)-1H-indole-2-carboxylate. 3.8 ml (51 mmol) of thionyl chloride are added dropwise to a solution of 5 g (17.2 mmol) of 5-fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole- 2-carboxylic acid in 50 ml of methanol cooled in an ice bath, and then the mixture is heated at reflux for 3 h. The mixture is concentrated under reduced pressure, water and dichloromethane are added, and the organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. 4.5 g (14 mmol) of product are obtained, which product is used as is in the following stage. 11.5. Methyl 3-(l-dimethylaminomethylidene-2-oxo-2- (pyrrolidin-1-yl)ethyl)-5-fluoro-1-methyl-1H- indole-2-carboxylate. A solution of 3.4 g of methyl 5-fluoro-3-(2- oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylate and 4.66 ml (35 mmol) of dimethylformamide dimethyl acetal in 34 ml pf N,N-dimethylformamide is heated at reflux for 30 h. The mixture is concentrated under reduced pressure, xylene is added and the solvents are evaporated under reduced pressure. 4 g of residue are obtained, which residue contains approximately 50% of the desired product (according to the proton magnetic resonance spectrum) and is used as is in the following stage. 11.6. 6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thia- diazol-2-yl)-4-(pyrrolidin-1-ylcarbonyl)- 2,9-dihydro-1H-pyrido[3,4-b]indol-1-one. A solution of 4 g of the residue obtained in the preceding stage and 1.04 g (5.5 mmol) of 4-methylbenzenesulphonic acid monohydrate in 40 ml of N,N"-dimethylf ormamide is stirred for 15 min. 0.65 g (6.4 mmol) of 2-amino-5-methyl-l,3,4-thiadiazole is added and the mixture is heated at reflux for 24 h. The mixture is poured into water and ethyl acetate. The precipitate is collected by filtration, washed with water, dried under reduced pressure and recrystallized from N, N- dimethy1 formamide. 1 g (2.4 mmol) of product is obtained. Melting point: 299-301°C. The chemical structures and the physical properties of a few compounds according to the invention are illustrated in the following table. Key Me denotes a methyl group, Et denotes an ethyl group, Pr denotes a propyl group, iPr denotes an isopropyl group, cPr denotes a cyclopropyl group, Ph denotes a phenyl group, 1-Napht and 2-Napht respectively denote naphth-1-yl and naphth-2-yl groups, x-Pyridyl denotes a pyridin-x-yl group, x-Thienyl denotes a thien-x-yl group, Piperid denotes a piperidin-1-yl group, Pyrrolid denotes a pyrrolidin-1-yl group, Morph denotes a morpholin-4-yl group, Azetid denotes an azetidin-1-yl group, 4-Me-piperaz denotes a 4-methylpiperazin-l-yl group, 5-Me-thiadiaz denotes a 5-methyl-1,3,4-thiadiazol-2-yl group, 5-Me-oxazol denotes a 5- methyl-l,2-oxazol-2-yl group, and Thiazolid denotes a thiazolidinyl group. In the column "3~4", "/" denotes a carbon-carbon single bond and "//" denotes a carbon-carbon double bond between the 3 and 4 atoms of the molecule. In the "M.p. (°C)" column, "d" denotes a melting point with decomposition. The compounds of the invention were subjected to pharmacological tests which demonstrated their advantage as substances having therapeutic activities. Study of membrane binding with respect to ?1 (type 1 benzodiazepine) and ?2 (type 2 benzodiazepine) receptors. The affinity of the compounds for the ?1 receptors of the cerebellum and ?2 receptors of the spinal cord was determined according to a variant of the method described by S.Z. Langer and S. Arbilla in Fund. Clin. Pharmacol., 2, 159-170 (1988), with the use of [3H] f lumazenil instead of [3H] diazepam as radioligand. The cerebellar or spinal cord tissue is homogenized for 60 s in 120 or 30 volumes, respectively, of ice-cold buffer (50 mM Tris-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl) and then, after dilution to 1/3, the suspension is incubated with [3H]flumazenil (specific activity 7 8 Ci/mmol, New England Nuclear) at a concentration of 1 nM and with the compounds of the invention at different concentrations, in a final volume of 525 µl. After 30 minutes of incubation at 0°C, the samples are filtered under reduced pressure on Whatman GF/B® filters and washed immediately with ice-cold buffer. The specific binding of [3H]flumazenil is determined in the presence of 1 µM unlabelled diazepam. The data are analysed according to standard methods and the IC50 concentration, the concentration which inhibits by 50% the binding of [3H]flumazenil, is calculated. The IC50 values of the most active compounds of the invention lie, in this test, between 10 and 1000 nM. Study of the anxiolytic activity: drink intake conflict test. The anxiolytic activity is evaluated in rats in the drink intake conflict test according to the method described by J.R. Vogel, B. Beer and D.E. Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971). After being deprived of water for 48 h, the rat is placed in a soundproof chamber equipped with a water pipette connected to an anxiometer which delivers a mild electric shock every 2 0 licks. The number of shocks received is automatically counted over 3 minutes and makes it possible to evaluate the anxiolytic activity of the tested compounds. The results are expressed by the minimum effective dose (MED), the dose which produces a significant increase in the number of shocks received, with respect to the number observed in the control animals. The MED values of the most active compounds lie, in this test, between 5 and 50 mg/kg via the intraperitoneal route. Study of the anxiolytic activity: test in a heightened cross-shaped maze The protocol of this test is a modification of that described by S. Pellow and S. File in Pharmacol. Biochem. Behav. (1986), 24, 525-529. After a period of accustomization to the experimental room lasting approximately 24 h, the rats are placed individually on the central platform, the muzzle directed towards one of the closed arms, and observed for 4 min using a video camera. The time spent by the animal in the open arms, the number of entries into the closed arms and into the open arms, the number of attempts to enter the open arms, followed by an avoidance response, and the exploration of the edges in the open arms are recorded. The results are expressed for each animal: 1) as percentage of passages into the open arms relative to the total number of entries into the four arms of the apparatus, 2) as percentage of time spent in the open arms relative to the total duration of the test (4 min), 3) as total number of abortive attempts made by the animal, 4) as total number of explorations. The products under study are administered intraperitoneally or orally at increasing doses. The results are expressed by the minimum effective dose (MED) which produces either a significant increase (activity in the open arms) or a significant decrease (attempts) relative to the performance observed in the control animals. The MED values of the most active compounds lie, in this test, between 3 and 50 mg/kg via the intraperitoneal or oral route. Study of the hypnotic activity. The sedative or hypnotic activity of the compounds was determined by observing their action on the rat"s electrocorticogram, according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere and M. Decobert, J. Pharmacol., (Paris), 14, 2, 195-265 (1983) . The products under study were administered intraperitoneally at increasing doses. They induce sleep patterns at doses ranging from 1 to 30 mg/kg. Study of the anticonvulsant activity; activity with respect to clonic convulsions induced in rats by injection of pentetrazol. The protocol of this test is a modification of that described by E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982) . The test products are administered to the animals intraperitoneally 3 0 min before an intravenous injection of 20 mg/kg of pentetrazol. Immediately after the injection, the number of animals exhibiting clonic convulsions is noted over 5 min. The results are expressed as the AD50, the dose which protects 50% of the animals, calculated according to the method of J.T. Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther. (1949), 96, 99-113) on the basis of 3 or 4 doses each administered to a group of 8 to 10 rats. The AD50 values of the most active compounds lie between 0.3 and 30 mg/kg via the intraperitoneal or oral route. Study of the anticonvulsant activity; activity with respect to isoniazid-induced convulsions in mice. The intrinsic activity of the compounds is determined by the latency time of onset of convulsions induced by the subcutaneous administration of isoniazid (800 mg/kg) simultaneously with the test compound injected intraperitoneally, according to the protocol described by G. Perrault, E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988). The results are expressed as the AD50, the dose which produces 50% of the maximum effect, relative to the control animals, determined on the basis of 3 or 4 doses each administered to a group of 8 to 10 mice. The AD50 values of the compounds of the invention lie, in this test, between 1 and 50 mg/kg via the intraperitoneal route and, depending on the compounds, the maximum effect can be as much as 300%. The results of the tests performed on the compounds of the invention show that, in vitro, they displace [3H]flumazenil from its specific binding sites in the cerebellum and the spinal cord; they exhibit a mixed affinity for the ?1 and ?2 (type 1 and type 2 benzodiazepine) sites situated in the GABAA - ? sites chlorine channel macromolecular complex. In vivo, they behave as full or partial agonists with respect to these receptors. They possess anxiolytic, hypnotic and anticonvulsant properties, and can consequently be used for the treatment of complaints associated with disorders of GABAergic transmission, such as anxiety, sleep disorders, epilepsy, spasticity, muscle contractures, cognitive disorders, withdrawal disorders related to alcoholism, tobacco or drugs, and the like. They can also be used for the treatment of Parkinson"s disease and all types of extrapyramidal syndromes. Finally, they can be used in premedication and as general anaesthetics for the induction and/or maintenance of anaesthesia, or as local anaesthetics, optionally in combination with other anaesthetics and/or muscle relaxants and/or analgesics. To this end, they may be presented in any pharmaceutical dosage form, in combination with suitable excipients, for enteral or parenteral administration, for example in the form of tablets, dragees, capsules including hard gelatin capsules, solutions or suspensions to be swallowed or injected, suppositories, and the like, containing a dose to permit a daily administration of 1 to 1000 mg of active substance. WE CLAIM: 1. 1H-pyrido [3, 4-b] indole-4-carboxamide derivatives of general formula (I) in which X represents a hydrogen or halogen atom or a (C1-C3) alkyl, (C1-C3) alkoxy, trif luoromethyl or phenylmethoxy group, R1 represents a hydrogen atom or a (C1-C3) alkyl, cyclopropylmethyl or phenylmethyl group, R2 represents either a (C1-C3) alkyl group optionally substituted by a methoxy group, or a phenyl (C1-C3) alkyl group optionally substituted on the phenyl ring by a halogen atom or a methyl or methoxy group, or a cyclohexylmethyl group, or a thienylmethyl group, or a pyridinylmethyl group, or a phenyl group optionally substituted by one or more halogen atoms or a (C1-C3) alkyl or (C1-C3) alkoxy group, or a pyridinyl group, or a 5-methyl-l,2-oxazolyl group, or a 5-methyl- 1,3,4-thiadiazolyl group, or a naphthalenyl group, R3 and R4, independently of one another, each represent a hydrogen atom, a (C1-C3)alkyl group, a 2-methoxyethyl group, a hydroxy (C2-C4) alkyl group, a carboxy- (C1-C3) alkyl group, a (C1-C3) alkoxycarbonyl (C1-C3) alkyl group or a phenyl (C1-C3) alkyl group, or else together form, with the nitrogen atom which carries them, either a pyrrolidinyl group optionally substituted by a hydroxyl, ethoxy, methoxycarbonyl or methoxymethyl group, or a piperidinyl group, or a morpholinyl group, or a 4-methylpiperazinyl group, or an azetidinyl group, or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is single or double. 2. Compound as claimed in Claim 1, wherein the compound is in the form of a pure optical isomer. 3. Compound as claimed in Claim 1, wherein the compound is in the form of a mixture of optical isomers. 4. Compound as claimed in Claim 1, wherein, in the general formula (I), X is in the 6 position and represents a fluorine atom. 5. Compound as claimed in Claim 1, wherein R1 represents a methyl group. 6. Compound as claimed in Claim 1, wherein R2 represents a phenyl group. 7. Compound as claimed in Claim 1, wherein R3 represents a methyl group and R4 represents an ethyl group. 8. Compound as claimed in Claim 1, wherein R3 and R4 form, with the nitrogen atom which carries them, a pyrrolidinyl ring. 9. Medicament composed of a compound as claimed in one of Claims 1 to 8. 10. Pharmaceutical composition containing a compound as claimed in one of Claims 1 to 8, in combination with an excipient. 11. Process for the preparation of a compound as claimed in Claim 1, wherein a compound of general formula (II) in which X and R1 are as defined in Claim 1 and R represents a (C1-C3) alkyl group, is reacted with ethyl pyruvate, in order to obtain the diester of general formula (IV) the latter is then treated with an amine of general formula R2NH2, in which R2 is as defined in Claim 1, in order to obtain an ester of general formula (V) which is converted to the corresponding acid, of general formula (VI) by hydrolysis, this acid is then converted to the primary, secondary or tertiary amide of general formula (I") by reaction with an amine of general formula HNR3R4, in which R3 and R4 are as defined in Claim 1, either through the imidazolide obtained by reaction with N,N"- carbonyldiimidazole or through the acid chloride, and, finally, if it is desired to prepare a compound in which the bond between the 3 and 4 positions is a double bond, the compound of general formual (I") is oxidized by means of 2,3-dichloro-5,6-dicyanocyclohexa- 2,5-diene-l,4-dione or of 3,4,5,6-tetrachlorocyclohexa- 3,5-diene-1,2-dione, in order to obtain the corresponding compound of general formula (I"") 12. Process for the preparation of a compound as claimed in Claim 1, wherein a compound of general formula (VIII) in which X is as defined in Claim 1, is reacted with 2-ketoglutaric acid, it is then treated in an acidic alcoholic medium, in order to obtain the diester of general formula (IX) in which R represents a (C1-C3) alkyl group, then, if desired, an alkylation reaction is carried out, in order to obtain the compound of general formula (X) in which R1 represents a (C1-C3)alkyl group, then the latter is converted in the presence of dimethylformamide dimethyl acetal, in order to obtain the compound of general formula (XI) or alternatively, if desired, the compound of general formula (IX) is directly converted to the compound of general formula (XI), in which R1 represents a methyl group, the latter is then treated with an amine of general formula H2NR2, in which R2 is as defined in Claim 1, in order to obtain the ester of general formula (V") the latter is then converted to the corresponding acid of general formula (VI") and, finally, this acid is converted to the primary, secondary or tertiary amide of general formula (I"") by reaction with an amine of general formula HNR3R4, in which R3 and R4 are as defined in Claim 1, either through the imidazolide obtained by reaction with N,N"- carbonyldimidazole or through the acid chloride. 11. Process for the preparation of a compound as claimed in Claim 1, wherein a diester of general formula (X) in which X and R1 are as described in Claim 1 and R represents a (C1-C3)alkyl group, is hydrolysed, in order to obtain the diacid of general formula (XII) which is converted to the anhydride, in order to obtain the compound of general formula (XIII) the latter is then converted by reaction with an amine of general formula HNR3R4, in which R3 and R4 are as defined in Claim 1, in order to obtain the compound of general formula (XIV) which is converted to the ester of general formula (XV) the latter is then treated in the presence of dimethylformamide dimethyl acetal, in order to obtain the compound of general formula (XVI) and, finally, the latter is reacted with an amine of general formula R2NH2, in which R2 is as defined in Claim 1, in order to obtain the compound of general formula (I"") and, finally, if desired, a secondary amide of general formula (I"") is converted to the tertiary amide by an alkylation reaction. 13. 1H-PYRIDO[3,4-b]INDOLE-4-CARBOXAMIDE DERIVATIVES, substantially as herein described, particularly with reference to the foregoing examples. 14. A pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples. 15. A process for the preparation of 1H-PYRIDO[3,4-b]INDOLE 4-CARBOXAMIDE DERIVATIVES, substantially as herein described, particularly with reference to the foregoing examples. 16. A process for preparation of a pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples. Compounds of general formula (I) in which X represents hydrogen or a halogen or an alkyl, alkoxy, trifluoromethyl or phenylmethoxy group, R1 represents hydrogen or an alkyl, cyclopropyl or phenylmethyl group, R2 represents either an optionally substituted alkyl group or an optionally substituted phenylalkyl group or a cyclohexylmethyl group or a thienylmethyl group or a pyridinylmethyl group or an optionally substituted phenyl group or a pyridinyl group or a 5-methyl-1,2-oxazolyl group or a 5-methyl- 1,3,4-thiadiazolyl group or a naphthyl group, R3 and R4 each represent hydrogen or an alkyl, 2-methoxyethyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl or phenylalkyl group or else together form, with the nitrogen atom which carries them, either an optionally substituted pyrrolidinyl group or a piperidinyl group or a morpholinyl group or a 4-methylpiperazinyl group or an azetidinyl group or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is single or double. Application in therapeutics.

Full Text

The subject of the present invention is
1H-pyrido[3,4-b]indole-4-carboxamide derivatives, their
preparation and their application in therapeutics.
The compounds of the invention correspond to
the general formula (I)
in which
X represents a hydrogen or halogen atom or a
(C1-C3) alkyl, (C1-C3) alkoxy, trifluoromethyl or
phenylmethoxy group,
R1 represents a hydrogen atom or a (C1-C3) alkyl,
cyclopropyl or phenylmethyl group,
R2 represents either a (C1-C3) alkyl group optionally
substituted by a methoxy group, or a phenyl(C1-C3)alkyl
group optionally substituted on the phenyl ring by a
halogen atom or a methyl or methoxy group, or a
cyclohexylmethyl group, or a thienylmethyl group, or a
pyridinylmethyl group, or a phenyl group optionally
substituted by one or more halogen atoms or a
(C1-C3)alkyl or (C1-C3) alkoxy group, or a pyridinyl
group, or a 5-methyl-l,2-oxazolyl group, or a 5-methyl-
1,3,4-thiadiazolyl group, or a naphthyl group,
R3 and R4, independently of one another, each represent
a hydrogen atom, a (C1-C3)alkyl group, a 2-methoxyethyl
group, a hydroxy (C2-C4) alkyl group, a carboxy-
(C1-C3)alkyl group, a (C1-C3) alkoxycarbonyl (C1-C3) alkyl
group or a phenyl (C1-C3) alkyl group, or else together
form, with the nitrogen atom which carries them, either
a pyrrolidinyl group optionally substituted by a
hydroxyl, ethoxy, methoxycarbonyl or methoxymethyl
group, or a piperidinyl group, or a morpholinyl group,
or a 4-methylpiperazinyl group, or an azetidinyl group,
or a thiazolidinyl group, and
the bond between the carbon atoms in the 3 and 4
positions is single or double.
Depending on the nature of this bond, a
compound according to the invention can optionally
exist in the form of a pure optical isomer or of a
mixture of such isoxners.
The preferred compounds are those in the
general formula of which X is in the 6 position and
represents a fluorine atom, R1 represents a methyl
group, R2 represents a phenyl group, R3 represents a
methyl group and R4 represents an ethyl group or else R3
and R4 form, with the nitrogen atom which carries them,
a pyrrolidinyl ring.
The compounds of general formula (I) can be
prepared by processes illustrated in the following
schemes.
According to Scheme 1, the starting compound
corresponds to the general formula (II), in which X is
as defined above and R1 is as defined above; when R1
represents hydrogen, it is possible, if desired, to
carry out an alkylation in order to produce a compound
of general formula (II) in which R1 represents a
(C1-C3)alkyl group. The compound of general formula (II)
is thus reacted with ethyl pyruvate of formula (III),
in acidic medium, for example in the presence of
gaseous hydrochloric acid in ethanol or in the presence
of sulphuric acid or of boron trifluoride etherate in
acetic acid, between room temperature and the reflux
temperature, in order to obtain the diester of general
formula (IV).
The latter is then treated in ethanol at the reflux
temperature with an amine of general formula R2NH2, in
which R2 is as defined above. An ester of general
formula (V) is obtained, which is converted to the
corresponding acid, of general formula (VI), by
hydrolysis in basic medium.
This acid is then converted to the primary, secondary
or tertiary amide of general formula (I") by reaction
with an amine of general formula HNR3R4, in which R3 and
R4 are as defined above, either through the imidazolide
obtained by reaction with N,N"-carbonyldiimidazole or
through the acid chloride.
In the compound of general formula (I") thus obtained,
the bond between the 3 and 4 positions is a single
bond. If it is desired to prepare a compound in which
this bond is a double bond, a compound of general
formula (I") is oxidized by means of 2,3-dichloro-
5,6-dicyanocyclohexa-2,5-diene-l,4-dione or of
3,4,5,6-tetrachlorocyclohexa-3,5-diene-l,2-dione, in a
solvent such as toluene or dichloromethane, between
room temperature and the reflux temperature, in order
to obtain the corresponding compound, in the structure
of which the bond between the carbon atoms in the 3 and
4 positions is double, which respectively has the
general formula (I""):
Finally, and if it takes place, the enantiomers can be
prepared from the racemates according to any known
method; thus, for example, an acid of general formula
(VI) can be reacted with an optically pure chiral
amine, such as a-methylbenzylamine, and the
diastereoisomers can be separated by fractional
crystallization in order to arrive at an optically pure
acid and then at the esters and amides which derive
therefrom.
In the case of an optically pure acid of
general formula (VI), the non-racemizing coupling
reaction can be carried out by any known method, for
example with use of (benzotriazol-1-yloxy)tris-
(pyrrolidin-1-yl)phosphonium hexafluorophosphate.
In the case where R2 is an aromatic ring, it
is possible, if desired, to convert the diester (IV) to
the amide (VII) by heating the reaction mixture at a
temperature of 100 to 200°C, in an inert solvent or
without solvent, for example at reflux of the
corresponding amine of general formula R2NH2. It is then
possible to convert the compound of general formula
(VII) either to the ester of general formula (V), in
refluxing ethanol, in acidic medium, for example in the
presence of concentrated hydrochloric acid, or to the
acid of general formula (VI), by hydrolysis in basic
medium.
The starting compounds of general formula
(II) , mainly with R1=H, are described in the literature;
the pyruvate of formula (III) is commercially
available.
According to Scheme 2, the starting compound
corresponds to the general formula (VIII), in which X
is as defined above. This compound is reacted with
2-ketoglutaric acid and is then treated in an acidic
alcoholic medium, for example in ethanol saturated with
gaseous hydrochloric acid, at the reflux temperature,
in order to obtain the diester of general formula (IX),
in which R represents a (C1-C3)alkyl group. If desired,
an alkylation reaction of this compound is then carried
out, in order to obtain the compound of general formula
(X), in which R1 represents a (C1-C3)alkyl group, and
then the latter is converted, in a protic solvent, for
example N,N-dimethylformamide, in the presence of
dimethylformamide dimethyl acetal, at the reflux
temperature, in order to obtain the compound of formula
(XI). If desired, the compound of general formula (IX)
can be directly converted to the compound of general
formula (XI), in which R1 represents a methyl group,
under the conditions described above.
The compound of general formula (XI) is then treated
with an amine of general formula H2NR2, in which R2 is
as defined above, in a protic solvent, for example
N,N-dimethylformamide, optionally in the presence of an
acid, for example 4-methylbenzenesulphonic acid, at the
reflux temperature, in order to obtain the ester of
general formula (V"). The latter is converted to the
corresponding acid of general formula (VI") by
hydrolysis in basic medium.
Finally, this acid is converted to the primary,
secondary or tertiary amide of general formula (I""),
either through the imidazolide obtained by reaction
with N,N"-carbonyldiimidazole or through the acid
chloride.
The starting compounds of general formula
(VIII) are commercially available. Some compounds of
general formulae (IX) and (X) are described in the
literature
According to Scheme 3, the starting material
is the diester of general formula (X), described with
respect to the process of Scheme 2. This diester is
hydrolysed in acidic medium in order to obtain the
diacid of general formula (XII), which is converted to
the anhydride, for example by using acetyl chloride at
the reflux temperature, in order to obtain the compound
of general formula (XIII). The latter is converted, by
reaction with an, amine of general formula HNR3R4, in
which R3 and R4 are as defined above, in a chlorinated
solvent, for example dichloromethane, in order to
obtain the compound of general formula (XIV), which is
converted to the ester of general formula (XV), the
latter is then treated in a protic solvent, for example
N/N-dimethylformamide, in the presence of
dimethylformamide dimethyl acetal, at the reflux
temperature, in order to obtain the compound of general
formula (XVI), and, finally, the latter is reacted with
an amine of general formula R2NH2, in which R2 is as
defined above, in a protic solvent, for example
N,N-dimethylformamide, optionally in, the presence of an
acid, for example 4-methylbenzenesulphonic acid, at the
reflux temperature, in order to obtain the compound of
general formula (I"").
Finally, if desired, a secondary amide of general
formula (I""), in which R3 or R4 represents hydrogen,
can be converted to the tertiary amide by an alkylation
reaction known to a person skilled in the art, by means
of an alkylating agent, for example an alkyl halide.
Likewise, a compound of general formula (I") or (I""),
in which R1 represents a hydrogen atom, can be converted
to a compound, in the formula of which R1 represents an
alkyl group, by an alkylation reaction of known type.
Compounds with chemical structures analogous to that of
the compounds of the invention are described in CA
83(13) 114712c, CA 94(9) 64698g and CA 96(9) 68779y.
Some cpmpounds of general formulae (XII),
(XIII), (XIV) and (XV) are described in the literature.
A compound of general formula (I) in which R3 and/or R4
represent a hydroxy (C2-C4)alkyl group can be obtained by
reaction of the corresponding acid of general formula
(VI) or (VI") with an alcohol protected by a
conventional protective group, followed by
deprotection.
A compound of general formula (I) in which R3 and/or R4
represent a carboxy(C2-C4)alkyl group can be obtained by
hydrolysis of a corresponding ester. A compound of
general formula (I) in which X represents a
phenylmethoxy group can be obtained in two stages,
known to a person skilled in the art, from a compound
of general formula (I) in which X represents a methoxy
group.
The following examples illustrate in detail
the preparation of a few compounds according to the
invention. The elemental microanalyses and the IR and
NMR spectra confirm the structures of the compounds
obtained
The numbers of the compounds shown between brackets in
the titles correspond to those in the table given
below.
Example 1 (Compound No. 20)
(±)-6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)-
2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-4-carboxamide
1.1. Ethyl 5-fluoro-l-methyl-lH-indole-2-
carboxylate.
1.1.1. Ethyl 5-fluoro-lH-indole-2-carboxylate.
150 g (0.92 mol) of 4-fluorophenylhydrazine
hydrochloride are added, while cooling the mixture, to
a preprepared solution of 23 g (1 mol) of sodium in 1.5
1 of methanol and the mixture is stirred at room
temperature for 3 0 min.
The solution is concentrated under reduced pressure,
the residue is taken up in dichloromethane and the
sodium chloride is separated by filtration. The solvent
is evaporated under reduced pressure, the residue is
dissolved in 830 ml of ethanol containing 4.4 ml of
acetic acid and 102 ml (0.91 mol) of ethyl pyruvate,
and the mixture is heated at reflux for 2 h.
The reaction mixture is concentrated under reduced
pressure, the residue is taken up in ethyl acetate, the
solution is washed with water and dried over sodium
sulphate, and the solvent is evaporated under reduced
pressure. 181.6 g (0.83 mol) of hydrazone are obtained.
214 g (1.12 mol) of 4-methylbenzenesulphonic acid
monohydrate, in solution of 2.5 1 of toluene, are
dehydrated by heating the reaction mixture for 2 h at
reflux in a Dean and Stark apparatus. 181.6 g (0.83
mol) of the hydrazone obtained above are added while
cold and the mixture is heated at reflux for 3 h.
The mixture is cooled, ethyl acetate and water are
added, the organic phase is separated and dried, and
the solvent is evaporated under reduced pressure. The
residue is recrystallized from propan-2-ol and the
mother liquors are purified by chromatography on a
column of silica gel, elution being carried out with
dichloromethane. 144 g (0.7 mol) of product are
obtained, which product is used as is in the following
stage.
1.1.2. Ethyl 5-fluoro-l-methyl-1H-indole-2-
carboxylate.
11.7 g (0.39 mol) of sodium hydride, as an
80% suspension in oil, are washed with petroleum ether
and then a solution of 62.1 g (0.3 mol) of ethyl
5-fluoro-1H-indole-2-carboxylate in 600 ml of
dimethylformamide is added. The mixture is stirred for
2 h at room temperature and then 24.3 ml (0.39 mol) of
methyl iodide, in solution in 50 ml of
dimethylformamide, are added. The mixture is stirred
for 20 h at room temperature and is then poured onto
ice-cold water. The reaction mixture is extracted with
ethyl acetate, the organic phase is washed and dried
over sodium sulphate, the solvent is evaporated under
reduced pressure and 62.5 g (0.28 mol) of solid product
are obtained, which product is used as is in the
following stage.
1.2. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-a-
methylene-1H-indole-3-acetate.
A solution of 10.5 g (48 mmol) of ethyl
5-fluoro-l-methyl-1H-indole-2-carboxylate, 18 g
(155 mmol) of ethyl pyruvate and 7.8 ml of concentrated
sulphuric acid in 100 ml of acetic acid is stirred at
room temperature for 1 h 30. The mixture is
concentrated under reduced pressure, hydrolysis is
carried out with ice-cold water, aqueous ammonia is
added until the pH is alkaline and extraction is
carried out with dichloromethane. The organic phase is
washed with water and dried over sodium sulphate, the
solvent is evaporated under reduced pressure and the
residue is recrystallized from a mixture of pentane and
diethyl ether. 13 g (42 mmol) of solid are obtained.
Melting point: 86-88°C.
1.3. Ethyl (±)-6-fluoro-9-methyl-l-oxo-2-
(phenylmethyl)-2,3,4,9 -tetrahydro-1H-
pyrido [3,4-b] indole-4 -carboxylate.
A solution of 7 g (23 mmol) of ethyl
2-(ethoxycarbonyl)-5-fluoro-1-methyl-a-methylene-1H-
indole-3-acetate and 15 ml (140 mmol) of benzylamine in
200 ml of ethanol is heated at reflux for 8 h. The
solvent is evaporated under reduced pressure and the
residue is taken up in dichloromethane and 1N
hydrochloric acid. The organic phase is washed with
water and is dried over sodium sulphate. The solvent is
evaporated under reduced pressure and the residue is
purified by chromatography on a column of silica gel,
elution being carried out with a mixture of
dichloromethane and ethyl acetate. 7 g (18 mmol) of
solid product are obtained, which product is used as is
in the following stage.
1.4. (±)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-
carboxylic acid.
6 g (16 mmol) of ethyl (±)-6-fluoro-9-methyl-
l-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-4-carboxylate are hydrolysed with
2.5 g of sodium hydroxide in a mixture of water and
ethanol, the mixture is concentrated under reduced
pressure, water and acetic acid are added, extraction
is carried out with ethyl acetate, the organic phase is
washed with water and dried over sodium sulphate, and
the solvent is evaporated under reduced pressure. 4 g
(11 mmol) of solid are obtained, which solid is used as
is in the following stage.
Melting point: 264-265°C.
1.5. (±)-6-Fluoro-N,N,9-trimethyl-l-oxo-2-
(phenylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido [3,4-b] indole-4-carboxamide.
A solution of 4 g (11 mmol) of (±)-6-fluoro-
9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido [3 , 4-b] indole-4-carboxylic acid and 2.2 g
(30 mmol) of 1,1"-carbonyldiimidazole in 200 ml of
tetrahydrofuran is heated at 40°C for 2 h. The reaction
mixture is cooled and a large excess of liquefied
dimethylamine is added and the mixture is allowed to
stir for a few hours.
The solvent is evaporated under reduced pressure, the
residue is taken up in dichloromethane and water, the
organic phase is separated, washed with water and dried
over sodium sulphate, the solvent is evaporated under
reduced pressure and the residue is purified by
chromatography on a column of silica gel, elution being
carried out with a mixture of dichloromethane and
methanol. The product is recrystallized from ethyl
acetate. 1.2 g (3 mmol) of product are obtained.
Melting point: 185-186°C.
Example 2 (Compound No. 59)
6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)-
2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.
A solution of 2 g (5 mmol) of (±)-6-fluoro-
N,N, 9-trimethyl-l-oxo-2-(phenylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido [3 , 4-b] indole-4-carboxamide and of
1.6 g (7 mmol) of 2,3-dichloro-5,6-dicyano-
1,4-benzoguinone in 2 50 ml of dichloromethane is
stirred for 1 h. The organic phase is washed and dried
over sodium sulphate. The solvent is evaporated under
reduced pressure and the residue is purified by
chromatography on a column of silica gel, elution being
carried out with a mixture of dichloromethane and ethyl
acetate. The product is crystallized from diethyl
ether. 1 g (2.6 mmol) of product is obtained.
Melting point: 192-193°C.
Example 3 (Compound No. 3 6)
6-Chloro-2-(2-methoxyethyl)-N,N,9-trimethyl-1-oxo-
2,3,4,9- tetrahydro-1H-pyrido [3,4 -b] indole-
4-carboxamide.
3.1. Ethyl 5-chloro-1-methyl-1H-indole-
2-carboxylate.
The preparation is carried out as in Example
1.1.2, from 8.95 g (40 mmol) of ethyl 5-chloro-
1H-indole-2-carboxylate, 1.6 g (52 mmol) of sodium
hydride, as an 80% suspension in oil, and 11.35 g
(80 mmol) of methyl iodide. 9.5 g (40 mmol) of solid
product are obtained, which product is used as is in
the following stage.
3.2. Ethyl 5-chloro-2-(ethoxycarbonyl)-1-methyl-a-
methylene-1H-indole-3-acetate.
A solution saturated with hydrochloric acid
and containing 9.5 g (40 mmol) of ethyl 5-chloro-1-
methyl-1H-indole-2-carboxylate and 8.8 ml (80 mmol) of
ethyl pyruvate is heated at reflux for 4 h. The solvent
is evaporated under reduced pressure, the residue is
taken up in ethyl acetate, which is washed to
neutrality, the organic phase is dried over sodium
sulphate and the solvent is evaporated under reduced
pressure. The product is purified by chromatography on
a column of silica gel, elution being carried out with
dichloromethane. 9.6 g (32 mmol) of solid product are
obtained, which product is used as is in the following
stage.
3.3. Ethyl (±)-6-chloro-2-(2-methoxyethyl)-
9-methyl-l-oxo-2,3,4,9-tetrahydro-
1H-pyrido [3,4-b] indole-4-carboxylate.
A solution of 9.5 g (31 mmol) of ethyl
5-chloro-2-(ethoxycarbonyl)-1-methyl-a-methylene-
1H-indole-3-acetate and 8.1 g (93 mmol) of 2-
methoxyethylamine in 2 0 ml of ethanol is heated at
reflux for 3 h.
The solvent is evaporated under reduced pressure and
the residue is taken up in ethyl acetate, which is
washed with water and dried over sodium sulphate. 9.7 g
(27 mmol) of solid product are obtained, which product
is used as is in the following stage.
3.4. (±)-6-Chloro-2-(2-methoxyethyl)-9-methyl-
1-oxo-2,3,4,9 -tetrahydro-1H-pyrido[3,4-
b] indole-4-carboxylic acid.
9.6 g (26 mmol) of ethyl (±)-6-chloro-2-
(2-methoxyethyl)-9-methyl-l-oxo-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indole-4-carboxylate are hydrolysed
with a solution of 3.1 g (80 mmol) of sodium hydroxide
in 260 ml of ethanol and 50 ml of water. The reaction
mixture is concentrated, the residue is taken up in
water and the aqueous phase is washed with ethyl
acetate and acidified to pH=l with concentrated
hydrochloric acid. Extraction is carried out with ethyl
acetate. The organic phase is washed with water and
dried with sodium sulphate. The solvent is evaporated
under reduced pressure and 8.3 g (26 mmol) of solid
product are obtained, which product is used as is in
the following stage.
3.5. (±)-6-Chloro-2-(2-methoxyethyl)-
N,N, 9-trimethyl-l-oxo-2,3,4,9-tetrahydro-
1H-pyrido [3,4-.b] indole-4-carboxamide.
The preparation is carried out as in Example
1.5, from 8.3 g (26 mmol) of (±)-6-chloro-2-(2-
methoxyethyl)-9-methyl-l-oxo-2,3,4, 9-tetrahydro-
1H-pyrido [3,4-b] indole-4-carboxylic acid and from
dimethylamine. 8.6 g of product are isolated, which
product is recrystallized from propan-2-ol. 6.9 g
(19 mmol) of product are obtained.
Melting point: 217-219°C.
Example 4 (Compound No. 77)
(+)-6-Fluoro-N,N,9-trimethyl-l-oxo-2-(phenylmethyl)-
2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b] indole-
4-carboxamide.
4.1. (+)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)-
2,3,4, 9-tetrahydro-1H-pyrido [3,4-b] indole-
4-carboxylic acid.
A solution of 20.5 g (58 mmol) of (±)-6-
fluoro-9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and
of 7.5 ml (58 mmol) of (R)-(+)-a-methylbenzylamine in
1000 ml of methanol is stirred. The mixture is
concentrated under reduced pressure, the residue is
taken up in 50 ml of ethyl acetate and 400 ml of
diethyl ether, and the precipitate is separated by
filtration and recrystallized three times from propan-
2-ol.
7.3 g (15 mmol) of diastereoisomer salt are isolated,
which salt is redissolved in 100 ml of methanol, 16 ml
of 1N hydrochloric acid and 200 ml of water are added,
and the precipitate is separated by filtration and
dried under reduced pressure at room temperature. 5.1 g
(15 mmol) of dextrorotatory acid are obtained.
Melting point: 264-269°C.
[a] 20D = +41.6° (c = 0.5, CH3OH) ee > 99% (HPLC).
4.2. (+)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-
(phenylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido [3,4-b] indole-4-carboxamide.
A solution of 0.5 g (1.3 mmol) of (+)-6-
fluoro-9-methyl-l-oxo-2-(phenylmethyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid,
0.11 g (1.3 mmol) of dimethylamine hydrochloride, dried
beforehand under reduced pressure, and 0.68 g (13 mmol)
of (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium
hexafluorophosphate in 10 ml of dichloromethane, passed
beforehand through an alumina column, is cooled to
-30°C and 0.68 ml (3.9 mmol) of N,N-di(l-
methylethyl)ethylamine, in solution in 5 ml of
dichloromethane, is added dropwise. The mixture is
stirred for 6 h at between -3 0°C and -2 0°C, hydrolysis
is carried out with 10 ml of 5% aqueous potassium
hydrogensulphate solution, the mixture is extracted
with dichloromethane, the organic phase is washed and
dried, the solvent is evaporated under reduced
pressure, the residue is purified by chromatography on
a column of silica gel, elution being carried out with
a mixture of dichloromethane and ethyl acetate, and the
product obtained is recrystallized from propan-2-ol.
0.37 g (1 mmol) of dextrorotatory amide is obtained.
Melting point: 199-202°C.
[a]20D = +6.3° (c = 1, CHC13) ee > 94% (HPLC) .
Example 5 (Compound No. 76)
(-) -6-Fluoro-N,N, 9-trimethyl-1-oxo-2- (phenylmethyl) -
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-
4-carboxamide.
5.1. (-)-6-Fluoro-9-methyl-l-oxo-2-(phenylmethyl)-
2,3,4, 9-tetrahydro-1H-pyrido[3,4-b] indole-
4-carboxylic acid.
The solvent from the various mother liquors
from the recrystallization of the diastereoisomer salt
of Example 4.1 is evaporated under reduced pressure,
water and concentrated hydrochloric acid are added, and
the precipitate is separated by filtration and dried
under reduced pressure at room temperature. 13.6 g
(3 8 mmol) of impure laevorotatory acid are obtained, to
which are added 250 ml of methanol and 4.97 ml
(38 mmol) of (S)-(-)-a-methylbenzylamine.
The mixture is stirred and concentrated under reduced
pressure and the precipitate is collected by filtration
and recrystallized three times from propan-2-ol. 7 g
(15 mmol) of diastereoisomer salt are obtained, which
salt is redissolved in the minimum amount of methanol,
15 ml of 1N hydrochloric acid are added and the volume
of the solution is doubled with water. The precipitate
is separated by filtration, washed with water,
superficially dried, and dried at room temperature
under reduced pressure. 5 g (14 mmol) of laevorotatory
acid are obtained.
Melting point: 264-269°C.
[a]20D = -42.2° (c = 0.5, CH3OH) ee > 99% (HPLC) .
5.2 . (-) -6-Fluoro-N,N, 9-trimethyl-1-oxo-2-
(phenylmethyl)-2,3,4,9-tetrahydro-1H-
pyrido [3 , 4-b] indole-4-carboxamide.
By carrying out the preparation as described
in Example 4.2, from (-)-6-fluoro-9-methyl-l-oxo-2-
(phenylmethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b]
indole-4-carboxylic acid and from dimethylamine,
0.3 g (0.8 mmol) of laevorotatory amide is obtained
after final recrystallization from ethyl acetate.
Melting point: 204-205°C.
[a]20D = -7.5° (c = 1, CHC13) ee > 98% (HPLC).
Example 6 (Compound No. 101)
6-Fluoro-N,N,9-trimethyl-l-oxo-2-phenyl-2,9-dihydro-1H-
pyrido [3 , 4-b] indole-4-carboxamide .
6.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-a-
methylene-1H-indole-3-acetate.
A solution of 37.2 g (180 mmol) of ethyl 5-
fluoro-1H-indole-2-carboxylate, 25.8 g (222 mmol) of
ethyl pyruvate and 31 ml of concentrated sulphuric acid
in 400 ml of acetic acid is stirred for 20 h.
The solvent is evaporated under reduced pressure, the
residue is taken up in water and ethyl acetate, the
organic phase is separated, washed with a dilute
aqueous ammonia solution and then with a saturated
aqueous sodium chloride solution and dried over sodium
sulphate, and the solvent is evaporated under reduced
pressure.
37.1 g (122 mmol) of solid product are obtained, which
product is used as is in the following stage.
6.2. 6-Fluoro-l-oxo-2-phenyl-2,3,4,9-tetrahydro-
1H-pyrido [3, 4-b] indole-4-carboxylic acid.
A mixture of 25 g (82 mmol) of ethyl
2-(ethoxycarbonyl)-5-fluoro-a-methylene-1H-indole-3-
acetate and 31.8 g (342 mmol) of aniline is heated at
reflux for 17 h. A dilute hydrochloric acid solution
and ethyl acetate are added, the organic phase is
separated, washed with water and dried with sodium
sulphate, and the solvent is evaporated under reduced
pressure. 3 0 g of residue are obtained, which residue
is hydrolysed with a solution of 43 ml of 3 0% sodium
hydroxide in 400 ml of ethanol at reflux for 1 h.
The mixture is concentrated under reduced pressure,
water is added, the mixture is washed with ethyl
acetate and dichloromethane, the aqueous phase is
acidified with concentrated hydrochloric acid, and the
precipitate is collected by filtration and dried under
reduced pressure.
18.5 g (57 mmol) of solid compound are obtained, which
compound is used as is in the following stage.
6.3. 6-Fluoro-N,N,9-trimethyl-l-oxo-2-phenyl-2,9-
dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.
5 g (15 mmol) of 6-fluoro-1-oxo-2-phenyl-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic
acid in 40 ml of thionyl chloride are heated at reflux
for 1 h. The solvent is evaporated under reduced
pressure, the residue is taken up in dichloromethane, a
large excess of liquefied dimethylamine is added, the
mixture is stirred for a few hours, water is added, and
the precipitate is separated by filtration and dried
under reduced pressure.
3.4 g (9 mmol) of compound are obtained.
2.5 g thereof are dissolved in 50 ml of dimethyl
sulphoxide, 0.6 g of powdered potassium hydroxide and
1.2 ml of iodomethane are added, and the mixture is
stirred for 5 h at 50°C and then for 20 h at room
temperature.
Dilute hydrochloric acid is added, extraction is
carried out with ethyl acetate, the organic phase is
dried over sodium sulphate, the solvent is evaporated
under reduced pressure and the residue is purified by
chromatography on a column of silica gel, elution being
carried out with a mixture of cyclohexane and ethyl
acetate.
2.2 g of a mixture containing 6-fluoro-N,N,9-trimethyl-
l-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-
4-carboxamide and 6-fluoro-N,N,9-trimethyl-1-oxo-2-
phenyl-2,3,4, 9 - tetrahydro-1H-pyrido [3,4-b] indole-
4-carboxamide are obtained.
This mixture is stirred with 1 g of 2,3-dichloro-5,6-
dicyano-l,4-benzoquinone for 20 h and is washed with a
saturated aqueous sodium hydrogencarbonate solution,
the organic phase is separated and dried over sodium
sulphate, the solvent is evaporated under reduced
pressure, the residue is purified by chromatography on
a column of silica gel, elution being carried out with
a mixture of cyclohexane and ethyl acetate, and the
product is recrystallized from ethyl acetate.
0.5 g (1.5 mmol) of compound is obtained.
Melting point: 195-197°C.
Example 7 (Compound No. 97)
N,N, 9-Trimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido [3,4-b] indole-4-carboxamide.
7.1. Ethyl 2-(ethoxycarbonyl)-a-methylene-1H-
indole-3-acetate
An ethanol solution saturated with gaseous
hydrochloric acid containing 39.1 g (207 mmol) of ethyl
1H-indole-2-carboxylate and 45.3 ml (410 mmol) of ethyl
pyruvate is brought to approximately 60°C for 3 h. The
mixture is concentrated under reduced pressure and the
residue is taken up in diethyl ether. The organic phase
is washed with water and dried over sodium sulphate.
The solvent is evaporated under reduced pressure and
the residue is crystallized from cyclohexane. 45.4 g
(158 mmol) of solid product are obtained, which product
is used as is in the following stage.
7.2. l-Oxo-N,2-diphenyl-2,3,4,9-tetrahydro-1H-
pyrido [3,4-b] indole-4-carboxamide.
A mixture of 32 g (111-mmol) of ethyl
2-(ethoxycarbonyl)-a-methylene-1H-indole-3-acetate and
of 47.5 g (511 mmol) of aniline is heated at reflux for
13 h. Dichloromethane is added and the organic phase is
washed with 1N hydrochloric acid. It is dried over
sodium sulphate and the solvent is evaporated under
reduced pressure. 38.8 g of impure product are
obtained, which product is used as is in the following
stage.
7.3. Ethyl l-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido [3,4-b] indole-4-carboxylate.
A solution of 3 8.8 g of impure 1-oxo-N,2-
dipheny1-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-
carboxamide in a mixture of ethanol, water and 37%
hydrochloric acid is heated at reflux for 8 h.
The reaction mixture is neutralized with concentrated
sodium hydroxide and extraction is carried out with
ethyl acetate. The organic phase is dried over sodium
sulphate and evaporated under reduced pressure. The
residue is purified by chromatography on a column of
silica gel, elution being carried out with a mixture of
dichloromethane and ethyl acetate. 22.6 g (68 mmol) of
product are obtained, which product is used as is in
the following stage.
7.4. 1-Oxo-2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-4-carboxylic acid.
22.6 g (68 mmol) of ethyl l-oxo-2-phenyl-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate
are hydrolysed with 200 ml of 1N sodium hydroxide in
500 ml of methanol. The reaction mixture is acidified
with 1N hydrochloric acid and the precipitate is
filtered off. It is dried under reduced pressure.
18.1 g (59 mmol) of solid product are obtained, which
product is used as is in the following stage.
7.5. N,N-Dimethyl-l-oxo-2-phenyl-2,3,4,9-
tetrahydro-1H-pyrido [3,4-b] indole-
4-carboxamide.
A solution of 10 g (33 mmol) of 1-oxo-
2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-
4-carboxylic acid in 3 0 ml of thionyl chloride is
heated at reflux for 4 h. The solvent is evaporated
under reduced pressure, the residue is taken up in
dichloromethane and a large excess of liquefied
dimethylamine is added. The mixture is stirred for
several hours and the solvent is evaporated under
reduced pressure. Water and ethyl acetate are added.
The precipitate is filtered off and dried under reduced
pressure. 8.2 g of impure product are obtained, which
product is used as is in the following stage.
7.6. N,N,9-Trimethyl-l-oxo-2-phenyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-4-
carboxamide
A mixture of 1.3 g (23 mmol) of powdered
potassium hydroxide and of 6 g of impure N,N-dimethy1-
1-oxo-2 -phenyl-2,3,4,9- tetrahydro-1H-pyrido [3,4-
b]indole-4-carboxamide in 60 ml of dimethyl sulphoxide
is heated at 40°C for 30 min. 2.5 ml (40 mmol) of
iodomethane are added and the reaction mixture is
stirred for 5 h at room temperature.
Water and dichloromethane are then added. The organic
phase is dried over sodium sulphate and evaporated
under reduced pressure. The residue is purified by
chromatography on a column of silica gel, elution being
carried out with a mixture of dichloromethane and ethyl
acetate. The product is recrystallized from ethyl
acetate. 1.9 g (5.5 mmol) of product are obtained.
Melting point: 196-197°C.
Example 8 (Compound No. 123)
N-Ethyl-6-fluoro-N,9-dimethyl-l-oxo-2-phenyl-2,9-
dihydro-1H-pyrido [3,4-b] indole-4-carboxamide .
8.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1H-indole-
3-acetate
A solution of 7.4 g (185 mmol) of sodium
hydroxide £n 75 ml of water is added to a solution of
3 0 g (185 mmol) of 4-fluorophenylhydrazine
hydrochloride in 3 00 ml of water, the mixture is
stirred for 15 min and then a solution of 29 g
(198 mmol) of ketoglutaric acid in 60 ml of water is
added. The reaction mixture is stirred at room
temperature for 3 h and is extracted with ethyl
acetate, and the organic phase is washed with water,
dried over sodium sulphate and evaporated under reduced
pressure. 42 g (144 mmol) of product are obtained,
which product is dissolved in 42 0 ml of ethanol
saturated with gaseous hydrochloric acid and heated at
reflux for 4 h.
The reaction mixture is concentrated under reduced
pressure, the residue is taken up in ethyl acetate, and
the organic phase is washed with normal sodium
hydroxide and then with water, dried over magnesium
sulphate and evaporated under reduced pressure. 42 g
(143 mmol) of solid product are obtained, which product
is used as is in the following stage.
8.2. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-
1H-indole-3-acetate.
A solution of 7.36 g (184 mmol) of 60% sodium
hydride, washed beforehand with petroleum ether, and
45 g (153 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-
1H-indole-3-acetate in 450 ml of N,N-dimethylformamide
is stirred for 2 h at room temperature and then a
solution of 19 ml (306 mmol) of iodomethane in 100 ml
of N,N-dimethylformamide is added. After stirring for
20 h, the reaction mixture is poured onto ice-cold
water, extraction is carried out with diethyl ether,
the organic phase is washed with water and dried over
magnesium sulphate, and the solvent is evaporated under
reduced pressure. 44.3 g (144 mmol) of product are
obtained, which product is used as is in the following
stage.
8.3. Ethyl a-(dimethylaminomethylidene)-
2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-
indole-3-acetate.
A solution of 44.3 g (144 mmol) of ethyl
2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole-
3-acetate and 57.4 ml of dimethylformamide dimethyl
acetal in 450 ml of N,N-dimethylformamide is heated at
reflux for 50 h. The solvent is evaporated under
reduced pressure and the residue is taken up in diethyl
ether. The insoluble material is removed by filtration
and the solvent is concentrated under reduced pressure.
49.3 g (13 6 mmol) of solid product are obtained, which
product is used as is in the following stage.
8.4. Ethyl 6-fluoro-9-methyl-l-oxo-2-phenyl-
2 , 9-dihydro-1H-pyrido [3,4-b] indole-
4-carboxylate.
A solution of 16.3 g (45 mmol) of ethyl
a-(dimethylaminomethylidene)-2-(ethoxycarbonyl)-5-
fluoro-1-methyl-1H-indole-3-acetate, 4.64 ml (50 mmol)
of aniline and 1.6 g (8 mmol) of 4-methylbenzene-
sulphonic acid monohydrate in 160 ml of N,N-
dimethylformamide is heated at reflux for 24 h.
3.3 g (31 mmol) of sodium carbonate are added in small
portions and reflux is continued for 2 h.
The solution is cooled and poured onto ice-cold water.
Extraction is carried out with ethyl acetate and the
organic phase is washed with water, dried over
magnesium sulphate and evaporated under reduced
pressure. The residue is purified by chromatography on
a column of silica gel, elution being carried out with
a mixture of dichloromethane and ethyl acetate. 10.9 g
(30 mmol) of product are obtained, which product is
used as is in the following stage.
8.5. 6-Fluoro-9-methyl-l-oxo-2-phenyl-2,9-dihydro-
1H-pyrido[3,4-b]indole-4-carboxylic acid.
A solution of 22.8 g (65 mmol) of ethyl
6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-
pyrido [3,4-b] indole-4-carboxylate and of 7.46 g
(186 mmol) of sodium hydroxide in a mixture of 1 1 of
ethanol and 100 ml of water is heated at reflux for
3 h. The mixture is concentrated under reduced
pressure, the residue is taken up in water and the
aqueous phase is washed with ethyl acetate.
Acidification is carried out with concentrated
hydrochloric acid to pH = 1 and the product is filtered
off, which product is rinsed several times with water.
It is dried under reduced pressure. 20.4 g (64 mmol) of
solid compound are obtained, which compound is used as
is in the following stage.
8.6. 6-Fluoro-N,9-dimethyl-l-oxo-2-phenyl-2,9-
dihydro-1H-pyrido [3,4-b] indole-4-carboxamide .
A solution of 5 g (15.6 mmol) of 6-fluoro-9-
methyl-1-oxo-2-pheny1-2,9-dihydro-1H-pyrido[3,4-b]-
indole-4-carboxylic acid and of 4.8 g (30 mmol) of
N,N"-carbonyldiimidazole in 100 ml of N,N-
dimethylformamide is stirred at 60°C for 4 h. A large
excess of liquefied methylamine is added at room
temperature and the reaction mixture is stirred for
20 h. The solution is poured onto ice-cold water and
the precipitate is collected by filtration, washed with
a saturated sodium hydrogencarbonate solution, with
water and then with ethyl acetate, and dried under
reduced pressure. 3.5 g of crude product are isolated.
The filtrates are combined and extracted with
dichloromethane. The organic phase is washed with a
sodium hydrogencarbonate solution and then with water
and dried over magnesium sulphate, and the solvent is
evaporated under reduced pressure. 1.5 g of additional
product are isolated. The two batches are combined and
purified by chromatography on a column of silica gel,
elution being carried out with a mixture of
dichloromethane and ethyl acetate. 4.7 g (13.5 mmol) of
solid product are obtained.
8.7. N-Ethyl-6-fluoro-N,9-dimethyl-1-oxo-2-phenyl-
2,9-dihydro-1H-pyrido[3,4-b] indole-4-
carboxamide.
A solution of 2.5 g (7.1 mmol) of 6-fluoro-
N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-
b]indole-4-carboxamide and of 0.3 6 g (9 mmol) of 60%
sodium hydride, washed beforehand with petroleum ether,
is stirred for 3 h at 50°C. 1.67 ml (21 mmol) of
iodoethane are added, stirring is maintained for 2 0 h,
and the solution is poured onto ice-cold water and
extracted with ethyl acetate. The organic phase is
washed with water, dried over magnesium sulphate and
evaporated under reduced pressure. The residue is
purified by chromatography on silica, the elution being
carried out with a mixture of dichloromethane and ethyl
acetate. The product is recrystallized from propan-
2-ol.
2.3 g of solid are obtained.
Melting point: 181-182°C.
Example 9 (Compound No. 98)
6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-ylcarbonyl)-
2,9-dihydro-1H-pyrido[3,4-b]indol-1-one.
A solution of 3.2 g (10 mmol) of 6-fluoro-
9-methyl-1-oxo-2 -pheny1-2,9-dihydro-1H-
pyrido [3,4-b] indole-4-carboxylic acid and of 3.2 g
(20 mmol) of N,N"-carbonyldiimidazole in 65 ml of
N,N-dimethylformamide is stirred for 4 h at 60°C.
2.5 ml (3 0 mmol) of pyrrolidine are added at room
temperature and the reaction mixture is stirred for
20 h.
The solution is poured onto ice-cold water and
extracted with ethyl acetate. The organic phase is
washed with water and dried over magnesium sulphate,
and the solvent is evaporated under reduced pressure.
The residue is purified by chromatography on a column
of silica gel, elution being carried out with a mixture
of dichloromethane and ethyl acetate. The product is
recrystallized from propan-2-ol.
3 g (7.7 mmol) of solid are obtained.
Melting point: 203-205°C
Example 10 (Compound No. 122)
6-Fluoro-N,N,9-trimethyl-l-oxo-2-(pyridin-2-yl)-
2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.
10.1. Methyl 6-fluoro-9-methyl-l-oxo-2-(pyridin-
2-yl) -2,9-dihydro-1H-pyrido [3,4-b] indole-
4-carboxylate.
A mixture of 4.1 g (12.2 mmol) of methyl
a-(dimethylaminomethylidene)-5-fluoro-2-
(methoxycarbonyl)-1-methyl-1H-indole-3-acetate and of
1.73 g (18.4 mmol) of 2-aminopyridine is heated at
180°C for 30 min. 7 ml of N,N-dimethylformamide are
added and heating is continued for 4 h.
The reaction mixture is cooled and poured onto a
mixture of water and ethyl acetate, and the insoluble
material is collected by filtration and dried under
reduced pressure. 1.8 g (5.1 mmol) of solid are
obtained, which solid is used as is in the following
stage.
10.2. 6-Fluoro-9-methyl-l-oxo-2-(pyridin-2-yl)-
2, 9-dihydro-lff-pyrido [3,4-b] indole-4-
carboxylic acid.
A solution of 3.3 g (9.4 mmol) of methyl
6-fluoro-9-methyl-l-oxo-2-(pyridin-2-yl)-2,9-dihydro-
1H-pyrido[3,4-b]indole-4-carboxylate in a mixture of
100 ml of ethanol and of 28 ml of 1N sodium hydroxide
is heated at reflux for 4 h. The mixture is
concentrated under reduced pressure, water is added,
acidification is carried out with concentrated
hydrochloric acid and the precipitate is collected by
filtration. It is washed with water and dried under
reduced pressure. 2.8 g (8.3 mmol) of solid product are
obtained, which product is used as is in the following
stage.
10.3. 6-Fluoro-N,N,9-trimethyl-l-oxo-2-(pyridin-
2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-
4-carboxamide.
A solution of 2.5 g (7.4 mmol) of 6-fluoro-
9-methyl-l-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-
pyrido[3,4-b]indole-4-carboxylic acid and of 2.4 g
(14.8 mmol) of N,N"-carbonyldiimidazole in 65 ml of
N,N-dimethylformamide is stirred for 4 h. The reaction
mixture is cooled and a large excess of liquefied
dimethylamine is added. The mixture is stirred for 48 h
at room temperature, poured into water and extracted
with ethyl acetate. The organic phase is washed with
water and dried over magnesium sulphate, and the
solvent is evaporated under reduced pressure. The
residue is purified by chromatography on a column of
silica gel, elution being carried out with a mixture of
dichloromethane and ethyl acetate. The product is
recrystallized from ethyl acetate.
1.6 g (4.4 mmol) of solid are obtained.
Melting point: 220-221°C
Example 11 (Compound No. 125)
6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-
4-(pyrrolidin-1-ylcarbonyl)-2,9-dihydro-1H-
pyrido [3,4-b] indol-1-one
11.1. 2-Carboxy-5-fluoro-1H-indole-3-acetic acid.
A solution of 26.5 g (103 mmol) of ethyl
2-(ethoxycarbonyl)-5-fluoro-1H-indole-3-acetate and
24 g of sodium hydroxide in a mixture of 530 ml of
ethanol and of 100 ml of water is heated at reflux. The
mixture is concentrated under reduced pressure, water
is added, and the aqueous phase is washed with ethyl
acetate and acidified with concentrated hydrochloric
acid. The precipitate is filtered off, rinsed with
water and dried under reduced pressure. 23.4 g
(98.7 mmol) of product are obtained, which product is
used as is in the following stage.
11.2 . 6-Fluoro-1,3,4,9-tetrahydropyrano [3,4-b] -
indole-1,3-dione.
A solution of 4.7 g (19.8 mmol) of 2-carboxy-
5-fluoro-1H-indole-3-acetic acid in 94 ml of acetyl
chloride is heated at reflux for 5 h. The mixture is
concentrated under reduced pressure, toluene is added

and the solVents are evaporated under reduced pressure.
4.5 g of solid product are obtained, which product is
used as in the following stage.
11.3. 5-Pluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-
1H-indole-2-carboxylic acid.
A solution of 4.4 g (20 mmol) of 6-fluoro-
1,3,4,9-tetrahydropyrano[3,4-b]indole-1,3-dione and of
8.3 ml (100 mmol) of pyrrolidine in 100 ml of
dichloromethane is stirred for 24 h at room
temperature. The mixture is concentrated under reduced
pressure, water is added and the aqueous phase is
washed with ethyl acetate. Acidification is carried out
with concentrated hydrochloric acid and ethyl acetate
is added. The precipitate is collected by filtration,
washed with water and dried under reduced pressure. 5 g
(17.2 mmol) of solid product are obtained, which
product is used as is in the following stage.
11.4. Methyl 5-fluoro-3-(2-oxo-2-(pyrrolidin-
1-yl)ethyl)-1H-indole-2-carboxylate.
3.8 ml (51 mmol) of thionyl chloride are
added dropwise to a solution of 5 g (17.2 mmol) of
5-fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-
2-carboxylic acid in 50 ml of methanol cooled in an ice
bath, and then the mixture is heated at reflux for 3 h.
The mixture is concentrated under reduced pressure,
water and dichloromethane are added, and the organic
phase is washed with water, dried over magnesium
sulphate and evaporated under reduced pressure. 4.5 g
(14 mmol) of product are obtained, which product is
used as is in the following stage.
11.5. Methyl 3-(l-dimethylaminomethylidene-2-oxo-2-
(pyrrolidin-1-yl)ethyl)-5-fluoro-1-methyl-1H-
indole-2-carboxylate.
A solution of 3.4 g of methyl 5-fluoro-3-(2-
oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylate
and 4.66 ml (35 mmol) of dimethylformamide dimethyl
acetal in 34 ml pf N,N-dimethylformamide is heated at
reflux for 30 h. The mixture is concentrated under
reduced pressure, xylene is added and the solvents are
evaporated under reduced pressure. 4 g of residue are
obtained, which residue contains approximately 50% of
the desired product (according to the proton magnetic
resonance spectrum) and is used as is in the following
stage.
11.6. 6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thia-
diazol-2-yl)-4-(pyrrolidin-1-ylcarbonyl)-
2,9-dihydro-1H-pyrido[3,4-b]indol-1-one.
A solution of 4 g of the residue obtained in
the preceding stage and 1.04 g (5.5 mmol) of
4-methylbenzenesulphonic acid monohydrate in 40 ml of
N,N"-dimethylf ormamide is stirred for 15 min. 0.65 g
(6.4 mmol) of 2-amino-5-methyl-l,3,4-thiadiazole is
added and the mixture is heated at reflux for 24 h.
The mixture is poured into water and ethyl acetate. The
precipitate is collected by filtration, washed with
water, dried under reduced pressure and recrystallized
from N, N- dimethy1 formamide.
1 g (2.4 mmol) of product is obtained.
Melting point: 299-301°C.
The chemical structures and the physical
properties of a few compounds according to the
invention are illustrated in the following table.
Key
Me denotes a methyl group, Et denotes an ethyl group, Pr denotes a propyl group, iPr denotes
an isopropyl group, cPr denotes a cyclopropyl group, Ph denotes a phenyl group, 1-Napht and
2-Napht respectively denote naphth-1-yl and naphth-2-yl groups, x-Pyridyl denotes a
pyridin-x-yl group, x-Thienyl denotes a thien-x-yl group, Piperid denotes a piperidin-1-yl
group, Pyrrolid denotes a pyrrolidin-1-yl group, Morph denotes a morpholin-4-yl group, Azetid
denotes an azetidin-1-yl group, 4-Me-piperaz denotes a 4-methylpiperazin-l-yl group,
5-Me-thiadiaz denotes a 5-methyl-1,3,4-thiadiazol-2-yl group, 5-Me-oxazol denotes a 5-
methyl-l,2-oxazol-2-yl group, and Thiazolid denotes a thiazolidinyl group.
In the column "3~4", "/" denotes a carbon-carbon single bond and "//" denotes a carbon-carbon
double bond between the 3 and 4 atoms of the molecule.
In the "M.p. (°C)" column, "d" denotes a melting point with decomposition.
The compounds of the invention were subjected
to pharmacological tests which demonstrated their
advantage as substances having therapeutic activities.
Study of membrane binding with respect to ?1 (type 1
benzodiazepine) and ?2 (type 2 benzodiazepine)
receptors.
The affinity of the compounds for the ?1
receptors of the cerebellum and ?2 receptors of the
spinal cord was determined according to a variant of
the method described by S.Z. Langer and S. Arbilla in
Fund. Clin. Pharmacol., 2, 159-170 (1988), with the use
of [3H] f lumazenil instead of [3H] diazepam as
radioligand.
The cerebellar or spinal cord tissue is homogenized for
60 s in 120 or 30 volumes, respectively, of ice-cold
buffer (50 mM Tris-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl)
and then, after dilution to 1/3, the suspension is
incubated with [3H]flumazenil (specific activity
7 8 Ci/mmol, New England Nuclear) at a concentration of
1 nM and with the compounds of the invention at
different concentrations, in a final volume of 525 µl.
After 30 minutes of incubation at 0°C, the samples are
filtered under reduced pressure on Whatman GF/B®
filters and washed immediately with ice-cold buffer.
The specific binding of [3H]flumazenil is determined in
the presence of 1 µM unlabelled diazepam. The data are
analysed according to standard methods and the IC50
concentration, the concentration which inhibits by 50%
the binding of [3H]flumazenil, is calculated.
The IC50 values of the most active compounds of the
invention lie, in this test, between 10 and 1000 nM.
Study of the anxiolytic activity: drink intake conflict
test.
The anxiolytic activity is evaluated in rats
in the drink intake conflict test according to the
method described by J.R. Vogel, B. Beer and D.E. Clody
in Psychopharmacologia (Berl.), 21, 1-7 (1971).
After being deprived of water for 48 h, the rat is
placed in a soundproof chamber equipped with a water
pipette connected to an anxiometer which delivers a
mild electric shock every 2 0 licks. The number of
shocks received is automatically counted over 3 minutes
and makes it possible to evaluate the anxiolytic
activity of the tested compounds. The results are
expressed by the minimum effective dose (MED), the dose
which produces a significant increase in the number of
shocks received, with respect to the number observed in
the control animals.
The MED values of the most active compounds lie, in
this test, between 5 and 50 mg/kg via the
intraperitoneal route.
Study of the anxiolytic activity: test in a heightened
cross-shaped maze
The protocol of this test is a modification
of that described by S. Pellow and S. File in
Pharmacol. Biochem. Behav. (1986), 24, 525-529.
After a period of accustomization to the experimental
room lasting approximately 24 h, the rats are placed
individually on the central platform, the muzzle
directed towards one of the closed arms, and observed
for 4 min using a video camera. The time spent by the
animal in the open arms, the number of entries into the
closed arms and into the open arms, the number of
attempts to enter the open arms, followed by an
avoidance response, and the exploration of the edges in
the open arms are recorded. The results are expressed
for each animal: 1) as percentage of passages into the
open arms relative to the total number of entries into
the four arms of the apparatus, 2) as percentage of
time spent in the open arms relative to the total
duration of the test (4 min), 3) as total number of
abortive attempts made by the animal, 4) as total
number of explorations.
The products under study are administered
intraperitoneally or orally at increasing doses.
The results are expressed by the minimum effective dose
(MED) which produces either a significant increase
(activity in the open arms) or a significant decrease
(attempts) relative to the performance observed in the
control animals.
The MED values of the most active compounds lie, in
this test, between 3 and 50 mg/kg via the
intraperitoneal or oral route.
Study of the hypnotic activity.
The sedative or hypnotic activity of the
compounds was determined by observing their action on
the rat"s electrocorticogram, according to the method
described by H. Depoortere, Rev. E.E.G. Neurophysiol.,
10, 3, 207-214 (1980) and by H. Depoortere and
M. Decobert, J. Pharmacol., (Paris), 14, 2, 195-265
(1983) .
The products under study were administered
intraperitoneally at increasing doses. They induce
sleep patterns at doses ranging from 1 to 30 mg/kg.
Study of the anticonvulsant activity; activity with
respect to clonic convulsions induced in rats by
injection of pentetrazol.
The protocol of this test is a modification
of that described by E.A. Swinyard and J.H. Woodhead in
Antiepileptic Drugs, Raven Press, New York, 111-126
(1982) .
The test products are administered to the animals
intraperitoneally 3 0 min before an intravenous
injection of 20 mg/kg of pentetrazol. Immediately after
the injection, the number of animals exhibiting clonic
convulsions is noted over 5 min.
The results are expressed as the AD50, the dose which
protects 50% of the animals, calculated according to
the method of J.T. Lichtfield and F. Wilcoxon
(J. Pharm. Exp. Ther. (1949), 96, 99-113) on the basis
of 3 or 4 doses each administered to a group of 8 to 10
rats.
The AD50 values of the most active compounds lie between
0.3 and 30 mg/kg via the intraperitoneal or oral route.
Study of the anticonvulsant activity; activity with
respect to isoniazid-induced convulsions in mice.
The intrinsic activity of the compounds is
determined by the latency time of onset of convulsions
induced by the subcutaneous administration of isoniazid
(800 mg/kg) simultaneously with the test compound
injected intraperitoneally, according to the protocol
described by G. Perrault, E. Morel, D. Sanger and
B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988).
The results are expressed as the AD50, the dose which
produces 50% of the maximum effect, relative to the
control animals, determined on the basis of 3 or 4
doses each administered to a group of 8 to 10 mice.
The AD50 values of the compounds of the invention lie,
in this test, between 1 and 50 mg/kg via the
intraperitoneal route and, depending on the compounds,
the maximum effect can be as much as 300%.
The results of the tests performed on the
compounds of the invention show that, in vitro, they
displace [3H]flumazenil from its specific binding sites
in the cerebellum and the spinal cord; they exhibit a
mixed affinity for the ?1 and ?2 (type 1 and type 2
benzodiazepine) sites situated in the GABAA - ? sites
chlorine channel macromolecular complex.
In vivo, they behave as full or partial agonists with
respect to these receptors.
They possess anxiolytic, hypnotic and anticonvulsant
properties, and can consequently be used for the
treatment of complaints associated with disorders of
GABAergic transmission, such as anxiety, sleep
disorders, epilepsy, spasticity, muscle contractures,
cognitive disorders, withdrawal disorders related to
alcoholism, tobacco or drugs, and the like.
They can also be used for the treatment of Parkinson"s
disease and all types of extrapyramidal syndromes.
Finally, they can be used in premedication and as
general anaesthetics for the induction and/or
maintenance of anaesthesia, or as local anaesthetics,
optionally in combination with other anaesthetics
and/or muscle relaxants and/or analgesics.
To this end, they may be presented in any
pharmaceutical dosage form, in combination with
suitable excipients, for enteral or parenteral
administration, for example in the form of tablets,
dragees, capsules including hard gelatin capsules,
solutions or suspensions to be swallowed or injected,
suppositories, and the like, containing a dose to
permit a daily administration of 1 to 1000 mg of active
substance.

WE CLAIM:
1. 1H-pyrido [3, 4-b] indole-4-carboxamide
derivatives of general formula (I)
in which
X represents a hydrogen or halogen atom or a
(C1-C3) alkyl, (C1-C3) alkoxy, trif luoromethyl or
phenylmethoxy group,
R1 represents a hydrogen atom or a (C1-C3) alkyl,
cyclopropylmethyl or phenylmethyl group,
R2 represents either a (C1-C3) alkyl group optionally
substituted by a methoxy group, or a phenyl (C1-C3) alkyl
group optionally substituted on the phenyl ring by a
halogen atom or a methyl or methoxy group, or a
cyclohexylmethyl group, or a thienylmethyl group, or a
pyridinylmethyl group, or a phenyl group optionally
substituted by one or more halogen atoms or a
(C1-C3) alkyl or (C1-C3) alkoxy group, or a pyridinyl
group, or a 5-methyl-l,2-oxazolyl group, or a 5-methyl-
1,3,4-thiadiazolyl group, or a naphthalenyl group,
R3 and R4, independently of one another, each represent
a hydrogen atom, a (C1-C3)alkyl group, a 2-methoxyethyl
group, a hydroxy (C2-C4) alkyl group, a carboxy-
(C1-C3) alkyl group, a (C1-C3) alkoxycarbonyl (C1-C3) alkyl
group or a phenyl (C1-C3) alkyl group, or else together
form, with the nitrogen atom which carries them, either
a pyrrolidinyl group optionally substituted by a
hydroxyl, ethoxy, methoxycarbonyl or methoxymethyl
group, or a piperidinyl group, or a morpholinyl group,
or a 4-methylpiperazinyl group, or an azetidinyl group,
or a thiazolidinyl group, and
the bond between the carbon atoms in the 3 and 4
positions is single or double.
2. Compound as claimed in Claim 1, wherein the
compound is in the form of a pure optical isomer.
3. Compound as claimed in Claim 1, wherein the
compound is in the form of a mixture of optical
isomers.
4. Compound as claimed in Claim 1, wherein, in the
general formula (I), X is in the 6 position and
represents a fluorine atom.
5. Compound as claimed in Claim 1, wherein R1
represents a methyl group.
6. Compound as claimed in Claim 1, wherein R2
represents a phenyl group.
7. Compound as claimed in Claim 1, wherein R3
represents a methyl group and R4 represents an ethyl
group.
8. Compound as claimed in Claim 1, wherein R3 and
R4 form, with the nitrogen atom which carries them, a
pyrrolidinyl ring.
9. Medicament composed of a compound as claimed in
one of Claims 1 to 8.
10. Pharmaceutical composition containing a
compound as claimed in one of Claims 1 to 8, in
combination with an excipient.
11. Process for the preparation of a compound as
claimed in Claim 1, wherein a compound of general
formula (II)
in which X and R1 are as defined in Claim 1 and R
represents a (C1-C3) alkyl group, is reacted with ethyl
pyruvate, in order to obtain the diester of general
formula (IV)
the latter is then treated with an amine of general
formula R2NH2, in which R2 is as defined in Claim 1, in
order to obtain an ester of general formula (V)
which is converted to the corresponding acid, of
general formula (VI)
by hydrolysis, this acid is then converted to the
primary, secondary or tertiary amide of general formula
(I")
by reaction with an amine of general formula HNR3R4, in
which R3 and R4 are as defined in Claim 1, either
through the imidazolide obtained by reaction with N,N"-
carbonyldiimidazole or through the acid chloride, and,
finally, if it is desired to prepare a compound in
which the bond between the 3 and 4 positions is a
double bond, the compound of general formual (I") is
oxidized by means of 2,3-dichloro-5,6-dicyanocyclohexa-
2,5-diene-l,4-dione or of 3,4,5,6-tetrachlorocyclohexa-
3,5-diene-1,2-dione, in order to obtain the
corresponding compound of general formula (I"")
12. Process for the preparation of a compound as
claimed in Claim 1, wherein a compound of general
formula (VIII)
in which X is as defined in Claim 1, is reacted with
2-ketoglutaric acid, it is then treated in an acidic
alcoholic medium, in order to obtain the diester of
general formula (IX)
in which R represents a (C1-C3) alkyl group, then, if
desired, an alkylation reaction is carried out, in
order to obtain the compound of general formula (X)
in which R1 represents a (C1-C3)alkyl group, then the
latter is converted in the presence of
dimethylformamide dimethyl acetal, in order to obtain
the compound of general formula (XI)
or alternatively, if desired, the compound of general
formula (IX) is directly converted to the compound of
general formula (XI), in which R1 represents a methyl
group, the latter is then treated with an amine of
general formula H2NR2, in which R2 is as defined in
Claim 1, in order to obtain the ester of general
formula (V")
the latter is then converted to the corresponding acid
of general formula (VI")
and, finally, this acid is converted to the primary,
secondary or tertiary amide of general formula (I"")
by reaction with an amine of general formula HNR3R4, in
which R3 and R4 are as defined in Claim 1, either
through the imidazolide obtained by reaction with N,N"-
carbonyldimidazole or through the acid chloride.
11. Process for the preparation of a compound as
claimed in Claim 1, wherein a diester of general
formula (X)
in which X and R1 are as described in Claim 1 and R
represents a (C1-C3)alkyl group, is hydrolysed, in order
to obtain the diacid of general formula (XII)
which is converted to the anhydride, in order to obtain
the compound of general formula (XIII)
the latter is then converted by reaction with an amine
of general formula HNR3R4, in which R3 and R4 are as
defined in Claim 1, in order to obtain the compound of
general formula (XIV)
which is converted to the ester of general formula (XV)
the latter is then treated in the presence of
dimethylformamide dimethyl acetal, in order to obtain
the compound of general formula (XVI)
and, finally, the latter is reacted with an amine of
general formula R2NH2, in which R2 is as defined in
Claim 1, in order to obtain the compound of general
formula (I"")

and, finally, if desired, a secondary amide of general
formula (I"") is converted to the tertiary amide by an
alkylation reaction.
13. 1H-PYRIDO[3,4-b]INDOLE-4-CARBOXAMIDE DERIVATIVES,
substantially as herein described, particularly with
reference to the foregoing examples.
14. A pharmaceutical composition, substantially as herein
described, particularly with reference to the foregoing
examples.
15. A process for the preparation of 1H-PYRIDO[3,4-b]INDOLE
4-CARBOXAMIDE DERIVATIVES, substantially as herein described,
particularly with reference to the foregoing examples.
16. A process for preparation of a pharmaceutical
composition, substantially as herein described, particularly
with reference to the foregoing examples.
Compounds of general formula (I)

in which X represents hydrogen or a halogen or an
alkyl, alkoxy, trifluoromethyl or phenylmethoxy group,
R1 represents hydrogen or an alkyl, cyclopropyl or
phenylmethyl group, R2 represents either an optionally
substituted alkyl group or an optionally substituted
phenylalkyl group or a cyclohexylmethyl group or a
thienylmethyl group or a pyridinylmethyl group or an
optionally substituted phenyl group or a pyridinyl
group or a 5-methyl-1,2-oxazolyl group or a 5-methyl-
1,3,4-thiadiazolyl group or a naphthyl group, R3 and R4
each represent hydrogen or an alkyl, 2-methoxyethyl,
hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl or
phenylalkyl group or else together form, with the
nitrogen atom which carries them, either an optionally
substituted pyrrolidinyl group or a piperidinyl group
or a morpholinyl group or a 4-methylpiperazinyl group

or an azetidinyl group or a thiazolidinyl group, and
the bond between the carbon atoms in the 3 and 4
positions is single or double.
Application in therapeutics.

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Patent Number

216315

Indian Patent Application Number

1884/CAL/1997

PG Journal Number

11/2008

Publication Date

14-Mar-2008

Grant Date

12-Mar-2008

Date of Filing

07-Oct-1997

Name of Patentee

SANOFI-AVENTIS

Applicant Address

174 AVENUE DE FRANCE

Inventors:

#	Inventor's Name	Inventor's Address
1	SANOFI-AVENTIS	174 AVENUE DE FRANCE

PCT International Classification Number

C07 231/56

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA