HK1023338B - 1h-pyrido [3,4-b] indole-4-carboxamide derivatives, preparation and application thereof in therapeutics - Google Patents

Description

1H-pyrido [3, 4-b ] indole-4-carboxamide derivatives, preparation thereof and therapeutic use thereof

The subject of the present invention is 1H-pyrido [3, 4-b ] indole-4-carboxamides derivatives, their preparation and their therapeutic use.

The inventionSome of the compounds of (a) correspond to the general formula (I)In which X represents a hydrogen or halogen atom or a (C)₁-C₃) Alkyl radical (C)₁-C₃) Alkoxy, trifluoromethyl or phenylmethoxy, R₁Represents a hydrogen atom or a (C)₁-C₃) Alkyl, cyclopropyl or benzyl, R₂Represents (C) optionally substituted by methoxy₁-C₃) Alkyl, or phenyl (C) optionally substituted on the phenyl ring by a halogen atom or a methyl or methoxy group₁-C₃) Alkyl, or a cyclohexylmethyl group, or a thienylmethyl group, or a pyridylmethyl group, or substituted by one or more halogen atoms or a (C)₁-C₃) Alkyl or (C)₁-C₃) Phenyl optionally substituted by alkoxy, or a pyridyl group, or a 5-methyl-1, 2-oxazolyl group, or a 5-methyl-1, 3, 4-thiadiazolyl group, or a naphthyl group, R₃And R₄Each represents, independently of the others, a hydrogen atom, a (C)₁-C₃) Alkyl, a 2-methoxyethyl, a hydroxy (C)₂-C₄) Alkyl, a carboxyl group (C)₁-C₃) Alkyl radical, one (C)₁-C₃) Alkoxycarbonyl (C)₁-C₃) Alkyl or a phenyl radical (C)₁-C₃) Alkyl, or other forms taken together, together with the nitrogen atom to which they are attached, is pyrrolyl optionally substituted by hydroxy, ethoxy, methoxycarbonyl or methoxymethyl, or a piperidinyl, or a morpholinyl, or a 4-methylpiperazinyl, or an azetidinyl, or a thiazolidinyl group, and the bond between the carbon atoms in the 3 and 4 positions is a single or double bond.

Depending on the nature of this bond, a compound of the invention may optionally exist in the form of a pure optical isomer or a mixture of such isomers.

Some preferred compounds are those of the above formula wherein X is in the 6 position andrepresents a fluorine atom, R₁Represents a methyl group, R₂Represents a phenyl radical, R₃Represents a methyl group and R₄Represents an ethyl group or other R₃And R₄Form (b) together with the nitrogen atom to which they are attached, form a pyrrolidinyl group.

Some of the compounds of formula (I) may be prepared according to the procedures illustrated in the following reaction schemes.

According to reaction scheme 1, the starting compound corresponds to the general formula (II) in which X and R₁As defined above; when R is₁In the case of hydrogen atoms, if desired, it is possible to carry out an alkylation reaction in order to form compounds of the general formula (I) in which R is₁Represents a (C)₁-C₃) An alkyl group. The compound of formula (II) is thus reacted with pyruvic acetic acid of formula (III) in an acidic medium, for example in ethanol in the presence of gaseous hydrochloric acid or in acetic acid in the presence of sulfuric acid or in the presence of boron trifluoride etherate, between room temperature and reflux temperature, so as to obtain the diester of formula (IV).

The latter (diester) is then reacted with a compound of the formula R in ethanol at reflux temperature₂NH₂By an amine of the formula₂Is as defined above. The result of the work-up is an ester which passes through (V) and is converted by hydrolysis in alkaline medium into the corresponding acid of the formula (VI).

The acid is then reacted with a compound of the formula HNH₃R₄Is converted into a primary, secondary or tertiary amide of the formula (I') in the general formula HNR₃R₄In R₃And R₄The above reaction is an imidazole amide obtained by the reaction with N, N-carbonyldiimidazole or an acid chloride.

Reaction scheme 1In the compound of the formula (I') thus obtained, between the 3-and 4-positionsThe bond is a single bond. If a compound is desired in which this bond is a double bond, the compound of the formula (I ') can be oxidized in a solvent such as toluene or dichloromethane at a temperature between room temperature and reflux temperature with 2, 3-dichloro-5, 6-dicyanocyclohexane-2, 5-diene-1, 4-dione or with 3,4, 5, 6-tetrachlorocyclohexane-3, 5-diene-1, 2-dione to give the corresponding compound whose structure has a double bond between the carbon atoms in positions 3 and 4, which has the formula (I'):finally, if this occurs, some enantiomers may be prepared from the racemate by any known method; thus, for example, an acid of formula (VI) may be reacted with an optically pure chiral amine such as α -methylbenzylamine, and some diastereomers may be separated by fractional crystallization to achieve an optically pure acid; and subsequently to esters and amides derived therefrom.

In the case of an optically pure acid of the general formula (VI), the non-racemic coupling reaction can be carried out by any known method, for example using (benzotriazol-1-yloxy) tris (pyrrolidin-1-yl) phosphonium hexafluorophosphate.

At R₂In the case of aromatic rings, it is possible, if desired, to convert the diester (IV) into the amide (VII) by heating the reaction mixture at a temperature of 100 ℃ and 200 ℃ in an inert solvent or without a solvent, for example by heating the compound of the formula R₂NH₂The corresponding amine of (a) is refluxed. The compound of formula (VII) can then either be converted into the ester of formula (V) in refluxing ethanol in an acidic medium, for example in the presence of concentrated hydrochloric acid, or into the acid of formula (VI) by hydrolysis in basic nature.

Having predominantly R₁Starting compounds of the general formula (II) ═ H, have been described in the literature; pyruvate of formula (III) is commercially available.

According to reaction scheme 2, the starting compounds correspond to general formula (VIII), wherein X is as defined above. The compound is reacted with 2-oxoglutaric acid and then in an acidic alcoholic medium, for example inTreatment in ethanol saturated with gaseous hydrochloric acid at reflux temperature, so as to obtain diesters of general formula (IX) in which R represents a (C)₁-C₃) An alkyl group. If desired, this compound can be subjected to a further alkylation reaction to obtain a compound of the general formula (X) wherein R is₁Represents a (C)₁-C₃) Alkyl and then subjecting the compound of formula (X) to conversion in a protic solvent such as N, N-dimethylamide in the presence of dimethylformamide dimethyl acetaldehyde diethyl acetal (acetic) and at reflux temperature, so as to obtain the compound of formula (XI). If desired, the compounds of the formula (IX) can be converted directly into compounds of the formula (XI) in which R is₁Represents a methyl group under the conditions described above. The compound of formula (XI) is then reacted with a compound of formula H₂NR₂By amine treatment of formula (II) wherein R₂Is used in the above definition, the treatment is carried out in a protic solvent, for example dimethylformamide, optionally in the presence of an acid, such as 4-methylbenzenesulfonic acid, at reflux temperature, in order to obtain the ester of the formula (V'). The latter is converted into the corresponding acid of the formula (VI') by hydrolysis in an alkaline medium. Finally, this acid is converted into a primary, secondary or tertiary amide of the formula (I'), or into an imidazoleamide by reaction with N, N-carbonyldiimidazole, or by acid chloride.

Reaction scheme 2

Reaction scheme 3

The starting compounds of the general formula (VIII) are commercially available. Certain compounds of the general formula (IX) and of the general formula (X) have been described in the literature.

According to scheme 3, the starting material is a diester of formula (X) as depicted in scheme 2. The diester is hydrolyzed in an acidic medium to give a diacid of the formula (XII) which is reacted at reflux temperature, for example, with acetyl chlorideIn turn, to the anhydride, to give the compound of the formula (XIII). The latter is obtained by reaction with a compound of formula HNR₃R₄By reaction with an amine of formula (II) wherein R is₃And R₄As defined above, in a chlorinated solvent such as dichloromethane, to give the compound of formula (XIV), which is converted into an ester of formula (XV), treating this ester in a protic solvent such as N, N-dimethylformamide in the presence of dimethylformamide dimethylacetaldehyde acetal at reflux temperature to give the compound of formula (XVI), and finally reacting the latter with the compound of formula R₂NH₂By reaction of an amine of formula (II) wherein R₂As defined above, the reaction is carried out in a protic solvent, for example in N, N-dimethylformamide, optionally in the presence of an acid, such as 4-methylbenzenesulfonic acid, at reflux temperature, in order to obtain the compounds of the general formula (I "). Finally, if desired, secondary amides of the formula (I'), in which R is₃Or R₄The hydrogen is typically converted to the tertiary amide by alkylation methods well known in the art, for example, with an alkylating agent such as an alkyl halide. Likewise, compounds of the general formula (I ') or (I'), in which R₁Represents a hydrogen atom and can be converted by alkylation of known type into a compound in which R is represented by the formula₁Represents an alkyl group. Some compounds having chemical structures similar to those of the compounds of the present invention have been described in the U.S. chemical abstracts CA83(13)114712C, CA 94(9)64698g and CA 96(9) 68779Y.

Certain compounds of the formulae (XII), (XIII), (XIV) and (XV) have been described in the literature. A compound of the general formula (I) wherein R₃And/or R₄Represents a hydroxyl group (C)₂-C₄) Alkyl groups, obtainable by reaction of the corresponding acids of the formula (VI) or (VI') with alcohols protected by a common protecting group, followed by deprotection.

A compound of the general formula (I) wherein R₃And/or R₄Represents a carboxyl group (C)₂-C₄) Alkyl, obtainable by hydrolysis of the corresponding ester, a compound of the general formula (I)Wherein X represents a phenylmethoxy group, can be obtained in two stages well known in the art, namely from a compound of formula (I) wherein X represents a methoxy group.

The following examples illustrate in detail the preparation of certain compounds of the invention. The structure of these prepared compounds was confirmed by microanalysis of the elements and by IR and NMR.

The numbers of the compounds shown in each bracket in the title correspond to the numbers of the compounds in the following table.

Example 1 (Compound No.20)

(±) -6-fluoro-N, 9-trimethyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide. 1.1. Ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate 1.1.1. Ethyl 5-fluoro-1H-indole-2-carboxylate

150 g (0.92 mol) of 4-fluorophenylhydrazine hydrochloride are added to a preliminary solution of 23 g (1 mol) of sodium in 1.5 l of methanol while the mixture is cooled, and the mixture is stirred at room temperature for 30 minutes.

The solution was concentrated under reduced pressure, the residue was collected in dichloromethane, and the sodium chloride was isolated by filtration. The solvent was evaporated under reduced pressure, the residue was 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 was heated under reflux for 2 hours.

The reaction mixture was concentrated under reduced pressure, the residue was collected in ethyl acetate, the solution was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. 181.6 g (0.83 mol) of hydrazine are obtained. 214 g (1.12 mol) of 4-methylbenzenesulfonic acid monohydrate in a solution of 2.5 l of toluene are dehydrated by heating the reaction mixture to reflux for 2 hours in a Dean and Stark apparatus. 181.6 g (0.83 mol) of hydrazine obtained above are added while cooling and the mixture is heated under reflux for 3 hours. The mixture was cooled, ethyl acetate and water were added thereto, the organic phase was separated and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from propan-2-ol and the mother liquor was purified by chromatography on a silica gel column eluting with dichloromethane. 144 g (0.7 mol) of the product are obtained and used in the following stage (process step). 1.1.2. Ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate

11.7 g (0.39 mol) of sodium hydride as a suspension in oil at 80% are washed with petroleum ether, to which is then added a solution of 62.1 g (0.3 mol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 600 ml of dimethylformamide. The mixture was stirred at room temperature for 2 hours, and then a solution of 24.3 ml (0.39 mol) of methyl iodide in 50 ml of dimethylformamide was added. The mixture was stirred at room temperature for 20 hours and then poured onto ice-cold water. The reaction mixture is extracted with ethyl acetate, the organic phase is washed and dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 62.5 g (0.28 mol) of solid product which is used in the subsequent process stage. 1.2 Ethyl 2- (ethoxycarbonyl) -5-fluoro-1-methyl-alpha-methylene-1H-indole-3-acetate

10.5 g (48 mmol) of ethyl-5-fluoro-1-methyl-1H-indole-2-carboxylate, 18 g (155 mmol) of ethyl pyruvate and 7.8 ml of concentrated sulfuric acid in 100 ml of acetic acid are stirred together at room temperature for 1 hour 30 minutes. The mixture was concentrated under reduced pressure, hydrolyzed with ice-cold water, to which liquid ammonia was added until the pH was basic and extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulfate, the solvent is evaporated off under reduced pressure and the residue is recrystallized from a mixture of pentane and diethyl ether. 13 g (42 mmol) of solid are obtained. The melting point is: 86-88 ℃. 1.3. Ethyl (±) -6-fluoro-9-methyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido- [3, 4-b ] indole-4-carboxylate.

7 g (23 mmol) of ethyl-2- (ethoxycarbonyl) -5-fluoro-1-methyl- α -methylene-1H-indole-3-acetate and 15 ml (140 mmol) of benzylamine in 200 ml of ethanol are heated to reflux for 8 hours. The solvent was evaporated off under reduced pressure and the residue was taken up in dichloromethane and 1N hydrochloric acid, the organic phase was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. 7 g (18 mmol) of solid product are obtained and used in the following process stages. 1.4. (±) -6-fluoro-9-methyl-1-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-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido- [3, 4-b ] indole-4-carboxylate are hydrolyzed with a solution of 2.5 g of sodium hydroxide in a mixture of water and alcohol, the mixture is concentrated under reduced pressure, water and acetic acid are added thereto and extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 4 g (11 mmol) of a solid are obtained and are used in the following process stages.

Melting point: 264 ℃ 265 (+ -) -6-fluoro-N, N-9-trimethyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide.

A solution of 4 g (11 mmol) (. + -.) -6-fluoro-9-methyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and 2.2 g (30 mmol) 1.1' -carbonyldipyridazole in 200 ml of tetrahydrofuran was heated at 40 ℃ for 2 hours. The reaction mixture was cooled, a large excess of liquefied dimethylamine was added to it and the mixture was stirred for several hours.

The solvent was distilled off under reduced pressure, the residue was taken up in dichloromethane and water, the organic phase was separated off, washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol. The product was recrystallized from ethyl acetate. 1.2 g (3 mmol) of product are obtained.

Melting point: 185 ℃ C

Example 2 (Compound No.59) 6-fluoro-N, N-9-trimethyl-1-oxo-2- (phenylmethyl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide.

A solution of 2 g (5 mmol) of (. + -.) -6-fluoro-N, N-9-methyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide and 1.6 g (7 mmol) of 2, 3-dichloro-5, 6-dinitrile-1, 4-benzoquinone in 250 ml of dichloromethane is stirred for one hour. The organic phase is washed and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. The product was crystallized from diethyl ether. 1 g (2.6 mmol) of product are obtained.

Melting point: 192 ℃ and 193 ℃.

Example 3 (Compound No.36)

6-fluoro-2- (2-methoxyethyl) -N, N-9-trimethyl-1-oxo-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide. 3.1. Ethyl 5-chloro-1-methyl-1H-indole-2-carboxylate

It was prepared as in example 1.1.2 from 8.95 g (40 mmol) of ethyl 5-chloro-1H-indole-2-carboxylate, 1.6 g (52 mol) 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 is used in the following process stages. 3.2 Ethyl-5-chloro-2- (ethoxycarbonyl) -1-methyl-alpha-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 under reflux for 4 hours. The solvent was evaporated off under reduced pressure, the residue was collected in ethyl acetate and washed to neutrality, the organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The product obtained is purified by chromatography on a silica gel column, eluting with dichloromethane. 9.6 g (32 mmol) of solid product are obtained, which can be used in the following process stages. 3.3. Ethyl (±) -6-chloro-2- (2-methoxyethyl) -9-methyl-1-oxo-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylate.

A solution of 9.5 g (31 mmol) ethyl 5-chloro-2- (ethoxycarbonyl) -1-methyl- α -methylene-1H-indole-3-acetate and 8.1 g (93 mmol) 2-methoxyethylamine in 20 ml ethanol was heated to reflux for 3 hours.

The solvent was evaporated under reduced pressure and the residue was collected in ethyl acetate, washed with water and dried over sodium sulfate. 9.7 g (27 mmol) of solid product are obtained, which can be used in the subsequent process stages. 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) ethyl (. + -.) -6-chloro-2- (2-methoxyethyl) -9-methyl-1-oxo-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylate were hydrolyzed with a solution of 3.1 g (80 mmol) sodium hydroxide in 260 ml ethanol and 50 ml water. The reaction mixture was concentrated, the residue was collected in water and the aqueous phase was washed with ethyl acetate and acidified to pH 1 with concentrated hydrochloric acid. Extraction was performed with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. The solvent was evaporated off under reduced pressure and 8.3 g (26 mmol) of solid product were obtained, which was used in the subsequent process stage. 3.5. (±) -6-chloro-2- (2-methoxyethyl) -N, 9-trimethyl-1-oxo-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide.

The procedure is as in example 1.5, from 8.3 g (26 mmol) (. + -.) -6-chloro-2- (2-methoxyethyl) -9-methyl-1-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 is recrystallized from propan-2-ol. 6.9 g (19 mmol) of product are obtained.

Melting point: 217 ℃ 219 DEG C

Example 4 (Compound No.77)

(±) -6-fluoro-N, 9-trimethyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide. 4.1. (+) -6-fluoro-9-methyl-1-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) (. + -.) -6-fluoro-9-methyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and 7.5 ml (58 mmol) of (R) - (+) - α -methylbenzylamine in 1000 ml of methanol was stirred. The mixture is concentrated under reduced pressure, the residue is collected in 50 ml of ethyl acetate and 400 ml of diethyl ether, and the precipitate is isolated by filtration and recrystallized three times from propan-2-ol.

7.3 g (15 mmol) of the diastereoisomeric salt are isolated, this salt is redissolved in 100 ml of methanol, 16 ml of 1N hydrochloric acid and 200 ml of water are added thereto, and the precipitate is isolated by filtration and then dried under reduced pressure at room temperature. 5.1 g (15 mmol) of D-propionic acid are obtained.

Melting point: 264-²⁰ _D＝+41.6°(C＝0.5，CH₃OH) ee > 99% (HPLC). 4.2. (±) -6-fluoro-N, 9-trimethyloxy-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide.

0.5 g (1.3 mmol) of (. + -.) -6-fluoro-9-methyl-1-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 hydrochloric acid were dried beforehand under reduced pressure and a solution of 0.68 g (13 mmol) of (benzotriazol-1-yloxy) tris (pyrrolidinyl) phosphonium hexafluorophosphate in 10 ml of dichloromethane was purified beforehand by means of an alumina column, cooled to-30 ℃ and 0.68 ml (3.9 mmol) of a solution of N, N-bis (1-methylethyl) ethylamine in 5 ml of dichloromethane was added dropwise thereto. The mixture is stirred for 6 hours at a temperature between-30 ℃ and-20 ℃, hydrolyzed with 10 ml of 5% aqueous potassium hydrogensulfate, the mixture is extracted with dichloromethane, the organic phase is washed and dried, the solvent is distilled off under reduced pressure, the residue is purified by chromatography on a silica gel column, eluted with a mixture of dichloromethane and ethyl acetate, and the product obtained is recrystallized from propan-2-ol. 0.37 g (1 mmol) of D-propionic acid are obtained.

Melting point: 199-²⁰ _D＝+6.3°(C＝1，CHCl₃)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-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid.

The mother liquors obtained in example 4.1 from the recrystallization of the diastereomers were freed of the solvent under reduced pressure, water and concentrated hydrochloric acid were added, the precipitate was isolated by filtration and dried under reduced pressure at room temperature. 13.6 g (38 mmol) of impure levo-acid are obtained, to which 250 ml of methanol and 4.97 ml (38 mmol) of (S) - (-) - α -methylbenzylamine are added. The mixture is stirred and concentrated under reduced pressure, the precipitate is collected by filtration and recrystallised three times from propan-2-ol to give 7 g (15 mmol) of the diastereomeric salt, this salt is redissolved in a minimum of methanol, 15 ml of 1N hydrochloric acid are added thereto, and the volume of the solution is doubled by dilution with water. The precipitate was isolated by filtration, washed with water, surface dried, and dried under reduced pressure at room temperature. 5 g (14 mmol) of levo-acid are obtained.

Melting point: 264-²⁰ _D＝-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-amide.

Preparation is carried out as described in example 4.2 from (-) -6-fluoro-9-methyl-1-oxo-2- (phenylmethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and from dimethylamine to give, after final recrystallization from ethyl acetate, 0.3 g (0.8 mmol) of the levoamide.

Melting point: 204 ℃ [ alpha ]²⁰ _D＝-7.5°(C＝1，CHCl₃) ee > 98% (HPLC) example 6 (Compound No.101)

6-fluoro-N, N, 9-trimethyl-1-oxo-2-benzene-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide 6, 1-ethyl 2- (ethoxycarbonyl) -5-fluoro-alpha-methylene-1H-indole-3-acetate

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 sulfuric acid are stirred in 400 ml of acetic acid for 20 hours. The solvent was evaporated off under reduced pressure, the residue was collected in water and ethyl acetate, the organic phase was separated off, washed with dilute aqueous ammonia solution and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was evaporated off under reduced pressure.

37.1 g (122 mmol) of a solid are obtained which is used in the subsequent process stage, 6.2.6-fluoro-1-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-. alpha. -methylene-1H-indole-3-acetate and 31.8 g (342 mmol) of aniline is heated and refluxed for 17 hours. To this was added a dilute hydrochloric acid solution and ethyl acetate, the organic phase was separated off, washed with water and dried over sodium sulfate, and the solvent was evaporated off under reduced pressure. 30 g of residue are obtained and the residue is hydrolyzed under reflux for 1 hour with a solution of 43 ml of water and 30% sodium hydroxide in 400 ml of ethanol. The mixture was concentrated under reduced pressure, water was added, the mixture was washed with ethyl ester and dichloromethane, the aqueous phase was acidified with concentrated hydrochloric acid, the precipitate was collected by filtration and dried under reduced pressure.

18.5 g (57 mmol) of solid compound are obtained which is used in the subsequent process stage. 6.3.6-fluoro-N, N, 9-trimethyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxamide

A solution of 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 is heated under reflux for 1 hour. The solvent is evaporated off under reduced pressure, the residue is taken up in dichloromethane, a large excess of liquefied dimethylamine is added, the mixture is stirred for a number of hours, water is added, the precipitate is isolated by filtration and dried under reduced pressure.

3.4 g (9 mmol) of the compound are obtained.

2.5 g of the above compound was dissolved in 50 ml of dimethyl sulfoxide, 0.6 g of powdery potassium hydroxide and 1.2 ml of methyl iodide were added, and the mixture was stirred at 50 ℃ for 5 hours and then at room temperature for 20 hours.

To this was added dilute hydrochloric acid, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column, eluting with a mixture of cyclohexane and ethyl acetate.

2.2 g of a mixture containing 6-fluoro-N, N, 9-trimethyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide and 6-fluoro-N, N, 9-trimethyl-1-oxo-2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide are obtained.

The mixture is stirred with 1 g of 2, 3-dichloro-5, 6-dinitrile-1, 4-benzoquinone for 20 hours and washed with saturated aqueous sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulfate, the solvent is distilled off under reduced pressure, the residue is purified by chromatography on a silica gel column, washed with a mixture of cyclohexane and ethyl acetate and the product is recrystallized from ethyl acetate. 0.5 g (1.5 mmol) of the compound are obtained.

Melting point: 195 + 197 deg.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-amide 7.1 ethyl 2- (ethoxycarbonyl) -alpha-methylene-1H-indole-3-acetate

A solution of ethyl alcohol 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 heated to about 60 ℃ for 3 hours. The mixture was concentrated under reduced pressure and the residue was collected in diethyl ether. The organic phase is washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by crystallization from cyclohexane. 45.4 g (156 mmol) of solid product are obtained, which is used in the subsequent process stages. 7.2.1-oxo-N, 2-diphenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amides

A mixture of 32 g (111 mmol) of ethyl 2- (ethoxycarbonyl) - α -methylene-1H-indole-3-acetate and 47.5 g (511 mmol) of aniline is heated for 13 hours. Dichloromethane was added and the organic phase was washed with 1N hydrochloric acid. Dried over sodium sulfate and the solvent evaporated under reduced pressure. 38.8 g of impure product are obtained, which will be used in the subsequent process stages. 7.3. Ethyl 1-oxo-2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylate

A solution of 38.8 g of impure 1-oxo-N, 2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide in a mixture of ethanol, water and 37% hydrochloric acid is heated at reflux for 8 hours. The reaction mixture was neutralized with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. 22.6 g (68 mmol) of product are obtained, which can be used in the subsequent process. 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 1-oxo-2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-carboxylate are hydrolyzed with a solution of 200 ml of 1N sodium hydroxide in 500 ml of methanol. The reaction mixture was acidified with 1N hydrochloric acid and the precipitate was filtered off. Drying under reduced pressure. 18.1 g (59 mmol) of solid product are obtained for the subsequent process stages. 7.5. N, N-dimethyl-1-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 30 ml of thionyl chloride is heated under reflux for 4 hours. The solvent was evaporated off under reduced pressure, the residue was taken up in dichloromethane and a large excess of liquefied dimethylamine was added. The mixture was stirred for several hours and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added. The precipitate was filtered off and dried under reduced pressure. 8.2 g of impure product are obtained, which are used in the subsequent process stages. 7.6. N, N, 9-trimethyl-1-oxo-2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide

A mixture of 1.3 g (23 mmol) of powdered potassium hydroxide and 6 g of impure N, N-dimethyl-1-oxo-2-phenyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b ] indole-4-amide in 60 ml of dimethyl sulfoxide is heated at 40 ℃ for 30 minutes. To this was added 2.5 ml (40 mmol) of methyl iodide and the mixture was stirred at room temperature for 5 hours. Then water and dichloromethane were added. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. The product was recrystallized from ethyl acetate. 1.9 g (5.5 mmol) of product are obtained.

Melting point: 196 ℃ C. sup.197 ℃ C. example 8 (Compound No.123)

N-Ethyl-6-fluoro-N-9-dimethyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxamide 8.1 Ethyl 2- (ethoxycarbonyl) -5-fluoro-1H-indole-3-acetic acid ester

A solution of 7.4 g (185 mmol) of sodium hydroxide in 25 ml of water is added to a solution of 30 g (185 mmol) of 4-fluorophenylhydrazine hydrochloric acid in 300 ml of water, the mixture is stirred for 15 minutes, and then a solution of 39 g (198 mmol) of oxoglutaric acid in 60 ml of water is added thereto. The reaction mixture was stirred at room temperature for 3 hours and extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. 42 g (144 mmol) of the product are obtained, which is dissolved in 420 ml of ethanol saturated with gaseous hydrochloric acid and heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was collected in ethyl acetate, and the organic phase was washed with conventional sodium oxy oxide, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. 42 g (143 mmol) of solid product are obtained, which can be used in the subsequent process stages. 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, previously washed 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 at room temperature for 2 hours, and then a solution of 19 ml (306 mmol) of iodomethane in 100 ml of N, N-dimethylformamide is added. After stirring for 20 hours, the reaction mixture was poured into ice-cold water, extracted with diethyl ether, the organic phase was washed with water and dried over magnesium sulfate, and the solvent was evaporated off under reduced pressure. 44.3 g (144 mmol) of product are obtained, which can be used in the subsequent process stages. 8.3. Ethyl alpha- (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 dimethylacetaldehyde diethylacetal in 450 ml of N, N-dimethylformamide is heated under reflux for 50 hours. The solvent was evaporated under reduced pressure and the residue was collected in diethyl ether. Insoluble material was filtered off and the solvent was concentrated under reduced pressure. 49.3 g (136 mmol) of solid product are obtained, which can be used in the subsequent process stages. 8.4. Ethyl 6-fluoro-9-methyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylate.

A solution of 16.3 g (45 mmol) of ethyl α - (dimethylaminomethylene) -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-toluenesulfonic acid monohydrate in 160 ml of N, N-dimethylamide is heated to reflux for 24H. 3.3 g (31 mmol) of sodium carbonate are added in small portions and the flow is continued for 2 hours. The solution was cooled and poured into ice cold water. Extraction with ethyl acetate and washing of the organic phase with water, drying over magnesium sulfate and evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with dichloromethane and ethyl acetate. 10.9 g (30 mmol) of product are obtained, which is used in the subsequent process stage. 8.5.6-fluoro-9-methyl-1-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 7.46 g (186 mmol) of sodium hydroxide in a mixture of 1 l of ethanol and 100 ml of water is heated at reflux for 3 hours. The mixture was concentrated under reduced pressure, the residue taken up in water and the aqueous phase rinsed with ethyl acetate. Acidification to PH 1 with concentrated hydrochloric acid, the product was filtered off and rinsed several times with water. Drying under reduced pressure. 20.4 g (64 mmol) of solid compound are obtained, which is used in the subsequent process stages. 8.6.6-fluoro-N, 9-dimethyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxamide

A solution of 5 g (15.6 mmol) 6-fluoro-9-methyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and 4.8 g (30 mmol) N, N' -carbonyldipyridazole in 100 ml N, N-dimethylformamide was stirred at 60 ℃ for 4 hours. A large excess of liquefied methylamine was added at room temperature and the reaction mixture was stirred for 20 hours. The solution was poured onto ice-cold water, the precipitate was collected by filtration, washed with saturated sodium bicarbonate solution, water and ethyl acetate, and dried under reduced pressure. 3.5 g of crude product are isolated. The filtrates were combined and extracted with dichloromethane. The organic phase is washed with sodium bicarbonate solution and subsequently with water, dried over magnesium sulfate and the solvent is evaporated off. 1.5 g of additional product were isolated. The two batches were combined and purified by chromatography on a silica gel column, eluting 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-methyl-1-oxo-2-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide and 0.36 g (9 mmol) of 60% sodium hydride was washed with petroleum ether in advance and stirred at 50 ℃ for 3 hours. 1.67 ml (21 mmol) of iodoethane was added, followed by stirring with an alkane for 20 hours, and the solution was poured into ice-cold water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate. The product was recrystallized from propan-2-ol. 2.3 g of a solid are obtained. Melting point: 181 plus 182 DEG 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-phenyl-2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and 3.2 g (20 mmol) of N, N' -carbonyldipyridazole in 65 ml of N, N-dimethylformamide is stirred at 60 ℃ for 4 hours. 2.5 ml (30 mmol) of pyrrolidine were added at room temperature and the reaction mixture was stirred for 20 hours.

The solution was poured into ice-cold water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. The product was recrystallized from propan-2-ol. 3 g (7.7 mmol) of solid are obtained. Alkyl point: 203 ℃ 205 ℃ example 10 (Compound No.122)

6-fluoro-N, N, 9-trimethyl-1-oxo-2- (pyridin-2-yl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide. 10.1. Methyl 6-fluoro-9-methyl-1-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) methyl α - (dimethylaminomethylene) -5-fluoro-2- (methoxycarbonyl) -1-methyl-1H-indole-3-acetate and 1.73 g (18.4 mmol) 2-aminopyridine was heated at 180 ℃ for 30 min. 7 ml of N, N-dimethylformamide were added and heating was continued for 4 hours. The reaction mixture was cooled and poured onto a mixture of water and ethyl acetate, and insoluble matter was collected by filtration and dried under reduced pressure. 1.8 g (5.1 mmol) of solid are obtained, which are used in the subsequent process stages. 10.2.6-fluoro-9-methyl-1-oxo-2- (pyridin-2-yl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid.

A solution of 3.3 g (9.4 mmol) methyl 6-fluoro-9-methyl-1-oxo-2- (pyridin-2-yl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylate in a mixture of 100 ml ethanol and 28 ml 1N sodium hydroxide was heated to reflux for 4 hours. The mixture was concentrated under reduced pressure, water was added, acidified with concentrated hydrochloric acid and the precipitate was collected by filtration. Washed with water and dried under reduced pressure. 2.8 g (8.3 mmol) of solid product are obtained, which is used in the subsequent process stages. 10.3.6-fluoro-N, N, 9-trimethyl-1-oxo-2- (pyridin-2-yl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-amide.

A solution of 2.5 g (7.4 mmol) 6-fluoro-9-methyl-1-oxo-2- (pyridin-2-yl) -2, 9-dihydro-1H-pyrido [3, 4-b ] indole-4-carboxylic acid and 2.4 g (14.8 mmol) N, N' -carbonyldipyridazole in 65 ml N, N-dimethylformamide was stirred for 4 hours. The reaction mixture was cooled and a large excess of liquefied dimethylamine was added. The mixture was stirred at room temperature for 48 hours, poured into water, and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. The product was purified by recrystallization from ethyl acetate. 1.6 g (4.4 mmol) of a solid are obtained. Melting point: 220 ℃ 221 ℃ 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-indol-3-acetic acid

A solution of 26.5 g (103 mmol) ethyl-2- (ethoxycarbonyl) -5-fluoro-1H-indole-3-acetate and 24 g sodium hydroxide in a mixture of 530 ml ethanol and 100 ml water is heated to reflux. The mixture was concentrated under reduced pressure. Water was added, the liquid phase was washed with ethyl acetate and acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried under reduced pressure. 23.4 g (98.7 mmol) of product are obtained, which can be used in the subsequent process stages. 11.2.6-fluoro-1, 3,4, 9-tetrahydropyran [3, 4-b ] indole-1, 3-dione

A solution of 4.7 g (19.8 mmol) 2-carboxy-5-fluoro-1H-indole-3-acetic acid in 94 ml acetyl chloride was heated to reflux for 5H. The mixture was concentrated under reduced pressure, toluene was added and the solvent was evaporated under reduced pressure. 4.5 g of solid product are obtained, which is used in the subsequent process stages. 11.3.5-fluoro-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 8.3 ml (100 mmol) of pyrrolidine in 100 ml of dichloromethane was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure, water was added and the aqueous phase was washed with ethyl acetate. Acidified with concentrated hydrochloric acid and ethyl acetate added. The precipitate was collected by filtration, washed with water, and dried under reduced pressure. 5 g (17.2 mmol) of solid product are obtained which can be used in the subsequent process stages. 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 and cooled in an ice bath, and the mixture is then heated under reflux for 3 hours. The mixture was concentrated under reduced pressure, water and dichloromethane were added, the organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. 4.5 g (14 mmol) of product are obtained, which is used in the subsequent process stages. 11.5. Methyl 3- (1-dimethylaminomethylene-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 (acetic) in 34 ml of N, N-dimethylformamide was heated under reflux for 30 hours. The mixture was concentrated under reduced pressure, xylene was added and the solvent was evaporated under reduced pressure. 4 g of residue are obtained which contains approximately 50% of the desired product (according to proton magnetic resonance spectrum) and is used in the subsequent process stages. 11.6.6-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

A mixture of 4 g of the residue obtained in the preceding process stage and 1.04 g (5.5 mmol) of 4-methylbenzenesulfonic acid hydrate in 40 ml of N, N-dimethylformamide is stirred for 15 minutes. 0.65 g (6.4 mmol) of 2-amino-5-methyl-1, 3, 4-thiadiazole are added and the mixture is heated under reflux for 24 hours. The mixture was poured into water and ethyl ester. Filtration, collection of the precipitate, washing with water, drying under reduced pressure and recrystallization from N, N-dimethylformamide. 1 g (2.4 mmol) of product dissolution point are obtained: 299 sub 301 DEG C

The chemical structures and physical properties of some of the compounds according to the invention are shown in the table below

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							1234567891011	HHHHHHHHHHH	MeMePrMeMePrMeMeMeMeEt	PrPrPrPhCH2PhCH2PhCH24-MeO-PhCH24-F-PhCH2PhCH2CH24-Cl-PhCH2PhCH2	NHMeNMe2NMe2NEt2NMe2NMe2NMe2NMe2NMe2NMe2NMe2	///////////	150-152142-144125-126107-109162-163178-180149-1501 -174138-139168-170172-174

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							1213141516171819202122232425262728	HHHHHHH5-F6-F7-F8-F6-MeO7-MeO6-Cl7-Cl8-Cl6-Me	MeMeMeMeEtMeMeMeMeMeMeMeMeMeMeMeMe	2-MeO-PhCH23-MeO-PhCH22-Me-PhCH23-Me-PhCH24-MeO-PhCH24-Me-PhCH2Ph(CH2)3PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2	NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2	/////////////////	162-163139-140154-156137-139149-150153-155118-120195-196185-186195-196188-190181-182208-210208-210209-210218-219209-210

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							2930313233343536373839404142434445	7-Me8-Me6-F6-F6-F6-F6-F6-Cl6-F6-F6-F6-F6-F6-F6-FHH	MeMeMeMeEtMeEtMeMeMeMeMeMeMeMePrMe	PhCH2PhCH2PhCH2PhCH22-MeO-PhCH2PhCH2PhCH2MeO(CH2)2PhCH22-Pyridyl-CH22-Thienyl-CH23-Pyridyl-CH2C6H11CH2PhCH2PhCH2PrPhCH2	NMe2NMe2NEt2NPr2NMe2NHMeNMe2NMe2NH2NMe2NMe2NMe2NMe2PiperidPyrrolidNMe2NNe2	///////////////////	203-205204-205120-121156-157136-137205-206206-207217-219259-260186-189191-193200-202209-211205-206228-229107-108130-131

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							4647484950515253545556575859606162	HHHHHHHHHHHH5-F6-F7-F8-F6-MeO	PrMeMeMeEtMeMeMeEtMeMeMeMeMeMeMeMe	PhCH24-MeO-PhCH24-F-PhCH24-Cl-PhCH2PhCH22-MeO-PhCH23-MeO-PhCH23-Me-PhCH24-MeO-PhCH22-Me-PhCH24-Me-PhCH2Ph(CH2)3PhCH2PhCH2PhCH2PhCH2PhCH2	NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2	//////////////////////////////////	160-16298-100105-106103-104168-170171-173168-170117-118127-128157-15898-100107-109168-170192-193142-144190-192178-180

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							6364656667686970717273747576777879	7-MeO6-Cl7-Cl6-Me7-Me8-Me6-F6-Cl6-F6-F6-F6-F6-F6-F6-FHH	MeMeMeMeMeMeEtMeMeMeMeEtMeMeMeHH	PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2PhCH2MeO-(CH2)22-Pyridyl-CH22-Thienyl-CH2C6H11CH22-MeO-PhCH23-Pyridyl-CH2PhCH2PhCH2PrPr	NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NHMeNMe2	//////////////////////////////	155-156200-202183-184158-160154-156168-169216-217179-180221-223164-165170-172199-200172-175204-205199-202215-217202-204

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							8081828384858687888990919293949596	HHHH6-F6-F6-F6-FH6-F6-F6-Cl6-MeO6-Me6-F6-F6-F	HHHHHHHHHHHHHHHHH	PrPrPrPhPhCH2PhCH2PhCH2PhCH2PhCH2MeiPrPhCH2PhCH2PhCH2PhPh2-Thienyl-CH2	NH2NHCH2PhNMe2NMe2NMe2NMe2NHMeNHMeNMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2	/////////////////////////////	220-222228-230244-247292-294298-301320-322271-273＞300268-269＞300284-285＞300＞300267-268295-297d300d318-320

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							979899100101102103104105106107108109110111112113	H6-F6-F6-F6-F6-F6-F6-F6-F6-Cl6-F6-MeH6-F6-F6-F6-F	MeMeMeMeMeMeEtMeMeMeMeMeMeMeMeMeMe	PhPh3-Thienyl-CH23-Thienyl-CH2PhPhPh2-F-Ph4-F-PhPh4-Me-PhPhPhPhPh3-F-Ph3-Cl-Ph	NMe2PyrrolidNMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NMe2NHCH2PhNHMeNMe2NMe2	///////////////////////////////	196-197203-205196-197172-174195-197213-215210-212235-237214-215195-196252-254192-193205-207243-244294-296199-202186-188

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							114115116117118119120121122123124125126127128129130	6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-Cl6-F6-F6-F	MeMeMeMeMeMeMeMeMeMeMeMeEtMeMeMeMe	3-MeO-PhPhPhPhPhPhPhPh2-PyridylPhPh5-Me-thiadiazPhPh5-Me-oxazolPhPh	NMe2Morph4 Me-piperazPiperidNEt2N(Me)(CH2)2OMe3-HO-pyrrolid3-EtO-pyrrolidNMe2N(Me)EtPyrrolidPyrrolidPyrrolidPyrrolidPyrrolidAzetidN(Me)Pr	//////////////////////////////////	215254-255224-226178-180164-165172-174201-202189-190220-221181-182203-205299-301172-174209-210248-250230-231172-173

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							131132133134135136137138139140141142143144145146	6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-F6-MeO6-F6-OCH2Ph6-CF36-F	PhCH2MecPrCH2MeMeMeMeMeMeMeMeMeEtMeMeH	PhPhPh1-Napht2-NaphtPhPhPhPhPhPhPhPhPhPhPh	NMe2N(Me)CH2PhNMe2NMe2NMe2(S)-2-MeOCH2-pyrrolidN(Me)CH2CH2PhN(Me)CH2CO2Et2-MeOCO-pyrrolidN(Me)CH2CH2PhThiazolidPyrrolidN(Me)EtPyrrolidPyrrolidPyrrolid	////////////////////////////////	201-203148-149178-179245-247185-18696-107174-176158-160115-118151-153187-188258-259174-175199-201211-212283-285

No.	X	R1	R2	NR3R4	3-4	M.p.(℃)
							147148149	6-F6-F6-F	MeMeMe	PhPhPh	NH(CH2)4OHNH(CH2)3CO2HNH(CH2)3CO2Me	//////	210-213278-279154-156

Description of keywords and code numbers in the table:

me is methyl, Et is ethyl, Pr is propyl, ipr is isopropyl, CPr is cyclopropyl, Ph is phenyl, 1-Napht and 2-Napht are naphthalene-1-yl and naphthalene-2-yl radicals, respectively, X-Pyridyl is a pyridin-X-yl radical, X-Thienyl is a thiophen-X-yl radical, pidid is a piperidin-1-yl radical, Pyrrolid is a pyrrolidin-1-yl radical, Morph is a morpholin-4-yl radical, Azetid is an azetidin-1-yl radical, 4-Me-piperaz is a 4-methylpiperazin-1-yl radical, 5-Me-thiadiazolyl is a 5-methyl-1, 3, 4-thiadiazolyl radical, 5-Me-oxazol is 5-methyl-1, 2-oxazol-2-yl group, and Thiazolid refers to thiazolidinyl. In the vertical rows "3-4", "/" refers to a carbon-carbon single bond, and "/" refers to a carbon-carbon double bond between 3 and 4 atoms of the molecule. In the "M.P. (° c)" vertical line, "d" means having a melting point of decomposition.

Various pharmacological tests have been carried out on some of the compounds of the invention, which have proven to be advantageous as substances having a therapeutic activity.

Membrane binding studies with the omega 1 (type 1 benzodiazepine *) and omega 2 (type 2 benzodiazepine *) receptors have been performed according to the protocol described in S.Z. Langer and S.Arbilla (Fund. Clin. Pharmacol., 2, 159-170(1988)) using [ (I)³H ] Flumazenil (flumazenil) instead of [ ]³Neuroleptics (diazepam) were used as radioligands and the affinity of these compounds for the omega 1 receptors of the cerebellum and the omega 2 receptors of the spinal cord was determined.

Cerebellum or spinal cord tissue was placed in 120 or 30 volumes of ice-cold buffer (50 mmol of tris)-HCl, pH 7.4, 12O mM NaCl, 5 mM KCl) for 60 seconds, and then, after dilution to 1/3, the suspension is mixed with a concentration of 1 nanomolar [ ]³H ] Flumazenil (specific activity 78 Curie/millimole, New England Nuclear) and incubated with various concentrations of some of the compounds of the invention, in a final volume of 525. mu.l. After incubation at 0 ℃ for 30 minutes, the samples were filtered under reduced pressure on Whatman GF/B filters and immediately washed with ice-cold buffer. Measured in the stable presence of 1. mu.M unlabeled³Specific binding of flumazenil. The data were analyzed according to standard methods and the IC was calculated₅₀Concentration, i.e., [ (50% ])³H ] concentration of flumazenil in combination. IC's of some of the most active compounds of the invention in this assay₅₀The value is between 10 and 1000 nanomoles. Anxiolytic activity studies: beverage intake conflict test

Anxiolytic activity was assessed by testing mice for conflict in beverage intake according to the methods described in j.r.vogel, b.beer and d.e.clody in psychopharmacogia (Berl.)21, 1-7 (1971).

After the mice had been kept out of water for 48 hours, the mice were placed in a sound-insulated chamber equipped with a water pipette, and the tube was connected to an anxiety meter which provided a gentle shock on electrical shock every 20 licks. The number of shocks received, 3 minutes free count, makes it possible to evaluate the anxiolytic activity of each compound tested. The results of the experiment are expressed as the Minimum Effective Dose (MED), i.e., the dose that significantly increases the number of electroseismic received, based on comparison to the number of electroseismic observed in control animals.

In this test, the MED values for the maximum active compounds, by the intraperitoneal route of administration, were between 5mg/kg and 50 mg/kg. Anxiolytic activity studies: cross maze test by heightening

This experimental protocol is a modification of the method described in the publication Pharmacol, biochem, Behev, (1986), 24, 525-529, by S.Pellow amd S.File. After some mice had become familiar to the laboratory for approximately 24 hours, they were individually placed on a central platform with their nose and mouth facing one of the closed arms and observed with a video camera for 4 minutes. The time spent by the mouse in each open arm, the number of entries into each closed arm and into each open arm, the number of attempts to enter each open arm, the subsequent avoidance response, and the probing of some of the edges in each open arm, etc. were recorded and the results for each animal are expressed as follows: (1) the percentage of access to each open arm relative to the total number of four arms of the access device; (2) percent time spent in each open arm relative to total cycle time of the experiment (4 minutes); (3) total number of animal attempts failed; (4) total number of probes.

The drugs under study were administered intraperitoneally or orally at escalating doses. Results are expressed as the Minimum Effective Dose (MED), which refers to a significant increase (activity in each open arm) or a significant decrease (number of trials) in the performance observed in control animals.

In this test, the MED values for some of the most active compounds, administered by intraperitoneal or oral route, were between 3mg/kg and 50 mg/kg. Study of hypnotic Activity

Sedative or hypnotic activity of each of the compounds of the invention was determined by observing the cortical electroencephalogram of these compounds in mice according to the methods described in h.deportere, rev.e.e.g.neurophysiol, 10, 3, 207-214(1980) and h.deportere and m.decobert, j.pharmacol, (paris), 14, 2, 195-265 (1983).

The product (drug) under investigation was administered intraperitoneally in escalating doses. These products induced sleep patterns at doses ranging from 1 to 30 mg/kg. Anticonvulsant activity study: activity of clonic convulsions induced in mice by injection of pentylenetetrazol (pentetrazol).

The test method is a modification of the method described in e.a. swinyard and j.h. woodhead, publications antibtiepilepticdugs, Raven publishers, New York, 111-.

The test product was administered to each animal as an intraperitoneal injection 30 minutes before the animals were injected intravenously with 20mg/kg of pentylenetetrazol. Immediately after injection, the number of animals showing clonic convulsions was recorded over a period of 5 minutes.

The results are expressed as AD₅₀I.e. a dose which is 50% protected in animals, calculated according to the method of j.t. lichtfield and f.wilcoxon (j.pharm.exp. ther. (1949), 96, 99-113). The results were calculated from 3 or 4 administrations to a group of 8-10 mice.

AD of some Compounds with maximal Activity₅₀Values, administered by intraperitoneal or oral route, are between 0.3mg/kg and 30 mg/kg. Anticonvulsant activity study: activity against Isoniazid-induced convulsions in mice

The intrinsic activity of the compounds of the invention was determined by the latency to onset of convulsions by administering isoniazid (800mg/kg) subcutaneously to induce convulsions in conjunction with intraperitoneal injection of these compounds according to the method described in g.perrault, e.morel, d.sanger and b.zivkovic, journal j.pharmacol., 156, 189-. Results in AD₅₀Indicating that the dose producing 50% of the maximal effect was measured relative to each control animal, as determined by 3-4 administrations to a group of 8-10 mice. AD of the compounds of the invention₅₀Values, in this test between 1mg/kg and 50mg/kg by intraperitoneal administration, depending on the compound, the maximum effect can be as high as 300%.

The results of the experiments conducted on the compounds of the present invention show that they displace binding to specific binding sites in the cerebellum and spinal cord in vitro experiments³H ] flumazenil; they show a mixed affinity for the ω 1 and ω 2 (type 1 and type 2 benzodiazepines *) sites in the GABA λ - ω monochloro channel macromolecular complex.

In vivo tests, they behave as agonists (agonsts) of all or part of these receptors.

They have anxiolytic, hypnotic and anticonvulsant properties and are therefore useful in the treatment of complaints associated with GABAergic delivery disorders such as anxiety, insomnia, epilepsy, spasticity, muscle contractions, disturbances of consciousness, autism, which are often associated with alcoholism, tobacco or drugs.

These compounds are also useful in the treatment of parkinsonism and all types of extrapyramidal syndromes. Finally, they are also used as preoperative drugs and as general anesthetics for inducing and/or maintaining an anesthetic state, or as local anesthetics, optionally in combination with other anesthetics and/or muscle relaxants and/or analgesics.

Finally, they may be presented in any pharmaceutical dosage form for enteral or parenteral administration, or in combination with suitable excipients, for example in the form of tablets, dragees, capsules, including hard gelatin capsules, swallowable injectable solutions or suspensions, suppositories, and the like, and contain dosages which permit the daily administration of from 1 to 1000 mg of the active substance.

Claims (10)

1. A compound of formula (I), optionally in the form of a pure optical isomer or a mixture of such isomersIn which X represents a hydrogen or halogen atom or a (C)₁-C₃) Alkyl radical (C)₁-C₃) Alkoxy, trifluoromethyl or benzyloxy radical, R₁Represents a hydrogen atom or a (C)₁-C₃) Alkyl, cyclopropyl or benzyl radicals, R₂Represents an optionally methoxy-substituted(C₁-C₃) Alkyl, or a phenyl (C) optionally substituted on the phenyl ring by a halogen atom or a methyl or methoxy group₁-C₃) Alkyl, or a cyclohexylmethyl group, or a thienylmethyl group, or a pyridylmethyl group, or by one or more halogen atoms or by one (C)₁-C₃) Alkyl or (C)₁-C₃) An alkoxy-optionally substituted phenyl group, or a pyridine group, or a 5-methyl-1, 2-oxazolyl group, or a 5-methyl-1, 3, 4-thiadiazolyl group, or a naphthyl group, R₃And R₄Are each, independently of one another, a hydrogen atom, a (C)₁-C₃) Alkyl, a 2-methoxyethyl group, a hydroxy group (C)₂-C₄) Alkyl radical, a carboxyl radical (C)₁-C₃) Alkyl radical, one (C)₁-C₃) Alkoxycarbonyl (C)₁-C₃) Alkyl radicals or a phenyl radical (C)₁-C₃) Alkyl groups, or combinations thereof, together with the nitrogen atom bearing them, are pyrrolidinyl optionally substituted with a hydroxy, 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 of the formula is a single or double bond.

2. A compound according to claim 1, wherein in formula (I), X is in the 6 position and represents a fluorine atom.

3. The compound of claim 1, wherein R is₁Represents a methyl group.

4. The compound of claim 1, wherein R is₂Represents a phenyl group.

5. The compound of claim 1, wherein R is₃Represents a methyl group and R₄Represents an ethyl group.

6. The compound of claim 1, wherein R is₃And R₄Form a pyrrolidine ring with the nitrogen atom carrying them.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 in association with an excipient.

8. A process for the preparation of a compound according to claim 1, characterized in that a compound of the general formula (II)In which X and R₁As defined in claim 1, R represents a (C)₁-C₃) Alkyl which is reacted with ethylpyruvate to give a diester of the formula (IV)The diester is then reacted with a compound of the formula R₂NH₂By reaction of an amine of formula (II) wherein R₂As defined in claim 1, to give esters of the formula (V)The ester is converted by hydrolysis into the corresponding acid of the general formula (VI)By reaction with N, N' -carbonyldiimidazole or by acid chloride, which is then reacted with an acid of the formula HNR₃R₄Wherein R in the formula₃And R₄As defined in claim 1, to primary, secondary or tertiary amines of the formula (IAnd finally, if it is desired to prepare a compound in which the bonds in the 3 and 4 positions are double bonds, the compounds of the formula (I') are cyclohexanecarbonylated with 2, 3-dichloro-5, 6-dinitriles2, 5-diene-1, 4-dione or 3,4, 5, 6-tetrachlorocyclohexa-3, 5-diene-1, 2-dione is oxidized in order to obtain the compound of the general formula (I')

9. A process for the preparation of a compound according to claim 1, characterized in that a compound of the general formula (VIII)Wherein X is as defined in claim 1, with 2-oxoglutaric acid and then in an acidic alcoholic medium, so as to obtain diesters of the general formula (IX)Wherein R represents a (C)₁-C₃) Alkyl and then, if desired, alkylation to give compounds of the formula (X)In the formula R₁Represents a (C)₁-C₃) Alkyl, followed by conversion of the compound of formula (X) in the presence of dimethylformamide dimethyl acetal, in order to obtain the compound of formula (XI)Alternatively, if desired, the compound of formula (IX) can be converted directly into a compound of formula (XI), wherein R is₁Represents a methyl group, and the compound of formula (XI) is reacted with a compound of formula H₂NR₂Treatment of formula (II) wherein R₂As defined in claim 1, to give esters of the formula (V')The formula (V ') is then converted into the corresponding acid of the formula (VI')And finally, the acid is converted into the primary, secondary and tertiary amides of the general formula (I ') by reaction with N, N' -carbonyldipyridazol or by acid chloride.

10. A process for preparing a compound according to claim 1, characterized in that the diester of formula (X)In which X and R₁As defined in claim 1, R is as defined in claim 9, is hydrolyzed to give a diacid of the general formula (XII)Conversion of the diacid into the anhydride, in order to obtain the compound of the formula (XIII)This compound is then reacted with a compound of the general formula HNR₃R₄Is reacted with an amine of formula (I), R in the formula₃And R₄As defined in 1, to give a compound of the formula (XIV)Conversion of formula (XIV) to esters of formula (XV)The compound of the general formula (XV) is further treated in the presence of dimethylformamide dimethyl acetal, so as to obtain the compound of the general formula (XVI)And finally, reacting the compound of the formula (XVI) with the formula R₂NH₂With an amine of formula (II) wherein R is₂As defined in claim 1, to give compounds of the general formula (I')And, finally, if desired, the secondary amide of the formula (I') is converted into the tertiary amide by means of an alkylation reaction.