RU2081117C1 - Lactam derivative of physiolocically acceptable salts or solvates - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: lactam derivatives of formula 1. Reagent 1: compound of formula 2. Reagent 2: alkylating agent of formula 3. Reaction conditions: in the presence of acid at elevated temperature. Structure of compounds of formula 1, 2, or 3 with respective meanings of radicals. EFFECT: improved properties. 5 cl

Description

 The invention relates to lactam derivatives, a method for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.

 The closest prior art to the claimed compounds are compounds disclosed in patents DE-A-3740352 and EP-A-0306323; the first of which relates to tricyclic ketones, and the second to unsubstituted lactams. However, neither one nor the other source does not reveal or anticipate the compounds of this invention.

 In particular, the invention relates to compounds that are potent and selective antagonists of 5-hydroxy-tryptamine (5-HT) at 5-HT receptors located at the ends of primary sensory (efferent) nerves. Receptors of this type are now referred to as 5-HTZ receptors and are also present in the central nervous system, 5-HT is widely found on the nerve pathways in the central nervous system, and a violation of these pathways containing 5-HT is known to cause changes in behavior syndromes such as depression, psychomotor activity, appetite and memory.

 We found a new group of compounds that differ in structure from those described previously and which are potent antagonists of the action of 5-HT receptors in 5-HTZ.

,
где I_m представляет собой имидазольную группу общей формулы:

,
а R¹ представляет собой атом водорода или группу, выбранную из C_1-6-алкил,-CH₂C_2-5 алкинил и C_3-7 циклоалкил C_1-4 алкил-; n-2 или 3; Q атом галогена или группа, выбранная из гидроксильной, фенил-C_1-3 алкокси-, C₁ балкильной и циано-групп; Q¹ атом водорода или фтора; а также физиологически приемлемые соли и сольваты этого лактама.In accordance with the invention, there is provided a tricyclic lactam of the general formula (I):

,
where I _m represents an imidazole group of the general formula:

,
and R ¹ represents a hydrogen atom or a group selected from C _1-6 alkyl, —CH ₂ C _2-5 alkynyl and C _3-7 cycloalkyl C _1-4 alkyl—; n-2 or 3; Q is a halogen atom or a group selected from hydroxyl, phenyl-C _1-3 alkoxy, C ₁ -alkyl and cyano groups; Q ^{1 is} a hydrogen or fluorine atom; as well as physiologically acceptable salts and solvates of this lactam.

 Suitable physiologically acceptable salts of the compounds of general formula (1) are those obtained by the addition of an acid, organic or inorganic, for example hydrochlorides, hydrobromides, sulfates, alkyl or aryl sulfonates (e.g. methanesulfonates or p-toluenesulfonates), phosphates, acetates, citrates, succinates , tartrates, fumarates and maleates. Solvates may be, for example, hydrates.

 All optical isomers of compounds of general formula (I) and mixtures thereof, including racemic mixtures and all geometric isomers of compounds of general formula (I) are encompassed by the present invention.

A particularly desirable group of compounds of general formula (I) are those in which R ¹ represents a hydrogen atom or a methyl, isopropyl, prop-2-ynyl or cyclopentylmethyl group; Q is a fluorine or bromine atom or a hydroxyl, phenylmethoxy, methyl or cyano group; Q ^{1 is} a hydrogen atom: a n 2.

Preferred compounds according to the present invention are: 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2- [5-methyl-1H-imidazol-4-yl] methyl 1H-pyrido [4, 3 -b] indol-on;
2,3,4,5-tetrahydro-5,6-dimethyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4, 3-b] indol-1-one ;
6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] 1H-pyrido [4, 3-b] indole- 1-on;
6-fluoro-2,3,4,5-tetrahydro-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -5- / 2-propinyl / -1H-pyrido [4,3-b ] indol-1-one;
2,3,4,5-tetrahydro-5-methyl-2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1-oxo-1H-pyrido [4,3-b] indol-6 -carbonitrile;
6-fluoro-2,3,4,5-tetrahydro-5- / 1-methylethyl / -2- [/ 5-methyl-1H-imidazole-4-ml / methyl] -1H-pyrido [4,3-b ] indol-1-one; and their physiologically acceptable salts and solvates.

The potent and selective 5-HT antagonism at the 5-HTZ receptors of the compounds of the present invention is confirmed by their ability to inhibit 3- / 5-methyl-1H-imidazol-4-yl / -1- [1] methyl-t ₃ / -1H-indole -3-yl / -1-propanone bound to the rat gastric membrane homogenate following the method described by I. Kilpatrick et al. in Nature, 1987, 330, 746 and / or their ability to inhibit depolarization caused by 5-HT vagus nerve isolated from rats.

 In addition to their activity as potent and selective 5-HT antagonists at 5-HTE receptors, the compounds of the present invention have the advantage of having a significant duration of action.

 A particularly desirable compound due to its high activity and duration of action is 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2- [/ 5-methyl-1H-imidazol-4-yl / methyl] - 1H-pyrido [4,3-b] indol-1-one; and its physiologically acceptable salts and solvates. The desired salts of this compound are hydrochlorides, maleates and benzoates.

 The compounds of formula (I), which are antagonists of the action of 5-HT at 5-HTZ receptors, are used in cases such as mental disorders (eg, schizophrenia and mania); in a state of increased anxiety; and with nausea and vomiting, especially when it is associated with the treatment of cancer with chemotherapy and radiotherapy, as well as with the same symptoms in the postoperative period. The compounds of formula (I) are also used in the treatment of gastric diseases; symptoms of gastrointestinal dysfunction, such as are observed with dispersion, gastric ulcer, narrowing of the esophagus, gas accumulation and irritation of the intestine; migraine; obesity and conditions such as increased hunger; and pain. The compounds of formula (I) can also be used after abuse of drugs and substances in depression, dementia and other recognized disorders.

 The invention also provides a pharmaceutical composition that contains at least one compound selected from the group of compounds of general formula (I), and their physiologically acceptable salts and solvates (e.g. hydrates) for use in treating a human or animal, and which prepared in such a way that it can be introduced in the usual way.

 Such compositions can be prepared in the usual way using one or more physiologically acceptable carrier and / or excipient.

 Such compounds according to the invention can be prepared for oral, parenteral or rectal administration or in a form suitable for administration by inhalation or by blowing (either through the mouth or through the nose).

 The proposed dose of the compounds of the present invention for administration to humans (having a weight of about 70 kg) is 0.001 to 100 mg, preferably from 0.01 to 50 mg, more preferably from 0.1 to 20 mg of the active substance per unit dose, expressed as a free weight basis, which can be entered, for example, from 1 to 4 times a day. This means that changes in dosage are possible, depending on the return and condition of the patient. The dosage also depends on the route of administration.

Compounds of the general formula (I) and physiologically acceptable salts and solvates thereof can be prepared by the usual methods described below. Earlier in the description of the group, R ¹ , QQ ¹ , n and Jm are the same as defined for the compound of general formula (I).

соединением формулы (III):
X Jm (III)
или защищенным его производным, где X представляет собой группу -CH₂, а L представляет собой остаточный атом или группу такую, как галоген (например, хлор, бром или йод) или ацилоксигруппу (например, трифторацетилокси или ацетокси) или сульфонилокси-группу (например, трифторметансульфонилокси, n-толуолсульфонилокси или метансульфонилокси), и реакцию проводят в присутствии основания; или X представляет собой группу -CH₂OH, а реакцию проводят в присутствии кислоты или повышенной температуре, что необходимо для удаления любой защищающей группы.According to the first method (A), a compound of general formula (I) can be prepared by alkylation of a compound of formula (II):

the compound of formula (III):
X Jm (III)
or a protected derivative thereof, where X is a —CH ₂ group, and L is a residual atom or group such as a halogen (eg, chlorine, bromine or iodine) or an acyloxy group (eg, trifluoroacetyloxy or acetoxy) or a sulfonyloxy group (eg , trifluoromethanesulfonyloxy, n-toluenesulfonyloxy or methanesulfonyloxy), and the reaction is carried out in the presence of a base; or X represents a —CH ₂ OH group, and the reaction is carried out in the presence of an acid or an elevated temperature, which is necessary to remove any protecting group.

According to (a) process (A), the reaction is carried out with a compound of formula III, where X is a —CH ₂ L group and L is preferably a halogen (eg, chlorine atom). The reaction can be carried out in an inert solvent such as ether (e.g. dimethoxyethane, diglyme or tetrahydrofuran), substituted amide (e.g. dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (e.g. toluene), ketone (e.g. acetone) or dimethyl sulfoxide temperature from ambient temperature to 100 ^o C, in the presence of a base. Suitable bases include alkali metal hydrides (e.g. sodium hydride), alkali metal carbonates (e.g. sodium carbonate), alkali metal amides (e.g. sodium amide), alkali metal alkoxides (e.g. potassium t-butoxide) or alkali metal hydroxides (e.g. sodium or potassium hydroxide).

According to (b) process (A), the reaction is carried out with a compound of formula (III), wherein X is a CH ₂ OH group in the presence of an acid. As the acid, for example, a strong inorganic acid (e.g. hydrochloric acid) or hydrocarbyl sulfonic acid (e.g. n-toluenesulfonic acid) can be used.

The reaction is conveniently carried out in a high-boiling polar solvent such as β-methypyrrolidinol or dimethylacetamide at elevated temperatures, for example in the range of 100 to 200 ^° C. In addition, the reaction can be conveniently carried out in water or alcohol (for example, isopropanol) at the boiling point solvent.

или слои или защищенного его производного, с последующим удалением защитных групп.According to another method (B), a compound of general formula (I) can be prepared by cyclization reaction of a compound of formula (IV):

or layers or a protected derivative thereof, followed by deprotection.

 It is noted that these compounds of formula (IV) can exist in the corresponding tautomeric form of enol-hydrazone. Cyclization can be carried out in an aqueous or non-aqueous medium, in the presence of an acid catalyst. When an aqueous medium is used, it may be water or a mixture of water and an organic solvent such as alcohol (e.g. methanol, ethanol or isopropanol) or ether (e.g. dioxane or tetrahydrofuran). The acid catalyst may be, for example, an inorganic acid, such as concentrated hydrochloric or sulfuric acid. In some cases, the acid catalyst may also act as a solvent in the reaction.

In an anhydrous reaction medium, which may contain one or more alcohol or ether (e.g., as described above), carboxylic acids (e.g., acetic acid) or esters (e.g. ethyl acetate), the acid catalyst may further be a Lewis acid, such as boron trifluoride, zinc chloride or magnesium chloride. The cyclization reaction can conveniently be carried out at a temperature of from 20 to 200 ^o C, preferably at temperatures from 20 to 125 ^o C.

 Alternatively, cyclization according to (a) of process (B) can be carried out in the presence of a polyphosphate ester in a reaction medium that may contain one or more organic solvents, preferably halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. Polyphosphate ester is a mixture of esters that can be obtained from phosphorus pentoxide, diethyl ether and chloroform in accordance with the procedure described in the book "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sons, 1967).

или его защищенного производного с формамидом при температуре в области от 150 до 200^oC для удаления любой защищенной группы.According to another method (C), a compound of general formula (I) can be prepared by the reaction of a compound of formula (Y):

or a protected derivative thereof with formamide at a temperature in the range of 150 to 200 ^° C. to remove any protected group.

 According to another method (D), a compound of general formula (I) can be converted to another compound of formula (I) using conventional techniques. Such conventional techniques include alkylation using protection and deprotection if necessary.

The term "alkylation" according to the main process (D) includes the introduction of groups such as cycloalkylalkyl and alkynyl. Thus, for example, a compound of formula (I) in which R ′ is C _1-6 alkyl, —CH ₂ C _2-5 alkynyl or C _3-7 cycloalkyl C _1-4 alkyl groups can be prepared by alkylating a compound of formula ( I), in which R 'represents a hydrogen atom, using conventional techniques, for example, as described in the description of European Patent No. 242973. Thus, this reaction can be carried out using a suitable alkylating agent of the formula R2Z (where R2 is a group which enter, and Z a residual atom or group), it is desirable to carry out the reaction in the presence of a base.

 It should be noted that the above transformations may be necessary or desirable in order to protect any sensitive groups in the molecule of the compound in order to prevent undesirable side reactions. For example, it may be necessary to protect indole and / or imidazole nitrogen atoms, for example, arylmethyl (e.g. tertyl), arylmethoxymethyl (e.g. phenylmethoxymethyl), alkyl (e.g. tert-butyl), alkoxymethyl (e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) or sulfonyl (e.g., N, N-dimethylaminosulfonyl) or n-toluenesulfonyl group. When Q is a hydroxyl group, it may be necessary to protect the hydroxyl group, for example, with an arylmethyl group (for example, benzyl or tertyl group).

 So, according to another method (E), a compound of general formula (I) can be obtained by removing any protecting groups from the protected form of a compound of formula (I). Exemption from protection can be accomplished using conventional techniques, such as those described in the book "Protective Jroup in Organic Synthesis", T.W. Jreen (John Wiley and Sons, 1981. For example, an arylmethoxymethyl-N-protected group can be cleaved by hydrogenolysis in the presence of a catalyst (eg, palladium on charcoal). The tertiary group can be cleaved by acid hydrolysis (for example, using dilute hydrochloric or acetic acid) An alkoxyalkyl group can be removed using an inorganic acid, for example, dilute hydrochloric or hydrobromic acid). The acyl group can be removed by hydrolysis in an acidic or alkaline medium (for example, using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide). The sulfonyl group can also be removed by alkaline or acid hydrolysis, and the N, N-dimethidaminosulfonyl group can also be removed (for example, from the imidazole nitrogen atom) by photolysis. The aryl methyl OH protecting group can be cleaved under an acidic environment (for example, using dilute acetic acid, hydrobromic acid or boron tribromide) or by hydrogenolysis in the presence of a catalyst (for example, palladium supported on charcoal).

где X водород или галоген (например, бром или йод).The compounds of formula (II), where R ¹ represents a hydrogen atom, can be obtained, for example, by cyclization of the compounds of formula (Y1):

where X is hydrogen or halogen (e.g. bromine or iodine).

 The cyclization can be carried out using methods similar to those described in J. Org. Chem, 1980, 45, 2938, H. Jida etal.

 Compounds of formula (II), where R 'is a group other than a hydrogen atom, can be obtained from a compound of formula (II), where R' is a hydrogen atom, by a conventional alkylation process, as described, for example, in the above intermolecular transformation process (D).

где X такой, как определено выше, с соединением формулы (YIII):

при повышенной температуре.Compounds of formula (VI) can be prepared, for example, by reacting a compound of formula (YII):

where X is as defined above, with a compound of formula (YIII):

at elevated temperature.

 The compounds of formula (III) and its derivatives with protected groups are either known or can be obtained, for example, by methods analogous to those published in the description of European Patent N 242973.

 Compounds of formula (IY) and (Y) can be obtained, for example, by methods analogous to those described in published European Patent Specification No. 306323A.

 Compounds of formula (YII) (YIII) are either known or may be prepared from known compounds by conventional methods.

 If it is desired to isolate the compound of the present invention as a salt, for example a physiologically acceptable salt, this can be achieved by reacting the compound of formula (I) as a free base with a suitable acid, preferably with an equivalent amount, in a suitable solvent such as alcohol (e.g. ethanol or methanol), aqueous alcohol (e.g., aqueous ethanol), a halogenated hydrocarbon (e.g. dichloromethane), ether (e.g. ethyl acetate), or ether (e.g. tetrahydrofuran).

 Physiologically acceptable salts can also be obtained from other salts, including other physiologically acceptable salts of the compounds of formula (I) using conventional production methods.

 The individual enantiomers of the compounds of the present invention can be obtained by separating a mixture of enantiomers (eg, a racemic mixture) by conventional methods, such as by using optically active resolving acids; see "Stereochemistry of carbon compounds" ("Stereochemistry of Carbon Compounds", E. J. Eliel Mc.Jraw Hill, 1962) and "Table of separating substances" "Tables of Pesolving Agents" S.H. "Wilen.

 The methods described above for preparing the compounds of the present invention can be used to introduce the desired groups at any stage during the formation of the desired compounds, and it should be noted that these methods can be combined in various ways in such multi-stage processes. The sequence of reactions in multi-stage processes should be chosen so that the reaction conditions that are used do not affect those groups in the molecule that are necessary in the final product.

The invention is illustrated by the following intermediates and examples. In all cases, the temperature is maintained at about 0 ^° C. Thin layer chromatography (tlc) is carried out on silica, and the evaporation column also has silica as the carrier (Merck 93851). The solvent system A used in chromatography is a solution of dichloromethane, ethanol, 0.88 ammonia. If necessary, the organic extracts were dried over magnesium sulfate or sodium sulfate. The following notation is used: DMF-dimethylformamide, THF tetrahydrofuran, DME-dimethoxyethane. The spectra of nuclear magnetic resonance (proton) ¹ HN.mr/ were obtained at 250 MHZ for dilute solutions in d6-dimethyl sulfoxide.

 Intermediate 1: 4 - [/ 2-fluorophenyl / amino] -5,6-dihydro-2 / 1H / -pyridinone.

A mixture of 2-fluoroaniline (0.98 g) and 2.4 dioxopiperidine (1.0 g) was heated at 120 ^° C. for 2 hours. The cooled mixture was triturated with dry ether (5x40 ml) and the solvent was decanted to obtain the title compound (1.495 g) with a melting point of 98-100 ^o C.

 Intermediate 2: 5,6-dihydro-4 - [/ 2-methylphenyl / amino] -2 / 1H / -pyridinone.

A mixture of o-toluidine (943 mg) and 2,4-dioxopiperidine (1.0 g) was heated at 120 ^° C. for 30 minutes. The oil was cooled, triturated with ether (30 ml), and the solvent was decanted to give the title compound (1.74 g) with a melting point of 155-158 ^° C.

 Intermediate 3: 4- [2,6-Dibromophenyl / amino] -5,6-dihydro-2 / 1H / -pyridinone.

A mixture of 2.6 dibromaniline (4.4 g) and 2.4 dioxopiperidine (2.0 g) was heated at 120 ^° C. for 2.5 hours. The mixture was then cooled to 0 ^° and triturated with ether (100 ml) to give a solid which was purified by eluting with FCC system A (100: 8: 1) to obtain the title compound (1.8 g) with a melting point of 240-243 ^° C.

 Intermediate 4: 4 - [/ 2,5-Difluorophenyl / amino] -5,6-dihydro-2 / 1H / -pyridinone.

A mixture of 2,5-difluoroaniline (6.45 g) and 2.4 dioxipiperidine (6.45 g) was heated under a nitrogen stream for 6 hours. Then, the reaction mixture was diluted with ethanol (50 ml), adsorbed on silica and purified, eluting. FCC system A (150: 8: 1), to obtain the named compound (2.3 g) with a melting point of 252-255 ^o C.

 Intermediate 5: 3 - [/ 2-fluorophenyl / amino / -2-cyclohexen-1-one.

2-fluoroaniline (10 g) and cyclohexane-1,3-dione (10 g) were heated together under a stream of nitrogen for 1 h at a temperature of 120 ^o C. The cooled mixture was triturated with ether and filtered to obtain the title compound (14.8 g ) with a melting point of 116-118 ^o C.

 Intermediate 6: 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one.

In a stream of nitrogen and with stirring, to the solution of 4 - [/ 3-fluorophenyl / amino] -5,6-dihydro-2 / 1H / -pyridinone (1.4 g) were added copper acetate (2.71 g) and palladium acetate ( II) (280 mg) in dry DMF (28 ml). The mixture was heated at 130 ^° C. for 1.5 hours, and the solvent was removed in vacuo. The residue was treated with methanol (50 ml), and the suspension was filtered and washed with hot methanol (3x50 ml). The combined filtrates were evaporated to give a gummy substance (2.16 g), which was purified by eluting with FCC system A (200: 10: 1) to obtain the title compound (490 g) with a melting point of 255-257 ^° .

 Intermediate 7: 2,3,4,5-tetrahydro-6-methyl-1H-pyrido [4,3-b] -indol-1-one.

To a solution of 5,6-dihydro-4 - [(2-methylphenyl) amino] -2 / 1H / -pyridinone (1.5 g), copper acetate (2.9 g) and acetate (II) (230 mg) were added with stirring ) in dry DMR (40 ml). The mixture was heated at 130 ^° C. for 1 h, evaporated in vacuo, and the residue was extracted with methanol (250 ml). This solution was concentrated in vacuo, and the residue was purified eluting with FCC system A (100: 8: 1) to obtain the title compound (360 g) with a melting point of 300 302 ^o C.

 Intermediate 8: 6-Bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one.

4 - [/ 2,6-Dibromophenyl / amino] -5,6-dihydro 2 / 1H / -pyridinone (0.5 g) was subjected to a cyclization reaction according to the method of producing intermediate 7 to obtain the title compound (250 g) with a melting point of 268 270 ^o C.

 Intermediate 9: 6,9-Difluoro 2,3,4,5-tetrahydro 1H-pyrido [4,3-b] indol-1-one.

4 [/ 2,5-Difluorophenyl / amino] -5,6-dihydro-2 / 1H / pyridinone (2.24 g) was subjected to a cyclization reaction according to the method of obtaining intermediate 6 to obtain the named compound (900 g) with a melting point of 221 223 ^o C.

 Intermediate 10: 8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one.

3 - [/ 2-fluorophenyl / amino] -2-cyclohexen-1-one (14.8 g), palladium (II) acetate (1 g) and copper (II) acetate (29.5 g) were heated together in a stream nitrogen at 140 ^o for 2 hours in a solution of DMR (100 ml). The solvent was removed in vacuo and the residue was purified by elution with FCC ether to give the title compound (10.1 g) with a melting point of 222 224 ^° C.

 Intermediate 11: 2,3,4,5-tetrahydro-6- (phenylmethoxy) -1n-pyrido [4,3-b] indol-1-one.

A mixture of 2- (phenylmethoxy aniline (7.6 g) and 2,4-dioxopiperidine (4.5 g) was heated under a stream of nitrogen at 120 ^{° C.} for 3 hours. Then the mixture was cooled and purified, eluting with FCC system A (100: 8 : 1), to obtain the title compound (5.4 g) This solid was processed according to the method for preparing intermediate 7 to obtain the title compound (4.0 g) with a melting point of 182-185 ^° .

 Intermediate 12: 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one.

Sodium hydride (60% dispersion in oil / 196 mg) was added to a suspension of 6-fluoro-2,3,4,5tetrahydro-1H-pyrido [4,3-b] indole -1-one (500 mg) with stirring in a stream nitrogen in dry DMF (10 ml). After 30 minutes, the solution was cooled (to 0 ^° C.) and methyl iodide (0.153 ml) was added thereto. After stirring for 15 minutes, the suspension was poured into water (50 ml) and extracted with dichloromethane (3x25 ml). The combined, dried organic extracts were evaporated to give a solid (530 mg), which was purified by FCC eluting with system A (250: 10: 1) to give the title compound (130 g) with a melting point of 242 ^° C.

 Intermediate 13: 2,3,4, -tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b] indol-1-one.

Sodium hydride (60% dispersion in oil, 140 mg) was added with stirring to a solution of 2,3,4,5-tetrahydro-6-methyl-1H-pyrido (4,3-b) indole -1-one (350 mg) in dry DMF (15 ml) at 21 ^o C in a stream of nitrogen. After 15 minutes, the solution was cooled (to 0 ^° C.) and 10 vol. Was added dropwise. a solution of methyl iodide in DMF (1.14 ml). After 10 minutes, water (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml), then evaporated to give a solid, which was purified by elution with FCC with a mixture of dichloromethane: ethanol (80: 1), to obtain the title compound (190 g) with a melting point of 298 300 ^o C.

 Intermediates 14 and 15 were obtained in the same manner as intermediate 13, that is, by methylation in the same manner as intermediate 13, that is, by methylation of the corresponding 2,3,4,5-tetrahydro-1H - pyrido [4,3-b] indole -1-she sodium hydride and methyl iodide in DMF.

 Intermediate 14: 6-Bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one.

Methylation of 6-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (200 mg) afforded the title compound (800 mg) with a melting point of 212 214 ^o C .

 Intermediate 15: 6,9-Difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one.

Methylation of 6,9-Difluoro-2,3,4,5 tetrahydro-1H-pyrido [4,3-b] indol-1-one (900 mg) afforded the title compound (110 mg) with a melting point of 226 229 ^° C (ahtom FCC was system A (150: 8: 1).

 Intermediate 16: 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one.

To a suspension of sodium hydride (80% dispersion in oil, 1.15 g) in dry THF (50 ml) in a stream of nitrogen was added 8-fluoro-1,2,3,9-tetrahydro 4H-carbazol-4-one (6, 5 g) in dry THF (5 ml) and the mixture was stirred for 1 h. Methyl iodide (4.1 ml) was added and the mixture was stirred for 3 h. Then the mixture was poured into brine (300 ml) and extracted with ether (2 x 300 mo ) The combined dried organic extracts were evaporated in vacuo to give the title compound (5.77 g) with a melting point of 126 128 ^o C.

 Intermediate 17: 2,3,4,5-tetrahydro-5-methyl-6- (phenylmethoxy) -1H-pyrido [4,3-b] indol -1-one.

2,3,4,5-tetrahydro-6- (phenylmethoxy) -1H-pyrido [4,3-b] indol-1-one (2.0 g) was methylated according to the method for preparing intermediate 12 to obtain the title compound (950 g ) with a melting point of 199 201 ^o C (Eluant FCC was the system A / 100: 8: 1 /.

 Intermediate 18: 6-fluoro-2,3,4,5-tetrahydro-5 [/ phenylmethoxy / methyl] -1H-pyrido [4,3-b] indol-1-one.

6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole -1-one (800 mg) was alkalized with benzyl chloromethyl ether (0.55 ml) according to the method for preparing intermediate 12 to obtain the title compound 220 g) melting point 130 132 ^° C. (FCC eluant was system A / 300: 10: 1 /.

 Intermediate 19: 2,3,4,5-tetrahydro-6 (phenylmethoxy) - 5 [(phenylmethoxy / methyl] -1 -pyrido [4,3-b] indol-1-one.

2,3,4,5-tetrahydro-6- (phenylmethoxy) 1H-pyrido [4,3-b] indole -1-one (1.8 g) was alkylated with benzyl chloromethyl ether (0.86 ml) according to the method for preparing the intermediate 13 to obtain the title compound (600 mg) with a melting point of 188 190 ^° C. (FCC eluant was System A (100: 8: 1).

 Intermediate 20: 6-fluoro-2,3,4,5-tetrahydro-5/1-methylethyl / -1H-pyrido [4,3-b] indol-1-one.

With stirring, a solution of 6 fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.006 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil, 333 mg) and stirring in a stream of nitrogen continued for another 1 hour. Then isopopyl bromide (663 mg) was added and the solution was stirred at room temperature for 30 minutes and then at 50 ^° C. for another 12 hours. Then the next portion of isopropyl bromide (150 mg) was added and the reaction was continued with stirring in a stream of nitrogen at 50 ^° C. for 60 hours. The mixture was then cooled to room temperature and added to water (300 ml). The mixture was then extracted with dichloromethane (3 × 200 ml), adsorbed on silica and purified by FCC, eluting with system A (150: 8: 1) to give a solid (240 mg), which was triturated with ether to give the title compound (130 mg) with a melting point of 183-184 ^o C.

 Intermediate 21: 5- (Cyclopentylmethyl) -6-fluoro-2, 3, 4, 5 - tetrahydro-1H-pyrido [4,3-b] indol-1-one.

With stirring, a solution of 6-fluoro-2, 3, 4, 5 tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.023 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% oil dispersion, 331 mg) and stirred in a stream of nitrogen at room temperature for 30 minutes. Then, a solution of cyclopentimethyl (methyl sulfonate) (893 mg) in dry DMF (20 ml) was added over 15 minutes and stirring was continued for another 5 days. Water (20 ml) was added to the reaction mixture, then the solution was concentrated in vacuo to a solid. It was dissolved in ethyl acetate (300 ml) and methanol (1 ml), and the resulting solution was washed with a saturated solution of sodium chloride (3 × 100 ml), and then adsorbed on silica. Purification by elution with FCC system A (150: 8: 1) gave a solid (283 mg), which was recrystallized from ethyl acetate to give the title compound (237 mg) with a melting point of 175-176 ^° C.

 Intermediate 22: 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one-oxime.

A mixture of 8-fluoro-1, 2, 3, 9-tetrahydro-9-methyl-4H-carbazol-4-one (3.0 g) and hydroxylamine hydrochloride (2.92 g) in pyridine (35 ml) was heated at 60 ^o C for 3 hours. The solution was concentrated in vacuo, then subjected to azeotropic drying with toluene (2x10 ml). The residue was treated with 8% sodium bicarbonate solution (125 ml) and extracted with ethyl acetate (3x100 ml). The combined extracts were filtered and concentrated in vacuo to give the title compound (1.8 g) as a tlc solid (system A, 100: 8: 1) with a refractive index of 0.66.

 Intermediate 23: 7-fluoro-3,4,5,6-tetrahydro-6-methylazepino [4,3-b] indol-1 (2H) -one.

A mixture of 8-fluoro-1, 2, 3, 9-tetrahydro-9-methyl-4H-carbazole-4-one oxime (1.8 g) and polyphosphoric acid (20 ml) in dioxane (30 ml) was stirred in a stream of nitrogen for 1 h at a temperature of 100-110 ^o C. After cooling, the reaction mixture was poured into ice water (1 l) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to obtain a solid, which was placed in methanol and adsorbed on silica. Purification by FCC elution with System A (200: 8: 1) afforded the title compound (850 mg) with a melting point of 233-235 ^° C.

 Intermediate 24: 2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile.

A mixture of 6-bromo-2, 3, 4, 5-tetrahydro-5-methyl-1H-pyrido [4,3-c] indol-1-one (1.1 g) and copper cyanide (1.1 g) in 1,3 dimethyl-3, 4, 5, 6-tetrahydro-2 / 1H / -pyrimidone (30 ml) was heated at 180 ^° C. for 24 hours. The mixture was poured into ice (500 ml) and iron (III) chloride ( 20 g) and stirred for another 1 hour. Then it was extracted with dichloromethane (3x300 ml), and the combined organic extracts were washed with water (2x300 ml) and concentrated in vacuo. The residue was triturated with hexane (250 ml), then with a mixture of ether and hexane (50:50; 100 ml) and finally with ether (60 ml) to obtain the title compound (620 g) with a melting point of 230-231 ^o C.

 Intermediate 25: 6-fluoro-2, 3, 4, 5-tetrahydro-2 - [/ 5 - methyl-1H-imidazol-4-yl / methyl] -5- [phenylmethoxy / methyl] -1H-pyrido [4 3-c] indol -1-one.

 Sodium hydride (60% dispersion in oil, 28 mg) was added with stirring to a solution of 6-fluoro-2, 3, 4, 5-tetrahydro-5- [/ phenylmethoxy / methyl] -1H-pyrido [4,3- c] indol-1-one (190 mg) in dry DME (10 ml).

The mixture was heated at 50 ^° C. for 6 hours and then treated with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (261 mg) and stirring was continued under a stream of nitrogen for 18 hours. Water was added. (2 ml) and acetic acid (2 ml) and the solution were heated to boiling and refluxed for 2.5 hours. The solution was poured into 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 × 25 ml). The combined, dried organic extracts were evaporated to an oil (750 mg), which was purified by elution with FCC by system A (200: 10: 1) to obtain the title compound (188 mg) tlc system A, 200: 10: 1 / refraction coefficient 0 , 33.

 Intermediate 26: 6-fluoro-2,3,4,5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4.3 -c) indole -1-he.

A solution of triphenylmethyl chloride (0.625 g) in dry DMF (10 ml) was added dropwise with stirring to a solution of 6 fluoro-2, 3, 4, 5-tetrahydro -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indol-1-one (530 mg) in dry DMF (20 ml) containing triethylamine (0.25 g). Then the reaction mixture was stirred at room temperature for 20 hours, added to water (500 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with water (2 x 300 ml), dried and adsorbed onto silica. Purification by elution with FCC on system A (150: 8: 1) gave the title compound (509 mg) with a melting point of 252-253 ^° C.

 Intermediate 27: 2,3,4,5-tetrahydro-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -6- (phenylmethoxy) -5 - [/ phenylmethoxy / methyl] -1H- pyrido [4,3-in] -indole -1-one.

2,3,4,5-tetrahydro-6- (phenylmethoxy) -5- [/ phenylmethoxy / methyl] -1H-pyrido [4,3-b] indol-1-one (500 mg) was reacted with 4- (chloromethyl ) -5-methyl) -1- (triphenylmethyl) -1H-imidazole (671 mg) according to the method for preparing intermediate 25 to obtain the title compound (340 mg) with a melting point of 170-172 ^o C. (FCC eluant was system A (100 : 8: 1).

 Intermediate 28: 4-amino-5,6-dihydro-1- [5 - methyl-1H-imidazol-4-yl / methyl] -2 (1H) -pyridinone.

To a solution of 5,6-dihydro-4-methoxy -1- [/ 5-methyl-1H-imidazol-4-yl / methyl] -2 (1H) -pyridinone (1.00 g) THF (10 ml) was added hydrochloric acid (4.3 ml) and the mixture was stirred for 24 hours at 25 ^o C.

The solvent was removed in vacuo. The residue was dissolved in methanol (10 ml), adsorbed on silica and purified by FCC, eluting with system A (50: 5-1), to obtain the title compound (286 mg) with a melting point of 268-271 ^o C.

 Intermediate 29: 4-2- [2-fluorophenyl / -2-methylhydrazine] -5,6 - dihydro-1 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -2 / 1H / -pyridinone .

 A mixture of 1 - / - fluorophenyl / -1-methylhydrazine (57 ml) and 4-amino-5,6-dihydro-1 [/ 5-methyl-1H-imidazole-4-yl / methyl] -2 (1H) pyridinone ( 70 mg) in absolute alcohol (ethanol) (3 ml) was stirred at room temperature for 4 hours, then at reflux for 20 hours. The solvent was removed in vacuo and the residue was purified with FCC, eluting with system A (75: 10: 1), to obtain the title compound (85 mg) as an oil, t, l, c. (System A, 200: 10: 1) The refractive index is 0.27.

 Intermediate 30: 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 4-methyloxazol-5-yl / methyl] -1H-pyridino [4,3-b] indole- 1-on.

To a suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-c] indol-1-one (500 mg) in dry DME (150 ml) was added with stirring sodium (73% dispersion in oil, 167 mg), and the suspension was stirred at 60 ^o C in a stream of nitrogen for 6 hours

Then, 5-chloromethyl-4-methyloxazole (440 mg) was added to the mixture and the mixture was stirred overnight at 60 ^° C. The following amount of sodium hydrate (73% dispersion in oil 84 mg) was added and the mixture was stirred for 3 hours and then cooled to 0 ^° C. Water (200 ml) was added and the mixture was extracted with dichloromethane (3 × 200 ml). The combined organic extracts were concentrated in vacuo, and the residue was purified by FCC, eluting with system A (100: 8: 1) to obtain the title compound (550 mg) as a solid with a melting point of 158-161 ^° C.

 Intermediate 31: Phenylmethyl-4 - [/ 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido (4,3-b] indol-2-yl- / methyl ] -5-methyl-1H-imidazole -1-carboxylate.

A solution of benzyl chloroformate (0.47 ml) in dichloromethane (1 ml) was added with stirring to a solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H - imidazole-4 -yl / methyl] -1H-pyrido [4,3-c] indol-1-one (496 mg) and triethylamine (0.67 ml) in dry dichloromethane (50 ml) at 20 ^o C in a stream of nitrogen, and the mixture stirred all night. The cooled reaction mixture was then added to 2 sodium hydroxide (100 ml) and extracted with dichloromethane (2x100 ml). The combined, dried organic extracts were adsorbed on silica and purified by FCC elution with system A (200: 8: 1) to obtain the title compound (442 mg) as a solid. The sample was recrystallized from hot ethyl acetate, and the solid obtained after recrystallization was triturated with ether to obtain a crystalline solid with a melting point of 126-128 ^o C.

 Example 1. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b ] indol-1-one maleate.

Sodium hydride (60% dispersion in oil, 25 mg) was added with stirring to a suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-c] -indole-1- it (115 mg) in dry DME (7.5 ml) in a stream of nitrogen. The mixture was heated at 50 ^{° C.} for 6 hours, then treated with 4- (chloromethyl) -5-methyl-1- [triphenylmethyl) -H-imidazole (236 mg), and stirring was continued at 50 ^{° C.} for 18 hours. water (1.25 ml) and acetic acid (1.25 ml), and the solution was heated under reflux for 6 hours. The mixture was poured into 8% sodium bicarbonate solution (40 ml) and extracted with dichloromethane (3 × 20 ml) ) The combined, dried organic extracts were evaporated to a solid (375 mg), which was purified by FCC elution with system A. (200: 10: 1) to give the free base of the title compound as a solid (147 mg). It was dissolved in dichloromethane (3 ml) and treated with a solution of maleic acid (55 mg) in absolute alcohol, ethanol (0.5 ml). The solvent was removed in vacuo, and the residue was triturated with dry ethers (3x5 ml) to obtain the title compound (185 mg) with a melting point of 178-180 ^o C.

Elemental analysis results:
Found, C 59.0, H 5.0, N 12.85
C ₁₇ H ₁₇ FN ₄₀
C ₄ H ₄ O ₄ , C 58.9 H 4.9, N 13.1.

 The experiment in examples 2 to 9 was carried out in the same manner as in example 1, i.e., by the reaction of the corresponding lactam with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (hereinafter, it will be called compound X ) in DME in the presence of sodium hydride.

 The release from the protecting groups was carried out with acetic acid and water, followed by alkalization of the solution with a 2N sodium hydroxide solution, and not with an 8% sodium bicarbonate solution.

 The alkaline solution was then extracted with dichloromethane (or ethyl acetate in examples 4 and 8), and the combined, dried organic extracts were evaporated in vacuo. The residue was purified by FCC elution with system A (examples 2, 4, 5, 8, 9 (150: 8-1) and examples 3.6, 7 (100: 8-1) to obtain the free base of the title compound. as described in example 1, except that, in contrast to example 1, methanol was used instead of ethanol as a solvent for recrystallization, and the mixture was heated in a steam bath for 10 minutes.

 The product was obtained from this methanol solution either by evaporation to dryness in vacuo followed by trituration of the residue with ether (examples 3, 6) or recrystallization of the residue from a mixture of methanol and ether (example 7), or the product was recrystallized from methanol solution by adding ether (examples 2, 4, 5, 8, 9).

 Example 2. 2,3,4,5-tetrahydro-5,6-dimethyl -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,6-b] indole - 1- he is maleate.

 After the reaction of 2,3,4,5, -tetrahydro-5,6 dimethyl-1H-pyrido (4,3-b) indol-1-one (150 mg) with compound X (260 mg), the free base of the title compounds (120 mg). The resulting maleate was the title compound (110 mg /, t.l.c.). System A 150: 8: 1 with a refractive index of 0.3.

¹ H-NMR δ 2.35 (3H, S), 2.75 (3H, S), 3.08 (2H, t), 3.64 (2H, t), 3.93 (3H, S), 4.62 (2H, S), 6.07 (2H, S), 6.90 (1H, brd), 7.01 (1H, t), 7.88 (1H, brd), 8.73 (1H , brd).

 Example 3. 6-Bromo-2,3,4,5-tetrahydro-5-methyl-2- [5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1-he is maleate.

The reaction of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-c] indol-1-one (140 mg) with compound X (280 mg) gave the free base the named compound (130 mg). The formation of maleate corresponded to the named compound (170 mg with a melting point of 155 ^o C).

Water analysis found: 2.86 weight. ≡ 0.79 mol of H ₂ O.

 Found by analysis: C 50.1, H 4.4, N 10.7.

For C ₁₇ H ₁₇ BrN ₄ O, C ₄ H ₄ O ₄ 0.79 H ₂ O required: C 50.1, H 4.5, 11.1%
Example 4. 6.9-Difluoro-2,3,4,5-tetrahydro-5-methyl-1 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3- b] indole -1- it is maleate.

According to the reaction of 6.9-Difluoro-2,3,4,5 tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (1.0 g) with compound X (1.7 g ) a free base of the title compound (846 mg) was obtained. The formation of maleate led to the named compound (920 mg) with a melting point of 206 208 ^o C.

 Found by analysis: C 56.1, H 4.6, N 12.6.

Required for C ₁₇ H ₁₆ N ₄ O • C ₄ H ₄ O ₄ C 56.5, H 4.5, N 12.6%
Example 5. 7-fluoro-3,4,5,6-tetrahydro-6-methyl-2 - [- / 5-methyl-1H-imidazol-4-yl / methyl] azepino [4,3-b] indole -1 (2H) -one maleate.

The reaction 7-fluoro-3,4,5,6-tetrahydro-6-methylzepino [4,3-b] -indole-1- (H) -one (850 mg) with compound X (1.64 g) was obtained the free base of the title compound (358 mg). The resulting maleate corresponded to the named compound (383 mg) with a melting point of 143 145 ^o C.

Found by water analysis: 1.19 weight. _ 0.29 mol of H ₂ O.

 Found from analysis: C 59.2 H 5.6, N 12.5.

C ₁₈ H ₁₉ N ₄ OF, C ₄ H ₄ O ₄ , 0.296 H ₂ O required C 59.0, H 5.3, N 12.5%
Example 6. 2,3,4,5, -tetrahydro-5-methyl -1- / 5-methyl-1H-imidazol-4-yl / methyl] -6- / phenylmethoxy / -1H-pyrido [4.3- b] indole -1- it is maleate.

The reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indole -1-one (900 mg) with compound X (1.6 g) gave the free base of the title compound (800 mg). Part of the free base (90 mg) was treated with maleic acid to obtain the title compound (90 mg) with a melting point of 158 160 ^o C.

 T.l.c. (system A, 100 8 1), refractive index 0.2.

 Example 7. 2,3,4,5-tetrahydro-5-methyl -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile maleate. By the reaction of 2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile (550 mg) with compound X (1.3 g) was obtained the free base of the title compound (410 mg). A portion of the free base (100 mg) was treated with maleic acid to give the title compound (50 mg), t.l.c. (system A: 100 8 1), refractive index 0.2.

 Found by analysis: C 60.4, H 4.8, N 15.6.

C ₁₈ H ₁₇ N ₅ O • C ₄ H ₄ O ₄ C 60.7, H 4.9, N 16.0%
Example 8. 6-fluoro-2,3,4,5-tetrahydro-5- / 1-methylethyl / -2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4, 3-b] indole -1- it is maleate.

By the reaction of 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-b] indol-1-one (130 mg) with compound X (295 mg) the free base of the title compound (69 mg) was obtained. Part of the free base (66 mg) was treated with maleic acid to obtain the title compound (179 mg) with a melting point of 85 187 ^o C.

 Found by analysis: C 60.2, H 5.6, N 12.0.

Required for C ₁₉ H ₂₁ FN ₄ O, C ₄ H ₄ O ₄ C 60.5, H 5.5, N 12.3%
Example 9. 5- (Cyclopentylmethyl) -6-fluoro-2,3,4,5-tetrahydro -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3- b] indole -1- it is maleate.

 By the reaction of 5- (cyclopentylmethyl) -6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (222 mg) with compound X (317 mg), the free base of the title compound (100 mg).

The formation of maleate corresponded to the named compound (85 mg) with a melting point of 164 166 ^o .

 Found by analysis: C 62.5, H 5.9, N 11.0.

Required for C ₂₂ H ₂₅ FN ₄ O • C ₄ H ₄ O ₄ , C 62.9, H 5.9, N 11.3%
Example 10. 6-fluoro-2,3,4,5-tetrahydro-2 - [/ 5 methyl / -1H-imidazol-4-yl / methyl] -5- / 2-propynyl / -1H-pyrido [4, 3-b] indole -1- it is maleate.

 With stirring, a solution of 6 fluoro-2,3,4,5-tetrahydro -2 - [/ 5-methyl-1- / triphenylmethyl / -1H-imidazol-4-yl / methyl] / -1H-pyrido [4.3- b] indol -1-one (228 mg) in dry acetone (40 ml) and anhydrous potassium carbonate (116 mg) was treated with propargyl bromide (10% by volume solution in dry acetone, 1 ml) and heated under reflux night. After cooling, the excess acetone was removed in vacuo, and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with water (2x250 ml), and the combined aqueous extracts were washed with ethyl acetate (50 ml). The combined organic extracts were then concentrated in vacuo, and the residue was dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and THF (15 ml) and heated under reflux for 2 hours.

 Then, the cooled solution was made basic with a 2N sodium hydroxide solution (100 ml) and extracted with ethyl acetate (2x100 ml).

 The combined, dried organic extracts were absorbed on silica and purified by FCC elution with system A (100 8 1) to obtain the free base of the title compound (95 mg).

 It was dissolved in a minimum amount of hot dry methanol and maleic acid (32 ml) was added.

 The solution was heated and then allowed to cool.

To precipitate the title compound, ether was added, the compound was obtained in an amount of 80 mg with a melting point of 123 124 ^o C.

Found by analysis: C 60.9, H 4.7, N 12.0;
Required for C ₁₉ H ₁₇ FN ₄ O, C ₄ H ₄ O ₄ C 61.1, H 4.7, N 12.4%
Example 11. 6-fluoro-2,3,4,5-tetrahydro-2 - [/ 5-methyl 1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indol-1-one maleate.

 Solution 6-fluoro-2,3,4,5-tetrahydro -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -5- / phenylmethoxymethyl / -1H-pyrido [4,3-b] indole -1-one (175 mg) in absolute ethanol (10 ml) and acetic acid (2.5 ml) were hydrogenated at room temperature and atmospheric pressure over the catalyst, 10% palladium supported on coal (50% aqueous paste, 45 mg) in absolute ethanol (2 ml) over 20 hours. Then a larger amount of catalyst (45 mg) was added and stirring was continued for 20 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3x25 ml).

 The combined, dried organic extracts were evaporated to give an oil (130 mg), which was purified by FCC, eluting with system A (150: 10: 1) to give the free base of the title compound (102 mg). It was dissolved in ethanol (2 ml) and treated with a solution of maleic acid (42 mg) in ethanol (0.5 ml).

The solvent was removed in vacuo and the residue was triturated with dry ether (5x5 ml) to give the title compound (120 mg) with a melting point of 186
188 ^o C.

 Found from analysis: C 57.8, H 4.7, N 13.2.

Required for C ₁₆ H ₁₅ FN ₄ OC ₄ H ₄ O ₄ C 58.0, H 4.6, N 13.5%
Example 12. 2,3,4,5-tetrahydro-6-hydroxy -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1- he is maleate.

 Solution 2,3,4,5-tetrahydro -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -6- / phenylmethoxy / -5- [(phenylmethoxy) methyl] -1H-pyrido [4 , 3-b] indole -1-one (600 mg) in absolute ethanol (80 ml) and glacial acetic acid (4 ml) were hydrogenated at room temperature and atmospheric pressure over a catalyst 10% palladium supported on coal (50% aqueous paste, 100 mg) for 24 hours

 Then the mixture was filtered, and the filtrate was concentrated in vacuo.

 The residue was treated with 8% sodium bicarbonate solution (150 ml) and filtered. The filtered solid was then washed with water (100 ml), dissolved in ethanol (200 ml) and concentrated in vacuo to obtain a solid (320 mg) of a substance that was purified by FCC, eluting with system A (100: 8: 1) to give the free base named compounds (100 mg). A solution of the free base (100 mg) in methanol (20 ml) was treated with maleic acid (39 mg).

 The solution was heated in a steam bath for 10 minutes and concentrated in vacuo.

A solution of the residue in methanol (2 ml) was treated with ether (80 ml) to obtain the title compound (100 mg) with a melting point of 130 ^{° C.} (system A, 100: 8: 1) (2 elution), refractive index 0.3 .

 Example 13. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1-he hydrochloride.

Solution 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole - 1-one (260 mg) in methanol (10 ml) was treated with ethereal hydrogen chloride, and the mixture was then concentrated in vacuo. The residue was triturated with ether (15 ml) to give the title compound (230 mg) as a solid with a melting point of 275-278 ^° C.

When analyzing water, it was found: 3.73% by weight. _ 0.075 mol of H ₂ O.

 Analysis found: C 55.8, H 5.3, N 15.2.

Required for C ₁₇ H ₁₇ FN ₄ O • HCL • 0.75 H ₂ OC 56.3, H 5.4, N 15.4%
Example 14. 6-fluoro-2,3,4,5-tetrahydro 5 methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl) -1H-pyridino (4,3, -c] indole - 1- he is benzoate.

Solution 6-fluoro-2,3,4,5 tetrahydro-5methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indol-1-one (170 mg) in methanol (10 ml) was treated with benzoic acid (66 mg). To precipitate a solid precipitate, ether was added, then the precipitate was filtered to obtain the title compound (220 mg) with a melting point of 169-171 ^o C.

 Found from the analysis: C 6.3, H 5.4, N 12.8.

Required for C ₁₇ H ₁₇ FN ₄ O • C ₇ H ₆ O ₂ C 66.3, H 5.3, N 12.9%
Example 15. 6-fluoro-2,3,4,5-tetrahydro-5-methyl -2- [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indol-1-one.

A solution of 6-fluoro-2,3,4,5 tetrahydro-5-methyl-1H-pyrido [4,3-c] indol-1-one (100 mg) in N-methylpyrrolidinone (10 ml) was treated with 4-toluenesulfonic acid monohydrate (17 mg) and 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg). The mixture was then heated to 125 ^{° C.} for 18 hours, during which time three portions of 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg) were added over 1, 2 and 3 hours, respectively. Then, the solution was poured into an 8% sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3x100 ml). The combined extracts were concentrated in vacuo and N-methylpyrrolidinone was distilled off at 100 ^° C. The residue was purified by FCC elution with system A (200: 8: 1) to obtain the title compound (100 mg) (system A, 100: 8: 1), the refractive index of 0.3.

¹ H-NMR δ 2.36 (3H, s), 3.12 (2H, t), 3.67 (2H, t), 3.90 (3H, s), 4.66 (2H, s), 6.07 (2H, s), 6.95-7.2 (2H, m), 7.80 (1H, d), 8.80 (1H, s).

 Example 16. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1-one.

 4- [2- / 2-fluorophenyl / -2-methylhydrazino] -5,6-dihydro -1 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -2 (1H) -pyridinone (65 mg ) treatment with concentrated sulfuric acid (0.5 mo) and left to stand for 5 minutes. Then the solution was neutralized with an 8% sodium bicarbonate solution (30 ml) and extracted with a mixture of dichloromethane: ethanol (5: 1) (3 × 15 ml). The combined, organic dried extracts were evaporated to give an oil (52 ml), which was purified by FCC elution with system A (200: 10: 1) to obtain the title compound (3 mg) (system A, 200: 10: 1), refractive index 0, 28.

 The H-NMR data obtained for this substance were comparable with the data obtained for the product of example 15.

 Example 17. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido (4.3-b] indole -1-he.

A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 4-methyloxazol-5-yl / methyl] -1H-pyrido [4,3-b] indole -1-one ( 180 mg) and formamide (20 ml) were heated to 180 ^{° C.} for 18 hours. Then the solution was cooled to 0 ^{° C.} , diluted with water (100 ml) and extracted with dichloromethane (3x100 ml). The combined extracts were concentrated in vacuo and purified by FCC elution with system A (100: 8: 1) to obtain the title compound (110 mg) with a melting point of 230-233 ^o C.

 The H-NMR data obtained for this substance were comparable with the data obtained for the product of example 15.

 Example 18. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1-he.

 With stirring, a solution of 6 fluoro-2,3,4,5-tetrahydride -2 - [/ 5-methyl-1- (triphenylmethyl) -1H-imidazol -4-yl / methyl] -1H-pyrido [4.3-c ] indol -1-one (100 mg) in dry DMF (15 ml) was treated with sodium hydride (73.2% dispersion in oil, 10.5 mg) and it was stirred in a stream of nitrogen at room temperature for another 20 min. Methyl iodide (2.3 vol. Solution in dry DMF, 1 ml) was added and the solution was stirred for another 20 minutes. Then the reaction mixture was added to water (100 ml) and was extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (2 x 100 ml), dried and concentrated in vacuo to obtain a solid.

This solid was dissolved in THF (10 ml), water (10 ml) and glacial acetic acid (10 ml) and heated under reflux for 3 hours. THF was removed in vacuo and the remaining solution was added to 2N sodium hydroxide pH -> 14 and extracted with ethyl acetate (3x50 ml). The combined organic extracts were adsorbed on silica and purified by FCC elution with system A (100 8 1) to obtain the title compound (45 mg) with a melting point of 234 235 ^o C.

 The H-NMR data obtained for this substance were comparable with the data obtained for the product of example 15.

 Example 19. 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl-1H-imidazol-4-yl / methyl] -1H-pyrido [4,3-b] indole -1-one.

Solution phenylmethyl 4 - [/ 6-fluoro-2,3,4,5 tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3] -indol-2-yl / methyl] -5-methyl-1H imidazole -1-carboxylate (100 mg) in ethanol (20 ml) and 2N hydrochloric acid (10 ml) were heated in a steam bath for 10 minutes. The cooled reaction mixture was then added to water (5 ml) and 2N sodium hydroxide (20 ml) and extracted with ethyl acetate (2x75 ml). The combined organic extracts were adsorbed on silica and purified by FCC, eluting with system A (100 8 1) to obtain a solid, which was triturated with ether to give the title compound (50 mg) with a melting point of 232,233 ^° C. Data ¹ H-NMR for this substance were comparable with the data obtained for the product of example 15.

 The following example illustrates a pharmaceutical composition according to the present invention containing 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [/ 5-methyl -1H-imidazol-1-yl / methyl] -1H-pyrido [4,3-b] indole -1-one as the active ingredient. Physiologically acceptable salts and / or solvates of this compound and other compounds of formula (I) and their physiologically acceptable salts and / or solvates can be formed in a similar manner.

 Oral Tablets / Tablets may be prepared by conventional methods such as direct compression or wet granulation. Sorting is carried out by a method suitable for direct pressing.

 The tablets may be coated with a film made from suitable film-forming substances, such as hydroxypropyl methylcellulose, using standard coating techniques. In addition, tablets can be coated with sugar.

Direct pressing
Mg tablet / tablet
Active ingredient 1.00
Anhydrous Lactose USNF 79.00
Microcrystalline Cellulose USNF 19.55
Magnesium Stearate BP 0.45
Compressed tablet weight 90.00
The active ingredient is passed through a sieve with a mesh diameter of 60 mesh, mixed with anhydrous lactose, microcrystalline cellulose and magnesium stearate. The resulting mixture is compressed into tablets using a suitable stamping and grinding machine with a diameter of 5.5 mm stamped tablets.

 Tablets that differ in strength from the above can be prepared by changing the ratio of active ingredient to lactose or the weight of the compressed tablets and using suitable stamping sets.

 Biological data.

 The potent and selective 5-HT antagonism at 5-HT3 receptors exhibited by the compounds of the present invention can be demonstrated in vitro by their ability to inhibit 3- (5 methyl-1H-imidazol-4-yl) -1- [1- (methyl-t3 ) -1H-indole-2-y1] -1-propanol binding in the entorhinal cortex of the rat brain homogenized by the following general method described by Kilpatrick et al. In Nature, 1987, 330, 746. The result of such tests is expressed by pKi values. The compounds of examples 1 and 3 12 give pKi values greater than 9.0.

 The antagonism of responses induced by 5-HT at 5-HTZ receptors by the compounds of the invention can be evaluated in vivo by determining the effect of these compounds on the 5-HT produced bezold-Jarish reflex in a cat. This test is performed in accordance with the method described by D.P. Collins and D.H. Fochyun, British Journal of Pharmacology, 1983, 80, 570F. The results are presented below as the duration of DR5, the compound was administered intravenously at a dose of 1 μg / kg. DR5 represents the approximate dose required to obtain a five-fold mixing to the right of the response curve for the dose of 2-methyl-5-HT.

Compound Example Duration DR5
1 52
2 87
4 63
The toxicity of the compounds can be assessed by intravenous administration of the mouse. For example, the compounds of examples 1, 3, 8, 9, and 10 did not produce harmful effects when a dose of 3 mg / kg was administered.

Claims (4)

1. Lactam derivatives of the general formula I

where I _m represents an imidazole group of the general formula

R ¹ represents hydrogen or a group selected from C ₁ -C ₆ -alkyl, -CH ₂ C ₂ C ₅ -alkynyl and C ₃ - C ₇ -cycloalkyl-C ₁ C ₄ alkyl;
n 2 or 3;
Q represents a halogen or a group selected from hydroxy-, phenyl-C ₁ C ₃ -alkoxy-, C ₁ C ₆ alkyl and cyano-;
Q ¹ represents hydrogen or fluorine,
or their physiological acceptable salts or solvates. 2. The compound according to claim 1, characterized in that R ¹ represents hydrogen, or methyl, isopropyl, propin-2-yl, or cyclopentylmethyl group; Q represents fluorine, or bromine, or hydroxyl, phenylmethoxy, methyl or cyano; Q ¹ represents hydrogen, and n 2.  3. The compound according to claim 1, characterized in that it is 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] - 1H-pyrido (4,3-b) indol-1-one or a physiologically acceptable salt or solvate thereof.  4. The compound according to claim 1, characterized in that it is selected from 2,3,4,5-tetrahydro-5,6-dimethyl-2 [(5-methyl-1H-imidazol-4-yl) methyl] -1H -p-irido (4,3-b) indol-1-one, 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazole-4 -yl) methyl] -1H-pyrido (4,3-b) indol-1-one, 6-fluoro-2,3,4,5-tetrahydro-2- [(5-methyl-1H-imidazole- 4-yl) methyl] -5- (2-propynyl) -1H-pyrido (4,3-b) indol-1-one, 2,3,4,5-tetrahydro-5-methyl-2- [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-1H-pyrido (4,3-b) indole-6-carbonitrile, 6-fluoro-2,3,4,5-tetrahydro -5- (1-methylethyl) -2 - [(5-methyl-1H imidazol-4-yl) methyl] -1H-pyrido (4,3-b) indol-1-one, or their physiologically acceptable salts solvates.