RU2067980C1 - Derivatives of lactam and pharmaceutical composition being antagonist of 5-oxytraptamine(5-ht) for 5-ht3 receptors or their pharmaceutically acceptable salts and solvates - Google Patents

Abstract

FIELD: organic chemistry, medicine. SUBSTANCE: desired compounds have common formula

where 1m represents imidazole group having formula

, R¹ represents atom of hydrogen or C_1-4 alkyl, C_3-4 alkenyl, C_3-4 alkynyl, C_5-6 cycloalkyl, C_5-6 cycloalkylmethyl, benzyl, phenylmethoxymethyl or N,N-diC_1-3 alkylcarboxamino group. EFFECT: improves quality of desired product. 1 tbl

Description

 The present invention relates to lactam derivatives, pharmaceutical compositions containing these derivatives, and their medical use.

In particular, the present invention relates to compounds that are potential and selective antagonists of 5-hydroxytryptamine (5-HT) at 5HT receptors located at the ends of primary afferent nerves. Receptors of this type are currently referred to as 5-HT ₃ receptors and are also present in the central nervous system. 5-HT are widely distributed in the nerve pathways in the central nervous system, and disruption of these 5-HT pathways contains behavioral syndromes such as mood, psychomotor activity, appetite, and memory.

где Im представляет имидазольную группу формулы

и R¹ представляет атом водорода или С_1-4(алкил) (например, метил или н-пропил), С_3-4алкенил (например, проп-2-енил), С_3-4алкинил (например, проп-2-инил), С_5-6циклоалкил (например, циклопентил), С_5-6циклоалкиметил (например, циклопентилметил), бензил, фенилметоксиметил, N,N-диС_1-3алкилкарбоксамидо (например, N,N-диметилкарбоксамид) группу и его физиологически приемлемые соли и сольваты.The present invention provides tricyclic lactams of the general formula (I)

where Im represents an imidazole group of the formula

and R ¹ represents a hydrogen atom or C _1-4 (alkyl) (e.g. methyl or n-propyl), C _3-4 alkenyl (e.g. prop-2-enyl), C _3-4 alkynyl (e.g. prop-2 -inyl), C _5-6 cycloalkyl (e.g. cyclopentyl), C _5-6 cycloalkylmethyl (e.g. cyclopentylmethyl), benzyl, phenylmethoxymethyl, N, N-diC _1-3 alkylcarboxamido (e.g. N, N-dimethylcarboxamide) group and its physiologically acceptable salts and solvates.

 Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed by organic and inorganic acids, for example dichlorides, hydrobromides, sulfates, alkyl or aryl sulfates (e.g. methanesulfonates or n-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 their racemic mixtures and all geometric isomers of compounds of formula (I), are encompassed by the present invention.

When R ¹ represents a C _3-4 alkenyl or a C _3-4 alkynyl group, the double or triple bond may not be adjacent to the nitrogen atom.

A partially preferred group of compounds of formula (I) is a group wherein R ¹ is methyl, n-propyl, prop-2-ynyl cyclopentyl, cyclopentmethyl, benzyl or N-dimethylcarboxamido.

The potential and selective 5HT antagonism at 5-HT ₃ receptors due to the compounds of the present invention is demonstrated by their ability to inhibit 3- (5-methyl-1H-imidazol-4-yl) -1 - / - 1 (methyl tert) -1H-indole -3-yl / -propane bond in rat entrogenic cortical homogenates (the general procedure is described by G. Kilpatric et al in Nature, 1987, 330, 746) and / or their ability to block 5-HT-induced depolarization of an isolated rat vagus nerve.

In addition to their activity as a potential and selective 5-HT antagonist at 5-HT ₃ receptors, some of the compounds of the present invention have the advantage of increased duration of action.

 In particular, the preferred compound of formula (I), taking into account its potency and duration of action, is 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. Preferred salts of this compound are hydrochlorides and maleates.

The compounds of formula (I), which counteract the effect of 5-HT on 5-HT ₃ receptors, are useful in the treatment of diseases such as psychopathic disorders (schizophrenia and mania); anxiety and nausea and vomiting, in particular those associated with chemotherapy and cancer radiotherapy. The compounds of formula (I) are also useful in the treatment of gastric stasis, symptoms of gastrointestinal dysfunction such as those associated with dyspepsia, peptic ulcer, inflammation of the esophagus, flatulence and irritable bowel syndrome, migraine and pain. The compounds of formula (I) may also be useful in the treatment of drug and substance dependence in addiction, depression, dementia and other mental disorders.

 Accordingly, the present invention also provides a pharmaceutical composition that includes at least one compound selected from compounds of general formula (I) and their pharmaceutically acceptable salts and solvates (e.g. hydrates) for use in medicine or veterinary medicine and prepared for use in any conventional manner.

 Such compositions can be prepared in the usual way using one or more physiologically acceptable carriers and / or receptive agents.

 Thus, the compounds of the present invention can be prepared for oral, alkaline, parenteral or rectal administration, or in a form suitable for inhalation or by injection (by mouth or nose).

 The proposed dose of the compounds of the present invention for administration to humans (approximately 70 kg) is 0.001 to 100 mg, preferably 0.01 to 50 mg, more preferably 0.1 to 20 mg of the active ingredient per unit dose, expressed as the mass of free base that could be administered, for example , 1 4 times a day. It is understood that the usual dosage changes may be made depending on the age and condition of the patient. The dosage will also depend on the route of administration.

The compounds of general formula (I) and their physiologically acceptable salts or solvates can be prepared by the usual methods described below. In the following description, the groups R ¹ and Im are similar to those described for the compounds of formula (I).

или его защищенного производного, с соединением формулы (III)
LCH₂-Im (III)
или его защищенным производным, где L представляет уходящий атом или группу, такие как атом галогена (например, хлор, бром или йод) или ацилоксигруппу (например, трифторацетилокси или ацетокси) или сульфонилоксигруппу (например, трифторметансульфонилокси, n-толуолсульфонилокси или метансульфонилокси), сопровождаемым, если необходимо, удалением любых защитных групп. L предпочтительно атом галогена (например, атом хлора).According to the method, a compound of general formula (I) can be obtained by alkylation of a compound of formula (II)

or a protected derivative thereof, with a compound of formula (III)
LCH ₂ -Im (III)
or a protected derivative thereof, where L represents a leaving atom or group, such as a halogen atom (e.g. chlorine, bromine or iodine) or an acyloxy group (e.g. trifluoroacetyloxy or acetoxy) or a sulfonyloxy group (e.g. trifluoromethanesulfonyloxy, n-toluenesulfonyloxy or methanesulfonyloxy), followed by if necessary, removing any protecting groups. L is preferably a halogen atom (e.g., a chlorine atom).

The reaction can be carried out in an inert solvent such as ether (e.g. dimethoxyethane, diglyme or tetrahydrofuran), saturated amide (e.g. dimethylformamide or N-methylpyrrolidone), aromatic hydrocarbon (e.g. toluene), ketone (e.g. acetone) or dimethyl sulfoxide temperature from ambient 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. sodium or potassium hydroxide).

 The term "alkylation" in accordance with the general method includes the introduction of groups such as cycloalkyl, alkenyl or benzyl groups.

Thus, for example, a compound of formula (I) in which R ¹ is C _1-4 alkenyl, C _3-4 alkynyl, C _5-6 cycloalkyl, C _5-6 cycloalkylmethyl, benzyl or phenylmethoxymethyl group can be obtained by alkylation of a compound of formula ( I), in which R ¹ represents a hydrogen atom using conventional procedures, for example, as described in the published description of European patent N242973. Thus, the reactions can be carried out using an appropriate alkylating agent of the formula R ¹ (where R ¹ is the group to be introduced and the Z-leaving group or atom), preferably in the presence of a base.

According to another example of a general process, a compound of formula (I), wherein R ¹ is N, N-di C _1-3 alkylcarboxamide group, can be obtained by acylation of a compound of formula (I), where R ¹ is hydrogen. These reactions can be carried out using the appropriate acylating agent in accordance with conventional procedures, for example, as described in published European patent specification N210840.

 It should be recognized that in the above transformations it may be necessary or desirable to protect any sensitive groups in the compound molecule in order to avoid undesirable side reactions. For example, it may be necessary to protect indole and / or imidazole azot atoms, for example, arylmethyl (e.g. trityl), arylmethoxymethyl (e.g. phenylmethoxymethyl), alkyl (e.g. tert-butyl), alkoxymethyl (e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) or sulfonyl group (e.g. n-toluenesulfonyl).

 Thus, in accordance with the general method, the compound of general formula (I) can be obtained by removing any protecting groups from the protected form of the compound of formula (I), deprotection can be carried out by conventional methods, such as described in Protective Groups in organic. Synthesis by T.W. Greene (John Wiley and Sons, 1981).

 For example, an arylmethoxymethyl-N-protecting group can be cleaved by hydrogenolysis in the presence of a catalyst (e.g., palladium on charcoal). The trityl group can be cleaved off by acid hydrolysis (for example, using dilute hydrochloric or acetic acid). The alkoxyalkyl group can be removed using mineral acid (for example, dilute hydrochloric or hydrobromic acid). The acyl group can be removed by hydrolysis under acidic or basic conditions (for example, using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide). The sulfonyl group can also be removed by basic or acid hydrolysis, and the N, N-dimethylaminosulfonyl group can also be removed (for example, from the imidazolazole atom) by photolysis.

или его защищенного производного. Перегруппировку Бекмана можно провести, используя обычные способы, например, используя кислоту (например, полифосфорную или серную кислоту или смесь из соляной, уксусного ангидрида и уксусной кислоты) в инертном растворителе, таком как простой эфир (например, диоксан), амид (например, диметилформамид) или углеводород (например, толуол или циклогексан) при высокой температуре, например, 50 120^oС).The compounds of formula (II) can be obtained by Beckman rearrangement of the oxime of formula (VI)

or a protected derivative thereof. Beckman rearrangement can be carried out using conventional methods, for example, using an acid (e.g. polyphosphoric or sulfuric acid or a mixture of hydrochloric, acetic anhydride and acetic acid) in an inert solvent such as ether (e.g. dioxane), amide (e.g. dimethylformamide ) or a hydrocarbon (e.g., toluene or cyclohexane) at high temperature, e.g., 50-120 ^{° C.} ).

Alternatively, the hydroxide group of an oxime of formula (VI) can be converted to a leaving group, such as chloride (using, for example, phosphorus pentoxide) or hydrocarbyl sulfonate (e.g., mesylate or tosylate) or trifluoroacetate (using conventional acylation methods). Subsequent heating at a temperature of 20 to 150 ^° C. in an inert solvent, as described above, gives a compound of formula (II).

или его защищенного производного, используя обычные методы, например, используя гидроксиламиногидрохлорид в растворителе, таком как пиридин.Compounds of formula (VI) can be prepared from the corresponding tricyclic ketone of formula (VII)

or a protected derivative thereof, using conventional methods, for example, using hydroxylamino hydrochloride in a solvent such as pyridine.

 The compounds of formula (III) or its protected derivatives are either known or can be obtained, for example, by the methods described in the description of the Federal Republic of Germany patent N3740352.

 Compounds of formula (VII) can be prepared, for example, by a method or methods similar to those described by K. Iida etal in Org. Chem. 1980, 45, 2983.

 Where it is necessary 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) in the form of a free base with an appropriate acid, preferably with an equivalent amount, in an acceptable solvent, such as an alcohol (e.g. ethanol or methanol), aqueous alcohol (e.g. aqueous ethanol), a halogenated hydrocarbon (e.g. dichloromethane), an ester (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran).

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

 The individual enantiomers of the compounds of the present invention can be obtained by separating a mixture of enantiomers (for example, a racemic mixture) using conventional means, such as an optically active resolving acid; see, for example, "Stereo Chemistry of Carbon Compaunds" by E.I. Elied (M. Grow Hill, 1962) and Tables of Resolving Agents "by S.H. Wiler.

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

The present invention is further illustrated by the following intermediates and examples. All temperatures are given in degrees Celsius. Thin layer chromatography (TLC) was performed on silica and flash column chromatography (TLC) on silica (Merck 9385). The solvent of system A used for chromatography means a solution of dichloromethane: ethanol, 0.88 ammonia. The organic extracts were dehydrated, where indicated, over magnesium or sodium sulfate. The following abbreviations are used: DMF-dimethylformamide, THF-tetrahydrofuran, DMZ-dimethoxyethane. ¹ H-NMR spectra were obtained for dilute solutions in d ₆ -dimethyl sulfoxide at 250 MHz.

Intermediate I
3,4-dihydro-4-methylcyclopent (b) indol-1 (2H) -onoxime.

3,4-dihydro-4-methylcyclopent (b) -1 (2H-one) (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60 ^{° C. for} 18 hours and cooled. The reaction mixture was evaporated in vacuo to a residue, to which 8% sodium bicarbonate (150 ml) was added. Extraction with ethyl acetate (300 ml) gave a suspension in the organic layer; this layer and the corresponding solid residue were separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solids) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to 50 ^° C. The residue was absorbed from the solution on silica gel ICC and fed to an ICC column. Elution with ethyl acetate (3 × 10% methanol) provided the title compound (1.69 g), mp 219 - 224 ^° (decomposition).

Intermediate 2
2,3,4,5-tetrahydro-5-methyl-1H-pyrido (4,3-b) indol-1-one
3,4-dihydro-4-methylcyclopent (b) indol-1 (2H) onoxime (1.53 g), polyphosphoric acid (40 g) and dioxane (15 ml) were heated at 110-120 ^{° for} 2.2 hours under nitrogen . The reaction mixture was cooled and treated with 2n. sodium carbonate solution (1l). The suspension was extracted with ethyl acetate (4x400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g), which was recrystallized from ethyl acetate / cyclohexane. This solid was purified by ICC, eluted with system A (200: 10: 1), and a solid (1.26 g) was obtained, which was recrystallized from ethanol (to obtain the target compound) (960 mg), etc. 234 238 ^o .

Intermediate 3
5,6-dihydro-4- (phenylamino) -1 (2H) -pyridinone.

A mixture of 2,4-dioxopiperidine (1.13 g) and aniline (930 mg) was heated at 120 ^° under a stream of nitrogen for 15 minutes. The resulting solid was triturated with ether and filtered to obtain the desired compound (1.74 g), i.e. 235 238 ^o .

Intermediate 4
2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indol-1-one
A solution of 5,6-dihydro-4- (phenylamino) -1 (2H) pyridinone (1.5 g) and palladium acetate (150 mg) in dry DMF (50 ml) was treated with copper acetate (3.2 g) and the resulting the mixture was heated under nitrogen at 120-130 ^{° for} 1.5 hours. This mixture was then concentrated in vacuo to give a solid, which was triturated with 2N. hydrochloric acid (250 ml). This acid was decanted and the remaining solid was extracted with ethyl acetate for 18 hours. The decanted acid was converted to base with 2N. sodium hydroxide and was extracted with ethyl acetate (3x100 ml). These organic extracts were combined with the previous ethyl acetate extracts and absorbed on silica. Purification by ICC with system A (100: 8: 1) gives the target compound (874 mg), etc. 212 215 ^o .

Intermediate 5
2,3,4,5-tetrahydro-5 - / (phenylmethoxy) methyl / -1H-pyrido (4,3-b) indol-1-one.

A solution of 2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indol-1-one (1.12 g) in dry DMF (60 ml) was treated with sodium hydride (60% dispersion in oil, 480 mg) and the resulting mixture was stirred under nitrogen until the rapid evolution of gas ceased. This mixture was then cooled to 0 ^° and dibenzyl ether (chloromethyl) (10% w / v solution in DMF; 08.835 ml) was added over 10 minutes. Stirring continued for another 5 minutes and then water (10 ml) was added. The reaction mixture was concentrated in vacuo to give an oil, which was dissolved in ethyl acetate (100 ml) and washed with water (3x100 ml). The organic phase was dehydrated and absorbed on silica ICH. Purification by ICC and elution with system A (150: 8: 1) gave the target compound (1.1 g), etc. 133 135 ^o .

 Intermediates 6 and 7 were obtained analogously to intermediate 5, i.e. treatment with 2,3,4,5-tetrahydro-1H-pyrido (4, 3-b) indol-1-one with sodium hydride, followed by treatment with an appropriate alkylating agent. Isolation and purification of products are described in intermediate 5, unless otherwise specified.

Intermediate 6
2,3,4,5-tetrahydro-5- (phenylmethyl) -1H-pyrido (4,3-b) indol-1-one.

2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 179 mg) and then mixed with benzyl bromide (513 mg ) at room temperature for 30 minutes. The ICH was purified by elution with dichloromethane: ethanol in the ratio (80: 1) to obtain the target compound (347 mg), etc. 209 212 ^o .

Intermediate 7
5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indol-1-one.

2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indol-1-one (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then mixed with cyclopentyl (methyl sulfonate) (909 mg) at room temperature for 7 days. The solid (570 mg) obtained by ICC was further purified by slow evaporation from a solution in methanol to obtain the target compound, etc. 179 181 ^o .

Intermediate 8
2,3,4,5-tetrahydro-2-5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / methyl / -1H-pyrido (4,3-b) indol-1-one.

A solution of triphenylmethyl chloride (3.36 g) in dry DMF (40 ml) was added dropwise to a stirred solution of 2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido (4,3-b) indol-1-one (2.8 g) in dry DMF (50 ml) containing triethylamine (1.52 g). When the addition was complete, stirring continued all night. This mixture was then poured into water (1000 ml) and the resulting suspension was extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with water (2x500 ml), dehydrated and concentrated on silica. ICC elution with system A (100: 8: 1) gives the target compound (4.3 g), etc. 235 236 ^o C.

Intermediate 9
5,6-dihydro-4-methoxy-1 - / (5-methyl-1- (triphenylmethyl)) - 1H-imidazol-4-yl) / - 2 (1H) -pyridinone.

Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry DMF (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2 (1H) -pyridinone (1.27 g) in dry DMF (20 ml) was slowly added. The resulting suspension was stirred at 20 ^° C. for 1 hour. Added 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) - 1H-imidazole (3.72 g) in dry DMF (50 ml) and after reducing the initial reaction, the mixture was heated to 50 ^o 4 hours and then cooled. Methanol (5 ml) was added dropwise and the solvent was removed in vacuo. An aqueous sodium bicarbonate solution (300 ml) was added to the residue, and the resulting solution was extracted with dichloromethane (2 × 300 ml), dried, evaporated in vacuo to give an oil, which was purified by ICLC elution with system A (200: 8: 1). Received the target compound (2.84 mg), etc. 181 184 ^o .

Intermediate 10
2,4-dioxo-1 - / (5-methyl-1H-imidazol-4-yl) methyl / piperidine.

To a solution of 5,6-dihydro-4-methoxy-1 - / (5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / methyl / -2 (1H-pyridinone (500 mg) in THF (4 ml) hydrochloric acid (5M; 1 ml) was added and the mixture was stirred at 50 ^° C. for 1 hour, the Solvent was removed in vacuo, triethylamine (1 ml) was added and the mixture was again evaporated to dryness. Elution ICH residue ethyl acetate: methanol: triethylamine (8: 4: 1) gives the target compound (139 mg), etc. 100 106 ^o C (decomposition).

Intermediate 11
5,6-dihydro-1 - / (5-methyl-1H-imidazol-4-yl) methyl / -4- (2-methyl-2-phenylhydrazino) -2 (1H) -pyridinone.

 2,4-dioxo-1 - / (5-methyl-1H-imidazol-4-yl) methyl / piperidine (20 mg) was dissolved in ethanol (2 mg) and N-methylphenylhydrazine (26 mg) was added. The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was purified by ILC elution with system A (75: 8: 1) and the target compound (24 mg) was obtained as a solid, TLC (system A, 75: 8: 1), Rf 027.

Intermediate 12
N, N-5-trimethyl-4 - // (trimethylsilyl) oxy / methyl / -1H-imidazole-1-sulfonamide.

 A suspension of 4- (oxymethyl) -5-methylimidazole hydrochloride (14.9 g) in dry dichloromethane (500 ml) containing triethylamine (50 mg) was treated with trimethylsilyl chloride (21.7 g) and the reaction mixture was stirred overnight at room temperature. Dimethyl sulfamoyl chloride (14.3 g) was added and the reaction mixture was again stirred overnight at room temperature. The resulting suspension was filtered and the collected solid was washed with dichloromethane (100 ml). The filtrate was concentrated on silica and purified by ICH elution with hexane: ether (4: 1), which afforded the target compound as an oil (7.2 g), TLC (ether), Rf 0.5.

Intermidiate 13
4- (oxymethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide.

A solution of N, N, 5-trimethyl-4 - // (trimethylsilyl) oxy / methyl1H-imidazole-1-sulfonamide (2.59 g) in dry THF (50 ml) was treated with a solution of tetrabutylammonium fluoride (1 M solution in THF; 10 ml ) and THF were immediately removed in vacuo. The residue was partitioned between water (100 ml) and dichloromethane (100 ml) and the aqueous layer was extracted with dichloromethane (100 ml). The combined dehydrated organic fractions were concentrated and the target compound (1.63 g) was obtained as a solid, the like. 134 136 ^o C.

Intermediate 14
4- (chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide.

A suspension of 4- (oxymethyl)) - N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (2.86 g) in dry dichloromethane (200 ml) containing DMF (0.5 ml) was treated dropwise with a solution thionyl chloride (1.178 g) in dichloromethane (10 ml). The reaction mixture was cooled on ice during the addition and covered with nitrogen. When the addition was completed (after about 5 minutes), stirring continued at 0 ^{° for} another 30 minutes. Then water (200 ml) was added and the organic phase was isolated, washed with 8% sodium bicarbonate (100 ml), dried, concentrated, and the target compound (2.3 g) was obtained as a solid, etc. 115 118 ^o C.

Intermediate 15
5,6-dihydro-4 - / (2-iodophenyl) methylamino / -2- (1H) -pyridinone.

A mixture of 2-iodo (N-methyl) aniline (1.17 g) and 2,4-dioxopiperidine (565 mg) was heated under nitrogen vapor for 7 hours at 110-120 ^° C. After cooling, the reaction mixture was dissolved in methanol and the solution was absorbed on silica ICH by elution with system A (150: 8: 1) and the target compound (1.03 g) was obtained, etc. 163 164 ^o C.

Intermediate 16
N, N, 5-trimethyl-4- / 1,2,3,6-tetrahydro-4 - / (2-iodophenyl) methyl-amino / -6-oxo-1-pyridine / methyl-1 Nimidazole-1-sulfonamide .

A suspension of 5,6-dihydro-4 - / (2-iodophenyl) methylamino / -2- (1H-pyridinone) (984 mg) in dry DMF (50 ml) was treated with sodium hydride (60% dispersion in oil; 140 mg) and the mixture was stirred under nitrogen for 6 hours. Then 4- (chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (832 mg) was added and the resulting mixture was stirred at 60 ^° overnight. After cooling, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate (2x50 ml). The combined, dehydrated extracts were concentrated, the resulting solid residue was purified by ICH elution with system A (150: 8: 1) to obtain the target compound (712 mg), TLC, system A (150: 8: 1), Rf 0.41.

Intermediate 17
N, N, 5-trimethyl - / (2,3,4-tetrahydro-5-methyl-1-oxo-1H-pyrido / 4,3-b / indo-2-yl) methyl / -1H-imidazole-1 sulfonamide.

 A solution of dimethylsulfamoyl chloride (0.107 ml) in dry dichloromethane was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2 / (5-methyl-1H-imidazol-4-yl) methyl / -1Npyrido / 4, 3-b / indol-1-one (0.294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) under nitrogen and the mixture was heated at reflux for about 24 hours. After cooling, the solution was concentrated on silica by ICC, purified by ICH by elution with system A (150: 8: 1), and an oil was obtained. This oil was triturated with ether to give a solid, which was further purified by slow evaporation from a solution in ethyl acetate and the desired compound (122 mg) was obtained, TLC (system A, 100: 8: 1), Rf 0.43.

Intermediate 18
Phenylmethyl 5-methyl-5 / (2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido / 4,3-b / indol-2-yl) methyl-1H-imidazol-1- carboxylate.

A solution of benzyl chloroformate (0.28 ml) in dichloromethane (10 ml) was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl- 1Npyrido / 4,3-b / indol-1-one (294 mg) and triethylamine (0.5 ml) in dichloromethane (30 ml) at 20 ^° under nitrogen and the mixture was stirred overnight. Then it was concentrated on silica by ICC, purified by ICC elution with system A (100: 8: 1) and the target compound (62 mg) was obtained, TLC (system A, 100: 8: 1), Rf 0.50.

Intermediate 19
2,3,4,5-tetrahydro-2 - // 1- (methoxymethyl) -5-methyl-1H-imidazol-4-yl / methyl / -5-methyl-1H-pyrido / 4,3-b / - indol-1-one 2-3-4-5-tetrahydro-2 - // 1- (methoxymethyl) -4-methyl-1H-imidazol5-yl / methyl // - 5-methyl-1H-pyrido / 4.3 -b / indol-1-one.

A solution of chloromethyl methyl ether (0.26 ml) in dichloromethane (10 ml) was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2 / (5-methyl-1H-imidazol-4-yl) methyl / -1Npyrido / 4,3-b / indol-1-one (500 mg) and triethylamine (0.49 ml) in dichloromethane (50 ml) at 20 ^° under nitrogen and the solution was stirred for 4 days. Then it was divided into parts between dichloromethane (50 ml) and sodium bicarbonate solution (2x50 ml). The organic extract was dehydrated, concentrated on silica ICH, then purified ICH by elution with system A (100: 8: 1) to obtain the target compound (139 mg). A portion of the target compounds was placed (64 mg) in hot ethyl acetate and purified by slow evaporation from ethyl acetate to obtain the target compounds.

Analysis found: C 67.3 H 6.9 N 16.5
C ₁₉ H ₂₂ N ₄ O ₂ requires C 67.4 H 6.6 N 16.6%
Example 1

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one maleate.

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido / 4,3-b / indol-1-one (0.6 g) and about 78% dispersion of sodium hydride in mineral oil (0.109 g) in dry DMF (15 ml) was stirred under nitrogen at 50 ^o until nitrogen evolution was complete (approximately 1.5 hours). The mixture was then cooled to 40 ^° and a solution of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.12 g) in dry THF (15 ml) was added. The reaction mixture was then stirred at 40 ^{° for} 3 hours, at 20 ^{° for} 16 hours, and an additional portion of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.12 g) in dry THF (15 ml) was added. ) The resulting mixture was heated at 40 ^o 3 hours, sharply cooled with water (20 ml) and acetic acid (20 ml) and heated at 100 ^o 2 hours. This mixture was then concentrated in vacuo to 60 ml, diluted with 1M hydrochloric acid (40 ml) and washed with ethyl acetate (3x50 ml). The organic phase was discarded and the acidic aqueous phase was transferred to the base (pH 9) with sodium carbonate and extracted with ethyl acetate: ethanol (20: 1, 3x100 ml). The extracts were combined, dried, evaporated to give a brown gum (about 1 g). This resin was absorbed on silica and purified by ICH eluting with System A (100: 8: 1) to give a light brown solid (0.8 g), etc. 238,240 ^° (decomposition). This solid was dissolved in a mixture of hot ethanol and methanol (1: 1, 100 ml) and treated with an ethanol solution of maleic acid (318 g). The resulting mixture was concentrated to 20 ml, diluted with dry diethyl ether (about 8 ml) and the target compound (0.75 g) was precipitated as an off-white solid, etc. 160 162 ^o C.

Analysis found: C 61.6 H 5.5 N 13.6
C ₁₇ H ₁₈ N ₄ O • C ₄ H ₄ O ₄ Calculation C 61.5 H 5.4 N 13.8%
Example 2

 2,3,4,5-tetrahydro-2 / (5-methyl-1H-imidazol-4-yl) methyl / - 5 - / (phenylmethoxy) methyl / -1H-pyrido / 4,3-b / indole-1 -onmaleat.

A suspension of 2,3,4,5-tetrahydro-5 - / (phenylmethoxy) methyl / - 1H-pyrido / 4,3-b / indol-1-one (920 mg) in dry DMF (75 ml) was treated with sodium hydride (60% dispersion in oil; 180 mg) under nitrogen and the reaction mixture was stirred at 60 ^{° for} 6 hours.

Then 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.11 g) was added and the mixture was stirred overnight at 60 ^° . Then acetic acid (10 ml), water (10 ml) and THF (10 ml) were added, and the resulting solution was heated at reflux for 6 hours. After cooling, 2n was added. sodium hydroxide (100 ml) and the resulting suspension was extracted with dichloromethane (3x100 ml). The combined, dehydrated organic extracts were absorbed on silica by ICC and ICC elution with system A (150: 8: 1) gave the free base of the target compound (1.08 g) as a foam. A small amount of this compound (200 mg) was dissolved in methanol (30 ml) and the resulting solution was treated with maleic acid (58 mg). The solution was heated for 10 minutes, cooled, dry ether was added, and the target compound (170 mg) was precipitated. 165 168 ^o C. Analysis of the water found 0.22 vol. 0.06 mol of H ₂ O.

Analysis found: C 64.5 H 5.6 N 10.7
C ₂₄ H ₂₄ N ₄ O • C ₄ H ₄ O ₄ • 0.06 H ₂ O Calculation C 65.0 H 5.5 N 10.8%
Examples 3 and 4 were obtained analogously to example 2.

 Example 3

 2,3,4,5-tetrahydro-5- (phenylmethyl) -2 - / (5-methyl-1H-imidazol-4-yl) - methyl / -1H-pyrido / 4,3-b / indole-onmaleate monohydrate.

2,3,4,5-tetrahydro-5- (phenylmethyl) -1H-pyrido / 4,3-b / indol-1-one (960 mg) was treated with sodium hydride (73% dispersion in oil; 132 mg) and then was mixed with 4- (chloromethyl-5-methyl-1- (triphenylmethyl) -1H-imidazole (1.3 g). The free base of the target compound was obtained as a solid by ICH eluting with system A (175: 8: 1). Maleate formation gives the target compound (420 mg), etc. 198,200 ^° C., TLC (system A, 100: 8: 1), Rf 0.3.

 Example 4

 5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-onmaleate .

5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyrido / 4,3-b / indol-1-one (200 mg) was treated with sodium hydride (60% dispersion in oil; 60 mg) and then stirred with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (280 mg). The free base of the target compound was obtained as a solid by ICH, eluting with system A (200: 8: 1). Education maleate gives the target compound (60 mg), etc. 81 83 ^o C, TLC (system A, 100: 8: 1), Rf 0.20.

 Example 5

 2,3,4,5-tetrahydro-N, N-dimethyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1-oxo-5H-pyrido / 4,3-b / indole -5-carboxamide maleate.

Solution 2,3,4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / methyl / -1H-pyrido / 4,3-b / indole-1- it (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Then, N, N-dimethylcarbamoyl chloride (1M solution in DMF; 1 ml) was added and the solution was stirred at room temperature for another 15 minutes. Water (1 ml) was carefully added and the reaction mixture was then poured into water (100 ml). The resulting mixture was extracted with ethyl acetate (2x50 ml) and the combined organic extracts washed with water (2x100 ml), concentrated and an oil was obtained. This oil was dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and THF (10 ml) and the solution was heated at reflux for 1.5 hours. After cooling, the solution was made base by the addition of 2N. sodium hydroxide (100 ml) and the resulting mixture was extracted with ethyl acetate (2x75 ml). The combined, dehydrated organic extracts were absorbed on silica ICH and obtained ICH eluting with system A (100: 8: 1) the free base of the target compound (110 mg) as a solid. It was dissolved in dry methanol (10 ml) and heated with maleic acid (36 ml) in a steam bath for 5 minutes. While cooling, dry ether (3 ml) was added and the target compound (105 mg) was precipitated. 161 163 ^o C.

Water analysis established 1.85 vol. 0.49 mol of H ₂ O.

Analysis found: C 57.8 H 5.4 N 14.3
C ₁₉ H ₂₁ N ₅ O ₂ • C ₄ H ₄ O ₄ • 0.49 H ₂ O Calculation C 68.0 H 5.5 N 14.7%
Unless otherwise specified, examples 6 and 7 are obtained analogously to example 5.

 Example 6

 2,3,4,5-tetrahydro-2 / (5-methyl-1H-imidazol-4-yl) methyl / -5- (2-propynyl) - 1H-pyrido / 4,3-N / indole-1- onmaleat.

Suspension of 2,3,4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / methyl / -1H-pyrido / 4,3-N / indole- 1-one (522 mg) and potassium carbonate (276 mg) in dry acetone (75 ml) were treated with propargyluromide (1 M solution in acetone; 2 ml) and the mixture was heated overnight at reflux. After cooling, excess acetone was removed in vacuo to give an oil, which was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was washed with ethyl acetate (50 ml) and the combined organic extracts were concentrated in vacuo. Deprotection, fine-tuning and purification give the free base of the target compound (100 mg) as a solid. The formation of maleate provides the target compound (89 mg), etc. 202 205 ^o C, TLC (system A, 100: 8: 1), Rf 0.29.

 Example 7

 2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -5- (2-propenyl) -1H-pyrido / 4,3-b / indol-1 -onmaleat.

 2,3,4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / methyl / -1H-pyrido / 4,3-b / indol-1-one (1.0 g) was treated with sodium hydride (60% dispersion in oil; 114 mg) and then stirred with allyl bromide (460 mg) for 1 hour. Deprotection, debugging and purification give the free base of the target compound (380 mg) as a solid. The formation of maleate provides the target compound (160 mg), TLC (system A, 100: 8: 1), Rf 0.3.

Analysis found: C 63.2 H 5.5 N 12.5
C ₁₉ H ₂₀ N ₄ O • C ₄ H ₄ O ₄ Calculation C 63.3 H 5.5 N 12.8
Example 8

 5-cyclo-pentyl-2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl / -1H-pyrido / 4,3-b / indol-1-onmaleate.

Solution 2,3,4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl / 1H-pyrido // 4,3-b / indo-1- it (523 mg) in dry DMF (30 ml) was treated with sodium hydride (60% dispersion in oil; 46 mg) and stirred for 15 minutes at 21 ^° under nitrogen. Then cyclopentyl bromide (298 mg) was added dropwise and the mixture was stirred for 1 hour and then heated at reflux for 4 hours. This solution was left at 21 ^° for 2 days and then treated with a mixture of acetic acid (7 ml), water (7 ml) and THF (8 ml). The resulting solution was heated at reflux for 4 hours, then turned into a 2n base. sodium hydroxide and was extracted with dichloromethane (3x25 ml). The combined extracts were washed with water (2x50 ml), concentrated in vacuo, purified by ICH elution with system A (100: 8: 1) and the free base of the target compound (42 mg) was obtained as a solid. Education maleate gives the target compound (38 mg), etc. 180 ^o C (decomposition), TLC (system A, 100: 8: 1), Rf 0.3.

 Example 9

 2,3,4,5-tetrahydro-2- / 5-methyl-1H-imidazol-4-yl / methyl / -5-propyl-1H-pyrido / 4,3-b / indol-1-onmaleate.

 Solution 2,3,4,5-tetrahydro-2 - / (5-methyl / 1H-imidazol-4-yl) methyl / -5- (2-propenyl) -1H-pyrido / 4,3-b / indole- 1-one (248 mg) in a mixture of ethanol (20 ml) and 1N. hydrochloric acid (0.5 ml) was hydrogenated at room temperature and atmospheric pressure on previously reduced 10% palladium oxide on carbon (50% aqueous paste; 50 mg). The mixture was then filtered and evaporated in vacuo. The residue was turned into a 2n base. sodium hydroxide (10 ml) and was extracted with dichloromethane (3x20 ml). The combined organic extracts were washed with water (30 ml), evaporated and the free base of the target compound (258 mg) was obtained as a solid. The formation of maleate provides the target compound (345 mg), TLC (system A, 100: 8: 1), Rf 0.4.

Water analysis established 1.13 vol. 0.28 mol of H ₂ O.

Analysis found: C 62.1 H 5.9 N 12.5
C ₁₉ H ₂₂ N ₄ O • C ₄ H ₄ O ₄ 0.28 H ₂ O Calculation C 62.2 H 6.0 N 12.6%
Example 10

 2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1Npyrido / 4,3-b / indol-1-onmaleate.

 Suspension of 2,3,4,5-tetrahydro-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -5 - / phenyl (methoxymethyl) / - 1H-pyrido / 4,3-b / indole -1-one (400 mg) in ethanol (20 mg) in glacial acetic acid (5 ml) was hydrogenated overnight at room temperature and atmospheric pressure over a previously reduced catalyst 10% palladium on carbon (50% aqueous paste; 100 mg) . The reaction mixture was filtered and the residue washed with ethanol (100 ml). The filtrate was concentrated in vacuo to give an oil to which 2N was added. sodium hydroxide (50 ml). The resulting suspension was extracted with dichloromethane (2x50 ml), the combined, dehydrated organic extracts were evaporated and a solid was obtained. It was purified by ICH by elution with system A (75: 8: 1) and the free base was obtained as a solid (240 mg), which was then dissolved in dry methanol (50 ml). The formation of maleate provides the target compound (261 mg), TLC (system A, 75: 8: 1), Rf 0.2.

Analysis found: C 60.3 H 5.2 N 13.8
C ₁₆ H ₁₆ N ₄ O • C ₄ H ₄ O ₄ Calculation C 60.5 N 5.1 N 14.1%
Example 11

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indole-1-onhydrochloride.

2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one (1 , 0 g) was suspended in ethanol (40 ml) and concentrated hydrochloric acid (1.0 ml) was added. The mixture was heated to 40 ^° C. and charcoal (0.25 g) was added. The resulting suspension was mixed and heated for 5 minutes and then filtered. The filtrate was evaporated in vacuo to 20 ml and allowed to cool to 20 ^o C. With stirring for 5 minutes, ether (40 ml) was added and the mixture was stored at 4 ^o C overnight. The resulting precipitate was filtered off, washed with ether (2x10 ml), dried in vacuo at room temperature for 2 hours and then at 70 ^{° for} 7 hours to obtain the desired compound (0.95 g), etc. 288-291 ^o C.

Analysis determined: C 61.4 H 5.8 N 16.7 Cl 10.7
C ₁₇ H ₁₈ N ₄ O • HCl Calculation C 61.7 H 5.8 N 16.9 Cl 10.7%
Example 12

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-onsulfate.

2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one (0 , 81 g) were suspended in absolute ethanol (6 ml) and heated at 50 ^° with concentrated sulfuric acid (0.15 ml). More ethanol (4 ml) was added and the mixture was stirred with charcoal (0.1 g). Then the suspension was filtered and the collected solid filtrate was washed with ethanol (3 ml). The resulting filtrate was stirred for 1 hour at room temperature, tert-butyl methyl ether (10 ml) was slowly added and the mixture was stirred for 20 minutes. The precipitate was filtered off, washed with a mixture of ethanol: tert-butyl methyl ether 1: 1.6 ml, then with tert-butyl methyl ether (6 ml), dehydrated in vacuum at 4 ^{° for} 4 days and the desired compound (0.4 g) was obtained, etc. 205 - 209 ^o C.

Analysis found: C 49.5 H 5.6 N 13.5 S 8.4
C ₁₇ H ₁₈ N ₄ O • 1.1 H ₂ O ₄ Calculation C 49.9 H 5.4 N 13.3 S 8.4%
Example 13

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / - 1H-pyrido / 4,3-b / indol-1-one.

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido / 4,3-b / - indol-1-one (400 mg) in dry DME (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg) and the mixture was stirred at 60 ^° under nitrogen for 6 hours. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (474 mg) was added and the reaction mixture was stirred at 60 ^° under nitrogen overnight. Then 2n was added. hydrochloric acid (10 ml) and water (10 ml) and the mixture was heated at reflux for 6 hours. After cooling, the mixture was turned into a 2n base. sodium hydroxide and the resulting mixture was extracted with ethyl acetate (2x50 ml). The combined, dehydrated organic extracts were concentrated on silica ICH, purified by ICH elution with system A (150: 8: 1) and the target compound (352 mg) was obtained as a solid, TLC (system A, 100: 8: 1), Rf 0, 28.

¹ H NMR δ 2.2 (3H, s), 3.04 (2H, t), 3.62 (2H, t), 3.82 (3H, s), 4.53 (2H, s), 7 1 7.28 (2H, s), 7.43 (1H, s), 7.47 7.55 (1H, dv) 7.94 8.03 (1H, dd).

 Example 14

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / 1H-pyrido / 4,3-b / indol-1-one.

Solution 2,3,4,5-tetrahydro-2 - / (5-methyl-1- (triphenylmethyl) -1Nimidazol-4-yl / methyl / -1H-pyrido / 4,3-b / indole-1- it (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg), the mixture was stirred at room temperature under nitrogen for 15 minutes, then iodomethane (0.5 M solution in DMF: 2 ml was added ) and stirring continued for another 15 minutes.The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (2x100 ml), dried, concentrated and obtained solid It was dissolved in a mixture of water (10 ml), THF (10 ml) and glacial acetic acid (10 ml) and heated at reflux for 2 hours. After cooling, the residual THF was removed in vacuo and the remaining solution turned into a base (to pH 14) ) by adding 2N sodium hydroxide The resulting suspension was extracted with ethyl acetate (2 x 50 ml) and the combined, dehydrated organic extracts were concentrated on silica (Merck 7385). ICC eluting with system A (100: 8: 1) afforded the target compound (81 mg) as a solid. The ¹ H NMR and TLC data obtained for this product are consistent with the data obtained for the product in Example 13.

 Example 15

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1Npyrido / 4,3-b / indol-1-one.

5,6-dihydro-1 / (5-methyl-1H-imidazol-4-yl) methyl / -4- (2-methyl-2-phenylhydrazino) -2- (1H) -pyridinone (20.0 mg) was dissolved in 98% sulfuric acid (1 ml) and the solution was stirred at 25 ^o 5 minutes. The mixture was carefully poured into an 8% aqueous sodium bicarbonate solution (60 ml) and extracted with a mixture of 10% methanol: dichloromethane (2x60 ml). The combined, dehydrated organic extracts were evaporated in vacuo to give an oil, which was purified by ICH eluting with System A (100: 8: 1) to give the target compound (13.5 mg) as a solid. The ¹ H NMR and TLC data obtained for this substance are consistent with the data obtained for the product of example 13.

 Example 16

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one.

 Solution N, N, 5-trimethyl-4- / 1,2,3,6-tetrahydro-4 - / (2-iodophenyl) methylamino / -6-oxo-1-pyridinyl / methyl-1H-imidazole-1- sulfonamide (264 mg) in a mixture of dioxane and acetonitrile (2: 1, 200 ml) containing triethylamine (2 ml) was irradiated in a pyrex immersion tank with a 125 W medium pressure mercury lamp at room temperature for 24 hours. Then the reaction mixture was concentrated on silica ICH, purified by ICH elution with system A (150: 8: 1) and the target compound (87 mg) was obtained as a solid.

Data ¹ H NMR and TLC obtained for this substance, coincide with the data obtained for the product of example 13.

 Example 17

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one.

Solution N, N, 5-trimethyl - / (2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido / 4,3-b / indol-2-yl) -1H-imidazole- 1-sulfonamide (86 mg) in 2N. hydrochloric acid (10 ml) and absolute ethanol (2 ml) were heated at 100 110 ^o 4 hours. Then the reaction mixture was cooled and 2N sodium hydroxide (50 ml) was added. The resulting solution was extracted with dichloromethane (2x50 ml), the combined, dehydrated organic extracts were concentrated on silica ICH, purified by ICH eluting with system A (100: 8: 1) to obtain a solid (36 mg). It was placed in hot ethyl acetate, purified by slow evaporation and the desired compound (12 mg) was obtained. The ¹ H NMR and TLC data obtained for this substance are consistent with the data obtained for the product of example 13.

 Example 18

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one.

Solution N, N, 5-trimethyl - / (2,3,4,5-tetrahydro-5-methyl-1-oxo-1N-pyrido / 4,3-b / indol-2-yl) methyl / -1Н-imidazole- 1-sulfonamide (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) was irradiated at room temperature with a medium-pressure mercury lamp for 24 hours. The reaction mixture was then concentrated in vacuo on silica by ICC, purified by ICH by elution with system A (100: 8: 1) to obtain the target compound (203 mg) as a solid. The ¹ H NMR and TLC data obtained for this substance are consistent with the data obtained for the product in Example 13.

 Example 19

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one.

Solution phenylmethyl 5-methyl-4 - / (2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido / 4,3-b / indol2-yl) methyl / -1H-imidazol-1 -carboxylate (134 mg) in a mixture of absolute ethanol and 2n. hydrochloric acid (2: 1, 30 ml) was heated in a steam bath for 15 minutes. After cooling, the solution was concentrated in vacuo to 20 ml and diluted with water (40 ml). The mixture was then washed with ethyl acetate (2 x 40 ml) and the acidic aqueous layer was turned into a base with a potassium carbonate solution. The solution was then extracted with ethyl acetate (3 × 50 ml), the combined, dehydrated extracts were concentrated on silica ICH, purified by ICH eluting with system A (150: 8: 1), and a solid was obtained. It was dissolved in hot methanol and triturated with ether to give the title compound (69 mg). Data ¹ H NMR and TLC for this substance are consistent with the data obtained for the product of example 13.

 Example 20

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one.

Solution 2,3,4,5-tetrahydro-2 - // 1- (methoxymethyl) -5-methyl1H-imidazol-4-yl / methyl / -5-methyl-1H-pyrido / 4,3-b / indole- 1-one and 2,3,4,5-tetrahydro-2 - // 1- (methoxymethyl) -4-methyl-1H-imidazol-5-yl / methyl / -5-methyl-1H-pyrido / 4.3 -b / indol-1-one (34 mg) in 49% hydrobromic acid (2 ml) was heated in a steam bath for 3 hours. After cooling, the reaction mixture was turned into a base by adding a solution of potassium carbonate and extracted with ethyl acetate (3x50 ml). The combined, dehydrated organic extracts were concentrated in vacuo to give the title compound (6 mg) as a solid. The ¹ H NMR and TLC data obtained for this substance are consistent with the data obtained for the product of example 13.

 Example 21

 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-4-yl) methyl / - 1H-pyrido / 4,3-b / indol-1-one.

5,6-dihydro-1 - / (5-methyl-1H-imidazol-4-yl) methyl / -4- (2-methyl-2-phenylhydrazino) -2- (1H) -pyridinone (60 mg) was dissolved in glacial acetic acid (4 ml). Anhydrous zinc chloride (600 mg) was added and the mixture was heated at 85 ^{° for} 1.5 hours. The cooled mixture was poured into an 8% aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate: methanol (10: 1) (2 x 100 ml). The combined, dehydrated organic extracts were evaporated in vacuo to give a solid, which was purified by ICH eluting with System A (100: 8: 1) to obtain the desired compound (26 mg). The ¹ H NMR and TLC data obtained for this substance are consistent with the data obtained for the product of example 13.

 The following example illustrates a pharmaceutical composition in accordance with the present invention containing 2,3,4,5-tetrahydro-5-methyl-2 - / (5-methyl-1H-imidazol-1-yl) methyl / -1H-pyrido / 4 , 3-b / indol-1-one as the active ingredient. Physiologically acceptable salts and / or solvates of this compound and other compounds of formula (1) and / or physiologically acceptable salts and solvates of these compounds can be used in a similar manner.

Tablets for oral administration
Tablets can be prepared by conventional methods, such as direct compression or wet granulation.

 These tablets can be coated with a film of suitable film-forming substances, such as hydroxypropyl methylcellulose, using standard methods. On the other hand, these tablets can be coated with sugar.

Direct pressing
Mg tablet / tablet
Active ingredient 0.50
Secondary Acid Calcium Phosphate BP ^x 87.25
Croscarmellosodium NF 1.80
Magnesium Stearate BP 0.45
Pressing weight 90.00
^x or a variety suitable for direct compression.

 The active ingredient is passed through a 60 mesh sieve, mixed with secondary acidic calcium phosphate, croscarmellose and magnesium stearate. The resulting mixture is compressed into tablets using a Manesty 73 tablet machine equipped with 5.5 mm flat chamfered dies.

Attachment 1
Biological Test Data
In continuation of the activity characteristics of compounds I, the test results are expressed as pKi values. All compounds of examples 1 to 10 have pKi greater than 9.0 in magnitude.

 The observed antagonism can be evaluated "in vivo" by determining the effect of the compounds on the Bezold-Yarish reflex in cats induced by 5-HT. The experiment is carried out in accordance with the method described by A. Butler et al. in the literature of the British Journal of Pharmacology, 1988, 94, p. 397.

In the table below, the results obtained are expressed as the duration of R ₅ , while the compounds are administered intraduodenally (into the duodenum 12). R ₅ represents the approximate dose required for a 5-fold shift to the right of the dose response curve with respect to 2-methyl-5-HT (see table). TTT1

Claims (6)

1. Lactam derivatives of the general formula I

where I _m imidazole group of the formula

R ^{1 is} hydrogen or C ₁ C ₄ alkyl, C ₃ is C ₄ alkenyl, C ₃ C ₄ alkynyl, C ₅ C ₆ cycloalkyl, C ₅ C ₆ cycloalkylmethyl, benzyl, phenylmethoxymethyl or N, N-di- C ₁ C ₃ -alkylcarboxamido group,
or their physiologically acceptable salts and solvates, which are potential and selective 5-HT antagonists at 5-HT ₃ receptors. 2. Compounds according to claim 1, characterized in that R ^{1 is} hydrogen or methyl, N-propyl, prop-2-enyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl, phenylmethoxymethyl or N, N-dimethylcarboxamido.  3. Compounds according to claim 1 or 2, characterized in that the compounds are physiologically acceptable salts and solvates.  4. Compounds according to any one of paragraphs. 1 to 3, characterized in that the compound of general formula I is hydrochloride, sulfate, alkyl sulfonate, arylsulfonate, phosphate, acetate, nitrate, succinate, tartrate, fumarate or maleate.  5. The compounds according to claim 1, characterized in that they are 2,3,4,5-tetrahydro-5-methyl-2- [1 (5-methyl-1H-imidazol-4-yl) methyl] -1H- pyrido [4,3-b] indol-1-one or a pharmaceutically acceptable salt or solvate or hydrochloride salt thereof. 6. A pharmaceutical composition that is an antagonist of 5-hydroxytryptamine (5-HT) at 5-HT ₃ receptors, containing an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance contains a compound of general formula I in an effective amount.

Images