HRP930480A2 - Antiviral tetrahydroimidazo (1,4) benzodiazepine-2-thiones - Google Patents

Description

The field of technology

The invention is from the field of pharmaceutical chemistry, closer to the organic synthesis of compounds that show antiviral activity.

Technical problem

The technical problem solved by this invention is a process for obtaining new tetrahydroimidazo/1,4/benzodiazepine-2-thiones which have the formula

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and their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, in which

R 1 C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, or C 1-6 alkyl substituted with aryl or with C 3-6 cycloalkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 4 and R 5 are each independently hydrogen, C 1-6 alkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy, C 1-6 alkyloxy, amino or mono- or di(C 1-6 alkylamino); and aryl is phenyl, optionally substituted with from 1 to 3 substituted independently selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkyloxy, amino, nitro and trifluoromethyl.

State of the art

In Eur. J. Med. Chem. 1978, 13, 53-59, three tetrahydroimidazo/4,5,1-jk//1,4/benzodiazepines are described. The compounds of the present invention differ from them in that the imidazo half is substituted with a thioxo group and that the said compounds exhibit antiviral activity.

Compounds of formula (I) can also exist in their tautomeric form. Said tautomeric form, although not specifically shown in the above formula, is intended to be included in the content of this invention.

In the preceding definitions, the term halo is related to fluorine, chlorine, bromine, and iodine; C1-6alkyl defines a normal and branched chain of saturated hydrocarbon radicals, having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, hexyl and the like; C3-6alkenyl defines a normal and branched series of hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl , pentenyl, hexenyl and the like; C3-5alkynyl defines a normal and branched series of hydrocarbon radicals, containing a triple bond and having from 3 to 6 carbon atoms, such as, for example, 2-propynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl and the like; C3-6cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Depending on the nature of the various substituents, compounds of formula (I) may have several asymmetric carbon atoms. Unless otherwise mentioned or shown, the chemical name of a compound means a mixture of all possible stereochemical isomeric forms. The mentioned mixtures contain all diastereomers and enantiomers of the basic molecular structure. The absolute configuration of each chiral center can be represented by the stereochemical descriptive symbols R and S, these R and S designations correspond to the rules described in Pure Appl. Chem. 1976, 45, 11-30. Stereochemically isomeric forms of the compounds of formula (I) are clearly intended to be included in the scope of the invention.

Stereochemically pure isomeric forms of the compounds of formula (I) can be obtained using known laboratory procedures. Diastereoisomers can be separated using physical separation methods, such as selective crystallization and chromatographic techniques, eg, countercurrent partitioning, liquid chromatography, and the like; and enantiomers can be separated from each other by selective crystallization of their diastereoisomeric salts, which are obtained with optically active acids. Stereochemically pure isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of a suitable starting material, if the reaction proceeds stereospecifically.

The compounds of formula (I) have basic properties and can therefore be converted into their therapeutically active non-toxic acid addition salts by treatment with suitable acids, such as, for example, inorganic acids, e.g., hydrochloric, hydrobromic and similar acids, sulfuric acid , nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanoic acid, propanoic acid, butanoic acid, (Z)-2-butanoic acid, 2-hydroxybutanoic acid, 2- hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxy-benzoic, 4-amino-2-hydroxybenzoic and similar acids.

Conversely, salts can be converted to free bases by treatment with alkali. The term pharmaceutically acceptable acid addition salt also includes solvates that the compounds of formula (I) can form, and said solvates are intended to be included in the scope of this invention. Examples of such solvates are, for example, hydrates, alcoholates and the like.

Specific compounds of formula (I) are those compounds in which the R1 group is C1-6alkyl, C3-6alkenyl, C3-6alkynyl or C1-6alkyl substituted with aryl or with C3-6cycloalkyl; and/or R 4 and R 5 are each independently hydrogen, C 1-6 alkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy or C 1-6 alkyloxy.

More specific are those specific compounds in which R1 is C3-6alkyl, C3-6alkenyl, or C1-6alkyl substituted with C3-6cycloalkyl; and/or R 2 is C 1-6 alkyl; and/or R 5 is hydrogen.

The first specific subgroup includes those more specific compounds in which R 1 is C 3-6 alkyl, C 3-6 alkenyl or (C 3-6 cycloalkyl) methyl; and/or R 2 is methyl; and/or R 4 is hydrogen; methyl, halogen, cyano, nitro or trifluoromethyl; and/or R 3 is hydrogen.

Another specific subgroup includes those more specific compounds in which R 2 is methyl; and/or R 3 is hydrogen; and/or R4 is hydroxy or C1-6 alkyloxy.

Particularly interesting compounds in the first specific subgroup are those compounds in which R1 is propyl, 2-propenyl, 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl or cyclopropylmethyl; and/or R4 is hydrogen, methyl or chlorine; and/or the carbon atom bearing R2 has the (S) configuration.

The most interesting compounds are 4,5,6,7-tetrahydro-5-methyl-6-propylimidazo-/4.5.1-jk//1,4/benzodiazepine-2(1H)-thione; (+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo/4,5,1-jk//1,4/benzo- diazepine-2(1H)-thione; (+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6.(3-methyl-2-butenyl)imidazo-/4,5,1-jk//1 ,4/benzodiazepine-2(1H)-thione and (+)-(S)6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-5-methylimidazo--/4,5,1-jk// 1,4/benzodiazepine-2(1H)-thione.

Solution of a technical problem with implementation examples

Compounds of formula (I) can usually be obtained by condensing 9-amino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepines of formula (II) with a reagent of formula (III), wherein L is the usual "leaving group ".

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N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-methyl-morpholine and similar amines. If said reagent of formula (III) is carbon disulfide, the reaction can conveniently be carried out in an alkanol, such as, for example, methanol, ethanol, propanol and the like, in the presence of a base, such as sodium or potassium hydroxide and the like, or carbon disulfide as a solvent and in the presence of a suitable base, such as, for example, an alkylmagnesium halide, e.g., ethylmagnesium bromide, some alkyl lithium, e.g., butyllithium, some amine, e.g., N,N-diethylethanamine, some carbodiimide, eg, N,N-dicyclohexylcarbodiimide and similar reagents. Or, alternatively, the latter reaction can also be carried out in a basic solvent, such as, for example, pyridine and the like, in the presence of a phosphite, such as, for example, diphenylphosphite.

Compounds of formula (I) can also be obtained by thionation of 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2-one of formula IV following reactions known in the art to convert carbonyls into thiocarbonyl

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For example, intermediates of formula (IV) can be reacted with a halogenated reagent, such as, for example, phosphoryl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, oxalyl chloride and similar reagents, optionally at elevated temperature, especially at at the reflux temperature of the reaction mixture, and optionally in the presence of an inert reaction solvent and a base, such as, for example, sodium carbonate, sodium bicarbonate, potassium carbonate and the like. The thus obtained 2-halo-4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine can be converted into compounds of formula (I) by reaction with thiourea or some alkali metal thiosulfate, e.g. , sodium thiosulfate in a suitable inert solvent, such as, for example, the like, in the presence of a phosphite, such as, for example, diphenylphosphite.

Compounds of formula (I) can also be obtained by thionation of 4,5,6,7-tetrahydroimidazo/4,5,1-jk//1,4/-benzodiazepine-2-one of formula (IV) following conversion reactions known in the art carbonyl to thiocarbonyl

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For example, intermediates of formula (IV) can be reacted with a halogenated reagent, such as, for example, phosphoryl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, oxalyl chloride and similar reagents, optionally at an elevated temperature, especially at reflux temperature reaction mixture, and optionally in the presence of an inert reaction solvent and a base, such as, for example, sodium carbonate, sodium bicarbonate, potassium carbonate and the like. The thus obtained 2-halo-4,5,6,7-tetrahydroimidazo/4,5,1-jk/ /1,4/benzodiazepine can be further converted into compounds of formula (I) by reaction with thiourea or some alkali metal thiosulfate, e.g. ., sodium thiosulfate in a conventional inert solvent, such as, for example, water or an alkanol, e.g., methanol, ethanol, 1-propanol, 2-propanol, butanol, 1,2-ethanediol and the like, optionally at elevated temperature, especially at the reflux temperature of the reaction mixture.

Alternatively, compounds of formula (I) can be obtained directly from intermediates of formula (IV) by thionation with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson -'s reagent) in some common inert reaction solvent, such as, for example, some aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene, a dipolar aprotic solvent, e.g., hexamethylphosphoric triamide (HMPA) and similar solvents; or by thionation with phosphorus pentasulfide.

Compounds of formula (I) can also be obtained by alkylating an intermediate of formula (V) with a reagent of formula R1-W (VIa) in which W represents a conventional reactive "leaving" group, such as, for example, halogen, e.g., chlorine , bromine or iodine; or a sulfonyloxy group, e.g., benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, methanesulfonyloxy and the like.

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Said N-alkylation reaction can be advantageously carried out in an inert reaction solvent, such as, for example, some aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; some lower alkanol, eg, methanol, ethanol, 1-butanol and the like; some ketone, eg, 2-propanone, 4-methyl-2-pentanone and the like; some ether, e.g., 1,4-dioxane, 1,1-oxybisethane, tetrahydrofuran, etc.; a dipolar aprotic solvent, eg, N,N-dimethylformamide, N,N-dimethylacetamide, nitrobenzene, dimethylsulfoxide, 1-methyl-2-pyrrolidone, etc., or a mixture of such solvents. Addition of a conventional base, such as, for example, an alkali metal carbonate or bicarbonate, e.g., sodium carbonate, sodium bicarbonate, sodium hydride, or an organic base, such as, for example, N,N-diethylethanamine or N -(1-methylethyl)-2-propanamine and the like can be used to accept the acid, which is released during the reaction. In some cases, it is advantageous to add some iodine salt, preferably some alkali metal iodide, for example, potassium iodide. Slightly elevated temperatures and stirring can increase the reaction rate.

Compounds of formula (I) in which R1 is different from C3-6alkenyl or C3-6alkynyl, and the carbon atom of the said R1 radical adjacent to the nitrogen atom, which carries the said R1, contains at least one hydrogen atom, said radicals which are represented by R1, and the mentioned compounds with the formula (I-a) can also be obtained by reductive N-alkylation of the intermediate of the formula (V) with a ketone or aldehyde of the formula R1-b=0 (VI-b). In formula (VI-b), R1-b represents a geminal bivalent radical, which is derived from R1-a-H in which two geminal hydrogen atoms are replaced by =0.

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The mentioned reductive N-alkylation reaction can conveniently be carried out by catalytic hydrogenation of the reactants in a common inert reaction solvent according to catalytic hydrogenation procedures known in the art. The reaction mixture can be stirred and/or heated to increase the reaction rate. Suitable solvents are, for example, water; C1-6alkanols, e.g., methanol, ethanol, 2-propanol, etc.; ethers, e.g., 1,4-dioxane, etc.; halogenated hydrocarbons, e.g., trichloromethane, etc.; dipolar aproric solvents, eg, N,N-dimethylformamide, dimethyl sulfoxide, etc.; esters, e.g., ethyl acetate, etc.; or a mixture of such solvents. The term "catalytic hydrogenation processes known in the art" means that the reaction is carried out in a hydrogen atmosphere and in the presence of a suitable catalyst, such as, for example, palladium on carbon, platinum on carbon, and the like. In order to prevent unwanted further hydrogenation of certain functional groups in reactants and reaction products, it can be useful to add a suitable catalytic poison to the reaction mixture. Alternatively, said reductive N-alkylation can be carried out following reduction procedures known in the art by treating the reactant mixture while stirring, and if desired, heating the reactant mixture with a reducing agent, such as, for example, sodium borohydride, sodium cyanoborohydride, ant acid or its salt, especially its ammonium salt.

Compounds of formula (I) can also be obtained by direct introduction of sulfur into tetrahydroimidazo/4,5,1-jk//1,4/benzodiazepine of formula (VII) with elemental sulfur at elevated temperature.

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The mentioned reaction can conveniently be carried out without a solvent at a temperature above 200°C, primarily at a temperature ranging from 230 to 150°C.

Compounds of formula (I) can also be obtained by combined reduction-thiocarbonylation of a 9-nitrobenzodiazepine of formula (VIII) in the presence of an alkali metal sulfide or hydrogen sulfide and carbon disulfide.

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The mentioned reduction-thiocarbonylation reaction can be advantageously performed by mechanical mixing of the reactants in an inert reaction solvent, optionally at an elevated temperature.

Compounds of formula (I) can be obtained by cyclization of benzimidazole-2-thione of formula (IX) in a common inert reaction solvent, optionally in the presence of a base and at an elevated temperature.

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In formula (IX), W represents a reactive "leaving" group, as previously defined. The mentioned cyclization reaction can conveniently be carried out by mixing and, if desired, heating the starting material. Favorable solvents are, for example, aromatic hydrocarbons, e.g., benzene, methylbenzene, dimethylbenzene, etc., halogenated hydrocarbons, e.g., trichloromethane, tetrachloromethane, chlorobenzene, etc., ethers, e.g., tetrahydrofuran, 1,4-dioxane, etc. ., dipolar aprotic solvents, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, pyridine, etc. Bases that can conveniently be used in the mentioned cyclization reaction are, for example, carbonates of alkali and alkaline earth metals, bicarbonates, hydroxides, oxides, amides, hydrides, etc. In some cases, it can be useful to add an iodine salt to the reaction mixture, primarily an alkali metal iodide, eg potassium iodide.

In all the previous and following production processes, the reaction product can be isolated from the reaction mixture, and if necessary, further purified according to the methodology that is generally known in the art.

Numerous intermediates and starting materials in previous syntheses are known compounds, which can be obtained according to methodologies known in the art for obtaining the mentioned or similar compounds, and some intermediates are new. A number of such methods of obtaining will be described below in more detail.

Intermediates of formula (II) can usually be obtained from 9-aminobenzodiazepines of formula (IIa) by following an N-alkylation reaction, as described above in the preparation of a compound of formula (I) from an intermediate of formula (V) with an alkylating reagent ( VI-a) or with an aldehyde or ketone of the formula (VI-b).

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In order to simplify the following reaction schemes, N-alkylated intermediates in which Rʹ is defined by formula (I), and N4-unsubstituted intermediates (in which Rʹ is replaced by hydrogen will be represented below by formulas, in which N4 is substituted by R1H, mentioned R1H which defines R1 is hydrogen In intermediates (X), XI), XIII), XVI) and (XVII) of scheme 1 below, R1H also defines C1-5alkylcarbonyl, arylcarbonyl, (C3-6cycloalkyl)carbonyl or /(aryl)- or C3 -6cycloalkyl)/C1-5alkylcarbonyl. Said intermediates can conveniently be obtained by following art-known N-acylation procedures from the corresponding intermediates in which R1H is hydrogen and can be reduced to the corresponding N-alkylated intermediates with metal-hydride complexes or hydrides as described in reaction step A in Scheme 1 In all reaction schemes that follow, intermediates in which R1H is hydrogen can also be converted to intermediates in which R1H is R1 following the N-alkylation procedures described above.

Intermediates of formula (II-H), said intermediates represented by intermediates of formula (II) and (IIa) can be obtained usually following the reaction steps shown below in reaction scheme 1.

Scheme 1

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The aniline derivatives in the above reaction scheme can be conveniently obtained by reducing the corresponding nitrobenzene derivatives following the procedures known in the art for the reduction of nitro to amino compounds (reaction stage A). Said reduction can conveniently be carried out by reacting said nitrobenzene with reducing agents, such as, for example, a metal hydride complex, e.g., lithium-aluminum-hydride; some hydride, e.g., diborane, aluminum hydride, etc., in an inert reaction solvent, such as, for example, 1,1-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., freely chosen in the presence of a solvent, such as an aromatic hydrocarbon, e.g., benzene, methylbenzene, etc., and, if desired, at an elevated temperature. Alternatively, said reduction can also be carried out by reacting said nitrobenzene derivatives with sodium dithionite, sodium sulfide, sodium hydrosulfide, titanium (III) chloride and similar reducing agents in a suitable solvent, especially water.

The mentioned nitro-amine reduction can also be carried out by following the catalytic hydrobenation procedures known in the art. For example, said reaction can be carried out by mixing the reactants in an atmosphere of hydrogen and in the presence of a suitable catalyst, such as, for example, palladium on carbon, platinum on carbon, Raney-nickel and similar catalysts. Suitable solvents are, for example, water, alkanols, e.g., methanol, ethanol, etc., esters, e.g., ethyl acetate, etc. In order to increase the speed of the mentioned reaction, it is useful to increase the temperature and/or pressure of the reaction mixture. Undesirable further hydrogenation of certain functional groups in the reactants and reaction products can be prevented by adding a catalytic poison, such as, for example, thiophene, etc., to the reaction mixture.

Nitrobenzene derivatives in the above reaction scheme 1 can be obtained from benzenamine derivatives, following nitration procedures known in the art (reaction step B). For example, starting materials can be nitrated by reaction with concentrated or fuming nitric acid in the presence of concentrated sulfuric acid and optionally in the presence of a cosolvent, such as, for example, a halogenated hydrocarbon, e.g., dichloromethane, trichloromethane, tetrachloromethane and similar solvents . Alternatively, the mentioned nitration can in some cases also be performed by adding the nitrate salt of the starting material to concentrated sulfuric acid.

The benzodiazepine derivatives (II-H), (X) and (XI) can be obtained from the corresponding aniline derivatives (XII), (XIII) and (XIV) following the cyclization procedure, as described above for the preparation of compounds of formula (I) from intermediate of formula (IX) (Reaction step C).

The aniline derivatives mentioned respectively, in which W is a reactive "leaving" group, as defined above, can be obtained from the corresponding alkanols by reaction with halogenating reagents, such as, for example, thionyl chloride, phosphoryl chloride, phosphoryl chloride, trichloride, etc.; or by reaction with a sulfonylation reagent, for example, methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride, etc. (Reaction stage D). Said alkanols can be obtained by N-alkylation of suitable substituted benzene derivatives of the formula (XVIII), (XX), or (XXI) with aminoethanol derivatives of the formula R1HNH-CH(R2)-CH(R3)OH (XIX) following procedures known in the art N -alkylation, as described above (Reaction step E).

Intermediates of formula (II-H) can be obtained by following the reaction step shown below in reaction scheme 2. The reaction steps labeled A through D are intended to refer back to the analogous reaction steps described in the previous reaction scheme.

For example, intermediates of the formula (II-H) can also be obtained from a 9-amino- or 9-nitrobenzodiazepine-5-one of the formula (XXII) or (XXIII) by reduction with a complex metal hydride, e.g., lithium-aluminum -hydride or the like in a suitable inert reaction solvent, such as, for example, 1,2-dimethoxyethane, 1,1-oxybis(2-methoxyethane), 2,5,8,11-tetraoxadodecane, methoxybenzene, etc. solvents (Reaction grade F and G).

In order to increase the speed of the mentioned reduction reaction, it is useful to use an excess of reducing agent and to carry out the mentioned reaction at an elevated temperature of the reaction mixture, primarily at the reflux temperature of the reaction mixture.

Intermediates of formula (XXIII) can alternatively be obtained from a suitable substituted nitrobenzene (XXXIV) by a condensation reaction (Reaction step H) with a diamino reagent R1HNH-CH(R2)-CH(R3)-NH2 of formula (XXXV) in a suitable reaction-inert solvent , such as, for example, some alkanol, e.g., methanol, ethanol, 2-propanol, 1-butanol, etc.; some aromatic hydrocarbon, eg, benzene, methylbenzene, dimethylbenzene, etc.; some halogenated hydrocarbon, e.g., trichloromethane, tetrachloromethane, etc.; some ether, eg, tetrahydrofuran, 1,4-dioxane, 1,1-oxybisbutane, 1,1-oxybis(2-methoxyethane) and the like; some ketone, e.g., 2-propanone, 4-methyl-2-pentanone, etc.; some dipolar aprotic solvent, eg, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like; or a mixture of such solvents. It may be advantageous to add a base, such as an alkali or alkaline earth metal carbonate, for example, sodium carbonate, sodium bicarbonate, etc., to the reaction mixture. The mentioned condensation reaction can conveniently be carried out at an elevated temperature, especially at the reflux temperature of the reaction mixture.

Scheme 2

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F: reduction of amide-to-amine

G: reduction of (nitro-do-amino) and (amide-do-amine)

H: cyclization; R1H-NH-CH(R2)-CH(R3)-NH2 (XXXV)

I: N-acylation reaction

Amide derivatives (XXVIII), (XXIX) and (XXX) in the above reaction scheme can be conveniently obtained by N-acylation of an ethanolamine of the formula R1HNH-CH(R2)-CH(R3)-OH (XIX) suitably substituted with a 2-aminobenzoic derivative acids of formula (XXXI), (XXXII) or (XXXIII) in which L represents a hydroxy or "leaving" group, such as, for example, halogen, e.g., chlorine, bromine, alkylcarbonyloxy, e.g., acetyl, alkyloxy, e.g. ., methoxy, ethoxy and the like, or imidazolyl and similar "leaving" groups. The mentioned N-acylation reaction (reaction stage I) can be performed by mechanical mixing of the reactants in an inert reaction solvent, if desired, at an elevated temperature. In these cases where L represents hydroxy, the mentioned N-acylation reaction can also be carried out by the action of reactants with reagents, which are capable of building amides, such as, for example, N,N-dicyclohexylcarbodiimide (DCC), optionally in the presence catalysts, such as hydroxybenzotriazole (HOBT) or 4-dimethylaminopyridine (DMAP); 2-chloro-1-methyl-pyridinium-iodide, 1,1-carbonylbis 1H-imidazole, 1,1-sulfonylbis 1H-imidazole and similar reagents. Suitable solvents are halogenated hydrocarbons, e.g., dichloromethane, trichloromethane, etc., ethers, e.g., tetrahydrofuran, 1,4-dioxane, and the like, dipolar aprotic solvents, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and the like; or mixtures of such solvents.

Intermediates of the formula (II-H) in which R3 is hydrogen, said intermediates are represented by the formula

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they can also be obtained from the benzodiazepinedione formula

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following a reduction procedure, as described above, in converting intermediate (XXII) or (XXIII) to intermediate (II-H). Intermediates of formula (XXXVI) can usually be obtained following the reaction flow, which is described in Scheme 3.

Scheme 3

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In all reactions in Scheme 3, those compounds in which R3 is hydrogen are designated by adding the suffix - to their numerical designation.

In a number of intermediates shown in Scheme 3, for example in (XXXVI), (XXXVII), (XXXVIII), (XL) and (XLI) it is possible to further selectively reduce functional groups, such as a nitro group, an ester group and/or an aliphatic amide group, in the presence of an aromatic amide group (reaction stage J). Said selective reduction can be carried out by reacting a suitable starting material with a complex metal hydride such as, for example, lithium aluminum hydride in an inert reaction solvent, such as, for example, tetrahydrofuran, 1,4-dioxane, etc. Alternatively, said selective reduction can be performed by reacting a suitable starting material with sodium bis(2-methoxyethoxy) aluminum hydride, or with sodium borohydride in the presence of a suitable metal salt, such as, for example, calcium chloride, cerium (III) chloride, aluminum -chloride, zirconium(IV)-chloride and similar metal salts, in an inert reaction solvent, especially an ether.

Benzodiazepinediones in scheme 3 can be obtained by cyclization (reaction stage K) of the corresponding acyclic intermediates of formula (XXXIX), (XL) and (XLI), in which R represents a group, such as C1-6alkyl or aryl:

a) by heating without solvent in an inert atmosphere, of free choice under reduced pressure;

b) by treatment with a bifunctional catalyst, such as, for example, acetic acid, 2-hydroxypyridine, pyrazole, 1,2,4-triazole and the like, in an inert reaction solvent, such as, for example, some aromatic hydrocarbon, e.g. ., methylbenzene, dimethylbenzene and the like, freely chosen at elevated temperature; or

c) by hydrolyzing the ester and then treating the corresponding carboxylic acid (R=H) with a suitable acid, such as, for example, hydrohalic acid, e.g., hydrochloric acid; sulfuric acid, phosphoric acid and similar acids; or with some halogenating agent, such as, for example, thionyl chloride and the like.

The mentioned intermediates, respectively, can be obtained from a suitable protected amino acid of the formula R1HNH-CH(R2)-COOR (XLV) in which R is C1-6alkyl or aryl, by N-acylation (reaction step L) with a suitably substituted isatinic anhydride derivative or some suitable with a 2-aminobenzoic acid derivative, by mechanically mixing the reactants at reflux temperature in an inert reaction solvent, such as, for example, trichloromethane, pyridine and similar solvents.

Intermediates of formula (II-H-a) can be prepared differently from some benzodiazepine-2-ones following the procedures described in Scheme 4.

Scheme 4

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Intermediates of the formula (II-H) in which R3 is C1-6alkyl, the mentioned radical represented by R3, and the mentioned intermediates with the formula

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they can be obtained by reducing an amine (XXII-b) or an imine (LV), following reduction procedures, as described above for the preparation of (II-H) from (XXII) or (XXIII).

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The imine (LV) can be obtained by reduction of the nitro-derivative (LVI) in the presence of hydrogen and a suitable metal catalyst, such as, for example, palladium on carbon, platinum oxide and similar catalysts. A ketone of the formula (LVI) can be obtained from 2-amino-3-nitrobenzoic acid or its functional derivative (XXXII) and an -aminoketone (LVII) following the N-acylation procedures known in the art.

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Intermediates of formula (IV) wherein R1, R2, R3 are as defined in formula (I) and

a) R4 and R5 are independently of each other C1-6alkyl, halogen, cyano, nitro, nitro, trifluoromethyl, hydroxy, C1-6alkyloxy, amino- or mono- or di(C1-6alkyl)amino, or

b) R4 is hydrogen, and R5 is cyano, nitro, trifluoromethyl, hydroxy, C1-6alkyloxy, amino or manno- or di(C1-6alkyl)amino;

The mentioned radicals R4 and R5 are represented by the radicals R4 and R5, and the mentioned intermediates of formula (IV) are new.

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Intermediates of formula (IV) can be prepared following the procedures described in EP-A-0,336,466, which is incorporated by this reference. For example, the mentioned intermediates of formula (IV), both known and new, can be obtained by N-alkylation of an intermediate of formula (IV-b) following the N-alkylation procedures known in the art, as described above in converting intermediate (V) into compounds of formula (I).

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Intermediates of formula (IV) and (IV-b) can be obtained from intermediates of formula (II-H) by reaction with a reagent of formula (LVIII) in which L is a suitable "leaving" group.

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Suitable agents of formula (LVIII) are, for example, urea, di(C 1-6 alkyl)carbonate, carboxylic acid dichloride, trichloromethylchloroformate, 1,1-carbonylbis 1H-imidazole, ethyl chloroformate and the like. Said reaction can conveniently be carried out following the procedures described above for the conversion of intermediates of formula (II) to compounds of formula (I).

The intermediates of formula (V), acid addition salt forms and stereochemically isomeric forms thereof, are new and can be obtained from the benzylated compound of formula (I-b) following hydrogenolysis procedures known in the art.

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In formulas (V) and (I-b), R 2 , R 3 , R 4 and R 5 have the previously defined meaning. The aforementioned debenzylation reaction can be carried out by mechanical mixing of the compound of formula (I-b) in a suitable inert reaction solvent in the presence of suitable metal catalysts and in a hydrogen atmosphere. Suitable solvents are, for example, alkanols, eg methanol, ethanol and the like; carboxylic esters, eg, ethyl acetate; carboxylic acids, eg, acetic acid, propanoic acid and the like. Examples of suitable metal catalysts include palladium on carbon, platinum on carbon and similar catalysts.

In order to prevent further hydrogenation of the starting material and/or the reaction product, it is convenient to add a catalytic poison to the reaction mixture, such as, for example, thiophene.

Intermediates of formula (V) can also be obtained by thionation of an intermediate of formula (IV-b) following the procedures described above for the preparation of compounds of formula (I) from intermediates of formula (IV).

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Alternatively, the mentioned intermediates (V) can be obtained from an intermediate (II) following a condensation reaction with a reagent of the formula L-C(=S)-L (III), as described above for obtaining a compound of the formula (I) from an intermediate of formula (II).

In all previous reaction schemes, the chemical name of the intermediate indicates a mixture of all possible stereochemically isomeric forms; mixtures of numerous possible stereochemically isomeric forms such as, for example, diastereoisomeric mixtures, enantiomeric mixtures, eg, racemates and enriched enantiomeric mixtures; and enantiomerically pure isomeric forms of the basic molecular structure.

Stereochemically isomeric forms of intermediates, which are described in the previous reaction schemes and compounds of formula (I) can be obtained using known methods in the technique. For example, diastereoisomers can be separated by physical separation methods, such as distillation, selective crystallization, chromatographic techniques, eg, countercurrent partitioning and liquid chromatography, and similar techniques.

Enantiomerically pure intermediates can advantageously be obtained from enantiomerically pure isomeric forms of suitable starting material, if the latter reactions are carried out stereospecifically. Particularly interesting enantiomerically pure starting materials used in the previous reaction schemes are amino acids and/or their substituted derivatives, which have the formula R1HNH-CHR2-COOR (XLV), and the corresponding amino alcohols and/or their substituted derivatives, which have the formula R1HNH-CHR2-CH (R3)OH (XIX).

Alternatively, enantiomerically pure intermediates can be obtained by separating the corresponding racemates, for example, by selective crystallization of their diastereomeric salts with an optically active resolving agent, chromatography of diastereomeric derivatives, chromatography of the racemate over some chiral stationary phase, and similar techniques.

Compounds of formula (I) and intermediates of formula (IVa) show antiviral and especially antiretroviral properties. Until recently, retroviruses were considered to be pathogenic agents only in numerous non-human warm-blooded animal diseases, in contrast to viruses that have recently been known to cause a large number of warm-blooded animal diseases, as well as humans.

However, since the retrovirus, human immunodeficiency virus (HIV), also known as LAV, HTLV-III or ARV, has been identified as the etiological agent of AIDS in humans, retroviral infections and the treatment of patients suffering from them have received the greatest attention. The HIV virus primarily infects human T-4 cells and destroys them or changes their normal function, especially the coordination of the immune system. As a result, the infected patient constantly loses the number of T-4 cells, which moreover behave abnormally. Hence, the immune defense system is disabled to suppress infections and neoplasms, and the HIV-infected patient usually dies from susceptible infections, such as pneumonia or cancer, rather than as a direct result of HIV infection. Other conditions associated with HIV infections include thrombocytopenia, Kaposi's sarcoma, and central nervous system infection characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysarthria, ataxia, and disorientation. HIV infection is further associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC). Antiviral, especially antiretroviral and especially anti-HIV properties of compounds of formula (I) and intermediates of formula (IV) lead to the thought that said compounds and intermediates would be a useful antiviral chemotherapeutic medium for the prophylaxis or treatment of warm-blooded animals suffering from viral infections. primarily for the treatment of people infected with the HIV virus, especially HIV-1.

Due to their antiviral, and especially their antiretroviral properties, compounds of formula (I) and intermediates of formula (IVa), their pharmaceutically acceptable salts and stereochemically isomeric forms, are useful for the treatment of warm-blooded animals infected with viruses, especially retroviruses, or for the prophylaxis of said warm-blooded animals animal. Examples of human retroviral infections include HIV, particularly HIV-1 and HTLV-I (human T-lymphotropic virus type I), which causes leukemia and lymphoma. FeLV (feline leukemia virus), which causes leukemia and immunodeficiency, should be mentioned as an example of non-human animal retroviral infections. Conditions that can be prevented or treated with the compounds of this invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as which is, for example, HIV-mediated dementia and multiple sclerosis.

Considering their antiviral, especially antiretroviral activities, the subject compounds can be put into different pharmaceutical forms for the purpose of application. In order to obtain the pharmaceutical preparations from this invention, an effective amount of a specific compound, in the form of a base or acid addition salt, as an active ingredient, is intimately mixed with a pharmaceutically acceptable carrier, a carrier that can take a wide variety of forms, which depends on the form before wants to change. These pharmaceutical preparations are preferably in unit dosage form suitable, primarily, for oral, rectal, percutaneous administration or parenteral injection.

For example, when preparing preparations in oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, and the like in the case of oral liquid preparations, such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, astringents, disintegrants and the like in the case of powders, pills, capsules and tablets. Due to their easy application, tablets and capsules represent the most convenient unit form of oral dosage, in which case solid pharmaceutical carriers are obviously used. For parenteral preparations, the vehicle usually contains sterile water, at least for the most part, although other ingredients, for example, may be included to aid solubility. Solutions for injection, for example, can be prepared, in which the carrier contains a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Suspensions for injection can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used.

In preparations suitable for percutaneous application, the carrier optionally contains some agent that enhances penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor amounts, additives that do not cause a significant adverse effect on the skin. The mentioned additives can facilitate the application on the skin and/or they can support the preparation of the desired preparations. These preparations can be applied in various ways, for example as a transdermal patch, as an adhesive mole, as an ointment. Acid addition salts (I) and (IV) due to their better solubility in water compared to the corresponding base forms, are obviously more suitable for preparing aqueous preparations.

It is particularly convenient that the above-mentioned pharmaceutical preparations are composed in unit dosage form for easier administration and uniformity of dosage. Unit dosage form, as used in the specification and claims refers to physical discrete units, which are suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powders, lozenges, injectable solutions and suspensions, teaspoonfuls, tablespoonfuls, and the like, and separate multiples thereof.

This invention also relates to a method for the treatment of viral diseases in warm-blooded animals suffering from said viral diseases by administering an effective antiviral amount of a compound of formula (I) or an intermediate of formula (IV), a pharmaceutically acceptable acid addition salt or a stereoisomeric thereof. shape. Experts in the treatment of viral diseases can easily determine the effective antiviral amount from the results of the test provided here. It is usually considered that the effective amount is from 0.01 mg/kg to 5 mg/kg of body weight. Advantageously, the required dose is administered as two, three, four or more subdoses per day at convenient intervals. Said subdoses can be composed as unit dosage forms, for example, to contain 1 to 1000 mg, and especially 5 to 200 mg of the active ingredient in a unit dosage form.

The following examples are intended to illustrate, and not to limit, the scope of the present invention in all its aspects. Unless otherwise indicated, quantity parts are by weight.

Example 1

a) To a mechanically stirred solution of 11.8 parts of 1-propanamine in 24.9 parts of 1,1-oxybisethane, a solution of 18.1 parts of ethyl-2-bromopropanoate in 24.9 parts of 1,1-oxybisethane is added at room temperature for 3 minutes. After stirring for 72 hours at room temperature, the reaction mixture is filtered and the filtrate is washed with a small amount of 1.1-oxybisethane. The layers of 1.1-oxybisethane are combined and evaporated under reduced pressure, whereby 15.9 parts (100%) of ethyl-N-propylalanine are obtained as a residue (interm. 1).

b) A mixture of 9.90 parts of 2-amino-3-nitrobenzoic acid and 32.4 parts of thionyl chloride is mechanically stirred for 15 minutes at reflux temperature in an argon atmosphere. After 15 min, excess thionyl chloride was removed under reduced pressure, giving 10.8 parts (100%) of 2-amino-3-nitrobenzoyl chloride as a residue (interm. 2).

c) To a solution of 8.65 parts of intermediate 1 and 5.52 parts of N,N-diethylethanamine, which is mechanically stirred and cooled (0°C), a suspension of 10.63 parts of intermediate 2 in 119.7 parts of dichloromethane in an argon atmosphere is added over a period of 10 minutes. After 5 minutes, the ice bath is removed and the mixing is continued for another 1 hour. The reaction mixture is gradually extracted with water, NaHCO3 solution (sat.), citric acid 2N and again with NaHCO3 solution (sat.). The organic layer is dried, filtered and evaporated, yielding 19.14 parts (100%) of ethyl-N-(2-amino-3-nitrobenzoyl). N-propylalanine (interm. 3).

d) A solution of 17.5 parts of intermediate 3 in 80 parts of ethanol is hydrogenated at 3.5 105 Pa and at room temperature with 2.0 parts of palladium on carbon 10%. After the calculated amount of hydrogen has been consumed, the catalyst is filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The resulting oil is heated under vacuum (3.3 103 Pa) in an oil bath at 100°C for 1.5 hours. After cooling, the oil is purified by column chromatography (silica gel; CH2Cl2/CH3OH 20:1), yielding 4.6 parts (34.4%) of 9-amino-3-methyl-4-propyl-3H-1,4-benzodiazepine- 2,5(1H,4H)-dione as residue (interm. 4).

e) To a suspension of 1.28 parts of lithium aluminum hydride in 52 parts of 1,2-dimethoxyethane, which is stirred and cooled (0°C), 1.39 parts of intermediate 4 are added in an argon atmosphere for 5 minutes. The reaction mixture was first stirred for 2 hours at 0°C, and then for 72 hours at reflux temperature. After cooling, the reaction mixture is quenched with a solution of 1.3 parts of water and 3.6 parts of tetrahydrofuran, 1.3 parts of a 15% sodium hydroxide solution, and 3.9 parts of water. After mixing for 1 hour, everything is filtered. The residue is heated under reflux for 5 minutes in 45 parts of tetrahydrofuran and then filtered. The combined filtrates were dried, filtered and evaporated under reduced pressure to give 1.24 parts (100%), 2,3,4,5-tetrahydro-3-methyl-4-propyl-1H-1,4-benzodiazepine-9-amine (interm. 5).

Example 2

a) Mixtures of 9.10 parts of 2-amino-3-nitrobenzoic acid, 6.95 parts of methyl-L--alanine monohydrochloride, 13.50 parts of 1-hydroxy-1H-1,2,4-benzotriazole-monohydrate and 178 parts of tetrahydrofuran which are mixed and cools (-12°C), 5.05 parts of N-methylmorpholine and, after 5 minutes, 10.3 parts of N,N-methanetetraylbis(cyclohexanamine) are added in portions under an argon atmosphere. Mixing is continued for 5 and a half hours at -12°C and for 5 hours at room temperature. After cooling to 0°C for half an hour, the reaction mixture is filtered. The filtrate is evaporated, and the residue is partitioned between ethyl acetate and NaHCO3 (sat.). The ethyl acetate layer is separated, washed with NaHCO3 (sat.), dried, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 13.08 parts (97.9%) (-)-methyl-(S)-2-(2-amino-3-nitrobenzoyl)amino/propanoate; tt. 132.9°C interm. 6).

b) A mixture of 12.58 parts of intermediate 6, 3.50 parts of palladium on carbon 10% and 158 parts of ethanol is hydrogenated in a Parr apparatus for 4 hours at room temperature and a pressure of 3.1 105 Pa. The catalyst is filtered through diatomaceous earth and the filtrate is evaporated. The oily residue is placed in a vacuum (3.3 103 Pa) and heated to 150°C for 10 minutes and to 202°C for 40 minutes with stirring. After cooling, the crushed solids are triturated with ethanol. The product is filtered off and washed with cold ethanol and 1,1-oxybisethane, which gives 5.58 parts (57.7%) of (+)-(S)-9-amino-3,4-dihydro-3-methyl-1H-1, 4-benzodiazepine-2,5-dione (interm. 7).

c) 5.00 parts of intermediate 7, at 25°C and in an argon current atmosphere, is added to a suspension of 5.55 parts of lithium aluminum hydride in 154.5 parts of 1,4-dioxane. The reaction mixture is refluxed for 5 hours. After cooling to 10°C, 5.55 parts of water, 9.16 parts of NaOH 15% and 16.65 parts of water are added successively. Everything is mixed for 2 hours and then filtered. The precipitate is successively washed with 178 parts of warm tetrahydrofuran and 133 parts of warm dichloromethane. The combined filtrates are dried, filtered and evaporated. The residue is poured into a solution of 7.36 parts of N-methylmorpholine in 133 parts of dichloromethane. All this is added to a solution of 4.82 parts of trichloromethyl-chloroformate in 160 parts of dichloromethane for 15 minutes at 0°C and in a stream of argon. After stirring for 10 minutes at 0°C, the reaction mixture was warmed to room temperature and concentrated by evaporation. 70 parts of an aqueous solution of 1,4-dioxane (15%) is added to the residue and the mixture is heated on a steam bath in a stream of nitrogen for 45 minutes, cooled and extracted with dichloromethane (2x66.5 parts). The aqueous layer is filtered and made basic with NH4OH (conc.). The precipitate is filtered off, washed with a small amount of cold water, dried and triturated twice with 6.24 parts of 2-propanol, which gives 1.59 parts (32.1%) of (+)-(S)-4,5,6,7-tetrahydro-5-methyl -imidazo /4,5,1-jk//1,4/benzodiazepine-2(1H)-one; tt. 206.5°C (interm. 8).

d) To a mixture of 0.64 parts of intermediate 8, 0.5 parts of sodium carbonate, 0.52 parts of potassium iodide and 9.4 parts of N,N-dimethylformamide which is stirred, 0.56 parts of 1-bromo-3-methyl-2-butene are added at room temperature in an atmosphere argon. After stirring for 24 hours, the solvent was removed under reduced pressure. The residue is partitioned between 32 parts of dichloromethane and 35 parts of sodium chloride solution. The aqueous phase is extracted again with 32 parts of dichloromethane. The combined organic layers are washed with 35 parts of sodium chloride solution, dried, filtered and evaporated in vacuo. The residue is crystallized from 6.5 parts of acetonitrile. The crystallized product was filtered off and dried for 16 hours at 81°C under high vacuum, yielding 0.38 parts (45%) of (+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3 -methyl-2-butenyl)imidazo[4,5,1-jk]-[1,4]benzodiazepine-2(1H)-one; tt. 136.4°C (interm. 9).

e) A suspension of 38.16 parts of intermediate 9 and 15 parts of sodium carbonate in 578 parts of phosphoryl chloride is stirred for 2 days at 60°C in a nitrogen atmosphere. Excess phosphoryl chloride is distilled off under vacuum at 30-50°C. The obtained solid product is cooled (ice bath) and then dissolved in 500 parts of water. During vigorous stirring, the solution was made basic by slowly adding 1000 ml of NaHCO3 (sat.). The product is extracted with dichloromethane (3x355 parts) and the combined extracts are washed with NaHCO3 (sat.) and NaCl (sat.), dried, filtered and evaporated, which gives 27 parts (66.5%) of (S)-2-chloro- 4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo/4,5,1-jk//1,4/ benzodiazepines (interm. 10).

Example 3

a) A solution of 2.6 parts of methyl-2-bromo-3-nitrobenzoate, 1.75 parts of N-/(2-amino-1-methyl)ethyl/benzenemethanamine and 1.06 parts of sodium carbonate in 8 parts of 1-butanol is mechanically stirred and refluxed during 30 minutes. The solvent evaporates. 20 parts of water are added to the residue and the product is extracted twice with 30 parts of trichloromethane. The combined extracts are dried, filtered and evaporated. From the oily free base, the hydrochloride salt is prepared in the usual way. The salt is filtered off, washed with 2-propanol and dried, which gives 3.4 parts (85.5%) of methyl 3-nitro-2//2-methyl-2-/(phenylmethyl)aminoethyl/amino/benzoate-hydrochloride; tt. 204°C (interm. 11).

b) A mixture of 3.8 intermediates, 11.15 parts of sodium hydroxide 2N and 4 parts of 2-propanol is mixed and refluxed for one hour. A solution of 3 parts of concentrated hydrochloric acid and 5 parts of water is added to the boiling reaction mixture. After cooling, the product is filtered, washed with water and recrystallized from 80 parts of glacial acetic acid, which gives 3 parts (82%) of 3-nitro-2-///2-/(phenylmethyl)amino/2-methyl/ethyl/ amino/-benzoic acids; tt. 227°C (interm. 12).

c) A mixture of 189.3 parts of intermediate 12, and 400 parts of thionyl chloride and 400 parts of methylbenzene is mixed and refluxed for 2 hours. The solvent is distilled off and the residue is taken up in 600 parts of methylbenzene. Everything is treated with sodium bicarbonate solution. The separated organic layer is dried with anhydrous sodium carbonate, filtered and concentrated to a volume of about 500 parts. After standing at room temperature, the product partially settles. It is filtered off (the filtrate is set aside), washed successively with 2-propanol and 1,1-oxybisethane and dried, which gives the first fraction of 123.5 parts of crude 2,3,4,5-tetrahydro-methyl-9-nitro-4 -(phenylmethyl)-1H-1,4-benzodiazepine-5-one. The solvent is distilled off from the mother solution. The residue is dissolved in 160 parts of boiling 2-propanol and crystallized at room temperature. The precipitated product is filtered, washed sequentially with 2-propanol and 1,1-oxybisethane and dried, giving a second less pure fraction of 28 parts of 2,3,4,5-tetrahydro-3-methyl-9-nitro-4-( phenylmethyl)-1H-1,4-benzodiazepine-5-one. Both crude fractions were recrystallized from ethanol, yielding 137 parts (85%) of 2,3,4,5-tetrahydro-3-methyl-8-nitro-4-(phenylmethyl)-1H-1,4-benzodiazepine-5- she; tt. 125°C (interm. 13).

d) A solution of 20.2 parts of intermediate 13 in 200 parts of tetrahydrofuran is added to a suspension of 14 parts of lithium aluminum hydride in 40 parts of benzene and 50 parts of tetrahydrofuran, which is mixed and refluxed for 2.5 hours. The reaction mixture is cooled in crushed ice and dissolved by successive addition of water, sodium hydroxide solution 15% and again with water. The inorganic material is filtered off and the filtrate is evaporated. To the residue was added 40 parts of methylbenzene and this solution was evaporated to dryness, yielding 19.8 parts (87%) of 9-amino-2,3,4,5-tetrahydro-3-methyl-4-methyl-(phenylmethyl)-1H -1,4-benzodiazepine-5-one, as a red-colored oily residue (interm. 14), which was used for the synthesis in the next step without further purification.

e) The mixture of 19.8 parts of intermediate 14 and 7.2 parts of urea is heated to a temperature between 210-220°C until the foaming and evolution of gaseous ammonia stops (about 10 minutes). The reaction is cooled to about 100°C and boiled with 120 parts of 1N hydrochloric acid solution. The solution is decanted from the oily residue, treated with activated carbon and filtered. The filter is cooled, alkalized with ammonium hydroxide and the product is extracted once with 75 parts of trichloromethane and once with 150 parts of trichloromethane. The combined extracts are dried and evaporated. The residue is triturated in 24 parts of 2-propanol, drained and recrystallized from ethanol and then from 4-methyl-2-pentanone, which gives 2.5 parts (11%) of 4,5,6,7-tetrahydro-5-methyl-6- (Phenylmethyl)imidazo-[4,5,1-jk//1,4/-benzodiazepine-2(2(1H)-one; mp 205°C (interm. 15).

f) A mixture of 8 parts of intermediate 15 and one part of palladium on carbon 10% in 80 parts of glacial acetic acid is hydrogenated at 38°C. After the calculated amount of hydrogen has been consumed, the catalyst is drained and the acetic acid is distilled off. The residue is dissolved in 75 parts of water and the solution is made alkaline with 30 parts of concentrated ammonium hydroxide. The product crystallizes at room temperature. It is drained, washed with water and recrystallized from 20 parts of 2-propanol, which gives 3.7 parts (66.8) of 4,5,6,7-tetrahydro-5-methyl-imidazo-/4,5,1-jk//1 ,4/benzodiazepine-2(1H)-one; tt. 190.5°C (interm. 16).

g) To solutions of 1.0 parts of intermediate 16, and 0.816 parts of potassium iodide and 0.782 parts of sodium carbonate in 56.4 parts of N,N-dimethylformamide, which is mechanically stirred, a solution of 0.88 parts of 1-bromo-3-methyl- 2-butene in 14 parts of N,N-dimethylformamide. After stirring for 22.5 hours at room temperature, the reaction mixture was concentrated in vacuo at 70°C. The residue is partitioned twice between 130 parts of dichloromethane and 100 parts of a mixture of water and a saturated solution of sodium bicarbonate in water (50:50 vol.). The combined aqueous layers are extracted with 78 parts of dichloromethane. The dichloromethane layers were combined and extracted with 100 parts of saturated sodium chloride solution. The extract is dried, strained and concentrated in a vacuum at 40°C. The residue is crystallized twice from 16 parts of acetonitrile. Everything is cooled during 45 minutes at 0-5°C; the crystalline product is filtered, washed with 4 parts of cold acetonitrile (0-5°C) and dried overnight in vacuum at 78°C, which gives 0.805 parts (60.3%) of (±)-4,5,6,7- tetrahydro-5-methyl-6-(3-methyl-2-

butenyl)imidazo[4,5,1-[[1,4]-benzodiazepine-2(1H)-one; tt. 158.0°C (interm. 17).

h) A suspension of 1.0 parts of intermediate 17 in 8.25 parts of phosphoryl chloride is heated for 15 minutes at 90°C in a nitrogen atmosphere. The reaction mixture was evaporated and the residue partitioned between NaHCO3 (sat.) and dichloromethane. The aqueous layer is re-extracted with dichloromethane. The combined organic layers are washed with NaHCO3 (sat.) and NaCl (sat.), dried, filtered and evaporated to give 1.05 parts (98.3%) of 2-chloro-4,5,6,7-tetrahydro-5-methyl -6-(3-methyl-2-butenyl)imidazo /4,5,1-jk//1,4/ benzodiazepines (interm. 18).

Example 4

a) A mixture of 41.49 parts of 6-chloro-2H-3,1-benzooxazin-2,4(1H)-dione and 31.40 parts of methyl-L--alanine monohydrochloride in 108 parts of pyridine is refluxed for 10 hours in an argon atmosphere. The reaction mixture is cooled and stirred at room temperature for 12 hours. The precipitate is drained, washed with water and triturated in ethanol. The product is drained and washed in ethanol, which gives 24.77 parts (52.5%) of (S)-7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione (interm. 19).

b) 24.55 parts of intermediate 19 are added in portions to 142 parts of nitric acid at 0°C and in an argon atmosphere. After 3 and a half hours at 0°C, the solution is slowly added to 450 parts of ice with stirring. The precipitate is drained, washed with water and dried overnight at room temperature. 27.84 parts (93.9%) of (S)-7-chloro-3,4-dihydro-3-methyl-9-nitro-1H-benzodiazepine-2,5-dione (interm. 20) are obtained.

c) To a cooled (0°C) suspension of 18.2 parts of lithium-aluminum-hydride in 261 parts of 1,2-dimethoxyethane, 16.14 parts of intermediate 20 are added in portions in a nitrogen atmosphere. The mixture is stirred for 2 hours at 0°C and for 40 hours at reflux temperature. After cooling to 0°C, a mixture of 18.2 parts of water and 48.1 parts of tetrahydrofuran, 21.1 parts of NaOH 15% and 54.6 parts of water is added. The mixture is stirred for 1 hour at room temperature and then strained. The precipitate is refluxed in tetrahydrofuran for 5 minutes and filtered again. The combined filtrates are dried, filtered and evaporated, and the residue is dissolved in 399 parts of dichloromethane. After cooling and straining, this solution is combined with 18.2 parts of N-methylmorpholine and added dropwise to a mixture of 11.9 parts of trichloromethyl-chloroformate and 665 parts of dichloromethane at 0°C and an argon atmosphere. Everything is evaporated and the residue collected in 150 ml of a mixture of water and 1,4-dioxane 85:15. The mixture is heated for 2 hours on a steam bath in a nitrogen atmosphere. After cooling, the solid is strained and dissolved in 80 parts water. The solution is alkalized with NH4OH and stirred for 45 minutes. The product was filtered and crystallized sequentially from acetonitrile and 2-propanol, yielding 2.28 parts (16%) of (±)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methylimidazo-/4,5 ,1-jk//1,4/benzodiazepine-2(1H)-one; tt. 202.2°C; 20D=+72.6° (c=0.98% in methanol) (interm. 21).

d) To a mixture of 2.99 parts of intermediate 21 and 2.00 parts of sodium carbonate and 2.08 parts of potassium iodide and 37.6 parts of N,N-dimethylformamide which is stirred, 2.24 parts of 1-bromo-3-methyl-2-butene are added under an argon atmosphere. After stirring for 4 days at room temperature, the reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer is washed with NaCl (sat.), dried, filtered and evaporated. The residue is crystallized from acetonitrile (2x). The product was drained, washed with cold acetonitrile and dried, yielding 1.74 parts (45.2%) of (+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6(3-methyl- 2-Butenyl)imidazo/4,5,1-jk//1,4/benzodiazepine-2(1H)-one; tt. 135.6°C (interm. 22).

e) A suspension of 2.5 parts of intermediate 22 and 0.87 parts of sodium carbonate in 33 parts of phosphoryl chloride is mixed for 24 hours at 90°C in a nitrogen atmosphere. Excess phosphoryl chloride is distilled off under vacuum. The obtained solid is cooled (ice bath) and then collected with water. With vigorous stirring, the mixture is alkalinized by slowly adding NaHCO3 (sat). The product is extracted with dichloromethane (3x44.3 parts) and the combined extracts are washed with NaHCO3 (sat.) and NaCl (sat.), dried, filtered and evaporated. 2.57 parts (97.0%) of (S)-2,9-dichloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo/4,5 ,1-jk//1,4/benzodiazepines (interm. 23).

f) A mixture of 298.42 parts of intermediate 20 and 3324 parts of ethanol is hydrogenated at 50°C and normal pressure with 21.04 parts of platinum on carbon 5%. At the end of hydrogenation, the temperature rises to 70°C. The reaction mixture is filtered while it is warm, and the catalyst is washed with boiling ethanol. The filtrate is stirred overnight in an ice bath and then concentrated. Cool the rest on ice. The precipitate is drained, washed with methylbenzene and dried in vacuo at 50°C, which gives 187.7 parts (74.6%) of (S)-9-amino-7-chloro-3,4-dihydro-3-methyl-1H-1, 4-benzodiazepine-2,5-dione (interm. 24).

g) To a cooled (ice bath) suspension of 29.3 parts of lithium aluminum hydride in 392 parts of 1,2-dimethoxyethane, 30.78 parts of intermediate 24 are added in portions in a nitrogen atmosphere. The mixture is refluxed for 22 hours, cooled from 0-5°C and then treated with a mixture of 36.5 parts of 1,2-dimethoxyethane and 42 parts of water. Next, 48.7 parts of NaOH 15% and 135 parts of water are added. After mixing for 15 minutes, everything is filtered and the precipitate is washed with 1,2-dimethoxyethane. The combined filtrates were evaporated and the residue dried to give 25.4 parts (93.7%) of (S)-7-chloro-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepine-9-amine (interm 25).

h) 1253 parts of N,N-dimethylformamide, 66.98 parts of sodium carbonate and 71.38 parts of potassium iodide are successively added to a heated (40°C) solution of 91 parts of intermediate 25 in 500 ml of 1,2-dimethoxyethane. After cooling to 0-5°C, a solution of 271.3 parts of 1-chloro-3-methyl-2-butane in 270 parts of N,N-dimethylformamide is added dropwise under a nitrogen atmosphere. Everything is mixed for 13 hours at 0-5°C and then separated between dichloromethane and water. The aqueous layer is separated and re-extracted with dichloromethane. The combined dichloromethane layers are washed with water (7x), dried, filtered and evaporated. The residue is purified by column chromatography (silica gel; C6H5CH3/i.C3H7OH 98:2). The eluent of the desired fraction was collected, yielding 43.64 parts (51.8%) of (S)-7-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1 ,4-benzodiazepine-9-amine

(inter. 26).

Example 5

To a mechanically stirred solution of 1.24 parts of intermediate 5 in 4.5 parts of ethanol and 1.1 parts of water, 0.36 parts of potassium hydroxide were added. After mixing for 8 minutes at room temperature, 0.5 parts of carbon-disulfide is added. The reaction mixture is stirred for 10 minutes and then heated for 1 hour in an oil bath at 90°C. After cooling to room temperature, the mixture is diluted with 5.6 parts of water and then 0.47 parts of acetic acid is added. The mixture is filtered and the filtrate is treated with concentrated ammonium hydroxide. Everything is extracted twice with 32.5 parts of dichloromethane. The combined extracts are dried, strained and evaporated under reduced pressure. The residue is purified in a chromatographic column (silica gel; CH2Cl2/CH3OH 10:1). The pure fractions are collected and the eluent is evaporated. The residue is triturated in acetonitrile. The product was drained and dried, yielding 0.30 parts (20.4%) of 4,5,6,7-tetrahydro-5-methyl-6-propylimidazo-/4,5,1-jk//1,4/benzodiazepine-2(1H )-thion; tt. 149-151°C (compound 1). Following the same procedure and starting from 2,3,4,5-tetrahydro-3-methyl-4-allyl-1H-1,4-benzodiazepine-9-amine, it is possible to obtain 4,5,6,7-tetrahydro -5-methyl-6-allylimidazo-/4,5,1-jk//1,4/benzodiazepine-2(1H)-thione (compound 2).

Example 6

To a solution of 2.57 parts of intermediate 23 in 27.7 parts of ethanol is added 1.21 parts of thiourea. After refluxing for 24 hours, the reaction mixture is evaporated and the residue partitioned between NaHCO3 (sat.) and dichloromethane. The organic layer is washed with NaHCO3 (sat.), water and NaCl (sat.), dried, filtered and evaporated. The residue is purified twice by column chromatography (current; silica gel; CH2Cl2/CH3OH 30:1; HPLC; silica gel; CH3COOC2H5/hexane 4:6). The eluent of the iron fraction was evaporated, yielding 0.34 parts (13.3%) of (+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl) imidazo/4,5,1-jk//1,4)benzodiazepine-2(1H)-thione; tt. 180.3°C; D 20 =+15.95° (c21% in ethanol) (compound 3).

I can be obtained in a similar way

(±)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo /4,5,1-jk//1,4/benzodiazepine-2(1H) -thion; tt. 128.0° (exp.) (compound 4).

(+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo /4,5,1-jk//1,4/benzodiazepine- 2(1H)-thione; tt. 174.5°;

D 20=+15.95° (c=1% in ethanol) (compound 5).

Example 7

A mixture of 43.0 parts of intermediate 26, and 3152 parts of dichloromethane and 30.1 parts of N,N-diethylethanamine is stirred at 0-5°C in a nitrogen atmosphere and protected from light. A solution of 16.3 parts of thiophosgene in 299 parts of dichloromethane is added dropwise at 0-5°C. Everything is mixed for 1 hour at 0-5°C and then concentrated to about 1000 ml. The residue is washed with water (2x), dried, strained and evaporated. The residue is purified by column chromatography (silica gel; C6H5CH3/CH3COOOC2H5 88:12). The eluent of the desired fraction was evaporated, yielding 19.5 parts of (+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo/4 ,5,1-jk//1,4/benzodiazepine-2(1H)-thione; tt. 186.3°C; D 20 = +11.79° (conc. = 1% in CH3OH) (compound 3).

All the compounds listed in Table I can be obtained by following the procedure from the example indicated in the column under no. ex.

[image]

Example 8

A rapid, sensitive and automated analytical procedure is used for the evaluation of anti-HIV agents in vitro. One HIV-1 transformed T4 cell line, MT-4, previously shown (Koyanagi et al., Int. J. Cancer, 34, 445-451, 1985) to be highly sensitive and susceptible to HIV infection, serves as the target cell strain. Inhibition of HIV-induced cytopathic effect is used as endpoint. The vitality of HIV, as falsely infected cells, is determined spectrophotometrically via in-situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium-bromide (MTT). The 50% cytotoxic dose (CD50u g/ml) is defined as the concentration of compounds that reduces the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells is calculated by the following formula:

(ODT)HIV - (ODC)HIV

_______________________ expressed in %

(ODC)FAKE-(ODC)HIV

where (ODT)HIV is the optical density measured with a given concentration of test compounds in HIV-infected cells; (ODC)HIV optical density measured for control untreated mock-infected cells; all optical density values were determined at 540 nm. The dose that achieves: 50% protection according to the formula below is defined as a 50% effective dose (ED50 in μg/ml). The ratio of CD50 to ED50 is defined as the Selective Index (SI).

Table 2: 50% cytotoxic (CD50), 50% effective dose (ED50) and selective index (SI)

[image] Example 9: Oral drops

500 parts of the active ingredient (A.I.) are dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of polyethylene glycol at 60-80°C. After cooling to 30-40°C, add 35 l of polyethylene glycol and mix well. Then add a solution of 1750 parts of sodium-saccharin in 2.5 l of purified water and add 2.5 l of cocoa flavoring and polyethylene glycol q.s. with mixing. up to a volume of 50 l, whereby an oral solution of drops containing 10 mg/ml of A.I. The resulting solution is filled into suitable containers.

Example 10: Oral solutions

9 parts of methyl-4-hydroxybenzoate and 1 part of propyl-4-hydroxybenzoate are dissolved in 4 l of boiling purified water. First, 10 parts of 2,3-dihydroxybutane diacid and then 20 parts of A.I. are dissolved in 3 l of this solution. The last solution is combined with the residual part of the previous solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol 70% solution are added to it. 40 parts of sodium saccharin are dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. Combine the latter solution with the former, add water q.s. up to a volume of 20 l, which gives an oral solution containing 5 mg of active ingredient per teaspoon (5 ml). The resulting solution is filled into suitable containers.

Example 11: Capsules

20 parts A.I., 6 parts sodium lauryl sulfate, 56 parts starch, 56 parts lactose, 0.8 parts colloidal silicon dioxide, and 1.2 parts magnesium stearate are mixed together vigorously mechanically. The resulting mixture is then filled into 1000 suitably hardened gelatin capsules, each of which contains 20 mg of the active ingredient.

Example 12: Layer-coated tablets

Obtaining a tablet substance

A mixture of 100 parts of A.I., 570 parts of lactose and 200 parts of starch is mixed well and then moistened with a solution of 5 parts of sodium dodecyl sulfate and 10 parts of polyvinylpyrrolidone (Kollidon-K 90R) in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then 100 parts of microcrystalline cellulose (AvicelR) and 15 parts of hydrogenated vegetable oil (SterotexR) are added. Everything is mixed well and compressed into tablets, resulting in 10,000 tablets, each containing 10 mg of the active ingredient.

Dragging

A solution of 5 parts of ethyl cellulose (Ethocel 22 cpsR) in 150 ml of dichloromethane is added to a solution of 10 parts of methyl cellulose (Methocel 60 HGR) in 75 ml of denatured ethanol. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 parts of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then 2.5 parts of magnesium octadecanoate, 5 parts of polyvinylpyrrolidone and 30 ml of concentrated colored suspension (Opaspray K.1-2109R) are added and everything is homogenized. Tablet substances are coated with the thus obtained mixture in one coating apparatus.

Example 13: Injection solution

1.8 parts of methyl-4-hydroxybenzoate and 0.2 parts of propyl-4-hydroxybenzoate are dissolved in about 0.5 l of boiling water for injections. After cooling to about 50°C, add 4 parts of lactic acid, 0.05 parts of propylene glycol and 4 parts of A.I. The solution is cooled to room temperature and supplemented with water for injections q.s. ad 1 l, giving a solution containing 4 mg/ml A.I. The solution is sterilized by filtration (U.S.P. XVII p.811) and filled into sterile containers.

Example 14: Suppositories

3 parts A.I. dissolve in a solution of 3 parts 2,3-dihydroxybutane diacid in 25 ml polyethylene glycol 400. 12 parts surfactant (SPANR) and triglyceride (WITEPSOL 555R) q.s. ad 300 parts melt together. The latter mixture is well mixed with the previous solution. The thus obtained mixture is poured into molds at a temperature of 37-38°, whereby 100 suppositories are obtained, each of which contains 30 mg/ml of A.I.

Example 15: Injection solution

50 parts of A.I. and 12 parts of benzyl alcohol are mixed well and sesame oil q.s. is added. ad 1 l, resulting in a solution containing 60 mg/ml A.I. The solution is sterilized and filled into sterile containers.

Claims (11)

1. Compound formula [image] a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, indicated that R1 represents C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, C3-6-cycloalkyl, or C1-6-alkyl substituted with aryl or with C3-6-cycloalkyl; R 2 is hydrogen or C 1-6 -alkyl; R 3 is hydrogen or C 1-6 -alkyl; each of R4 and R5 independently represents hydrogen or C1-6-alkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy, C1-6-alkyloxy, amino or mono- or di(C1-6-alkyl)amino; and aryl is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6-alkyl, halogen, hydroxy, C1-6-alkyloxy, amino, nitro and trifluoromethyl. 2. Compound according to claim 1, characterized in that R1 represents C1-6alkyl, C3-6-alkenyl, C3-6-alkynyl or C1-6-alkyl substituted with aryl or with C3-6-cycloalkyl; each of R4 and R5 independently represents hydrogen, C1-6-alkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy or C1-6-alkyloxy. 3. A compound according to claim 2, characterized in that R1 represents C3-6-alkyl, C3-6-alkenyl or C1-6-alkyl substituted with C3-6-cycloalkyl; R 2 is C 1-6 -alkyl; R5 is hydrogen. 4. Compound according to claim 3, characterized in that R1 represents C3-6-alkyl, C3-6-alkenyl or (C3-6-cycloalkyl)-methyl; R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen, methyl, halogen, cyano, nitro or trifluoromethyl. 5. Compound according to claim 4, characterized in that R1 represents propyl, 2-propenyl, 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl or cyclopropylmethyl ; R 4 is hydrogen, methyl or chlorine. 6. The compound according to claim 1, characterized in that it is selected from the group consisting of 4,5,6,7-tetrahydro-5-methyl-6-propylimidazo[4,5,1-jk]-[1,4]benzodiazepine-2(1H)thione; (+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine- 2(1H)thione; (+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1, 4]benzodiazepine-2(1H)thione; their pharmaceutically acceptable acid addition salts and their stereochemically isomeric forms. 7. Compound formula [image] its pharmaceutically acceptable acid addition salt or its stereochemically isomeric form, characterized in that R2, R3, R4 and R5 are defined as in claim 1. 8. Compound formula [image] its pharmaceutically acceptable acid addition salt or its stereochemically isomeric form, characterized in that R1, R2 and R3 are defined as in claim 1; and (a) each of R4 and R5 independently represents C1-6-alkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy, C1-6-alkyloxy, amino or mono- or di(C1-6alkyl)amino, or (b) R4a is hydrogen and R5a is cyano, nitro, trifluoromethyl, hydroxy, C1-6alkyloxy, amino or mono- or di(C1-6alkyl)amino. 9. Pharmaceutical composition, characterized in that it contains as an active ingredient a therapeutically effective amount of the compound according to any of claims 1 to 6 and claim 8. 10. A method for preparing a pharmaceutical composition according to claim 10, characterized in that a therapeutically effective amount of the compound defined in any of claims 1 to 6 and claim 8 is thoroughly mixed with a pharmaceutical carrier. 11. A process for the production of a compound according to any claim from 1 to 6, characterized in that it is carried out (a) condensation of 9-amino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine of the formula [image] wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined as in formula (I), with a reagent of formula L-C(=S)-L (III), wherein L represents a leaving group, in a reaction-inert solvent; (b) thionation of 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2-one of the formula [image] in which R1, R2, R3, R4 and R5 are defined as in formula (I), i) reaction with a halogenating agent and conversion of the thus obtained 2-halo-4,5,6,7-tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepine with thiourea or with alkali metal thiosulfate in a reaction-inert solvent; or ii) thionation with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide or phosphorus pentasulfide in an inert solvent; c) N-alkylation of intermediates of the formula [image] wherein R2, R3, R4 and R5 are defined as in formula (I), with a reagent of formula R1-W (VIa), wherein W represents a reactive leaving group and R1 is defined as in formula (I), in reaction inert solvent; d) N-alkylation of intermediates of the formula [image] in which R2, R3, R4 and R5 are defined as in formula (I), with a ketone or aldehyde of the formula R1-b=O (VI-b), in which R1-b represents a geminal divalent radical derived from R1-a-H, at wherein R1a represents C1-6-alkyl, C3-6-cycloalkyl or C1-6-alkyl substituted with aryl or with C3-6-cycloalkyl, and wherein the two geminal hydrogen atoms are replaced by =O, in a reaction-inert solvent , which gives the compound of the formula [image] e) thiation of tetrahydroimidazo[4,5,1-jk][1,4]benzo-diazepine of the formula [image] in which R2, R3, R4 and R5 are defined as in formula (I), with elemental sulfur at elevated temperature; f) reduction and thiocarbonylation of 9-nitrobenzodiazepines of the formula [image] wherein R 2 , R 3 , R 4 and R 5 are as defined in formula (I), in the presence of alkali metal sulfide or hydrogen sulfide, and carbon disulfide; g) cyclization of benzimidazol-2-thione of the formula [image] wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined as in formula (I) and W represents a reactive leaving group, in a reactively inert solvent, and optionally, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt form treatment with acid; or vice versa, converting an acid salt into a free base with an alkali; and/or preparation of its stereochemically isomeric forms.