HU207322B - Process for producing imidazo-benzodiazepin-2/1h/-one derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Imidazo-benzodiazepine derivs. of formula (I), their pharmaceutically acceptable acid addn. salts and their stereochemically isomeric forms are new. R1 = 1-6C alkyl (opt substd. by aryl or 3-6C cycloalkyl), 3-6C alkenyl, 3-6C alkynyl or 3-6C cycloalkyl; R2 and R3 = H or 1-6C alkyl; R4 and R5 = H, 1-6C alkyl, halo, CN, NO2, CF3, OH, 1-6C alkoxy, NH2 or mono- or di-(1-6C alkyl) amino; aryl = phenyl opt. substd. by 1-3 of 1-6C alkyl, halo, OH, 1-6C alkoxy, NH2, NO2 or CF3.

Description

The present invention relates to a process for the preparation of a compound of formula (I): wherein:

R ¹ is hydrogen or C 3 -C 6 alkenyl,

R ² is C 1-6 alkyl,

R ⁴ is a halogen atom and pharmaceutically acceptable salts and stereochemically isomeric forms thereof.

The compounds of formula (I) may also exist in tautomeric forms. Although these tautomeric forms are not specifically designated by the above formula, the present invention also applies to these tautomers.

In the above definitions, the term halogen generally refers to fluorine, chlorine, bromine and iodine.

On the one hand, the compounds of the present invention are useful intermediates for the compounds of formula (I)

R ¹ is C 1 -C 6 alkyl, C 3 -C 6 alkenyl or C 3 -C 6 cycloalkyl substituted with C 1 -C 6 alkyl,

R ² is hydrogen or C 1-6 alkyl,

R ³ is hydrogen or C 1-6 alkyl,

R ⁴ and R 'are each independently hydrogen or halogen, or C 1 -C 6 alkyl, nitro or trifluoro, while the other hydrogen is a potent antiviral compound on its own.

As used herein, C 1-6 alkyl is understood to mean a straight or branched saturated hydrocarbon group, e.g. methyl, ethyl, propyl,

methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl. C 3-6 alkenyl is understood to mean a straight or branched C 3 -C 6 hydrocarbon containing a double bond, e.g. 2-propenyl, 2-butenyl, 2-methyl-2-propenyl, pentenyl, hexenyl and the like.

Depending on the nature of the various substituents, the compounds of formula I may contain a number of asymmetric carbon atoms. Unless specifically mentioned or indicated, the chemical designation refers to a mixture of all possible stereochemically isomeric forms of the compounds. These mixtures contain all diastereomers and enantiomers of the parent molecular structure. The absolute configuration of all chiral carbon atoms can be denoted by the letters R and S used in the stereochemical notation. R and S are defined as described in Pure Appl. Chem. 1987, 45, 11-30. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of this specification.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by methods known per se. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques such as countercurrent partition chromatography, liquid chromatography and the like. The enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Pure stereochemically isomeric forms may be prepared using appropriate stereochemically pure starting materials, provided that the reaction is stereospecifically performed.

The compounds of formula (I) possess the essential fartnacological properties and can therefore be converted into their pharmaceutically active non-toxic addition salts. This conversion can be carried out using appropriate acids such as inorganic acids (such as hydrochloric, hydrobromic and the like, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2- hydroxypropionic acid, 2-oxopropionic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butanedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2, 3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4 amino-2-hydroxybenzoic acid and the like. Conversely, the salt compounds can be converted to the free base form by treatment with alkalis. The term pharmaceutically acceptable acid addition salt also encompasses solvates of the compounds of formula (I) and are therefore intended to be included within the scope of this invention. Examples of solvates include hydrates, alcoholates and the like.

A preferred group of compounds of formula I are those wherein R ¹ is C 3 -C 6 alkenyl.

The most valuable compound is:

(+) - (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.

The compounds of formula (I) are generally prepared from a 9-amino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine of formula (II) and a reagent of formula (III) wherein L and L 'are the same or by condensation of a different suitable leaving group (see Scheme a). In formula (II), R ¹ , R ² and R ⁴ are as defined in formula (I).

Examples of suitable reagents of formula (III) are urea, di (C 1-6 alkyl) carbonate, carbonyl dichloride. trichloromethyl chloroformate. 1,1 '-carbonylbis [1H-imidazole], ethyl chloroformate and the like.

The above-mentioned condensation reaction may be carried out under stirring and optionally heating in a reaction-inert solvent, preferably of relatively high boiling point, such as an aromatic hydrocarbon (benzene, methylbenzene, dimethylbenzene and the like), a halogenated hydrocarbon (e.g. methane, tetrachloromethane, chlorobenzene and the like), an ether (e.g., tetrahydrofuran, 1,4-dioxane, Ι, Γ-χχί-bis-butane, 1,1'-oxybis (2-methoxyethane), 1,2 bis (2-methoxyethoxy) ethane and

EN 207 322 Β similar], a dipolar aprotic solvent (e.g., N, N-dimethylformamide, Ν, Ν-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, pyridine, methylpyridine, dimethylpyridine, tetrahydro). -thiophene-1,1-dioxide and the like) or a mixture of the abovementioned solvents. In many cases, the reactants are preferably heated without the use of a solvent. Further, it may be advantageous to add bases such as a tertiary amine (e.g., Ν, Ν-diethylethanamine, N- (1-methylethyl) -2-propanamine, 4-methylmorpholine and the like) to the reaction mixture. administration.

The compounds of formula (I) may also be prepared according to the processes described in European Patent Application EP 0336466. For example, compounds of formula (I) may be prepared by Nalkenylation of a compound of formula (I-b) according to methods known per se (see Scheme b).

In all of the processes described above and in the following, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to generally known procedures.

Many of the intermediates and starting materials for the above processes are known compounds, which may be prepared according to methods already known for the preparation of similar compounds, and some intermediates are new. Many of these methods are described in detail below.

Intermediates of formula (II) ¹ is not a hydrogen atom, R can be prepared by generally known in the N-unsubstituted amino-9-benzodiazepinekből formula (II) manner.

Methods for preparing the intermediates of formula (II) are outlined in Scheme 1.

In the formulas (X), (XI), (XIII), (XIV), (XVI) and (XVII) in Scheme 1, R ^{1 is C} 1-5 alkylcarbonyl, arylcarbonyl, (3- C6 cikloalkilj-carbonyl or [(aryl) (C 3-6 cycloalkyl)] -! -. 5 carbon atoms, an alkylcarbonyl group of these intermediates may be prepared by known N-substitution of the appropriate intermediates wherein ^R1 is hydrogen, the , and hydrogenation to the corresponding N-substituted intermediates can be carried out with complex metal hydrides or hydrides which are

Scheme 1, step A). In each of the following reactions wherein R ^{1 in} the intermediate is hydrogen, the N-substitution procedures described above can be used to convert the compounds into an intermediate in which R ¹ is other than hydrogen.

The aniline derivatives of Scheme 1 may be prepared by reduction of the corresponding nitrobenzene derivative known per se (Step A). This reduction can be accomplished by treating the nitrobenzene with a reducing agent such as a complex metal hydride such as lithium aluminum hydride, a hydride such as diborane, aluminum hydride and the like. Examples of reaction-inert solvents include 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. If desired, the above may be combined with other solvents such as aromatic hydrocarbons, including benzene, methylbenzene and the like, and the reaction may be carried out at elevated temperature if desired. In addition, the above reaction may be supplemented by treating the nitrobenzene derivative with a reducing agent such as sodium dithionite, sodium sulfide, sodium bisulfide, titanium (III) chloride and the like in a suitable solvent, preferably water.

The above nitro → amine reduction may also be carried out by the following catalytic hydrogenation methods known per se. For example, the reduction can be accomplished by mixing the reagents under a hydrogen atmosphere while a suitable catalyst is present, such as palladium on charcoal or platinum, Raney nickel and the like. Suitable solvents include, for example, water, alkanols such as methanol, ethanol and the like, esters such as ethyl acetate and the like. It may be advantageous to increase the temperature and / or the pressure to facilitate the reduction reaction. Catalyst poisons such as thiophene and the like can be added to avoid undesired hydrogenation of certain functional groups of products and reagents.

The nitrobenzene derivatives of Scheme 1 can be prepared from benzene amine derivatives by known nitration procedures (Step B). For example, the starting materials may be nitrated in the presence of concentrated sulfuric acid by treatment with concentrated or fuming nitric acid. If desired, the above reaction may be carried out in the presence of a solvent, such as a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane and the like. However, in many cases, the above nitration can be accomplished by adding the nitrated salt of the starting materials to concentrated sulfuric acid.

The benzodiazepine derivatives (II), (X) and (XI) may be obtained by cyclization of the corresponding aniline derivatives (XII), (XIII) and (XIV).

These aniline derivatives, wherein W represents a reactive leaving group, can be prepared by treating the corresponding alkanols with a halogenating reagent such as thionyl chloride, phosphoryl chloride, phosphorus trichloride and the like, or by sulfonylating a reagent such as methanesulfonyl chloride. methylbenzenesulfonyl chloride and the like (Step D). The above alkanols can be prepared from the corresponding substituted benzene derivatives (XVIII), (XX) and (XXI) using an amino ethanol derivative of R ¹ NH-CH (R ² ) -CH ₂ OH described above, known per se. according to the alkylation reactions [reaction step E],

The intermediates of formula (II) may be prepared according to the reaction steps outlined in Scheme 2

HU 207 322 Β is. Reaction steps A) to D) are intended to refer back to analogous reaction steps of the above reaction scheme.

For example, the intermediate of formula (II) may be prepared by reacting a 9-amino or 9-nitrobenzodiazepin-5-one of formula (XXII) or (XXIII) with a complex metal hydride such as lithium aluminum hydride and the like in a suitable inert solvent. such as 1,2-dimethoxyethane, 1,1'-oxybis (2-methoxyethane), 2,5,8,11-tetraoxadodecane, methoxybenzene and the like in solvents [F] and G ). In order to facilitate the above reduction reaction, it may be advantageous to use an excess of the reducing reagent and conduct the reaction at elevated temperature, preferably at reflux temperature.

Intermediate XXIII can also be obtained by condensing a corresponding substituted nitrobenzene XXXIV with a diamine reagent R'NH-CH (R ² ) -CH ₂ NH ₂ (XXXV) which can be carried out. in a suitable inert solvent such as an alkanol such as methanol, ethanol, 2-propanol, 1-butanol and the like, an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like, a halogenated hydrocarbon such as such as trichloromethane, tetrachloromethane and the like in an ether such as tetrahydrofuran, 1,4-dioxane, 1,1'-oxybis-butane, 1,1'-oxybis (2-methoxyethane) and the like in a ketone such as 2-propanone, 4-methyl2-pentanone and the like, in a dipolar aprotic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, dimethylsulfoxide and the like p agent mixture. It may be advantageous to add a base such as an alkali or alkaline earth metal carbonate such as sodium carbonate, sodium bicarbonate and the like to the solvent. The above condensation reaction is conveniently carried out at elevated temperature, preferably at reflux temperature.

The amide derivatives (XXVIII), (XXIX), and (XXX) in Scheme 2 may be prepared from an appropriately substituted (XXXI), (XXXII), R'NH-CH (R ² ) -CH ₂ OH ethanolamine of formula (XIX). or by N-acylation with a 2-aminobenzoic acid derivative of the Formula XXXIII, in which L is hydroxy, or another leaving group such as halogen (such as chlorine or bromine), alkylcarbonyloxy, acetylalkyloxy; , methoxy, ethoxy and the like, or imidazolyl and the like leaving groups. The above N-acylation reaction (Step I) can be carried out by stirring the reactants in an inert solvent, which is preferably carried out at elevated temperature. In cases where L is hydroxy, the above N-acylation reaction may be carried out with a reagent capable of forming an amide. Examples of such compounds are Ν, Ν-dicyclohexylcarbodiimide (DGC), preferably in the presence of a catalytic amount of hydroxybenzotriazole (HOBT), or 4-dimethylaminopyridine (DMAP), 2-chloro-1-methylpyridinium, iodide, Ι, Γ-carbonyl bis (1H-imidazole), 1,1'-sulfonyl bis (1H-imidazole) and the like. Suitable solvents include hydrocarbons such as dichloromethane, trichloromethane and the like, ethers such as tetrahydrofuran, 1,4-dioxane and the like, dipolar aprotic solvents such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide. , pyridine and the like, or a mixture of the above solvents.

The intermediates of formula (II) may also be prepared from a benzodiazepinedione (XXXVI) by converting a compound of formula (XXII) or (XXIII) to an intermediate of formula (II) according to the reduction procedures described above. The preparation of intermediates of formula (XXXVI) may generally be carried out according to the reaction routes outlined in Scheme 3.

Many of the intermediates in Scheme 3, such as (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL) and (XLI), are capable of selectively reducing certain functional groups such as nitro, ester and / or an aliphatic amide group in the presence of an aromatic amide group (Step J). This selective reduction can be accomplished by treating the appropriate starting material with a complex metal hydride such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran, 1,4-dioxane and the like. In addition, the above selective reaction can also be carried out by treating the appropriate starting material with sodium bis (2-methoxyethoxy) aluminum hydride or sodium borohydride, which is a suitable metal salt such as calcium chloride, cerium (III) chloride, aluminum chloride, In the presence of (IV) chloride and the like metal salts, it is carried out in a reaction-inert solvent.

The benzodiazepinedione derivatives of Scheme 3 can be prepared by cyclizing the appropriate acyclic intermediates of formula (XXXIX), (XL) and (XLI) wherein R is C 1-6 alkyl or aryl.

(a) heating in an inert atmosphere, preferably under reduced pressure,

b) treatment with a bifunctional catalyst which may be, for example, acetic acid, 2-hydroxypyridine, pyrazole, 1,2,4-triazole and the like; treatment with an inert solvent such as an aromatic hydrocarbon such as methylbenzene, dimethylbenzene and the like, and optionally at elevated temperature, or

c) hydrolyzing the ester and treating the corresponding carboxylic acid (R = H) with a suitable acid such as a hydrogen halide such as hydrochloric acid, sulfuric acid, phosphoric acid and the like or treatment with a halogenating reagent such as thionyl chloride and the like finally.

The above intermediates may also be prepared from an appropriately protected R 1 -NH-CH (R ² ) -COOR (XLV) wherein R is C 1-6 alkyl or aryl.

322 Β, also by N-acylation reaction (reaction step L). Another reaction partner for the N-acylation reaction is an appropriately substituted isatoic anhydride or a suitable 2-aminobenzoic acid derivative. Reagents are reacted in a reaction inert solvent with stirring at reflux temperature. Trichloromethane, pyridine and the like may be used as the solvent.

The intermediates of formula (Π) may also be prepared from benzodiazepin-2-one derivatives according to the procedures outlined in Scheme 4.

Examples of suitable reagents of formula (IH) are urea, di (C 1-6 alkyl) carbonate, carbonyl dichloride, trichloromethyl formate. 1,1'-carbonylbis (1 H -imidazole), ethyl chloroformate and the like.

In all of the above schemes, the chemical designation of the intermediates defines a mixture of all possible stereochemically isomeric forms. This includes, for example, diastereomeric mixtures, enantiomeric mixtures such as racemates and mixtures enriched in one of the enantiomers, and optically pure isomeric forms of the basic molecular structure.

Stereochemically isomeric forms of the compounds of formula (I) and intermediates in the above Schemes can be prepared by methods known per se. For example, diastereomers may be separated by physical separation techniques such as distillation, selective crystallization, chromatographic techniques such as counter-current distribution, liquid chromatography, and the like.

Optically pure intermediates may be prepared from the corresponding optically pure intermediates, provided that the reactions are stereospecifically performed. Particularly important optically pure starting materials in the above schemes are the amino acids R'NH-CHR ² -COOR (XLV) and / or substituted derivatives thereof, and the corresponding aminoalkanols and / or R'NH-CHR of formula XIX ² CH ₂ OH substituted derivatives.

In addition, optically pure intermediates may be prepared by separation of the appropriate racemates, such as by selective crystallization of diastereomeric salts with optically active resolving agents, or by chromatography of the diastereomeric derivatives, chiral phase chromatography of the racemates and the like.

The compounds of the formula I possess antiviral, in particular anti-retroviral, properties. Until recent years, retroviruses have been considered as pathogenic agents for many warm-blooded animals, but in the meantime it has become known that viruses cause many diseases in both warm-blooded animals and humans. Retrovirus infections and the treatment of infections have been of particular interest since it has been discovered that a retrovirus, namely the Human Immunodeficiency Virus (HIV), also known as LAV, HTLV-III or ARV, is the causative agent in humans ( Acquired Immune Deficiency Syndrome). The HIV virus infects primarily human T4 cells and either destroys them or causes a change in their normal function, primarily their immune system coordination. As a result, the infected patient has fewer and fewer T-4 cells and is behaving abnormally. Thus, the immune defense system is unable to cope with infections and pathological tissue formation, and the HIV-infected patient usually dies from another infection, such as pneumonia or even cancer, and not directly from HIV infection. Other phenomena associated with HIV infection include platelet loss, Kaposi's sarcoma, CNS infection and associated progressive demyelinating, which causes dementia, and symptoms such as progressive speech disorder, disorientation, and disorientation. HIV infection is often associated with peripheral neuropathy, Progressive Generalized Lymphadenopathy (PGL), and AIDS-related Complex (ARC). Based on the antiviral properties of the compounds of Formula I, in particular antiretroviral, including anti-HIV, these compounds are effective antiviral chemotherapies for controlling viral infection of warm-blooded animals, including human HIV, and more particularly HIV-1. for the treatment of infections.

In addition, the compounds of formula (I), due to their antiviral properties, including antiretroviral properties, and their pharmaceutically acceptable salts and stereochemically isomeric forms, are useful in the treatment and prevention of viral infections in warm-blooded animals, including retroviruses. Human retroviruses, including HIV, especially HIV-1 and HTLV-1 (human T-lymphotropic type I virus) cause white blood cells and lymphoid tumors. An example of a non-human, i.e. animal, retroviral infection is the FeLV virus (feline leukemia virus), which results in white blood and immune deficiency disease. Symptoms that can be prevented or treated with the compounds of the present invention, particularly those associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex disease (ARC), progressive general lymph node disease, CNS diseases caused by retroviruses. HIV-mediated dementia and multiple sclerosis.

Due to their antiviral, especially antiretroviral, activity, the compounds of the present invention can be converted into various pharmaceutical compositions for use. In preparing the pharmaceutical compositions of the present invention, an effective amount of the active compound, or base or acid addition form thereof, is admixed with pharmaceutically acceptable substances. The aforementioned carriers can be selected from a wide variety according to the desired dosage form. The pharmaceutical compositions are conveniently formulated in unitary doses, preferably oral,

322 Β rectal, percutaneous or parenteral injection. For example, any conventional substance may be used in the preparation of compositions for oral administration. For the preparation of liquids for oral use such as suspensions, syrups, elixirs and solutions, water, glycols, oils, alcohols and the like may be used. For the preparation of powders, tablets, capsules, pills, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be used. Because of their ease of administration, the most advantageous oral dosage forms are tablets and capsules containing, of course, solid pharmaceutical carriers. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, and may also contain other additives such as solubility enhancers. Injectable solutions, for example, may be prepared from a carrier consisting of physiological saline, glucose solution, or a mixture thereof. Injectable suspensions may be formulated with liquid carriers, suspending agents, and the like. In the case of formulations suitable for percutaneous administration, the carrier will advantageously include absorption enhancers and / or appropriate wetting agents, optionally containing small amounts of other natural additives which will not cause significant deleterious effects to the skin. These materials facilitate absorption into the skin and / or preparation of the desired composition. These compositions can be used in a variety of ways, such as patches, flastromas, or ointments. The acid addition salts of the compounds of formula I are obviously more advantageous in the preparation of aqueous compositions because of their increased water solubility compared to the corresponding base form. The dosage unit used herein and in the claims relates to a physically discrete unit that permits uniform administration, and each unit contains a predetermined amount of active compound that is capable of delivering the desired effect in association with the pharmaceutical carriers employed. Examples of dosage units are tablets (including coated and uncoated tablets), capsules, pills, lozenges, wafers, injectable solutions or suspensions, teaspoonfuls or broths, and the like, and isolated multiplications thereof.

Those skilled in the art of treating viral diseases can readily determine the doses required for antiviral therapy based on the test results described herein. In general, the effective amount will be in the range of 0.01 mg to 20 mg / kg body weight, preferably 0.1 to 5 mg / kg body weight. It may be desirable to separate the desired dose into two, three, four desires into several smaller doses and to administer these at different times of the day. These lower doses may be converted into dosage units, for example 1 to 1000 mg, preferably

In units containing 5-200 mg of active ingredient.

The following examples are intended to illustrate the process of the invention in greater detail. Unless specifically stated, percentages that determine concentration ratios are by weight.

Example 1

a) A mixture of 41.49 parts of 6-chloro-2H-3,1-benzoxazine-2,4 (1H) -dione and 31.40 parts of methyl-La-alanine monohydrochloride in 108 parts of pyridine is heated at reflux for 10 hours. under an argon atmosphere. The reaction mixture was cooled and stirred at room temperature for 12 hours. The precipitate was filtered off, rinsed with water and triturated with ethanol. The product is filtered off and rinsed with ethanol. 24.77 parts (52.5%) of (S) -7-chloro-3,4-dihydro-3-methyl-1H-4-benzodiazepine-2,5-dione are obtained (interm. 19).

b) 24.55 parts of intermediate compound 19 are added in portions to 142 parts of nitric acid at 0 ° C under argon. After 3.5 hours at 0 ° C, the solution is slowly added to 450 parts of ice with stirring. The precipitate was filtered off, washed with water and dried at room temperature overnight. 27.84 parts (93.9%) of (S) -7-chloro-3,4-dihydro-3-methyl-9-nitro-1H-1,4-benzodiazepine-2,5-dione are obtained (interm. 20).

c) To a suspension of 18.2 parts of lithium aluminum hydride in 261 parts of cooled (0 ° C) in 1,2-dimethoxyethane is added 16.14 parts of intermediate 20 under a nitrogen atmosphere. The mixture was stirred for 2 hours at 0 ° C and refluxed for 40 hours. After cooling to 0 ° C, a mixture of 18.2 parts of water and 48.0 parts of tetrahydrofuran, 21.1 parts of 15% NaOH and 54.6 parts of water is added. The mixture was stirred for 1 hour at room temperature and then filtered. The precipitate was refluxed in tetrahydrofuran for 5 minutes and then filtered again. The combined filtrates were dried, filtered and evaporated, and the residue was dissolved in 399 parts of dichloromethane. After drying and filtration, this solution was 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 under argon. The solution was evaporated and the residue was taken up in 150 ml of a 85:15 mixture of water and 1,4-dioxane. The mixture was heated in a steam bath for 2 hours under a nitrogen atmosphere. After cooling, the solid is filtered off and dissolved in 80 parts of water. The solution was basified with ammonia water and stirred for 45 minutes. The product was filtered off and then crystallized from acetonitrile and then 2-propanol. 2.28 parts (16%) of (+) - (S) -9-chloro-4,5,6,7-tetrahydro-5-methylimidazo [4,5,1-jk] - [1,4] benzodiazepine -2 (1H) -ont_ is obtained. M.p .: 202.2 ° C [α] D 20 = + 72.6 ° (c = 0.98%, methanol).

d) 2.99 parts of the preceding product, 2.00 parts of sodium carboxyl

To a stirred mixture of 2.08 parts of potassium iodide, 2.08 parts of Ν, Ν-dimethylformamide, 2.24 parts of 1-bromo-3-methyl-2-butene are added under an argon atmosphere. After stirring at room temperature for 4 days, the reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was washed with saturated NaCl solution, dried, filtered and evaporated. The residue was crystallized twice from acetonitrile. The product is filtered off, washed with cold acetonitrile and dried. 1.74 parts (45.2%) of (+) - (S) -9-chloro-4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4.5 1,1-jk] - [1,4] benzodiazepin-2 (1H) -one is obtained. Melting point: 135.6 ° C.

The product thus obtained is desalkenylated to give the product of (c).

Preparation Examples

Example 2

Drops suitable for oral administration

500 parts of the compound of the invention 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, 35 liters of polyethylene glycol are added and the mixture is vigorously stirred. Subsequently, a solution of 1750 parts of sodium saccharin in 2.5 liters of purified water was added, followed by the addition of 2.5 liters of cocoa water, followed by the addition of polyethylene glycol to a final volume of 50 liters. Thus, a solution for oral administration in the form of a drop containing 10 mg / ml of the compound of the invention is obtained. The resulting solution is filled into suitable small containers.

Example 3

A solution of oral solution of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxybenzoate in 4 liters of boiling purified water was added. 10 liters of 2,3-dihydroxysuccinic acid are dissolved in 3 liters of the solution thus obtained, followed by 20 parts of the compound of the invention. The latter solution was combined with the remainder of the first solution and 12 l 1,2,3-propanetriol and 3 l 70% sorbitol solution were added. Dissolve 40 parts of sodium saccharin in 0.5 L of water and add 2 ml of raspberry and 2 ml of gooseberry essence. The latter solution is combined with the former solution and made up to a final volume of 20 liters with water. Thus, a solution for oral administration containing 5 mg of active ingredient per teaspoonful (5 ml) was prepared. The resulting solution is filled into suitable small containers.

Example 4

Capsules of the compound of the invention, 6 parts of sodium lauryl sulfate, 56 parts of starch, 56 parts of lactose, 0.8 parts of colloidal silicon dioxide and 1.2 parts of magnesium stearate are vigorously mixed. The resulting mixture is filled into 1000 gelatin capsules of suitable strength, each containing 20 mg of the active ingredient of the invention.

Example 5

Film-coated tablets

Preparation of the tablet core

A mixture of 100 parts of the compound of the invention, 570 parts of lactose and 200 parts of starch is mixed well with a solution of 5 parts of sodium dodecyl sulfate and 10 parts of polyvinylpyrrolidone (Kollidon-K 90 ^R ) in 200 ml of water. The wet powder mixture is sieved, dried and then sieved again. Then, 100 parts of microcrystalline cellulose (Avicel ^R ) and 15 parts of hydrogenated vegetable oil (Sterotex ^R ) are added to the powder. The material thus obtained is well mixed and then compressed into tablets. This gives about 10,000 tablets each containing 10 mg of the active ingredient of the invention.

Coating Preparation To a mixture of a portion of methylcellulose (Methocel 0 HG ^R ) in 75 ml of denatured ethyl alcohol was added a solution of 5 parts of ethylcellulose (Ethocel 22 cps ^R ) in 150 ml of dichloromethane. Dichloromethane (75 mL) and 1,2,3-propanetriol (2.5 mL) were then added to the solution. 10 parts of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former, followed by the addition of 2.5 parts of magnesium octadecanate, 5 parts of polyvinylpyrrolidone and 30 ml of concentrated coloring suspension (Opaspray K-1-2109 ^R ) and homogenization. Using a suitable apparatus, the tablet cores are coated with the resulting mixture.

Example 6

Solution for injection

1.0 parts of methyl 4-hydroxybenzoate and 0.2 parts of propyl 4-hydroxybenzoate are dissolved in about 0.5 liters of boiling water for injection. After cooling to 50 ° C, 4 parts of lactic acid, 0.05 parts of propylene glycol and 4 parts of a compound of the invention are added with stirring. The solution is cooled to room temperature and made up to about 1 liter with water for injection. This gives a solution containing the compound of the invention at a concentration of 4 mg / ml. The solution is sterilized by filtration (USPXVII, page 811) and filled into sterile containers.

Example 7

Suppositories Part of the compound of the invention is dissolved in 3 parts of a solution of 2,3-dihydroxybutyric acid in 25 ml of polyethylene glycol-400. 12 parts of surfactant (SPAN ^R ) and about 300 parts of triglyceride (Witepsol 555 ^R ) are fused. The latter mixture is mixed with the previously prepared solution. The resulting mixture was poured into molds at 37-38 ° C. This gives about 100 suppositories each containing 30 mg / ml of the compound of the invention.

HU 207 322 B

Example 8

A solution of the compound of the invention and 12 parts of benzyl alcohol in the injectable solution are mixed well, and to this solution is added sesame oil to a final volume of 1 liter. A solution containing 60 mg / ml of the compound of the invention is thus obtained. The solution is sterilized and filled into sterile containers.

1-4. The meaning of the letters in your reaction sketches is summarized below:

A: nitro → amine reduction;

B: nitration,

C: cyclization,

D: OH to W group conversion;

E: N-alkylation with R ¹ NH-CH (R ² ) -CH ₂ OH (XIX);

F: amide → amine reduction;

G: reduction of nitro to amine and amide to amine;

H: cyclization with R ¹ -NH-CH (R ² ) -CH ₂ NH ₂ (XXXV);

I: N-acylation reaction;

J: reduction of nitro → amine and aliphatic amide → amine;

K: cyclization to benzodiazepine ton;

L: N-acylation of an R ^iH -NH-CH ^(R2) -COOR (XLV) of the compound of formula.

Example 9

Pharmacological Example

A rapid, sensitive, and automated assay was used to estimate the anti-HIV property in vitro. A HIV-1-transformed T4 cell line, the ΜΤ-4 cell line, was used as a target cell line, previously described (Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985) to be yes. are susceptible and susceptible to HIV infection. Inhibition of HIV-induced cytopathic effect was used as an endpoint. The viability of both HIV and fake infected cells was estimated spectrophotometrically by in situ reduction with 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic dose (CD ₅₀ set, pg / ml) concentrations were determined as the concentration at which the compound in question has reduced the absorbance of the mock-infected control sample by 50%. The percent protection of the compound in question against an HIV-infected cell was calculated using the following formula:

(ODt) hiv - (ODc) mv

expressed in%.

(od _c ) á _l - (Od _c ) _h1v

(OD _T ) _H1V is the optical density measured at the concentration of the test compound in the HIV-infected cell; (OD _c ) _{H 1 V} is the optical density measured in untreated HIV-infected control cells. (OD _C ) _{AI is} the optical density measured in untreated sham infected control cells. Total optical density values were determined at 540 nm. The 50% protection dose calculated according to the above formula is referred to as the 50% effective dose (expressed in pg / ml). Called CD _5O / _5O ED values as the selectivity index (SI). Table 1 shows the CD _50, the ED and SI values.

/. spreadsheet

R ¹ ED50 (Gg / ml) cd ₅₀ (hp / ml) Ski -CH ₂ -CH = C (CH ₃ ) ₂ 2.84 151.02 53 -CH ₂ -CH = C (CH ₃ ) ₂ 0.86 127.53 148 -CH ₂ -CH = C (CH ₃ ) ₂ 0.09 22.71 251

Claims (4)

PATENT CLAIMS A process for the preparation of a compound of formula (I): R ¹ is hydrogen, C 3 -C 6 alkenyl, R ² is C 1-6 alkyl, R ⁴ is a halogen atom and pharmaceutically acceptable salts and stereochemically isomeric forms thereof for the preparation of a compound of formula II wherein R ¹ , R ² , R ⁴ are as defined above with a compound of formula III L and L 'are leaving groups - condensed in an inert solvent and then i) optionally alkenylating a compound of formula I wherein R 'is hydrogen, and / or ii) optionally preparing a compound of formula I wherein R ^{1 is} other than hydrogen; In the preparation of compounds of formula (I) wherein R ¹ is hydrogen, a resulting compound of formula (I) wherein R ¹ is other than hydrogen is desalkenylated and, if desired, a compound of formula (I) prepared as above into its pharmaceutically active non-toxic acid addition salt. or converting the acid addition salt to the free base form and / or separating the stereochemically isomeric forms. A process for the preparation of a compound of formula (I) according to claim I wherein: R ¹ is C 3 -C 6 alkenyl, R ² is C 1 -C 6 alkyl, characterized in that the appropriate starting materials are used. The process of claim 1, wherein the (+) - (S) -9-chloro-4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) -imidazo [4,5- l-jk] - [1,4] benzodiazepin-2 (lH) -one and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, wherein the appropriate starting materials are used. 4. A process for the preparation of a pharmaceutical composition comprising the steps of 1-3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable carrier and / or excipient.