RU2024523C1 - Method of synthesis of tetrahydro-[1,4]-benzodiazepine-2-thiones or their pharmaceutically acceptable acid additive salts or stereochemical isomers - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product of the formula (I) (image) where R₁ - C₃-C₆-alkyl substituted with C₃-C₆-cycloalkyl; R₂ and R₃ - independently mean hydrogen or C₁-C₆-alkyl; R₄ and R₅ - independently mean hydrogen, C₁-C₆-alkyl, halide, cyano, nitro or trifluoromethyl; or pharmaceutically acceptable salts. Reagent 1: corresponding 4,5,6,7- tetrahydroimidazo -[4,5-ik] [1,4]-benzodiazepine -2-one. Reagent 2: halide. Reagent 3: thiourea. Reaction conditions: in the medium of inert organic solvent. EFFECT: improved method of synthesis. 3 tbl

Description

 The invention relates to organic synthesis and relates to a method for producing tetrahydro [1,4] benzodiazepin-2-thiones.

 In the magazine Eur. J. Med. Chem, 1978, 13, 53-59, describes three tetrahydroimidazo [4,5,1-jk] [1,4] benzodiazepines. The compounds according to the invention differ from them in that the imidazo group is substituted with a thioxo group and in that these compounds exhibit an antiviral effect.

R₂ в которой R₁ означает алкенил С₃-С₆ или замещенный циклоалкилом С₃-С₆алкил С₁-С₆;
R₂ - атом водорода или алкил С₁-С₆;
R₃ - атом водорода или алкил С₁-С₆;
R₄ и R₅ независимо друг от друга означают атом водорода, алкил С₁-С₆, атом галогена, циано-, нитрогруппу или трифторметил,
а также их аддитивных или стереохимических изомеров.The invention relates to the production of tetrahydro [1,4] benzodiazepin-2-thions having the formula I
R

R ₂ wherein R ₁ is alkenyl, C ₃ -C ₆ cycloalkyl or substituted C ₃ -C ₆ alkyl, C ₁ -C _6;
R ₂ is a hydrogen atom or C ₁ -C ₆ alkyl;
R ₃ is a hydrogen atom or C ₁ -C ₆ alkyl;
R ₄ and R ₅ independently of one another represent a hydrogen atom, C ₁ -C ₆ alkyl, a halogen atom, a cyano, nitro group or trifluoromethyl,
as well as their additive or stereochemical isomers.

 Depending on the nature of the various substituents, the compounds of formula I may contain several asymmetric carbon atoms. The chemical designation of the compounds covers possible stereochemically isomeric forms, including diastereoisomers and enantiomers of the basic molecular structure. The absolute configuration of each chiral center can be shown by the stereochemical designations R and S, and this R and S designation follows the rules described in Pure Appl. Chem, 1976, 45, 11-30.

 Stereochemically isomeric forms of the compounds of formula I are encompassed by the scope of the invention.

 Pure stereochemical isomeric forms of the compounds of formula I can be obtained by known methods. Diastereosiomers can be isolated by physical separation methods, such as selective crystallization and chromatography, for example countercurrent distribution, liquid chromatography, etc .; and enantiomers can be resolved by selective crystallization of their diastereoisomeric salts formed with optically active acids. Pure stereochemical isomeric forms can also be separated from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that a stereospecific reaction is carried out.

 The compounds of formula I have basic properties and therefore can be converted into their therapeutically active non-toxic acid addition salts by treatment with suitable acids, such as inorganic acids, for example hydrochloric acid, hydrobromic acid and others, nitric acid, phosphoric acid and others; organic acids, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, ethanodic acid, propanedic acid, butanodic acid (Z) -2-butanodic acid, (E) -2-butanodic acid, 2-hydroxybutanedic acid, 2,3-dioxobutanedic acid , 2,3-dioxobutanoic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and etc. Conversely, a salt can be converted into a free base by treatment with alkali. The term “pharmaceutically acceptable acid addition salts” also encompasses solvates with which compounds of formula 1 can be formed, and these solvates are encompassed by the scope of the invention. Examples of such solvates are hydrates, alcoholates, and others. In the case where said reagent of formula III is carbon disulfide, the reaction can also be carried out in an alkanol such as methanol, ethanol, propanol, etc., in the presence of a base such as sodium hydroxide, potassium hydroxide, and t .d. or in a carbon disulfide serving as a solvent, and in the presence of a suitable base, such as an alkyl magnesium halide, for example ethyl magnesium bromide, such as alkyl lithium, for example butyllithium, such as an amine, for example N, N-diethylethanamine, such as carbodiimide, for example N, N- dicyclohexylcarbodiimide, etc. In addition, as a possible option, the latter reaction can also be carried out in a basic solvent, such as pyridine and others, in the presence of a phosphite, such as diphenyl phosphite.

(1)
Промежуточные продукты формулы IV могут химически реагировать с галогенирующим реагентом, таким как фосфорилхлорид, трихлорид фосфора, трибромид фосфора, хлористый тионил, оксалилхлорид и др. реагенты, при желании при повышенной температуре, особенно при температуре флегмообразования реакционной смеси, и при желании в присутствии инертного к реагентам растворителя и в присутствии основания, такого как карбонат натрия, бикарбонат натрия, карбонат калия и другие. Полученный таким образом 2-галогено-4,5,6,7-тетрагидроимидазо[4,5,1-jk//1,4/-бензодиазепин может быть далее превращен в соединения формулы I путем реакции с тиомочевиной или с тиосульфатом щелочного металла, например тиосульфатом натрия, в подходящем инертном к реагентам растворителе, таком как вода или алканол, например, метанол, этанол, 1-пропанол, 2-пропанол, бутанол, 1,2-этандиол и т.д., при желании при повышенной температуре, особенно при температуре флегмообразования реакционной смеси.The compound of formula I is obtained by thionation of 4,5,6,7-tetrahydroimidazo / 4,5,1-jk // 1,4 / -benzodiazepin-2-one

(1)
Intermediates of formula IV can chemically react with a halogenating reagent such as phosphoryl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, oxalyl chloride and other reagents, if desired at elevated temperature, especially at reflux temperature of the reaction mixture, and if desired in the presence of an inert solvent reagents and in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate and others. 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 with an alkali metal thiosulfate, for example sodium thiosulfate, in a suitable reagent inert solvent, such as water or alkanol, for example methanol, ethanol, 1-propanol, 2-propanol, butanol, 1,2-ethanediol, etc., if desired at elevated temperature, especially at the reflux temperature of the reaction mixture.

 If desired, compounds of formula I can also be directly prepared from intermediates of formula IV by thionation with 2,4-bis (4-methoxyphenyl) -1,3-dithio-2,4-diphosphatan-2,4-disulfide (reagent Lawesson) in a suitable reagent inert solvent, such as an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene, a bipolar aprotic solvent, for example hexamethylphosphotriamide (HMPA) and other solvents; or by thionation with phosphorus pentasulfide.

 Then, if desired, the compounds of formula I are converted into a therapeutically active non-toxic acid addition salt by treatment with an acid, or, conversely, the acid salt is converted to the free base by alkali, and / or its stereochemically isomeric forms are obtained.

 The reaction products can be isolated from the reaction mixture and, if necessary, further purified according to well-known methods.

 Intermediates and starting materials are already known compounds that can be prepared according to accepted procedures for the preparation of similar compounds, and some intermediates are new products.

Intermediates of formula IV in which R ₁ , R ₂ and R _{3 are} defined by formula I and (A) R ₄ and R _{5 are} each independently C ₁ -C ₆ alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy , C ₁ -C ₆ alkyloxy, amino, or mono- or di (C ₁ -C ₆ -alkyl) amino, or c) R ₄ is hydrogen and R ₅ is cyano, nitro, trifluoromethyl, hydroxy, C ₁ -C ₆ alkyloxy, amino, or mono- or di (C ₁ -C ₆ alkyl) amino;
and said R ₄ and R ₅ radicals are represented by R _4-a and R _5-a radicals, respectively; and also said intermediates described by formula (IV-a) are novel compounds.

Эти промежуточные соединения формулы IV могут быть получены согласно процедурам, описанным в ЕР-А-0336466. Так например, указанные промежуточные соединения формулы IV как известные, так и новые могут быть получены путем N-алкилирования промежуточного соединения формулы IV-в согласно известным процедурам N-алкилирования, как описано выше для превращения промежуточных соединений V в соединения формулы I.

These intermediates of formula IV can be prepared according to the procedures described in EP-A-0336466. For example, these intermediate compounds of formula IV, both known and new, can be prepared by N-alkylating an intermediate of formula IV-b according to known N-alkylation procedures as described above for the conversion of intermediates V into compounds of formula I.

IV
Промежуточные соединения формулы (IV) и (IV-в) могут быть получены из промежуточного соединения формулы (П-Н) путем реакции с химическим реагентом формулы (LVIII), в которой L представляет собой подходящую удаляемую группу.

IV
Intermediates of formula (IV) and (IV-c) can be prepared from an intermediate of formula (PN) by reaction with a chemical reagent of formula (LVIII) in which L is a suitable leaving group.

Подходящие реагенты формулы (LVIII) представляют собой, например мочевину, ди(С₁-С₆ алкил) карбонат, дихлорид угольной кислоты, трихлорметилхлорформат, 1,1'-карбонилбис[1H-имидазол] , этилхлорформат и другие. Данная реакция может легко осуществляться согласно процедурам, описанным выше для превращения промежуточных соединений формулы II в соединения формулы I.

Suitable reagents of formula (LVIII) are, for example, urea, di (C ₁ -C ₆ alkyl) carbonate, carbonic acid dichloride, trichloromethyl chloroformate, 1,1'-carbonylbis [1H-imidazole], ethyl chloroformate and others. This reaction can be easily carried out according to the procedures described above for the conversion of intermediate compounds of formula II into compounds of formula I.

 In all of these reaction schemes, the chemical designation of the intermediates encompasses a mixture of all possible stereochemically isomeric forms, mixtures of a number of possible stereochemically isomeric forms as such, for example diastereoisomeric mixtures, enantiomeric mixtures, for example racemic and enriched enantiomeric mixtures, and enantiomerically pure isomeric forms of the basic molecular structure.

 Stereochemically isomeric forms of the intermediates described in the above reaction schemes and compounds of formula I can be prepared by methods well known in the art. For example, diastereoisomers can be separated by physical separation methods, such as distillation, selective crystallization, chromatographic separation methods, for example by countercurrent distribution, liquid chromatography and others.

Enantiomerically pure intermediates can easily be obtained from enantiomerically pure isomeric forms of the corresponding starting materials, provided that the subsequent reactions are stereospecific. The most interesting enantiomerically pure starting materials for use in these reaction schemes are amino acids and / or their substituted derivatives having the formula R _1H NH-CHR ₂ -COOR (XLY), and the corresponding aminoalkanols and / or their substituted derivatives having the formula R _1H NH-CHR ₂ -CH (R ₃ ) OH (XIX).

 Alternatively, enantiomerically pure intermediates can also be obtained by resolution of the corresponding racemates by, for example, selective crystallization of their diastereoisomeric salts by optically active resolving agents, by chromatographic separation of the diastereomeric derivatives, by chromatographic separation of the racemate using a chiral stationary phase, etc. .

 Compounds of formula I and intermediates of formula IV-a possess antiviral and especially antiretroviral properties. Until recently, retroviruses were considered as pathogenic agents for a number of diseases of warm-blooded animals, excluding humans, in contrast to viruses that have been known for some time as the cause of a large number of diseases of warm-blooded animals, including humans. However, after this it was found that retrovirus, the human immune deficiency virus, HIV, also known as LAV, HTLV-III or ARV, is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans, retroviral infections, and the treatment of subjects suffering from him, began to deserve the most attention. The HIV virus preferably infects human T-4 cells and destroys them or alters their normal function, especially the coordination of the immune system. As a result, the infected patient has a constantly decreasing number of T-4 cells, which in addition behave abnormally. Because of this, the immune defense system is not able to fight against infections and neoplasms, and the HIV-infected subject usually dies when infected with opportunistic bacteria, as a result of diseases such as pneumonia, cancer, and not as a result of direct HIV infection. Other diseases associated with HIV infection are thrombasthenia, Kaposi's sarcoma, and damage to the central nervous system, characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysarthria, ataxia, and disorientation. In addition, HIV infection is associated with progressive neuropathy, progressive disseminated lymphadenopathy (PGL), and AIDS-related complex (ARC).

 The antiviral, in particular antiretroviral and especially anti-HIV properties of the compounds of formula (I) and intermediates of formula IV-a confirm that these compounds and intermediates are valuable antiviral chemotherapeutic agents for the prevention or treatment of warm-blooded animals suffering from viral infections in in particular for treating people infected with HIV, especially HIV-1.

 As a result of the antiviral and especially antiretroviral properties, the compounds of formula I and intermediates of formula IV-a, their pharmaceutically acceptable salts and their stereochemically isomeric forms are used to treat warm-blooded animals infected with viruses, in particular retroviruses, or to prevent these warm-blooded animals. Examples of human retroviral infections are HIV, in particular HIV-1 and HTLV-1 (human type I T-lymphotropic virus), causing leukemia and lymphoma. FeLV (feline leukemia virus), which causes leukemia and immune deficiency, can be called animal retroviral infection. Conditions that can be prevented or that can be treated with compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS (AIDS), AIDS-related complex (ARS), progressive common lymphadenopathy (PGL), and also chronic CNS diseases caused by retroviruses, such as HIV-induced dementia and multiple sclerosis.

 Due to the antiviral and especially antiretroviral effect, the compounds of the invention can be formulated in various pharmaceutical formulations for administration to the body. For the preparation of pharmaceutical compositions of the invention, an effective amount of the compound, in the form of its basic or acid salt serving as an active ingredient, is thoroughly mixed with a pharmaceutically acceptable carrier, which (carrier) can have a wide variety of forms, depending on what is desired for administration into the body of the drug form. It is desirable that these pharmaceutical compositions have a unit dosage form suitable for administration to the body, preferably orally, through the rectum, subcutaneously or parenterally. For example, in the preparation of compositions in a dosage form for oral administration to the body, any conventional pharmaceutical medium may be used, for example, water, glycols, oils, alcohols and others that are used for oral administration of liquid preparations, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starch, sugars, kaolin, lubricants, binders, disintegrating agents and others in the case of powders, pills, capsules and tablets may be used. Due to their ease of administration, tablets and capsules are the most preferred oral dosage forms, in which case pharmaceutical carriers are used. For compositions administered parenterally, sterile water is usually used as a carrier, at least in large part, although other ingredients may be included to impart solubility.

 Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and other substances may also be used. In compositions suitable for subcutaneous administration, the carrier, if desired, includes a penetration enhancing agent and / or a suitable wetting agent, if desired in combination with suitable additives of any type, introduced in small proportions, which (additives) do not cause significant harmful effects on the skin. These additives may facilitate the administration of the drug to the skin and / or may assist in the preparation of the desired compositions. These compositions can be introduced into the body in various ways, for example transdermally, both locally and with the application of an ointment. Acid addition salts I and IV-a, due to their increased water solubility in comparison with the corresponding basic form, are most likely more suitable in the preparation in the form of an aqueous composition. It is especially desirable to prepare said pharmaceutical compositions in unit dosage form to facilitate administration and uniform dosage. A unit dosage form, as defined in the application description and in the claims, refers to physically discrete dosage units suitable as unitary dosages, each unit containing a predetermined amount of the active ingredient, calculated so as to obtain the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including plain or coated tablets), capsules, pills, powder sachets, injectable solutions or suspensions, teaspoon-administered preparations, tablespoon-administered preparations, segregated divided doses thereof .

 The compounds of the invention can be used to treat viral diseases of warm-blooded animals suffering from these viral diseases by administering to the body an amount of a compound of formula I or an intermediate of formula IV-a effective against the virus, their pharmaceutically acceptable acid addition salt, or their stereoisomeric form. Specialists in the treatment of viral diseases can easily determine the effective antiviral amount as a result of the test, which is described in this application. Typically, an effective amount of this compound should be 0.01-20 mg / kg body weight, and especially 0.1-5 mg / kg body weight. It may be desirable to administer the desired dose in two, three, four or more divided doses and at suitable intervals throughout the day. These divided doses can be prepared in unit dosage forms containing, for example, 1-1000 mg, and especially 5-200 mg of the active ingredient per unit dosage form.

 The following examples serve to illustrate the present invention. All parts are bulk.

experimental part
A. Preparation of Intermediates
PRI me R 1. a) To a stirred chilled (-12 ^about C) mixture of 9.10 parts of 2-amino-3-nitrobenzoic acid, 6.95 parts of methyl-L-α-alanine monohydrochloride, 13, 50 parts of 1-hydroxy-1H-1,2,4-benzotriazole monohydrate and 178 parts of tetrahydrofuran are added in portions of 5.05 parts of N-methylmorpholine and then, after 5 minutes in an argon atmosphere, 10.3 parts of N, N′-methantetrailbis [cyclohexanamine]. Stirring was continued for 5.5 hours at -12 ^{° C} and for 15 hours at room temperature. After cooling for an hour at 0 ^C. The reaction mixture was filtered. The filtrate was evaporated and the precipitate was partitioned in a separatory funnel between ethyl acetate and saturated NaHCO ₃ solution. The ethyl acetate layer was separated, washed with saturated NaHCO ₃ solution, dried, filtered and evaporated. The residue was triturated with hexane, filtered and dried, yielding 13.08 parts (97.9%) of (-) - methyl- (S) -2 - [(2-amino-3-nitrobenzoyl) amino] propanoate (intermediate I) with temp. melted 132.9 ^about S.

c) A mixture of 12.58 parts of intermediate 1, 3.50 parts of palladium-carbon catalyst (10%) and 158 parts of ethanol is hydrogenated in a Parr apparatus for 4 hours at room temperature and a pressure of 3.1 × 10 ⁵ Pa. The catalyst was filtered on diatomaceous earth and the filtrate was evaporated. The oily residue was heated in vacuo (3,3˙ 10 ³ Pa) at ¹⁵⁰ ° C for 10 minutes and at 202 ^{° C} for 40 minutes with stirring. After cooling, the crushed solid material is triturated with ethanol. The resulting product was filtered and washed with ethanol and 1,1'-hydroxybisethane. Yield: 5.58 parts (57.7%) (+) - (S) -9-amino-3,4-dihydro-3-methyl-1H-benzodiazepin-2,5-one (intermediate 2).

c) To a suspension of 5.55 hours. lithium aluminum hydride in 154.5 parts. 1,4 dioxane under argon at ²⁵ ° C was added 5.00 hours. Intermediate (2). The reaction mixture is boiled for 5 hours under reflux. After cooling ^to 10 ° C were successively added thereto 5.55 hours. Water, 9.16 hr. Of a 15% NaOH solution and 16.65 hours. The water. The mixture was stirred for 2 hours and then filtered. The precipitate was washed successively with 178 parts of hot tetrahydrofuran and 133 parts of hot dichloromethane. The combined filtrates were dried, filtered and evaporated. The residue was poured into a solution of 3.76 parts of N-methylmorpholine in 133 parts of dichloromethane. The resulting mixture was added to a solution of 4.82 hours. Trihlormetilformiata 160 h. Dichloromethane for 15 min at 0 ° ^C under argon. After stirring for 10 min at 0 ^C. The reaction mixture was warmed to room temperature and concentrated by evaporation. To the residue was added 70 parts of a 15% aqueous solution of 1,4-dioxane, and the mixture was heated in a steam bath under nitrogen for 45 minutes, then cooled and extracted with dichloromethane (twice, in 66.5 parts each). The aqueous layer was filtered and basified with a concentrated solution of NH ₄ OH. The precipitate is filtered off, washed with a small amount of cold water, dried and triturated twice with 6.24 parts of 2-propanol, resulting in 1.59 parts (31.2%) (+) - (S) -4.5, 6,7-tetrahydro-5-methylimidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) - she. Temp. melted 206.5 ^about C (intermediate compound 3).

d) To a stirred mixture of 0.64 parts of intermediate (3), 0.5 parts of sodium carbonate, 0.52 parts of potassium iodide and 9.4 parts of N, N-dimethylformamide are added under argon at room temperature 0 56 parts of 1-bromo-3-methyl-2-butene. After stirring for 24 hours, the solvent was distilled off under reduced pressure. The residue was partitioned between 32 parts of dichloromethane and 35 parts of sodium chloride solution in a separatory funnel. The aqueous phase is again extracted with 32 parts of dichloromethane. The combined organic layers were washed with 35 parts of sodium chloride solution, dried, filtered and evaporated in vacuo. The residue was recrystallized from 6.5 parts of acetonitrile. The crystalline product was filtered off and dried for 16 hours at 81 ^{° C} under high vacuum, yielding 0.38 parts (45%) (+) -. ( S) -4,5,6,7- tetrahydro-5-methyl -6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -one (intermediate 4). Mp 136.4 ^about S.

e) A suspension of 38.16 hours. Intermediate (4) and 15 parts of sodium carbonate in 578 hours. The phosphoryl chloride was stirred for 2 days at 60 ° ^C under a nitrogen atmosphere. Excess of phosphoryl chloride was distilled off in vacuo at 30-50 ^C. The resulting solid material is cooled in an ice bath and dissolved in 500 hours. The water. With vigorous stirring, the solution was made alkaline by slowly adding 1000 ml of a saturated solution of NaHCO ₃ . The resulting product was subjected to extraction with dichloromethane three times in 355 h portions. The combined extracts were washed with saturated NaHCO ₃ and saturated NaCl, dried, filtered and evaporated, yielding 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] benzodiazepine (intermediate 5).

In a similar manner to Id, (+) - (S) -4,5,6,7-tetrahydro-5-methyl-6- (2-methyl-2-propenyl) imidazo [4,5,1-jk] [1] is obtained , 4] benzodiazepine 2 (1H) -one (intermediate 6). Mp 152.4 ^about S.

Example 2 a) A solution of 2.6 parts of methyl 2-bromo-3-nitrobenzoate, 1.75 parts of N - [(2-amino-1-methyl) ethyl] benzomethanamine and 1.06 including sodium carbonate in 8 parts of 1-butanol is stirred and boiled for 30 minutes under reflux. After this, the solvent is distilled off, 20 parts of water are added to the residue, and the obtained product is subjected to extraction twice with 30 parts of trichlomethane. The combined extracts were dried, filtered and evaporated. The hydrochloride salt is obtained from the oily free base in the usual manner. The salt obtained is filtered off, washed with 2-propanol and dried. Yield 3.4 parts (89.5%) of 3-nitro-2 - [[2-methyl-2 - [(phenylmethyl) amino] ethyl] amino] benzoate hydrochloride (intermediate 7). Mp 204 ^about S.

c) A mixture of 3.8 parts of intermediate (7), 15 parts, 2 n. a solution of sodium hydroxide and 4 parts of 2-propanol are stirred and boiled for one hour under reflux. A solution of 3 parts of concentrated hydrochloric acid and 5 parts of water is then added to the boiling reaction mixture. After cooling, it is filtered off, washed with water and recrystallized from 80 parts of glacial acetic acid to give 3 parts (82%) of 3-nitro-2 - [[[2 - [(phenylmethyl) amino] -2-methyl] ethyl] amino] -benzoic acid (intermediate 8). Mp 227 ^about S.

c) A mixture of 189.3 parts of intermediate 8,400 parts of thionyl chloride and 400 parts of methylbenzene was stirred and refluxed for 2 hours. After this, the solvent was distilled off, and the residue was dissolved in 600 parts of methylbenzene. The resulting solution is treated with a solution of sodium bicarbonate. After separation, the organic layer is dried over anhydrous sodium carbonate, filtered and concentrated to a volume of about 500 hours. When standing at room temperature, the product partially precipitates. It is filtered off (the filtrate is discarded), washed successively with 2-propanol and 1,1'-hydroxybisethane and dried, resulting in the first fraction of 123.5 parts of crude 2,3,4,5-tetrahydro-3-methyl-9-nitro -4- (phenylmethyl) -1H-1,4-benzodiazepin-5-one. The solvent is distilled off from the mother liquor. The residue was dissolved in 160 parts of boiling 2-propanol and crystallization was carried out at room temperature. The precipitated product is filtered off, washed successively with 2-propanol and 1,1'-hydroxybisethane and dried, resulting in a second, less pure fraction of 28 parts of 2,3,4,5-tetrahydro-3-methyl-9- nitro-4- (phenylmethyl) -1H-1,4-benzodiazepin-5-one. Both crude fractions were recrystallized from ethanol to give 137.4 parts (85%) of 2,3,4,5-tetrahydro-3-methyl-9-nitro-4- (phenylmethyl) -1H-1,4-benzodiazepine -5-one (intermediate 9). Mp 125 ^about S.

 d) To a suspension of 14 parts of lithium aluminum hydride in 40 parts of benzene and 50 parts of tetrahydrofuran, stirred and refluxing, a solution of 20.2 parts of intermediate (9) in 200 parts of tetrahydrofuran is added and the mixture is continued to mix and reflux for 2.5 hours. The reaction mixture is cooled, then with crushed ice and decomposed by successive addition of water, a 15% sodium hydroxide solution and again water. The inorganic product was filtered off and the filtrate was evaporated. 40 parts of methylbenzene were added to the residue and the resulting solution was evaporated to dryness, resulting in 19.8 parts (87.6%) of 9-amino-2,3,4,5-tetrahydro-3-methyl-4-) (phenylmethyl ) -1H-1,4-benzodiazepin-5-one in the form of a red oily liquid (intermediate 10), which is used without further purification in the next step.

e) A mixture of 19.8 hours. The intermediate (10) and 7.2 hours. The urea was heated at 210-220 ^{° C} until the termination of foaming and formation of ammonia gas (about 10 min). The reaction mixture was cooled to about 100 ^{° C} and boiled with 120 h. 1N. hydrochloric acid solution. The solution was separated by decantation from the oily residue, which was treated with activated carbon and filtered. The filtrate is cooled, alkalinized with ammonium hydroxide and subjected to extraction once 75 and once 150 parts of trichloromethane. The combined extracts were dried and evaporated. The residue was triturated in 24 parts of 2-propanol, filtered and recrystallized from ethanol and then from 4-methyl-2-pentatnone, resulting in 2.5 parts (11.5%) 4,5,6,7-tetrahydro -5-methyl-6- (phenylmethyl) imidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -one (intermediate II). Pace. melted 205 ^about S.

f) A mixture of 8 hours. The intermediate compounds (II), 1 hr. 10% palladium on carbon catalyst in 80 hours. The glacial acetic acid was hydrogenated at about 38 ^C. After the calculated amount of hydrogen, the catalyst was filtered off and acetic acid was distilled off. The residue was dissolved in 75 parts of water and the solution was alkalinized with 30 parts of a concentrated solution of ammonium hydroxide. The product is crystallized at room temperature, filtered off, washed with water and recrystallized from 20 parts of 2-propanol, resulting in 3.7 parts (66.8%) of 4,5,6,7-tetrahydro-5-methylimidazo [4 , 5.1-jk] [1,4] benzodiazepin-2- (1H) -one (intermediate 12). Pace. melted 190.5 ^about S.

d) To a stirred solution of 1.0 parts of intermediate (12), 0.816 parts of potassium iodide and 0.782 parts of sodium carbonate in 56.4 parts of N, N-dimethylformamide, a solution of 0.88 parts of 1-bromo is added dropwise. -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 about 70 ° ^C. The residue was twice partitioned between 130 parts of dichloromethane and 100 parts of a mixture of water and a saturated aqueous solution of sodium hydrogen carbonate (volume ratio 50..: fifty). The combined aqueous layers were extracted with 78 parts of dichloromethane. The dichloromethane layers are combined and 100 parts of a saturated solution of sodium chloride are extracted from them. The extract was dried and concentrated in vacuo at a temperature of about 40 ° ^C. The residue is recrystallized twice from 16 hours. The acetonitrile. The resulting product was cooled for 45 minutes at ^0-5 ° C, crystals were filtered, washed 4 hours. The cold ^(0-5 ° C) acetonitrile and dried overnight under vacuum at 78 ^C. There was thus obtained 0.805 h. (60 , 3%) (±) -4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] -benzodiazepin-2 (1H) -one (intermediate 13). Mp 158.0 ^about S.

h) A suspension of 1.0 h. The intermediate 13 in 8.25 hours. The phosphoryl chloride was heated for 15 hours at 90 ° ^C under a nitrogen atmosphere. The reaction mixture was then evaporated and the residue was partitioned between a saturated NaHCO ₃ solution and dichloromethane in a separatory funnel. The aqueous layer is back-extracted with dichloromethane. The combined organic layers were washed successively with saturated NaHCO ₃ and NaCl, dried, filtered and evaporated, yielding 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] benzodiazepine (intermediate 14).

 PRI me R 3. a) A mixture of 41.49 parts of 6-chloro-2H-3,1-benzoxazine-2,4 (1H) -dione and 31,40 parts of methyl-L-α-alanine monohydrochloride at 108 parts, pyridine is boiled for 10 hours under reflux in an argon atmosphere. The reaction mixture was then cooled and stirred for 12 hours at room temperature. The precipitate is filtered off and washed with ethanol, yielding 24.77 parts (52.5%) of (S) -7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine 2,5- dione (intermediate compound 15).

c) 24.55 h. The intermediate 15 was added portionwise at ⁰ ° C under argon for 142 h. The nitric acid. After aging for 3.5 h at ⁰ C, the solution slowly with stirring, was added to 450 parts of ice. The precipitate formed is filtered off, washed with water and dried at room temperature to obtain 27.84 parts (93.9%) of (S) -7-chloro-3,4-dihydro-3-methyl-9-nitro-1H- benzodiazepine-2,5-dione (intermediate 16).

c) To a cooled (0 ° ^C) suspension of 18.2 hours. lithium aluminum hydride in 261 hours. 1,2-dimethoxyethane were added portionwise 16.14 hours. The intermediate 16 under an argon atmosphere. The mixture was stirred for 2 hours at 0 ^C and then for a further 40 hours at reflux temperature. After cooling ^to 0 ° C the mixture was added thereto 18.2 hours. The water and 48.1 hours. The tetrahydrofuran was 21.1 hours. 15% aqueous NaOH solution, and 54.6 hours. The water. The mixture was stirred for one hour at room temperature and filtered. The precipitate was boiled for 5 min in tetrahydrofuran and the mixture was filtered again. The combined filters are dried, filtered and evaporated. The residue was dissolved in 399 parts of dichloromethane. After drying and filtration, the solution is mixed with 18.2 hours. N-methylmorpholine and the whole was added dropwise at ⁰ ° C under argon to a mixture of 11.9 hours. Trichloromethyl chloroformate and 665 hours. The dichloromethane. The mixture was evaporated and the residue was dissolved in 150 ml of a mixture of water and 1,4-dioxane taken in a ratio of 85:15. The mixture is heated for 2 hours in a steam bath under nitrogen. After cooling, the solid material is filtered off and dissolved in 80 parts of water. The solution was made basic with NH ₄ OH and stirred for 45 minutes. The resulting product is filtered off and successively recrystallized from acetonitrile and 2-propanol, resulting in 2.28 parts (16%) of (+) - (S) -9-chloro-4,5,6,7-tetrahydro-5-methylimidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -one (intermediate 17). Pace. melted 202.2 ^C. [α] _D ²⁰ = 72.6 ^o (c = 0.98% in methanol).

d) To a stirred mixture of 2.99 parts of intermediate (17), 2.00 parts of sodium carbonate, 2.08 parts of potassium iodide and 37.6 parts of N, N-dimethylformamide, 2.24 parts of 1- bromo-3-methyl-2-butene in an argon atmosphere. After stirring for 4 days at room temperature, the reaction mixture was evaporated and the residue was partitioned in a separatory funnel between water and dichloromethane. The organic layer was washed with saturated NaCl, dried, filtered and evaporated. The residue was recrystallized twice from acetonitrile. The product is filtered off, 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] benzodiazepin-2 (1H) -one (intermediate 18). Mp 135.6 ^about S.

e) A suspension of 2.5 h. The intermediate 18 and 0.87 h. The sodium carbonate in 33 hours. The phosphoryl chloride was stirred for 24 hours at 90 ° ^C under a nitrogen atmosphere. Excess phosphoryl chloride is distilled off in vacuo. The resulting solid is cooled in an ice bath and dissolved in water. With vigorous stirring, the mixture was alkalinized by slowly adding to it a saturated solution of NaHCO ₃ . The product is extracted with dichloromethane (three times in 44.3 parts each) and the combined extracts are washed successively with saturated solutions of NaHCO ₃ and NaCl, dried, filtered and evaporated, yielding 2.57 parts (97.0%) (S) -2 , 9-dichloro-4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazepine (intermediate 19 )

 In a similar manner, (S) -2,8-dichloro-4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] is obtained [1,4] benzodiazepine (intermediate 23).

EXAMPLE EXAMPLE 4 a) To a cooled ^(-35 ° C) mixture of 7.4 hours. The intermediate 3 and 395 hours. The acetonitrile was added 24.8 hours. The anhydride (1,1-dimethylethoxy) formic acid and 0 45 parts of N, N-dimethyl-4-pyridinamine. The mixture was allowed to stand at room temperature for 12 hours, after which it was evaporated. The residue was purified by flash chromatography on a silica gel column using a mixture of CH ₂ Cl ₂ and CH ₃ OH in the ratio 99: 1 as the mobile phase. The desired eluate fraction was evaporated and the residue was stirred for 3 hours with a mixture of 79 parts of methanol and 1.5 parts of potassium carbonate. The solvent is then distilled off and the residue is distributed in a separatory funnel between ethyl acetate and water. The organic layer was separated, dried, filtered and evaporated, yielding 6.4 parts (57.5%) of (1,1-dimethylethyl) - (S) -1,2,4,5,6,7-hexahydro 5-methyl-2-oxoimidazo [4,5,1-jk] [1,4] benzodiazepine-6-carboxylate (intermediate 20).

f) 5.43 parts of intermediate 20 and 224 parts of trichloromethane are mixed at room temperature under argon. After cooling to -35 ^{° C} was added to a mixture of 2.29 h. N-bromosuccinimide, the whole mass was kept for 6 hours at this temperature, then allowed to warm to room temperature and left to stand for 12 hours. The reaction mixture was then concentrated and the residue was purified by LC column chromatography; RP). The desired eluent fraction was evaporated, yielding 2.10 parts (30.7%) (1,1-dimethyl) - (-) - (S) -8-bromo-1,2,4,5,6,7 -hexahydro-5-methyl-2-oxoimidazo [4,5,1-jk] [1,4] benzodiazepine-6-carboxylate (intermediate 21). Mp 228.6 ^about C; [α] _D ²⁵ = -60.0 ^about (conc. = 0.30 in methanol).

f) To 2.96 h. The cooled ⁽⁰ ° C) trifluoroacetic acid was added 2.0 hours. The intermediate 21 under an argon atmosphere. After stirring for 2 hours at 0 ^C the mixture was evaporated. 18.8 parts of N, N-dimethylformamide, 0.86 parts of 1-bromo-3-methyl-2-butene, 3.0 parts of sodium carbonate and 0.96 parts of potassium iodide were successively added to the residue, the mixture was stirred overnight at room temperature and evaporated. The residue was partitioned between water and ethyl acetate in a separatory funnel. The organic layer was separated, washed successively with saturated solutions of NaHCO ₃ and NaCl, dried, filtered and evaporated. The residue was recrystallized from acetonitrile. The product was filtered off and dried overnight in vacuo at 60 ° ^C, yielding 1.5 parts (81,7%) (+) - . (S) -8- bromo-4,5,6,7-tetrahydro- 5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -one (intermediate 22). Mp 125.2 ^about C; [α] _D ²⁵ = +12.6 ^about (conc. = 1% in CH ₃ O).

B. Preparation of target compounds
Example 5. To a solution of 2.57 parts of intermediate 19 in 27.7 parts of ethanol, 1.21 parts of urea was added. After refluxing for 24 hours, the reaction mixture was evaporated and the residue was partitioned between a saturated NaHCO ₃ solution and dichloromethane in a separatory funnel. The organic layer was washed successively with saturated NaHCO ₃ solution, water and saturated NaCl solution, dried, filtered and evaporated. The residue was purified twice by column chromatography (flash chromatography; silica gel; CH ₂ Cl ₂ / CH ₃ OH = 30: 1; high performance liquid chromatography; silica gel; CH ₃ COOC ₂ H ₅ (hexane = 4: 6). The desired fraction the eluate 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] benzodiazepin-2 (1H) -thione (compound I) mp 180.3 ^C;. [α] _D ²⁰ = +8.3 ^o (c = 0.96% in methanol).

In a similar manner, (±) -4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazene is obtained pin-2 (1H) -thione (compound 2). Pace. melted 128.0 ^{° C} (with decomposition);
(+) - (S) -4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] - 2 (1H) -thione (compound 3); pace. melted 174.5 ^about C; [α] _D ²⁰ = 15.95 ^{° C} (c = 1% in ethanol).

EXAMPLE Example 6 a) To a solution of 2.5 hours. The intermediate 23 in 12.6 hours. Ethanol at ²⁰ ° C was added 0.53 h. Thiourea. After refluxing for 1.5 hours under reflux with stirring, the reaction mixture was cooled to ^0-5 ° C and filtered at 0 ^C. The residue was dried in vacuo ^at 30 ° C, yielding 1.70 h. (75.4 %) (-) - (S) -8-chloro-4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo / 4,5,1-jk) / 1,4 benzodiazepine-2 (1H) -thion of monohydrochloride (compound 17). Melting point 230 ^{° C} [α] _D ²⁰ = -76.61 ^o (c = 1% in _CH3OH).

c) 0.5 part of compound 17 is distributed in a separatory funnel between dichloromethane and water. The whole mixture was made basic, the organic layer was separated, dried, filtered and evaporated. The product was dried in vacuo ^at 40 ° C, yielding 0.43 parts (95,7%) (+) - . (S) -8- chloro-4,5,6,7-tetrahydro-5-methyl-6 - (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -thione (compound 22). Pace. melted 163.3 ^about C; [α] _D ²⁵ = +9.37 ^o (c = 1% in methanol).

Example 7 1.16 parts of intermediate 6 and 1.65 parts of phosphoryl chloride are mixed in an argon atmosphere, and the mixture is refluxed for 5.5 hours. The excess phosphoryl chloride is distilled off, 10 parts of water are added and the mixture is neutralized with saturated aqueous NaHCO ₃ solution. The resulting product was extracted with dichloromethane and the extract was dried, filtered and evaporated. 7.9 parts of ethanol and 1.00 parts of thiourea were added to the residue, and the mixture was refluxed for 2 hours. Then it is evaporated and the residue is distributed in a separatory funnel between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH ₂ Cl ₂ / C ₂ H ₅ OH = 96: 5). The desired eluate fraction was evaporated, yielding 0.29 parts of (+) - (S) -4,5,6,7-tetrahydro-5-methyl-6- (2-methyl-2-propenyl) imidazo [4,5 , 1-jk] [1,4] benzodiazepine-2 (1H) -thione (compound 6). Pace. melted 137.6 ^about C; [α] _D ²⁵ = 26.2 ^{° C} (conc. = 1.09% in _CH3OH).

EXAMPLE Example 8. To a cooled ^(-78 ° C) solution of 1.18 hours. The intermediate 22 in 100 h. Of dichloromethane is added under argon 1.26 hours. The trifluoroacetic anhydride, after 15 min 0.61 h 2,6-dimethylpyridine and after another 15 minutes 21.1 ml of 1,1'-hydroxybisethane saturated with HCl. The mixture was stirred for half an hour and then neutralized with saturated NaHCO ₃ solution. The resulting product was extracted twice with dichloromethane, in portions for 66.5 hours, and the combined extracts were dried, filtered and evaporated. The residue was purified by flash column chromatography (silica gel; CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH = 98: 2: 0.1). The eluate fraction containing the desired product was evaporated and the residue was dissolved in 7.9 parts of ethanol. 2.0 parts of thiourea are added to the solution and the mixture is refluxed for 6 hours and then evaporated. The residue is distributed in a separatory funnel between water and dichloromethane. The organic layer was separated, washed successively with saturated solutions of NaHCO ₃ and NaCl, dried, filtered and evaporated. The residue was purified by flash column chromatography (silica gel; CH ₃ COOC ₂ H ₅ / hexane = 25:75). The eluate fraction containing the desired product was evaporated and the residue was recrystallized from acetonitrile. The product was filtered off and dried in vacuo at 60 ° ^C, yielding 0.284 parts (20,2%) (+) - . (S) -8- bromo-4,5,6,7-tetrahydro-5-methyl-6 - (3-methyl-2-butenyl) imidazo [4,5,1-jk] [1,4] benzodiazepin-2 (1H) -thione (compound 19). Pace. melted 161.1 ^about C; [α] _D ²⁵ = + 4.6 ^o (conc. = 1% in methanol).

 All other compounds listed in table 1 can be obtained by the method in accordance with the specified example.

выражено в %. где (OD_т)_HIV - оптическая плотность, измеренная в зараженных HIV клетках при заданной концентрации испытываемого соединения: (OD_c)_HIV - оптическая плотность контрольных необработанных зараженных HIV клеток; (OD_c)_мocк - оптическая плотность контрольных необработанных зараженных мок клеток; все значения оптической плотности определены при 540 нм. Доза, обеспечивающая 50% защиты согласно указанной выше формуле определяется как 50% эффективная доза (ЕД₅₀ в мкг/мл). Отношение CД₅₀ к ЕД₅₀ определяется как показатель избирательности (SI).C. Pharmacological Test Example
PRI me R 9. For evaluation in vitro anti-HIV agents carried out a quick sensitive and automated analysis procedure. The transformed HIV-1 cell line T-4, i.e., MT-4, which was previously described (Koganagi et al., Int. J. Caneer, 36. 445-451, 1985), is used as a test cell line. highly sensitive and possible for infectious infection. The ultimate goal is to inhibit the HIV-induced cytopathic (disease-related cell) effect. The viability of infected HIV and Mock cells is determined spectrophotometrically by directly recovering 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazol bromide (MTT) under the given conditions. A 50% cytotoxic dose (DM ₅₀ in μg / ml) is defined as the concentration of a compound that reduces the absorption capacity of the infected Mock control sample by 50%. The percentage of protection provided by this compound in HIV-infected cells is calculated by the following formula:

expressed in%. where (OD _t ) _HIV is the optical density measured in HIV infected cells at a given concentration of the test compound: (OD _c ) _HIV is the optical density of control untreated HIV infected cells; (OD _c ) _mock - optical density of the control untreated infected mock cells; all optical density values were determined at 540 nm. A dose providing 50% protection according to the above formula is defined as a 50% effective dose (ED ₅₀ in μg / ml). The ratio of DM ₅₀ to ED ₅₀ is defined as an indicator of selectivity (SI).

50% cytotoxic (DM ₅₀ ), 50% effective dose (ED ₅₀ ) and SI selectivity are shown in Table 2.

D. Examples of composition
PRI me R 9. Orally administered drops.

500 h. Of the active ingredient is dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80 ^C. After cooling to 30-40 ^{° C} is introduced 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then, a solution of 1750 parts of sodium saccharin in 2.5 L of purified water is introduced and 2.5 L of cocoa powder and polyethylene glycol are added with stirring to a volume of 50 L, resulting in a solution for drip oral administration containing 10 mg / ml of the active ingredient. The resulting solution is introduced into appropriate containers.

 PRI me R 10. The solution for oral administration.

 9 parts of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxybenzoate are dissolved in 4 liters of boiling purified water. First, 10 parts of 2,3-dioxibutanedioic acid and then 20 parts of the active ingredient are dissolved in 3 l of this solution. The last solution is mixed with the rest of the first solution, and 12 liters of a solution of 1,2,3-propanetriol and 3 liters of sorbitol at a concentration of 70% are introduced into it. 40 parts of sodium saccharin are dissolved in 0.5 l of water and raspberry (2 ml) and gooseberry (2 ml) essence are introduced. The last solution is mixed with the first, water is injected to a volume of 20 l, and an oral solution is obtained containing 5 mg of the active ingredient per teaspoon (5 ml). The resulting solution is introduced into appropriate containers.

 PRI me R 11. Capsules.

 20 parts of the active ingredient, 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 thoroughly mixed with each other. The resulting mixture is then filled with 1000 suitable cured gelatin capsules, each containing 20 mg of the active ingredient.

PRI me R 12. Film-coated tablets
Cooking a tablet core.

) и 15 ч. гидрогенизированного растительного масла (Sterotex

). Весь объем смеси тщательно перемешивается и прессуется в таблетки, и получается 10000 таблеток, каждая из которых содержит 10 мг активного ингредиента.A mixture of 100 parts of active ingredient, 570 parts of lactose and 200 parts of starch is thoroughly mixed and then moistened with a solution of 5 parts of sodium dodecyl sulfate and 10 parts of polyvinylpyrrolidone (Kollidon-K 90 ^R ) in about 200 ml of water. The wetted powder mixture is sieved, dried and sieved again. Then 100 parts of microcrystalline cellulose (Avice

) and 15 parts of hydrogenated vegetable oil (Sterotex

) The entire volume of the mixture is thoroughly mixed and pressed into tablets, and 10,000 tablets are obtained, each of which contains 10 mg of the active ingredient.

 Coating.

) в 75 мл денатурированного этанола вводят раствор 5 ч. этилцеллюлозы (Ethocel 22 cps

) в 150 мл дихлорметана. Затем в него вводится 75 мл дихлорметана и 2,5 мл 1,2,3-пропантриола, 10 ч. полиэтиленгликоля расплавляются и растворяются в 75 мл дихлорметана. Последний раствор вводится в первый и затем вводится 2,5 ч. октадеканоата магния. 5 ч. поливинилпирролидона и 30 мл концентрированной суспензии красителя (Opaspray K-1-2109

) и вся смесь гомогенизируется. Эти ядра таблеток покрываются полученной таким путем смесью в аппаратуре для нанесения покрытия.Into a solution of 10 parts of methyl cellulose (Metgael60 HG

) in 75 ml of denatured ethanol a solution of 5 parts of ethyl cellulose (Ethocel 22 cps

) in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are introduced into it, 10 parts of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The latter solution is introduced into the first and then 2.5 parts of magnesium octadecanoate is introduced. 5 parts of polyvinylpyrrolidone and 30 ml of a concentrated dye suspension (Opaspray K-1-2109

) and the whole mixture is homogenized. These tablet cores are coated with the mixture thus obtained in a coating apparatus.

PRI me R 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 injection. After cooling to ^about 50 ° C introduced with stirring for 4 hours. Lactic acid, 0.05 parts. Propylene glycol and 4 h. Of active ingredient.

 The solution is cooled to room temperature and supplemented with water for injection to a volume of 1 l and the result is a solution containing 4 mg / ml of the active ingredient. This solution is sterilized by filtration (US Pharmacopoeia, CLE, p. 811) and introduced into sterile containers.

 PRI me R 14. Candles.

) и триглицериды (Witepsol 555

) дополненные до объема 300 ч. , расплавляются вместе друг с другом. Последняя смесь тщательно перемешивается с первым раствором. Полученная таким путем смесь вливается в формы при 37-38^оС и в результате получается 100 свечей, каждая из которых содержит по 30 мг/мл активного ингредиента.3 parts of the active ingredient are dissolved in a solution of 3 parts of 2,3-dioxibutanedioic acid in 25 ml of polyethylene glycol 400. 12 parts of a surfactant (SPAN

) and triglycerides (Witepsol 555

) supplemented to a volume of 300 hours, are melted together. The last mixture is thoroughly mixed with the first solution. So obtained mixture was poured into molds at 37-38 ^C. and the result is 100 suppositories each containing 30 mg / ml of active ingredient.

 PRI me R 15. Injection solution.

 60 parts of the active ingredient and 12 parts of benzyl alcohol are thoroughly mixed and sesame oil is added to a volume of 1 liter, and a solution is obtained containing 60 mg / ml of the active ingredient. This solution is sterilized and introduced into sterile containers.

 Comparative biological data.

 Compounds 1,3,4,8 and 9, obtained according to the invention, and their structural analogues (compounds AE), were tested according to the described test. The obtained data on the biological activity of the compounds according to the invention and known compounds are presented in table.3.

The index of diabetes ₅₀ means the value of 50% of the cytotoxic dose.

Index ED ₅₀ means the value of 50% of the effective antiviral zone.

- показатель относительной безопасности лекарства.Selectivity Index SJ =

- an indicator of the relative safety of the drug.

Claims (1)

The method of obtaining tetrahydro [1,4] -benzodiazepin-2-thiones of the General formula
R

R ₂
where R ₁ -C ₃ -C ₆ alkenyl or substituted C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl;
R ₂ and R ₃ are independently hydrogen or C ₁ -C ₆ alkyl;
R ₄ and R ₅ are independently hydrogen, C ₁ -C ₆ alkyl, halogen, cyano, nitro or trifluoromethyl radical,
or their pharmaceutically acceptable acid addition salts or stereochemical isomers, characterized in that 4,5,6,7-tetrahydroimidazo [4,5-jk] [1,4] benzodiazepin-2-one of the General formula

where R ₁ -R ₅ have the indicated meanings,
halogen and the obtained 2-halogen-4,5,6,7-tetrahydroimidazo [4,5-jk] [1,4] benzodiazepine is reacted with thiourea in an inert organic solvent and, if necessary, the target product obtained by treating it with an acid is converted into a therapeutically active non-toxic acid addition salt or an acid salt, by treating it with alkali it is converted to the free base and / or its stereochemical isomers are obtained.

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