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    • 专利摘要:
    Imidazo[1,5-a][1,4]diazepine compounds of the formula <IMAGE> in which the symbols <IMAGE>, A, R1, R2 and R3 have the meaning given in Claim 1, analogues thereof as are defined in Claims 2 to 4, and pharmaceutical utilisable acid addition salts of these compounds have useful muscle-relaxant, sedative and anti-convulsive properties. They are particularly suitable for the preparation of injection solutions on account of the good water solubility of their acid addition salts. The compounds are prepared by dehydrogenation of the corresponding 3a,4-dihydro derivatives and optional N-oxidation, reduction or reaction with ethylene oxide or propylene oxide.
    公开号:SU814278A3
    申请号:SU752170852
    申请日:1975-09-10
    公开日:1981-03-15
    发明作者:Аэн Фрайер Родний；Вальзер Армин
    申请人:Ф.Гоффманн-Лярош И Ко Аг (Фирма)；
    IPC主号:
    专利说明:

    (54) CnOqOB PREPARATION OF COMPOUNDS INIDAZO (1,5-a) (1,4) DIAZEPINE OR. THEIR PHARMACEUTICALALLY LUMP OF SALTS
    in free form or in salt form.
    The lower alkyl used in the present description means C, C-f is a hydrocarbon residue with both unbranched and branched chains, preferably also a C-C -hydrocarbon residue
    as methyl, ethyl, propyl, isopropyl, butyl, etc. Expression
    lower alkanoyl
    means the acyl part., preferably. With-C-alkanoic acid, for example acetyl, propionyl, butyryl, etc., part of the structural formula T-C, where it means alkyl or hydrogen. The expression lower gshkanoil means cyclic-acetal or ketal with the number of carbon atoms from 2 to 7, i.e. structure group
    to 20
    U
    .0
    where ng is C, -C-alkyl or hydrogen.
    Ketal or acetal is used to prevent the conversion of the contained ketone or aldehyde) during oxidation, reduction and condensation processes. The expression halogen means fluorine, chlorine bromine and iodine. The expression pharmaceutically acceptable salts includes salts with both organic and inorganic, pharmaceutically compatible acids such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, antramino, maleic, acetic, amber, vinna, methane sulfonic, toluene sulfonic acid etc. These salts can be obtained (fairly simply) by known methods, taking into account the preparation of the compounds as a salt.
    The most preferred pharmaceutically compatible acid addition salts of the compounds of general formula (1) are 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazoX1 5-a) (1,4) benzodiazepine maleate and 8-chloro 1, 4-dimethyl-6- (2-fluorophenyl) -4H-imidazo (1.5) (1,4) benzodiazepine leat.
    I It was found that certain g compounds of structural formula (1) in solution open to form compounds of structural formula
    BR-Y91:
    1 where TK,, T, i,, RA and TJ are as defined above;
    Y is the anion of an organic or inorganic acid.
    Such open compounds are pH dependent pH equilibrium in solution with compounds of structural formula (1) i.e. and corresponding connections with a closed ring. The compounds of structural formula (ID) can be isolated in the form of acid addition salts by treating their corresponding ring-capped compounds with aq. Mineral acid followed by evaporation of the solvent. After isolation, these salts exhibit a pharmacological activity comparable to that of their respective related compounds with a closed M ring.
    The following examples are illustrative, but not in any way limiting, of the present invention.
    Example 1. A mixture of 3.4 g of 8-chloro-Za, 4-DIHIDRO-1-ETHIL-6- (2-fluorophenyl) -ZH-imidazo.1, 5-0) (1,4) benzodiazepine, 400 ml of toluene and 30 g of activated manganese dioxide is heated under reflux by separating water using a Dean-Stark trap for 2 hours. Manganese dioxide is separated by filtration on cellite and the filtrate is evaporated. The crystallization of the residue from ether gives 1.4 g of 8-chloro-1-ethyl-b-. (2-fluorophenyl) -4H-imidazo (1, 5-al 1, 4) benzodiazepine with m.p. 140-143 ° C. For the purposes of analysis, the latter was recrystallized from ether (mp. 143-145 ° C)
    Example 2. Resinous 8-chloro-3a, 4-dihydro-b- (2-fluorophenyl) -1-methyl-3H-imidazo (1,5-d) (1,4) -benzodiazepine, obtained from 6.16 g crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepna and 7 ml of acetic anhydride, mixed with 500 ml of toluene and 30 g of manganese dioxide and heated with reverse refrigerator for 0.5-1 hours. Manganese dioxide is separated by filtration on cellite. The filtrate is evaporated and the residue is crystallized from ether to obtain 1.2 g (19.5%) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imide 30 (1,5-d) (1.4 ) benzodiazepine with m.p. 152-154 ° C. A sample was recrystallized from methylene chloride (hexane).
    Example 3. 1.3 g of resinous 8-chloro-b- (2-chlorophenyl) -3a, 4-dihydro-1-methyl-ZN-imidazo (1,5-c () (1,4) benzi; LkNayyyt 1c g manganese dioxide in 200 ml of toluo; A. After heating to reflux for 0.5-1 h, the manganese dioxide is separated and the filtrate is evaporated. Crystallization of the residue from ethyl ether gives 0.5 g of 8-chloro-6 - (2-chlorophenyl) -1-methyl-4K-imidazo-tl, 5-a) (1,4) benzodiazepine with m.p. 140-144c. In order to analyze, the latter is recrystallized from methylene chloride (hexane); m.p. 142-144 ° C.
    Example 4. A mixture consisting of 3.1 g (0.01 mol) of 8-chloro-3H, 4-dihydro-1-methyl-6-phenyl-3H-imide 3o (1,) (1,4) benzodiazepine, 20 g of activated manganese dioxide and 150 ml of toluene are heated under reflux for one hour. Manganese dioxide is removed by filtration on cellite and washed thoroughly with methylene chloride. The filtrate is evaporated and the residue is crystallized from ether to obtain 1.5 g (50%) of 8-chloro-1-methyl-6-phenyl-4H-imidazo (1,5-a) (1,4) benzodiaepine as colorless crystals from m.p. 187-188p.
    Example 5. A mixture consisting of 5.1 g of 8-chloro Za, 4-dihydro-1,4-dimethyl-b- (2-fluorophenyl) -ZH-imidog3o (l, 5-a) (1,4 a) Benzodiazepine, 20 g of activated manganese dioxide and 300 ml of toluene, is heated for 3 hours with a reflux condenser, then udgsh water using a Dean-Stark trap. Manganese dioxide is removed by filtration on cellite and washed thoroughly with methylene chloride. The filtrate is evaporated and the residue is subjected to chromatography under pressure on 150 g of silica gel H using 3% ethanol in methylene chloride i. First, the eluted base component of 8-ChLOR-1, 4-dimethyl-6- (2-fluorophenyl) -4H-imidazo11, 5-a) (1,4) benzodiazepine The latter is converted to crystalline dihydrochloride by treatment with ethanolic hydrogen chloride in ether; m.p. 247-250 ° С (with decomposition). Total yield 1.5g.
    The more polar component can be crystallized from methylene chloride (ether; hexane) to give 0.3 g of 8-chloro-1,3-dimethyl-b-2-fluorophenyl-4H-imidazoC, 5-g of 1,4-benzodiazepine o m.p. 178180 C.
    Example b. A warm solution of 6.5 g (0.02 mol) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo (1,5-O) (1,4) benzodiazepine1, in 30 ml of ethanol is mixed with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. The mixture is diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals are collected, washed with ether and dried in vacuo to give 8.2 g (93%) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo maleate (1.5-aj (1 , 4) benzodiazepine with a melting point of 148-1-51 ° C.: Example 7. Oily 8-chloro-Za, 4-dihydro-b- (2-fluorophenyl) -1-methyl-3N-nmidazo 11, 5-o) (1,4) benzodiazepine obtained from 14.2 g of 2-aminomethyl-7-chloro-5- (2-fluorophenyl) -2, 3-dihydro-ltt-1, 4-benzodiaepine and 14. ml of triethyl orthoacetate, dissolved in 500 ml of xylene. After the addition of 50 g of activated manganese dioxide, the mixture is stirred and heated to reflux for 0.5-1 h, and the water is removed using a Dean-Stark trap. The inorganic material is removed by filtration and the filtrate is evaporated to give 10 g of a brown oil. A warm solution of 4.65 g (0, O4 mol) of maleic acid in 50 ml of ethanol is added to the resulting residue. After preparing the finished solution, the product is crystallized by the addition of ether. The product is collected, washed with ether to give 5.3 g of 8-chloro-b- (2-fluorophenyl) -1-methyl 4H-imidazo (1,5-oiJf (1.4) benzodiazepine meleate), mp. 112-115 ° C. When heated under vacuum to EO-CQ, the resulting substance is converted into a product with a higher melting point, namely, 148-151 ° C.
    Example 8, a solution of 0.32 g: (1 mmol) 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1,5-o) (1,4) benzodiazepine in 5 ml of ethanol is treated with ethanol hydrogen chloride in excess. The salt is crystallized by the addition of 2-propanol and ether. Colorless crystals of sobirgiot were washed with ether and dried to give 0.37 g of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo (1.5-0) (1,4) benzodiazepine dichloride. square 290-295 s.
    Example 9. A solution of 0.325 g (1 mmol) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo {1, 5-a} (1,4) benzodiazepine in 3 ml of ethanol is combined with a suspension 0.4 g (1 mmol) dihydrochloride of this compound in 5 ml of ethanol. After filtration, the solution is treated with ether and heated in a steam bath for 5 minutes. The resulting crystals are collected, washed with ether and dried to give 0.5 g of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazoO 5-a) (1,4) benzodiazepine hydrochloride, m.p. 295-297 p.
    Example 10.2, bg Over, 4-di hydro-1-methyl-b-phenyl-3H-imidazo (l, 5-q) (1,4) benzodiazepine is heated in 50 ml of toluene together with 7 g of activated manganese DIOK11SI to temperature reflux distilled for 0.51 h. The inorganic material is filtered off. and the filtrate is evaporated. The residue is purified by chromatography on 30 g of silica gel using 10% ethanol in methylene chloride. Pure fractions are combined and evaporated. As a result of crystallization of the residue from ether, 0.7 g (29%) of 1-methyl-b-phenyl-4H-imidazo (1,5-D) (1,4) benzodiazepine is obtained. .pl. 180-1820C. Example I. 4.5 g (92%) of crude 8-chloro-Za, 4 - digidE5o-1, 4-dimethyl-b- {2-fluorophenyl) -ZN-imidazo (1-a5 ( 1,4) Benzodiazepine is mixed with 20 g of activated dioxygen xymanganese and 200 ml of toluene and heated to reflux temperature for 2 h. The mixture is filtered and the manganese oxide is washed with methylene chloride. g of a brown rubber-like substance, 8-chloro-1,4-dimethyl-b- (2-fluorophenyl) -4H-imide 30 (1,5-a) (1,4) benzodiazepine dihydrochloride as a white powder obtained They are mixed by mixing the substance with ethanol chlorofluoride for a few minutes; mp 247-2500 C. Example 12, Crude 8-acetylamino-3, 4-dihydro-b- (2-fluorophenyl) -1-methyl-3H-imidazo ( .1,5-a) (1,4) benz diazepine, obtained from 25 g of 4-hydroxy -1, 3-dihydro-5- (2-fluorophenyl) -7-nitro-2-nitromethylene-2H-1, 4 -benzodiaz pina (as in Example 10), dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The mixture is heated at reflux and stirred for 9 hours using a Dean Stark trap. Additionally, 25 g of activated dioxide is added. marg After four hours at reflux, manganese dioxide is removed by filtration and washed with 500 ml of tetrahydrofuran. The filtrates are combined and evaporated to dryness. 8-acetylamino-b- (2-fluorophenyl) -1-methyl-4n-amidazo (1.5-0) (1.4) benzodiazepine is obtained, Example 13, Mixture consisting of 17 g (0.05 mol ) racemic 8-chloro-1,4-dimethyl-b- (2-fluorophenyl) -4H-imidazo (1, 5-a) (1,4) -benzodiazepine isolated in its free state from its dihydrochloride by distribution between the chloride methylene and water, 18.8 ((05 mol) of 0,0-dibenzoyl-1-tartaric acid hydrate and 170 ml of ethanol are boiled until solution is obtained. For crystallization, the solution is kept overnight. The individual crystals are collected, washed with ethanol and ether to give 8.4 g (47%) 0, o-dibenzoyl-d-tartpra with mp 140-142 ° C. After recrystallization from ethanol (ether), the product is obtained with mp, 141-142 C IIX -43.39 ( IB methanol). A solution of 1.6 g (0.0106 mol, E-tartaric acid in 11 ml of ethanol is added to a solution of 3.5 g of a levorotary base, isolated in a free state from the above-named O, O-dibenzoyl-th-t in 11 ml of ethanol. The resulting crystals are collected and washed with ethanol and ether to give 2.8 g (55%) of (+) - 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H -imidazo (, i, 5-a) (1, 4) benzodiazepine with m.p. 178180 ° C, Recrystallization from Tanoli obtained product with m. pl. 183185 ° C and M + 25.69 ° (from 1.012% in methanol), the amorphous base isolated in the free form from this salt shows a rotation of CoQ.-36.74 (from 0.939% in methylene chloride). Example 14 The mother liquor remaining after separation of the crystalline salt of O, 0-dibenzoyl-d-tartaric acid according to the above example, is evaporated and made into the base by distribution between aqueous ammonia and methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated to give 12 g of partially dissolved base. A solution of 9.7 g (0.029 mol) of this material in 15 ml of ethanol is treated with a solution of 4.4 rd-tartaric acid in 14 ml of ethanol. The crystals which separated out after a few hours were collected, obtaining 3.2 g (23%) of d-tartrate of (-) - 8 chloro-1,4-dimethyl-6- (1-fluorophenyl) -4H-imidazo (1,5-d ) (1,4) benzodiazepine with m, pl, 17b-17BPC. After recrystallization from ethanol, a product is obtained with m.p., 182 -: 184 s and iaijjy -24.96 (C 0.9616% in methanol). The amorphous base, isolated in the free form from this salt, shows a rotation of 37, b (C 1.0% in methylene chloride). Example 15. A solution containing 3.8 g (0.0105 mol) of crude 30, 4-dihydro-1-methyl-8- (1-methyl-2,3-dioxolan-2-yl) -6-phenyl-3N -imidazo (l, 5-0} (1, 4) benzodiazepine and 18 g of activated manganese dioxide in 100 ml of toluene, heated under reflux with stirring for 2 h using a Dean-Stark trap. Filtered and washed with a mixture of 250 rll dichloromethane and 250 ml of tetrahydrofuran. The filtrates are evaporated and dissolved in a small amount of isopropanol, followed by treatment with 1.4 g (0.0121 mol) of maleic acid in ethanol. Ether is added and the precipitate is filtered and recrystallized from a mixture of methanol and ether to obtain 0.9 g of 1-methyl-8- (2-methyl-1, 3-dioxolan-3-yl) -6-phenyl-4H-imidazo maleate (l, 5 -or) (1.4) benodyazepine (1/2) in the form of off-white prisms with mp 179-182 0. Total yield 20%.
    Example 16. 0.8 g of Za, 4-Dihydro-8-ethyl-b- (2-fluorophenyl) -1-methyl-3H-imidazo (1,5-a) (1,4) benzodiazepine is dissolved in 50 ml of toluene . The solution is heated under reflux for one hour after the addition of 5 g of activated manganese dioxide. The inorganic material is separated by filtration. The filtrate is evaporated. The residue is dissolved in ether and treated with ethanolic hydrogen chloride and acetone. The crystalline dihydrochloride salt (mp. 248-255 ° C) is collected and converted back to the base by distribution between methylene chloride and aqueous ammonia. The chloromethylene layer is dried and evaporated. Crystallization of the residue of simple ether (hexane) gives 0.28 g of 8-ethyl-b- (2-fluorophenyl.) -1-methyl-4H-imidazo (1,5-a) (1,4) benzodiazepine with m.p. . 152-154 p.
    Example 17. 3.6 g of crude CZ (, 4-dihydro-b- (2-fluorophenyl) -1-methyl-ZN-imidazo 1, 5-a (1,4) benzodiazepine is dissolved in 100 ml of toluene, treated with using 18 g of activated manganese dioxide, the mixture is stirred and heated under reflux for 3.5 hours using a Dean-Stark trap. The reaction mixture is filtered through celite. and the residue is dissolved in 25 ml of dichloromethane. This solution is chromatographed through a column of florisil with dichloromethane, then eluted with ether, by elution using ethyl acetate and then 10% by volume of a solution of methanol in an ecylate tetat, a raw product is obtained which is crystallized from ether and then recrystallized from ethyl acetate to obtain 0.8 g (19%) b (2-fluorophenyl) -1-methyl-4n-imidazo (1,5-a) (1,4) benzodiazepine in the form of white prisms with m.p. 1b4-168C.;
    Example 18 50 ml of mesitylene and 0.5 g of 10% palladium on animal charcoal are stirred and heated under reflux for 28 hours, then filtered and evaporated to dryness. 0.5 g (42%) of b -. (2-fluorophenyl) -1-methyl-4H-imidazo (1,5-a) (1,4) benzodiazepine is obtained in the form of white prisms with mp . 1b2-1b7 ° C
    and with a mixed melting point of the authentic product at 1b2-1b8 C, Example 19. 41.3 g of 8-chloro-1,4-dimethyl-b- (2-, -fluorophenyl) -4H-imidazo dichloride {1,5-a ) (1,4) benzodiazepine is distributed between methylene chloride and aqueous ammonia. The methylene chloride solution is washed with water, dried over sodium sulfonate and evaporated to give a free base. This material is dissolved in 50 ml of 2-propanol and the solution is treated using a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution is slowly diluted using
    5 300 ml of ether. Fallen out
    the crystals are collected and dried to obtain 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo (1,5-o) (1,4) benzodiazepine maleate with m.p. 1300 132 ° C, after recrystallization from ethanol (ether).
    Example 20, 1-Methyl-Za, 4-dihydro-b-phenyl-3N-imidazb (1,5t-a) thieno (2,3-K) (1,4) diazepine, obtained from 1 g of 2-aminomethyl- 2,3- -dihydro-5-phenyl-1H-thieno (3,2-e) 1 (1,4) diazepine dimgsheat and 1 g of tri-ethyl ethyl acetate are heated to heat ;. reflux distilled in 3.0 ml of toluene with 2 g of activated dioxide
    manganese for 2 h. Manganese dioxide is filtered and carefully. washed with methylene chloride. The filtrate is evaporated and the residue is chromatographed on 7 g of silica gel using 3% by volume of ethanol in chlorine. tom methylene. Fractions containing. pure product, combined and evaporated. After crystallization from methylene chloride (ether) and recrystallization from ethyl acetate (hexane), 40 mg (11.5%) of 1-methyl-6-phenyl-4H-imidazo (1,) thieno (2,3-f) diazepine are obtained m.p. 223-225 ° C.
    i Example 21. Crude 8-chloro-1-methyl-Zo, 4-dihydro-6-phenyl-3,4-imidazoC1, 5-o) thieno (3,2 - {) (1,4) diazepine obtained from 0.52 g of 2-aminomethyl-7-chloro-2, 3-dihydro-5-phenyl-1H-thieno 2, 3rd (1.4) diazepine dimaleate and 0.5 ml of triethyl orthoacetate a | is dissolved in 25 ml of toluene, and the solution is heated under reflux for 1.5 h after reaching 2.5 g of activated manganese dioxide. The manganese dioxide is then filtered and the filtrate is evaporated. The residue is chromatographed on 6 g of silica gel using
    4 vol% ethanol in methylene chloride Fractions containing the pure compound are combined and evaporated. After crystallization of the residue from ether (hexach), 12 mg (4%) is obtained
    ; 8-hlrr-1-methylgb-f, enyl-4H-imidazo; (l, 5-L) thieno (3,2-f) {1,4) diazepine with m.p. 168-170 C. Example 22. In a solution of 0.5 g (1.52 mmol.) 8-chloro Za, 4-dihydro-6 (2-ft6phenyl) -1-methyl-4H-imidazo (1,5-a ) (1,4) benzodiaepine in 2 O ml of dry toluene, 1.2 (7.6 mmol) potassium permanganate, 1.1 g (9.12 gl lol} magnesium sulfate and one drop of dicyclohexyl-18-crown -6 The reaction mixture is stirred for 3 hours at and then for 3 hours at 70 ° C. It is filtered and the precipitate is washed with a mixture of tetra hydrofuran and methylene chloride (1: 1). The filtrates are evaporated and 0.2 g (1.72 g mmol) maleic acid, the mixture is crystallized from isopropanol (ether) to obtain 0.15 g (22%) maleate 8- lor-b- (2g-fluorophenyl) -1-methyl-4H-imidazo (1,5-a) (1,4) benzodiazepine with mp, 111114-s after recrystallization from ethanol (ether) in the form of solvated white prisms Mixed t, mp 111-115 C is obtained with the original sample. Preparation of the starting material Example 23 .. a) Solution 200 g (0.695 mol.) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) - 2H-1,4-benzodiazepin-2-one in 2 l of tetrahydrofuran and 250 ml of benzene are saturated with methylamine while cooling in an ice bath. A solution of 190 g (1 mol) of four titanium chloride in 250 ml of benzene is then added through a dropping funnel over 15 minutes. After the addition, the mixture is stirred and heated under reflux for an additional 3 hours. Water (600 ml) is added to the cooled reaction mixture. ml) The inorganic material is separated by filtration and washed thoroughly with tetrahydrofuran. The aqueous layer is separated and the org phase is dried on sodium sulfate and evaporated. The crystalline residue is collected 25 g (96%) of 7-chlorogb- (2-fluorophenyl) -2g-methylamine -NH-1,4-benzodiazepine c-mp, 204,206. The sample for analysis is recrystallized from methylene chloride (ethanol), receiving the product of art. 204-20b C. portions of sodium nitrate 8.63 (0.125 mol) are added over 15 minutes to a solution of 30.15 g (0.1 mol 7-chloro-5- (2-fluorophenyl) -2-methylamine -ZH- 1,4-benzodiazepine in 150 ml of acetic acid. After stirring for 1 hour at room temperature, the reaction mixture is diluted with water and extracted with methylene chloride. The extracts are washed with saturated sodium bicarbonate solution, dried on sodium sulfate and evaporated In order to obtain 29 g of 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethyl-amino) -ZP-J, 4-beneodiazepine, in the form of a yellow oil. in a mixture with toluene, azeotropic is carried out. The resulting product is dissolved in 100 ml of dimethylformamide and 200 ml of dimethylformamide, 50 ml of nitromethane and 11.1 g, 0.1 mol of potassium butoxide are added to the mixture, which are stirred under a nitrogen atmosphere. min After stirring for one hour at room temperature, the reaction mixture is acidified by adding glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water, dried over sodium sulfate and evaporated. By crystallization of the residue from the ether, 9.2 g of 7-HLOR-1, 3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1, 4-benzodiazepine with m.p. 170-172 ° C. The sample for analysis is recrystallized from methylene chloride (ethanol), t, pl. 174-176С. A solution of 16.5 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1, 4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol are hydrogenated, apply 5 teaspoons of Rene nickel, for 0.5-2 hours at atmospheric pressure. After removal of the catalyst and evaporation, 14 g of crude 2-amino-methyl-7-HLOR-2, 3-dihydro-5- (2-fluorophenyl) -1H-1, 4-benzodiazepine remain. 5) A mixture of 2-carboxamide 7-chloro-1, 3-dihydro-5- (2-fluorophenyl) -2H-1, 4-benzodiazepine (64 ml, 0.2 mol of lithium aluminum hydride (15 mg, 0.4 mmol) in dry tetrahydrofuran (.3 4 l) is boiled for 15 minutes, the reaction mixture is cooled by the addition of a saturated aqueous solution of sodium sulfate. A thin layer analysis of the resulting solution shows the presence of starting material as the main, more mobile component, and the free base of 2-aminomethyl-7 -chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4benzodiazepine as a side component. The solution is peremeshayut n mediocre on cm-sized plates (silica gel) prepared for thin-layer chromatography that exhibit Ethanol. The lower yellow band is removed and extracted twice with methanol (methylene chloride) (2: 1). A clear, colorless oil is obtained by evaporation of the filtered extract. The latter is dissolved in ethanol (1 ml), treated with maleic acid in excess (50 mg) and you {overnight in a refrigeration unit. The yellow crystals are collected, washed with ether and dried in air. The product was determined with 2-aminomethyl-7-chloro-2, 3-dihydro-5- (2-fluorophenyl 1H-1,4-benodiazepine dimaleate), comparing its IR spectrum in nujol and its mp 185-186, The initial sample (m.p.). The melting point of the mixture is 184-187 ° C. &gt; Propionic anhydride (20 ml) is added to a solution of 12 g of the above-mentioned compound in 300 ml of methylene chloride. The solution is stratified with 300 ml of 10% aqueous sodium carbonate and the biphasic mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with sodium carbonate solution and dried on sodium sulfate. Condensed to obtain 12 g of crude 7-chloro-2,3-dihydro-5- (2-fluorophenyl) -2-propionyl aminomethyl-1H-1,4-benzodiazepine. The resulting product is heated in 50 g of polyphosphoric acid at 150-170 ° C for 10 minutes. The reaction mixture is cooled, dissolved in water and brought to an alkaline reaction with concentrated ammonia and ice. The base is extracted with methylene chloride, the extracts are dried on sodium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel using 20% methanol in methylene chloride. Pure fractions are combined and evaporated. The residue is crystallized from ether to give 4.7 g of 8-chloro-3sg, 4-dihydro-1-ethyl-b- (2-fluorophenyl) -3a-imidazo (1-a) (1,4) benzodiazepine with m.p. . 131-133 ° C. Example 24. Acetic anhydride (7 ml) was added to the growth of a thief, 6.16 g of crude 2-aminomethyl-7-chloro-2, 3-dihydro-5- (2-fluorophenyl) -1H-1,4 -benzodiazepine in 200 ml of methylene chloride. The solution is stratified by means of 200 ml of a saturated aqueous solution of sodium bicarbonate and the mixture is stirred for 20 minutes. The organic layer is separated by sodium bicarbonate, dried on sodium sulfate, and evaporated to give a resinous 2-acetoaminomethyl-7-chloro-2, 3-dihydro-5- (2-fluorophenyl) -1H-1, 4-benzodiazepine. The resulting product is heated together with 40 g of polyfrasoric acid ua il50c for 10 minutes. The cooling reaction mixture is dissolved in water, hydrated with ice and brought to an alkaline reaction and extracted with methylene chloride. The extracts are dried and evaporated, the residue is subjected to chromatography on 120 g of silica gel using 20% methanol in methylene chloride. The pure fractions are combined and evaporated to give a resinous 8-chloro-3A, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo 1, 5-O (1,4) benzodiazepine. Example 25. A suspension of 17 g (0.05 mol) of oxide-7-chloro-1, 3-dihydro-5- (2-fluoro (enyl) -2-nitromethylene-2H-1, 4-benzodiazepine-4 in 200 ml tetrahydrofuran and 100 ml of methanol are hydrogenated in the presence of 17 g of Rene nickel at an initial pressure of 10.8 atm for 24 h. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in 50 ml of 2-propanol and heated in a steam bath. A warm solution is added 17 g of malic acid in 60 ml of ethanol, and the salt is subjected to crystallization by cooling in an ice bath. Dimelate 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzod azazepine consists of yellow crystals with mp 196-198 C. 8.0 g (0.015 mol) of 2-amino-methylmethyl-7-chloro-2, 3-dihydro-5- (2-fluorophenyl) -1H-1 dimaloate, The 4-benzodiazepine is distributed between methylene chloride and aqueous solvent. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. OCTSJTOK is dissolved in 50 ml of pyridine. After adding 10 ml of acetic anhydride, the mixture is heated in a steam bath for 4 The reagents are concentrated under reduced pressure and the residue is distributed between methylene chloride and a bic aqueous solution. sodium arbonate. The organic layer is dried and evaporated. By crystallization of the residue from chlb | ristrogo methylene (ether) by seeding, 1-acetyl-2-acetyl1 inomethyl-7-chloro-2, 3-dihydro-5- (2-fts) rpheny) -1H-1,4beneodiazepi with t .pl. 213-215 0. Seed crystals are obtained by chromatography on silica gel (40 times the amount) using 10% by volume of ethanol — In methylene chloride for the purpose of eluation. Analytically pure sample is recrystallized from ethyl acetate (hexane); m.p. 215-217c, A mixture of 0.5 g of 1-acetyl-2-acetyl aminomethyl-7-chloro-2, 3-dihydro-5- (2-ft fensh1) -1H-1,4-benzodiazepine and 10 g of polyphosphoric acid is heated to 10 minutes . The cold reaction mixture is dissolved in ice water and the solution is subjected to ammonia. the base is then extracted with methylene chloride. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 10 g of oilycage using 20% methanol in methylene chloride. Pure fractions are collected and evaporated. The residue is crystallized from ether to give 8-chloro-Csg, 4-dihydro-b- (2-fluorophenyl) -1-methyl-4H-imidazo (1.5-a) (1,4) benzodiazepine with m.p. 142144 ° C.
    Example 26, Reaction (see Example 23, a) 152.5 g- (0.5 mol) 7-chloro-5- (2-hlrphenyl) -1,3-dihydro-2H-1, 4-benzrdiazepine-2 -one saturated with methylamine with 133 g (0.7 mol) of titanium tetrachloride in 2 l of tetrahydrofuran and 400 ml of benzene gives 145.8 g (91.5%) of 7-HLOR-5- (2-chlorophenyl) -2-methylamino -ZN-1, 4-benzodiazepine with m.p. 216219 C, The sample for analysis is recrystallized from methylene chloride (ethanol); mp 217-219 ° C,
    10 g (O, 145 mol) of sodium nitrate are added in portions over 45 minutes to a solution of 22.4 g (0.07 mol) of 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-1, 4-benzodiazepine in 150 ml of glacial acetic acid. After the addition, stir for another 20 minutes under a nitrogen atmosphere. The product is precipitated by adding ice water, collected and dissolved in toluene. The solution is washed with a saturated aqueous solution of sodium bicarbonate, dried and evaporated under reduced pressure. According to the thin-layer chromatogram, the yellow viscous oil mainly consists of the needs of nitrosoamidine. This substance is dissolved in -100 ml of dimethylformamide and added to a mixture of 30 ml of nitro methane, 100 ml of dimethylformamide and 10 t potassium butylate. The reaction mixture is slowly heated to 85 ° C with stirring, passing a stream of nitrogen. After 5 min, the reaction mixture is cooled and acidified by adding 10 ml of glacial acetic acid. The product is crystallized, and water is gradually added with persecution (lumps are obtained by chromatography on silica gel, apply 10% ethyl acetate in methylene chloride). Separated crystals are collected, washed with water and recrystallized: from methylene chloride (ethanol.), after which 8 g (3.3%) of Tr-chloro-b- (2-chlorophenyl) - 1,3-dihydro-2-nitromethylene-2H: -1, 4- enzodiazepina with mp 182-185 C. Hydrogenation of 7 g of 7-chloro-5- (2-chlorophenyl) -1 H-Dihydro-2-nitromethylene-2H-1, 4 benzodiazepine. 300 ml of tetrahydrofuran and 150 ml of methanol in the presence of Renee nickel (5 teaspoons) for one hour get crude 2-aminomtil-7-HLOR-5- (2-chlorophenyl) -2,3-dihydro-1H-1, 4-benediaminepine The latter is acetylated in a known manner to give oily 2-acetoaminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1H-1, 4-benzodiazepine,
    which is heated in 15 g of polyphosphoric acid for 10 minutes at 140-150 ° C. In a known manner, 3 g of a yellow resin is obtained, which is chromatographed on 250 g of silica gel using 20% methanol in methylene chloride. 1.3 g of resinous 8-chloro-b- (2-chlorophenyl), 4-dihydro-1-methyl-ZN-imide 3 (1, 5-ci) (1,4) benzodiazepine are obtained in pure fractions. Example 27. A solution of 33 g
    (0.1 mol) 7-chloro-2- (I-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml of dimethylformamide is added to the mixture 50 ml
    5 nitromethane, 12.5 g (0.11 mol) of potassium t-butylate and 100 ml of dimethylformamide. The reaction mixture is stirred in a stream of nitrogen for about an hour. After adding 10 ml of ice
    0 acetic acid crystallizes the product, gradually adding 250 ml of water. The precipitated yellow substance is collected, pierced with water, matanol and ether, after which
    5 get 23.5 g (71%) of 4-oxide 7-chloro-1, 3-dihydro-2-nitromethylene-5-phenyl-2H-1, 4-benzodiazepine with t, mp, 253-255 C ); The sample for analysis is recrystallized from methylene chloride;
     tpl is the same.
    Rene Nickel (5 teaspoons) is added to a solution of 16.5 g (0.05 mol; 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1; 45-benzodiazepine 4 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture is hydrogenated for 5 hours at atmospheric pressure .i The catalyst is removed by filtration and the filtrate
    0 is evaporated, the residue is dissolved in -propanol-and the solution is brought to a strongly acidic reaction, using ethanolic hydrogen chloride, the product dihydrochloride crystallizes after packing a part of the solvent. Orange crystals are collected and 13.2 g (73%) of 2-aminomethyl. -7-chloro-2,3-dihydro-5-phenyl-1H-1, 4-benzodiazepine dichloride are obtained. 230-240 ° C,
    Acetic anhydride (10 ml) is added to a solution of 10 g of the aforementioned dihydrochloride in 50 ml of water and 50 ml of methanol, added with stirring. Within S min
    5 A 10% aqueous solution of sodium carbonate (100 ml). After the addition, the mixture is kept stirring for 10 minutes, after which it is extracted with methylene chloride. The Extraction is washed with sodium carbonate solution, dried on sodium sulfate, evaporated and subjected to azeotropic distillation at the end with toluene. Obtain 10 g of 2-acetamine 5-TIL-7-HLOR-2,3-dihydro-5-phenyl-1H-1, 4-6-benzodiazepine as a yellow resin,
    The substance mentioned above is heated in 50 g of polyphosphoric acid to 135-140 s for 10 minutes. The color of the reaction mixture (orange first) turns light yellow. The cooled reaction mixture is dissolved in water, brought to an alkaline state using concentrated ammonia and ice, and extracted with methylene chloride. The extracts are dried and evaporated. The yellow resin is dissolved in 2-propanol and treated with ethanol: 1 ml of hydrogen chloride, after which 5.5 g (51.5%) of the colorless dichlorohydrate of the product crystallizes with mp 24040 C. This hydrochloride is partitioned between methylene chloride and aqueous ammonia. The organic phase is dried and evaporated. After crystallization of the residue from ether, 2.5 g of 8-chloro 3-4-dihydro-1-methyl-6-phenyl-3H-imidazo (1,5--o) (1/4) benzodiazepine are obtained as a colorless product. m.p. IB-FROM
    Example 28. A mixture consisting of 11.2 g (0.1 mol) of potassium t-butylate, 50 ml of nitroethane and 200 ml of dimethylformamide was stirred at room temperature for 15 minutes. Then a solution of 29 g (O, 088 mol) of crude 7-chloro-5- (2-fluorophenyl-2-O-nitrosomethylamino) -N-1,4-benzodiazepine in 100 dimethylformamide is added and the mixture is stirred under nitrogen for further b.The reaction mixture is neutralized by the addition of glacial acetic acid and diluted with water. The product is extracted with ether. The extracts are dried with a saturated solution of sodium bicarbonate, dried on sodium sulfate and evaporated. Crystallization from ether gives 8.1 g (26.5%) of 7-chloro-1, 3-dihydro-5- (2-fluorophenyl) -2- (1.-Nitroethylene) -2H-1,4-benzodiazepine in yellow crystals with m.p. 136-142 s.
    To a solution of 17.3 g (0.05 mol.} 7-chloro-1,3-dihydro-5- (2-fluoroufil) -2- (1-nitroethylene) -2H-1,4-benzodiazepine in 750 ml of tetrahydrofuran Rene nickel (5 teaspoons) is added. The mixture is hydrogenated at atmospheric pressure for 4 hours. The catalyst is removed by filtration on cellite and washed thoroughly with methanol. After evaporation of the filtrate, 14.1 g of crude 2- (1-aminoethyl) -7- chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine as: reddish oil. The resulting substance is dissolved in 300 ml of methylene chlorine. -After adding 14 ml of acetic anhydride, 300 ml of saturated aqueous sodium bicarbonate solution and the biphasic mixture is stirred at room temperature for one hour. The methylene chloride layer is separated, washed with bicarbonate, dried on sodium sulfate and evaporated. The residue is heated with 40 g of polyphosphoric acid for 10 minutes at 1bO-170 ° C. The cooled reaction mixture is diluted with water, brought to alkaline state 0 or using aivo uiaKa and extracted with methylene chloride. The extracts are washed with water, dried and evaporated to give a brown residue, which is chromatographed on 250 g of silica gel using 20% by volume of methanol in methylene chloride. Fractions homogeneous by thin layer chromatography were combined to obtain 5.1 g of a resin consisting of 8-chloro-Zo, 40 -dihydro-1,4-dimethyl-6- (2-chlorophenyl) -3H-imidazo (1, 5-a) (1, 4) -g-benzodiazepine.
    Example 29. A mixture consisting of 17.4 g (0.05 mol) of 4-hydroxy
    5 7-ChLOR-1, 3-dihydro-5- (2-fluorophenyl) -2- {1-nitromethylene) -2H-1,4-benzodiazepine, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaspoons of Rene nickel are hydrogenated at atmospheric pressure for 5 h. The catalyst is filtered, and the filtrate is evaporated at the end by azeotropic distillation using xylene. 14.2 g of 45-aminomethyl-7-chloro-5- (2-fluorophenyl) -2, 3-dihydro-1H-1, 4-benzodiazepine, are obtained. The resulting material was dissolved in 200 ml of ethanol, and the solution was heated under reflux for 2 hours after addition, 14 ml of 1,1,1-triethoxyethane and 2.8 g of p-toluenesulfonic acid. The solution is evaporated under reduced pressure and the residue is distributed between methylene chloride and 10% hydrogen chloride.
    5 aqueous solution of sodium carbonate. The organic layer is dried and evaporated to obtain oily B-chloro-FTA, 4-dihydro-b- (2-fluorophenyl) -. -1-methyl-3N-imidazo (1,) (1,4) benzr-i
    0 diazepine.
    Example 30. A solution of 23.6 g (0.10 mol) of 1,3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one in 1 l of tetrahydrofuran containing about
    5 20 moles monomethylamine) are cooled in an ice bath. 14 ml (0 1.73; 0.125 mol) of titanium tetrachloride in 20 TH g of benzene are added to this mixture. The resulting mixture was stirred at room temperature for two days. The titanium complex is decomposed with 20 ml of water. Inorganic salts are precipitated and removed by filtration. The solvent is evaporated in vacuo, and the residue is
    limit goth between methylene chloride and water. The colorless amorphous solid with mp. 227-229 ° was removed by filtration. An additional sample (m.p. 226-228 o of colorless solid is obtained from the mother liquor) of methylene chloride solution after. drying on anhydrous sulphate; sodium evaporation to dryness and crystallization from ethyl acetate. Overall. yield 22.5 g (90%). A sample for analysis is obtained by recrystallization from dimethylformamide, which gives colorless prisms with m.p. 227-229C. To chilled; (up to 10 ° C), a stirred solution of 10.0 g (0.04 mol) of 2-methylamino-5-phenyl-3H-1, 4-benzodiazepine in 100 ml of pyridine was added 100 ml of a saturated solution of nitrosyl chloride in acetic anhydride . The solution is stirred for 3.5 hours at room temperature. The solution is poured into 300 ml of ice water. The aqueous solution is extracted with 5 ml of 150 ml of methylene chloride. The combined organic extracts are washed with water and toluene and dried (over CaSO4), the solvent is removed under reduced pressure to give a dark semi-solid. As a result of chromatography on 500 g of silica gel (chloroform zylation), 10.9 g (98%) of 2- (N-i-nitrosomethylamino) -5-phenyl-3H1, 4-benzodiazepine with m.p. 192-199 C (with decomposition).
    The product obtained is used in the following reaction. The base of nitromethane, conjugated with acid, is obtained by treating with 50 ml of nitromethane in 200 ml of dimethylformamide and 5.7 g (0., O5 mol) of tert-butylate, potassium. The yellow suspension obtained with stirring is treated with 10.9 g of crude 2- (N-nitrosomethylamino) -5-phenyl-3H-1, .4-benzodiazepine in 100 ml of dimethylformamide. The dark mixture obtained in this way. sew 2 h at and 1 h at, and then cooled to and poured into water (1 l). After acidification with acetic acid, the aqueous solution is extracted with 4 portions (mp 250 ml) of methylene opjCToro jj, after which the combined organic extracts are washed with water and toluene, dried (over CaSO) and concentrated in vacuo to give a dark mass, which is purified by chromatography kg of silica gel (elution CHCKj). As a result of the operations performed, 9.1 g (81%) of crude 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1, 4-benzodiazepine with m.p. 131-142C. A sample for (with a mp of 141-142C) is obtained by recrystallizing from ethanol. A mixture consisting of 8.4 g 0.03 mol
    1,3-dihydro-2-nitromethylene-5-phenyl-2H-1, 4-benzodiazepine, 75 ml of tetrahydrofuran, 75 ml of methanol and 2 tea spoons of Rene nickel are hydrogenated at atmospheric pressure for 6 hours evaporated to obtain 5.9 g of crude 2-aminomethyl-2, 3-dihydro-5-phenyl-1H-1,4-benzodiazepine. The resulting material is dissolved in 50 ml of methylene chloride and treated with 6 ml of acetic anhydride and 200 ml of saturated aqueous sodium bicarbonate solution for 15 minutes with stirring. The methylene chloride layer is removed, washed with sodium bicarbonate solution, dried and evaporated. The residue is treated with 25 g of polyphosphoric acid at 130-150 ° C for 15 minutes. The cooled reaction mixture is partitioned between-water and ether. The aqueous phase is made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated. As a result of chromatography of the residue on 70 g of silica gel using 20% by volume of ethanol in methylene chloride, 2.6 g (31.5%) are obtained. For 4-dihydro-1-Methyl-6-phenyl-3N-imidazo 1,5- Q) (1,4) Benzodiazepine as a light yellow gum.
    Example 31. To a stirred solution of 6 g (0.02 mol) of 7-chloro-1, 3-dihydro-5- (2-fluorophenyl) -3-methyl-2H-1, 4-benzodiazepin-2-one in 100 ml of dry tetrahydrofuran, 1.05 g (0.25 mol) of a 57% sodium hydrate dispersion in mineral oil was added. The mixture was placed in an argon atmosphere and heated to reflux for an hour. After cooling to room temperature, the mixture is treated with 7.4 g (0.03 mol) of dimorpholinophos of finic chloride and continued to stir under argon at room temperature for 2 hours. The mixture is filtered and evaporated under reduced pressure to give a rubber-forming residue. By stirring this residue with 100 ml of anhydrous ether, white crystals are obtained, which are collected by filtration, washed with a small amount of ether and dried in air. Thus, 8.5 g (82%) of 7-chloro-2-di (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3H-1,4 benzodiazepine with m.p. 90-95 C.
    A stirred solution of 2.4 g (0.04 mol J. Of nitromethane in 50 ml of dry danethylformamide is treated with 1 g (0.024 mol) of 57% dis (Persig sodium hydride in mineral oil at room temperature in the a1 atmosphere of argon. After one hour of stirring at room temperature the mixture is treated with 5.2 g (0.01 mol 7-HLOR-2-di (morpholino) phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3N-1,4-benodiazepine (in one portion) and continue to mix during the day at room temperature in an argon atmosphere. The dark mixture is poured onto a mixture of ice and ice acetic slots with stirring to give a yellow solid and continue stirring until the ice has melted. The solid residue is filtered, washed with water and dried in a funnel on air to obtain 2.9 g (84%) of 7-chloro-1,3-di-hydro-5 - (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1, 4-6enzodiaeepine with mp 215s (with decomposition) By recrystallization of the sample from methanol (methylene chloride) (1: 1), a yellow needle crystal with m.p. 219-221 C (with decomposition).
    A solution of 5.2 g (0.015 mol) of 7-chloro-1, 3-dihydro-5- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1, 4 benzodiazepine in 450 ml of tetrahydrofuran (methanol) (2: 1) hydrogenated for 3 hours at an initial pressure of 1.25 aTMi using a Parr device and Rene nickel as a catalyst (3 teaspoons). The smay is filtered and evaporated under reduced pressure to give 4.6 g (96%) of crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -3-methyl-1H1, 4-benzodiazepine in as a yellow oil.
    The crude aminomethyl compound is mixed with 5 ml of triztil orthoacetate and 0.5 g of α-toluenesulfonic acid monohydrate in 10 ml of tananol. After heating to reflux for 2 hours, the solution is evaporated under reduced pressure. The residue is cooled to room temperature, treated with a mixture of ice with concentrated ammonium hydroxide and extracted with methylene chloride. By stripping the dried extracts in vacuo, 4.5 g (32%) of crude 8-chloropa, 4-dihydro-1, 4-dimethyl-b- (2-fluorophenyl-3H-imidazo (1,5-a)) are obtained ( 1,4) benzodiazepine in the form of rubber.
    Example 32. A mixture consisting of 100 g (0.8 mol) dimethyl acetal of chloroacetic aldehyde and 100 1.5 n. hydrochloric acid is heated under reflux for 15 minutes, then cooled and 130 g (0.5 mol) of 2-amino-2-fluoro-5-nitrobenzophenone and 46 g (0.2.8 mol) of sulfate are added to the solution hydroxylamine in 1 liter of ethanol. The mixture is stirred at room temperature for 2 hours, then heated to reflux for 1.5 hours. The mixture is cooled and the product is obtained by filtration. Recrystallization from a mixture of chloroform and methanol gives pure 2-chloromethyl-4- (2-fluorophenyl) -b-nitro-1,2-dihydroquinazoline in the form of yellow prisms with m. 220-224 ° C.
    A solution of 142 g (O, 423 mol) of 3-oxide of 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-1, 2-dihydroquinazoline in 2.3 l of dichloromethane is treated with 400 g of manganese dioxide. After stirring for 18 h solution
    5 filtered. Manganese dioxide is heated with 600 ml of tetrahydrofuran and 800 ml of dichloromethane. The combined filtrates are concentrated to a volume of 400 ml and 1 L of ether is added. The resulting material was cooled and filtered to obtain 115 g (82%) of 2-chloromethyl-4- (2-fluorophenyl) -b-nitroquinazoline 3-oxide. The sample is recrystallized from a mixture of dichloromethane and methanol c.
    5 Obtaining a pure product in the form of light yellow prisms with so pl. 127130 ° C.
    To 500 ml of dimethyl sulfoxide and 75 ml (1.4 mol) of nitromethane was added with stirring under a nitrogen atmosphere 15.6 g (0.678 mol of lithium amide. After 30 min, the solution was cooled to and slowly added 104 g (0.31 mol) 3-oxides of 3-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline, maintaining the temperature below 8 C. After 68 at room temperature, the reaction mixture is poured into a mixture of 2.5 liters
    0; ice and water and 25 ml of acetic acid, followed by filtration. The rubber-like residue is dissolved in 1 liter of dichloromethane, washed with dilute ammonium hydroxide, dried on anhydrous sodium sulphate and evaporated. The residue is crystallized from ethyl acetate to obtain 20 g (18%) of 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2-nitromethylene-2H-1, 4-benzodiazepine 4-oxide;
    0 is evaporated, dissolved in dichloromethane and filtered through a sintered glass funnel containing 200 g of phlorisil. Florizil zlyuyut dichloromethane (600 ml), simple ether
    5 (600 ml) and ethyl acetate (1.2 l). The ethyl and ethyl acetate fractions are combined and concentrated to obtain 20 g (18%) of additional desired product. The sample is recrystallized from a mixture of tetra0 hydrofuran and hexane- and the pure product is obtained as yellow prisms / sec 216-220 C.
    Suspension 25 g (0.0698 mol) 4-oxide 1, 3-dihydro-5- (2-fluorophenyl) -7-nitro5
    -2-nitromethylene-2H-1,4-benzodiazepine in 1.3 liters of absolute ethanol is treated with 10 teaspoons of Rene nickel and hydrogenated at atmospheric pressure. And at room temperature for 9 hours. The mixture is filtered through celite, and the filtrate is evaporated to dryness. A sample of the oil is crystallized from tetrahydrofuran to obtain the intermediate 7-amino-2-aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine as yellow prisms with mp. 185-192 ° С (with decomposition). The oil obtained as a result of the recovery is heated without further purification for 2 hours to a reflux temperature in a solution of 300 ml of absolute ethanol containing 4.5 ml (O, 0257 MOL) of ethanolic hydrogen chloride and 50 g (0.309 mol) of triethyl orthoacetate. The mixture is then evaporated to dryness, the residue is dissolved in 150 ml of dichloromethane, washed with 100 ml of dilute ammonium hydroxide, dried on anhydrous sodium sulfate and evaporated to dryness to give crude 8-acetylamino-3at 4-dihydro-b- {.2-fluorophenyl) - 1-methyl-3H-imidazo (1,5-a) (1,4) benzodiazepine.
    Example 33. A solution of 19.3 g (0.06 mol) of 1,3-dihydro-7- {2-methyl-1, 3-dioxolan-2-yl) -5-phenyl-2H-1, 4-benzodiazepine 2-in ZOO ml of dry tetrahydrofuran is treated under argon with 3.1 g (0.075 mol) of a 57% suspension of sodium hydride in mineral oil. The mixture is heated to reflux for an hour and then cooled to room temperature after the addition of 22.2 g (0.87 mole of dimorpholinophosphine chloride. The mixture is stirred at room temperature for 2 hours and then held overnight. The sodium chloride is removed by filtration. After, after removing the solvent and crystallizing the residue from ether, a crude 7- (2-methyl-1,3-dioxolan-2-yl) -2-bis (morpholino) phosphinyloxy-5-phenyl-3H-1, 4- benzodiazepine. A mixture consisting of 100 ml of dry H, 13-dimethyl forms and 6.8 H1 tromethane 2.8 g (0, .066 mol) of 57% sodium hydride in mineral oil are bathed in an argon atmosphere of argon. The mixture is stirred for an hour at room temperature after adding a solution of 18 g (0.033 mol) of crude 7- (2-methyl -1, 3-dioxolan-2-yl) (morpholino) phosphinyloxy-5-phenyl-3H-1, 4-benzodiazepine in 50 dry T-dimethylformamide, after the dark viscous liquid is poured onto a mixture of ice and dilute acetic acid, reaction mixture
    kept at room temperature for 15 hours. The bright yellow precipitate is removed by filtration, dissolved in dichloromethane, washed with dilute aglmonium hydroxide and fresh DPI, dried over anhydrous
    sodium sulfate and evaporated. The initial filtrate is extracted with dichloromethane, which is washed, dried and evaporated according to the above method. Both crude residues are combined and chromatographed on Florisil. Using dichloromethane, 10% by volume of ether, as eluent, the thin layer chromatography fraction is collected, several fractions containing the product are collected and evaporated. Crystallization and recrystallization from a mixture of dichloromethane and hexane gives pure 2,3-dihydro-7- (2-methyl-0 -1, 3-dioxolan-2-yl) -2-nitromethylene-5-phenyl-1H-1, 4- benzodiazepine in the form of light yellow prisms with so pl. 158 - 161 ° С. a hydriro of 5 g (0.0137; mol) 2,3-dihydro-7- (1iC-methyl-1, 3-dioxolan-2-yl) -2-nitromethylene-5-phenyl-1H-1, 4-benzodiazepine in 150 ml of absolute ethanol in the presence of 1 teaspoon of Rene nickel for 3.5 hours gives crude 2-amino-methyl-2,3-dihydro-7- (1-methyl-1, 3-dioxolan-2-yl) - 5-phenyl-1H-1, 4-benzodiazepine. 0.7 g (0.0037 mol) is added to a solution of 4 g (O, 0119 MOL) of this compound in 75 ml of absolute ethanol.
    5 and-toluensulfonate acid and
    b g (0.037 mol) of triethyl orthoacetate. The mixture is heated to reflux for 2 hours and evaporated to dryness. The residue is dissolved in
    0 50 ml of dichloromethane. The solution is washed with 25 ml of dilute ammonium hydroxide, dried with anhydrous sodium sulfate and evaporated to obtain 4.3 g of crude Za, 4-dihydros -1-methyl-8- (1-methyl 2,3-dioxolan-2-yl) - &amp;; -phenyl-3H-imidazo (1,5-a); (1,4) benzodiazepine in the form of oil.
     PRI me R 34. A solution of 56,4 g (0.20 mol) of 1,3-dihydro-7-ethyl-50 (2 FtOrfonyl) -2H-1,4-benzodiazepin-2-one and 2, O l of tetrahydrofuran containing 4 moles of monomethylamine is cooled in an ice bath. Then, 33.0 ml (0.30 mol) of four are added. titanium chloride in 350 i «in benzene. The mixture is stirred at room temperature for three days. Titanium tetrachloride is destroyed by using 100 ml of water. Inorganic salts are removed by filtration. The filtrate is evaporated to dryness in vacuo. Remainder
    partitioned between methylene chloride and water. The methylene chloride layer is dried with anhydrous sodium sulfate and evaporated to dryness in vacuo.
    5 The residue after recrystallization from acetonitrile gives 40.5- (70.6%) 7-ETHYL-5- (2-fluorophenyl) -2-methylamine -NH-1,4-benzodiazepine as light yellow prisms with m.p. . 172174 ° C. By recrystallization from acetonitrile, to obtain light yellow prisms with mp. 172-174®C, manufactured analytically pure. sample. In three steps, 8.6 g (0.125 mol) of sodium nitrate was added to a solution in a solution of 29.5 g (0.1 lb) of the above benzodiazepine in 100 ml of glacial acetic acid. After half an hour of stirring at room temperature, the mixture is diluted with ice water and extracted with methylene chloride. The extracts are washed with water and aqueous bicarbonate, dried with sodium sulfate and evaporated to dryness to obtain 21.7 g of 7-ITLA-5- (2-fluorophenyl) -2 - (N-nitrosomethylamino) -ZN-1., 4-benzodiazepine as a yellow oil. The resulting material is dissolved in 100 ml of dimethylformamide. The solution is added to a mixture of 100 ml of dimethylformamide, 35 ml of nitromethane and 9.9 g of tertiary potassium butoxyd, stirred for half an hour at room temperature. At the end of the addition, the reaction. the mixture is stirred for one hour at room temperature and then for another 30 minutes in a steam bath. The cooled solution is acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water, dried and evaporated. The residue is dissolved in 50 ml of ethanol, after which the residue crystallizes in a refrigerator overnight after seeding. The yellow crystals are collected and recrystallized from ethanol to give 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1, 4-benzodiazepine. 138-14b c. Seed crystals are obtained by chromatography of the crude product by 40 times the amount of silica gel using 5% by volume ethyl acetate in methylene chloride. The analytically pure sample is recaptured from ether (hexane); mp, 138-141 ° C, 2.6 g of the above benzodisepine are hydrogenated for 4 hours using Rene nickel (one tsp) in 30 ml of ethanol. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in ether. The amine is extracted with 10% aqueous acetic acid. The extracts are washed with ether and brought to alkaline with aiimiac. The precipitated amine is extracted with methylene chloride. The extracts are dried and evaporated to give 1.5 g of crude 2-aminomethyl-2,3-dihydro-7-ethyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. This product is dissolved in 50 ml of xylene, then the solution is heated for 2 hours under reflux after adding 3 ml of triethyl orthoacetate. The residue obtained after evaporation under reduced pressure is chromatographed on 50 g of silica gel using 20% methanol in methylene chloride. Homogeneous fractions are combined and evaporated. This is aimed at obtaining 0.8 g of AP / 4-dihydro-8-ethyl-b- (2-fluorophenyl) -1 -1-methyl-3H-imidazo (1, 5-) (1,4) ben diazepine. Example 35 A solution of 2.9 g (0.00927 mol) of 2,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-1H-1, 4-benzodiazepine-4 oxide in a mixture consisting of 1 tea spoons of Rene nickel, 90 ml of tetrahydrofuran and 45 ml of methanol, hydrogenated at atmospheric pressure and room temperature for 2.3 hours. The mixture is filtered and the nickel is washed with dichloromethane. The collected filtrate was evaporated, and the resulting oil was dissolved in 50 ml of dichloromethane, which was washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of 2.2 g (0.019 mol) of maleic acid and 15 MP of ethanol was added to the oil, and after adding ether, 2-aminomethyl-2, 3-dihydro-5- (2-fluoromethyl) -1H- 1 hemihydrate, 4-benzodiazepine dimaleita in the form of crystals. Recrystallization from a mixture of methanol and ether yields 3.3 g (70%) of a yellow product, which is rod-shaped, with mp 147150CC. A solution of 4.0 g (0.0149 mol) of the base of the hemihydrate of 2-aminomethyl, -2, 3-dihydro-5- (2-fluorophenyl) -1Hg-1, 4-benzodiazepine dimaleiate in 125 ml of absolute ethanol is treated with 4 g (0.0247 cules) of triethyl ortho-acetate and 0.5 g of 1 (0.00263 mol) p-toluenesulfonic acid. The mixture is heated under reflux for 2 hours, then evaporated to dryness. The resulting oil is dissolved in 50 ml of dichloromethane, which is washed with 50 ml of dilute ammonium dioxide, dried over anhydrous sodium sulfate and evaporated to dryness to obtain 3.6 g of crude Zst, 4-dihydro-b- (-2-fluorophenyl) - 1-methyl-3H-imidazo (1,5-chz |) (1,4) benzo; diazepine in the form of oil. Example 36. A mixture consisting of 10 g (0.036 mol) of 1,3-dihydro-5-phenyl-2H-thieno (3,) (1,4) cyazepin-2-one in 50 ml of benzene and 300 ml of tetrahydrofuran, mix in an ice bath and saturate with gaseous methylamine, a solution of sodium titanium powder (9.48 g, 0.05 mol) in 50 ml of benzene is added dropwise to this mixture, after which the mixture is stirred in an ice bath for 15 min The ice bath is then replaced with a jacket for heating and the mixture is heated for. 0.5 h to reflux temperature. Cool and carefully add 100 g of ice. The mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates are combined, dried and evaporated. The product is crystallized from methylene chloride to give 2-methy-amino-5-phenyl-3H-thieno (3,2-e) (1,4) -diazepine with m.p. 223-227 ° C. From the concentrated mother liquor, an additional product is obtained with m.p. 222-225 0. Total yield 9.6 (92.5%). The sample for analysis is recrystallized and called: from methylene chloride; m.p. 222-229 ° C. . Nitrosyl chloride is introduced into a solution of 7.8 g (0.03 mol) of 2.-methylamino-5-phenyl-3H-thienoM3 / 2-e) (1,4) diazepine in 100 ml of methylene chloride and 40 ml of pyridine, cooled with ice water. The reaction is monitored by thin layer chromatography. With the disappearance of the starting material, the addition of nitrosyl chloride is stopped and the reaction mixture is distributed between methylene chloride and water. A solution of methylene chloride is sutured and evaporated. As a result of crystallization of the residue from methylene chloride (hexane), 7.9 g (91%) of 2- (N-nitrosomethylamino) -5-phenyl-3H-thieno {3,2- -e) ( 1,4) diazepine in the form of yellow crystals with so pl. 156-159 ° C. A sample is recrystallized for analysis from njpocToro ether (hexane) f m.p. 158-1 ° C,. 5.7 g (0.02 mole) 2-03-nitrosomethylamino) r-5-fvnil-3N-thieno {3,2-- i-e (1,4) diazepine is added to the mixture 15 ml of nitromethane, 4, 5 g of potassium t-butylate and 60 ml of dimethylformamide stirred for 10 minutes at room temperature. After the addition, the reaction mixture is stirred under an a.root atmosphere and heated in a steam bath for 10 minutes. After acidification with 4 ml of glacial acetic acid, the mixture is partitioned between methylene chloride and toluene and saturated with solution. rum bicarbonate sodium. Organically the layer is washed with water, dried and evaporated. After crystallization of the residue from methanol, seeding, 2.6 g (45%) of 1,2-dihydro2-nitromethylene-5-phenyl-3H-thieno (3,2-e) (1,4) diazepine are obtained as yellow crystals. m.p. 160-163®C, Cobbles are obtained after purification by chromatography through silica gel (30 folds in total) using .10 vol.% Ethyl acetate in methylene chloride. The sample for analysis is recrystallized from methanol; t, pl. 163-1b4s. Solution 1.42. g (5 mmolO 1,2-digidro-2-nitromethylene-5-phenyl-3H-thieno {3, 2-6) (1,4) diazepine in 200 ml of ethanol is hydrogenated on Rene nickel (2 teaspoons) for an hour at atmospheric pressure. The catalyst was removed by filtration, and the filtrate was evaporated. The residue is treated with 1.2 g of maleic acid in 10 ml of 2-propanol. The salt is recrystallized by adding ether to give 1.2 (49%) of 2-aminometi-2, 3-dihydro-5-phenyl-1H-thieno (3,2-e) (1,4) diazepine dimaleate (diazepine) as yellow crystals. from m.p. 170-173 sec. The analytical sample is recrystallized from methanol (2-propanol); m.p. 187-189 ° C. 1 g (2 mmol) of 2-aminomethyl-2, 3-dig11Cro-5-phenyl-1H-thieno (3,2-e) (1,4) diazepine dimel eate (3,2-e) (1,4) diazepine is distributed between methylene chloride and aqueous ailmiac. The methylene chloride layer is dried and evaporated. The residue is heated under reflux for one hour along with 1 ml of 1,1,1-triethoxyethane in 20 MP of xylene. The solution is evaporated under reduced pressure and the residue is crystallized from 2-propanol (ether) to obtain 1-methyl-3A, 4-dihydro-6-feyl-3N-630C, 5-a) thieno (2,3-f) ( 1,4) -diazepine with m.p. 150g152 ° C. Example 37. A mixture consisting of 7.7 g (0.278 mol.) 7-chloro-1, 3-dihydro 5-phenyl-2H-thieno {2,3-in (1,4) diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran are mixed in an ice bath and saturated with gaseous 1 with methylamine. To the mixture is added a solution of titanium chloride of 7.38 gO, 0389 mol in 50 ml of benzene from an addition funnel, after which the mixture is stirred in an ice bath for 15 minutes. The ice bath is replaced with a heating jacket and the reaction mixture is heated under reflux for 20 minutes. The mixture is cooled and 100 g of ice are carefully added. The mixture is filtered and the residue is washed with tetrahydrofuran. The filtrate is combined, dried and evaporated. The residue is crystallized from methylene chloride (ether) to obtain 5.5 g (68.4%) of 7-chloro-5-phenyl-5-methylamino-3H-thieno (2,3-e) (1,4) -diazepine from m.p. 246-249 ° C. The sample for analysis is recrystallized from methylene chloride; m.p. 2472500s Nitrosyl chloride is introduced into a solution of 5 ... 8 g (0.02 mol O 7-HLOR-5-phenyl-2-methylamino-ZN-thieno 2,3-e) (1.4; diazepine in 100 mp of methylene chloride and 50 ml of pyridine until the end of the reaction by means of a thin layer xpoMaTorpaNMe, the mixture is distributed between water and toluene. The organic phase is dried and evaporated. After crystallization of the residue from ether (hexane), 4.7 g (80%) of 7-ChLOR-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno 2,3-ej (1,4) diepine in the form of yellow crystals with a melting point of 108-1100 sec. For purposes of analysis, the product is recrystallized from ether ( hexane); mp 111-113 with.
    3.2 g (0.01 mol) of 7-chlorop-2- (N-nitrosomethylsmino) -5-phenyl-3H-thieno 2, B) (1,4) diazepine is added to a mixture of 10 ml of nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 mol) of potassium butylate, which is stirred under a nitrogen atmosphere for 10 minutes at room temperature. After heating in a steam bath for 10 minutes, the reaction mixture is acidified by adding 2 ml of glacial acetic acid and partitioned between water and toluene. The toluene layer is washed with water, dried and evaporated. The residue is crystallized from ethyl acetate (hexane), according to a crude 7-HLOR-2, 3-dihydro-2-nitromethylene-5-phenyl-1H-thieno (2,3-e) (1,4) diazepine beam. The product is purified by chromatography on 40 g of silica gel using 10% v / v ethyl acetate in methylene chloride. 2.2 (68%) pure product is obtained in the form of yellow crystals with m.p. 154-156 0. O) A solution of 320 ml (1 mmol) of 7-chloro-2, 3-dihydro-2-nitromethylene-5-phenyl-1H-thieno (2,3-e) (1,4) diazepine in 20 ml of ethanol is hydrogenated on nickel Rene for 5 h at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated. The residue is subjected to chromatography on 7 g of silica gel using methylene chloride, methanol and triethylamine in a ratio of 13: 6: 1. Fractions containing the pure product are combined, evaporated and the residue is treated with maleic acid in 2-propanol. Crystallization of the dimaleate salt from 2-propanol (ether and recrystallization from ethyl acetate) of ethanol gives 65 mg (12.5%) of 2-amino-dimaleate. methyl-7-chloro-p-2,3-dihydro-5- (enyl-1 gTieno (2 ;, 3-e) (1,4) dia-, zepi | ca S in the form of yellow crystals ,, ,, ,, with tpp, 176-17700,.,
    8) A solution of 320 mg (1 "mmol)." 7-hl9Pr2, 3-dihydro-2-ni; thromium, ne, p-5-phenyl-1H-thieno {2, 3-e) (1,4) diazepine. in 3 ml of tetrahydrofura lobutus suspension of 0.8 lithium aluminum hydride in 20 ml of tetrahydrofuran. After heating to reflux for 5 min, the reaction mixture is cooled and hydrolyzed by adding 5 ml of water. The inorganic material is separated by filtration and the filtrate is evaporated. The residue is chromatographed (as described above). and the pure product is converted to maleate to obtain 150 mg (28%) of 2-amnnomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-dihydro-o-2-phenyl-1H-1,4-diazepine dimaleate with t, sh1, 176-178 C.
    0.52 g (1 th) of 2-aminomethyl-7-chloro-2, 3-dihydro-5-phenyl-1H-thieno {.2,3-е1 (1,4) diazepine dimaleate dialepine is distributed between methylene chloride ammonia water. The methylene chloride solution is dried and evaporated. The residue is heated to reflux for an hour along with 0.5 ml of triethyl orthoacetate in
    0; 10 ml xylen. The crude product obtained after evaporation under reduced pressure consists of 8-chloro-1-methyl-4-dihydro-6-phenyl-3H-imidazo Ci, 5-a) thieno 13,2-f} (1,4) dia Yepin
    five
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining compounds of imilazo (1.5-0 (1,4) diazepine oOcium structural formula 1
    40
    where, are the same or different and mean hydrogen and lower alkyl;
    Rj is phenyl and mono-0-haf loidphenyl; (2 DO means a group of formulas:
    S)
    tlT
    55
    where X is hydrogen or chlorine;
    1Y.- hydrogen, halogen, lower al. chi; ... (. Kil, alkanolamines or iizshiy Gshkanoil,
    or their pharmaceutically applicable mudflows, q t {t and t. and y and y and so that, in order to obtain new compounds that expand, the Arsenal has a means of affecting living rrga. 3181427832
    niam, dehydrogenate the compound in chlorinated or aromatic
    formula 11 hydrocarbon solution using
    Manganese dioxide, palladium on coal
    yl manganic acid potassium with PpoN. following the selection (1 st target proC-5 product in a free state or in
     Avide salt.
    AiJl -iZi,.
    With sN. Sources of information,
    taken into account during the examination
      . .. to l.Houeieian W.I. Indoges, p.I
    where T,, 124,,, ь, and © G have when Dehydrogenation of
    higher values. Other Reduced IndoEes, 1972, p, 160.
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    同族专利:
    公开号 | 公开日
    FR2303016B1|1982-07-09|
    DE2540522A1|1976-04-08|
    PH15091A|1982-08-03|
    BR7505864A|1976-08-03|
    DK404175A|1976-03-12|
    FR2285890B1|1981-12-31|
    HK63381A|1981-12-24|
    IE41844L|1976-03-11|
    SE7902668L|1979-03-23|
    NO147109C|1983-02-02|
    YU40267B|1985-12-31|
    FI752517A|1976-03-12|
    NO146573C|1982-10-27|
    DD121640A5|1976-08-12|
    NO146573B|1982-07-19|
    BE833248A|1976-03-10|
    MY8200214A|1982-12-31|
    SE440504B|1985-08-05|
    DE2540522C2|1988-10-20|
    AU8470475A|1977-03-17|
    GB1527131A|1978-10-04|
    AU505998B2|1979-12-13|
    SE449098B|1987-04-06|
    AT360023B|1980-12-10|
    FI63234C|1983-05-10|
    FI63234B|1983-01-31|
    MX160600A|1993-09-01|
    FR2285890A1|1976-04-23|
    SE425785B|1982-11-08|
    LU73356A1|1977-05-11|
    IL48069D0|1975-11-25|
    CH619953A5|1980-10-31|
    CU34346A|1982-08-24|
    NO148188B|1983-05-16|
    DK157615B|1990-01-29|
    JPS562073B2|1981-01-17|
    IE41844B1|1980-04-09|
    NO148188C|1983-08-24|
    NO802720L|1976-03-12|
    NL171060C|1983-02-01|
    CA1067491A|1979-12-04|
    NO147914C|1983-07-06|
    DK157615C|1990-06-25|
    NL7510620A|1976-03-15|
    CU20892L|1982-08-24|
    IL48069A|1980-09-16|
    NO753069L|1976-03-12|
    PL106563B1|1979-12-31|
    SE7902667L|1979-03-23|
    CH628053A5|1982-02-15|
    ES440850A1|1977-07-01|
    SE433080B|1984-05-07|
    SE7902666L|1979-03-23|
    SE7509991L|1976-03-12|
    ATA697775A|1980-05-15|
    HU174752B|1980-03-28|
    NZ178635A|1982-12-21|
    NO802719L|1976-03-12|
    FR2303016A1|1976-10-01|
    YU228575A|1983-01-21|
    KE3173A|1982-01-08|
    NO802718L|1976-03-12|
    NO147914B|1983-03-28|
    PH16152A|1983-07-12|
    JPS51125099A|1976-11-01|
    ZA755418B|1977-06-29|
    NO147109B|1982-10-25|
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    US50492474A| true| 1974-09-11|1974-09-11|
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