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    • 专利摘要:
    Novel (1H-imidazol-1-ylmethyl) substituted benzimidazole derivatives of formula <CHEM> wherein A is a bivalent radical having the formula <CHEM> the pharmaceutically acceptable salts and possible stereochemically isomeric forms thereof, which compounds possess androgen formation inhibiting properties; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1662350A3
    申请号:SU874203300
    申请日:1987-09-14
    公开日:1991-07-07
    发明作者:Герман Маргарета Реймакерс Альфонс；Жан Эдгард Фрейн Эдди；Шарль Санз Жерар
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of novel (1H-imidazol-1-ylmethyl) -substituted benzimidazole derivatives, their salts and stereoisomers, which can be used in the treatment of androgen-dependent disorders.
    The purpose of the invention is the synthesis of new compounds superior in properties to a structural analogue.
    (
    Intermediate products are obtained as follows.

    about
    Example 1. A solution of 40 parts of 4-chloro-3-nitrobenzaldehyde and 338 parts of 1-propanamine is stirred and boiled for 1.50 hours. The reaction mixture is evaporated, yielding 53.7 parts of 2-nitro M-propyl -4- | Hpropilimino) metshlbenzolamin (1) as a residue.
    A mixture of 53.7 parts of 2-nitro-H-propyl-4-Ј (propylimino) methyl-benzamine, 360 parts of concentrated hydrochloric acid and 300 parts of water is stirred and boiled for 30 minutes. The reaction mixture is cooled and the product is extracted with trichloromethane. The extracts are dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected and the eluant was evaporated, yielding 20.4 p. H-nitro-4- (propylamino) benzaldehyde (2), mp. 73.6.
    A mixture of 10.4 parts of 3-nitro-4- (propyl-amino) benzaldehyde and 200 parts of methanol is hydrogenated in a Parr apparatus with a 3-hour Rane nickel as a catalyst. After passing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is acidified with 3 parts of acetic acid. The solvent was evaporated, yielding 12 parts (100%) of 3-amino-4- (propylamino) benzenemethanol acetate (1: 1) as residue (3).
    A mixture of 8 parts of 3-amino-4- (propylamino) benzenemethanol, 14.05 parts of ethyl 3-pyridinecarboxyimidate dihydrochloride, 9.8 parts of sodium acetate and 96 parts of ethanol is stirred for 16 hours at room temperature. The reaction mixture is evaporated. The residue is dissolved in water and treated with ammonia. The precipitated product is filtered, washed with water and dissolved in dichloromethane. The organic layer is dried, filtered and evaporated. The residue was washed with 2,2-oxibispropane, to give 9.9 parts (81.4%) of 1-propyl-2-p-pyridinyl -1 H-benzimidazole-5-methanol (4) as a residue.
    Similarly, receive intermediate products 5-14, are given in table. one.
    Similarly, 1,3-dihydro-5- (hydroxymethyl-2H-benzimidazol-2-one) is obtained, m.p. 238.2 ° C (15).
    To a stirred solution of 4.01 hours
    1-propyl-2- (3-pyridinyl) -1-benzimide-azole-5-methanol in 65 parts of dichloromethane and 3 parts of M, N-diethylethanamine added 2.23 parts of methanesulfonyl chloride. Everything is stirred for 45 minutes at room temperature.
    0
    .
    g
    5 0 5
    0
    five
    temperature The mixture is drunk into crushed ice, the dichloromethane elephant is separated, dried, filtered and evaporated. The residue is dissolved in methylbenzene. The precipitate was filtered off and the filtrate was evaporated, yielding 2.3 parts (66%) of 5- (chloromethyl) -1-propyl-2- (3-pyridinyl) -1H-benzimidazole (16) as a residue. Similarly, receive intermediate
    products 17-27 listed in table 2.
    t
    Similarly, 5- (chloromethyl) -1,3-dihydro-2H-benzimidazol-2-one is obtained (28).
    Example 2. To a stirred solution of 1.4 parts of ethyl glycine hydrochloride in 10 parts of water, a solution of 1.7 parts of 4-fluoro-3-nitrobenzaldehyde in 8 parts of ethanol is added. Then 1.76 parts of sodium bicarbonate was added thereto and stirring at room temperature was continued for 48 hours. The precipitated product was filtered, washed effectively with water, ethanol and 2.2 U-oxibispropane, dried, yielding 2 hours (79%) ethyl -M- (4-formyl-2-nitrophenyl) - glycine (29), m.p. 90 ° C.
    To a stirred solution of 47.8 parts of ethyl-P- (4-formyl-2-nitrophenyl) glycine in 280 parts of ethanol was added in small portions of 3.8 parts of sodium tetrahydroborate. All is stirred for 30 minutes at room temperature. The reaction mixture is decomposed with a solution of 12 parts of acetic acid in 50 parts of water. The mixture is concentrated. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 34.1 h (70.6%) ethyl-L-4-hydroxymethyl-2-nitrophensh1 glycine (30).
    A mixture of 2.6 parts of ethyl-H-4- (hydroxymethyl) -2-nitrophenyl glycine, 8.3 parts of potassium carbonate and 40 parts of ethanol is stirred and refluxed for 2 hours. After cooling, add a solution 7.2 parts of acetic acid in 8 parts of ethanol and stirring is continued for 1 hour. The reaction mixture is evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and ethanol (90:10 by volume) as eluent. Collect the pure fractions and evaporate the eluent. The residue is converted into the hydrochloride salt in 2-propanol.
    The salt is filtered off and dried, yielding 1.1 parts (40%) of monohydrochloride.
    516
    ethyl 1-hydroxy-6- (hydroxymethyl) -1H-benimimidazole-2-carboxylate (31), so pl. 178.0 ° C.
    To a stirred solution of 0.92 parts of sodium in 32 parts of ethanol was added 5.46 hours of ethyl 1-hydroxy-6- (hydroxymethyl) -1H-benimidazole-2-carboxylate monohydrochloride. Mix everything for 10 minutes and concentrate. 18 parts of methylbenzene are added and the mixture is evaporated. 13.5 parts of M-dimethylformamide and a solution of 2.84 parts of sweep in 4.5 parts of H, M-dimethylformamide are added. After stirring for 30 minutes, the reaction mixture was evaporated. The residue was purified by column chromatography on silicone, using a mixture of trichloromethane and acetonitrile (80:20 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2-oxybispropane (1: 4 by volume). The product is filtered off and dried, yielding 2.5 parts (50%) of ethyl-b- (hydroxymethyl) -1-methoxy-1H-benzimidazole-2-carboxylate (32), m.p. 110.1 ° C.
    A mixture of 4.2 parts of ethyl 6- (hydroxymethyl) -1-methoxy-1H-benzimidazole-2-carboxylate and 60 parts of concentrated hydrochloric acid was stirred for 1 hour at boiling point. The reaction mixture is concentrated and the residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 3.1 parts (79.2%) of 6- (chloromethyl) -1-methoxy-1H-benzimidazole monohydrochloride (33), mp. 158 ° C.
    Example 3. A mixture of 20 parts of (3,4-diaminophenyl) - (3-fluorophenyl) methanone, 27 parts of ethyl ethanimidate hydrochloride and 80 parts of methanol is stirred for 17 hours at the boiling point. The reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in a 10% potassium carbonate solution and the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of dichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 15.6 parts (70.5%) of (3-fluorophenyl) - (2-methyl-2-1H-benzimidazol-5-yl) methanone (34) as a residue.
    To a stirred solution of 14 parts of (3-fluorophenyl) - (methyl-1H-benzimidazol-5-yl) -methanone in 80 parts of methanol with
    five
    0
    five
    0
    five
    0
    5 portions of sodium tetrahydroborate at room temperature are added in portions. After the entire addition, stirring at room temperature is continued for 1 hour. The reaction mixture is drunk into water and the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue is converted to its hydrochloric acid salt in 80 hours, methanol and ethanol. The mixture was evaporated to dryness to give 15.1 parts (93.7%) of o- (3-fluorophenyl) -2-methyl-1H-benzimidazole-5-methanone monohydrochloride (35) as a residue.
    Similarly receive the following products:
    hydrochloride-2-methyl-oЈ-phenyl-1H-benzimidazole-5-methanol, so pl. 300 C (decomp.) (36);
    1-methyl-oC-phenyl-1H-benzimidazole-5-methanol, m.p. 170.7 ° C (37),
    1, 2-dimethyl-o-phenyl-1H-benzimide-azol-6-methanol, so pl. 206.6 ° C (38);
    1-methyl-2-in 1-diphenyl-1 H-benzimide-azole-6-methanol as residue (39),
    2-phenyl-oЈ- (2-thienyl) -11-benzimide-azole-5-methanol, so pl. 243 ° C (40) J
    2- (4-thiazolyl) -oЈ- (2-thionyl) -1H-benzimidazole-5-methanol (41);
    Od- (5-bromo-2-furanyl) -1H-benzimidazole-5-methanol as residue (42); oЈ- (2-furanyl) -1P-benzimidazole-5-methanol as residue (43);
    bЈ- (3-fluorophenyl) -1H-benimidazole-5-methanol as residue (44).
    A mixture of 13 parts of monogndrochloride-ob-G (3-fluorophenyl) -2-methyl -1H-benzimidazole-5-methanol and 81 parts of thionyl chloride was stirred overnight at room temperature. The reaction mixture is evaporated to dryness to obtain 12 parts (86.8%) of 5-chloro- (3-fluorophenyl) methyl 2-methyl-1H-benzimidazole monohydrochloride (45) as a residue.
    I
    Similarly, 2-methyl-0Ј-phenyl-1H-benzimidazole-5-methanol methanesulfonate (46) is obtained as a residue and 5--chloro- (3-fluorophenyl) methyl 7-1H-benzimidazole (47) as the remainder.
    Example 4. To a stirred solution of 16 parts of phenyl- (3-amino-4-nitrophenyl) methanone in 195 parts of dichloromethane was added 7.8 parts of acetyl chloride. After stirring for 17 hours at room temperature, the reaction mixture is evaporated. The residue is crystallized from a mixture of ethyl acetate and 2,2-oxibispropane.
    The product is filtered off and dried, yielding 15 parts (31%) of N- (5-benzoyl-2-nitrophenyl) acetamide (48), m.p. 97.3 ° C.
    Wash 5.6 parts of K- (5 benzoyl-2-nitrophenyl) acetamide, 2 parts of a 4% solution of thiophene in methanol, 200 parts of methanone and 7 parts of 2-propanol, saturated with hydrogen chloride, hydro- or at normal pressure and room temperature in the presence of 1 part of platinum on carbon as a catalyst. After passing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is washed with 2-propane and dried, yielding 4.2 parts (73%) of monohydrochloride (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone (49) as a residue.
    11.55 parts of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone monohydrate was added to the stirred solution of 1.84 parts of sodium in 80 parts of methanol. After stirring for 15 minutes at room temperature, the solvent is evaporated and the residue is taken up in methylbenzene. After evaporation, the residue was dissolved in 54 parts of M, N-dimethylformamide and 6.24 parts of sweep-in was added. The reaction mixture is stirred for 2 hours at room temperature. Layer of N, N-dimethylformamide and evaporation in vacuum. The residue is taken up in water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue was washed with 2,2-oxibispropane to obtain 6.4 parts (60.0%) (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone (50), mp, 67, 7 ° C.
    To a stirred solution of 3.4 parts of (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone in 64 parts of methanol was added 0.6 parts of sodium tetraborate. After stirring for 30 minutes at room temperature, the methanol layer is evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 45 parts of ethyl acetate. The product is filtered off and dried, yielding 2.8 parts (80%) of 1-methoxy-2-methyl-Cx, α-phenyl-1H-benzimidaeol-5-methanol (51).
    Similarly receive the following products:
    five
    0
    five
    0
    five
    0
    five
    0
    five
    1-methoxy-cЈ-2-diphenyl-1H-benzimide-aeol-6-methanol (52),
    1-methoxy-o-2-diphen-w-1H-benimide-azole-5-methanol, mp. 142.4 ° C (53);
    1-methoxy- (X-phenyl-1H-benzimidazole-6-methanol (54);
    1-methoxy-o6 2-dimethyl-1H-benzimide-azol-6-methanol (55),
    1-methoxy-2-methyl-oC-phenyl-1 H-benzimidazole-6-methanol (56).
    Example 5. A mixture of 104 parts of ethylbenzenecarbimidate hydrochloride 97.1 parts of 3-amino-4- (propylamino) benzoic acid and 1200 parts of acetic acid are stirred for 60 minutes at room temperature and 20 hours at the boil. The reaction mixture was evaporated and water was added to the residue. The precipitated product is filtered, washed with water and acetonitrile, and crystallized from acetic acid to give 58.5 parts of 2-phenyl-1-propyl-1H-ben-imidazole-5-carboxylic acid (57), mp. 223.4 ° C.
    To a stirred solution of 112.13 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylic acid, 525 parts of trichloromethane and 142 parts of thionyl chloride were added to 525 parts. Stirring is continued for 30 minutes at boiling point. The reaction mixture was evaporated to give 134 parts (100%) of 2-phenyl-1-pro monohydrochloride-1H-benzimidaz ol-5-carbonyl chloride monohydrochloride (58) as a residue. I
    To a stirred solution of 134 hours 2-phenyl-1-propyl-1H-benzimidazole-5-carbonyl chloride monohydrochloride in 300 parts of trichloromethane was added 240 parts of methanol and stirring was continued for 20 minutes at boiling point. The reaction mixture is evaporated. The residue is washed with 4-methyl-2-pentanone and dissolved in water. The free base is isolated by a conventional method, acting on ammonium hydroxide and extracting with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 175 parts of 2,2-oxybis propane. The product is filtered off and dried, yielding 91 parts (77.3%) of methyl 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylate (59}, mp 79.8 ° C.
    To a stirred and cooled solution (ice on a bath) of 103.9 parts of dihydro-bis- (2-methoxyethoxy) sodium aluminate in 45 parts of methylbenzene, a solution of 88.5 parts of methyl 2plates-1 - propyl-1H-ben zimidazole-5-carboxylate in 270 parts of methyl benzene. After the addition is complete, stirring is continued for 1 hour at room temperature. The reaction mixture is decomposed by adding a mixture of 200 parts, 7.5 n. sodium hydroxide solution and 200 parts of water. The methylbenzene phase is separated, dried, filtered and evaporated. The residue is washed with 210 parts of 2,2-oxybispropane. The product is filtered off and dried, yielding 73 parts (91%) of 2-phenyl-1-propyl-1I-benzimidazole-5-methanol (60), mp. 112.9 ° C.
    A solution of 70.5 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol in 300 parts of trichloromethane is saturated with gaseous hydrogen chloride. Then 55.9 parts of thionyl chloride (exothermic reaction) are added dropwise. After completion, stirring is continued for 30 minutes at boiling point. The reaction mixture is evaporated, the residue is taken up in 90 parts of methylbenzene and the latter is again evaporated. The residue is crystallized from 320 parts of 4-methyl-2-pentenone, giving 80 parts of 5- (chlorophenyl) -2-phenyl-1-propyl-1H-benzimidazole ionohydrochloride (61), mp. 138.5 ° C.
    Similarly, 4- (chloromethyl) -1H-beneimidazole monohydrochloride (62) is obtained in residue water, 7- (chloromethyl) -2- (3-pyridinyl) -1H- benzimidazole (63) dihydrochloride and 7-chloromethyl-2-phenyl -1H-benzimidazole (64).
    Example 6. A mixture of 17h. ethyl 2,3-diaminobenzoate, 14 parts of ethyl ethanimidate hydrochloride in 240 parts of ethanol is stirred for 19 hours at reflux temperature. The residue after evaporation is taken up in a 10% potassium carbonate solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 19 parts (95.6%) of ethyl 2-methyl-1H-benzimidazole-4-carboxylate (65) as a residue.
    A cooled (0 ° C) solution of 10 parts of ethyl-2-methyl-1H-benzimidazole-4-carboxyl silat in 45 parts of tetrahydrofuran is added dropwise to a suspension of tetrahydroaluminate lithium in 45 parts of tetrahydrofuran. After completion of the addition, the temperature spontaneously reaches room temperature. After addition of ethyl acetate and water, the reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated, getting
    ,
    ten
    15
    20
    25
    thirty
    35
    40
    five
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    6.3 parts (79.4%) of 2-methyl-1H-benzimide-azole-4-methanol (66) as a residue.
    Mixture of 10 parts 2-methyl-1H-benzimide-azol-4-methanol, Yut. manganese oxide (IV) and 180 hours. Ethyl acetate is stirred for 19 hours at room temperature. The reaction mixture is filtered through diatomaceous earth and washed with a mixture of ethyl acetate and methanol (80:20 by volume). The filtrate is evaporated, the residue is crystallized from 2-butanone. The product is filtered off and dried, yielding 3.5 parts (35.2%) of 2-methyl-1H-benzimidazole-4-carboxaldehyde (67).
    To a stirred solution of 3 parts of 2-methyl-111-benzimidazole-4-carboxaldehyde in 45 parts of dry tetrahydrofuran was added at 20 ° C. 15.3 parts of phenyl lithium. The reaction mixture is stirred for 30 minutes at room temperature. The mixture is drunk into water. The precipitated product is filtered and dried, yielding 4 parts (89.7%) of 2-methyl-oC-phenyl-1H-benzimidazole-4-methanol (68).
    The final compounds are prepared as follows.
    Example 7. A mixture of 6.8 parts of 1H-imidazole, 4.9 parts of monohydrochloride 5- (chloromethyl) -1-ethyl-1-methyl-1H-benimidazole and 80 parts of acetonitrile are stirred and boiled for 3 hours. the mixture is evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethyl acetate. The product is filtered, washed with 2,2-oxy-bipropane and dried, yielding 2.6 parts (54%) of 2-ethyl-5- (1H-imidazol-1-ylmethyl) -1-methyl-1H-benzimidazole, m.p. 127.3 ° C. (compound 1).
    Similarly, compounds 2–20 are obtained, which are listed in Table 1. 3
    Similarly, 5-Ј (3-fluorophenyl) - (1H-imidazol-1-yl) methyl -2-methyl-1H-benzimidazole, m.p. 128.8 ° C (compound 21), and 5- Ј (3-fluorophenyl) - (1 H-imidazol-1-yl) methyl -1 -1-benzimidazole, m.p. 85.6 ° C (compound 22).
    Example 8. A mixture of 7.5 parts of 1H-imidazole, 12.6 parts of 2-methyl-O, phenyl-1H-benzimidazole-5-methanol, methane sulfo-1 nata (ester) and 30 parts of acetonitrile are stirred and boiled 18 h. The reaction mixture is evaporated. Add
    water and separating the oily layer, which is dissolved in dichloromethane. It is dried5 is filtered off and evaporated. The residue is purified twice by column chromatography on a frit, using as eluent a mixture of trichloromethane, methanol and methanol saturated with ammonia (95: 5: 5 by volume). Collect the pure fractions and evaporate the eluent. The residue is further purified by liquid reversed phase chromatography (PCF) using a mixture of 60% methanol containing 0.8% N-d-methylethyl) -2-propanamine and 50% water containing 0.5% ammonium acetate. The pure fractions were collected and the eluent was evaporated, obtained after drying in vacuum for 12 hours at 95 ° C, 1.8 hours. (15%) 5- (1H-imidazol-1-yl) phenylmethyl-2-methyl-1H-benzimidazole, m.p. 118.4 ° C. (compound 23).
    Example 9. A mixture of 6.35 parts of 5- (chloromethyl) -1,3-dihydro-2H-benzimidazole 2-one, 11.9 parts of 1H-imidazole and 135 parts of H, M-dimethyl ormamide was stirred overnight at 80 ° C. Contents evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as ellent.
    Pure fractions are collected and the solvent is evaporated. After standing for a day at room temperature, the residue hardens. The product is dissolved into powder and mixed with acetonitrile. The product is filtered and purified by column chromatography on silica gel, using as eluent a mixture of trichloromethane and methanol (87:13 by volume). Collect the pure fractions and evaporate the eluent. The residue is dried in Isher’s pistol at 130 ° C, obtaining 0.75 hours. (10%) 1,3-dihydro-5- (1H-imidazole 1-ylmethyl) -2H-benzimidazol-2-one, m.p. 254.5 ° C (compound 24).
    Example 10. A solution of 0.7 parts of methyl 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylate in 2.7 parts 1 n. The sodium hydroxide solution is stirred for 3 hours at 20.degree. After adding ethanol, the contents are evaporated to dryness at 60 ° C. The residue is taken up in 2-propanone. The product is filtered off and dried for 1 hour at 80 ° C, obtaining 0.7 parts (94.8%) of 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-carboxy hemihydrate
    sdlata, some 25).
    m.p. 253.3 C (connect
    five
    0
    five
    0
    5 0 5
    Q
    five
    245.6 ° C
    Analogously, (1H-imidazol-1-yl) ethyl -1H-benzimidazole-2-sodium carboxylate, m.p. (compound 26).
    Example 11. Analogously to the procedures of Examples 7-9, the following compounds were prepared:
    5- G (1H-imidazol-1-yl) - (2-thienyl) -methylT-2- (4-thiazolyl) -1H-benzimidazole, m.p. 188 ° C (compound 27 ;;
    4- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazole, m.p. 140 ° C (compound 28),
    5- Ј (5-bromo-2-furanyl) - (1H-imidazol-1-yl) methyl -1H-benzimidazoleethioate (2: 3), T.rLn. 116 ° C (compound 29)
    5- (2-furanyl) - (1H-imidazol-1-yl) - methyl -1H-benzimidazole, m.p. 151 ° C (compound 30);
    2- (4-fluorophenyl) (1H-imide z ol-1-yl) heptyl1-1H-benzimidazole, m.p. 122 ° C (compound 31),
    5- (1H-imidazol-1-ylmethyl) -2- (3-pyridinylmethyl) -1H-benzimidazoltrigidrochloride, m.p. 255 ° C (compound 32),
    (E) -5- (1H-imidazol-1-ylmethyl) -2-2- (4-pyridinyl) ethenyl -1 H-benzimidazole, m.p. 234 ° C (compound 33);
    5- (1H-imidazol-1-ylmethyl) -2- (2-tie-yl) -1H-benzimidazole, m.p. 196 ° C (compound 34)
    2-Ј2- (1H-imidazol-5-yl) ethenyl-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole trihydrochloride, m.p. 237 ° C (compound 35);
    5-H 1H-imidazol-1-yl) phenylmethyl-2- (4-methoxyphenyl) -1H-benzimidaeol, m.p. 237 ° C (compound 36);
    3-JJ3- (1 H-imidazol-1-methylmethyl) -1H-benzimidazole-2-shLhinolin, m.p. Above 300 ° C (compound 37);
    3-p- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl 1 -2-pyridinamine, m.p. 268 ° C (compound 38);
    2- (4-fluorophenyl) -5-JJ - (1H-imidazol-1-yl) -4-methylbetyl} -1 H-benzimidazole, m.p. 188 ° C (compound 39), g
    5-JJ - (1H-imidazol-1-yl) -3-methylbutyl. 1 -2-Phenyl-1I-benzim Dazoldioate (2: 3), mp. 106 ° C (compound 40) 1,
    5-, 1 - (1 H-imidazol-1 -yl-) e t pcs -2-phenyl-1H-benzimidazole, so pl. 196 ° C (compound 41) j
    5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-methanol dihydrochloride, m.p. 241 ° C (compound 42) -,
    5- (1H-imidazol-1-ylmethyl) -2- (1H-indol-3-ylmethyl) -1H-benzimidazole, m.p. 125 ° C (compound 43) -,
    5- (1H-imidazol-1-ylmethyl) -2-H3- (2-thienyl) propyl -1 P-benzimidazole dihydrochloride, m.p. 220 С (connection 44)
    2- (difluoromethyl) -5-- (1 H-imidazol-1-yl) ethyl -1H-benzimidazole, so pl. 141 ° C (compound 45);
     1H-imidase ol-1-yl) phenylmethyl - 0-phenyl-1H-benzimidazol-2-methanol, so pl. 261 ° C (compound 46);
    5- l - (1 H-imidazol-1-yl) heptyl -2- (trifluoromethyl) -1H-benzimidazol-ethane-dioat (2: 3), so pl. 96 ° C (compound
    47H
    5- | (3-chlorophenyl) - (1-imidazol-1-yl) methyl -1H-benzimidazole, m.p. 108 ° C (compound 48);
    5- (4-fluorophenyl) - (1H-imidazol-1-yl) methyl -1H-benzimidazole, m.p. 104 ° C (compound 49);
    5-Gbis- (1 H-imidazol-1-yl) methyl - 1H-benzimidazole, m.p. 74 ° C (compound 50);
    5-p 2,4-dichlorophenyl- (1H-imidazol-1-yl) methyl} -1H-benzimidazole, m.p. 122 ° C (compound 51)
    5-G (1 1-imidazol-1-yl) - (3-methylphenyl) methyl -1 H-benzimidazole, so pl. 105 ° C (compound 52);
    5-cyclopropyl- (1H-imidazol-1-yl) -methyl -1H-benzimchdazole, m.p. 74 ° C (compound 53),
    5-Ј (1H-imidazol-1-yl) - (4-methoxy-phenyl) MeTHjfJ-1H-benzimidazole, so pl. 111 ° C (compound 54),
    6- (1H-imidazol-1-ylmethyl) -1- (phenylmethyl) -1H-benzimidazole, m.p. 143 ° C (compound 55),
    6- (1H-imidazol-1-ylmethyl) -1- (2-phenylethyl) -1H-benzimidazole dihydrochloride, m.p. 270 ° C (compound 56);
    1-cycloheptyl-6- (1H-imidazol-1-ylmethyl) -1H-benzimidazole, m.p. 95 Ct (compound 57),
    5-X1 H-imidazol-1 -yl) phenylmethyl - 1H-benzimidazole, m.p. 186 C (Compound 58);
    5-Ј (1H-imidazol-1-yl) phenylmethyl-2-methoxy-1H-benzimidazole, m.p. 110 ° C (compound 59);
    2- (fluoromethyl) -5-1- (1H-imidazol-1-yl) -2-methylpropyl -1H-benzimidazol-ethanedioate (1: 1), m.p. 192 ° C (compound 60);
    5- (3-chlorophenyl) - (1H-imidazol-1-yl) methyl -2-methyl-1H-benzimidazole, (mp. 117 ° C (compound 61);
    5- Ј (1H-imidazol-1-yl) - (3-pyridinyl) methyl -2-methyl-1H-benzimidazol monohydrate, m.p. 131.2 ° C (compound
    62) -;
    5- G (TH-imidaeol-1-yl) -2- (thienyl) -methyl -2-methyl-1H-benzimidazole, m.p. 109 ° C (compound 63);
     1H-imidazol-1-yl) phenylmethyl -2- (phenylmethyl) -1H-benzimidazole, m.p. 190 ° C (compound 64),
    5-p 1 H-imidazol-1-yl) phenylmethyl-2-octyl-1H-benzimidazoleethanoate (2: 5), so pl. 115 ° C (compound 65);
    ethyl 4-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl-benzoate, m.p. 213 ° C (compound 66),
    2-cyclopropyl-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole, m.p. 184 C (compound 67),
    5-Ј (1H-imidazol-1-yl) phenylmethyl -2- (4-methylphenyl) -1H-benzimidazoldi-hydrochloride, m.p. 205 ° C (compound 68)
    2- (2-furanyl) -5- (1 H-imidazol-1-yl) phenylmethyl -1 H-benzimidazole dihydrochloride, m.p. 211 ° C (compound 69),
    2,5-bis- (1H-imidazol-1-ylmethyl) -1H-benzimidazole trihydrochloride, m.p. 254 ° C (compound 70);
    5- Ј (1 H-imidazol-1-yl) phenylmethyl - (trifluoromethyl) phenyl -1H-benzimidazole, m.p. 182 ° C (compound 71) j
    1- (cyclohexylmethyl) -6- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazole, m.p. 139 ° C (compound 72);
    5- (1H-imidazol-1-ylmethyl) -2- (3-pyridinyl) -1- (3-pyridinylmethyl) -1H-benzimidazole, m.p. 180 ° C (compound 73);
    (E) -2- 2- (2-furanyl) ethenshL -5- {(1H-imidazol-2-yl) feshmethyl1-1H-benzimidazole, m.p. 135 ° C (compound 74);
    (E) -5- (1H-imidazol-1-yl) phenylme--2- (2-phenyl tenyl) -1 H-benzimidol, m.p. 141 ° C (compound 75),
    6- (1H-imidazol-1-ylmethyl) -2- (3-pyididinyl) -1H-benzimidazol-1-ol, mp. 08 ° C (compound 76);
    5- (1H-imidazol-1-ylmethyl) -1-methyl-1H-benzimidazol-2-ol, mp. 207 ° C (compound 77)
    5-G (1H-imidazol-1-yl) phenylmethyl - H-benzimidazol-2-thiol, so pl. 260 ° C connection 78) -,
    ethyl- (phenylmethyl) -4- “iperidinyl amino-Thioxomethyl amino-α-pyridinyl-D-amino ethyl carbonate in an ide residue (compound 79);
    6-X1H-imidazol-1-yl) phenylmethyl1-1-methoxy-2-methyl-1H-benzimidazole, m.p. 118 ° C (compound 80);
    2- (4-fluorophenyl) -6- (1 H-imidazol-1 yl) phenylmethyl-1- (1-methylethoxy) -1H-benzimidazole, m.p. 147ftC (connection 81),
    2- (4-fluorophenyl) -6- (1- (1H-imidazol-1-yl) ethyl -1-methoxy-1H-benzimidazol monohydrate, mp 90 ° C (compound 82);
    2- (4-fluorophenyl) -6-Ј (1H-imidazol-1-yl) phenylmetip -1- (phenylmethoxy) 1H-benzimidazole, m.p. Note 83) j
    178 ° C (connect
    2- (4-fluorophenyl) -6- (1H-imidazol-1-yl) Phenylmethyl -1- (2-propenyloxy) -1H-benzimidazole, m.p. 152bS (compound 84)
    2- (4-fluorophenyl) -6- Ј (1H-imidazol-1-yl) phenylmethyl -1- (2-propenshkshi) - 1H-benzimidazole, so pl. 109.8 ° C (compound 85),
    2- (1H-imidazol-1-yl) -5- (1H-imidazol-1-ylmethyl) -1 H-benzimidazole, so pl. 226 ° C (compound 86);
    P - H1H-imidazol-1-yl) phenylmethyl - 1H-bsnzimidazol-2-wG phenylmethanone, so pl. 223 ° C (compound 87),
    methyl 5- (j- (1H-imidazol-1-yl) ethylT-1H-benzimidazol-2-carboxylate, mp 162 ° C (compound 88);
    1-cyclopentyl-6- (1H-imidazol-1-ylmethyl) -1H-benzimidazole. m.p. 122.6 ° C (Compound 89)
    1-cyclohexyl-6- (1H-imidazol-1-ylmethyl) - H-benzimidazole, m.p. 143.4 ° C (compound 90) h
    5- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (3-pyridinylmethoxy) -1H-benzimidazole monohydrate, m.p. 118.2 ° C (Compound 91);
    1 - (cycloexylmethyl oxy) -6- (1H-imidazol-1-ylmethyl) -2-phenyl-1I-benzimidazole, m.p. 131.0 ° C (compound 92),
    6- (1H-imidazol-1-ylmethyl) -1,2-diphenyl-1H-benzimidazole, m.p. 169.9 ° C (compound 93) J
    5- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (2-thienylmethoxy) -1H-benzimidazole, m.p. 123.5 C (compound 94) -,
    J- (cyclopropylmethyl) -6- (1H-imidazol-1-ylmethyl) -1H-benzimidazole, m.p. 107.4 ° C (compound 95);
    5- Ј (3-chlorophenyl) - (1H-imidazol-1- | yl) methyl -1H-benzimidazol monohydrochloride, m.p. 200.2 ° C (compound 96)
    0
    five
    0
    five
    thirty

    40
    45
    50
    55
    2- (2-fluorophenyl) 1H-imidazol-1-ylmethyl) phenylmeeth-1H-benzimidaeol-ethanedioate (2: 3), so pl. 112.5 ° C (compound 97),
    5- G (1 H-imidazol-1-yl) phenylmethyl-2- (trifluoromethyl) -1H-benimidazole, m.p. 194.3 ° C (compound 98);
    5-Ј (3-fluorophenyl) - (1H-imidazol-1-yl) methyl} -1 H-benzimidazole, so pl. 85.6 ° C (compound 99).
    Pharmacological examples.
    The beneficial properties associated with the inhibition of the biosynthesis of androgenic hormones by the compounds of formula (I) are demonstrated in the following test procedures. I
    Example 12. Microsome test of pig testes.
    For example, it is possible to analyze spectral changes in the spectrum of cytochrome P-450 (cy.), Which indicate the interaction of compounds of formula (I) with isocymes cy. P-450 in isolated subcellular fractions, such as, for example, porcine testicular microsomes microsomes of the adrenal cortex and mitochondria of the adrenal cortex of the bull. Pork (21 days) samples are obtained by castration. Samples were decanted, ground in a 0.15 M KCl solution, washed and homogenized in two volumes (relative to the initial volume) of a 0.25 M sucrose solution containing 20 mmol KCl, 1 mmol EDTA (ethylenediaminetetraacetic acid) and 20 mmol tris -buffer (pH 7.4). The hydrogenation is centrifuged (1500 g of granules in 10 minutes), and the supernatant (10,000 g in 20 minutes), free from cells, is centrifuged. The precipitated mitochondrial fraction is removed, and microsomal membranes are collected by centrifuging (105,000 g in 60 min.). The precipitate after centrifugation, containing microsomal membranes, is suspended in potassium phosphate buffer (pH 7.4) and stored at -80 ° C. The content of cit.P-450 is determined by calculating the distinguishing features in the spectrum after reduction with carbon monoxide, using 91 as the coefficient estinction. To calculate the content of cit. P-450, an absorption increment between 450 and 450 nm is used.
    The interaction of compounds of formula (I) with cit. R-450 in the isolated membrane fraction is established by analyzing the spectral changes of cyt. R-450 caused by this compound. Membrane fractions are diluted with 0.1 M potassium phosphate buffer (pH 7.4) to obtain a cy content. R-450 0.1 nmol / ml. The suspension is divided between the reference and test cells. Establish a baseline of uniform light absorption. Increasing concentrations of the compound of formula (.1) dissolved in dimethyl sulfoxide (DMSO) are placed in the test cuvette, while the same amounts of DMSO are added to the reference cuvette. Isozymes isoenzymes cy. R-450 is reduced in several granules of sodium dithionite. The cuvettes are flushed with CO for 30 seconds and tightly closed. After the addition of a reducing agent, ditnonite, and CO saturation, the recovered cy. cit. The P-450 — CO complex gives a typical spectrum with an absorption peak in the region of 450 nm. However, when isocymes cy. P-450 is brought into contact with the compound of formula (I) before the reduction and saturation of CO, only a small absorption peak is observed at 450 nm. after barbation of CO. The difference in the spectrum thus obtained is fixed 30 seconds after the addition of the reducing agent. Using an estimated nonlinear regressive procedure, a sigoidal dose-type model is created for the individual observations and the corresponding IC values are determined (50% reduction in the height of the peak of the soret band of the reduced CO-complex). The mentioned values for a series of compounds of formula (I) are listed in Table. four.
    Example 13. Testosterone in the tests.
    Oral test compounds are administered to male rats as a solution or suspension in an aqueous medium. One hour after administration of this drug or placebo, an intramuscular hormone is administered intramuscularly, releasing the hormone of the corpus luteum, and an intraperitoneal anesthetic drug. Two hours after oral administration of the test substance, the rats are decapitated and blood is drawn from heparin. Testeron and plasma concentrations are calculated by standard radioimmunoassays: 50% inhibition relative to placebo is considered as
    criteria of inhibition of testosterone activity. ED50 values are determined by sample analysis. The aforementioned ED50 values for a number of compounds of formula (I) are listed in Table. 4 (the results in Table 4 are not intended to limit the scope of the invention, but only in order to confirm by example the useful pharmacological properties of all compounds of formula (I)).
    Example 14. Comparative experiments in vivo.
    Male dogs are given orally 2.5 mg / kg of the test compound. Eight hours after administration of the test compound, blood is taken and collected on heparin. The concentration of testosterone is then determined by standard immunological methods. The values of inhibition in percent compared with the inert agent for the proposed compounds are given in | Tab. five.
    Inhibition of testosterone release 8 hours after oral administration of a known ketoconazole compound
    ABOUT
    II H3C-C-N



    in the amount of 2.5 mg / kg is 13%.
    Pharmacological data are given in table. 4 indicates the activity of all proposed compounds with respect to inhibition of testosterone release. At the same time, the data table. 5 indicates a higher activity of the proposed compounds compared with the known compound ketoconazole, which is an effective steroid inhibitor, i Firm-i of the invention
    The method of obtaining derivatives of (1H-imidazol-1-ylmethyl) -substituted benzimidazole of the general formula
    N
    U n
     R is hydrogen, C, -C6-alkyl, cycloalkyl, phenyl, optionally substituted with two substituents selected from halo, C-C-alkyl, 0 ,, alkyloxycarbonyl, carboxyl or C, -C4 alkyloxy, thienylfuranyl, halofuranyl, imidazolyl or pyridinyl, JQ R, is hydrogen, C-C7-cycloalkyl,
    phenyl, C.-Cg-alkyl, optionally substituted by phenyl, C ,, -C7-cycloalkyl or pyridinyl, hydroxy, kiloxy, optionally substituted by phenyl, C-C7-cycloalkyl, pyridinyl, and tynyl, C -Sf-alkenyloxy, optionally substituted by phenyl, or C-Cg-alkynyloxy,
    A - bivalent radical having the formula
    -CRj N- -l 25
    20
    (but)
    or
    X
    -C-NR4
    (B)
     where the carbon atom in the divalent radical (a) or (b) is attached to hydrogen, Cz-C4 alkyl, substituted by three halogen atoms, 35 Ca-C-p-cycloalkyl, phenyl, optionally substituted by halogen, C 1 -C4 alkyloxy, C | alkyloxycarbonyl, carboxyl, trifluoromethyl, or 40 thiazolyl, thienyl, furanyl, pyridinyl, aminopyridinyl, quinolyl, C (-C, 0 alkyl, C (alkyl, substituted by phenyl, Ca-C7-iikloalkyl, pyridine-45nyl, indolinyl, thyme scrap, imidazolyl or hydroxyl, C-C-alkyloxy, C-C-alkenyl, optionally substituted by phenyl, pyri-Q dynyl, furanyl or imidazolyl, or o (, phenylmethanol, X is oxygen or sulfur,
    Ri is hydrogen, C -C-alkyl or
    benzyl;
    or their pharmaceutically acceptable acid salts, or metal salts, or stereoisomers, characterized in that the 1H-imidazole of the formula
    om
    N N
    and
    or its alkali metal salt N-alkylated with benzimidazole of the general formula

    Ws
    -to
    III
    R,
    five
    0
    5 0 5 Q
    where U is a reactive leaving group,
    in an inert solvent medium, if necessary in the presence of a base, and isolate the desired product or, if necessary, 0-alkylate a compound of the general formula (I) having a hydroxyl radical, with an appropriate alkylating agent in the presence of a base such as sodium hydride, sodium hydroxide or sodium methoxide, or convert a compound of general formula (I) containing an ester group to the corresponding carboxylic acid by treating the compound of general formula (I) with an alkali or acid solution or convert carb The new acid is converted into the corresponding alkyl ester by further treating the starting compound of general formula (I) with thionyl chloride and sodium methoxide in methanol and, if necessary, converting the resulting compounds of formula (l) into a pharmaceutically acceptable acid salt by treating with an appropriate acid or metal salt by treating with a base, or converting an acid salt to a free base by treating with an alkali or acid, or stereochemically isomeric forms of the compounds of general formula (I) are obtained.
    Table 1
    no-ns
    table 2
    1662350-2T
    Table3

      N
    -R:
    CH, -Ј I
    58 77 63 49 51
    -R:
    2161635U
    Continuation of table 4
    / Jo
    Continuation of the table. And
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives of (1Nimidazol-1-ylmethyl) -substituted benzimidazole of the General formula
    1662350. ' where R is hydrogen, C ( -C ^ -alkyl, C. ^ - Sucycloalkyl, phenyl optionally substituted with two substituents selected from halo, Cή-C ^ -alkyl, C 5 -C ^ alkyloxycarbonyl, carboxyl or C, - C 4 -alkyloxy, thienylfuranyl, halofuranyl, imidazolyl or pyridinyl, jq R, is hydrogen, C ^ -C7 “cycloalkyl, phenyl, C ^ -Cg-alkyl optionally substituted with phenyl, C ^ -Cu-cycloalkyl or pyridinyl, hydroxy, C ^ -C ^ -alkyloxy optionally substituted with phenyl, C 3 ~ C 7 ~ cycloalkyl, pyridinyl and thienyl, C3-C ^ -alkenyloxy optionally substituted with phenyl, or Cg-Cg-alkynyloxy,
    A is a divalent radical having the formula
    -CR = Ν- (a) 25 or
    X - C ~ NRi | (B) 30 where the carbon atom in the divalent radical (a) or (b) is attached to —NR ^; Rj - hydrogen, C ^ - C ^ alkyl, substituted by three halogen atoms, 35 Cj-Cy-cycloalkyl, phenyl optionally substituted with halogen, C ή-C 4 -alkyloxy, C (-C 4 alkyloxycarbonyl, carboxyl, trifluoromethyl, or thiazolyl, thienyl, furanyl, pyridinyl, aminopyridinyl, quinolyl, C (-C w -alkyl, Cf-C ^ alkyl substituted with phenyl, C 3 -C 7 -cycloalkyl, pyridin-45-nyl, indolinyl, thienyl, imidazolyl or hydroxyl, C ^ -C4 ~ alkyloxy, CC-C ^ -alkenyl, optionally substituted with phenyl, pyridinyl, furanyl or imidazolyl, or (/, phenylmethanol,
    X is oxygen or sulfur,
    R ^ is hydrogen, C 3 -C 4 alkyl or benzyl;
    or their pharmaceutically acceptable salts of acid, or metal salts, or stereoisomers, characterized in that 1H-imidazole of the formula
    N and
    H or its alkali metal salt is N-alkylated with benzimidazole of the general formula 111
    R
    where W is a reactive cleavable group in an inert solvent, if necessary in the presence of a base, and the desired product is isolated or, if necessary, a 0-alkylation of a compound of general formula (I) having a hydroxyl radical is carried out with a corresponding alkylating agent in the presence of a base such as sodium hydride, sodium hydroxide or sodium methoxide, or convert a compound of general formula (I) containing an ester group into the corresponding carboxylic acid by treating a compound of general formula (I) with alkali or acid rum or they convert the carboxylic acid into the corresponding alkyl ester by treating the starting compound of the general formula (I) with thionyl chloride and sodium methoxide in methanol and, if necessary, convert the obtained compounds of the formula (I) into a pharmaceutically acceptable acid salt by treating the corresponding acid or metal salt by treatment with a base, or turn an acid salt into a free base by treatment with alkali or acid, or get stereochemically isomeric rmy compounds of general formula (I).
    ί '
    Table 1
    Product Κι r 2Substance Mp.° C 5 Η 11 P 1 a i «· 11111111111111 HC1 200 6 ΗC 6 H 5 HC1 220  7 Η sn 3 - sn 2 - sn 2Base - 8 Η CH 3 -CH 2 - 9 CH 0 H 2 —CH aH34.8 Yu sun 3H152.3 eleven sun 3Cjh 5 148 12 sun 3S1Ts-CH 2HC1 234.8 thirteen CHj-C11 2 -CH 2CH 3 -CH 2HC1 - 14 CH 3c Base -
    Table 2 R, jOCir R 2 Cl-CHp ^ N 1 ProductR 1R 2 Substance Mp.° C 17 H IIIIIIIIIIIIIII wI aboutII HC1 205 18 HC 6 H 5 HC1 228 19 H sn 3 - sn g - sn 2HC1 - 20 H sn 3 - sn gHC1 - 21 CH 3ch 3HC1 204 22 sn 3 - sn g - sn 2H HC1 165.6 23 sun 3H HC1 1 / 2H Z O 169.3 24 ch 3 C 6 n 5 HC1 210.7 25 CH 3cn 3- sn 2HC1 - 26 CH 3 —CH 2 —CH 2CHj-CH 2HC1 - 27 ch 3CF 3HC1 -
    1662350 24
    Table 3
    ConnectednationR zSubstance Position Mp.° C 2 nc 3 ii 7sun 31.1 / 2 (COOH) 35 194.6 3 sun 3SL 3Base 5 185.3 4 n sun 3- 5 158.3 5 N-S E N 7Η _ P__ 5 100.9 6 nc 3 h 7 C 6 H 55 115.5 7 ns r n 5 _P_ 5 174.2 8 sun 3nc 3 h 7_n_ 5 113.2 9 nC b N 5 2 HC1 5 203.8 10 n nc 3 h 72 (COOH) £ 1/2 H 2 0 5 132.0 eleven sun 3 C 6 H 5 2 (С00Н) g5 168.4 12 nc 3 h 7 2'CH1'N 2 O 5 141.5 thirteen nc 3 h 73-pyridineniya 3 (С00Н) 2 · Н 2 0 5 119.1 14 ΗC 6 H 5 Base 5 218.4 fifteen DOS 3n HC1 · 2 H 2 0 6 163.3 16 Η n 2 HC1 '4 267.9 17 Η Z-PyridiNile 3 HC1 4 261.0 18 Η from 6 n Base 4 229.8 19 0Η 3n5 135.2 20 0Η 3from5 124.8
    Table 4Continuation tabl Compound- Cit. P-450 Testosterone, 1 ( 2 | 3 nie 10 0 values, ED 50 , mg / kg mole48 0.2 2,5 1 2 3 61 0.1 2,5 52 0.1 - 58 oh s <10 54 0.1 - 77 1,1 <2.5 68 0.2 ^ 2,5 63 0.2 2,5 36 0.5 <2.5 49 0.2 - 97 0.3 <2.5 51 0.2 - 43 - 2,5
    /about
    Continuation, table 4 _____ · ________ Continuation of table 4
    4 2 3 ί 2 thirteen........ 38 0.6 2,5 . 82 0,073 2,5 59 0.2 2,5 27 0.17 <2.5 80 0.1 2,5 45 0.32 2,5 39 0.11 - 87 0.33 - 31 0.11 - 29th 0, 15 - 41 0,095 - 55 0.43 <2.5 47 0,085 -
    Table 5 2 -sn
    Compound r 2 Inhibition of testosterone release 8 hours after administration of the test compound in an amount of 2.5 mg / kg,% 96 3-C1-C 6 n n- 82 972F-C 6 H ._- 88 98C 6 H 5 “ CF 3- 65 99 3F-c 6 H 5Η- 67
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    ES2053524T3|1994-08-01|
    PT85692B|1990-06-29|
    JPS6485975A|1989-03-30|
    NO167202B|1991-07-08|
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    US90790386A| true| 1986-09-15|1986-09-15|LV920226A| LV5029A3|1986-09-15|1992-11-27|Method for obtainingsubstituted benzimidazole derivatives or islands or metal islands or stereoisomers of pharmaceuticals suitable for the pharmaceutical industry|
    LTRP374A| LT2087B|1986-09-15|1993-02-26| DETAILED DESCRIPTION OF THE DETAILED DESCRIPTION OF THE INVENTION OF THE INVENTION OF THE INVENTION OF THE INVENTION OF THE INVENTION OF THE INVENTION OF THE|
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