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    • 专利摘要:
    Novel 5-[4-(diarylmethyl)-1-piperazinylalkyl]benzimidazole derivatives having antiallergic and antihistaminic properties.
    公开号:SU986297A3
    申请号:SU782595004
    申请日:1978-03-29
    公开日:1982-12-30
    发明作者:Херман Маргарета Рэймэкер Альфонс；Людовик Юберт Ван Желдер Жозеф；Мариа Боекк Гюстав；Люсиа Ван Эмельдонк Лодевижк
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    39 Nylamine- {lower alkyl carbonyloxy- (lower alkyl), aryloxy (lower alkyl), (lower alkyl) -oxycarbonylamine or (lower alkyl) -oxycarbonyl (lower alkyl); Lg-dH - Ar, Ra. have the indicated values, cyclization with a compound of the formula D C - Ra, where Ra-has the indicated values; D is O or NH; E, 0- (lower alkyl) or NH or D and. E, together-N, provided that if D is NH, then E is O- (lower alkyl), if Ra is hydrogen, then D is O, and E is OH; if Ra is an amino group, then D and E together - N ;.   if Ra is (lower alkyl) -drbonylamino- (lower alkyl), carbonyloxy (lower alkyl), aryl- (lower alkyl), (lower alkyl) -oxycarbonylamino or (lower alkyl) -oxycarbonyl - (lower alkyl), then D is NH as well E - O- (lower alkyl), in the environment of the corresponding solvent with the release of the target product.  BUT.  Antihistamine action i p V i t th.  The guinea pig intestinal tissue strips were suspended in 100 ml of a thyroid bath at 37.5 ° C in an amount of 0.75 g.  95 oxygen and 5 carbon dioxide were passed into the suspension.  Spasms caused by 0.5 mg / l of histamine were recorded on a kymograph with an isotonic lever giving a 5-fold increase.  The interaction of the test compound was studied. A incubation period of 5 min) with an agonist.  When tested under these conditions, a compound of formula (I) and their pharmaceutically compatible acid addition salts showed an inhibition of histamine-induced spasm at a concentration of 0.0025 to 0.16 mg / l.  7 RO | - hydrogen, lower alkyl aryl (lower alkyl), lower oxyalkyl, cycloalkyl, (lower alkyl) -oxy- (lower alkyl), or their salts, subjecting compounds of the general formula HHg c.  Anti-anaphylactic and anti-histamine action in vivo.  The anti-anaphylactic and anti-histamine effects of compounds (I) and their salts in vivo on guinea pigs were studied.  Guinea pigs weighing 00-500 g were sensitized to the egg protein by injecting 0.05 ml of antiserum under the sole of the hind left paw.  Animals were deprived of food for.   h after,.  sensitization, then they were given an orally given dose of the test compound or isotonic solution (control ones).  Two hours after oral administration of the compound, histamine injection (50 µg dose) was administered to the rear right side of the animals.  First, the diameters of both hind paws were measured before histamine injection, and then the measurement was repeated after 10.  min .  30 minutes after histamine injection, 0.6 mg of egg protein was injected intravenously into animals.  All control animals developed typical primary symptoms of anaphylactic shock (cough, heavy breathing, convulsions); 85 control animals died 15 minutes after the injection of egg protein.  Prevention of death was taken as a criterion for the effect of the drug.  .  The average swelling of the paw under the action of histamine in 200 control animals 10 minutes after the administration of histamine was 15 units.  (1 item    0.1 mm).  The reaction is below 10 units. , occurring in less than 5% of control animals, indicated an effective inhibition of histamine edema in treated animals.  The compounds of formula (1) and their salts have a 100% effect against 59% anaphylaxis. in guinea pigs, administered orally 2.5 mg / kg.  At such doses, they are effective in reducing the histamine-induced swelling of paw C.  Action against passive cutaneous anaphylaxis in rats.  As a model of instantaneous hypersensitivity due to reactive antibodies, passive skin anaphylaxis has been widely studied in rats.  For these tests, serum containing this type of antibodies was prepared according to the procedure described in Jmmunology 7.681, 196 g. , and entered subcutaneously at two different points of the test animal's back.  After k8 h, the egg white and triptan blue were injected intravenously.  Two observers independently assessed the condition at both reaction points on the inner side of the skin by comparison with the intensity of the standard reaction.  The highest intensity score for a single reaction point is equal, so the highest score for the length of one rat is 16 (4 X 2 points.  X 2 observers).  Before injection of egg protein, animals were given for 2 h. test compound or water (control animals).  Treatment efficacy was evaluated by comparing the color intensity of triptan blue at the reaction point in animals treated with water and compound.   The dose (Edd) required to create a 50% inhibition of induced passive skin anaphylaxis in rats for the compounds of formula (I) and their salts is 0.1b-5.  mg / kg  The pharmacological properties of compounds (I) and their pharmaceutically acceptable salts, the addition of acids determine their activity as anti-histamine, anti-allergic and anti-asthma drugs in doses of 0.2 to mg / kg body weight when administered systematically to warm-blooded animals. .  Based on the important antihistamine, anti-allergic and anti-asthma action of the compound according to the proposed method, it can be used in various pharmaceutical forms depending on the method of their introduction into the organism.  To obtain the pharmaceutical compositions of the invention having an effective anti-histamine, anti-allergic, anti-anaphylactic or anti-asthmatic effect, the compound as a base or an acid addition salt as the active ingredient is mixed with a pharmaceutically acceptable carrier in various forms depending on the method of administration.  These pharmaceutical compositions are preferably made in single doses suitable for oral, rectal or parenteral administration. For example, oral preparations are prepared using a conventional pharmaceutical environment, such as water, glycols, populations, alcohols (liquid preparations, such as suspensions, syrups, elixirs and solutions}, or solid carriers, such as starch, sugar, kaolin, lubricants binders, disintegrants (powders, pills, capsules and tablets, tablets and capsules are the most advantageous dosage forms that use solid pharmaceutical carriers,).  For parenteral compositions, sterilized water is most often used as a carrier, although other components are also used, for example, to facilitate the dissolution of the active ingredient.  Injection solutions can be prepared in which isotbnic solutions, glucose solution or a mixture of salt and glucose solutions are used as a carrier.  Injectable suspensions may also be prepared in which the appropriate liquid carrier suspending agents are used.  Addition salts of acids (I) are preferably used for the preparation of aqueous compositions due to their increased water solubility compared to free bases.  Preferably, single dose physically discrete forms are used, t.  e.  tablets (including Coated or. notched), capsules, pills, powders, solutions or suspensions for injection, doses of a teaspoon, doses of a tablespoon, and their section, 1-multiple. doses.   The compounds of formula (D) are also active against vessels, as a result of which they can be used to treat patients with diseases of the vascular system, especially peripheral vessels. Example 1.  A mixture of 10.3 wt. h  1-chloro- - (chloromethyl) -2-nitrobenzene, 25.2 wt. h; 1- (defenylmethyl) -piperazine and 120 wt. h, ethanol is mixed and heated by reverse distillation if h.  Then the reaction mixture is cooled and evaporated.  The residue is washed away 100 weight.  h  water.  The product is extracted with methylbenzene.  The extract is washed with water, dried, filtered and evaporated.  The residue is purified on a chromatographic column with silica gel and eluted with trichloromethane.  Pure fractions are collected.  The eluent is evaporated.  The residue is crystallized from a mixture of 2,2-oxybispropane and hexane (1: 2 by volume).  The product is filtered, washed with hexane and dried.  Get 19.6 weight.  1 - (-chloro-3 nitrophenylmethyl) (diphenylmethyl) -piperazine Art.  square  101.6 ° C.  The following compounds are prepared analogously: 1 - (A-chloro-3-itrophenylmethyl) -4- - G (A-fluorophenyl) -phenylmethyl-piperazine s.  square  99, (, fluorophenyl) -methylZ- - (- chlorop-3 nitrophenylmethyl) -piperazine with t.  square .  105.9 ° C; 1- (diphenylmethyl) -4 - (- methoxy-3-nitrophenylmethyl) -piperazine dichlorohydrate monohydrate with t.  square  257 ° C.  Example 2  A mixture of 13.9 wt. h  1 - (diphenylmethyl) piperazmna, 8.35 weight. h  2-bromo-1 - (- chloro-3-H-trophenyl) -ethanol and O wt. h  The 2-propanone is stirred for 30 minutes at room temperature.  The precipitate formed is filtered off.  210 wt.% Is added to the filtrate. h  2,2-oxybase n. The whole mixture is treated with activated carbon.  The latter is filtered off.  An excess of 2-propanol, previously saturated with gaseous hydrogen chloride, is added to the filtrate. The hydrochloride salt formed is filtered off and mixed with 80 wt. h, 2-propanol, filtered and. crystallized from ethanol.  The product is filtered and recrystallized from 2-methoxyethanol.  Get 6, weight. h  1- (2-chloro-3-nitrophenyl) (diphenylmethyl) -1-piperazinyl3-ethanol dihydrochloride with t; pl.  .  To a stirred mixture consisting of 5.2 wt. h  1 - (- chloro-3-nitrophenyl) (diphenylmethyl) -1 -piperazinyl-ethanol dihydrochloride and kQ weight. Methanol is added in portions to 0.76 wt. h  sodium borohydride.  After the addition is complete, stirring is continued for 30 minutes at room temperature.  The reaction mixture is decomposed by adding a mixture of 2 wt. h  acetic acid and 10 wt. h  water.  . The solvent is distilled off.  50 wt. h  water.  The mixture is alkalinized with ammonium hydroxide.  The precipitated product is filtered, washed with water and a small amount of 2-propanol and crystallized from ethanol.  Get k, 3 wt. h  (95.1%) ot - (4-chloro-3-nitrophenyl) (diphenylmethyl) -1-piperazine ethanol with m. square  163. .  Example 3  Within 20 hours  methaneamine gas is bubbled through a hot (60-70 ° C) stirred mixture of 63.3 wt. h  1- (-chlor. -3-nitrophenylmethyl) -4- (diphenylmethyl) -piperazine and 50 wt. h  Dimethyl sulfoxide.  Then the reaction mixture is cooled and poured into a mixture of water and ice.  The precipitated product is filtered off, washed with water and washed with methyl benzene.  The latter is dried, filtered.  and evaporated.  The residue is purified by chromatography on silica gel using a mixture (98: 2 by volume) of trichloromethane and methanol as eluent.  Pure fractions are collected.  | Eluel1 is distilled off.  The remainder of the crista is lysed from 2,2-oxybispropane.  Get 30.4 weight. h .  (diphenylme-.  thyl) -1-piperazinylmethyl 1-M-methyl-2-nitrobenzamine with t.  square  120 ,.  Example k.  Analogously to Example 3, using instead of methanamine an equivalent amount of the corresponding amine, either in a gaseous form (ethanamine) or in a liquid form (other amides), the compounds shown in Table 2 form this half.  one.  Example 5  The following compounds are prepared in analogy to Example 3: k- (diphenylmethyl) -oi- 4- (ethylamine) -3-nitrophenyl -1-piperazine ethanol with m.  square  138 ° C; 4- (diphenylmethyl) - / -GZ-nitro-4- (propylamine) -phenyl -1-piperazine ethanol with t. square   (Diphenylmethyl) -1-piperazinylmethyl -M- (2-methoxyethyl) -2-nitrrbenzamine SL-.  square  97. 2 ° C in the interaction of 1- (diphenylmethyl) -A- (-methoxy-3 nitrophenylmethyl) -piperazine dichlorohydrate with 2-methoxyethanamine.  Example 6  Solution 5 wt. h   (Diphenylmethyl) -1 -piperazinylmethyl-M-methyl-2-nitrobenzenamine in Vto weight, h.  methanol hydrated n0f normal pressure and at room temperature 2 weight. h  Rene nickel catalyst.  After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. Get 4.6 weight.  h  UOO (diphenylmethyl) -1 piperazinylmethyl -N-methyl-1, 2-benzenediamine as a residue.  Example 7  Analogously to example 6, using an equivalent amount of one of the products obtained in examples 4 and 5 as starting materials, get in the form of the residue of the dynenium, presented a table.  2  . -Prime 8.  Analogously to Example 6, d-3-amine-4- (ethylamine-phenyl (diphenylmethyl) -1-piperazine ethanol is obtained as an oily residue, as well as o, - 3-amine- - (propylamine) -phenyl (dkphenylmethyl) -1 piperazine ethanol as an oily residue.  Example 9  A mixture of 7.1 weight. h  fluorine-5 -nitrobenzoic acid, j9,1 weight. h  1-propanamine and 25 wt. h  dimethyl sulfoxide is stirred for 3 h at 60 ° C.  Then the reaction mixture is poured into 150 weight. h  water.  The precipitated product is filtered, washed with water and dried.  Get 8.8 weight. . h, 3-nitro- (propylamine) -benzoic acid Art.  square  208 ° C.  A mixture of 4.5 wt.  h  3 nitro - {propylamine) -benzoic acid and 80 wt.  methanol is hydrogenated at normal pressure and room temperature with 2 wt. h  rene nickel as a catalyst.  After uptake of the calculated amount of hydrogen, the catalyst is filtered off.  To the filtrate add 100 weight. h  acetic acid and the whole mixture is evaporated.  Get k, 5 wt. h 3-amino-4-. (propylamine) -benzoic acid as a residue.  A mixture of k, S weight. h  Z-amino-4- (propine amine) -benzoic acid, 2.6 wt. h, ethylethancarboximidate hydrochloride and 50 wt. h  Acetic acid is first stirred for 20 min at room temperature, then for 10 min at reflux temperature.  The reaction mixture is evaporated.  The residue is crystallized from 2-propanol.  The product is filtered, washed with water and 2-propanol and dried.  Get 1.8 weight. h  2-methyl-1-propyl-1H-benzimidazole-5-carboxylic acid Art.  square  260 S.  To a stirred mixture consisting of 18 wt. . h  2-methyl-1-popil-1H-benzimidazole-5-carboxylic acid and 150 weight. h  trichloromethane, 29.8 wt. added dropwise. h  thionyl chloride.  Stirring is continued for 20 minutes at reflux temperature.  Then the reaction mixture is cooled, dried, filtered and evaporated.  Get 22.5 weight. h  2-methyl-1-propyl-1H-benzimidazole-5-carbonyl chloride monochlorohydrate as a residue.  A solution of 22.5 wt. h  2-methyl-1-propyl-1H-benzimidazole-5-carbonyl chloride monochlorohydrate in 150 wt. c.  trichloroethane decompose 32 wt. h  metaiol.  After stirring for 10 minutes at reflux temperature, the reaction is carried out. the mixture is evaporated, the residue is washed with water and alkalized with ammonium hydroxide.  The product is extracted twice with 120 wt. h  dichloromethane.  The combined extracts are dried, filtered and evaporated.  The solid residue is washed with 2,2-oxybispropane and dried. .  Get 18.8 weight. h  methyl 2-methyl-1-propyl-1H-benzimidazole-5-carboxylate.  To the stirred solution. containing 18 wt. h  sodium dihydrobis (2-methoxyethoxy) aluminate and.  22.5 wt. h  methylbenzene, a solution of 11.6 wt. is added dropwise. h  methyl 2 1-propyl-1H-benzimidazole-5-carboxylate in kS weight. h  methylbenzene.  Stir for 15 minutes at room temperature.  Then the reaction mixture is decomposed 10 n. sodium hydroxide solution.  The organic phase is converted to the hydrochloride salt in 2-propanone and 2-propanol.  The salt is filtered and dried.  Get 6.7 weight. h  2-methyl-1-propyl-1H-benzimidazole-5-methanol monochlorohydrate with t. square  .  A solution containing 36 wt. h  2-methyl-1-propyl-1H-benzimidazole-5-methanol and 150 weight. h  trichloromethane, acidified with excess gaseous hydrogen chloride.  Then, 32 wt. h  thionyl chloride.  The mixture is stirred for 1 h.  at room temperature.  The reaction mixture is evaporated and the residue is crystallized from 2-propanol.  The product is filtered, washed with 2-propanone and dried.  Get 40.9 weight. h  monohydrochloride-5- (chloromethyl) -2-methyl-1-propyl-1Nbenzimidazole with t. square  .  Similarly, get monochlor. 5- (chloromethyl) -1-ethyl-2-phenyl-1H-benzimidazole hydrate with m. square  175,  Example 10  A mixture of 8.3 wt. h  -amino-3-nitro-6-aldehyde and. 200 weight. h  methanol is hydrogenated at normal pressure and room temperature to 5 wt. h  rene nickel as a catalyst.  After uptake of the calculated amount of hydrogen, the catalyst is filtered off, and |) the filtrate is evaporated.  Get 3, -diaminobenzenemethanol &, 5 wt. h  p the form of an oily residue.  Example P.  A mixture of 6.9 wt. h  , - diaminobenzenemethanol, 8.3 wt. h of ethylbutanolimidate and 30 wt. h  ethanol is first stirred at room temperature for 2 hours, then at reflux temperature for 2 hours.  The reaction mixture is evaporated.  The residue is stirred in water.  The mixture is alkalinized with ammonium hydroxide.  The product is extracted with β-methyl-2-pentanone.  The extract is dried. filtered and evaporated.  Get 6.2 weight. h  2-propyl-1H-benzimidazol-5-methanol as a residue.  The following compounds are prepared analogously: 2-methyl-1H-benzimidazo-5-methanol hydrochloride with m. square  200 C; 2-phenyl-1H-benzimidazo 5-methanol hydrochloride with t. square   2- (1-methylstil) -1H-benzimidazol-5-methanol as a residue; 2-ethyl-1H-benzimidazol-5-methanol as a residue; 2-cyclopentyl-1H-benzimidazol-5-methanol is in the form of a residue; 2-cyclopropyl-1H benzimidazol-5-methanol as a residue; about(.   (Diphenylmethyl) -1 -piperazinyl methyl J-1-ethyl-2-methyl-1H benzimidazole-5-methanol with m.  square  174.6 ° C; ot (diphenylmethyl) -1-piperazinyl methyl -2-methyl-1-propyl-1H-benzimide sol-5-methanol with m.  , pl.  146.6 ° C; d (diphenylmethyl) -1-piperazinyl methyl 3-2-Ethyl-1-propyl-1H-benzimidazole-5-methanol as an oily residue; -.  cft trichlorohydrate (diphenylmethyl-1-piperazinylmethyl -1,2-dipropyl-1H-benaimidazol-5-methanol with t.  square  235-240 ° C.  Example 12  To 8.5 weight-. h  3,4-diaminobenzenemethanol is added successively 35 wt. h  1,1, l-metil tilidene-tris- (oxy) -trisethane and 3 drops of acetic acid.  A mixture of stirrers 7 is sewn by reverse distillation for 2 hours.  The reaction mixture is evaporated.  The residue is converted to the hydrochloride salt in 2-propamol.  The salt is filtered and washed with a small amount of 2-pro panol.  Receive after drying At, weight. h  1H-benzimidagol-5-methanol hydrochloride with m.p.  190 ° C.  Example 13  A mixture of 2i, 8 wt. h  3 L-Diaminobenzenemethanol, 7 weight h.  chlorohydrate 2- (ethoxyimino) ethyl benzoate and 320 weight, h.  ethanol is stirred for 20 h at room temperature.  The solvent is distilled off.  The residue is dissolved in kQ weight. h  methanol.  The solution is alkalinized with ammonium hydroxide and 900 wt. h  trichloromethane.  The ammonium chloride formed is filtered off.  The filtrate is dried, filtered and evaporated.  The residue is dissolved in 750 wt. h  trichloromethane.  The solution is treated with activated carbon and filtered.  The filtrate is evaporated.  Get it. 3 wt. h  (66.9. ) C5- (hydroxymethyl) -1H-benzimidazol-2-ylmethyl-benzoate as a residue.  Example T.  To stirred; mixtures containing 6.2, weight. h  2-propyl-1H-benzimidazol-5-methanol and 38 wt. h  trichloromethane, 40 wt. h .  thionyl chloride.  Pe-  Stir for 15 minutes at reflux temperature.  The solvent is distilled off.  The residue is dissolved in 80 wt. h  2-propanone.  The product is crystallized.  The crystals are filtered and dried.  Get 4.3 weight. h  chlorohydrate 5- (chloromethyl) -2-propyl-1H-benzimidazole.  PRI me R 15.  Analogously to Example 14, the compounds presented in the tab.  3 “PRI me R 16.  To a stirred mixture of 10.3 wt. h  (diphenylmethyl) -1-piperazinylmethyl 1-ethyl-2-methyl-1H-benzimidazole-5-methanol trichlorohydrate and 75 wt. h  trichloromethane was added 4.3 pounds by weight. h  thiog, nilchloride at room temperature.  Stir for 30 minutes at reflux temperature.  After cooling, the precipitated product is filtered off, washed with trichloromethane and 2.2-oxybispropane and dried.  Get 9 weight. h  (85.8) 5-C-chloro-2-4- (diphenylmethyl) - -piperazinyl-ethyl-1-ethyl-2-methyl-1H-benzimidazole trichlorohydrate.  , 1398 Similarly, the following cb- (units: 5 {1 chloro-2- - (diphenylmethyl) -1-piperazinylZ-ethyl-2-methyl-1-propyl-1H-6enzimidazole trichlorohydrate) are obtained.  170-1 ° C (decomp. ); 5 chloro-2-14- (diphenylmethyl) -1-piperazinyl-ethyl -2-ethyl-1-propyl-1H-benzimidazole trichlorohydrate with m, pl.  180 ° C; 5 - {1-chloro-2- 1 - (diphenylmethyl) -1-piperazinyl-ethyl -1,2-dipropyl-1H-benzimidazole trichlorohydrate.  Example 17  A mixture of k (weight.  h  (Diphenylmethyl) -piperazinylmethyl JN-methyl-1, 2-benzenediamine, 3.71 wt. h  methyl M, M -bis- (methoxycarbonyl) -carbamidothioate, t, 32 wt. h; acetic acid and 15 wt% h  trichloromethane is stirred at a temperature of reverse distillation for 22 hours  The reaction mixture is cooled to room temperature and evaporated.  The residue is washed off 100 weight, h.  water.  The precipitate is filtered off, the filtrate is alkalinized with ammonium hydroxide.  The product is extracted with trichloromethane.  The extract is washed with water, dried, filtered and evaporated.  . ,,,, . .  . .   The residue is purified by chromatography on a column of silica gel, eluted with a mixture of trichloromethane and methanol (95: 5 by volume).  Pure fractions are collected.  The eluent is evaporated.  The residue is crystallized from 2-propanol.  The product is filtered off, washed with 2-pro panol and 2,2-oxybispropane and dried.  Get 2.6 weight. h  methyl (diphenylmethyl) -1-piperazinylmethyl -1-methyl-1H-benzimidazol-2-yl1-carbamate with t. square  196.5 ° C.  The following compounds are prepared analogously: methyl- (5- {- (- fluorophenyl) -phenylmethyl -1-piperazinylmethyl-3-methyl-1H-benzimidazol-2-yl / -carbamate with m.  square  191.2 ° C; Methyl- / 5- {- bis-4-fluoro-phenyl) -methyl -1-piperazinylmethyl -1-methyl-1H-benzimidazol-2-yl / -carbamate monohydrate with t.  square  156, methyl-5 f (diphenylmethyl) -1-piperazinylmethylJ-1-propyl-1H-benzimidazole -2-yl-carbamate with t. square  139 ,.  Example 18  Mixture, 6 wt. h - t- (diphenylmethyl) -1-piperazinylmethyl - N-methyl-1, 2-benzenediamine and 1.2 weight. h  urea is stirred by heating for 1.5 hours at 190 C.  The reaction mixture is cooled and dissolved in a mixture of 150 wt. h  water and 6 wt. h  10 n. hydrochloric acid solution.  The solution is treated with activated carbon.  and filtered.  The filtrate is alkalinized 5 n. sodium hydroxide solution.  The product is extracted three times with dichloromethane.  The combined extracts are dried, filtered and evaporated.  The solid residue is stirred in 20 wt. h  ethanol.  The product is filtered and purified on a chromatographic column with silica gel using a mixture of trichloromethane and methanol (5 by volume) as eluent.  Pure fractions are collected.  The eluent is distilled off.  The solid residue is treated with 20 wt. h   ethanol.  The product is filtered, washed with a small amount of ethanol and dried.  Get 1.7 weight. h  5 (diphenylmethyl) -1-piperazinylmethyl} -1, 3-dihydro-1-methyl-2H-benzimidazol-2-one with t. square   WITH.  Similarly, 5- (difvnylmethyl) -1-piperazinylmethyl -1-ethyl-1 is obtained. 3-dihydro-2H-benzimidazol-2-one with t. square  239. 8 ° C.  Example 19  A mixture of 5 wt. h  - - {diphenylmethyl) -1-piperazinylme IN -propyl-1,2-benzenediamine, 35 weight. h  1,1, 1 - methylidedentris- (oxy) -trisethane and 1.5 wt. h  acetic acid is stirred at a reflux temperature for 2 hours  The reaction mixture is cooled and evaporated.  The residue is washed off 100 weight. h  water and add 10 n. hydrochloric acid solution before. complete dissolution of the substance.  The solution is treated with activated carbon and filtered.  The filtrate is alkalinized with sodium hydroxide solution.  The product is extracted with dichloromethane.  The extract is dried, filtered and evaporated.  The residue is purified by chromatography on a column of silica gel and eluted with a mixture of trichloromethane and methanol (95: 3 by volume).  Pure fractions are collected.  The eluent is evaporated.  The residue is crystallized from -methyl-2-pentanone.  The product is filtered off, washed with a small amount of 4-methyl-2-pentanone and 2,2-oxybis-propane and dried.  Get 2.2 weight. h  5 (diphenylmethyl) -1 -piperazinylmethyl -1-propyl-1H-benzimidazole with t. square  five,.  Example 20  Analogously to Example 19, using equivalent coliarest (diarylmethyl) -1-piperazinylmethyl-1, 2-benzenediamine instead of (diphenylmethyl) -1-piperazinylmethyl-H-propyl-1, 2-benzenediamine, is obtained as the free base or in the hydrochloride form after treatment of the base with hydrochloric acid in a mixture of ethanol and 2-propanol, the compounds shown in table.  k, Example 21.  Similarly to Example 19, (diphenylmethyl) -1-piperazinylmethyl -1- (2-methoxyistil) -1H-benzimidazole is obtained with m. square  1b1,7 ° C at interaction of k- ik- (diphenylmethyl) -1.  -piperazinylmethyl-H- (2-methoxyethyl -1,2-benzenediamine with trimethoxymethane.  Example 22  Mixture, 6 wt. h  , - {diphenylmethyl) - -piperazinylmethyl 1 -N -methyl, l-1, 2-benzenediamine,.  1, A8 weight. h, ethylethanimidate hydrochloride and 80 wt. four.  The 2-propanol is gently heated until the solid is completely dissolved.  Stir first for 1 hour at room temperature, flow for 3 hours at reflux temperature.  The reaction mixture is cooled to room temperature and filtered.  The filtrate is evaporated. .  The residue is washed with water and a solution of hydrochloric acid is added until complete dissolution of the solid, parts 14.  The solution is treated with activated carbon-m and filtered.  The filtrate is alkalinized with 60% solution of units. whom rub.  The product is extracted with dichloromethane.  The extract is washed with a jelly, dried, filtered and evaporated. The residue is purified by chromatography on a column of silica gel and eluted with a mixture of trichloromethane, methanol and ammonium hydroxide (97: 2: 1 by volume).  Pure fractions are collected. Eluent issue. ryvaet.  The residue is crystallized from 2-propanol.  The product is filtered off.  washed with 2-propanol and 2,2-oxybispropane and dried in vacuo at 80 ° C for a day off.  Get 2.3 weight. m  (Diphenylmethyl) -1-piperazinylmethyl -, 2-dimethyl-1H-benzimidazole with m. square  206 ,.  .  Similarly, 5-C “- (diphenyl azinylmethyl-α-methylmethyl) -1-piperazinylmethyl -2-feiyl-1H-benzimidazole is obtained with m. . square  189. 6C.  Example 23  A mixture of 4.8 weight. h  (diphenylmethyl) -1-piperaaininylmethylJ-M-ethyl-1,2-benzenediamine and 25 wt. h  Acetic acid is stirred at room temperature until all solids are completely dissolved.  add 1.73 wt. h  ethyl ethanimidate hydrochloride and stirred for 1 hour at room temperature, then 1 hour at reflux temperature.  The reaction mixture is evaporated.  The residue is stirred in water.  The mixture is alkalinized with sodium hydroxide solution.  The product is extracted with dichloromethane.  The extract is dried, filtered and evaporated.  The residue is purified by chromatography on a column of silica gel and eluted with a mixture of trichloromethane and methanol (98: 2 by volume).  Pure fractions are collected, the eluent is evaporated.  The residue is crystallized from -methyl-2-pentanone.  The product is filtered off. they are put and dried.  Get 2.7 weight. h  (Diphenylmethyl) -: -1-piperazinylmethyl - - ethyl-2-methyl-1H-benzimidazole with m. square  152.9 ° C.  Example 24  Analogously to Example 23, using equivalent amounts of the corresponding starting materials, the compounds j presented in Table 2 are obtained as a free base or as an acid addition salt after treating the free base with an appropriate acid.  five.  PRI me R 25.  Analogously to Example 23, using equivalent amounts of the corresponding starting materials, the compounds shown in Table 2 are obtained.  6  Example 26  A mixture of 5.6.  3- {2-amine-4-C4- (diphenylmethyl) -1-pipa razinylmethyl 3 Phenyl-amine-1-propanol, 2.8 wt. h  ethylbenzenecarboximidate hydrochloride and 50 wt. h  Acetic acid is stirred overnight at room temperature, then for 1 hour at the temperature of reverse distillation.  The solvent is distilled off in vacuo.  The residue is stirred in water.  The mixture is alkalinized with ammonium hydroxide.  The product is extracted with trichloromethane.  The extract is dried and evaporated.  The residue is purified on a chromatographic column with silica gel and elkziruyut mixture of trichloromethane and methanol (98: 2,.  About volume).  Fractions with the highest Rj are collected.  The eluent is distilled off.  The residue is crystallized from 35 wt. h  2,2-oxybispropane.  The product is filtered off and dried.  Get 1.8 weight. h  (2.8%) / 3- {5- - (diphenylmethyl) -1 -piperazinylethyl -2-phenyl-1H-benzimidazol-1. Gil J-propyl / -acetate with m. square  111.5 ° C.  Similarly receive / 3 {5 C Tdienylmethyl) -1-piperazinylmethyl -2-, -methyl-1H-benzimidazol-1-yl3-propyl / -acetate with t.  square  12b, in the interaction of 3-12-amine - + - 2- (diphenylmethyl) -1-piperazinylmethyl-phenyl 3 -amine-1-propanol with ethyl ethene imidate hydrochloride, and also 1-butyl-GZ-G - (diphenylmethyl) - - piperazinylmethyl-1H-ben imidazol-2-ylmethyl 3-acetate with t.  square  151.2 ° C in the reaction of N-butyl-p-C- (diphenylmethyl) -1-piperazinylme, 2-benzenediamine with ethyl 2-hydroxyethanimidate hydrochloride.  Example 27  A mixture of 3.9 wt. h  t (diphenylmethyl) -1 -piperazinylmethyl JN-methyl-1, 2-benzenediamine, 2.5 weight. h  t-chlorobenzaldehyde and 18 wt. h  The nitrobenzene is stirred in an oil bath, first for 1 hour and then for 1.5 hours at -120 ° C.  The reaction mixture is cooled and settled overnight at room temperature.  Add about 100 wt. h  water and the mixture is acidified with 10 n. hydrochloric acid solution.  The product is extracted with 2,2-oxybispropane.  The aqueous phase is treated. activated carbon and filtered.  The filtrate is alkalinized with 50% sodium hydroxide solution. The product is extracted with dichloromethane.  The extract is washed with water, dried, filtered, and evaporated.  The balance of Cree steel is from 35 wt. h  1, T-oxybis ethane.  The product is filtered, pro. washed with 1,1-oxybisethane and dried.  Get 1.3 weight. h  2- C-chlorophenyl) -5- (diphenylmethyl) -1 -piperazinylmethyl J-1-methyl-1H-benzimidazole with t. square  198.3C.  P r and m e p 28.  Analogously to Example 27, the following compounds are prepared: 2- (2-Chlorophenyl) -3-C - (diphenylmethyl) -1-piperazinylmethyl J-1-methyl-1H-benzimidazole with m.  square  216.6 C; 2- (3-chlorophenyl) (diphenylmethyl) -1-piperazinylmethylJ-1-methyl-1H-benzimidazole st.  square  CE, 5-C2- (diphenylmethyl) -1-piperazinyl methyl -1-methyl-2- (2-methylphenyl) -1H-benzimidazole with t.  square  200.2 ° C; nzimidazole with t.  square  iSUU, /: - L; 5 - i (diphenylmethyl) -1-piperazini methyl - - methyl-2- (4-pyridinyl) -1H-benzimidazole with t. square  149.6 ° C; (diphenylmethyl) - - piperazinylmethyl -2- (2-furanyl) -1-methyl-1H-benzimidazole hemihydrate with t. square  185.8 ° C.  PRI me R 29.  A mixture of k, OS weight. h 1 - (C-fluorophenyl) -phenylmethyl-piper 9 7 zine, 3.9 weight. h  5 (chloromethyl) -2-methyl-1-propyl-1H-benzimidazole, 8 wt. h  carbonate and weight. h  N, N-dimethylformamide is stirred for 3 hours at SO-S. C.  Y, M-dimethylformamide is distilled off and 100 weight% is added. . h  water.  The product is extracted twice with methylbenzene.  The combined extracts are dried, filtered and evaporated.  The residue is converted to the hydrochloride salt of b 2-propanol.  The salt is filtered off and the free base is isolated with an aqueous solution of ammonium hydroxide.  The product is extracted twice with dichloromethane.  The combined extracts are dried, filtered and evaporated.  The residue is crystallized from 2,2-oxibispropane at room temperature.  Receive after drying -, 4.8 weight. h  {5-4- {t-fluorophenyl) -phenylmethyl 3-1 -piperazinylmethyl} -2-methyl-1-propyl-1H-benzimidazole with t. square  105.1 ° C.  PRI me R 30.  Analogously to Example 29, using equivalent amounts of the corresponding starting materials, the compounds are obtained as a free base or as an acid addition salt after treating the free base with an appropriate acid (Table 1).  7).  Example 31  To a stirred solution containing weight. h  caustic soda and 50 wt. h  water, add k, 7 wt. h  methyl- {5- t- (diphenylmethyl) -1-piperazinylmethyl -1-methyl-1H-benzimidazol-2-yl3-carbamate.  The mixture was stirred at reflux for 3.5 hours.  The reaction mixture is cooled, settled in; overnight and acidified with 10N. hydrochloric acid solution.  The precipitated product is filtered, washed with water and boiled in ethanol.  After cooling, the product is filtered off, washed with ethanol and 2,2-oxybispropane and dried.  Get 2.5 weight. h  5- (diphenylmethyl} -1-piperazinylmethyl -1-methyl-1H-benzimidazol-2-amine with m. square  2b7. Similarly, 5- {4-1 (-fluorophenyl) -phenylmethyl -1-piperazinyl-1-methyl-1H-benzimidazol-2-amine is obtained with t. square  235, and (4-fluorophenylmethyl) 3- piperazinylmethyl} - -methyl-1H "benzimidazol-2-amine as a residue.  Example 32  Mix i, weight. h   (Diphenylmethyl) - -piperazinylmethyl -1-these l-1H-benzimide ash, 1.2 wt. h  sodium amide and 20 wt. h  N, N -dimethylbenzeneamine mixed and slowly heated to 135 ° C.  Stir at 135 ° C for 3 h.  The reaction mixture is cooled and poured into water.  The product is extracted with trichloromethane.  The extract is dried, filtered and evaporated.  The residue is purified by chromatography on a column of silica gel, eluted with trichloromethane and methanol (95: 5 by volume) and a small amount of ammonium hydroxide.  The fist fractions are collected.  The eluent is evaporated.  The residue is crystallized from methylbenzene.  The product is filtered and dried.  Get 1.5 weight. h  5 (diphenylmethyl) -1-piperazinylmethyl3-1-ethyl-1H-benzimidazol-2-amine with m. square  21L, 3 ° C.  Example 33  To a stirred mixture of 4.1 wt. h  5-C - (diphenylmethyl) - -piperazinylmethyl-methyl-1H-benzimidazol-2-amine and 25 wt. h  pyridine, 0.79 wt. h  acetylchloride when cooled to 0-5 ° C.  Stirred 1. h at 80 ° C.  The reaction mixture is cooled to room temperature, poured into ice-cold water and alkalinized with ammonium hydroxide.  The product is extracted with methyl benzene.  The extract is washed with water, dried, filtered and evaporated.  The residue is chromatographed on a silica gel column, eluting with a mixture of trichloromethane and methanol (95: 5 by volume).  Pure fractions are collected.  The eluent is evaporated.  The residue is crystallized from 2-propanol.  The product is filtered, washed with 2-prPanol and 2,2-hydroxy-bispropane and dried.  Get 3 weight. N- {5- - (Diphenylmethyl) -1-piperazinylmethyl 1-1-methyl-1H-benzimidazol-2-yl-acetamide. with t. square  202.5 ° C.  The following compounds are prepared analogously: M 5-; G4- (diphenylmethyl) -1-piperazinylmethyl-α-ethyl-1H-benzimidazol-2-yl-acetamide with m. square  125 7 ° C; N-fSt - (fluorophenyl) -phenylmethyl-1-piperazinylmethyl 3-1 methyl-1H-benzimy dazol-2-yl} -acetamide with m. square   N / 5- {-bis- (fluorophenyl) -methyl} -1-piperazinylmethyl - -methyl-1H-benzimidazol-2-yl / -acetamide with t. square  198 ,.  Example 3f.  A mixture of 1.9 wt. h  (Diphenylmethyl) -1-piperazinylmethyl -1-methyl-1H-benzimidazole-2-methanol, 1.55 wt. h  acetic anhydride and k5 weight. h  methylbenzene is stirred during the reverse distillation for 2 hours  The reaction mixture is cooled and washed with a dilute ammonium hydroxide solution.  Salts are separated.  The organic phase is dried, filtered and evaporated.  The residue is crystallized from a mixture of methylbenzene and 2,2-oxybispropane (20:20 by volume).  The product is filtered and dried.  Get 1.5.  weight. h  , (7,) 5-G | - (diphenylmethyl) -1-piperazinylmethyl 1-methyl-1 H-. benzimidazol-2-ylmethyl 3-acetate with t. square  201.1 ° C.  Example 35  Similarly to Example 3, the following acetates are obtained from the corresponding alcohols: {5- - (diphenylmethyl) -1-piperazinylmethyl 1-ethyl-1H-benzimidazol-2-ylmethyl-acetate with m. square  159С; (Diphenylmethyl) -1-piperazinylmethyl -1-propyl-1H-benzimidazol-2-ylmethyl-acetate with t. square  138, {5- (diphenylmethyl) -1-piperazinylmethyl - - (1-methylethyl) -1H-benzimidazol-2-ylmethyl-acetate with t. square  , (diphenylmethyl) - -piperazinylmethyl (2-methylpropyl) -H-benzimidazol-2-ylmethyl-acetote with t. square  238.9 ° C (decomp. ); (Diphenylmethyl) - -piperazinylmethyl - -pentyl-H-benzimidazol-2-ylmethyl} -acetate with t.  square  , t 153, 2 “C; (Diphenylmethyl) - -piperazinylmethyl - -hexyl-H-benzimidazol-2-ylmethyl-acetate with t. square  , 7 ° С; {-cyclopropyl-5-Ct- (diphenylmethyl) - -piperazylmethyl - H-benzimidazol-2-ylmethyl1-acetate with t.  square  , {-cyclopentyl-5- - (diphenylmethyl) -1-piperazinylmethyl -1H-benzimidazole 2-ylmethyl-acetate with t. square  190,2193, / 2- (5- - (diphenylmethyl) -1-piperazinylmethyl g1H-benzimidazol-1-yl-ethyl acetate with t. square  152.2 ° C; / (diphenylmethyl) -1-piperazinylmethyl -2-methyl-1H-benzimidazol-1-yl3-ethyl / -acetate with t. square  158 С; (2- {5- (diphenylmethyl) -piperidonyl) methyl -2-phenyl-N-benzimidazol-1-yl-ethyl / -acetate with m. square  ; 3 ° C; I (acetyloxymethyl) (diphenylmethyl) -1-piperazinylmethyl -1H-benzimidazol-yl-3-propyl / -acetate t. square  00.8C. , Example 36.  To the stirred mixture, cocto ly from 8,8 weight. h  (diphenylmethyl) -1-piperazinylmethyl) -1H-benzimidazol-2-ylmethyl-benzoate and 120 wt. h  methanol, 13.5 wt. h, boron sodium hydroxide solution.  The mixture was stirred at reflux for 30 minutes.  The reaction mixture is evaporated.  The residue is stirred in water.  The product is extracted with dichloromethane.  The extract is dried, filtered and evaporated.  The residue is purified on a chromatographic column with silica gel and eluted with a mixture of trichloromethane and methanol (90:10 by volume).  Pure fractions are collected.  Eluent you. soar.  The residue is crystallized from tS weight. h  . methylbenzene.  The product is filtered, washed with 2,2-hydroxy.  . Bispropane and dried.  Get i weight. h  (57%) (diphenylmethyl) -1-piperazinylmethyl -1 H-benzimidazol-2-methanol, with t. square  137L S.   For example, p 37.  A mixture of 4.1 weight.  h  S-Lt- (diphenylmethyl) -1-piperazinylmethyl 3-1 -methyl-1H-benzimidazol-2-amine 1 weight. h  1-isocyanatobutane and jl80 weight.  h  The tetra hydrofur is stirred at reflux temperature during the day off.  After cooling to room temperature, the reaction mixture is filtered.  The filtrate is evaporated.  The residue is purified by chromatography on a column of silica gel and eluted.  a mixture of trichloromethane and methanol (95: 5 by volume).  Pure fractions are collected. . The eluent is evaporated. The residue is crystallized from ethanol.  The product is filtered, washed with ethanol and 2,2-oxybispropane and dried.  Get 3, weight. h  (66.7%) N-butyl-H- (diphenylmethyl) -1-pylerasinylmethyl -1-methyl-1H-benzimidazol2-yl 5-urea, with t. square  195.8 p.  Similarly, N-butyl-L- {5-1 - (diphenylmethyl) -1-piperazinylmethyl -1-ethyl-1H-benzimidazol-2-yl} -urea1 is obtained; square  186.4 ° C.  PRI me R 38.  To the stirred solution containing 4 wt. h (diphenylmethyl) -1-piperazinylmethyl -2-methyl-1H-benzimidazol-1-ethanol and 25 wt. h  pyridine, add 1.3 wt. h  methansul fonylchloride.  Stir for 1 h at room temperature.  Pyridine is distilled off and 250 wt. h  water.  The product is extracted three times with methyl benzene.  The combined extracts are dried, filtered and evaporated.  The residue is stirred in a small amount of 2,2-oxybispropane.  The solid is filtered off and dried.  Get it.  4, if weight. h  (8k, kl} / 2- (5-14- (diphenylmethyl) -1-piperazinylmethyl 3-2-methyl-1H-benzimidazol-1-ylZ-ethyl / methanesulfonate with t. square  162,  Example 39  Mixable mixture consisting of 5.03 wt. h  (Diphenylmethyl) - -piperazinylmethyl -2-phenyl-1H-benzimidazole-1-ethanol and. 75 weight. h  trichloromethan, acidified with gaseous hydrogen chloride.  Then, 2.4 wt. h  tyonyl chloride at room temperature.  Stir for 20 minutes at the reflux temperature.  The reaction mixture is evaporated.  100 wt. h  water.  The mixture is alkalinized with sodium bicarbonate.  The product is extracted with dichloromethane.  The extract is washed with WATER, dried, filtered and evaporated.  The remainder. it is purified by chromatography on a column of silica gel and is eluted with a mixture of trichloromethane and methiol (95: 5 by volume).  Frequent fractions are collected.  The eluent is evaporated.  The residue is crystallized from methylbenzene.  The product is filtered and dried. Get 3.1 weight. h  1- (2-chloro-ethyl-5-L4- (diphenylmethyl) -1-piperazinylmethyl -2-phenyl-1H-benzimidazole with m. square  173.3179, 6 ° C.  Similarly, 1- (2-chloroethyl) (dipheylmethyl) -1-piperazinylmethyl-1H-benzimidazole is obtained with t. square  20b, 3C.  Example40.  To a stirred solution containing 0.127 wt. h  sodium and 20 wt. h  methanol, add; 0.6T weight. h  benzylthiol.  The mixture is stirred for several minutes.  The methanol is distilled off.  The residue is washed off 18.  ve h  methylbenzene and the latter are again distilled.  The residue is dissolved in 22.5 wt. h  N, N-dimethylformamide and 2.6 wt. h  (2- {5-t4- (diphenylmethyl) -I-piperazinylmethyl -2-methyl-1H-benzimidazol-1-yl-ethyl / -methanesulfonate.  The reaction mixture is stirred at room temperature for 30 minutes.  Y, M-Dimethylformamide is distilled off.  100 wt. h  water.  The product is extracted twice with dichloromethane.  The combined extracts are dried, filtered and evaporated.  The residue is crystallized from 2-propanol.  The product is filtered and dried.  Get 2.4 weight. h  (90, U) 5-. 4-tflMphenylmethyl) -1-piperazinylmethyl -2.  , 239 -methyl-bf2- (phenylthio) -ethylJ-1H-6enzi midazole with t. pl, 170.3 ° C.  Similarly, (diphenyl methyl) -1-piperazinylmethyl 3-2-phenyl-1 (phenylthio) ethyl 1 H-benzimidazole is obtained with m. square  118-125С in the interaction of 1- (2-chloroethyl) (diphenylmethyl) -1-piperazinylmethyl -2-phenyl-1H-benzim azole with benzenethiol, and also (diphenylmethyl) -1-piperazinylmethyl (phenylthio) -ethyl J-1H-benzimidazo with t. mp, 172 ° C in the interaction of 1- (2-chloroethyl) (diphenylmethyl) -1 -piperazinylmethyl - H-benzimidazole with benzenethiol.  Example 1 K2 weight h  a solution containing 2 wt. h  thiophene and 0 wt. h  ethanol, plus lot 9 wt. h trichlorohydrate 51-chloro-2- 4- (diphenyl methyl) -1-pip8razinyl ethyl 3-ethyl-2-methyl-1H-benzimidazole and weight. h  methanol.  The mixture is hydrogenated at normal pressure and room temperature, weight. h  10% palladium carbon as a catalyst.  After uptake of the calculated amount of hydrogen, the catalyst is filtered off.  The filtrate is evaporated.  The residue is washed off 100 weight. h  water.  The mixture is alkalinized with ammonium hydroxide.  The product is extracted twice with dichloromethane.  The combined extracts are dried, filtered and evaporated.  The residue is purified by chromatography on a column of silica gel and eluted with a mixture of trichloromethane and methanol (95: 5.  by volume).  Pure fractions are collected.  The eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered and dried.  Half 7 is 2, t is weight. h  (35.5) monohydrate (diphenylmethyl) - -piperazinylethyl -1-ethyl-2-methyl-1H-benzimidazole with t. square  95-105 ° C.  The following compounds are prepared analogously: (diphenylmethyl) -1-piperazinyl ethyl -2-methyl-1-propyl-1H-benzimidazole with m. square  115.6 ° C; (diphenylmethyl) -1-piperazinyl ethyl 3-2-ethyl-1-propyl-1H-benzimidazole trichlorohydrate with t. square  2b1.2s; trichlorohydrate (diphenylmethyl -1-piperazinylethyl -1,. 2-dipropyl-1 H-benzimidazole with t. square  250-255s  Example 42  To mix a mixture of 5.03 weight. h  5-t- (diphenylmethyl) - -piperazinylmethyl1-2-phenyl-1H-benzimidazol-β-ethanol and 50 wt. h  pyridine is added dropwise 3 wt. h  benzoyl chloride at room temperature.  Stir at room temperature for 2 hours.  The reaction mixture is evaporated. Water is added to the residue.  The product is extracted with dichloromethane.  The extract is washed with water, dried, filtered and evaporated.  The residue is crystallized from 20 wt. h  2-propanol.  The product is filtered off, washed with 2-propanol and 2,2-oxybispropane and dried.  Get 4 weight. h . (66.5%) / 2- (diphenylmethyl) -1-piperazinylmethyl 3-2-phenyl-1H-benzimidazol-1-yl-ethyl / -benzoate with t. square  64, p.  Similarly, 2-propanolate / 2- {5-4 (diphenylmethyl) - -piperazinylmethyl - H-benzimidazol- -yl-ethyl-benzoate (2 :) s t. square  21t, 6 ° C.  Table 1
    25
    26
    986297 Continuation of the table. one
    27
    98629728
    Continued table. 2
    CH (CH3) 2
    -but
    sn.
    SbH5 CHj
    Also
    sn2-o-s (
     clH-i / V- dHp
    SbN5SbN5SNz
    The sameC-jHs
    205 215 228
    Table i
    179
    Foundation I6i, 3 Same
    29
    986297
    30 Continued table. f
     SnAr
    CH2-CH2-CH20N
    SbH5
    Same CH-CHjOH
    - -. Also
     II and
     II - II
     II
     II
     II С H5GHj-CHgQH
    The same CHg-CHj-CHg
    - -CHjCH OH
    - -CHj-CHjj-CHjOH -F-C H4 CHj
    H4
    -To sameTo
     zhe- ii -
     II II
     and CHj-CHj-O-CH
    - i -.
    CHj-CHj-CH
    CH (SNE) 2
    Also
    (CH,) s-CH3 and
    CH2-CH (CH3) 2
     II
    (CH2) 4-CH3 II
    191.2 1b1., 9 166.8
    H 171.6 Y2.8
    177I
    206
    210.7
    137.5
    153.8
    183
    166.3
    157.6
    187.7
    150.8 5 H
    202
    187 4
    1J2,3
    ,eight
    ,
    150.8
    182,6
    121 2-122.8
    39
    kO
    986297 Continuation of the table, 6
    D
    n
    sc;
    Yu (D H
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives
    5- (4-diarylmethyl) -1-piperazinylal formulas where Ar 1 and Ar 2
    Ra - phenyl, halogen substituted phenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, thienyl and pyridyl dinil 15 - hydrogen, lower alkyl, aryl (lower alkyl), lower hydroxyalkyl, aryl TSIKLO8LKIL OR r0, amino, (lower alkyl ) -carbonylamine- (lower alkyl), carbonyloxy- (lower
    Ra alkyl), aryloxy- (lower alkyl), (lower alkyl) -oxycarbonyl * amine or (lower alkyl) -oxycarbonyl- (lower alkyl);
    Ra is hydrogen, lower alkyl, aryl- (lower alkyl), lower hydroxyalkyl, cycloalkyl (lower alkyl) -oxy- (lower alkyl). ' or their salts, characterized in that the compounds of General formula (II)
    Lg 1 - en-ΐθτ.Αχ 2
    Ra where Ar 1 , Ar 2 and Ra have the indicated 3 meanings, are cyclized with a compound of the general formula
    D = C-Ra 1
    I 3
    E where Ra 'has the indicated meanings;
    D is 0 or .NH;
    E is OH, 0- (lower alkyl) or NH 2 , or D and E together are N, provided that if D is NH, then E is 0- (lower alkyl); if Ra 'is hydrogen, then D is 0, and E OH;
    if Ra 'is an amino group, then D and E together are 1 ;
    if Ra 1 - (lower alkyl) -carbonylamine- (lower alkyl), carbonyloxy- (lower alkyl), aryl- (lower alkyl), (lower alkyl) -oxycarbonylamine or (lower alkyl) -oxycarbonyl- (lower alkyl), then 0 is NH, and E is 0- (lower alkyl), <
    in the environment of an appropriate solvent with the release of the target product.
    . VNIIIPI Order 10194/79
    Featured Priority
    03/30/77 · When Ar 1 and Ar 2 - phenyl, halogen, substituted phenyl, nitrophenyl and pyridinyl;
    Ra 'is hydrogen, lower alkyl, phenyl- (lower alkyl), lower hydroxyalkyl, cycloalkyl or aryl, amino group, (lower alkyl) -carbonylamine- (lower. Alkyl), (lower alkyl) -oxycarbonylamine or (lower alkyl) -oxycarbonyl - (lower alkyl);
    Ra ‘- hydrogen, lower alkyl, phenyl- (lower alkyl), lower hydroxyalkyl, cycloalkyl.
    01/04/78. When Ag 4 and Ag 2 - lower alkyl phenyl, lower alkoxyphenyl, thienyl;
    Ra is aryl- (lower alkyl), (lower alkyl) -oxy- (lower alkyl);
    Ra 1 is aryl- (lower alkyl), carbonyl oxy- (lower alkyl), aryloxy- (lower alkyl), (lower alkyl) -oxycarbonylamino or (lower alkyl) -oxycarbonyl- (lower alkyl).
    The remaining values of the radicals relate to conventional priority 1 of 03.30.77.
    Circulation 445 Subscription branch PPP Patent, Uzhhorod, st. Project, 4
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    同族专利:
    公开号 | 公开日
    HU180477B|1983-03-28|
    PT67855B|1980-03-04|
    IT7848628D0|1978-03-28|
    FR2385713A1|1978-10-27|
    IL54373A|1982-03-31|
    SE7803057L|1978-10-01|
    IE780608L|1978-09-30|
    GB1598278A|1981-09-16|
    GR66124B|1981-01-16|
    PT67855A|1978-04-01|
    AT368136B|1982-09-10|
    AU3431378A|1979-09-27|
    IL54373D0|1978-06-15|
    CA1119597A|1982-03-09|
    NL7803312A|1978-10-03|
    AU517661B2|1981-08-20|
    NZ186836A|1981-03-16|
    ATA220978A|1982-01-15|
    DE2813523A1|1978-10-05|
    PL118310B1|1981-09-30|
    ES468077A1|1979-09-01|
    PH16204A|1983-08-02|
    FI780954A|1978-10-01|
    NO781078L|1978-10-03|
    US4179505A|1979-12-18|
    IE46507B1|1983-06-29|
    DK135878A|1978-10-01|
    IT1103464B|1985-10-14|
    FR2385713B1|1983-12-23|
    PL205650A1|1979-04-09|
    JPS53141287A|1978-12-08|
    JPS6339591B2|1988-08-05|
    LU79326A1|1978-06-29|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US78265177A| true| 1977-03-30|1977-03-30|
    US05/866,882|US4179505A|1977-03-30|1978-01-04|5-[4--1-piperazinylalkyl]benzimidazole derivatives|
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