Method for preparation of 1=alkyl-substituted senzimidazole derivatives

专利摘要:
Novel 1-alkyl substituted benzimidazole derivatives of formula wherein    -A¹=A²-A³=A⁴- is a bivalent radical having the formula -CH=CH-CH=CH- (a-1), -N=CH-CH=CH- (a-2), -CH=N-CH=CH- (a-3), -CH=CH-N=CH- (a-4), -CH=CH-CH=N- (a-5), -N=CH-N=CH- (a-6), or -CH=N-CH=N- (a-7);    B is NR³, CH₂, O, S, SO or SO₂;    L is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆alkyloxycarbonyl, Ar²-C₁₋₆alkyloxycarbonyl, Ar²-carbonyl, Ar²-sulfonyl, C₃₋₆cycloalkyl, C₂₋₆alkenyl optionally substituted with Ar², C₁₋₁₂alkyl, a radical of formula -Alk-R⁴ (b-1), -Alk-Y-R⁵ (b-2), -Alk-Z¹-C(X)-Z²-R⁶ (b-3), or -CH₂-CHOH-CH₂-O-R⁷ (b-4);the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, which compounds are anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1637663A3
申请号:SU884355374
申请日:1988-03-05
公开日:1991-03-23
发明作者:Эдуард Жанссенс Франс；Станислас Марселла Дил Гастон；Лео Гисланус Торреманс Жозеф；Мария Саммен Франсуа
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

provided that L H, C (-C4.1 Lkyl, benzyl and IU-G-Alk C-CL-alkyloxyethyl, then the group: Ј-CH CH-CH CH-with antihistamine action and, in comparison with the known , more active and less toxic 7 scoreboards
This invention relates to a process for the preparation of 1-alkyl-substituted benzimidazoles with beneficial pharmacological properties.
The purpose of the invention is the synthesis of new compounds in their activity superior to astemizole, which has the same type of activity.
A „Preparation of intermediate compounds.
Example 1. 2350 parts of hydrogen chloride are bubbled after 5600 hours of chilled ethanol (ice bath) at 10 ° C. Then, 1- (phenylmethyl) -4-piperidine acetonitrile is added dropwise over a 45-minute period of time 1500 hours. Upon completion, the contents are stirred for 20 hours at room temperature. The reaction mixture is evaporated and the residue is stirred at 2400 hours of acetonitrile. The reaction product is filtered off, washed with 560 h, acetonitrile and dried, yielding 2000 parts (85.7%) of O-ethyl-1- (phenylmethyl) -4-piperidineethanimidate dihydrochloride (compound 1P).
Example 2
a) A mixture of 46 parts of hexahydro-4-oxo-1H-azepin-1-carboxylic acid ethyl ester, 26 parts of benzylamine,
2 parts of a 4% solution of thiophene in methanol and 400 parts of methanol are hydrogenated at normal pressure and at room temperature with 4 parts of a 10% catalyst of palladium on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, obtaining 69.1 h of (100%) ethyl ester of hexahydro-4- (phenyl methyl) -amino 1-1H-azepine-1-carboxylic acid as a residue (compound 2P).
b) 69.1 parts of hexahydro-4-Kphenylmethyl) -amino -1H-azepine-1-carboxylic acid ethyl ester are hydrogenated in the presence of 4% solution of thiophene in methanol and methanol at normal pressure and at room temperature with 4 h with a 10% catalyst palladium on charcoal. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, yielding 46.9 parts (100%) of 4-aminohexahydro-1H-azepine-1-carboxylic acid ethyl ester as a residue (compound ZP).
c) To a stirred and cooled () mixture of 63 parts of carbon disulfide,
52.1h N, M-methane-tetrayl bis (cyclohexanamine) and 360 parts of tetrahydrofuran are added dropwise, 46.9 parts of 4-aminohexahydro-1H-azepine-1-carboxylic acid ethyl ester. After the addition is complete, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the residue is stirred in diisopropyl ether. The precipitate is filtered off and the filtrate is evaporated, yielding 70.75 parts (100%) of hexahydro-4-isothiocyanato-1H-azepine-1-carboxylic acid ethyl ester as a residue (compound 4P).
Example 3. To a stirred and cooled mixture of 4 parts of sodium hydroxide, in 60 hours of water, 7.9 parts of carbon disulfide are successively added.
17.2h ethyl ester of 4-amino-1-piperidinecarboxylic acid at a temperature below 10 ° C. Stirring is continued for 30 minutes at this temperature. Then 10.9 parts of ethyl chlorotic acid ester are added dropwise to the mixture (exothermic reaction: the temperature rises to about 35 ° C). After the completion of the addition, stirring is continued for 2 hours at 60 ° C. The reaction mixture is cooled and the reaction product is extracted with toluene. The extract is dried, filtered and evaporated, yielding 22 parts (10%) of 4-isothiocyanato-1-piperidinecarboxylic acid ethyl ester as a residue (compound 5P),
Similarly, also receive: 4-isothiocyanato-1- (phenylmethyl) -piperidine as a residue (compound 6P)
3-isothiocyanato-1-pyrrolidinecarboxylic acid ethyl ester as a residue (compound 7Г1).
PRI me R 4.
a) A mixture of 19 parts of 2-chloro-3-nitropyridine, 13.5 parts of 2-ethoxyethanamine, 13 hours of sodium hydrogen carbonate and 240 parts of ethanol is stirred for 6 hours at reflux temperature. After cooling, the mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 25.5 h.
(100%) M- (2-ethoxyethyl) -3-nitro-2-pyridinamine as a residue (compound 8P).
b) A mixture of 25.5 hours, M- (2-ethoxyethyl) -3-nitro-2-pyridine amide, 2 parts of a 4% solution of thiophene in methanol and 200 parts of methanol is hydrogenated at normal pressure and at 50 ° C using 3 hours
10% catalyst palladium on charcoal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 25 parts (100%) of (2-ethoxyethyl) -2,3-pyridinediamine as a residue (compound 9P).
c) A mixture of 25 hours, K (2-ethoxyethyl) - 2,3-pyridinediamine, 43 parts of 4-isothiocyanato-1-piperidine-carboxylic acid ethyl ester and 450 parts of tetrahydrofuran are stirred overnight at reflux temperature. a fridge. The reaction mixture is evaporated and the residue is treated with trichloromethane. The organic layer is washed twice with water, dried, filtered and evaporated. The residue is crystallized from a mixture of acetonitrile and diisopropyl ether. The reaction product is filtered and dried, yielding 35 hr (73.7%) of ethyl ether.
4- 2-E2-ethoxyethyl) -amino3 3-pi10
15
the furan is stirred and refluxed for 2 hours. The contents are evaporated to give 44 hours {100%) M- (2-amino-5-methoxyphenyl) - N - (1-methyl-4-piperidinyl) -thiourea - as residue (compound 26P).
b) A mixture of 44 parts of K- (2-amino-5-methoxyphenyl) -Y (- (1-methyl-4-piperidinyl) -thiourea, 38.9 parts of mercury (II) oxide and 270 parts of tetrahydrofuran stir and reflux for 2 hours at reflux temperature. The reaction mixture is filtered hot over diatomaceous earth and the filtrate is evaporated. The residue is purified by column chromatography over silica gel, first using a mixture of trichloromethane and methanol ( 95: 5 by volume), and then a mixture of trichloromethane and methanol saturated with ammonia (85:15 by volume), as A pure fraction was collected and the eluent was evaporated, yielding 50.5 parts (100%) of 5-MeTOKCH-N- (1-methyl-4-piperidinyl) -1H benzimidazole-2-amine as a residue (compound 27P).
In a similar way receive also
3Q 5,6-dimethoxy-L- (1-methyl-4-piperidinyl) -1 Y-benzimidazop-2-amine (compound 28P).
EXAMPLE 6, Mixture 32 parts of 1-chloro-2-ethoxyethane, 94.5 parts of K- (4-piperidinyl) -1H-benzimidazole-220 dibromhydrate
35
amine, 90 parts sodium carbonate and 540 hours.
The M, N-dimethylacetamide is stirred at 70 ° J overnight. After cooling, the reaction mixture is poured into bo-. do The reaction product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is boiled in acetonitrile. After cooling, the precipitated product of the reaction, ridinyl-amino-thiooxomesh1-amino-3-, is filtered off and dried, yielding 1-piperidinecarboxylic acid as 42.4 parts (58.8%) of N- (1- (2-ethoxyethyl) 4-piperidinyl -1H-benzimidazole-2-amino; TLL) 212 ° C (compound 29P).
Example 7o A mixture of 36.6 parts of M- (4-piperidinyl) -1H-benzimidazol-2-amine di-bromohydrate, 10 parts of poly- (oxymethylene), 2 parts of a 4% thiophene solution in methanol, 200 hours of methanol and 20 hours of potassium hydroxide are hydrogenated at normal pressure and at room
residue (compound 10P).
The compounds listed in Table 1 are also prepared in a similar manner.
In addition, (diethylamino) ethyl ethyl-amino-3-pyridinyl-amino-thiooxo-methyl D-amino -1-piperidinecarboxylic acid ethyl ester is obtained as a residue (compound 24P).
Example 5
a) A mixture of 37.5 parts of 4-isothiocyanato-, 1-methylpiperidine, 21.8 parts of 4-methoxy-1,2-benzenediamine and 270 parts of tetrahydro55
temperature using 4 parts of a 10% catalyst of palladium on charcoal. After absorbing the calculated amount of hydrogen, the catalyst is filtered.
five
the furan is stirred and refluxed for 2 hours. The contents are evaporated to give 44 hours {100%) M- (2-amino-5-methoxyphenyl) - N - (1-methyl-4-piperidinyl) -thiourea - as residue (compound 26P).
b) A mixture of 44 parts of K- (2-amino-5-methoxyphenyl) -Y (- (1-methyl-4-piperidinyl) -thiourea, 38.9 parts of mercury (II) oxide and 270 parts of tetrahydrofuran stir and reflux for 2 hours at reflux temperature. The reaction mixture is filtered hot over diatomaceous earth and the filtrate is evaporated. The residue is purified by column chromatography over silica gel, first using a mixture of trichloromethane and methanol ( 95: 5 by volume), and then a mixture of trichloromethane and methanol saturated with ammonia (85:15 by volume), as Pure fractions are collected and the eluent is evaporated, yielding 50.5 parts (100%) of 5-MeTOKCH-N- (1-methyl-4-piperidinyl) -1H benzimidazole-2-amine as a residue (compound 27P).
In a similar way receive also
Q 5,6-dimethoxy-Y- (1-methyl-4-piperidinyl) -1 Y-benzimidazop-2-amine (compound 28P).
EXAMPLE 6 A mixture of 32 parts of 1-chloro-2-ethoxyethane, 94.5 parts of K- (4-piperidinyl) -1H-benzimidazole-20 dibromhydrate
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amine, 90 parts sodium carbonate and 540 hours.
Example 7o A mixture of 36.6 parts of M- (4-piperidinyl) -1H-benzimidazol-2-amine dibromide, 10 parts of poly- (oxymethylene), 2 parts of a 4% thiophene solution in methanol, 200 h of methanol and 20 h of potassium hydroxide are hydrogenated at normal pressure and at room
temperature using 4 parts of a 10% catalyst of palladium on charcoal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is treated with a solution of hydro--. sodium oxide. The precipitated product was filtered off and dried, yielding 13.7 parts (59.4%) of N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2-amine (PSO compound).
Example To a stirred dispersion of 28.9 hours of ethyl ether
4- (1H-benzimidazol-2-ylamino) -1-pyperidinecarboxylic acid in 282 parts of M, M-dimethylformamide was added 4.8 parts of 50% sodium hydride dispersion under nitrogen atmosphere (release of the pelvis, slightly exothermic reaction). The mixture is stirred for 1.5 hours at room temperature. 8.3 parts of chloroacetonitrile are added dropwise at 10.degree. C. while cooling on an ice bath, 2 nons. After the addition is complete, the temperature is allowed to reach room temperature and then stirred overnight. The reaction mixture is evaporated and the residue is dissolved in water and 4-methyl-2-pentanone. The separated organic layer is washed three times with water, dried, filtered and evaporated. The residue is purified by column chromatography over 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 toluene. The reaction product is filtered off and dried, yielding 12.4 parts (37.8%) of ethyl 4-1-cyanomethyl) -1H-benzimidazol-2-wG-amino 1-1-piperidinecarboxylic acid as a residue (compound 31P)
PRI me R 9. A mixture of 9 parts of ethyl ester of C (2-ethoxyethyl) -ami but -3-pyridinyl amino} thiooxomethyl 1 amine dj-1-piperidinecarboxylic acid 13 parts of mercury oxide (11), 0.1 h Sulfur and 120 parts of ethanol are stirred for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue is converted to the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 6.5 hours, (71.0%) of 4- 3- (2-ethoxyethyl) -NH-imidazo (4,5-b) pyridin-2-ylZamino1-1-piP redincar ethyl ester monochlorohydrate - bonoic acid; Tnf, 185IS (connection 32P) o
,
50
five
0
35
40
45
50
five
In a similar way, the compounds shown in Table 2 are obtained.
In addition, 12- (diethylamino) -ethyl} -ZN-imidazo-C4,5-bJ-pyridin-2-yl-amino-1-piperidinecarboxylic acid ethyl ester is obtained as a residue (Compound 4b).
Example 10. A mixture of 22.4 parts of C (2-ethoxyethyl) amino-5-pyrimidinyl-N-1- (phenylmethyl) -4-piperidinyl D-thiourea, 17.3 parts of mercury (II) oxide , 0.1 parts of sulfur and 270 parts of tetrahydrofuran are stirred for
2h at reflux temperature. The reaction mixture was filtered hot over diatomaceous earth. The filtrate is evaporated and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 16.3 parts (79.3%) of 9- (2-ethoxyethyl) -M-1- (phenylmethyl) -4-piperidinyl1-9H-purine-8-amine as residue (compound 42P).
Similarly, 4-Ј1- (2-ethoxy3-ethyl) -1H-imidaz ethyl ester, 5-c3-pyridine-2-pc-amino-1-piperidine sar lateral acid is also obtained in the form of a residue (compound 43P);
ethyl ester (2-ethoxyethyl) - ZN-imidazo | 4,5-c} -pyridin-2-yl-amino-1-piperidinecarboxylic acid as a residue (compound 44P);
4-GGZ-G (2-ethoxyethyl) -ZN-imidazo-J4,5-bJ-pyridin-2-yl} -amino7-hexahydro-1H-azepin-1-carboxylic acid ethyl ester as a residue (compound 45P);
(cis + trans) (2-ethoxyethyl) -ZH-imidazo-4,5-b-pyridin-2-yl-amino-1-3-methyl-1-piperidinecarboxylic acid methyl ester as a residue (compound 46P).
Example 11. A mixture of 13 4 .. Ј2-ethoxyethyl) amino-5-methylphenyl - N - (1-methyl-4-piperidinyl; -thiourea, 8.8 h of mercury (II) oxide and 90 parts of tetrahydrofuran stirred for 1 hour at reflux temperature. The reaction mixture was filtered hot over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated ammonia 4, (95 : 5 by volume) as eluent "Pure fractions are collected and the eluent is evaporated. The residue is converted to ( a) ethylenedicarbonate salt in ethanol. The salt is filtered and dried, yielding 6.2 h (30.5%) of (E) -edicarbonate salt of 1- (2-ethoxyethyl) -5-methyl-M- (1-methyl- 4-piperidinyl) -1H-benzimidazole-2-amine; Ttm 218.4 ° C (compound 47P).
Example 12. A mixture of 120 parts of 0-ethyl-1- (phenylmethyl) -4-piperidine ethanimidate dichlorohydrate, 45.9 hours „2- (2.3 diamino-2-pyridinyl) -ethanol and 400 hours of methanol is stirred for overnight at reflux temperature. Another portion of 60 hours of O-ethyl-1- (phenylmethyl) -4-piperidineethanimidate dichlorohydrate is added and stirring is continued for 8 hours at reflux temperature. After cooling, the reaction mixture is evaporated and the residue is dissolved in water. The aqueous layer is treated with ammonium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, getting 87 h (82.7%) 2-0- (Phenylmethyl) -4-piperidinstD-metsht} -ZH-imide-, 5-G} pyridine-3-ethanol as a residue (compound 48P) „
Similarly, 3- (2-ethoxyethyl) -2-CЈ1- (phenylmethyl) 4-pip eridinyl-methyl 3 ZN-imide az o-14,5-tQ-pyridine is also obtained as a residue (compound 49П) „
Example 13. To a stirred mixture, 36.64 parts of 4-oxo-1-piperidinecarboxylic acid ethyl ester and 940 parts of N, N-dimethylformamide were added in portions of 10 hours about 50% sodium hydride dispersion at room temperature in nitrogen atmosphere. After the addition is complete, stirring is continued for 1 hour at room temperature. A solution of 45 parts of 2-chloro-1- (2-ethoxyethyl) -1H-benzimidazole in H, M-dimethylformamide is added
0
five
0
five
0
five
0
five
0
five
dropwise at 50 ° C. Upon completion, the contents are stirred overnight at 50 ° C. The reaction mixture was poured into ice water and the reaction product was extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 50 parts (69.1%) of ethyl 4- ЈC1- (2-ethoxyethyl) -1H-benzimidazol-2-yl-oxy-1-piperidinecarboxylic acid as a residue (compound 50P).
Example 14. A mixture of 14 h, 4-Ј13- (2-hydroxyethyl) -NH-imidazo-4, 5-bJ-pyridine-2-pc-amino-1-piperidinecarboxylic acid ethyl ester, 22 parts of potassium hydroxide and 160 parts of 2-propanol is stirred overnight at reflux temperature. The reaction mixture is evaporated and the residue is dissolved in water. The aqueous layer was salted out with potassium carbonate and the reaction product was extracted with tetrahydrofuran. The extract is dried, filtered and evaporated. The residue is crystallized from acetonitrile. “The reaction product is filtered and dried, yielding 5.5 p. (52.3%) 2- (4-piperidinylamino) -ZN-imidazo-4,5-b} -pyridin-3-ethanolJ Tpc 156.9 ° C (compound 5Sh).
The compounds shown in Table 3 are similarly prepared.
In addition, the following is obtained: M, M-dimethyl-2- (4-piperidinylamino) -1H-benzimidazol-1-ethanamine | T l „. 126.5 ° C (compound 63P);
(E) N, N-diethyl-2- (4-piperidinylamino) -ZH-imidazo-4,5-1-pyridine-3-ethanamine (E) -endicarbonate salt; Tnh 180.8 ° C (compound 64P);
1- C (2-methoxyethoxy) -methylH-N- (4-piperidinyl) -1H-benzimidazol-2-amine; T pc 148,5 ° C (compound 65P) ",
Example 15. A mixture of 27 parts of hexahydro-4-tl-2 (2-pyrimidinyloxy) -ethyl} -1H-benimidazol-2-yl-amino-1-carboxylic acid ethyl ester, 160 including 1-butanol, 28 hours about potassium hydroxide and 2 parts of water, stirred overnight at reflux temperature. The reaction mixture is diluted with water and the contents are extracted with 1-butanolomo. The extract is dried, filtered and evaporated. The residue is dissolved in water and the reaction product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is converted to the (E) -endicarbonate salt in ethanol. The salt is filtered off and dried, yielding 9.77 parts (38.5%) of (E) -ethenylcarbonate salt (1: 2) 2- (hexahydro-1H-azepin-4-yl) -amino 1H-benzimidazol-1-ethanol ; Тг 176.1 ° С (compound 66П).
Likewise, (E) -enecate carbonate salt (2: 3) is also obtained.
3- (2-ethoxyethyl) -M- (hexahydro-1H-azepin-4-yl) -ZH-imidazo-4,5-bl-pyridine-2-amine; T P1CH 180.0 ° C (compound 67P).
Example 16. A mixture of 105 hours, 4- 0- (2-ethoxyethyl) -1H-benzimidazol-2-yl 1-amino} -hexa-hydro-1H-azepine-1-carboxylic acid ethyl ester, 79 parts of hydroxide potassium and 833 parts of 1-2-ethanediol are stirred at reflux overnight. The reaction mixture is distilled under vacuum and the residue is dissolved in dichloromethane. The organic phase is filtered and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the salt of oxalic acid. The salt is filtered and crystallized from 2-propanol. The reaction product is filtered off and dried, yielding 16.4 h (9.9%) of the oxalate salt (1: 3) monohydrate (1: 3) 1- (2-ethoxyethyl) - N- (g Exo-o-1H-azepin-4-yl) - 1H-ben zimidazol-2-amine (compound 68P).
Example 17. A mixture of 140 parts 2-7. 0 - (phenylmethyl) -4-piperidine-npgG -aminaz -1 -1H-b azim-1 enimimide -1 - ethoxyD-ethanol and 480 parts of methanol is hydrogenated at normal pressure and at room temperature from -
power of 5 hours. 10% catalyst of palladium on charcoal. After absorbing the calculated amount of hydrogen, the catalyst is filtered off over diatomaceous earth and the filtrate is evaporated. The residue is crystallized twice from acetonitrile. The reaction product is filtered off and dried, yielding 53.3 parts (46.0%) of 2 - 2 - 2- (4-piperidinylamino) -111-benzimidazole 1-yl-ethoxy-ethanol; T pl 163.7 C (compound 69P) In a similar way, also prepared:
(E) -E dicarbonate salt (2: 3) 3- (2-ethoxyethyl) -2- (4-piperidinylmethyl) -ZH-imidazo-4,5-bJ-pyridine; T CP 177.9 ° C (compound 70P);
oxalate salt (1: 3 ethyl N-2-C2- (4-piperidinylamino) -3H-imidazo-4,5-b} pyridine 3-yl} -ethyl-glycine dihydrate; T Of, 187, ( compound 71P) and
L-ethyl-M C2-12- (4-piperidinylamino) -ZH-imidazo-4, 5-b-pyrid-1-yl 1-ethyl-acetamide; Th 156.7 ° C (compound 72P) o
Example 18. A mixture of 16.3 parts of 9- (2-ethoxyethyl) -M-Ј1- (phenylmethyl) -4 piperidine-9H-purin-8-amine and 200 hours of methanol is hydrogenated at normal pressure and at room temperature with 4 hours. 10% catalyst palladium on charcoal and 6 hours. Catalyst Raney nickel. The absorption field of the calculated hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (90:10 by volume) as eluent, the first fraction is collected and the eluent is evaporated. The residue is converted to the (E) -endicarbonate salt in methanol. The salt is filtered and dried, yielding 1.98 parts (8.6%) of the hemihydrate of (E) -endicarbonate salt (1: 2) 9- (2-ethoxyethyl) - ( 4-piperidinyl) -9H-purin-8-amine; T nft 192,8 ° C (compound 73P).
Example 19. To a stirred and refluxing mixture of 13.5 parts of 2- 0- (phenylmethyl) -4-piperidinyl methyl2-3-Ј2- (2-propenyl-oxy) -ethyl-ZN-imidazo | 4, -pyridine and 90 parts of toluene are added dropwise in 5.4 hours from ethyl chlorocarbonate. After the addition is complete, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is diluted with water and the content is treated with potassium carbonate. The reaction product is extracted with toluene. The extract is dried, filtered and evaporated, with 14 hours o (75.1%) ethyl 12- (2-propenyloxy) ethyl - 3H-imidazo-C4,5-1-pyridin-2-shG-methyl (- 1-piperidinecarboxylic acid in the form of a residue (compound 74P).
B. Obtaining target compounds. Example 20. A mixture of 1.08 parts of 1-chloro-2-ethoxyethane, 2.9 parts of 3- (2-ethoxyethyl) -M- (4-piperidinyl) -ZN-imidazo = 4.5-tQ- pyridin-2-amine, 1.06 parts of sodium carbonate and 45 parts of N, N-dimethyl-acetamide are stirred overnight at 70 ° C. The reaction mixture is poured into water and the reaction product is extracted with 4-methyl-2-pentanoneMo The extract is dried, filtered and evaporated. The residue is purified by filtration on silica gel using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the oxalate salt in methanol. The salt is filtered off and dried, yielding 0.7 parts (12.9%) of the oxalate salt (1: 2) 3- (2-ethoxyethyl) -N-J- (2-ethoxyethyl) - 4- (piperidinyl -ZN-imidazo - 4, 5-b - pyridin-2-amine; mp 176.1 ° C (compound 1).
In a similar way, the compounds shown in Table 4 are also prepared.
Following similar methods are also obtained:
1- (2-methoxyethoxy) -methyl -N-i- 2- (4-methoxyphenyl) -ethyl-4-piperidinyl -1H-benzimidazole -2-amine (compound 32) and (E) -2-butevdioate (1: 2); Tw
1- (. (2-methoxyethoxy) -methyl -N- (.1 - (2-ethoxyethyl) -4-piperidinyl - 1H-benzimidazol-2-amine (compound 33) and (E) -2-butenioate (2: 3); Tn (V 160,
Example 21 “Mix 6 parts of 1- (2-br omethyl) -1,3-dihydr O-2H-6 enimidazol-2-one, 7.63 h“ 2- (4-piperidinynyl) -ZH -and: gidazo-4,5-b-pyridin-2-yl-ethoxy-ethanol, 3 parts of sodium carbonate and 47 hours M, G-dimethyl acetamide are mixed overnight at 70 ° C. After cooling, the reaction mixture is drunk in water and the reaction product is extracted with dichloromethane. Ext. The powder is dried, filtered and evaporated. “The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized twice from 2-propanol. The reaction product is filtered and dried, yielding 6.8 parts (58.4%) 1.3-1,3-dihydro 112-14- 3- & (2-hydroxyethoxy) -ethyl-ZN-imidazo 4, 5 H-pyridin-2-yl-amino-1-piperidinyl-ethyl -2H-benzimidazol-2-o:
GTL
177 ° C (compound 34),
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0
five
0
five
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five
0
five
The compounds listed in Table 5 are also prepared in a similar manner.
Example 22. A mixture of 3.1 parts of methanesulfonate (ester) 2-thiophenethanol, 7 parts of the oxalate (1: 2) 3- (2-ethoxyethyl) -N- (4-piperidinyl) -ZN- imidazo-4, 5-bj-pyridin-2-amine, 1.6 parts of sodium carbonate and 75 parts of M, M-dimethylacetamide are stirred overnight at 80 ° C. The reaction mixture was poured into water and the reaction product was extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97 Hg by volume) as elgoente. Pure fractions are collected in eluent, evaporated. The residue is converted to the oxalate salt in methanol. The salt is filtered off and dried, yielding 4.59 h, (52.7%) of the oxalate salt (1: 2) of 3- (2-ethoxyethyl) -N- (2-thienyl) -ethyl-4-piperidinyl-3H-imidazo {4,5-b-pyridin-2-amine; TT 218.2HP (compound 48),
Example 23, a Mixture of 9.4 h „2 - chloroacetonitrile, 30 h, 3- (2-ethoxyethyl) -N- (4-nnn-idridyl) -NH-imidazo-{4,5-bJ-pyridin-2-amine, 11 including sodium carbonate and 658 parts. NjN-dimethylformamide is stirred for two days at room temperature. The reaction mixture is drunk in water and the reaction product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is stirred in diisopropyl ether. The reaction product is filtered off and dried, yielding 7.2 parts (21%) of 4- 3- (2-ethoxyethyl) -NH-imidazo-4,5-b-pyridin-2-yl3 -amino -1-piperidine acetonitrile. TSN 141S4 ° C (compound 49).
In a similar way, N- Јl- (2,3-dihydro-1,4-benzodioxin-2-yl) -methyl | -4-piperide (2-ethoxyethyl) -ZH-imidazor (, 5 -bj-pyridin-2-amine; Tm 140.7 ° C (compound 50);
3- (2-ethoxyethyl) - N- | j - (4-methyl-1H-imidazol-5-yl) methyl-4-piperidinyl} -ZN-imidazo-, 5-bl-pyridin-2-amine ; Tnft 187.9 ° C (compound 51);
oxalic acid salt (1: 2) of ethyl (2-ethoxyethyl) -ZH-imidazo-4,5-z-pyridin-2-yl-amino-1-piperidineacetic acid ethyl ester; T e 186,5 ° C (compound 52);
E-etindicarbonate (2: 5) and 2-propionic acid (1: 1) salt 3-Ј2 - {. 4-LP 12- (dimethylamino) -ethyl -1H-benzimidazole-2-shL-aminoZ-T -piperidinyl-3-ethyl-methyl-H-pyrido-JJ, 2-a} -pyrimidin-4-one; T rtN 174.6 ° C (compound 53);
3- 2- (4-.3- | 2- (diethylamino) -ethyl-3H-imidazo-4,5-b (-pyridin-2-yl-Zamino -1-piperidinyl | -ethyl - 2-methyl-4H-pyrido- | j, 2-a-pyrimidin-4-one; Tnft 132.3 ° C (compound 54);
hemihydrate of (K) -entenicarbonate salt (2: 3) 6-2-C4-p- (2-ethoxyethyl)} -ZH -; midazo {4, 5-b-pyridin-2-yl-metipZ 1 -piperidinyl-ethyl-7-methyl-5H-thiazolo-3,2-aJ-pyrimidine-5-one; T P1 (152.4 ° C. (Compound 55).
Example 24. A mixture of 3.7 h, | G (2-bromoethiO-sulphonut -benzene, 4.34 h. 3- (2-ethoxyethyl) -M- (4-piperidinyl) -ZN-imidazo-f4, 5- a-pyridin-2-amine, 2.5 parts of sodium bicarbonate and 120 hours of ethanol are stirred for 2 hours at reflux temperature. The reaction mixture is filtered over diatomaceous earth and the filtrate is evaporated. The residue is dissolved in water and the product the reaction is extracted with 4-methyl-2-pentanone, the extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichlorome ana and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated C. The residue is crystallized from a mixture of tetrahydrofuran and diisopropyl ether. The reaction product is filtered and dried to give 2.6 hours ( 37.1% of 3- (2-ethoxyethyl) -N-1-2-phenylsulfonyl) -ethyl-J-4-piperidinyl i-3H-imidazo-4,5-bj-pyridin-2-amine half-half; T P | 101.9 ° C (compound 56).
Similarly, also receive:
five
0
five
3- (2-ethoxyethyl) -N- Јl - Ј2- (phenyl-thio) -ethyl-4-piperidinyl -ZN-imidazo-4,5---pyridin-2-amine; T PP 102.5VS (compound 57);
(2-ethoxyethyl) -ZH-imidazo-J, 5-b-pyridin-2-yl-amino} -H- (1-methyl-ethyl) -1-piperidinpropanamide; T ni 163.7 ° C (compound 58); Q-salt-rich acid salt 1: 2 3- (2-ethoxyethyl) -K- (1- (2-propenyl) -4-pyrididinyl-3H-imidazo-4, 5-b} -pyridine-2-amine; mp 183, 8 ° C (compound 59);
4-p- (2-ethoxyethyl) -ZH-imidazo, 5-b-pyridin-2-yl-methyl} -N- (1-methylethyl) -1-piperidipropanamide ;; Mp 98.8 ° C (compound 60).
Example 25. A mixture of 4.53 parts of chlorocetonitrile, 17.3 parts of 3- (2-ethoxyethyl) -2- (4-piperidinylmethyl) -3H-imidazo-4,5-b-pyridine, 6 hours H , N-diethyl-ethanamine (triethylamine) and 94 parts of NjN-dimethylformamide are stirred for 3 hours at room temperature. The reaction mixture is taken up in water and the reaction product is extracted with diethyl ether. The extract is dried, filtered and evaporated, yielding 23.75 hours. (100%) 4-b- (2-ethoxyethyl) -ZH-imidazo- {4,5-bz pyridin-2-yl} -methylZ-1-piperidineacetonitrile as a residue (compound 61).
i
II p and meper 26. To mix
mixtures of 2.6 parts of 2- (4-piperidinylamino) -3H-imidazo-4,5-b} -pyridin-3-ethanol and 90 parts of NjN-dimethylformamide add 0.5 hours about 50% hydride dispersion After stirring for 30 minutes at room temperature, 1.2 hours of 3-bromo-1-propene are added dropwise with cooling. After the addition is complete, stirring is continued for 1 h. The reaction mixture is drunk into water and the reaction product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the 5 oxalate in ethanol. The salt is filtered off and dried, yielding 1 part (20.7%) of the oxalate salt (1: 2) (2-propenyl) -4-piperidine | -amino -ZH0
five
0
five
0
imidazo-4, 5-b-pyridin-3-ethanol; TP 188, (compound 62).
Example 27, To a stirred and cooled () mixture of 4.34 parts of 3- (2-ethoxyethyl) -M- (4-piperidinyl) - 3H-imidazo, 5-1-pyridin-2-amine, 1.53 including triethylamine and 130 parts of dichloromethane, a solution of 1.63 parts of ethyl ester of chlorogolic acid in dichloromethane is added dropwise. After the addition is complete, the temperature is brought to room temperature. The mixture is washed with water and partitioned with hexahydro-4-l (j-I2- (2-pyrimidinyloxy) ethyl) -1H benzyl ether and the organic layer is dried,
filtered and evaporated. The residue of purification of zimidazol-2-yl-amino-1H-azepin-1-is carried out with the help of column chromatograph-carboxylic acid as a residue.
fii over silica gel using mixture (compound 69) |
trichloromethane and ethanol (95: 5-obo- (E) -endicarbonate salt (1: 3)
mu) as eluent. Pure frac-M- (1-methyl-4-piperidinyl) -3-2- (2c is collected and the eluent is evaporated. 20 Propynyloxy) -ethyl 31.-ZN-imidaz-4.5 Residue is converted to pyridin-2-amine; , 2 ° C (coybonate salt in ethanol. The salt is filtered and dried, yielding 0.02 hour (25.1%) of (E) -2-ethylene carbonate salt (2: 3) of ethyl ester (2 ethoxyethyl) -ZH-imidazo-4 , 5-b-pyridin-2-yl-amino-1-pip-yperidinecarboxylic acid, mp: 153.8 ° C (compound 63).
The oxalate salt (2: 5) of 4-Gy- (2-ethoxyethyl) -1H-imidazo-4,5-cJ-pyridin-2-yl (1-amino-1 doping) 70) is also obtained in this way.
Example 29. To a stirred solution of 11.9 parts of 2-p- (phenylmethyl) -4-piperidinyl-amino-3H-imidazo-4,5-b-pyridine-3-ethanamine in 160 parts of NjN-dimethylformamide are added 4 , 41h. ethyl chlorofluate and 4.05 parts of triethylamine “The reaction mixture is slowly heated to 50 ° C and stirred first for 18 hours at this temperature and then for 18 hours at 70 ° C. The reaction mixture is evaporated and the residue is heated to 50.degree. C. and stirred first for 18 hours at this temperature and then for 18 hours at 70.degree. The reaction mixture was evaporated and the residue was dissolved in a solution of sodium carbonate in water. The reaction product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. Purify the residue with copiperidine carboxylic acid; T p),
157.3 ° C (compound 64).
Example 28. To mix
mixtures of 4.13 parts of 2- (1-methyl-4-piperidinyl) -amino | -3H-imidazo-4,5-y-pyridine-3-ethanol and 90 parts of NjN-dimethylformamide were added 0.75 hours 50% 40% chromatographic chromatography on sodium hydride silica gel. After conversion, using a mixture of trichloromethane
stirring for 30 minutes with a mixture of methanol (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue 45 is converted to the oxalate salt in 2-propanol. The salt is filtered and crystallized twice from ethanol. The reaction product is filtered off and dried, yielding 6.6 parts (26.7%) of the hydrostatic agent is crystallized from the acetohydrite-5Q oxhydrate oxalate salt (1: 3)
la The reaction product is filtered off with ethyl N-2-2-C1-1 (phenyl is dried, yielding 1.7 hours (32.0%)
1.8 h0 2-chloropyrimidine is added to the N- (methyl-4-piperidinyl) -3- 2- (2-pyrimidinyloxy) ethyl-3-3H-imidazonate temperature. The contents were stirred for 1 hour at room temperature and the reaction mixture was poured into water. The reaction product is extracted with trichloromethane. The extract is dried, filtered and evaporated.
C4,5-b1-pyridin-2-amine; T PC 158.1 ° C (compound 65).
In a similar way, also obtained: oxalic acid salt (1: 2) N- (4-piperidinyl) -3-2- (2-pyrimidinyl) 55
methyl) -4-piperidinylZ-amino} -ZH-imidazo-4,5-b-pyridin-3-yl | -ethylZ-glycine; Tnft 169.5 ° C (compound 71).
Example 30. A mixture of 1.6 parts of poly- (hydroxymethylene), 8.1 parts of 4- EO- (2-aminoethyl) -1H-benzimidazol-2-yl-1-amino 3-piperidinecarboxylic acid ethyl ester and 200 parts of methanol hydrioxy-ethyl-1-ZN-imidazo-4,5-b-pyrindine-2-amine; Mp 172, (compound 66);
oxalic acid salt (1: 2) N- (1-methyl-4-piperidinyl) -3- 2- (2-pyrimidinoxy) ethyl} -ZH-imidazo-4, ridin-2-amine; T PG 188, (compound 67);
(Phenylmethyl) -4-piperidinyl-0 methyl 1-3- (2-propenyloxy) ethyl-3-ZN-imidazo-4,5-b} -pyridine as a residue (compound 68);
hexahydro-4- l (j-I2- (2-pyrimidinyloxy) -ethyl} -1H-benzimidazol-2-yl-amino--1H-azepine-1-carboxylic acid ethyl ester as a residue
dining 70)
Example 29. To a stirred solution of 11.9 parts of 2-p- (phenylmethyl) -4-piperidinyl-amino-3H-imidazo-4,5-b-pyridine-3-ethanamine in 160 parts of NjN-dimethylformamide are added 4 , 41h. ethyl chlorofluate and 4.05 parts of triethylamine “The reaction mixture is slowly heated to 50 ° C and stirred first for 18 hours at this temperature and then for 18 hours at 70 ° C. The reaction mixture is evaporated and the residue is taken up in a solution of sodium carbonate in water. The reaction product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified using N-Ј2-2C1- (phenyl
five
methyl) -4-piperidinylZ-amino} -ZH-imidazo-4,5-b-pyridin-3-yl | -ethylZ-glycine; Tnft 169.5 ° C (compound 71).
Example 30. A mixture of 1.6 parts of poly- (hydroxymethylene), 8.1 parts of 4- EO- (2-aminoethyl) -1H-benzimidazol-2-yl-1-amino 3-piperidinecarboxylic acid ethyl ester and 200 parts of methanol hydri,
Run at normal pressure and at room temperature using 2 parts of a 10% palladium catalyst on charcoal. After absorbing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95; 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 9.2 parts (100%) of ethyl 4 -) (dimethylamino) - ethyl} -1H-benzimidazol-2-yl-amino-3-1-piperidinecarboxylic acid as a residue (compound 72) „
EXAMPLE 31 about 7.8 parts. M-ethyl-2-C 0x- (Phenylmethyl) -4-piperidinyl 1-amino-3H-imidazo-4,5-a-pyridine 3-ethanamine is treated in 75 h, trichloromethane. 1.51 parts of acetic anhydride are added (exothermic reaction). The reaction mixture is stirred for 18 hours at room temperature. The contents are filtered over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95: 5 by volume), in the amount of eluent. Pure fractions are collected and the eluent is evaporated. The residue was treated with toluene and the contents evaporated again, yielding 8.5 parts (100%) of M-ethyl-L 2- | 2- 0- (phenylmethyl) -4-piperidinyl1-amino} -ZH-imidazo- (4, 5-bj-pyridin-3-yl | -ethylZ acetamide in vi, g, e residue (compound 73).
Example 32. A mixture of 2.7 parts of a 50% dispersion of sodium hydride and 182 hours of 1, M-dimethylformamide is stirred at room temperature under nitrogen atmosphere. To this mixture is added portionwise 18.8 hours of ethyl ester 4- 3- (2-ethoxyethyl) -ZN-imidazo-4,5-b pyridin-2-yl} -amino} -1-piperidinecarboxylic acid. After the addition is complete, stirring is continued for 1 hour at room temperature. 10 h is added dropwise. (bromomethyl) benzene and after the addition is complete, stirring is continued for 1 hour. The reaction mixture is divided into parts with water (decomposed with water) and the reaction product is extracted with 4-methyl-2-p-tanone. Extract extract, filter and evaporate. The residue is purified by column chromatography over silica 5.
20
.
25 p
40 45 JQ „gel, using a mixture of trichloromethane in ethanol (98: 2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from diisopropyl ether. The reaction product is filtered and dried, yielding 3.2 parts (13.6%) of 4- (3- (2-ethoxyethyl) - 3H-imidazo-J4,5-b ethyl ester or n-2-yl - ( phenylmethyl) amino3 1-piperidinecarboxylic acid; T Pc 115.0 ° C (compound 74).
PRI me R 33. A mixture of 23.75 parts of 4- (3- (2-ethoxyethyl) -ZH-imidazo-4, 5-b-pyridin-2-yl 1-methyl -1-piperidinacetonitrile and 400 parts of methanol, saturated with ammonia, are hydrogenated at normal pressure and at room temperature with 6 parts of Rene’s nickel catalyst. After absorbing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, yielding 22.7 parts (100%) 4-ЈЈ3- (2-ethoxyethyl) -ZH-imidazo 4,5---pyridin-2-yl-methyl 1-1-pip er or n-ethanamine as a residue (compound 75).
Example 34. A mixture of 10.4 parts of (cyanomethyl) -1H-benzimidazol-2-yl1-aminoJ-1-piperidinecarboxylic acid ethyl ester and 160 parts of methanol saturated with ammonia is hydrogenated at normal pressure and at room temperature with 2 h. , catalyst Rene nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:: 10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the oxalate salt in 2-propanol. The salt is filtered and crystallized from ethanol. The reaction product is filtered off and dried, yielding 6.5 parts (39.5%) of the oxalate salt 1: 2 monohydrate of 1: 2 ethyl ester of 4-GR- (2-aminoethyl) -Sh-benzimidazol-amino} -1-piperidinecarboxylic acid; T Pl 176.1 ° C (compound 76).
Example 35. A mixture of 5.5 parts of 4-C13 (2-ethoxyethyl) ethyl-3H-imidazo-4,5-b-ether-pyridin-2-yl-amino-T-piperidine acetic acid, 15 h., 1H. sodium hydroxide solution
Pu, 100 parts of water and 16 parts of ethanol are stirred overnight at room temperature. The reaction mixture is evaporated. The residue is treated with water, washed with dichloromethane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (80:20 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The reaction product is filtered off and dried, yielding 1 h. (19.1%) 4- (2-ethoxyethyl) -ZH-imidazo-4,5-b-pyridin-2-yl-1-amino-1-piperidine-acetic acid; T nlv 227.3 ° C (compound 77).
Example 36 about 2.4 hours. A 50% dispersion of sodium hydride is added in portions to 147 hours. M, M-dimethylformamide in a nitrogen atmosphere. After the addition to the mixture 12.5 parts is added partly. Np- (2-e t hydroxy ethyl) -4-pip er epidi nyl -1 -1H-benzimidazol-2-amine. After the addition is complete, stirring is continued for 1 hour at room temperature. The contents were cooled and 9.85 parts of 2- (bromomethoxy) ethyl acetate were added (exothermic reaction). The reaction mixture is stirred for
2h at room temperature. The mixture is decomposed with water and the reaction product is extracted with trichloromethane. The extract is dried, filtered and evaporated. A mixture of the residue and 160 parts of methanol saturated with ammonia is stirred for 5 hours at room temperature. The reaction mixture is evaporated and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl 2-pentanone. The reaction product is filtered off and dried, yielding
0.98 parts (6.3%) of (ethoxy3-yl) -4-pipediphenyl by J-but-J-1H-b-benzimidazol-1 -yl 7-methoxy 1-ethanol; Mp 109.0 ° C (compound 78).

Similarly, (2-hydroxyethoxy) -methyl / -1H-benzimidazol-2-yl ethyl ester is also prepared.
0
amino -1-piperidinecarboxylic acid; T c | 142.8 ° C (compound 79);
2- 2-HS1- (2- (4-methoxyphenyl) e type -4-piped eridium H-benzimidazol-1 -yl} -methoxy j-ethanol {Tpc 142, (compound 80);
2- 2-C 1-methyl-4-piperidinyl) -amyno} -1 Hb of the imimide C al-1 -yl-methoxy-1 ethanol (compound 81).
Example 37o A mixture of 20 h, 2-Ј2-1- (phenylmethyl) -4-piperidinyl ethyl-3-amino-3H-imidazo-4,5-bl-pyridin-3-yl-ethyl 3-carbamic acid ethyl ester, 26.3 including potassium hydroxide and 200 parts of 2-propanol are stirred for 1.5 hours at reflux temperature. The reaction mixture is evaporated and the residue is treated with water. The contents are evaporated again. Remaining processing
Wash with a small amount of water and extract the reaction product with dichloromethane. “The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methane saturated with ammonia (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is boiled in diisopropyl ether (+ activated charcoal) and the contents filtered over diatomaceous earth. The filtrate is allowed to crystallize. The crystallized reaction product is filtered off (the filtrate is set aside and ignored) and dried to obtain the first fraction from 6.7 h. (40.6%) 2- 0- (phenylmethyl) -2-piperidinyl-amino 7-ZN-imidazou, 5-bJ-pyridine-3-ethanamine. The filtrate, which is not taken into account, is evaporated, obtaining a second fraction of 6.6 h, (40.0%) of EP- (Phenylmethyl) -4-piperidinyl-amino-3H-imvdazo-4,5-b | -pyridin-3- ethanamine. Total yield 13.3 hours (80.6%)
 0 (Phenylmethyl) 4-piperidinylZ-amino} -ZN-imidazo-4,5-1-pyridine-3-ethanamine; TPC 101, (compound 81).
Similarly, M-ethyl-2-} - (phenylmethyl) -4-piperidinyl} -amino-3H-imidazo- {. 4,5-b | -pyridin-3-ethanamine trichlorohydrate is also prepared; , 4 ° C (compound 82).
Example 38. To a stirred solution of 3.46 h of ethyl ester K-Ј2-H2- (4-pip yrididinylamino) -ZH-im10
dazo-4, 5-b-pyridin-3-yl-ethyl-glycine and 1.12 h of water was added in 25 hours. potassium hydroxide. After stirring for 18 hours at room temperature, the reaction mixture was washed with dichloromethane and acidified with concentrated hydrochloric acid. The content is evaporated to dryness and the residue is purified by reversible phase chromatography (JHAD) over a Li Chroprer RP 18 j phase using a mixture of 80% methanol and 20% water containing 0.25% ammonium acetate, the eluent is collected as eluent and evaporated. The residue is converted to the hydrochloride salt in 2-propanol, ethanol and hexa. The salt is dried, yielding 1.18 parts (2654%) of the dihydrochloride dihydrochloride (4-piperidinylamino) -ZH-imidazo | 4 s S-bJ -pyridin-3-yl-ethyl - glycium; Mp 242.6 C (compound 83).
Similarly, M 2 2 p-methyl-4-piperidinyl) -ami is also prepared.
(E) -E dicarbonate salt (2: 5) 3- (2-ethoxyethyl) -M-methyl-M- (methyl-4-piperidinyl) -NH-imidazo-G4,5-b-pyridine-2-amine ; Mp 153.5 ° C (compound 86).
Similarly, also receive:
3- (2-ethoxyethyl) -I- (1-methyl-4-piperidinyl) - (phenylmethyl) -ZH-imidazo-4,5-b-pyridin-2-amine hemihydrate; Tnft 68.3 ° C (Compound 87).
Example 40. Compounds are prepared analogously to the procedures described in one of Examples 20 to 39, and are prepared:
3- (2-ethoxyethyl) -N- (1-methyl-4-piperidinyl) -ZH-imidazo-4, 5-b-pyridine-2-amine dihydrochloride; TPP 260 ° C (compound 88);
(4-methoxyphenyl) piperidinyl-1- (2-phenoxyethyl) -1H-benzimidazol-2-amine; Mp 132 ° C (comp. 89);
N- (1-cyclohexyl-4-pip eridinyl) -3 UZ-3H-imidazo-4, 5-b-pyridin-3-yl} - 25 (2-ethoxyethyl) -ZH-imidazo-4, ethyl-oxy α-acetic acid (co-ridin-2-amine ethanedioate (1: 2); TPP
202 ° C (compound 90);
Nepie 84). T
pl
214.8
 C and hemihydrate
oi, - (phenylmethyl) -4 piperidi-1 nyl-amino-3N-imidazo-4,5-bJ-pyri202 ° C (compound 90);
9- (2-ethoxyethyl) -M- (piperidinyl) -9H-purine-8
din - 3 il-ethyl-hydroxy-acetic acid-30 8 ° C (compound 91);
40
you (compound 85); TPL 140.1 ° C.
Example 39. To a stirred mixture of 21 parts of a solution of lithium aluminum hydride in diethyl ether in 45 parts of tetrahydrofuran was added dropwise a solution of 4S9 parts of ethyl ether of 4-ЈЈ3- (2-ethoxyethyl) -ZN-imide- о ™ ™ (4 s 5 bJ-pyridin-2-yl3-methyl-amino-J-1-piperidinecarboxylic acid in 45 parts of tetrahydrofuran for 10 minutes under nitrogen atmosphere. After completion of the addition, stirring is continued for 1 hour at reflux temperature. After cooling the reaction mixture is decomposed with ethyl acetate, 15% sodium hydroxide solution and 5 parts of water The mixture was filtered over diatomaceous earth and the filtrate was evaporated.The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonia (95: 2.5: 2.5 by volume) as eluent. Pure fractions were collected and the eluent is evaporated. The residue is converted to (E) -ethynedicarbonate salt in 2-propanol, The salt is filtered and dried, yielding 3.2 parts (40.5%)
4- (3- (2-ethoxyethyl) H, 5-bJ-pyridin-2-igH {-a-noxymethyl) -1-piperidine rochloride; Mp 251 ° С (with
(2-ethoxy imidazo-4,5-b) -pyridine -1-piperidinyl-ethyl 1H-pyrrole-2-carboxamide (1: 2); M.p. 188 ° C (connect
3- (2-ethoxyethyl) -N- (peridinyl) -ZN-imidazo-4 din-2-amine ethanedioate (1 (compound 94);
3- (2-ethoxyethyl) -H-midinylamino) -ethylZ-4-pi 3N-imidazo-4,5-b | -pyrid Tpd 150 ° C (compound 95
3- (2-ethoxyethyl) -H-tyl-1,3-5-thiadiazol-2-yl 3THnJ-5-nHnepHflHminJ-3HL4, 5-bJ-pyridin-2-amino (1: 2), hemihydrate; TDP 1 nenie 96);
H-2-C4-GZ- (2-ethoxy-dazo-4,5-b-pyridin-2-and piperidinylJ-ethyl} -N-meth per ethanedioate (1: 2) monogue 167 ° С (compound 97);
45
0
(E) -E dicarbonate salt (2: 5) 3- (2-ethoxyethyl) -M-methyl-M- (methyl-4-piperidinyl) -NH-imidazo-G4,5-b-pyridine-2-amine ; Mp 153.5 ° C (compound 86).
Similarly, also receive:
3- (2-ethoxyethyl) -I- (1-methyl-4-piperidinyl) - (phenylmethyl) -ZH-imidazo-4,5-b-pyridin-2-amine hemihydrate; Tnft 68.3 ° C (Compound 87).
Example 40. Compounds are prepared analogously to the procedures described in one of Examples 20 to 39, and are prepared:
3- (2-ethoxyethyl) -N- (1-methyl-4-piperidinyl) -ZH-imidazo-4, 5-b-pyridine-2-amine dihydrochloride; TPP 260 ° C (compound 88);
(4-methoxyphenyl) piperidinyl-1- (2-phenoxyethyl) -1H-benzimidazol-2-amine; Mp 132 ° C (comp. 89);
N- (1-cyclohexyl 4-pip yrididin) -35 (2-ethoxyethyl) -ZH-imidazo-4, reedin-2-amine ethanedioate (1: 2); TPP
 (2-ethoxyethyl) -ZH-imidazo-4, 5-b reedin-2-amine ethanedioate (1: 2); TPP
202 ° C (compound 90);
9- (2-ethoxyethyl) -M- (1-methyl-4-piperidinyl) -9H-purin-8-amine; Tgl
 8 ° C (compound 91);
0 to 8 ° C (compound 91);
0
five
4- (3- (2-ethoxyethyl) -ZN-imidazo-H, 5-bJ-pyridin-2-igH {-amino - (Ј- (phenoxymethyl) -1-piperidineethanol dihydrochloride; mp 251 ° С (compound 92);
(2-ethoxyethyl) -ZN-imidazo-4,5-b) -pyridin-2-sh-ami--1-piperidinyl-ethyl -1 -methyl - 1H-pyrrole-2-carboxamide ethanedioate (1: 2); Mp 188 ° C (compound 93);
3- (2-ethoxyethyl) -N- (1-ethyl-4-piperidinyl) -ZH-imidazo-4,5---pyridine-2-amine ethanedioate (1: 2); T PL 201 ° C (compound 94);
3- (2-ethoxyethyl) (2-pyrimidinylamino) -ethylZ-4-piperidinyl) - 3H-imidazo-4,5-b | -pyridin-2-amine; Mpd 150 ° C (compound 95);
3- (2-ethoxyethyl) (5-methyl-1,3-5-thiadiazol-2-yl) -amino | -3THnJ-5-nHnepHflHminJ-3HHMHfla3o-L4,5-bJ-pyridine-2-aminoethanedioate ( 1: 2), hemihydrate; Mpd 198 ° C (compound 96);
H-2-C4-GZ- (2-ethoxyethyl) -ZH-imidazo-4,5-b-pyridin-2-yl-amino-1 - piperidinylJ-ethyl} -N-methylthiourea ethanedioate (1: 2) monohydrate; Tnft 167 ° C (compound 97);
five
25
 (2-ethoxyethyl) -M-1-2-1H-dazo-4, 5-c5J-pyridin-2-yl-amino-1-aminoethyl-4-pipyridinyl) -ZN-imidazo-4, 5-b-pyridine -2-amine (E) -bundiatoate (2: 9); T „l 194 ° C (compound 98);
(ethenyloxy) ethyl 1-K- (1-methyl-4-piperidinyl) -1 H-benzimidazol-2-amine; Mp 129 ° C (compound 99);
(ethylthio) -ethyl-M- (1-methyl-4-pip eridinyl) -1H-b of the enzimide with ol-2-amine (E) -2-butandioate (1: 2); T PL 237 ° C (compound 100);
(2-ethoxyethyl) -ZH-imidazo-4, -pyridin-2-yl-methyl-1-piperidshk-ganol (E) -2-butandioate (2: 3); Mpd 146-148 ° С (compound 101);
1- (2-ethoxyethyl) -5-fluoro-y- (1-methyl l-4-pipedideridyl) -1H-b en zimide zol-2-amine (E) -2-butandioate (1: 2) ; Mp 213 ° C (compound 102);
cis-M- (13-dimethyl-4-piperidinyl) -3- (2-ethoxyethyl) -ZH-imidazo-4,5-b is pyridine-2-aminoethanedioate (2: 3) hemihydrate; TPC 140 ° C (compound 103);
(2-ethoxyethyl) -ZN-imidazo-4,5-bJ-pyridin-2-yl-methyl-1-piperidinyl-euyl | -2-thiazolecarboxamide; Mp 144 ° C (compound 104);
3- (2-ethoxyethyl) (2-pyrimidinyl oxy) -e TWSI-4-pip yrididinyl-methyl} -ZH-imidazo-4,5-b-pyridine ethanedioate (1: 2); Mpd 140 ° C (compound 105);
3- (2-ethoxyethyl) (2-pyridyl) ethyl-4-piperidinyl-3H-imide, 5-b} -pyridine ethane (1: 3);
pl
158 C (compound 106);
1H-C2- 4- 3- (2-ethoxyethyl) -ZH-imidazo-4, 5-b-pyridin-2-yl methyl - 1-piperidinylZ-ethyl} -3-furancarbokamid itself ethandioate (1: 1) ; Mp 207 ° C (compound 107);
1- (2-ethoxyethyl) -5,6-dimethoxy-N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2-amine (E) -2-butandioate (1: 2);
sixteen
P1
194 C (compound 108);
N, M-diethyl-2-Ј (1-methyl-4-piperidinyl) amino-3H-imidazo-4, ridin-3-ethanamine (E) -2-butandioate (2: 7); TPA 193 ° C (compound 109).
In pharmacological examples.
The beneficial antihistamine properties of the compounds of formula (I) are demonstrated in the following test procedure.
PRI me R 41. Protection of rats from death induced by the compound 48/80.
ten
- - -;
. ,
-
- -,
-
40
.
63766326
Compound 48/80, a mixture of oligomers obtained by condensation of 4-methoxy-M-methylbenzeneethanamine and formaldehyde, has been described as a potent histamine-releasing substance flut. Arch. Allergy, 13, 336 (1958) J. Protection against the lethal circulatory collapse induced by compound 48/80 seems to be a simple way to quantify the antihistamine activity of the tested compounds. The male rats of the inbred Wistar line weighing 240-260 g were used in the experiment. After fasting overnight (from evening and all night), the rats were transferred to air-conditioned laboratories (temperature 2ljf1 C, relative humidity 65 + 5%). Rats are treated (treated) subcutaneously or orally with the test compound or with a solvent (NaCl solution, 0.9%). After 1 h after treatment of the rats with the test compound with a solvent, they were subjected to intravenous injection of 48/80 compound freshly dissolved in water at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight). In control experiments in which 250 solvent-treated animals were injected with a standard dose of 48/80, no more than 2.8% of the animals survived after 4 hours. Therefore, survival after 4 hours is considered a salvage criterion due to the protective effect of the medication. .
The values of ED for the compounds of formula (I) are listed in Table 6. Indicated
20
25

ED5 () - values are the values at which test compounds protect 50% of animals tested against mortality induced by 48/80.
Example 42. Protection against mortality of guinea pigs from internal administration of histamine after oral administration.
The ability of test compounds to protect guinea pigs from death by intravenous infusion of histamine was determined by the following method. Male albino guinea pigs (280- 360 g) of both sexes were tested in comparison with the intravenous administration of 1.25 mg / kg of histamine dihydrochloride with different time intervals (1,
3 and 8 hours after oral administration of the test compound.
The results of the effect of the test compounds are presented in Table 7 as effective dose values for EDS09 t, e. values at which test compounds protect 50% of the test animals from a lethal intravenous dose of histamine. Between 4 and 6 guinea pigs per dose and time interval were used for each of at least three doses from geometric rows of 0.0025, 0.005, 0.001,. .., 28 5.5 mg / kg.
Example 43. An indicative group of the proposed compounds was administered to rats at a dose of 40 mg / kg. No lethal cases were observed for compounds 2, 3, 6S 18 - 25, 27S 30, 37E 39, 57, 88, 93 - 95 and 104-106. Consequently, the ED0 values for these compounds will be more than 40 mg / kg body.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 1-alkyl-substituted benzimidazoles of the general formula
AU-G-R,
Il
L- rVB-VV "Nfe J-LЈ
BUT,
L2 L3
de A AZ-A3 A - bivalent
radical of formula 40
, (a-1).
-N CH-CH CH-5 (a-2)
,, (a-3)
, (a-4)
-CH CH-CH N-9 (a-5) 45
(a-6)
whether
(a-7)
where one or two hydrogen atoms in the radicals (a-1) to (a-5) independently of one another can be substituted by halogen, C-C4 alkyl or C-C-alkoxy; R, is hydrogen, C2-Sb-alkenyl,
Cj-Cg-alkynyl, phenyl, substituted phenyl, pyrimidyl or C-C-alkyl, which may be substituted by phenyl, furanyl, thienyl, pyridinium50
scrap, hydroxyl, C ,, kiloxy, carboxyl, C-alkyloxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl;
-0.8 or RJ ,, with Cg being hydrogen, C —C alkyl, C, —C4 alkylcarbonyl, C —G} alkyloxycarbonyl or benzyl;
- NR3, СNE or 0, and R3 - in one ord, С {-С kil or benzyl;
- hydrogen or Cj-C-alkyl;
- 0, 1 or 2;
- hydrogen, C-C4 alkylcarbonyl,) .- alkylsulfonyl, alkyloxycarbonyl, phenyl-C-C 4 alkyloxycarbonyl, phenylcarbonyl, phenylsulfonyl, Cg-Cg-cycloalkyl, C-Su-alkenyl, possibly substituted by phenyl, kil radical of general formula
-Alk - R5, (b-1)
-Alk - Y - R6) (b-2)
thirty
-Alk
L
- - Z2 - R7 (b-3)
or
-CH2-CHOH-CH2-0-Rg
(b-4),
where R is phenyl, substituted phenyl, Het or cyano;
R is hydrogen, phenyl, substituted phenyl or Het;
R7 is hydrogen, phenyl, substituted phenyl or Het;
R is phenyl, substituted phenyl or naphthalenyl;
Y is O, S or NRg, and Rn is hydrogen or C1-C-alkyl, each of the elements Z and Z independently of the other is O, S, NRiq or a simple bond, or Rq is hydrogen, or R C4 .- alkyl;
X is 0 or S;
Alk - each independently of the other C, | -C6-alkanediyl | Het (I) is a possibly substituted five-membered six-membered heterocyclic ring containing
1,2,3 or 4 heteroatoms selected from the group include 10
15
oxygen, sulfur and nitrogen, provided that no more than two oxygen or sulfur atoms are present;
Do not t5
(Ii) is a possibly substituted five-membered six-membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group comprising oxygen, sulfur and nitrogen, and it is orthocondensed with a possibly substituted five- or six-membered ring to two carbon atoms in a heterocycle or one the carbon atom in the heterocycle and one nitrogen atom in the heterocycle and contains only carbon atoms in the rest of the fused ring;
Do not t
(Iii) a possibly substituted five or six membered heterocyclic ring containing
1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and it is orthocondensed
with a possibly substituted five- or six-membered heterocyclic ring at two carbon atoms in the heterocycle or one carbon atom in the heterocycle and one nitrogen atom in the heterocycle and contains in the rest of the fused ring 1 or
2 heteroatom selectable
from the group consisting of oxygen, sulfur and nitrogen;
20
25
thirty
35
40
if het
monocyclic ring system, it can be 45
substituted by 1-3 substituents, and if Het is a bicyclic ring system, it can be substituted by 1-6 substituents, and the indicated substituents of the element Het are selected from the forms of the group comprising the divalent radical of the formulas X-, halo, isocyanato , isothiocyanato, nitro-55 ro, cyano, trifluoromethyl, a radical of the formula -A, a radical of the formula YA or a radical of the formula (X) Z2-A, where
five
0
five
0
five
element X, independently of other elements, has the same meaning as element X, and A — oxygen, phenyl, substituted phenyl or Cg-alkyl, possibly substituted by phenyl, substituted phenyl, C -Cg-alkyloxy, phenyl, substituted phenoxy, hydroxyl or C -Cg-alkyloxycarbonyl, and Ґ, Z 1 and Z2 independently 1 friend have the same meaning as the previously defined elements Y, ZjH Z, moreover, if in the radical (X) -Z2-A A - hydrogen, a Z, - NR, 0 or S, then Z2 is not 0 or S, and the substituted phenyl is phenyl substituted by halogen, hydroxyamino, C4-alkyloxy or C-C-alk, provided if L is hydrogen, C4-C4-alkyl or benzyl, and R f is G-Alk-C, -C-alkyloxyethyl, C3-C4-alkenyloxyethyl or phenoxyethyl, the radical A And is not a bivalent radical of the formula -CH CH-CH CH Dot, in that
compound of general formula
AIK-G-R
40
L-K
(Id
where R4, B, n, G, R {, A, -A4. have the combined values indicated by the formula
L - W.
where L has the indicated meanings;
W is a reactive leaving group,
in an inert to the reaction solvent and / or in the presence of a base and, if necessary, convert compounds of the general formula (I) to a therapeutically active non-toxic acid addition salt by treatment with an acid, or convert an acid salt to the free base with alkali or
0-alkylation of compounds of the general formula (I), where G is oxygen and RJJ is hydrogen, is carried out using a 0-alkylation agent in a polar aprotic solvent to give the corresponding compounds in which RJ is other than hydrogen, or N-alkopyirovaniya compounds of General formula (I), where G is H and R is hydrogen, in a polar aprotic solvent using a carboxylic acid or its derivatives, or carry out reductive M-alkylation of compounds of general formula (I), where G - NH and R - hydrogen, in an atmosphere of hydrogen in the presence of and a catalyst, or converted to compound
NH-CH2-CH2-G-R,
ROIn
4 "N.i
L NH-C-NH-C1. H) n
five
General formula (I), where the nitrogen atom in the piperazine or hexahydro-1H-1,4-diazepine group is replaced by the alkypoxycarbonyl group, to the corresponding compounds, where the nitrogen atom in the ring is replaced by methyl when the lithium aluminum hydride is reduced; of general formula (I), where R is Cj-C-alkyloxycarbonyl, in the presence of a base of the obtained compounds, where R is carboxyl, or hydrogenation of compounds of general formula (I) containing cyano substituents in the presence of a catalytically active noble metal in to give those compounds containing aminomethyl.
Table 1
i
L-Q-NH-Afa V (CH2) n J-D
Table 2
CH2-CH2-G-R,
(E) 2-butandioate
i
CHn CHf j 2 2
B-1O-in-Yv
- MSnOp li-AA
tt
BUT
2 i СН3-0-Л-СН2-СН2-i NH 0 -sn-сн,
, d.
Ny CHz-CHjs- 0
/
A CH3-0-J-CH2 CH25CH3-CHu-0-CHe-CHe
6SI% -CHV-0-
1 NH O-CHU-CH3-N CH-CH ° CH1 NH O -H 1 NH O -H
-N "CH-CH CH-N CH-CH CH1NH O -CH1VJ X -N-CH-CH CH LJ
CHrO-Hf ×) -CH;
 I
sn,
1 NH O-OH, 0 -N-CH-CH-CH; TQ
N OH,
/ - 3
CH2-CH2-Vy „2 CH2
about
1 NH 0T. -N "CH-CH-CH2LJ
1 NH
. (- ii 0 -N-CH-CH CH2TJ)
10 CH3-0 CH21 NH
Continuation of table 3
4-trans (ethanol) Tp „181.0 С
Table4
-AA
tt
BUT
-N-CH-CH-CHTn 116,
Tn. 134,4-C
-N "CH-CH CHTnA 132.3" C
2 (COOH) t, Tal 189.9 ° C
2 (COOH) I, TPA 182,5 ° C
-N-CH-CH-CH
-N "CH-CH-CH
-N-CH-CH CH
-N CH-CH CH
2 HC1, G „l
T ,,, 142.9 ° C Tpl 183, GS
T „. 116.5 С
Continuation of table 4
jinn
26 GN, O
i
SI,
t
2 NH O-CH4-CH3-CH CH-CH CH- (1: 2)
T „1
2
JO ii.
1 NH O -CHЈ-CH3-H CH-CH CHO
gn2-ch2
2B
CH3
С п f С Н f
2 neither about -sn, -sn3 -sn thu -sn-un
S HZ0-CH, 1G .1.
2 2
SI,
1 CHa -o -CHa-CH9-N CH-CH-CH30
i3s (sn2) 20 N M
Zpo ty-l o
A.CH, Si3
31 Q, v 3
-Sk
about
SP2-CM21 CH O-CH, -CH3-N CH-CH
 A1
V- / VC VH2)
37
/ HbrSj-CH, 2 CH2
Continuation of table 4
t
eight
(1: 2)
T „177.1“ С
1/2 Hgo
T "L 94,9-C
3 (COOH) 4, mp 100,
2.5 (COOH) ft,
Mp 157,
P: 2) TP 134,
2 (COOH) a / H, 0 TP | 104.6 "C
Street 5
one
CHft-CH-CBf N
2 HCl / 1.5 H40 p "67,"
TIT 167,
41
 (E) -buttsdioat
1637663
42 Continuation of table. five
Table
Continuation of table 6

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EP0282133A3|1989-06-07|

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

RU2540074C2|2007-06-21|2015-01-27|Кара Терапеутикс, Инк|Imidazopyrazine or imidazodiazepine derivatives, active with respect to receptor cb2|CA1140119A|1978-04-03|1983-01-25|Joseph Torremans|N-heterocyclyl-4-piperidinamines|

---

US4556660A|1982-07-12|1985-12-03|Janssen Pharmaceutica N.V.|N--4-piperidinamines|

---

US4634704A|1983-10-06|1987-01-06|Janssen Pharmaceutica, N.V.|Anti-allergic five membered heterocyclic ring containing N--4-piperidinamines|

---

EP0144101B1|1983-11-30|1991-02-06|Janssen Pharmaceutica N.V.|Bicyclic heterocyclyl containing n--4-piperidinamines|

---

PH23995A|1984-01-09|1990-02-09|Janssen Pharmaceutica Nv|4-methyl and hetero)piperidines|

---

US4588722A|1984-01-09|1986-05-13|Janssen Pharmaceutica N.V.|N- bicyclic condensed 2-imidazolamine derivatives|

---

GB8515934D0|1985-06-24|1985-07-24|Janssen Pharmaceutica Nv|purines|

---

EP0232937B1|1986-02-03|1992-08-19|Janssen Pharmaceutica N.V.|Anti-histaminic compositions containing n-heterocyclyl-4-piperidinamines|IL90879D0|1988-09-02|1990-02-09|Janssen Pharmaceutica Nv|3-piperidinyl-indazole derivatives,their preparation and antihypertensive compositions containing them|

---

GB8900380D0|1989-01-09|1989-03-08|Janssen Pharmaceutica Nv|2-aminopyrimidinone derivatives|

---

ES2013411A6|1989-03-28|1990-05-01|Espanola Prod Quimicos|Process for preparing new 1-diphenylmethylpiperidine derivatives.|

---

IT1229230B|1989-05-08|1991-07-26|Dompe Farmaceutici Spa|PHARMACOLOGICALLY ACTIVE PIPERIDYLIMIDAZOPYRIDINS.|

---

DE3915025A1|1989-05-08|1990-11-15|Dompe Farmaceutici Spa|2-SUBSTITUTED 3--ETHYL) -IMIDAZOPYRIDINE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM|

---

IT1229231B|1989-05-08|1991-07-26|Dompe Farmaceutici Spa|PHARMACOLOGICALLY ACTIVE AMINOIMIDAZOPIRIDINE|

---

GB9008850D0|1990-04-19|1990-06-13|Janssen Pharmaceutica Nv|Novel 2,9-disubstituted-4h-pyridolpyrimidin-4-ones|

---

FR2668150B1|1990-10-17|1994-11-18|Theramex|NOVEL DERIVATIVES OF TERBUTYLPHENYL 1-AMINO 4-HYDROXYBUTANE, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|

---

AU3347493A|1992-01-09|1993-08-03|Janssen Pharmaceutica N.V.|Pharmaceutically active substituted benzimidazole derivatives|

---

KR970703301A|1994-05-18|1997-07-03|쇼오다 오사무|Novel Diaminomethylidene Derivatives |

---

DE4425145A1|1994-07-15|1996-01-18|Basf Ag|Use of thiazole and thiadiazole compounds|

---

US6211199B1|1995-11-17|2001-04-03|Aventis Pharmaceuticals Inc.|Substituted 4-piperidines useful for the treatment of allergic diseases|

---

US6194406B1|1995-12-20|2001-02-27|Aventis Pharmaceuticals Inc.|Substituted 4-[1,4]diazepanes useful for the treatment of allergic disease|

---

US6423704B2|1995-12-20|2002-07-23|Aventis Pharmaceuticals Inc.|Substituted 4-[1,4]diazepanes useful for the treatment of allergic diseases|

---

TW429256B|1995-12-27|2001-04-11|Janssen Pharmaceutica Nv|1--4--piperidine derivatives|

---

US5932571A|1996-02-21|1999-08-03|Hoechst Marion Roussel, Inc.|Substituted N-methyl-N- {1,4}diazepan-1-yl)-2- butyl) benzamides useful for the treatment of allergic diseases|

---

US5922737A|1996-02-21|1999-07-13|Hoechst Marion Roussel, Inc.|Substituted N-methyl-N- piperidin-1-YL)-2- butyl) benzamides useful for the treatment of allergic diseases|

---

US5998439A|1996-02-21|1999-12-07|Hoescht Marion Roussel, Inc.|Substituted N-methyl-N--2-butyl)benzamides useful for the treatment of allergic diseases|

---

FR2771093B1|1997-11-19|2000-01-21|Synthelabo|IMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|

---

WO2001000612A2|1999-06-28|2001-01-04|Janssen Pharmaceutica N.V.|Respiratory syncytial virus replication inhibitors|

---

KR100453916B1|2002-03-11|2004-10-20|주식회사 코오롱|Tetrahydropyridinylbenzimidazole derivatives and method for preparing the same|

---

JP4596915B2|2002-09-06|2010-12-15|ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ|Thienopyrrolyl and furanopyrrolyl compounds and their use as histamine H4 receptor ligands|

---

WO2006067532A1|2004-12-24|2006-06-29|Prosidion Ltd|G-protein coupled receptor agonists|

---

WO2006094948A1|2005-03-08|2006-09-14|Janssen Pharmaceutica N.V.|Diaza-spiro-[4.4]-nonane derivatives as neurokininantagonists|

---

CZ307500B6|2012-08-15|2018-10-24|Zentiva, K.S.|A method of the preparation of a 2-methyl-2'-phenylpropionic acid derivative employing novel intermediates|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US2373987A| true| 1987-03-09|1987-03-09|

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