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    • 专利摘要:
    Novel N-heterocyclyl-4-piperidinamines wherein said heterocyclic radical is an optionally substituted 1H-benz-imidazol-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl radical, said compounds being useful as antihistaminic agents.
    公开号:SU1056902A3
    申请号:SU792747000
    申请日:1979-04-03
    公开日:1983-11-23
    发明作者:Хансен Франс；Стокброкс Раймон；Торреман Жозеф；Люйкс Марсель
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    where R, R, R, R, and Q have the above 3 steps, are brought into contact with the corresponding ester of the formula III:
    LU, where L has the indicated values,
    U - halogen, methylsulfonyloxy,
    or 4-methylphenylsulfonyloxy, in an inert solvent in the presence of a base at a temperature from room temperature to the reflux temperature of the medium, followed by isolation of the desired product as a base or salt.
    Priority signs: 0.30.78 at1
    R is hydrogen, methyl, R is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, R is hydrogen, and Ci-alkyl, Cj-Cd-cycloalkyl, alkyl substituted with one or two substituents from the group phenyl, halophenyl nitrophenyl, halomethylphenyl;
    kz hydrogen. Halogen, methyl, trifluoromethyl;
    Q - CH or nitrogen,
    L is aryl, aryloxy, diphenyl C-alkyl, di (halophenyl) e-alkyl, 2-propenyl, Z-aryl-2-propenyl, Z-aryloxy-2-hydroxypropyl, or the radical 2 - Cp, H2 where m is an integer from 1 to 4 inclusive; and Z is 4-aryl-4,5-dihydro-5-oxo-1H-tetrazol-1-yL, C | - C4-alkyl-4,5-dihydro-5-oxo-1H -tetrazol-1-yl, 2, 3-dihydrr-2-oxo-1H-benzimidazol-1-yl, arylcarbonyl 10.01.79. - all other radicals.
     This invention relates to organic chemistry and relates to a process for the preparation of new N-heterocyclic 4-piperidines or their salts having biological activity.
    The reaction of scouring amines ij is known.
    The purpose of the invention is to obtain new derivatives of H-heterocyclyl-4-piperidinamines, which have biological activity and expand the range of means of influence on a living organism.
    i The goal is achieved based on a well-known reaction: a method of producing derivatives. H-heterocycles of the l-y-piperidinamines of the formula J: ...
    where in - hydrogen, methyl;
    B. hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl R — hydrogen, alkyl C and C, cycloalkyl Cj-Cf, phenyl, halophenyl, alkyl C, substituted with one or two substituents from the group phenyl, halophenyl, nitrophenyl, halomethylphenyl ,
    R is hydrogen, halogen, methyl,
    trifluoromethyl / Q — CH group or nitrogen; L is alkyl Cd, substituted by cyanoprop, hydroxyl, alkyygroup C4,
     C4-alkylcarbonyloxy, aryl, aryloxy, arylthio or amino, diphenyl — G — C} -alkyl, di-. (Halo-phenyl) —C — C4-alkyl, 3-cyano-3/3-diphenylpropyl, 2-propenyl, 3- aryl-2-propenyl, 3-aryloxy-2-hydroxypropyl, or a radical of the form r-Cn, m is an integer from 1 to 6 4 inclusive, and Z is 4-aryl-4, 5-dihydro-5-oxo-1H- tetrazol-1-yl, Cis-C, j-alkyl-4, 5-dihydro-5-oxo -1H-tetrazol-1-yl, 2,3-dihydro-1, 4-benzodioxin-2-yl, 2, 3-dihydro-1,4-benzodioxin-b-yl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, 2,3-dihydro-oxo-1H-benzoxazing4-yl, (S, 11-dihydro-5H-benzo- / a, o / -cyclohepten-5-yl den) methyl, 4-morpholinyl, arylcarbonyl, arylaminocarbonyl C1 in which the substituted phenyl has 1-3 substituents, each of KflPfope is independently selected from the group halo, methyl, C 4 C -alkoxy, trifluoromethyl,. hydroxyl, nitro, amino ,. and of which one substituent may be selected from the group of methylthio, C1-alkoxycarbonylmethoxy, phenylcetyloxy, phenylmethoxycarbonyloxy, methoxybenzoyloxy, phenylmethoxy- (C | G4) -alkyloxycarbonyloxy, methylsulfonyl, cyanomethoxy,
    the salts thereof, which consists in the reaction of the general formula II:
    - (,
    where R, R, n, k and Q have the indicated meanings: with a corresponding elephant ester of the formula 111:
    L-y, where L - has the indicated values, Y - halogen, methylsulfonyloxy or 4-methylphenylsulfonyloxy, in an inert solvent in the presence of a base at a temperature from room temperature to reflux temperature of the medium, followed by isolation of the target product as a base or salt.
    The condensation reaction of a compound of formula I with a compound of formula 111 is carried out in a known manner in an inert organic solvent such as hydrocarbons, such as benzene, methylbenzene, dig methylbenzene, and the like. lower alkanols, for example, methanol, ethanol, 1-butanol and the like, ketones, for example 4-methyl-2-pentanones, and the like, N, N-dimethylformamides (DMF), nitrobenzenes, and the like. ,
    To remove the acid that is released during the reaction, an appropriate base can be added, for example an alkali metal carbonate or an acidic alkali metal carbonate, or an organic base, for example L, M-dimethylethanamine or N- (1-methylethyl -2-propanamine. in cases it is more preferable to add iodide, preferably alkali metal iodide. To increase the rate of the reaction, elevated temperatures can be used.
    The reaction product can be isolated from the reaction mixture and, if necessary, further subjected to purification by known methods.
    The compounds of the formula D can be converted to therapeutically active non-toxic salts by the addition of acids as a result of treatment with a corresponding acid, for example an inorganic acid, such as hydrohalohydrogen, for example hydrochloric, hydrobromic and the like; sulfuric, nitric, phosphoric acids, etc., or an organic acid, such as acetic, propanoic, 2-hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, dipropanoic, dibutanoic,
    (2) -2-dibutene, (E) -2-butene, 2-oxydibutane, 2,3-dioxydibutane, 2-OX.I-1,2,3-paropantricarboxylic, benzoic, Z-phenyl-2-propenoic, OS-hydroxybenzeneacetic, methane
    (, mono) sulfonic acid,) sulfonic acid, benzene (mono) sulfonic acid, 4-methylbenzene (mono) sulfonic acid, cyclohexanesulfamic 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and other similar acids.
    Conversely, the said salts can be converted by treatment with alkalis into free bases.
    The compounds of formula 1 and their pharmaceutically acceptable acid addition salts are potent antihistamine agents that can be used to obtain valuable
    medicines for use in the treatment of humans and animals.
    The antihistamine properties of the compounds of formula I can be established using the following method
    test).
    Ratstsitsita rats from action - compounds that cause the death of the animal.
    This compound is a mixture of oligomers, obtained by condensation of para-methoxy-m-methylphenatilamine and formaldehyde, and is a potent, histamine-releasing agent. Protection against the lethal circulating collapse, which is caused by the presence of this compound, makes it possible to quantify the antihistamine activity of the test compound. In the experiment, male Wistar rats weighing 240-260 g were used. After a period of fasting, the rats were transferred overnight.
    in laboratory conditions (temperature: 21 + 1 ° С, relative humidity 65 + 5%);:
    The rats are exposed to a test compound that can
    use together with a solvent (sodium chloride solution). 0.9% of the compound is administered to the rat either subcutaneously or by stomatological means. One hour after the treatment of the rats described intravenously.
    A test compound is injected, which is dissolved in water at a dose of 0.5 mg / kg (o, 2 ml / 100 g animal weight) just prior to administration. AT
     control experiments where 250 rats are used, a solvent is administered to all rats, and a standard dose of the test compound is administered to all rats in the control group. After 4 hours, no more than 2.8% of the animals survived. Such an experiment result can be considered as a reliable criterion of the protective effect of using the investigational medicinal product.
    The compounds of the formula I and their pharmaceutically acceptable acid addition salts are highly active in the described experiment, they have a protective effect and protect the animals from the lethal effects that the compound causes, and are administered subcutaneously or stomatologically in doses not exceeding 2 5 mg / kg. The proposed compounds are effective even in doses below 0.16 mg / kg.
    Due to their strong antihistamine activity, the proposed compounds can be used in a wide variety of pharmaceutical forms. To prepare pharmaceutical. Which composition, effective antihistaminic amount of one of the compounds (in the form of a base or an acid addition salt), as an active ingredient, is thoroughly mixed with a carrier acceptable from a pharmaceutical viewpoint; moreover, a wide variety of materials can be chosen as a carrier, depending on the form of use of the preparation. . Such pharmaceutical compositions are preferably in unit dosage form suitable for use, preferably by the oral, rectal and parenteral route. For example, to obtain compositions in the form of dosages for dental use, it is clear to use any of the known pharmaceutical media, such as water, glycols, oil, alcohols, and so on, when preparing liquid preparations for dental use — suspensions, syrups, elixirs, and solutions. Solid carriers; such as starch, sugar, kaolin, carrier lubricants, dispersing agents, and t, n, can be used in the preparation of powders, granules, capsules and tablets. Because of its simple use, tablets and capsules will preferably be used to obtain dental single doses; in this case
    use solid pharmaceutical carriers. To obtain parenteral compositions (in general) the carrier contains sterile water, which constitutes the majority of the carrier, other ingredients may also be contained, for example, to increase solubility. Injection solutions can be prepared in which the carrier contains saline solution, glucose solution or a mixture of salt and glucose solutions. Injectable suspensions may also be prepared in which the appropriate liquid carriers, suspending agents and t, p are used. The added salts of the acid of the compound of formula 1, due to their higher solubility compared with the corresponding base form, are more suitable for the preparation of aqueous compositions
    in particular, it is preferable that said pharmaceutical compositions be prepared in the form of unit doses, since in this case the use of the preparation is greatly facilitated and the uniformity of its use is improved for the required period of time. Dosage unit forms are physically discrete units that are used as unit doses, each unit containing a predetermined amount of the active ingredient, which is calculated based on the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets, capsules, granules, sachets of powders, wafers, injection solutions or suspensions, full teaspoons, full tablespoons, and t, n, or individual portions of said unit doses.
    Example 1, Mixture of 2 parts, 2- (bromoethoxy) benzene, 3 hours, 1 - (phenylmethyl) -N- (4-piperidinyl | -1H benzimidazole-2-amine, 2 hours, sodium carbonate, 0.1 hour, potassium iodide and 90 h, N, H-dimethylformamide is stirred overnight at, the reaction mixture is cooled and poured into water. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted into hydrochloride and 2-propanone. The salt is separated and dried. , resulting in 3.5 hours, (70%) n-G1- (2-phenoxyethyl) -4-piperidinyl -1- (phenylmethyl) 1H-benzimidazole-2-amine chlorohydrate monohydrate with mp, 197.6 ° C,
    Example 2 In accordance with the procedure of Example 1 and using equivalent amounts of the appropriate starting materials, the compounds are obtained in the form of free bases or in the form of attached acid salts by reacting the free base with a suitable acid and are shown in Table 2. 1 and 2..
    Example 3. A mixture of 2.4 parts of (2-bromoethyl) benzene, 6 parts 5 (6) -fluoro-1 (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-aminobromohydrate, 4 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone are stirred and refluxed overnight using a water separator. The reaction mixture is cooled and poured into water. The layers are separated and the aqueous phase is extracted three times with trichloro (ethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3, volume proportions as eluent The pure fractions are collected and the eluent is evaporated. The residue is separated on a silica gel chromatography column using a mixture of ethyl acetate and methanol (93t7, volume proportions) as eluant. The first fraction A-isomer is collected and the eluent is evaporated. The residue is washed with a mixture of 2, 2-hydroxy-511C-propane, and petroleum ether and dried, resulting in 1 hour (17.5% b-fluoro-1- (4-fluorophenylmethyl) -N- (1- phenylethyl) -4-piperidinyl-1H-benzyl midazol-2-amine with mp 178 ,.
    The second fraction (b-isomer) is collected and the eluent is evaporated. The residue is washed with a mixture of 2, 2.-hydroxy-8g of c-propane and petroleum ether, and dried, resulting in the formation of 1.2 p. Of 5-fluoro-1- (4-fluorophenylmethyl -) - Nl- (2-phenylethyl) -4-piperidinyl) -1H-benzimidazole-2-amino monohydrate with so pl. 188.8 ° C.
    Example 4. A mixture of 4 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 1 part 1- (phenylmethyl) -Y- ( 4-piperidinyl) -1H-benzimidazole-2-aminobromohydrate, 5 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N, N-dimethylformamide are stirred and maintained at 70 ° C overnight. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. After stirring for 1 hour, the solvent is evaporated and the residue is taken up in water. The free base is released by known methods using ammonium hydroxide,
    and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is separated by filtration and dried, resulting in 3.3 parts (45.7%) of 1,3-dihydro-1- (phenylmethyl) -1H-benzimidazol-2-ylamino-1-piperidinyl propyl -2H-benzyl Shda evil-2-she with so-called 243.1 ° C.
    In accordance with a similar procedure and using equivalent amounts of the corresponding starting materials, (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino -1-piperidinyl-propyl -1, 3-dihydro-2H-benzimidazrl-2-one with m.p. . 327,6®C; l -, (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamiHoJ-3-methyl-1-piperidium 11l-propyl, 3-dihydro-2H-benzimidazol-2-one chlorohydrate-2-propanolate (1: 1) with mp 244.10 s; 3- (4-fluorophenylmethyl) -3H-imidazo Ji, 5-pyridin-2-ylamino -1-piperidinyl-propyl -1,3-dihydro-2H-benzimidazol-one, mp 202 , 1,3-dihydro-1-G3-4- (1-phenyl-1H-benimidazol-27-ylamino) -1-piperidyl propyl) -2H-benzimidazol-2-one, so pl. 185,: i- 3- {4- 1- (4-fluorophenyl) -1H-benzimidazol-2-ylamino.-1-piperidinyl1 | ppil-1, 3-dihydro-2Y-benzimidazole-2on, so pl. 188.9 ° C, 1,3-dihydro-1-3-f4-phenylmethyl) -3H-imidazo114, 5-to pyridin-2-ylamino-1-piperdinyl-propyl} -2H-benzimidaeol-2-one, t .pl. 221.7 seconds
    Example 5. A mixture of 2.3 parts of 2- (4-methoxyphenyl) -ethyl methanesulfonate, 4.9 parts of 1- (4-fluorophenyl) methyl -N- (4-piperidinyl) -1H-benzimidazole-2- amine bromo dihydrate, 3.2 parts sodium carbonate, 0.1 parts potassium iodide and 90 parts N, H-dimethylformamide are stirred overnight at 70 ° C. The reaction mixture is poured into water. The product is extracted with methyl benzene. The extract is washed with water, dried, filtered and evaporated. The residue was purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (98: 2 volume proportions) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-hydroxy-.StiC-propane, resulting in 2.2 parts (48%) of 1- (4-fluorophenylmethyl) (4-methoxyphenyl) ethyl-4-piperidinyl-1H-benzimidazole- 2-amine, so pl. 172,
    Example 6 In accordance with the procedure of Example 5 and using equivalent amounts of the appropriate starting materials, the compounds are obtained in the form of a free base or in the form of an acid addition salt by reacting the free base with a suitable acid, as shown in Table 2. 3. Example 7. A mixture of 2.8 parts of 2- (2-thienyl ethyl -4-methylbenzenesul fonate, 4.9 parts 1-1 4-fluorophenyl) methyl -N- (4-piperidinyl) -1H-benzimidazole2- amine bromide dihydrate, 2.1 hours, sodium carbonate, 0.1 parts potassium iodide and 90 hours, N, N-I-dimethylformamide is stirred overnight at, The reaction mixture is cooled and poured into water. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated, the residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (98: 2, volume proportions) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered and dried, resulting in 2.3 hours (53%) of 1- (4-fluoro-phenylmethyl) 2- (2-thienyl-ethyl-4-piperidinyl 5-Sh-benzig / Shdazol2-amine, mp. 151 , 6 ° C. According to the same procedure and using: equivalent amounts of the corresponding starting materials, 1- (phenylmethyl) 2- (2-thienyl ethyl -4-piperidinyl-1H-benzimidazol-2-amine chlorohydride monohydrate, so pl. 259 273 ° C; 1- (4-ftrrphenylmethyl) 2- (1-naphthalenin ethyl-4-piperidyl nyl-Sh-benzimidazole-2-amine, mp 143,1ci 3- (4-fluorophenylmethyl-M-1 1- 2- (2-thienyl) ethyl 3-piperidyl-3H-imidazo 4, 5-1} pyridin-2-amine , mp. 176.2c. Following the procedure of Example 7, (2-bromo-4-methoxyphenyl ethyl 1-4-piperidine or J-1- (4-fluorophenyl methyl -1H benzimidazole 2-amine) is obtained; 133, (R 47.195). Example B. A mixture of 3.3 h of H-methyl-N-t l- (2-phenylethyl) -4-piperidinyl-g-1H-benzimidazol-2- stirred and cooled below 5 ° C. amine, 100 parts of dimethyl sulfoxide and 90 hours of benzene were added to 0.65 hours, 30% sodium hydrate dispersion. After stirring for 30 minutes, 1.5 parts of 1- (chloromethyl-4-fluorobenzene and stirring continue overnight, warm to room temperature. The reaction mixture is poured onto water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated .. The residue is converted to the hydrochloride in 2-propanone. The salt is separated by filtration and crystallized from 2-pr6Pan 6L, resulting in (those that are obtained 2, B h. (54.4% j 1- (4-fluorophenyl) methyl-C-methyl-K-1- (2-phenylethyl ) -4-piperidinyl -1H-benzimidazole-12-amine chlorohydrate, mp 246 ,, I According to the same procedure and using equivalent amounts of the corresponding starting materials, 1- (4-chlorophenyl) methyl -N-Ll- ( 2-phenylethyl) -4-piperidinyl - M-Cphenylmethyl) -1H-benzimidazol-2-amine, mp 13Bc 1-C2-methoxyphenyl) methyl-N- {l C2-phenylethyl) -4-piperidinyl .- n (phenylmethyl) -1H-benzimidazol-2-amine, so pl. 148.3 ° C, -. 1 - {(4-methoxyphenyl) methyl -N-tl- (2-phenylethyl) -4-piperidinylZ-H- (phenylmethyl) -1H-benzimidazole-2-amine, m.p. 122, 1- (4-fluorophenyl) methyl-Nl- (2-phenylethyl) -4-piperidinyl-N- (phenylmethyl -1H-benzimidazol-2-amine, mp 139.3 C, 1- (4- methylphenyl) methyl (2-phenylethyl) -4-piperidinyl-K-phenylmethyl) -1H-benzimidazol-2-amine, m.p. 123, 1- (2-chlorophenylmethyl) (2-phenylethyl-4-piperidinyl-N- (phenylmethyl) -1H-benzimidazol-amine, mp 105, 1-butyl-N- i- (2-phenylethyl-4 -piperidinyl N- (phenylmethyl) -1H-benzimidazol-2-amine, mp 76.5 ° C; 1-ethyl-N- 1- (2-phenylethyl) -4-piperidinyl | -N- (phenylmethyl) -1H-benzimidazole 2-amine chlorohydride dihydrate, mp 157.2 ° C. Example 9. Mixture of 1.6 h 1- (1-chloroethyl) -2-fluorobenzene, 3.2 parts N-Ll- 12-phenylstil) -4-piperidinyl-1H-benzimidazol-2-amine, 1 part of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. use separator in The reaction mixture is cooled, poured into water, and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified on a chromatography column over silica gel using a mixture of trichloromethane and methanol (98: 2, volume proportions) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-hydroxy-isopropane. The product is separated by filtration and dried, resulting in 1, Part (40, (4-fluorophenyl) ethyl-Htl- (2-Phenylethyl) -4-piperidinyl 1 -1H-benzimidazol-2-amine, m.p. G61 ,. P p i. meper, 10. In accordance with the procedures of examples 5 and 6 and using equivalent amounts of the corresponding starting material, the compounds are obtained in the form of free fertilization or in the form of an added acid salt after the reaction of the free base with the corresponding acid, presented in Table. four.
    The data of elemental analysis are given in table. five.
    Example 11. A mixture of 3.2 parts of N- {1- (2-phenylethyl) -4-piperidinyl) -1H-benzimidazol-2-amine, 2.9 parts of 2- (2-thienyl) ethyl-4- methylbenzolsulfonate, including sodium carbonate and 135 parts of 4-methyl-2-pentanone are stirred and refluxed overnight in the presence of a water separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2, volume proportions as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2-hydroxy-5c-propane and 2 -propanone resulting in 1 part (23.2%) of N-.1- (2-phenylethyl) -4-piperidinyl (2-thienyl) ethyl -1H-benzimidazol-2-amine with mp 118, Example 12. In a stirred and cooled (below 5c) mixture of 4 hours, (2-phenylethyl) -4-piperidinyl - - (phenylmethyl) -1H-benzimdazole-2-amine, 100 parts of dimethyl sulfide. and 90 parts of benzene are added. 0.5 hours of a dispersion of the SO3% sodium hydride dispersion. After stirring for 30 minutes.
    At a temperature below 5 ° C, 1.3 parts of chloromethylbenzene are added to the mixture. and stirring is continued for 4 hours, while the mixture is allowed to warm to room temperature. The reaction mixture is poured onto water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is purified on a silica gel column chromatography using a mixture of trichloromethane and methanol (97: 3, volume proportions) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to nitrate in 2-propanone. The salt is isolated by filtration and dried, resulting in 1.5 hours (24%) of (2-phenylethyl) -4-piperidyl.an, N3-n, 1-5-y- {phenylmethyl) 1H-benzimide: sol-2. -amindinitrate with so pl. 15b, 9s
    Example 13. A mixture of 1.2 parts of 3-bromo-1-propene, 4 parts of 4-t2-4-.1- / 4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino-1-pyridinyl ethyl phenol , 1.4 parts of potassium carbonate and 160 parts of 2-propanone are stirred and refluxed overnight. The reaction portion is filtered and the filtrate is evaporated. The residue is subjected
    chromatography on silica gel using a mixture of three spormethane and methanol (98: 2, volume proportions) as eluent. Pure fractions are collected and
    the eluent is evaporated. The residue is converted to the hydrochloride in 2-propanone. The salt is separated by filtration and dried, whereby 1 hour is obtained. (19, 9%) 1- (4-fluorophenylmethyl) -N-tir2-4- (2-propenyloxy) phenyl ethyl g-4-piperidinyl-Sh-benzimidazole - / - amine hydrochloride with mp. 224.7 ° C.
    Example 14.. Cjiecb .. and, from 15 parts of thionyl chloride, 4 parts of 4-tl- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamine 1 -1-pi-pyridine ethanol chloroyl dihydrate and 375 parts of trichloromethane are mixed and refluxed during nights- The precipitated product is isolated
    filtration and dried, resulting in 13 parts (83%) of (2-chloroethyl) -4-piperidinyl1-1- (4; -fluorophenylmethyl) -1H-benzimidazole-2-amine hydrochloride with m.p. 260 ° C.
     EXAMPLE 15 To a stirred mixture of 4.5 parts of (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino -1-piperidineethanol, 2 parts of N, K-diethylethanamine and 195 parts of dichloromethane are added dropwise. 1. A solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane is added. Upon completion. stirring is continued overnight at room temperature. Water is then added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (98: 2, volume proportions) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into hydrochloride in
    2-propanone. The salt is isolated by filtration and dried, resulting in 2.5 hours (43.5%) of 2- {4-1- (4-fluoro-phenylmethyl -1H-benzimidazol-2-yl-ylamyl) -1-piperidinyl ethyl. 4-methoxybenzoate, hemihydrate chlorohydrate with
    m.p. 189.2 ° C.
    In accordance with a similar procedure and using equivalent amounts of the appropriate starting materials, the following are also obtained.
    Compounds: l- (4-fluoro | enylmethyl -1H-be113 Imidazol-2-ylamino -1-piperidinyl ethyl phenyl benzene acetate, mp 135.10s, 4- 2-4-tl- (4-fluorophenylmethyl -1H- benzimidazol-2-ylamino -1-piperidinyl 5-ethyl phenyl. -methoxybenzoate, mp 157.1 ° C, (4-fluorophenylmethyl) -1N-benzimidazol-2-ylamino -1-piperidinyl these phenyl methyl carbonate, mp.
    134.5C and (4- 2- {4- 1- (4-fluorophenylmethyl) -1H-yenzimydaeol-2-ylaminoT 1-piperidinyl ethyl phenyl | -phenylmethylcarbonate, mp. 147.8 ° C.
    Example 16. In a stirred mixture of 3.8 parts and -1.2-aminoethyl) 1-4-piperidinyl -1- (4-fluorophenylmethyl} -1H-benimimidazol-2-amine, 1.h. N, N-diethylethanamine and 195 parts of dichloromethane is added dropwise a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. After the addition is complete, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and The residue is purified on a chromatography column over silica gel using a mixture of trichloromethane and methane. ol (98: 2, volume ratio). zlyuenta as pure fractions were collected and the eluent was evaporated The residue was converted into the hydrochloride salt in 2-propanol The salt is isolated by filtration and dried to give 1h...
    I-C2-4- 1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino3 -1-piperidinyl-ethyl2-4-methoxy-H- {4-meter-xibenzo-4l) benzamide chlorohydrate with m.p. 161 ,.
    With p 17. A mixture of 5.5 parts of H- l- (1N.benzimidazol-2-yl) -4-piperidinyl-I- (phenylmethyl) -1H-benzimidazol-2-amindinitrate, 1.5 hours 1- (chloromethyl) -4-fluorobenzene, 5 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone are mixed and refluxed overnight using a water separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2, volume proportions) as elvent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2- hydroxy-5cc-propane. The product is isolated by filtration and dried, resulting in 1.5 hours (28.3%) of (4-fluorophenylmethyl) 1H-benzimidazol-2-yl -4-piperidineyl- (phenylmethyl) - 1H-benzimidazole-2-amine with mp 163,
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    Table 5
    49
    69.44
    69.05
    48,832
    50
    1056902
    Continued table. five
    13.84
    13.96
    6.26 6.44
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives
    N-heterocyclyl-4-piperidine amines of the formula P: _.
    where R is hydrogen, methyl, '
    R * is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl;
    R 2 is hydrogen, Cj is Cc and C 7 alkyl, Cj is C J -cycloalkyl, phenyl, halo phenyl, Cd is Cd alkyl substituted with one or two substituents from the group phenyl, halo phenyl, nitrophenyl halo methyl phenyl;
    H 3 is hydrogen, halogen, methyl, trifluoromethyl;
    Q is CH or nitrogen;
    L - Ci - Cd-alkyl substituted with cyano, hydroxyl, C - C 4 -alkoxy, Cd - Cd-alkylcarbonyloxy, aryl, aryloxy, arylthio or amino, diphenyl - Cd - Cd-alkyl, di- (halo-phenyl) - C, - - Cd'alkyl,
    3-cyano-3,3-diphenylpropyl, 2-propenyl, 3-aryl-2-propenyl, 3-aryloxy-2-hydroxypropyl, or a radical of the form g-CiHH ^, where w is an integer from 1 to 4 inclusive and Z is 4-aryl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, Cd is Cd-alkyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, 2 3-dihydro-1,4-beneodioxin-2-yl, 2, 3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, 2, 3-dihydro-3-oxo-1H-benzoxazin-4-yl (10,11-dihydro-5H-dibenzo- (a, o / cycloheptes-5-ylidene) methyl, 4-morpholinyl, arylcarbonyl, arylaminocarbonyl, Cd Sde-alkylamino-carbonylamino, arylcarbonylamino, Sd - C 4 -a mino, aminocarbonylamino, arylamino-carbonyl-yl-amino, or arylamino-kylcarbonylate, wherein aryl is phenyl, substituted phenyl, naphthalenyl, thienyl or pyridinyl, in which substituted phenyl has 1-3 substituents, each of which is independently selected from the group of halogen, methyl, Cd-Cd-alkoxy, trifluoromethyl, hydroxyl, nitro, amino, and of which one substituent may be selected from the group of methylthio, Cd-Cd-alkoxycarbonylmethoxy, phenylacetyloxy, phenylmethoxycarbonyloxy, methoxybenzoyloxy, phenylmethoxy- (Cd-Cd) .alkyloxycarbonyl ethysulfonyl.,. cyanomethoxy, or their salts, characterized in that the compound of general formula II:
    SLU 1056902 where R, R <, R 2 , r3 and Q are given values, are introduced into the interaction with the corresponding ester of the formula Ills
    LY, where L has the indicated meanings, Y is halogen, methylsulfonyloxy, or 4-methylphenylsulfonyloxy in an inert solvent in the presence of a base at room temperature to reflux temperature, followed by isolation of the target product as a base or soda.
    Priority by signs:
    0.30.78 at, I
    R is hydrogen, methyl,
    R * - hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl
    R 4 is hydrogen, Cd-Cd- and Cy-alkyl, C 3 -C 5 -cycloalkyl, Cd-Cd-alkyl substituted with one or two substituents from the group phenyl, halo phenyl, nitrophenyl, halogenmethyl phenyl;
    - hydrogen, halogen, methyl, trifluoromethyl;
    Q - CH or nitrogen /
    L - aryl, aryloxy, diphenyl Sd- Cq-alkyl, di (halophenyl) Sd- C 4 -alkyl, 2-propenyl, Z-aryl-2-propenyl, Z-aryloxy-2-hydroxypropyl, or a radical 2.- C m H 2fr < where w is an integer from 1 to 4 inclusive; Z represents 4-aryl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, C | - Cd-alkyl-4,5- dihydro-5-oxo-1H-tetrazol-1-yl, 2, 3-dihydro-2-oxo-1H-benzimidazol-1-yl, arylcarbonyl ;. 01/10/79. - all other radicals.
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    同族专利:
    公开号 | 公开日
    JPH0240666B2|1990-09-12|
    GR64907B|1980-06-07|
    EG13913A|1982-09-30|
    PL214648A1|1980-03-24|
    CS222779A2|1987-03-12|
    MY8500046A|1985-12-31|
    YU78479A|1983-10-31|
    YU42484B|1988-10-31|
    JPS54151982A|1979-11-29|
    AU4529679A|1979-10-18|
    CS256358B2|1988-04-15|
    DK129879A|1979-10-04|
    YU43158B|1989-04-30|
    NO154058B|1986-04-01|
    DK169325B1|1994-10-10|
    FI64801C|1984-01-10|
    IL56992D0|1979-07-25|
    JPS641477B2|1989-01-11|
    NO791097L|1979-10-04|
    DE2961740D1|1982-02-25|
    EP0005318A1|1979-11-14|
    JPH01117880A|1989-05-10|
    YU50283A|1983-12-31|
    PT69429A|1979-05-01|
    ZA791557B|1980-11-26|
    IE47818B1|1984-06-27|
    HU182965B|1984-03-28|
    NO154090C|1986-07-16|
    CA1140119A|1983-01-25|
    NZ189978A|1984-05-31|
    FI791084A|1979-10-04|
    PH15877A|1983-04-13|
    FI64801B|1983-09-30|
    ES479206A1|1979-12-16|
    NO154090B|1986-04-07|
    RO79320A|1982-08-17|
    IE790676L|1979-10-03|
    PL123380B1|1982-10-30|
    EP0005318B1|1982-01-06|
    SG29883G|1984-04-19|
    IL56992A|1983-03-31|
    NO842563L|1979-10-04|
    AT373887B|1984-02-27|
    CY1250A|1984-08-31|
    AU523352B2|1982-07-22|
    BG38164A3|1985-10-15|
    HK3184A|1984-01-20|
    NO154058C|1986-07-09|
    ATA242579A|1983-07-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US89253478A| true| 1978-04-03|1978-04-03|
    US06/002,276|US4219559A|1979-01-10|1979-01-10|N-Heterocyclyl-4-piperidinamines|LV920187A| LV5016A3|1978-04-03|1992-11-09|Method of obtaining N-heterocyclyl-4-piperidinamines derivatives or islands thereof|
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