Patent GB-1382513-A (GB)
Title: 1-pyridylalkyl-indole derivatives
IPC: C07D213/56
Filed: 1972-08-11
Abstract: 1382513 1-Pyridylalkyl-indole derivatives F HOFFMANN-LA ROCHE & CO AG 11 Aug 1972 [13 Aug 1971] 37567/72 Heading C2C Novel 1-pyridylalkyl-indole derivatives of the general formula wherein each of n and r is 1 or 2, q is 0 or 1-4, R 1  is a hydrogen or halogen atom or a C 1-7  hydroxyalkyl, C 1-7  alkyl, C 1-7  alkoxy, acyl, benzyloxy, hydroxy, C 1-7  alkylthio, trifluoromethyl, carboxy, cyano, carbo (C 1-7  alkoxy), nitro, amino, mono- or di-C 1-7  alkyl-amino, sulphamoyl, di-C 1-7  alkylsulphamoyl or difluoromethylsulphonyl or, when r is 2, two adjacent R 1 s are a C 1-7  alkylenedioxy group, R 2  is a (CHY)mA group, in which A is a cyano, hydroxy or alkoxy group, Y is a hydrogen atom or methyl group and m is 0 or 1-7, or a (Q)p-COB group, in which B is a hydroxy, carboxy, C 1-7  alkyl, C 1-7  alkoxy, amino, hydroxylamino, mono- or di-C 1-7  alkylamino, amino-C 1-7  alkoxy, or mono- or di-C 1-7  alkylamino-C 1-7  alkoxy group, Q is a C 1-7  alkylene group and p is 0 or 1, R 3  is a hydrogen atom or a hydroxy or C 1-7  alkyl group and X is a group having one of the formulae in which R 5  is a hydrogen atom or C 1-7  alkyl group, and acid addition salts thereof, base addition salts of those derivatives wherein at least one R 1  is a carboxy group and/or R 2  is a (Q)pCOB group, in which B is a hydroxy or carboxy group and quaternary salts thereof at the pyridine nitrogen atom, are prepared (a) by reaction of a phenylhydrazine of the general formula wherein at least one carbon atom of the phenyl ring in the ortho-position to the carbon atom linked to the nitrogen atom is unsubstituted, or a salt thereof with a cycloalkanone of the general formula wherein at least one carbon atom of the cycloalkane ring adjacent to the carbon atom linked with the oxygen atom is unsubstituted, or a salt thereof; (b) when at least one of R 1  and R 2  is a hydroxymethyl group, by reduction of the corresponding compound of the first general formula above wherein at least one of R 1  and R 2  is a carbo (C 1-7  alkoxy) group or a salt thereof; (c) when the derivative is a carboxylic acid or salt thereof, by hydrolysis of a corresponding carboxylic acid ester of the first general formula above or a salt thereof; (d) when the derivative is a carboxylic acid or a salt thereof, by esterification of a corresponding carboxylic acid of the first general formula above or a salt thereof; (e) when R 2  is a (Q)pCOB group, in which B is a hydroxylamino group, by reaction of the corresponding compound of the first general formula above wherein B is a C 1-7  alkoxy group with hydroxylamine; (f) by salification of an acid or base of the first general formula above to give the corresponding base or acid addition salts, respectively; and (g) by resolution of a compound of the first general formula above or salt thereof in the form of a racemate to give the optically active isomers. 1 - (p - Chlorophenyl) - 1 - [2 - (2 - methyl - 5- pyridyl) - 2 - hydroxyethyl]hydrazine is prepared by treatment of 4-chloro-N-[2-(2-methyl-5-pyridyl)-2-hydroxyethyl] aniline dihydrochloride with aqueous sodium nitrite and reduction of the resulting 4 - chloro - N - [2 - (2 - methyl - 5- pyridyl) - 2 - hydroxyethyl] - N - nitrosoaniline with zinc and acetic acid. 1-[5-(4-Pyridyl)- pentyl] - 1 - (p - tolyl) - hydrazine and 1 - (pchlorophenyl) - 1 - [2 - (2 - methyl - 5 - pyridyl)- ethyl]hydrazine dihydrochloride are obtained analogously from the appropriate aniline derivative. 4 - Chloro - N - [2 - (2 - methyl - 5 - pyridyl)- 2-hydroxyethyl]aniline dihydrochloride is prepared by reaction of 5-(α-bromoacetyl)-2-methylpyridine with p-chloroaniline and reduction of the resulting 4-chloro-N-(6-methylnicotinylmethyl)aniline with sodium borohydride, followed by alcoholic hydrogen chloride. N - [5 - (4 - pyridyl)pentyl] - p - toluidine is prepared by reaction of 5-(4-pyridyl)valeric acid hydrochloride with p-toluidine and reduction of the resulting 5 - (4 - pyridyl) - N - (p - tolyl)- valeric acid amide with lithium aluminium hydride. 4 - Chloro - N - [2 - (2 - methyl - 5 -pyridyl)- ethyl]aniline dihydrochloride is obtained analogously. 5 - (4 - Pyridyl)valeric acid hydrochloride is prepared by reaction of 3-(4-pyridyl)- propyl bromide with diethyl malonate in the presence of sodium and ethanol and acid hydrolysis and decarboxylation of the resulting [3-(4- pyridyl)propyl]malonic acid diethyl ester. Pharmaceutical compositions having hypolipidemic activity comprise, as active ingredient, a 1-pyridylalkyl-indole derivative of the first general formula above or a pharmceutically acceptable salt thereof, in association with a compatible pharmaceutical carrier.