Patent GB-1002187-A (GB)
Title: New quinoline derivatives
IPC: C07D295/205
Filed: 1962-05-25
Abstract: The invention comprises compounds of the formula <FORM:1002187/C2/1> and non-toxic acid addition salts thereof, wherein the chlorine atom is in the 6- or 7-position of the quinoline ring, A represents a divalent straight or branched chain aliphatic hydrocarbon containing 2 to 6 carbon atoms, Z represents an aromatic heterocyclic group linked to the diazacycloalkane ring through a carbon atom (the heterocyclic atoms of which consist of one or two nitrogen atoms), unsubstituted or substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy, dialkyl sulphamoyl, amino, alkanoylamino, trifluoromethyl, phenyl, phenylamino, and phenyl and phenylamino substituted in the phenyl group by one or more halogen atoms or alkyl groups, n is 2 or 3, and the diazocycloalkyl ring may carry one or more alkyl groups containing at most 4 carbon atoms, or phenyl groups, and the preparation thereof (a) by reacting a compound of the formula <FORM:1002187/C2/2> with a quinoline of the formula <FORM:1002187/C2/3> wherein X1 represents a chlorine atom or a phenoxy radical; or (b) by reacting a compound X2-Z where X2 is a halogen atom, a phenoxy radical or the acid residue of a reactive sulphuric or sulphonic acid with a compound <FORM:1002187/C2/4> or (c) by reacting a compound of the formula <FORM:1002187/C2/5> with a quinoline of the formula <FORM:1002187/C2/6> wherein R is a hydrogen atom or an alkanoy group containing up to 4 carbon atoms or a benzyl group, X3 is a chlorine atom or the residue of a reactive sulphuric or sulphonic ester, and where R is an acyl or a benzyl group, deacylating or debenzylating the resultant product, or (d) by reducing the carbonyl group of a quinoline of the formula <FORM:1002187/C2/7> where B represents a divalent grouping -CO-A1- or -A1-CO in which A1 is an aliphatic hydrocarbon radical containing up to 5 carbon atoms and is such that CH2-A1 or A1-CH2 is identical with the hydrocarbon radical A, to a methylene group.  4 - (5 - 11 - Piperazinyl - 2 - pentyl)amino - 7 - chloroquinoline is prepared from 4-amino pentanol and 4,7-dichloroquinoline through 4,51 - hydroxy - 21 - pentylamino - 7 - chloroquinoline and 4,51 - chloro - 2 - pentylamino - 7 - chloroquinoline. Similarly are prepared the corresponding 6-chloro-compounds; 4-31-hydroxy- and 4 - 31 - chloro - 11 - propylamino - 7 - chloroquinoline and 4 - (3 - 11 - piperazinyl - 1 - propyl)amino - 7 - chloroquinoline; 4 - (3 - 1 - piperazinyl - 2 - propyl)amino - 7 - chloroquinoline; 4 - 21 - hydroxy- and 4 - 21 - chloro - 11 - iso butyl - ethylamino - 7 - chloroquinoline and 4 - (2 - 11 - piperazinyl - 1 - isobutyl - ethyl)amino - 7 - chloroquinoline; 4 - 21 - hydroxy - and 4 - 21 - chloromethyl - 11 - propylamino - 7 - chloroquinoline and 4 - (3 - 11 - piperazinyl - 2 - methyl - 1 - propyl)amino - 7 - chloroquinoline (2 - hydroxymethyl - propylamine is prepared by reduction of ethyl a -cyanopropionate); 4-(2-11-piperazinyl - 1 - ethyl - ethyl)amino - 7 - chloroquinoline; D(-) 4 - 31 - hydroxy- and D(-) 4 - 31 - chloro - 2 - propylamino - 7 - chloroquinoline and D(-) 4 - (3 - 11 - piperazinyl - 2 - propyl)amino - 7 - chloroquinoline and the corresponding L(+) isomers.  4 - (3 - 11 - Piperazinyl - 2 - propyl)amino - 7 - chloroquinoline is prepared by chloroacetone oxime and ethoxycarbonyl piperazine through 1-21-oximino-11-propyl-4-ethoxycarbonyl piperazine, 1 - 21 - amino - 1 - propyl4 - 4 - ethoxycarbonyl piperazine and 1 - (2 - 71 - chloro - 41 - quinolinylamino - propyl) - 4 - ethoxycarbonyl piperazine. Similarly is prepared 1-31. - oximino - 21,21 - dimethyl - 11 - propyl - 4 - ethoxycarbonyl piperazine (through 1-21-formyl-21 - methyl - 11 - propyl - 4 - ethoxycarbonylpiperazine by Mannich reaction from formaldehyde, isobutyraldehyde and ethoxy carbonylpiperazine), 1 - 31 - amino - 21,21 - dimethyl - 11 - propyl - 4 - ethoxycarbonylpiperazine, 1 - (3 - 71 - chloro - 41 -quinolinylamino - 2,2 - dimethyl - 1 - propyl) - 4 - ethoxycarbonylpiperazine and 4 - (3 - 11 - piperazinyl - 2,2 - dimethyl - 1 - propyl) - amino - 7 - chloroquinoline; 1 - (3 - oximino - 1 - butyl) - 4 - ethoxycarbonylpiperazine (from 1 - (3 - oxo - 1 - butyl) - 4 - ethoxycarbonylpiperazine), 1 - (3 - amino - 1 - butyl) - and 1 - (3 - 71 - chloro - 4 - quinolylamino - 1 - butyl) - 4 - ethoxycarbonylpiperazine and 4 - (4 - 11 - piperazinyl - 2 - butyl)amino - 7 - chloroquinoline; and 4 - (4 - 11 - piperazinyl - 1 - butyl)amino - 7 - chloroquinoline. 4 - (5 - Methanesulphonyloxy - 2 - pentyl - acetylamino) - 7 - chloroquinoline is prepared by acetylating 4 - (5 - hydroxy - 2 - pentyl)amino - 7 - chloroquinoline to give 4 - (5 - acetoxy - 2 - pentyl)acetylamino - 7 - chloroquinoline thence through 4 - (5 - hydroxy - 2 - pentyl)acetylamino - 7 - chloroquinoline.  1 - (1 - Methyl - 2 - aminoethyl)piperazine is prepared from 1 - benzyl - 4 - (1 - cyano - ethyl) - piperazine (from N-benzylpiperazine, acetaldehyde sodium cyanide and sodium metabisulphite) through 1-benzyl-4-(1methyl - 2 - amino - ethyl)piperazine; 1 - (5 -amino - 1 - pentyl)piperazine from 1 - (5 - phthalimido - 1 - pentyl) - 4 - ethoxy - carbonylpiperazine (in turn from 1-phthalimido-5-bromopentane and N-ethoxycarbonyl piperazine); and 1 - (3 - amino - 1 - propyl) - 4 - (7 - chloro - 4 - quinolyl)piperazine from 4,7-dichloroquinoline and N - 3 - phthalimido - 1 - propylpiperazine through 1 - (3 - phthalimido - 1 - propyl) - 4 - (7 - chloro - 4 - quinolyl)piperazine.  1 - (4 - 71 - Chloro - 41 - quinolylamino - 1 - pentyl) - hexahydro - 1,4-diazepine is prepared from 4-(5-chloro - 2 - pentyl)amino - 7 - chloroquinoline and hexahydro -1,4-diazepine.  Pharmaceutical compositionc comprise the 4aminoquinolines of the invention or non-toxic acid addition salts thereof together with a pharmaceutical carrier or coating, and are formulated as tablets, pills, dispersible powders, granules, emulsions, solutions, suspensions, syrups and elixirs.  The compositions are useful as antimalarials, anthelmintics or amoebicides.