Patent GB-991838-A (GB)
Title: Quinoline derivatives
IPC: C07D295/185
Filed: 1963-06-14
Abstract: The invention comprises compounds of general formula <FORM:0991838/C2/1> wherein A is any C1-C12 hydrocarbon group, R and R1 are halogen or alkoxy (C1-C4) in the 6- or 7-position of the quinoline nucleus, and the piperazine rings may be substituted with one or more alkyl (C1-C4) groups, and non-toxic acid addition salts thereof, and the preparation of the above compounds by one of the following methods: (a) by reacting a compound of formula <FORM:0991838/C2/2> with a compound of formula <FORM:0991838/C2/3> wherein Y represents the acid residue of a reactive ester such as a halogen atom or a sulphuric or sulphonic ester residue, and other symbols have the above meaning; (b) by reacting 2 mols. of a compound of the third formula above with 1 mol. of a diester Y-A-Y, symbols being defined as above; (method (a) or (b) may optionally be carried out in an inert solvent in the presence of an alkali metal derivative or tertiary amine as condensing agent); (c) by reacting a quinoline derivative of formula <FORM:0991838/C2/4> with a compound of formula <FORM:0991838/C2/5> wherein X represents a halogen atom a methoxy or phenoxy group and other sumbols are as defined above; (d) by reacting 2 mols. of a quinoline derivative as in (c) with a compound of general formula <FORM:0991838/C2/6> the symbols being as defined above; (method (c) or (d) may be carried out in an inert organic solvent with a high boiling-point, for example, between 110 DEG  and 200 DEG  C.); (e) by reducing the carbonyl group or groups of a compound of formula <FORM:0991838/C2/7> wherein either or both B1 and B are carbonyl groups at least one being carbonyl, A1 is a hydrocarbon group of not more than 10 carbon atoms and other symbols are as defined above, to a methylene group or groups preferably with lithium aluminium hydride in an inert solvent between 20 DEG  and 50 DEG  C.; (f) in the case where A is a saturated hydrocarbon group by hydrogenating the corresponding compounds in which A contains an ethynylene or vinylene grouping, preferably in the presence of a Raney nickel or Adam's platinum catalyst (in the case where the reactant contains an ethynylene group, the hydrogenation may be stopped at the stage where a vinylene group is formed).  1,5 - Bis - 1 - piperazinyl - pentane is prepared by debenzylating 1,5 - bis - (1 - benzyl-4 - piperazinyl - pentane using hydrogen in the presence of palladium on charcoal, the latter compound is obtained by condensing glutaryl chloride with 1-benzylpiperazine and reducing with lithium aluminium hydride, the resulting 1,5 - bis - (1 - benzyl - 4 - piperazinyl) - 1,5-dioxo-pentane. By a similar method there are prepared 1,5 - bis - 11 - piperazinyl - 3,3-dimethylpentane is prepared the intermediates are 1,5 - bis - (4 - benzyl - 1 - piperazinyl) -3,3-dimethylpentane, and 1,5 - bis - (4 - benzyl - 1 -piperazinyl) -1,5-dioxo-3,3-dimethylpentane) and 1,4 - bis - 11-piperazinylbutane (the intermediates are 1,4-bis-(4-benzyl - 1 - piperazinyl)-butane, and 1,4 - bis - (4 - benzyl - 1 - piperazinyl)-1,4-dioxo-butane).  1,9 - Bis - 11 - piperazinyl - nonane is prepared by reducing 1,9-bis-11-piperazinyl-1,9-dioxo-nonane with lithium aluminium hydride and the latter compound is prepared by reacting benzylpiperazine and azeloyl chloride and debenzylating the resulting 1,9-bis-(4-benzyl-1-piperazinyl)-1,9-dioxo-nonane.  1,4 - Bis - 11 - piperazinylmethyl - benzene is prepared by reacting p-xylylene chloride and piperazine.  7 - Chloro - 4 - 11 - piperazinyl - quinoline is prepared by condensing 4,7-dichloroquinoline and piperazine.  By a similar method 1-(7-methoxy - 4 - quinolyl) - piperazine is prepared from 7 - methoxy - 4 - chloro - quinoline and 1 - (6 - chloro - 4 - quinolyl) - piperazine is obtained from 4,6-dichloroquinoline.  1 - (1 - 71 - Chloro - 41 - quinolyl - 4 -piperazinyl)-2-chloroethane is prepared by condensing 1 - 21 - hydroxyethyl - piperazine with 4,7-dichloro-quinoline and treating the resulting 2 - (1 - 71 - chloro - 41 - quinolyl - 4 -piperazinyl)-ethanol with thionyl chloride.  1,4 - Dichlorobut - 2 - yne is prepared by chlorinating but-2-yne-1,4-diol in pyridine.  1,4 - Bis - (1 - 71 - chloro - 41 - quinolyl - 4 -piperazinyl) - 1 - oxo - butane is prepared by reacting 1 - 71 - chloro - 41 - quinolyl - piperazine with 4-chlorobutyryl chloride, and reacting the resulting 1-(1-71-chloro-41-quinolyl-4-piperazinyl - 1 - oxo - 4 - chlorobutane (the picrate thereof is also prepared) with 1-71-chloro-41-quinolylpiperazine.  1 - (7 - Chloro - 4 - quinolyl) - trans - 2,5-dimethyl - piperazin is prepared by reacting 4,7 - dichloroquinoline with trans - 2,5 - dimethylpiperazine and phenol. 1 - (1 - 71 - Chloro - 41 - quinolyl - 4 - piperazinyl) - 3 - chloropropane is prepared by condensing 4,7 - dichloroquinoline and 1 - (3-hydroxypropyl) - piperazine and 4,7 - dichloroquinoline and treating the resulting 3-(1-71-chloro - 41 - quinolyl - 4 - piperazinyl) - propanol with thionyl chloride.  By a similar method 1 - (1 - 71 - methoxy - 41 - quinolyl - 4 -piperazinyl) - 3 - chloropropane and the intermediate 3 - (1 - 71 - methoxy - 41 - quinolyl - 4 -piperazinyl) - propanol are prepared.  Substituted quinolines of the third general formula above may be obtained from compounds of general formula <FORM:0991838/C2/8> wherein R1 and A have the above meaning by methods known per se, for example, chlorination with thionyl chloride.  Substituted piperazines of general formula <FORM:0991838/C2/9> wherein the symbols have the above meaning, may be prepared by condensation of an alpha, omega, dihaloalkane with a 1-ethoxycarbonyl-piperazine, followed by hydrolysis of the ethoxycarbonyl groups in the resulting alpha, omega - bis - (1 - ethoxycarbonyl) - 4 - piperazinyl(-alkane.  Substituted quinolines of the formula <FORM:0991838/C2/100> wherein the symbols have the above meaning, may be obtained by reacting compounds of the general formula <FORM:0991838/C2/111> wherein the symbols have the above meaning with compounds of the formula <FORM:0991838/C2/122> respectively, wherein the symbols have the above meaning, or by reacting two mols. of a compound of the general formula <FORM:0991838/C2/133> wherein the symbols have the above meaning, with one mol of Cl-CO-A1-CO-Cl, or by reacting a compound of one of the general formulae <FORM:0991838/C2/144> with a compound of the general formula <FORM:0991838/C2/155>  The invention also provides pharmaceutical compositions useful as antimalarials, anthelmintics and amoebicides which comprise a compound of the first general formula above, or a non-toxic acid addition salt thereof, and a pharmaceutical carrier such as an inert solid or liquid, the compositions being for oral, rectal or parenteral administration.