N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation a

Details N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation a N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation a

1996-12-16

1998-04-07

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546163, A61K 3147, C07D21546

Patent

active

057365571

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/EP 95/02123, filed on Jun. 3, 1995, WO 95/35287, published on Dec. 28, 1995.
The invention is concerned with novel diamines, namely N,N'-bis(quinolin-4-yl)-diamine derivatives of the general formula ##STR2## wherein R.sup.1 signifies halogen or trifluoromethyl, R.sup.2 signifies hydrogen or halogen, A signifies cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3, phenylene-1,2, ethene-1,2-diyl or ethyne-1,2-diyl and n and m can be the same or different and signify 0, 1 or 2, as well as their pharmaceutically acceptable salts.
These novel compounds have very good activities against not only chloroquine-sensitive, but also against chloroquine-resistant malaria pathogens. For this reason they are very well suited for preventing malaria and for treating it, especially where the pathogens are resistant to chloroquine.
Objects of the present invention are the novel bis-quinoline derivatives of general formula I as well as pharmaceutically usable salts thereof per se and as pharmaceutically active substances, the manufacture of these compounds and salts, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the production of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of malaria, and, respectively, for the production of such medicaments.
In formula I R.sup.1 preferably signifies chlorine, A preferably signifies cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 or phenylene-1,2 and n and m preferably signify 0 or 1.
Compounds of formula I in which R.sup.1 signifies chlorine, A signifies ethene-1,2-diyl and n and m signify 1 are also preferred.
Particularly preferred compounds of general formula I are: e, e e,
.+-.-trans-N,N'-bis-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine,
cis-N,N'-bis-(7-chloroquinolin-4-yl)-cyclohexane- 1,4-diamine,
cis-N,N'-bis-(7-chloroquinolin-4-yl)-cyclohexane- 1,3-diamine,
.+-.-trans-N,N'-bis-(7-chloroquinolin-4-yl)-cyclohexane-1,3-diamine,
cis,cis-N,N'-bis-(7-chloroquinolin-4-yl)-2-methyl-cyclohexane-1,3-diamine,
N,N'-bis-(7-chloroquinolin-4-yl)-phenylene-1,3-diamine,
cis-N,N'-bis-(7-chloroquinolin-4-yl)-cyclopentane-1,3-diamine, thyl!-amine,
N,N'-bis(7-chloroquinolin-4-yl)-dicyclohexylmethane-4,4'-diamine and
N,N'-bis-(7-chloroquinolin-4-yl)-2-butene-1,4-diamine.
The novel compounds of formula I can be manufactured in accordance with the invention by ##STR3## wherein R.sup.1 and R.sup.2 have the significance set forth above and X signifies a leaving group, with a diamine of the general formula addition salt thereof, and acceptable acid addition salt.
Bis-quinoline derivatives of general formula I are manufactured according to variant a) of the process in accordance with the invention by reacting a corresponding compound of general formula II with the corresponding diamines of general formula III. .alpha.,.alpha.'-Diamino-o-xylene, .alpha.,.alpha.'-diamino-m-xylene, .alpha.,.alpha.'-diamino-p-xylene, .+-.-trans-cyclohexane-1,4-diamine, cis-cyclohexane-1,4-diamine, cis-cyclohexane-1,3-diamine, .+-.-trans-cyclohexane-1,3-diamine, cis,cis-2-methyl-cyclohexane-1,3-diamine, phenylene-1,3-diamine, cis-cyclopentane-l,3-diamine, 1,3-bis-(aminomethyl)-cyclohexane, 4,4'-diamino-dicyclohexylmethane or trans-2-butene-1,4-diamine can be used, for example, as the diamine. In place of the free diamines, their acid addition salts can also be used.
Suitable compounds of formula II are, for example, 4,7-dichloroquinoline or 4-chloro-7-trifluoromethyl-quinoline.
The reaction is conveniently effected under a protective gas atmosphere in a temperature range of 100.degree.-200.degree. C. and in a solvent, with phenol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, ethoxyethanol or acetoni

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