The present invention is directed to aminoquinoline derivatives of the general formula ##STR2## wherein R.sup.1 to R.sup.6 are independently selected from hydrogen or alkyl, provided that no more than two substituents from R.sup.1 to R.sup.6 may be simultaneously alkyl; R.sup.7 and R.sup.8 signify alkyl, alkenyl or aralkyl, or together with the N atom signify pyrrolidine or piperidine, which optionally can be substituted by alkyl, or octahydroindole or 3-azabicyclo[3,2,2]nonane; and n=0 or 1; or
wherein the symbols R.sup.1 and R.sup.3 signify tri- or tetramethylene; R.sup.2 and R.sup.4 to R.sup.6 signify hydrogen; n=0; and R.sup.7 and R.sup.8 are defined as above; or PA1 wherein the symbols R.sup.1 and R.sup.7 signify methylene or dimethylene and n=1, or PA1 remaining substituents signify hydrogen, except R.sup.8 which signifies alkyl, alkenyl or alkynyl; or PA1 wherein the symbols R.sup.3 and R.sup.5 signify tri- or tetramethylene and n=1; all remaining substituents to R.sup.6 signify hydrogen; and R.sup.7 and R.sup.8 signify alkyl, alkenyl or aralkyl or together with the N atom signify pyrrolidine or piperidine, which optionally can be substituted by alkyl; R.sup.9 signifies hydrogen or halogen; and R.sup.10 signifies halogen or trifluoromethyl, PA1 N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-ethane-1,2-diamine, PA1 N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-ethane-1,2-diamine, PA1 N.sub.3 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-propane-1,3-diamine, PA1 N.sub.3 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-propane-1,3-diamine, PA1 (7-chloro-quinolin-4-yl)-(2-piperidin-1-yl-ethyl)-amine, PA1 (7-chloro-quinnolin-4-yl)-[(1-ethyl-pyrrolidin-2-yl)-methyl]-amine, PA1 (7-chloro-quinolin-4-yl)-(1-methyl-pyrrolidin-2-yl-methyl)-amine, PA1 (7-chloro-quinolin-4-yl)-(1-methyl-piperidin-2-yl-methyl)-amine and PA1 (7-chloro-quinolin-4-yl)-(1-methyl-piperidin-3-yl)-amine. PA1 (S)-N.sub.2 -(7-Chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-propane-1,2-diamine, PA1 (R)-N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-propane-1,2-diamine, PA1 N.sub.1 -(7-chloro-quinolin-4-yl)-2,N.sub.2,N.sub.2 -trimethyl-propane-1,2-diamine, PA1 N.sub.3 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-propane-1,3-diamine, PA1 (RS)-(7-chloro-quinolin-4-yl)-(1-methyl-piperidin-3-yl)-amine and PA1 (RS)-(7-choro-quinolin-4-yl)-(1-methyl-pyrrolidin-3-yl)-amine. PA1 (RS)-N.sub.2 -(7-Chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-propane-1,2-diamine, PA1 (RS)-N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-propane-1,2-diamine, PA1 (S)-N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-propane-1,2-diamine, PA1 (R)-N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-propane-1,2-diamine, PA1 (RS)-7-chloro-quinolin-4-yl)-(1-methyl-2-pyrrolidin-1-yl-ethyl)-amine, PA1 N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-ethane-1,2-diamine, PA1 N.sub.2 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -diethyl-ethane-1,2-diamine, PA1 N.sub.3 -(7-chloro-quinolin-4-yl)-N.sub.1,N.sub.1 -dimethyl-propane-1,3-diamine, PA1 (R)-N.sub.1 -(7-chloro-quinolin-4-yl)-N.sub.2,N.sub.2 -dimethyl-propane-1,2-diamine, PA1 (S)-N.sub.1 -(7-chloro-quinoline-4-yl)-N.sub.2,N.sub.2 -dimethyl-propane-1,2-diamine and PA1 (RS)-(7-chloro-quinolin-4-yl)-(1-methyl-pyrrolidin-2-yl-methyl)-amine. PA1 a) reacting quinoline derivatives of the general formula ##STR3## wherein R.sup.9 and R.sup.10 have the above significances and R signifies a leaving group, with amino compounds of the general formula ##STR4## wherein the substituents R.sup.1 to R.sup.8 have the above significances, or PA1 b) reacting alkylamino-quinoline derivatives of the general formula ##STR5## wherein R.sup.1 to R.sup.6 and R.sup.9 and R.sup.10 have the above significances and R signifies a leaving group, with amines of the formula EQU HNR.sup.7 R.sup.8 V PA1 wherein R.sup.7 and R.sup.8 have the above significances, or PA1 c) reacting compounds of formula I in which R.sup.1 to R.sup.6 as well as R.sup.9 and R.sup.10 have the above significance and R.sup.7 and R.sup.8 signify hydrogen or one of them signifies hydrogen and the other signifies an alkyl group with alkylating agents which are suitable for the alkylation of amino groups, and PA1 d) if desired, converting a basic compound of formula I into a pharmaceutically usable salt by means of an acid.
R.sup.1 and R.sup.7 signify di- or trimethylene and n=0, or PA2 R.sup.3 and R.sup.7 signify di- or trimethylene and n=1, or PA2 R.sup.3 and R.sup.7 signify tri- or tetramethylene and n=0, or PA2 R.sup.5 and R.sup.7 signify tri- or tetramethylene and n=1, or PA2 R.sup.1 and R.sup.5 signfly di- or tri-methylene and n=1, and the
and pharmaceutically acceptable salts and hydrolyzable esters thereof.
These compounds are useful in the treatment and prevention of malaria.
The compounds described above are novel with the exception of the following specific compounds, which are hereinafter referred to as the "Z-compounds":
All of the foregoing compounds including the Z-compounds, have the surprising and newly discovered property that they have an equally good effect not only against chloroquine-sensitive malaria pathogens, but also against chloroquine-resistant malaria pathogens, that is to say, they exhibit no cross-resistance with chloroquine.
Not only the absence of cross-resistance, but also the good activity, which is to some extent better compared with chloroquine, were surprising. Hitherto it had been assumed that cross-resistance exists between chloroquine-like compounds. Only certain bis-quinolines, which contain two quinoline rings and which bear little structural relationship to chloroquine, have a definite activity against chloroquine-resistant malaria pathogens, especially the compounds which have been described by J. L. Vennerstrom (J. L. Vennerstrom et al, J. Med. Chem., 35, 2129-2134 (1992). Further, it had hitherto been assumed that chloroquine analogues having shortened or lengthened side-chains were less active against malaria pathogens compared with chloroquine (R. L. O'Brien and F. E. Hahn, Chloroquin Structural Requirements for Binding to Deoxyribonucleic Acid and Antimalarial Activity, Antimicrob. Agents Chemother, 1965, 315-320).
Simple analogues of chloroquine have therefore hitherto been considered to be uninteresting and not suitable for the treatment for malaria. In contrast to this assumption, it has now been found that the compounds of formula I are outstandingly suitable for the prophylaxis of malaria and for its treatment, especially in cases where the pathogens are resistant to chloroquine.
The objects of the present invention are the use of compounds of formula I and the Z-compounds and of pharmaceutically usable salts and hydrolyzable esters thereof in the control or prevention of malaria, especially in the control of chloroquine-resistant and of chloroquine-sensitive malaria pathogens; the novel compounds of formula I; the manufacture of the compounds of formula I and pharmaceutically acceptable salts and esters thereof, as well as pharmaceutical compositions containing said compounds or salts or hydrolyzable esters thereof, and the manufacture of such pharmaceutical compositions.
USPTO Backgrounds
USPTO Backgrounds