Patent GB-834300-A (GB)
Title: Improvements in and relating to quinoline derivatives and the manufacture thereof
Inventor: WALLS LESLIE PERCY
IPC: C07D295/205
Filed: 1957-03-22
Abstract: The invention comprises compounds of the formula <FORM:0834300/IV (b)/1> and their acid addition salts, wherein R1 is hydroxyl or C1-4 alkoxyl, R2 is hydrogen, hydroxyl or C1-4 alkoxyl, R3 is a C1-4 alkyl group or an alkoxycarbonyl group wherein the alkyl group has 1-4 carbon atoms and X is a straight or branched alkylene chain of 2-8 carbon atoms.  The compounds are made by reacting an amine of the formula A-X-Y with an amine of the formula H.B wherein one of the radicals A and B is a group of the formula <FORM:0834300/IV (b)/2> and the other is a piperazinyl radical of the formula <FORM:0834300/IV (b)/3> and Y is a halogen or a similar reactive ester group such as an alkane-, arane- or aralkanesulphonyloxy group, e.g. methanesulphonyloxy, benzylsulphonyloxy or p-toluenesulphonyloxy group, R4 being a C1-4 alkoxyl group and R5\h being hydrogen or a C1-4 alkoxyl group, to give a compound of the formula I bearing the substituents R1 and R2 corresponding to R4 and R5, and when it is desired to obtain a product wherein R1 and/or R2 are hydroxyl groups, replacing alkoxyl groups R4 and R5 by hydroxyl by acid hydrolysis. Compounds wherein R3 is a methyl group may also be prepared by first forming a compound wherein R3 is an alkoxycarbonyl which is then treated with a powerful reducing agent such as lithium aluminium hydride.  The products are used therapeutically as antiprotozoal agents (see Group VI), suitably in the form of acid addition salts. Preferred products include 6-methoxy-, 6-ethoxy- and 6-hydroxy -, 8 - (3 - N1 - methylpiperazinopropylamino) - quinoline, 6 - hydroxy - 8 - (3 - N1-ethylpiperazinopropylamino) quinoline and 6-hydroxy - 8 - (6 - N1 - methylpiperazinohexylamino) quinoline and their acid addition salts such as the hydrochlorides.  Examples describe the preparation of 6-methoxy-, 6-ethoxy-, 6-hydroxy -, 5 : 6 - dimethoxy - and 5 : 6 - dihydroxy - derivatives of many 8 - N1 - (methyl-, ethyl-, propyl-, butyl-, isopropyl-, isobutyl- or carbethoxy -) piperazino - (ethyl -, propyl-, butyl- or hexyl-) amino-quinolines.  Piperazinoalkyl-halides used as starting materials are made as follows: N-(2-chloroethyl-N1 - methylpiperazine, N - (2 - chloropropyl-N1 - methylpiperazine and N - (2 - chloropropyl-N1-ethylpiperazine, by reaction of thionyl chloride on the corresponding N-hydroxyalkylpiperazine; N - (3 - chloropropyl) - N1 - methylpiperazine and N - (3 - chloropropyl) - N1-carbethoxypiperazine, by reaction of trimethylene chlorobromide with the appropriate N1-substituted piperazine; N - (3 - bromopropyl)-N1 - ethylpiperazine and N - (6 - bromohexyl)-N1-methylpiperazine by cleavage with HBr of the corresponding phenoxypropylpiperazine and methoxyhexylpiperazine compounds respectively and N - (3 - bromobutyl) - N1 - methylpiperazine by the action of HBr on N-(3-hydroxybutyl)-N1-methylpiperazine.  N - Alkylpiperazines.  N - Propyl -, N - isopropyl -, N - butyl - and N - isobutyl -, piperazine are prepared by treating N-ethoxycarbonylpiperazine with n-propyl-toluene-p-sulphonate or the corresponding isopropyl, butyl or isobutyl compound and hydrolysing the resulting N-ethoxycarbonyl-N1-alkyl-piperazine.  N - Ethyl - N1 - 3 - phenoxypropyl - piperazine is made by treating N-ethylpiperazine with 3-phenoxypropyl bromide.  N - Methyl - N1 - 6 - methoxyhexyl - piperazine is made by treating N-methylpiperazine with 1-bromo-6-methoxyhexane.  1 - N1 - Methylpiperazino - butan - 3 - ol is made by the action of 1-chloro-butan-3-ol on N-methylpiperazine.ALSO:Antiprotozoal pharmaceutical preparations comprise quinoline compounds of the formula <FORM:0834300/VI/1> or acid addition salts thereof, e.g. the trihydrochlorides, wherein R1 is a hydroxyl or C1-4 alkoxyl group, R2 is hydrogen or a hydroxyl or C1-4 alkoxyl group, R3 is a C1-4 alkyl group or an alkoxycarbonyl group wherein the alkyl radical has 1-4 carbon atoms and X is a straight or branched alkylene chain of 2-8 carbon atoms (see Group IV (b)), together with a suitable carrier. The preparations suitably take the form of tablets, capsules, solutions and suspensions, for example aqueous solutions, suspensions in oil, gelatine capsules or tablets comprising a granulating agent (starch or gelatine), a lubricant (magnesium stearate), an excipient (lactose), and a binding agent (starch). Examples describe preparations containing 6 - methoxy - 8 - (3 - N1 - methylpiperazinopropylamino) quinoline trihydrochloride in aqueous solution for injection and in gelatin capsules for oral administration.  Corresponding 6-hydroxy and 6-ethoxy compounds are also referred to.