Patent GB-794043-A (GB)
Title: New quinoline derivatives
Inventor: AINLEY ARTHUR DONALD
IPC: C07D401/12
Filed: 1955-06-03
Abstract: The invention comprises quinoline derivatives, which are quaternary salts, of the general formula <FORM:0794043/IV (b)/1> (wherein R and R1 may be the same or different and represent alkyl radicals, R2 represents a phenyl radical optionally bearing halogen, alkyl or alkoxy substituents, R3 and R4 both represent hydrogen or one hydrogen and the other an alkyl radical, R5 represents hydrogen, R6 hydrogen or an alkyl radical of not more than 4 carbon atoms and X an anion), and the manufacture thereof by (a) (when R=R1) treating a compound of the general formula <FORM:0794043/IV (b)/2> with a quaternary salt-forming agent RX, or (b) interaction of a compound of the formula <FORM:0794043/IV (b)/3> with a compound of the formula <FORM:0794043/IV (b)/4> (wherein Y represents a halogen atom), or (c) replacing anions other than X by X by the action of a mineral acid or salt containing the anion X.  The products are useful as chemotherapeutic agents, especially for treating babesiasis.  In examples: (1) 2-amino-4-chloro-6-methylpyrimidine 1-methiodide is refluxed in water with 4:6 - diamino - 2 - phenylquinoline methochloride hydrochloride and the product is treated with hydrochloric acid to give 4-amino-6 - (21 - amino - 61 - methylpyrimidyl - 41 - amino) - 2 - phenylquinoline 1:11 - dimethochloride; (2) 4-amino-6-(21-amino-61-methylpyrimidyl - 41 - amino) - 2 - phenylquinoline is heated with dimethyl sulphate in nitrobenzene to produce its 1:11-dimethosulphate, which is converted to the product of (1) by treatment with aqueous sodium chloride solution; (3) 4-amino - 6 - (21 - aminopyrimidyl - 41 - amino) - 2 - phenylquinoline is similarly converted to its dimethosulphate, which is treated with sodium iodide to produce the dimethiodide; (4) 2-amino - 4 - chloro - 6 - methylpyrimidine 1 - methiodide and 6 - amino - 4 - methylamino - 2 - phenylquinoline methochloride are refluxed in dilute hydrochloric acid to produce 4-methylamino - 6 - (21 - amino - 61 - methylpyrimidyl - 41 - amino) - 2 - phenylquinoline 1:11 - dimethochloride; (5) 4:6 - diamino - 2 - p - chlorophenylquinoline methochloride hydrochloride and 2 - amino - 4 - chloro - 6 - methylpyrimidine 1 - methiodide are refluxed in water and the reaction mixture is poured into saturated aqueous sodium chloride solution to precipitate 4-amino-6-(21-amino-61-methylpyrimidyl-41-amino) - 2 - p - chlorophenylquinoline 1:11 - dimethochloride; (6) similarly, except that hydrochloric acid is used instead of sodium chloride solution, 4:6 - diamino - 2 - p - methoxyphenylquinoline methochloride hydrochloride yields the corresponding p-methoxy compound.  Starting materials.  Pyrimidylaminoquinolines of the second general formula above are obtainable by interaction of the corresponding 6-aminoquinoline compounds with the corresponding 4-halopyrimidine compounds in an aqueous acid medium.  The 6-aminoquinoline compounds may be prepared by ring-closing the condensation product of a p-acylaminoaniline with a compound of the formula R2.COCH2-COOR7 (where R7 is a lower alkyl radical) to form a 6-acylamino-4-hydroxyquinoline, replacing the hydroxy group by a halogen atom, e.g. by means of POCl3, reacting the product with ammonia or a monoalkylamine and subjecting the resulting 6-acylaminoquinoline compound to acid hydrolysis.  The preparation of the starting materials of Examples (2) and (3) is described in detail. 4:6-Diamino-2-phenylquinoline methochloride hydrochloride is obtained by the action of dimethyl sulphate, followed by refluxing with dilute hydrochloric acid, from 6 - acetamido - 4 - amino - 2 - phenylquinoline, itself prepared as indicated above from the condensation product of p-aminoacetanilide and ethyl benzoylacetate. 6-Amino-4-methylamino-2-phenylquinoline methochloride is similarly prepared from the analogously obtained 6-acetamido - 4 - methylamino - 2 - phenylquinoline.  Ethyl p-chloro- and p-methoxy-benzoylacetate similarly yield 4:6-diamino-2-p-chloro- and -p-methoxy-phenylquinoline methochloride hydrochlorides via 6-acetamido-4-hydroxy- and -4-amino-2-p-chloro- and -p-methoxyphenylquinoline.