Patent GB-709906-A (GB)
Title: New triazine derivatives
Inventor: CROWTHER ALBERT FREDERICK
IPC: C07D251/10
Filed: 1950-09-12
Abstract: The invention comprises compounds of the formula <FORM:0709906/IV (b)/1> wherein Ar stands for an aromatic hydrocarbon residue which may optionally be substituted in the meta or para positions and wherein A, B, R and R1 stand for hydrogen or for hydrocarbon radicals which may optionally be substituted, provided that both R and R1 be not hydrogen at the same time and wherein R and R1 may be combined to form a homocyclic ring.  For use as antimalarials the preferred compounds are those of the above formula wherein Ar represents <FORM:0709906/IV (b)/2> in which X stands for hydrogen, alkyl, alkoxy, chlorine, bromine or iodine and Y and Z stand for hydrogen, alkyl, alkyl, chlorine, bromine or iodine, and wherein A and B stand for hydrogen or alkyl, R stands for hydrogen or alkyl, and R1 stands for hydrocarbon which may bear substituents and wherein R and R1 may be combined to form a homocyclic ring.  Such compounds may be prepared by reacting a biguanide of the formula <FORM:0709906/IV (b)/3> with an aldehyde or ketone of the formula RR1CO, preferably in the presence of at least one equivalent proportion of acid, e.g. by using the biguanide as its dibasic salt with mineral acid, or as monobasic salt in a medium containing acid.  In place of the biguanide and/or the aldehyde or ketone may be used a substance or substances which under the conditions of the reaction react like such compounds.  Thus in place of the compound RR1CO may be used a functional derivative thereof, e.g. the acetal, derived Schiff's base such as the anil, an alkali metal bisulphite compound or an ester of the enol form of the aldehyde or ketone, e.g. isopropenyl acetate in the case of acetone. Substances giving rise to the aldehyde or ketone by synthesis may also be used, e.g. acetylene in acid medium in the presence of a catalyst such as mercuric chloride in place of acetaldehyde.  In place of the biguanide of above formula may be used, e.g., a salt of the amine ArNH2, and the dicyandiamide CN - NH - C(=NH) - NAB.  Both the biguanide and aldehyde or ketone may simultaneously be generated in situ.  Thus the anil of the aldehyde or ketone with the amine ArNH2 may be used, and in place of biguanide the dicyandiamide may be added, which may ract with the amine ArNH2 liberated from the anil to give the substituted biguanide.  In examples: (1) 2 : 4-diamino-1-p-chlorophenyl-6 : 6 - dimethyl - 1 : 6 - dihydro - 1,3,5 - triazine is prepared by reacting N1-p-chlorophenyl-biguanide hydrochloride and acetone and converted into its picrate; (2) the same product as in (1) is prepared, hydrochloric acid being present in the reaction mixture. Similarly produced from the appropriately substituted biguanide are 2 : 4 - diamino - 1 - p - iodophenyl-6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine, 2 : 4 - diamino - 1 - (3 : 4 : 5 - trichlorophenyl) - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine and 2 : 4 - diamino - 1 - p - chlorophenyl - 6 : 6 - cyclotetramethylene - 1 : 6-dihydro - 1 : 3 : 5 - triazine (from cyclopentanone).  Similarly produced are (3) 2 : 4-diamino-1 - (3 : 4 - dichlorophenyl) - 6 : 6 - dimethyl - 1 : 6-dihydro - 1 : 3 : 5 - triazine; (4) 2 : 4 - diamino - 1 - p - chlorophenyl - 6 - ethyl - 6 - methyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (5) and (6) 2 : 4 - diamino - 1 - p - bromophenyl - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine. m - Chloro - phenyl - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5-triazine is also described; (8) 2 : 4-diamino - 1 - (3 : 4 - dibromophenyl) - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (9) 2 : 4 - diamino - 1 - (3 : 5 - dichlorophenyl) - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (10) 2 : 4 - diamino - 1 - (3 : 4 - dichlorophenyl) - 6 - methyl - 6 - ethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; 2 : 4 - diamino - 1 - (3 : 4 - dichlorophenyl) - 6 - ethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; 2 : 4 - diamino - 1 - m - chlorophenyl - 6 - methyl - 6 - ethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; 2 : 4 - diamino - 1 - p - chlorophenyl - 6 - n - propyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; 2 : 4 - diamino - 1 - (3 - bromo - 4 - chlorophenyl)-6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine, and the corresponding compounds wih at 1 - (3 - chloro - 4 - iodophenyl) -, 1 - m - nitrophenyl-, or 1-p-ethylsulphonyl-phenyl group.  In further examples are produced: (11) and (12) 2 : 4 - diamino - 1 - (3 : 4 - dichlorophenyl) - 6 - iso- or n-propyl-1 : 6-dihydro-1 : 3 : 5-triazines; (13), (16) and (17) 2 : 4-diamino-1-p-chlorophenyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazines having in the 6-position an ethyl-, methyl or iso-propyl group; (14) 2 : 4-diamino-1-m-chlorophenyl - 6 - ethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (15) 2 : 4 - diamino - 1 - phenyl 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 ; 5 - triazines.  In examples (18) to (21) and (23) to (25) there are reacted acetone and p-chlorophenylbiguanide or its hydrochloride and an acid, the temperature and amount of acid employed being varied, and the acid being hydrochloric, hydrobromic or sulphuric acid to give the same product as in (1).  In example (22) 2 : 4-diamino-1-(3 : 4-dichlorophenyl) - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5-triazine is produced.  In examples (26) and (27) acetaldehyde diethyl acetal and p-chlorophenyl- or 3 : 4-dichlorphenyl-biguanide are reacted to give 2 : 4-diamino-1-p-chlorophenyl- or 1-(3 : 4-dichlorophenyl)-6-methyl-1 : 6 - dihydro - 1 : 3 : 5 - triazine; (28) similarly to (26) the m-chlorophenyl isomer is prepared; (29) to (31) 2 : 4-diamino-1-p-chlorophenyl - 6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5-triazine is prepared by reacting p-chlorophenylbiguanide hydrochloride and acetone diethyl acetal, acetone sodium bisulphite compound and isopropenyl acetate respectively.  The same product is prepared (example 32) by reacting p-chloraniline, dicyandiamide, acetone and hydrochloric acid.  In further examples: (33) 2 - amino - 1 - p - chlorophenyl - 6 : 6 - dimethyl - 4 - methylamino - 1 : 6 - dihydro - 1 : 3 : 5 - triazine is prepared by reacting N1-p-chlorophenyl-N5-methylbiguanide hydrochloride with acetone and hydrochloric acid; (34) N1-p-chlorophenyl-N5 : N5-dimethyl-biguanide hydrochloride and acetone with hydrochloric acid are reacted to give 2 - amino - 1 - p - chlorophenyl - 6 : 6 - dimethyl - 4 - dimethylamino - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (35) p-chlorophenylbiguanide, and acetylene are reacted in the presence of hydrochloric acid and mercuric chloride to give 2 : 4 - diamino - 1 - p - chlorophenyl - 6 - methyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine; (36), (37) 2 : 4-diamino - 1 - p - chlorophenyl - 6 - phenyl - 1 : 6 - dihydro-1 : 3 : 5-triazine and 2 : 4-diamino-1-p-chlorophenyl - 6 - p - dimethylaminophenyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine are prepared by reacting p-chlorophenylbiguanide with benzaldehyde and p-dimethylaminobenzaldehyde respectively in acid solution; (38) 2 : 4-diamino-1 : 6 - diphenyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine is prepared by reacting dicyandiamide and benzylidene aniline in acid solution.  In example (7) p-chloroaniline and dicyandiamide are reacted, and the product on reaction with acetone gives 2 : 4-diamino-1-p-chlorophenyl-6 : 6 - dimethyl - 1 : 6 - dihydro - 1 : 3 : 5 - triazine.  Similar compounds with the corresponding 1-substituent are obtained if the p-chloraniline is replaced by p-anisidine, p-phenetidine, p-toluidine, 3 : 4-xylidine, m-bromoaniline, m-iodoaniline, aniline, and 4-chloro-3-methylaniline. The products may be obtained in the form of their salts.  The aryl-substituted biguanides employed as starting-materials may be obtained by reacting the appropriate dicyandiamide with the appropriate amine ArNH2.  The Provisional Specification describes products of the formula <FORM:0709906/IV (b)/4> wherein Ar stands for an optionally substituted aromatic radical and A, B, R, R1 and R11 stand for hydrogen or hydrocarbon radicals.  Preferred as antimalarials are those compounds believed to be of the formula <FORM:0709906/IV (b)/5> wherein X is chlorine, bromine or iodine, Y and Z are chosen from hydrogen, chlorine, bromine and lower alkyl radicals, A and B are hydrogen or lower alkyl radicals, R and R1 are each hydrogen or a lower alkyl radical and R11 is a lower alkyl radical, such that R, R1 and R11 contain together at least one but not more than seven carbon atoms.