Patent GB-702664-A (GB)
Title: Chemical substances having trypanocidal activity
Inventor: LOURIE EMANUEL MANNIE
IPC: C09B43/40
Filed: 1950-07-05
Abstract: The invention comprises symmetrical dialkyl halide quaternary salts of cinnolines having the formula <FORM:0702664/IV(b)/1> where Y is -NH-C(:NH)-NH-, -NH-CO-NH- or -N = N- and R is NH2 or (if Y is azo) NHCH3.  The alkyl groups have 1-8 carbon atoms.  These compounds are made as follows:-(1) 4-chloro-6-nitrocinnoline is reacted with ammonia to give the 4-amino compound and this reduced to the diamine with stannous chloride; the latter is treated with thiophosgene to yield bis - (4-amino-6-cinnolyl)-thiourea (dihydrochloride) which is converted into the guanidine by the action of mercuric oxide and alcoholic ammonia (purified via the trihydrochloride); final quaternization with methyl iodide gives N:N1-bis-(4-amino-6-cinnolyl)-guanidine dimethiodide; (2) 2-acetamido - 5 - nitroacetophenone is reduced to the 5-amino compound either by catalytic hydrogenation or with iron and acetic acid; one portion of the amine is oxidized to the 5-nitroso compound with Caro's acid and then reacted with the remaining portion to give 4:41 - diacetamido - 3:31 - diacetyl - azobenzene, hydrolyzed to the 4:41-diamino compound; treatment of the latter with sodium nitrite and formic acid yields 4:41-dihydroxy-6:61-azocinnoline, converted by phosphorus chlorides into the 4:41-dichloro compound and thence by potassium phenolate into 4:41-diphenoxy-6:61-azocinnoline; treatment of this with ammonia gives 4:41-diamino-6:61-azocinnoline (purified via dihydrochloride) Which yields a bis-quaternary salt with methyl iodide, converted into a mixture of two isomeric bismethochlorides by hydrochloric acid and silver chloride; alternatively the 4:41-diamino compound is N:N1-diacetylated, bis-quaternated with methyl toluene-p-sulphonate and converted (a) by sodium iodide into the bis-methiodide which is then deacetylated, or (b) by hydrochloric acid directly into the two isomeric deacetylated bis-methochlorides; (3) 4:41-diphenoxy-6:61-azocinnoline is treated with methylamine to give the 4:41-bis-methylamino compound (purified via dihydrochloride) which is quaternated with methyl iodide; treatment of the product with hydrochloric acid and silver chloride gives a mixture of two isomeric bismethochlorides; (4) 4:6-diamino-1-methylcinnolinium iodide is treated with phosgene to yield N:N1 - di - (4 - amino - 6 - cinnolyl) - urea dimethochloride.  The Provisional Specification refers in general to quaternary salts where the cation comprises two bicyclic heterocyclic radicals connected by an N-containing or an unsaturated linkage, each of such radicals having one ring containing two nitrogen atoms.  Quinazoline, phthalazine and quinoxaline nuclei are mentioned in addition to cinnoline.  Preferably there is an amino group in the 4- or 2-position.ALSO:The invention comprises symmetrical dialkyl halide quaternary salts of cinnolines having the formula <FORM:0702664/IV(c)/1> where Y is an azo linkage (or guanidine or urea, [see Group IV(b)] and R is -NH2 or -NHCH3.  The alkyl groups have 1-8 carbon atoms.  These are made as follows: 2-acetamido-5-amino-acetophenone is condensed with 2-acetamido-5-nitrosoacetophenone to give 4 : 4\sv - diacetamido - 3 : 3\sv - diacetyl-azobenzene, hydrolysed to the 4:4\sv-diamino compound; treatment of the latter with sodium nitrite and formic acid yields 4:4\sv-dihydroxy-6:6\sv-azocinnoline, converted by phosphorus chlorides into the 4:4\sv-dichloro compound and thence by potassium phenolate into 4:4\sv-diphenoxy-6:6\sv-azocinnoline; treatment of this with ammonia gives 4 : 4\sv - diamino-6 : 6\sv-azocinnoline (purified via dihydrochloride) which yields a bis-quaternary salt with methyl iodide, converted into a mixture of two isomeric bis-methochlorides by hydrochloric acid and silver chloride; alternatively the 4:4\sv-diamino compound is N : N\sv diacetylated, bis-quaternated with methyl toluene-p-sulphonate and converted (a) by sodium iodide into the bis-methiodide which is then deacetylated, or (b) by hydrochloric acid directly into the two isomeric deacetylated bis-methochlorides.  Similarly 4:4\sv-diphenoxy - 6 : 6\sv - azocinnoline is treated with methylamine to give the 4:4\sv-bis-methylamino compound (purified via dihydrochloride) which is quaternated with methyl iodide; treatment of the product with hydrochloric acid and silver chloride gives a mixture of two isomeric bis-methochlorides.  The Provisional Specification refers in general to quaternary salts where the cation comprises two bicyclic heterocyclic radicals connected by an N-containing or an unsaturated linkage, each of such radicals having one ring containing two nitrogen atoms.  Quinazoline, phthalazine and quinoxaline nuclei are mentioned in addition to cinnoline.  Preferably there is an amino group in the 4- or 2-position.