GB664262A - Manufacture of heterocyclically substituted diaminoquinazolines - Google Patents

Abstract

Heterocyclically - disubstituted quinazolines are prepared by treating a quinazoline having in the 2- or 4-position a halogen atom or a substituted hydroxy or mercapto group and in the other of these positions a substituted amino group wherein the substituent contains a tertiary amino group, with an amino compound, the amino group of which is directly bound to the carbon atom in the 2-position of a thiazole or imidazole ring; alternatively, the same products may be obtained by reacting an amino-substituted tertiary amine with the appropriate thiazoylamino- or imidazolylaminoquinazoline. The thiazole or imidazole ring may be present in the form of benzthiazole or benzimidazole and in general may have fusedon aromatic or heterocyclic nuclei. The products may contain alkyl, phenyl, nitro, amino, cyano, halogen or free or substituted hydroxyl substituents. The residue containing a tertiary amino group may be a straight or branched aliphatic residue (with or without interrupting heteroatoms such as oxygen and sulphur) or a carboxylic or aliphatic-carbocyclic residue containing as substituent a dialkylamino group, or a chain terminated by a cyclic group such as piperidino or morpholino. The reaction may be carried out in the presence or absence of a diluent, an acid-binding agent, a condensing agent or a catalyst. The products (if obtained as free bases) may be converted into salts with acids such as hydrochloric, sulphuric, phosphoric, methane sulphonic, toluene sulphonic, acetic, oxalic and citric acids. Nitro groups in the products may be reduced to amino groups. Many examples are given, the residues being those of (1) quinoxaline and 6 - chloro - quinoxaline; (2) 2 - amino - benzthiazole, 2 - amino - 4 - methyl - benzthiazole, 2 - amino - 6 - methyl - benzthiazole, 2 - amino - 6 - chloro - benzthiazole, 2 - amino - 6 - methoxy - benzthiazole, 2 - amino - 4 : 7 - dimethyl - benzthiazole, 2 - amino - 6 - nitro - benzthiazole, 2 - amino - 6 - cyano - benzthiazole, 2 - amino - 6 - n - butoxy - benzthiazole, 2 - amino - 6 - acetamino - benzthiazole, 2 - amino - naphthothiazole, 2-amino-thiazole, 2-amino-4-phenylthiazole, 2 - amino - 4 - p - bromophenyl - thiazole, 2 - amino - 4 : 5 - diphenyl - thiazole and 2 - amino - benzimidazole; (3) b - diethylamino - ethylamine, g - diethylamino - propylamine, N - (b - diethylamino - ethyl) - aniline, 1 - diethylamino - 3 - amino - butane, b - piperidino - ethylamine and p - (b - diethylamino - ethoxy)-aniline. The starting materials are obtained by reacting a quinazoline substituted in the 2- and 4-positions by exchangeable groups (e.g. 2 : 4-dichloroquinazoline, 2-chloro-4-hydroxy-quinazoline) with the appropriate amine. Compounds thus prepared are 2-chloro-4-[N-phenyl-N - (b - diethylamino - ethyl) - amino - ] quinazoline, 2 - [61 - methyl - benzthiazolyl - 21 - amino] - 4 - hydroxy - quinazoline (converted into the 4-chloro-compound with phosphorus oxychloride), 2-(b -diethylamino-ethylamino)-4-hydroxy-quinazoline (converted into the 4-chloro-compound with phosphorus oxychloride), 2 - chloro - 4 - [p - (b - diethylamino - ethoxy) - anilino] - quinazoline and 2 - chloro - 4 - [11 - diethylamino - butyl - 31 - amino] - quinazoline. 2 - Amino - 4 : 7 - dimethyl - benzthiazole is obtained from 2 : 5-dimethyl-phenyl-thiourea by normal methods. 2 - Methoxy - 4 - (b - diethylamino - ethylamino)-quinazoline is obtained from the 2-chloro-compound and sodium methoxide. Samples have been furnished under Sect. 2 (5) of (1) 2-[41-p-tolyl-thiazolyl-21-amino]-4-(b -diethylamino -ethylamino)-quinazoline prepared from 2 - amino - 4 - p - tolyl - thiazole and 2 - chloro - 4 - (b - diethylamino - ethylamino) - quinazoline; and (2) 2-[61-methyl-benzthiazolyl-21 - amino] - 4 - [b - (b 1 - diethylamino - ethylthio) - ethylamino] - quinazoline prepared by reacting 2 : 4-dichloro-quinazoline with b -amino-b 1 - diethylamino - diethyl sulphide and treating the resulting 2-chloro-4-[b -(b 1-diethylaminoethylthio) - ethylamino] - quinazoline with 2 - amino-6-methyl-benzthiazole. The Specification as open to inspection under Sect. 91 refers to compounds containing in place of the tertiary amino group any strongly basic group, e.g. primary or secondary amino. It also mentions compounds containing mercapto substituents. The attachment to the thiazole or imidazole ring is not limited to the 2-position. This subject-matter does not appear in the Specification as accepted.