Patent GB-1156973-A (GB)
Title: Quinazoline Derivatives
IPC: C07D239/95
Filed: 1966-06-30
Abstract: 1,156,973. Quinazoline derivatives. CHAS. PFIZER & CO. Inc. 30 June, 1966 [6 July, 1965; 7 June, 1966], No. 29544/66. Heading C2C. Novel quinazolines of formulµ I, II and III, in which R 1 , R 2 , R 3  and R 4  are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, propargyl, phenyl, C 1-5  hydroxyalkyl, C 7-12  alkoxyphenyl, benzyl, phenylethyl, alkyl or dialkyl substituted-phenyl where alkyl has from 1 to 6 carbon atoms, chlorophenyl, bromophenyl, fluorophenyl, hydroxyphenyl, dichlorophenyl, dibromophenyl, difluorophenyl or 2,2,2-trifluoroethyl; R 5  and R 6  are hydrogen, alkoxy having from 1 to 5 carbon atoms, alkyl having from 1 to 3 carbon atoms, at least one of R 5  and R 6  being alkyl or alkoxy, or wherein R 5  and R 6  together are benzo or an alkylenedioxy group (with the proviso that in a quinazoline of Formula I, when R 5  and R 6  are both methoxy and R 3  and R 4  are both hydrogen, then R 1  and R 2  may not both be methyl or hydrogen); Z is 1-piperazinyl, 4- alkyl-1-piperazinyl where alkyl has from 1 to 5 carbon atoms, 4 - hydroxyalkyl - 1 - piperazinyl where alkyl has from 1 to 5 carbon atoms, 4- alkanoyl-1-piperazinyl where alkanoyl has from 2 to 7 carbon atoms, 3-oxo-1-piperazinyl, 4-benzoyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 4- allyl-1-piperazinyl, morpholino, 2,6-dialkyl-morpholino where alkyl has from 1 to 5 carbon atoms, 1-pyrrolidinyl, 1-azacycloheptyl, 1-azacyclooctyl, piperidino, 2-hydroxy-piperidino, 3-hydroxypiperidino, 4-hydroxypiperidino, 2- alkoxypiperidino, 3-alkoxypiperidino, and 4- alkoxypiperidino where alkoxy has from 1 to 4 carbon atoms, 2-alkylpiperidino, 3-alkylpiperidino, and 4-alkylpiperidino where alkyl has from 1 to 6 carbon atoms, 2-benzylpiperidino, 4-benzylpiperidino, 2 - hydroxyalkylpiperidino, 3 - hydroxyalkylpiperidino, and 4-hydroxyalkylpiperidino where alkyl has from 1 to 6 carbon atoms, 4 - (2 - halophenyl) - 1 - piperazinyl, 4 - (3 - halophenyl) - 1 - piperazinyl, 4 - (4 - halophenyl) - 1 - piperazinyl, 4 - (2 - halobenzoyl) - 1 - piperazinyl, 4 - (3 - halobenzoyl) - 1-piperazinyl or 4-(4-halobenzoyl)-1-piperazinyl where halo is chloro or bromo, 4-piperazinyl-1- carboxylic acid alkyl ester where alkyl has from 1 to 6 carbon atoms, 4-piperazinyl-1-carboxylic acid alkenyl ester where alkenyl has from 2 to 6 carbon atoms, 4-(2-furoyl)-1-piperazinyl, 4-(3- furoyl)-1-piperazinyl, 4-(2-thenoyl)-1-piperazinyl, 4 - (3 - thenoyl) - 1 - piperazinyl, 4 - (2 - methylallyl) - 1 - piperazinyl, 4 - crotonyl - 1 - piperazinyl, cycloalkylamino where alkyl has from 3 to 7 carbon atoms, 4-carbamoyl-1-piperazinyl where carbamoyl has the Formula IV where R m  and R n  are hydrogen or alkyl having from 1 to 6 carbon atoms, 4-(2-methoxyphonyl)- 1-piperazinyl, 4 - (3 - methoxyphenyl) - 1 - piperazinyl, 4 - (4 - methoxyphenyl) - 1 - piperazinyl, 4 - (2 - trifluoromethylphenyl)- 1 - piperazinyl, 4 - (3 - trifluoromethylphenyl) - 1 - piperazinyl, 4 - (4 - trifluoromethylphenyl)- 1 - piperazinyl, 4 - (2 - methylphenyl) - 1 - piperazinyl, 4 - (3 - methylphenyl) - 1 - piperazinyl, 4 - (4 - methylphenyl) - 1 - piperazinyl, 4 - (2 - methylbenzoyl) - 1 - piperazinyl, 4 - (3 - methylbenzoyl) - 1 - piperazinyl, 4 - (4 - methylbenzoyl) - 1 - piperazinyl, 4 - (2 - trifluoromethylbenzoyl) - 1 - piperazinyl, 4 - (3 - trifluoromethylbenzoyl) - 1 - piperazinyl, 4 - (4 - trifluoromethylbenzoyl)- 1 - piperazinyl, 4 - (2 - methoxybenzoyl) - 1 - piperazinyl, 4 - (3 -methoxybenzoyl) - 1 - piperazinyl, 4 - (4 - methoxybenzoyl) - 1 - piperazinyl, and the pharmaceutically-acceptable acid addition salts thereof, are prepared by (a) halogenation of a 6-R 5 -7-R 6 -2-Z (or -NR 1 R 2 )-3,4-dihydroquinazoline-4-one to yield the corresponding substituted-4-haloquinazoline, followed by reaction with an appropriate nitrogen-containing compound at position 4; (b) thiolation of a 6-R 5 -7- R 6 -(1H,3H)-quinazoline-2,4-dione with or without subsequent alkylation or benzylation and reaction with an appropriate nitrogen-containing compound; (c) alkylation, alkanoylation, aroylation and arylation of a piperazino group attached to position 2 or 4 of the quinazoline nucleus; (d) reaction of an appropriate guanidine with 2-amino-4-R 6 -5-R 5 -benzonitriles to form 2 - amino - 4 - substituted - 6 - R 5  - 7 - R 6  - quinazolines; (e) reaction of appropriate guanidines with 2-chloro-4-R 6 -5-R 5 -benzonitriles to form 2 - substituted - 4 - amino - 6 - R 5  - 7 - R 6  - quinazolines; (f) reaction of appropriate guanidines with 2-amidino-4-R 5 -5-R 6 -anilines to form 2 - substituted - 4 - amino - 6 - R 5  - 7 - R 6  - quinazolines; (g) reaction of 2-chloro-4-(alkoxyphenoxy- or benzyloxy-) - 6 - R 5  - 7 - R 6  - quinazolines with ammonia or amino compounds to form 2,4 - disubstituted - 6 - R 5  - 7 - R 6  - quinazolines; or (h) reaction of 2-chloro-4-alkylthio- 6-R 5 -7-R 6 -quinazolines with ammonia or amino compounds to form 2,4-disubstituted-6-R 5 -7- R 6 -quinazolines. The novel compounds are also prepared by reacting a 6-R 5 -7-R 6 -2,4-dichloroquinazoline with ammonia or an appropriate amine to form a 2-chloro-4-substituted-quinazoline and then reacting this with ammonia or an appropriate amine. 2,4 - Dichloro - 6 - methoxy - 7 - amyloxyquinazoline is prepared by reacting 4-amyloxy-5- methoxy anthranilic acid amide with sodium cyanate to give 2-ureido-4-amyloxy-5-methoxybenzamide and heating this with hydrochloric acid. 2,4 - Dichloro - 6,7 - diamyloxyquinazoline is similarly prepared via 2-ureido-4,5-diamyloxybenzamide. 2 - Methylthio - 4 - amino - 6,7 - dimethoxyquinazoline is prepared by reacting 6,7-dimethoxy- (1H,3H)-quinazoline-dione to give 6,7-dimethoxy - (1H,3H) - quinazolinedithione, reacting this with methyl iodide to give 2,4-di-methylthio - 6,7 - dimethoxyquinazoline and reacting this with anhydrous ammonia. Isobutyl 1-piperazine carboxylate is prepared by reacting piperazine with isobutyl chloroformate. Pharmaceutical compositions having hypotensive activity, for oral or parenteral administration, comprise a compound of the invention together with a carrier.