Claims for Patent: 5,770,599
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Summary for Patent: 5,770,599
Title: | Quinazoline derivatives |
Abstract: | The invention concerns quinazoline derivatives of the formula I ##STR1## wherein n is 1, 2 or 3 and each R.sup.2 is independently halogeno, trifluoromethyl or (1-4C)alkyl; R.sup.3 is (1-4C)alkoxy; and R.sup.1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(2-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R.sup.1 substituents comprising a CH.sub.2 (methylene) group which is not attached to a N or O atom optionally bears on said CH.sub.2 group a hydroxy substituent; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them, and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of proliferative disease such as cancer. |
Inventor(s): | Gibson; Kieth Hopkinson (Macclesfield, GB) |
Assignee: | Zeneca Limited (London, GB) |
Application Number: | 08/638,331 |
Patent Claims: |
1. A quinazoline derivative of the formula I ##STR5## wherein n is 1, 2 or 3 and each R.sup.2 is independently halogeno or trifluoromethyl
R.sup.3 is (1-4C)alkoxy; and R.sup.1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(2-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R.sup.1 substituents comprising a CH.sub.2 (methylene) group which is not attached to a N or O atom optionally bears on said CH.sub.2 group a hydroxy substituent; or a pharmaceutically-acceptable salt thereof. 2. A quinazoline derivative of the formula I as claimed in claim 1 wherein n is 1, 2 or 3 and each R.sup.2 is independently halogeno or trifluoromethyl; R.sup.3 is (1-4C)alkoxy; and R.sup.1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy or di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, and wherein any of the above-mentioned R.sup.1 substituents comprising a CH.sub.2 (methylene) group which is not attached to a N or O atom optionally bears on said CH.sub.2 group a hydroxy substituent; or a pharmaceutically-acceptable salt thereof. 3. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R.sup.2).sub.n is 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R.sup.3 is methoxy; and R.sup.1 is 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy; or a pharmaceutically-acceptable mono- or di-acid-addition salt thereof. 4. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R.sup.2).sub.n is 3'-chloro, 3'-bromo, 2',4'-difluoro, 2',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R.sup.3 is methoxy; and R.sup.1 is 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 5. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R.sup.2).sub.n is 3'-chloro, 3'-bromo, 2',4'-difluoro, 2',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R.sup.3 is methoxy; and R.sup.1 is 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-morpholinopropoxy or 3-morpholino-2-hydroxypropoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 6. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R.sup.2).sub.n is 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R.sup.3 is methoxy; and R.sup.1 is 3-morpholinopropoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 7. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-pyrrolidin-1-ylethoxy)quinazo line; or a pharmaceutically-acceptable acid-addition salt thereof. 8. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-morpholinoethoxy)quinazoline; or a pharmaceutically-acceptable acid-addition salt thereof. 9. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-6-(3-diethylaminopropoxy)-7-methoxyquinazoli ne; or a pharmaceutically-acceptable acid-addition salt thereof. 10. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinaz oline; or a pharmaceutically-acceptable acid-addition salt thereof. 11. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazol ine; or a pharmaceutically-acceptable acid-addition salt thereof. 12. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline; or a pharmaceutically-acceptable acid-addition salt thereof. 13. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-piperidinopropoxy)quinazoline or a pharmaceutically-acceptable acid-addition salt thereof. 14. The quinazoline derivative of the formula I as claimed in claim 1 being 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline ; or a pharmaceutically-acceptable acid-addition salt thereof. 15. The hydrochloride salt of the quinazoline derivative of the formula I as claimed in claim 14. 16. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15 which comprises (a) the reaction of a quinazoline of the formula II ##STR6## wherein Z is a displaceable group, with an aniline of the formula III ##STR7## (b) for the production of those compounds of the formula I wherein R.sup.1 is an amino-substituted (2-4C)alkoxy group, the alkylation of a quinazoline derivative of the formula I wherein R.sup.1 is a hydroxy group; (c) for the production of those compounds of the formula I wherein R.sup.1 is an amino-substituted (2-4C)alkoxy group, the reaction of a compound of the formula I wherein R.sup.1 is a hydroxy-(2-4C)alkoxy group, or a reactive derivative thereof, with an appropriate amine; or (d) for the production of those compounds of the formula I wherein R.sup.1 is a hydroxy-amino-(2-4C)alkoxy group, the reaction of a compound of the formula I wherein R.sup.1 is a 2,3-epoxypropoxy or 3,4-epoxybutoxy group with an appropriate amine. and when a pharmaceutically-acceptable salt of a quinazoline derivative of the formula I is required it may be obtained by reaction of said compound with a suitable acid using a conventional procedure. 17. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15 in association with a pharmaceutically-acceptable diluent or carrier. 18. A method for producing an anti-proliferative effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15. 19. The quinazoline derivative of the formula I as claimed in claim 1 selected from the group consisting of: 4-(3'-chloro-4'-fluoroanilino)-6-(2-dimethylaminoethoxy)-7-methoxyquinazoli ne; 4-(2',4'-difluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline; 4-(2',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline; 4-(3'-chloro-4'-fluoroanilino)-6-(2-imidazol-1-ylethoxy)-7-methoxyquinazoli ne; and 4-(3'-chloro-4'-fluoroanilino)-6-(3-imidazol-1-ylpropoxy)-7-methoxyquinazol ine; or a pharmaceutically-acceptable acid-addition salt thereof. |