Claims for Patent: 5,770,599

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 R2 is independently halogeno, trifluoromethyl or (1-4C)alkyl;R3 is (1-4C)alkoxy; andR1 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 R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 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):	Kieth Hopkinson Gibson
Assignee:	AstraZeneca UK Ltd , Syngenta Ltd
Application Number:	US08/638,331
Patent Claims:	1. A quinazoline derivative of the formula I ##STR5## wherein n is 1, 2 or 3 and each R2 is independently halogeno or trifluoromethylR3 is (1-4C)alkoxy; and R1 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 R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 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 R2 is independently halogeno or trifluoromethyl;R3 is (1-4C)alkoxy; and R1 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 R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 group a hydroxy substituent; or a pharmaceutically-acceptable salt thereof. 3. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R2)n is3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R3 is methoxy; and R1 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(R2)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; R3 is methoxy; and R1 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(R2)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; R3 is methoxy; and R1 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 1wherein (R2)n is 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R3 is methoxy; and R1 is 3-morpholinopropoxy;or a pharmaceutically-acceptable acid-addition salt thereof. 7. The quinazoline derivative of the formula I as claimed in claim 1 being4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-pyrrolidin-1-ylethoxy)quinazoline;or a pharmaceutically-acceptable acid-addition salt thereof. 8. The quinazoline derivative of the formula I as claimed in claim 1 being4-(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 being4-(3'-chloro-4'-fluoroanilino)-6-(3-diethylaminopropoxy)-7-methoxyquinazoline;or a pharmaceutically-acceptable acid-addition salt thereof. 10. The quinazoline derivative of the formula I as claimed in claim 1 being4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline;or a pharmaceutically-acceptable acid-addition salt thereof. 11. The quinazoline derivative of the formula I as claimed in claim 1 being4-(3'-chloro-4'-fluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline;or a pharmaceutically-acceptable acid-addition salt thereof. 12. The quinazoline derivative of the formula I as claimed in claim 1 being4-(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 being4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-piperidinopropoxy)quinazolineor a pharmaceutically-acceptable acid-addition salt thereof. 14. The quinazoline derivative of the formula I as claimed in claim 1 being4-(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 R1 is an amino-substituted (2-4C)alkoxy group, the alkylation of a quinazoline derivative of the formula I wherein R1 is a hydroxy group; (c) for the production of those compounds of the formula I wherein R1 is an amino-substituted (2-4C)alkoxy group, the reaction of a compound of the formula I wherein R1 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 R1 is a hydroxy-amino-(2-4C)alkoxy group, the reaction of a compound of the formula I wherein R1 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-methoxyquinazoline; 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-methoxyquinazoline; and 4-(3'-chloro-4'-fluoroanilino)-6-(3-imidazol-1-ylpropoxy)-7-methoxyquinazoline;or a pharmaceutically-acceptable acid-addition salt thereof.