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Claims for Patent: 5,770,599

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Claims 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.
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