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Claims for Patent: 7,173,038

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Claims for Patent: 7,173,038

Title:Quinazoline derivatives as VEGF inhibitors
Abstract:The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R.sup.1 represents halogeno or C.sub.1-3alkyl; X.sup.1 represents --O--; R.sup.2 is selected from one of the following three groups: 1) C.sub.1-5alkylR.sup.3 (wherein R.sup.3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy; 2) C.sub.2-5alkenylR.sup.3 (wherein R.sup.3 is as defined hereinbefore); 3) C.sub.2-5alkynylR.sup.3 (wherein R.sup.3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof, processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as a active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of number of disease states including cancer and rheumatoid arthritis.
Inventor(s): Thomas; Andrew Peter (Macclesfield Cheshire, GB), Stokes; Elaine Sophie Elizabeth (Macclesfield Cheshire, GB), Hennequin; Laurent Francois Andre (Reims Cedex, FR)
Assignee: AstraZeneca AB (Sodertalje, SE)
Application Number:10/129,336
Patent Claims: 1. A quinazoline derivative of the formula I: ##STR00018## wherein: m is an integer from 1 to 3; R.sup.1 represents halogeno or C.sub.1-3alkyl; X.sup.1 represents --O--; R.sup.2 is selected from one of the following three groups: 1) C.sub.1-5alkylR.sup.3, wherein R.sup.3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy; 2) C.sub.2-5alkenylR.sup.3, wherein R.sup.3 is as defined herein; 3) C.sub.2-5alkynylR.sup.3, wherein R.sup.3 is as defined herein; and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; or a salt thereof.

2. The quinazoline derivative as claimed in claim 1 wherein the phenyl group of formula I together with the (R.sup.1).sub.m substituent: ##STR00019## forms a group selected from 2-fluoro-4-methylphenyl, 4-chloro-2,6-difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl.

3. The quinazoline derivative as claimed in claim 1 wherein R.sup.2 is C.sub.1-5alkylR.sup.3, wherein R.sup.3 is as defined in claim 1.

4. The quinazoline derivative as claimed in claim 1 wherein R.sup.2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C.sub.1-4alkyl.

5. A quinazoline derivative of the formula II: ##STR00020## wherein: ma is an integer from 1 to 3; R.sup.1a represents halogeno or C.sub.1-3alkyl; X.sup.1a represents --O--; R.sup.2a is selected from one of the following three groups: 1) C.sub.1-5alkylR.sup.3, wherein R.sup.3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy; 2) C.sub.2-5alkenylR.sup.3, wherein R.sup.3 is as defined herein; 3) C.sub.2-5alkynylR.sup.3, wherein R.sup.3 is as defined herein; or a salt thereof.

6. A quinazoline derivative selected from: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)q- uinazoline, 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)q- uinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)qu- inazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin- -4-ylmethoxy)quinazoline, 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethox- y)quinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoli- ne, 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinaz- oline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quin- azoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmetho- xy)quinazoline, and 4-(4-bromo-2, 6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, or a salt thereof.

7. A quinazoline derivative selected from: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)q- uinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)qu- inazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin- -4-ylmethoxy)quinazoline, and 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethox- y)quinazoline, or a salt thereof.

8. A quinazoline derivative selected from: 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)qu- inazoline or a salt thereof.

9. A quinazoline derivative as claimed in any one of claims 1 8 in the form of a pharmaceutically acceptable salt.

10. A process for the preparation of a quinazoline derivative of formula I, as defined in claim 1, or a salt thereof which comprises: (a) the reaction of a compound of the formula III: ##STR00021## wherein R.sup.2 and X.sup.1 are as defined in claim 1 and L.sup.1 is a displaceable moiety, with a compound of the formula IV: ##STR00022## wherein R.sup.1 and m are as defined in claim 1; (b) the reaction of a compound of the formula V: ##STR00023## wherein m, X.sup.1 and R.sup.1 are as defined in claim 1 with a compound of formula VI: R.sup.2--L.sup.1 (VI) wherein R.sup.2 is as defined in claim 1 and L.sup.1 is as defined herein; (c) the reaction of a compound of the formula VII: ##STR00024## with a compound of the formula VIII: R.sup.2--X.sup.1--H (VIII) wherein R.sup.1, R.sup.2, m and X.sup.1 are as defined in claim 1 and L.sup.1 is as defined herein; or (d) the deprotection of a compound of the formula IX: ##STR00025## wherein R.sup.1, m and X.sup.1 are as defined in claim 1, and R.sup.4 represents a protected R.sup.2 group wherein R.sup.2 is as defined in claim 1 but additionally bears one or more protecting groups; and when a pharmaceutically acceptable salt of a quinazoline derivative of formula I is required, reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt.

11. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in any one of claims 1 8 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
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