Quinazoline Derivatives as VEGF Inhibitors

Abstract

The invention relates to quinazoline derivatives of formula (I), wherein in is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; X1 represents —O—; R2 is selected from one of the following three groups: 1) C1-5akylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy; 2) C2-5alkynylR3 (wherein R3 is as defined hereinbefore); 3) C2-5alkynylR3 (wherein R3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alynyl 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 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 a number of disease states including cancer and rheumatoid arthritis.

1 - 13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising 100 mg to 300 mg of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is formulated for oral administration. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , in the form of a tablet. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the tablet is coated. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the coating is an enteric coating. 
     
     
         19 . The pharmaceutical composition according to  claim 14 , wherein the amount of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline is 100 mg. 
     
     
         20 . The pharmaceutical composition according to  claim 14 , wherein the amount of the pharmaceutically acceptable salt of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline is 100 mg. 
     
     
         21 . The pharmaceutical composition according to  claim 14 , wherein the amount of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline is 300 mg. 
     
     
         22 . The pharmaceutical composition according to  claim 14 , wherein the amount of the pharmaceutically acceptable salt of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline is 300 mg. 
     
     
         23 . The pharmaceutical composition according to  claim 14 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of lactose, croscarmellose sodium, maize starch, polyvinylpyrollidone and magnesium stearate. 
     
     
         24 . The pharmaceutical composition according to  claim 14 , comprising 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline. 
     
     
         25 . The pharmaceutical composition according to  claim 14 , comprising a pharmaceutically acceptable salt of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline. 
     
     
         26 . A pharmaceutical composition comprising 100 mg of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a tablet. 
     
     
         27 . A pharmaceutical composition comprising 300 mg of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a tablet.