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 1 represents halogeno or C 1-3 alkyl; X 1 represents —O—; R 2 is selected from one of the following three groups: 1) C 1-5 alkylR 3 (wherein R 3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; 2) C 2-5 alkenylR 3 (wherein R 3 is as defined hereinbefore); 3) C 2-5 alkynylR 3 (wherein R 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 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 . A quinazoline derivative of the formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         m is an integer from 1 to 3; 
         R 1  represents halogeno or C 1-3 alkyl; 
         X 1  represents —O—; 
         R 2  is selected from one of the following three groups: 
         1) C 1-5 alkylR 3  (wherein R 3  is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; 
         2) C 2-5 alkenylR 3  (wherein R 3  is as defined herein); 
         3) C 2-5 alkynylR 3  (wherein R 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 . A quinazoline derivative as claimed in  claim 1  wherein the phenyl group bearing (R 1 ) m  is 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 . A quinazoline derivative as claimed in  claim 1  or  claim 2  wherein R 2  is C 1-5 alkylR 3  (wherein R 3  is as defined in  claim 1 ). 
     
     
         4 . A quinazoline derivative as claimed in  claim 1  wherein R 2  is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C,4alkyl. 
     
     
         5 . A quinazoline derivative as claimed in  claim 1  of the formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         ma is an integer from 1 to 3; 
         R 1a  represents halogeno or C 1-3 alkyl; 
         X 1a  represents —O—; 
         R 2a  is selected from one of the following three groups: 
         1) C 1-3 alkylR 3  (wherein R 3  is as defined in  claim 1 ); 
         2) C 2-5 alkenylR 3  (wherein R 3  is as defined in  claim 1 ); 
         3) C 2-5 alkynylR 3  (wherein R 3  is as defined in  claim 1 ); 
         or a salt thereof. 
       
     
     
         6 . A quinazoline derivative as claimed in  claim 1  selected from:
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1 -methylpiperidin-4-ylmethoxy)quinazoline, 
 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, 
 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-ylmethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 
 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 
 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and 
 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and salts thereof. 
 
     
     
         7 . A quinazoline derivative as ed in  claim 1  selected from:
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, 
 4-(4-chloro-2, 6-difluoroanilino)-6-methoxy-7-(1 -methy Ipiperidin-4-ylmethoxy)quinazoline, and 
 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1 -methylpiperidin-4-ylmethoxy)quinazoline, and salts thereof. 
 
     
     
         8 . A quinazoline derivative as claimed in  claim 1  selected from:
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline and salts thereof. 
 
     
     
         9 . A quinazoline derivative as claimed in  claim 1  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:   
       
         
           
           
               
               
           
         
         wherein R 2  and X 1  are as defined in  claims 1  and L 1  is a displaceable moiety, with a compound of the formula IV: 
       
       
         
           
           
               
               
           
         
         wherein R 1  and m are as defined in  claim 1 ; 
         (b) the reaction of a compound of the formula V: 
       
       
         
           
           
               
               
           
         
         wherein m, X 1  and R are as defined in  claim 1  with a compound of formula VI:
   R 2 -L 1    (VI)
 
 
         wherein R 2  is as defined in  claims 1  and L 1  is as defined herein; 
         (c) the reaction of a compound of the formula VII: 
       
       
         
           
           
               
               
           
         
         with a compound of the formula VIII:
   R 2 —X 1 —H   (VIII)
 
 
         wherein R 1 , R 2 , m and X 1  are as defined in  claim 1  and L 1  is as defined herein; or 
         (d) the deprotection of a compound of the formula IX: 
       
       
         
           
           
               
               
           
         
         wherein R 1 , m and X 1  are as defined in  claim 1 , and R 4  represents a protected R 2  group wherein R 2  is as defined in  claim 1  but additionally bears one or more protecting groups P 2 ; 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  claim 1  or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier. 
     
     
         12 . (canceled) 
     
     
         13 . A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof.