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 piperidinyl-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 - 17 . (canceled)  
   
   
       18 . A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need thereof which comprises administering to said animal an effective amount of a compound 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 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 pharmaceutically acceptable salt thereof.  
 
 
   
   
       19 . A method for the treatment of a disease selected from the group consisting of cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation, in a warm-blooded animal in need thereof which comprises administering to said animal an effective amount of a compound 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 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 pharmaceutically acceptable salt thereof.  
 
 
   
   
       20 . The method according to  claim 19  wherein said disease is cancer.  
   
   
       21 . A method for the treatment of a solid tumour in a warm-blooded animal in need thereof which comprises administering to said animal an effective amount of a compound 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 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 pharmaceutically acceptable salt thereof.  
 
 
   
   
       22 . The method according to  claim 21  wherein said solid tumour is associated with VEGF.  
   
   
       23 . The method according to  claim 21  wherein said solid tumour is associated with EGF.  
   
   
       24 . The method according to  claim 21  wherein said solid tumour is associated with both VEGF and EGF.  
   
   
       25 . The method according to  claim 21  wherein said solid tumour is selected from a tumour of the colon, breast, prostate, lung, vulva or skin.  
   
   
       26 . The method according to any one of claims  18 ,  19  and  21  wherein in the compound of formula I, the phenyl group together with the (R 1 ) m  substituent:  
     
       
         
         
             
             
         
       
     
     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.  
   
   
       27 . The method according to any one of claims  18 ,  19  and  21  wherein in the compound of formula I, R 2  is C 1-5 alkylR 3 .  
   
   
       28 . The method according to any one of claims  18 ,  19  and  21  wherein in the compound of formula I, R 2  is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C 1-4 alkyl.  
   
   
       29 . The method according to any one of claims  18 ,  19  and  21  wherein the compound of formula I is a compound of 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 1-5 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;  
 or a pharmaceutically acceptable salt thereof.  
 
 
   
   
       30 . The method according to any one of claims  18 ,  19  and  21  wherein the compound of formula I is 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,    or a pharmaceutically acceptable salt thereof.    
   
   
       31 . The method according to any one of claims  18 ,  19  and  21  wherein the compound of formula I is 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-methylpiperidin-4-ylmethoxy)quinazoline, and    4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,    or a pharmaceutically acceptable salt thereof.    
   
   
       32 . The method according to any one of claims  18 ,  19  and  21  wherein the compound of formula I is selected from: 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,    or a pharmaceutically acceptable salt thereof.