Quinazoline derivatives and pharmaceutical compositions containing them

Abstract

The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6 (wherein R 5 and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R 3 represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X 1 represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10 and R 11 each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); R 4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, 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 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 2; 
         R 1  represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6  (wherein R 5  and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); 
         R 2  represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; 
         R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; 
         X 1  represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10  and R 11  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); 
         R 4  is selected from one of the following thirteen groups: 
         1) C 1-5 alkylR 12  (wherein R 12  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C 1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) or C 1-5 alkylR 13  (wherein R 13  is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         2) C 2-5 alkenylR 14  (wherein R 14  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         3) C 2-5 alkynylR 15  (wherein R 15  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         4) C 1-5 alkylX 2 C 1-5 alkylX 3 R 16  (wherein X 2  and X 3  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 17 CO—, —CONR 18 —, —SO 2 NR 19 —, —NR 20 SO 2 — or —NR 21 — (wherein R 17 , R 18 , R 19 , R 20  and R 21  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 1-5 alkylX 2 C 1-5 alkylX 3 R 16 ; 
         5) C 1-5 alkylX 4 COR 22  (wherein X 4  represents —O— or —NR 23 — (wherein R 23  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 22  represents —NR 24 R 25  or —OR 26  (wherein R 24 , R 25  and R 26  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl)); 
         6) C 1-5 alkylX 5 R 27  (wherein X 5  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 28 CO—, —CONR 29 —, —SO 2 NR 30 —, —NR 31 SO 2 — or —NR 32 — (wherein R 28 , R 29 , R 30 , R 31  and R 32  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) or X 5  is carbonyl, and R 27  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl or R 27  is C 1-3 alkyl with the proviso that when R 27  is C 1-3 alkyl, X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30 — or —NR 31 SO 2 — and X 1  is not —CH 2 —); 
         7) C 1-3 alkoxyC 2-4 alkyl provided that X 1  is —S—, —SO— or —SO 2 —; 
         8) C 1-3 alkoxyC 2-4 alkyl or C 1-4 alkyl provided that X 1  is —O—; 
         9) C 1-5 alkylX 6 C 1-5 alkylR 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 34 CO—, —CONR 35 —, —SO 2 NR 36 —, —NR 37 SO 2 — or —NR 38 — (wherein R 34 , R 35 , R 36 , R 37  and R 38  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         10) R 39  (wherein R 39  is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         11) C 1-5 alkylR 40  (wherein R 40  is piperazin-1-yl which bears at least one substituent selected from C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 hydroxyalkyl and —CONR 41 R 42  (wherein R 41  and R 42  each independently represents hydrogen or C 1-4 alkyl); 
         12) C 1-5 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) with the proviso that when R 4  is C 1-5 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —; and 
         13) C 1-5 alkylR 44  (wherein R 44  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
         with the further proviso that when R 4  is selected from group 8) R 1  and/or R 2  is/are nitro or at least one R 3  is C 1-3 alkanoyloxy;] 
         and salts thereof. 
       
     
     
         2 . A quinazoline derivative as claimed in  claim 1  wherein R 1  represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. 
     
     
         3 . A quinazoline derivative as claimed in  claim 1  or  claim 2  wherein R 2  is hydrogen. 
     
     
         4 . A quinazoline derivative as claimed in any one of the preceding claims wherein the phenyl group bearing (R 3 ) m  is of the formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R a  represents hydrogen, methyl, fluoro or chloro; 
         R b  represents hydrogen, methyl, methoxy, bromo, fluoro or chloro; 
         R c  represents hydrogen or hydroxy; 
         R d  represents hydrogen, fluoro or chloro. 
       
     
     
         5 . A quinazoline derivative as claimed in any one of the preceding claims wherein X 1  represents —O—, —S—, —NR 7 CO—, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 10  and R 11  each independently represents hydrogen, C 1-2 alkyl or C 1-2 alkoxyethyl). 
     
     
         6 . A quinazoline derivative as claimed in any one of the preceding claims wherein R 4  is selected from one of the following eleven groups:
 1) C 1-4 alkylR 12  (wherein R 12  is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or C 2-4 alkylR 45  (wherein R 45  is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl);   2) 1-R 46 prop-1-en-3-yl, 1-R 46 but-2-en-4-yl, 1-R 46 but-1-en-3-yl, 1-R 46 pent-2-en-4-yl or 2-R 46 pent-3-en-5-yl (wherein R 46  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or 1-R 47 but-2-en-4-yl, 1-R 47 pent-2-en-4-yl or 2-R 47 pent-3-en-5-yl (wherein R 47  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl);   3) 1-R 48 prop-1-yn-3-yl, 1-R 48 but-2-yn-4-yl, 1-R 48 but-1-yn-3-yl, 1-R 48 pent-2-yn-4-yl or 2-R 48 pent-3-yn-5-yl (wherein R 48  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or 1-R 49 but-2-yn-4-yl, 1-R 49 pent-2-yn-4-yl or 2-R 49 pent-3-yn-5-yl (wherein R 49  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3  alkoxycarbonyl);   4) C 2-3 alkylX 2 C 1-3 alkylX 3 R 16  (wherein X 2  and X 3  are as defined in  claim 1  and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 2-3 alkylX 2 C 1-3 alkylX 3 R 16 ;   5) C 2-3 alkylX 4 COR 22  (wherein X 4  is as defined in  claim 1  and R 22  represents —NR 24 R 25  or —OR 26  (wherein R 24 , R 25  and R 26  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-2 alkoxyethyl));   6) C 2-3 alkylX 5 R 27  (wherein X 5  is as defined in  claim 1  and R 27  represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X 5  through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl or R 27  is C 1-3 alkyl with the proviso that when R 27  is C 1-3 alkyl, X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30 — or —NR 31 SO 2 — and X 1  is not —CH 2 —);   7) C 1-2 alkoxyC 2-3 alkyl provided that X 1  is —S—, —SO— or —SO 2 —;   8) C 2-3 alkylX 6 C 2-3 alkylR 33  (wherein X 6  is as defined in  claim 1  and R 33  represents a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl, and C 1-3 alkoxycarbonyl);   9) C 2-3 alkylR 40  (wherein R 40  is piperazin-1-yl which bears at least one substituent selected from acetyl, C 1-2 alkoxycarbonyl, C 1-2 hydroxyalkyl and CONR 41 R 42  (wherein R 41  and R 42  each independently represents hydrogen or C 1-2 alkyl);   10) C 2-3 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl) with the proviso that when R 4  is C 2-3 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —; and   11) C 2-3 alkylR 44  (wherein R 44  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl).   
     
     
         7 . A quinazoline derivative as claimed in  claim 6  wherein R 4  is selected from one of the following nine groups:
 1) C 1-3 alkylR 12  (wherein R 12  is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl) or C 2-3 alkylR 45  (wherein R 45  is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl); 
 2) 1-R 50 but-2-en-4-yl (wherein R 50  is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl); 
 3) 1-R 51 but-2-yn-4-yl (wherein R 51  is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl); 
 4) C 2-3 alkylX 2 C 1-3 alkylX 3 R 16  (wherein X 2  and X 3  are as defined in  claim 1  and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 2-3 alkylX 2 C 1-3 alkylX 3 R 16 ; 
 5) C 1-2 alkoxyC 2-3 alkyl provided that X 1  is —S—, —SO— or —SO 2 —; 
 6) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-( N , N -dimethylcarbamoyloxy)ethyl, 3-( N , N -dimethylcarbamoyloxy)propyl, 2-( N -methylcarbamoyloxy)ethyl, 3-( N -methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, 2-(1,3,3-trimethylureido)ethyl, 3-(1,3,3-trimethylureido)propyl, 2-(isopropoxycarbonylamino)ethyl, 3-(isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl, 3-(isobutoxycarbonylamino)propyl, 2-(t-butoxycarbonylamino)ethyl or 3-(t-butoxycarbonylamino)propyl; 
 7) C 2-3 alkylX 5 R 27  (wherein R 27  is C 1-2 alkyl and X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30 — or —NR 31 SO 2 — and with the proviso that X 1  is not —CH 2 —); 
 8) C 2-3 alkylX 6 C 2-3 alkylR 33  (wherein X 6  is as defined in  claim 1  and R 33  represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl); and 
 9) C 2-3 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl) with the proviso that when R 4  is C 2-3 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —. 
 
     
     
         8 . A compound as claimed in  claim 1  of the formula Ia: 
       
         
           
           
               
               
           
         
         [wherein: 
         R 1a  is hydrogen or methoxy; 
         R 2a  is hydrogen; 
         the phenyl group bearing (R 3a ) ma  is the 4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group; 
         X 1a  is —O—, —S—, —NR 5a CO— or —NR 6a SO 2 — (wherein R 5a  and R 6a  each independently represents hydrogen or C 1-2 alkyl); 
         R 4a  is selected from one of the following eleven groups: 
         1) C 1-4 alkylR 7a  (wherein R 7a  is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or C 2-4 alkylR 8a  (wherein R 8a  is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl); 
         2) 1-R 9a prop-1-en-3-yl, 1-R 9a but-2-en-4-yl, 1-R 9a but-1-en-3-yl, 1-R 9a pent-2-en-4-yl or 2-R 9a pent-3-en-5-yl (wherein R 9a  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or 1-R 10a but-2-en-4-yl, 1-R 10a pent-2-en-4-yl or 2-R 10a pent-3-en-5-yl (wherein R 10a  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl); 
         3) 1-R 11a prop-1-yn-3-yl, 1-R 11a but-2-yn-4-yl, 1-R 11a but-1-yn-3-yl, 1-R 11a pent-2-yn-4-yl or 2-R 11a pent-3-yn-5-yl (wherein R 11a  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl) or 1-R 12a but-2-yn-4-yl, 1-R 12a pent-2-yn-4-yl or 2-R 12a pent-3-yn-5-yl (wherein R 12a  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl and C 1-3 alkoxycarbonyl); 
         4) C 2-3 alkylX 2a C 1-3 alkylX 3a R 13a  (wherein X 2a  and X 3a  which may be the same or different each represents —O—, —S—, —SO—, —SO 2 —, —NR 14a CO—, or —NR 15a — (where R 14a  and R 15a  each independently represents hydrogen, C 1-2 alkyl or C 1-2 alkoxyethyl) and R 13a  represents hydrogen or C 1-3 alkyl); 
         5) C 2-3 alkylX 4a COR 16a  (wherein X 4a  represents —O— or —NR 17a — (wherein R 17a  represents hydrogen, C 1-3 alkyl or C 1-2 alkoxyethyl) and R 16a  represents —NR 18a R 19a  or —OR 20a  (wherein R 18a , R 19a  and R 20a  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-2 alkoxyethyl)); 
         6) C 2-3 alkylX 5a R 21a  (wherein X 5a  represents carbonyl, —O—, —S—, —SO—, —SO 2 —, —NR 22a CO—, —NR 23a SO 2 — or —NR 24a — (wherein R 22a , R 23a  and R 24a  each independently represents hydrogen, C 1-2 alkyl or C 1-2 alkoxyethyl) and R 21a  represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X 5a  through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C 1-2 alkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl or R 21a  is C 1-3 alkyl with the proviso that when R 21a  is C 1-3 alkyl, X 5a  is —S—, —SO—, —SO 2 — or —NR 23a SO 2 —); 
         7) C 1-2 alkoxyC 2-3 alkyl provided that X 1a  is —S—; 
         8) C 2-3 alkylX 6a C 2-3 alkylR 25a  (wherein X 6a  represents —O—, —S—, —SO—, —SO 2 —, —NR 26a CO—, —NR 27a SO 2 — or —NR 28a — (wherein R 26a , R 27a  and R 28a  each independently represents hydrogen, C 1-2 alkyl or C 1-2 alkoxyethyl) and R 25a  represents a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N , N -di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl, and C 1-3 alkoxycarbonyl); 
         9) C 2-3 alkylR 29a  (wherein R 29a  is piperazin-1-yl which bears at least one substituent selected from acetyl, C 1-2 alkoxycarbonyl, C 1-2 hydroxyalkyl and CONR 30a R 31a  (wherein R 30a  and R 31a  each independently represents hydrogen or C 1-2 alkyl); 
         10) C 2-3 alkylR 32a  (wherein R 32a  is morpholino which may bear one or two substituents selected from oxo, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl) with the proviso that when R 4a  is C 2-3 alkylR 32a , X 1a  is —S— or —NR 6a SO 2 — (wherein R 6a  is as defined herein); and 
         11) C 2-3 alkylR 33a  (wherein R 33a  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl,  N , N -di(C 1-2 alkyl)carbamoyl, acetyl and C 1-2 alkoxycarbonyl);] 
         and salts thereof. 
       
     
     
         9 . A quinazoline derivative as claimed in  claim 1  selected from:—
 4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline, 
 (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-([ N -methyl- N -methylsulphonyl]amino)propoxy)quinazoline, 
 7-(2-[ N -tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-([ N -methyl- N -methylsulphonyl]amino)propoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxoimidazolidin-1-yl)ethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline, 
 (S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline, 
 (S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline and 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline 
 and salts thereof. 
 
     
     
         10 . A quinazoline derivative as claimed in  claim 1  selected from:—
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-2-(2-methoxyethoxy)ethoxyquinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline, 
 4-(4-bromo-2-fluoroanilino)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline, 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropylthio)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([ N -methyl- N -methoxyacetyl]amino)ethoxy)quinazoline and 
 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline 
 and salts thereof. 
 
     
     
         11 . A quinazoline derivative as claimed in  claim 1  selected from:—
 (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline, 
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline, 
 (S)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline and 
 (R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline 
 and salts thereof. 
 
     
     
         12 . A quinazoline derivative as claimed in  claim 1  selected from:—
 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline and salts thereof. 
 
     
     
         13 . A quinazoline derivative as claimed in any one of the preceding claims in the form of a pharmaceutically acceptable salt. 
     
     
         14 . A process for the preparation of a quinazoline derivative of formula I or salt thereof (as defined in  claim 1 ) which comprises:—
 (a) the reaction of a compound of the formula III: 
 
       
         
           
           
               
               
           
         
         (wherein R 1 , R 2 , X 1  and R 4  are as defined in  claim 1  and L 1  is a displaceable moiety), with a compound of the formula IV: 
       
       
         
           
           
               
               
           
         
         (wherein R 3  and m are as defined in  claim 1 ) whereby to obtain compounds of the formula I and salts thereof; 
         (b) for the preparation of compounds of formula I and salts thereof in which the group of formula IIa: 
       
       
         
           
           
               
               
           
         
         (wherein R 3  and m are as defined in  claim 1 ) represents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V: 
       
       
         
           
           
               
               
           
         
         (wherein X 1 , m, R 1 , R 2 , R 3  and R 4  are as defined in  claim 1 , P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m-p1 is equal to the number of R 3  substituents which are not protected hydroxy); 
         (c) for the preparation of those compounds of formula I and salts thereof wherein the substituent X 1  is —O—, —S—, —NR 11 —, —SO 2 —, —CONR 8 — or —SO 2 NR 9 —, the reaction of a compound of the formula VI: 
       
       
         
           
           
               
               
           
         
         (wherein m, X 1 , R 1 , R 2  and R 3  are as defined in  claim 1 ) with a compound of formula VII:
   R 4 -L 1   (VII)
 
 
         (wherein R 4  is as defined in  claim 1  and L 1  is as defined herein); 
         (d) the reaction of a compound of the formula VIII: 
       
       
         
           
           
               
               
           
         
         with a compound of the formula IX:
   R 4 —X 1 —H  (IX)
 
 
         (wherein R 1 , R 2 , R 3 , R 4 , m and X 1  are as defined in  claim 1  and L 1  is as defined herein); 
         (e) for the preparation of compounds of formula I and salts thereof wherein R 4  is C 1-5 alkylR 53 , [wherein R 53  is selected from one of the following three groups: 
         1) X 7 R 27  (wherein X 7  represents —O—, —S—, —SO 2 —, —NR 54 CO—, —NR 55 SO 2 — or —NR 56 — (wherein R 54 , R 55  and R 56  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 27  is as defined in  claim 1 ); 
         2) X 8 C 1-5 alkylX 3 R 16  (wherein X 8  represents —O—, —S—, —SO 2 —, —NR 57 CO—, —NR 58 SO 2 — or —NR 59 — (wherein R 57 , R 58  and R 59  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and X 3  and R 16  are as defined in  claim 1 ); and 
         3) X 9 C 1-5 alkylR 33  (wherein X 9  represents —O—, —S—, —SO 2 —, —NR 60 CO—, —NR 61 SO 2 — or —NR 62 — (wherein R 60 , R 61  and R 62  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined in  claim 1 );], 
         the reaction of a compound of the formula X: 
       
       
         
           
           
               
               
           
         
         (wherein X 1 , R 1 , R 2 , R 3  and m are as defined in  claim 1 , L 1  is as defined herein and R 63  is C 1-5 alkyl) with a compound of the formula XI:
   R 53 —H  (XI)
 
 
         (wherein R 53  is as defined herein) to give a compound of the formula I; 
         the preparation of compounds of the formula I wherein R 4  is C 2-5 alkylR 45 , (wherein R 45  is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl), the reaction of a compound of formula X (wherein R 63  is C 2-5 alkyl) with a compound of the formula XIa:
   R 45 —H  (XIa)
 
 
         (wherein R 45  is as defined herein) to give a compound of the formula I; 
         (f) for the preparation of those compounds of the formula I and salts thereof wherein the substituent R 1  is represented by —NR 5 R 6 , where one or both of R 5  and R 6  are C 1-3 alkyl, the reaction of compounds of formula I wherein the substituent R 1  is an amino group with an alkylating agent; 
         (g) for the preparation of compounds of formula I and salts thereof wherein one or more of the substituents R 1 , R 2  or R 3  is an amino group, the reduction of a corresponding compound of formula I wherein the substituent(s) at the corresponding position(s) of the quinazoline and/or aniline ring is/are a nitro group(s); 
         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. 
       
     
     
         15 . 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. 
     
     
         16 . 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 or a pharmaceutically acceptable salt thereof as defined in  claim 1 .