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Details for Patent: 6,673,803

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Details for Patent: 6,673,803

Title: Quinazoline derivatives and pharmaceutical compositions containing them
Abstract:The invention relates to quinazoline derivatives of formula (I) ##STR1## wherein m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --O--, CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl);R.sup.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.
Inventor(s): Thomas; Andrew Peter (Macclesfield, GB), Johnstone; Craig (Macclesfield, GB), Stokes; Elaine Sophie Elizabeth (Macclesfield, GB), Lohmann; Jean-Jacques Marcel (Reims Cedex, FR), Hennequin; Laurent Francois Andre (Reims Cedex, FR)
Assignee: Zeneca Limited (London, GB)
Filing Date:Feb 25, 2002
Application Number:10/080,716
Claims:1. A quinazoline derivative of the formula I: ##STR27##

wherein: m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl); R.sup.4 is selected from one of the following twelve groups: 1) C.sub.1-5 alkylR.sup.12 (wherein R.sup.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.sub.1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) or C.sub.1-5 alkylR.sup.13 (wherein R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 2) C.sub.2-5 alkenylR.sup.14 (wherein R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 3) C.sub.2-5 alkynylR.sup.15 (wherein R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 4) C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 which may be the same or different are each --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.17 CO--, --CONR.sup.18 --, --SO.sub.2 NR.sup.19 --, --NR.sup.20 SO.sub.2 -- or --NR.sup.21 -- (wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso that X.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 ; 5) C.sub.1-5 alkylX.sup.4 COR.sup.22 (wherein X.sup.4 represents --O-- or --NR-- (wherein R represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.22 represents --NR.sup.24 R.sup.25 or --OR.sup.26 (wherein R.sup.24, R.sup.25 and R.sup.26 which may be the same or different each represents hydrogen, C.sub.1-4 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl)); 6) C.sub.1-5 alkylX.sup.5 R.sup.27 (wherein X.sup.5 represents --O--, --S--, --SO--, --SO.sub.2 --, --OCO--, --NR.sup.28 CO--, --CONR.sup.29 --, --SO.sub.2 NR.sup.30 --, --NR.sup.31 SO.sub.2 -- or --NR.sup.32 -- (wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) or X.sup.5 is carbonyl, and R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl or R.sup.27 is C.sub.1-3 alkyl with the proviso that when R.sup.27 is C.sub.1-3 alkyl, X.sup.5 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and X.sup.1 is not --CH.sub.2 --); 7) C.sub.1-3 alkoxyC.sub.2-4 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.2 --; 8) C.sub.1-5 alkylX.sup.6 C.sub.1-5 alkylR.sup.33 (wherein X.sup.6 represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.34 CO--, --CONR.sup.35 --, --SO.sub.2 NR.sup.36 --, --NR.sup.37 SO.sub.2 -- or --NR.sup.38 -- (wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 9) R.sup.39 (wherein R.sup.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.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 10) C.sub.1-5 alkylR.sub.40 (wherein R.sub.40 is piperazin-1-yl which bears at least one substituent selected from C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 hydroxyalkyl and --CONR.sup.41 R.sup.42 (wherein R.sup.41 and R.sup.42 each independently represents hydrogen or C.sub.1-4 alkyl); 11) C.sub.1-5 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.1-5 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or --NR.sup.10 SO.sub.2 --; and 12) C.sub.1-5 alkylR.sup.44 (wherein R.sup.44 is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); and salts thereof.

2. A quinazoline derivative as claimed in claim 1 wherein R.sup.1 hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R.sup.2 is hydrogen.

4. A quinazoline derivative as claimed in claim 1 or claim 2 wherein the phenyl group bearing (R.sup.3)m is of the formula II: ##STR28##

wherein: R.sup.a represents hydrogen, methyl, fluoro or chioro; R.sup.b represents hydrogen, methyl, methoxy, bromo, fluoro or chloro; R.sup.c represents hydrogen or hydroxy; R.sup.d represents hydrogen, fluoro or chloro.

5. A quinazoline derivative as claimed in claim 1 or claim 2 wherein X.sup.1 represents --S--, --NR.sup.7 CO--, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-2 alkyl or C.sub.1-2 alkoxyethyl).

6. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R.sup.4 selected from one of the following eleven groups: 1) C.sub.1-4 alkylR.sup.12 (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or C.sub.2-4 alkylR.sup.45 (wherein R45 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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl); 2) 1R.sup.46 prop-1-en-3-yl, 1-R.sup.46 but-2-en-4-yl, 1-R.sup.46 but-1-en-3-yl, 1-R.sup.46 pent-2-en-4-yl or 2-R.sup.46 pent-3-en-5-yl (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or 1-R.sub.47 but-2-en-4-yl, l-R.sup.47 pent-2-en-4-yl or 2-R.sup.47 pent-3-en-5-yl (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl); 3) 1-R.sup.48 prop-1-yn-3-yl, 1-R.sup.48 but-2-yn-4-yl, 1-R.sup.48 but-1-yn-3-yl, 1-R.sup.48 pent-2-yn-4-yl or 2-R.sup.48 pent-3-yn-5-yl (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or 1-R.sup.49 but-2-yn-4-yl, 1-R.sup.49 pent-2-yn-4-yl or 2-R.sup.49 pent-3-yn-5-yl (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl); 4) C.sub.2-3 alkylX.sup.2 C.sub.1-3 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 are as defined in claim 1 and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso that X.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.2-3 alkylX.sup.2 C.sub.1-3 alkylX.sup.3 R.sup.16; 5) C.sub.2-3 alkylX.sup.4 COR.sup.22 (wherein X.sup.4 is as defined in claim 1 and R.sup.22 represents --NR.sup.24 R.sup.25 or --OR.sup.26 (wherein R.sup.24, R.sup.25 and R.sup.26 which may be the same or different each represents hydrogen, C.sub.1-4 alkyl or C.sub.1-2 alkoxyethyl)); 6) C.sub.2-3 alkylX.sup.5 R.sup.27 (wherein X.sup.5 is as defined in claim 1 and R.sup.27 represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X.sup.5 through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl or R.sup.27 is C.sub.1-3 alkyl with the proviso that when R.sup.27 is C.sub.1-3 alkyl, X.sup.5 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and X.sup.1 is not --CH.sub.2 --); 7) C.sub.1-2 alkoxyC.sub.2-3 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.2 --; 8) C.sub.2-3 alkylX.sup.6 C.sub.2-3 alkylR.sup.33 (wherein X.sup.6 is as defined in claim 1 and R 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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl, and C.sub.1-3 alkoxycarbonyl); 9) C.sub.2-3 alkylR.sup.40 (wherein R.sup.40 is piperazin-1-yl which bears at least one substituent selected from acetyl, C.sub.1-2 alkoxycarbonyl, C.sub.1-2 hydroxyalkyl and CONR.sup.41 R.sup.42 (wherein R.sup.41 and R.sup.42 each independently represents hydrogen or C.sub.1-2 alkyl); 10) C.sub.2-3 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.2-3 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or --NR.sup.10 SO.sub.2 --; and 11) C.sub.2-3 alkylR.sup.44 (wherein R.sup.44 is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, carbamoyl, C.sub.1-2 alkylcarbamoyl N N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl).

7. A quinazoline derivative as claimed in claim 6 wherein R.sup.4 selected from one of the following nine groups: 1) C.sub.1-3 alkylR.sup.12 (wherein R.sup.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.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl) or C.sub.2-3 alkylR.sup.45 (wherein R.sup.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.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl); 2) 1-R.sup.50 but-2-en-4-yl (wherein R.sup.50 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.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl); 3) 1-R.sup.51 but-2-yn-4-yl (wherein R.sup.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.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl); 4) C.sub.2-3 alkylX.sup.2 C.sub.1-3 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 are as defined in claim 1 and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso thatX.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.2-3 alkylX.sup.2 C.sub.1-3 alkylX.sup.3 R.sup.16 ; 5) C.sub.1-2 alkoxyC.sub.2-3 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.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- (isopropoxycarboylamino)ethyl, 3 (isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl, 3 (isobutoxycarbonylamiflo)propyl, 2-(t-butoxycarbonylamino)ethyl or 3(t-butoxycarbonylamiflo)propyl; 7) C.sub.2-3 alkylX.sup.5 R.sup.27 (wherein R.sup.27 is C.sub.1-2 alkyl and X.sup.5 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and with the proviso that X.sup.1 is not --CH.sub.2 --); 8) C.sub.2-3 alkylX.sup.6 C.sub.2-3 alkylR.sup.33 (wherein X.sup.6 is as defined in claim 1 and R.sup.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.sub.2-3 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.2-3 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or --NR.sup.10 SO.sub.2 --.

8. A compound as claimed in claim 1 of the formula Ia: ##STR29##

wherein: R.sup.1a is hydrogen or methoxy; R.sup.2a is hydrogen; the phenyl group bearing (R.sup.3a).sub.ma is the 4-chloro-2-fluoropheiiyl group or the 4-bromo-2-fluoropheiiyl group; X.sup.1a is --S--, --NR.sup.5a CO-- or --NR.sup.6a SO.sub.2 -- (wherein R.sup.5a and R.sup.6a each independently represents hydrogen or C.sub.1-2 alkyl); R.sup.4a is selected from one of the following eleven groups: 1) C.sub.1-4 alkylR.sup.7a (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamOyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or C.sub.2-4 alkylR.sup.8a (wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) 2) 1-R.sup.9a prop-1-en-3-yl, 1-R.sup.9a but-2-en-4-yl, 1-R.sup.9a but-1-en-3-yl,1-R.sup.9a pent-2-en-4-yl or 2-R.sup.9a pent-3-en-5-yl (wherein R.sup.9a is embered 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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or 1-R.sup.10a but-2-en-4-yl, 1-R.sup.10a pent-2-en-4-yl or 2-R.sup.10a pent-3-en-5-yl(wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl); 3) 1-R.sup.11a prop-1-yn-3-yl, 1-R.sup.11a but-2-yn-4-yl, 1-R.sup.11a but-1-yn-3-yl, 1-R.sup.11a pent-2-yn-4yl or 2-R.sup.11a pent-3-yn-5-yl(wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) or 1-R.sup.12a but-2-yn-4-yl, R.sup.12a pent-2yn-5-yl(wherein R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl and C.sub.1-3 alkoxycarbonyl) 4) C.sub.2-3 alkylX.sup.2a C.sub.1-3 alkylX.sup.3a R.sup.13a (wherein X.sup.2a and X.sup.3a which may be the same or different each represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.14a CO--, or --NR.sup.15a -- (wherein R.sup.14a and R.sup.15a each independently represents hydrogen, C.sub.1-2 alkyl or C.sub.1-2 alkoxyethyl) and R.sup.13a represents hydrogen or C.sub.1-3 alkyl); 5) C.sub.2-3 alkylX.sup.4a COR.sup.16a (wherein R.sup.17a represents hydrogen, C.sub.1-3 alkyl or C.sub.1-2 alkoxyethyl) and R.sup.16a represents --NR.sup.18a R.sup.19a or --OR.sup.20a (wherein R.sup.18a, R.sup.19a and R.sup.20a which maybe the same or different each represents hydrogen, C.sub.1-4 alkyl or C.sub.1-2 alkoxyethyl)); 6) C.sub.2-3 alkylX.sup.5a R.sup.21a (wherein X.sup.5a represents carbonyl, --O--, --S--, --SO--, --SO.sub.2 --, NR.sup.22a CO--, --NR.sup.23a SO.sub.2 -- or --NR.sup.24a -- (wherein R.sup.22a, R.sup.23a and R.sup.24a each independently represents hydrogen, C.sub.1-2 alkyl or C.sub.1-2 alkoxyethyl) and R.sup.21a represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X.sup.5a through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, C.sub.1-2 alkoxy, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl or R.sup.21a is C.sub.1-3 alkyl with the proviso that when R.sup.21a is C.sub.1-3 alkyl, X.sup.5a is --S--, --SO--, --SO.sub.2 -- or --NR.sup.23a SO.sub.2 --); 7) C.sub.1-2 alkoxy C.sub.2-3 alkyl provided that X.sup.1a is --S--; 8) C.sub.2-3 alkyX.sup.6a C.sub.2-3 alkylR.sup.25a (wherein X.sup.6a represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.26a CO--, --NR.sup.27a SO.sub.2 -- or --NR.sup.28a -- (wherein R.sup.26a R.sup.27a and R.sup.28a each independently represents hydrogen, C.sub.1-2 alkyl or C.sub.1-2 alkoxyethyl) and R.sup.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.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.1-3 alkoxy, carbamoyl, C.sub.1-3 alkylcarbamoyl, N,N-di(C.sub.1-3 alkyl)carbamoyl, C.sub.2-3 alkanoyl, and C.sub.1-3 alkoxycarbonyl); 9) C.sub.2-3 alkylR.sup.29a (wherein R.sup.29a is piperazin-1-yl which bears at least one sub stituent selected from acetyl, C.sub.1-2 alkoxycarbonyl, C.sub.1-2 hydroxyalkyl and CONR.sup.30a R.sup.31a (wherein R.sup.30a and R.sup.31a each independently represents hydrogen or C.sub.1-2 alkyl); 10) C.sub.2-3 alkylR.sup.32a (wherein R.sup.32a is morpholino which may bear one or two substituents selected from oxo, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl) with the proviso that when R.sup.4a is C.sub.2-3 alkylR.sup.32a, X.sup.1a is --S-- or --NR.sup.6a SO.sub.2 -- (wherein R.sup.6a is as defined herein); and 11) C.sub.2-3 alkylR.sup.33a (wherein R.sup.33a is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-2 alkyl, C.sub.1-2 hydroxyalkyl, carbamoyl, C.sub.1-2 alkylcarbamoyl, N,N-di(C.sub.1-2 alkyl)carbamoyl, acetyl and C.sub.1-2 alkoxycarbonyl); and salts thereof.

9. A quinazoline derivative as claimed in claim 1 selected from 4-(4-chloro-2-fluroanilino)-6-methoxy-7(3-morpholionopropylthio)quinazolin e and salts thereof.

10. A quinazoline derivative as claimed in any one of claims 1, 2, 8 and 9 in the form of a pharmaceutically acceptable salt.

11. 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: ##STR30## (wherein R.sup.1, R.sup.2, X.sup.1 and R.sup.4 are as defined in claim 1 and L.sup.1 is a displaceable moiety), with a compound of the formula IV: ##STR31## (wherein R.sup.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: ##STR32## (wherein R.sup.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: ##STR33## (wherein X.sup.1, m, R.sup.1, R.sup.2, R.sup.3 and R.sup.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.sup.3 substituents which are not protected hydroxy); (c) for the preparation of those compounds of formula I and salts thereof wherein the substituent X.sup.1 is --S--, --NR.sup.11 --, --SO.sub.2 NR.sup.9 --, the reaction of a compound of the formula VI: ##STR34## (wherein m, X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1) with a compound of formula VII: (wherein R.sup.4 is as defined in claim 1 and L.sup.1 is as defined herein); (d) the reaction of a compound of the formula VIII: ##STR35## with a compound of the formula IX:

12. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in any one of claims 1, 2, 8, and 9 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

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 or a pharmaceutically acceptable salt thereof as defined in any one of claims 1, 2, 8, and 9.
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