Claims for Patent: RE42353

Summary for Patent: RE42353

Title:	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; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents —O—, —CH2—, —S—, —SO—, —SO2—, —NR7CO—, —CONR8—, —SO2NR9—, —NR10SO2— or —NR11— (wherein R7, R8, R9, R10 and R11 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl); R4 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):	Andrew Peter Thomas, Craig Johnstone, Edward Clayton, Elaine Sophie Elizabeth Stokes, Jean-Jacques Marcel Lohmann, Laurent Francois Andre Hennequin
Assignee:	Syngenta Ltd, Genzyme Corp
Application Number:	US12/170,027
Patent Claims:	1. A quinazoline derivative of the formula I: wherein: m is an integer from 1 to 2; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2 represents hydrogen, hydroxy, halogeno, methoxy, or aminoor nitro; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents —O—, —O—; R4 is selected from one of the following eleven groups: 1) C1-5alkylR12 (wherein R12 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 C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); 2) C2-5alkenylR14 (wherein R14 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 substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); 3) C3-5alkynylR15 (wherein R15 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 substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); 4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR17CO—, —CONR18—, —SO2NR19—, —NR20SO2— or —NR21— (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl); 5) C1-5alkylX4COR22 (wherein X4 represents —O— or —NR23— (wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —NR24R25 or —OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl)); 6) C1-5alkylX5R27 (wherein X5 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR28CO—, —CONR29—, —SO2NR30—, —NR31SO2— or —NR32— (wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 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 substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3allyl C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —S—, —SO—, —SO2—, —SO2NR30— or —NR31SO2— or —NR31SO2—); 7) C1-3alkoxyC2-4alkyl or C1-4alkyl; 8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —O—, —S—, —SO—, —SO2—, —NR34CO—, —CONR35—, —SO2NR36—, —NR37SO2— or —NR38— (wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 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 substitutes substituents selected from oxo, hydroxy, halogeno, C1-4alkyl), C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); 9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl piperidin-3-yl and piperidin-4-yl which group may bear one or two substituent substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); 10) C1-5alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl) or C1-4alkyl)); and 11) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituent substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl); with the further proviso that when R4 is selected from group 7) R1 and/or R2 is/are nitro or at least one R3 is C1-3alkanoyloxy; or a salt thereof. 2. A quinazoline derivative as claimed in claim 1 wherein R1 represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. 3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R2 is hydrogen. 4. A quinazoline derivative as claimed in claim 1 or claim 2 wherein the phenyl group bearing (R3)m is of the formula II: wherein: Ra represents hydrogen, methyl, fluoro, or chloro; Rb represents hydrogen, methyl, methoxy, bromo, fluoro or chloro; Rc represents hydrogen or hydroxy; Rd represents hydrogen, fluoro or chloro. 5. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R4 is selected from one of the following nine groups: 1) C1-4alkylR12 (wherein R12 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, piperidine-2-yl, piperidine-3-yl, piperidine-4-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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or C2-4alkylR45 (wherein R45 is a group selected from imidazolidine-1-yl, imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl); 2) 1-R46prop-1-en-3-yl, 1-R46but-2-en-4-yl, 1-but-1-en-3-yl, 1-R46but-1-en-3-yl, 1-R46pent-2-en-4-yl or 2-R46pent-3-en-5yl (wherein R46 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 substituent substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R47but-2-en-4-yl, 1-R47pent-2-en-4-yl or 2-R47pent-3-en-5-yl (wherein R47 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl); 3) 1-R48prop-1-yn-3-yl, 1-R48but-2-yn-4-yl, 1-R48but-1-yn-3-yl, 1-R48pent-2-yn-4-yl or 2-R48pent-3-yn-5-yl (wherein R48 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R49but-2-yn-4-yl, 1-R49pent-2-yn-4-yl or 2-R49pent-3-yn-5-yl (wherein R49 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkylcarbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl); 4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 1 and R16 represents hydrogen or C1-3alkyl); 5) C2-3alkylX4COR22 (wherein X4 is as defined in claim 1 and R22 represents —NR24R25 or —OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-2alkoxyethyl)); 6) C2-3alkylX5R27 (wherein X5 is as defined in claim 1 and R27 represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X5 through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl or R27 is C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —S—, —SO—, —SO2—, —SO2N30— or —NR31SO2—); 7) C2-3alkylX6C2-3alkyl33 (wherein X6 is as defined in claim 1 and R33 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 substituent substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl, and C1-3alkoxycarbonyl); 8) C2-3alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from acetyl, C1-2alkoxycarbonyl, C1-2hydroxyalkyl and CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-2alkyl) or C1-2alkyl)); and 9) C2-3alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituents selected from oxo, C1-2alky, C1-2alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acaetyl acetyl and C1-2alkoxycarbonyl). 6. A quinazoline derivative as claimed in claim 5 wherein R4 is selected from one of the following seven groups: 1) C1-3alkylR12 C1-3alkylR12 (wherein R12 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, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl) or C2-3alkylR45 (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, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylkcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl); 2) 1-R50but-2-en-4-yl (wherein R50 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, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl). 3) 1-R51but-2-yn-4-yl (wherein R51 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, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl); 4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 1 and R16 represents hydrogen or C1-3alkyl); 5) 2-(3,3-dimethylureido)ethyl, 3-(3,3dimethylureido)propyl, 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, 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; 6) C2-3alkylX5R27 (wherein R27 is C1-2alkyl and X5 is —S—, —SO—, —SO2—, —SO2NR30— or —NR31 SO2— or —NR31SO2—); and 7) C2-3alkyX6C2-3alkylR33 (wherein X6 is as defined in claim 1 and R33 represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl). 7. A quinazoline derivative of the formula 1a: wherein: R1a is hydrogen or methoxy; R2a is hydrogen; the phenyl group bearing (R3a)ma is the 4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group; X1a is —O—; R4a is selected from one of the following nine groups: 1) C1-4alkylR7a (wherein R7a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or C2-4alkylR8a (wherein R8a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl); 2) 1-R9aprop-1-en-3-yl, 1-R9abut-2-en-4-yl, 1-R9abut-1-en-3-yl, 1-R9apent-2-en-4-yl or 2-R9apent-3-en-5-yl (wherein R9a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R10abut-2-en-4-yl, 1-R10apent-2-en-4-yl or 2-R10apent-3-en-5-yl (wherein R10a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbomoyl, N,N-di(C1-3alkyl)carbamoyl, C1-3alkanoyl and C1-3alkoxycarbonyl); 3) 1-R11aprop-1-yn-3-yl, 1-R11abut-2-yn-4-yl, 1-R11abut-1-yn-3-yl, 1-R11apent-2-yn-4-yl or 2-R11apent-3-yn-5-yl (wherein R11a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R12abut-2-yn-4-yl, 1-12apent-2-yn-4-yl 1-R12apent-2-yn-4-yl or 2-R12apent-3-yn-5-yl (wherein R12a 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, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbarmoyl, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbarmoyl, C1-3alkanoyl N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl); 4) C2-3alkylX2aC1-3alkylX3aR13a (wherein X2a and X3a which may be the same or different each represents, —O—, —S—, —SO—, —SO2—, —NR14aCO—, or —NR15a— (wherein R14a and R15a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R13a represents hydrogen or C1-3alkyl); 5) C2-3alkylX4aCOR16a C2-3alkylX4aCOR16a (wherein X4a represents —O— or —NR17a—(wherein R17a represents hydrogen, C1-3alkyl or C1-2alkoxyethyl) and R16a represents —NR18aR19a or —OR20a (wherein R18a, R19a and R20a which may be the same or different each represents hydrogen, C1-4alkyl or C1-2alkoxyethyl)); 6) C2-3alkylX5aR21a (wherein X5a represents carbonyl, —O—, —S—, —SO—, —SO2—, —NR22aCO—, —NR23aSO2—, or —NR24a— (wherein R22a, R23a and R23a each independently R24a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R21a represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X5a through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl or R21a is C1-3alkyl with that proviso the proviso that when R21a is C1-3alkyl, X5a is —S—, —SO—, —SO2— or —NR23aSO2—); 7) C2-3alkylX6aC2-3alkylR25a (wherein X6a represents —O—, —S—, —SO—, —SO2—, —NR26aCO—, —NR27aSO2— or —NR28a-(wherein R26a, R27a and R28a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R25a represents a 5 or 6 membered saturated heterocyclic group with one or two heteratoms selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)cabamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl, and C1-3allkoxycarbonyl); C1-3alkoxycarbonyl); 8) C2-3alkylR29a (wherein R29a is piperizin-1-yl piperazin-1-yl which bears at least one substituent selected from acetyl, C1-2alkoxycarbonyl, C1-2hydroxyalkyl and CONR30aR31a (wherein R30a and R31a each independently represents hydrogen or C1-2alkyl) or C1-2alkyl)); and 9) C2-3alkylR33a (wherein R33a is morpholino which bears at least one and optionally two substituents selected from oxo, C1-2alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl); or a salt thereof. 8. A quinazoline derivative as claimed in claim 1 selected from: 4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinzoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-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. 9. A quinazoline derivative as claimed in claim 1 selected from: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)-methoxyquinazoline; 4-(4-bromo-2-fluoroanilino)-7-3-(1,1-dixothiomorpholino)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-(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. 10. 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. 11. 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. 12. A quinazoline derivative as claimed in any one of claims 1 and 7-11 claim 1 or claim 7 in the form of pharmaceutically acceptable salt. 13. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R1 represents methoxy. 14. A quinazoline derivative as claimed in claim 1 or claim 2 wherein m is 2. 15. A quinazoline derivative as claimed in claim 1 or claim 2 wherein the phenyl group bearing (R3)m is the 4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group. 16. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R4 is selected from one of the following six groups: 1) C1-3alkylR12 (wherein R12 is 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4- yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, piperazin-2-yl, 1-methylpiperazine-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazin-2-yl, morpholin-2-yl, morpholin-3-yl, 4-methylmorpholin-2-yl or 4-methylmorpholin-3- yl) or C2-3alkylR45 (wherein R45 is pyrrolidin-1-yl, thiomorpholino, 1,1- dioxothiomorpholino, 2-oxopyrrolidin-1-yl, 2-(N-methylcarbamoyl)pyrrolidin-1-yl, 2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl, 2-carbamoylpyrrolidin-1yl, 2- oxoimidazolidin-1-yl or 3-methyl-2-oxoimidazolidin-1-yl); 2) 1-R50but-2-en-4-yl (wherein R50 is 2-oxoimidazolidin-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, 1-methylpiperidin-4- yl, pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, piperidino or 3-methyl-2-oxoimidazolidin- 1-yl); 3) 1-R51but-2-yn-4-yl (wherein R51 is 2-oxoimidazolidin-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, 1-methylpiperidin-4- yl, pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, piperidino or 3-methyl-2-oxoimidazolidin- 1-yl); 4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 17 and R16 represents hydrogen or C1-3alkyl); 5) C2-3alkylX5R27 (wherein R27 is C1-2 alkyl and X5 is -S-, -SO-, -SO2-, -SO2NR30-or- NR31SO2-(wherein R30 and R31 are as defined in claim 1)); and 6) C2-3alkylX6C2-3alkylR33 (wherein X6 is as defined in claim 1 and R33 represents a group selected from pyrrolidin-1-yl, 4-methylpiperazin-1-yl and morpholino). 17. A quinazoline derivative of the formula I: wherein: m is an integer from 1 to 2; R1 represents hydrogen, hydroxy, halogeno, nitro, trifuloromethyl, eyano, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or -NR5R6 (wherein R5and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2R2 represents hydrogen, hydroxy, halageno,halogeno, methoxy,or aminoor nitro; R3R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents -O-; R4 is selected from one of the following seven groups: 1) C1-5alkylR12 (wherein R12 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 C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy) or C1-5alkylR13 (wherein R13 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, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy); 2) C2-5alkenylR 14 C2-5alkenylR14 (wherein R14 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, C1-4alkyl, C1-4hydroyalkyl C1-4hydroxyalkyl and C1-4alkoxy); 3) C2-5alkynylR15 (wherein R15 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, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy); 4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each -O-, -S-, -SO-, -SO2-, -NR17CO-, -CONR18-, -SO 2NR19-, -NR20SO2- —SO2NR19—, —NR20SO2— or -NR21- (wherein R17, R18, R19, R20 and R21 each independetly independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl); 5) C1-5alkylX4COR22 (wherein X4 represents -O- or -NR23-(wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents -NR24R25 or -OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl)); 6) C1-5alkylX5R27 (wherein X5 represents -O-, -S-, -SO2-, -OCO-, -NR28CO-, -CONR29-, -SO2NR30-, -NR31SO2- or -NR32-(wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R27 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, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy and C1-4alkoxy); and 7) C1-3alkoxyC2-4alkyl or C1-4alkyl; with the proviso that when R4 is selected from group 7) R1 and/or R2 is/are nitro or at least one R3 is C1-3alkanoyloxy; and salts thereof. 18. A quinazoline derivative as claimed in claim 17 wherein R1 represents methoxy. 19. A quinazoline derivative as claimed in 17 or claim 18 wherein R2 represents hydrogen. 20. A quinazoline derivative as claimed in claim 17 or claim 18 wherein the phenyl group bearing (R3)m is of the formula II: wherein: Ra represents hydrogen, methyl, fluoro or chloro; Rb represents hydrogen, methyl, methoxy, bromo, fluoro or chloro; Rc represents hydrogen or hydroxy; Rd represents hydrogen, fluoro or chloro. 21. 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 R1, R2, X1 and R4 are as defined in claim 1 and L1 is a displaceble moiety), with a compound of the formula IV: (wherein R3 and m are as defined in claim 1) whereby to obtain compounds of the formula I and salts thereof; (b) for the preperation preparation of compounds of formula I and salts thereof in which the group of formula IIa: (wherein R3 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 X1, m, R1, R2, R3 and R4 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 R3 substituents which are not protected hydroxy); (c) for the preparation of those compounds of formula I and salts thereof wherein the substituent X1 is —O—, the reaction of a compound of the formula VI: (wherein X1, R1, R2 and R3 are as defined in claim 1) with a compound of formula VII: R4—L1 (VII) (wherein R14 R4 is as defined im in claim 1 and L1 is as defined herein); (d) the reaction of a compound of the formula VII: with a compound of the formula IX: R4—X1—H (IX) (wherein R1, R2, R3, R4, m and X1 are as defined in claim 1 and L1 is as defined herein); (e) for the preparation of compounds of formula I and salts thereof wherein R4 is C1-5alkylR53, wherein R53 is selected from one of the following three groups: 1) X7R27 (wherein X7 represents —O—, —S—, —SO2—, —NR54CO—, —NR55SO2— or —NR56— (wherein R54, R55 and R56 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R27 is as defined in claim 1); 2) X8C1-5alkylX3R16 (wherein X8 represents —O—, —S—, —SO12—, —SO2—, —NR57CO—, —NR58SO2— or —NR59— (wherein R57, R58 and R59 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and X3 and R16 are as defined in claim 1); and 3) X9C1-5alkylR33 (wherein X9 represents —O—, —S—, —SO2—, —NR60CO—NR61SO2— or —NR62— (wherein R60, R61 and R62 each independently represent represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 is as defined in claim 1); the reaction of a compound of the formula X: (wherein X1, R1, R2, R3 and m are as defined in claim 1, L1 is as defined herein and R63 is C1-5alkyl) with a compound of the formula XI: R53—H (XI) (wherein R53 is as defined herein) to give a compound of the formula I; (f) for the preparation of compounds of the formula I wherein R4 is C2-5alkylR45, (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, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl), the reaction of a compound of formula X (wherein R63 is C2-5alkyl) with a compound of the formula XIa: R45—H (XIa) (wherein R45 is as defined herein) to give a compound of the formula I; (g) for the preparation of those compounds of the formula I and salts thereof wherein the substituent R1 is represented by —NR5R6 where one or both of R5 and R6 are C1-3alkyl, the reaction of compounds of formula I wherein the substituent R1 is an amino group with an alkylating agent; (h) for the prepation of compounds of formula I and salts thereof wherein one or more of the substituents R1, R2 or R3 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. 22. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in any one of claims 1 and 7-11 claim 1 or claim 7 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier. 23. 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 and 7-11.