Quinazoline derivatives and pharmaceutical compositions containing them

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, or aminoor 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—, —O—;

R 4 is selected from one of the following eleven 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 substituent 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 substituent 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 substituent 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 3-5 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 substituent 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);

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 substituent 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 allyl 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 — or —NR 31 SO 2 —);

7) C 1-3 alkoxyC 2-4 alkyl or C 1-4 alkyl;

8) 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 substitutes substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl), 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);

9) R 39 (wherein R 39 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, 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) 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) or C 1-4 alkyl)); and

11) C 1-5 alkylR 44 (wherein R 44 is morpholino which bears at least one and optionally two substituent 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 7) R 1 and/or R 2 is/are nitro or at least one R 3 is C 1-3 alkanoyloxy;

or a salt 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 claim 1 or claim 2 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 claim 1 or claim 2 wherein R 4 is selected from one of the following nine 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, 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, 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 imidazolidine-1-yl, 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-but-1-en-3-yl, 1-R 46 but-1-en-3-yl, 1-R 46 pent-2-en-4-yl or 2-R 46 pent-3-en-5yl (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 substituent 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 alkylcarbamoyl, 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);

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 N 30 — or —NR 31 SO 2 —);

7) C 2-3 alkylX 6 C 2-3 alkyl 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 substituent 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);

8) 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) or C 1-2 alkyl)); and

9) 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 alky, C 1-2 alkyl, C 1-2 hydroxyalkyl, carbamoyl, C 1-2 alkylcarbamoyl, N,N-di(C 1-2 alkyl)carbamoyl, acaetyl acetyl and C 1-2 alkoxycarbonyl).

6. A quinazoline derivative as claimed in claim 5 wherein R 4 is selected from one of the following seven groups:

1) C 1 -3alkylR 12 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 alkylkcarbamoyl, 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-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).

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);

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) 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 — or —NR 31 SO 2 —); and

7) C 2-3 alkyX 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).

7. A quinazoline derivative of the formula 1a:

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—;

R 4a is selected from one of the following nine 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 alkylcarbomoyl, N,N-di(C 1-3 alkyl)carbamoyl, C 1-3 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- 12a pent-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, carbarmoyl, carbamoyl, C 1-3 alkylcarbamoyl, N,N-di(C 1-3 alkyl)carbarmoyl, C 1-3 alkanoyl 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 — (wherein 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) C2-3alkylX 4a COR 16a 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 23a each independently 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 that proviso 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 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 heteratoms 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)cabamoyl, N,N-di(C 1-3 alkyl)carbamoyl, C 2-3 alkanoyl, and C1-3allkoxycarbonyl); C 1-3 alkoxycarbonyl);

8) C 2-3 alkylR 29a (wherein R 29a is piperizin-1-yl 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) or C 1-2 alkyl)); and

9) 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);

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 R 1 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 (R 3 )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 R 4 is selected from one of the following six groups:

1) C 1-3 alkylR 12 (wherein R 12 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 C 2-3 alkylR 45 (wherein R 45 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-R 50 but-2-en-4-yl (wherein R 50 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-R 51 but-2-yn-4-yl (wherein R 51 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) C 2-3 alkylX 2 C 1-3 alkylX 3 R 16 (wherein X 2 and X 3 are as defined in claim 17 and R 16 represents hydrogen or C 1-3 alkyl);

5) 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 -(wherein R 30 and R 31 are as defined in claim 1 )); and

6) 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 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;

R 1 represents hydrogen, hydroxy, halogeno, nitro, trifuloromethyl, eyano, 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 R 2 represents hydrogen, hydroxy, halageno, halogeno, methoxy, or aminoor nitro;

R 3 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-;

R 4 is selected from one of the following seven 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 and C 1-4 alkoxy) 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 and C 1-4 alkoxy);

2) C 2-5alkenylR 14 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 hydroyalkyl C 1-4 hydroxyalkyl and C 1-4 alkoxy);

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 and C 1-4 alkoxy);

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 - —SO 2 NR 19 —, —NR 20 SO 2 — or -NR 21 - (wherein R 17 , R 18 , R 19 , R 20 and R 21 each independetly 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);

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 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) 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 and C 1-4 alkoxy and C 1-4 alkoxy); and

7) C 1-3 alkoxyC 2-4 alkyl or C 1-4 alkyl;

with the proviso that when R 4 is selected from group 7) R 1 and/or R 2 is/are nitro or at least one R 3 is C 1-3 alkanoyloxy;

and salts thereof.

18. A quinazoline derivative as claimed in claim 17 wherein R 1 represents methoxy.

19. A quinazoline derivative as claimed in 17 or claim 18 wherein R 2 represents hydrogen.

20. A quinazoline derivative as claimed in claim 17 or claim 18 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.

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 R 1 , R 2 , X 1 and R 4 are as defined in claim 1 and L 1 is a displaceble 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 preperation 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—, the reaction of a compound of the formula VI:

 (wherein 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 14 R 4 is as defined im in claim 1 and L 1 is as defined herein);

(d) the reaction of a compound of the formula VII:

 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 12 —, —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 represent 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;

(f) for 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;

(g) 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;

(h) for the prepation 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.

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 .