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