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Details for Patent: 6,897,210

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Details for Patent: 6,897,210

Title: Quinazoline derivatives and pharmaceutical compositions containing them
Abstract:The invention relates to quinazoline derivatives of formula (I) wherein m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --O--, --CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl); R.sup.4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compostions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGP, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis. ##STR1##
Inventor(s): Thomas; Andrew Peter (Macclesfield, GB), Johnstone; Craig (Macclesfield, GB), Clayton; Edward (Macclesfield, GB), Stokes; Elaine Sophie Elizabeth (Macclesfield, GB), Lohmann; Jean-Jacques Marcel (Reims Cedex, FR), Hennequin; Laurent Francois Andre (Reims Cedex, FR)
Assignee: Zeneca Limited (London, GB) Zeneca Pharma S. A. (Reims Cedex, FR)
Filing Date:Nov 03, 2003
Application Number:10/698,388
Claims:1. A method for producing an anti-cancer effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of formula I: ##STR27##

wherein: m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl); R.sup.4 is selected from one of the following twelve groups: 1) C.sub.1-5 alkylR.sup.12 (wherein R.sup.12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C.sub.1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) or C.sub.1-5 alkylR.sup.13 (wherein R.sup.13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 2) C.sub.2-5 alkenylR.sup.14 (wherein R.sup.14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.4 alkyl)carbamoyl, C.sub.4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 3) C.sub.2-5 alkynylR.sup.15 (wherein R.sup.15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 4) C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 which may be the same or different are each --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.17 CO--, --CONR.sup.18 --, --SO.sub.2 NR.sup.19 --, --NR.sup.20 SO.sub.2 -- or --NR.sup.21 -- (wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso that X.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 ; 5) C.sub.1-5 alkylX.sup.4 COR.sup.22 (wherein X.sup.4 represents --O-- or --NR.sup.23 -- (wherein R.sup.23 represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.22 represents --NR.sup.24 R.sup.25 or --OR.sup.26 (wherein R.sup.24, R.sup.25 and R.sup.26 which may be the same or different each represents hydrogen, C.sub.1 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl)); 6) C.sub.1-5 alkylX.sup.5 R.sup.27 (wherein X.sup.5 represents --O--, --S--, --SO--, --SO.sub.2 --, --OCO--, --NR.sup.28 CO--, --CONR.sup.29 --, --SO.sub.2 NR.sup.30 --, --NR.sup.31 SO.sub.2 -- or --NR.sup.32 -- (wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) or X.sup.5 is carbonyl, and R.sup.27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl or R.sup.27 is C.sub.1-3 alkyl with the proviso that when R.sup.27 is C.sub.1-3 alkyl, X.sup.5 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and X.sup.1 is not --CH.sub.2 --); 7) C.sub.1-3 alkoxyC.sub.2-4 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.2 --; 8) C.sub.1-5 alkylX.sup.6 C.sub.1-5 alkylR.sup.33 (wherein X.sup.6 represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.34 CO--, --CONR.sup.35 --, SO.sub.2 NR.sup.36 --, --NR.sup.37 SO.sub.2 -- or NR.sup.31 -- (wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.3 alkoxyC.sub.2-3 alkyl) and R.sup.33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 9) R.sup.39 (wherein R.sup.39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 10) C.sub.1-5 alkylR.sup.40 (wherein R.sup.40 is piperazin-1-yl which bears at least one substituent selected from C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 hydroxyalkyl and --CONR.sup.41, R.sup.42 (wherein R.sup.41 and R.sup.42 each independently represents hydrogen or C.sub.1-4 alkyl); 11) C.sub.1-5 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.1-5 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or --NR.sup.10 SO.sub.2 --; and 12) C.sub.1-5 alkylR.sup.44 (wherein R.sup.44 is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl);

or a pharmaceutically acceptable salt thereof.

2. A method for inhibiting the effects of VEGF in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I: ##STR28## wherein: m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl); R.sup.4 is selected from one of the following twelve groups; 1) C.sub.1-5 alkylR.sup.12 (wherein R.sup.12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C.sub.1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) or C.sub.1-5 alkylR.sup.13 (wherein R.sup.13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 2) C.sub.2-5 alkenylR.sup.14 (wherein R.sup.14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 3) C.sub.2-5 alkynylR.sup.15 (wherein R.sup.15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 4) C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 which may be the same or different are each --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.17 CO--, --CONR.sup.18 --, --SO.sub.2 NR.sup.19 --, --NR.sup.20 SO.sub.2 -- or --NR.sup.21 -- (wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso that X.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 ; 5) C.sub.1-5 alkylX.sup.4 COR.sup.22 (wherein X.sup.4 represents --O-- or --NR.sup.23 -- represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.22 represents --NR.sup.24 R.sup.25 or --OR.sup.26 (wherein R.sup.24, R.sup.25 and R.sup.26 which may be the same or different each represents hydrogen, C.sub.1-4 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl)); 6) C.sub.1-5 alkylX.sup.5 R.sup.27 (wherein X.sup.5 represents --O--, --S--, --SO--, --SO.sub.2 --, --OCO--, --NR.sup.28 CO--, --CONR.sup.29 --, --SO.sub.2 NR.sup.30 --, --NR.sup.31 SO.sub.2 -- or --NR.sup.32 -- (wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) or X.sup.5 is carbonyl, and R.sup.27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl or R.sup.27 is C.sub.1-3 alkyl with the proviso that when R.sup.27 is C.sub.1-3 alkyl, X.sup.5 is --S--, --SO--,--SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and X.sup.1 is not --CH.sub.2 --); 7) C.sub.1-3 alkoxyC.sub.2-4 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.2 --; 8) C.sub.1-5 alkylX.sup.6 C.sub.1-5 alkylR.sup.33 (wherein X.sup.6 represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.34 CO--, --CONR.sup.35, --SO.sub.2 NR.sup.36 --, --NR.sup.37 SO.sub.2 -- or --NR.sup.38 -- (wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 9) R.sup.39 (wherein R.sup.39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 10) C.sub.1-5 alkylR.sup.40 (wherein R.sup.40 is piperazin-1-yl which bears at least one substituent selected from C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 hydroxyalkyl and --CONR.sup.41 R.sup.42 (wherein R.sup.41 and R.sup.42 each independently represents hydrogen or C.sub.1-4 alkyl); 11) C.sub.1-5 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.1-5 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or NR.sup.10 SO.sub.2 --; and 12) C.sub.1-5 alkylR.sup.44 (wherein R.sup.44 is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl);

or a pharmaceutically acceptable salt thereof.

3. A method for inhibiting the effects of VEGF and EGF in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I as claimed in claim 2 or a pharmaceutically acceptable salt thereof.

4. A method for inhibiting the growth of a solid tumour of the colon, breast, prostate, lung or skin in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I: ##STR29##

wherein: m is an integer from 1 to 2; R.sup.1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, or --NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents hydrogen or C.sub.1-3 alkyl); R.sup.2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R.sup.3 represents hydroxy, halogeno, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X.sup.1 represents --CH.sub.2 --, --S--, --SO--, --SO.sub.2 --, --NR.sup.7 CO--, --CONR.sup.8 --, --SO.sub.2 NR.sup.9 --, --NR.sup.10 SO.sub.2 -- or --NR.sup.11 -- (wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl); R.sup.4 is selected from one of the following twelve groups: 1) C.sub.1-5 alkylR.sup.12 (wherein R.sup.12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C.sub.1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) or C.sub.1-5 alkylR.sup.13 (wherein R.sup.13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 2) C.sub.2-5 alkenylR.sup.14 (wherein R.sup.14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 3) C.sub.2-5 alkynylR.sup.15 (wherein R.sup.15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 4) C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 (wherein X.sup.2 and X.sup.3 which may be the same or different are each --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.17 CO--, --CONR.sup.18 --, --SO.sub.2 NR.sup.19 --, --NR.sup.20 SO.sub.2 -- or --NR.sup.21 -- (wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.16 represents hydrogen or C.sub.1-3 alkyl) with the proviso that X.sup.1 cannot be --CH.sub.2 -- when R.sup.4 is C.sub.1-5 alkylX.sup.2 C.sub.1-5 alkylX.sup.3 R.sup.16 ; 5) C.sub.1-5 alkylX.sup.4 COR.sup.22 (wherein X.sup.4 represents --O-- or --NR.sup.23 -- (wherein R.sup.23 represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) and R.sup.22 represents --NR.sup.24 R.sup.25 or --OR.sup.26 (wherein R.sup.24, R.sup.25 and R.sup.26 which may be the same or different each represents hydrogen, C.sub.1-4 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl)); 6) C.sub.1-5 alkylX.sup.5 R.sup.27 (wherein X.sup.5 represents --O--, --S--, --SO--, --SO.sub.2 --, --OCO--, --NR.sup.28 CO--, --CONR.sup.29 --, --SO.sub.2 NR.sup.30 --, --NR.sup.31 SO.sub.2 -- or --NR.sup.32 -- (wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R .sup.32 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxyC.sub.2-3 alkyl) or X.sup.5 is carbonyl, and R.sup.27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteratoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl or R.sup.27 is C.sub.1-3 alkyl with the proviso that when R.sup.27 is C.sub.1-3 alkyl, X.sup.5 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.30 -- or --NR.sup.31 SO.sub.2 -- and X.sup.1 is not --CH.sub.2 --); 7) C.sub.1-3 alkoxyC.sub.2-4 alkyl provided that X.sup.1 is --S--, --SO-- or --SO.sub.2 --; 8) C.sub.1-5 alkylX.sup.6 C.sub.1-5 alkylR.sup.33 (wherein X.sup.6 represents --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.34 CO--, --CONR.sup.35 --, --SO.sub.2 NR.sup.36 --, --NR.sup.37 SO.sub.2 -- or --NR.sup.38 -- (wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each independently represents hydrogen, C.sub.1-3 alkyl or C.sub.1-3 alkoyxC.sub.2-3 alkyl) and R.sup.33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 9) R.sup.39 (wherein R.sup.39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkoxy, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl); 10) C.sub.1-5 alkylR.sup.40 (wherein R.sup.40 is piperazin-1-yl which bears at least one substituent selected from C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 hydroxyalkyl and --CONR.sup.41 R.sup.42 (wherein R.sup.41 and R.sup.42 each independently represents hydrogen or C.sub.1-4 alkyl); 11) C.sub.1-5 alkylR.sup.43 (wherein R.sup.43 is morpholino which may bear one or two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl) with the proviso that when R.sup.4 is C.sub.1-5 alkylR.sup.43, X.sup.1 is --S--, --SO--, --SO.sub.2 --, --SO.sub.2 NR.sup.9 -- or --NR.sup.10 SO.sub.2 --; and 12) C.sub.1-5 alkylR.sup.44 (wherein R.sup.44 is morpholino which bears at least one and optionally two substituents selected from oxo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoyl and C.sub.1-4 alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4 wherein the tumour is of the colon.

6. The method according to claim 4 wherein the tumour is of the lung.
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