Substituted quinazolines
First Claim
1. A quinazoline derivative of the formula I:
- ##STR27## wherein;
Y1 represents --O--, --S--, --CH2 --, --SO--, --SO2 --, --NR5 CO--, --CONR6 --, --SO2 NR7 --, --NR SO2 -- or --NR9 --,wherein R5, R6, R7, R8 and R9 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, or NR10 R11,wherein R10 and R11, which may be the same or different, each represents hydrogen or C1-3 alkyl;
R2 represents hydrogen, hydroxy, halogeno, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, cyano, amino or nitro;
m is an integer from 1 to 5;
R3 represents hydroxy, halogeno, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
R4 is selected from one of the following eight groups;
1) X1, wherein X1 represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C1-4 alkylamino, C1-4 hydroxyalkoxy, carboxy, cyano, --CONR12 R13 and --NR14 COR15,wherein R12, R13, R14 and R15, which may be the same or different, each represents hydrogen, C1-4 alkyl or C1-3 alkoxyC2-3 alkyl;
2) C1-5 alkylX1, wherein Xl is as defined hereinbefore;
3) C2-5 alkenylX1, wherein X1 is as defined hereinbefore;
4) C2-5 alkynylX1, wherein X1 is as defined hereinbefore;
5) C1-5 alkylY2 X1, wherein Y2 represents --O--, --S--, --SO--, --SO2--, --OCO--, --NR16 CO--, CONR17 --, --SO2 NR18 --, --NR19 SO2 -- or --NR20 --,wherein R16, R17, R18, R19 and R20 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore;
6) C2-5 alkenylY3 X1, wherein Y3 represents --O--, --S--, --SO--, --SO2 --, --OCO--, --NR21 CO--, --CONR22 --, --SO2 NR23 --, --NR24 SO2 -- or --NR25 --,wherein R21, R22, R23, R24, and R25 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl) and X1 is as defined hereinbefore;
7) C2-5 alkynylY4 X1, wherein Y4 represents --O--, --S--, --SO--, --SO2 --, --OCO--, --NR26 CO--, --CONR27 --, --SO2 NR28 --, --NR29 SO2 -- or --NR30 --,wherein R26, R27, R28, R29 and R30 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore; and
8) C1-3 alkylY5 C1-3 alkylX1, wherein Y5 represents --O--, --S--, --SO--, --SO2 --, --NR31 CO--, --CONR32 --, SO2 NR33 --, --NR34 SO2 -- or --NR35 --,wherein R31, R32, R33, R34 and R35 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore;
Z represents --NH--;
with the proviso that where R4 is selected from one of the groups
1),
2), and
5) above and X1 is unsubstituted phenyl or substituted phenyl with 1 to 2 substituents selected from halogeno, C1-4 alkyl and C1-4 alkoxy, then m is an integer from 3 to 5;
and salts thereof.
6 Assignments
0 Petitions
Accused Products
Abstract
The invention relates to quinazoline derivatives of the formula: ##STR1## wherein: Y1 represents --O--, --S--, --CH2 --, --SO--, --SO2 --, --NR5 CO--, --CONR6 -, --SO2 NR7 -, --NR8 SO2 -- or --NR9 - (wherein R5, R6, R7, R8 and R9 each independently represents hydrogen, alkyl or alkoxyalkyl);
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino.
R2 represents hydrogen, hydroxy, halogeno, alkyl, alkoxy, trifluoromethyl, cyano, amino or nitro;
m is an integer from 1 to 5;
R3 represents hydroxy, halogeno, alkyl, alkoxy, alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
R4 represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group! and salts thereof; processes for their preparation and pharmaceutical compositions 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 VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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Citations
14 Claims
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1. A quinazoline derivative of the formula I:
- ##STR27## wherein;
Y1 represents --O--, --S--, --CH2 --, --SO--, --SO2 --, --NR5 CO--, --CONR6 --, --SO2 NR7 --, --NR SO2 -- or --NR9 --,wherein R5, R6, R7, R8 and R9 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, or NR10 R11, wherein R10 and R11, which may be the same or different, each represents hydrogen or C1-3 alkyl; R2 represents hydrogen, hydroxy, halogeno, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from 1 to 5; R3 represents hydroxy, halogeno, C1-3 alkyl, C1-3 alkoxy, C1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R4 is selected from one of the following eight groups; 1) X1, wherein X1 represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C1-4 alkylamino, C1-4 hydroxyalkoxy, carboxy, cyano, --CONR12 R13 and --NR14 COR15, wherein R12, R13, R14 and R15, which may be the same or different, each represents hydrogen, C1-4 alkyl or C1-3 alkoxyC2-3 alkyl; 2) C1-5 alkylX1, wherein Xl is as defined hereinbefore; 3) C2-5 alkenylX1, wherein X1 is as defined hereinbefore; 4) C2-5 alkynylX1, wherein X1 is as defined hereinbefore; 5) C1-5 alkylY2 X1, wherein Y2 represents --O--, --S--, --SO--, --SO2--, --OCO--, --NR16 CO--, CONR17 --, --SO2 NR18 --, --NR19 SO2 -- or --NR20 --, wherein R16, R17, R18, R19 and R20 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore; 6) C2-5 alkenylY3 X1, wherein Y3 represents --O--, --S--, --SO--, --SO2 --, --OCO--, --NR21 CO--, --CONR22 --, --SO2 NR23 --, --NR24 SO2 -- or --NR25 --, wherein R21, R22, R23, R24, and R25 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl) and X1 is as defined hereinbefore; 7) C2-5 alkynylY4 X1, wherein Y4 represents --O--, --S--, --SO--, --SO2 --, --OCO--, --NR26 CO--, --CONR27 --, --SO2 NR28 --, --NR29 SO2 -- or --NR30 --, wherein R26, R27, R28, R29 and R30 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore; and 8) C1-3 alkylY5 C1-3 alkylX1, wherein Y5 represents --O--, --S--, --SO--, --SO2 --, --NR31 CO--, --CONR32 --, SO2 NR33 --, --NR34 SO2 -- or --NR35 --, wherein R31, R32, R33, R34 and R35 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and X1 is as defined hereinbefore; Z represents --NH--; with the proviso that where R4 is selected from one of the groups
1),
2), and
5) above and X1 is unsubstituted phenyl or substituted phenyl with 1 to 2 substituents selected from halogeno, C1-4 alkyl and C1-4 alkoxy, then m is an integer from 3 to 5;and salts thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
- ##STR27## wherein;
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12. A quinazoline derivative selected from the group consisting of:
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4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7- 2(4-oxo-1,4-dihydro-1-pyridyl)ethoxy!quinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(-1-methylimidazol-2-ylthio)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline; and salts thereof.
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13. A quinazoline derivative selected from the group consisting of:
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4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinazoline; 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline; 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline; 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline; 7-((2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline; 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline; 7-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((1-methylimidazol-2-yl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline; and salts thereof.
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14. A quinazoline derivative selected from the group consisting of:
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4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-( N-methyl-N-(4-pyridyl)!amino)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7- 2-(2oxo-1,2-dihydro-1-pyridyl)ethoxy!quinazoline; 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline; 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline; 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl- 1,2,4!-triazol-4-yl)ethoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(2,4-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-4-yl)ethoxy)quinazoline; 4-(4-bromo-2-fluoroanilino)-7-(2-( 1,2,4!-triazol-1-yl)ethoxy)-6-methoxyquinazoline; and salts thereof.
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Specification