Quinazoline derivatives
First Claim
1. A quinazoline derivative of the formula I ##STR13## wherein X1 is a direct link;
- wherein Q1 is a 5-membered heteroaryl moiety containing one heteroatom selected from oxygen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q1 optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alklenedioxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di- (1-4C)alkyl!amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di- (1-4C)alkyl!amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH2 (methylene) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;
wherein m is 1 or 2 and each R1 is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di- (1-4C)alkyl!carbamoyl;
and wherein Q2 is phenyl optionally bearing up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, or Q2 is a group of the formula II ##STR14## wherein X2 is a group of the formula CO, C(R3)2, CH(OR3), C(R3)2 --C(R3)2, C(R3)═
C(R3), C.tbd.C, CH(CN), O, S, SO, SO2, N(R3), CON(R3), SO2 N(R3), N(R3)CO, N(R3)SO2, OC(R3)2, SC(3)2, C(R3)2 O or C(R3)2 S wherein each R3 is independently hydrogen or (1-4C)alkyl, Q3 is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heteroaryl moiety is a single ring or is fused to a benzo ring, and wherein said phenyl or naphthyl group or heteroaryl moiety optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di- (1-4C)alkyl!carbamoyl, n is 1, 2 or 3 and each R4 is independently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino or (2-4C)alkanoylamino;
or a pharmaceutically-acceptable salt thereof.
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Accused Products
Abstract
The invention concerns quinazoline derivatives of the formula I ##STR1## wherein X1 is a direct link or a group such as CO, C(R2)2 and CH(OR2);
wherein Q1 is phenyl, naphthyl or a 5- or 6-membered heteroaryl moiety and Q1 optionally bears up to 3 substituents;
wherein m is 1 or 2 and each R1 may be a group such as hydrogen, halogeno and trifluoromethyl; and
wherein Q2 may be phenyl or a 9- or 10-membered bicyclic heterocyclic moiety and Q2 optionally bears up to 3 substituents;
or a pharmaceutically-acceptable salt thereof;
processes for their preparation, pharmaceutical compositions containing them and the use of their receptor tyrosine kinase inhibitory properties in the treatment of proliferative disease such as cancer.
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Citations
11 Claims
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1. A quinazoline derivative of the formula I ##STR13## wherein X1 is a direct link;
- wherein Q1 is a 5-membered heteroaryl moiety containing one heteroatom selected from oxygen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q1 optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alklenedioxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di- (1-4C)alkyl!amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di- (1-4C)alkyl!amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH2 (methylene) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;
wherein m is 1 or 2 and each R1 is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di- (1-4C)alkyl!carbamoyl; and wherein Q2 is phenyl optionally bearing up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, or Q2 is a group of the formula II ##STR14## wherein X2 is a group of the formula CO, C(R3)2, CH(OR3), C(R3)2 --C(R3)2, C(R3)═
C(R3), C.tbd.C, CH(CN), O, S, SO, SO2, N(R3), CON(R3), SO2 N(R3), N(R3)CO, N(R3)SO2, OC(R3)2, SC(3)2, C(R3)2 O or C(R3)2 S wherein each R3 is independently hydrogen or (1-4C)alkyl, Q3 is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heteroaryl moiety is a single ring or is fused to a benzo ring, and wherein said phenyl or naphthyl group or heteroaryl moiety optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di- (1-4C)alkyl!carbamoyl, n is 1, 2 or 3 and each R4 is independently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino or (2-4C)alkanoylamino;or a pharmaceutically-acceptable salt thereof. - View Dependent Claims (2, 3, 4, 6, 7, 8, 9, 10, 11)
- wherein Q1 is a 5-membered heteroaryl moiety containing one heteroatom selected from oxygen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q1 optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alklenedioxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di- (1-4C)alkyl!amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di- (1-4C)alkyl!amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH2 (methylene) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;
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5. A quinazoline derivative selected from the group consisting of:
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4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline, 4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline, 4-(3-chloro-4-fluoroanilino)-6- 5-(2-morpholinoethyl)thien-2-yl!quinazoline, and 4-(3-chloro-4-fluoroanilino)-6-(5-morpholinomethylthien-3-yl)quinazoline; or a pharmaceutically-acceptable acid-addition salt thereof.
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Specification