Quinazoline derivatives as anti-proliferative agents
First Claim
1. A method for producing an anticancer effect in a warm-blooded animal having an EGF-type receptor tyrosine kinase sensitive cancer which comprises administering to said animal an effective amount of a quinazoline derivative of the formula Iwhereinm is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, a 6- or 7-methoxy, ethoxy, propoxy, isopropoxy or butoxy group, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido;
- n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.
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Accused Products
Abstract
The invention concerns quinazoline derivatives of the formula I ##STR1## wherein m is 1, 2 or 3 and each R1 includes hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkoxyamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy and (1-3C)alkylenedioxy;
n is 1 or 2 and each R2 includes hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano and (1-4C)alkyl; or a pharmaceutically-acceptable salt thereof;
processes for their preparation; pharmaceutical compositions containing them; and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of cancer.
226 Citations
12 Claims
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1. A method for producing an anticancer effect in a warm-blooded animal having an EGF-type receptor tyrosine kinase sensitive cancer which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I
wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, a 6- or 7-methoxy, ethoxy, propoxy, isopropoxy or butoxy group, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido; n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.
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2. A method for producing an anticancer effect in a warm-blooded animal having an EGF-type receptor tyrosine kinase sensitive cancer which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR7## wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-urido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamino). 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido);
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
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3. A method for producing an anti-proliferative effect mediated alone or in part by inhibition of an EGF-type receptor tyrosine kinase enzyme in a warm-blooded animal which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR8## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, a 6- or 7-methoxy, ethoxy, propoxy, isopropoxy or butoxy group, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido;
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n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl; or a pharmaceutically-acceptable salt thereof.
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4. A method for producing an anti-proliferative effect mediated alone or in part by inhibition of an EGF-type receptor tyrosine kinase enzyme in a warm-blooded animal which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR9## wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-urido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamino). 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido);
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
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5. A method for producing an EGF-type receptor tyrosine kinase inhibitory 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 the formula I ##STR10## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, a 6- or 7-methoxy, ethoxy, propoxy, isopropoxy or butoxy group, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido;
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n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl; or a pharmaceutically-acceptable salt thereof.
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6. A method for producing an EGF-type receptor tyrosine kinase inhibitory 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 the formula I ##STR11## wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-urido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamino). 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido);
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
- and (R2)n is hydrogen, 4'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 3'"'"',4'"'"'-dichloro, 4'"'"'-fluoro-3'"'"'-chloro, 3'"'"'-trifluoromethyl, 4'"'"'-fluoro-3'"'"'-trifluoromethyl, 3'"'"'-nitro, 3'"'"'-nitro-4'"'"'-chloro, 3'"'"'-nitro-4'"'"'-fluoro or 3'"'"'-methyl;
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7. A method for producing an anticancer effect in a warm-blooded animal having an EGF-type receptor tyrosine kinase sensitive cancer which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR12## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(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, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy; or a pharmaceutically-acceptable salt thereof.
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8. A method for producing an anticancer effect in a warm-blooded animal having an EGF-type receptor tyrosine kinase sensitive cancer which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR13## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkylthio (1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl -(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, benzamido, benzenesulphonamido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy -(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl -(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano or (1-4C)alkyl; or a pharmaceutically-acceptable salt thereof.
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9. A method for producing an anti-proliferative effect mediated alone or in part by inhibition of an EGF-type receptor tyrosine kinase enzyme in a warm-blooded animal which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR14## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(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, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl -(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy; or a pharmaceutically-acceptable salt thereof.
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10. A method for producing an anti-proliferative effect mediated alone or in part by inhibition of an EGF-type receptor tyrosine kinase enzyme in a warm-blooded animal which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I ##STR15## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, _N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio (1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, benzamido, benzenesulphonamido, halogeno-(2-4 C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl -(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano or (1-4C)alkyl; or a pharmaceutically-acceptable salt thereof.
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11. A method for producing an EGF-type receptor tyrosine kinase inhibitory 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 the formula I ##STR16## wherein m is 1, 2 or 3 and each Rm is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(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, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl -(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl or (1-4C)alkoxy; or a pharmaceutically-acceptable salt thereof.
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12. A method for producing an EGF-type receptor tyrosine kinase inhibitory 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 the formula I ##STR17## wherein m is 1, 2 or 3 and each R1 is independently 6-hydroxy, 7-hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, (1-4C)alkyl, 6-(1-4C)alkoxy, 7-(1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, bromomethyl, dibromomethyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(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, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(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, (2-4C)alkanoylamino, benzamido, benzenesulphonamido, halogeno-(2-4 C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl -(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino;
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n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano or (1-4C)alkyl; or a pharmaceutically-acceptable salt thereof.
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Specification