Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
First Claim
1. A method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such proliferation comprising administering to a patient a pharmaceutical composition comprising an EGF and/or PDGF receptor inhibiting effective amount of a compound of the formula ##STR80## wherein:
- Ar II is a substituted or unsubstituted mono- or bicyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms or at least one ring is a substituted or unsubstituted saturated carbocyclic of about 3 to about 7 atoms where each monocyclic ring may contain 0 to about 2 hetero atoms and where the hetero atoms are selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;
X is (CHR1)0-4 or (CHR1)m --Z--(CHR1)n ;
Z is O, NR'"'"', S, SO or SO2 ;
m and n are 0-3 and m+n=0-3;
R substitution besides hydrogen independently includes alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, acyloxy, halo, haloalkyl, nitro, amino, mono-and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, phenyl, halophenyl, thienyl, halothienyl, pyridyl, 1H-tetrazolyl or benzoyl;
R and R together may also be keto;
R1 and R'"'"' are hydrogen or alkyl;
oran N-oxide or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
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Accused Products
Abstract
This invention relates to bis mono- and/or bicyclic aryl and/or heteroaryl compounds exhibiting protein tyrosine kinase inhibition activity. More specifically, it relates to the method of inhibiting abnormal cell proliferation in a patient suffering from a disorder characterized by such proliferation comprising the administration thereto of an EGF and/or PDGF receptor inhibiting effective amount of said bis mono- and/or bicyclic aryl and/or heteroaryl compound and to the preparation of said compounds and their use in pharmaceutical compositions used in this method.
314 Citations
20 Claims
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1. A method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such proliferation comprising administering to a patient a pharmaceutical composition comprising an EGF and/or PDGF receptor inhibiting effective amount of a compound of the formula ##STR80## wherein:
- Ar II is a substituted or unsubstituted mono- or bicyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms or at least one ring is a substituted or unsubstituted saturated carbocyclic of about 3 to about 7 atoms where each monocyclic ring may contain 0 to about 2 hetero atoms and where the hetero atoms are selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;
X is (CHR1)0-4 or (CHR1)m --Z--(CHR1)n ; Z is O, NR'"'"', S, SO or SO2 ; m and n are 0-3 and m+n=0-3; R substitution besides hydrogen independently includes alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, acyloxy, halo, haloalkyl, nitro, amino, mono-and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, phenyl, halophenyl, thienyl, halothienyl, pyridyl, 1H-tetrazolyl or benzoyl; R and R together may also be keto; R1 and R'"'"' are hydrogen or alkyl;
oran N-oxide or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. - View Dependent Claims (2, 3, 4, 5, 6, 7)
- Ar II is a substituted or unsubstituted mono- or bicyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms or at least one ring is a substituted or unsubstituted saturated carbocyclic of about 3 to about 7 atoms where each monocyclic ring may contain 0 to about 2 hetero atoms and where the hetero atoms are selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;
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8. A pharmaceutical composition for inhibiting cell proliferation comprising an EGF and/or PDGF receptor inhibiting effective amount of a compound or a pharmaceutically acceptable salt thereof selected from:
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2-(thien-3-yl)-6,7-dimethylquinoxaline; 2-(thien-3-yl)-6,7-dimethoxyquinoxaline; 2-(thien-3-yl)-6,7-diethoxyquinoxaline; 2-(5-chlorothien-2-yl)-6,7-diethoxyquinoxaline; 2-(5-chlorothien-2-yl)-6,7-dimethoxyquinoxaline; 2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline; 2-(thien-2-yl)-6,7-diethoxyquinoxaline; 2-(thien-2-yl)-6,7-dimethoxyquinoxaline; 2-(thien-2-yl)-6,7-dicarboxyquinoxaline; 2-phenyl-6,7-dimethylquinoxaline, 2-phenyl-6,7-dichloroquinoxaline, 2-phenyl-6,7-dimethoxyquinoxaline, 2-phenyl-6,7-dimethoxyquinoxaline-4-N-oxide, 2-phenyl-6,7-diethoxyquinoxaline, 2-(4-fluorophenyl)-6,7-diethoxyquinoxaline, 2-(4-fluorophenyl)-6,7-dimethylquinoxaline, 2-(4-fluorophenyl)-6-aminoquinoxaline, 2-(4-fluorophenyl)-6-acetamidoquinoxaline, 2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline, 2-phenethyl-6,7-diethoxyquinoxaline, 2-phenyl-6,7-dicarboxyquinoxaline 2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline and 2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline-4-N-oxide in admixture with a pharmaceutically acceptable carrier.
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9. A compound selected from:
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2-phenyl-6,7-dimethylquinoxaline, 2-phenyl-6,7-dichloroquinoxaline, 2-phenyl-6,7-dimethoxyquinoxaline, 2-phenyl-6,7-diethoxyquinoxaline, 2-(4-fluorophenyl)-6,7-diethoxyquinoxaline, 2-(4-fluorophenyl)-6,7-dimethylquinoxaline, 2-(4-fluorophenyl)-6-aminoquinoxaline, 2-(4-fluorophenyl)-6-acetamidoquinoxaline, 2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline, 2-phenethyl-6,7-diethoxyquinoxaline, 2-phenyl-6,7-dicarboxyquinoxaline, 2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline, or an N-oxide or a pharmaceutically acceptable salt thereof. - View Dependent Claims (11, 15, 16, 17, 18, 19)
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10. A compound selected from:
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2-(thien-3-yl)quinoxaline, 2-(thien-3-yl)-6,7-dimethylquinoxaline, 2-(thien-3-yl)-6,7,-dimethoxyquinoxaline, 2-(thien-3-yl)-6,7,-diethoxyquinoxaline, 2-(5-chlorothien-3-yl)-6,7,-diethoxyquinoxaline, 2-(5-chlorothien-3-yl)-6,7,-dimethoxyquinoxaline, 2-(5-fluorothien-3-yl)-6,7,-diethoxyquinoxaline, 2-(thien-2-yl)-6,7,-diethoxyquinoxaline, 2-(thien-2-yl)-6,7,-dimethoxyquinoxaline, 2-(thien-2-yl)-6,7,-dicarboxyquinoxaline or an N-oxide or a pharmaceutically acceptable salt thereof. - View Dependent Claims (12, 13, 14, 20)
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Specification