Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
AssigneeRhone-Poulenc Rorer Pharmaceuticals Inc.
InventorsAlfred P. Spada, Michael R. Myers, Martin P. Maguire, Paul E. Persons
Life of this patent
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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.
Claims20
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 (CHR.sub.1).sub.0-4 or (CHR.sub.1).sub.m --Z--(CHR.sub.1).sub.n :
- Z is O, NR', S, SO or SO.sub.2 :
- 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;
- R.sub.1 and R' are hydrogen or alkyl;
- or
- an N-oxide or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
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:
- 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.
A compound selected from:
- 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.
A compound selected from:
- 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.
Dependencies are inferred from the claim text.