Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase

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.

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Claims

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 (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, arylamino, 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.

2. A method according to claim 1 where the compound is described by: ##STR81## wherein Ar II is phenyl, naphthyl, thienyl, cyclohexyl or cyclopentyl; and

X is a bond, methyl, ethyl, propyl or (CHR.sub.1).sub.m --Z--(CHR.sub.1).sub.n where Z is O, S, SO, SO.sub.2 or NR', and n and m are 0-1 and n+m is 0 or 1.

3. A method according to claim 2 comprising administering to said patient a pharmaceutically effective amount of a pharmaceutical composition containing, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, of the formulae: ##STR82##

4. A method according to claim 3 where said compound is described by the formula: where:

X is a bond, O, NR', methyl, ethyl or propyl.

5. A method according to claim 3 where said compound is selected from the formula: ##STR83## where: X is a bond, O, NR', methyl, ethyl or propyl.

6. A method according to claim 4 where the compound administered is selected from:

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.

7. A method according to claim 5 where the compound administered is 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 and
2-(thien-2-yl)-6,7-dicarboxyquinoxaline.

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:

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-aminoquinoxalne,
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-dimethoxyquinoxaline4-N-oxide in admixture with a pharmaceutically acceptable carrier.

11. A compound according to claim 9 which is 2-phenyl-6,7-dimethylquinoxaline or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 10 which is 2-(thien-2-yl)-6,7-diethoxyquinoxaline or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 10 which is 2-(thien-2-yl)-6,7dimethoxyquinoxaline or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 10 which is 2-(thien-3-yl)quinoxaline or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 9, which is 2-(4-fluorophenyl)-6,7-diethoxyquinoxaline or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 9 which is 2-(4-fluorophenyl)-6,7-dimethoxyquinoxaline or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 9 which is 2-(4-fluorophenyl)-6-acetamidoquinoxaline or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 9 which is 2-phenethyl-6,7-diethoxyquinoxaline or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 9 which is 2-phenyl-6,7-dichloroquinoxaline or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 10 which is 2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline or a pharmaceutically acceptable salt thereof. ##STR84##

Referenced Cited
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3715358 February 1973 Witzel et al.
3718743 February 1973 Shen et al.
3985749 October 12, 1976 Foster
4322420 March 30, 1982 Kobayashi et al.
4464375 August 7, 1984 Kobayashi et al.
4465686 August 14, 1984 Lesher et al.
4599423 July 8, 1986 Lesher et al.
4661499 April 28, 1987 Young et al.
5134148 July 28, 1992 Crawley et al.
5409930 April 25, 1995 Spada et al.
Foreign Patent Documents
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Patent History
Patent number: RE36256
Type: Grant
Filed: Dec 10, 1997
Date of Patent: Jul 20, 1999
Assignee: Rhone-Poulenc Rorer Pharmaceuticals, Inc. (Collegeville, PA)
Inventors: Alfred P. Spada (Lansdale, PA), Michael R. Myers (Reading, PA), Martin P. Maguire (Mont Clare, PA), Paul E. Persons (King of Prussia, PA)
Primary Examiner: Richard L. Raymond
Law Firm: Bell, Boyd & Lloyd
Application Number: 8/988,005