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##
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. |
9331010 | January 1993 | AUX |
0520722 | December 1992 | EPX |
1543560 | April 1979 | GBX |
9220642 | November 1992 | WOX |
- Tamao et al., "Nickel-Phosphine Complex-Catalyzed . . . ", Tetrahedron, vol. 38, No. 22, pp. 3347-3354, 1982. Yamamoto et al., "General Method for Synthesis of Bipyridines: Palladium . . . ", Synthesis, pp. 564-565, 1986. Yamamoto et al., "Studies on Organometallic Compounds. III. Reaction of . . . ", Chem. Pharm. Bull., vol. 30, No. 6, pp. 2003-2010, 1982. Ishikura et al., "A Simple & Regioselective Preparation of 2-or 3-. . . ", Heterocycles, vol. 23, No. 9, pp. 2375-2386, 1985. Stem et al., "Potential-Dependent Surface Chemistry of . . . ", J. Am. Soc., vol. III. No. 3, pp. 877-891, 1989. Yoshina, "Quinoline Derivatives", Chemical Abstracts, vol. 84, Abstract #164632t, p. 453, 1976. Barker et al., "Dehalogenation of 1-Halothienyldi & tetra . . . ", Chemical Abstracts, vol. 103, Abstract #123292z, p. 709, 1985. Epling et al., "Sulfur-Containing 2-Anylquinoline Methanols . . . ", Chemical Abstracts, vol. 108, Abstract #55860j, 704, 1988. Beilstein--band EIII/IV 21, p. 2436, 1978. Saeed et al., "Preparation of Phenylquinoxaline from .alpha., .alpha.-diamino . . . ", J. Heterocyclic Chem., vol. 20, pp. 1739-1740, 1983.
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
International Classification: A61K 31495; A61K 31535; C07D24152; C07D24154;