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

• US 5,409,930 A
• Filed: 11/08/1993
• Issued: 04/25/1995
• Est. Priority Date: 05/10/1991
• Status: Expired due to Term

• Current Assignee: Aventis Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Original Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Maquire, Martin P., Myers, Michael R., Spada, Alfred P., Persons, Paul E.
• Primary Examiner(s): LONE, WERREN
• Application Number:
  US08/146,072
• Time in Patent Office: 533 Days
• Field of Search: 544/354, 544/355, 544/353, 546/167, 514/249, 514/314, 514/311, 514/313
• US Class Current: 514/248
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 43/2055 containing more than one ether bond
• CPC Class Codes: C07C 43/225 containing halogen
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 215/18 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 215/20 Oxygen atoms
• CPC Class Codes: C07D 215/233 only one oxygen atom which is attached in position 4
• CPC Class Codes: C07D 215/50 attached in position 4
• CPC Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 239/91 : with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/93 : Sulfur atoms
• CPC Class Codes: C07D 239/94 : Nitrogen atoms
• CPC Class Codes: C07D 241/42 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/52 : Oxygen atoms
• CPC Class Codes: C07D 265/22 : Oxygen atoms
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

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.

Claims

1. A compound selected from the group consisting of:

3-(thien-3-yl)-6,7-dimethoxyquinoline;

3-(thien-3-yl)-7-methoxyquinoline;

3-(4-methoxyphenyl)-6,7-dimethoxyquinoline;

3-(5-chlorothien-2-yl)-6,7-dimethoxyquinoline;

3-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinoline;

3-(2-chlorothien-2-yl)-5,7-dimethoxyquinoline;

3-(thien-3-yl)-6,7-dimethylquinoline;

3-(1-cyclopent-1-enyl)-6,7-dimethoxyquinoline;

3-cyclopentyl-6,7-dimethoxyquinoline;

4-(3-phenylpropyloxy)-6,7-dimethoxyquinoline;

3-(thien-3-yl)-6,7-dimethoxyquinoline-N-oxide;

3-(2-chlorothien-5-yl)-5,7-dimethoxyquinoline;

3-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinoline;

3-(3-fluorophenyl)-6,7-dimethoxyquinoline;

4-(2-phenylethoxy)-6,7-dimethoxyquinoline;

3-(4-methoxybenzyloxy)-6,7-dimethoxyquinoline;

2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline;

2-(thien-3-yl)-6,7-dimethoxyquinoxaline;

2-phenyl-6,7-dimethoxyquinoxaline;

3. A pharmaceutical composition wherein the active ingredient is selected from the compounds of claim 1.

4. A compound according to claim 1 selected from

3-(thien-3-yl)-6,7-dimethoxyquinoline;

3-(thien-3-yl)-6,7-dimethoxyquinoline-N-oxide;

3-(thien-3-yl)-6,7-dimethylquinoline;

3-(thien-3-yl)-6,7-difluoroquinoline;

3-(thien-3-yl)-5,7-dimethylquinoline;

or

3-(thien-3-yl)-7-methoxyquinoline.

5. A compound according to claim 1 selected from

3-(2-chlorothien-5-yl)-6,7-dimethoxyquinoline;

3-(2-chlorothien-5-yl)-5,7-dimethoxyquinoline;

or

3-(2-chlorothien-5-yl)-6,7-dimethylquinoline.

6. A compound according to claim 1 selected from

3-(4-methoxyphenyl)-6,7-dimethoxyquinoline;

3-(3-fluorophenyl)-6,7-dimethoxyquinoline;

or

3-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinoline.

7. A compound according to claim 1 which is 3-(3-fluoro-4-methoxyphenyl)-7-fluoroquinoline.

8. A compound according to claim 1 selected from

3-(1-cyclopent-1-enyl)-6,7-dimethoxyquinoline;

or

3-cyclopentyl-6,7-dimethoxyquinoline.

9. A compound according to claim 1 selected from

4-(3-phenylpropyloxy)-6,7-dimethoxyquinoline;

or

4-(2-phenylethoxy)-6,7-dimethoxyquinoline.

10. A compound according to claim 1 which is 3-(4-methoxybenzyloxy)-6,7-dimethoxyquinoline.

11. A compound according to claim 1 selected from

2-phenyl-6,7-dimethoxyquinoxaline;

2-phenyl-6,7-diethoxyquinoxaline;

or

2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline.

12. A compound according to claim 1 selected from

2-(5-chlorothien-2-yl)-6,7-diethoxyquinoxaline;

or

2-(5-chlorothien-2-yl)-6,7-dimethoxyquinoxaline.

13. A compound according to claim 1 selected from

2-(thien-3-yl)-6,7-dimethoxyquinoxaline;

2-(thien-3-yl)-6,7-diethoxyquinoxaline;

or

2-(thien-3-yl)-6,7-dimethylquinoxaline.

14. A compound according to claim 1 which is 3-(4-methoxyphenyl)-7-methoxy-1-naphthalenol.

2. 7-dimethyl-2-(thien-3-yl)-quinoxaline;

2-phenyl-6,7-diethoxyquinoxaline;

2-(3-thienyl)-6,7-diethoxyquinoxaline;

2-(5-chloro-2-thienyl)-6,7-diethoxyquinoxaline;

2-(5-chloro-2-thienyl)-6,7-dimethoxyquinoxaline;

3-(3-fluoro-4-methoxyphenyl)-7-fluoroquinoline;

3-(thien-3-yl)-5,7-dimethylquinoline;

3-(5-chlorothien-2-yl)-6,7-dimethylquinoline;

3-(thien-3-yl)-6,7-difluoroquinoline or

3-(4-methoxyphyenyl)-7-methoxy-1-naphthalenol.