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

• US RE36,256 E
• Filed: 12/10/1997
• Issued: 07/20/1999
• Est. Priority Date: 05/10/1991
• Status: Expired due to Term

• Current Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Original Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Maguire, Martin P., Myers, Michael R., Spada, Alfred P., Persons, Paul E.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/988,005
• Time in Patent Office: 587 Days
• Field of Search: 544/353, 544/354, 544/356, 514/234.8, 514/249, 514/353
• US Class Current: 514/249
• CPC Class Codes: N/A

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 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, 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;

R₁ 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 (CHR₁)_m --Z--(CHR₁)_n where Z is O, S, SO, SO₂ 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.

9. 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.

11. A compound according to claim 9 which is 2-phenyl-6,7-dimethylquinoxaline 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.

10. 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.

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.

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