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

• US 6,057,320 A
• Filed: 06/25/1997
• Issued: 05/02/2000
• Est. Priority Date: 05/10/1991
• Status: Expired due to Fees

• Current Assignee: Aventis Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Original Assignee: Aventis Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Maguire, Martin P., Myers, Michael R., Spada, Alfred P., Persons, Paul E.
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US08/881,991
• Time in Patent Office: 1,042 Days
• Field of Search: 544/283, 544/285, 544/289, 544/290, 544/292, 544/284, 514/248, 514/249, 514/259, 514/260
• US Class Current: 514/249
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• 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 method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such cell proliferation comprising administering to the patient a pharmaceutically effective amount of a compound of formula I ##STR80## is a substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl ring system of about 5 to about 12 atoms, wherein the monocyclic ring system optionally contains 0 to about 3 hetero atoms and the bicyclic ring system optionally contains 0 to about 4 hetero atoms, wherein the hetero atoms are selected from N, O and S, or optionally the ring of the monocyclic ring system is a saturated carbocyclic optionally containing 0 to about 2 hetero atoms or optionally at least one ring of the bicyclic ring system is a saturated carbocyclic optionally containing 0 to about 4 hetero atoms, wherein the carbocyclic is of about 3 to about 7 atoms, provided that the hetero atoms are not vicinal oxygen or sulfur atoms, said rings optionally substituted with 0 to about 3 R groups and located at any appropriate position of the ring system;

X is (CHR₁)₀ 4 or (CHR₁)_m --Z--(CHR₁)_n ;

Z is O, NR'"'"', S, SO or SO₂ ;

m and n are independently 0 to 3, provided that the sum of m and n is 0 to 3;

R is hydrogen, 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 or benzoyl;

or R and R taken together form a ketone group; and

R₁ and R'"'"' are independently hydrogen or alkyl, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

3. The method according to claim 1 wherein the compound is of the formula ##STR82## or a pharmaceutically acceptable salt thereof or N-oxide thereof.

4. The method according to claim 1 wherein the compound is of the formula ##STR83## is phenyl, naphthyl, thienyl, cyclohexyl or cyclopentyl;

X is a bond, methylenyl, ethylenyl, propylenyl or (CHR₁)_m --Z--(CHR₁)_n,

Z is O, S, SO, SO₂ or NR'"'"'; and

m and n are independently 0 to 1, provided that the sum of m and n is 0 to 1, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

5. The method according to claim 1 wherein the compound is of the formula ##STR84## where:

X is a bond, O, NR'"'"' methylenyl, ethylenyl or propylenyl, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

6. The method according to claim 1 wherein the compound is of the formula:

##STR85## where;

X is a bond, O, NR'"'"', methylenyl, ethylenyl or propylenyl or a pharmaceutically acceptable salt thereof or N-oxide thereof.

11. A method of inhibiting cell proliferation comprising contacting an effective amount of a compound according to claim 1 with an EGF receptor.

12. A method of inhibiting cell proliferation comprising contacting an effective amount of a compound according to claim 1 with an PDGF receptor.

13. A method of inhibiting cell proliferation comprising contacting an effective amount of a compound according to claim 1 with an EGF and PDGF receptor.

2. A method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such cell proliferation comprising administering to the patient a pharmaceutically effective amount of a compound which is of the formula:

##STR81## is a substituted or unsubstituted monocyclic or bicyclic aryl or heteroaryl ring system of about 5 to about 12 atoms, wherein the monocyclic ring system optionally contains 0 to about 3 hetero atoms and the bicyclic ring system optionally contains 0 to about 4 hetero atoms, wherein the hetero atoms are selected from N, O and S, or optionally the ring of the monocyclic ring system is a saturated carbocyclic optionally containing 0 to about 2 hetero atoms or optionally at least one ring of the bicyclic ring system is a saturated carbocyclic optionally containing 0 to about 4 hetero atoms, wherein the carbocyclic is of about 3 to about 7 atoms, provided that the hetero atoms are not vicinal oxygen or sulfur atoms, said rings optionally substituted with 0 to about 3 R groups and located at any appropriate position of the ring system;

X is (CHR₁)_0-4 or (CHR₁)_m --Z--(CHR₁)_n ;

Z is O, NR'"'"', S, SO or SO₂ ;

m and n are independently 0 to 3, provided that the sum of m and n is 0 to 3;

R is hydrogen, 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 or benzoyl;

or R and R taken together form a ketone group; and

R₁ and R'"'"' are independently hydrogen or alkyl, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

7. A compound which is 6,7-dimethoxy-4-naphthalen-2-ylethynylquinazoline, 4-phenylacetylenyl-6,7-dimethoxyquinazoline, 4-(2-phenylethylenyl)-6,7-dimethoxyquinazoline, or 6,7-dimethoxy-4-naphthalen-1-yl-ethynylquinazoline, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

9. A method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such cell proliferation comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 7, or

a pharmaceutically acceptable salt thereof or N-oxide thereof.

8. A compound which is (6,7-dimethoxyquinazolin-4-yl)-N-phenylethylamine, (6-chloroquinazolin-4yl)methylphenylamine, (quinazolin-4-yl)-N-phenylmethylamine hydrochloride, (6,8-dimethylquinazolin-4-yl)-N-phenylmethylamine, (6,7-dimethoxyquinazolin-4-yl)-4-morpholin-4-yl-phenyl)amine, or 4-(cyclohexylamino)-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable salt thereof or N-oxide thereof.

10. A method of inhibiting cell proliferation in a patient suffering from a disorder characterized by such cell proliferation comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 8, or

a pharmaceutically acceptable salt thereof or N-oxide thereof.