Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase

• US 5,710,158 A
• Filed: 04/19/1994
• Issued: 01/20/1998
• 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: Maguire, Martin P., Myers, Michael R., Spada, Alfred P., Persons, Paul E.
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): Cebulak, Mary C.
• Application Number:
  US08/229,886
• Time in Patent Office: 1,372 Days
• Field of Search: 544/293, 544/283, 544/284, 544/287, 514/259
• US Class Current: 514/266.2
• 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: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• 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 the modulation and/or inhibition of cell signaling, cell proliferation, cell inflammatory response, the control of abnormal cell growth and cell reproduction. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds in inhibiting cell proliferation, including compounds which are useful protein tyrosine kinase (PTK) inhibitors. The method of treating cell proliferation using said quinazoline compounds and their use in pharmaceutical compositions is described.

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 compound of the formula:

##STR89## wherein Ar is selected from substituted or unsubstituted phenyl, α

-naphthyl, β

-naphthyl, indazolyl, indanyl, pyrazolyl, pyridinyl, indol-3-yl, benzodioxan-6-yl, 1,2,3,4-tetrahydroquinolin-1-yl, or 2,3-dihydroindol-1-yl where the substituents may be located at any appropriate position of the ring system and are described by R;

X is a bond, O, S, NHCH₂ or NR₄ ;

R independently includes hydrogen, alkyl, hydroxy, alkoxy, phenyl, aralkyl, alkylsulphonyl, haloalkyl or halo;

R₅ is hydrogen or alkoxy;

R₆ and R₇ are alkoxy; and

R₄ is hydrogen, methyl, ethyl or benzyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein the compound is selected from the group consisting of:

4-(3,4,5-trimethoxyphenylamino)-6,7-dimethoxyquinazoline,

4-(N-methyl-3,4,5-trimethoxyanilino)-6,7-dimethoxyquinazoline,

4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline,

4-(N-methyl-4-chloroanilino)-6,7-dimethoxyquinazoline,

(6,7-dimethoxyquinazolin-4-yl)methyl-(3-trifluoromethylphenyl)amine,

(3-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)methylamine,

N-phenyl-N-(6,7,8-dimethoxyquinazolin-4-yl)methylamine,

benzyl-(6,7-dimethoxyquinazolin-4-yl)phenylamine,

(3-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)ethylamine,

(6,7-dimethoxyquinazolin-4-yl) methyl-p-tolyl-amine,

(4-methoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine,

(3,5-dimethoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine,

4-(pyrazol-3-ylamino)-6,7-dimethoxyquinazoline, and

6,7-dimethoxy-4-(N-methylanilino)quinazoline;

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 wherein the compound is 4-(pyrazol-3-ylamino)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 wherein the compound is selected from the group consisting of:

(6,7-dimethoxyquinazolin-4-yl)-5-indazolylamine,

4- N-(5-indanyl)amino!-6,7-dimethoxyquinazoline,

4-(3,6-dioxananilino)-6,7-dimethoxyquinazoline,

6,7-dimethoxy-4-(α

-naphthylamino)quinazoline, and

6,7-dimethoxy-4-(β

-naphthylamino)quinazoline;

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 wherein the compound is selected from the group consisting of:

4-(3,4,5-trimethoxyphenoxyl)-6,7-dimethoxyquinazoline,

4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline,

4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline, and

4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline;

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 wherein the compound is selected from the group consisting of:

4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline,

4-(naphthalen-1-yl)-6,7-dimethoxyquinazoline,

4-(naphthalen-2-yl)-6,7-dimethoxyquinazoline,

4-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinazoline,

4-(3-phenylphenyl)-6,7-dimethoxyquinazoline,

4-(2-methoxypyridin-5-yl)-6,7-dimethoxyquinazoline,

4-(1 -benzylindol-3-yl)-6,7-dimethoxyquinazoline,

4-(indol-3-yl)-6,7-dimethoxyquinazoline,

4-(1 -methylindol-3-yl)-6,7-dimethoxyquinazoline,

4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline,

(±

)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline,

4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline, and

4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline;

or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of:

4-(3,4,5-trimethoxyphenylamino)-6,7-dimethoxyquinazoline,

4-(N-methyl-3,4,5-trimethoxyanilino)-6,7-dimethoxyquinazoline,

4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline,

4-(N-methyl-4-chloroanilino)-6,7-dimethoxyquinazoline,

(6,7-dimethoxyquinazolin-4-yl)methyl-(3-trifluoromethylphenyl)amine,

(3-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)methylamine,

N-phenyl-N-(6,7,8-dimethoxyquinazolin-4-yl)methylamine,

(3-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)ethylamine,

(6,7-dimethoxyquinazolin-4-yl)methyl-p-tolyl-amine,

(4-methoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine,

(3,5-dimethoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine, and

6,7-dimethoxy-4-(N-methylanilino)quinazoline;

or a pharmaceutically acceptable salt thereof.

8. A compound which is 4-(pyrazol-3-ylamino)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.

9. A compound selected from the group consisting of:

(6,7-dimethoxyquinazolin-4-yl)-5-indazolylamine,

4- N-(5-indanyl)amino!-6,7-dimethoxyquinazoline,

4-(3,6-dioxananilino)-6,7-dimethoxyquinazoline,

6,7-dimethoxy-4-(α

-naphthylamino)quinazoline, and

6,7-dimethoxy-4-(β

-naphthylamino)quinazoline;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 9 which is 6,7-dimethoxy-4-(α

-naphthylamino)quinazoline or a pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of:

4-(3,4,5-trimethoxyphenoxy)-6,7-dimethoxyquinazoline,

4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline,

4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline, and

4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline;

or a pharmaceutically acceptable salt thereof.

11. A compound selected from the group consisting of:

4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline,

4-(naphthalen-1-yl)-6,7-dimethoxyquinazoline,

4-(naphthalen-2-yl)-6,7-dimethoxyquinazoline,

4-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinazoline,

4-(3-phenylphenyl)-6,7-dimethoxyquinazoline,

4-(2-methoxypyridin-5-yl)-6,7-dimethoxyquinazoline,

4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline,

4-(indol-3-yl)-6,7-dimethoxyquinazoline,

4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline,

4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline,

(±

)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline,

4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline, and

4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline;

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 11 which is 6,7-dimethoxy-4-(1-methylsulphonylindol-3-yl)quinazoline or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 11 which is 4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.