Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties

• US 5,721,237 A
• Filed: 06/06/1995
• Issued: 02/24/1998
• Est. Priority Date: 05/10/1991
• Status: Expired due to Term

• Current Assignee: Aventisub LLC (Sanofi )
• Original Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi )
• Inventors: Maguire, Martin P., Myers, Michael R., Spada, Alfred P., Persons, Paul E.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/469,147
• Time in Patent Office: 994 Days
• Field of Search: 544/283, 544/284, 544/287, 544/293, 514/255, 514/259
• US Class Current: 514/266.1
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 239/74 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 a method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2). More specifically, this invention relates to the use of substituted or unsubstituted mono- or bi-cyclic aryl, heteroaryl, cycloalkyl or heterocycloalkyl compounds in selectively regulating cell growth. Pharmaceutical compositions useful for the selective treatment of cell growth and differentiation are also described.

Claims

1. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR12## wherein A is a substituted or unsubstituted monocyclic aryl or heteroaryl ring selected from phenyl, pyrrolyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl and oxazolyl;

X is a bond, O, S, SO, SO₂, OCH₂, CR₄ ═

CR₄, C.tbd.C, NR₄ or NR₄ CH₂ ;

R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R₄ is hydrogen, alkyl or aralkyl; and

R₅, R₆, R₇ and R₈ are independently hydrogen, alkoxy or aralkoxy;

or

a pharmaceutically acceptable salt thereof.

7. A method according to claim 1 where the compound administered is 4-(2-phenylethylenyl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable thereof.

2. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR13## wherein A is a substituted or unsubstituted bicyclic aryl or heteroaryl ring selected from naphthyl, tetralinyl, 1,2,3,4-tetrahydroquinolinyl, benzofuryl, benzothienyl, indanyl, indolyl, indolinyl, 1,3-benzodioxolyl, benzodioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl.

X is a bond, O, S, SO, SO₂, OCH₂, CR₄ ═

CR₄, C.tbd.C, NR₄ or NR₄ CH₂ ;

R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R₄ is hydrogen, alkyl or aralkyl; and

R₅, R₆, R₇ and R₈ are independently hydrogen, alkoxy or aralkoxy;

or a pharmaceutically acceptable salt thereof.

8. A method according to claim 2 where said compound administered is 6,7-dimethoxy-4-naphthalen-1yl-ethynylquinazoline or a pharmaceutically acceptable thereof.

3. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR14## wherein A is a substituted or unsubstituted monocyclic cycloalkyl or heterocycloalkyl ring selected from cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, piperdinyl, piperazinyl, morpholinyl or decahydroquinolinyl.

X is a bond, O, S, SO, SO₂, OCH₂, CR₄ ═

CR₄, C.tbd.C, NR₄ or NR₄ CH₂ ;

R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R₄ is hydrogen, alkyl or aralkyl; and

R₅, R₆, R₇ and R₈ are independently hydrogen, alkoxy or aralkoxy;

or a pharmaceutically acceptable salt thereof.

4. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR15## wherein A is a substituted or unsubstituted bicyclic cycloalkyl or heterocycloalkyl ring selected from decalinyl or decahydroquinolinyl.

X is a bond, O, S, SO, SO₂, OCH₂, CR₄ ═

CR₄, C.tbd.C, NR₄ or NR₄ CH₂ ;

R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R₄ is hydrogen, alkyl or aralkyl; and

R₅, R₆, R₇ and R₈ are independently hydrogen, alkoxy or aralkoxy;

or a pharmaceutically acceptable salt thereof.

5. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR16## wherein A is substituted and unsubstituted phenyl, pyridyl, thienyl, furyl, pyrazolyl, naphthyl, tetralinyl, 1,2,3,4-tetrahydroquinolinyl, indanyl, indolyl, indolinyl, quinolinyl, tetrahydroquinolinyl, cyclohexyl, piperdinyl or piperazinyl;

X is a bond, O, S, or NR₄ ;

R is hydrogen, alkyl, alkoxy, halo, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenyl and aralkyl;

R₄ is hydrogen, alkyl or aralkyl; and

R₅, R₆, R₇, and R₈ are independently hydrogen or alkoxy;

or a pharmaceutically acceptable salt thereof.

9. A method according to claim 5 where said compound administered is selected from:

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

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

4- 4-(3-chlorophenyl)piperazin-1-yl!-6,7-dimethoxyquinazoline and

4-(1,2,3,4-tetrahydroquinolin-1 -yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable thereof.

10. A method according to claim 5 where said compound administered is selected from:

6,7-dimethoxy-4-(β

-naphthylamino)quinazoline,

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

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

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

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

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

4-(cyclohexylanilino)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable thereof.

11. A method according to claim 5 where the compound administered is 6,7-dimethoxy-4-(α

-naphthylamino)quinazoline or a pharmaceutically acceptable salt thereof.

6. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:

##STR17## wherein A is substituted and unsubstituted phenyl, naphthyl or indolyl;

X is a bond;

R is hydrogen, methoxy, ethoxy, chloro, trifluoromethyl, methylsulfonyl, phenyl and benzyl;

R₄ is hydrogen, methyl or benzyl; and

R₅, R₆, R₇, and R₈ are independently hydrogen or methoxy;

or a pharmaceutically acceptable salt thereof.

12. A method according to claim 6 where said compound administered is selected from:

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

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

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

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

4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.

13. A method according to claim 6 where the compound administered is 4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.