Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
AssigneeRhone-Poulenc Rorer Pharmaceuticals Inc.
InventorsMichael R. Myers, Alfred P. Spada, Martin P. Maguire, Paul E. Persons
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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.
Claims13
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, SO.sub.2, OCH.sub.2, CR.sub.4 .dbd.CR.sub.4, C.tbd.C, NR.sub.4 or NR.sub.4 CH.sub.2 ;
- 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;
- R.sub.4 is hydrogen, alkyl or aralkyl;
- and
- R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, alkoxy or aralkoxy;
- or
- a pharmaceutically acceptable salt thereof.
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, SO.sub.2, OCH.sub.2, CR.sub.4 .dbd.CR.sub.4, C.tbd.C, NR.sub.4 or NR.sub.4 CH.sub.2 ;
- 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;
- R.sub.4 is hydrogen, alkyl or aralkyl;
- and
- R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, alkoxy or aralkoxy;
- or a pharmaceutically acceptable salt thereof.
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, SO.sub.2, OCH.sub.2, CR.sub.4 .dbd.CR.sub.4, C.tbd.C, NR.sub.4 or NR.sub.4 CH.sub.2 ;
- 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;
- R.sub.4 is hydrogen, alkyl or aralkyl;
- and
- R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, alkoxy or aralkoxy;
- or a pharmaceutically acceptable salt thereof.
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, SO.sub.2, OCH.sub.2, CR.sub.4 .dbd.CR.sub.4, C.tbd.C, NR.sub.4 or NR.sub.4 CH.sub.2 ;
- 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;
- R.sub.4 is hydrogen, alkyl or aralkyl;
- and
- R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, alkoxy or aralkoxy;
- or a pharmaceutically acceptable salt thereof.
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 NR.sub.4 ;
- R is hydrogen, alkyl, alkoxy, halo, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenyl and aralkyl;
- R.sub.4 is hydrogen, alkyl or aralkyl;
- and
- R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently hydrogen or alkoxy;
- or a pharmaceutically acceptable salt thereof.
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;
- R.sub.4 is hydrogen, methyl or benzyl;
- and
- R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently hydrogen or methoxy;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.