US 2006/0135592 A1Published application

Indolinones and their use as antiproliferative agents

AssigneeBoehringer Ingelheim International GmbH

InventorsDarryl McConnell, Ulrike Weyer-Czernilofsky, Maria Impagnatiello, Steffen Steurer, Ralph Brueckner, Bernd Krist, Bodo Betzemeier, Frank Hilberg, Armin Heckel, Gerald Roth, Joerg Kley, Thorsten Lehmann-Lintz

Life of this patent

Estimating the term…

Abstract

The invention relates to indolinone compounds of formula (I), wherein Y and R1 to R8 are defined as in claim 1, which are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation and the use thereof for preparing a pharmaceutical composition.

Claims16

Dependent claims

A compound of formula (I)

wherein
R1 is H or methyl;
and
R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, cyano, isocyanato, isothiocyanato, hydroxy, halo, nitro, thiocyanato, thiol, —(CH2)xC(═O)Ra, —(CH2)xC(═NH)NRaR′a, —(CH2)xC(═O)NRaR′a, —(CH2)xNRaC(═O)R′a, —(CH2)xNRaR′a, —(CH2)xNRaOR′a, —(CH2)xONRaR′a, —(CH2)xOC(═O)NRaR′a, —(CH2)xNRaC(═O)OR′a, —(CH2)xOC(═O)Ra, —(CH2)xC(═O)ORa, —(CH2)xORa, —(CH2)xNHC(═NH)NHRf, —(CH2)xC(═O)NORa, —(CH2)x(Ra)C═NRd, —Si(Re)3, —(CH2)xS(═O)2Ra, —(CH2)xS(═O)Ra, —(CH2)xSRa, —(CH2)xS(═O)2ORa, —(CH2)xOS(═O)2Ra, —(CH2)xNR″aS(═O)2NRaR′a, —(CH2)xS(═O)2NRaR′a, —(CH2)xNRaS(═O)2R′a, —(CH2)xC(═S)Ra, —(CH2)xOC(═S)NRaR′a, —(CH2)xNRaC(═S)OR′a, —(CH2)xC(═S)NRaR′a, —(CH2)xNRaC(═S)R′a, —(CH2)xNR″aC(═O)NRaR′a and —[(CH2)xO—]yRg or from an optionally substituted group consisting of C1-6alkyl, biaryl, carbocyclic aryl, heteroalicyclo and heteroaryl and
R6, R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, thiol, halo, cyano, amino, methylamino, dimethylamino, nitro and CF3 or from an optionally substituted group selected from C1-4alkoxy, C1-4alkylthio, C1-6alkyl, wherein the substituents are selected from the group consisting of halo, hydroxy and oxo;
and Y is selected from the group consisting of cyano, isocyanato, isothiocyanato, hydroxy, halo, nitro, thiocyanato, thiol, —(CH2)xC(═O)Ra, —(CH2)xC(═NH)NRaR′a, —(CH2)xC(═O)NRaR′a, —(CH2)xNRaC(═O)R′a, —(CH2)xNRaR′a, —(CH2)xNRaOR′a, —(CH2)xONRaR′a, —(CH2)xOC(═O)NRaR′a, —(CH2)xNRaC(═O)OR′a, —(CH2)xOC(═O)Ra, —(CH2)xC(═O)ORa, —(CH2)xORa, —(CH2)xNHC(═NH)NHRf, —(CH2)xC(═O)NORa, —(CH2)x(Ra)C═NRd, —Si(Re)3, —(CH2)xS(═O)2Ra, —(CH2)xS(═O)Ra, —(CH2)xSRa, —(CH2)xS(═O)2ORa, —(CH2)xOS(═O)2Ra, —(CH2)xNR″aS(═O)2NRaR′a, —(CH2)xS(═O)2NRaR′a, —(CH2)xNRaS(═O)2R′a, —(CH2)xC(═S)Ra, —(CH2)xOC(═S)NRaR′a, —(CH2)xNRaC(═S)OR′a, —(CH2)xC(═S)NRaR′a, —(CH2)xNRaC(═S)R′a and —(CH2)NR″aC(═O)NRaR′a or from an optionally substituted group consisting of C1-6alkyl, biaryl, carbocyclic aryl, heteroalicyclo and heteroaryl;
and
R2 and R3, R4 and R5 and R7 and Y may also combine to form a cycloalkyl, cycloalkenyl, cycloalkynyl, carbocyclic aryl, heteroalicyclo or heteroaryl ring;
and
x is an integer selected from 0, 1, or 2;
and
y is an integer selected from 1, 2 or 3;
and
Ra, R′a and R″a are independently selected from hydrogen or from an optionally substituted group consisting of C1-6alkyl, cycloalkyl, heteroalicyclo and aryl;
wherein optionally Ra and R′a, Ra and R′a and R′a and R″a, may combine to form a heteroalicyclic ring;
and
Rd is selected from hydrogen or from an optionally substituted group consisting of amino, C1-6alkyl, cycloalkyl, heteroalicyclo, carbocyclic aryl, heteroaryl, C1-4alkoxy, aryloxy, N-amido, N-thioamido and urea;
and
Re is selected from the group consisting of hydrogen and hydroxy or from an optionally substituted group consisting of C1-6alkyl, C1-4alkoxy, aryloxy, cycloalkyl, heteroalicyclo, carbocyclic aryl and heterocyclic aryl;
and
Rf is selected from the group consisting of hydrogen and cyano or from an optionally substituted group consisting of C1-6alkyl, cycloalkyl, heteroalicyclo, carbocyclic aryl and heterocyclic aryl;
and
Rg is selected from the group consisting of hydrogen and C1-6alkyl, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

20 more elements

A pharmaceutical composition comprising a compound of formula (I)

or a salt thereof or a pharmaceutically acceptable derivative thereof, wherein
R1 is H or methyl;
and
R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, cyano, isocyanato, isothiocyanato, hydroxy, halo, nitro, thiocyanato, thiol, —(CH2)xC(═O)Ra, —(CH2)xC(═NH)NRaR′a, —(CH2)xC(═O)NRaR′a, —(CH2)xNRaC(═O)R′a, —(CH2)xNRaR′a, —(CH2)xNRaOR′a, —(CH2)xONRaR′a, —(CH2)xOC(═O)NRaR′a, —(CH2)xNRaC(═O)OR′a, —(CH2)xOC(═O)Ra, —(CH2)xC(═O)ORa, —(CH2)xORa, —(CH2)xNHC(═NH)NHRf, —(CH2)xC(═O)NORa, —(CH2)x(Ra)C═NRd, —Si(Re)3, —(CH2)xS(═O)2Ra, —(CH2)xS(═O)Ra, —(CH2)xSRa, —(CH2)xS(═O)2ORa, —(CH2)xOS(═O)2Ra, —(CH2)xNR″aS(═O)2NRaR′a, —(CH2)xS(═O)2NRaR′a, —(CH2)xNRaS(═O)2R′a, —(CH2)xC(═S)Ra, —(CH2)xOC(═S)NRaR′a, —(CH2)xNRaC(═S)OR′a, —(CH2)xC(═S)NRaR′a, —(CH2)xNRaC(═S)R′a, —(CH2)xNR″aC(═O)NRaR′a and —[(CH2)xO—]yRg or from an optionally substituted group consisting of C1-6alkyl, biaryl, carbocyclic aryl, heteroalicyclo and heteroaryl;
and
R6, R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, thiol, halo, cyano, amino, methylamino, dimethylamino, nitro and CF3 or from an optionally substituted group selected from C1-4alkoxy, C1-4alkylthio, C1-6alkyl, wherein the substituents are selected from the group consisting of halo, hydroxy and oxo;
Y is selected from the group consisting of cyano, isocyanato, isothiocyanato, hydroxy, halo, nitro, thiocyanato, thiol, —(CH2)xC(═O)Ra, —(CH2)xC(═NH)NRaR′a, —(CH2)xC(═O)NRaR′a, —(CH2)xNRaC(═O)R′a, —(CH2)xNRaR′a, —(CH2)xNRaOR′a, —(CH2)xONRaR′a, —(CH2)xOC(═O)NRaR′a, —(CH2)xNRaC(═O)OR′a, —(CH2)xOC(═O)Ra, —(CH2)xC(═O)ORa, —(CH2)xORa, —(CH2)xNHC(═NH)NHRf, —(CH2)xC(═O)NORa, —(CH2)x(Ra)C═NRd, —Si(Re)3, —(CH2)xS(═O)2Ra, —(CH2)xS(═O)Ra, —(CH2)xSRa, —(CH2)xS(═O)2ORa, —(CH2)xOS(═O)2Ra, —(CH2)xNR″aS(═O)2NRaR′a, —(CH2)xS(═O)2NRaR′a, —(CH2)xNRaS(═O)2R′a, —(CH2)xC(═S)Ra, —(CH2)xOC(═S)NRaR′a, —(CH2)xNRaC(═S)OR′a, —(CH2)xC(═S)NRaR′a, —(CH2)xNRaC(═S)R′a and —(CH2)xNR″aC(═O)NRaR′a or from an optionally substituted group consisting of C1-6alkyl, biaryl, carbocyclic aryl, heteroalicyclo and heteroaryl;
and
R2 and R3, R4 and R5 and R7 and Y may also combine to form a cycloalkyl, cycloalkenyl, cycloalkynyl, carbocyclic aryl, heteroalicyclo or heteroaryl ring;
and
x is an integer selected from 0, 1, or 2;
and
y is an integer selected from 1, 2 or 3;
and
Ra, R′a and R″a are independently selected from hydrogen or from an optionally substituted group consisting of C1-6alkyl, cycloalkyl, heteroalicyclo and aryl;
wherein optionally Ra and R′a, Ra and R″a and R′a and R″a, may combine to form a heteroalicyclic ring;
and
Rd is selected from hydrogen or from an optionally substituted group consisting of amino, C1-6alkyl, cycloalkyl, heteroalicyclo, carbocyclic aryl, heteroaryl, C1-4alkoxy, aryloxy, N-amido, N-thioamido and urea;
and
Re is selected from the group consisting of hydrogen and hydroxy or from an optionally substituted group consisting of C1-6alkyl, C1-4alkoxy, aryloxy, cycloalkyl, heteroalicyclo, carbocyclic aryl and heterocyclic aryl;
and
Rf is selected from the group consisting of hydrogen and cyano or from an optionally substituted group consisting of C1-6alkyl, cycloalkyl, heteroalicyclo, carbocyclic aryl and heterocyclic aryl;
and
Rg is selected from the group consisting of hydrogen and C1-6alkyl;
at least one different cytostatic and/or cytotoxic active ingredient or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.

22 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…