US 5,965,619 AGranted

Method for treating patients having precancerous lesions with substituted indene derivatives

AssigneeCell Pathways, Inc.

InventorsRifat Pamukcu, Gary A. Piazza, Paul Gross, Gerhard Sperl, Klaus Brendel

Life of this patent

Estimating the term…

Abstract

Substituted indene derivatives are useful for treating patients having precancerous lesions and for inhibiting the growth of neoplastic cells.

Claims29

Dependent claims

A method for treating a patient having precancerous lesions comprising administering a pharmacologically effective amount of a compound of formula I below:

##STR13## wherein R is H, loweralkyl, trihaloalkyl or cycloalkyl;
R.sup.1 is --CHR.sup.4 COOR wherein R.sup.4 is hydrogen, hydroxy, loweralkyl, amino, alkylamino or benzylamino;
--CH.dbd.CHR;
--(CH.sub.2).sub.m CONRR.sup.4 ;
--CHOH--CHOH--R;
--(CH.sub.2).sub.m R.sup.5 wherein R.sup.5 represents R, OR, SR, S-phenyl, S-phenyl-(R.sup.8)m, SOR, SO.sub.2 R, CN, --O--COR, --NHCOR, --NRCOOR, --NRCONRR.sup.4, --O--CONRR.sup.4, --NRR.sup.4, halo, or Y, wherein Y is a heterocycle selected from the group consisting of pyrimidinyl, pyridyl, imidazolyl, tetrazolyl, isothiazolyl and morpholinyl, and m is 1 to 4;
R.sub.2 is independently --NHSO.sub.2 R.sup.6 ;
hydrogen;
lower alkyl;
--NHCOR.sup.6 ;
--NRR.sup.4 ;
--OR.sup.7 wherein R.sup.7 is H, R, lower alkenyl, lower alkynyl;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.2 are joined together to form a fused ring, and where m represents 1, 2 or 3;
halo;
trihaloalkyl;
--SO.sub.2 NRR.sup.4 ;
--SO.sub.2 NHY wherein Y is a heterocycle as defined;
--SO.sub.2 NHX wherein X is CONH.sub.2, --CSNH.sub.2 or --C(.dbd.NH)NH.sub.2 ;
--SO.sub.2 CF.sub.3 ;
--CN;
--SO.sub.2 NR.sup.4 COR.sup.6 ;
or --COOR.sup.6 ;
R.sup.3 is independently hydrogen;
hydroxy;
lower alkyl;
lower alkoxy;
--OR.sup.7 ;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.3 are joined together to form a fused ring and wherein m is 1, 2 or 3;
halo;
--O--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 OR.sup.6 ;
--SR.sup.6 ;
--S--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 --S--R.sup.6 ;
--SOR.sup.6 ;
--SO.sub.2 R.sup.6 ;
--OCOR.sup.6 ;
--NRR.sup.4 ;
--NH.sub.2 ;
--NR.sup.4 COOR.sup.6 ;
--NHCOR.sup.6 ;
or --OCOOR.sup.6 ;
R.sup.6 is selected from the group consisting of R, --CF.sub.3, unsubstituted phenyl or phenyl substituted with R.sup.8 ;
R.sup.8 is independently hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, lower di-alkyl amino, halo, cyano or halo substituted lower alkyl;
and
n is 1, 2 or 3;
p is 1, 2 or 3.

44 more elements

A method for inhibiting the growth of neoplastic cells comprising exposing the cells to an effective amount of a compound of formula I below:

##STR14## wherein R is H, loweralkyl, trihaloalkyl or cycloalkyl;
R.sup.1 is --CHR.sup.4 COOR wherein R.sup.4 is hydrogen, hydroxy, loweralkyl, amino, alkylamino or benzylamino;
--CH.dbd.CHR;
--(CH.sub.2).sub.m CONRR.sup.4 ;
--CHOH--CHOH--R;
--(CH.sub.2).sub.m R.sup.5 wherein R.sup.5 represents R, OR, SR, S-phenyl, S-phenyl-(R.sup.8)m, SOR, SO.sub.2 R, CN, --O--COR, --NHCOR, --NRCOOR, --NRCONRR.sup.4, --O--CONRR.sup.4, --NRR.sup.4, halo, or Y, wherein Y is a heterocycle selected from the group consisting of pyrimidinyl, pyridyl, imidazolyl, tetrazolyl, isothiazolyl and morpholinyl, and m is 1 to 4;
R.sub.2 is independently --NHSO.sub.2 R.sup.6 ;
hydrogen;
lower alkyl;
--NHCOR.sup.6 ;
--NRR.sup.4 ;
--OR.sup.7 wherein R.sup.7 is H, R, lower alkenyl, lower alkynyl;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.2 are joined together to form a fused ring and where m represents 1, 2 or 3;
halo;
trihaloalkyl;
--SO.sub.2 NRR.sup.4 ;
--SO.sub.2 NHY wherein Y is a heterocycle as defined;
--SO.sub.2 NHX wherein X is --CONH.sub.2, --CSNH.sub.2 or --C(.dbd.NH)NH.sub.2 ;
--SO.sub.2 CF.sub.3 ;
--CN;
--SO.sub.2 NR.sup.4 COR.sup.6 ;
or --COOR.sup.6 ;
R.sup.3 is independently hydrogen;
hydroxy;
lower alkyl;
lower alkoxy;
--OR.sup.7 ;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.3 are joined together to form a fused ring and wherein m is 1, 2 or 3;
halo;
--O--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 OR.sup.6 ;
--SR.sup.6 ;
--S--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 --S--R.sup.6 ;
--SOR.sup.6 ;
--SO.sub.2 R.sup.6 ;
--OCOR.sup.6 ;
--NRR.sup.4 ;
--NH.sub.2 ;
--NR.sup.4 COOR.sup.6 ;
--NHCOR.sup.6 ;
or --OCOOR.sup.6 ;
R.sup.6 is selected from the group consisting of R, --CF.sub.3, unsubstituted phenyl or phenyl substituted with R.sup.8 ;
R.sup.8 is independently hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, lower di-alkyl amino, halo, cyano or halo substituted lower alkyl;
and n is 1, 2 or 3;
p is 1, 2 or 3.

43 more elements

A method for regulating apoptosis in human cells comprising exposing said cells to an effective amount of a compound of the formula:

##STR15## wherein R is H, loweralkyl, trihaloalkyl or cycloalkyl;
R.sup.1 is --CHR.sup.4 COOR wherein R.sup.4 is hydrogen, hydroxy, loweralkyl, amino, alkylamino or benzylamino;
--CH.dbd.CHR;
--(CH.sub.2).sub.m CONRR.sup.4 ;
--CHOH--CHOH--R;
--(CH.sub.2).sub.m R.sup.5 wherein R.sup.5 represents R, OR, SR, S-phenyl, S-phenyl-(R.sup.8)m, SOR, SO.sub.2 R, CN, --O--COR, --NHCOR, --NRCOOR, --NRCONRR.sup.4, --O--CONRR.sup.4, --NRR.sup.4, halo, or Y, wherein Y is a heterocycle selected from the group consisting of pyrimidinyl, pyridyl, imidazolyl, tetrazolyl, isothiazolyl and morpholinyl, and m is 1 to 4;
R.sub.2 is independently --NHSO.sub.2 R.sup.6 ;
hydrogen;
lower alkyl;
--NHCOR.sup.6 ;
--NRR.sup.4 ;
--OR.sup.7 wherein R.sup.7 is H, R, lower alkenyl, lower alkynyl;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.2 are joined together to form a fused ring and where m represents 1, 2 or 3;
halo;
trihaloalkyl;
--SO.sub.2 NRR.sup.4 ;
--SO.sub.2 NHY wherein Y is a heterocycle as defined;
--SO.sub.2 NHX wherein X is --CONH.sub.2, --CSNH.sub.2 or --C(.dbd.NH)NH.sub.2 ;
--SO.sub.2 CF.sub.3 ;
--CN;
--SO.sub.2 NR.sup.4 COR.sup.6 ;
or --COOR.sup.6 ;
R.sup.3 is independently hydrogen;
hydroxy;
lower alkyl;
lower alkoxy;
--OR.sup.7 ;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.3 are joined together to form a fused ring and wherein m is 1, 2 or 3;
halo;
--O--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 OR.sup.6 ;
--SR.sup.6 ;
--S--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 --S--R.sup.6 ;
--SOR.sup.6 ;
--SO.sub.2 R.sup.6 ;
--OCOR.sup.6 ;
--NRR.sup.4 ;
--NH.sub.2 ;
--NR.sup.4 COOR.sup.6 ;
--NHCOR.sup.6 ;
or --OCOOR.sup.6 ;
R.sup.6 is selected from the group consisting of R, --CF.sub.3, unsubstituted phenyl or phenyl substituted with R.sup.8 ;
R.sup.8 is independently hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, lower di-alkyl amino, halo, cyano or halo substituted lower alkyl;
and n is 1, 2 or 3;
p is 1, 2 or 3.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/996,944Filed 23 Dec 1997 · continuation
Priority: 13 Jun 1996
Granted: 12 Oct 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

A61K 31/195
Carboxylic acids, e.g. valproic acid: having an amino group
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides
A61K 31/192
Carboxylic acids, e.g. valproic acid: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
A61K 31/216
Of carboxylic acids: of acids having aromatic rings, e.g. benactizyne, clofibrate

Family

Serial662,458Parent of this continuation · filed 13 Jun 1996
US 5,965,619 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Substituted indene derivatives are useful for treating patients having precancerous lesions and for inhibiting the growth of neoplastic cells.

A method for treating a patient having precancerous lesions comprising administering a pharmacologically effective amount of a compound of formula I below:

##STR13## wherein R is H, loweralkyl, trihaloalkyl or cycloalkyl;
R.sup.1 is --CHR.sup.4 COOR wherein R.sup.4 is hydrogen, hydroxy, loweralkyl, amino, alkylamino or benzylamino;
--CH.dbd.CHR;
--(CH.sub.2).sub.m CONRR.sup.4 ;
--CHOH--CHOH--R;
--(CH.sub.2).sub.m R.sup.5 wherein R.sup.5 represents R, OR, SR, S-phenyl, S-phenyl-(R.sup.8)m, SOR, SO.sub.2 R, CN, --O--COR, --NHCOR, --NRCOOR, --NRCONRR.sup.4, --O--CONRR.sup.4, --NRR.sup.4, halo, or Y, wherein Y is a heterocycle selected from the group consisting of pyrimidinyl, pyridyl, imidazolyl, tetrazolyl, isothiazolyl and morpholinyl, and m is 1 to 4;
R.sub.2 is independently --NHSO.sub.2 R.sup.6 ;
hydrogen;
lower alkyl;
--NHCOR.sup.6 ;
--NRR.sup.4 ;
--OR.sup.7 wherein R.sup.7 is H, R, lower alkenyl, lower alkynyl;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.2 are joined together to form a fused ring, and where m represents 1, 2 or 3;
halo;
trihaloalkyl;
--SO.sub.2 NRR.sup.4 ;
--SO.sub.2 NHY wherein Y is a heterocycle as defined;
--SO.sub.2 NHX wherein X is CONH.sub.2, --CSNH.sub.2 or --C(.dbd.NH)NH.sub.2 ;
--SO.sub.2 CF.sub.3 ;
--CN;
--SO.sub.2 NR.sup.4 COR.sup.6 ;
or --COOR.sup.6 ;
R.sup.3 is independently hydrogen;
hydroxy;
lower alkyl;
lower alkoxy;
--OR.sup.7 ;
--O--(CH.sub.2).sub.m --O-- when two adjacent R.sup.3 are joined together to form a fused ring and wherein m is 1, 2 or 3;
halo;
--O--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 OR.sup.6 ;
--SR.sup.6 ;
--S--CH.sub.2 -phenyl or phenyl substituted with R.sup.8 ;
--CH.sub.2 --S--R.sup.6 ;
--SOR.sup.6 ;
--SO.sub.2 R.sup.6 ;
--OCOR.sup.6 ;
--NRR.sup.4 ;
--NH.sub.2 ;
--NR.sup.4 COOR.sup.6 ;
--NHCOR.sup.6 ;
or --OCOOR.sup.6 ;
R.sup.6 is selected from the group consisting of R, --CF.sub.3, unsubstituted phenyl or phenyl substituted with R.sup.8 ;
R.sup.8 is independently hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, lower di-alkyl amino, halo, cyano or halo substituted lower alkyl;
and
n is 1, 2 or 3;
p is 1, 2 or 3.

44 more elements

Facts

Application

08/996,944Filed 23 Dec 1997 · continuation

Priority

13 Jun 1996

Granted

12 Oct 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

A61K 31/195
Carboxylic acids, e.g. valproic acid: having an amino group
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides
A61K 31/192
Carboxylic acids, e.g. valproic acid: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
A61K 31/216
Of carboxylic acids: of acids having aromatic rings, e.g. benactizyne, clofibrate