US 7,115,619 B2Granted

N8, N13 -disubstituted quino[4,3,2-kl]acridinium salts as therapeutic agents

AssigneeCancer Research Technology Limited

InventorsMalcolm F. G. Stevens, Lloyd R Kelland, Robert A Heald

Life of this patent

Estimating the term…

Loading patent…

Abstract

The present invention pertains to certain N8,N13-disubstituted quino[4,3,2-kl]acridinium salts of formula (Q−) which inhibit telomerase wherein: p is an integer from 0 to 4; q is an integer from 0 to 3; r is an integer from 0 to 4; each RA is —H or a ring substituent; each RB is —H or a ring substituent; each RC is —H or a ring substituent; RN8 is a nitrogen substituent; RN13 is a nitrogen substituent; and, Q is an anion. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit telomerase, to regulate cell proliferation, and in the treatment of proliferative conditions, such as cancer.

Claims58

Dependent claims

A compound selected from compounds of the following formula, and pharmaceutically acceptable salts and solvates thereof:

wherein:
each one of RA1, RA2, RA3, and RA4 is independently —H or a ring substituent;
each one of RB5, RB6, and RB7 is independently —H or a ring substituent;
each one of RC9, RC10, RC11, and RC12 is independently —H or a ring substituent;
RN8 is independently a nitrogen substituent;
RN13 is independently a nitrogen substituent;
and,
Q is independently an anion;
wherein:
said ring substituents are independently selected from:
halo;
hydroxy;
ether;
formyl;
acyl;
carboxy;
ester;
acyloxy;
oxycarbonyloxy;
amido;
acylamido;
tetrazolyl;
amino;
nitro;
cyano;
azido;
sulfhydryl;
thioether;
sulfonamido;
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7carboxyalkyl;
C1-7acyloxyalkyl;
C1-7oxycarbonylalkyl;
C1-7oxycarbonyloxyalkyl;
C1-7aminoalkyl;
C1-7amidoalkyl;
C1-7acylamidoalkyl;
C1-7cyanoalkyl;
and
C5-20aryl-C1-7alkyl;
and
said nitrogen substituents are independently selected from:
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7alkoxyalkyl;
C1-7carboxyalkyl;
C1-7aminoalkyl;
C5-20aryl-C1-7alkyl;
C3-20heterocyclyl;
C5-20aryl;
C1-7alkyl-C5-20aryl;
and
C5-20haloaryl;
and wherein:
each alkyl group is aliphatic, and is saturated or partially unsaturated;
and
each aryl group is a carboaryl group or a heteroaryl group;
with the proviso that the compound is not:
8,13-diethyl-6-methyl-8H-quino[4,3,2-kl]acridinium iodide;
or,
8,13-diethyl-3,6,11-trimethyl-8H-quino[4,3,2-kl]acridinium iodide.

61 more elements

A method of inhibiting telomerase in vitro or in vivo, comprising contacting a cell with an effective amount of compound selected from compounds of the following formula, and pharmaceutically acceptable salts and solvates thereof:

wherein:
each one of RA1, RA2, RA3, and RA4 is independently —H or a ring substituent;
each one of RB5, RB6, and RB7 is independently —H or a ring substituent;
each one of RC9, RC10, RC11, and RC12 is independently —H or a ring substituent;
RN8 is independently a nitrogen substituent;
RN13 is independently a nitrogen substituent;
and,
Q is independently an anion;
wherein:
said ring substituents are independently selected from:
halo;
hydroxy;
ether;
formyl;
acyl;
carboxy;
ester;
acyloxy;
oxycarbonyloxy;
amido;
acylamido;
tetrazolyl;
amino;
nitro;
cyano;
azido;
sulfhydryl;
thioether;
sulfonamido;
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7carboxyalkyl;
C1-7acyloxyalkyl;
C1-7oxycarbonylalkyl;
C1-7oxycarbonyloxyalkyl;
C1-7aminoalkyl;
C1-7amidoalkyl;
C1-7acylamidoalkyl;
C1-7cyanoalkyl;
and
C5-20aryl-C1-7alkyl;
and,
said nitrogen substituents are independently selected from:
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7alkoxyalkyl;
C1-7carboxyalkyl;
C1-7aminoalkyl;
C5-20aryl-C1-7alkyl;
C3-20heterocyclyl;
C5-20aryl;
C1-7alkyl-C5-20aryl;
and
C5-20haloaryl;
and wherein:
each alkyl group is aliphatic, and is saturated or partially unsaturated;
and
each aryl group is a carboaryl group or a heteroaryl group.

57 more elements

A method of treating cancer in a subject comprising administering to said subject a therapeutically-effective amount of a compound selected from compounds of the following formula and pharmaceutically acceptable salts and solvates thereof:

wherein:
each one of RA1, RA2, RA3, and RA4 is independently —H or a ring substituent;
each one of RB5, RB6, and RB7 is independently —H or a ring substituent;
each one of RC9, RC10, RC11, and RC12 is independently —H or a ring substituent;
RN8 is independently a nitrogen substituent;
RN13 is independently a nitrogen substituent;
and,
Q is independently an anion;
and,
wherein:
said ring substituents are independently selected from:
halo;
hydroxy;
ether;
formyl;
acyl;
carboxy;
ester;
acyloxy;
oxycarbonyloxy;
amido;
acylamido;
tetrazolyl;
amino;
nitro;
cyano;
azido;
sulfhydryl;
thioether;
sulfonamido;
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7carboxyalkyl;
C1-7acyloxyalkyl;
C1-7oxycarbonylalkyl;
C1-7oxycarbonyloxyalkyl;
C1-7aminoalkyl;
C1-7amidoalkyl;
C1-7acylamidoalkyl;
C1-7cyanoalkyl;
and
C5-20aryl-C1-7alkyl;
and,
said nitrogen substituents are independently selected from:
unsubstituted C1-7alkyl;
C1-7haloalkyl;
C1-7hydroxyalkyl;
C1-7alkoxyalkyl;
C1-7carboxyalkyl;
C1-7aminoalkyl;
C5-20aryl-C1-7alkyl;
C3-20heterocyclyl;
C5-20aryl;
C1-7alkyl-C5-20aryl;
and
C5-20haloaryl;
and wherein:
each alkyl group is aliphatic, and is saturated or partially unsaturated;
and
each aryl group is a carboaryl group or a heteroaryl group.

58 more elements

Dependencies are inferred from the claim text.