US 6,028,103 AGranted

Triaryl methane compounds and analogues thereof useful for the treatment or prevention of sickle cell disease or diseases characterized by abnormal cell proliferation

AssigneesChildren's Medical Center Corporation, Ion Pharmaceuticals, Inc.

InventorsCarlo Brugnara, Jose Halperin, Emile M. Bellot, Jr., Mark Froimowitz, Richard John Lombardy, John J. Clifford, Ying-Duo Gao, Reem M. Haidar, Eugene W. Kelleher, Falguni M. Kher, Adel M. Moussa, Yesh P. Sachdeva, Minghua Sun, Heather N. Taft

Life of this patent

Estimating the term…

patentgrep

Loading patent…

Abstract

The present invention provides a class of chemical compounds useful as efficacious drugs in the treatment of sickle cell disease and diseases characterized by unwanted or abnormal cell proliferation. The active compounds are substituted triaryl methane compounds or analogues thereof where one or more of the aryl groups is replaced with a heteroaryl, cycloalkyl or heterocycloalkyl group and/or the tertiary carbon atom is replaced with a different atom such as Si, Ge, N or P. The compounds inhibit mammalian cell proliferation, inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation.

Claims42

Dependent claims

A compound selected from the group consisting of:

a compound having the formula:
##STR101## or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
R.sub.1 is --H, --OR, --SR, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, --C(S)NR.sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, --CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2 ;
R.sub.2 is --F, --Cl, --Br or --I;
R.sub.3 is --R, --OR or --SR;
R.sub.4 is --H or --NR.sub.2 ;
R.sub.5 is --H, --F, --Cl, --Br or --I;
and
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy,
with the provisos that (i) when n is 0 and R.sub.1 is --H or --OH, R.sub.3 is other than --H;
and (ii) when n is 0 and R.sub.1 is --H, R.sub.3 is other than --OH;
a compound having the formula:
##STR102## or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
R.sub.1 is --NR.sub.2, --C(O)R, --C(S)R, --C(O)NR'.sub.2 or --C(S)NR'.sub.2 ;
R.sub.2 is --F, --Cl, --Br or --I;
R.sub.3 is --F, --Cl, --Br or --I;
R.sub.4 is --F, --Cl, --Br or --I;
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
and
a compound having the formula:
##STR103## or a pharmaceutically acceptable salt or hydrate thereof wherein:
n is 0, 1, 2, 3, or 4;
Ar.sub.1 is phenyl or cyclohexyl;
R.sub.1 is --NR.sub.2, --CH[C(O)OR].sub.2, --CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2, --C(O)NR.sub.2 or --C(S)NR.sub.2 ;
and
each R is independently selected from the group consisting of --H, (C.sub.1 C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy,
with the proviso that when R.sub.1 is --NH.sub.2 or --C(O)NH.sub.2, is 1, 2 or 3.

28 more elements

A pharmaceutical composition comprising a compound in admixture a pharmaceutically acceptable excipient, carrier or diluent, said compound having the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent, (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkenyl, or (C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge:
R.sub.1 is absent, -halo, --R, --OR, --SR, --NR.sub.2, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O) SR, --C(S)SR, --C(O)NR.sub.2, --C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), C(O)NR(SR), C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.8) cycloalkyl or (C.sub.5 -C.sub.8) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, --R, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR' and --C(S)SR';
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN--C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR', --C(S)SR', aryl, .gamma.-butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

A method of inhibiting calcium-activated potassium transport of a cell, said method comprising the step of contacting a cell in situ with an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent, (C.sub.1 -C.sub.3), C.sub.1 -C.sub.3) alkenyl, or C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge:
R.sub.1 is absent, --halo, --R, --OR, --SR, --NR.sub.1, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), --C(O)NR(SR), --C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, ----CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, --CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(O)SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroarly other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.5) cycloakyl or (C.sub.5 -C.sub.5) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H. (C.sub.1 -C.sub.6) alkyl, substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of --halo, trihalomethyl, --R, --R --OR, --SR, --NR.sub.2, --NO.sub.2, --CN, ----C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, and- --C(O)SR;
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of --halo, --R --OR, --SR, --NR.sub.2, --NO.sub.2, --CN, ----C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, aryl, .gamma.-butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

A method for reducing sickle erythrocyte dehydration or delaying the occurrence of erythrocyte sickling or deformation, said method comprising the step of contacting a sickle erythrocyte in situ with an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent, (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkenyl, or (C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge;
R.sub.1 is absent, -halo, --R, --OR, --SR, --NR.sub.2, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, --C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), C(O)NR(SR), C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2 --CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C (S) SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.8) cycloalkyl or (C.sub.5 -C.sub.8) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl. substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 1.varies.C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, --R, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR'and --C(S)SR';
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of --halo, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR', --C(S)SR', aryl, .gamma.-butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

A method of treating or preventing sickle cell disease, said method comprising the step of administering to a subject suffering from sickle cell disease a therapeutically effective amount of a compound having the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkenyl or (C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge;
R.sub.1 is absent, -halo, --R, --OR, --SR, --NR.sub.2, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, --C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), --C(O)NR(SR), C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, --CH[C(S)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.8) cycloalkyl or (C.sub.5 -C.sub.8) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H, (C.sub.1 ---C.sub.6) alkyl, substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, --R, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR' and --C(S)SR';
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR',--C(S)OR', --C(O)SR', --C(S)SR', aryl, .gamma.-butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

A method of inhibiting mammalian cell proliferation, said method comprising the step of contacting a mammalian cell in situ with an effective amount of a compound having the formula:

or pharmaceutically acceptable salts of hydrates thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent, (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkenyl or (C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge;
R.sub.1 is absent, -halo, --R, --OR, --SR, --NR.sub.2, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, --C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), --C(O)NR(SR), C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.8) cycloalkyl or (C.sub.5 -C.sub.8) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, --R, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR' and --C(S)SR';
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR', --C(S)SR', aryl, .gamma.-butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

A method of treating a disorder characterized by abnormal cell proliferation, said method comprising the step of administering to a subject a therapeutically effective amount of a composition having the formula:

or pharmaceutically acceptable salts of hydrates thereof, wherein:
n is 0, 1, 2, 3 or 4;
X is absent (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkenyl or (C.sub.1 -C.sub.3) alkynyl;
Y is C, N, P, Si or Ge;
R.sub.1 is absent, -halo, --R, --OR, --SR, --NR.sub.2, --ONR.sub.2, --NO.sub.2, --CN, --C(O)R, --C(S)R, --C(O)OR, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NR.sub.2, C(S)NR.sub.2, --C(O)NR(OR), --C(S)NR(OR), --C(O)NR(SR), C(S)NR(SR), --CH(CN).sub.2, --CH[C(O)R].sub.2, --CH[C(S)R].sub.2, --CH[C(O)OR].sub.2, --CH[C(O)SR].sub.2, --CH[C(O)SR].sub.2, --CH[C(S)SR].sub.2 or aryl;
Ar.sub.1 is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C.sub.5 -C.sub.8) cycloalkyl or (C.sub.5 -C.sub.8) heterocycloalkyl;
Ar.sub.2 is aryl or substituted aryl;
Ar.sub.3 is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;
each R is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, substituted (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, substituted (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, substituted (C.sub.1 -C.sub.6) alkynyl and (C.sub.1 -C.sub.6) alkoxy;
the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, --R, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR' and --C(S)SR';
the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, --R', --OR', --SR', NR'.sub.2, --NO.sub.2, --CN, --C(O)R', --C(S)R', --C(O)OR', --C(S)OR', --C(O)SR', --C(S)SR', aryl, .gamma.butyrolactonyl, pyrrolidinyl and succinic anhydridyl;
and
each R' is independently selected from the group consisting of --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl and (C.sub.1 -C.sub.6) alkynyl.

10 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/822,550Filed 19 Mar 1997 · continuation in part
Priority: 20 Mar 1996
Granted: 22 Feb 2000
Term ends: Not estimatedThe source records don’t support an estimate.

Classification48 codes

C07F 9/5352
Organo-phosphoranes: phosphoranes containing the structure P=C-
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 15/16
Polycyclic non-condensed hydrocarbons: containing at least two phenyl groups linked by one single acyclic carbon atom