US 6,369,098 B1Granted

Dithiolane derivatives

AssigneeBethesda Pharmaceuticals, Inc.

InventorsHarrihar A. Pershadsingh, Mitchell A. Avery

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Abstract

The present invention describes methods for synthesizing novel dithiolane derivatives, ligands with high affinity for the nuclear hormone receptors, peroxisome proliferator-activated receptor-γ (PPARγ) and/or PPARα. Methods for using these compounds in the treatment of endocrine, skin, cardiovascular, immunological, neurological, neuropsychiatric, neoplastic and chronic viral diseases of various organs, including the eye are described. Methods of treating proliferative and inflammatory diseases, degenerative diseases, and age-related dysregulations, caused by an hereditary (genetic) condition or an environmental insult are also provided. In addition, methods are provided for treating conditions and diseases comprising the step of administering to a human or an animal in need thereof a therapeutic amount of pharmacological compositions comprising a pharmaceutically acceptable carrier, a PPARα agonist, and a second agent selected from the following: a PPARγ ligand, or an RXR ligand (rexinoid), or a PPARγ/RXR ligand, effective to reverse, slow, stop, or prevent the pathological inflammatory or degenerative process.

Claims42

Dependent claims

A compound having the formula

wherein:
R is a member selected from the group consisting of R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl), R or S or racemic S,S′-diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,S′-diacyl-[2-(1,3-dithiopropanyl)];
and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl;
R1 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;
R11 is a member selected from the group consisting of R, S or racemic—CH2(Z)CHCO2R12, —CH2CO2R12, —CO2R12, wherein R12 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;
A is oxygen or, together with the carbon to which it is bound is a methylene group;
B is a member selected from the group consisting of N, O and S, provided that when B is 0 or S then R1 is absent;
X is a member selected from the group consisting of hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3 wherein R3 and R10 are each independently a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Y is a member selected from the group consisting of oxygen, S, SO, SO2, SO2NH, SO2NR12, SO3, NH, NR12, wherein R12 is a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Z is a member selected from the group consisting of R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O—phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl, haloalkyl, NHR13, NR13R14, wherein R13 and R14 are each independently a member selected from the group consisting of —(CO)alkyl, optionally substituted —(CO)aryl, optionally substituted —(CO)arylalkyl, optionally substituted —(CO)heteroaryl and —CHO;
m is an integer from 1 to 8 inclusive;
r is 0 or 1;
n is 0, 2, 3, 4;
and
p is 0 or 1, with the proviso that when n is 0 then Y is not O, S, N, resulting in N-O, N-S, and N-N bonds.

12 more elements

A compound having the formula

wherein:
R is a member selected from the group consisting of R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl), R or S or racemic S,S′-diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,S′-diacyl-[2-(1,3-dithiopropanyl)];
and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl;
R1 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;
R2 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl;
R4 is a member selected from the group consisting hydrogen and alkyl;
A is a member selected from the group consisting of oxygen or, together with the carbon to which it is bound is a methylene group;
X is a member selected from the group consisting of hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3 wherein R3 and R10 are each independently a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Y is a member selected from the group consisting of oxygen, S, SO, SO2, SO2NH, SO2NR3, SO3, NH, NR3, wherein R3 is a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
t is an integer from 1 to 5 inclusive;
v is an integer from 2 to 8 inclusive;
y is an integer from 2 to 4 inclusive;
and
p is 0 or 1.

11 more elements

A pharmaceutical composition comprising a compound having the formula:

wherein:
R is a member selected from the group consisting of R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl), R or S or racemic S,S′-diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,S′-diacyl-[2-(1,3-dithiopropanyl)];
and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl;
R1 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;
R11 is a member selected from the group consisting of R, S or racemic—CH2(Z)CHCO2R12, —CH2CO2R12, —CO2 R12, wherein R12 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl,
A is oxygen or, together with the carbon to which it is bound is a methylene group;
B is a member selected from the group consisting of N, O and S, provided that when B is O or S then R1 is absent;
X is a member selected from the group consisting of hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3 wherein R3 and R10 are each independently a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Y is a member selected from the group consisting of oxygen, S, SO, SO2, SO2NH, SO2NR12, SO3, NH, NR12, wherein R is a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Z is a member selected from the group consisting of R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O-phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl, haloalkyl, NHR13, NR13R14, wherein R13 and R14 are each independently a member selected from the group consisting of —(CO)alkyl, optionally substituted —(CO)aryl, optionally substituted —(CO)arylalkyl, optionally substituted —(CO)heteroaryl and —CHO;
m is an integer from 1 to 8 inclusive;
r is 0 or 1;
n is 0, 2, 3, 4;
p is 0 or 1, with the proviso that when n is 0 then Y is not O, S, N, resulting in N—O, N—S, and N—N bonds;
and
a pharmaceutically acceptable carrier therefor.

13 more elements

A method of treating a PPARγ or PPARα mediated disease or oxidative stress, said method comprising administering to a subject a therapeutically effective amount of a compound of the formula

wherein:
R is a member selected from the group consisting of R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl), R or S or racemic S,S′-diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,S′-diacyl-[2-(1,3-dithiopropanyl)];
and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl;
R1 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;
R11 is a member selected from the group consisting of R, S or racemic—CH2(Z)CHCO2R12, —CH2CO2R12, —CO2R12, wherein R12 is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl,
A is oxygen or, together with the carbon to which it is bound is a methylene group;
B is a member selected from the group consisting of N, O and S, provided that when B is O or S then R1 is absent;
X is a member selected from the group consisting of hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3 wherein R3 and R10 are each independently a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Y is a member selected from the group consisting of oxygen, S, SO, SO2, SO2NH, SO2NR12, SO3, NH, NR12, wherein R12 is a member selected form the group consisting of hydrogen, alkyl, arylalkyl and aryl;
Z is a member selected from the group consisting of R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O-phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl, haloalkyl, NHR13, NR13R14, wherein R13 and R14 are each independently a member selected from the group consisting of —(CO)alkyl, optionally substituted —(CO)aryl, optionally substituted —(CO)arylalkyl, optionally substituted —(CO)heteroaryl and —CHO;
m is an integer from 1 to 8 inclusive;
r is 0 or 1;
n is 0, 2, 3, 4;
and
p is 0 or 1, with the proviso that when n is 0 then Y is not O, S, N, resulting in N—O, N—S, and N—N bonds or a pharmaceutical acceptable salt or solvate thereof, thereby treating said PPARγ or PPARα mediated disease or oxidative stress.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/684,738Filed 4 Oct 2000 · us provisional application
Priority: 5 Oct 1999
Granted: 9 Apr 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 339/04
Five-membered rings: having the hetero atoms in positions 1 and 2, e.g. lipoic acid
A61K 31/195
Carboxylic acids, e.g. valproic acid: having an amino group
A61K 31/198
The amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine,…:…
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol