N-substituted dithiocarbamates for the treatment of biological disorders
AssigneeAtheroGenics, Inc.
InventorsRussell M. Medford, Uday Saxena, Lee K. Hoong, Patricia K. Somers
Life of this patent
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Abstract
N-substituted dithiocarbamate esters, pharmaceutical compositions containing them, and methods of treating hyperproliferative disorders such as cancer by administering the N-substituted dithiocarbamate esters.
Claims59
A method of treating a tumor comprising administering an antiproliferative agent in combination with a effective amount of a N-substituted dithiocarbamate ester compound or a pharmaceutically acceptable salt thereof, wherein the N-substituted dithiocarbamate ester compound is defined by the following formula (I):
- or its pharmaceutically acceptable salt, wherein:
- a) X is oxolane;
- b) Y is C(O)OR,
- c) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties;
- and
- d) linker1 and linker2 are independently alkyl, alkenyl, or alkynyl.
A method of treating a tumor comprising administering an effective amount of a N-substituted dithiocarbamate ester compound or a pharmaceutically acceptable salt thereof, wherein the N-substituted dithiocarbamate ester is defined by the following structure (I):
- wherein:
- a) X is oxolane;
- b) Y is C(O)OR,
- c) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties;
- and
- d) linker1 and linker2 are independently alkyl, alkenyl, or alkynyl.
A method of treating a VCAM-1 mediated condition comprising administering an effective amount of a N-substituted dithiocarbamate ester compound or a pharmaceutically acceptable salt thereof, wherein the N-substituted dithiocarbamate ester is defined by the following structure (I):
- wherein:
- a) X is oxolane;
- b) Y is C(O)OR,
- c) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties;
- and
- d) linker1 and linker2 are independently alkyl, alkenyl, or alkynyl.
An N-substituted dithiocarbamate ester compound of the formula (II):
- or its pharmaceutically acceptable salt, wherein:
- a) X is oxolane;
- b) Y is C(O)OR,
- c) n and m are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- d) and R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties.
A compound of the structure:
- or its pharmaceutically acceptable salt, wherein:
- a) Y is C(O)OR;
- b) R is hydrogen, lower alkyl or substituted lower alkyl;
- c) n is 1-12;
- and
- d) m is 1-12.
The compound
- or its pharmaceutically acceptable salt.
A compound of the formula:
- or its pharmaceutically acceptable salt, wherein:
- a) R is H or independently substituted lower alkyl;
- and
- b) n and m are independently 1, 2, 3, 4, 5, 6, 7, 8 or 10.
A compound selected from:
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid alkyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid methyl ester;
- (Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)acetic acid methyl ester;
- 3-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-propionic acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester;
- 6-(Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)hexanoic acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 4-oxo-pentyl ester;
- and
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-cyano-propyl ester;
- 2-Amino-3-(tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)propionic acid;
- 2-Amino-4-(tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-carbamoyl-propyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-dimethylcarbamoyl-propyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid benzyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,4-dichloro-benzyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 4-chloro-phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,4-difluoro-phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrothiophen-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid thiophen-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrothiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid thiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,5-dichloro-thiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3,3-dimethyl-2-oxo-butyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrofuran-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid furan-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrofuran-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid furan-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid pyridin-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid pyridin-3-ylmethyl ester;
- 4-((S)-Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid methyl ester;
- 4-((R)-Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylsulfanyllthio-carbonylamino)butyric acid ethyl ester;
- 4-(Tetrahydrofuran-3-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- 4-(3S,4R-Dihydroxytetrahydrofuran-2S-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- 4-(3R,4R-Dihydroxytetrahydrofuran-2R-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- and
- 4-(3R,4R-Dihydroxy-5R-methyltetrahydrofuran-2S-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester;
- or its pharmaceutically acceptable salt, thereof.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate ester compound of the formula (II):
- or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, wherein:
- a) X is oxolane;
- b) Y is C(O)OR;
- c) n and m are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- and
- d) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate ester compound of the structure:
- or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, wherein:
- a) Y is C(O)OR,
- b) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties;
- and
- c) n and m are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate ester compound of the structure:
- or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, wherein:
- a) Y is C(O)OR,
- b) R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, which can be optionally substituted with non-heterocyclic moieties;
- c) n is 1-3;
- and
- d) m is 1-6.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate ester compound of the structure:
- or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate ester compound of the structure:
- or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, wherein:
- a) R is H or independently substituted lower alkyl;
- and
- b) n and m are independently 1, 2, 3, 4, 5, 6, 7, 8 or 10.
A pharmaceutical composition comprising an effective treatment amount of an N-substituted dithiocarbamate selected from:
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid alkyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid methyl ester;
- (Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)acetic acid methyl ester;
- 3-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-propionic acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester;
- 6-(Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)hexanoic acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 4-oxo-pentyl ester;
- and
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-cyano-propyl ester;
- 2-Amino-3-(tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)propionic acid;
- 2-Amino-4-(tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-carbamoyl-propyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3-dimethylcarbamoyl-propyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid benzyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,4-dichloro-benzyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 4-chloro-phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,4-difluoro-phenyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrothiophen-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid thiophen-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrothiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid thiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 2,5-dichloro-thiophen-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid 3,3-dimethyl-2-oxo-butyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrofuran-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid furan-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid tetrahydrofuran-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid furan-3-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid pyridin-2-ylmethyl ester;
- (Tetrahydrofuran-2-ylmethyl)dithiocarbamic acid pyridin-3-ylmethyl ester;
- 4-((S)-Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid methyl ester;
- 4-((R)-Tetrahydrofuran-2-ylmethylthiocarbamoyl-sulfanyl)butyric acid methyl ester;
- 4-(Tetrahydrofuran-2-ylmethylsulfanyllthio-carbonylamino)butyric acid ethyl ester;
- 4-(Tetrahydrofuran-3-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- 4-(3S,4R-Dihydroxytetrahydrofuran-2S-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- 4-(3R,4R-Dihydroxytetrahydrofuran-2R-ylmethylthiocarbamoylsulfanyl)butyric acid methyl ester;
- and
- 4-(3R,4R-Dihydroxy-5R-methyltetrahydrofuran-2S-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester;
- or its pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.