Hydroxyeicosatrienoic acid compounds and their use as therapeutic agents
AssigneeThe Regents of the University of Michigan
InventorsMichael Holinstat, Theodore R. Holman, Andrew White
Life of this patent
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Abstract
12(S)-hydroxyeicosatrienoic acid (12(S)-HETrE) compounds and compositions comprising the same are disclosed. Methods of using the compounds in the prevention and treatment of thrombosis and thrombotic disorders are also disclosed.
Claims45
A compound of Formula (0), or a pharmaceutically acceptable salt thereof:
- wherein:
- A is —COOR1, —OSO3R1, —OPO3(R1)2, or -G-HET;
- each R1 independently is H or C1-6alkyl;
- R2 is H or OH;
- each is a single or double bond, provided that (i) when at bond 2 is a single bond, then at bond 1 is a trans double bond and R2 is OH, and (ii) when at bond 1 is a single bond, then at bond 2 is a cis double bond and R2 is H;
- HET is an unsubstituted or substituted 5 to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, or O;
- G is O, S, NH, or absent;
- Cx is an alkylene group having x carbon atoms;
- Cy is an alkyl group having y carbon atoms;
- x is 3, 4, 5, 6, or 7;
- y is 4, 5, 6, 7;
- and each carbon atom of the compound of Formula (I) independently is unsubstituted or substituted with one or more deuterium or fluorine atoms;
- with the proviso that when x is 6, y is 5, and each carbon atom of Formula (I) is unsubstituted, then A is not —COOH.
The compound of any one of claim 113, wherein at least one carbon atom is substituted with fluorine.
A method of treating a thrombotic disorder in a subject in need thereof comprising administering a compound selected from 12(S)-hydroxyeicosatrienoic acid (12(S)-HETrE), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing:
- wherein:
- A is —COOR1, —OSO3R1, —OPO3(R1)2, or -G-HET;
- each R1 independently is H or C1-6alkyl;
- HET is an unsubstituted or substituted 5 to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, or O;
- G is O, S, NH, or absent;
- Cx is an alkylene group having x carbon atoms;
- Cy is an alkyl group having y carbon atoms;
- x is 3, 4, 5, 6, or 7;
- y is 4, 5, 6, 7;
- and each carbon atom of the compound of Formula (I) independently is unsubstituted or substituted with one or more deuterium or fluorine atoms;
- with the proviso that when x is 6, y is 5, and each carbon atom of Formula (I) is unsubstituted, then A is not —COOH;
- to the subject in an amount effective to inhibit thrombus formation while maintaining hemostasis.
A method of preventing thrombosis in a subject in need thereof comprising administering a compound selected from 12(S)-hydroxyeicosatrienoic acid (12(S)-HETrE), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt of any of the foregoing:
- wherein:
- A is —COOR1, —OSO3R1, —OPO3(R1)2, or -G-HET;
- each R1 independently is H or C1-6alkyl;
- HET is an unsubstituted or substituted 5 to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, or O;
- G is O, S, NH, or absent;
- Cx is an alkylene group having x carbon atoms;
- Cy is an alkyl group having y carbon atoms;
- x is 3, 4, 5, 6, or 7;
- y is 4, 5, 6, 7;
- and each carbon atom of the compound of Formula (I) independently is unsubstituted or substituted with one or more deuterium or fluorine atoms;
- with the proviso that when x is 6, y is 5, and each carbon atom of Formula (I) is unsubstituted, then A is not —COOH;
- to the subject in an amount effective to inhibit thrombus formation while maintaining hemostasis.
A method of treating thrombocytopenia in a subject in need thereof comprising administering a compound selected from 12(S)-hydroxyeicosatrienoic acid (12(S)-HETrE), a compound of Formula (I), a compound of Formula (II) or a pharmaceutically acceptable salt of any of the foregoing:
- wherein:
- A is —COOR1, —OSO3R1, —OPO3(R1)2, or -G-HET;
- each R1 independently is H or C1-6alkyl;
- HET is an unsubstituted or substituted 5 to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, or O;
- G is O, S, NH, or absent;
- Cx is an alkylene group having x carbon atoms;
- Cy is an alkyl group having y carbon atoms;
- x is 3, 4, 5, 6, or 7;
- y is 4, 5, 6, 7;
- and each carbon atom of the compound of Formula (I) independently is unsubstituted or substituted with one or more deuterium or fluorine atoms;
- with the proviso that when x is 6, y is 5, and each carbon atom of Formula (I) is unsubstituted, then A is not —COOH;
- to the subject in an amount effective to prevent or inhibit loss of platelet cells.
Dependencies are inferred from the claim text.