Hydroxyeicosatrienoic acid compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11111222-B2
Application number	US-201716312721-A
Country	US
Kind code	B2
Filing date	Jun 23, 2017
Priority date	Jun 23, 2016
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

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.

First claim

What is claimed:

1. A compound of Formula (0), or a pharmaceutically acceptable salt thereof:

wherein:
A is —COOR 1 , —OSO 3 R 1 , —OPO 3 (R 1 ) 2 , or -G-HET;
B is a bond each R 1 independently is H or C 1−6 alkyl;
R 2 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 R 2 is OH, and (ii) when —at bond 1 is a single bond, then —at bond 2 is a cis double bond and R 2 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;
C x is an alkylene group having x carbon atoms;
C y 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 (0) 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.

2. The compound of claim 1 , having a Formula (I) or (II):

3. The compound of claim 1 , wherein A is —COOR 1 , —OSO 3 R 1 , or —OPO 3 (R 1 ) 2 .

4. The compound of claim 1 , wherein R 1 is H or CH 3 .

5. The compound of claim 1 , wherein A is -G-HET.

6. The compound of claim 5 , wherein HET is a 5- or 6-membered heteroaryl group.

7. The compound of claim 6 , wherein HET is tetrazolyl, triazolyl, or isoxazolyl.

8. The compound of claim 1 , wherein G is absent.

9. The compound of claim 1 , wherein G is O or S.

10. The compound of claim 1 , wherein x is 4, 5, or 6; and/or y is 5.

11. The compound of claim 1 , wherein at least one carbon atom is substituted with deuterium; and/or at least one carbon atom is substituted with fluorine.

12. The compound of claim 11 , wherein the carbon atom at position 13 is disubstituted with deuterium or fluorine.

13. The compound of claim 1 , wherein each carbon atom is mono- or disubstituted with either deuterium or fluorine.

14. The compound of claim 2 , wherein the compound is of Formula 1 and has a structure selected from the group consisting of:

or wherein the compound is of Formula (II) and has a structure selected from the group consisting of:

15. A composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method of treating a thrombotic disorder, preventing thrombosis, or treating thrombocytopenia in a subject having a thrombotic disorder thereof comprising administering a compound selected from 12(S)-hydroxy-8Z, 10E, 14Z-eicosatrienoic acid, a compound of claim 1 , or a pharmaceutically acceptable salt of any of the foregoing to the subject in an amount effective to inhibit thrombus formation and/or loss of platelet cells while maintaining hemostasis.

17. The method of claim 16 , wherein the subject has a thrombotic disorder selected from arterial thrombosis, deep vein thrombosis, pulmonary embolism, ischemic stroke, immune thrombocytopenia (ITP), Heparin-induced thrombocytopenia (HIT), and Heparin-induced thrombocytopenia and thrombosis (HITT).

18. The method of claim 16 , comprising administering the compound to the subject before, during, and/or after a surgical procedure.

19. The method of claim 16 , comprising administering the compound in an amount effective to:
(i) inhibit platelet aggregation; or
(ii) inhibit platelet integrin activation; or
(iii) inhibit Rap1 activation; or
(iv) activate G α s -linked G Protein-coupled receptors (GPCRs); or
(v) activate cAMP; or
(vi) activate protein kinase A (PKA); or
(vii) inhibit thrombus growth; or
(viii) combinations thereof.

20. The method of claim 16 , comprising administering the compound to the subject at a dose between about 0.1 mg/kg and about 50 mg/kg and/or administering the compound orally or intravenously.

Assignees

• Univ Michigan Regents
• Univ California

Inventors

• Holinstat Michael
• Holman Theodore R
• White Andrew

Classifications

• A61K31/42

  Oxazoles · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61K31/202

  having three or more double bonds, e.g. linolenic (eicosanoids, e.g. leukotrienes A61K31/557) · CPC title

• C07D233/84

  Sulfur atoms · CPC title