Inhibitors of platelet function and methods for use of the same

Patent metadata

Field	Value
Publication number	US-12269805-B2
Application number	US-202217969519-A
Country	US
Kind code	B2
Filing date	Oct 19, 2022
Priority date	Apr 17, 2018
Publication date	Apr 8, 2025
Grant date	Apr 8, 2025

Abstract

Disclosed herein are small molecule inhibitors of platelet function, and methods of using the small molecules to treat diseases, such as platelet hemostasis and thrombosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.

First claim

We claim:

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

wherein:
each of R 1 and R 2 independently is C 6-10 aryl optionally substituted with 1-2 groups selected from C 1-6 alkyl, halo, and aryl;
L is —(CO 2 ) s —(CH 2 ) m -(Cy) r -(CH 2 ) n —;
Cy is C 3-8 cycloalkylene;
m is 1 or 2;
n is 1, 2, 3, 4, or 5; and
r and s are each independently 0 or 1.

2. The compound or salt of claim 1 , wherein each of R 1 and R 2 independently is C 6-10 aryl.

3. The compound or salt of claim 2 , wherein R 1 and R 2 are each phenyl optionally substituted with 1-2 groups selected from C 1-6 alkyl, halo, and aryl.

4. The compound or salt of claim 3 , wherein:
(i) each phenyl is unsubstituted; or
(ii) at least one phenyl is substituted with halo.

5. The compound or salt of claim 4 , wherein halo is Cl.

6. The compound or salt of claim 1 , wherein r and s are each 1.

7. The compound or salt of claim 6 , wherein Cy is cyclopentylene or cyclohexylene.

8. The compound or salt of claim 6 , wherein m is 1, and/or n is 1 or 2.

9. The compound or salt of claim 1 , wherein r and s are each 0.

10. The compound or salt of claim 9 , wherein n+m is 3, 4, 5, or 6.

11. A compound or pharmaceutically acceptable salt thereof having a structure

12. The compound or salt of claim 11 having a structure

13. The compound or salt of claim 11 , having a structure of

14. A pharmaceutical composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier.

15. A method of inhibiting platelet aggregation or platelet integrin activation in a cell, comprising contacting the cell with the compound of claim 1 in an amount effective to inhibit platelet aggregation or platelet integrin activation.

16. A method of activating one or more of Gα s -linked G Protein-coupled receptors (“GPCRs”), cAMP, and protein kinase A (“PKA”) in a cell, comprising contacting the cell with the compound of claim 1 in an amount effective to activate GPCRs, cAMP and/or PKA.

17. A method of inhibiting thrombus growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

18. A method of treating a thrombotic disorder or thrombocytopenia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

19. The method of claim 18 , wherein the thrombotic disorder is selected from arterial thrombosis, deep vein thrombosis (“DVT”), pulmonary embolism (“PE”), ischemic stroke, immune thrombocytopenia (“ITP”), Heparin-induced thrombocytopenia (“HIT”), and Heparin-induced thrombocytopenia and thrombosis (“HITT”).

20. A method of preventing thrombosis in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

Assignees

• Univ Michigan Regents
• Univ California

Inventors

• Holinstat Michael
• Adili Reheman
• White Andrew
• Holman Theodore R

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C07D249/12 Primary

  Oxygen or sulfur atoms · CPC title