INHIBITORS OF MICROBIAL BETA-GLUCURONIDASE ENZYMES AND USES THEREOF

• US 20190330237A1
• Filed: 07/20/2017
• Published: 10/31/2019
• Est. Priority Date: 07/21/2016
• Status: Active Grant

• Current Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Redinbo, Matthew R., Jin, Jian, James, Lindsey, Pellock, Sam, Ariyarathna, Ranathunga Arachchillage Yamu, Frye, Stephen
• Granted Patent: US 11,339,178 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: C07D 495/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Compounds and compositions are provided that comprise selective b-glucuronidase inhibitors. The compounds and compositions can ameliorate the side effects of chemotherapeutic agents and can improve the efficacy of such agents, including irinotecan and non-steroidal anti-inflammatory drugs.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein R₄ and R₅ are taken together with the carbon to which each is attached to form an optionally substituted C_5-7 membered ring.

3. The compound of claim 2, wherein X is N.

4. The compound of claim 3, wherein R₂ is heterocycloalkyl.

7. The compound of claim 4, wherein R₂ is morpholinyl.

8. The compound of claim 7, wherein R₁ is

—

NR_BR_C, wherein R_B and R_C are each independently selected from the group consisting of H, optionally substituted benzyl, C_2-5 heteroaryl, C_2-5 heteroalkyl, and C_3-5 cycloalkyl;

R₁ is C_2-5 heteroaryl optionally substituted with hydroxyl, halo, or amino;

or

R₁ is

10. The compound of claim 8, wherein R₁ is

13. The compound of claim 3, wherein R₁ is

15. The compound of claim 13, wherein R₁ is

19. The compound of claim 15, wherein R₂ is heterocycloalkyl.

20. The compound of claim 19, which is

21. The compound of claim 15, wherein R₂ is —

NR_FR_G, wherein

R_F and R_G are independently selected from the group consisting of H, linear or branched C_1-6 alkyl optionally substituted with halo, amino or hydroxyl, optionally substituted benzyl, and C_3-8 cycloalkyl.

23. The compound of claim 21, which is selected from

25. The compound of claim 1, wherein R₄ and R₅ are H.

26. The compound of claim 25, wherein R₁ is

30. The compound of claim 26, wherein R₁ is piperazinyl.

31. The compound of claim 30, wherein R₂ is H;

aryl, heterocycloalkyl, or —

NR_FR_G, wherein

R_F and R_G are independently selected from the group consisting of H, linear or branched C_1-6 alkyl, optionally substituted benzyl, and C_3-8 cycloalkyl.

32. The compound of claim 31, wherein R₂ is aryl.

34. The compound of claim 31, wherein R₂ is heterocycloalkyl.

38. The compound of claim 31, wherein R₂ is —

NR_FR_G, wherein

R_F and R_G are independently selected from the group consisting of H, linear or branched C_1-6 alkyl optionally substituted with halo, amino or hydroxyl, optionally substituted benzyl, and C_3-8 cycloalkyl.

41. The compound of claim 38, selected from

43. The compound of claim 1, having one of the following structures:

44. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

45. A method of ameliorating a side effect in a human in need thereof, comprising administering to said human an effective amount of a compound of claim 1.

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