Heterocyclic boronic acid ester derivatives and therapeutic uses thereof

• US 9,012,491 B2
• Filed: 08/30/2012
• Issued: 04/21/2015
• Est. Priority Date: 08/31/2011
• Status: Expired due to Fees

• Current Assignee: The Medicines Company (San Diego), LLC. (Novartis Ag)
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Reddy, Raja K., Boyer, Serge Henri, Totrov, Maxim, Hecker, Scott
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US14/241,412
• Publication Number:
  US 20140206648A1
• Time in Patent Office: 964 Days
• Field of Search: 549/29, 549/74, 549/76, 514/438
• US Class Current: 514/438
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to cyclic boronate compounds and their use as therapeutic agents.

Claims

1. A compound having the structure of formula I:

2. The compound of claim 1, having the defined stereochemistry at 3-position shown in formula Ia:

3. The compound of claim 1 wherein Y is CR⁶, having the defined 3,7-trans-stereochemistry shown in formula Ib:

4. The compound of claim 1 wherein Y is CR⁶, having the defined 3,7-cis-stereochemistry shown in formula Ic:

5. The compound of claim 1, wherein R¹ is —

NHC(═

O)R⁹.

6. The compound of claim 5, wherein R⁹ is —

C_1-9alkylR¹¹.

7. The compound of claim 6, wherein R¹¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

8. The compound of claim 7, wherein R¹¹ is thien-2-yl.

9. The compound of claim 1, wherein R¹ is —

N(R⁹)C(═

O)C(═

NR¹⁰)R⁹.

10. The compound of claim 1, wherein R¹ is —

N(R⁹)C(═

O)C(═

C R⁹R¹⁰)R⁹.

11. The compound of claim 1, wherein R⁹ is —

C_1-9alkyl.

12. The compound of claim 1, wherein R⁹ is —

C_1-9alkylR¹¹.

13. The compound of claim 1, wherein R⁹ is —

C_1-9alkylCO₂R¹².

14. The compound of claim 1, wherein R⁹ is substituted or unsubstituted heteroaryl.

15. The compound of claim 1, wherein G¹ is a bond.

16. The compound of claim 1, wherein G² is —

C(R^eR^f)—

.

17. The compound of claim 1, wherein G² is —

C(═

O)—

.

18. The compound of claim 1, wherein G² is —

C(═

O)C(R^eR^f)—

.

19. The compound of claim 1, wherein G¹ is —

C(R^aR^b)— and

G² is —

C(R^eR^f)—

.

20. The compound of claim 1, wherein Z is —

O—

.

21. The compound of claim 1, wherein Z is —

S—

.

22. The compound of claim 1, wherein Z is —

N(R⁹)—

.

23. The compound of claim 1, wherein Z is —

N[C(═

O)R⁹]—

.

24. The compound of claim 1, wherein Z is —

N[C(═

O)OR⁹]—

.

25. The compound of claim 1, wherein Z is —

N(R^k)—

.

26. The compound of claim 1, wherein Y is CR⁶.

27. The compound of claim 1, wherein Y is N.

28. The compound of claim 1, wherein m is 1.

29. The compound of claim 1, wherein R⁷ and R⁸ are H.

30. The compound of claim 1, wherein R¹⁰ is —

OR⁹—

.

31. The compound of claim 1, wherein R¹⁰ is —

C(═

O)OR⁹—

.

32. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted aryl.

33. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted heteroaryl.

34. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted carbocyclyl.

35. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted heterocyclyl.

36. The compound of claim 1, wherein X is —

CO₂R¹² or carboxylic acid isosteres.

37. The compound of claim 36, wherein X is —

CO₂H.

38. The compound of claim 1, having a structure selected from the group consisting of:

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.