Cyclic boronic acid ester derivatives and therapeutic uses thereof

• US 8,680,136 B2
• Filed: 08/08/2011
• Issued: 03/25/2014
• Est. Priority Date: 08/10/2010
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hirst, Gavin, Reddy, Raja, Hecker, Scott, Griffith, David C., Rodny, Olga, Dudley, Michael N., Boyer, Serge, Totrov, Maxim
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US13/205,112
• Publication Number:
  US 20120040932A1
• Time in Patent Office: 960 Days
• Field of Search: 549/29, 549/74, 549/76, 548/146, 548/190, 548/194, 546/304, 546/311, 514/352, 514/365, 514/370, 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 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• 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 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 1 cyclic boronic acid ester derivatives and their use as therapeutic agents.

Claims

1. A compound having the structure of formula I:

2. The compound of claim 1, having the structure of formula II:

3. The compound of claim 2 having the defined 3,6-cis-stereochemistry shown in formula IIa:

4. The compound of claim 2 having the defined 3,6-trans-stereochemistry shown in formula IIb:

5. The compound of claim 2, wherein:

R¹ is selected from a group consisting of —

NR⁹R¹⁰, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

CH(OH)C_1-9alkylR⁹, —

CH(OH)C_2-9alkenylR⁹, —

CH(OH)C_2-9alkynylR⁹, —

C(═

O)R⁹, —

C(═

O)C_1-9alkylR⁹, —

C(═

O)C_2-9alkenylR⁹, —

C(═

O)C_2-9alkynylR⁹, —

C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)OR⁹, —

N(R⁹)C(═

O)C(═

NR¹⁰)R⁹, —

N(R⁹)C(═

O)C_1-4-alkylN(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

NR¹⁰)R⁹, —

C(═

NR¹⁰)NR⁹R¹⁰, —

N═

C(R⁹)NR⁹R¹⁰, —

N(R⁹)SO₂R⁹, —

N(R⁹)SO₂NR⁹R¹⁰, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

R⁶ is selected from a group consisting of H, —

C_1-9alkyl, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

C(═

O)OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or alternatively R⁶ and an R⁷ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁷ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, R⁶ and an R⁷ or independently an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁸ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁹ is independently selected from a group consisting of H, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —

(CH₂)_0-3-carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R¹⁰ is independently selected from a group consisting of H, —

C_1-9alkyl, —

OR⁹, —

CH(═

NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and

X is selected from a group consisting of —

CO₂H and carboxylic acid isosteres.

6. The compound of claim 2, wherein n is 1.

7. The compound of claim 2, wherein R², R³, R⁴, and R⁵ are hydrogen.

8. The compound of claim 1, having the structure of formula IIIa:

9. The compound of claim 8, having the 3,7-cis-stereochemistry shown in formula IIIe:

10. The compound of claim 1, having the 3,7-trans-stereochemistry shown in formula IIIe:

11. The compound of claim 1, having the structure of formula IVa:

12. The compound of claim 11, having the 3,8-cis-stereochemistry shown in formula IVd:

13. The compound of claim 11, having the 3,8-trans-stereochemistry shown in formula IVg:

14. The compound claim 1, wherein R⁶ and each R⁷ and R⁸ is hydrogen.

15. The compound of claim 14, wherein m is 1.

16. The compound of claim 15, wherein R¹ is —

NHC(═

O)C_1-9alkylR¹¹.

17. The compound of claim 16, wherein R¹¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

18. The compound of claim 17, wherein R¹¹ is thien-2-yl.

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

NHC(═

O)C(═

NOR⁹)R^9′

, wherein R^9′

is selected from the group consisting of C_1-9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl.

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

CO₂H.

21. The compound of claim 1, wherein X is a carboxylic acid isostere.

22. The compound of claim 21, wherein the carboxylic acid isostere is selected from the group consisting of —

P(O)(OR⁹)₂, —

P(O)(R⁹)(OR⁹), —

P(O)(OR^12′

)₂, —

P(O)(R⁹)(OR^12′

), —

CON(R⁹)OH, —

SO₃H, —

SO₂N(R⁹)OH, and

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

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

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

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

27. The compound of claim 1, having the structure: