Boronic acid derivatives and therapeutic uses thereof

• US 9,132,140 B2
• Filed: 01/02/2014
• Issued: 09/15/2015
• Est. Priority Date: 01/04/2013
• Status: Active Grant

• Current Assignee: Qpex Biopharma, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Reddy, Raja K., Glinka, Tomasz, Totrov, Maxim, Hecker, Scott
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/146,643
• Publication Number:
  US 20140194384A1
• Time in Patent Office: 621 Days
• US Class Current: 1/1
• 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 31/546 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: 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 31/06 for tuberculosis
• 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: 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 boronic acid derivatives and their use as therapeutic agents.

Claims

1. A compound having the structure of Formula (I-1) or Formula (I-2):

2. The compound of claim 1, wherein R⁸ is H and R⁹ is H.

3. The compound of claim 1, wherein:

Y is selected from the group consisting of —

S—

, —

O—

, —

CH₂—

;

G is selected from the group consisting of —

C(O)NR¹R²;

—

C(O)NR¹OR³;

—

NR¹C(O)R⁵;

—

NR¹C(O)NR²R^1a;

—

NR¹C(O)OR³;

—

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a;

—

C(═

NR¹)R⁵;

—

C(═

NR¹)NR²R^1a;

—

NR¹CR⁵(═

NR²);

—

NR¹C(═

NR²)NR^1aR^2a;

—

C_6-10aryl optionally substituted with 0-2 substituents selected from the group consisting of —

C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —

C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —

C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

R is selected from the group consisting of —

H, —

C_1-9alkyl, —

CR⁵R⁶OC(O)C_1-9alkyl, and

4. The compound of claim 1, having the structure of Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id)

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

CH₂—

, —

O—

or —

S—

.

6. The compound of claim 1, wherein:

Y is —

O—

or —

S—

;

G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵, wherein R¹, R² and R⁵ in G are independently selected from —

H and —

C_1-4alkyl; and

J, L and M are CR⁷.

7. The compound of claim 1, wherein n is 0 or 1.

8. The compound of claim 1, wherein the compound of formula (I) has the structure of formula (Ie):

9. The compound of claim 1, wherein G is selected from the group consisting of thiadiazole;

thiadiazole optionally substituted with —

NR¹R² or —

NR¹C(O)R⁵;

triazole optionally substituted with —

NR¹R² or C_1-4 alkyl;

tetrazole optionally substituted with methyl;

pyridine;

thiazole;

phenyl;

or azetidine; and

wherein R¹, R² and R⁵ in G are independently —

H or —

C_1-4alkyl.

10. The compound of claim 1, wherein:

Y is —

S—

;

n is 1 or 2;

G is —

C(O)NR¹R²; and

J, L and M are CR⁷.

11. The compound of claim 1, wherein:

Y is —

CH₂—

;

n is 0 to 2;

G is —

C(O)NR¹R²; and

J, L and M are CR⁷.

12. The compound of claim 1, wherein R⁷ is selected from the group consisting of —

H, —

OH, —

C_1-4alkyl, —

O—

C_1-4alkyl, —

S—

C_1-4alkyl, halogen, —

CF₃, and cyano.

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

CR⁵R⁶OC(O)C_1-9alkyl or —

CR⁵R⁶OC(O)OC_1-9alkyl.

14. The compound of claim 1, wherein M′

is selected from the group consisting of —

C(O)NR¹R²;

—

C(O)NR¹OR³;

—

NR¹C(O)R⁵;

—

NR¹C(O)NR²R^1a;

—

NR¹C(O)OR³;

—

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a;

—

C(═

NR¹)NR²R^1a;

—

NR¹CR⁵(═

NR²);

—

NR¹C(═

NR²)NR^1aR^2a;

C_6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

4-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵.

15. The compound of claim 1, wherein R¹ is H and R² is H.

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

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

18. The composition of claim 17, wherein the pharmaceutically acceptable excipient is meglumine.

19. The pharmaceutical composition of claim 17, further comprising an additional medicament, and wherein the additional medicament is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

20. The composition of claim 19, wherein the additional medicament is a β

-lactam antibacterial agent, and wherein the β

-lactam antibacterial agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam.

21. A method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound according to claim 1.

22. The method of claim 21, further comprising administering to the subject an additional medicament, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent.

23. The method of claim 21, wherein the additional medicament is a β

-lactam antibacterial agent, and wherein the β

-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

24. A chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound of claim 1.

25. The chemical complex of claim 24, wherein the monosaccharide derivative is meglumine.

26. A compound having the structure of: