Boronic acid derivatives and therapeutic uses thereof

• US 9,642,869 B2
• Filed: 01/02/2014
• Issued: 05/09/2017
• 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:
  US14/146,671
• Publication Number:
  US 20140194385A1
• Time in Patent Office: 1,223 Days
• 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 31/04 Antibacterial agents
• 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 boronic acid derivatives and their use as therapeutic agents. Other embodiments relate to pharmaceutical compositions containing boronic acid derivatives and additional excipient such as meglumine.

Claims

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

2. The compound of claim 1 having the structure of Formula (I):

3. The compound of claim 1, wherein:

each R⁴ is independently selected from the group consisting of —

H, methyl, ethyl, propyl, iso-propyl, —

OH, —

O—

C_1-4alkyl, and halogen; and

Z is selected from the group consisting of aryl optionally substituted with C_1-4alkyl, amino, hydroxy, or halogen and heteroaryl optionally substituted with C_1-4alkyl, amino, hydroxy, or halogen.

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

5. The compound of claim 1, wherein R is H, CR¹R²OC(O)C_1-5alkyl, or —

CR¹R²OC(O)OC_1-5alkyl, wherein R¹ in R is H and R² in R is H or —

CH₃.

6. The compound of claim 1, wherein R⁴ is selected from H, F, Cl, —

CH₃, —

CF₃, —

OCH₃, and —

SCH₃.

7. The compound of claim 1, wherein G is NH₂, C(O)NR¹R², or CH₂C(O)NR¹R², and wherein R¹ and R² in G are each independently selected from —

H and C_1-4alkyl.

8. The compound of claim 7, wherein R¹ in G is —

CH₃ and R² in G is H or —

CH₃.

9. The compound of claim 1, wherein:

G is —

CH₂—

Y—

Z;

Y is —

S—

; and

Z is selected from the group consisting of imidazole, N-methylimidazole, aminoimidazole, triazole, N-methyltriazole, aminotriazole, tetrazole, N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole, aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, azitidine and piperdine.

10. The compound of claim 9, wherein Z is N-methyltetrazole, thiadiazole, aminothiadiazole, or azitidine.

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

SCH₃ or —

CH₂—

Y—

X, wherein Y is —

S—

, and wherein X is —

CH₃, —

CH₂CN, —

CH₂N₃, —

CH₂F, —

CHF₂, or —

CF₃.

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

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

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

20. The pharmaceutical composition of claim 18, further comprising an additional medicament, and wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

21. The composition of claim 20, 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.

22. A method of therapeutically treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound according to claim 1, wherein the bacterial infection comprises a bacteria that produces a beta-lactamase.

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

24. The method of claim 23, 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.

13. A compound having the structure of formula II or Formula II.1:

14. The compound of claim 13 having the structure of Formula (II)

15. The compound of claim 13, wherein G is selected from the group consisting of

16. The compound of claim 13, having the structure of Formula IIa or Formula IIa.1:

17. The compound of claim 13, having the structure selected from the group consisting of:

25. A pharmaceutical composition, comprising:

a monosaccharide or monosaccharide derivative, wherein the monosaccharide or monosaccharide, derivative is meglumine, and

a compound of Formula (IIIa) or (IIIb);

26. The composition of claim 25, wherein the compound of formula (IIIb) has the structure of Formula (IIIc):

27. The composition of claim 25, wherein R^a is C(O)OR and R is H or —

CR⁵R⁶OC(O)C_1-9 alkyl, and wherein each R⁵ and R⁶ is hydrogen.

28. The composition of claim 25, wherein R^e is independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl, optionally substituted C_6-10aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

29. The composition of claim 25, wherein R^f is independently selected from the group consisting of —

C(O)G, —

C(O)OG, and —

S(O)₂G.

30. The composition of claim 25, wherein G is selected from the group consisting of

31. The composition of claim 25, wherein G is —

NH₂, —

NH—

C_1-4 alkyl, —

C(O)NR¹R², —

CH₂C(O)NR¹R², or —

O—

(CH₂)_n—

C(O)NR¹R², wherein n in G is 0-3, and wherein R¹ and R² in G are each independently selected from —

H and C_1-4alkyl.

32. The composition of claim 31, wherein G is —

O—

CH₂—

C(O)NH₂.

33. The composition of claim 25, wherein

G is —

(CH₂)_n—

Y—

Z;

n in G is 0-3,

Y is —

S—

; and

Z is selected from the group consisting of imidazole, N-methylimidazole, aminoimidazole, triazole, N-methyl triazole, aminotriazole, tetrazole, N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole, aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, azetidine and piperdine, each optionally substituted with one or more C_1-4alkyl, —

NR¹R², hydroxy, or halogen.

34. The composition of claim 33, wherein Z is thiadiazole optionally substituted with one or more C_1-4alkyl, —

NR¹R², hydroxy, or halogen;

aminothiadiazole optionally substituted with one or more C_1-4alkyl, —

NR¹R², hydroxy, or halogen;

or azitidine optionally substituted with one or more C_1-4alkyl, —

NR¹R², hydroxy, or halogen.

35. The composition of claim 25, wherein

G is —

(CH₂)_n—

Y—

X;

n in G is 0-3;

Y is —

S—

; and

X is hydrogen or optionally substituted C_1-4alkyl.

36. The composition of claim 35, wherein X is —

CH₃, —

CH₂CN, —

CH₂N₃, —

CH₂F, —

CHF₂, or —

CF₃.

37. The composition of claim 25, wherein

G is —

(CH₂)_n—

Y—

Z;

n in G is 0-3,

Y is —

CH₂—

, —

O—

, —

O—

CH₂—

, —

C(O)—

; and

Z is selected from the group consisting of phenyl, naphthyl, indole, pyrrolidine, thiophene, cyclopropyl, or cyclohexyl, each optionally substituted with one or more C_1-4alkyl, —

NR¹R², hydroxy, or halogen.

38. The composition of claim 25, wherein

G is —

(CH₂)_n—

Y—

X;

n in G is 0-3;

Y is —

O—

or —

CH₂—

; and

X is C_1-4alkyl optionally substituted with one or more halogen, cyano, or azido.

40. The composition of claim 25, wherein the pH of the composition is in the range of about 5 to about 9.

41. The composition of claim 40, wherein the pH of the composition is in the range of about 7.1 to about 7.3.

42. The composition of claim 25, further comprising an additional pharmaceutically acceptable carrier or excipient.

43. The composition of claim 25, further comprising one or more additional medicament, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

44. The composition of claim 43, 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.

45. A method of therapeutically treating a bacterial infection, comprising administering to a subject in need thereof, a composition according to claim 25, wherein the bacterial infection comprises a bacteria that produces a beta-lactamase.

46. The method of claim 45, further comprising administering to the subject an additional medicament, and wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

47. The method of claim 46, 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.

39. A pharmaceutical composition, comprising a monosaccharide or monosaccharide derivative, wherein the monosaccharide or monosaccharide, derivative is meglumine, and a compound having the structure selected from the group consisting of:

48. A chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative, wherein the monosaccharide or monosaccharide derivative is meglumine, and a compound having the structure of formula (IIIa) or (IIIb):