BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20170088561A1
• Filed: 05/18/2015
• Published: 03/30/2017
• Est. Priority Date: 05/19/2014
• Status: Active Grant

• Current Assignee: Qpex Biopharma, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Reddy, Raja, Glinka, Tomasz, Hecker, Scott, Totrov, Maxim, Rodny, Olga
• Granted Patent: US 9,963,467 B2
• Time in Patent Office: 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 31/43 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 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• 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: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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.

Claims

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

2. The compound of claim 1, wherein R^b is —

C(O)G, —

C(O)OG, —

S(O)₂G, —

C(═

NR¹R²)G or —

C(═

NOR³)G.

3. The compound of claim 1, having the structure of Formula Ia or IIa:

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

5. The compound of claim 1, having the structure of (Ia-1) or (Ia-2):

7. The compound of claim 1, wherein R⁵ is hydrogen.

8. The compound of claim 1, wherein at least one R⁵ is a halogen.

9. The compound of claim 8, wherein at least one R⁵ is —

F or Cl.

11. The compound of claim 1, wherein R⁴ is selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl, C₁-C₆ heteroalkyl, 5-10 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, cyano, hydroxy, —

OR³, —

SR³, —

S(O)₂M′

, —

P(O)R¹M′

, and halogen.

12. The compound of claim 11, wherein R⁴ is —

SO₃H, —

PO₃H₂, F, Cl, Me, —

CF₃ or —

(CH₂)_m—

Y′

—

(CH₂)_nM′

wherein m and p are 0.

17. The compound of claim 1, wherein R⁴ is —

(CH₂)m-Y′

—

(CH₂)pM′

wherein;

m is 0;

p is 0 to 3; and

Y′

is O or S; and

M′

is hydrogen;

hydroxyl;

—

C(O)NR¹²;

COOH;

C₁-C₄ alkyl optionally substituted with one or more substituents selected from the group consisting of —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C_3-10cycloalkyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C₆-C₁₀ aryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

5 to 10 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)-amino, hydroxy, cyano, azido, and halogen; and

4 to 10 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen.

19. The compound of claim 17, wherein R⁴ is —

O—

C(O)NR¹R², —

S—

C ₁-C₆alkyl, —

S—

C₁-C₅cycloalkyl, —

S—

C₁-C₅cycloalkyl, —

S—

C₁-C₆heterocycle, or —

O—

C₁-C₆alkyl, and R¹ and R² in R⁴ are each independently selected from hydrogen and hydroxy.

31. The compound of claim 1, wherein R⁶ and R⁷ are independently selected from the group consisting of hydrogen, hydroxy, and −

C₁-C₄alkyl.

32. The compound of claim 1, wherein Q is —

COOR, and R is selected from the group consisting of hydrogen, C_1-9alkyl, —

CR⁶R⁷OC(O)C_1-9alkyl, —

CR⁶R⁷OC(O)OC_1-9alkyl, CR⁶R⁷OC(O)C_6-10aryl, CR⁶R⁷OC(O)OC_6-10aryl, and

35. The compound of claim 32, wherein R is —

CH₂OC(O)CH₃, —

CH₂OC(O)CH₂CH₃, —

CH₂OC(O)CH₂CH₂CH₃, —

CH₂OC(O)CH(CH₃)₂, or —

CH₂OC(O)C(CH₃)₃.

40. The compound of claim 1, wherein G is H, —

SO₃H, —

PO₃H₂,

43. The compound of claim 1, wherein G is is selected from the group consisting of C₁-C₁₀ alkyl optionally substituted with one or more substituents selected from the group consisting of —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C_3-7 carbocyclyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

5-10 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C_6-10aryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen; and

5-10 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

C₆-C₁₀aryl, 5-10 membered heteroaryl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen.

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

C(O)NR¹R² and R¹ and R² are each independently selected from hydrogen and C₁-C₆alkyl;

—

CH₂OC(O)R¹R² and R¹ and R² are each independently selected from hydrogen and hydroxy;

—

CH₂C(O)NR¹R² and R¹ and R² are each independently selected from hydrogen and C₁-C₄alkyl;

or —

CH₂C(O)OR³ and R³ is hydrogen or C₂-C₆alkyl.

56. The compound of claim 1, wherein:

G is —

CH₂—

Y—

Z; and

Y is —

S—

;

—

S(O)₂—

, or CH₂—

.

59. The compound of claim 56, wherein Z is —

CH₃,

66. The compound of claim 56, wherein Z is selected from the group consisting of thiophene, 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.

72. The compound of claim 66, wherein Z is selected from the group consisting of

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

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

82. The pharmaceutical composition of claim 81, wherein the pharmaceutically acceptable excipient is meglume.

84. The pharmaceutical composition of claim 81, further comprising an additional medicament selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

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

100. The method of claim 99, further comprising administering to the subject an additional medicament selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

102. The method of claim 100, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Ceftibuten, Panipenein, Aztreonam, Tigemonam, BAL30072 SYN 2416, or Carunionam.

6. (canceled)

10. (canceled)

13-16. -16. (canceled)

18. (canceled)

20. (canceled)

21. (canceled)

22. The compound of claim 172, wherein R⁴ is —

S—

CH₃,

23-30. -30. (canceled)

33. (canceled)

34. (canceled)

36. (canceled)

37. (canceled)

38. (canceled)

39. (canceled)

41. (canceled)

42. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

48-55. -55. (canceled)

57. (canceled)

58. (canceled)

60. (canceled)

61. (canceled)

62. (canceled)

63. (canceled)

64. (canceled)

65. (canceled)

67. (canceled)

68. (canceled)

69. (canceled)

70. (canceled)

71. (canceled)

73. (canceled)

75-80. -80. (canceled)

83. (canceled)

85. (canceled)

86. The composition of claim 85, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Ceftibuten, Panipenem, Aztreonam, Tigemonam, BAL30072, SY 2416, Carumonam.

87-98. -98. (canceled)

101. (canceled)

103-118. -118. (canceled)