Boron-containing small molecules as anti-inflammatory agents

• US 8,039,450 B2
• Filed: 03/05/2009
• Issued: 10/18/2011
• Est. Priority Date: 03/06/2008
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Ding, Charles Z., Sharma, Rashmi, Chen, Daitao, Lu, Xiaosong, Sales, Marcelo, Freund, Yvonne, Jacobs, Robert, Xia, Yi, Akama, Tsutomu, Plattner, Jacob J., Alley, Michael Richard Kevin, Singh, Rajeshwar, Baker, Stephen J., Maples, Kirk R., Zhang, Yong-Kang, Nieman, James A., Sanders, Virginia
• Primary Examiner(s): Aulakh; Charanjit
• Application Number:
  US12/399,015
• Publication Number:
  US 20090291917A1
• Time in Patent Office: 957 Days
• Field of Search: 514/64, 558/288, 546/284.1, 546/290
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• 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

Compounds and methods of treating anti-inflammatory conditions are disclosed.

Claims

1. A compound having a structure according to the formula:

2. The compound of claim 1, or a salt thereof, wherein R³ is a member selected from H and unsubstituted alkyl.

3. The compound of claim 1, or a salt thereof, the compound has a structure according to the formula:

4. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

5. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

6. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

7. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

8. The compound of claim 1, or a salt thereof, the compound has a structure according to the formula:

9. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

10. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

11. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

12. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

13. The compound of claim 1, or a salt thereof, the compound has a structure according to the formula:

14. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

15. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

16. The compound of claim 1, or a salt thereof the compound has a formula which is a member selected from:

17. The compound of claim 1, or a salt thereof, the compound has a formula which is a member selected from:

18. The compound of claim 1, or a salt thereof, wherein R^b is a member selected from fluorine and chlorine.

19. The compound of claim 1, or a salt thereof, wherein R^b is a member selected from OR⁴ and NR⁴R⁵.

20. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

21. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted cycloalkyl.

22. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is unsubstituted C₁-C₆ alkyl.

23. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is unsubstituted cycloalkyl.

24. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with a member selected from substituted or unsubstituted C₁-C₆ alkoxy.

25. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with at least one halogen.

26. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with at least one oxo moiety.

27. The compound of claim 1, or a salt thereof, wherein R^b is OR⁴, and R⁴ is a member selected from —

CH₃, —

CH₂CH₃, —

(CH₂)₂CH₃, —

CH(CH₃)₂, —

CH₂CF₃, —

CH₂CHF₂, —

CH₂CH₂(OH), —

CH₂CH₂(OCH₃), —

CH₂CH₂(OCH(CH₃)₂), —

C(O)CH₃, —

CH₂CH₂OC(O)CH₃, —

CH₂C(O)OCH₂CH₃, —

CH₂C(O)OC(CH₃)₃, —

(CH₂)₃C(O)CH₃, CH₂C(O)OC(CH₃)₃, cyclopentyl, cyclohexyl,

28. The compound of claim 1, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ and R⁵ are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

29. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is H or unsubstituted alkyl;

and R⁵ is unsubstituted alkyl or alkyl substituted with a member selected from hydroxyl, phenyl, unsubstituted alkoxy and alkoxy substituted with a phenyl.

30. The compound of claim 29, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is a member selected from H or CH₃.

31. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ and R⁵ are each members independently selected from substituted or unsubstituted alkyl.

32. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl;

and R⁵ is substituted or unsubstituted alkyl.

33. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl;

and R⁵ is alkyl, substituted with a member selected from substituted or unsubstituted alkoxy and hydroxyl.

34. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl;

and R⁵ is alkyl, substituted with unsubstituted alkoxy.

35. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl;

and R⁵ is alkyl, substituted with alkoxy, substituted with phenyl.

36. The compound of claim 28, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl;

and R⁵ is alkyl, substituted with unsubstituted alkoxy.

37. The compound of claim 28, or a salt thereof, wherein R^b is a member selected from N(CH₃)₂, N(CH₃)(CH₂CH₂(OCH₃)), N(CH₃)(CH₂CH₂OH), NH₂, NHCH₃, NH(CH₂CH₂(OCH₃)), NH(CH₂CH₂(OCH₂Ph), NH(CH₂Ph), NH(C(CH₃)₃) and NH(CH₂CH₂OH).

38. The compound of claim 1, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to which they are attached, are combined to form a 4- to 8-membered substituted or unsubstituted heterocycloalkyl ring.

39. The compound of claim 38, or a salt thereof, wherein R^b is NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to which they are attached, are combined to form a 5- or 6-membered substituted or unsubstituted heterocycloalkyl ring.

40. The compound of claim 1, or a salt thereof, wherein R^b is a member selected from:

41. A pharmaceutical formulation comprising:

(a) the compound, or a pharmaceutically acceptable salt thereof, of claim 1; and

(b) a pharmaceutically acceptable excipient.

42. The formulation of claim 41, wherein the formulation is in a unit dosage fowl.

43. The formulation of claim 41, wherein the formulation is for oral or topical use.

44. The compound of claim 1, or a salt thereof, wherein the compound is

45. The compound of claim 1, or a salt thereof, wherein the compound is

46. The compound of claim 1, or a salt thereof, wherein the compound is

47. The compound of claim 1, or a salt thereof, wherein the compound is

48. The compound of claim 1, or a salt thereof, wherein the compound is

49. The compound of claim 1, or a salt thereof, wherein the compound is

50. The compound of claim 1, or a salt thereof, wherein the compound is

51. The compound of claim 1, or a salt thereof, wherein the compound is

52. The compound of claim 1, or a salt thereof, wherein the compound is

53. The compound of claim 1, or a salt thereof, wherein the compound is

54. The compound of claim 1, or a salt thereof, wherein the compound is

55. The compound of claim 1, or a salt thereof, wherein the compound is

56. The compound of claim 1, or a salt thereof, wherein the compound is

57. The compound of claim 1, or a salt thereof, wherein the compound is

58. The compound of claim 1, or a salt thereof, wherein the compound is

59. The compound of claim 1, or a salt thereof, wherein the compound is

60. The compound of claim 1, or a salt thereof, wherein the compound is

61. The compound of claim 1, or a salt thereof, wherein the compound is

62. The compound of claim 1, or a salt thereof, wherein the compound is

63. The compound of claim 1, or a salt thereof, wherein the compound is

64. The compound of claim 1, or a salt thereof, wherein the compound is

65. The compound of claim 1, or a salt thereof, wherein the compound is

66. The compound of claim 1, or a salt thereof, wherein the compound is

67. The compound of claim 1, or a salt thereof, wherein the compound is

68. The compound of claim 1 or a salt thereof, wherein the compound is

69. The compound of claim 1, or a salt thereof, wherein the compound is

70. The compound of claim 1, or a salt thereof, wherein the compound is

71. The compound of claim 1, or a salt thereof, wherein the compound is

72. The compound of claim 1, or a salt thereof, wherein the compound is

73. The compound of claim 1, or a salt thereof, wherein the compound is

74. The compound of claim 1, or a salt thereof, wherein the compound is

75. The compound of claim 1, or a salt thereof, wherein the compound is

76. The compound of claim 1, wherein the compound is

77. The compound of claim 1, wherein the compound is

78. The formulation of claim 41, which is a topical formulation.

79. The formulation of claim 41, wherein the formulation is a member selected from a simple solution, lacquer, lotion, cream, gel, ointment, paste, and spray.

80. The formulation of claim 41, wherein the formulation is a gel.

81. The formulation of claim 41, wherein the formulation is a cream.

82. The formulation of claim 41, wherein the formulation is an ointment.

83. The formulation of claim 41, wherein the formulation further comprises one or more members selected from an emulsifier, emollient, antioxidant, preservative, chelating agent, neutralizing agent, viscosity increasing agent, penetration enhancer, anti-inflammatory agent, vitamin, anti-aging agent, sunscreen, psoriasis-treating agent, and acne-treating agent.

84. The formulation of claim 41, wherein the formulation further comprises a member selected from the group consisting of a thickener, a gel phase carrier, nail penetration enhancer, and a viscosity increasing agent.

85. The formulation of claim 41, wherein the formulation comprises a chelating agent.

86. The formulation of claim 85, wherein the chelating agent is selected from the group selected from citric acid, ethylene diamine tetraacetic acid (EDTA), ethylene glycol-bis(beta-aminoethyl ether)-N,N,N′

,N′

-tetraacetic acid (EGTA and 8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N′

,N′

-tetraacetic acid, tetrapotassium salt (QUIN-2).

87. The formulation of claim 85, wherein the chelating agent is ethylene diamine tetraacetic acid.

88. The formulation of claim 85, wherein the chelating agent is present in an amount of between 0.005% to 2% by weight.

89. The formulation of claim 41, wherein the formulation comprises an antioxidant.

90. The formulation of claim 89, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone and tocopherol and pharmaceutically acceptable salts and esters of these compounds.

91. The formulation of claim 89, wherein the antioxidant is butylated hydroxytoluene.

92. The formulation of claim 89, wherein the antioxidant is present in an amount of from about 0.001 to 0.5 wt %, preferably 0.05 to about 0.5 wt %, more preferably 0.1%.

93. The formulation of claim 41, wherein the formulation comprises petroleum or petroleum derivative.

94. The formulation of claim 41, wherein the formulation comprises a member selected from cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate, oleyl alcohol, glyceryl distearate, ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate, diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate, polyoxyethylene lauryl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (21) stearyl ether, polyoxyethylene monostearate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, and sodium oleate.

95. The formulation of claim 41, wherein the formulation comprises glyceryl monostearate or glyceryl distearate.

96. The formulation of claim 41, wherein the formulation comprises wax.

97. The formulation of claim 41, wherein the formulation comprises alcohol.

98. The formulation of claim 97, wherein the alcohol is ethanol, ethylene glycol, propanol, polypropylene glycol, isopropanol or butanol.

99. The formulation of claim 41, wherein the compound is present in said formulation in a concentration from about 0.0001% to about 60% w/v.

100. The formulation of claim 41, wherein the compound is present in said formulation in a concentration from about 0.01% to about 10% w/v.

101. The formulation of claim 41, wherein the compound is present in said formulation in a concentration from about 0.5% to about 5% w/v.

102. The formulation of claim 41, wherein the compound is present in said formulation in a concentration from about 10% to about 20% w/v.

103. The formulation of claim 41, wherein the compound is present in a form which is a hydrate with water or a solvate with an alcohol.

104. A compound having a structure according to the formula:

105. A pharmaceutical formulation comprising:

(a) compound having a structure according to the formula;

106. A compound having a structure according to the formula:

107. A pharmaceutical formulation comprising:

(a) compound having a structure according to the formula;