Formulation of boronic acid compounds

• US 6,958,319 B2
• Filed: 09/18/2003
• Issued: 10/25/2005
• Est. Priority Date: 01/25/2001
• Status: Expired due to Term

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Gupta, Shanker Lal
• Primary Examiner(s): Price, Elvis O.
• Assistant Examiner(s): Henry, Michael C.
• Application Number:
  US10/664,732
• Publication Number:
  US 20040063623A1
• Time in Patent Office: 768 Days
• Field of Search: 514/2, 514/18, 514/19, 514/64, 536/17.1, 544/229, 530/322
• US Class Current: 514/16.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention provides stable compounds prepared from boronic acid and lyophilized compounds thereof of the formula (1):
in which Z¹ and Z² are moieties derived from sugar. The invention also provides methods for preparing such compounds. Lyophilizing a mixture comprising a boronic acid compound and a moiety derived from sugar produces a stable composition that readily releases the boronic acid compound upon reconstitution in aqueous media.

Claims

1. A compound of the formula (1):

wherein

P is hydrogen or an amino-group protecting moiety;

R is hydrogen or alkyl;

A is 0, 1, or 2;

R¹, R², and R³ are each independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R¹, R², R³, or R⁵ can be optionally substituted; and

Z¹ and Z² together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.

2. The compound of claim 1, wherein the sugar is a monosaccharide or disaccharide.

3. The compound of claim 1, wherein the sugar is a reduced sugar.

4. The compound of claim 3, wherein the reduced sugar is sorbitol.

5. The compound of claim 1, wherein A is 0.

6. The compound of claim 1, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

7. The compound of claim 6, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

8. The compound of claim 7, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

9. The compound of claim 6, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

10. The compound of claim 9, wherein P is (2-pyrazine)sulfonyl.

11. The compound of claim 1, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂—

R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

12. The compound of claim 1, wherein said compound is a sugar ester of:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;

or

N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.

13. The compound of claim 1, wherein said compound is a sugar ester of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

47. A composition comprising the compound of claim 1 and a pharmaceutically-acceptable carrier.

48. A composition comprising the compound of claim 6 and a pharmaceutically-acceptable carrier.

49. A composition compiising the compound of claim 10 and a pharmaceutically-acceptable carrier.

50. A composition comprising the compound of claim 13 and a pharmaceutically-acceptable carrier.

71. The compound of claim 9, wherein P is (2-pyrazine)carbonyl.

72. A composition comprising the compound of claim 71 and a pharmaceutically-acceptable carrier.

79. The compound of claim 1, wherein P and R together form a cyclic moiety.

80. The compound of claim 79, wherein Z¹ and Z² together form a moiety derived from a monosaccharide or disaccharide.

81. The compound of claim 80, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl;

R³ is C₁-C₆ alkyl; and

P is (2-pyrazine)carbonyl.

82. A composition comprising the compound of claim 79 and a pharmaceutically-acceptable carrier.

83. A composition comprising the compound of claim 80 and a pharmaceutically-acceptable carrier.

84. A composition comprising the compound of claim 81 and a pharmaceutically-acceptable carrier.

14. A lyophilized compound of the formula (1):

wherein

P is hydrogen or an amino-group protecting moiety;

R is hydrogen or alkyl;

A is 0, 1, or 2;

R¹, R², and R³ are each independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, hererocyclyl, or heteroaryl in R¹, R², R³, or R⁵ can be optionally substituted; and

Z¹ and Z² together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.

15. The compound of claim 14, wherein the sugar is a monosaccharide or disaccharide.

16. The compound of claim 14, wherein the sugar is a reduced sugar.

17. The compound of claim 14, wherein A is 0.

18. The compound of claim 16, wherein the reduced sugar is sorbitol.

19. The compound of claim 14, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂-, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

20. The compound of claim 19, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

21. The compound of claim 20, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

22. The compound of claim 19, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

23. The compound of claim 22, wherein P is (2-pyrazine)sulfonyl.

24. The compound of claim 14, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂—

R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

25. The compound of claim 20, wherein said compound is a sugar ester of:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-(O-benzyl)-L-trosine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;

or

N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.

26. The lyophilized compound of claim 20, wherein said compound is a sugar ester of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

27. The compound of claim 14, wherein the compound is stable at 0°

C. for at least one month.

28. The compound of claim 14, wherein the compound is stable at 40°

C. for at least one month.

46. A lyophilized cake comprising the compound of claim 14.

51. A composition comprising the compound of claim 14 and a pharmaceutically-acceptable carrier.

52. A composition comprising the compound of claim 19 and a pharmaceutically-acceptable carrier.

53. A composition comprising the compound of claim 23 and a pharmaceutically-acceptable carrier.

54. A composition comprising the compound of claim 26 and a pharmaceutically-acceptable carrier.

55. A lyophilized cake comprising the compound of claim 19.

56. A lyophilized cake comprising the compound of claim 23.

57. A lyophilized cake comprising the compound of claim 26.

73. The compound of claim 22, wherein P is (2-pyrazine)carbonyl.

74. A composition comprising the compound of claim 73 and a pharmaceutically-acceptable carrier.

75. A lyophilized cake comprising the compound of claim 73.

85. The compound of claim 14, wherein P and R together form a cyclic moiety.

86. The compound of claim 85, wherein Z¹ and Z² together form a moiety derived from a monosaccharide or disaccharide.

87. The compound of claim 86, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl;

R³ is C₁-C₆ alkyl; and

P is (2-pyrazine)carbonyl.

88. A composition comprising the compound of claim 85 and a pharmaceutically-acceptable carrier.

89. A composition comprising the compound of claim 86 and a pharmaceutically-acceptable carrier.

90. A composition comprising the compound of claim 87 and a pharmaceutically-acceptable carrier.

91. A lyophilized cake comprising the compound of claim 85.

92. A lyophilized cake comprising the compound of claim 86.

93. A lyophilized cake comprising the compound of claim 87.

29. A method of preparing a lyophilized compound of the formula (1):

wherein

P is hydrogen or an amino-group protecting moiety;

R is hydrogen or alkyl;

A is 0, 1, or 2;

R¹, R², and R³ are each independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

R⁵ in each instance is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R¹, R², R³, or R⁵ can be optionally substituted; and

Z¹ and Z² together form a moiety derived from a sugar;

the method comprising;

(a) preparing a mixture comprising

(i) water,

(ii) a compound of formula (3).

wherein P, R, A, R¹, R², and R³ are as described above; and

Z′ and

Z″

are OH; and

(iii) a sugar; and

(b) lyophilizing the mixture.

30. The method of claim 29, wherein the sugar is a monosaccharide or disaccharide.

31. The method of claim 29, wherein the sugar is a reduced sugar.

32. The method of claim 31, wherein the reduced sugar is sorbitol.

33. The method of claim 29, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

34. The method of claim 33, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

35. The method of claim 34, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

36. The method of claim 29, wherein

A is zero;

R is hydrogen or C₁-C₆ alkyl; and

R³ is C₁-C₆ alkyl.

37. The method of claim 36, wherein P is (2-pyrazine)sulfonyl.

38. The method of claim 29, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂—

R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

39. The method of claim 29, wherein the compound of formula (3) is:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;

or

N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.

40. The method of claim 39, wherein the compound of formula (3) is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

41. The method of claim 29, wherein the mixture further comprises a water-miscible solvent.

42. The method of claim 41, wherein the water-miscible solvent is an alcohol.

43. The method of claim 42, wherein the alcohol is tert-butanol.

44. The method of claim 29, wherein the sugar and the compound of formula (3) are present in at least a 1:

1 raiio.

45. The method of claim 29, wherein the sugar and the compound of formula (3) are present in at least a 5:

1 ratio.

58. The method of claim 37, wherein A is 0.

59. The method of claim 29 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

60. The method of claim 33 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

61. The method of claim 37 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

62. The method of claim 40 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

63. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 29 and (ii) a pharmaceutically-acceptable carrier.

64. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 33 and (ii) a pharmaceutically-acceptable carrier.

65. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 37 and (ii) a pharmaceutically-acceptable carrier.

66. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 40 and (ii) a pharmaceutically-acceptable carrier.

67. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 29.

68. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 33.

69. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 37.

70. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 40.

76. The method of claim 36, wherein P is (2-pyrazine)carbonyl.

77. A composition comprising the compound of claim 76 and a pharmaceutically-acceptable carrier.

78. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 76.

94. The method of claim 29, wherein P and R together form a cyclic moiety.

95. The method of claim 94, wherein Z¹ and Z² together form a moiety derived from a monosaccharide or disaccharide.

96. The method of claim 95, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl;

R³ is C₁-C₆ alkyl; and

P is (2-pyrazine)carbonyl.

97. The method of claim 94 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

98. The method of claim 95 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

99. The method of claim 96 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

100. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 94 and (ii) a pharmaceutically-acceptable carrier.

101. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 95 and (ii) a pharmaceutically-acceptable carrier.

102. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 96 and (ii) a pharmaceutically-acceptable carrier.

103. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 94.

104. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 95.

105. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 96.