Formulation of boronic acid compounds

• US 20020188100A1
• Filed: 01/25/2002
• Published: 12/12/2002
• Est. Priority Date: 01/25/2001
• Status: Active Grant

• Current Assignee: Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services, Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Adams, Julian, Grenier, Louis, Plamondon, Louis, Gupta, Shanker Lal
• Granted Patent: US 6,699,835 B2
• Time in Patent Office: Days
• US Class Current: 530/322
• 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 invention relates to the formulation of pharmaceutical compounds. More particularly, the invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds and methods for preparing the compositions. The invention also provides novel boronate ester compounds. The invention further provides boronic acid anhydride compounds useful in the methods of the invention.

Claims

1. A compound having formula (1):

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 mannitol or sorbitol.

5. The compound of claim 1, wherein Z¹ and Z² together form a moiety derived from D-mannitol.

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

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

,

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

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially unsaturated, 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)carbonyl or (2-pyrazine)sulfonyl.

11. The compound of claim 6, wherein:

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

CH₂—

R⁵;

R⁵, in each instance, is one of 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;

where the ring portion of any of 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 one of:

D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronate;

D-Mannitol N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronate;

or

D-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.

17. The composition of claim 16, wherein P is one of R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

—

C(O)—

;

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

C(O)—

or R⁷—

S(O)₂—

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

18. The composition of claim 17, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

19. The composition of claim 18, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

20. The composition of claim 17, wherein:

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C ₆ alkyl.

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

22. The composition of claim 16, wherein the compound having at least two hydroxyl groups is a sugar.

23. The composition of claim 22, wherein the sugar is a monosaccharide or disaccharide.

24. The composition of claim 22, wherein the sugar is a reduced sugar.

25. The composition of claim 24, wherein the reduced sugar is mannitol or sorbitol.

26. The composition of claim 16, wherein Z³ and Z⁴ together form a moiety derived from mannitol.

27. The composition of claim 26, wherein the mannitol is D-mannitol.

28. The composition of claim 17, wherein:

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

CH₂—

R⁵;

R⁵, in each instance, is one of 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;

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

29. The composition of claim 16, comprising one of:

D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronate;

D-Mannitol N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronate;

or

D-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.

13. The compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

14. A compound having formula (8):

15. A compound having formula (9):

16. A composition comprising a compound of formula (2)

30. A composition, comprising D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate in a lyophilized powder.

31. A composition, comprising a compound of formula (8):

32. A composition, comprising a compound of formula (9):

33. A method for formulating a boronic acid compound, the method comprising:

(a) preparing an aqueous mixture comprising

(i) a boronic acid compound; and

(ii) a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and

(b) lyophilizing the mixture.

34. The method of claim 33, wherein the boronic acid compound has formula (3):

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

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

,

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

C(O)—

or R⁷—

S(O)₂—

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

36. The method of claim 35, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

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

38. The method of claim 35, wherein:

A is zero;

R is hydrogen or C₁-C₁₀ alkyl; and

R³ is C₁-C₆ alkyl.

39. The method of claim 38, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

40. The method of claim 35, wherein:

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

CH₂—

R⁵;

R⁵, in each instance, is one of 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;

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

41. The method of claim 33, wherein the boronic acid compound is one 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;

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

42. The method of claim 33, wherein the boronic acid compound is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

43. The method of claim 33, wherein the compound having at least two hydroxyl groups is pharmaceutically acceptable.

44. The method of claim 43, wherein the compound having at least two hydroxyl groups is a sugar.

45. The method of claim 44, wherein the sugar is a monosaccharide or disaccharide.

46. The method of claim 45, wherein the sugar is a reduced sugar.

47. The method of claim 46, wherein the reduced sugar is mannitol or sorbitol.

48. The method of claim 33, wherein the compound having at least two hydroxyl groups is mannitol.

49. The method of claim 48, wherein the mannitol is D-mannitol.

50. The method of claim 33, wherein the aqueous mixture further comprises a water-miscible co-solvent.

51. The method of claim 50, wherein the water-miscible co-solvent is an alcohol.

78. A composition prepared according to the method of claim 33 or 52.

52. A method for formulating a boronic acid compound, the method comprising:

(a) preparing a boronic acid anhydride compound;

(b) mixing the boronic acid anhydride compound with water and a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and, optionally, a heteroatom or heteroatoms which can be N, S, or O to produce an aqueous mixture; and

(c) lyophilizing the mixture.

53. The method of claim 52, wherein the boronic acid anhydride compound comprises one or more compounds of formulae (4) and (5):

54. The method of claim 53, wherein P is one of R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

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

C(O)—

or R⁷—

S(O)₂—

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

55. The method of claim 54, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

56. The method of claim 55, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

57. The method of claim 54, wherein:

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³is C₁-C₆ alkyl.

58. The method of claim 57, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

59. The method of claim 54, wherein:

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

CH₂—

R⁵;

R⁵, in each instance, is one of 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;

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

60. The method of claim 52, wherein the boronic acid anhydride compound comprises an anhydride of one 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;

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

61. The method of claim 52, wherein the boronic acid anhydride compound comprises an anhydride of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

62. The method of claim 53, wherein the compound having at least two hydroxyl groups is pharmaceutically acceptable.

63. The method of claim 62, wherein the compound having at least two hydroxyl groups is a sugar.

64. The method of claim 63, wherein the sugar is a monosaccharide or disaccharide.

65. The method of claim 64, wherein the sugar is a reduced sugar.

66. The method of claim 65, wherein the reduced sugar is mannitol or sorbitol.

67. The method of claim 62, wherein the compound having at least two hydroxyl groups is mannitol.

68. The method of claim 67, wherein the mannitol is D-mannitol.

69. The method of claim 53, wherein the aqueous mixture further comprises a water-miscible co-solvent.

70. The method of claim 69, wherein the water-miscible co-solvent is an alcohol.

71. The method of claim 53, wherein n is 0, 1, 2, 3, or 4.

72. The method of claim 53, wherein the boronic acid anhydride compound comprises a compound of formula (5), wherein n is 1.

73. The method of claim 53, wherein the boronic acid anhydride compound consists essentially of a compound of formula (5), wherein n is 1.

74. The method of claim 53, wherein the boronic acid anhydride compound comprises a boroxine having formula (7):

75. The method of claim 53, wherein the boronic acid anhydride compound consists essentially of a boroxine having formula (7):

76. The method of claim 53, wherein the boronic acid anhydride compound is prepared by recrystallization of a boronic acid compound.

77. The method of claim 76, wherein the recrystallization solvent is selected from the group consisting of ethyl acetate, dichloromethane, hexanes, ether, acetonitrile, ethanol, and mixtures thereof.

80. The boronic acid anhydride compound of claim 79, wherein n is 0, 1, 2, 3, or 4.

81. The boronic acid anhydride compound of claim 79, wherein the boronic acid anhydride compound comprises a compound of formula (5), wherein n is 1.

82. The boronic acid anhydride compound of claim 79, wherein the boronic acid anhydride compound consists essentially of a compound of formula (5), wherein n is 1.

83. The boronic acid anhydride compound of claim 79, wherein P is one of R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

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

C(O)—

or R⁷—

S(O)₂—

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

84. The boronic acid anhydride compound of claim 79, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

85. The boronic acid anhydride compound of claim 84, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

86. The boronic acid anhydride compound of claim 83, wherein:

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

87. The boronic acid anhydride compound of claim 86, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

88. The boronic acid anhydride compound of claim 83, wherein:

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

CH₂—

R⁵;

R⁵, in each instance, is one of 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;

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

89. The boronic acid anhydride compound of claim 79, wherein the boronic acid anhydride compound comprises an anhydride of one 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;

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

79. A boronic acid anhydride compound comprising one or more compounds of formulae (4) and (5):

90. A boronic acid anhydride compound, comprising an anhydride of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

91. A boronic acid anhydride compound comprising a boroxine having formula (7):

92. A boronic acid anhydride compound consisting essentially of a boroxine having formula (7):