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Claims for Patent: 6,713,446

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Claims for Patent: 6,713,446

Title: Formulation of boronic acid compounds
Abstract:The present invention provides stable compounds prepared from boronic acid and lyophilized compounds thereof of the formula (1): ##STR1## in which Z.sup.1 and Z.sup.2 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.
Inventor(s): Gupta; Shanker Lal (Rockville, MD)
Assignee: The United States of America as represented by the Secretary of the Department of Health and Human Services (Washington, DC)
Application Number:10/056,567
Patent Claims: 1. A compound of the formula (1): ##STR11##

wherein P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2; R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted; and Z.sup.1 and Z.sup.2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom, and wherein the sugar is mannitol.

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

3. The compound of claim 1, wherein P is R.sup.7 --C(O)--, R.sup.7 --S(O).sub.2 --, R.sup.7 --NH--C(O)--, or R.sup.7 --O--C(O)--; where R.sup.7 is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, R.sup.7 can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

4. The compound of claim 3, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 is an aromatic heterocycle.

5. The compound of claim 4, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

6. The compound of claim 3, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

7. The compound of claim 6, wherein P is (2-pyrazine)sulfonyl.

8. The compound of claim 1, wherein R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5 in each instance is C.sub.6 -C.sub.10 aryl, (C.sub.6 -C.sub.10)ar(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alk(C.sub.6 -C.sub.10)aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.8 alkoxy, or C.sub.1 -C.sub.8 alkylthio; wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted.

9. The compound of claim 1, wherein said compound is: 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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronate; D-Mannitol N-(8-quinoline)sulfonyl-.beta.-(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.

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

11. A lyophilized compound of the formula (1): ##STR12##

wherein P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2; R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5 in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; wherein the ring portion of any said aryl, aralkyl, alkyaryl, cycloalkyl, heterocyclyl, or heteroaryl in R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted; and Z.sup.1 and Z.sup.2 together form a moiety derived from sugar, wherein the atom attached to boron in each case is an oxygen atom, and wherein the sugar is mannitol.

12. The compound of claim 11, wherein A is 0.

13. The compound of claim 11, wherein P is R.sup.7 --C(O)--, R.sup.7 --S(O).sub.2 --, R.sup.7 --NH--C(O)--, or R.sup.7 --O--C(O)--; where R.sup.7 is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, R.sup.7 can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

14. The compound of claim 13, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 is an aromatic heterocycle.

15. The compound of claim 14, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

16. The compound of claim 13, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

17. The compound of claim 16, wherein P is (2-pyrazine)sulfonyl.

18. The compound of claim 11, wherein R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5 in each instance is C.sub.6 -C.sub.10 aryl, (C.sub.6 -C.sub.10)ar(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alk(C.sub.6 -C.sub.10)aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.8 alkoxy, or C.sub.1 -C.sub.8 alkylthio; wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted.

19. The compound of claim 14, wherein said compound is: 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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronate; D-Mannitol N-(8-quinoline)sulfonyl-.beta.-(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.

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

21. The compound of claim 11, wherein the compound is stable at 0.degree. C. for at least one month.

22. The compound of claim 11, wherein the compound is stable at 40.degree. C. for at least one month.

23. A method of preparing a lyophilized compound of the formula (1): ##STR13##

wherein P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2; R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5 in each instance is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; wherein the ring portion of any said aryl, aralkyl, alkyaryl, cycloalkyl, heterocyclyl, or heteroaryl in R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted; and Z.sup.1 and Z.sup.2 together form a moiety derived from a sugar; the method comprising: (a) preparing a mixture comprising (i) water, (ii) a compound of formula (3), ##STR14## wherein P, R, A, R.sup.1, R.sup.2, and R.sup.3 are as described above; and Z.sup.1 and Z.sup.2 are OH; and (iii) mannitol; and (b) lyophilizing the mixture.

24. The method of claim 23, wherein P is R.sup.7 --C(O)--, R.sup.7 --S(O).sub.2 --, R.sup.7 --NH--C(O)--, or R.sup.7 --O--C(O)--; where R.sup.7 is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, R.sup.7 can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

25. The method of claim 24, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 is an aromatic heterocycle.

26. The method of claim 25, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

27. The method of claim 23, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.6 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

28. The method of claim 27, wherein P is (2-pyrazine)sulfonyl.

29. The method of claim 23, wherein R.sup.1, R.sup.2, and R.sup.3 are each independently hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5 in each instance is C.sub.6 -C.sub.10 aryl, (C.sub.6 -C.sub.10)ar(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alk(C.sub.6 --C.sub.10)aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.8 alkoxy, or C.sub.1 -C.sub.8 alkylthio; wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R.sup.1, R.sup.2, R.sup.3, or R.sup.5 can be optionally substituted.

30. The method of claim 23, 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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid; N-(8-quinoline)sulfonyl-.beta.-(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.

31. The method of claim 23, wherein the compound of formula (1) is D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

32. The method of claim 30, wherein the compound of formula (3) is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

33. The method of claim 23, wherein the mixture further comprises a water-miscible solvent.

34. The method of claim 33, wherein the water-miscible solvent is an alcohol.

35. The method of claim 34, wherein the alcohol is tert-butanol.

36. The method of claim 23, wherein mannitol and the compound of formula (3) are present in at least a 1:1 ratio.

37. The method of claim 23, wherein the mannitol and the compound of formula (3) are present in at least a 5:1 ratio.

38. A lyophilized cake comprising the compound of claim 11.

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

40. A composition comprising the compound of claim 3 and a pharmaceutically-acceptable carrier.

41. A composition comprising the compound of claim 7 and a pharmaceutically-acceptable carrier.

42. A composition comprising the compound of claim 10 and a pharmaceutically-acceptable carrier.

43. A composition comprising the compound of claim 11 and a pharmaceutically-acceptable carrier.

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

45. A composition comprising the compound of claim 17 and a pharmaceutically-acceptable carrier.

46. A composition comprising the compound of claim 20 and a pharmaceutically-acceptable carrier.

47. A lyophilized cake comprising the compound of claim 13.

48. A lyophilized cake comprising the compound of claim 17.

49. A lyophilized cake comprising the compound of claim 20.

50. The method of claim 23 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

51. The method of claim 24 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

52. The method of claim 28 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

53. The method of claim 31 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

54. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 23 and (ii) a pharmaceutically-acceptable carrier.

55. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 24 and (ii) a pharmaceutically-acceptable carrier.

56. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 28 and (ii) a pharmaceutically-acceptable carrier.

57. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 31 and (ii) a pharmaceutically-acceptable carrier.

58. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 23.

59. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 24.

60. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 28.

61. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 31.

62. The compound of claim 6 wherein P is (2-pyrazine)carbonyl.

63. A composition comprising the compound of claim 62 and a pharmaceutically-acceptable carrier.

64. The compound of claim 16, wherein P is (2-pyrazine)carbonyl.

65. A composition comprising the compound of claim 64 and a pharmaceutically-acceptable carrier.

66. A lyophilized cake comprising the compound of claim 64.

67. The method of claim 27, wherein P is (2-pyrazine)carbonyl.

68. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 67 and (ii) a pharmaceutically-acceptable carrier.

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

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

71. The compound of claim 70, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from D-mannitol.

72. The compound of claim 71, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.6 alkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl; and P is (2-pyrazine)carbonyl.

73. A composition comprising the compound of claim 70 and a pharmaceutically-acceptable carrier.

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

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

76. The compound of claim 11, wherein P and R together form a cyclic moiety.

77. The compound of claim 76, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from D-mannitol.

78. The compound of claim 77, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.6 alkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl; and P is (2-pyrazine)carbonyl.

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

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

81. A composition comprising the compound of claim 78 and a pharmaceutically-acceptable carrier.

82. A lyophilized cake comprising the compound of claim 76.

83. A lyophilized cake comprising the compound of claim 77.

84. A lyophilized cake comprising the compound of claim 78.

85. The method of claim 23, wherein P and R together form a cyclic moiety.

86. The method of claim 85, wherein A is zero; R is hydrogen or C.sub.1 -C.sub.8 alkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl; and P is (2-pyrazine)carbonyl.

87. The method of claim 88 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

88. The method of claim 86 further comprising (c) reconstituting the lyophilized mixure with a pharmaceutically-acceptable carrier.

89. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 85 and (ii) a pharmaceutically-acceptable carrier.

90. A composition comprising (i) the compound of formula (1)prepared in accordance with the method of claim 86 and (ii) a pharmaceutically-acceptable carrier.

91. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 85.

92. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 86.
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