[의약품]Millennium Pharmaceuticals, Inc. 대 Hetero Labs Limited/ Hetero USA, Inc. 간의 의약품 관련 특허 분쟁

발생일자 2015.01.14

사건번호 1:15-cv-00039

법원국가 UNITED STATES OF AMERICA

관할법원명 D.C.Delaware(지방법원)

침해권리 특허

원고명 Millennium Pharmaceuticals, Inc. ( 미국 / 외국기업 )

피고명 Hetero Labs Limited/ Hetero USA, Inc. ( 미국 / 외국기업 )

소송유형 침해금지

분쟁내용

[Millennium Pharmaceuticals, Inc. v. Hetero Labs Limited et al] 사건번호 1:15-cv-00039에 따르면 원고 Millennium Pharmaceuticals, Inc.는 피고 Hetero Labs Limited/ Hetero USA, Inc.을 상대로 특허 US6713446, US6958319 을 침해하였다는 이유로 미국 델라웨어 지방법원에 소를 제기하였다. 원고 Millennium Pharmaceuticals, Inc.는 또한 동일 특허 침해를 이유로 Onco Therapies Limited/ Agila Specialties, Inc.를 상대로도 같은 날 동일법원에 소를 제기하였다

분쟁결과 분쟁중

산업분류 화학∙바이오 > 의약품

계쟁제품 Bortezomib for injection, 3.5 mg/vial, a generic version of VELCADE for Injection

지재권번호/명칭

US6713446 Formulation of boronic acid compounds

US6958319 Formulation of boronic acid compounds

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.

Formulation of boronic acid compounds

Claims

What is claimed is:

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.

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.

Claims

What is claimed is:

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.

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 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.

7. The compound of claim 6, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

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

11. 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.

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-.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.

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

14. 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, alkaryl, cycloalkyl, hererocyclyl, 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.

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 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.

20. The compound of claim 19, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

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

24. The compound of claim 14, 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.

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-.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-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.degree. C. for at least one month.

28. The compound of claim 14, wherein the compound is stable at 40.degree. C. for at least one month.

29. 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, 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; 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' 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 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.

34. The method of claim 33, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.6 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

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

38. The method of claim 29, 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.

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-.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.

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.

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

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.

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.

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.

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.

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.

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.

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

80. The compound of claim 79, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from a monosaccharide or disaccharide.

81. The compound of claim 80, 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.

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.

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

86. The compound of claim 85, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from a monosaccharide or disaccharide.

87. The compound of claim 86, 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.

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.

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

95. The method of claim 94, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from a monosaccharide or disaccharide.

96. The method of claim 95, 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.

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.