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Details for Patent: 6,699,835

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Details for Patent: 6,699,835

Title: Formulation of boronic acid compounds
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.
Inventor(s): Plamondon; Louis (Watertown, MA), Grenier; Louis (Medford, MA), Adams; Julian (Brookline, MA), Lal Gupta; Shanker (Rockville, MD)
Assignee: The United States of America as represented by the Department of Health and Human Services (Washington, DC) N/A (Cambridge, MA) Millennium Pharmaceuticals, Inc. (N/A)
Filing Date:Jan 25, 2002
Application Number:10/056,563
Claims:1. A compound having formula (1): ##STR16##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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 mannitol or sorbitol.

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

6. The compound of claim 1, wherein P is one of 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 one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y 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 unsaturated, 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)carbonyl or (2-pyrazine)sulfonyl.

11. The compound of claim 6, wherein: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, or C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of 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; where the ring portion of any of 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 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-.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.

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

14. A compound having formula (8): ##STR17##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; and R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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.

15. A compound having formula (9): ##STR18##

16. A composition comprising a compound of formula (2) ##STR19##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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.3 and Z.sup.4 together form a moiety derived from a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O;

in a lyophilized powder.

17. The composition of claim 16, wherein P is one of 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 one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y 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 unsaturated, or aromatic heterocycle.

18. The composition of claim 17, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C .sub.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 Z.sup.3 and Z.sup.4 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: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, or C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of 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; where the ring portion of any of 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.

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-.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.

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): ##STR20##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; and R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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;

in a lyophilized powder.

32. A composition, comprising a compound of formula (9): ##STR21##

in a lyophilized powder.

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): ##STR22##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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.5 and Z.sup.6 are each OH.

35. The method of claim 34, wherein P is one of 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 one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y 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 unsaturated, or aromatic heterocycle.

36. The method of claim 35, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.10 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

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

40. The method of claim 35, wherein: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, or C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of 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; where the ring portion of any of 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.

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-.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; 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.

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): ##STR23##

wherein: n is an integer from 0 to about 10; W, at each occurrence, has formula (6): ##STR24##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; and R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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.

54. The method of claim 53, wherein P is one of 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 one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y 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 unsaturated, or aromatic heterocycle.

55. The method of claim 54, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 alkyl.

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

59. The method of claim 54, wherein: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, or C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of 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; where the ring portion of any of 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.

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-.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; 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): ##STR25##

75. The method of claim 53, wherein the boronic acid anhydride compound consists essentially of a boroxine having formula (7): ##STR26##

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.

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

79. A boronic acid anhydride compound comprising one or more compounds of formulae (4) and (5): ##STR27##

wherein: n is an integer from 0 to about 10; W, at each occurrence, has formula (6): ##STR28##

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 independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; and R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of 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.

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 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 one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when Y 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 unsaturated, or aromatic heterocycle.

84. The boronic acid anhydride compound of claim 79, wherein P is R.sup.7 --C(O)-- or R.sup.7 --S(O).sub.2 --, and R.sup.7 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 C.sub.1 -C.sub.8 alkyl; and R.sup.3 is C.sub.1 -C.sub.6 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: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, or C.sub.6 -C.sub.10 aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of 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; where the ring portion of any of 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.

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

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): ##STR29##

92. A boronic acid anhydride compound consisting essentially of a boroxine having formula (7): ##STR30##
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