Formulation of boronic acid compounds
DC CAFCFirst Claim
Patent Images
1. A compound of the formula (1):
-
whereinP is hydrogen or an amino-group protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3, or R5 can be optionally substituted; and
Z1 and Z2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
2 Assignments
Litigations
0 Petitions
Accused Products
Abstract
The present invention provides stable compounds prepared from boronic acid and lyophilized compounds thereof of the formula (1):
in which Z1 and Z2 are moieties derived from sugar. The invention also provides methods for preparing such compounds. Lyophilizing a mixture comprising a boronic acid compound and a moiety derived from sugar produces a stable composition that readily releases the boronic acid compound upon reconstitution in aqueous media.
110 Citations
105 Claims
-
1. A compound of the formula (1):
-
wherein P is hydrogen or an amino-group protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3, or R5 can be optionally substituted; and Z1 and Z2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 47, 48, 49, 50, 71, 72, 79, 80, 81, 82, 83, 84)
R is hydrogen or C1-C8 alkyl; and
R3 is C1-C6 alkyl.
-
-
10. The compound of claim 9, wherein P is (2-pyrazine)sulfonyl.
-
11. The compound of claim 1, wherein
R1, R2, and R3 are each independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or — - CH2—
R5;
R5 in each instance is C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6)alk(C6-C10)aryl, C3-C10 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkylthio;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R1, R2, R3, or R5 can be optionally substituted.
- CH2—
-
12. The compound of claim 1, wherein said compound is a sugar ester of:
-
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;
N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(8-quinoline)sulfonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;
orN-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
-
-
13. The compound of claim 1, wherein said compound is a sugar ester of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.
-
47. A composition comprising the compound of claim 1 and a pharmaceutically-acceptable carrier.
-
48. A composition comprising the compound of claim 6 and a pharmaceutically-acceptable carrier.
-
49. A composition compiising the compound of claim 10 and a pharmaceutically-acceptable carrier.
-
50. A composition comprising the compound of claim 13 and a pharmaceutically-acceptable carrier.
-
71. The compound of claim 9, wherein P is (2-pyrazine)carbonyl.
-
72. A composition comprising the compound of claim 71 and a pharmaceutically-acceptable carrier.
-
79. The compound of claim 1, wherein P and R together form a cyclic moiety.
-
80. The compound of claim 79, wherein Z1 and Z2 together form a moiety derived from a monosaccharide or disaccharide.
-
81. The compound of claim 80, wherein
A is zero; -
R is hydrogen or C1-C8 alkyl;
R3 is C1-C6 alkyl; and
P is (2-pyrazine)carbonyl.
-
-
82. A composition comprising the compound of claim 79 and a pharmaceutically-acceptable carrier.
-
83. A composition comprising the compound of claim 80 and a pharmaceutically-acceptable carrier.
-
84. A composition comprising the compound of claim 81 and a pharmaceutically-acceptable carrier.
-
14. A lyophilized compound of the formula (1):
-
wherein P is hydrogen or an amino-group protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, hererocyclyl, or heteroaryl in R1, R2, R3, or R5 can be optionally substituted; and Z1 and Z2 together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom. - View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 46, 51, 52, 53, 54, 55, 56, 57, 73, 74, 75, 85, 86, 87, 88, 89, 90, 91, 92, 93)
R is hydrogen or C1-C8 alkyl; and
R3 is C1-C6 alkyl.
-
-
23. The compound of claim 22, wherein P is (2-pyrazine)sulfonyl.
-
24. The compound of claim 14, wherein
R1, R2, and R3 are each independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or — - CH2—
R5;
R5 in each instance is C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6)alk(C6-C10)aryl, C3-C10 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkylthio;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R1, R2, R3, or R5 can be optionally substituted.
- CH2—
-
25. The compound of claim 20, wherein said compound is a sugar ester of:
-
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;
N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(8-quinoline)sulfonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-(O-benzyl)-L-trosine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;
orN-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
-
-
26. The lyophilized compound of claim 20, wherein said compound is a sugar ester of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.
-
27. The compound of claim 14, wherein the compound is stable at 0°
- C. for at least one month.
-
28. The compound of claim 14, wherein the compound is stable at 40°
- C. for at least one month.
-
46. A lyophilized cake comprising the compound of claim 14.
-
51. A composition comprising the compound of claim 14 and a pharmaceutically-acceptable carrier.
-
52. A composition comprising the compound of claim 19 and a pharmaceutically-acceptable carrier.
-
53. A composition comprising the compound of claim 23 and a pharmaceutically-acceptable carrier.
-
54. A composition comprising the compound of claim 26 and a pharmaceutically-acceptable carrier.
-
55. A lyophilized cake comprising the compound of claim 19.
-
56. A lyophilized cake comprising the compound of claim 23.
-
57. A lyophilized cake comprising the compound of claim 26.
-
73. The compound of claim 22, wherein P is (2-pyrazine)carbonyl.
-
74. A composition comprising the compound of claim 73 and a pharmaceutically-acceptable carrier.
-
75. A lyophilized cake comprising the compound of claim 73.
-
85. The compound of claim 14, wherein P and R together form a cyclic moiety.
-
86. The compound of claim 85, wherein Z1 and Z2 together form a moiety derived from a monosaccharide or disaccharide.
-
87. The compound of claim 86, wherein
A is zero; -
R is hydrogen or C1-C8 alkyl;
R3 is C1-C6 alkyl; and
P is (2-pyrazine)carbonyl.
-
-
88. A composition comprising the compound of claim 85 and a pharmaceutically-acceptable carrier.
-
89. A composition comprising the compound of claim 86 and a pharmaceutically-acceptable carrier.
-
90. A composition comprising the compound of claim 87 and a pharmaceutically-acceptable carrier.
-
91. A lyophilized cake comprising the compound of claim 85.
-
92. A lyophilized cake comprising the compound of claim 86.
-
93. A lyophilized cake comprising the compound of claim 87.
-
29. A method of preparing a lyophilized compound of the formula (1):
-
wherein P is hydrogen or an amino-group protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5 in each instance is aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3, or R5 can be optionally substituted; and Z1 and Z2 together form a moiety derived from a sugar;
the method comprising;
(a) preparing a mixture comprising (i) water, (ii) a compound of formula (3). wherein P, R, A, R1, R2, and R3 are as described above; and Z′ and
Z″
are OH; and
(iii) a sugar; and
(b) lyophilizing the mixture. - View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 76, 77, 78, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105)
R is hydrogen or C1-C6 alkyl; and
R3 is C1-C6 alkyl.
-
-
37. The method of claim 36, wherein P is (2-pyrazine)sulfonyl.
-
38. The method of claim 29, wherein
R1, R2, and R3 are each independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or — - CH2—
R5;
R5 in each instance is C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6)alk(C6-C10)aryl, C3-C10 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkylthio;
wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R1, R2, R3, or R5 can be optionally substituted.
- CH2—
-
39. The method of claim 29, wherein the compound of formula (3) is:
-
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;
N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(8-quinoline)sulfonyl-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;
N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;
orN-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.
-
-
40. The method of claim 39, wherein the compound of formula (3) is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.
-
41. The method of claim 29, wherein the mixture further comprises a water-miscible solvent.
-
42. The method of claim 41, wherein the water-miscible solvent is an alcohol.
-
43. The method of claim 42, wherein the alcohol is tert-butanol.
-
44. The method of claim 29, wherein the sugar and the compound of formula (3) are present in at least a 1:
- 1 raiio.
-
45. The method of claim 29, wherein the sugar and the compound of formula (3) are present in at least a 5:
- 1 ratio.
-
58. The method of claim 37, wherein A is 0.
-
59. The method of claim 29 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
60. The method of claim 33 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
61. The method of claim 37 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
62. The method of claim 40 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
63. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 29 and (ii) a pharmaceutically-acceptable carrier.
-
64. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 33 and (ii) a pharmaceutically-acceptable carrier.
-
65. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 37 and (ii) a pharmaceutically-acceptable carrier.
-
66. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 40 and (ii) a pharmaceutically-acceptable carrier.
-
67. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 29.
-
68. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 33.
-
69. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 37.
-
70. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 40.
-
76. The method of claim 36, wherein P is (2-pyrazine)carbonyl.
-
77. A composition comprising the compound of claim 76 and a pharmaceutically-acceptable carrier.
-
78. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 76.
-
94. The method of claim 29, wherein P and R together form a cyclic moiety.
-
95. The method of claim 94, wherein Z1 and Z2 together form a moiety derived from a monosaccharide or disaccharide.
-
96. The method of claim 95, wherein
A is zero; -
R is hydrogen or C1-C8 alkyl;
R3 is C1-C6 alkyl; and
P is (2-pyrazine)carbonyl.
-
-
97. The method of claim 94 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
98. The method of claim 95 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
99. The method of claim 96 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
-
100. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 94 and (ii) a pharmaceutically-acceptable carrier.
-
101. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 95 and (ii) a pharmaceutically-acceptable carrier.
-
102. A composition comprising (i) the compound of formula (1) prepared in accordance with the method of claim 96 and (ii) a pharmaceutically-acceptable carrier.
-
103. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 94.
-
104. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 95.
-
105. A lyophilized cake comprising the compound of formula (1) prepared in accordance with the method of claim 96.
Specification