Formulation of boronic acid compounds
First Claim
Patent Images
1. A compound having 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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of 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.
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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.
93 Citations
92 Claims
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1. A compound having 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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of 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)
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.
-
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7. The compound of claim 6, wherein P is R7—
- C(O)—
or R7—
S(O)2—
, and R7 is an aromatic heterocycle.
- C(O)—
-
8. The compound of claim 7, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
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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.
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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.
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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;
orD-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.
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13. The compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.
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14. A compound having formula (8):
-
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5; and
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5can be optionally substituted.
-
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15. A compound having formula (9):
-
16. A composition comprising a compound of formula (2)
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
Z3 and Z4 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. - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
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.
-
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18. The composition of claim 17, wherein P is R7—
- C(O)—
or R7—
S(O)2—
, and R7 is an aromatic heterocycle.
- C(O)—
-
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.
-
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21. The composition of claim 20, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
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22. The composition of claim 16, wherein the compound having at least two hydroxyl groups is a sugar.
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23. The composition of claim 22, wherein the sugar is a monosaccharide or disaccharide.
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24. The composition of claim 22, wherein the sugar is a reduced sugar.
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25. The composition of claim 24, wherein the reduced sugar is mannitol or sorbitol.
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26. The composition of claim 16, wherein Z3 and Z4 together form a moiety derived from mannitol.
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27. The composition of claim 26, wherein the mannitol is D-mannitol.
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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.
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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;
orD-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.
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30. A composition, comprising D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate in a lyophilized powder.
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31. A composition, comprising a compound of formula (8):
-
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5; and
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted;
in a lyophilized powder.
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32. A composition, comprising a compound of formula (9):
-
in a lyophilized powder.
-
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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. - View Dependent Claims (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 78)
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted; and
Z5 and Z6 are each OH.
-
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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.
- C(O)—
-
36. The method of claim 35, wherein P is R7—
- C(O)—
or R7—
S(O)2—
, and R7 is an aromatic heterocycle.
- C(O)—
-
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.
-
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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.
-
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42. The method of claim 33, wherein the boronic acid compound is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.
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43. The method of claim 33, wherein the compound having at least two hydroxyl groups is pharmaceutically acceptable.
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44. The method of claim 43, wherein the compound having at least two hydroxyl groups is a sugar.
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45. The method of claim 44, wherein the sugar is a monosaccharide or disaccharide.
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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.
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49. The method of claim 48, wherein the mannitol is D-mannitol.
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50. The method of claim 33, wherein the aqueous mixture further comprises a water-miscible co-solvent.
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51. The method of claim 50, wherein the water-miscible co-solvent is an alcohol.
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78. A composition prepared according to the method of claim 33 or 52.
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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. - View Dependent Claims (53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)
wherein; n is an integer from 0 to about 10;
W, at each occurrence, has formula (6);
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5; and
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted.
-
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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.
- C(O)—
-
55. The method of claim 54, wherein P is R7—
- C(O)—
or R7—
S(O)2—
, and R7 is an aromatic heterocycle.
- C(O)—
-
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
R3 is C1-C6 alkyl.
-
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58. The method of claim 57, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
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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.
-
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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.
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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.
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62. The method of claim 53, wherein the compound having at least two hydroxyl groups is pharmaceutically acceptable.
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63. The method of claim 62, wherein the compound having at least two hydroxyl groups is a sugar.
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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.
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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.
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79. A boronic acid anhydride compound comprising one or more compounds of formulae (4) and (5):
-
wherein; n is an integer from 0 to about 10;
W, at each occurrence, has formula (6);
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 independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5; and
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —
W—
R6, where W is a chalcogen and R6 is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3 or R5 can be optionally substituted. - View Dependent Claims (80, 81, 82, 83, 84, 85, 86, 87, 88, 89)
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.
- C(O)—
-
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.
-
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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):
Specification