Formulation of boronic acid compounds
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorShanker Lal Gupta
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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.
Claims92
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, and wherein the sugar is mannitol.
The compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.
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, alkyaryl, cycloalkyl, heterocyclyl, or heteroaryl in R1, R2, R3, or R5 can be optionally substituted;
- and
- Z1 and Z2 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.
The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.
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, alkyaryl, 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 Z1 and Z2 are OH;
- and
- (iii) mannitol;
- and
- (b) lyophilizing the mixture.
The method of claim 88 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.
Dependencies are inferred from the claim text.