Formulation of boronic acid compounds

Details Formulation of boronic acid compounds Formulation of boronic acid compounds

2002-01-25

2004-03-30

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S019300, C514S064000, C536S017100, C562S007000, C530S322000

Reexamination Certificate

active

06713446

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the formulation of pharmaceutical compounds. More particularly, the invention relates to stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also relates to methods for preparing such compositions.
BACKGROUND OF THE INVENTION
Boronic acid and ester compounds display a variety of pharmaceutically useful biological activities. Shenvi et al., U.S. Pat. No. 4,499,082 (1985), discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Pat. No. 5,187,157 (1993); U.S. Pat. No. 5,242,904 (1993); and U.S. Pat. No. 5,250,720 (1993), describe a class of peptide boronic acids that inhibit trypsin-like proteases. Kleeman et al., U.S. Pat. No. 5,169,841 (1992), discloses N-terminally modified peptide boronic acids that inhibit the action of renin. Kinder et al., U.S. Pat. No. 5,106,948 (1992), discloses that certain tripeptide boronic acid compounds inhibit the growth of cancer cells.
Adams et al., U.S. Pat. No. 5,780,454 (1998), U.S. Pat. No. 6,066,730 (2000), U.S. Pat. No. 6,083,903 (2000), and U.S. Pat. No. 6,297,217 (2001), hereby incorporated by reference in their entirety, describe peptide boronic ester and acid compounds useful as proteasome inhibitors. The references also describe the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-&kgr;B in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, to inhibit antigen presentation in a cell, to inhibit NF-&kgr;B dependent cell adhesion, and to inhibit HIV replication. Brand et al., WO 98/35691, teaches that proteasome inhibitors, including boronic acid compounds, are useful for treating infarcts such as those that occur during stroke or myocardial infarction. Elliott et al., WO 99/15183, teaches that proteasome inhibitors are useful for treating inflammatory and autoimmune diseases.
Unfortunately, alkylboronic acids are relatively difficult to obtain in analytically pure form. Snyder et al.,
J. Am. Chem. Soc
., 3611 (1958), teaches that alkylboronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions. Also, alkylboronic acids and their boroxines are often air-sensitive. Korcek et al.,
J. Chem. Soc., Perkin Trans
. 2 242 (1972), teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid. These difficulties limit the pharmaceutical utility of boronic acid compounds, complicating the characterization of pharmaceutical agents comprising boronic acid compounds and limiting their shelf life.
There is thus a need in the art for improved formulations of boronic acid compounds. Ideally, such formulations would be conveniently prepared, would exhibit enhanced stability and longer shelf life as compared to the free boronic acid compound, and would readily liberate the bioactive boronic acid compound when administered to a subject in need of boronic acid therapy.
SUMMARY OF THE INVENTION
The present invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also provides methods for preparing such compositions. The invention provides the discovery that lyophilization of an aqueous mixture comprising a boronic acid compound and a compound having at least two hydroxyl groups produces a stable composition that readily releases the boronic acid compound upon dissolution in aqueous media.
In a first aspect, the invention provides compounds having formula (1):
wherein:
P is hydrogen or an amino-group protecting moiety;
R is hydrogen or alkyl;
A is 0, 1, or 2;
R
1
, R
2
, and R
3
are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH
2
—R
5
;
R
5
, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —W—R
6
, where W is a chalcogen and R
6
is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R
1
, R
2
, R
3
or R
5
can be optionally substituted; and
Z
1
and Z
2
together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
In a second aspect, the invention provides 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;
R
1
, R
2
, and R
3
are independently hydrogen, alkyl, cycloalkyl, aryl, or —CH
2
—R
5
;
R
5
, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —W—R
6
, where W is a chalcogen and R
6
is alkyl;
where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R
1
, R
2
, R
3
or R
5
can be optionally substituted; and
Z
3
and Z
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.
In a third aspect, the invention provides a method for formulating a boronic acid compound, the method comprising:
(a) preparing a mixture comprising
(i) water,
(ii) a boronic acid compound; and
(iii) 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.
In a fourth aspect, the invention provides compositions prepared by the methods of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
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.
For purposes of the present invention, the following definitions will be used:
As used herein, the terms “formulate” and “formulation” refer to the preparation of a boronic acid compound in a form suitable for administration to a mammalian subject, preferably a human. Often, formulation of the boronic acid compound comprises addition of pharmaceutically acceptable excipients, diluents, or carriers. In some embodiments, formulation of the boronic acid compound comprises formation of a chemical derivative of the boronic acid compound, preferably formation of a boronate ester. The term “formulation” refers to any form commonly used for pharmaceutical administration, including solids, liquids, suspensions, creams, and gels. For purposes of the present invention, the formulation is preferably a lyophilized powder.
As used herein, the term “lyophilized powder” refers to any solid material obtained by lyophilization of an aqueous mixture.
By “stable formulation” is meant any formulation having sufficient stability to have utility as a pharmaceutical agent. Preferably, the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0° C. and 40° C., for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
As employed herein, the term “boronic acid” refers to any chemical compound comprising a —B(OH), moiety. Snyder et al.,
J. Am. Chem. Soc
. 3611 (1958), teaches that alkyl boronic acid compounds readily form oligomeric anhydrides by dehydration of the boronic acid moiety. Thus, unless otherwise apparent from context, the term “boronic acid” is expressly intended to encompass free boronic acids, oligomeric anhydrides, including, but not limited to, dimers, trimers, and tetramers, and mixtures thereof.
As employed herein, the term “compound having at least two hydroxyl groups” refers to any compound having two or more hydroxyl groups. For purposes of the present invention, the two hydroxyl groups are p

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