U.S. patent application number 15/309425 was filed with the patent office on 2017-06-22 for salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof.
The applicant listed for this patent is Rempex Pharmaceuticals, Inc.. Invention is credited to Joanna A. Bis, Pingyun Chen, Senthil Kumar Kusalakumari Sukumar.
Application Number | 20170173055 15/309425 |
Document ID | / |
Family ID | 54392859 |
Filed Date | 2017-06-22 |
United States Patent
Application |
20170173055 |
Kind Code |
A1 |
Bis; Joanna A. ; et
al. |
June 22, 2017 |
SALTS AND POLYMORPHS OF CYCLIC BORONIC ACID ESTER DERIVATIVES AND
THERAPEUTIC USES THEREOF
Abstract
Disclosed herein is the crystalline form of the potassium salt
of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. The crystalline form maybe formulated for treating
subjects with bacterial infection. Accordingly, some embodiments
relate to compositions and methods of administering the potassium
salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
Inventors: |
Bis; Joanna A.; (Cary,
NC) ; Chen; Pingyun; (Chapel Hill, NC) ;
Kusalakumari Sukumar; Senthil Kumar; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rempex Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
54392859 |
Appl. No.: |
15/309425 |
Filed: |
April 29, 2015 |
PCT Filed: |
April 29, 2015 |
PCT NO: |
PCT/US15/28265 |
371 Date: |
November 7, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61988524 |
May 5, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02A 50/401 20180101;
Y02A 50/471 20180101; A61P 31/04 20180101; C07F 5/025 20130101;
A61K 31/69 20130101; Y02A 50/473 20180101; Y02A 50/475 20180101;
A61K 31/397 20130101; Y02A 50/483 20180101; Y02A 50/30 20180101;
A61P 31/10 20180101; A61K 2121/00 20130101; A61K 2300/00 20130101;
A61K 31/545 20130101; Y02A 50/47 20180101; Y02A 50/478
20180101 |
International
Class: |
A61K 31/69 20060101
A61K031/69; A61K 31/397 20060101 A61K031/397; A61K 31/545 20060101
A61K031/545; C07F 5/02 20060101 C07F005/02 |
Claims
1. A potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
2. The potassium salt of claim 1, wherein the potassium salt is in
a crystalline form exhibiting an X-ray powder diffraction pattern
comprising at least three characteristic peaks selected from the
group consisting of peaks at approximately 7.3.degree.,
13.9.degree., 16.9.degree., 19.1.degree., 20.8.degree., and
25.2.degree. 2.theta..
3. The potassium salt of claim 2, exhibiting an X-ray powder
diffraction pattern comprising at least peaks at approximately 7.3,
13.9.degree., 16.9.degree., 19.1.degree., 20.8.degree., and
25.2.degree. 2.theta..
4. The potassium salt of claim 3, exhibiting an X-ray powder
diffraction pattern comprising at least peaks at approximately
7.3.degree., 13.9.degree., 14.6.degree., 16.9.degree.,
17.9.degree., 19.1.degree., 20.8.degree., 21.3.degree.,
25.2.degree., and 25.6.degree. 2.theta..
5. The potassium salt of claim 1, wherein said crystalline form has
a melting point of 199.0.degree. C.
6. The potassium salt of claim 1 having an X-ray powder diffraction
pattern substantially the same as shown in FIG. 1.
7. A pharmaceutical composition comprising the potassium salt of
claim 1 and a pharmaceutically acceptable excipient or a
pharmaceutically acceptable liquid carrier.
8. (canceled)
9. The pharmaceutical composition of claim 7, further comprising an
additional medicament selected from an antibacterial agent,
antifungal agent, an antiviral agent, an anti-inflammatory agent,
or an anti-allergic agent.
10. (canceled)
11. The pharmaceutical composition of claim 10, wherein the
additional medicament is a .beta.-lactam antibacterial agent
selected from Ceftazidime, Biapenem, Doripenem, Ertapenem,
Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN
2416, or Carumonam.
12. (canceled)
13. (canceled)
14. (canceled)
15. The pharmaceutical composition of claim 7, comprising a unit
dose from 0.1 mg to 5 g of the crystalline form of the potassium
salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
16. A method of treating a bacterial infection, comprising
administering to a subject in need thereof, a composition according
to claim 7.
17. The method of claim 16, further comprising administering an
additional medicament selected from all antibacterial agent,
aritifungal agent, an antiviral agent, an anti-inflammatory agent,
or an anti-allergic agent.
18. (canceled)
19. The method of claim 17, wherein the additional medicament is a
.beta.-lactam antibacterial agent selected from Ceftazidime,
Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem,
Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
20. (canceled)
21. (canceled)
22. (canceled)
23. The method of claim 16, wherein the subject is a mammal.
24. The method of claim 23, wherein the mammal is a human.
25. (canceled)
26. (canceled)
27. The method of claim 16, comprising administering the
composition intravenously or orally to the subject.
28. (canceled)
29. A sterile container, comprising: the composition according to
claim 7.
30. A sterile container, comprising: the potassium salt according
to claim 1.
31. A method of preparing a pharmaceutical composition for
administration, comprising reconstituting the contents of the
sterile container of claim 29 using a pharmaceutically acceptable
liquid carrier.
32. The method of any one of claims 31, wherein the liquid carrier
is a saline solution or dextrose solution.
33. (canceled)
34. (canceled)
35. A process of making a crystalline form of a potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid, comprising: combining a purified
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid with a solvent to form an intermediate solution;
intermixing a potassium ion with the intermediate solution; and
isolating the crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
36. The process of claim 35, wherein the potassium ion is from
potassium hydroxide or potassium t-butoxide.
37. (canceled)
38. The process of claim 35, wherein the solvent is selected from
the group consisting of tetrahydrofuran, 1,4-dioxane, acenitrile,
acetone, ethyl acetate, methyl tert-butyl ether, water, and any
combinations thereof.
39. The process of claim 38, wherein the solvent is acetone or
acenitrile.
Description
BACKGROUND OF THE INVENTION
[0001] Field of the Invention
[0002] The present invention relates to salts and polymorphs of
cyclic boronic acid ester derivatives, compositions, their use and
preparation as therapeutic agents for treating bacterial infection.
In particular, the present invention relates to a potassium salt of
2-((3R,6S)-2-hydroxy-3
-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
[0003] Description of the Related Art
[0004] Antibiotics have been effective tools in the treatment of
infectious diseases during the last half-century. From the
development of antibiotic therapy to the late 1980s there was
almost complete control over bacterial infections in developed
countries. However, in response to the pressure of antibiotic
usage, multiple resistance mechanisms have become widespread and
are threatening the clinical utility of anti-bacterial therapy. The
increase in antibiotic resistant strains has been particularly
common in major hospitals and care centers. The consequences of the
increase in resistant strains include higher morbidity and
mortality, longer patient hospitalization, and an increase in
treatment costs
[0005] Various bacteria have evolved .beta.-lactam deactivating
enzymes, namely, .beta.-lactamases, that counter the efficacy of
the various .beta.-lactams. .beta.-lactamases can be grouped into 4
classes based on their amino acid sequences, namely, Ambler classes
A, B, C, and D. Enzymes in classes A, C, and D include active-site
serine .beta.-lactamases, and class B enzymes, which are
encountered less frequently, are Zn-dependent. These enzymes
catalyze the chemical degradation of .beta.-lactam antibiotics,
rendering them inactive. Some .beta.-lactamases can be transferred
within and between various bacterial strains and species. The rapid
spread of bacterial resistance and the evolution of multi-resistant
strains severely limits .beta.-lactam treatment options
available.
[0006] The increase of class D .beta.-lactamase-expressing
bacterium strains such as Acinetobacter baumannii has become an
emerging multidrug-resistant threat. A. baumannii strains express
A, C, and D class .beta.-lactamases. The class D .beta.-lactamases
such as the OXA families are particularly effective at destroying
carbapenem type .beta.-lactam antibiotics, e.g., imipenem, the
active carbapenems component of Merck's Primaxin.RTM. (Montefour,
K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert
Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J.
Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou,
G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This
has imposed a pressing threat to the effective use of drugs in that
category to treat and prevent bacterial infections. Indeed the
number of catalogued serine-based .beta.-lactamases has exploded
from less than ten in the 1970s to over 300 variants. These issues
fostered the development of five "generations" of cephalosporins.
When initially released into clinical practice, extended-spectrum
cephalosporins resisted hydrolysis by the prevalent class A
.beta.-lactamases, TEM-1 and SHV-1. However, the development of
resistant strains by the evolution of single amino acid
substitutions in TEM-1 and SHV-1 resulted in the emergence of the
extended-spectrum .beta.-lactamase (ESBL) phenotype.
[0007] New .beta.-lactamases have recently evolved that hydrolyze
the carbapenem class of antimicrobials, including imipenem,
biapenem, doripenem, meropenem, and ertapenem, as well as other
.beta.-lactam antibiotics. These carbapenemases belong to molecular
classes A, B, and D. Class A carbapenemases of the KPC-type
predominantly in Klebsiella pneumoniae but now also reported in
other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter
baumannii. The KPC carbapenemase was first described in 1996 in
North Carolina, but since then has disseminated widely in the US.
It has been particularly problematic in the New York City area,
where several reports of spread within major hospitals and patient
morbidity have been reported. These enzymes have also been recently
reported in France, Greece, Sweden, United Kingdom, and an outbreak
in Germany has recently been reported. Treatment of resistant
strains with carbapenems can be associated with poor outcomes.
[0008] Another mechanism of .beta.-lactamase mediated resistance to
carbapenems involves combination of permeability or efflux
mechanisms combined with hyper production of beta-lactamases. One
example is the loss of a porin combined in hyperproduction of ampC
beta-lactamase results in resistance to imipenem in Pseudomonas
aeruginosa. Efflux pump over expression combined with
hyperproduction of the ampC .beta.-lactamase can also result in
resistance to a carbapenem such as meropenem.
[0009] Because there are three major molecular classes of
serine-based .beta.-lactamases, and each of these classes contains
significant numbers of .beta.-lactamase variants, inhibition of one
or a small number of .beta.-lactamases is unlikely to be of
therapeutic value. Legacy .beta.-lactamase inhibitors are largely
ineffective against at least Class A carbapenemases, against the
chromosomal and plasmid-mediated Class C cephalosporinases and
against many of the Class D oxacillinases. Therefore, there is a
need for improved .beta.-lactamase inhibitors.
SUMMARY OF THE INVENTION
[0010] The present invention relates to antimicrobial agents and
potentiators thereof. Some embodiments include salts, polymorphs,
compounds, compositions, pharmaceutical compositions, use and
preparation thereof. In particular, come embodiments relate to
salts and polymorphs of cyclic boronic acid ester derivatives.
[0011] Some embodiments relate to a potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
[0012] In some embodiments, the potassium salt is in a crystalline
form exhibiting an X-ray powder diffraction pattern comprising at
least three characteristic peaks selected from the group consisting
of peaks at approximately 7.3.degree., 13.9.degree., 16.9.degree.,
19.1.degree., 20.8.degree., and 25.2.degree. 2.theta..
[0013] Some embodiments include a pharmaceutical composition
comprising the potassium salt described herein.
[0014] Some embodiments include a pharmaceutical composition
prepared by dissolving the potassium salt described herein.
[0015] Some embodiments include a method of preventing a bacterial
infection, comprising administering to a subject in need thereof, a
composition described herein.
[0016] Some embodiments include a sterile container, comprising any
one of the foregoing composition or any one of the foregoing
potassium salt.
[0017] Some embodiments include a method of preparing a
pharmaceutical composition for administration, comprising
reconstituting the contents of any one of the foregoing the sterile
container using a pharmaceutically acceptable liquid carrier.
[0018] Some embodiments relate to a process of making a crystalline
form of a potassium salt of 2-((3R,6S)-2-hydroxy-3
-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid,
comprising combining a purified
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid with a solvent to form an intermediate solution;
intermixing a potassium counterion with the intermediate solution;
and isolating the crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of the
crystalline form of Compound 1A.
[0020] FIG. 2 shows a polarized light microscopy (PLM) image of a
sample containing the crystalline form of Compound 1A.
[0021] FIG. 3 shows thermo gravimetric (TGA) and digital scanning
calorimetry (DSC) analysis results of the crystalline form of
Compound 1A.
[0022] FIG. 4 shows a FT-Roman spectrum of the crystalline form of
Compound 1A.
[0023] FIG. 5 shows a high-performance liquid chromatography (HPLC)
analysis of the crystalline form of Compound 1A.
[0024] FIG. 6 shows the X-ray powder diffraction pattern of sodium
chloride and Compound 1 before and after purification.
[0025] FIG. 7 is the TGA of Compound 1 after purification.
[0026] FIG. 8 shows a (HPLC) analysis of Compound 1 after
purification.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] The present invention relates to salts and polymorphs of
cyclic boronic acid ester derivatives and pharmaceutical
compositions comprising the same. Some embodiments include uses
thereof, including methods of preparation, and methods of
treatment. In particular, the present invention relates to
polymorphs of a salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. More specifically, the present invention relates to
polymorphs of a potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
Compound 1
[0028] Compound 1 as used herein refers to
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2
oxaborinan-6-yl)acetic acid as shown in the structure below.
##STR00001##
[0029] Compound 1 can be made by known methods such as the
procedures described in US 2012/0040932, which is incorporated by
reference in its entirety. More specifically, the skilled artisan
given the disclosure in Example 1 of US 2012/0040932 is well
equipped to prepare Compound 1.
[0030] Compound 1 contains a boronic acid moiety that is chemically
stable in solutions having pH values between 2 and 8. The pKa of
Compound 1 is measured to be 3.92. When combined with counterions
such as potassium at suitable pH, Compound 1 can be converted into
a salt.
[0031] Some embodiments relate to a pharmaceutically acceptable
salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutically acceptable
salt is a potassium salt. In some embodiments, the pharmaceutically
acceptable salt is a calcium salt. In some embodiments, the
pharmaceutically acceptable salt is a magnesium salt.
Crystalline Form of Compound 1A
[0032] Compound 1A as used herein refers to the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. Compound 1A can be made into a pure and stable
crystalline form under controlled conditions. The X-ray powder
diffraction (PXRD) pattern of Compound 1A is substantially the same
as shown in FIG. 1, with corresponding tabulated peak data shown in
Table 1.
TABLE-US-00001 TABLE 1 Peak Data of X-ray powder diffraction (PXRD)
pattern of Compound 1A No. Pos. [.degree.2Th.] d-spacing [.ANG.]
Height [cts] 1 7.25 12.19 5999.35 2 9.23 9.59 213.77 3 13.87 6.38
1059.91 4 14.61 6.06 813.31 5 16.94 5.23 1005.45 6 17.07 5.19
664.12 7 17.45 5.08 358.32 8 17.94 4.94 635.36 9 19.05 4.66 1027.85
10 20.75 4.28 1510.77 11 21.26 4.18 654.04 12 23.34 3.81 216.52 13
23.66 3.76 379.78 14 25.15 3.54 964.68 15 25.58 3.48 484.34 16
28.33 3.15 246.72 17 31.05 2.88 304.67 18 31.38 2.85 435.25 19
32.10 2.79 311.25 20 33.65 2.66 239.27 21 34.12 2.63 196.90
[0033] Compound 1A is in a crystalline form exhibiting an X-ray
powder diffraction pattern that includes at least three
characteristic peaks selected from the group consisting of peaks at
approximately 7.3.degree., 13.9.degree., 16.9.degree.,
19.1.degree., 20.8.degree., and 25.2.degree. 2.theta.. In some
embodiments, the crystalline form of Compound 1A exhibits an X-ray
powder diffraction pattern comprising at least peaks at
7.3.degree., 13.9.degree., 16.9.degree., 19.1.degree.,
20.8.degree., and 25.2.degree. 2.theta.. In some embodiments, the
crystalline form of Compound 1A exhibits an X-ray powder
diffraction pattern comprising at least peaks at approximately
7.3.degree., 13.9.degree., 14.6.degree., 16.9.degree.,
17.9.degree., 19.1.degree., 20.8.degree., 21.2.degree.,
25.2.degree., and 25.6.degree. 2.theta..
[0034] As is well understood in the art, because of the
experimental variability when X-ray diffraction patterns are
measured on different instruments, the peak positions are assumed
to be equal if the two theta (2.theta.) values agree to within
0.2.degree. (i.e., .+-.0.2.degree.). For example, the United States
Pharmacopeia states that if the angular setting of the 10 strongest
diffraction peaks agree to within .+-.0.2.degree. with that of a
reference material, and the relative intensities of the peaks do
not vary by more than 20%, the identity is confirmed. Accordingly,
peak positions within 0.2.degree. of the positions recited herein
are assumed to be identical.
[0035] FIG. 3 shows digital scanning calorimetry (DSC) analysis
results of the crystalline form of Compound 1A. As shown in FIG. 3,
the crystalline form of the potassium salt has a melting point of
199.0.degree. C.
Process of making Crystalline Form of Compound 1A
[0036] One process for making a crystalline form of Compound 1A can
include combining a purified Compound 1 with a solvent to form an
intermediate solution; intermixing a potassium ion with the
intermediate solution; and isolating the crystalline form of
Compound 1A.
[0037] The source of potassium ion can vary. In some embodiment,
the potassium ion is from potassium hydroxide. In some embodiment,
the potassium ion is from potassium t-butoxide.
[0038] The solvent used for salt formation can vary depending on
the source of the potassium ion and reaction conditions. In some
embodiment, the solvent is selected from the group consisting of
tetrahydrofuran, 1,4-dioxane, acenitrile, acetone, ethyl acetate,
methyl tert-butyl ether, water, and any combinations thereof. In
some embodiment, the solvent is acetone or acenitrile. In some
embodiment, the solvent is acetone. In some embodiment, the solvent
is acenitrile.
Administration and Pharmaceutical Compositions
[0039] Some embodiments include pharmaceutical compositions
comprising the potassium salt described herein and a
pharmaceutically acceptable carrier. Such a composition can be
administered to a subject as part of a therapeutic treatment.
[0040] Compound 1A described herein can be administered at a
therapeutically effective dosage, e.g., a dosage sufficient to
provide treatment for disease states described herein. Suitable
dosage levels may be from about 0.1 mg/kg to about 200 mg/kg or
more of body weight, from about 0.25 mg/kg to about 120 mg/kg or
more of body weight, from about 0.5 mg/kg or less to about 70
mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or
from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for
administration to a 70 kg person, the dosage range would be from
about 17 mg per day to about 8000 mg per day, from about 35 mg per
day or less to about 7000 mg per day or more, from about 70 mg per
day to about 6000 mg per day, from about 100 mg per day to about
5000 mg per day, or from about 200 mg to about 3000 mg per day. The
amount of active compound administered will, of course, be
dependent on the subject and disease state being treated, the
severity of the affliction, the manner and schedule of
administration and the judgment of the prescribing physician.
[0041] In some embodiments, the pharmaceutical composition
described herein includes a unit dose from 0.01 mg to 10 g of the
crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutical composition
described herein includes a unit dose from 0.1 mg to 5 g of the
crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutical composition
described herein includes a unit dose from 0.1 mg to 2.5 g of the
crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutical composition
described herein includes a unit dose from 1.5 g to 2.5 g of the
crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutical composition
described herein includes a unit dose of less than 5 g, less than
4.5 g, less than 4g, less than 3.5 g, less than 3 g, less than 2.5
g of the crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid. In some embodiments, the pharmaceutical composition
described herein includes a unit dose more than 0.1 mg, more than
0.5 mg, more than 10 mg, more than 50 mg, more than 100 mg, more
than 150 mg, more than 200 mg, more than 500 mg, more than 1 g,
more than 2 g of the crystalline form of the potassium salt of
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid.
[0042] Administration of the compounds disclosed herein or the
pharmaceutically acceptable salts thereof can be via any of the
accepted modes of administration for agents that serve similar
utilities including, but not limited to, orally, subcutaneously,
intravenously, intranasally, topically, transdermally,
intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,
rectally, or intraocularly. Oral and parenteral administrations are
customary in treating the indications that are the subject of the
preferred embodiments.
[0043] The compounds useful as described above can be formulated
into pharmaceutical compositions for use in treatment of these
conditions. Standard pharmaceutical formulation techniques are
used, such as those disclosed in Remington's The Science and
Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins
(2005), incorporated by reference in its entirety.
[0044] In addition to the selected compound useful as described
above, come embodiments include compositions containing a
pharmaceutically-acceptable carrier. The term
"pharmaceutically-acceptable carrier", as used herein, means one or
more compatible solid or liquid filler diluents or encapsulating
substances, which are suitable for administration to a mammal. The
term "compatible", as used herein, means that the components of the
composition are capable of being commingled with the subject
compound, and with each other, in a manner such that there is no
interaction, which would substantially reduce the pharmaceutical
efficacy of the composition under ordinary use situations.
Pharmaceutically-acceptable carriers must, of course, be of
sufficiently high purity and sufficiently low toxicity to render
them suitable for administration preferably to an animal,
preferably mammal being treated.
[0045] Some examples of substances, which can serve as
pharmaceutically-acceptable carriers or components thereof, are
sugars, such as lactose, glucose and sucrose; starches, such as
corn starch and potato starch; cellulose and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose, and methyl
cellulose; powdered tragacanth; malt; gelatin; talc; solid
lubricants, such as stearic acid and magnesium stearate; calcium
sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame
oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the TWEENS; wetting
agents, such sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents, stabilizers; antioxidants; preservatives;
pyrogen-free water; isotonic saline; and phosphate buffer
solutions.
[0046] The choice of a pharmaceutically-acceptable carrier to be
used in conjunction with the subject compound is basically
determined by the way the compound is to be administered.
[0047] The compositions described herein are preferably provided in
unit dosage form. As used herein, a "unit dosage form" is a
composition containing an amount of a compound that is suitable for
administration to an animal, preferably mammal subject, in a single
dose, according to good medical practice. The preparation of a
single or unit dosage form however, does not imply that the dosage
form is administered once per day or once per course of therapy.
Such dosage forms are contemplated to be administered once, twice,
thrice or more per day and may be administered as infusion over a
period of time (e.g., from about 30 minutes to about 2-6 hours), or
administered as a continuous infusion, and may be given more than
once during a course of therapy, though a single administration is
not specifically excluded. The skilled artisan will recognize that
the formulation does not specifically contemplate the entire course
of therapy and such decisions are left for those skilled in the art
of treatment rather than formulation.
[0048] The compositions useful as described above may be in any of
a variety of suitable forms for a variety of routes for
administration, for example, for oral, nasal, rectal, topical
(including transdermal), ocular, intracerebral, intracranial,
intrathecal, intra-arterial, intravenous, intramuscular, or other
parental routes of administration. The skilled artisan will
appreciate that oral and nasal compositions comprise compositions
that are administered by inhalation, and made using available
methodologies. Depending upon the particular route of
administration desired, a variety of pharmaceutically-acceptable
carriers well-known in the art may be used.
Pharmaceutically-acceptable carriers include, for example, solid or
liquid fillers, diluents, hydrotropies, surface-active agents, and
encapsulating substances. Optional pharmaceutically-active
materials may be included, which do not substantially interfere
with the inhibitory activity of the compound. The amount of carrier
employed in conjunction with the compound is sufficient to provide
a practical quantity of material for administration per unit dose
of the compound. Techniques and compositions for making dosage
forms useful in the methods described herein are described in the
following references, all incorporated by reference herein: Modern
Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes,
editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms:
Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage
Forms 8th Edition (2004).
[0049] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. These oral
forms comprise a safe and effective amount, usually at least about
5%, with a maximum of about 90%, of the compound. Tablets can be
compressed, tablet triturates, enteric-coated, sugar-coated,
film-coated, or multiple-compressed, containing suitable binders,
lubricants, diluents, disintegrating agents, coloring agents,
flavoring agents, flow-inducing agents, and melting agents. Liquid
oral dosage forms include aqueous solutions, emulsions,
suspensions, solutions and/or suspensions reconstituted from
non-effervescent granules, and effervescent preparations
reconstituted from effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, melting agents, coloring agents and flavoring
agents.
[0050] The pharmaceutically-acceptable carrier suitable for the
preparation of unit dosage forms for peroral administration is
well-known in the art. Tablets typically comprise conventional
pharmaceutically-compatible adjuvants as inert diluents, such as
calcium carbonate, sodium carbonate, mannitol, lactose and
cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and croscarmelose;
lubricants such as magnesium stearate, stearic acid and talc.
Glidants such as silicon dioxide can be used to improve flow
characteristics of the powder mixture. Coloring agents, such as the
FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable
tablets. Capsules typically comprise one or more solid diluents
disclosed above. The selection of carrier components depends on
secondary considerations like taste, cost, and shelf stability,
which are not critical, and can be readily made by a person skilled
in the art. suspensions, and the like. The
pharmaceutically-acceptable carriers suitable for preparation of
such compositions are well known in the art. Typical components of
carriers for syrups, elixirs, emulsions and suspensions include
ethanol, glycerol, propylene glycol, polyethylene glycol, liquid
sucrose, sorbitol and water. For a suspension, typical suspending
agents include methyl cellulose, sodium carboxymethyl cellulose,
AVICEL RC-591, tragacanth and sodium alginate; typical wetting
agents include lecithin and polysorbate 80; and typical
preservatives include methyl paraben and sodium benzoate. Peroral
liquid compositions may also contain one or more components such as
sweeteners, flavoring agents and colorants disclosed above.
[0051] Such compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
the subject compound is released in the gastrointestinal tract in
the vicinity of the desired topical application, or at various
times to extend the desired action. Such dosage forms typically
include, but are not limited to, one or more of cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and
shellac.
[0052] Compositions described herein may optionally include other
drug actives.
[0053] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as sucrose, sorbitol and mannitol; and
binders such as acacia, microcrystalline cellulose, carboxymethyl
cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants,
sweeteners, colorants, antioxidants and flavoring agents disclosed
above may also be included.
[0054] A liquid composition, which is formulated for topical
ophthalmic use, is formulated such that it can be administered
topically to the eye. The comfort should be maximized as much as
possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case
that comfort cannot be maximized, the liquid should be formulated
such that the liquid is tolerable to the patient for topical
ophthalmic use. Additionally, an ophthalmically acceptable liquid
should either be packaged for single use, or contain a preservative
to prevent contamination over multiple uses.
[0055] For ophthalmic application, solutions or medicaments are
often prepared using a physiological saline solution as a major
vehicle. Ophthalmic solutions should preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0056] Preservatives that may be used in the pharmaceutical
compositions disclosed herein include, but are not limited to,
benzalkonium chloride, PHMB, chlorobutanol, thimerosal,
phenylmercuric, acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful
vehicles may be used in the ophthalmic preparations disclosed
herein. These vehicles include, but are not limited to, polyvinyl
alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,
carboxymethyl cellulose, hydroxyethyl cellulose and purified
water.
[0057] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0058] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable. For
many compositions, the pH will be between 4 and 9. Accordingly,
buffers include acetate buffers, citrate buffers, phosphate buffers
and borate buffers. Acids or bases may be used to adjust the pH of
these formulations as needed.
[0059] In a similar vein, an ophthalmically acceptable antioxidant
includes, but is not limited to, sodium metabisulfite, sodium
thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene.
[0060] Other excipient components, which may be included in the
ophthalmic preparations, are chelating agents. A useful chelating
agent is edetate disodium, although other chelating agents may also
be used in place or in conjunction with it.
[0061] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound disclosed herein are
employed. Topical formulations may generally be comprised of a
pharmaceutical carrier, co-solvent, emulsifier, penetration
enhancer, preservative system, and emollient.
[0062] For intravenous administration, the compounds and
compositions described herein may be dissolved or dispersed in a
pharmaceutically acceptable diluent, such as a saline or dextrose
solution. Suitable excipients may be included to achieve the
desired pH, including but not limited to NaOH, sodium carbonate,
sodium acetate, HCl, and citric acid. In various embodiments, the
pH of the final composition ranges from 2 to 8, or preferably from
4 to 7. Antioxidant excipients may include sodium bisulfite,
acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,
thiourea, and EDTA. Other non-limiting examples of suitable
excipients found in the final intravenous composition may include
sodium or potassium phosphates, citric acid, tartaric acid,
gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
Further acceptable excipients are described in Powell, et al.,
Compendium of Excipients for Parenteral Formulations, PDA J Pharm
Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their
Role in Approved Injectable Products: Current Usage and Future
Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of
which are incorporated herein by reference in their entirety.
Antimicrobial agents may also be included to achieve a
bacteriostatic or fungistatic solution, including but not limited
to phenylmercuric nitrate, thimerosal, benzethonium chloride,
benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0063] The resulting composition may be infused into the patient
over a period of time. In various embodiments, the infusion time
ranges from 5 minutes to continuous infusion, from 10 minutes to 8
hours, from 30 minutes to 4 hours, and from 1 hour to 3 hours. In
one embodiment, the drug is infused over a 3 hour period. The
infusion may be repeated at the desired dose interval, which may
include, for example, 6 hours, 8 hours, 12 hours, or 24 hours.
[0064] The compositions for intravenous administration may be
provided to caregivers in the form of one more solids that are
reconstituted with a suitable diluent such as sterile water, saline
or dextrose in water shortly prior to administration. Reconstituted
concentrated solutions may be further diluted into a parenteral
solutions having a volume of from about 25 to about 1000 ml, from
about 30 ml to about 500 ml, or from about 50 ml to about 100 ml.
In other embodiments, the compositions are provided in solution
ready to administer parenterally. In still other embodiments, the
compositions are provided in a solution that is further diluted
prior to administration. In embodiments that include administering
a combination of a compound described herein and another agent, the
combination may be provided to caregivers as a mixture, or the
caregivers may mix the two agents prior to administration, or the
two agents may be administered separately.
[0065] The actual dose of the active compounds described herein
depends on the specific compound, and on the condition to be
treated; the selection of the appropriate dose is well within the
knowledge of the skilled artisan.
Kits for Intravenous Administration
[0066] Some embodiments include a sterile container having the
composition described herein. Some embodiments include a sterile
container having Compound 1A described herein. Some embodiments
include a kit comprising a potassium salt described herein and an
additional agent, such as an antimicrobial agent. In one
embodiment, both components are provided in a single sterile
container. In the case of solids for reconstitution, the agents may
be pre-blended and added to the container simultaneously or may be
dry-powder filled into the container in two separate steps. In some
embodiments, an additional agent is a sterile crystalline product.
In other embodiments, the additional agent is a lyophile.
Non-limiting examples of agents to aid in lyophilization include
sodium or potassium phosphates, citric acid, tartaric acid,
gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
One embodiment includes non-sterile solids that are irradiated
either before or after introduction into the container.
[0067] In the case of a liquid, the agents may be dissolved or
dispersed in a diluent ready for administration. In another
embodiment, the solution or dispersion may be further diluted prior
to administration. Some embodiments include providing the liquid in
an IV bag. The liquid may be frozen to improve stability.
[0068] In one embodiment, the container includes other ingredients
such as a pH adjuster, a solubilizing agent, or a dispersing agent.
Non-limiting examples of pH adjusters include NaOH, sodium
carbonate, sodium acetate, HCl, and citric acid. In some
embodiments, the liquid carrier is a saline solution.
[0069] The molar ratio of Compound 1A described herein to
additional agent (e.g., antibacterial agent) may be from about 10:1
to 1:10, 8:1 to 1:8, 5:1 to 1:5, 3:1 to 1:3, 2:1 to 1:2, or about
1:1. In various embodiments the amount of compound described herein
may be from 100 mg to 5 g, 500 mg to 2 g, or about 1 g. Similarly,
in various embodiments the amount of additional agent may be from
100 mg to 5 g, 500 mg to 2 g, or about 1 g.
[0070] In an alternative embodiment, the two components may be
provided in separate containers. Each container may include a
solid, solution, or dispersion. In such embodiments, the two
containers may be provided in a single package or may be provided
separately. In one embodiment, the compound or composition
described herein is provided as a solution while the additional
agent (e.g., antibacterial agent) is provided as a solid ready for
reconstitution. In one such embodiment, the solution of the
compound or composition described herein is used as the diluent to
reconstitute the other agent.
[0071] In case of preparing a pharmaceutical composition for
administration, the contents of the sterile container can be
reconstituted using a pharmaceutically acceptable liquid carrier.
In some embodiments, the liquid carrier is a saline solution. In
some embodiments, the liquid carrier is a dextrose solution. In
some embodiments, the method of administration, comprising
administering the reconstituted solution described herein
intravenously to a subject.
Methods of Treatment
[0072] Some embodiments of the present invention include methods of
treating bacterial infections with the compounds and compositions
described herein. Some methods include administering a compound,
composition, pharmaceutical composition described herein to a
subject in need thereof. In some embodiments, a subject can be an
animal, e.g., a mammal, a human. In some embodiments, the bacterial
infection comprises a bacteria described herein. As will be
appreciated from the foregoing, methods of treating a bacterial
infection include methods for preventing bacterial infection in a
subject at risk thereof.
[0073] Further embodiments include administering a combination of
compounds to a subject in need thereof. A combination can include a
compound, composition, pharmaceutical composition described herein
with an additional medicament.
[0074] Some embodiments include co-administering a compound,
composition, and/or pharmaceutical composition described herein,
with an additional medicament. By "co-administration," it is meant
that the two or more agents may be found in the patient's
bloodstream at the same time, regardless of when or how they are
actually administered. In one embodiment, the agents are
administered simultaneously. In one such embodiment, administration
in combination is accomplished by combining the agents in a single
dosage form. When combining the agents in a single dosage form,
they may be physically mixed (e.g., by co-dissolution or dry
mixing) or may form an adduct or be covalently linked such that
they split into the two or more active ingredients upon
administration to the patient. In another embodiment, the agents
are administered sequentially. In one embodiment the agents are
administered through the same route, such as orally. In another
embodiment, the agents are administered through different routes,
such as one being administered orally and another being
administered i.v.
[0075] Examples of additional medicaments include an antibacterial
agent, antifungal agent, an antiviral agent, an anti-inflammatory
agent and an anti-allergic agent.
[0076] Some embodiments include co-administration of a compound,
composition or pharmaceutical composition described herein with an
antibacterial agent such as a .beta.-lactam. Examples of such
.beta.-lactams include Amoxicillin, Ampicillin (e.g.,
Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,
Talampicillin), Epicillin, Carbenicillin (Carindacillin),
Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,
Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),
Clometocillin, Benzathine benzylpenicillin, Procaine
benzylpenicillin, Azidocillin, Penamecillin,
Phenoxymethylpenicillin (V), Propicillin, Benzathine
phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g.,
Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin,
Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,
Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile,
Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine,
Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur,
Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox,
Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,
Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole,
Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene,
Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime,
Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide,
Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene,
Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome,
Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428,
MC-04,546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinome,
Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441,
and RWJ-333442.
[0077] Preferred embodiments include .beta.-lactams such as
Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,
ME1036, Tomopenem, Razupenem, and Panipenem.
[0078] Some embodiments include co-administration of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises a
monobactam. Examples of monobactams include aztreonam, tigemonam,
BAL 30072, SYN 2416 (BAL19764), and carumonam.
[0079] Some embodiments include co-administration of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises a
Class A, B, C, or D beta-lactamase inhibitor. An example of a class
B beta lactamase inhibitor includes ME1071 (Yoshikazu Ishii et al,
"In Vitro Potentiation of Carbapenems with ME1071, a Novel
Metallo-.beta.-Lactamase Inhibitor, against Metallo-B-lactamase
Producing Pseudomonas aeruginosa Clinical Isolates." Antimicrob.
Agents Chemother. doi:10.1128/AAC.01397-09 (July 2010)). Other
examples of beta-lactamase inhibitors administered as an additional
agent include clavulanic acid, tazobactam, sulbactam, avibactam
(NXL-104), MK-7655, and BAL29880. MK-7655 has the following
structure:
##STR00002##
Indications
[0080] The compounds and compositions described herein can be used
to treat bacterial infections. Bacterial infections that can be
treated with the compounds, compositions and methods described
herein can comprise a wide spectrum of bacteria. Example organisms
include gram-positive bacteria, gram-negative bacteria, aerobic and
anaerobic bacteria, such as Staphylococcus, Lactobacillus,
Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella,
Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter,
Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus,
Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella
and other organisms.
[0081] More examples of bacterial infections include Pseudomonas
aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans,
Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas
maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium,
Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis,
Shigella dysenteriae, Shigella flexneri, Shigella sonnei,
Enterobacter cloacae, Enterobacter aerogenes, Klebsiella
pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella
tularensis, Morganella morganii, Proteus mirabilis, Proteus
vulgaris, Providencia alcalifaciens, Providencia rettgeri,
Providencia stuartii, Acinetobacter baumannii, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,
Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Bordetella pertussis, Bordetella parapertussis, Bordetella
bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,
Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus
ducreyi, Pasteurella multocida, Pasteurella haemolytica,
Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Kingella, Moraxella, Gardnerella vaginalis,
Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A
homology group, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, Bacteroides splanchnicus, Clostridium difficile,
Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus
agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
Enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus saprophyticus, Staphylococcus
intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus
haemolyticus, Staphylococcus hominis, or Staphylococcus
saccharolyticus.
[0082] The following examples will further describe the present
invention, and are used for the purposes of illustration only, and
should not be considered as limiting.
EXAMPLES
Example 1
Salt Screening Study
Step 1. Purification and Characterization of Compound 1
[0083] Compound 1, 2-((3R, 6
S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic
acid, was found to often contain undesired NaCl salt. FIG. 6 shows
the PXRD pattern of the NaCl, Compound 1 before purification and
after purification. As shown in FIG. 6, the peak at 31.6.degree.
2.theta. in the PXRD pattern is characteristic for the NaCl salt.
The PXRD pattern for Compound 1 after purification shows
significantly reduced or no presence of the NaCl salt.
[0084] During the purification process, compound 1 was combined
with water (15.0 mL) and the suspension was stirred at room
temperature for 4 hrs. The solids were isolated using a Buchner
funnel and Whitman #1 filter paper. After filtration, the compound
was air-dried for 15 hrs. The yield of the procedure was 87% by
weight.
[0085] After the purification step, the purified compound was
analyzed using HPLC, PXRD and TGA. The PXRD pattern of the purified
compound 1 is shown in FIG. 6. As shown in FIG. 6, the
characteristic peaks of the NaCl salt in the purified compound
disappeared as compared with the compound before purification. FIG.
7 shows the TGA trace of the purified compound 1. In FIG. 7,
compound 1 underwent about 6.25% weight loss which was attributed
to the loss of water due to a reversible reaction involving the
boronic acid moiety. FIG. 8 is the HPLC analysis of the purified
Compound 1. The HPLC chromatogram in FIG. 8 shows a retention peak
of 2.52 for Compound 1 and no other peaks for NaCl or water. The
analysis data confirmed that the material was
2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)a-
cetic acid and did not contain the undesired NaCl or
crystallization solvent (water).
Step 2. Salt-Screening
[0086] During the salt-screening step, 60 combinations of seven
counterions with nine solvent systems were tested. These
combinations were subject to a series of crystallization modes and
resulted in approximately 360 screening experiments.
Counterion Selection
[0087] Compound 1 has a pKa of 3.92 and was expected to form salts
with strong bases. Because of a possible high projected dose (3
g/day) of compound 1, the counterion selection was limited to Class
1 molecules having low toxicity. (Handbook of Pharmaceutical Salts
Properties, Selection, and Use P. H. Stahl, C. G. Wermuth, (2002)
Wiley-VCH, Weinheim). Table 1 lists seven basic counterions
selected for the salt screen study, their pKa values, and the
corresponding stoichiometry and dosing strategies.
TABLE-US-00002 TABLE 1 Counterions used in the salt-screening study
No. Counterion pKa3 Equivalent Dosing 1 Potassium ~14 1 3.6M in
Water hydroxide 2 Potassium ~14 1 1.0M in t-BuOH t-butoxide 3
Choline >11 1 3.8M in Water hydroxide 4 L-Lysine 10.8; 9.2; 2.2
1 1.5M in Water 5 L-Arginine 13.2; 9.1; 2.2 1 0.5M in Water 6
Meglumine 8.0 1 1.5M in Water 7 Calcium 12.6; 11.6 0.5; 1 Solid
hydroxide 8 Magnesium 11.4 0.5; 1 Solid hydroxide
Solvent Selection
[0088] Nine solvent systems were evaluated in the Salt-screening
study. The solvents were selected based on the solubility data
accumulated during preceding studies. In addition, solvents
represented a diverse set of polarities, dielectric constants,
dipole moments, and hydrogen-bond donor/acceptor attributes to
promote crystallization of salts. The solvents and rationale for
their selection are summarized in Table 2.
TABLE-US-00003 TABLE 2 Solvents used in salt-screening study No.
Solvent Attributes Rationale for Selection 1 THF:Water Ether
(Polar, Aprotic) High solubility of Compound 1 (95:5% vol.) Water
(Polar, Protic) (S >>1 mg/mL) 2 1,4-Dioxane Ether Moderate
solubility of Compound (Non-polar, Aprotic 1 (S = 1-10 mg/mL)
Afforded crystalline sodium salt 3 ACN Nitrile Low solubility of
Compound 1 (Polar, Aprotic) (S <1 mg/mL) 4 Acetone Ketone Low
solubility of Compound 1 (Polar, Aprotic) (S <1 mg/mL) Afforded
crystalline sodium salt 5 Ethyl Acetate Ester Low solubility of
Compound 1 (Polar, Aprotic) (S <1 mg/mL) 6 MTBE Ether Low
solubility of Compound 1 (Non-polar, Aprotic) (S <1 mg/mL)
Afforded crystalline sodium salt 7 Water Water Low solubility of
Compound 1 (Polar, Protic) Expected high(er) solubility of a salt 8
ACN:Water Nitrile (Polar, Modest solubility of Compound 1 (90:10%
vol.) Aprotic) (S <20 mg/mL) Water Use instead of MTBE in
reactions (Polar, Protic) with Ca.sup.2+ and Mg.sup.2+ counterions
9 Acetone:Water Ketone, Low/modest solubility of (50:50% vol.)
(Polar, Aprotic) Compound 1 Water Expected high(er) solubility of a
salt (Polar, Protic)
Crystallization Modes
[0089] The salt-screening experiments were set up by combining
20.0.+-.0.5 mg of Compound 1 with 300-500 .mu.L of the solvent and
the counterion in a stoichiometric amount. The screening studies
were conducted in two stages.
[0090] In Stage 1, the samples involving counterion Nos. 1-6 listed
in Table 1 were paired with solvent Nos. 1-6 listed in Table 2,
whereas samples involving counterion Nos. 7 and 8 were paired with
solvent Nos. 1-5 and 8.
[0091] All samples were subject to the following processing steps:
1) Stirring for 48 hrs while maintaining the cycling temperature
between 5.degree. C.-40.degree. C.; 2) Stirring for 6 hrs at
40.degree. C.; 3) Stirring for 24 hrs at 20.degree. C.; 4) solvent
addition (same solvent in the same amount); 5) Stirring for 72 hrs
while maintaining the cycling temperature between 10.degree.
C.-30.degree. C.; 6) Stirring for 72 hrs at 5.degree. C.; 7)
Solvent addition (the solvent type and amount was adjusted based on
the observed solubility and the solvent can be the same solvent
previously used, water, or DMSO); 8) Stirring for 24 hrs while
maintaining the cycling temperature between 5.degree. C.-30.degree.
C.; the solutions obtained from the above steps were 9) cooled to
5.degree. C. and held at 5.degree. C. for 72 hrs; 10) allowed to
evaporate at ambient conditions over 3-14 days.
[0092] In Stage 2, a few samples that remained undissolved and
amorphous in the first stage were 1) subjected to rapid solvent
evaporation under vacuum; 2) dissolved in solvent Nos. 7-9 listed
in Table 2; 3) cooled to 5.degree. C. and held at 5.degree. C. for
72 hrs; and 4) allowed to evaporate at ambient conditions over 3-7
days.
[0093] All samples were inspected visually and by Polarized light
microscopy at every step listed above to check any formation of
crystalline products. Any crystalline products obtained from these
procedures were isolated by vacuum filtration and, where possible,
analyzed by FT-Raman. Unique crystalline products were subjected to
further analyses by PXRD, DSC, TGA-IR, and HPLC, as necessary.
Results of Salt-Screening Study
[0094] A majority of the experiments produced amorphous products,
including oils, gums, and powders. Some crystalline screening
products underwent partial or complete deliquescence upon
isolation, some screening products were mixtures of unreacted
components, and some screening products were mixtures of decomposed
components. The counterion Nos. 3-8 listed in Table 1 did not yield
a pure stable crystalline form of Compound 1A. Only the potassium
salt of compound 1 yielded crystalline products. The results of
some experiments are summarized in Table 3.
TABLE-US-00004 TABLE 3 Examples of Screening Crystalline Form
Crystallization Test Counterions Method Solvent Results 1 Potassium
hydroxide Stage 1 Acetone G 2 Potassium hydroxide Stage 1 ACN G 3
Potassium hydroxide Stage 1 MTBE NG 4 Potassium hydroxide Stage 1
THF:Water NG (95:5 vol %) 5 Potassium hydroxide Stage 1 1,4-dioxane
G 6 Potassium hydroxide Stage 1 EtOAc NG 7 Potassium hydroxide
Stage 2 Water NG 8 Potassium hydroxide Stage 2 ACN:Water NG (90:10
vol %) 9 Potassium t-butoxide Stage 1 Acetone G 10 Potassium
t-butoxide Stage 1 ACN NG 11 Potassium t-butoxide Stage 1 MTBE NG
12 Potassium t-butoxide Stage 1 THF:Water NG (95:5 vol %) 13
Potassium t-butoxide Stage 1 1,4-dioxane NG 14 Potassium t-butoxide
Stage 1 EtoAc NG 15 Choline hydroxide Stage 1 Acetone NG 16 Choline
hydroxide Stage 1 ACN NG 17 Choline hydroxide Stage 1 MTBE NG 18
Choline hydroxide Stage 1 THF:Water NG (95:5 vol %) 19 Choline
hydroxide Stage 1 1,4-dioxane NG 20 Choline hydroxide Stage 1 EtOAc
NG 21 Choline hydroxide Stage 2 Water NG 22 Choline hydroxide Stage
2 ACN:Water NG (90:10 vol %) 23 Choline hydroxide Stage 2
Acetone:Water NG (50:50 vol %) 24 L-Lysine Stage 1 Acetone NG 25
L-Lysine Stage 1 ACN NG 26 L-Lysine Stage 1 MTBE NG 27 L-Lysine
Stage 1 THF:Water NG (95:5 vol %) 28 L-Lysine Stage 1 1,4-dioxane
NG 29 L-Lysine Stage 1 EtOAc NG 30 L-Lysine Stage 2 Water NG 31
L-Lysine Stage 2 ACN:Water NG (90:10 vol %) 32 L-Lysine Stage 2
Acetone:Water NG (50:50 vol %) 33 L-Arginine Stage 1 Acetone NG 34
L-Arginine Stage 1 ACN NG 35 L-Arginine Stage 1 MTBE NG 36
L-Arginine Stage 1 THF:Water NG (95:5 vol %) 37 L-Arginine Stage 1
1,4-dioxane NG 38 L-Arginine Stage 1 EtOAc NG 39 L-Arginine Stage 2
Water NG 40 L-Arginine Stage 2 ACN:Water NG (90:10 vol %) 41
L-Arginine Stage 2 Acetone:Water NG (50:50 vol %) 42 Meglumine
Stage 1 Acetone NG 43 Meglumine Stage 1 ACN NG 44 Meglumine Stage 1
MTBE NG 45 Meglumine Stage 1 THF:Water NG (95:5 vol %) 46 Meglumine
Stage 1 1,4-dioxane NG 47 Meglumine Stage 1 EtOAc NG 48 Meglumine
Stage 2 Water NG 49 Meglumine Stage 2 ACN:Water NG (90:10 vol %) 50
Calcium hydroxide Stage 1 Acetone NG (0.5 equivalent) 51 Calcium
hydroxide Stage 1 ACN NG (0.5 equivalent) 52 Calcium hydroxide
Stage 1 THF:Water NG (0.5 equivalent) (95:5 vol %) 53 Calcium
hydroxide Stage 1 1,4-dioxane NG (0.5 equivalent) 54 Calcium
hydroxide Stage 1 EtOAc NG (0.5 equivalent) 55 Calcium hydroxide
Stage 2 Water NG (0.5 equivalent) 56 Calcium hydroxide Stage 2
ACN:Water NG (0.5 equivalent) (90:10 vol %) 57 Calcium hydroxide
Stage 1 Acetone NG (1 equivalent) 58 Calcium hydroxide Stage 1 ACN
NG (1 equivalent) 59 Calcium hydroxide Stage 1 THF:Water NG (1
equivalent) (95:5 vol %) 60 Calcium hydroxide Stage 1 1,4-dioxane
NG (1 equivalent) 61 Calcium hydroxide Stage 1 EtOAc NG (1
equivalent) 62 Calcium hydroxide Stage 2 Water NG (1 equivalent) 63
Calcium hydroxide Stage 2 ACN:Water NG (1 equivalent) (90:10 vol %)
64 Magnesium hydroxide Stage 1 Acetone NG (0.5 equivalent) 65
Magnesium hydroxide Stage 1 ACN NG (0.5 equivalent) 66 Magnesium
hydroxide Stage 1 THF:Water NG (0.5 equivalent) (95:5 vol %) 67
Magnesium hydroxide Stage 1 1,4-dioxane NG (0.5 equivalent) 68
Magnesium hydroxide Stage 1 EtOAc NG (0.5 equivalent) 69 Magnesium
hydroxide Stage 2 ACN:Water NG (0.5 equivalent) (90:10 vol %) 70
Magnesium hydroxide Stage 1 Acetone NG (1 equivalent) 71 Magnesium
hydroxide Stage 1 ACN NG (1 equivalent) 72 Magnesium hydroxide
Stage 1 THF:Water NG (1 equivalent) (95:5 vol %) 73 Magnesium
hydroxide Stage 1 1,4-dioxane NG (1 equivalent) 74 Magnesium
hydroxide Stage 1 EtOAc NG (1 equivalent) 75 Magnesium hydroxide
Stage 2 Water NG (1 equivalent) 76 Magnesium hydroxide Stage 2
ACN:Water NG (1 equivalent) (90:10 vol %) 77 Magnesium hydroxide
Stage 2 Acetone:Water NG (1 equivalent) (50:50 vol %) 78 Magnesium
hydroxide Stage 2 Acetone:Water NG (1 equivalent) (50:50 vol %) 79
Magnesium hydroxide Stage 2 Acetone:Water NG (1 equivalent) (50:50
vol %) 80 Magnesium hydroxide Stage 2 Acetone:Water NG (1
equivalent) (50:50 vol %) 81 Magnesium hydroxide Stage 2
Acetone:Water NG (1 equivalent) (50:50 vol %) 82 Magnesium
hydroxide Stage 2 Acetone:Water NG (1 equivalent) (50:50 vol %) 83
Magnesium hydroxide Stage 2 Acetone:Water NG (1 equivalent) (50:50
vol %) G--pure and stable crystalline form yielded NG--no pure and
stable crystalline form yielded
[0095] Table 3 only listed 83 examples of the approximately 360
screening experiments performed using various combinations of
counterions, solvent systems, and crystallization mode. Most of the
screening experiments produced amorphous powders, oils, gums. For
example, those experiments that involved calcium and magnesium
counterions yielded products that were mixtures of the unreacted
substrates. The FT-Raman and PXRD analysis of the products showed
that no pure and stable crystalline salt was formed in the
experiments involving calcium or magnesium counterions. For another
example, when the screening experiments involved the solvent system
of THF and Water (95:5 vol %) and a range of counterions
(potassium, choline, calcium, and magnesium), the HPLC analysis
confirmed significant decomposition present in those products.
[0096] Among the approximately 360 screening experiments performed,
only the potassium salt Compound 1A in four experiments yielded a
pure and stable crystalline form after long-term (>4 days)
stirring of the initially amorphous products (gums and oils). The
potassium salt was subsequently reproduced at 50 mg and 300 mg
scales using seeding, which facilitated crystallization of the
several hours of amorphous intermediate phase. The potassium salt
may undergo deliquescence when isolated in open air; however, the
deliquescence may be significantly reduced and/or eliminated by
using the nitrogen blanket. Once a free-flowing powder was
isolated, the powder was stable in open-air for at least 7
days.
[0097] In addition, only one crystalline form of the potassium salt
was observed during the course of the presented study. This single
crystalline form also showed that Compound 1A has a low propensity
for polymorphism.
Example 2
Preparation of Potassium Salt at 50 mg Scale
[0098] 48.7 mg of Compound 1 was combined with acetone (1.0 mL) in
a 2-mL vial containing a stir bar. The suspension was stirred at
40.degree. C. for 10 min and seeded with about 1 mg of potassium
salt. 164.0 .mu.L of potassium t-butoxide (1.0eq. of compound 1;
1.0M solution in t-BuOH) was added in five aliquots: 10 .mu.L, 20
.mu.L, 20 .mu.L, 20 .mu.L, 93 .mu.L in every 5 min. Gum was formed
upon the counterion addition. The sample was stirred for 15 hrs
while the cycling temperature was maintained between 40.degree.
C.-45.degree. C., during which the gum changed into a free-flowing
suspension. The suspension was equilibrated at 5.degree. C. for 30
min and the solids were isolated on a Buchner funnel under nitrogen
blanket and allowed to dry for 30 min. The yield of this
preparation procedure was 70% wt.
Example 3
Preparation of Potassium Salt at 300 mg Scale
[0099] Compound 1 (302.6 mg) was combined with ACN (15.0 mL) in a
20-mL vial containing a stir bar. The suspension was stirred at
50.degree. C. for 30 min and seeded with about 3 mg of potassium
salt. 256.7 .mu.L of potassium hydroxide (0.9 eq. of compound 1;
3.57M aqueous solution) was added in eight aliquots: 20 .mu.L, 20
.mu.L, 20 .mu.L, 20 .mu.L, 20 .mu.L, 50 .mu.L, 50 .mu.L, 56.7 .mu.L
in every 15 min. Partial conversion to a gum upon the counterion
addition was observed. The suspension was stirred at 50.degree. C.
for 60 min, cooled to 5.degree. C. at 0.1.degree. C./min rate (7.5
hrs), and subjected to stirring while the cycling temperature was
maintained between 40.degree. C.-45.degree. C. for 10 hrs. The
temperature cycle involved holding at 40.degree. C. for 1 hr
followed by cooling at 0.5.degree. C./min, and then holding at
5.degree. C. for 2 hrs followed by heating to 40.degree. C. at a
maximum rate. The suspension was equilibrated at 5.degree. C. for 2
hrs. The solids were isolated on a Buchner funnel under nitrogen
blanket, allowed to dry for 60 min at room temperature and then at
40.degree. C. under vacuum for 3 hrs. The yield of this procedure
was 65% wt.
Example 4
Characterization of Potassium Salt
[0100] The potassium salt is a crystalline powder, as indicated by
PXRD data in FIG. 1 and PLM image in FIG. 2. FIG. 3 is the TGA and
DSC analysis and FIG. 4 shows the FT-Raman spectrum of the
crystalline form of Compound 1A. The DSC trace in FIG. 3 shows a
melting endotherm at 199.0.degree. C. The TGA analysis of Compound
1A in FIG. 3 also indicates a gradual weight loss of .about.0.7%
wt. over the temperature range 25-150.degree. C., which can be
contributed to a loss of residual or surface solvent, and a major
weight loss at temperatures above 160.degree. C. that was
attributed to decomposition. The HPLC analysis of the potassium
salt as shown in FIG. 5 confirmed the absence of decomposition of
Compound 1. The inductively coupled plasma atomic emission
spectroscopy (ICP-AES) analysis confirmed the presence of potassium
cations in the amount of 13.1% by weight. This result closely
corresponds to a mono-salt composition because the theoretical
content of 1 eq. of potassium is about 11.6% by weight.
Example 5
Studies of Sodium Salt
[0101] Studies of a possible sodium salt crystalline form were
performed using purified compound 1 and amorphous sodium salt of
compound 1 as the starting materials and explored diverse
crystallization modes, solvents and temperatures.
[0102] The studies discovered five crystalline forms of the sodium
salt (Groups A-E). Groups A and B were obtained from the screening
experiments using compound 1 as the starting material. The PXRD
pattern of Group A showed broad peaks indicative of poor
crystallinity. The isolated material was found to be sticky and
deliquesced readily (<5 minutes) when exposed to ambient
conditions. PXRD pattern of Group B showed sharper peaks compared
to Group A. The isolated Group B material was free flowing and easy
to handle. Thermal analyses of Group B of sodium salt showed this
form is a methanol/water solvate which converted to a hydrate on
drying at 60.degree. C.
[0103] Attempts to prepare Groups A and B using purified compound 1
led to two new crystalline forms of sodium salt (Groups D and E).
These forms did not deliquesce when exposed to ambient conditions
and were free-flowing solids. However, the DSC data of these two
new forms showed broad endotherms below 150.degree. C. indicative
of a solvated/hydrated form.
[0104] Group C was isolated from a single crystallization
experiment using amorphous sodium salt as the input. Group C of
sodium salt showed physical properties similar to Group B and was
found to be an acetone/water solvate which desolvated on drying at
60.degree. C.
[0105] These results showed that the sodium salt of compound 1 is
not a desirable crystalline form because of poor crystallinity,
complicated polymorphism, poor thermal properties and
hygroscopicity. In contrast, as described above, the potassium salt
surprisingly demonstrated better crystallinity with a single
crystalline form.
* * * * *