U.S. patent application number 13/967255 was filed with the patent office on 2013-12-12 for polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)ace- tic acid and uses thereof.
This patent application is currently assigned to Ardea Biosciences, Inc.. The applicant listed for this patent is Ardea Biosciences, Inc.. Invention is credited to Jean-Luc GIRARDET, Laszlo R. TREIBER, Irina ZAMANSKY.
Application Number | 20130331403 13/967255 |
Document ID | / |
Family ID | 46381300 |
Filed Date | 2013-12-12 |
United States Patent
Application |
20130331403 |
Kind Code |
A1 |
TREIBER; Laszlo R. ; et
al. |
December 12, 2013 |
POLYMORPHIC FORMS OF
2-(5-BROMO-4-(4-CYCLOPROPYLNAPHTHALEN-1-YL)-4H-1,2,4-TRIAZOL-3-YLTHIO)ACE-
TIC ACID AND USES THEREOF
Abstract
Crystalline polymorph forms of 2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid are
described. Pharmaceutical compositions and the uses of such
compounds, compound forms, and compositions for the treatment of a
variety of diseases and conditions are also presented.
Inventors: |
TREIBER; Laszlo R.; (San
Diego, CA) ; ZAMANSKY; Irina; (Oceanside, CA)
; GIRARDET; Jean-Luc; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ardea Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
Ardea Biosciences, Inc.
San Diego
CA
|
Family ID: |
46381300 |
Appl. No.: |
13/967255 |
Filed: |
August 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13339283 |
Dec 28, 2011 |
8546436 |
|
|
13967255 |
|
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|
|
61428660 |
Dec 30, 2010 |
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Current U.S.
Class: |
514/263.3 ;
514/365; 514/384 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
19/06 20180101; A61K 31/519 20130101; C07D 249/06 20130101; C07D
249/12 20130101; A61P 3/00 20180101; A61K 31/4196 20130101; A61P
19/00 20180101; A61K 31/426 20130101; A61K 31/522 20130101; A61P
13/12 20180101; A61P 19/02 20180101; A61P 13/00 20180101 |
Class at
Publication: |
514/263.3 ;
514/365; 514/384 |
International
Class: |
C07D 249/12 20060101
C07D249/12; A61K 31/426 20060101 A61K031/426; A61K 31/4196 20060101
A61K031/4196; A61K 31/522 20060101 A61K031/522 |
Claims
1. A method for treating or preventing gout, comprising
administering an effective amount of a crystalline polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid: ##STR00009## characterized by peaks at 10.46, 18.76, and
19.83.degree. 2.theta..+-.0.1.degree. 2.theta..
2. The method of claim 1, wherein the crystalline polymorph is
further characterized by at least one further peak at 18.21 or
23.08.degree. 2.theta..+-.0.1.degree. 2.theta..
3. The method of claim 1, wherein the crystalline polymorph
exhibits an x-ray powder diffraction pattern substantially the same
as the x-ray powder diffraction pattern shown in FIG. 5.
4. The method of claim 1, wherein the crystalline polymorph is
prepared by a method comprising the step of crystallizing
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and ethyl acetate.
5. The method of claim 1, further comprising administering
allopurinol.
6. The method of claim 1, further comprising administering
febuxostat.
7. A method for treating hyperuricemia, comprising administering an
effective amount of a crystalline polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid: ##STR00010## characterized by peaks at 10.46, 18.76, and
19.83.degree. 2.theta..+-.0.1.degree. 2.theta..
8. The method of claim 7, wherein the crystalline polymorph is
further characterized by at least one further peak at 18.21 or
23.08.degree. 2.theta..+-.0.1.degree. 2.theta..
9. The method of claim 7, wherein the crystalline polymorph
exhibits an x-ray powder diffraction pattern substantially the same
as the x-ray powder diffraction pattern shown in FIG. 5.
10. The method of claim 7, wherein the crystalline polymorph is
prepared by a method comprising the step of crystallizing
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and ethyl acetate.
11. The method of claim 7, further comprising administering
allopurinol.
12. The method of claim 7, further comprising administering
febuxostat.
13. A method for treating or preventing a disease caused by
elevated uric acid levels, comprising administering an effective
amount of a crystalline polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid: ##STR00011## characterized by peaks at 10.46, 18.76, and
19.83.degree. 2.theta..+-.0.1.degree. 2.theta..
14. The method of claim 13, wherein the crystalline polymorph is
further characterized by at least one further peak at 18.21 or
23.08.degree. 2.theta..+-.0.1.degree. 2.theta..
15. The method of claim 13, wherein the crystalline polymorph
exhibits an x-ray powder diffraction pattern substantially the same
as the x-ray powder diffraction pattern shown in FIG. 5.
16. The method of claim 13, wherein the crystalline polymorph is
prepared by a method comprising the step of crystallizing
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and ethyl acetate.
17. The method of claim 13, further comprising administering
allopurinol.
18. The method of claim 13, further comprising administering
febuxostat.
19. A method of treating hyperuricemia, treating or preventing
gout, or a treating or preventing a disease caused by elevated uric
acid levels, comprising administering an effective amount of a
crystalline polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-
acetic acid: ##STR00012## characterized by peaks at 10.32, 18.84
and 20.75.degree. 2.theta..+-.0.1.degree. 2.theta..
20. The method of claim 19, wherein the crystalline polymorph is
further characterized by at least two further peaks at 6.80, 21.54,
24.97, 25.53, 27.28 or 27.60.degree. 2.theta..+-.0.1.degree.
2.theta..
21. The method of claim 19, wherein the crystalline polymorph
exhibits an x-ray powder diffraction pattern substantially the same
as the x-ray powder diffraction pattern shown in FIG. 1.
22. The method of claim 19, wherein the crystalline polymorphic
form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid is prepared by a method comprising the step of
crystallizing
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and acetic acid.
23. The method of claim 19, further comprising administering
allopurinol.
24. The method of claim 19, further comprising administering
febuxostat.
Description
CROSS-REFERENCE
[0001] This application is a divisional patent application of
co-pending U.S. application Ser. No. 13/339,283, filed Dec. 28,
2011, which claims priority to U.S. Provisional Application No.
61/428,660, filed Dec. 30, 2010, all of which are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] Described herein are polymorphic forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, which is known to decrease uric acid levels.
BACKGROUND OF THE INVENTION
[0003] Gout is associated with elevated levels of uric acid that
crystallize and deposit in joints, tendons, and surrounding
tissues. Gout is marked by recurrent attacks of red, tender, hot,
and/or swollen joints.
SUMMARY OF THE INVENTION
[0004] Described herein are crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid:
##STR00001##
[0005] In one aspect described herein are crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid
characterized by peaks at 10.32, 18.84 and 20.75.degree.
2.theta..+-.0.1.degree. 20. In further embodiments, such a
crystalline polymorph is further characterized by at least two
further peaks at 6.80, 21.54, 24.97, 25.53, 27.28 and 27.60.degree.
2.theta..+-.0.1.degree. 20. In yet further embodiments, the
crystalline polymorph exhibits an x-ray powder diffraction pattern
substantially the same as the x-ray powder diffraction pattern
shown in FIG. 1. In yet further embodiments, the crystalline
polymorph exhibits an x-ray powder diffraction pattern
substantially the same as the x-ray powder diffraction pattern
shown in FIG. 2. In a related aspect described herein are
crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-
acetic acid, characterized by an endothermic point onset at about
151.degree. C., as determined by differential scanning calorimetry.
In a further embodiment, the crystalline polymorph is characterized
by a differential scanning calorimetry pattern substantially the
same as the differential scanning calorimetry pattern shown in FIG.
3. In another related aspect described herein is the crystalline
polymorph form 1 of 2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. Also
described herein are crystalline polymorphic forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid made by a method comprising the step of crystallizing
amorphous
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and acetic acid. In a related
aspect described herein, are solid pharmaceutical compositions
comprising an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, an
effective amount of the crystalline polymorph characterized by the
aforementioned differential scanning calorimetry patterns, or an
effective amount of the crystalline polymorph form 1, as an active
ingredient; and at least one excipient or carrier. Also described
herein are methods for treating or preventing hyperuricemia or a
disease caused by elevated uric acid levels, comprising
administering an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, an
effective amount of the crystalline polymorph characterized by the
aforementioned differential scanning calorimetry patterns, or an
effective amount of the crystalline polymorph form 1. Also
described herein are methods for treating or preventing gout,
comprising administering an effective amount of the crystalline
polymorph characterized by the aforementioned diffraction patterns,
an effective amount of the crystalline polymorph characterized by
the aforementioned differential scanning calorimetry patterns, or
an effective amount of the crystalline polymorph form 1.
[0006] In another aspect, described herein are crystalline
polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid characterized by peaks at 10.46, 18.76, and 19.83.degree.
2.theta..+-.0.1.degree. 20. In further embodiments, such a
crystalline polymorph is further characterized by at least one
further peak at 18.21 or 23.08.degree. 2.theta..+-.0.1.degree. 20.
In yet further embodiments, the crystalline polymorph exhibits an
x-ray powder diffraction pattern substantially the same as the
x-ray powder diffraction pattern shown in FIG. 5. In yet further
embodiments, the crystalline polymorph exhibits an x-ray powder
diffraction pattern substantially the same as the x-ray powder
diffraction pattern shown in FIG. 6. In a related aspect described
herein are crystalline polymorphs of 2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid,
characterized by an endothermic point onset at about 175.degree.
C., as determined by differential scanning calorimetry. In a
further embodiment, the crystalline polymorph is characterized by a
differential scanning calorimetry pattern substantially the same as
the differential scanning calorimetry pattern shown in FIG. 8. In
another related aspect described herein is the crystalline
polymorph form 2 of 2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. Also
described herein are crystalline polymorphic forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid made by a method comprising the step of crystallizing
amorphous
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid from a mixture of water and ethyl acetate. In a related
aspect described herein are solid pharmaceutical compositions
comprising an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, an
effective amount of the crystalline polymorph characterized by the
aforementioned differential scanning calorimetry patterns, or an
effective amount of the crystalline polymorph form 2, as an active
ingredient; and at least one excipient or carrier. Also described
herein are methods for treating or preventing hyperuricemia or a
disease caused by elevated uric acid levels, comprising
administering an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, an
effective amount of the crystalline polymorph characterized by the
aforementioned differential scanning calorimetry patterns, or an
effective amount of the crystalline polymorph form 2. Also
described herein are methods for treating or preventing gout,
comprising administering an effective amount of the crystalline
polymorph characterized by the aforementioned diffraction patterns,
an effective amount of the crystalline polymorph characterized by
the aforementioned differential scanning calorimetry patterns, or
an effective amount of the crystalline polymorph form 2.
[0007] In a further aspect are solid pharmaceutical compositions
comprising an effective amount of at least two of the
aforementioned crystalline polymorph forms of
2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid; and at
least one excipient or carrier.
[0008] In a further aspect are methods for treating or preventing
hyperuricemia or a disease caused by elevated uric acid levels,
comprising administering an effective amount of at least two of the
aforementioned crystalline polymorph forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid; and at least one excipient or carrier.
[0009] In a yet further aspect are methods for treating or
preventing gout, comprising administering an effective amount of at
least two of the aforementioned crystalline polymorph forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid; and at least one excipient or carrier.
INCORPORATION BY REFERENCE
[0010] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0012] FIG. 1 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph form 1 (Raw Data).
[0013] FIG. 2 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph form 1 (Background Subtracted and K.alpha.2
Stripped).
[0014] FIG. 3 represents an illustrative Differential Scanning
calorimetry pattern of Polymorph form 1.
[0015] FIG. 4 represents illustrative Thermogravimetric Analyses
(a) Rep 1 and (b) Rep 2 of Polymorph form 1.
[0016] FIG. 5 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph form 2 (Raw Data).
[0017] FIG. 6 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph form 2 (Background Subtracted and K.alpha.2
Stripped).
[0018] FIG. 7 represents an illustrative overlay of X-ray Powder
Diffraction Patterns of Polymorph form 1 (lower) and form 2
(upper).
[0019] FIG. 8 represents an illustrative Differential Scanning
calorimetry pattern of Polymorph form 2.
[0020] FIG. 9 represents an illustrative .sup.1H NMR (DMSO-d.sub.6)
spectrum of Polymorph form 2.
[0021] FIG. 10 represents an illustrative HPLC trace of Polymorph
form 2.
[0022] FIG. 11 represents an illustrative Thermogravimetric
Analysis trace of Polymorph form 2.
[0023] FIG. 12 represents an illustrative Gravimetric Vapor
Sorption study of Polymorph form 1 and 2.
DETAILED DESCRIPTION OF THE INVENTION
[0024] While certain embodiments of the present invention have been
shown and described herein, it will be obvious to those skilled in
the art that such embodiments are provided by way of example only.
Numerous variations, changes, and substitutions will occur to those
skilled in the art without departing from the invention. It should
be understood that various alternatives to the embodiments
described herein are, in some circumstances, employed in practicing
the invention. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
[0025] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, without limitation, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0026] The present invention relates to polymorphic forms of
2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid, which is
known to decrease uric acid levels.
[0027] The term "polymorph form 1" refers to a crystalline form of
2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid that
exhibits an x-ray powder diffraction pattern substantially the same
as that shown in FIG. 1, and/or FIG. 2 and/or a differential
scanning calorimetry profile substantially the same as that shown
in FIG. 3.
[0028] The term "polymorph form 2" refers to a crystalline form of
2-(5-bromo-4-(4-cyclopropyl
naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid that
exhibits an x-ray powder diffraction pattern substantially the same
as that shown in FIG. 5, and/or FIG. 6 and/or a differential
scanning calorimetry profile substantially the same as that shown
in FIG. 8.
[0029] The present invention also relates to solid pharmaceutical
compositions, comprising, as an active ingredient, an effective
amount of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as the crystalline polymorph form 1, the crystalline
polymorph form 2, or a combination thereof.
[0030] The present invention also relates to methods for treating
or preventing diseases, comprising administering an effective
amount of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as the crystalline polymorph form 1, the crystalline
polymorph form 2, or a combination thereof.
[0031] Also described are processes for the preparation of the
crystalline polymorph forms 1 and 2.
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acet-
ic acid
[0032] Described herein are polymorph forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid which is known to decrease uric acid levels.
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid and related compounds are described in US Patent
Application Publications 2008-0176850, US 2009-0197825, US
2010-0056464, US 2010-0056465, US 2010-0069645, and US
2010-0081827.
Polymorph Form 1
[0033] In one embodiment,
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form 1 exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 1A or
Table 1B. In some embodiments, provided herein is a polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B. In certain embodiments, provided herein is a
polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 4 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 6 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 8 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 10 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A, at least 15 peaks of (.+-.0.1.degree. 2.theta.) of Table
1A, at least 20 peaks of (.+-.0.1.degree. 2.theta.) of Table 1A, at
least 25 peaks of (.+-.0.1.degree. 2.theta.) of Table 1A, or at
least 30 peaks of (.+-.0.1.degree. 2.theta.) of Table 1A.
TABLE-US-00001 TABLE 1A form 1 .degree.2.theta. d space (.ANG.)
Intensity (%) 10.32 8.562 100 18.84 4.706 32.7 20.75 4.277 23.2
27.28 3.266 13.6 27.60 3.229 11 21.54 4.123 10.4 25.53 3.487 9.8
6.80 12.989 9.4 24.97 3.563 9.1 28.43 3.137 8.4 19.98 4.441 6.9
29.35 3.040 6.7 15.88 5.577 5.4 23.13 3.842 4.8 26.34 3.381 4.8
18.56 4.777 4.1
TABLE-US-00002 TABLE 1B form 1 .degree.2.theta. d space (.ANG.)
Intensity (%) 10.32 8.562 100 18.84 4.706 32.7 20.75 4.277 23.2
27.28 3.266 13.6
[0034] In one embodiment provided herein, the polymorph form 1 of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
10.32, 18.84, and 20.75.degree. 2.theta..+-.0.1.degree. 2.theta..
In further embodiments, the polymorph form 1 is further
characterized by at least one peak appearing at 6.80, 21.54, 24.97,
25.53, 27.28 and 27.60.degree. 2.theta..+-.0.1.degree. 2.theta.. In
further embodiments, the polymorph form 1 is further characterized
by at least two peaks appearing at 6.80, 21.54, 24.97, 25.53, 27.28
and 27.60.degree. 2.theta..+-.0.1.degree. 2.theta.. In yet still
further embodiments, the polymorph exhibits an x-ray powder
diffraction pattern substantially the same as the x-ray powder
diffraction pattern shown in FIG. 1.
Polymorph Form 2
[0035] In one embodiment,
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form 2 exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 2A or
Table 2B. In some embodiments, provided herein is a polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A or 2B. In certain embodiments, provided herein is a
polymorph of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 4 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A or 2B, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A or 2B, at least 6 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A or 2B, at least 8 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A or 2B, at least 10 peaks of (.+-.0.1.degree. 2.theta.) of
Table 2A, at least 15 peaks of (.+-.0.1.degree. 2.theta.) of Table
2A, at least 20 peaks of (.+-.0.1.degree. 2.theta.) of Table 2A, at
least 25 peaks of (.+-.0.1.degree. 2.theta.) of Table 2A, or at
least 30 peaks of (.+-.0.1.degree. 2.theta.) of Table 2A.
TABLE-US-00003 TABLE 2A form 2 Observed .degree.2.theta. d space
(.ANG.) Intensity (%) 7.97 11.086 13.8 9.66 9.148 26.1 10.46 8.449
83.8 11.96 7.394 41.3 12.55 7.046 16.7 12.94 6.836 15.7 13.82 6.402
41.6 16.19 5.471 49.8 18.21 4.867 74.0 18.76 4.727 81.4 19.02 4.662
35.6 19.51 4.548 15.9 19.83 4.474 100.0 20.40 4.349 13.4 21.36
4.157 12.3 22.50 3.948 36.7 22.88 3.884 30.6 23.08 3.850 56.1 24.01
3.704 42.1 25.15 3.539 35.2 25.46 3.496 20.5 26.06 3.417 13.4 26.51
3.360 35.7 27.97 3.187 26.8 29.93 2.983 37.0 30.42 2.936 12.4 31.77
2.814 17.1 32.35 2.765 38.2 34.26 2.615 12.8 38.01 2.366 16.5 38.88
2.314 10.0
TABLE-US-00004 TABLE 2B form 2 Representative .degree.2.theta. d
space (.ANG.) Intensity (%) 19.83 4.474 100.0 10.46 8.449 83.8
18.76 4.727 81.4 18.21 4.867 74.0 23.08 3.850 56.1
[0036] In one embodiment provided herein, the polymorph form 2 of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
10.46, 18.76, and 19.83.degree. 2.theta..+-.0.1.degree. 2.theta..
In further embodiments, the polymorph form 2 is further
characterized by at least one peak appearing at 18.21, or
23.08.degree. 2.theta..+-.0.1.degree. 2.theta.. In further
embodiments, the polymorph form 2 is further characterized by two
peaks appearing at 18.21, or 23.08.degree. 2.theta..+-.0.1.degree.
2.theta.. In yet still further embodiments, the polymorph form 2
exhibits an x-ray powder diffraction pattern substantially the same
as the x-ray powder diffraction pattern shown in FIG. 5.
[0037] In certain instances, the crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were found to exhibit increased stability in comparison to the
amorphous solid state form of the carboxylic acid. In some
instances, improved stability of the crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate provides for the preparation of pharmaceutical dosage forms
displaying reduced variability in the dosage present in a given
dosage form, reduction in the presence of impurities in the final
pharmaceutical product, and an improved shelf life of formulated
dosage forms when compared to the pharmaceutical dosage form
prepared with the amorphous solid state form of the carboxylic
acid. In some embodiments, a polymorph described herein (e.g., Form
1 or Form 2) demonstrates no degradation (e.g., less than 0.01%,
less than 0.1%, less than 0.5% by wt.) for at least 3 months under
accelerated conditions (e.g., 40.degree. C.-75% RH), for at least 4
months under accelerated conditions (e.g., 40.degree. C.-75% RH),
for at least 5 months under accelerated conditions (e.g.,
40.degree. C.-75% RH), for at least 6 months under accelerated
conditions (e.g., 40.degree. C.-75% RH), for at least 9 months
under accelerated conditions (e.g., 40.degree. C.-75% RH), for at
least 12 months under accelerated conditions (e.g., 40.degree.
C.-75% RH), and/or (ii) for at least 12 months under long-term
conditions (e.g., 25.degree. C.-60% RH), for at least 18 months
under long-term conditions (e.g., 25.degree. C.-60% RH), for at
least 24 months under long-term conditions (e.g., 25.degree. C.-60%
RH).
[0038] Additionally, in certain instances, the crystalline
polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were found to exhibit decreased hygroscopicity compared to
other solid state forms as determined by gravimetric vapor sorption
(GVS) studies. FIG. 12 illustrates a GVS study of form 1 and form
2. Form 1 was found to adsorb <0.2% w/w at high humidity and
Form 2 was found to adsorb <0.1% w/w at high humidity. This
property of decreased hygroscopicity greatly aids in the
preparation of solid pharmaceutical dosage forms.
Admixture with Amorphous Solid State Forms
[0039] In certain embodiments, any of the polymorphs described
herein (e.g., Form 1) optionally comprises (or is intermixed or in
combination with) a certain amount of amorphous
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate. In some embodiments, the amorphous component of the polymorph
(e.g., Form 1) or polymorph combination comprises less than 50 wt.
% of the polymorph or polymorph combination, less than 25 wt. % of
the polymorph or polymorph combination, less than 15 wt. % of the
polymorph or polymorph combination, less than 10 wt. % of the
polymorph or polymorph combination, or less than 5 wt. % of the
polymorph or polymorph combination.
Particle Size
[0040] In certain embodiments, provided herein is a
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph particle (e.g., crystalline, or comprising a
crystalline component). In some embodiments, provided herein is a
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph (e.g., crystalline, or comprising a crystalline
component) having a particle size of about 5-50 microns. In some
embodiments, the average particle size is at least 10 microns,
15-50 microns, 15-35 microns, 35-45 microns, 35-40 microns, about
40 microns, or the like. In some embodiments, particles of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., crystalline, or comprising a crystalline component,
such as a polymorph of Form 1) having an average diameter of
greater than 5 or 10 microns have improved stability parameters
compared to smaller diameters.
[0041] Uric acid is the result of the oxidation of xanthine.
Disorders of uric acid metabolism include, but are not limited to,
polycythemia, myeloid metaplasia, gout, a recurrent gout attack,
gouty arthritis, hyperuricaemia, hypertension, a cardiovascular
disease, coronary heart disease, Lesch-Nyhan syndrome,
Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney
failure, joint inflammation, arthritis, urolithiasis, plumbism,
hyperparathyroidism, psoriasis or sarcoidosis.
DEFINITIONS
[0042] The term "subject", as used herein in reference to
individuals suffering from a disorder, and the like, encompasses
mammals and non-mammals. In one embodiment of the methods and
compositions provided herein, the mammal is a human.
[0043] The terms "effective amount", "therapeutically effective
amount" or "pharmaceutically effective amount" as used herein,
refer to an amount of at least one agent or compound being
administered that is sufficient to treat or prevent the particular
disease or condition. The result is the reduction and/or
alleviation of the signs, symptoms, or causes of a disease, or any
other desired alteration of a biological system. For example, an
"effective amount" for therapeutic uses is the amount of the
composition comprising a compound as disclosed herein required to
provide a clinically significant decrease in a disease. An
appropriate "effective" amount in any individual case is determined
using techniques such as a dose escalation study.
[0044] The term "substantially the same as" as used herein, refers
to a powder x-ray diffraction pattern or differential scanning
calorimetry pattern that is non-identical to those depicted herein,
but that falls within the limits of experimental error, when
considered by one of ordinary skill in the art.
Modulating URAT-1 Activity
[0045] Also described herein are methods of modulating URAT-1
activity by contacting URAT-1 with an amount of a polymorphic form
of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to modulate the activity
of URAT-1. The term "modulate" refers to either inhibiting or
activating URAT-1 activity. In some embodiments are provided
methods of inhibiting URAT-1 activity by contacting URAT-1 with an
amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-
acetic acid, as described herein, sufficient to inhibit the
activity of URAT-1. In some embodiments are provided methods of
inhibiting URAT-1 activity in a solution by contacting said
solution with an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein sufficient to inhibit the activity of
URAT-1 in said solution. In some embodiments are provided methods
of inhibiting URAT-1 activity in a cell by contacting said cell
with an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to inhibit the activity
of URAT-1 in said cell. In some embodiments are provided methods of
inhibiting URAT-1 activity in a tissue by contacting said tissue
with an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to inhibit the activity
of URAT-1 in said tissue. In some embodiments are provided methods
of inhibiting URAT-1 activity in blood by contacting the blood with
an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to inhibit the activity
of URAT-1 in blood. In some embodiments are provided methods of
inhibiting URAT-1 activity in plasma by contacting the plasma with
an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to inhibit the activity
of URAT-1 in plasma. In some embodiments are provided methods of
inhibiting URAT-1 activity in an animal by contacting said animal
with an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein sufficient to inhibit the activity of
URAT-1 in said animal. In some embodiments are provided methods of
inhibiting URAT-1 activity in a mammal by contacting said mammal
with an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein sufficient to inhibit the activity of
URAT-1 in said mammal. In some embodiments are provided methods of
inhibiting URAT-1 activity in a human by contacting said human with
an amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, sufficient to inhibit the activity
of URAT-1 in said human.
Pharmaceutical Compositions
[0046] Described herein are pharmaceutical compositions comprising
an effective amount of a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein. In some embodiments, the
pharmaceutical compositions comprise an effective amount of a
polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein, and at least one pharmaceutically
acceptable carrier. In some embodiments, the pharmaceutical
compositions comprise an effective amount of polymorphic form 1, as
described herein, and at least one pharmaceutically acceptable
carrier. In some embodiments, the pharmaceutical compositions
comprise an effective amount of polymorphic form 2, as described
herein, and at least one pharmaceutically acceptable carrier. In
some embodiments, the pharmaceutical compositions comprise an
effective amount of a combination of polymorphic form 1 and form 2,
as described herein, and at least one pharmaceutically acceptable
carrier. In some embodiments the pharmaceutical compositions are
for the treatment of disorders. In some embodiments the
pharmaceutical compositions are for the treatment of disorders in a
mammal. In some embodiments the pharmaceutical compositions are for
the treatment of disorders in a human. In some embodiments the
pharmaceutical compositions are for the treatment or prophylaxis of
disorders of uric acid metabolism. In some embodiments the
pharmaceutical compositions are for the treatment or prophylaxis of
hyperuricemia. In some embodiments the pharmaceutical compositions
are for the treatment or prophylaxis of gout.
Modes of Administration, Formulations and Dosage Forms
[0047] Described herein are pharmaceutical compositions comprising
a polymorphic form of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid, as described herein. The compound, compound forms and
compositions described herein are administered either alone, or in
combination with, pharmaceutically acceptable carriers, excipients,
or diluents in a pharmaceutical composition, according to standard
pharmaceutical practice. Administration is effected by any method
that enables delivery of the compounds to the site of action. These
methods include, though are not limited to delivery via enteral
routes (including oral, gastric or duodenal feeding tube, rectal
suppository and rectal enema), parenteral routes (injection or
infusion, including intraarterial, intracardiac, intradermal,
intraduodenal, intramedullary, intramuscular, intraosseous,
intraperitoneal, intrathecal, intravascular, intravenous,
intravitreal, epidural and subcutaneous), inhalational,
transdermal, transmucosal, sublingual, buccal and topical
(including epicutaneous, dermal, enema, eye drops, ear drops,
intranasal, vaginal) administration, although the most suitable
route depends upon, for example, the condition and disorder of the
recipient. Those of skill in the art will be familiar with
administration techniques that can be employed with the compounds,
compound forms, compositions and methods described herein. By way
of example only, the compounds, compound forms and compositions
described herein are, in some embodiments, administered locally to
the area in need of treatment, by for example, local infusion
during surgery, topical application such as creams or ointments,
injection, catheter, or implant, said implant made for example, out
of a porous, non-porous, or gelatinous material, including
membranes, such as sialastic membranes, or fibers. The
administration is, in some embodiments, by direct injection at the
site of a diseased tissue or organ.
[0048] The pharmaceutical compositions described herein are, for
example, in a form suitable for oral administration as a tablet,
capsule, pill, powder, sustained release formulations, solution,
suspension, for parenteral injection as a sterile solution,
suspension or emulsion, for topical administration as an ointment
or cream or for rectal administration as a suppository. The
pharmaceutical composition is, in some embodiments, in unit dosage
forms suitable for single administration of precise dosages.
Pharmaceutical compositions include a compound or compound form as
described herein as an active ingredient, and a conventional
pharmaceutical carrier or excipient. In some embodiments these
compositions include other or additional medicinal or
pharmaceutical agents, carriers, adjuvants, etc.
[0049] Pharmaceutical compositions are conveniently presented in
unit dosage form. In some embodiments, they are prepared with a
specific amount of active compound by any of the methods well known
or apparent to those skilled in the pharmaceutical arts.
Doses
[0050] The amount of pharmaceutical compositions administered will
firstly be dependent on the mammal being treated. In the instances
where pharmaceutical compositions are administered to a human
subject, the daily dosage will normally be determined by the
prescribing physician with the dosage generally varying according
to the age, sex, diet, weight, general health and response of the
individual patient, the severity of the patient's symptoms, the
precise indication or condition being treated, the severity of the
indication or condition being treated, time of administration,
route of administration, the disposition of the composition, rate
of excretion, drug combination, and the discretion of the
prescribing physician. Also, the route of administration vary
depending on the condition and its severity. The pharmaceutical
composition is, in some embodiments, in unit dosage form. In such
form, the preparation is subdivided into unit doses containing
appropriate quantities of the active component, e.g., an effective
amount to achieve the desired purpose. Determination of the proper
dosage for a particular situation is within the skill of the art.
For convenience, in some embodiments, the total daily dosage is
divided and administered in portions during the day if desired. The
amount and frequency of administration will be regulated according
to the judgment of the attending clinician physician considering
such factors as described above. Thus the amount of pharmaceutical
composition to be administered is variable depending upon the
circumstances. Administration occurs in an amount of between about
0.001 mg/kg of body weight to about 100 mg/kg of body weight per
day (administered in single or divided doses), or at least about
0.1 mg/kg of body weight per day. A particular therapeutic dosage
includes, in some embodiments, from about 0.01 mg to about 7000 mg
of compound, or, from about 0.05 mg to about 2500 mg. The quantity
of active compound in a unit dose of preparation is, in some
embodiments, varied or adjusted from about 0.1 mg to 1000 mg, from
about 1 mg to 300 mg, or 10 mg to 200 mg, according to the
particular application. In some instances the particular
therapeutic dosage is about 200 mg, about 300 mg, about 400 mg,
about 500 mg, about 600 mg, about 700 mg or about 800 mg. In some
instances, dosage levels below the lower limit of the aforesaid
range are more than adequate, while in other cases still larger
doses are employed without causing any harmful side effect, e.g. by
dividing such larger doses into several small doses for
administration throughout the day. In combinational applications in
which the compound is not the sole therapy, it is possible to
administer lesser amounts of compound and still have therapeutic or
prophylactic effect.
Combination Therapies
[0051] The compounds and compound forms described herein are
administered as a sole therapy or in combination with another
therapy or therapies.
[0052] By way of example only, if one of the side effects
experienced by a patient upon receiving a compound or compound form
as described herein is hypertension, then it may be appropriate to
administer an anti-hypertensive agent in combination with the
compound. Or, by way of example only, the therapeutic effectiveness
of a compound or compound form as described herein may be enhanced
by administration of an adjuvant (i.e., by itself the adjuvant may
only have minimal therapeutic benefit, but in combination with
another therapeutic agent, the overall therapeutic benefit to the
patient is enhanced). Or, by way of example only, the benefit
experienced by a patient may be increased by administering a
compound or compound form as described herein with another
therapeutic agent (which also includes a therapeutic regimen) that
also has therapeutic benefit. Regardless of the disease, disorder
or condition being treated, the overall benefit experienced by the
patient may simply be additive of the two therapeutic agents or the
patient may experience a synergistic benefit.
[0053] In the instances where the compounds or compound forms as
described herein are administered with other therapeutic agents,
they need not be administered in the same pharmaceutical
composition as other therapeutic agents, and may, because of
different physical and chemical characteristics, be administered by
a different route. For example, the compound or compound form as
described herein may be administered orally to generate and
maintain good blood levels thereof, while the other therapeutic
agent may be administered intravenously. The determination of the
mode of administration and the advisability of administration,
where possible, in the same pharmaceutical composition, is well
within the knowledge of the skilled clinician. The initial
administration can be made according to established protocols known
in the art, and then, based upon the observed effects, the dosage,
modes of administration and times of administration can be modified
by the skilled clinician.
[0054] The compounds, compound forms and compositions described
herein (and where appropriate other chemotherapeutic agent) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) sequentially
or separately, depending upon the nature of the disease, the
condition of the patient, and the actual choice of other
chemotherapeutic agent to be administered. For combinational
applications and uses, the compounds, compound forms and
compositions described herein and the chemotherapeutic agent need
not be administered simultaneously or essentially simultaneously.
Thus, the compounds, compound forms and compositions as described
herein may be administered first followed by the administration of
the chemotherapeutic agent; or the chemotherapeutic agent may be
administered first followed by the administration of the compounds,
compound forms and compositions as described herein. This alternate
administration may be repeated during a single treatment protocol.
The determination of the order of administration, and the number of
repetitions of administration of each therapeutic agent during a
treatment protocol, is well within the knowledge of the skilled
physician after evaluation of the disease being treated and the
condition of the patient. For example, the chemotherapeutic agent
may be administered first, especially if it is a cytotoxic agent,
and then the treatment continued with the administration of the
compounds, compound forms and compositions as described herein
followed, where determined advantageous, by the administration of
the chemotherapeutic agent, and so on until the treatment protocol
is complete. Thus, in accordance with experience and knowledge, the
practicing physician can modify each administration protocol for
treatment according to the individual patient's needs, as the
treatment proceeds. The attending clinician, in judging whether
treatment is effective at the dosage administered, will consider
the general well-being of the patient as well as more definite
signs such as relief of disease-related symptoms. Relief of
disease-related symptoms such as pain, and improvement in overall
condition can also be used to help judge effectiveness of
treatment.
[0055] Specific, non-limiting examples of possible combination
therapies include use of the compounds, compound forms and
compositions described herein with Febuxostat, Allopurinol,
Probenecid, Sulfinpyrazone, Losartan, Fenofibrate, Benzbromarone or
PNP-inhibitors (such as, but not limited to Forodesine, BCX-1777 or
BCX-4208). This list should not be construed to be closed, but
should instead serve as an illustrative example common to the
relevant therapeutic area at present. Moreover, combination
regimens may include a variety of routes of administration,
including but not limited to oral, intravenous, intraocular,
subcutaneous, dermal, and inhaled topical.
Diseases
[0056] Described herein are methods of treating a disease or
disorder in an individual suffering from the disease or disorder
comprising administering to said individual an effective amount of
a polymorph form as described herein of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid.
[0057] Also described herein are methods of preventing a disease or
disorder in an individual comprising administering to said
individual an effective amount of a polymorph form as described
herein of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid.
[0058] The invention extends to the use of the compounds, compound
forms and compositions described herein, in the manufacture of a
medicament for treating or preventing a disease or disorder.
[0059] In some embodiments, the disease or disorder is
hyperuricemia. In certain instances, hyperuricemia is characterized
by higher than normal blood levels of uric acid, sustained over
long periods of time. In certain instances, increased blood urate
levels may be due to enhanced uric acid production (.about.10-20%)
and/or reduced renal excretion (.about.80-90%) of uric acid. In
certain instances, causes of hyperuricemia may include
obesity/weight gain, excessive alcohol use, excessive dietary
purine intake (foods such as shellfish, fish roe, scallops, peas
lentils, beans and red meat, particularly offal--brains, kidneys,
tripe, liver), certain medications, including low-dose aspirin,
diuretics, niacin, cyclosporine, pyrazinamide, ethambutol, some
high blood pressure drugs and some cancer chemotherapeutics,
immunosuppressive and cytotoxic agents, specific disease states,
particularly those associated with a high cell turnover rate (such
as malignancy, leukemia, lymphoma or psoriasis), and also including
high blood pressure, hemoglobin diseases, hemolytic anemia, sickle
cell anemia, various nephropathies, myeloproliferative and
lymphoproliferative diseases, hyperparathyroidism, renal disease,
conditions associated with insulin resistance and diabetes
mellitus, and in transplant recipients, and possibly heart disease,
inherited enzyme defects, abnormal kidney function (e.g. increased
ATP turn over, reduced glomerular urate filtration) and exposure to
lead (plumbism or "saturnine gout").
[0060] In certain instances, hyperuricemia may be asymptomatic,
though is associated with the following conditions: gout, gouty
arthritis, uric acid stones in the urinary tract (urolithiasis),
deposits of uric acid in the soft tissue (tophi), deposits of uric
acid in the kidneys (uric acid nephropathy), and impaired kidney
function, possibly leading to chronic and acute renal failure.
[0061] In further or additional embodiments, the disease or
disorder is gout, which is a condition that results from uric acid
crystals depositing in tissues of the body. It is often related to
an inherited abnormality in the body's ability to process uric
acid, but may also be exacerbated by a purine rich diet. Defective
uric acid processing may lead to elevated levels of uric acid in
the blood causing recurring attacks of joint inflammation
(arthritis), uric acid deposits in and around the joints,
tophaceous gout, the formation of tophi, decreased kidney function,
and kidney stones. Approximately 3-5 million people in the United
States suffer from attacks of gout with attacks more prevalent in
men than in women. In certain instances, gout is one of the most
common forms of arthritis, accounting for approximately 5% of all
arthritis cases. In certain instances, kidney failure and
urolithiasis occur in 10-18% of individuals with gout and are
common sources of morbidity and mortality from the disease.
[0062] Gout is associated with hyperuricemia. In certain instances,
individuals suffering from gout excrete approximately 40% less uric
acid than non-gouty individuals for any given plasma urate
concentration. In certain instances, urate levels increase until
the saturation point is reached. In certain instances,
precipitation of urate crystals occurs when the saturation point is
reached. In certain instances, these hardened, crystallized
deposits (tophi) form in the joints and skin, causing joint
inflammation (arthritis). In certain instances, deposits are be
made in the joint fluid (synovial fluid) and/or joint lining
(synovial lining). Common areas for these deposits are the large
toe, feet, ankles and hands (less common areas include the ears and
eyes). In certain instances, the skin around an affected joint
becomes red and shiny with the affected area being tender and
painful to touch. In certain instances, gout attacks increase in
frequency. In certain instances, untreated acute gout attacks lead
to permanent joint damage and disability. In certain instances,
tissue deposition of urate leads to: acute inflammatory arthritis,
chronic arthritis, deposition of urate crystals in renal parenchyma
and urolithiasis. In certain instances, the incidence of gouty
arthritis increases 5 fold in individuals with serum urate levels
of 7 to 8.9 mg/dL and up to 50 fold in individuals with levels
>9 mg/dL (530 mmol/L). In certain instances, individuals with
gout develop renal insufficiency and end stage renal disease (i.e.,
"gouty nephropathy"). In certain instances, gouty nephropathy is
characterized by a chronic interstitial nephropathy, which is
promoted by medullary deposition of monosodium urate.
[0063] In certain instances, gout includes painful attacks of
acute, monarticular, inflammatory arthritis, deposition of urate
crystals in joints, deposition of urate crystals in renal
parenchyma, urolithiasis (formation of calculus in the urinary
tract), and nephrolithiasis (formation of kidney stones). In
certain instances, secondary gout occurs in individuals with
cancer, particularly leukemia, and those with other blood diseases
(e.g. polycythemia, myeloid metaplasia, etc).
[0064] In certain instances, attacks of gout develop very quickly,
frequently the first attack occurring at night. In certain
instances, symptoms include sudden, severe joint pain and extreme
tenderness in the joint area, joint swelling and shiny red or
purple skin around the joint. In certain instances, the attacks are
infrequent lasting 5-10 days, with no symptoms between episodes. In
certain instances, attacks become more frequent and last longer,
especially if the disease is not controlled. In certain instances,
episodes damage the affected joint(s) resulting in stiffness,
swelling, limited motion and/or persistent mild to moderate
pain.
[0065] Plumbism or "saturnine gout," is a lead-induced
hyperuricemia that results from lead inhibition of tubular urate
transport causing decreased renal excretion of uric acid. In
certain instances, more than 50% of individuals suffering from lead
nephropathy suffer from gout. In certain instances, acute attacks
of saturnine gout occur in the knee more frequently than the big
toe. In certain instances, renal disease is more frequent and more
severe in saturnine gout than in primary gout. In certain
instances, treatment consists of excluding the individual from
further exposure to lead, the use of chelating agents to remove
lead, and control of acute gouty arthritis and hyperuricemia. In
certain instances, saturnine gout is characterized by less frequent
attacks than primary gout. In certain instances, lead-associated
gout occurs in pre-menopausal women, an uncommon occurrence in non
lead-associated gout.
[0066] In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's
syndrome) affects about one in 100,000 live births. In certain
instances, LNS is caused by a genetic deficiency of the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In certain
instances, LNS is an X-linked recessive disease. In certain
instances, LNS is present at birth in baby boys. In certain
instances, the disease leads to severe gout, poor muscle control,
and moderate mental retardation, which appear in the first year of
life. In certain instances, the disease also results in
self-mutilating behaviors (e.g., lip and finger biting, head
banging) beginning in the second year of life. In certain
instances, the disease also results in gout-like swelling in the
joints and severe kidney problems. In certain instances, the
disease leads neurological symptoms include facial grimacing,
involuntary writhing, and repetitive movements of the arms and legs
similar to those seen in Huntington's disease. The prognosis for
individuals with LNS is poor. In certain instances, the life
expectancy of an untreated individual with LNS is less than about 5
years. In certain instances, the life expectancy of a treated
individual with LNS is greater than about 40 years of age.
[0067] In certain instances, hyperuricemia is found in individuals
with cardiovascular disease (CVD) and/or renal disease. In certain
instances, hyperuricemia is found in individuals with
prehypertension, hypertension, increased proximal sodium
reabsorption, microalbuminuria, proteinuria, kidney disease,
obesity, hypertriglyceridemia, low high-density lipoprotein
cholesterol, hyperinsulinemia, hyperleptinemia,
hypoadiponectinemia, peripheral, carotid and coronary artery
disease, atherosclerosis, congestive heart failure, stroke, tumor
lysis syndrome, endothelial dysfunction, oxidative stress, elevated
renin levels, elevated endothelin levels, and/or elevated
C-reactive protein levels. In certain instances, hyperuricemia is
found in individuals with obesity (e.g., central obesity), high
blood pressure, hyperlipidemia, and/or impaired fasting glucose. In
certain instances, hyperuricemia is found in individuals with
metabolic syndrome. In certain instances, gouty arthritis is
indicative of an increased risk of acute myocardial infarction. In
some embodiments, administration of a compound described herein to
an individual are useful for decreasing the likelihood of a
clinical event associated with a disease or condition linked to
hyperuricemia, including, but not limited to, prehypertension,
hypertension, increased proximal sodium reabsorption,
microalbuminuria, proteinuria, kidney disease, obesity,
hypertriglyceridemia, low high-density lipoprotein cholesterol,
hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral,
carotid and coronary artery disease, atherosclerosis, congestive
heart failure, stroke, tumor lysis syndrome, endothelial
dysfunction, oxidative stress, elevated renin levels, elevated
endothelin levels, and/or elevated C-reactive protein levels.
[0068] In some embodiments, a compound or compound form as
described herein is administered to an individual suffering from a
disease or condition requiring treatment with a diuretic. In some
embodiments, a compound or compound form as described herein is
administered to an individual suffering from a disease or condition
requiring treatment with a diuretic, wherein the diuretic causes
renal retention of urate. In some embodiments, the disease or
condition is congestive heart failure or essential
hypertension.
[0069] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
improving motility or improving quality of life.
[0070] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
treating or decreasing the side effects of cancer treatment.
[0071] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
decreasing kidney toxicity of cis-platin.
[0072] In certain instances, gout is treated by lowering the
production of uric acid. In certain instances, gout is treated by
increasing the excretion of uric acid. In certain instances, gout
is treated by a URAT 1 inhibitor, a xanthine oxidase inhibitor, a
xanthine dehydrogenase inhibitor, a xanthine oxidoreductase
inhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a
uric acid transporter (URAT) inhibitor, a glucose transporter
(GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier family 2
(facilitated glucose transporter), member 9 (SLC2A9) inhibitor, an
organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, or
combinations thereof. In general, the goals of gout treatment are
to i) reduce the pain, swelling and duration of an acute attack,
and ii) prevent future attacks and joint damage. In certain
instances, gout attacks are treated successfully using a
combination of treatments. In certain instances, gout is one of the
most treatable forms of arthritis.
[0073] i) Treating the Gout Attack.
[0074] In certain instances, the pain and swelling associated with
an acute attack of gout can be addressed with medications such as
acetaminophen, steroids, nonsteroidal anti-inflammatory drugs
(NSAIDs), adrenocorticotropic hormone (ACTH) or colchicine. In
certain instances, proper medication controls gout within 12 to 24
hours and treatment is stopped after a few days. In certain
instances, medication is used in conjunction with rest, increased
fluid intake, ice-packs, elevation and/or protection of the
affected area/s. In certain instances, the aforementioned
treatments do not prevent recurrent attacks and they do not affect
the underlying diseases of abnormal uric acid metabolism.
[0075] ii) Preventing Future Attacks.
[0076] In certain instances, reducing serum uric acid levels below
the saturation level is the goal for preventing further gout
attacks. In some cases, this is achieved by decreasing uric acid
production (e.g. allopurinol), or increasing uric acid excretion
with uricosuric agents (e.g. probenecid, sulfinpyrazone,
benzbromarone).
[0077] In certain instances, allopurinol inhibits uric acid
formation, resulting in a reduction in both the serum and urinary
uric acid levels and becomes fully effective after 2 to 3
months.
##STR00002##
[0078] In certain instances, allopurinol is a structural analogue
of hypoxanthine, (differing only in the transposition of the carbon
and nitrogen atoms at positions 7 and 8), which inhibits the action
of xanthine oxidase, the enzyme responsible for the conversion of
hypoxanthine to xanthine, and xanthine to uric acid. In certain
instances, it is metabolized to the corresponding xanthine
analogue, alloxanthine (oxypurinol), which is also an inhibitor of
xanthine oxidase. In certain instances, alloxanthine, though more
potent in inhibiting xanthine oxidase, is less pharmaceutically
acceptable due to low oral bioavailability. In certain instances,
fatal reactions due to hypersensitivity, bone marrow suppression,
hepatitis, and vasculitis have been reported with Allopurinol. In
certain instances, the incidence of side effects may total 20% of
all individuals treated with the drug. Treatment for diseases of
uric acid metabolism has not evolved significantly in the following
two decades since the introduction of allopurinol.
[0079] In certain instances, uricosuric agents (e.g., probenecid,
sulfinpyrazone, and benzbromarone) increase uric acid excretion. In
certain instances, probenecid causes an increase in uric acid
secretion by the renal tubules and, when used chronically,
mobilizes body stores of urate. In certain instances, 25-50% of
individuals treated with probenecid fail to achieve reduction of
serum uric acid levels <6 mg/dL. In certain instances,
insensitivity to probenecid results from drug intolerance,
concomitant salicylate ingestion, and renal impairment. In certain
instances, one-third of the individuals develop intolerance to
probenecid. In certain instances, administration of uricosuric
agents also results in urinary calculus, gastrointestinal
obstruction, jaundice and anemia.
[0080] Successful treatment aims to reduce both the pain associated
with acute gout flare and long-term damage to the affected joints
Therapeutic goals include providing rapid and safe pain relief,
preventing further attacks, preventing the formation of tophi and
subsequent arthritis, and avoiding exacerbating other medical
conditions. Initiation of treatment depends upon the underlying
causes of hyperuricemia, such as renal function, diet, and
medications. While gout is a treatable condition, there are limited
treatments available for managing acute and chronic gout and a
number of adverse effects are associated with current therapies.
Medication treatment of gout includes pain management, prevention
or decrease in joint inflammation during an acute gouty attack, and
chronic long-term therapy to maintain decreased serum uric acid
levels.
[0081] Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective
anti-inflammatory medications for acute gout but are frequently
associated with irritation of the gastrointestinal (GI) system,
ulceration of the stomach and intestines, and occasionally
intestinal bleeding. Colchicine for acute gout is most commonly
administered orally as tablets (every 1-2 hours until there is
significant improvement in pain or the patient develops GI side
effects such as severe diarrhea, nausea and vomiting), or
intravenously. Corticosteroids, given in short courses, can be
administered orally or injected directly into the inflamed
joint.
[0082] Medications are available for reducing blood uric acid
levels that either increase renal excretion of uric acid by
inhibiting re-uptake or reduce production of uric acid by blockade
of xanthine oxidase. These medicines are generally not initiated
until after the inflammation from acute gouty arthritis has
subsided because they may intensify the attack. If they are already
being taken prior to the attack, they are continued and only
adjusted after the attack has resolved. Since many subjects with
elevated blood uric acid levels may not develop gouty attacks or
kidney stones, the decision for prolonged treatment with uric
acid-lowering medications is individualized.
Kits
[0083] The compounds, compound forms, compositions and methods
described herein provide kits for the treatment of diseases and
disorders, such as the ones described herein. These kits comprise a
compound, compound form, compounds, compound forms or compositions
described herein in a container and, optionally, instructions
teaching the use of the kit according to the various methods and
approaches described herein. Such kits, in some embodiments, also
include information, such as scientific literature references,
package insert materials, clinical trial results, and/or summaries
of these and the like, which indicate or establish the activities
and/or advantages of the composition, and/or which describe dosing,
administration, side effects, drug interactions, or other
information useful to the health care provider. Such information
may be based on the results of various studies, for example,
studies using experimental animals involving in vivo models and
studies based on human clinical trials. Kits described herein are
provided, marketed and/or promoted to health providers, including
physicians, nurses, pharmacists, formulary officials, and the like.
Kits are also, in some embodiments, marketed directly to the
consumer.
[0084] Provided in certain embodiments, are compositions or kits
comprising
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., a polymorph thereof, such as Form 1), a double low
density polyethylene plastic bag, and an HDPE container. In further
embodiments, the composition or kit further comprises a foil bag
(e.g., an anhydrous foil bag, such as a heat sealed anhydrous foil
bag). In some embodiments, the composition or kit further comprises
a desiccant; in still other embodiments, a desiccant is not
necessary and/or present. In some instances, such packing improves
the stability of the
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., Form 1).
[0085] In some embodiments, the compounds, compound forms and
pharmaceutical compositions described herein are utilized for
diagnostics and as research reagents. For example, in some
embodiments, the compounds, compound forms and pharmaceutical
compositions, either alone or in combination with other compounds,
are used as tools in differential and/or combinatorial analyses to
elucidate expression patterns of genes expressed within cells and
tissues. As one non-limiting example, expression patterns within
cells or tissues treated with one or more compounds are compared to
control cells or tissues not treated with compounds and the
patterns produced are analyzed for differential levels of gene
expression as they pertain, for example, to disease association,
signaling pathway, cellular localization, expression level, size,
structure or function of the genes examined. These analyses are
performed on stimulated or unstimulated cells and in the presence
or absence of other compounds which affect expression patterns.
[0086] Besides being useful for human treatment, the compounds,
compound forms and pharmaceutical compositions described herein are
also useful for veterinary treatment of animals.
[0087] The examples and preparations provided below further
illustrate and exemplify the compounds of the present invention and
methods of preparing such compounds. It is to be understood that
the scope of the present invention is not limited in any way by the
scope of the following examples and preparations.
EXAMPLES
I. Preparation of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid
Example 1A
Preparation of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid via methyl
2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate intermediate
[0088]
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetic acid was prepared according to previously described
procedures (see US patent application publication US 2009/0197825)
as outlined in the scheme below.
##STR00003##
Example 1B
Preparation of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid via
2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)a-
cetic acid intermediate
##STR00004##
[0090] Preparation of 1-cyclopropyl-4-isothiocyanatonaphthalene has
been previously described (see US patent application publication US
2009/0197825). In brief, 1-bromonaphthalene is coupled with
cyclopropylmagnesium bromide to form 1-cyclopropylnaphthalene.
Reaction with sodium nitrite forms the nitro derivative which is
reduced by treatment with hydrogen over Pd/C to form
1-amino-4-cyclopropylnaphthalene. Finally, reaction with
thiophosgene provides
1-cyclopropyl-4-isothiocyanatonaphthalene.
[0091] 1-Cyclopropyl-4-isothiocyanatonaphthalene is reacted with
hydrazine and then cyclized in the presence of dimethyl carbonate
to form
4-(4-cyclopropylnaphthalen-1-yl)-5-mercapto-4H-1,2,4-triazol-3-ol.
[0092] Coupling of
4-(4-cyclopropylnaphthalen-1-yl)-5-mercapto-4H-1,2,4-triazol-3-ol
with 2-chloroacetic acid provides
2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)a-
cetic acid.
[0093] Bromination of
2-(4-(4-cyclopropylnaphthalen-1-yl)-5-hydroxy-4H-1,2,4-triazol-3-ylthio)a-
cetic acid, utilizing protecting groups as required (such as
protecting the acid as the i-propyl ester), provides
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid.
Example 1C
Preparation of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate from methyl
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
##STR00005##
[0095] Aqueous sodium hydroxide solution (1N, 3.0 L, 3.0 mol, 1.25
eq) was added to a cooled (15-18.degree. C.) mixture of methyl
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate-form 2 (1.0 kg, 2.39 mol, 1 eq) and ethanol (9 L), at a rate
to maintain an internal temperature <25.degree. C. The mixture
was then stirred at 20-25.degree. C. (maintaining pH .gtoreq.12),
while monitoring by HPLC and considered complete when the sum of
methyl and ethyl esters <0.5%, (.about.3 hours). The mixture was
filtered through a medium frit funnel (10-16 micron) and the
filtrate concentrated in vacuo (40.degree. C.) to a final volume of
5.2 L. Water (0.6 L) was added and the solution cooled to
0-5.degree. C. with stirring. The resulting slurry was warmed
(17-18.degree. C.) over 1 h, then cooled (0-5.degree. C.) over 2-3
h, and held at 0-5.degree. C. for an additional 6-9 h. The slurry
was then filtered through a jacketed filter funnel (0-5.degree. C.)
lined with filter paper (3 micron) or filter cloth. The resulting
cake was washed with pre-chilled (3-5.degree. C.) water
(3.times.1.25 L), allowed to de-liquor on the funnel (at least 3
h), and further dried in a vacuum oven (18-25.degree. C., nitrogen
sweep) until water content <13% w/w (.about.8 days). Sodium
2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate was isolated as a light yellow solid (696.4 g; KF=13%).
II. Preparation of crystalline polymorph forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid
Example 2
Preparation of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-form 1
[0096]
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetic acid-form 1 is prepared from crude sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate as described below:
##STR00006##
[0097] Step 1:
[0098] Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (60 g) and water (300 mL) were stirred and briefly heated
(40-50.degree. C.) until all solids dissolved. The solution was
cooled and stirred in an ice bath for 1-2 hrs, after which time
crystals began to form (or if crystallization had not begun, the
solution was seeded with a small amount of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate crystals). Stirring in the ice bath was continued until
crystallization was complete, and then the solid isolated by
filtration through a sintered filter funnel (medium porosity) under
vacuum. The filter cake was washed with ice-cold water (sufficient
to cover the filter cake) and the liquid completely drained under
vacuum to provide wet filter cake (126.5 g).
[0099] Step 2:
[0100] The filter cake was dissolved in water (.about.70 g present
in the filter cake plus 130 mL; concentration 200-250 mg/mL) at
60-70.degree. C., and slowly added to acetic acid (200 mL). The
acetic acid/water (1:1 v/v) solution was cooled to room temperature
under continuous stirring, and then further cooled to 0.degree. C.,
resulting in the formation of crystals which were isolated by
vacuum filtration over a medium porosity sintered filter funnel.
The solids were washed with ice-cold acid/water (1:1 v/v) and dried
in a vacuum oven to provide
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid (39.5 g, 78%).
Example 3
Preparation of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-form 2
[0101]
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetic acid-form 2 is prepared from sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate as described below:
##STR00007##
[0102] A suspension of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (50.0 g of crude sample 97.6% a/a; KF=12.6%; 43.3 g calculated
actual) and deionized water (217 mL) was heated (30-35.degree. C.)
with vigorous stirring for 10-15 min, during which time the slurry
dissolved leaving only trace solids. The mixture was filtered
through a medium-frit filter funnel and the clear filtrate cooled
to 10.degree. C. Approximately one half of a mixture of aqueous
hydrogen bromide solution (48 wt %, 18 g, 106.8 mmol, 1.05 eq) and
deionized water (.about.13 mL) was added to the filtrate over 10
min, at 10-15.degree. C., during which time some solids were
formed. Ethyl acetate (347 mL) was added with vigorous stirring
resulting in dissolution of all solids. The remaining hydrogen
bromide solution was added over 10 min at 10.degree. C., and
stirring continued for 5-10 min, during which time a cloudy
suspension formed. Stirring was stopped, the phases allowed to
separate and the aqueous layer removed. The organic layer was
washed with deionized water (110 mL) with vigorous stirring for
5-10 min, and after phase separation the aqueous layer removed. The
organic layer was heated to 45-50.degree. C. and solvents removed
using gentle vacuum, resulting in the formation of a slurry (final
volume .about.200 mL), which was warmed (45-50.degree. C.) with
moderate stirring for 1 h, gradually (3-4 h) cooled to
20-25.degree. C., and held at 20-25.degree. C. for an additional 12
h, and finally cooled to 5-10.degree. C. and held for 20-30 min.
The slurry was then filtered under vacuum through a Buchner funnel
lined with Whatman No. 3 filter paper. There were fast filtering
solids and the mother liquor was cycled through the vessel to
recover residual solids which were collected with the initial
batch. The solids were washed with cold (5.degree. C.) ethyl
acetate (26 mL) and allowed to dry on the funnel for at least 10
min, then soaked in n-heptane (30 mL) for at least 10 min and the
vacuum reapplied for .about.6 h. The solids were transferred to a
drying dish and dried in a vacuum oven (25 mmHg) for at least 16 h
at 35-40.degree. C., with nitrogen sweep.
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-form 2 was obtained as a free flowing off-white solid
(28.39 g, 69%), containing trace amounts of water (0.16 wt %) and
ethyl acetate (700 ppm).
TABLE-US-00005 Materials Amount Sodium 2-(5-bromo-4-(4-cyclopropyl
naphthalen-1- 50.0 g crude yl)-4H-1,2,4-triazol-3-ylthio)acetate
(43.3 g corrected) Hydrogen bromide (48 wt %) 18.0 g Water 217 mL
Ethyl acetate 346.7 mL Water (wash 1) 108.3 mL Water (wash 2) 108.3
mL Ethyl acetate (wash) 26 mL n-Heptane (wash) 30 mL
Example 4
Conversion of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-Polymorph form 1 to Polymorph form 2
##STR00008##
[0103] Method 1
[0104] Ethyl acetate (200 mL) was added to a solution of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-polymorph form 1 (30 g) in acetone (200 mL) at 60.degree.
C. A portion of the solvent (.about.200 mL) was removed under low
vacuum and fresh ethyl acetate (200 mL) was added, followed by
another distillation cycle, during which crystallization began. The
temperature of the water bath was slowly increased to 70.degree.
C., during which time four additional ethyl acetate
addition/distillation cycles were carried out to a final volume of
.about.200 mL. The mixture was allowed to cool slowly to room
temperature and then placed in the fridge overnight. Solids were
isolated by filtration, washed with ice-cold ethyl acetate and
dried in a vacuum oven to provide of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-form 2.
Method 2
[0105] A solution of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid-form 1 in one of the solvents listed below was slowly
evaporated at room temperature to crystallize, refrigerated, the
solid crystals isolated and washed with solvent to produce Solid
Polymorph form 2, containing trace amounts of solvent and water, as
indicated.
TABLE-US-00006 Solvent content Water Polymorph Solvent (%) content
(%) Purity Form Butan-2-one 0.35 0.36 2 0.49 0.53 tert-Butanol 0.32
0.17 94% 2 0.72 0.5 4% impurities Dichloromethane 0.3 0.5 2
Method 3
[0106] Solid Polymorph form 1 was held in equilibrium with its
saturated acetonitrile, ethyl acetate or toluene solution at
60.degree. C. for 6 days to produce Solid Polymorph form 2.
[0107] Solid Polymorph form 1 held in equilibrium with its
saturated acetone solution at 60.degree. C. for 6 days resulted in
decomposition.
Method 4
[0108] Solid Polymorph form 1 and solvent (20 .mu.L) were heated at
60.degree. C. for 13 days to produce Solid Polymorph form 2.
TABLE-US-00007 form 1 (mg) Solvent Polymorph Form Isolated 928 DMF
2 927 Dioxane 2 883 Acetic acid 2 844 Toluene 2 844
Acetonitrile/toluene (20 .mu.L each) 2 844 Acetonitrile 1 & 2
867 iso-Propanol 1 & 2 944 Water 1
III. Analysis of crystalline polymorph forms of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid
Example 5A
Analysis of Crystalline Polymorph Form 1
X-Ray Powder Diffraction
[0109] The X-ray powder diffraction pattern of polymorph form 1 is
shown in FIGS. 1 (raw data) and 2 (background subtracted and
K.alpha.2 stripped); observed and representative peaks in the XRPD
pattern are shown in the tables below (generated on background
corrected and K.alpha.2 stripped file).
TABLE-US-00008 form 1 Representative .degree.2.theta. d space
(.ANG.) Intensity (%) 10.32 8.562 100 18.84 4.706 32.7 20.75 4.277
23.2 27.28 3.266 13.6
TABLE-US-00009 form 1 Observed .degree.2.theta. d space (.ANG.)
Intensity (%) 10.32 8.562 100 18.84 4.706 32.7 20.75 4.277 23.2
27.28 3.266 13.6 27.60 3.229 11 21.54 4.123 10.4 25.53 3.487 9.8
6.80 12.989 9.4 24.97 3.563 9.1 28.43 3.137 8.4 19.98 4.441 6.9
29.35 3.040 6.7 15.88 5.577 5.4 23.13 3.842 4.8 26.34 3.381 4.8
18.56 4.777 4.1
Differential Scanning calorimetry (DSC)
[0110] The differential scanning calorimetry trace for form 1 is
shown in FIG. 3; a transition temperature of 150.7.degree. C. was
recorded.
Scanning Electron Microscopy (SEM)
[0111] SEM analysis showed form 1 primary crystals are composed of
agglomerates (typical size .about.25 .mu.m) of plate-like crystals
(size .about.5 .mu.m).
Thermogravimetric Analysis (TGA)
[0112] Replicate TGA scans for form 1 are shown in FIGS. 4 (a) and
(b), indicating the material does not contain significant levels of
volatiles
Solubility
[0113] Form 1 (.about.25 mg) and acetate buffer (25 mM, pH 5, 4
mL), prepared with and without sodium chloride (ionic strength
adjusted to =0.1M), were placed in a glass vial which was sealed
and placed on a laboratory rotator in a 25.degree. C. incubator.
After 1, 5, and 7 days the samples were filtered and assayed by
HPLC. Form 1 solubility (mg/mL), at the various time points, with
and without sodium chloride, is shown in the table below:
TABLE-US-00010 Day 1 Day 5 Day 7 No NaCl 0.2652 (pH 4.95) 0.2134
(pH 4.85) 0.1569 (pH 4.75) NaCl (I = 0.1) 0.2995 0.2566 (pH 4.79)
0.3045 (pH 4.81)
Example 5B
Analysis of Crystalline Polymorph form 2
X-Ray Powder Diffraction
[0114] The X-ray powder diffraction pattern of polymorph form 2 is
shown in FIGS. 5 (raw data) and 6 (background subtracted and
K.alpha.2 stripped); observed and representative peaks in the XRPD
pattern are shown in the tables below (generated on background
corrected and K.alpha.2 stripped file).
TABLE-US-00011 form 2 Observed .degree.2.theta. d space (.ANG.)
Intensity (%) 7.97 11.086 13.8 9.66 9.148 26.1 10.46 8.449 83.8
11.96 7.394 41.3 12.55 7.046 16.7 12.94 6.836 15.7 13.82 6.402 41.6
16.19 5.471 49.8 18.21 4.867 74.0 18.76 4.727 81.4 19.02 4.662 35.6
19.51 4.548 15.9 19.83 4.474 100.0 20.40 4.349 13.4 21.36 4.157
12.3 22.50 3.948 36.7 22.88 3.884 30.6 23.08 3.850 56.1 24.01 3.704
42.1 25.15 3.539 35.2 25.46 3.496 20.5 26.06 3.417 13.4 26.51 3.360
35.7 27.97 3.187 26.8 29.93 2.983 37.0 30.42 2.936 12.4 31.77 2.814
17.1 32.35 2.765 38.2 34.26 2.615 12.8 38.01 2.366 16.5 38.88 2.314
10.0
TABLE-US-00012 form 2 Representative .degree.2.theta. d space
(.ANG.) Intensity (%) 19.83 4.474 100.0 10.46 8.449 83.8 18.76
4.727 81.4 18.21 4.867 74.0 23.08 3.850 56.1
[0115] FIG. 7, shows an overlay of the XRPD Patterns (y-axis
offset) of form 1 (lower) and form 2 (upper).
Differential Scanning Calorimetry (DSC)
[0116] The differential scanning calorimetry trace for form 2 is
shown in FIG. 8, a melting point at 174.7.degree. C. was
recorded.
.sup.1H NMR Spectroscopy
[0117] The .sup.1H NMR spectrum, taken in DMSO-d.sub.6, of
polymorph form 2 is shown in FIG. 9 and the major peaks listed in
the table below:
TABLE-US-00013 ppm peak integration 12.96 s 1.00 8.58 d 1.01 7.74
td 1.01 7.65 m 2.02 7.44 d 1.01 7.16 d 1.00 3.99 d 2.02 2.49-2.58 m
1.00 1.16 m 2.03 0.88 d 2.01
HPLC
[0118] The HPLC trace of polymorph form 2 is shown in FIG. 10. The
peak listing for the trace is given in the table below:
TABLE-US-00014 Peak Area # Ret time (min) Type Width (min) (mAU *
s) Area (%) 1 6.111 BB 0.0621 5.24158 0.0438 2 11.514 VB 0.1157
39.57644 0.3311 3 13.741 BB 0.1436 2.56681 0.0215 4 143676 BB
0.1463 3.02621 0.0253 5 17.694 BB 0.1785 3.37245 0.0282 6 18.791 BB
0.2269 11,881.6 99.3931 7 19.891 BB 0.2502 5.15241 0.0431 8 32.169
BB 0.1785 8.54182 0.0715 9 41.636 BB 0.1163 5.06670 0.0424
Scanning Electron Microscopy (SEM)
[0119] SEM analysis showed form 2 primary crystals are composed of
agglomerates (typical size .about.25 .mu.m) of column-like crystals
(size .about.10 .mu.m).
Thermogravimetric Analysis (TGA)
[0120] Overlay of TGA scans for form 2 are shown in FIG. 11,
indicating the material does not contain significant levels of
volatiles.
Solubility
[0121] Form 2 (.about.25 mg) and acetate buffer (25 mM, pH 5, 4
mL), prepared with and without sodium chloride (ionic strength
adjusted to =0.1M), were placed in a glass vial which was sealed
and placed on a laboratory rotator in a 25.degree. C. incubator.
After 1, 5, and 7 days the samples were filtered and assayed by
HPLC. Form 2 solubility (mg/mL), at the various time points, with
and without sodium chloride, is shown in the table below:
TABLE-US-00015 Day 1 Day 5 Day 7 No NaCl 0.1867 (pH 4.91) 0.1957
(pH 4.73) 0.1337 (pH 4.79) NaCl (I = 0.1) 0.2192 0.2441 (pH 4.83)
0.2157 (pH 4.85)
[0122] Form 2 of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate was tested under various conditions to determine drug
substance stability. No degradation of packaged Form 2 was observed
for 1 month under accelerated conditions (40.degree. C.-75% RH, or
25.degree. C.-60% RH). Packaging was in a double low density
polyethylene plastic bags inside a HDPE container.
Stability of crystalline polymorph
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0123] The crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were found to exhibit increased stability in comparison to the
amorphous solid state form of the carboxylic acid. The improved
stability of the crystalline polymorphs of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate provides for the preparation of pharmaceutical dosage forms
displaying reduced variability in the dosage present in a given
dosage form, reduction in the presence of impurities in the final
pharmaceutical product, and an improved shelf life of formulated
dosage forms when compared to the pharmaceutical dosage form
prepared with the amorphous solid state form of the carboxylic
acid.
IV. Analytical Techniques
Example 6A
X-Ray Powder Diffraction (XRPD)
[0124] XRPD patterns were collected on a Bruker D8 Advance
diffractometer in the Bragg-Brentano theta/theta configuration. An
incident x-ray beam was produced using a CuK.alpha. (.lamda.=1.5418
.ANG.) anode (tube voltage=40 kV, current=40 mA), made parallel
with a 1.0 mm primary Soller slit on the source side and 1.0 mm
secondary Soller slit on the detector side. CuK.beta. radiation was
removed with a graphite monochromator slit of 1.0 mm on the
detector side. A scintillation detector (NaI) was used with slit of
0.1 mm. A continuous scan of 0.02.degree. 2.theta. step size and 5
s per step from 2-50.degree. 2.theta. was used. Approximately 25 mg
of material was carefully pressed onto a Si zero background wafer
to ensure a flat preparation. Data were collected using Bruker
Diffrac.sup.plus XRD Commander v2.3 software. Peak lists were
generated using Bruker Diffrac.sup.plus EVA v9.0 software with
background subtraction and K.alpha.2 stripping. The instrument
alignment check was done with a NIST alumina standard SRM1976. XRPD
(Bruker D8 Advance) instrument conditions are summarized in the
table below:
TABLE-US-00016 Instrument Parameter Setting Configuration
Bragg-Brentano Theta/theta Detector Type Scintillation (NaI) Source
Type CuK.alpha. = 1.5418 .ANG. Source Primary Soller Slit 1.0 mm
Detector Secondary Soller Slit 1.0 mm Detector Slit 0.1 mm
Monochromator (graphite) Slit 1.0 mm Scan Range 2 to 50
.degree.2.theta. Step Size 0.02 .degree.2.theta. Time per Step 5
sec
Example 6B
Differential Scanning Calorimetry (DSC)
[0125] Differential scanning calorimetry was performed using a TA
Instruments Q2000 differential scanning calorimeter. Temperature
calibration was performed using NIST traceable indium metal.
Duplicate samples were prepared by sealing approximately 2-5 mg
(accurately recorded) of material into a TA Tzero non-hermetic pan.
A Tzero non-hermetic pan/lid was weighed and used on the reference
side of the cell. Samples were heated at a rate of 10.degree.
C./min from 25.degree. C. to 200.degree. C., using a 50 mL/min
nitrogen purge gas flow rate. The melting temperature (T.sub.m) and
the heat of melting (.DELTA.H.sub.m) were measured using TA
Universal Analysis software v4.4.
Example 6C
Scanning Electron Microscopy (SEM)
[0126] SEM images were collected on a JEOL SEM model JSM-6100. The
sample was sprinkled onto an SEM stub containing double-sided
carbon tape and was sputter coated with gold for 60 s using the
Denton Desk II unit. The SEM was operated at 15 kV accelerating
voltage. Images were collected using software DIPS v2.5 (Digital
Imaging Processing System) with the slow scan set to 800.times.640
pixels and integrator at 50 .mu.s with no averaging. Images were
collected at magnification ranging from 50.times. to
5000.times..
Example 6D
Thermogravimetric Analysis (TGA
[0127] Thermogravimetric analysis (TGA) was performed using a TA
Instrument Q5000. Weight calibration was checked using a certified
50 mg weight. Duplicate samples were prepared by weighing
.about.5-10 mg material into a TA Pt pan. Samples were heated at a
rate of 10.degree. C./min to 200.degree. C., using a 25 mL/min
nitrogen purge gas flow rate. Weight losses were measured using TA
Universal Analysis software v4.4.
* * * * *