U.S. patent application number 17/537663 was filed with the patent office on 2022-03-24 for analogs of deutetrabenazine, their preparation and use.
The applicant listed for this patent is Auspex Pharmaceuticals, Inc.. Invention is credited to James Kerr, Chengzhi Zhang.
Application Number | 20220088006 17/537663 |
Document ID | / |
Family ID | 1000006000412 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220088006 |
Kind Code |
A1 |
Zhang; Chengzhi ; et
al. |
March 24, 2022 |
ANALOGS OF DEUTETRABENAZINE, THEIR PREPARATION AND USE
Abstract
The disclosure is directed to deutetrabenazine analogs,
compositions comprising same and methods of detecting same in
compositions comprising deutetrabenazine.
Inventors: |
Zhang; Chengzhi; (San Diego,
CA) ; Kerr; James; (Parsippany, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Auspex Pharmaceuticals, Inc. |
Parsippany |
NJ |
US |
|
|
Family ID: |
1000006000412 |
Appl. No.: |
17/537663 |
Filed: |
November 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15922329 |
Mar 15, 2018 |
|
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17537663 |
|
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62471484 |
Mar 15, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/14 20180101;
A61K 31/4745 20130101; C07D 471/04 20130101; A61P 25/28 20180101;
A61K 31/473 20130101 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61P 25/14 20060101 A61P025/14; A61P 25/28 20060101
A61P025/28; C07D 471/04 20060101 C07D471/04; A61K 31/473 20060101
A61K031/473 |
Claims
1. Deutetrabenazine drug substance comprising Compound 2 in an
amount that is about 0.15 area-% or less of Compound 2, relative to
the concentration of the deutetrabenazine, based on a determination
by an HPLC method comprising a C18, 150.times.4.6 mm, 3.5 m column
and a photodiode array/ultraviolet detector at 220 nm.
##STR00026##
2. The deutetrabenazine drug substance of claim 1, comprising about
0.05 area-% to about 0.15 area-% of Compound 2, relative to the
concentration of the deutetrabenazine.
3. The deutetrabenazine drug substance of claim 1, comprising about
0.05 area-% to about 0.1 area-% of Compound 2, relative to the
concentration of the deutetrabenazine.
4. The deutetrabenazine drug substance of claim 1, comprising about
0.15 area-% of Compound 2, relative to the concentration of the
deutetrabenazine.
5. The deutetrabenazine drug substance of claim 1, comprising about
0.1 area-% of Compound 2, relative to the concentration of the
deutetrabenazine.
6. The deutetrabenazine drug substance of claim 1, comprising about
0.05 area-% of Compound 2, relative to the concentration of the
deutetrabenazine.
7. The deutetrabenazine drug substance claim 1, wherein the
deutetrabenazine has a deuterium enrichment of no less than about
50%.
8. The deutetrabenazine drug substance of claim 1, wherein the
deutetrabenazine has a deuterium enrichment of no less than about
90%.
9. The deutetrabenazine drug substance of claim 1, wherein the
deutetrabenazine has a deuterium enrichment of no less than about
95%.
10. The deutetrabenazine drug substance of claim 1, wherein the
deutetrabenazine has a deuterium enrichment of no less than about
98%.
11. The deutetrabenazine drug substance of claim 1, wherein the
Compound 2 has a deuterium enrichment of no less than about
50%.
12. The deutetrabenazine drug substance of claim 1, wherein the
Compound 2 has a deuterium enrichment of no less than about
90%.
13. The deutetrabenazine drug substance of claim 1, wherein the
Compound 2 has a deuterium enrichment of no less than about
95%.
14. The deutetrabenazine drug substance of claim 1, wherein the
Compound 2 has a deuterium enrichment of no less than about
98%.
15. A method of producing a deutetrabenazine drug product
comprising: a. obtaining the deutetrabenazine drug substance of
claim 1; b. admixing the deutetrabenazine drug substance with one
or more suitable excipient.
16. A process for determining the amount of Compound 2 in the
deutetrabenazine drug substance of claim 1 comprising: a. obtaining
the deutetrabenazine drug substance; b. determining the amount of
the Compound 2 in the deutetrabenazine drug substance, based on a
determination by the HPLC method.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/922,329, filed Mar. 15, 2018, which claims the benefit of
U.S. Provisional Application No. 62/471,484, filed Mar. 15, 2017,
the entireties of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] Tetrabenazine (NITOMAN.TM., XENAZINE.TM., Ro 1-9569),
1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quin-
oline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor.
Tetrabenazine is commonly prescribed for the treatment of
Huntington's disease (Savani et al., Neurology 2007, 68(10), 797;
and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1),
7-17).
##STR00001##
Tetrabenazine
[0003] d.sub.6-Tetrabenazine (USAN and INN: Deutetrabenazine) is a
deuterated analog of tetrabenazine marketed in the United States
under the tradename AUSTEDO.RTM.. It has improved pharmacokinetic
properties when compared to the non-deuterated drug. See, e.g.,
U.S. Pat. No. 8,524,733.
##STR00002##
d.sub.6-Tetrabenazine (Deutetrabenazine)
[0004] Processes of synthesis of deutetrabenazine are disclosed in
U.S. Published Application No. 2015/0152099. Pharmaceutical
compositions comprising deutetrabenazine are disclosed in U.S. Pat.
No. 9,233,959. U.S. Published Application No. 2016/0287574
discloses deutetrabenazine for the treatment of abnormal
involuntary movement disorders. Despite the desirable and
beneficial effects of deutetrabenazine, there is a continuing need
for high quality compositions to treat the aforementioned
disorders.
[0005] To provide assurance that a drug product performs as
intended, Applicants seeking marketing approval are required to
summarize impurities identified in the drug product, both as
produced using the proposed commercial manufacturing process, as
well as after storage. Applicants must establish that the
impurities are biologically safe at the levels identified in the
drug product after manufacture and after storage. Drug products
containing an acceptable impurity profile are needed.
BRIEF SUMMARY OF THE INVENTION
[0006] The disclosure is directed to pharmaceutical compositions
comprising an admixture of a deutetrabenazine drug substance and a
pharmaceutically acceptable carrier, wherein the deutetrabenazine
drug substance comprises deutetrabenazine; 0.5 area-% or less of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method; and 0.15 area-% or less
of Compound 2, relative to the concentration of deutetrabenazine,
based on a determination by the HPLC method; and wherein the
pharmaceutical composition is stable when stored at room
temperature for one to twenty-four months. The chemical structures
of Compound 1 and Compound 2 are provided:
##STR00003##
[0007] The disclosure is directed to isolated compounds having the
structures of Compound 1 or Compound 2, and the salts and
stereoisomers thereof:
[0008] Compositions comprising Compound 1 and/or Compound 2 are
also described, as well as methods of using the compounds as
reference standards.
[0009] The disclosure is also directed to processes for testing
whether a sample of a composition comprising deutetrabenazine
contains an undesirable impurity. Processes for producing a
deutetrabenazine drug product are also described, as well as
processes of distributing a deutetrabenazine drug product
comprising a deutetrabenazine drug substance. Processes for
validating a pharmaceutical product containing deutetrabenazine and
a pharmaceutically acceptable carrier for distribution are
described.
[0010] Methods of using the compounds and compositions described
herein for treating subjects afflicted with a hyperkinetic movement
disorder are also described.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1: FTIR Spectra of Compound 1.
[0012] FIG. 2: .sup.1H NMR of Compound 1.
[0013] FIG. 3: .sup.13C NMR of Compound 1.
[0014] FIG. 4: Representative Chromatogram of Compound 1.
[0015] FIG. 5: FTIR Spectra of Compound 2.
[0016] FIG. 6: .sup.1H NMR of Compound 2.
[0017] FIG. 7: .sup.13C NMR of Compound 2.
[0018] FIG. 8: Representative Chromatogram of Compound 2.
DETAILED DESCRIPTION OF THE INVENTION
[0019] In the present disclosure the singular forms "a", "an" and
"the" include the plural reference, and reference to a particular
numerical value includes at least that particular value, unless the
context clearly indicates otherwise. Thus, for example, a reference
to "a material" is a reference to at least one of such materials
and equivalents thereof known to those skilled in the art, and so
forth.
[0020] When a value is expressed as an approximation by use of the
descriptor "about" it will be understood that the particular value
forms another embodiment. In general, use of the term "about"
indicates approximations that can vary depending on the desired
properties sought to be obtained by the disclosed subject matter
and is to be interpreted in the specific context in which it is
used, based on its function. In some aspects of the disclosure,
"about" refers to a range of values that is .+-.10% of the recited
value. For example, "about 10," refers to "9 to 11," as well as
"10." The person skilled in the art will be able to interpret this
as a matter of routine. In some cases, the number of significant
figures used for a particular value may be one non-limiting method
of determining the extent of the word "about". In other cases, the
gradations used in a series of values may be used to determine the
intended range available to the term "about" for each value. Where
present, all ranges are inclusive and combinable. That is,
references to values stated in ranges include every value within
that range. It is understood that where a parameter range is
provided, all integers within that range, and tenths thereof, are
also provided by the invention. For example, "20-40 mg" includes
20.0 mg, 20.1 mg, 20.2 mg, 20.3 mg, etc. up to 40.0 mg.
[0021] When a list is presented, unless stated otherwise, it is to
be understood that each individual element of that list and every
combination of that list is to be interpreted as a separate
embodiment. For example, a list of embodiments presented as "A, B,
or C" is to be interpreted as including the embodiments, "A," "B,"
"C," "A or B," "A or C," "B or C," or "A, B, or C."
[0022] It is to be appreciated that certain features of the
invention which are, for clarity, described herein in the context
of separate embodiments, may also be provided in combination in a
single embodiment. That is, unless obviously incompatible or
excluded, each individual embodiment is deemed to be combinable
with any other embodiment(s) and such a combination is considered
to be another embodiment. Conversely, various features of the
invention that are, for brevity, described in the context of a
single embodiment, may also be provided separately or in any
sub-combination. It is further noted that the claims may be drafted
to exclude any optional element. As such, this statement is
intended to serve as antecedent basis for use of such exclusive
terminology as "solely," "only" and the like in connection with the
recitation of claim elements, or use of a "negative" limitation.
Finally, while an embodiment may be described as part of a series
of steps or part of a more general structure, each said step may
also be considered an independent embodiment in itself.
[0023] The disclosure is directed to deutetrabenazine
pharmaceutical compositions that are stable when stored at room
temperature. In some aspects, the pharmaceutical compositions are
stable when stored at room temperature for about one to about
twenty-four months. In some aspects, the pharmaceutical
compositions are stable when stored at room temperature for about
one to about eighteen months. In some aspects, the pharmaceutical
compositions are stable when stored at room temperature for about
one to about twelve months. In some aspects, the pharmaceutical
compositions are stable when stored at room temperature for about
one to about six months. In some aspects, the pharmaceutical
compositions are stable when stored at room temperature for about
one to about three months. In some aspects, the pharmaceutical
compositions are stable when stored at room temperature for about
one month. For example, the pharmaceutical compositions of the
disclosure are stable when stored at room temperature for about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, or about 24 months.
[0024] The pharmaceutical compositions of the disclosure comprise
an admixture of a deutetrabenazine drug substance and a
pharmaceutically acceptable carrier. According to the disclosure,
the deutetrabenazine drug substance comprises deutetrabenazine,
Compound 1, and Compound 2. In particularly preferred aspects, the
deutetrabenazine drug substance comprises deutetrabenazine, 0.5
area-% or less of Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method; and
0.15 area-% or less of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by the HPLD method.
[0025] In preferred aspects, the deutetrabenazine drug substance,
in addition to deutetrabenazine, comprises about 0.5 area-% or less
of Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. Exemplary HPLC methods
are disclosed herein. In some aspects, the deutetrabenazine drug
substance comprises about 0.1 area-% to about 0.5 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.1 area-% to about
0.4 area-% of Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method. In
some aspects, the deutetrabenazine drug substance comprises about
0.1 area-% to about 0.3 area-% of Compound 1, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. In some aspects, the deutetrabenazine drug substance
comprises about 0.1 area-% to about 0.2 area-% of Compound 1,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.1 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.15 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.2 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.25 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.3 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.35 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.4 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.45 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In some aspects, the
deutetrabenazine drug substance comprises about 0.5 area-% of
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method.
[0026] In preferred aspects, the deutetrabenazine drug substance,
in addition to deutetrabenazine, comprises about 0.15 area-% or
less of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method.
Exemplary HPLC methods are disclosed herein. In some aspects, the
deutetrabenazine drug substance comprises about 0.05 area-% to
about 0.15 area-% of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method. In
some aspects, the deutetrabenazine drug substance comprises about
0.05 area-% to about 0.1 area-% of Compound 2, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. In some aspects, the deutetrabenazine drug substance
comprises about 0.15 area-% of Compound 2, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. In some aspects, the deutetrabenazine drug substance
comprises about 0.1 area-% of Compound 2, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. In some aspects, the deutetrabenazine drug substance
comprises about 0.05 area-% of Compound 2, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method.
[0027] In some aspects, the pharmaceutical compositions of the
disclosure comprise about 3 area-% or less of Compound 1, relative
to the concentration of deutetrabenazine, based on a determination
by an HPLC method. In other aspects, the pharmaceutical
compositions of the disclosure comprise about 0.4 area-% or less of
Compound 2, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. In yet other aspects,
the pharmaceutical compositions of the disclosure comprise about 3
area-% or less of Compound 1 and about 0.4 area-% or less of
Compound 2, each relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method.
[0028] In some aspects, the pharmaceutical compositions of the
disclosure comprise 0.007 area-% to 3 area-% of Compound 1,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method. In some aspects, the
pharmaceutical compositions of the disclosure comprise 0.01 area-%
to 3 area-% of Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method. In
some aspects, the pharmaceutical compositions of the disclosure
comprise 0.1 area-% to 3 area-% of Compound 1, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. In some aspects, the pharmaceutical compositions of
the disclosure comprise 1 area-% to 3 area-% of Compound 1,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method. For example, the pharmaceutical
compositions of the disclosure comprise 0.01, 0.02, 0.03, 0.04,
0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,
0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,
2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 area-% of Compound 1,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method.
[0029] In some aspects, the pharmaceutical compositions of the
disclosure comprise 0.007 area-% to 0.4 area-% of Compound 2,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method. In some aspects, the
pharmaceutical compositions of the disclosure comprise 0.03 area-%
to 0.4 area-% of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method. In
some aspects, the pharmaceutical compositions of the disclosure
comprise 0.1 area-% to 0.4 area-% of Compound 2, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. For example, the pharmaceutical compositions of the
disclosure comprise 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,
0.15, 0.2, 0.25, 0.3, 0.35, or 0.4 area-% of Compound 2, relative
to the concentration of deutetrabenazine, based on a determination
by an HPLC method.
[0030] According to the disclosure, pharmaceutical compositions of
the disclosure include deutetrabenazine drug substances having a
deuterium enrichment of no less than about 50%. In some aspects of
the disclosure, pharmaceutical compositions of the disclosure
include deutetrabenazine drug substances having deuterium
enrichment of no less than about 90%. In some aspects,
pharmaceutical compositions of the disclosure include
deutetrabenazine drug substances having deuterium enrichment of no
less than about 95%. In some aspects, pharmaceutical compositions
of the disclosure include deutetrabenazine drug substances having
deuterium enrichment of no less than about 98%.
[0031] In some aspects of the disclosure, the deutetrabenazine in
the deutetrabenazine drug substances of the disclosure has a
deuterium enrichment of no less than about 50%, at each of the
methoxy moieties. In some aspects of the disclosure, the
deutetrabenazine in the deutetrabenazine drug substances of the
disclosure has a deuterium enrichment of no less than about 90%, at
each of the methoxy moieties. In some aspects of the disclosure,
the deutetrabenazine in the deutetrabenazine drug substances of the
disclosure has a deuterium enrichment of no less than about 95%, at
each of the methoxy moieties. In some aspects of the disclosure,
the deutetrabenazine in the deutetrabenazine drug substances of the
disclosure has a deuterium enrichment of no less than about 98%, at
each of the methoxy moieties.
[0032] In some aspects of the disclosure, the Compound 1 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 50%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 1 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 90%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 1 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 95%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 1 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 98%, at each of the methoxy
moieties.
[0033] In some aspects of the disclosure, the Compound 2 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 50%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 2 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 90%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 2 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 95%, at each of the methoxy
moieties. In some aspects of the disclosure, the Compound 2 in the
deutetrabenazine drug substances of the disclosure has a deuterium
enrichment of no less than about 98%, at each of the methoxy
moieties.
[0034] This disclosure is also directed to isolated compounds
having the structures:
##STR00004##
as well as the salts and stereoisomers thereof.
[0035] In an embodiment of the present invention, the isolated
compound has the structure:
##STR00005##
[0036] In an embodiment of the present invention, the isolated
compound has the structure:
##STR00006##
[0037] The invention further provides isolated Compounds 1 or 2,
wherein each position represented as D has deuterium enrichment of
no less than about 10%. Preferably, no less than about 50%. More
preferably, no less than about 90%. Most preferably, no less than
about 98%.
[0038] This invention also provides a composition comprising
deutetrabenazine and at least one compound which has the
structure:
##STR00007##
wherein the ratio of the weight of the compound relative to the
weight of the deutetrabenazine in the composition is from 99:1 to
1:99.
[0039] In an embodiment, the ratio of the weight of the compound
relative to the weight of the deutetrabenazine in the composition
is from 90:10 to 10:90 or from 85:15 to 15:85. For example, in some
aspects, the ratio of the weight of the compound relative to the
weight of the deutetrabenazine in the composition is 95:5, 90:10,
85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, 50:50, 45:55,
40:60, 35:65, 30:70, 25:75, 20:80, 15:85, 10:90, or 5:95. In other
aspects, the ratio of the weight of the compound relative to the
weight of the deutetrabenazine in the composition is 5:95, 10:90.
15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45,
60:40, 65:35, 70:30, 75:25, 88:20, 85:15, 90:10, or 95:5.
[0040] The disclosure also provides a composition comprising at
least one compound having the structure:
##STR00008##
wherein the composition is substantially free of deutetrabenazine.
As used herein, "substantially free of deutetrabenazine" refers to
having less than 1 wt. % of deutetrabenazine, preferably less than
0.1 wt. % of deutetrabenazine. As used herein, "free of
deutetrabenazine" refers to having no amount of deutetrabenazine,
as determined by an HPLC method.
[0041] Compound 1 is a diastereomer of deutetrabenazine. It can
appear in the drug substance as a by-product of the manufacturing
process. The amount of Compound 1 can increase over time, as the
drug substance or drug product (pharmaceutical composition) is
stored. According to the disclosure, in order to ensure stability
over time in a pharmaceutical composition that will not contain
more than 3 area-% of Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method, it
has been determined that the deutetrabenazine drug substance used
to prepare the pharmaceutical composition should have 0.5 area-% or
less of Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by the HPLC method.
[0042] Compound 2 can form from the oxidation/dehydrogenation of
deutetrabenazine. It can appear in the drug substance as a
by-product of the manufacturing process. The amount of Compound 2
can increase over time, as the drug substance (pharmaceutical
compositions) or drug product is stored. According to the
disclosure, in order to ensure stability over time in a
pharmaceutical composition that will not contain more than 0.4
area-% of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method, it
has been determined that the deutetrabenazine drug substance used
to prepare the pharmaceutical composition should have 0.15 area-%
or less of Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by the HPLC method.
[0043] According to the disclosure, in order to ensure stability
over time in a pharmaceutical composition that will not contain
more than 3 area-% of Compound 1 and 0.4 area-% of Compound 2, each
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method, the deutetrabenazine drug
substance used to prepare the pharmaceutical composition should
have 0.5 area-% or less of Compound 1 and 0.15 area-% or less of
Compound 2, each relative to the concentration of deutetrabenazine,
based on a determination by the HPLC method.
[0044] The disclosure also provides pharmaceutical compositions
comprising an amount of deutetrabenazine and at least one of
Compound 1 and Compound 2 wherein [0045] a) Compound 1 is present
in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of deutetrabenazine, based on
a determination by an HPLC method, or [0046] b) Compound 2 is
present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method.
[0047] The disclosure also provides pharmaceutical compositions
comprising an amount of deutetrabenazine and at least one of
Compound 1 and Compound 2 wherein [0048] a) Compound 1 is present
in the pharmaceutical composition in an amount not more than 3
area-% relative to the concentration of deutetrabenazine, based on
a determination by an HPLC method, or [0049] b) Compound 2 is
present in the pharmaceutical composition in an amount not more
than 0.4 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method.
[0050] In one embodiment, at least one of Compound 1 and Compound 2
are present in the described pharmaceutical compositions.
[0051] In an embodiment, the pharmaceutical composition is in the
form of a capsule, a tablet, or a liquid suspension. In another
embodiment, the pharmaceutical composition is in an oral dosage
unit form.
[0052] In an embodiment, the pharmaceutical composition comprises
between 5-30 mg deutetrabenazine. In another embodiment, the
pharmaceutical composition comprises between 6-24 mg
deutetrabenazine. In another embodiment, the pharmaceutical
composition comprises about 6 mg deutetrabenazine. In another
embodiment, the pharmaceutical composition comprises about 9 mg
deutetrabenazine. In another embodiment, the pharmaceutical
composition comprises about 12 mg deutetrabenazine. In another
embodiment the pharmaceutical composition comprises about 15 mg
deutetrabenazine. In another embodiment, the pharmaceutical
composition comprises about 18 mg deutetrabenazine. In another
embodiment, the pharmaceutical composition comprises about 21 mg
deutetrabenazine. In another embodiment, the pharmaceutical
composition comprises about 24 mg deutetrabenazine.
[0053] In another embodiment, the pharmaceutical composition is
prepared for once daily administration. In another embodiment, the
pharmaceutical composition is prepared for more than once daily
administration, for example, twice daily, three times daily, four
times daily, etc.
[0054] The disclosure also provides a process for isolating
Compound 1 comprising recrystallization of a mixture of
deutetrabenazine and Compound 1 from ethanol to produce Compound
1.
[0055] The disclosure also provides a process for preparing
Compound 2 comprising oxidation of deutetrabenazine to form
Compound 2.
[0056] The disclosure also provides a process for testing whether a
sample of a composition comprising deutetrabenazine contains an
undesirable impurity, i.e., an undesirable amount of Compound 1
and/or Compound 2, which comprises the step of determining whether
the sample contains a compound having the structure:
##STR00009##
[0057] This invention also provides a process for producing a
deutetrabenazine drug product comprising obtaining a
deutetrabenazine drug substance and mixing the deutetrabenazine
drug substance with suitable excipients so as to produce the
deutetrabenazine drug product, wherein the deutetrabenazine drug
substance comprises: [0058] i) an amount of Compound 1 in the
deutetrabenazine drug substance that is not more than 0.5 area-%
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method, or [0059] ii) an amount
of Compound 2 in the deutetrabenazine drug substance that is not
more than 0.15 area-% Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method.
[0060] In one embodiment, the process further comprises determining
the amount of the at least one of Compound 1 and Compound 2 in the
deutetrabenazine drug substance, based on a determination by an
HPLC method.
[0061] This invention also provides a process for producing a
deutetrabenazine drug product for commercial sale and/or human
administration comprising obtaining a batch of deutetrabenazine
drug product that comprises: [0062] i) an amount of Compound 1 in
the batch of deutetrabenazine drug product that is not more than 3
area-% Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method, or
[0063] ii) an amount of Compound 2 in the batch of deutetrabenazine
drug product that is not more than 0.4 area-% Compound 2, relative
to the concentration of deutetrabenazine, based on a determination
by an HPLC method and preparing the batch of deutetrabenazine drug
product for commercial sale and/or human administration.
[0064] In one embodiment, the process further comprises determining
the amount of the at least one of Compound 1 and Compound 2 in the
deutetrabenazine drug product.
[0065] This invention also provides a process of distributing a
deutetrabenazine drug product comprising a deutetrabenazine drug
substance comprising:
[0066] a) obtaining the deutetrabenazine drug product wherein the
deutetrabenazine drug substance comprises: [0067] i) an amount of
Compound 1 in the deutetrabenazine drug substance that is not more
than 0.5 area-% Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method, or
[0068] ii) an amount of Compound 2 in the deutetrabenazine drug
substance that is not more than 0.15 area-% Compound 2, relative to
the concentration of deutetrabenazine, based on a determination by
an HPLC method; and
[0069] b) distributing the deutetrabenazine drug product comprising
the deutetrabenazine drug substance.
[0070] This invention also provides a process of distributing a
deutetrabenazine drug product comprising,
[0071] a) obtaining the deutetrabenazine drug product that
comprises: [0072] i) an amount of Compound 1 in the
deutetrabenazine drug product that is not more than 3 area-%
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method, or [0073] ii) an amount
of Compound 2 in the deutetrabenazine drug product that is not more
than 0.4 area-% Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method;
and
[0074] b) distributing the deutetrabenazine drug product.
[0075] This invention also provides an impurity for use, as a
reference standard to detect trace amounts of the impurity in a
pharmaceutical composition comprising deutetrabenazine, wherein the
impurity is Compound 1 or Compound 2.
[0076] This invention also provides a method of determining the
concentration of an impurity in a composition comprising
deutetrabenazine, the method comprising: [0077] a) preparing a
sample solution from the pharmaceutical composition, [0078] b)
preparing a diluent solution comprising acetonitrile, [0079] c)
preparing a standard solution comprising deutetrabenazine and the
diluent solution, [0080] d) preparing a resolution solution
comprising deutetrabenazine and the impurity, e) preparing a buffer
solution by dissolving 770 mg of ammonium acetate in 1000 mL of
water, [0081] f) injecting into the HPLC the diluent solution, the
resolution solution, the standard solution, and the sample
solution, [0082] g) running the HPLC using ultraviolet absorption
at 190-400 nm (preferably 220 nm) of the buffer solution and
diluent as the mobile phase with a gradient program started with
80% buffer/20 diluent and ramp up to 100% buffer over 20 mins,
[0083] h) determining the retention time (RT) and the areas of the
peaks of the impurity in the chromatograms of the sample solution,
and [0084] i) performing quantitation of the impurity with respect
to the corresponding peaks in the chromatograms of the sample
solution, wherein the impurity is Compound 1 or Compound 2.
[0085] This invention also provides a method of determining the
concentration of an impurity in a pharmaceutical composition
comprising deutetrabenazine and a pharmaceutically acceptable
carrier, the method comprising, [0086] a) preparing a sample
solution from the pharmaceutical composition, [0087] b) preparing a
diluent solution comprising isopropyl alcohol and acetonitrile, c)
preparing a standard solution comprising deutetrabenazine and the
diluent solution, [0088] d) preparing a resolution solution
comprising deutetrabenazine and the impurity, [0089] e) preparing a
buffer solution by dissolving ammonium acetate in water, [0090] f)
injecting into the HPLC the diluent solution, the resolution
solution, the standard solution, and the sample solution, [0091] g)
running the HPLC using ultraviolet absorption at 190-400 nm or 220
nm and a mixture of the buffer solution and acetonitrile as the
mobile phase, [0092] h) determining the retention time (RT) and the
areas of the peaks of the impurity in the chromatograms of the
sample solution, and [0093] i) performing quantitation of the
impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
[0094] wherein the impurity is Compound 1 or Compound 2.
[0095] This invention also provides a method of treating a subject
afflicted with a hyperkinetic movement disorder comprising
administering to the subject a pharmaceutical composition of the
invention.
[0096] This invention also provides a method of treating a subject
afflicted with Huntington's disease comprising administering to the
subject a pharmaceutical composition of the invention.
[0097] This invention also provides a method of treating a subject
afflicted with chorea related to Huntington's disease comprising
administering to the subject a pharmaceutical composition of the
invention.
[0098] This invention also provides a method of treating a subject
afflicted with tardive dyskinesia comprising administering to the
subject a pharmaceutical composition of the invention.
[0099] This invention also provides a method of treating a subject
afflicted with a tic associated with Tourette syndrome, comprising
administering to the subject a pharmaceutical composition of the
invention.
[0100] This invention also provides a process for validating a
batch of a pharmaceutical product containing deutetrabenazine and a
pharmaceutically acceptable carrier for distribution comprising:
[0101] a) determining the amount of at least one of Compound 1 and
Compound 2 based on a determination by an HPLC method; and [0102]
b) validating the batch for distribution only if [0103] i) the
batch is determined to have not more than 3 area-% Compound 1,
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method or [0104] ii) the batch is
determined to have not more than 0.4 area-% Compound 2, relative to
the concentration of deutetrabenazine, based on a determination by
an HPLC method.
[0105] This invention also provides a process for preparing a
validated pharmaceutical composition comprising deutetrabenazine
comprising: [0106] a) obtaining a batch of deutetrabenazine drug
substance; [0107] b) determining the amount of at least one of
Compound 1 and Compound 2, based on a determination by an HPLC
method; and [0108] c) preparing the pharmaceutical composition from
the batch only if [0109] i) the batch is determined to have not
more than 0.5% Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method or
[0110] ii) the batch is determined to have not more than 0.15%
Compound 2, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method.
[0111] Each embodiment disclosed herein is contemplated as being
applicable to each of the other disclosed embodiments. Thus, all
combinations of the various elements described herein are within
the scope of the invention.
[0112] For example, the elements recited in the packaging and
pharmaceutical composition embodiments can be used in the method
and use embodiments described herein.
Terms
[0113] As used herein, and unless stated otherwise, each of the
following terms shall have the definition set forth below.
[0114] Asymmetric centers exist in the compounds disclosed herein.
These centers are designated by the symbols "R" or "S," depending
on the configuration of substituents around the chiral carbon atom.
It should be understood that the invention encompasses all
stereochemical isomeric forms, including diastereomeric,
enantiomeric, and epimeric forms, as well as D-isomers and
L-isomers, and mixtures thereof. Individual stereoisomers of
compounds can be prepared synthetically from commercially available
starting materials which contain chiral centers or by preparation
of mixtures of enantiomeric products followed by separation such as
conversion to a mixture of diastereomers followed by separation or
recrystallization, chromatographic techniques, direct separation of
enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of
particular stereochemistry are either commercially available or can
be made and resolved by techniques known in the art. Additionally,
the compounds disclosed herein may exist as geometric isomers. The
present invention includes all cis, trans, syn, anti, entgegen (E),
and zusammen (Z) isomers as well as the appropriate mixtures
thereof. Additionally, compounds may exist as tautomers; all
tautomeric isomers are provided by this invention. Additionally,
the compounds disclosed herein can exist in unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like. In general, the solvated forms are
considered equivalent to the unsolvated forms.
[0115] The terms "3S,11bS enantiomer" or the term "3R,11bR
enantiomer" refers to either of the deutetrabenazine stereoisomers
having the structural formulas shown below:
##STR00010##
[0116] In certain embodiments, a chemical structure may be drawn as
either the 3S,11bS enantiomer or the 3R,11bR enantiomer, but the
text of the specification may indicate that the 3S,11bS enantiomer,
the 3R,11bR enantiomer, a racemic mixture thereof (which may be
described as (RR, SS)-d6-tetrabenazine), or all of the foregoing
may be intended to be described.
[0117] As used herein, "drug substance" refers to the active
ingredient in a drug product or to the composition containing the
active ingredient before it is formulated into in a drug product,
which provides pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or prevention of
disease, or to affect the structure or any function of the body of
man or animals.
[0118] As used herein, "drug product" refers to the formulated or
finished dosage form containing the drug substance as well as at
least one pharmaceutically acceptable carrier.
[0119] As used herein, an "isolated" compound is a compound
isolated from the crude reaction mixture following an affirmative
act of isolation. The act of isolation involves separating the
compound from the other known components of the crude reaction
mixture, with some impurities, unknown side products and residual
amounts of the other known components of the crude reaction mixture
permitted to remain. Purification is an example of an affirmative
act of isolation.
[0120] As used herein, the term "stable," in reference to
deutetrabenazine, means deutetrabenazine wherein the level of a
specific impurity (for example, Compound 1, Compound 2, or a
combination thereof) does not increase to more than a specific
limit, when maintained at a specific temperature for a specific
period of time. More specifically, the term "stable" means
deutetrabenazine wherein the level of Compound 1, does not increase
to more than 3% of the total amount of deutetrabenazine area as
measured by HPLC, or wherein the level of Compound 2, does not
increase to more than 0.4% of the total amount of deutetrabenazine
area as measured by HPLC, when maintained at room temperature, for
about 1 to about 24 months.
[0121] As used herein, "room temperature" refers to a temperature
ranging from about 20.degree. C. to about 30.degree. C.
[0122] As used herein, "stability testing" refers to tests
conducted at specific time intervals and various environmental
conditions (e.g., temperature and humidity) to see if and to what
extent a drug product degrades over its designated shelf life time.
The specific conditions and time of the tests are such that they
accelerate the conditions the drug product is expected to encounter
over its shelf life. For example, detailed requirements of
stability testing for finished pharmaceuticals are codified in 21
C.F.R .sctn. 211.166, the entire content of which is hereby
incorporated by reference.
[0123] As used herein, "approximately" in the context of a
numerical value or range means.+-.5% of the numerical value or
range recited or claimed.
[0124] As used herein, an "amount" of a compound as measured in
milligrams refers to the milligrams of compound present in a
preparation, regardless of the form of the preparation. An "amount
of compound which is 40 mg" means the amount of the compound in a
preparation is 40 mg, regardless of the form of the preparation.
Thus, when in the form with a carrier, the weight of the carrier
necessary to provide a dose of 40 mg compound would be greater than
40 mg due to the presence of the carrier.
[0125] As used herein, "treating" and "treatment" encompasses,
e.g., inducing inhibition, regression, or stasis of a disease,
disorder or condition, or ameliorating or alleviating a symptom of
a disease, disorder or condition. "Ameliorating" or "alleviating" a
condition or state as used herein shall mean to relieve or lessen
the symptoms of that condition or state. "Inhibition" of disease
progression or disease complication in a subject as used herein
means preventing or reducing the disease progression and/or disease
complication in the subject.
[0126] "Administering to the subject" means the giving of,
dispensing of, or application of medicines, drugs, or remedies to a
subject to relieve, cure, or reduce the symptoms associated with a
condition, e.g., a pathological condition.
[0127] The drug substance of the present invention, e.g.,
deutetrabenazine, may be administered in admixture with suitable
pharmaceutical diluents, extenders, excipients, or carriers
(collectively referred to herein as a pharmaceutically acceptable
carrier) suitably selected with respect to the intended form of
administration and as consistent with conventional pharmaceutical
practices. Capsules or tablets may contain suitable binders,
lubricants, disintegrating agents, diluents, coloring agents,
flow-inducing agents, and melting agents.
[0128] A dosage unit of the compounds used in the method of the
present invention may comprise a single compound or mixtures
thereof with additional therapeutic agents.
[0129] A "dose" or "dosage unit" or "unit dosage" of
deutetrabenazine as measured in milligrams refers to the milligrams
of deutetrabenazine present in a preparation, regardless of the
form of the preparation. A dosage unit may comprise a single
compound or mixtures of compounds thereof. A dosage unit can be
prepared for oral dosage forms, such as tablets, capsules, pills,
powders, liquid suspensions, and granules. For example, the "dose"
or "dosage unit" of deutetrabenazine may be 6, 9, 12, 15, 18, 21 or
24 mg.
[0130] As used herein, a "pharmaceutically acceptable" component is
one that is suitable for use with humans and/or animals without
undue adverse side effects (such as toxicity, irritation, and
allergic response) commensurate with a reasonable benefit/risk
ratio.
[0131] The subject invention is also intended to include all
isotopes of atoms occurring on the compounds disclosed herein,
including impurities. Isotopes include those atoms having the same
atomic number but different mass numbers. By way of general example
and without limitation, isotopes of hydrogen include tritium and
deuterium. Isotopes of carbon include C-12, C-13, and C-14.
[0132] As used herein, "detection limit" for an analytical method
used in screening or testing for the presence of a compound in a
sample is a threshold under which the compound in a sample cannot
be detected by the analytical method used. The detection limits of
a given HPLC method for detecting an impurity in a sample
containing of deutetrabenazine may vary based on the method and the
impurity or impurities being detected. For example, the detection
limit of the typical HPLC method for detecting Compound 1 is 0.01
area-% and the detecting limit for detecting Compound 2 is 0.03
area-%.
[0133] As used herein, "quantitation limit" for an analytical
method used in screening or testing for the presence of a compound
in a sample is a threshold under which the compound in a sample
cannot be quantified by the analytical method used. The
quantitation limits of a given HPLC method for detecting an
impurity in a sample containing of deutetrabenazine may vary based
on the impurity or impurities being detected. For example, the
quantitation limit of the typical HPLC method for quantifying
Compound 1 is 0.007 area-% and the quantitation limit for Compound
2 is 0.007 area-%.
[0134] A characteristic of a compound refers to any quality that a
compound exhibits, e.g., peaks or retention times, as determined by
1H nuclear magnetic spectroscopy, mass spectroscopy, infrared,
ultraviolet or fluorescence spectrophotometry, gas chromatography,
thin layer chromatography, high performance liquid chromatography,
elemental analysis, Ames test, dissolution, stability and any other
quality that can be determined by an analytical method. Once the
characteristics of a compound are known, the information can be
used to, for example, screen or test for the presence of the
compound in a sample.
[0135] As used herein, "NMT" means no more than. As used herein,
"LT" means less than.
[0136] The amount of impurities is measured by reverse phase HPLC
unless otherwise specified.
[0137] As used herein, the term "effective amount" refers to the
quantity of a component that is sufficient to yield a desired
therapeutic response without undue adverse side effects (such as
toxicity, irritation, or allergic response) commensurate with a
reasonable benefit/risk ratio when used in the manner of this
invention, i.e. a therapeutically effective amount. The specific
effective amount will vary with such factors as the particular
condition being treated, the physical condition of the patient, the
type of mammal being treated, the duration of the treatment, the
nature of concurrent therapy (if any), and the specific
formulations employed and the structure of the compounds or its
derivatives.
[0138] As used herein, "preparing drug product for commercial sale"
means an activity undertaken in preparation for commercial sale.
Examples include, but are not limited to, coloring, coding,
stamping, packaging the drug product.
[0139] As used herein, "deuterium enrichment" refers to the
percentage of incorporation of deuterium at a given position in a
molecule in the place of hydrogen. For example, deuterium
enrichment of 1% at a given position means that 1% of molecules in
a given sample contain deuterium at the specified position. Because
the naturally occurring distribution of deuterium is about 0.0156%,
deuterium enrichment at any position in a compound synthesized
using non-enriched starting materials is about 0.0156%. The
deuterium enrichment can be determined using conventional
analytical methods known to one of ordinary skill in the art,
including mass spectrometry and nuclear magnetic resonance
spectroscopy.
[0140] As used herein, "is/are deuterium," when used to describe a
given position in a molecule or the symbol "D", when used to
represent a given position in a drawing of a molecular structure,
means that the specified position is enriched with deuterium above
the naturally occurring distribution of deuterium. In one
embodiment deuterium enrichment is no less than about 1%, in
another no less than about 5%, in another no less than about 10%,
in another no less than about 20%, in another no less than about
50%, in another no less than about 70%, in another no less than
about 80%, in another no less than about 90%, or in another no less
than about 98% of deuterium at the specified position.
Pharmaceutical Compositions
[0141] While the compounds for use according to the invention may
be administered in the form of the raw compound, it is preferred to
introduce the active ingredients, optionally in the form of
physiologically acceptable salts, in a pharmaceutical composition
together with one or more adjuvants, excipients, carriers, buffers,
diluents, and/or other customary pharmaceutical auxiliaries.
[0142] In an embodiment, the invention provides pharmaceutical
compositions comprising the active compounds or pharmaceutically
acceptable salts or derivatives thereof, together with one or more
pharmaceutically acceptable carriers therefore, and, optionally,
other therapeutic and/or prophylactic ingredients know and used in
the art. The carrier(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
harmful to the recipient thereof.
[0143] Table 1 shows the structures of Compounds 1-2.
TABLE-US-00001 TABLE 1 Compound 1 ##STR00011## (RS, SR)-
1,3,4,6,7,11b- hexahydro-9,10- di(methoxy-d3)-3- (2-methylpropyl)-
2H- benzo[a]quinolizin- 2-one Compound 2 ##STR00012##
(RS))-3,4,6,7- tetrahydro-9,10- di(methoxy-d3)-3- (2-methylpropyl)-
2H- benzo[a]quinolizin- 2-one
[0144] This invention will be better understood by reference to the
Experimental Details which follow, but those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention as described more fully in the
claims which follow thereafter.
EXPERIMENTAL DETAILS
Examples
Example 1--Preparation of Compound 1
##STR00013##
[0146] The crude material (10 g) which was obtained from mother
liquor of deutetrabenazine was purified by recrystallization with
EtOH (2.times.3V) to give 2.5 g of compound 1 as an off white
solid.
NMR Identity Analysis of Compound 1
Compound 1:
[0147] The following data in Table 2 was determined using a sample
of Compound 1, in CDCl.sub.3 (99.9 atom % D), using a 300 MHz NMR
instrument. See FIGS. 2 and 3.
TABLE-US-00002 TABLE 2 Assignment of .sup.1H NMR and .sup.13C
NMR.sup.a,c ##STR00014## .sup.1H chemical shift Position (split
pattern, coupling constant) 1 2.61 (m, 1H), 2.84 (m, 1H), 2 N/A 3
2.53 (m, 1H) 4 2.71 (m, 1H), 2.98 (m, 1H) 5 N/A 6 2.53 (m, 2H),
3.02 (m, 2H) 7 3.14 (m, 1H), 2.65 (m, 1H) 8 6.56 (s, 1H) 9 N/A 10
N/A 11 6.61 (s, 1H) 11b 3.42 (d, J = 10.8 Hz, 1H) 12 1.54 (m, 1H),
1.80 (m, 1H) 13 1.55 (m, 1H) 14 0.92 (m, 6H) 15 N/A 16 N/A 17 N/A
18 N/A N/A N/A .sup.13C chemical shift Position (split pattern,
coupling constant) 1 45.22 (s) 2 212.42 (s) 3 49.06 (s) 4 59.66 (s)
5 N/A 6 51.62 (s) 7 29.19 (s) 8 107.67 (s) 9 147.67 (s) 10 147.43
(s) 11 111.40 (s) 11b 62.01 (s) 12 40.54 (s) 13 25.74 (s) 14 22.71
(d) 15 128.67 (s) 16 126.43 (s) 17 N/A 18 N/A N/A N/A .sup.aThe
assignment is based on the chemical shifts and 1H-13C couplings
extracted from HSQC (Heteronuclear Single Quantum Coherence
Spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation)
experiments. .sup.bSpectra is calibrated by reference to the NMR
solvent peak.
Example 2--Preparation of Compound 2
##STR00015##
[0149] To deutetrabenazine (31.7 g, 10.0 mmol) and chloranil (26 g,
10.5 mmol) was added toluene (300 mL), and the mixture was heated
at reflux for 2.5 h. To the dark solution was added toluene (500
mL) and the mixture was washed with 300 mL of 2 N NaOH and
H.sub.2O. The toluene solution was dried (Na.sub.2SO.sub.4),
filtered, and evaporated to dryness. The residue was crystallized
from ethyl acetate to give 21 g (66%) of Compound 2 as off-white
crystalline solid.
NMR Identity Analysis of Compound 2
Compound 2:
[0150] The following data in Table 3 was determined using a sample
of Compound 2, in CDCl.sub.3 (99.9 atom % D), using a 300 MHz NMR
instrument.
TABLE-US-00003 TABLE 3 Assignment of .sup.1H NMR and .sup.13C
NMR.sup.a,b ##STR00016## .sup.1H chemical shift Position (split
pattern, coupling constant) 1 5.67 (s, 1H) 2 N/A 3 2.47 (m, 1H) 4
3.66 (dd, J = 5.4 Hz, J = 12.6 Hz, 1H) 3.32 (dd, J = 8.7 Hz, J =
12.3 Hz, 1H) 5 N/A 6 3.40 (m, 2H) 7 2.96 (m, 2H) 8 6.67 (s, 1H) 9
N/A 10 N/A 11 7.17 (s, 1H) 11b N/A 12 1.32 (m, 1H) 1.73 (m, 1H) 13
1.72 (m, 1H) 14 0.92 (m, 6H) 15 N/A 16 N/A 17 N/A 18 N/A N/A N/A
.sup.13C chemical shift Position (split pattern) 1 94.09 (s) 2
195.29 (s) 3 41.95 (s) 4 55.71 (s) 5 N/A 6 48.97 (s) 7 28.37 (s) 8
110.35 (s) 9 156.46 (s) 10 151.40 (s) 11 108.16 (s) 11b 120.68 (s)
12 37.42 (s) 13 25.43 (s) 14 23.45 (d) 15 147.92 (s) 16 128.91 (s)
17 N/A 18 N/A N/A N/A .sup.aThe assignment is based on the coupling
pattern of the signals, coupling constants and chemical shifts.
.sup.bSpectra is calibrated by reference to the NMR solvent peak.
See FIGS. 6 and 7
Example 3--Preparation of Crude Deutetrabenazine
Step 1: 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium Iodide
[0151] 3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526
mol, 1.00 eq) was charged with methyl tert-butyl ether (1.35 L,
15.0 vol) and cooled 0-10.degree. C. Methyl iodide (171 g, 1.209
mol, 2.3 eq) was added slowly to the reaction mixture and stirred
for 15 hours at 25-35.degree. C. The reaction was warmed to
35-40.degree. C. for 2 hours. The precipitated solid was filtered
under nitrogen and was washed with methyl tert-butyl ether (900 mL,
10.0 vol). The crude product was further purified by slurrying in
ethyl acetate (1.46 L, 10 vol) and filtered to give
2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (146 g) as a
white solid.
Step 2
[0152] 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide is
charged to a suspension containing d.sub.6-6,7-dimethoxy-3,
4-dihydroisoquinoline (hydrochloride or freebase, 1.00 eq) and
solvent. (If d.sub.6-6,7-dimethoxy-3, 4-dihydroisoquinoline
hydrochloride is used, a base is added to the reaction mixture at
room temperature.) The reaction mixture is stirred at the
appropriate temperature, cooled, and water is added. The reaction
mass is filtered and the solids are washed with water and dried to
afford the product.
Example 4--Analysis of the Amounts of Compounds 1 and 2 in a Sample
of Deutetrabenazine Drug Substance
[0153] Compounds 1 and 2 are useful to determine the purity of a
deutetrabenazine containing composition. See FIGS. 4 and 8
TABLE-US-00004 TABLE 4 Apparatus Instrument High pressure liquid
chromatography Detector PDA/UV detector Column X-Bridge, C18, 150
.times. 4.6 mm, 3.5 .mu.m or Equivalent Wavelength 220 nm Injection
volume 10.0 .mu.L Column oven temperature 30.degree. C. Flow rate
1.0 mL/min Run time 25 min Mobile phase A: 10 mM Ammonium Acetate
aqueous solution Mobile phase B: Acetonitrile Diluent:
Acetonitrile
TABLE-US-00005 TABLE 5 Gradient program: Time Flow Mobile Mobile
(min) (mg/mL) phase-A % phase-B % 0.01 1.0 80 20 8.0 1.0 50 50 18.0
1.0 0 100 20.0 1.0 0 100 20.1 1.0 80 20 25.0 1.0 80 20
TABLE-US-00006 TABLE 6 Retention time and Relative retention time
for determination of related substances: Name RT (mm) RRT
Deutetrabenazine 13.16 1.00 Compound 1 14.25 1.08 Compound 2 9.94
0.76
Example 4: Fourier Transform Infrared Spectroscopic (FTIR)
Analysis
[0154] FTIR spectra of Compounds 1 and 2 are depicted in FIGS. 1
and 5.
Example 4--Long Term Stability in Deutetrabenazine Drug Product
TABLE-US-00007 [0155] TABLE 7 7.5 mg tablets stored at room
temperature 1 3 6 9 12 18 24 Attribute T = 0 month month month
month month month month Assay 101.1 99.6 100.3 95.6 102.3 102.9
104.0 99.7 Compound 1 0.29 0.40 0.40 0.50 0.54 0.53 0.52 0.49
Compound 2 0.17 0.19 0.18 0.20 0.22 0.28 0.25 0.24
TABLE-US-00008 TABLE 8 15 mg tablets stored at room temperature 1 3
6 9 12 18 24 Attribute T = 0 month month month month month month
month Assay 94.8 101.3 97.1 99.3 101.0 99.6 99.8 105.3 Compound 1
0.14 0.25 0.33 0.31 0.31 0.24 0.25 0.25 Compound 2 0.22 0.19 0.34
0.17 0.17 0.18 0.20 0.19
Example 5
[0156] A 90-day GLP general rat toxicology study was conducted with
Compound 1. In that study, the no observed adverse effect level
(NOAEL) dose for deutetrabenazine was 10 mg/kg/day. Those doses
were shown to provide 0.346 mg of Compound 1/kg/day in rats, which
approximates a human equivalent dose of 0.056 mg/kg.
Example 6
[0157] A 3-day GLP mouse micronucleus study was conducted with
Compound 1. That study included a GLP Bacterial Reverse Mutation
Assay of deutetrabenazine with Compound 1. That study also included
an in vitro Chromosome Aberration Test in Cultured Human Peripheral
Blood Lymphocytes. In the study, the highest level of 80 mg/kg/day
of deutetrabenazine was not genotoxic in males and females. That
dose level was predicted to provide 2.77 mg Compound 1/kg/day in
mice, which approximates to a human equivalent dose of 0.23
mg/kg.
Aspects
[0158] Aspect 1. An isolated compound having the structure:
##STR00017##
[0159] or a salt or stereoisomer thereof. [0160] Aspect 2. The
isolated compound of Aspect 1, which has the structure:
##STR00018##
[0161] or a salt or stereoisomer thereof. [0162] Aspect 3. The
isolated compound of Aspect 1, which has the structure:
##STR00019##
[0163] or a salt or stereoisomer thereof. [0164] Aspect 4. A
composition comprising deutetrabenazine and at least one compound
which has the structure:
##STR00020##
[0164] wherein the ratio of the weight of the compound relative to
the weight of the deutetrabenazine. in the composition is from 99:1
to 1:99. [0165] Aspect 5. A composition comprising a compound
having the structure:
##STR00021##
[0166] wherein the composition is substantially free of
deutetrabenazine. [0167] Aspect 6. The composition of any one of
Aspects 4 or 5, wherein the compound has the structure:
[0167] ##STR00022## [0168] Aspect 7. The composition of any one of
Aspects 4 or 5, wherein the compound has the structure:
[0168] ##STR00023## [0169] Aspect 8. A pharmaceutical composition
comprising an amount of deutetrabenazine and at least one of
Compound 1 and Compound 2 wherein [0170] a) Compound 1 is present
in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of deutetrabenazine, based on
a determination by an HPLC method, or [0171] b) Compound 2 is
present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. [0172] Aspect 9. The
pharmaceutical composition of Aspect 8, wherein [0173] a) Compound
1 is present in the pharmaceutical composition in an amount not
more than 3 area-% relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method, or
[0174] b) Compound 2 is present in the pharmaceutical composition
in an amount not more than 0.4 area-% relative to the concentration
of deutetrabenazine, based on a determination by an HPLC method.
[0175] Aspect 10. The pharmaceutical composition of Aspect 9,
wherein [0176] a) Compound 1 is present in the pharmaceutical
composition in an amount not more than 0.15 area-% relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method, or [0177] b) Compound 2 is present in the
pharmaceutical composition in an amount not more than 0.15 area-%
relative to the concentration of deutetrabenazine, based on a
determination by an HPLC method. [0178] Aspect 11. The
pharmaceutical composition of Aspect 9, wherein [0179] a) Compound
1 is present in the pharmaceutical composition in an amount greater
than 0.01 area-%, and not more than 3 area-% relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method, or [0180] b) Compound 2 is present in the
pharmaceutical composition in an amount greater than 0.01 area-%,
and not more than 0.4 area-%, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method.
[0181] Aspect 12. The pharmaceutical composition of Aspect 9,
wherein [0182] a) Compound 1 is present in the pharmaceutical
composition in an amount greater than 0.01 area-%, and not more
than 0.15 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method, or [0183] a) Compound 2
is present in the pharmaceutical composition in an amount greater
than 0.01 area-%, and not more than 0.15 area-%, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method. [0184] Aspect 13. The pharmaceutical composition of
any one of Aspects 11-12, wherein [0185] a) Compound 1 is present
in the pharmaceutical composition in an amount less than 0.04
area-% relative to the concentration of deutetrabenazine, based on
a determination by an HPLC method, or [0186] b) Compound 2 is
present in the pharmaceutical composition in an amount less than
0.04 area %, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. [0187] Aspect 14. The
pharmaceutical composition of Aspect 9, wherein [0188] a) Compound
1 is present in the pharmaceutical composition in an amount less
than 0.01 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method, or [0189] b) Compound 2
is present in the pharmaceutical composition in an amount less than
0.01 area-% relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method. [0190] Aspect 15. The
pharmaceutical composition of any one of Aspects 8-14, comprising
Compound 1 and Compound 2. [0191] Aspect 16. The pharmaceutical
composition of any one of Aspects 8-14, comprising Compound 1.
[0192] Aspect 17. The pharmaceutical composition of any one of
Aspects 8-14, comprising Compound 2. [0193] Aspect 18. The
pharmaceutical composition of any one of Aspects 8-17, comprising
deutetrabenazine. [0194] Aspect 19. The pharmaceutical composition
of any one of Aspects 8-18, in the form of a capsule, a tablet, or
a liquid suspension. [0195] Aspect 20. The pharmaceutical
composition of Aspect 19, in an oral dosage unit form. [0196]
Aspect 21. The pharmaceutical composition of Aspect 20, comprising
between 5-30 mg deutetrabenazine. [0197] Aspect 22. The
pharmaceutical composition of Aspect 21, comprising between 6-24 mg
deutetrabenazine. [0198] Aspect 23. The pharmaceutical composition
of Aspect 22, comprising about 6 mg deutetrabenazine. [0199] Aspect
24. The pharmaceutical composition of Aspect 22, comprising about 9
mg deutetrabenazine. [0200] Aspect 25. The pharmaceutical
composition of Aspect 22, comprising about 12 mg deutetrabenazine.
[0201] Aspect 26. The pharmaceutical composition of Aspect 22,
comprising about 15 mg deutetrabenazine. [0202] Aspect 27. The
pharmaceutical composition of Aspect 22, comprising about 18 mg
deutetrabenazine. [0203] Aspect 28. The pharmaceutical composition
of Aspect 22, comprising about 21 mg deutetrabenazine. [0204]
Aspect 29. The pharmaceutical composition of Aspect 22, comprising
about 24 mg deutetrabenazine. [0205] Aspect 30. The pharmaceutical
composition of Aspect 22, prepared for once daily administration.
[0206] Aspect 31. The pharmaceutical composition of Aspect 22,
prepared for more than once daily administration. [0207] Aspect 32.
A process for testing whether a sample of a composition comprising
deutetrabenazine contains an undesirable impurity which comprises
the step of determining whether the sample contains at least one
compound having the structure:
##STR00024##
[0207] based on a determination by an HPLC method. [0208] Aspect
33. A process for producing a deutetrabenazine drug product
comprising obtaining a deutetrabenazine drug substance and mixing
the deutetrabenazine drug substance with suitable excipients so as
to produce the deutetrabenazine drug product, wherein the
deutetrabenazine drug substance comprises: [0209] i) an amount of
Compound 1 in the deutetrabenazine drug substance that is not more
than 0.5 area-% Compound 1, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method or
[0210] ii) an amount of Compound 2 in the deutetrabenazine drug
substance that is not more than 0.15 area-% Compound 2, relative to
the concentration of deutetrabenazine, based on a determination by
an HPLC method. [0211] Aspect 34. The process of Aspect 33, wherein
the process further comprises determining the amount of the at
least one of Compound 1 and Compound 2 in the deutetrabenazine drug
substance. [0212] Aspect 35. A process for producing a
deutetrabenazine drug product for commercial sale comprising
obtaining a batch of deutetrabenazine drug product that comprises:
[0213] i) an amount of Compound 1 in the batch of deutetrabenazine
drug product that is not more than 3 area-% Compound 1, relative to
the concentration of deutetrabenazine, based on a determination by
an HPLC method or [0214] ii) an amount of Compound 2 in the batch
of deutetrabenazine drug product that is not more than 0.4 area-%
Compound 2, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method and
[0215] preparing the batch deutetrabenazine drug product for
commercial sale. [0216] Aspect 36. The process of Aspect 35,
wherein the process further comprises determining the amount of the
at least one of Compound 1 and Compound 2 in the batch of
deutetrabenazine drug product. [0217] Aspect 37. A process of
distributing a deutetrabenazine drug product comprising a
deutetrabenazine drug substance comprising: [0218] a) obtaining the
deutetrabenazine drug product wherein deutetrabenazine drug
substance comprises: [0219] i) an amount of Compound 1 in the
deutetrabenazine drug substance that is not more than 0.5 area-%
Compound 1, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method or [0220] ii) an amount
of Compound 2 in the deutetrabenazine drug substance that is not
more than 0.15 area-% Compound 2, relative to the concentration of
deutetrabenazine, based on a determination by an HPLC method; and
[0221] b) distributing the deutetrabenazine drug product comprising
the deutetrabenazine drug substance. [0222] Aspect 38. A process of
distributing a deutetrabenazine drug product comprising, [0223] a)
obtaining the deutetrabenazine drug product that comprises: [0224]
i) an amount of Compound 1 in the deutetrabenazine drug product
that is not more than 3 area-% Compound 1, relative to the
concentration of deutetrabenazine, based on a determination by an
HPLC method or [0225] ii) an amount of Compound 2 in the
deutetrabenazine drug product that is not more than 0.4 area-%
Compound 2, relative to the concentration of deutetrabenazine,
based on a determination by an HPLC method; and [0226] b)
distributing the deutetrabenazine drug product. [0227] Aspect 39.
An impurity for use as a reference standard to detect trace amounts
of the impurity in a pharmaceutical composition comprising
deutetrabenazine, wherein the impurity is
[0227] ##STR00025## [0228] Aspect 40. A method of treating a
subject afflicted with a hyperkinetic movement disorder comprising
administering to the subject the pharmaceutical composition of any
one of Aspects 8-31. [0229] Aspect 41. The method of Aspect 40,
wherein the hyperkinetic movement disorder is Huntington's disease.
[0230] Aspect 42. The method of Aspect 40 where in the hyperkinetic
movement disorder is chorea related to Huntington's disease. [0231]
Aspect 43. The method of Aspect 40 where in the hyperkinetic
movement disorder is tardive dyskinesia. [0232] Aspect 44. The
method of Aspect 40 where in the hyperkinetic movement disorder is
a tic associated with Tourette syndrome. [0233] Aspect 45. A
process for validating a batch of a pharmaceutical product
containing deutetrabenazine and a pharmaceutically acceptable
carrier for distribution comprising: [0234] a) determining the
amount of at least one of Compound 1 and Compound 2 in the batch;
and [0235] b) validating the batch for distribution only if [0236]
i) the batch is determined to have not more than 3 area-% Compound
1, relative to the concentration of deutetrabenazine, or [0237] ii)
the batch is determined to have not more than 0.4 area-% Compound
2, relative to the concentration of deutetrabenazine. [0238] Aspect
46. A process for preparing a validated pharmaceutical composition
comprising deutetrabenazine comprising: [0239] a) obtaining a batch
of deutetrabenazine drug substance; [0240] b) determining the
amount of at least one of Compound land Compound 2 in the batch;
and [0241] c) preparing the pharmaceutical composition from the
batch only if [0242] i) the batch is determined to have not more
than 0.5% Compound 1, relative to the concentration of
deutetrabenazine, or [0243] ii) the batch is determined to have not
more than 0.15% Compound 2, relative to the concentration of
deutetrabenazine
* * * * *