Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02732479 2011-02-23
4-HYDROXYBUTYRIC ACID ANALOGS
BACKGROUND OF THE INVENTION
[11 4-Hydroxybutyric acid is a well-known hypnotic agent. Though its
mechanism of action is poorly understood, 4-hydroxybutyrate has been
characterized
as inhibiting polysynaptic reflexes while retaining monosynaptic reflexes. It
typically induces sleep while maintaining good respiration (Basil, B. et al.,
Br J
Pharmacol Chemother, 1964, 22:318 and increases delta sleep (stage 3 and stage
4)
while decreasing light or stage 1 sleep (Scrima, L. et al., Sleep, 1990,
13:479; Pardi,
D. and Black, J., CNS Drugs, 2006, 20:993.
[21 The sodium salt of 4-hydroxybutyric acid, known generically as sodium
oxybate and marketed as Xyrem , is approved for the treatment of excessive
daytime
sleepiness and cataplexy in patients with narcolepsy. It is effective for
relieving pain
and improving function in patients with fibromyalgia syndrome (Scharf, MB et
al., J
Rheumatol, 2003, 30:1070; Russell, IJ et al., Arthritis Rheum 2009, 60:299).
Sodium
oxybate has also been reported to be effective in alleviating excessive
daytime
sleepiness and fatigue in patients with Parkinson's disease, improving
myoclonus and
essential tremor, and reducing tardive dyskinesia and bipolar disorder (Ondo,
WG et
al., Arch Neurol, 2008, 65:1337; Frucht, SJ et al, Neurology, 2005, 65:1967;
Berner,
JE, J Clin Psychiatry, 2008, 69:862).
[31 Despite a general record of safety when used as prescribed, impaired
respiration has been reported in some patients following a typical dose of
sodium
oxybate (see, e.g., FDA product label dated 11/13/2006 for NDA no. 021196).
Headache, nausea, and dizziness were observed in clinical trials at rates of
17-22%.
These adverse effects were dose-dependent.
[41 The use of 4-hydroxybutyric acid can be inconvenient because of its very
short
half life in humans (0.5 - 1 hour). Many patients report needing to take two
separate
doses of the drug during the night to maintain sleep. Consequently, despite
the
desirable and beneficial effects of 4-hydroxybutyric acid, there is a
continuing need
for new compounds to treat the aforementioned diseases and conditions.
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SUMMARY OF THE INVENTION
[51 This invention relates to novel derivatives of 4-hydroxybutyric acid and
prodrugs thereof, and pharmaceutically acceptable salts of the foregoing. This
invention also provides pharmaceutical compositions comprising a compound of
this
invention and the use of such compositions in methods of selectively
inhibiting
polysynaptic reflexes without significantly affecting monosynaptic reflexes,
and
treating narcolepsy, fibromyalgia, other disorders and conditions that are
beneficially
treated by improving nocturnal sleep or by administering sodium oxybate.
DETAILED DESCRIPTION
[61 The term "treat" as used herein means decrease, suppress, attenuate,
diminish,
arrest, or stabilize the development or progression of a disease (e.g., a
disease or
disorder delineated herein), lessen the severity of the disease or improve the
symptoms associated with the disease.
[71 "Disease" means any condition or disorder that damages or interferes with
the
normal function of a cell, tissue, or organ.
[8] It will be recognized that some variation of natural isotopic abundance
occurs
in a synthesized compound depending upon the origin of chemical materials used
in
the synthesis. Thus, a preparation of sodium oxybate will inherently contain
small
amounts of deuterated isotopologues. The concentration of naturally abundant
stable
hydrogen and carbon isotopes, notwithstanding this variation, is small and
immaterial
as compared to the degree of stable isotopic substitution of compounds of this
invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15; Gannes,
LZ et
al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.
[91 In the compounds of this invention any atom not specifically designated as
a
particular isotope is meant to represent any stable isotope of that atom.
Unless
otherwise stated, when a position is designated specifically as "H" or
"hydrogen", the
position is understood to have hydrogen at its natural abundance isotopic
composition.
Also unless otherwise stated, when a position is designated specifically as
"D" or
"deuterium", the position is understood to have deuterium at an abundance that
is at
least 3340 times greater than the natural abundance of deuterium, which is 0.0
15%
(i.e., at least 50.1% incorporation of deuterium).
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[10] The term "isotopic enrichment factor" as used herein means the ratio
between
the isotopic abundance and the natural abundance of a specified isotope.
[11] In other embodiments, a compound of this invention has an isotopic
enrichment factor for each designated deuterium atom of at least 3500 (52.5%
deuterium incorporation at each designated deuterium atom), at least 4000 (60%
deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at
least 5000
(75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000
(90%
deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at
least
6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium
incorporation),
or at least 6633.3 (99.5% deuterium incorporation).
[12] The term "isotopologue" refers to a species that differs from a specific
compound of this invention only in the isotopic composition thereof.
[13] The term "compound," when referring to a compound of this invention,
refers
to a collection of molecules having an identical chemical structure, except
that there
may be isotopic variation among the constituent atoms of the molecules. Thus,
it will
be clear to those of skill in the art that a compound represented by a
particular
chemical structure containing indicated deuterium atoms, will also contain
lesser
amounts of isotopologues having hydrogen atoms at one or more of the
designated
deuterium positions in that structure. The relative amount of such
isotopologues in a
compound of this invention will depend upon a number of factors including the
isotopic purity of deuterated reagents used to make the compound and the
efficiency
of incorporation of deuterium in the various synthesis steps used to prepare
the
compound. However, as set forth above the relative amount of such
isotopologues in
toto will be less than 49.9% of the compound. In other embodiments, the
relative
amount of such isotopologues in toto will be less than 47.5%, less than 40%,
less than
32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than
3%, less
than 1%, or less than 0.5% of the compound.
[14] The invention also provides salts of the compounds of the invention.
[15] A salt of a compound of this invention is formed between an acid and a
basic
group of the compound, such as an amino functional group, or a base and an
acidic
group of the compound, such as a carboxyl functional group. According to
another
embodiment, the compound is a pharmaceutically acceptable acid addition salt.
[16] The term "pharmaceutically acceptable," as used herein, refers to a
component
that is, within the scope of sound medical judgment, suitable for use in
contact with
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the tissues of humans and other mammals without undue toxicity, irritation,
allergic
response and the like, and are commensurate with a reasonable benefit/risk
ratio. A
"pharmaceutically acceptable salt" means any non-toxic salt that, upon
administration
to a recipient, is capable of providing, either directly or indirectly, a
compound of this
invention. A "pharmaceutically acceptable counterion" is an ionic portion of a
salt
that is not toxic when released from the salt upon administration to a
recipient.
[17] Acids commonly employed to form pharmaceutically acceptable salts include
inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic
acid,
hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids
such as
para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid,
ascorbic acid,
maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid,
formic acid,
glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic
acid, lactic
acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic
acid, citric
acid, benzoic acid and acetic acid, as well as related inorganic and organic
acids.
Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate,
bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate,
propiolate,
oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-
1,4-dioate,
hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene
sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,
f3-
hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate,
propanesulfonate,
naphthalene- l-sulfonate, naphthalene-2- sulfonate, mandelate and other salts.
In one
embodiment, pharmaceutically acceptable acid addition salts include those
formed
with mineral acids such as hydrochloric acid and hydrobromic acid, and
especially
those formed with organic acids such as maleic acid.
[18] The pharmaceutically acceptable salt may also be a salt of a compound of
the
present invention having an acidic functional group, such as a carboxylic acid
functional group, and a base. Exemplary bases include, but are not limited to,
hydroxide of alkali metals including sodium, potassium, and lithium;
hydroxides of
alkaline earth metals such as calcium and magnesium; hydroxides of other
metals,
such as aluminum and zinc; ammonia, organic amines such as unsubstituted or
hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;
tributyl
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amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-,
bis-,
or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-
hydroxyethyl)amine
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine;
thiomorpholine;
piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the
like.
[19] The compounds of the present invention (e.g., compounds of Formula I),
may
contain an asymmetric carbon atom, for example, as the result of deuterium
substitution or otherwise. As such, compounds of this invention can exist as
either
individual enantiomers, or mixtures of the two enantiomers. Accordingly, a
compound of the present invention may exist as either a racemic mixture or a
scalemic mixture, or as individual respective stereoisomers that are
substantially free
from another possible stereoisomer. The term "substantially free of other
stereoisomers" as used herein means less than 25% of other stereoisomers,
preferably
less than 10% of other stereoisomers, more preferably less than 5% of other
stereoisomers and most preferably less than 2% of other stereoisomers, or less
than
"X"% of other stereoisomers (wherein X is a number between 0 and 100,
inclusive)
are present. Methods of obtaining or synthesizing an individual enantiomer for
a
given compound are known in the art and may be applied as practicable to final
compounds or to starting material or intermediates.
[20] Unless otherwise indicated, when a disclosed compound is named or
depicted
by a structure without specifying the stereochemistry and has one or more
chiral
centers, it is understood to represent all possible stereoisomers of the
compound.
[21] The term "stable compounds," as used herein, refers to compounds which
possess stability sufficient to allow for their manufacture and which maintain
the
integrity of the compound for a sufficient period of time to be useful for the
purposes
detailed herein (e.g., formulation into therapeutic products, intermediates
for use in
production of therapeutic compounds, isolatable or storable intermediate
compounds,
treating a disease or condition responsive to therapeutic agents).
[22] "D" and "d" both refer to deuterium. Unless otherwise indicated,
"stereoisomer" refers to both enantiomers and diastereomers.
[231 The term "optionally substituted with deuterium" means that one or more
hydrogen atoms in the referenced moiety may be replaced with a corresponding
number of deuterium atoms.
[24] The term "C2_10 alkoxyalkyl" refers to a moiety of the formula
-(CH2)a O-(CH2)b, wherein each of a and b is an integer between 1 and 9; and
the sum
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of a + b is an integer between 2 and 10.
[25] Throughout this specification, a variable may be referred to generally
(e.g.,"each R") or may be referred to specifically (e.g., R', R2, R3, etc.).
Unless
otherwise indicated, when a variable is referred to generally, it is meant to
include all
specific embodiments of that particular variable.
THERAPEUTIC COMPOUNDS
[26] The present invention provides a compound of Formula B:
Y2 Y2 0
X1-O
Y3 Y3Y1 Y' B,
or a pharmaceutically acceptable salt thereof, wherein:
A' is hydrogen, deuterium, -CH2-C(O)OR2' or -CH(R")-C(O)OR2';
R" is C1.6 alkyl, C2_,o alkoxyalkyl, phenyl, -(C1_3 alkyl)-(C3_6 cycloalkyl),
or C3-
6 cycloalkyl, wherein R" is optionally substituted with C 1.3 alkyl, C 1.3
alkoxy, phenyl,
or -O-(CH2CH2O)õCH3, wherein n is 1, 2, or 3;
R2, is hydrogen; deuterium; -C1_4 alkyl optionally substituted with phenyl; -
(C3.6 cycloalkyl) optionally substituted with phenyl or methyl; -CH2-(C3_6
cycloalkyl)
wherein the C3_6 cycloalkyl is optionally substituted with phenyl; phenyl; or
biphenyl;
X' is hydrogen, deuterium, -C(O)-indanyl, -C(O)-indenyl, -C(O)-
tetrahydronaphthyl, -C(O)-C,-6 alkyl, -C(O)-C,_6 alkenyl, -C(O)-C1_6 alkynyl,
-C(O)-C1_3 alkyl optionally substituted with C3.6 cycloalkyl, or -C(O)-C3_6
cycloalkyl
optionally substituted with C 1.6 alkyl, phenyl or naphthyl; and
each Y is independently selected from hydrogen and deuterium,
provided that:
(i) when A' is hydrogen or deuterium, at least one Y is deuterium; and
(ii) when X' is hydrogen or deuterium, each Y2 is deuterium, and each Y3 is
deuterium, then A' is not hydrogen or deuterium.
[27] In one embodiment of Formula B, at least one Y is deuterium. In one
aspect
of this embodiment, X' is not hydrogen or deuterium.
[28] In one embodiment of Formula B, R2' is hydrogen, -C, _4 alkyl, -C3_6
cycloalkyl, -CH2-(C3_6 cycloalkyl), phenyl or benzyl, and at least one Y is
deuterium.
[29] In a more specific embodiment of a compound of Formula B, A' is -CH2-
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C(O)OR2' or -CH(R'')-C(O)OR2'; R" is C1_4 alkyl; each Y' is the same; each Y2
is the
same; each Y3 is hydrogen; X' is hydrogen, -C(O)CH3, or -C(O)CH2Ph, provided
that
at least one of Y' and Y2 is deuterium. In one aspect of this embodiment, R2'
is -CH3,
-CH2CH3, or benzyl.
[30] In another embodiment of Formula B: A' is hydrogen; each Y' is the same;
each Y2 is the same; each Y3 is hydrogen; and X1 is selected from acetyl and
benzoyl,
provided that at least one of Y' and Y2 is deuterium. In one aspect of this
embodiment, each Y' is deuterium.
[31] In one embodiment of Formula B, A' is -CH(R'')-C(O)OR2', the compound
having the structure of Formula B-II:
Y2 Y2 0 R"
X1-O O O~R2'
Y3 Y3 Yl 0
B-II,
or a pharmaceutically acceptable salt thereof, wherein X', Y, R" and R2' are
as
described above for Formula B.
[32] In compounds of Formula B-II, the carbon atom bearing R" has a chiral
center. In one embodiment, the compound of Formula B-II has the (S)
configuration
at that chiral center as shown in Formula (S)-B-11 below.
Y2 Y2 0 R1.
X1-O O, R2
Y3 Y3 Y1 Y1 O O [33] (S)-B-11
[34] In certain embodiments of compounds of Formula B, B-II and (S)-B-II, each
Y' is the same; each Y2 is the same; and each Y3 is the same, and at least one
pair of
Y (e.g., each Y'; each Y2; or each Y3) is deuterium. In one specific aspect,
each Y3 is
hydrogen.
[35] Another embodiment of Formula B provides a compound wherein each Y3 is
hydrogen and A' is -CH2-C(O)OR2', the compound having the structure shown in
Formula B-III:
Y2 Y2 0 H2
XI-O OC O"R2
H H Y' Y~
0 B-III,
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or a pharmaceutically acceptable salt thereof, wherein the X', Y and R2'
variables are
as described above for Formula B.
[36] In certain embodiments of compounds of Formula B -III, each Y' is the
same;
each Y2 is the same; and each Y3 is the same, and at least one pair of Y
(e.g., each Y';
each Y2; or each Y3) is deuterium. In one specific aspect, each Y3 is
hydrogen.
[37] The present invention also provides a compound of Formula I:
Y2 Y2 0
X-O
4_~Ax O-A
X
Y3 Y3 Y1 Y'
or a pharmaceutically acceptable salt thereof, wherein:
A is hydrogen, deuterium, -CH2-C(O)OR2 or -CH(R')-C(O)OR2;
R' is a C1_6 alkyl, C2.1o alkoxyalkyl, or C3_6 cycloalkyl group that is
optionally
substituted by an R3 group;
R3 is C 1.3 alkyl, C 1.3 alkoxy, phenyl, -O-(CH2CH2O)õ-CH3, or -(heterocyclyl)-
C1.3 alkyl where the heterocyclyl moiety is a four to six-membered ring having
an oxygen ring atom;
nis 1, 2, or 3;
R2 is hydrogen, deuterium, -C 1.4 alkyl, -C 1.4 alkyl-phenyl, -C3_6
cycloalkyl,
-C3_6 cycloalkyl-phenyl, -CH2-(C3_6 cycloalkyl), -CH2-(C3_6 cycloalkyl)-
phenyl,
phenyl, or biphenyl;
X is hydrogen, deuterium, -C(O)-indanyl, -C(O)-indenyl, -C(O)-
tetrahydronaphthyl, -C(O)-C 1-6 alkyl, -C(O)-C 1.6 alkenyl, -C(O)-C 1.6
alkynyl,
-C(O)-C1.3 alkyl-(C3_6 cycloalkyl), or -C(O)-C3.6 cycloalkyl optionally
substituted by
C 1.6 alkyl, phenyl or naphthyl; and
each Y is independently selected from hydrogen and deuterium,
provided that when A is hydrogen at least one Y is deuterium.
[38] In one embodiment of Formula I, each Y is independently selected from
hydrogen and deuterium, provided that when A is hydrogen at least one Y is
deuterium and X is not hydrogen.
[39] Examples of the R3 heterocyclyl moiety of Formula I include oxetane,
tetrahydrofuran, furan, tetrahydropyran and pyran.
[40] In one embodiment of Formula I, R2 is hydrogen, -C1.4 alkyl, -C3_6
cycloalkyl,
-CH2-(C3_6 cycloalkyl), phenyl or benzyl.
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[41] In a more specific embodiment of a compound of Formula I A is -CH2-
C(O)OR2 or -CH(R')-C(O)OR2; R' is C1-4 alkyl; each Y' is the same; each Y2 is
the
same; each Y3 is hydrogen; X is hydrogen, -C(O)CH3, or -C(O)CH2Ph. In one
aspect
of this embodiment, R2 is -CH3, -CH2CH3, or benzyl.
[42] In another embodiment of Formula I: A is hydrogen; each Y' is the same;
each Y2 is the same; each Y3 is hydrogen; and X is selected from acetyl and
benzoyl.
In one aspect of this embodiment, each Y' is deuterium.
[43] In one embodiment of Formula I. A is -CH(R')-C(O)OR2, the compound
having the structure of Formula II:
Y2 Y2 O R1
X-O O O'R2
Y3 Y3 Y1 Y1 0
II,
or a pharmaceutically acceptable salt thereof, wherein X, Y, R' and R2 are as
described above for Formula I.
[44] In compounds of Formula II, the carbon atom bearing R' has a chiral
center.
In one embodiment, the compound of Formula II has the (S) configuration at
that
chiral center as shown in Formula (S)-II below.
Y2 Y2 O R1
X-O O O-R2
Y3 Y3 Y1 Y1 0
(S)-II.
[45] In certain embodiments of compounds of Formula I, II and S-II, each Y' is
the same; each Y2 is the same; and each Y3 is the same. In one specific
aspect, each
Y3 is hydrogen.
[46] Another embodiment of Formula II provides a compound wherein each Y3 is
hydrogen and R' is hydrogen, the compound having the structure shown in
Formula
III:
Y2 Y2 0 H
2
X_O O"CYO'R2
H H Y1 Y1 0
III,
or a pharmaceutically acceptable salt thereof, wherein the X, Y and R2
variables are as
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described above for Formula I.
1471 Table I shows examples of specific compounds of Formula III.
Table 1. Examples of Specific Compounds of Formula III
Compound # X Each Y Each Y R
100 H H H CH
101 H H H QH5
102 H H H CH2C6H5
103 H D H CH3
104 H D H C2H5
105 H D H CH2C6H5
106 H H D CH3
107 H H D C2H5
108 H H D CH2C6H5
109 Ac H H CH3
110 Ac H H C2H5
111 Ac H H CH2C6H5
112 Ac D H CH3
113 Ac D H C2H5
114 Ac D H CH2C6H5
115 Ac H D CH3
116 Ac H D C2H5
117 Ac H D CH2C6H5
118 H H H H
[291 In certain embodiments, the compound of Formula III is a pharmaceutically
acceptable salt of any one of the compounds set forth in Table 1.
[30) In another embodiment of Formula I, the compound is a compound of
Formula IV:
Y2 Y2 0
X-O O,.A
D D Y1 Y~ IV,
or a pharmaceutically acceptable salt thereof, wherein the X, Y and A
variables are as
described above for Formula I.
In one embodiment, the compound is a compound of formula IV'
Y2 Y2 0
H-O C` ~o11H
D D Y1 Y~ IV',
or a pharmaceutically acceptable salt thereof, wherein the X, Y and A
variables are as
described above for Formula I.
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In one embodiment of Formula IV, the compound is a compound of Formula IV-a:
H H O
H-O 011H D D H H IV-a,
or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula IV, the compound is a compound of Formula
IV-b:
H H O
H-O D O,H
D D IV-b,
or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula IV, the compound is a compound of Formula
IV-c:
D D O
H-O D D OOH
H H IV-c,
or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula IV, the compound is a compound of Formula
IV-d:
D D O
H-O D D D OOH
IV-d,
or a pharmaceutically acceptable salt thereof.
Under certain synthetic conditions, Compounds of formula IV' may be
prepared with an isotopic abundance at each position indicated as "D" of at
least about 75%. Under other synthetic conditions, Compounds of formula
IV' may be prepared with an isotopic abundance at each position indicated as
"D" of greater than about 95%.
Under certain synthetic conditions, Compounds IV-a, IV-c, and IV-d may be
prepared with an isotopic abundance at each position indicated as "D" of at
least
about 75%.
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Under other synthetic conditions, Compounds IV-a, IV-c, and IV-d may be
prepared with an isotopic abundance at each position indicated as "D" of
greater than
about 95%.
Under the synthetic conditions disclosed hereinbelow, Compound IV-b has
been prepared with an isotopic abundance at each position indicated as "D" of
at least
about 95%.
[311 In another embodiment the invention provides a compound selected from any
O
HO OH D D 0
HO
one of D D and OH, or a pharmaceutically
acceptable salt thereof .
[32] In another embodiment the invention provides the compound
D D O
HO,,; OH
D D , or a pharmaceutically acceptable salt thereof.
[331 In yet another embodiment, the invention provides a compound selected
from
any one of HO-CH2-CH2-CD2-C(O)-O- Na+, HO-CH2-CD2-CD2-C(O)-O- Na+, and
HO-CH2-CD2-CH2-C(O)-O' Na+.
[341 In another set of embodiments, any atom not designated as deuterium in
any of
the embodiments set forth above is present at its natural isotopic abundance.
[351 In one embodiment the invention provides any one of the following
compounds, where any atom not designated as deuterium is present in its
natural
abundance:
0 CH3 O CH3
HO~JLO 0CH3 Ho" '0 O'_~CH3
D D 0
101 O 104
0 CH3
D D 0 CH3 H3C`~0~L0 OCH3
HO~~~ O O~CH II
O 0
107 O 110
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O CH3
H3C o--~~ " 0 J-~ O~CH3
D p
O 0
113
D D O CH3 D D O CH3
H3C 0~~ `O J_~ 01-11-ICH3 HO\>
OJ_~ OH
O
116 ,and 118 0 ora
pharmaceutically acceptable salt of any of the foregoing.
[36] The synthesis of compounds of Formula I can be readily achieved by
synthetic
chemists of ordinary skill. Relevant procedures and intermediates such as
methyl,
ethyl, and benzyl lactate esters, as well as acetic anhydride and benzoic
anhydride are
commercially available. Methods for esterifying alcohols are described in
Greene
TW et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and
Sons
(1999).
[37] Such methods can be carried out utilizing corresponding deuterated and
optionally, other isotope-containing reagents and/or intermediates to
synthesize the
compounds delineated herein, or invoking standard synthetic protocols known in
the
art for introducing isotopic atoms to a chemical structure.
EXEMPLARY SYNTHESIS
[38] A convenient method for synthesizing compounds of Formula I is depicted
in
Scheme 1.
[39] Compounds of this invention can readily be made by means known in the art
of organic synthesis.
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1401 Scheme 1. A General Method for Making Compounds of Formula I
Y2 Y2 0 K2C03 Y2 Y2 O ~/
HO 0 ~\
1 O C6H5CH2Br p
Y3 Y3 Y1 Y 10 y3 y3 Y1 Y1 11
R1
HCI f I Y2 Y2 O HO O,R2
13
0
OH
Y3 Y3 Y1 Y1 DCC, 4-DMAP
12
R1 Y2 Y2 0 R1
Y2 Y2 0
0 O pPd(OH)2 HO p O,R2
3 Y1 Y~"'~'R2
Y3
14 0 Y3 Y3 Y1 Y1 0
Formula I (X=H)
DIPEA Y2 Y2 O R1
(C1-6 alkyl-CO)20 C1_6 alkyl O p,R2
1 Y1
O Y3 Y3 Y 0
Formula I (X=C(O)C1_6alkyl)
[411 Scheme 1 shows a general method for making compounds of Formula I.
Alkylation of the alcohol group of an appropriately deuterated tert-butyl
ester of 4-
hydroxybutyric acid 10 is achieved by means known in the art, for instance by
using
benzyl bromide as an alkylating agent with potassium carbonate as a base in an
aprotic solvent to produce the benzyl ester 11. Acidolytic removal of the tert-
butyl
group, for instance by using excess anhydrous hydrogen chloride dissolved in
an inert
solvent, produces the corresponding acid 12. Esterification of the resulting
acid 12
with an appropriate ester 13 using dicyclohexylcarbodiimide ("DCC") with
catalytic
4-dimethylaminepyridine ("4-DMAP") produces the corresponding diester 14. The
benzyl group is then removed by catalytic hydrogenation using palladium
hydroxide
as the catalyst to produce a compound of Formula I, wherein X is hydrogen.
Acetylation of this compound of Formula I using an anhydride and a tertiary
amine
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base such as diisopropylethylamine ("DIPEA") produces a compound of Formula I,
where X is -C(O)-C I -C6 alkyl.
1421 Scheme 2. Synthesis of a Deuterated Tert-butyl Ester of 4-hydroxybut is
acid wherein each Y' is deuterium (10-2,2-d2)
CH3
O~ CH3 D20ZHHO'HO 3
0~CH
3 CH
D D 3
10-2,2-d2
1431 Scheme 2 shows a method for the regioselective deuteration of the 2
position
of commercially available 4-hydroxybutyric acid tert-butyl ester (10) to yield
the 2,2-
dideutero species (10-d2). Reaction with a deuterium donor such as D20,
optionally
using a co-solvent such as THF, and a base such K2C03 provides 4-
hydroxybutyrate
compounds where each Y' is deuterium. In order to obtain the desired level of
deuterium substitution, several such exchange reactions may be carried out in
sequence. Such a sequence may provide deuterium incorporation of at least 90%
and
typically greater than 95% at each Y' position. The resulting selectively
deuterated
compound can then be carried through the reaction sequence specified in Scheme
1 to
produce compounds of Formula I. wherein each Y' is deuterium.
1441 Scheme 3. Synthesis of a Deuterated Tert-butyl Ester of 4-hydroxybutyric
acid wherein each Y2 is deuterium (10-3,3-d2)
O 0
HO,,,,_,kO (CH3)30D HO,_ , O I , Ru04
C6H5CH2OD, K2CO3 D D lo~
21
1. DCI/4-DMAP, H C 0
HO~~ O tBuOH 3 O THE Borane
O D D I / H3C OH
22 2. PdOH CH3 D D
23
H3C O
OH
H3C CH3 O D D
10-3,3-d2
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[45] Scheme 3 shows a method for selective deuterium substitution at the 3-
position (Y). Deuterium substitution of commercially available benzyl 4-
hydroxybutyrate (20), using (CH3)30D and a small amount of C6H5CH2OD as
deuterium donors, and a base such as K2CO3, produces the 2,2-dideutero alcohol
species 21. The oxidation of the alcohol 21 using ruthenium tetroxide under
neutral
conditions produces the carboxylic acid 22. Tert-butyl esterification of the
carboxylic
acid 22 using DCC with a catalytic amount of 4-dimethylaminepyridine and tert-
butyl
alcohol is followed by cleavage of the benzyl ester by catalytic hydrogenation
using
palladium hydroxide to produce the t-butoxy carboxylic acid 23. Selective
reduction
of the carboxylic acid 23 using borane in THE complex produces 3,3-dideutero-4-
hydroxybutyric acid tert-butyl ester (10-3,3-d2), which can be used in Scheme
1 to
produce compound of Formula I, wherein Y3 is deuterium.
[46] Scheme 4. General Method for Making Compounds of Formula IV' or salts
thereof.
Y2 0 O
Y2 LiAID4 Y2 0 1. Na, McO(Y')
O ---- Y2
Y2 Y2 0 THE Y2 Y2 D D 2. (Y1)CI, (Y')20
O Y2 Y2 O
Y O NaO(Y') HO
ONa
Y Y2 Y2 D McO(Y1) D D Y1 Y1
[4'7] D
[48]
[49] The specific approaches and compounds shown above are not intended to be
limiting. The chemical structures in the schemes herein depict variables that
are
hereby defined commensurately with chemical group definitions (moieties,
atoms,
etc.) of the corresponding position in the compound formulae herein, whether
identified by the same variable name (i.e., R', R2, R3, etc.) or not. The
suitability of a
chemical group in a compound structure for use in the synthesis of another
compound
is within the knowledge of one of ordinary skill in the art.
[50] Analogous methods to the ones shown in Schemes 1-3 for compounds of
Formula I may be used for synthesizing compounds of Formula B as.
[51] Additional methods of synthesizing compounds of Formula I or Formula B
and their synthetic precursors, including those within routes not explicitly
shown in
-16-
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schemes herein, are within the means of chemists of ordinary skill in the art.
Synthetic chemistry transformations and protecting group methodologies
(protection
and deprotection) useful in synthesizing the applicable compounds are known in
the
art and include, for example, those described in Larock R, Comprehensive
Organic
Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in
Organic Synthesis, 3d Ed., John Wiley and Sons (1999); Fieser L et al., Fieser
and
Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and
Paquette
L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons
(1995)
and subsequent editions thereof.
[52] Combinations of substituents and variables envisioned by this invention
are
only those that result in the formation of stable compounds.
COMPOSITIONS
[531 The invention also provides pyrogen-free pharmaceutical compositions
comprising an effective amount of a compound of Formula I (e.g., including any
of
the compounds of formulae II, (N)-II, III or IV (including IV', IV-a, IV-b, IV-
c and
IV-d) herein) or Formula B, B-II, (S)-B-II or B-III, or a pharmaceutically
acceptable
salt thereof; and a pharmaceutically acceptable carrier. The carrier(s) are
"acceptable" in the sense of being compatible with the other ingredients of
the
formulation and, in the case of a pharmaceutically acceptable carrier, not
deleterious
to the recipient thereof in an amount used in the medicament.
[541 Pharmaceutically acceptable carriers, adjuvants and vehicles that may be
used
in the pharmaceutical compositions of this invention include, but are not
limited to,
ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as
human
serum albumin, buffer substances such as phosphates, glycine, sorbic acid,
potassium
sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water,
salts or
electrolytes, such as protamine sulfate, disodium hydrogen phosphate,
potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene
glycol,
sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[551 If required, the solubility and bioavailability of the compounds of the
present
invention in pharmaceutical compositions may be enhanced by methods well-known
in the art. One method includes the use of lipid excipients in the
formulation. See
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"Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-
Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed.
Informa
Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and
Parenteral
Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed.
Wiley-Interscience, 2006.
[56] Another known method of enhancing bioavailability is the use of an
amorphous form of a compound of this invention optionally formulated with a
poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block
copolymers of ethylene oxide and propylene oxide. See United States patent
7,014,866; and United States patent publications 20060094744 and 20060079502.
[57] The pharmaceutical compositions of the invention include those suitable
for
oral, rectal, nasal, topical (including buccal and sublingual), vaginal or
parenteral
(including subcutaneous, intramuscular, intravenous and intradermal)
administration.
In certain embodiments, the compound of the formulae herein is administered
transdermally (e.g., using a transdermal patch or iontophoretic techniques).
Other
formulations may conveniently be presented in unit dosage form, e.g., tablets,
sustained release capsules, and in liposomes, and may be prepared by any
methods
well known in the art of pharmacy. See, for example, Remington's
Pharmaceutical
Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
[58] Such preparative methods include the step of bringing into association
with
the molecule to be administered ingredients such as the carrier that
constitutes one or
more accessory ingredients. In general, the compositions are prepared by
uniformly
and intimately bringing into association the active ingredients with liquid
carriers,
liposomes or finely divided solid carriers, or both, and then, if necessary,
shaping the
product.
1591 In certain embodiments, if a protic solvent such as water or alcohols is
used to
dissolve or suspend a compound of this invention in a pharmaceutical
composition,
the solvent is preferably deuterated (e.g. D20, CH3CH2OD, CH3CH2OD). In these
cases the proton on the hydroxy groups of the compound of Formula I or B will
be
partially or mostly replaced with deuterium. Compounds of Formula I or B
comprising a deuterated hydroxy group in place of -OH are also part of the
present
invention.
1601 In certain embodiments, the compound is administered orally. Compositions
of the present invention suitable for oral administration may be presented as
discrete
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units such as capsules, sachets, or tablets each containing a predetermined
amount of
the active ingredient; a powder or granules; a solution or a suspension in an
aqueous
liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-
oil liquid
emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can
be useful
for containing such suspensions, which may beneficially increase the rate of
compound absorption.
[61] In the case of tablets for oral use, carriers that are commonly used
include
lactose and corn starch. Lubricating agents, such as magnesium stearate, are
also
typically added. For oral administration in a capsule form, useful diluents
include
lactose and dried cornstarch. When aqueous suspensions are administered
orally, the
active ingredient is combined with emulsifying and suspending agents. If
desired,
certain sweetening and/or flavoring and/or coloring agents may be added.
[62] Compositions suitable for oral administration include lozenges comprising
the
ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and
pastilles
comprising the active ingredient in an inert basis such as gelatin and
glycerin, or
sucrose and acacia.
[63] Compositions suitable for parenteral administration include aqueous and
non-
aqueous sterile injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes which render the formulation isotonic with the blood
of the
intended recipient; and aqueous and non-aqueous sterile suspensions which may
include suspending agents and thickening agents. The formulations may be
presented
in unit-dose or multi-dose containers, for example, sealed ampules and vials,
and may
be stored in a freeze dried (lyophilized) condition requiring only the
addition of the
sterile liquid carrier, for example water for injections, immediately prior to
use.
Extemporaneous injection solutions and suspensions may be prepared from
sterile
powders, granules and tablets.
[64] Such injection solutions may be in the form, for example, of a sterile
injectable aqueous or oleaginous suspension. This suspension may be formulated
according to techniques known in the art using suitable dispersing or wetting
agents
(such as, for example, Tween 80) and suspending agents. The sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-
toxic
parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-
butanediol. Among the acceptable vehicles and solvents that may be employed
are
mannitol, water, Ringer's solution and isotonic sodium chloride solution. In
addition,
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sterile, fixed oils are conventionally employed as a solvent or suspending
medium.
For this purpose, any bland fixed oil may be employed including synthetic mono-
or
diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives
are useful in
the preparation of injectables, as are natural pharmaceutically-acceptable
oils, such as
olive oil or castor oil, especially in their polyoxyethylated versions. These
oil
solutions or suspensions may also contain a long-chain alcohol diluent or
dispersant.
[65] The pharmaceutical compositions of this invention may be administered in
the
form of suppositories for rectal administration. These compositions can be
prepared
by mixing a compound of this invention with a suitable non-irritating
excipient which
is solid at room temperature but liquid at the rectal temperature and
therefore will
melt in the rectum to release the active components. Such materials include,
but are
not limited to, cocoa butter, beeswax and polyethylene glycols.
[66] The pharmaceutical compositions of this invention may be administered by
nasal aerosol or inhalation. Such compositions are prepared according to
techniques
well-known in the art of pharmaceutical formulation and may be prepared as
solutions
in saline, employing benzyl alcohol or other suitable preservatives,
absorption
promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing
or
dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC,
US
Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
[67] Topical administration of the pharmaceutical compositions of this
invention is
especially useful when the desired treatment involves areas or organs readily
accessible by topical application. For topical application topically to the
skin, the
pharmaceutical composition should be formulated with a suitable ointment
containing
the active components suspended or dissolved in a carrier. Carriers for
topical
administration of the compounds of this invention include, but are not limited
to,
mineral oil, liquid petroleum, white petroleum, propylene glycol,
polyoxyethylene
polyoxypropylene compound, emulsifying wax, and water. Alternatively, the
pharmaceutical composition can be formulated with a suitable lotion or cream
containing the active compound suspended or dissolved in a carrier. Suitable
carriers
include, but are not limited to, mineral oil, sorbitan monostearate,
polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and
water. The
pharmaceutical compositions of this invention may also be topically applied to
the
lower intestinal tract by rectal suppository formulation or in a suitable
enema
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formulation. Topically-transdermal patches and iontophoretic administration
are also
included in this invention.
[681 Application of the subject therapeutics may be local, so as to be
administered
at the site of interest. Various techniques can be used for providing the
subject
compositions at the site of interest, such as injection, use of catheters,
trocars,
projectiles, pluronic gel, stents, sustained drug release polymers or other
device which
provides for internal access.
[69] Thus, according to yet another embodiment, the compounds of this
invention
may be incorporated into compositions for coating an implantable medical
device,
such as prostheses, artificial valves, vascular grafts, stents, or catheters.
Suitable
coatings and the general preparation of coated implantable devices are known
in the
art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121. The
coatings are typically biocompatible polymeric materials such as a hydrogel
polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid,
ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be
further
covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene
glycol,
phospholipids or combinations thereof to impart controlled release
characteristics in
the composition. Coatings for invasive devices are to be included within the
definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as
those terms
are used herein.
1701 According to another embodiment, the invention provides a method of
coating
an implantable medical device comprising the step of contacting said device
with the
coating composition described above. It will be obvious to those skilled in
the art that
the coating of the device will occur prior to implantation into a mammal.
1711 According to another embodiment, the invention provides a method of
impregnating an implantable drug release device comprising the step of
contacting
said drug release device with a compound or composition of this invention.
Implantable drug release devices include, but are not limited to,
biodegradable
polymer capsules or bullets, non-degradable, diffusible polymer capsules and
biodegradable polymer wafers.
[721 According to another embodiment, the invention provides an implantable
medical device coated with a compound or a composition comprising a compound
of
this invention, such that said compound is therapeutically active.
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[73] According to another embodiment, the invention provides an implantable
drug
release device impregnated with or containing a compound or a composition
comprising a compound of this invention, such that said compound is released
from
said device and is therapeutically active.
[74] Where an organ or tissue is accessible because of removal from the
patient,
such organ or tissue may be bathed in a medium containing a composition of
this
invention, a composition of this invention may be painted onto the organ, or a
composition of this invention may be applied in any other convenient way.
[75] In another embodiment, a composition of this invention further comprises
a
second therapeutic agent. The second therapeutic agent may be selected from
any
compound or therapeutic agent known to have or that demonstrates advantageous
properties when administered with sodium oxybate.
[76] In one embodiment, the second therapeutic agent is useful in the
treatment of
abnormal nocturnal sleep, and conditions beneficially treated by improving
nocturnal
sleep, such as narcolepsy, and fibromyalgia. In another embodiment, the second
therapeutic agent is useful in selectively inhibiting polysynaptic reflexes in
a patient
without significantly affecting monosynaptic reflexes.
[77] In another embodiment, the second therapeutic agent is selected from dual
serotonin-norepinephrine reuptake inhibitors and alpha2-delta subunit calcium
channel modulators.
[78] Examples of dual serotonin-norepinephrine reuptake include, but are not
limited to, duloxetine, milnacipran, and venlafaxine.
[79] Examples of alpha2-delta subunit calcium channel modulators include, but
are
not limited to, pregabalin, gabapentin, and prodrugs thereof.
[80] In another embodiment, the invention provides separate dosage forms of a
compound of this invention and one or more of any of the above-described
second
therapeutic agents, wherein the compound and second therapeutic agent are
associated
with one another. The term "associated with one another" as used herein means
that
the separate dosage forms are packaged together or otherwise attached to one
another
such that it is readily apparent that the separate dosage forms are intended
to be sold
and administered together (within less than 24 hours of one another,
consecutively or
simultaneously).
[81] In the pharmaceutical compositions of the invention, the compound of the
present invention is present in an effective amount. As used herein, the term
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"effective amount" refers to an amount which, when administered in a proper
dosing
regimen, is sufficient to treat (therapeutically or prophylactically) the
target disorder.
For example, to reduce or ameliorate the severity, duration or progression of
the
disorder being treated, prevent the advancement of the disorder being treated,
cause
the regression of the disorder being treated, or enhance or improve the
prophylactic or
therapeutic effect(s) of another therapy. In one embodiment, the effective
amount is
an amount effective in the treatment , in a patient in need thereof, of
abnormal
nocturnal sleep, and of conditions beneficially treated by improving nocturnal
sleep,
such as narcolepsy, and fibromyalgia. In one embodiment, the amount is an
amount
effective in the treatment of abnormal nocturnal sleep. In one particular
embodiment,
the amount is an amount effective in improving nocturnal sleep. In one
embodiment,
the amount is an amount effective in the treatment of narcolepsy. In one
embodiment,
the amount is an amount effective in the treatment of fibromyalgia. In one
embodiment, the amount is an amount effective in selectively inhibiting
polysynaptic
reflexes in a patient in need thereof without significantly affecting
monosynaptic
reflexes.
[821 The interrelationship of dosages for animals and humans (based on
milligrams
per meter squared of body surface) is described in Freireich et al., (1966)
Cancer
Chemother. Rep 50: 219. Body surface area may be approximately determined from
height and weight of the patient. See, e.g., Scientific Tables, Geigy
Pharmaceuticals,
Ardsley, N.Y., 1970, 537.
In one embodiment, an effective amount of a compound of this invention can
range from about 0.05 - 2.5 mmol of a compound of Formula I or
pharmaceutically
acceptable salt thereof /kg of body weight, preferably between about 0.15 -
1.5
mmol/kg. When treating a human patient in need of improved nocturnal sleep,
the
selected dose is preferably administered orally from 1-2 times daily. More
preferably
the selected dose is administered orally 1 time daily.
[831 Effective doses will also vary, as recognized by those skilled in the
art,
depending on the diseases treated, the severity of the disease, the route of
administration, the sex, age and general health condition of the patient,
excipient
usage, the possibility of co-usage with other therapeutic treatments such as
use of
other agents and the judgment of the treating physician. For example, guidance
for
selecting an effective dose can be determined by reference to the prescribing
information for sodium oxybate.
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CA 02732479 2011-02-23
[84] For pharmaceutical compositions that comprise a second therapeutic agent,
an
effective amount of the second therapeutic agent is between about 20% and 100%
of
the dosage normally utilized in a monotherapy regime using just that agent.
Preferably, an effective amount is between about 70% and 100% of the normal
monotherapeutic dose. The normal monotherapeutic dosages of these second
therapeutic agents are well known in the art. See, e.g., Wells et al., eds.,
Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn.
(2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,
Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are
incorporated herein by reference in their entirety.
[85] It is expected that some of the second therapeutic agents referenced
above will
act synergistically with the compounds of this invention. When this occurs, it
will
allow the effective dosage of the second therapeutic agent and/or the compound
of
this invention to be reduced from that required in a monotherapy. This has the
advantage of minimizing toxic side effects of either the second therapeutic
agent of a
compound of this invention, synergistic improvements in efficacy, improved
ease of
administration or use and/or reduced overall expense of compound preparation
or
formulation.
METHODS OF TREATMENT
[86] According to another embodiment, the invention provides a method of
treating
a disease or condition that is beneficially treated by a sodium oxybate in a
patient in
need thereof, comprising the step of administering to the patient an effective
amount
of a compound or a composition of this invention. Such diseases and conditions
include, but are not limited to, abnormal nocturnal sleep, and conditions
beneficially
treated by improving nocturnal sleep, such as narcolepsy, and fibromyalgia. In
another embodiment, the method is used to selectively inhibit polysynaptic
reflexes in
a patient without significantly affecting monosynaptic reflexes.
[87] In one particular embodiment, the method of this invention is used to
improve
nocturnal sleep in a patient in need thereof.
[88] Identifying a patient in need of such treatment can be in the judgment of
a
patient or a health care professional and can be subjective (e.g. opinion) or
objective
(e.g. measurable by a test or diagnostic method).
1891 In another embodiment, any of the above methods of treatment comprises
the
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further step of co-administering to the patient in need thereof one or more
second
therapeutic agents. The choice of second therapeutic agent may be made from
any
second therapeutic agent known to be useful for co-administration with sodium
oxybate. The choice of second therapeutic agent is also dependent upon the
particular
disease or condition to be treated. Examples of second therapeutic agents that
may be
employed in the methods of this invention are those set forth above for use in
combination compositions comprising a compound of this invention and a second
therapeutic agent.
In particular, the combination therapies of this invention include co-
administering a compound of Formula I or Formula B or pharmaceutically
acceptable
salt thereof and a second therapeutic agent to a patient in need thereof
selected from
dual serotonin-norepinephrine reuptake inhibitors and alpha2-delta subunit
calcium
channel modulators.
1901 In one embodiment, the second therapeutic agent is a dual serotonin-
norepinephrine reuptake selected from duloxetine, milnacipran, and
venlafaxine.
[91] In another embodiment, the second therapeutic agent is an alpha2-delta
subunit calcium channel modulators selected from pregabalin, gabapentin, and
prodrugs thereof.
1921 The term "co-administered" as used herein means that the second
therapeutic
agent may be administered together with a compound of this invention as part
of a
single dosage form (such as a composition of this invention comprising a
compound
of the invention and an second therapeutic agent as described above) or as
separate,
multiple dosage forms. Alternatively, the additional agent may be administered
prior
to, consecutively with, or following the administration of a compound of this
invention. In such combination therapy treatment, both the compounds of this
invention and the second therapeutic agent(s) are administered by conventional
methods. The administration of a composition of this invention, comprising
both a
compound of the invention and a second therapeutic agent, to a patient does
not
preclude the separate administration of that same therapeutic agent, any other
second
therapeutic agent or any compound of this invention to said patient at another
time
during a course of treatment.
1931 Effective amounts of these second therapeutic agents are well known to
those
skilled in the art and guidance for dosing may be found in patents and
published
patent applications referenced herein, as well as in Wells et al., eds.,
Pharmacotherapy
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CA 02732479 2011-02-23
Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR
Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon
Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is
well
within the skilled artisan's purview to determine the second therapeutic
agent's
optimal effective-amount range.
[941 In one embodiment of the invention, where a second therapeutic agent is
administered to a subject, the effective amount of the compound of this
invention is
less than its effective amount would be where the second therapeutic agent is
not
administered. In another embodiment, the effective amount of the second
therapeutic
agent is less than its effective amount would be where the compound of this
invention
is not administered. In this way, undesired side effects associated with high
doses of
either agent may be minimized. Other potential advantages (including without
limitation improved dosing regimens and/or reduced drug cost) will be apparent
to
those of skill in the art.
In yet another aspect, the invention provides the use of a compound of
Formula I Formula I or pharmaceutically acceptable salt thereof alone or
together
with one or more of the above-described second therapeutic agents in the
manufacture
of a medicament, either as a single composition or as separate dosage forms,
for
treatment or prevention in a patient of a disease, disorder or symptom set
forth above.
Another aspect of the invention is a compound of Formula I or pharmaceutically
acceptable salt thereof for use in the treatment or prevention in a patient of
a disease,
disorder or symptom thereof delineated herein.
EXAMPLES
Example 1. Sodium 2,2-Dideutero-4-hydroxybutanoate
101 1. Na, CH3OD D 0 H 0
NaOH, McOH 2
H2C 0 D 0 HO,CIC ONa
H2C-CH2 2. DCI, D20 H2C-CH2 H2 D D
7
3,3-Dideuterodihydrofuran-2(3H)-one (7): Prepared according to the procedure
for
the synthesis of lactone 4 employing dihydrofuran-2(3H)-one to afford 3,3-
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dideuterodihydrofuran-2(3H)-one (7) as a clear oil (4.14 g, 81%). 'H NMR
(CDC13,
400 MHz) 6 4.35 (t, J= 7.1 Hz, 2H), 2.25 (t, J= 7.1 Hz, 2H).
Sodium 2,2-Dideutero-4-hydroxybutanoate: Prepared according to the procedure
for C-10290 employing lactone 7 to afford sodium 2,2-dideutero-4-
hydroxybutanoate
(C-10293) as a white solid (2.54 g, 88%). 'H NMR (CDCl3, 400 MHz) S 3.38 (t, J
=
5.8 Hz, 2H), 1.55 (t, J= 5.8 Hz, 2H).
Example 2. Synthesis of Sodium 3,3-dideutero-4-hydroxybutanoate
H2 IOI D D O 1. NaBH4, H2O
McOUC-HOH Na, CHgOD MeO\ XC)~OH
IIOII H2 O H2 2. HC{, H2O
1
0
H1 2C McOH D D O
D~ 2 HO,CXC ONa
D H2 H2
2
3,3-Dideutero-4-methoxy-4-oxobutanoic acid (1): A sample of 4-methoxy-4-
oxobutanoic acid (4.44 g, 33.6 mmol) was dissolved in CH30D (Aldrich, 99 atom
%D) and concentrated under reduced pressure. This process was repeated for a
total
of three cycles in order to provide 4-methoxy-4-oxobutanoic acid-OD. In a
separate
flask, several small pieces of sodium metal (1.19 g, 51.7 mmol, washed in
heptane)
were added slowly to CH3OD (60 mL) and allowed to stir until fully dissolved.
4-
Methoxy-4-oxobutanoic acid-OD (4.44 g, 33.6 mmol) was then added as a solution
in
CH3OD and the reaction stirred at reflux for 20 hours. Upon cooling to room
temperature the reaction was quenched with acetic acid-OD (1.50 mL, Alrich, 99
atom %D) and concentrated under reduced pressure. The resulting residue was
diluted with D20 (Cambridge Isotope Laboratories, 99 atom %D) and acidified to
pH=2 with conc. 12N DCl (Aldrich, 99 atom % D) then extracted with EtOAc (3 x
100 mL). The organic layers were combined, dried (Na2SO4), filtered and
concentrated under reduced pressure followed by azeotropic removal of acetic
acid
with toluene to afford 3,3-dideutero-4-methoxy-4-oxobutanoic acid (1) as a
white
solid (4.21 g, 93%). 'H NMR (CDC13, 400 MHz) 8 3.70 (s, 3H), 2.68 (s, 2H).
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4,4-Dideuterodihydrofuran-2(3H)-one (2): To a solution of 1 (4.21 g, 31.4
mmol)
in water (50 mL) was slowly added NaBH4 (10.09 g, 267 mmol). Additional water
(15 mL) was then added and the reaction stirred at room temperature for 15
hours.
Upon cooling to 0 C, the reaction was quenched via slow addition of 12N HCl
(29
mL). Additional 12N HCl (6 mL) was then added and the reaction was stirred at
110
C for 1 hour. The reaction was then cooled to room temperature, diluted with
brine
and extracted with DCM (3 x 100 mL). The organic layers were combined, dried
(MgSO4), filtered and concentrated uder reduced pressure. The resulting oil
was
purified via Kugelrohr distillation to afford 4,4-dideuterodihydrofuran-2(3H)-
one (2)
as a clear oil (654 mg, 24%). 'H NMR (CDC13, 400 MHz) 8 4.33 (s, 2H), 2.47 (s,
2H).
Sodium 3,3-dideutero-4-hydroxybutanoate To a solution of 2 (2.06 g, 23.4 mmol)
in methanol (100 mL) was added solid sodium hydroxide (918 mg, 22.9 mmol). The
reaction stirred at reflux for 5 hours then was concentrated under reduced
pressure to
afford sodium 3,3-dideutero-4-hydroxybutanoate (C-10290) as a white solid
(2.75 g,
92%). 'H NMR (CDC13, 400 MHz) 6 6.17 (s, 1 H), 3.38 (s, 2H), 2.01 (s, 2H).
Example 3. Synthesis of Sodium 2,2,3,3-tetradeutero-4-hydroxybutanoate
O O CH30D HO D D O 1. NaBH42H2O
D 0 fDXD OMe
D D D 2. HCI, H2O
D 0 D D 0
D 0 NaOH, McOH_ HO, C~ ONa
D CH2 H2 D D
D
6
2,2,3,3-Tetradeutero-4-methoxy-4-oxobutanoic acid (5): A solution of succinic
acnhydride-d4 (3.00 g, 28.8 mmol, CDN Isotopes, 98 atom %D) in CH3OD (Aldrich,
99 atom %D) was stirred at reflux for 2 hours then concentrated under reduced
pressure to afford 2,2,3,3-tetradeutero-4-methoxy-4-oxobutanoic acid (5) as a
white
solid (3.45 g, 88%). 'H NMR (CDC13, 400 MHz) 8 3.70 (s, 3H).
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CA 02732479 2011-02-23
3,3,4,4-Tetradeuterodihydrofuran-2(3H)-one (6): Prepared according to the
procedure for the synthesis of lactone 4 employing carboxylic acid 5 to afford
3,3,4,4-
tetradeuterodihydrofuran-2(3H)-one (6) as a clear oil (1.38 g, 61%). 'H NMR
(CDC13, 400 MHz) S 4.33 (s, 2H).
Sodium 2,2,3,3-tetradeutero-4-hydroxybutanoate: Prepared according to the
procedure for C-10290 employing lactone 6 to afford sodium 2,2,3,3-
tetradeutero-4-
hydroxybutanoate (C-10292) as a white solid (1.77 g, 89%). 'H NMR (CDCl3, 400
MHz) S 3.38 (s, 2H).
Example 4. Synthesis of Sodium 2,2,4,4-tetradeutero-4-hydroxybutanoate (IVb
sodium salt)
O
O O LIAID4, THE H2CA0 1. Na, CH3OD -jW
H2C,CO H2C- D 2. DCI, D20
H2 D
3
O 0
D\O NaOH, McOH HO C2
D WONa
H2C-~-D D DD D
D
4
5,5-Dideuterodihydrofuran-2(3H)-one (3): A suspension of LiAlD4 (1.27 g, 30.0
mmol, Cambridge Isotope Laboratories, 98 atom%D) in THE (100 mL) was stirred
at
reflux for 1 hour then cooled to -78 C. Succinic anhydride (5.00 g, 50.0
mmol) was
then added dropwise as a solution in THE (80 mL) and the reaction was allowed
to
warm to room temperature over 1.5 hours. The reaction was then cooled to -20
C
and was quenched with 6M HCl (20 mL). The reaction then stirred at room
temperature for 15 hours then was subsequently diluted with brine. The
resulting
solution was extracted with MTBE (5 x 50 mL), dried (Na2SO4), filtered and
concentrated under reduced pressure. The resulting oil was purified via
Kugelrohr
distillation to afford 5,5-dideuterodihydrofuran-2(3H)-one (3) as a clear oil
(1.75 g,
35%). 'H NMR (CDC13, 400 MHz) 6 2.48 (t, J = 7.8 Hz, 2H), 2.24 (t, J = 8.3 Hz,
2H).
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3,3,5,5-Tetradeuterodihydrofuran-2(3H)-one (4): Several small pieces of sodium
metal (253 mg, 11.0 mmol, washed in heptane) were added slowly to CH3OD (20
mL) at 40 C and allowed to stir until fully dissolved. 5,5-
Dideuterodihydrofuran-
2(3H)-one (3) (1.75 g, 20.0 mmol) was then added as a solution in CH3OD (20
mL)
and the reaction stirred at reflux for 15 hours. Upon cooling to room
temperature the
reaction was quenched with acetic acid-OD (1.00 mL, Alrich, 99 atom %D) and
12N
DCl (2 drops) and subsequently concentrated under reduced pressure. The
resulting
resiude was diluted with DCM, filtered through Celite , and concentrated under
reduced pressure. The resulting residue was then dissolved in D20 (35 mL) and
12N
DCl (3 mL) was added. After stirring at 110 C for 1 hour, the reaction was
cooled to
room temperature, diluted with brine and extracted with DCM (3 x 100 mL). The
organic layers were combined, dried (MgSO4), filtered and concentrated uder
reduced
pressure. The resulting oil was purified via Kugelrohr distillation to afford
3,3,5,5-
tetradeuterodihydrofuran-2(3H)-one (4) as a clear oil (536 mg, 30%). 'H NMR
(CDC13, 400 MHz) 8 2.23 (s, 2H).
Sodium 2,2,4,4-tetradeutero-4-hydroxybutanoate: Prepared according to the
procedure for C-10290 employing lactone 4 to afford sodium 2,2,4,4-
tetradeutero-4-
hydroxybutanoate (C-10291) as a white solid (1.57 g, 85%). 'H NMR (CDC13, 400
MHz) S 1.53 (s, 2H).
[951 If desired, the above-identified deuterated 4-hydroxybutyrate sodium
salts are
converted to their corresponding esters by treatment with the corresponding
alkyl
halide in the presence of an aqueous base in a manner analogous to the
procedure of
U.S. Patent No. 5,250,696.
[961
Example 5.
- In vivo pharmacokinetic studies.
The pharmacokinetics of exemplary compounds was determined by comparison with
4-hydroxybutyric acid by dosing the compounds in rats according to the
following
study design and sampling procedure.
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Study Design:
Treatmen Test Dosin Animals Dose Dosing Dosing Vehicle Sampling Time Points
t Group Compound g N= mg/kg Solution Volume
Route Conc. mL/kg
mg/mL
1 4- IV 4 200 40 5 SWFI Predose, 2, 7, 15, 30
hydroxybut min, 1, 2, and 4 hours
yric acid
sodium salt
2 PO 4 200 40 5 SWFI Predose, 5, 15, 30 min,
1, 2, 4, and 6 hours
3 IV-b IV 4 200 40 5 SWFI Predose, 2, 7, 15, 30
sodium salt min, 1, 2, and 4 hours
4 PO 4 200 40 5 SWFI Predose, 5, 15, 30 min,
1,2,4, and 6 hours
2,2- IV 4 200 40 5 SWFI Predose, 2, 7, 15, 30
Dideutero- min, 1, 2, and 4 hours
4-
hydroxybut
6 anoic acid, PO 4 200 40 5 SWFI Predose, 5, 15, 30 min,
sodium salt 1, 2, 4, and 6 hours
SWFI: Sterile water for injection
Sampling procedure:
5.1 Sampling
Frequency: See Study Design
Blood samples were collected via the jugular cannula, placed into chilled
tubes
Collection: containing K2EDTA as the anticoagulant, and kept on ice until
centrifugation in a
refrigerated centrifuge.
The samples were centrifuged at a temperature of 4 C, at 3,000xg, for 5
minutes.
Preparation and Storage: Plasma were collected into a 96-well plate after
centrifugation of the blood samples
and frozen on dry ice. Plasma samples and leftover formulations were stored
frozen at
-60 C to -80 C until shipped frozen on dry ice.
The results of the in vivo studies are disclosed in the following table (Table
2):
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Table 2
Compd ID Dose ROA Rat # T_, C, .. C,,,;n' AUCn-õ CL V ttl2b
(mg/kg) (hr) (ug/mL) (ug/mL) (hr*ug/mL) (mL/min/kg) (Ukg) (hr)
4- 200 IV Mean - - 8 427 8 0.2 026
hydroxybutyric SD - - 2 30 1 0 0.02
acid, sodium PO Mean 0.5 150 2 170 - 0.61
salt SD 0 45 1 50 - 0.04
%F 40%
IV-b, sodium 200 IV Mean 76 651 5 0.3 0.63
salt
SD 16 28 0 0 0.09
PO Mean 0.63 151 5 260 0.94
SD 0.25 73 2 127 0.75
%F 40%
2,2-Dideutero-4- 200 IV Mean 19 476 7 0.2 0.33
hydroxybutanoic
acid, sodium salt
SD 19 76 1 0.1 0.12
PO Mean 0.63 153 1 193 0.59
(+1.I X)
SD 0.25 9 0 34 0.14
%F 41%
a 2 hr for IV and 4 hr for PO
b calculated upto 2hr for IV and 4 hr for PO
[97] As shown in Table 2, the pharmcokinetics of IV-b, sodium salt was
considerably increased relative to 4-hydroxybutyric acid, sodium salt. This is
particularly clear from a comparison of the relative values of AUCn-~ and of
tai, for the
two compounds.
[98] Without further description, it is believed that one of ordinary skill in
the art
can, using the preceding description and the illustrative examples, make and
utilize
the compounds of the present invention and practice the claimed methods. It
should
be understood that the foregoing discussion and examples merely present a
detailed
description of certain preferred embodiments. It will be apparent to those of
ordinary
skill in the art that various modifications and equivalents can be made
without
departing from the spirit and scope of the invention.
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