# Patent

## Title
4-hydroxybutyric acid analogs

## Abstract

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 treating narcolepsy, fibromyalgia, other disorders or conditions that are beneficially treated by improving nocturnal sleep or by administering sodium oxybate.

## Background
RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 13/372,989, filed Feb. 14, 2012, which claims the benefit of U.S. Provisional Patent Application No. 61/442,451, filed Feb. 14, 2011 and U.S. Provisional Patent Application No. 61/484,296, filed May 10, 2011. The contents of the foregoing applications are incorporated herein by reference.


BACKGROUND OF THE INVENTION
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) and decreasing light or stage 1 sleep (Scrima, L. et al., Sleep, 1990, 13:479; Pardi, D. and Black, J., CNS Drugs, 2006, 20:993.
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 reported to be effective for relieving pain and improving function in patients with fibromyalgia syndrome (Scharf, M B et al., J Rheumatol, 2003, 30:1070; Russell, I J 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, W G et al., Arch Neurol, 2008, 65:1337; Frucht, S J et al, Neurology, 2005, 65:1967; Berner, J E, J Clin Psychiatry, 2008, 69:862). Sodium oxybate is in or has been in clinical trials for treatment of fibromyalgia, Parkinson's disease, obstructive sleep apnea syndrome, insomnia associated with schizophrenia, sleep initiation and maintenance disorders (chronic insomnia), chronic fatigue syndrome, essential tremor, hemiplegia, sedative abuse and binge-eating disorder (see http://clinicaltrials.gov/ct2/results?term=sodium+oxybate).
The very short half life of sodium oxybate in humans (0.5-1 hour) is a major limitation in its use. The recommended dosing schedule for 4-hydroxybutyric acid is twice nightly, first upon entering bed and again 2.5 to 4 hours later (see, e.g., FDA product label dated Nov. 13, 2006 for NDA no. 021196). This schedule can be quite inconvenient to the patient. 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.
SUMMARY OF THE INVENTION
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
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.
“Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
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, L Z et al., Comp Biochem Physiol Mol lntegr Physiol, 1998, 119:725.
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 0.015% (i.e., at least 50.1% incorporation of deuterium).
The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
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).
The term “isotopologue” refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.
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.
The invention also provides salts of the compounds of the invention.
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.
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 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.
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, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-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.
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 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.
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.
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.
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).
“D” and “d” both refer to deuterium. Unless otherwise indicated, “stereoisomer” refers to both enantiomers and diastereomers.
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.
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 of a+b is an integer between 2 and 10.
Throughout this specification, a variable may be referred to generally (e.g., “each R”) or may be referred to specifically (e.g., R1, 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
The present invention provides a compound of Formula B:




or a pharmaceutically acceptable salt thereof, wherein:

A1 is hydrogen, deuterium, —CH2—C(O)OR2′ or —CH(R1′)—C(O)OR2′;
R1′ is C1-6 alkyl, C2-10 alkoxyalkyl, phenyl, —(C1-3 alkyl)-(C3-6 cycloalkyl), or C3-6 cycloalkyl, wherein R1′ is optionally substituted with C1-3 alkyl, C1-3 alkoxy, phenyl, or —O—(CH2CH2O)n—CH3, 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;
X1 is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl, —C(O)-tetrahydronaphthyl, —C(O)—C1-6 alkyl, —C(O)—C1-6 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 C1-6 alkyl, phenyl or naphthyl; and
each Y is independently selected from hydrogen and deuterium, provided that:
(i) when A1 is hydrogen or deuterium, at least one Y is deuterium; and
(ii) when X1 is hydrogen or deuterium, each Y2 is deuterium, and each Y3 is deuterium, then A1 is not hydrogen or deuterium.
In one embodiment of Formula B, at least one Y is deuterium. In one aspect of this embodiment, X1 is other than hydrogen or deuterium.
In one embodiment of Formula B, R2′ is hydrogen, —C1-4 alkyl, —C3-6 cycloalkyl, —CH2—(C3-6 cycloalkyl), phenyl or benzyl, and at least one Y is deuterium.
In a more specific embodiment of a compound of Formula B, A1 is —CH2—C(O)OR2′ or —CH(R1′)—C(O)OR2′; R1′ is C1-4 alkyl; each Y1 is the same; each Y2 is the same; each Y3 is hydrogen; X1 is hydrogen, —C(O)CH3, or —C(O)CH2Ph, provided that at least one of Y1 and Y2 is deuterium. In one aspect of this embodiment, R2′ is —CH3, —CH2CH3, or benzyl.
In another embodiment of Formula B: A1 is hydrogen; each Y1 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 Y1 and Y2 is deuterium. In one aspect of this embodiment, each Y1 is deuterium.
In another embodiment of Formula B, each Y is independently selected from hydrogen and deuterium; wherein each Y1 is the same, each Y2 is the same and each Y3 is the same, wherein at least one pair of Y is deuterium; wherein each Y3 is deuterium, provided that: when X1 is hydrogen or deuterium, each Y2 is deuterium, and each Y3 is deuterium, then A1 is not hydrogen or deuterium. The remainder of the variables are as defined in paragraph 25.
In one embodiment of Formula B, A1 is —CH(R1′)—C(O)OR2′, the compound having the structure of Formula B-II:




or a pharmaceutically acceptable salt thereof, wherein X1, Y, R1′ and R2′ are as described above for Formula B.

In compounds of Formula B-II, the carbon atom bearing R1′ 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-II below.




In certain embodiments of compounds of Formula B, B-II and (S)-B-II, each Y1 is the same; each Y2 is the same; and each Y3 is the same, and at least one pair of Y (e.g., each Y1; each Y2; or each Y3) is deuterium. In one specific aspect, each Y3 is hydrogen.
Another embodiment of Formula B provides a compound wherein each Y3 is hydrogen and A1 is —CH2—C(O)OR2′, the compound having the structure shown in Formula B-III:




or a pharmaceutically acceptable salt thereof, wherein the X1, Y and R2′ variables are as described above for Formula B.

In certain embodiments of compounds of Formula B-III, each Y1 is the same; each Y2 is the same; and each Y3 is the same, and at least one pair of Y (e.g., each Y1; each Y2; or each Y3) is deuterium. In one specific aspect, each Y3 is hydrogen.
The present invention also provides a compound of Formula I:




or a pharmaceutically acceptable salt thereof, wherein:

A is hydrogen, deuterium, —CH2—C(O)OR2 or —CH(R1)—C(O)OR2;
R1 is a C1-6 alkyl, C2-10 alkoxyalkyl, or C3-6 cycloalkyl group that is optionally substituted by an R3 group;
R3 is C1-3 alkyl, C1-3 alkoxy, phenyl, —O—(CH2CH2O)n—CH3, or -(heterocyclyl)-C1-3 alkyl where the heterocyclyl moiety is a four to six-membered ring having an oxygen ring atom;
n is 1, 2, or 3;
R2 is hydrogen, deuterium, —C1-4 alkyl, —C1-4 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)—C1-6 alkyl, —C(O)—C1-6 alkenyl, —C(O)—C1-6 alkynyl, —C(O)—C1-3 alkyl-(C3-6 cycloalkyl), or —C(O)—C3-6 cycloalkyl optionally substituted by C1-6 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.
In one embodiment of Formula I, when A is deuterium, at least one Y is deuterium.
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.
Examples of the R3 heterocyclyl moiety of Formula I include oxetane, tetrahydrofuran, furan, tetrahydropyran and pyran.
In one embodiment of Formula I, R2 is hydrogen, —C1-4 alkyl, —C3-6 cycloalkyl, —CH2—(C3-6 cycloalkyl), phenyl or benzyl.
In a more specific embodiment of a compound of Formula I A is —CH2—C(O)OR2 or —CH(R1)—C(O)OR2; R1 is C1-4 alkyl; each Y1 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.
In another embodiment of Formula I: A is hydrogen; each Y1 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 Y1 is deuterium.
In one embodiment of Formula I, A is —CH(R1)—C(O)OR2, the compound having the structure of Formula II:




or a pharmaceutically acceptable salt thereof, wherein X, Y, R1 and R2 are as described above for Formula I.

In compounds of Formula II, the carbon atom bearing R1 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.




In certain embodiments of compounds of Formula I, II and S-II, each Y1 is the same; each Y2 is the same; and each Y3 is the same. In one specific aspect, each Y3 is hydrogen.
Another embodiment of Formula II provides a compound wherein each Y3 is hydrogen and R1 is hydrogen, the compound having the structure shown in Formula III:




or a pharmaceutically acceptable salt thereof, wherein the X, Y and R2 variables are as described above for Formula I.

Table 1 shows examples of specific compounds of Formula III.







TABLE 1







Examples of Specific Compounds of Formula III













Compound #
X
Each Y1
Each Y2
R2







100
H
H
H
CH3



101
H
H
H
C2H5



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










In certain embodiments, the compound of Formula III is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.
In another embodiment of Formula I, the compound is a compound of Formula 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′




or a pharmaceutically acceptable salt thereof, wherein the X, Y and A variables are as described above for Formula I.

Specific examples of compounds of Formula IV′ include the following:




or a pharmaceutically acceptable salt of one of IV-a, IC-b, IV-c, or IV-d.
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 of Formula IV-a, IV-b, IV-c, and IV-d 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-a, IV-b, 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 herein, the Compound of Formula IV-b has been prepared with an isotopic abundance at each position indicated as “D” of at least about 95%.
In one embodiment of Formula IV, the compound is a compound of Formula IV′′:




or a pharmaceutically acceptable salt thereof,
wherein A is —CH2—C(O)OR2 or —CH(R1)—C(O)OR2;
R1 is —C1-6 alkyl; and
R2 is —C1-4 alkyl; and
X is hydrogen, deuterium or —C(O)—C1-6 alkyl.
In one embodiment of Formula IV′′, the compound is a compound of Formula IV′′-a:




or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula IV′′, the compound is a compound of Formula IV′′-b:




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 of Formula IV′′-a and IV′′-b 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′′-a and IV′′-b may be prepared with an isotopic abundance at each position indicated as “D” of greater than about 95%.
In one embodiment of Formula IV, the compound is a compound of Formula IV′′′




wherein X is hydrogen, deuterium or —C(O)—C1-6 alkyl.
In one embodiment, X is —C(O)—C1-6 alkyl.
Specific examples of compounds of Formula IV′′′ include the following:




or a pharmaceutically acceptable salt of one of the foregoing.
In one embodiment the invention is directed to a compound of Formula V:




or a pharmaceutically acceptable salt thereof, wherein
wherein
each Y is independently selected from hydrogen and deuterium,
R4 is —C1-6 alkyl or C6-C10 aryl; and
X is hydrogen, deuterium or —C(O)—C1-6 alkyl.
In one embodiment of formula V, if X is hydrogen, then at least one Y is deuterium.
In one embodiment of Formula V, the compound is a compound of Formula V-a:




In one aspect of Formula V-a, R4 is methyl.

In one embodiment of Formula V, the compound is a compound of Formula V-b:




In one aspect of Formula V-b, R4 is methyl.

In one embodiment of Formula V, the compound is a compound of Formula V-c:




In one aspect of Formula V-c, R4 is methyl.

In one embodiment of Formula V, the compound is a compound of Formula V-d:




In one aspect of Formula V-d, R4 is methyl.

In one embodiment of Formula V, the compound is a compound of Formula V-e:




In one aspect of formula V-e, R4 is methyl.

In another embodiment the invention provides a compound selected from any one of




or a pharmaceutically acceptable salt thereof.

In another embodiment the invention provides the compound




or a pharmaceutically acceptable salt thereof.

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+.
In yet another embodiment, the invention provides a compound selected from any one of HO—CD2-CH2—CH2—C(O)—O−Na+, HO—CD2-CH2—CD2-C(O)—O−Na+, HO—CD2-CD2-CH2—C(O)—O−Na+ and HO—CD2-CD2-CD2-C(O)—O−Na+. In yet another embodiment, the invention provides a composition comprising such compound. In yet another embodiment, the invention provides a method of treating an indication disclosed herein comprising administering to a patient an effective amount of such compound.
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.
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:




or a pharmaceutically acceptable salt of any of the foregoing.

In one embodiment, the present invention provides a compound of Formula 32:




wherein each Y is independently selected from hydrogen and deuterium. In one aspect of this embodiment, each Y2 is the same and each Y1 is the same.

One embodiment of Formula 32 provides a compound where each Y1 is hydrogen. Another embodiment of Formula 32 provides a compound where each Y1 is deuterium.
In one embodiment, the compound of formula 32 is a compound of Formula 3




In one embodiment, the compound of formula 32 is a compound of Formula 4




In one embodiment, the compound of formula 32 is a compound of Formula 32-a:




In one embodiment, the compound of formula 32 is a compound of Formula 32-b:




Under certain synthetic conditions, Compounds of Formula 32 (including compounds of formula 31, 3, 4, 32-a and 32-b) may be prepared with an isotopic abundance at each position indicated as “D” of at least about 90%, such as at least about 95%, as determined by 1H NMR.
In one embodiment the invention provides a compound of formula VIa




wherein:

R6 is C1-6 alkyl, C2-6 alkenyl, or C3-8 cycloalkyl, wherein R6 is optionally substituted with C3-8 cycloalkyl, C6-10 aryl, NR2R3 or —X—P(═O)(OR4)(OR5), wherein
X is O or a direct bond;
R4 and R5 are each independently C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
R2 and R3 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
or R2 and R3 taken together with the nitrogen attached to R2 and R3 form a three- to seven-membered heterocyclyl optionally substituted with halo and containing one nitrogen atom and optionally an oxygen atom or an additional nitrogen atom;
and
each Y2 is hydrogen or deuterium.
In one embodiment of the compound of formula VIa, each Y2 is hydrogen. In another embodiment, each Y2 is deuterium.
In one embodiment the invention provides a compound of formula VIb




wherein:

R6 is C1-6 alkyl, C2-6 alkenyl, or C3-8 cycloalkyl, wherein R6 is optionally substituted with C3-8 cycloalkyl, C6-10 aryl, NR2R3 or —X—P(═O)(OR4)(OR5), wherein
X is O or a direct bond;
R4 and R5 are each independently C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
R2 and R3 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
or R2 and R3 taken together with the nitrogen attached to R2 and R3 form a three- to seven-membered heterocyclyl optionally substituted with halo and containing one nitrogen atom and optionally an oxygen atom or an additional nitrogen atom;
each Y2 is hydrogen or deuterium; and
each Y1 is hydrogen or deuterium.
In one embodiment of the compound of formula VI, Y1 and Y2 are the same. In one aspect of this embodiment, each Y1 and each Y2 is hydrogen. In another aspect of this embodiment, each Y1 and each Y2 is deuterium.
In one embodiment of the compound of formula VIb, each Y1 is deuterium. In one aspect of this embodiment, each Y2 is hydrogen.
In one embodiment the invention provides a compound of formula VII




or a pharmaceutically acceptable salt thereof, wherein
R6 is C1-6 alkyl, C2-6 alkenyl, or C3-8 cycloalkyl, wherein R6 is optionally substituted with C3-8 cycloalkyl, C6-10 aryl, NR2R3 or —X—P(═O)(OR4)(OR5), wherein
X is O or a direct bond;
R4 and R5 are each independently C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
R2 and R3 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl or C6-10 aryl;
or R2 and R3 taken together with the nitrogen attached to R2 and R3 form a three- to seven-membered heterocyclyl optionally substituted with halo and containing one nitrogen atom and optionally an oxygen atom or an additional nitrogen atom;
R7 is C1-6 alkyl, C2-6 alkenyl, or C3-8 cycloalkyl, wherein R6 is optionally substituted with C3-8 cycloalkyl, C6-10 aryl, —C(O)OC1-6 alkyl optionally substituted with C6-10 aryl, NR2R3, or hydrogen;
each Y2 is hydrogen or deuterium; and
each Y1 is hydrogen or deuterium.
In one embodiment of the compound of formula VII, Y1 and Y2 are the same. In one aspect of this embodiment, each Y1 and each Y2 is hydrogen. In another aspect of this embodiment, each Y1 and each Y2 is deuterium.
In one embodiment of the compound of formula VIb, each Y1 is deuterium. In one aspect of this embodiment, each Y2 is hydrogen.
In one embodiment of the compound of formula VII, R7 is hydrogen and the compound is a carboxylic acid. In one embodiment of the compound of formula VII the compound is the sodium salt of the acid.
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
A convenient method for synthesizing compounds of Formula I is depicted in Scheme 1.
Compounds of this invention can readily be made by means known in the art of organic synthesis.




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 base such as diisopropylethylamine (“DIPEA”) produces a compound of Formula I, where X is —C(O)—C1-C6 alkyl.




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 D2O, optionally using a co-solvent such as THF, and a base such K2CO3 provides 4-hydroxybutyrate compounds where each Y1 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 Y1 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 Y1 is deuterium.




Scheme 3 shows a method for selective deuterium substitution at the 3-position (Y2). Deuterium substitution of commercially available benzyl 4-hydroxybutyrate (20), using (CH3)3OD 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 THF 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.




As shown in Scheme 4, treatment of an appropriately deuterated succinic anhydride (30) with lithium aluminum deuteride in a manner analogous to Keay, B. A., et al., J. Org. Chem. 2007, 72, 7253-7259, followed by opening and exchange of the gamma-dideuterolactone upon treatment with sodium in methanol or deuterated methanol, and re-lactonization with an acid or deuterated acid such as HCl in H2O or DCl in D2O, provides an appropriately deuterated lactone (31). Ring opening to afford the sodium salt of a compound of Formula IV′ is accomplished by treatment with sodium hydroxide or deuteroxide and appropriately deuterated methanol, in a manner analogous to Goto, G., et al, Chem. Pharm. Bull. 1985, 33, 4422-4431
Compounds of Formula IV′′ wherein A is —CH2—C(O)OR2 or —CH(R1)—C(O)OR2 and X is —C(O)—C1-6 alkyl may be prepared from compounds of Formula IV′ as shown below:




As shown in Scheme 5, treatment of the sodium salt of a compound of formula IV′ with acetic anhydride in a manner analogous to Goto, G. et al. Chem. Pharm. Bull. 1985, 33, 4422-4431 provides an acetylated sodium salt which is treated with an α-hydroxy ester in a manner analogous to Bettolo, R. M. et al., Helv. Chim. Acta 2005, 88, 154-159 to provide a compound of formula IV′′. As one skilled in the art will readily appreciate, a suitable anyhydride or other source of —C(O)—C1-6 alkyl may be used in place of acetic anhydride in the first step, and/or an ester of formula HO—CH2—C(O)OR2 may be used in the second step in place of the α-hydroxy ester shown in Scheme 5.
By procedures similar to Schemes 4 and 5, compounds of formula IV, including IV′′′, may also be obtained.




As shown in Scheme 6(a), treatment of a compound of formula IV′ (obtained, for example, by treatment with dilute acid of the sodium salt of a compound of formula IV′ obtained in Scheme 5) with sulfonamide R4SO2NH2 and carbodiimidazole (CDI) provides a compound of formula V (in which X is acetyl). Alternatively, as shown in Scheme 6(b), treatment of the sodium salt of a compound of formula IV′ (obtained, for example, as shown in Scheme 5) with sulfonamide R4SO2NH2 and CDI provides a compound of formula V (in which X is hydrogen).




Ring-opening of optionally deuterated succinic anhydride in a manner analogous to the one disclosed in patent publication WO 2011019839 provides the optionally deuterated succinic acid t-butyl monoester shown in the scheme. Anhydride formation by treatment with i-butyl chloroformate followed by reduction with sodium borodeuteride affords the deuterated 4-hydroxybutyric acid t-butyl ester. Esterification of the alcohol with a suitable acylating agent R6C(O)X followed by hydrolysis of the t-butyl group yields 4-acyloxy butyric acid 41.

B) Synthesis of Deuterated Butanediol 42




Reductive ring-opening of optionally deuterated succinic anhydride with deuterium over Pd/C in a manner analogous to the one disclosed in Japanese patent publication 07082190 (1995) provides deuterated butanediol 42.
C) Synthesis of Compound of Formula VIa




Compounds 41 and 42 in a 2:1 mole ratio are coupled in the presence of EDC to give the compound formula Via.
b) Compounds of Formula VIb or Salts Thereof
A) Synthesis of 4-Acyloxy Butyric Acid 43




Ring-opening of optionally deuterated succinic anhydride in a manner analogous to the one disclosed in patent publication WO 2011019839 provides the optionally deuterated succinic acid t-butyl monoester shown in the scheme. Treatment of the monoester with t-BuOY1 in the presence of potassium t-butoxide accomplishes exchange at the carbon adjacent to the ester carbonyl. Anhydride formation by treatment with i-butyl chloroformate followed by reduction with sodium borodeuteride affords the deuterated 4-hydroxybutyric acid t-butyl ester. Esterification of the alcohol with a suitable acylating agent R6C(O)X followed by hydrolysis of the t-butyl group yields 4-acyloxy butyric acid 43.
A) Synthesis of Deuterated Butanediol 44




Reduction of 43 with lithium aluminum hydride provides deuterated butanediol 42.
B) Synthesis of Compound of Formula VIb




Compounds 43 and 44 in a 2:1 mole ratio are coupled in the presence of EDC to give the compound formula VIb.




Coupling of compounds 43 and 44 in the presence of EDC gives compound 45. Hydrolysis of the t-butyl group of 45 yields 46, which is coupled with 44 in the presence of EDC to give compound 47. Hydrolysis of the t-butyl group of 47 yields 48, which is treated with R7OH to provide the compound of formula III.

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., R1, 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.
Analogous methods to the ones shown in Schemes 1-3 for compounds of Formula I may be used for synthesizing compounds of Formula B.
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 T W et al., Protective Groups in Organic Synthesis, 3rd 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.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
Compositions
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, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c and IV-d, IV′′, IV′′-a, IV′′-b, IV′′′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e, or VIa, VIb, or VII 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.
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.
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 “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.
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 U.S. Pat. No. 7,014,866; and United States patent publications 20060094744 and 20060079502.
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).
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.
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. D2O, 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.
In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete 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.
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.
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.
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.
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, 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.
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.
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 J D and Zaffaroni A C, U.S. Pat. No. 6,803,031, assigned to Alexza Molecular Delivery Corporation.
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 formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
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.
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 U.S. Pat. Nos. 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.
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.
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.
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.
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.
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.
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.
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.
In another embodiment, the second therapeutic agent is selected from dual serotonin-norepinephrine reuptake inhibitors and alpha2-delta subunit calcium channel modulators.
Examples of dual serotonin-norepinephrine reuptake include, but are not limited to, duloxetine, milnacipran, and venlafaxine.
Examples of alpha2-delta subunit calcium channel modulators include, but are not limited to, pregabalin, gabapentin, and prodrugs thereof.
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).
In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term “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 means an amount effective to treat, in a patient in need thereof, abnormal nocturnal sleep or a condition 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. In one embodiment, the amount is an amount effective in the treatment of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, Parkinson's disease, narcolepsy with cataplexy, obstructive sleep apnea syndrome, insomnia including insomnia associated to schizophrenia, sleep initiation and maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with alternating hemiplegia of childhood, sedative abuse, or binge eating disorder.
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 (e.g., including any of the compounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c, IV-d, IV′′, IV′′-a, IV′′-b, IV′, IV′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e, or pharmaceutically acceptable salt thereof/kg of body weight, preferably between about 0.15-1.5 mmol/kg.
In one embodiment, an effective amount of a compound of this invention can range from about 1.9 mmol to about 65 mmol of a compound of Formula I (e.g., including any of the compounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c, IV-d, IV′′, IV′′-a, IV′′-b, IV′′′, IV′′′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e, or a pharmaceutically acceptable salt thereof per kg of body weight, preferably between about 0.02 and about 1.5 mmol/kg. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 0.5 g to less than 9 g, such as from about 0.5 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 1 g to less than 9 g, such as from about 1 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 2 g to less than 9 g, such as from about 2 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 3 g to less than 9 g, such as from about 3 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g.
In the embodiments of the invention where the compound is a compound of formula VIa, VIb, or VII VIa, VIb, or VII, an effective amount of compound can range from about 0.015-0.8 mmol or pharmaceutically acceptable salt thereof/kg of body weight.
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 once daily. For example, the compound or its sodium salt may be administered orally in an amount disclosed once daily. As another example, the compound or its sodium salt may be administered orally in one-half of an amount disclosed hereinabove two times daily.
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.
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.
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
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 of this invention, including a compound of Formula I (e.g., including any of the compounds of formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c and IV-d, IV′′, IV′′-a, IV′′-b, IV′′′, IV′′′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or Formula V including Va-e, or a composition of this invention.
In one embodiment of the method, the effective amount of the compound of this invention can range from about 1.9 mmol to about 65 mmol of a compound of Formula I (e.g., including any of the compounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c, IV-d, IV′′, IV′′-a, IV′′-b, IV′′′, IV′′′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e, or a pharmaceutically acceptable salt thereof per kg of body weight, preferably between about 0.02 and about 1.5 mmol/kg. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 0.5 g to less than 9 g, such as from about 0.5 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 1 g to less than 9 g, such as from about 1 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 2 g to less than 9 g, such as from about 2 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In one embodiment, the effective amount of the compound or its sodium salt ranges from about 3 g to less than 9 g, such as from about 3 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5 g.
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 a method to selectively inhibit polysynaptic reflexes in a patient without significantly affecting monosynaptic reflexes.
In another embodiment, the invention provides a method of treating excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, Parkinson's disease, narcolepsy with cataplexy, obstructive sleep apnea syndrome, insomnia including insomnia associated to schizophrenia, sleep initiation and maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with alternating hemiplegia of childhood, sedative abuse, or binge Eating Disorder.
In one particular embodiment, the method of this invention is used to improve nocturnal sleep in a patient in need thereof.
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).
In another embodiment, any of the above methods of treatment comprises the 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 (e.g., including any of the compounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c and IV-d, IV′′, IV′′-a, IV′′-b, IV′′′, IV′′′-a, IV′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e 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.
In one embodiment, the second therapeutic agent is a dual serotonin-norepinephrine reuptake selected from duloxetine, milnacipran, and venlafaxine.
In another embodiment, the second therapeutic agent is an alpha2-delta subunit calcium channel modulators selected from pregabalin, gabapentin, and prodrugs thereof.
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.
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 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.
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.
Pharmaceutical Kits
The present invention also provides kits for use in treating abnormal nocturnal sleep, and conditions beneficially treated by improving nocturnal sleep, such as narcolepsy, and fibromyalgia. In one embodiment, the invention provides a kit for use in treating excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, Parkinson's disease, narcolepsy with cataplexy, obstructive sleep apnea syndrome,
insomnia including insomnia associated to schizophrenia,
sleep initiation and maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with alternating hemiplegia of childhood, sedative abuse, or binge eating disorder.
These kits comprise (a) a pharmaceutical composition comprising a compound of Formula I (e.g., including any of the compounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c and IV-d, IV′′, IV′′-a, IV′′-b, IV′′′, IV′′′-a, IV′′′-c and IV′′′-d herein) or Formula B, B-II, (S)-B-II or B-III, or V including Va-e, or VIa, VIb, or VII or a pharmaceutically acceptable salt thereof, such as a sodium salt, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition.
EXAMPLES
Example 1
Synthesis of Sodium 2,2-d2-4-Hydroxybutanoate




Step 1. 3,3-d2-Dihydrofuran-2(3H)-one (7)
Lactone 7 was prepared according to the procedure for the synthesis of lactone 4 (see Example 4) employing dihydrofuran-2(3H)-one to afford 3,3-dideuterodihydrofuran-2(3H)-one (7) as a clear oil (4.14 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 4.35 (t, J=7.1 Hz, 2H), 2.25 (t, J=7.1 Hz, 2H).
Step 2. Sodium 2,2-d2-4-Hydroxybutanoate
The final product was prepared according to the procedure for the preparation of sodium 3,3-d2-4-hydroxybutanoate (see Example 2) employing lactone 7 to afford sodium 2,2-dideutero-4-hydroxybutanoate as a white solid (2.54 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 3.38 (t, J=5.8 Hz, 2H), 1.55 (t, J=5.8 Hz, 2H).
Example 2
Synthesis of Sodium 3,3-d2-4-Hydroxybutanoate




Step 1. 3,3-d2-4-methoxy-4-oxobutanoic acid (1)
A sample of 4-methoxy-4-oxobutanoic acid (4.44 g, 33.6 mmol) was dissolved in CH3OD (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 D2O (Cambridge Isotope Laboratories, 99 atom % D) and acidified to pH=2 with conc. 12N DCl (Aldrich, 99 atom % D) then extracted with EtOAc (3×100 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%). 1H NMR (CDCl3, 400 MHz) δ 3.70 (s, 3H), 2.68 (s, 2H).
Step 2. 4,4-d2-dihydrofuran-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 (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated under 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%). 1H NMR (CDCl3, 400 MHz) δ 4.33 (s, 2H), 2.47 (s, 2H).
Step 3. Sodium 3,3-d2-4-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 as a white solid (2.75 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 6.17 (s, 1H), 3.38 (s, 2H), 2.01 (s, 2H).
Example 3
Synthesis of Sodium 2,2,3,3-d4-4-hydroxybutanoate




Step 1. 2,2,3,3-d4-4-methoxy-4-oxobutanoic acid (5)
A solution of succinic anhydride-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%). 1H NMR (CDCl3, 400 MHz) δ 3.70 (s, 3H).
Step 2. 3,3,4,4-d4-dihydrofuran-2(3H)-one (6)
Lactone 6 was prepared according to the procedure for the synthesis of lactone 4 (see Example 4) employing carboxylic acid 5 to afford 3,3,4,4-tetradeuterodihydrofuran-2(3H)-one (6) as a clear oil (1.38 g, 61%). 1H NMR (CDCl3, 400 MHz) δ 4.33 (s, 2H).
Step 3. Sodium 2,2,3,3-d4-4-hydroxybutanoate
The final compound was prepared according to the procedure for the preparation of sodium 3,3-d2-4-hydroxybutanoate (see Example 2) employing lactone 6 to afford sodium 2,2,3,3-tetradeutero-4-hydroxybutanoate as a white solid (1.77 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 3.38 (s, 2H).
Example 4
Synthesis of Sodium 2,2,4,4-d4-4-hydroxybutanoate (IVb sodium salt)




Step 1. 5,5-d2-dihydrofuran-2(3H)-one (3)
A suspension of LiAlD4 (1.27 g, 30.0 mmol, Cambridge Isotope Laboratories, 98 atom % D) in THF (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 THF (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 (5×50 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%). 1H NMR (CDCl3, 400 MHz) δ 2.48 (t, J=7.8 Hz, 2H), 2.24 (t, J=8.3 Hz, 2H).
Step 2. 3,3,5,5-d4-dihydrofuran-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, Aldrich, 99 atom % D) and 12N DCl (2 drops) and subsequently concentrated under reduced pressure. The resulting residue was diluted with CH2Cl2, filtered through Celite®, and concentrated under reduced pressure. The resulting residue was then dissolved in D2O (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 CH2Cl2 (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated under 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%). 1H NMR (CDCl3, 400 MHz) δ 2.23 (s, 2H).
Step 3. Sodium 2,2,4,4-d4-4-hydroxybutanoate (IVb sodium salt)
The final product was prepared according to the procedure for the preparation of sodium 3,3-d2-4-hydroxybutanoate (see Example 2) employing lactone 4 to afford sodium 2,2,4,4-d4-4-hydroxybutanoate as a white solid (1.57 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 1.53 (s, 2H).
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. Pat. No. 5,250,696.
Example 5
Synthesis of Exemplary Acids and Esters of Formula IV
Exemplary compounds 51-59 and 61, the structures of which are shown below, may be prepared as discussed in the following examples. In structures 51-59 and 61, “Me” is CH3; “Et” is ethyl; “t-Bu” is t-butyl; “Bn” is benzyl; “Ac” is CH3CO; and any atom not designated as deuterium is present at its natural isotopic abundance.




a) 4-(tert-butoxy)-3,3-dideutero-4-oxobutanoic acid (57)
A sample of 4-(tert-butoxy)-4-oxobutanoic acid (2.00 g, 11.5 mmol) was added to a solution of potassium tert-butoxide (1.54 g, 13.8 mmol) in tBuOD (45 mL, Cambridge Isotope Labs, 99 atom % D). The reaction stirred at reflux for 15 hours then was cooled to room temperature and quenched with acetic acid-OD (1.50 mL, Aldrich, 99 atom % D) and concentrated under reduced pressure. The resulting residue was diluted with 1N HCl and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 4-(tert-butoxy)-3,3-dideutero-4-oxobutanoic acid (57) as a white solid (1.48 g, 73%). MS (ESI) 175.1 [(M−H)].
b) tert-butyl-2,2,4,4-tetradeutero-4-hydroxybutanoate (58)
To a solution of 57 (1.48 g, 8.41 mmol) and 4-methyl morpholine (925 μL, 8.41 mmol) in THF (10 mL) at 0° C. was added isobutyl cholorformate (1.10 mL, 8.41 mmol) dropwise. The resulting slurry stirred at room temperature for 30 minutes then was filtered through Celite® rinsing with additional THF (3×5 mL). The clear solution was then cooled to 0° C. and a solution of sodium borodeuteride (530 mg, 12.6 mmol, Cambridge Isotope Labs, 99 atom % D) in D2O (15 mL, Cambridge Isotope Labs, 99 atom % D) was added dropwise. The reaction was immediately diluted with D2O (50 mL) and stirred for 5 minutes. The reaction was then diluted with 1N HCl (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to afford tert-butyl-2,2,4,4-tetradeutero-4-hydroxybutanoate (58) as a clear oil (1.26 g, 91%) which was used without further purification.
c) Tert-butyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (59)
To a solution of 58 (1.26 g, 7.68 mmol), 4-methyl morpholine (1.69 mL, 15.4 mmol) and DMAP (94 mg, 0.77 mmol) in THF (25 mL) was added acetic anhydride (872 μL, 9.22 mmol). The reaction stirred for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated to afford tert-butyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (59) as a clear oil (1.40 g, 90%). 1H NMR (CDCl3, 400 MHz) δ 2.04 (s, 3H), 1.89 (s, 2H), 1.44 (s, 9H).
d) 4-Acetoxy-2,2,4,4-tetradeuterobutanoic acid (61)
To a solution of 59 (1.40 g, 6.80 mmol) in DCM (8 mL) was added trifluoroacetic acid-OD (8 mL, Cambridge Isotope Labs, 99.5 atom % D). The reaction stirred for 2 hours then was concentrated to afford 4-acetoxy-2,2,4,4-tetradeuterobutanoic acid (61) as a clear oil (1.00 g, 98%). MS (ESI) 149.1 [(M−H)−].




e) (S)-1-Methoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (51)
To a solution of 61 (166 mg, 1.11 mmol), (S)-methyl lactate (212 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated. Residual (S)-methyl lactate and N,N-dimethylacetamide were then removed under reduced pressure to afford (S)-1-methoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (51) as a clear oil (162 mg, 62%). 1H NMR (CDCl3, 400 MHz) δ 5.10 (q, J=7.1 Hz, 1H), 3.74 (s, 3H), 2.05 (s, 3H), 1.96 (br s, 2H), 1.48 (d, J=7.1 Hz, 3H). MS (ESI) 237.2 [(M+H)+].




f) (S)-1-Ethoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (52)
To a solution of 61 (166 mg, 1.11 mmol), (S)-ethyl lactate (255 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated under reduced pressure. Residual (S)-ethyl lactate and N,N-dimethylacetamide were then removed under reduced pressure to afford (S)-1-ethoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeutero-butanoate (52) as a clear oil (176 mg, 63%). 1H NMR (CDCl3, 400 MHz) δ 5.07 (q, J=7.1 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.05 (s, 3H), 1.97 (br s, 2H), 1.48 (d, J=7.1 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H). MS (ESI) 251.1 [(M+H)+].




g) (S)-1-Benzyloxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (53)
To a solution of 61 (166 mg, 1.11 mmol), (S)-benzyl lactate (357 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated under reduced pressure. Residual N,N-dimethylacetamide was then removed under reduced pressure and the resulting material was purified via column chromatography (SiO2, 0-40% EtOAc/heptanes) to afford (S)-1-benzyloxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeutero-butanoate (53) as a clear oil (87 mg, 25%). 1H NMR (CDCl3, 400 MHz) δ 7.40-7.30 (m, 5H), 5.24-5.10 (m, 3H), 2.04 (s, 3H), 1.94 (br s, 2H), 1.50 (d, J=7.1 Hz, 3H). MS (ESI) 313.1 [(M+H)+].




h) 2-Methoxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (54)
To a solution of 61 (166 mg, 1.11 mmol), methyl glycolate (171 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated. Residual methyl glycolate and N,N-dimethylacetamide were then removed under reduced pressure to afford 2-methoxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (54) as a clear oil (183 mg, 74%). 1H NMR (CDCl3, 400 MHz) δ 4.63 (s, 2H), 3.76 (s, 3H), 2.05 (s, 3H), 1.98 (br s, 2H). MS (ESI) 223.1 [(M+H)+].




i) 2-Ethoxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (55)
To a solution of 61 (166 mg, 1.11 mmol), ethyl glycolate (210 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated. Residual ethyl glycolate and N,N-dimethylacetamide were then removed under reduced pressure to afford 2-ethoxy-2-oxoethyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (55) as a clear oil (176 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 4.61 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 2.05 (s, 3H), 1.98 (br s, 2H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI) 237.3 [(M+H)+].




j) 2-Benzyloxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (56)
To a solution of 61 (166 mg, 1.11 mmol), benzyl glycolate (315 μL, 2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) and N,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol) followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at room temperature for 15 hours then was diluted with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with 1N HCl, dried (Na2SO4), filtered and concentrated. Residual N,N-dimethylacetamide was then removed under reduced pressure and the resulting material was purified via column chromatography (SiO2, 0-40% EtOAc/heptanes) to afford 2-benzyloxy-2-oxoethyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (56) as a clear oil (163 mg, 49%). 1H NMR (CDCl3, 400 MHz) δ7.41-7.32 (m, 5H), 5.20 (s, 2H), 4.67 (s, 2H), 2.04 (s, 3H), 1.97 (br s, 2H). MS (ESI) 299.2 [(M+H)+].
Example 6
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.
Study Design:























Dosing










Solution
Dosing

Sampling


Treatment
Test
Dosing
Animals
Dose
Conc.
Volume

Time


Group
Compound
Route
N =
mg/kg
mg/mL
mL/kg
Vehicle
Points







1
4-
IV
4
200
40
5
SWFI
Predose,



hydroxybutyric






2, 7, 15, 30



acid sodium salt






min, 1, 2,










and 4 hours


2

PO
4
200
40
5
SWFI
Predose,










5, 15, 30










min, 1, 2, 4,










and 6 hours


3
IV-b sodium
IV
4
200
40
5
SWFI
Predose,



salt






2, 7, 15, 30










min, 1, 2,










and 4 hours


4

PO
4
200
40
5
SWFI
Predose,










5, 15, 30










min, 1, 2, 4,










and 6 hours


5
2,2-
IV
4
200
40
5
SWFI
Predose,



Dideutero-4-






2, 7, 15, 30



hydroxybutanoic






min, 1, 2,



acid, sodium salt






and 4 hours


6

PO
4
200
40
5
SWFI
Predose,










5, 15, 30










min, 1, 2, 4,










and 6 hours





SWFI: Sterile water for injection






Sampling Procedure:

6.1 Sampling













Frequency:
See Study Design


Collection:
Blood samples were collected via the jugular cannula,



placed into chilled tubes containing K2EDTA as the



anticoagulant, and kept on ice until centrifugation in a



refrigerated centrifuge.


Preparation
The samples were centrifuged at a temperature of 4° C., at


and Storage:
3,000xg, for 5 minutes. 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):


















TABLE 2













CL





Dose


Tmax
Cmax
Cmina
AUC0-∞
(mL/min/
Vz
t1/2b


Compd ID
(mg/kg)
ROA
Rat #
(hr)
(ug/mL)
(ug/mL)
(hr*ug/mL)
kg)
(L/kg)
(hr)

























4-hydroxy-
200
IV
Mean
—
—
 8′
427
8
0.2
0.26


butyric


SD
—
—
2
30
1
0
0.02


acid,

PO
Mean
0.5
150
2
170
—

0.61


sodium


SD
0
45
1
50
—

0.04


salt


% F



40%


IV-b,
200
IV
Mean


76 
651
5
0.3
0.63


sodium


SD


16 
28
0
0
0.09


salt

PO
Mean
0.63
151
5
260


0.94





SD
0.25
73
2
127


0.75





% F



40%


2,2-
200
IV
Mean


19 
476
7
0.2
0.33


Dideutero-


SD


19 
76
1
0.1
0.12


4-hydroxy-

PO
Mean
0.63
153
1
193


0.59


butanoic






(+1.1X)


acid,


SD
0.25
9
0
34


0.14


sodium salt


% F



41%





a2 hr for IV and 4 hr for PO


bcalculated up to 2 hr for IV and 4 hr for PO






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 AUC0-∞ and of t1/2 for the two compounds.
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.

## Claims

1. A pharmaceutical composition comprising an effective amount of a compound of Formula IV-a, wherein the compound of Formula IV-a is represented by the following structural formula:




or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

2. The composition of claim 1, additionally comprising a second therapeutic agent selected from the group consisting of a dual serotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunit calcium channel modulator.

3. The composition of claim 2, wherein the second therapeutic agent is selected from the group consisting of duloxetine, milnacipran, venlafaxine, pregabalin, gabapentin, and a prodrug thereof.

4. The composition of claim 1 wherein the composition is pyrogen-free.

5. The composition of claim 1 wherein the pharmaceutically acceptable salt is a sodium salt.

6. The composition of claim 5 where the compound has an isotopic abundance at each position indicated as “D” of at least 75%.

7. The composition of claim 6 where the compound has an isotopic abundance at each position indicated as “D” of at least 95%.

8. The composition of claim 5 where the compound has an isotopic abundance at each position indicated as “D” of at least 82.5%.

9. The composition of claim 5 where the compound has an isotopic abundance at each position indicated as “D” of at least 90%.

10. The composition of claim 5 where the compound has an isotopic abundance at each position indicated as “D” of at least 97%.

11. A method of treating a disease or disorder selected from the group consisting of excessive daytime sleepiness (EDS), narcolepsy with cataplexy, and obstructive sleep apnea syndrome, comprising the step of administering to a patient in need of such treatment an effective amount of the composition of claim 1.

12. The method of claim 11 comprising the additional step of administering to the patient in need thereof a second therapeutic agent selected from the group consisting of a dual serotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunit calcium channel modulator.

13. The method of claim 12, wherein the second therapeutic agent is selected from the group consisting of duloxetine, milnacipran, venlafaxine, pregabalin, gabapentin, and a prodrug thereof.