Gamma-hydroxybutyrate delivery compounds and processes for making and using same - Patents.com

Abstract

Disclosed are compounds comprising chemically modified gamma-hydroxybutyrate (GHB) having the structure of formula I and salts of such compounds (GHB delivery compounds and their salts). Also disclosed are compositions comprising at least one GHB delivery compound, or its salt, methods of making such compounds, and methods of using such GHB delivery compounds and compositions. Also disclosed are methods of treatment. Another aspect of the present technology is at least one kit comprising a therapeutically effective amount of any one of the disclosed GHB delivery compounds or its pharma- ceutically acceptable salts (said compounds being present in unit dosage form) and instructions for use. TIFF2025513295000101.tif2033

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 333,391, filed April 21, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] background Gamma-hydroxybutyrate (or γ-hydroxybutyrate "GHB") is a fast-acting CNS (central nervous system) depressant and naturally occurring neurotransmitter. Pharmaceutical salts of GHB, including sodium oxyvert (XYREM®) and a mixture of calcium, magnesium, potassium, and sodium oxyvert (XYWAV®), have been approved by the U.S. FDA for the treatment of narcolepsy and idiopathic hypersomnia. Without wishing to be bound by any particular theory, it is believed that these pharmaceutical preparations act primarily by producing a sedative effect and improving sleep consolidation, thereby resulting in better nighttime rest and reduced daytime sleepiness. However, high doses of the drug are required, in part due to suboptimal pharmacokinetics and oral bioavailability. Thus, currently approved drugs require patients to administer the drug split into two doses. The first dose is taken at bedtime, and the second dose is typically taken about 2.5 to about 4 hours later. As a result, there is a need for treatment options with improved pharmacokinetics (e.g., including higher oral bioavailability and / or longer duration of action). Summary of the Invention [Means for solving the problem]

[0003] overview The present technology provides one or more compounds that deliver GHB to a human or animal subject. In some embodiments, these compounds have increased bioavailability, a longer duration of action, or both, when compared to sodium oxyvert (NaGHB). In other embodiments, based on their improved bioavailability, the compounds of the present technology can be administered to a human or animal subject at a therapeutically equivalent lower molar dose when compared to NaGHB. These GHB delivery compounds are prodrugs or precursors of gamma-hydroxybutyrate, salts of such compounds, and combinations thereof. In some embodiments, the prodrugs of GHB of the present invention / technology described herein, 2-hydroxytetrahydrofuran (2-OH-THF), and 1,4-butanediol (BD), provide similar or improved oral bioavailability of GHB, similar or extended release of GHB, and / or less or no sodium content compared to NaGHB. When administered as intended, the compounds of the presently described and claimed technology provide therapeutic plasma concentrations of GHB in a human or animal subject.

[0004] In at least one embodiment of the present technology, a compound of formula I: [ka]

[0005] wherein L is hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, M is selected from the group consisting of amino acids, peptides, salts thereof, and combinations thereof; M is hydrogen, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohols, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetra ... lytol, polyglycitol, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl,or a pharma- ceutically acceptable salt thereof, is provided, which is selected from the group consisting of cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and combinations thereof.

[0006] Another embodiment of the present technology is a compound of formula II: [ka]

[0007] wherein G is S or O and R is [ka] , hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, a R is selected from the group consisting of arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and combinations thereof; 1 includes compounds having the structure shown in which is an amino acid or a peptide (e.g., a dipeptide or tripeptide) or a pharma- ceutically acceptable salt thereof.

[0008] Another aspect of the present technology is a compound of formula III: [ka]

[0009] wherein Z is gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl or a pharmaceutically acceptable salt thereof) or a compound having the structure:

[0010] Another embodiment of the present technology is a compound of formula IV: [ka]

[0011] (In the formula, Y 1 and Y 2 are hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, a ... and combinations thereof).

[0012] Another embodiment of the present technology is a compound of formula V: [ka]

[0013] (wherein M is hydrogen, 1,4-butanediol, 2-hydroxytetrahydrofuran, gamma-hydroxybutyrate, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, gamma-aminobutyric acid, phosphate, sulfate, sulfamate, alkenyl, alkenyl Aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, aryla ammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof,and combinations thereof), or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments of the technology described herein, the amino acids in Formulas I-V are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and / or salts thereof. In some embodiments, the peptide may be a dipeptide or a tripeptide.

[0015] In some embodiments, at least one compound of the technology described herein has the structure of formula I, [ka] [ka] [ka] is selected from.

[0016] In some embodiments, at least one compound of the technology described herein has the structure of formula II: [ka] [ka] is selected from.

[0017] In some further embodiments, one or more compounds of the technology described herein having the structure of formula III: [ka] [ka] is selected from.

[0018] In some still further embodiments, at least one compound of the technology described herein has the structure of formula IV: [ka] is selected from.

[0019] In some further embodiments, one or more compounds of the technology described herein having the structure of formula V: [ka] is selected from.

[0020] Another aspect of the present technology includes at least one composition comprising at least one of the disclosed GHB delivery compounds or compositions, or pharma- ceutically acceptable salts of the aforementioned compound(s) or compositions. In a further aspect of the present technology, those skilled in the art should recognize that compositions comprising unmodified GHB / NaGHB in combination with one or more of the GHB delivery compounds described and claimed herein are also contemplated.

[0021] In a further aspect of the present technology, at least one method is provided for preventing or treating sleep disorder in a subject in need of such prevention or treatment, comprising administering to the subject a composition comprising any one of the GHB delivery compounds of the present disclosure or the pharma- ceutically acceptable salts of the aforementioned compounds.In some embodiments, the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treating a neurodegenerative disease or disorder with a drug or therapeutic compound.In a further aspect, the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and / or idiopathic parkinsonism.

[0022] In some embodiments of at least one of the methods of the present technology, the composition further comprises amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, and solriamfetol, or a combination thereof.

[0023] In another embodiment, the sleep disorder is excessive daytime sleepiness associated with central hypersomnia, obstructive sleep apnea, or shift work disorder. In a further embodiment, the central hypersomnia is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, and / or insufficient sleep syndrome.

[0024] In some embodiments, one or more compositions of the present technology further comprise one or more additives, wherein the additives are selected from the group comprising anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and / or combinations thereof.

[0025] In some embodiments, the compositions of the present technology have a dosing regimen that is once a day. In other embodiments, the compositions of the present technology have a dosing regimen that is about twice a day.

[0026] In some embodiments, the compositions of the present technology are administered orally to a human or animal subject.

[0027] Another aspect of the present technology is at least one kit comprising a therapeutically effective amount of any one of the disclosed GHB delivery compounds or pharma- ceutically acceptable salts thereof, said compounds being present in a unit dosage form, and instructions for use thereof.

[0028] In some embodiments, the unit dosage form is selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, troches, lozenges, oral powders, solutions, liquids, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, buccal tablets, and / or suppositories. In further embodiments, the unit dosage form is selected from the group of transdermal patches, intranasal sprays, intramuscular injections, depot injections, subcutaneous injections, and / or intravenous injections. In one embodiment, the unit dosage form can be packaged as a blister pack or similar packaging or system for delivery of unit dosages.

[0029] In another embodiment, one or more kits of the technology of the present invention further comprise additional therapeutic compounds.In some embodiments, the additional therapeutic compounds are selected from the group comprising amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, and / or solriamfetol, and combinations thereof.In further embodiments, the additional therapeutic compounds are present in unit dosage form. In still further aspects, the unit dosage form is a sublingual tablet, gummy, chewable tablet, fast dissolving tablet, tablet, capsule, caplet, troche, lozenge, oral powder, water, liquid, thin strip, orally disintegrating film (OTF), oral strip, syrup, suspension, slurry, sachet, buccal tablet, and / or suppository.

[0030] In some embodiments, the GHB delivery compound(s) are in a liquid dosage form and the additional therapeutic compound(s) are in an oral powder or sachet form. In other embodiments, the GHB delivery compound(s) and the additional therapeutic compound(s) may be in a combination of different dosage forms, including, but not limited to, a capsule and a thin film, or a liquid and a tablet.

[0031] In a further embodiment, the additional therapeutic compound is added to a liquid dosage form of the GHB delivery compound prior to administration.

[0032] In some embodiments, the kit includes instructions for use. In further embodiments, the instructions include instructions for administration of at least one of the GHB delivery compound, the additional therapeutic compound, and / or a salt thereof, or a combination thereof.

[0033] Another aspect of the present technology is an oral formulation comprising a therapeutically effective dose (eg, for the treatment of a sleep disorder) of any one of the disclosed GHB delivery compounds, or a pharma- ceutically acceptable salts thereof.

[0034] In some embodiments, the oral formulation further comprises one or more additives, wherein the additives are anti-adhesive agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and / or combinations thereof.In another embodiment, the therapeutically effective dose is present in a unit dosage form.In a further embodiment, the unit dosage form is a sublingual tablet, a gummy, a chewable tablet, a fast-dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a water, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, and / or an oral tablet.

[0035] In some embodiments, the oral formulation(s) have a dosing regimen that is about twice daily. In some embodiments, the oral formulation(s) have a dosing regimen that is about once daily. In other embodiments, the oral formulation(s) are orally administered to a human or animal subject.

[0036] In some embodiments, the pharma- ceutically acceptable salt is an acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, Tolate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, acetate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, ede nitrate, ethyl sulfate, furanate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate The salts of the present invention include, but are not limited to, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and / or mixtures thereof.

[0037] In other embodiments and aspects of the present technology, the pharma- ceutically acceptable salt may be an amphetaminium or celdexmethylphenidate.

[0038] Another embodiment of the present technology comprises at least one method for preventing or treating a sleep disorder in a subject in need thereof, comprising: [ka] or a pharma- ceutically acceptable salt of said compound to said subject.

[0039] In some embodiments of the method, the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treating the neurodegenerative disease or disorder with a drug or therapeutic compound.In another embodiment, the neurodegenerative disease or disorder is Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0040] In another embodiment of the method, the composition further comprises amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, and solriamfetol, or a combination thereof.

[0041] In another embodiment, the sleep disorder is excessive daytime sleepiness associated with central hypersomnia, obstructive sleep apnea, or shift work disorder. In another embodiment, the central hypersomnia disorder is narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, insufficient sleep syndrome, and / or combinations thereof.

[0042] In some embodiments of the method, the composition further comprises one or more additives, wherein the additives are anti-adhesive agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and / or combinations thereof.In another embodiment, the composition has a dosing regimen that is about twice a day.In another embodiment, the composition has a dosing regimen that is once a day.In some embodiments, the composition is orally administered to a human or animal subject.

[0043] Another aspect of the present technology is a kit comprising any one of the compositions of the present disclosure in a therapeutically effective amount, wherein said composition is present in a unit dosage form.In an aspect, the unit dosage form is sublingual tablet, gummy, chewable tablet, fast-dissolving tablet, tablet, capsule, caplet, troche, lozenge, oral powder, water, liquid, thin strip, oral disintegrating film (OTF), oral strip, syrup, suspension, sachet, slurry, oral tablet, and / or suppository.In one aspect, the unit dosage form can be packaged as blister pack or similar package or system for delivery of unit dosage.

[0044] In another embodiment, the kit further comprises additional therapeutic compound.In a further embodiment, the additional therapeutic compound is amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, and / or solriamfetol, and combinations thereof.In yet a further embodiment, the additional therapeutic compound is present in unit dosage form.

[0045] In another embodiment, the unit dosage form is a sublingual tablet, gummy, chewable tablet, fast dissolving tablet, tablet, capsule, caplet, troche, lozenge, oral powder, solution, liquid, thin strip, orally disintegrating film (OTF), oral strip, syrup, suspension, sachet, slurry, buccal tablet, and / or suppository.

[0046] In another embodiment, the pharma- ceutically acceptable salt is an acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, ester, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, acetate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate ester, ethyl sulfate, furanate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisylate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate , salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and / or mixtures thereof.

[0047] In other embodiments, the pharma- ceutically acceptable salt may be amphetaminium or celdexmethylphenidate.

[0048] Various aspects of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings. [Brief description of the drawings]

[0049] [Figure 1] FIG. 1 shows the metabolic pathways of 2-hydroxytetrahydrofuran and 1,4-butanediol to gamma-hydroxybutyrate.

[0050] [Diagram 2] FIG. 2 shows a comparison of the pharmacokinetic profiles of NaGHB and 3CPr O-(ethoxycarbonyl)-GHB (4a) following oral administration in rats (all doses were the molar equivalent of 70 mg / kg NaGHB).

[0051] [Diagram 3] FIG. 3 shows a comparison of the pharmacokinetic profiles of NaGHB and 3CPr O-(ethoxycarbonyl)-GHB (4a) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0052] [Figure 4] FIG. 4 shows a comparison of the pharmacokinetic profiles of NaGHB and 3CPr sulfamate (33) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0053] [Diagram 5] FIG. 5 shows a comparison of the pharmacokinetic profiles of NaGHB and (2-THF) salicylate (34b) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0054] [Figure 6]FIG. 6 shows a comparison of the pharmacokinetic profiles of NaGHB with O-(2-THF)-glutaric acid (35) and bis(2-THF) malonate (41c) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0055] [Figure 7] FIG. 7 shows a comparison of the pharmacokinetic profiles of NaGHB with O-(2-THF)O-(ethoxycarbonyl)-GHB (38) and bis(2-THF)maleate (39) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0056] [Figure 8] FIG. 8 shows a comparison of the pharmacokinetic profiles of NaGHB, bis(2-THF) glutarate (41a), and bis(2-THF) succinate (41b) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0057] [Figure 9] FIG. 9 shows a comparison of the pharmacokinetic profiles of NaGHB and bis(2-THF) adipate (41d) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0058] [Figure 10] FIG. 10 shows a comparison of the pharmacokinetic profiles of NaGHB and O-(2-THF)-GHB (58) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0059] [Figure 11]FIG. 11 shows a comparison of the pharmacokinetic profiles of NaGHB with 4-hydroxybutyl(O-ethoxycarbonyl)-GHB (63a) and 4-hydroxybutyl-O-acetyl-GHB (63b) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0060] [Figure 12] FIG. 12 shows a comparison of the pharmacokinetic profiles of NaGHB and O-(2-THF)BD(66) following oral administration in rats (all doses were the molar equivalent of 80 mg / kg NaGHB).

[0061] [Figure 13] FIG. 13 shows a comparison of the pharmacokinetic profiles of NaGHB and O-(2-THF)BD(66) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0062] [Figure 14] FIG. 14 shows a comparison of the pharmacokinetic profiles of NaGHB and glycerol tris-O-(2-THF) ether (69a) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0063] [Figure 15] FIG. 15 shows a comparison of the pharmacokinetic profiles of NaGHB with erythritol tetrakis-O-(2-THF) ether (69b) and xylitol pentakis-O-(2-THF) ether (69c) following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0064] [Figure 16] FIG. 16 shows a comparison of the pharmacokinetic profiles of NaGHB and 2-OH-THF following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0065] [Figure 17] FIG. 17 shows a comparison of the pharmacokinetic profiles of NaGHB with GBL and BD following oral administration in rats (all doses were the molar equivalent of 100 mg / kg NaGHB).

[0066] [Figure 18] FIG. 18 shows a comparison of the pharmacokinetic profiles of NaGHB and O-(ethoxycarbonyl)-GHB following oral administration in rats (all doses were the molar equivalent of 80 mg / kg NaGHB). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] Detailed Description The present technology generally describes novel compounds and compositions that deliver gamma-hydroxybutyrate ("GHB") to human or animal subjects. In some embodiments, these compounds have increased bioavailability, or longer duration of action, or both, when compared to sodium gamma-hydroxybutyrate ("NaGHB"). In further embodiments, due to their increased bioavailability, the compounds of the present technology can be administered to human or animal subjects at therapeutically equivalent lower molar doses when compared to NaGHB. These GHB delivery compounds are prodrugs or precursors of gamma-hydroxybutyrate, their salts, their other derivatives, and combinations thereof. The present technology also generally relates to methods and kits for making these novel compounds and compositions, including GHB delivery compounds.

[0068] It should be understood by those of skill in the relevant art that the present disclosure is not limited to the particular methodology, protocols, and reagents described herein, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosure or the appended claims.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described herein belong.

[0070] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. These articles refer to one or more than one (i.e., at least one). The term "and / or" means any one or more of the items in the list connected by "and / or." As an example, "x and / or y" means any element of the 3-element set {(x), (y), (x,y)}. In other words, "x and / or y" means "one or both of x and y." As another example, "x, y, and / or z" means any element of the 7-element set {(x), (y), (z), (x,y), (x,z), (y,z), (x,y,z)}. In other words, "x, y, and / or z" means "one or more of x, y, and z."

[0071] The term "about" when used in conjunction with numerical values ​​throughout this specification and claims indicates an interval of accuracy known and acceptable to those of skill in the art. Typically, such an interval of accuracy is + / - 10%.

[0072] When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed in ranges can assume any specific value or subrange within the stated ranges in different embodiments of the present disclosure, down to one-tenth of the unit of the lower limit of said range, unless the context clearly indicates otherwise.

[0073] The term "exemplary" means serving as a non-limiting example, instance, or illustration. As used herein, the words "eg," and "for example" highlight a list of one or more non-limiting aspects, examples, instances, or illustrations.

[0074] Use of the terms "gamma-hydroxybutyrate," "γ-hydroxybutyric acid," or "GHB" are synonymous and include salt forms thereof.

[0075] Use of the term "GHB delivery compound" refers to compounds configured to deliver GHB to a human or animal subject. In some embodiments, after administration, these compounds will be converted to GHB in the body.

[0076] In some aspects, the GHB delivery compound contains one or more chiral centers. In some embodiments, these chiral centers are part of the ligands and / or linkers attached to, for example, GHB, 2-OH-THF, or 1,4-butanediol, resulting in a chiral GHB delivery compound. In further aspects, the compositions of these chiral GHB delivery compounds contain racemic mixtures. In other aspects, the compositions containing GHB delivery compounds are not racemic mixtures. In still further aspects, the compositions containing one or more chiral GHB delivery compounds can be optically active mixtures, racemic mixtures, single stereoisomers, single enantiomers, mixtures of stereoisomers, mixtures of enantiomers, or combinations thereof.

[0077] The term "oxoacid" (i.e., oxyacid, oxygen acid, oxy acid, oxyacid, oxacid) refers to a class of compounds that contain oxygen, at least one other element, and at least one hydrogen bonded to the oxygen and produce a conjugate base by loss of a positive hydrogen ion(s) (proton).

[0078] "Amino acid" refers to an organic compound that contains both a carboxyl group (-COOH) and an amino group (-NH2), as well as a variable side chain group. The amino acids that can be used in the present technology can be natural, standard, non-standard, unusual, synthetic, and / or essential amino acids, and can be L-amino acids or D-amino acids, or combinations thereof.Examples of amino acids that may be used in practicing the present technology include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, gamma-aminobutyric acid, 6-aminohexanoic acid, sarcosine, carnitine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, Thiocysteine, cystathionine, homocysteine, β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl-alanine, L-abrine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclohexane propyl-1-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2-chlorophenylglycine, 3-guanidino-propionic acid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid, allo-isopropyl These include, but are not limited to, leucine, tert-leucine, 3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioic acid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid, 5-aminovaleric acid, 4-(dimethylamino)cinnamic acid, 2-pyridylalanine (2-Pal), and 3-pyridylalanine (3-Pal).

[0079] As used herein, the term "prodrug" refers to a substance that converts from the inactive form of a drug into an active drug in the body by chemical or biological reaction.In an embodiment of the present technology, the prodrug is, for example, a conjugate of at least one drug (GHB) and at least one ligand.Therefore, in an embodiment of the present technology, the GHB delivery compound is a prodrug.

[0080] As used herein, the term "ligand" refers to a portion of the structure of a GHB delivery compound that is neither GHB nor a GHB precursor component.

[0081] As used herein, the term "precursor" refers to a substance that is converted into another substance by metabolic process or biological reaction in the body.In an embodiment of the present technology, the GHB delivery compound is, for example, a precursor or a conjugate of the precursor and at least one ligand.Therefore, in an embodiment of the present technology, the GHB delivery compound is a prodrug of the precursor.In an embodiment of the present technology, the precursor is converted into GHB in the body ("GHB precursor").In an embodiment of the present technology, the precursor can be, for example, 2-hydroxytetrahydrofuran or 1,4-butanediol.

[0082] As used herein, "3CPr" means 3-carboxypropyl, "BD" means 1,4-butanediol or 1,4-dihydroxybutane, "2-THF" means tetrahydrofuran-2-yl or 2-tetrahydrofuranyl, "2-OH-THF" means 2-hydroxytetrahydrofuran, "Bn" means benzyl, "BOP" means benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, "DCC" means N,N'-dicyclohexylcarbodiimide, "DCM" means dichloromethane, "DIPEA" means N,N-diisopropylethylamine, "DMAP" means 4-dimethylaminopyridine, "DMF" means dimethylformamide, "HATU" means azabenzotriazole tetramethyluranium hexafluorophosphate, "HOBt" means benzotriazole tetramethyluranium hexafluorophosphate, means hydroxybenzotriazole, "HOSu" means N-hydroxysuccinimide, "HPLC" means high performance liquid chromatography, "PPTS" means pyridinium p-toluenesulfonate, "TEA" means trimethylamine, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, and "TLC" means thin layer chromatography.

[0083] Prodrugs are often useful because in some embodiments they may be easier to administer or process than the parent drug. For example, the prodrug may be more bioavailable by oral administration, whereas the parent drug may not. The prodrug may also have improved solubility and / or stability in pharmaceutical compositions than the parent drug. Without wishing to be bound by any particular theory, it is anticipated that in at least one embodiment, the GHB delivery compound is designed to be a prodrug of a precursor that is metabolized to GHB upon release (i.e., when available). In certain embodiments, upon in vivo administration, the prodrug is chemically converted to a biologically, pharma- ceutical, or therapeutically more active form of the compound. In certain embodiments, the prodrug is enzymatically or chemically metabolized by one or more steps or processes to a biologically, pharma- ceutical, or therapeutically more active form of the compound. Also, without wishing to be bound by any particular theory, to produce the prodrug, the pharma- ceutical active compound is modified such that said active compound is released / available upon in vivo administration. Prodrugs are, in certain embodiments, designed to alter the metabolic, pharmacokinetic, or transport properties of a drug in order to reduce side effects or toxicity, increase tolerability, improve tolerance, improve bioavailability and / or water solubility, improve the flavor of the drug, or alter other characteristics or properties of the drug in other different embodiments.

[0084] General Structure

[0085] According to some embodiments, the present technology provides GHB in a compound form. More specifically, the GHB delivery compound comprises at least one organic compound covalently bonded or covalently attached to GHB, 2-OH-THF, and / or 1,4-butanediol. One general structure of the GHB delivery compound of the present technology can be represented by the following general formula I: [ka]

[0086] wherein L comprises at least one member selected from the group comprising hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amino acid, peptide, and / or salts thereof.

[0087] In some embodiments, L comprises at least two of these components, alternatively at least three of these components, alternatively at least four of these components, or alternatively five or more of these components. Particular combinations of L will be readily apparent to one of ordinary skill in the art.

[0088] M is hydrogen, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohols, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, Alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, aryl At least one member selected from the group including carbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and / or combinations thereof.

[0089] In some embodiments, M comprises at least two of these components, alternatively at least three of these components, alternatively at least four of these components, alternatively five or more of these components. Particular combinations of M will be readily apparent to one of ordinary skill in the art.

[0090] Specific compounds of formula I are [ka] [ka] [ka] Including, but not limited to:

[0091] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structure II: [ka]

[0092] (Wherein, G is S or O;

[0093] R is [ka] , hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, aryl R is selected from the group comprising arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and / or combinations thereof; 1 is an amino acid or peptide).

[0094] Specific compounds of formula II are [ka] [ka] Including, but not limited to:

[0095] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula III: [ka]

[0096] wherein Z is gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl , arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, dicarboxylic acid, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and / or combinations thereof.

[0097] In some embodiments, Z comprises at least two of these elements, alternatively at least three of these elements, alternatively at least four of these elements, or alternatively five or more of these elements. Particular combinations of Z will be readily apparent to one of ordinary skill in the art.

[0098] Specific compounds of formula III are [ka] [ka] Including, but not limited to:

[0099] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structure IV: [ka]

[0100] (In the formula, Y 1 and Y 2are hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, aryl and at least one (1) to five (5) times independently selected from the group comprising sulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and / or combinations thereof.

[0101] In some embodiments, Y 1 and / or Y 2Each of Y is independently selected at least 2 times and at least 5 times from the groups / components listed in paragraph

[0100] above. The independent selection is 1 or Y 2 and also, Y 1 and Y 2 In some embodiments, Y 1 and / or Y 2 Each of Y includes, inter alia, at least two of these components, or at least three of these components, or at least four of these components, or five or more of these components. 1 and Y 2 The particular combinations of Y will be readily apparent to one of skill in the art. For example, in one embodiment, 1 contains three components, e.g., O-(2-THF)-GHB-GHB, and Y 2 contains two components, such as, for example, BD-GHB.

[0102] Specific compounds of formula IV are [ka] Including, but not limited to:

[0103] Another structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula V: [ka]

[0104] (wherein M is hydrogen, 1,4-butanediol, 2-hydroxytetrahydrofuran, gamma-hydroxybutyrate, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, gamma-aminobutyric acid, phosphate, sulfate, sulfamate, alkenyl, alkenyl Aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, aryla ammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof,and / or combinations thereof).

[0105] In some embodiments, M comprises at least two of these components, alternatively at least three of these components, alternatively at least four of these components, alternatively at least five of these components, alternatively at least six or more of these components, among others. Particular combinations of M will be readily apparent to one of ordinary skill in the art.

[0106] In further embodiments, M comprises, inter alia, at least one sugar alcohol component and additionally at least one hydroxytetrahydrofuran component, alternatively at least one sugar alcohol component and at least two hydroxytetrahydrofuran components, alternatively at least one sugar alcohol component and at least two hydroxytetrahydrofuran components, alternatively at least one sugar alcohol component and at least three hydroxytetrahydrofuran components, alternatively at least one sugar alcohol component and at least four hydroxytetrahydrofuran components, alternatively at least one sugar alcohol component and at least five hydroxytetrahydrofuran components, alternatively at least one sugar alcohol component and at least six or more hydroxytetrahydrofuran components.

[0107] Specific compounds of formula V are [ka] Including, but not limited to:

[0108] The GHB delivery compound may also be present in a salt form.In some embodiments, the pharma- ceutically acceptable salt of the GHB delivery compound is a single salt or a mixed salt, wherein one or more of the foregoing salts are acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, or the like. ester, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cyano ... Pionate, dichloroacetate, edentate, ethyl sulfate, flurate, fusidate, galactate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate The salts are selected from the group comprising phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and / or mixtures thereof.

[0109] In other embodiments, the pharma- ceutically acceptable salt may be amphetaminium or celdexmethylphenidate.

[0110] The GHB delivery compound of the present technology can be formulated into a composition for administration to humans or animals.The composition can further comprise one or more additives, wherein the additives are selected from the group consisting of anti-adhesive agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and / or combinations thereof.

[0111] Physiological Benefits

[0112] Without wishing to be bound by any particular theory, it is believed that the above-defined GHB delivery compounds of the claimed and herein described technology can be given orally and, when administered, release active GHB or GHB precursors after hydrolysis in the body. Because many of the phosphate, oxoacid, amino acid, and / or peptide components ("ligands") of the present invention are naturally occurring metabolites or mimetics thereof, or pharmacologic active compounds, these GHB delivery compounds can be easily recognized by physiological systems, thereby undergoing hydrolysis to release GHB. The claimed compounds themselves have no or limited pharmacological activity, and therefore may follow a different metabolic pathway than pharmacologic active GHB drugs. By selecting a suitable ligand, the release of GHB or GHB precursors into the systemic circulation can be regulated even when the GHB delivery compounds are administered via a route other than oral.

[0113] In at least one embodiment, the GHB delivery compound(s) may release GHB or GHB precursor(s) in a manner similar to free or unmodified GHB / NaGHB or GHB precursor. In other embodiment(s), the GHB delivery compound(s) may release GHB or GHB precursor(s) in a controlled or sustained manner, or in a prolonged manner. In yet another embodiment(s), some amount or a portion of the dose of the GHB delivery compound administered to a human or animal subject provides an immediate release of GHB or GHB precursor(s), and some amount or a portion of the same dose of the GHB delivery compound administered to a human or animal subject provides GHB or GHB precursor(s) in a controlled or sustained manner, or in a prolonged manner. This can be done, for example, by designing a GHB delivery compound that is easily absorbed and somewhat, but not completely, resistant to first-pass metabolism. As a result, some amount or portion of a dose of GHB delivery compound administered to a human or animal subject will release GHB or GHB precursor(s) earlier into the system, providing a spike in blood concentration of GHB or GHB precursor(s), and some amount or portion of the same dose of GHB delivery compound administered to a human or animal subject will be absorbed unchanged into the systemic circulation where it will slowly release GHB or GHB precursor(s) in a controlled, sustained, or prolonged manner.

[0114] In further embodiment(s), the composition comprising the GHB delivery compound of the present technology comprises at least two different GHB delivery compounds, where at least one GHB delivery compound releases GHB or GHB precursor(s) similar to free or unmodified GHB / NaGHB or GHB precursor(s) and at least one other GHB delivery compound releases GHB or GHB precursor(s) in a controlled or sustained or prolonged manner.

[0115] In yet another embodiment(s), the composition comprising the GHB delivery compound(s) of the present technology comprises unmodified GHB / NaGHB and at least one GHB delivery compound, where the unmodified GHB / NaGHB provides a fast onset of GHB blood levels and the at least one GHB delivery compound will release GHB or GHB precursor(s) in a controlled or sustained or prolonged manner.

[0116] Without wishing to be bound by any particular theory, it is believed that in at least one further embodiment, the controlled release of GHB or GHB precursor(s) can potentially alleviate certain side effects and improve the safety profile of the parent drug.These side effects can include, for example, anxiety, imbalance, teeth grinding, confusion, loss of appetite, depressed mood, depression, diarrhea, dizziness, dry mouth, bedwetting, low mood, fatigue, drunkenness, headache, excessive sweating, insomnia, irritability, muscle spasms, nausea, parasomnia, paresthesia, snoring, somnolence, tremors, vomiting, and weight loss.In addition, GHB is also prone to substance abuse.

[0117] When GHB or GHB precursor(s) are bound to certain ligands, most or at least some amount or portion of the resulting GHB delivery compound ("prodrug") is stable through the first-pass metabolic process via the liver after oral administration. Also, without wishing to be bound by any particular theory, it is believed that in some embodiments, the GHB delivery compound then releases GHB or GHB precursor(s) into the systemic circulation in a controlled, sustained, or prolonged manner. In other embodiments, GHB delivery compounds that can at least partially survive first-pass metabolism have improved bioavailability and / or preferential uptake in the brain when compared to unmodified GHB / NaGHB. As a result, these GHB delivery compounds of the technology described and claimed herein can be administered at lower molar doses to obtain equivalent therapeutic effects when compared to unmodified GHB / NaGHB.

[0118] The GHB delivery compounds of the present disclosure may be used to prevent or treat sleep disorders, particularly those sleep disorders that affect subjects with a neurodegenerative disease or disorder.

[0119] Additionally, other GHB-related compounds may also be formulated into compositions and used to prevent or treat sleep disorders, such as sleep disorders affecting subjects with neurodegenerative diseases or disorders. These GHB-related compounds include [ka] These may include, but are not limited to:

[0120] These sleep disorders include, but are not limited to, daytime sleepiness associated with central hypersomnia, obstructive sleep apnea, or shift work disorder.Non-limiting examples of central hypersomnia include narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to medical conditions, hypersomnia due to drugs or substances, hypersomnia due to psychiatric conditions, and insufficient sleep syndrome.

[0121] Some sleep disorders (including, for example, excessive daytime sleepiness, hypersomnia, and hypersomnia) may be the primary symptoms of neurodegenerative diseases or disorders, or may be the result of the treatment of neurodegenerative diseases or disorders.Non-limiting examples of neurodegenerative diseases or disorders include Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0122] In some treatment regimes, GHB delivery compound or GHB related compound has been found to be particularly useful in providing improved sleep quality in subjects with nighttime sleep disorders.Depending on the sleep disorder to be prevented or improved, GHB delivery compound or GHB related compound can be given in combination with one or more therapeutic compounds that improve daytime wakefulness.In non-limiting examples, these therapeutic compounds can be amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate and solriamfetol, or combinations thereof.

[0123] In some treatment regimes, GHB delivery compounds or GHB-related compounds have been found to be particularly useful in treating sleep disorders in subjects suffering from Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism. Depending on the sleep disorder to be prevented or improved, GHB delivery compounds or GHB-related compounds can be given in combination with another therapeutic compound. In non-limiting examples, the therapeutic compound can be amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, and solriamfetol, or combinations thereof.

[0124] Further, depending on the treatment method, the composition can be taken about twice a day, or at least about once a day. The composition can be formulated for oral administration, for example as an oral formulation, but it should be recognized by those skilled in the relevant art that the composition can be formulated for any method of administration, including, but not limited to, intravenous or intranasal administration.

[0125] The GHB delivery compound, GHB related compound, or composition can also be provided as a kit, for example, a kit containing a therapeutically effective amount of any one of the GHB delivery compounds or GHB related compounds of the present disclosure. The kit can also include instructions for use and administration. The GHB delivery compound or composition can also be formulated into a unit dosage form. This formulation allows for easy administration, as the kit can include one unit dosage form or multiple unit dosage forms. For example, if the GHB delivery compound in the kit is intended to be administered once a day for 30 days, the kit can include 30 individual unit dosage forms. The unit dosage form can be, for example, a sublingual tablet, a gummy, a chewable tablet, a fast-dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a sachet, a slurry, an oral tablet, and / or a suppository. In one embodiment, the unit dosage form can be packaged as a blister pack or similar packaging or system for delivery of unit dosages.

[0126] In some embodiments, the kit can include additional therapeutic compounds.For example, when the kit is intended to be used to treat the sleep disorder that affects subjects with neurodegenerative disease or disorder, the kit can further include amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, solriamfetol, or combinations thereof.

[0127] In one embodiment, the GHB delivery compound or GHB-related compound is present in a liquid dosage form and the additional therapeutic compound is present in an oral powder or sachet form.

[0128] In some embodiments, the additional therapeutic compound is added to the liquid dosage form of the GHB delivery compound before administration. In some embodiments, the unit dose of the GHB delivery compound can be the maximum tolerated dosage. The maximum tolerated dosage is the highest dose of the GHB delivery compound that does not cause unacceptable side effects. In these embodiments, the GHB delivery compound can be provided in a liquid dosage form of at least about 5 mL, alternatively at least about 10 mL, alternatively at least about 25 mL, alternatively at least about 50 mL, alternatively at least about 75 mL, or alternatively at least about 100 mL. The additional therapeutic compound can then be added to the liquid dosage form (e.g., a bottle) and shaken to mix with the GHB delivery compound. The subject can then drink the combined dose from the liquid dosage form or pour it into a glass, cup, or other delivery container.

[0129] In some embodiments, the GHB delivery compound of the present technology is present in the composition in an amount that is the molar equivalent to a dose of NaGHB in the range of about 0.1 g to about 18 g / day, alternatively in the range of about 1 g to about 14 g / day, alternatively in the range of about 2 g to about 10 g / day, alternatively in the range of about 4.5 g to about 9 g / day. It should be recognized by one of skill in the art that the technology described herein and the ranges herein include all subranges (and subranges within these subranges) within the described ranges on a per day (i.e., 24 hour) basis and divided doses within a day (24 hour period). For example, among others, 0.1g, ~0.2g, ~0.3g, ~0.4g, ~0.5g, ~0.6g, ~0.7g, ~0.8g, ~0.9g, ~1.0g, ~1.1g, ~1.2g, ~1.3g, ~1.4g, ~1.5g, ~1.6g, ~1.7g, ~1.8g, ~1.9g, ~2.0g, ~2.1g, ~2.2g, ~2.3g, ~2.4g, ~2.5g, ~2.6g, ~2.7g, ~2.8g, ~2.9g, ~3.0g, ~3.1g, ~3.2g, ~3.3g, ~3.4g, ~ 3.5g, ~3.6g, ~3.7g, ~3.8g, ~3.9g, 4.0g, ~4.1g, ~4.2g, ~4.3g, ~4.4g, ~4.5g, ~4.6g, 4.7g, ~4.8g, ~4.9g, ~5.0g, ~5.1g, ~5.2g, ~ 5.3g, ~5.4g, ~5.5g, ~5.6g, ~5.7g, ~5.8g, ~5.9g, ~6.0g, ~6.1g, ~6.2g, ~6.3g, ~6.4g, ~6.5g, ~6.6g, ~6.7g, ~6.8g, ~6.9g, ~7.0g ~7.1g, ~7.2g, ~7.3g, ~7.4g, ~7.5g, ~7.6g, ~7.7g, ~7.8g, ~7.9g, ~8.0g, ~8.1g, ~8.2g, ~8.3g, ~8. 4g, ~8.5g, ~8.6g, ~8.7g, ~8.8g, ~8.9g, 9.0g, ~9.1g, ~9.2g, ~9.3g, ~9.4g, ~9.5g, ~9.6g, ~9.7g, ~ 9.8g, ~9.9g, ~10.0g, ~10.1g, ~10.2g, ~10.3g, ~10.4g, ~10.5g, ~10.6g, ~10.7g, ~10.8g, ~10.9g, ~11.0g, ~11.1g, ~11.2g, ~11.3g, ~11.4g, ~11.5g, ~11.6g, ~11.7g, ~11.8g, ~11.9g, ~12.0g, ~12.1g, ~12.2g, ~12.3g, ~12.4g, ~12.5g, ~12.6g, ~12.7g, ~12.8g, ~12.9g, ~13.0g, ~13.1g, ~13.2g, ~13.3g, ~13.4g, ~13.5g, ~13.6g, ~13.7g, ~13.8g, ~13.9g, ~14.0g, ~14.1g, ~14.2g, ~14.3g, ~14.4g, ~14.5g, ~14.6g, ~14.7g, ~14.8g, ~15.0g, ~15. 1g, ~15.2g, ~15.3g, ~15.4g, ~15.5g, ~15.6g, ~15.7g, ~15.8g, ~15.9g, ~16.0g, ~16.1g, ~16.2g, ~16.3g, ~16.4g, ~16.5g, 16.6g, ~16.7g, ~16.8g, ~16.9g, ~17.0g, 17.1g, ~17.2g, ~17.3g, ~17.4g, ~17.5g, ~17.6g, ~17.7g, ~17.8g, ~17.9g, ~18.0g. It should be appreciated that the present technology may be therapeutically dosed as needed in its appropriate measured (e.g., milligrams, grams, etc.) dosage range.

[0130] Synthesis scheme

[0131] The technology described herein and its advantages will be better understood by referring to the following synthetic schemes. These schemes are provided to illustrate specific aspects of the technology. By providing these specific schemes, the applicant does not limit the scope and spirit of the technology.

[0132] Synthesis of benzyl O-benzyl GHB (2): [ka]

[0133] Scheme 1. (a) TEA, DMAP, DCM; (b) BH3·Me2S, THF

[0134] O-Benzyl succinic acid (1)

[0135] To a stirred mixture of succinic anhydride (1 g, 10 mmol) in anhydrous DCM (10 mL) was added benzyl alcohol (1.2 g, 11 mmol), Et3N (1.1 g, 11 mmol), and a catalytic amount of DMAP at room temperature. After stirring overnight, the reaction was diluted with 100 mL of DCM and further extracted with 5% aqueous NaHCO3 (3 x 50 mL). The aqueous layer was acidified to pH 3 with 0.5 M HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and then evaporated under vacuum to give compound 1 as a white solid (1.58 g, 76%).

[0136] O-benzyl GHB(2)

[0137] To a stirred solution of mono-benzyl succinate 1 (1 g, 4.8 mmol) in anhydrous THF (10 mL) was added borane dimethylsulfide (0.471 g, 6.24 mmol) dropwise at -20°C. The reaction was stirred at -20°C for 1 h, followed by stirring at room temperature for an additional 5 h. The reaction was cooled by placing on an ice bath and diluted with 150 mL of Et2O. The ether layer was washed with K2CO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and then evaporated under vacuum to give compound 2 as a colorless viscous liquid (0.484 g, 52%).

[0138] Synthesis of 3CPr GHB conjugates (4a-b): [ka]

[0139] Scheme 2. (a) Ethyl chloroformate, pyridine, DCM, 0-5 °C; (b) Ac2O, pyridine, DCM (for compound 3b); (c) Pd / C, H2, EtOH; (d) 2, DCC, DMAP (catalytic amount), DCM

[0140] O-(Ethyloxycarbonyl)-GHB (3a):

[0141] A solution of ethyl chloroformate (0.615 mL, 6.42 mmol) in DCM (2 mL) was added to a solution of benzyl-4-hydroxy-butyrate 2 (1.00 g, 5.14 mmol) and pyridine (0.62 mL, 7.7 mmol) in DCM (10 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 5% NH4Cl and brine, dried over anhydrous Na2SO4, and evaporated to dryness to give benzyl O-(ethoxycarbonyl)-GHB as an oil (1.35 g, 99%).

[0142] A suspension of benzyl O-(ethoxycarbonyl)-GHB (1.3 g, 4.85 mmol), Pd / C (10% Pd, 0.75 g) in EtOH (25 mL) was stirred under H2 (balloon) at room temperature for 1.5 h. The reaction mixture was filtered through Celite®. The filter cake was washed with EtOH (2 x 10 mL). The combined filtrate was evaporated to dryness to give 3a as an oil in quantitative yield.

[0143] 3CPr O-(ethoxycarbonyl)-GHB (4a):

[0144] A solution of DCC (0.54 g, 2.62 mmol) in DCM (4 mL) was added dropwise to a solution of 3a (0.44 g, 2.5 mmol), 2 (0.49 g, 2.5 mmol), and DMAP (0.05 g) in DCM (10 mL) at 0-5° C. The reaction mixture was allowed to reach room temperature and stirred for 3 h. The precipitate was filtered, washed with DCM, and the combined filtrate was evaporated to dryness. The crude product was purified by preparative HPLC to give O-benzyl-3CPr O-(ethoxycarbonyl)-GHB as an oil (0.75 g, 85%).

[0145] A suspension of O-benzyl-3CPr O-(ethoxycarbonyl)-GHB (0.74 g, 2.1 mmol) and Pd / C (10% Pd, 0.4 g) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 1 h. The reaction mixture was filtered through Celite®. The filter cake was washed with EtOH (2 x 5 mL). The combined filtrate was evaporated under reduced pressure to dryness to give 4a as an oil (0.51 g, 92%).

[0146] O-Acetyl-GHB(3b):

[0147] To a solution of compound 2 (0.6 g, 3.09 mmol), pyridine (0.38 mL, 4.6 mmol), and DMAP (0.05 g) in DCM (10 mL) was added a solution of AcO (0.36 mL, 3.86 mmol) in DCM (2 mL) dropwise at 0-5 °C. After addition, the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and DCM was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 10% aqueous NHCl, brine, dried over anhydrous NaSO, and evaporated to dryness to give benzyl O-acetyl-GHB (0.72 g, 98%) as an oil.

[0148] Compound 3b was synthesized in quantitative yield following the same procedure as described for 3a above.

[0149] 3CPr O-acetyl-GHB(4b):

[0150] 3CPr O-acetyl-GHB 4b was synthesized in 75% overall yield following the same synthetic procedure as 4a.

[0151] Synthesis of GHB-Gly-GHB-GHB (10): [ka]

[0152] Scheme 3. (a) HATU, DIPEA, DMF; (b) Pd / C, H2, MeOH; (c) 4-benzyloxybutanoic acid, HATU, DIPEA, DMF; (d) TFA, DCM; (e) 5, HATU, DIPEA, DMF; (f) Pd / C, H2, EtOH

[0153] Cbz-Gly-GHB- t Bu(6a)

[0154] To a stirred solution of benzyloxy(carbonyl)glycine (2 g, 9.56 mmol), HATU (4 g, 10.51 mmol), and DIPEA (6.2 g, 47.8 mmol) in 20 mL of anhydrous DMF, tert-butyl 4-hydroxybutanoate 5 (1.53 g, 9.56 mmol) was added dropwise at room temperature under an argon atmosphere. After stirring for 12 h, the reaction was quenched by pouring into 5% aqueous bicarbonate solution. The aqueous layer was extracted with 3×50 mL of EtOAc. The organic layer was washed successively with water and brine and dried over anhydrous Na2SO4. The organic layer was filtered, evaporated under vacuum, and the residue was purified on silica gel (EtOAc:Hexane, 1:4) to give compound 6a (2.64 g, 78%).

[0155] Gly-GHB- t Bu(6b)

[0156] A solution of 6a (2.64 g, 7.5 mmol) in anhydrous EtOH (30 mL) was stirred at room temperature in the presence of Pd / C (1 g) under H. After stirring for 2 h, the reaction was filtered through a Celite® pad and the filtrate was evaporated in vacuum to give compound 6b as a colorless viscous liquid in quantitative yield.

[0157] O-Benzyl-GHB-Gly-GHB- t Bu(8a)

[0158] Compound 8a was obtained by adopting the procedure described for 6a. Yield: 38%.

[0159] O-Benzyl-GHB-Gly-GHB (8b)

[0160] Compound 8a was treated with 30% TFA in DCM at room temperature for 30 min. After completion of the reaction, the solvent was removed under vacuum to yield the desired product 8b as a sticky solid, which was used in the next step without further purification.

[0161] O-Benzyl-GHB-Gly-GHB-GHB- t Bu(9)

[0162] Compound 9 was synthesized by adopting the procedure described above (for 6a).

[0163] GHB-Gly-GHB-GHB(10)

[0164] Deprotection of compound 9 was first achieved using 30% TFA in DCM, followed by catalytic hydrogenation to give compound 10.

[0165] Synthesis of bis(3CPr) carbonates (13a-b): [ka]

[0166] Scheme 4. (a) triphosgene, pyridine, toluene; (b) 2, N-methylimidazole; (c) 1,4-cyclohexadiene, Pd / C, MeOH; (d) NaHCO3, water / CH3CN

[0167] Benzyl O4-chlorocarbonyl-GHB (11)

[0168] A solution of triphosgene (3 g, 10.1 mmol) in toluene (10 mL) was cooled on an ice-water bath (0-5 °C). To this, anhydrous pyridine (0.913 g, 11.6 mmol) was added dropwise under inert atmosphere. After stirring for 30 min, benzyl 4-hydroxybutanoate (1.5 g, 7.7 mmol) was added dropwise to the reaction mixture. The ice-water bath was removed and the reaction was stirred for an additional 1.5 h. The reaction mixture was filtered and diluted with EtOAc. The organic layer was washed with water and dried over anhydrous Na2SO4. The EtOAc layer was filtered and the filtrate was evaporated under vacuum to give the chloroformate derivative 11 as a colorless oil, which was used in the next step without further purification.

[0169] Bis(O-benzyl-3CPr) carbonate (12)

[0170] A solution of benzyl 4-hydroxybutanoate 2 (0.755 g, 3.89 mmol) in 3 mL of N-methylimidazole was cooled on an ice-water bath (0-5 °C) under inert atmosphere. To this, a solution of chloroformate 11 (1 g, 3.89 mmol) in DCM (2 mL) was added dropwise. The ice-water bath was removed and the reaction was allowed to proceed for another 2 h. The reaction was quenched by diluting with EtOAc. The EtOAc layer was washed with water and dried over anhydrous Na2SO4. The organic layer was evaporated under vacuum and the residue was purified on silica gel (hexane:EtOAc, 9:1) to give the desired product 12 as a viscous liquid (1.2 g, 74%).

[0171] Bis(3CPr)carbonate(13a)

[0172] To a stirred solution of dibenzyl 4,4'-(carbonylbis(oxy))dibutyrate 12 (1.03 g, 2.49 mmol) in 20 mL of anhydrous methanol under inert atmosphere was added 1,4-cyclohexadiene (2 g, 24.9 mmol, 10 equiv.), and 10% Pd / C (2 g). The precursor was found to be completely consumed by 90 min as detected by TLC analysis. The suspension was filtered through a Celite® pad, and the filtrate was evaporated under vacuum to give the desired compound 13a as a waxy solid (0.54 g, 92%).

[0173] Bis(3CPr)carbonate, disodium (13b)

[0174] Acid 13a was converted to its sodium salt by treatment with 2 equivalents of NaHCO3 solution. The solution was lyophilized to give the disodium salt 13b as a white solid. Yield: quantitative.

[0175] Synthesis of 3CPr carbonate: [ka]

[0176] Scheme 5. (a) Glycerol, pyridine, CHCl3; (b) Pd / C, H2, EtOH; (c) 4-benzyloxybutanol, pyridine, DCM

[0177] Glycerol tris(O-benzyl-3CPr carbonate) (14)

[0178] To a solution of glycerol (0.103 g, 1.12 mmol) and pyridine (1 mL) in chloroform (9 mL) was added dropwise a solution of chloroformate 11 (1.024 g, 4 mmol) in CHCl3 (2 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 5 h, quenched with water (few drops) and evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative HPLC to give carbonate derivative 14 (0.42 g, 56%) as an oil.

[0179] Glycerol Tris(3CPr carbonate)(15):

[0180] A suspension of compound 14 (0.4 g, 0.53 mmol), Pd / C (0.6 g) in MeOH / EtOH (1:1, 15 mL) was stirred under H (balloon) at room temperature for 5 h. The reaction mixture was filtered, washed with MeOH (3×5 mL) and the combined filtrate was evaporated under reduced pressure to give carbonate derivative 15 (0.22 g, 86%) as a viscous oil.

[0181] O-benzyl-4-hydroxybutyl O-benzyl-3CPr carbonate (16)

[0182] To a solution of 4-benzyloxybutanol (0.27, 1.5 mmol) and pyridine (0.25 mL, 3 mmol) in DCM (8 mL) was added a solution of chloroformate 11 (0.385 g, 1.5 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (80 mL), washed with water, brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to give the carbonate derivative 16 (0.41 g, 68%) as an oil.

[0183] 4-Hydroxybutyl 3CPr carbonate (17)

[0184] A suspension of 16 (0.41 g, 1.02 mmol), Pd / C (0.4 g) in EtOH (15 mL) was stirred under H (balloon) at room temperature for 4 h. The reaction mixture was filtered, washed with EtOH (2×5 mL) and the combined filtrate was evaporated under reduced pressure to give 4-hydroxybutyl 3CPr carbonate 17 (0.21 g, 93%) as an oil.

[0185] Synthesis of sulfonyl 3CPr carbamates (19a-j and 21): [ka]

[0186] Scheme 6. DCM, 0-5°C; (b) TEA, benzyl-protected amino acid, DCM, 0-5°C; (c) Pd / C, H2, EtOH; (d) NH3 / EtOH

[0187] O-Benzyl-(Val)-N-yl-sulfonyl O-benzyl-3CPr carbamate (18a)

[0188] To a solution of benzyl-4-hydroxybutyrate 2 (0.3 g, 1.55 mmol) in DCM (10 mL) was added chlorosulfonyl isocyanate (0.135 mL, 1.55 mmol) in DCM (1 mL) at 0 °C. After stirring at 0 °C for 1 h, Val-OBn·HCl (0.38 g, 1.55 mmol) and TEA (0.54 mL, 3.9 mmol) were added and the reaction mixture was stirred at 0 °C for 1.5 h. The reaction was quenched with water (a few drops) and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (120 mL), washed with 2% NaHSO4 (70 mL), brine, dried over anhydrous Na2SO4 and evaporated to dryness to give 18a (0.71, 90%) as an oil.

[0189] (Val)-N-yl-sulfonyl 3CPr carbamate (19a)

[0190] A suspension of 18a (0.7 g, 1.38 mmol), Pd / C (0.65 g) in EtOH (25 mL) was stirred under H (balloon) at room temperature for 3 h. The reaction mixture was filtered through Celite®, washed with EtOH (2×10 mL) and the combined filtrate was evaporated under reduced pressure to dryness to give 19a as a white solid (0.43 g, 95%).

[0191] (Amino acid)-N-yl-sulfonyl 3CPr carbamates (19b-j)

[0192] (Ala)-N-yl-sulfonyl 3CPr carbamate (19b), (β-Ala)-N-yl-sulfonyl 3CPr carbamate (19c), (Phe)-N-yl-sulfonyl 3CPr carbamate (19d), (Tyr)-N-yl-sulfonyl 3CPr carbamate (19e), (Ser)-N-yl-sulfonyl 3CPr carbamate (19f), (Lys)-N-yl-sulfonyl 3CPr carbamate (19g), (Asp)-N-yl-sulfonyl 3CPr carbamate (19h), (Gly)-N-yl-sulfonyl 3CPr carbamate (19i), and (Gly-Gly)-N-yl-sulfonyl 3CPr carbamate (19j) were synthesized according to the same synthetic procedure as that described for 19a.

[0193] Ethoxysulfonyl O-benzyl-3CPr carbamate (20)

[0194] To a solution of benzyl-4-hydroxybutyrate 2 (0.29 g, 1.49 mmol) in DCM (10 mL) was added chlorosulfonyl isocyanate (0.135 mL, 1.49 mmol) at 0-5 °C. After stirring at 0-5 °C for 1.5 h, ethanolic ammonia (2 M, 1.5 mL) was added and the reaction mixture was stirred at 0-5 °C for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude product was purified by preparative HPLC to give 20 (0.24 g, 47%) as an oil.

[0195] Ethoxysulfonyl 3CPr carbamate (21)

[0196] Compound 20 was deprotected following the same procedure as described for 18a to give the title compound 21 as an oil.

[0197] Synthesis of acyl 3CPr carbamates (23a-b): [ka]

[0198] Scheme 7. (a) Benzoyl isocyanate, DCM; (b) Ethoxycarbonyl isocyanate, DCM; (c) Pd / C, H2, EtOH

[0199] Benzoyl O-benzyl-3CPr carbamate (22a)

[0200] To a solution of benzyl-4-hydroxybutanoate 2 (0.29 g, 1.5 mmol) in DCM (8 mL) was added a solution of benzoyl isocyanate (0.25 g, 1.7 mmol) in DCM at 0-5 °C. The reaction mixture was stirred for another 1 h at 0-5 °C and then quenched with water (few drops). The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (75 mL), washed with water, brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to give 22a as an oil (0.45 g, 88%).

[0201] Benzoyl 3CPr carbamate (23a)

[0202] A suspension of compound 22a (0.45 g, 1.31 mmol), Pd / C (0.25 g, 10% Pd) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 2.5 h. The reaction mixture was filtered through Celite®. The filter cake was washed with EtOH (2 x 8 mL) and the combined filtrate was evaporated under reduced pressure to give 23a (0.32 g, 97%) as a white solid.

[0203] N-(ethoxycarbonyl)3CPr carbamate (23b)

[0204] Compound 23b was synthesized in 71% overall yield as a white solid following the same procedure as described for 23a.

[0205] Synthesis of N-(ethoxycarbonyl)3CPr thiocarbamate (25): [ka]

[0206] Scheme 8. (a) EtOC(O)NCS, TEA, DCM; (b) Pd / C, H2, EtOH

[0207] N-(ethoxycarbonyl)O-benzyl-3CPr thiocarbamate (24)

[0208] To a solution of benzyl-4-hydroxybutanoate 2 (0.72 g, 3.7 mmol) and TEA (0.82 mL, 5.9 mmol) in DCM (10 mL) was added ethoxycarbonyl isothiocyanate (0.56 mL, 4.8 mmol) at 0-5 °C. The mixture was stirred at 0-5 °C for 3 h. The reaction was quenched with water (a few drops) and the solvent was evaporated to dryness. The residue was dissolved in EtOAc (100 mL), washed with 10% aqueous NH4Cl (50 mL), brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative HPLC to give compound 24 as an oil (0.35 g, 29%).

[0209] N-(ethoxycarbonyl)3CPr thiocarbamate (25)

[0210] Deprotection of 24 under catalytic hydrogenation as described above gave compound 25 in 98% yield.

[0211] Synthesis of phenylsulfonyl 3CPr carbamate (27): [ka]

[0212] Scheme 9. (a) PhC(O)NCO, DCM; (b) Pd / C, H2, EtOH

[0213] Phenylsulfonyl O-benzyl-3CPr carbamate (26)

[0214] To a solution of benzyl-4-hydroxybutanoate 2 (0.41 g, 2.1 mmol) in DCM (10 mL) was added a solution of benzenesulfonyl isocyanate (0.35 mL, 2.6 mmol) in DCM (2 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for another 2 h, quenched with water (few drops) and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC to give 26 as an oil (0.62 g, 78%).

[0215] Phenylsulfonyl 3CPr carbamate (27)

[0216] A suspension of compound 26 (0.61 g, 1.61 mmol), Pd / C (0.31 g, 10% Pd) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 1.5 h. The reaction mixture was filtered through Celite®. The filter cake was washed with EtOH (2 x 8 mL) and the combined filtrate was evaporated under reduced pressure to give 27 (0.41 g, 89%) as a solid.

[0217] Synthesis of phosphoryl 3CPr carbamates (29a-c): [ka]

[0218] Scheme 10. (a) Dichlorophosphoryl isocyanate, DCM; (b) NaOEt, EtOH; (c) Gly-OEt.HCl, TEA, DCM; (d) 2, pyridine, DCM; (e) Pd / C, H2, EtOH

[0219] Diethoxyphosphoryl O-benzyl-3CPr carbamate (28a)

[0220] Dichlorophosphoryl isocyanate (0.142 mL, 1.44 mmol) was added to a solution of benzyl-4-hydroxybutanoate (0.28 g, 1.44 mmol) in DCM (10 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1 h. A solution of NaOEt in EtOH (1.5 mL, 21 wt%) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for 3 h and then quenched with 10% aqueous NH4Cl (10 mL). DCM was removed under reduced pressure. The residue was partitioned between EtOAc (80 mL) and 10% aqueous NH4Cl (50 mL). The EtOAc portion was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to give 28a (0.36 g, 67%) as an oil.

[0221] Diethoxyphosphoryl 3CPr carbamate (29a)

[0222] A suspension of 28a (0.36 g, 0.96 mmol), Pd / C (10% Pd, 0.16 g) in EtOH (12 mL) was stirred under H (balloon) for 1.5 h. The reaction mixture was filtered through Celite®, washed with EtOH (2×4 mL), and the combined filtrate was evaporated under reduced pressure to give compound 29a as an oil in quantitative yield.

[0223] Bis(O-ethylglycine)-phosphoryl O-benzyl-3CPr carbamate (28b)

[0224] To a solution of benzyl-4-hydroxybutanoate 2 (0.27 g, 1.39 mmol) in DCM (10 mL) was added dichlorophosphoryl isocyanate (0.137 mL, 1.39 mmol) at 0-5 °C. The mixture was stirred at 0-5 °C for 1.5 h. Gly-OEt·HCl (0.43 g, 3.05 mmol) and TEA (0.55 mL, 4 mmol) were added and the reaction mixture was stirred at 0-5 °C for 2 h and then at room temperature for 1 h. The reaction was quenched with water and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with 10% aqueous NH4Cl and brine, dried over anhydrous Na2SO4 and evaporated to dryness. The product was purified by preparative HPLC to give 28b as an oil (0.44 g, 65%).

[0225] Bis(O-ethylglycine)-phosphoryl 3CPr carbamate (29b)

[0226] Compound 28b was deprotected following the same procedure as described for 27a to give compound 29b in 81% yield.

[0227] Bis(3CPr)-phosphoryl O-benzyl-3CPr carbamate (28c)

[0228] To a solution of benzyl-4-hydroxybutanoate 2 (0.74 g, 3.78 mmol) in DCM (12 mL) was added dichlorophosphoryl isocyanate (0.125 mL, 1.26 mmol) and pyridine (0.32 mL, 4 mmol) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 5 h and then at room temperature for 2 h. The reaction was quenched with water and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with 10% aqueous NH4Cl (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and evaporated to dryness. The product was purified by preparative HPLC to give 28c as an oil (0.43 g, 51%).

[0229] Bis(3CPr)-phosphoryl 3CPr carbamate (29c)

[0230] Compound 28c was deprotected following the same procedure as described for 27a to give compound 29c in quantitative yield.

[0231] Synthesis of diethyl 3CPr phosphate (31): [ka]

[0232] Scheme 11. (a) Diethyl chlorophosphate, pyridine, DCM; (b) Pd / C, H2, EtOH

[0233] Diethyl O-benzyl-3CPr phosphate (30)

[0234] A solution of diethyl chlorophosphate (0.58 mL, 4 mmol) in DCM (3 mL) was added to a solution of benzyl-4-hydroxybutanoate 2 (0.625 g, 3.2 mmol) and pyridine (0.77 mL, 9.5 mmol) in DCM (10 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 3 h, quenched with water, and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with 10% aqueous NH4Cl (50 mL), 5% aqueous NaHCO3 (50 mL), and brine, dried over anhydrous Na2SO4, and evaporated to dryness. The phosphate derivative was purified by preparative HPLC to give diethyl O-benzyl-3CPr phosphate 30 as an oil (0.9 g, 85%).

[0235] Diethyl 3CPr phosphate (31)

[0236] Deprotection of 30 under catalytic hydrogenation as described above gave compound 31 as an oil in 96% yield.

[0237] Synthesis of 3CPr sulfamate: [ka]

[0238] Scheme 12. (a) Sulfamoyl chloride, dimethylacetamide, 0–5°C; (b) Pd / C, H2, EtOH

[0239] O-Benzyl-3CPr sulfamate (32)

[0240] To a solution of benzyl-4-hydroxybutanoate 2 (1.1 g, 5.66 mmol) in dimethylacetamide (5 mL) was added sulfamoyl chloride (1.31 g, 11.34 mmol) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1 h and then poured into 10% aqueous NaCl solution (975 mL). The aqueous solution was extracted with EtOAc (100 mL), and the extract was washed with 10% aqueous NaCl solution, dried over anhydrous Na2SO4, and evaporated to dryness. The crude product was purified on silica gel (EtOAc:Hexane, 1:1) to give 32 as an oil (1.41 g, 91%).

[0241] 3CPr Sulfamate (33)

[0242] A suspension of 32 (0.93 g) and Pd / C (0.4 g) in EtOH (25 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered through Celite® and the filter cake was washed with EtOH (2×10 mL). The combined filtrate was evaporated under reduced pressure to give 33 as a white solid in quantitative yield.

[0243] Synthesis of (2-THF) esters (34a-b and 35): [ka]

[0244] Scheme 13. (a) PPTS, DCM; (b) Pd / C, H2, EtOH

[0245] (2-THF)benzoate (34a)

[0246] A solution of benzoic acid (1 g, 8.2 mmol) and pyridinium p-toluenesulfonate (PPTS) (0.021 g, 0.08 mmol) in anhydrous DCM was cooled on an ice-water bath (0-5 °C) with stirring. To this mixture, 2,3-dihydrofuran (0.743 g, 10.6 mmol) was added dropwise under inert atmosphere. Upon completion of the addition, the ice-water bath was removed. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solutions. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum and the residue was purified on silica gel (hexane:EtOAc, 9:1) to give 34a (1.1 g, 72%) as a colorless liquid.

[0247] (2-THF)salicylate (34b)

[0248] (2-THF) salicylate (34b) was synthesized as a colorless liquid in 67% yield according to the procedure described above.

[0249] Benzyl (2-THF) glutarate (34c)

[0250] To a stirred solution of mono-benzyl glutarate (0.5 g, 2.25 mmol) and 5 mg of pyridinium p-toluenesulfonate (PPTS) (0.02 mmol) in anhydrous dichloromethane was added dropwise at 0° C. under an inert atmosphere. The reaction mixture was allowed to warm slowly to room temperature. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solutions. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum. The residue was passed through a short silica gel column (hexane:EtOAc, 9:1) to give the desired product 34c as a colorless liquid (0.570 g, 87%).

[0251] O-(2-THF)-glutaric acid (35)

[0252] Benzyl (2-THF) glutarate 34c (0.57 g, 1.95 mmol) was dissolved in anhydrous tetrahydrofuran and stirred at room temperature in the presence of 10% Pd / C (0.6 g) under H2. After 3 h, the suspension was passed through a Celite® pad. The filtrate was removed under vacuum to give the desired product 35 (0.337 g, 86%) as a viscous liquid.

[0253] Synthesis of O-(2-THF)O-(ethoxycarbonyl)-GHB (38): [ka]

[0254] Scheme 14. (a) Ethyl chloroformate, pyridine; (b) Pd / C, H2, THF; (c) PPTS, DCM

[0255] Benzyl O-(ethoxycarbonyl)-4-hydroxybutyrate (36)

[0256] With stirring, ethyl chloroformate (0.805 g, 7.42 mmol) was added dropwise to a solution of benzyl 4-hydroxybutanoate 2 (1.2 g, 6.18 mmol) in anhydrous pyridine (15 mL) at 0-5 °C under inert atmosphere. The reaction was allowed to warm slowly to room temperature and stirred. After 2 h, the reaction was stopped and the volume reduced in vacuum. The residue was taken up in EtOAc and the organic layer was washed with saturated aqueous NH4Cl, water, and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuum. The residue was purified on silica gel (hexane:EtOAc, 9:1) to give the carbonate derivative 36 as a viscous liquid.

[0257] O-(ethoxycarbonyl)-GHB (37)

[0258] A solution of compound 36 (0.68 g, 3.9 mmol) in anhydrous THF (25 mL) was stirred at room temperature in the presence of 10% Pd / C (0.2 g) under H2 atmosphere. After 3 h, the reaction was stopped and passed through a Celite® pad. The filtrate was evaporated under vacuum to give O-(ethoxycarbonyl)-GHB 37 as a viscous liquid. Yield: 0.45 g (65%).

[0259] O-(2-THF)O-(ethoxycarbonyl)-GHB (38)

[0260] To a stirred solution of compound 37 (0.45 g, 2.55 mmol) and 8 mg of p-toluenepyridinium sulfonate (0.03 mmol) in anhydrous dichloromethane was added dropwise at 0° C. under inert atmosphere. The reaction mixture was allowed to warm slowly to room temperature. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solution. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum. The residue was passed through a short silica gel column (hexane:EtOAc, 9:1) to give the desired product 38 as a viscous liquid (0.385 g, 61%).

[0261] Synthesis of bis(2-THF) carboxylates (39, 40, 41a-d). [ka]

[0262] Scheme 15. (a) PPTS, DCM

[0263] Bis(2-THF)maleate(39)

[0264] With stirring, 2,3-dihydrofuran (1.2 g, 16.8 mmol) was added dropwise to a solution of maleic acid (0.75 g, 6.5 mmol) and pyridinium p-toluenesulfonate (PPTS) (0.033 g, 0.13 mmol) in anhydrous DCM over an ice-water bath (0-5 °C) under inert atmosphere. Upon complete addition, the ice-water bath was removed. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solutions. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum. The residue was passed through a short silica gel column (hexane:EtOAc, 9:1) to give 39 (1.39 g, 85%) as a waxy solid.

[0265] Bis(2-THF) fumarate (40)

[0266] Bis(2-THF) fumarate (40) was synthesized as a viscous liquid in 75% yield following the procedure described above (for 39).

[0267] Bis(2-THF)dicarboxylates (41a-d)

[0268] Similarly, the compounds bis(2-THF) glutarate (41a), bis(2-THF) succinate (41b), bis(2-THF) malonate (41c), and bis(2-THF) adipate (41d) were obtained as colorless viscous liquids in 61%, 67%, 53%, and 73% yields, respectively.

[0269] Synthesis of bis-O-(2-THF) ethers (42 and 43). [ka]

[0270] Scheme 16. (a) PPTS, DCM

[0271] Bis-O-(2-THF)BD(42)

[0272] With stirring, 2,3-dihydrofuran (0.778 g, 11.1 mmol) was added dropwise to a solution of 1,4-butanediol (0.5 g, 5.5 mmol) and pyridinium p-toluenesulfonate (PPTS) (0.028 g, 0.11 mmol) in anhydrous DCM under inert atmosphere over an ice-water bath (0-5 °C). Upon completion of the addition, the ice-water bath was removed. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solutions. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum. The residue was passed through a short silica gel column (hexane: EtOAc, 9: 1) to give compound 42 (1.06 g, 84%) as a colorless oil.

[0273] Bis-O-(2-THF)1,3-dihydroxypropanone (43)

[0274] Bis-O-(2-THF) 1,3-dihydroxypropanone (43) was synthesized as a colorless oil in 66% yield following the same procedure described above.

[0275] Synthesis of coumaric acid conjugate of (2-THF) (44): [ka]

[0276] Scheme 17. (a) PPTS, DCM

[0277] (2-THF)O-(2-THF)p-coumarate (44)

[0278] With stirring, 2,3-dihydrofuran (0.194 g, 2.77 mmol) was added dropwise to a mixture of p-coumaric acid (0.35 g, 2.13 mmol) and p-toluenepyridinium sulfonate (0.005 g, 0.02 mmol) in anhydrous dichloromethane at 0° C. under an inert atmosphere. The mixture was allowed to warm slowly to room temperature. The reaction was monitored by TLC and stopped upon completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% aqueous NaHCO3 and brine solutions. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum. The residue was passed through a short silica gel column (hexane:EtOAc, 9:1) to give the desired product 44 (0.222 g, 34%) as a viscous liquid.

[0279] Synthesis of O-acetyl-4-hydroxybutyl salicylate (45): [ka]

[0280] Scheme 18.

[0281] O-Acetyl-4-hydroxybutyl salicylate (45)

[0282] With stirring, 4-bromobutyl acetate (0.8 g, 4.1 mmol) was added dropwise to a solution of silver salicylate (1 g, 4.1 mmol) in anhydrous pyridine (10 mL) at room temperature. After stirring overnight, the solvent was reduced in vacuum and the residue was taken up in EtOAc. The organic layer was washed with saturated NH4Cl solution, water, and brine. The EtOAc layer was collected with anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuum and the residue was purified on silica gel (hexane:EtOAc, 9:1) to give the desired product 45 (0.297 g, 37%) as a viscous liquid.

[0283] Synthesis of GHB amides (47a-i): [ka]

[0284] Scheme 19. (a) HOBt, DCC, THF; (b) HATU, DIPEA, DMF; (c) HOSu, DCC, THF; (d) amino acid / peptide benzyl ester, THF; (e) Pd / C, H2, EtOH, or MeOH (for 47c).

[0285] O-Benzyl-GHB-Phe-O-benzyl (46a)

[0286] To a solution of 4-benzyloxybutanoic acid (0.3 g, 1.5 mmol), HOBt (0.23 g, 1.6 mmol) in THF (10 mL) was added DCC (0.33 g, 1.6 mmol) in THF (3 mL) dropwise at room temperature. After stirring for 1 h, TEA (0.42 mL, 3 mmol) and Phe-OBn·HCl (0.46 g, 1.57 mmol) were added. The reaction mixture was stirred at room temperature for 4 h and then filtered. The filtrate was evaporated to dryness. The residue was dissolved in EtOAc (100 mL) and the resulting solution was washed with 10% aqueous NH4Cl (50 mL), 5% aqueous NaHCO3 (50 mL), and brine (25 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified on silica gel to give O-benzyl-GHB-Phe 46a (0.61 g, 93%).

[0287] GHB-Phe(47a)

[0288] A suspension of 46a (0.61 g, 1.4 mmol), Pd / C (0.5 g, 10% Pd) in EtOH (15 mL) was stirred under H (balloon) at room temperature for 5 h, the reaction mixture was filtered through Celite® and the filter cake was washed with EtOH (2×8 mL). The combined filtrate was evaporated under reduced pressure to give 47a (0.33 g, 94%) as a solid.

[0289] GHB-Tyr (47b), GHB-Lys (47c), and GHB-Pro (47d) were synthesized following the same procedure as described for 47a.

[0290] O-Benzyl-GHB-Leu-O-benzyl (46e)

[0291] To a solution of 4-benzyloxybutanoic acid (0.305 g, 1.5 mmol), NHS (0.182 g, 1.57 mmol) in THF (9 mL) was added a solution of DCC (0.325 g, 1.57 mmol) in (3 mL) at 0-5 °C. After stirring for 6 h at room temperature, the suspension was filtered and the filtrate was evaporated to dryness to give the hydroxysuccinimide ester 48. To a stirred solution of Leu-OBn·TsOH (0.61, 1.5 mmol) and TEA (0.55 mL, 4 mmol) in THF (6 mL) was added a solution of 48 in THF (4 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 5% aqueous NaHCO3 (50 mL) and brine (40 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified on silica gel to give the amide 46e as an oil (0.54 g, 90%).

[0292] GHB-Leu(47e)

[0293] A suspension of benzyl (4-(benzyloxybutanoyl))leucinate (0.54 g, 1.4 mmol), Pd / C (0.3 g, 10% Pd) in EtOH (12 mL) was stirred under H2 (balloon) at room temperature for 5 h, the reaction mixture was filtered through Celite® and the filter cake was washed with EtOH (2 x 8 mL). The combined filtrate was evaporated under reduced pressure to dryness to give 47e (0.29 g, 99%) as a white solid.

[0294] GHB-Val (47f) and GHB-Phe-Leu (47g)

[0295] GHB-Val (47f) and GHB-Phe-Leu (47g) were synthesized according to the procedure described above.

[0296] O-Benzyl-GHB-Ala-O-benzyl (46h)

[0297] With stirring, DIPEA (2 g, 15.3 mmol) and Ala-OBn·TsOH (1.8 g, 5.1 mmol) were added to a mixture of 4-(benzyloxy)butanoic acid (1 g, 5.1 mmol) and HATU (1.9 g, 5.1 mmol) in anhydrous DMF (8 mL) at room temperature. After stirring for 12 h, the reaction was quenched by pouring into 5% aqueous bicarbonate solution. The aqueous layer was extracted with 3×50 mL of EtOAc. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was filtered and evaporated under vacuum. The residual was purified using silica gel (EtOAc:Hexane, 1:4) to give 46h (1.3 g, 72%).

[0298] GHB-Ala(47h)

[0299] Benzyl (4-(benzyloxy)butanoyl)alaninate 46h (1.3 g, 3.7 mmol) was dissolved in anhydrous EtOH (20 mL) and subjected to hydrogenation in the presence of Pd / C (0.5 g, 10% Pd). After stirring for 3 h, the reaction was stopped, filtered through a Celite® pad, and the filtrate was evaporated in vacuo to give the desired amide 47h (0.61 g, 95%) as a waxy solid.

[0300] GHB-Asp(47i)

[0301] GHB-Asp (47i) was synthesized according to the procedure described above.

[0302] Synthesis of GHB amide esters (52a-c): [ka]

[0303] Scheme 20. (a) BOP, HOBt, DIPEA, DMF; (b) 4N HCl / dioxane; (c) HATU, DIPEA, DMF; (d) Pd / C, H2, EtOH

[0304] Boc-Ser-GHB-O-benzyl (49a)

[0305] With stirring, benzyl 4-hydroxybutanoate (0.35 g, 1.8 mmol) and DIPEA (0.650 g, 4.8 mmol) were added to the Boc-Ser( t To a solution of Bu)-OH (0.428 g, 1.6 mmol), BOP (0.796 g, 1.8 mmol), and HOBt (0.243 g, 1.8 mmol) in anhydrous DMF was added at room temperature under an inert atmosphere. After stirring for 12 h, the reaction was quenched by pouring into 5% aqueous bicarbonate solution. The aqueous layer was extracted with 3×50 mL of EtOAc. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was filtered and evaporated under vacuum. The residue was purified on silica gel (EtOAc:Hexane, 1:4) to give serine ester 49a (0.45 g, 64%).

[0306] Ser-GHB-O-benzyl (50a)

[0307] Compound 49a (0.9 g, 2 mmol) was dissolved in 4(N)HCl / dioxane (12 mL) and stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was coevaporated with isopropyl acetate to give the deprotected compound 50a in quantitative yield.

[0308] O-Benzyl-GHB-Ser-GHB-O-benzyl (51a)

[0309] With stirring, DIPEA was added dropwise to a mixture of compound 50a (0.653 g, 2.1 mmol), 4-(benzyloxy)butanoic acid (0.42 g, 2.2 mmol), and HATU (0.82 g, 2.2 mmol) in anhydrous DMF at room temperature. After stirring for 12 h, the reaction was quenched by pouring into 5% aqueous bicarbonate solution. The aqueous layer was extracted with 3×50 mL of EtOAc. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was filtered and evaporated under vacuum. The residue was purified using silica gel (EtOAc:Hexane, 1:4) to give 51a (0.61 g, 63%).

[0310] GHB-Ser-GHB(52a)

[0311] Compound 51a (0.55 g, 1.2 mmol) was dissolved in anhydrous EtOH and stirred in the presence of 10% Pd / C (0.5 g) under an atmosphere of H. After stirring overnight, the reaction mixture was filtered through a Celite® pad and the filtrate was removed under vacuum to give the desired product 52a (0.324 g, 97%) as a sticky solid.

[0312] GHB-Asp(GHB)-GHB(52b)

[0313] GHB-Asp(GHB)-GHB (52b) was synthesized using an analogous procedure.

[0314] GHB-Ala-GHB(52c)

[0315] GHB-Ala-GHB (52c) was synthesized using an analogous procedure.

[0316] Synthesis of di-O-(3CPr) lactate: [ka]

[0317] Scheme 21. (a) Ac2O, DMAP, DCM; (b) Ethyl chloroformate, DMAP, DIPEA, DCM; (c) Pd / C, H2, EtOH, (d) 2, DCC, DMAP, DCM

[0318] O-Acetolactic acid (53a)

[0319] With stirring, acetic anhydride (0.85 g, 8.3 mmol) was added to a solution of benzyl lactate (1 g, 5.5 mmol) and DMAP (0.067 g, 0.55 mmol) in anhydrous DCM over an ice bath (0-5 °C). Upon complete addition, the ice bath was removed and the reaction was stirred at room temperature for an additional 1.5 h. The reaction was quenched by pouring into water and the mixture was extracted with 3 x 50 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum to give the acetate ester, which was used in the next step without further purification.

[0320] The acetate was subjected to hydrogenation in the presence of 10% Pd / C (0.2 g) in ethanol (25 mL) at room temperature. After stirring for 1 h, the reaction was filtered through a Celite® pad. The filtrate was evaporated in vacuum to give compound 53a as a pale yellow viscous oil (0.38 g, 55% for two steps).

[0321] 3CPr O-acetolactate (54a)

[0322] With stirring, benzyl 4-hydroxybutanoate 2 (0.56 g, 2.9 mmol) was added to a solution of O-acetolactate 53a (0.38 g, 2.09 mmol), DCC (0.595 g, 2.88 mmol), and DMAP (0.037 g, 0.3 mmol) in anhydrous DCM at 0-5 °C. The reaction mixture was allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under vacuum to give a viscous oil. The crude product was purified using silica gel (hexane:EtOAc, 9:1) to give the intermediate benzyl ester as a colorless oil, which was subjected to hydrogenation as described above to give GHB O-acetolactate 54a as a pale yellow oil (0.25 g, 40% for two steps).

[0323] Di-O-(3CPr)O-acetolactate (56a)

[0324] Di-O-(3CPr)O-acetolactate (56a) was synthesized in 48% yield (from 54a) following the same synthetic procedure as described for 54a.

[0325] O-(Ethoxycarbonyl)lactic acid (53b)

[0326] With stirring, DIPEA (1.78 g, 13.7 mmol), ethyl chloroformate (0.746 g, 6.9 mmol), and catalytic amount of DMAP were added to a solution of benzyl lactate (1 g, 5.5 mmol) in anhydrous DCM at 0-5 °C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by pouring into water and extracted with 3 x 50 mL of DCM. The DCM layer was washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under vacuum to give an oily residue. The residue was purified on silica gel (hexane: EtOAc, 95:5) to give the ethyl carbonate intermediate as a colorless oil.

[0327] The ethyl carbonate intermediate was subjected to hydrogenation in the presence of 10% Pd / C (0.25 g) in ethanol at room temperature. After stirring for 1 h, the reaction was filtered through a Celite® pad. The filtrate was evaporated in vacuo to give 53b as a pale yellow oil (0.52 g, 62% for two steps).

[0328] 3CPr O-(ethoxycarbonyl)lactate (54b)

[0329] 3CPr O-(ethoxycarbonyl)lactate (54b) was synthesized by adapting the procedure described above.

[0330] Di-O-(3CPr)O-(ethoxycarbonyl)lactate (56b)

[0331] Di-O-(3CPr)O-(ethoxycarbonyl)lactate (56b) was synthesized by employing the same procedure as described for 54a.

[0332] Synthesis of O-(2-THF)-GHB (58) [ka]

[0333] Scheme 22. (a) DCM, PPTS; (b) H2, Pd / C (10%), MeOH

[0334] Benzyl O-(2-THF)-GHB (57)

[0335] A solution of 4-hydroxybutanoate 2 (1 g, 5.1 mmol) and pyridinium p-toluenesulfonate (0.026 g, 0.1 mmol) in anhydrous dichloromethane (15 mL) was stirred on an ice bath. To this mixture, 2,3-dihydrofuran (0.43 g, 6.2 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature. After stirring for 3 h, the reaction mixture was diluted by adding 50 mL of DCM. The organic layer was transferred to a separatory funnel and washed with 5% NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under vacuum to give a pale yellow liquid. The crude product was purified on silica gel (hexane:EtOAc, 9:1) to give 57 as a colorless oil (1.18 g, 86%).

[0336] O-(2-THF)-GHB(58)

[0337] A suspension of benzyl O-(2-THF)-GHB 57 (1.1 g, 4.2 mmol) and 10% Pd / C (0.44 g) in anhydrous methanol (30 mL) was stirred under H2 at room temperature. After 1 h, the reaction was stopped and the mixture was passed through Celite®. The filtrate was evaporated in vacuo to give the desired compound 58 as a colorless oil (0.69 g, 95%).

[0338] Synthesis of 4-hydroxybutyl-O-(2-THF)-GHB (62): [ka]

[0339] Scheme 23. (a) DCM, Et3N, DMAP; (b) BH3.Me2S, anhydrous THF; (c) 2,3-dihydrofuran, PPTS, DCM; (d) H2, 10% Pd / C, MeOH

[0340] O-Benzyl-4-hydroxybutylsuccinate (59)

[0341] To a solution of 4-(benzyloxy)butan-1-ol (2 g, 11.1 mmol) in anhydrous DCM (15 mL) was added triethylamine (1.23 g, 12.2 mmol), dimethylaminopyridine (0.014 g, 0.1 mmol), and succinic anhydride (1.2 g, 12.2 mmol). After stirring at room temperature overnight, the reaction was transferred to a separatory funnel, diluted with DCM (70 mL), and extracted with 5% sodium bicarbonate solution. The bicarbonate layer was adjusted to pH 2 by addition of 0.5 M HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under vacuum to give O-benzyl-4-hydroxybutylsuccinate 59 as a waxy solid (2.41 g, 77%).

[0342] O-Benzyl-4-hydroxybutyl GHB(60)

[0343] A solution of compound 59 (1.58 g, 5.6 mmol) in anhydrous THF was cooled to -20 °C. To this was added a solution of BH3·Me2S (3.7 mL, 7.3 mmol) in THF dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was quenched by the addition of 100 mL of diethyl ether and washed with 2% aqueous potassium carbonate. The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under vacuum to give a pale yellow viscous liquid. The crude product was purified on silica gel to give compound O-benzyl-4-hydroxybutyl GHB 60 as a colorless oil (1.2 g, 80%).

[0344] O-Benzyl-4-hydroxybutyl O-(2-THF)-GHB (61)

[0345] A solution of compound 60 (1.7 g, 6.4 mmol) and pyridinium p-toluenesulfonate (0.032 g, 0.13 mmol) in anhydrous dichloromethane (15 mL) was stirred on an ice bath. To this mixture, 2,3-dihydrofuran (0.58 g, 8.3 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature. After stirring for 3 h, the reaction mixture was diluted by adding 50 mL of DCM. The organic layer was transferred to a separatory funnel and washed with 5% NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified on silica gel (hexane:EtOAc, 9:1) to give compound 61 as a colorless oil (1.03 g, 48%).

[0346] 4-Hydroxybutyl O-(2-THF)-GHB (62)

[0347] A suspension of compound 61 (1.03 g, 3.0 mmol), 10% Pd / C (0.5 g) in anhydrous methanol (30 mL) was stirred at room temperature under H2 (balloon). After stirring for 1 h, the suspension was filtered through Celite®. The filtrate was evaporated in vacuum to give compound 62 as a colorless oil (0.624 g, 84%).

[0348] Synthesis of 4-hydroxybutyl GHB esters (63a-b): [ka]

[0349] Scheme 24: (a) 4-benzyloxybutanol, DCC, DMAP, DCM; (b) Pd / C, H2, EtOH

[0350] O-Benzyl-4-hydroxybutyl O-(ethoxycarbonyl)-GHB

[0351] A solution of DCC (0.43 g, 2.1 mmol) in CHCl (4 mL) was added dropwise to a solution of 3a (0.35 g, 2.0 mmol), 4-benzyloxybutanol (0.36 g, 2.0 mmol), and DMAP (0.03 g) in CHCl (8 mL) at 0-5° C. The reaction mixture was allowed to reach room temperature and stirred for 4 h. The precipitate was filtered, washed with DCM, and the combined filtrate was evaporated to dryness. The crude product was purified by preparative HPLC to give O-benzyl-4-hydroxybutyl O-(ethoxycarbonyl)-GHB as an oil (0.455 g, 67%).

[0352] 4-Hydroxybutyl(O-ethoxycarbonyl)-GHB (63a)

[0353] A suspension of O-benzyl-4-hydroxybutyl O-(ethoxycarbonyl)-GHB (0.45 g, 1.33 mmol) and Pd / C (10% Pd, 0.3 g) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 5 h. The reaction mixture was filtered through Celite® and washed with EtOH (2 x 5 mL). The combined filtrate was evaporated under reduced pressure to dryness to give 63a as an oil (0.3 g, 91%).

[0354] 4-Hydroxybutyl O-acetyl-GHB (63b)

[0355] 4-Hydroxybutyl-O-acetyl-GHB 63b was synthesized following the same synthetic procedure as 63a.

[0356] Synthesis of di-O-(3CPr)O-(ethoxycarbonyl)-GHB (64): [ka]

[0357] Scheme 25: (a) 2, DCC, DMAP, DCM; (b) Pd / C, H2, EtOH

[0358] Di-O-(3CPr)O-(ethoxycarbonyl)-GHB (64)

[0359] Di-O-(3CPr)O-(ethoxycarbonyl)-GHB 64 was synthesized following the same synthetic procedure as that described for 4a.

[0360] Synthesis of O-(2-THF)BD (66): [ka]

[0361] Scheme 26: (a) PPTS, DCM; (b) Pd / C, H2, MeOH

[0362] O-(2-THF)O-benzyl-BD(65)

[0363] With stirring, 2,3-dihydrofuran (0.34 g, 4.8 mmol) was added dropwise to a solution of 4-benzyloxybutanol (0.72 g, 4 mmol) and pyridinium p-toluenesulfonate (0.01 g, 0.04 mmol) in anhydrous DCM (8 mL) at 0-5 °C. After addition, the reaction mixture was allowed to warm slowly to room temperature. After stirring for 2 h, the mixture was diluted by adding 50 mL DCM. The organic layer was washed with 5% NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give a pale yellow liquid. The crude product was purified on silica gel (hexane:EtOAc, 9:1) to give O-(2-THF)O-benzyl-BD 65 as a colorless oil (0.82 g, 83%).

[0364] O-(2-THF)BD(66)

[0365] A suspension of O-(2-THF)O-benzyl-BD 65 (0.82 g, 3.3 mmol), Pd / C (10% Pd, 0.25 g) in anhydrous EtOH (30 mL) was stirred under H for 2 h. The reaction mixture was filtered through Celite® and the filtrate was removed in vacuo and dried to give 66 as a pale yellow oil (0.31 g, 58%).

[0366] Synthesis of bis(3CPr) sulfite 68: [ka]

[0367] Scheme 27: (a) SOCl2, pyridine, DCM; (b) Pd / C, H2, EtOH

[0368] Bis(O-benzyl-3CPr)sulfite(67)

[0369] To a solution of 2 (0.52 g, 2.68 mmol) and pyridine (0.22 mL, 2.75 mmol) in DCM (10 mL) was added a solution of SOCl2 in DCM dropwise at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1 h and then at room temperature for 2 h. The reaction was quenched with water (a few drops) and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (80 mL) and washed with 10% aqueous NH4Cl (60 mL) and brine (50 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to give bis(O-benzyl-3CPr)sulfite 67 as a colorless oil (0.43 g, 37%).

[0370] Bis(3CPr)sulfite(68)

[0371] A suspension of 67 (0.43 g, 1 mmol) and Pd / C (10% Pd, 0.3 g) in absolute ethanol (20 mL) was stirred under H for 2 h. The reaction mixture was filtered through Celite® and the filtrate was evaporated to dryness. The residue was redissolved in EtOH and hydrogenated a second time under the same conditions for 1 h to give 68 as a viscous oil (0.21 g, 82%).

[0372] Synthesis of sugar alcohol O-(2-THF) ethers 69a-d: [ka]

[0373] Scheme 28.

[0374] General synthetic procedure

[0375] To a solution of sugar alcohol (1 equiv.) and 2,3-dihydrofuran (1.5 equiv. per sugar alcohol hydroxy group) was added PPTS (0.01 equiv. per hydroxy group). The reaction mixture was stirred at room temperature for 2–4 days. The reaction was quenched with 5% aqueous NaHCO3 (1–2 mL) and most of the dioxane was evaporated under reduced pressure. The residue was taken up in EtOAc and washed with 5% aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness to give 69a–d as viscous oils. The crude products were purified on silica gel (EtOAc / hexanes) to produce 69a–d in 85–90% yields.

[0376] Synthesis of ascorbate tetrakis-O-(tetrahydrofuran-2-yl) ether (70):

[0377] Ascorbate tetrakis-O-(tetrahydrofuran-2-yl) ether 70 was synthesized following the same general procedure described above for sugar alcohol O-(2-THF) ethers and was obtained in 33% yield as a pale yellow viscous oil.

[0378] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] EXAMPLES

[0379] Pharmacokinetic profile of GHB delivery compounds

[0380] Studies were conducted in rats to assess the pharmacokinetics of various conjugated GHB delivery compounds. Table 2 shows the mean pharmacokinetic parameters of GHB in plasma in Sprague-Dawley rats after administration via oral gavage. Blood was collected at 0.25, 0.5, 1, 2, 3, and 4 hours after dosing of the GHB delivery compounds. The GHB delivery compounds were formulated in compositions containing water, PEG-400 / water (1:1), or PEG-400 / water (1:3). Unless otherwise indicated, each administered dose was the molar equivalent of 100 mg / kg sodium oxyvert (NaGHB).

[0381] [Table 2-1] [Table 2-2] a The dose in this study was equivalent to 70 mg / kg NaGHB. The data presented have been extrapolated to 100 mg / kg (assuming dose proportionality) to facilitate comparison with other studies. b Vehicle = PEG-400 / water (1:1) c Vehicle = Water d Vehicle = PEG-400 / water (1:3) e The dose in this study was equivalent to 80 mg / kg NaGHB. The data presented have been extrapolated to 100 mg / kg (based on dose proportionality) to facilitate comparison with other studies.

[0382] The pharmacokinetic data from these studies were also used to assess the relative oral bioavailability of GHB compared to sodium oxyvate following administration of the GHB delivery compound in Sprague-Dawley rats (Table 3). Calculated % parameters (i.e., %C max or %AUC) equals the mean conjugate PK parameter / mean comparator PK parameter.

[0383] [Table 3-1] [Table 3-2] a The dose in this study was equivalent to 70 mg / kg NaGHB. The data presented have been extrapolated to 100 mg / kg (assuming dose proportionality) to facilitate comparison with other studies. b Vehicle = PEG-400 / water (1:1) c Vehicle = Water d Vehicle = PEG-400 / water (1:3) e The dose in this study was equivalent to 80 mg / kg NaGHB. The data presented have been extrapolated to 100 mg / kg (based on dose proportionality) to facilitate comparison with other studies.

[0384] All features disclosed in this specification (including the claims, abstract, and drawings), and all steps in any method or process disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0385] Unless expressly indicated otherwise, each feature disclosed in this specification (including the claims, abstract, and drawings) may be replaced with alternative features serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a generic series of equivalent or similar features.

[0386] Paragraph Claim Set A: Paragraphs [0387-0408]

[0387] Claim 1. In one embodiment of the present invention, a compound of formula I: [ka] wherein L is selected from the group consisting of hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amino acids, peptides, salts thereof, and combinations thereof; M is hydrogen, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohols, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, phosphate, sulfate, sulfamate, alkenyl, alkenylamino Carbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium nium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salt thereof,and combinations thereof), or a pharma- ceutically acceptable salt thereof.

[0388] Claim 2. The compound of formula I (claim 1), wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and salts thereof.

[0389] Claim 3. A compound of formula I (claim 1 or claim 2), wherein the peptide is a dipeptide or a tripeptide.

[0390] Claim 4. The compound, [ka] [ka] [ka] A compound of formula I (claim 1) selected from the group consisting of:

[0391] Claim 5. A composition comprising a compound of formula I (claims 1-4) or a pharma- ceutically acceptable salt of said compound, said pharma-ceutically acceptable salt being acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate. , sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, spiritol ... nitrate, dichloroacetate, edentate, ethyl sulfate, furanate, fusidate, galactate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophos The composition is selected from the group consisting of phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and mixtures thereof.

[0392] Claim 6. A method for preventing or treating a sleep disorder or syndrome in a subject in need thereof, comprising administering to the subject a composition comprising a composition of formula I (claim 5).

[0393] Claim 7. The method of claim 6 (Formula I), wherein the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treatment of a neurodegenerative disease or disorder with a drug or therapeutic compound, and the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0394] 8. The method of any one of claims 6-7, wherein the composition further comprises amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, or a combination thereof.

[0395] Claim 9. The method of any one of claims 6 to 8, wherein the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea, or shift work disorder, and the central hypersomnia disorder is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, and insufficient sleep syndrome.

[0396] Claim 10. The composition of claim 5 or the method of any one of claims 6-9, wherein the composition further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0397] Claim 11. The composition of claim 5 or the method of any one of claims 6 to 10, wherein the composition has a dosing regimen of about 1 to 2 times daily.

[0398] Claim 12. The composition of claim 5 or the method of any one of claims 6 to 11, wherein the composition has a dosing regimen of about once per day, and the composition is orally administered to a human or animal subject.

[0399] Claim 13. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, and instructions for use, wherein the compound is present in a unit dosage form, and further wherein the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, an oral tablet, and a suppository.

[0400] 14. The kit of claim 13, further comprising an additional therapeutic compound, wherein the additional therapeutic compound is selected from the group consisting of amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, and combinations thereof. In another aspect of the invention there is provided a kit as claimed in claim 14, wherein said instructions for use comprise instructions for the administration of at least one of the compounds as claimed in claims 1 to 4, a further therapeutic compound, and / or a salt thereof, or a combination thereof.

[0401] Claim 15. The kit of claim 14, wherein the additional therapeutic compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0402] Claim 16. The kit of claim 15, wherein the compound of any one of claims 1 to 4 is present in a liquid dosage form and the further therapeutic compound is present in oral powder or sachet form.

[0403] Claim 17. The kit of claim 16, wherein the additional therapeutic compound is added to a liquid dosage form of the compound prior to administration.

[0404] Claim 18. An oral formulation comprising a therapeutically effective dose of a compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0405] Claim 19. The oral formulation of claim 18, wherein the oral formulation further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0406] Claim 20. The oral formulation of claim 18 or claim 19, wherein the therapeutically effective dose is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, and a buccal tablet.

[0407] Claim 21. The oral formulation of any one of claims 18 to 20, wherein the oral formulation has a dosing regimen of about 1 to 2 times per day.

[0408] Claim 22. The oral formulation of any one of claims 18-21, wherein the oral formulation has a dosing regimen that is about once per day, and wherein the oral formulation is orally administered to a human or animal subject.

[0409] Paragraph Claim Set B: Paragraphs [0409-0433]

[0410] Claim 1. In one embodiment of the present invention, a compound of formula II: [ka] (Wherein, G is S or O; R is [ka] , hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, a arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acids, peptides, salts thereof, and combinations thereof; R 1 is an amino acid or peptide), or a pharma- ceutically acceptable salt thereof.

[0411] Claim 2. In one embodiment of the present invention, the compound of formula IV: [ka] (In the formula, Y1 and Y 2 each of which is selected from the group consisting of hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl ... and n is independently selected from the group consisting of aryl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof, and combinations thereof.

[0412] Claim 3. The compound of claim 1 or claim 2, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and salts thereof.

[0413] Claim 4. The compound according to claims 1 to 3, wherein the peptide is a dipeptide or a tripeptide.

[0414] Claim 5. The compound, [ka] [ka] 2. The compound of claim 1, selected from the group consisting of:

[0415] Claim 6. The compound, [ka] 3. The compound of claim 2, selected from the group consisting of:

[0416] Claim 7. A composition comprising a compound according to claims 1 to 6 or a pharma- ceutically acceptable salt of said compound, wherein said pharma-ceutically acceptable salt is acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate. , sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, spiritol ... nitrate, dichloroacetate, edentate, ethyl sulfate, furanate, fusidate, galactate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophos The composition is selected from the group consisting of phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and mixtures thereof.

[0417] Claim 8. A method for preventing or treating a sleep disorder or syndrome in a subject in need thereof, comprising administering to the subject a composition comprising the composition of claim 7.

[0418] 9. The method of claim 8, wherein the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treatment of a neurodegenerative disease or disorder with a drug or therapeutic compound, and further wherein the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0419] 10. The method of any one of claims 8-9, wherein the composition further comprises amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, or a combination thereof.

[0420] Claim 11. The method of any one of claims 8 to 10, wherein the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea, or shift work disorder, and the central hypersomnia disorder is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, and insufficient sleep syndrome.

[0421] Claim 12. The composition of claim 7 or the method of any one of claims 8-11, wherein the composition further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0422] Claim 13. The composition of claim 7 or the method of any one of claims 8-12, wherein the composition has a dosing regimen of about 1-2 times per day.

[0423] Claim 14. The composition of claim 7 or the method of any one of claims 8-13, wherein the composition has a dosing regimen of about once per day.

[0424] Claim 15. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, and instructions for use, wherein the compound is present in a unit dosage form, the unit dosage form being selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0425] 16. The kit of claim 15, further comprising an additional therapeutic compound, wherein the additional therapeutic compound is selected from the group consisting of amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, and combinations thereof.

[0426] Claim 17. The kit of claim 16, wherein the additional therapeutic compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0427] Claim 18. The kit of claim 17, wherein the compound of any one of claims 1 to 4 is present in a liquid dosage form and the further therapeutic compound is present in oral powder or sachet form.

[0428] Claim 19. The kit of claim 18, wherein the further therapeutic compound is added to a liquid dosage form of the compound prior to administration. In another aspect of the invention, there is provided a kit of any one of claims 16-19, wherein the instructions comprise instructions for administration of at least one of the compounds of claims 1-6, a further therapeutic compound, and / or a salt thereof, or a combination thereof.

[0429] Claim 20. An oral formulation comprising a therapeutically effective dose of a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

[0430] Claim 21. The oral formulation of claim 20, wherein the oral formulation further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0431] Claim 22. The oral formulation of claim 20 or claim 21, wherein the therapeutically effective dose is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, and a buccal tablet.

[0432] Claim 23. The oral formulation of any one of claims 20-22, wherein the oral formulation has a dosing regimen of about 1-2 times per day.

[0433] Claim 24. The oral formulation of any one of claims 20-23, wherein the oral formulation has a dosing regimen of about once per day, and further wherein the oral formulation is orally administered to a human or animal subject.

[0434] Paragraph claim set C: Paragraphs [0435-0456]

[0435] Claim 1. In one embodiment of the present invention, a compound of formula III: [ka] wherein Z is gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl ... or a pharmaceutically acceptable salt thereof.

[0436] Claim 2. The compound of claim 1, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and salts thereof.

[0437] Claim 3. The compound of claim 1 or 2, wherein the peptide is a dipeptide or a tripeptide.

[0438] Claim 4. The compound, [ka] [ka] 2. The compound of claim 1, selected from the group consisting of:

[0439] Claim 5. A composition comprising a compound according to claims 1 to 4 or a pharma- ceutically acceptable salt of said compound, wherein said pharma-ceutically acceptable salt is acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate. , sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, spiritol ... nitrate, dichloroacetate, edentate, ethyl sulfate, furanate, fusidate, galactate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophos The composition is selected from the group consisting of phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and mixtures thereof.

[0440] Claim 6. A method for preventing or treating a sleep disorder or syndrome in a subject in need thereof, comprising administering to the subject a composition comprising the composition of claim 5.

[0441] Claim 7. The method of claim 13, wherein the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treatment of a neurodegenerative disease or disorder with a drug or therapeutic compound, and the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0442] 8. The method of any one of claims 6-7, wherein the composition further comprises amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, or a combination thereof.

[0443] Claim 9. The method of any one of claims 6 to 8, wherein the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea, or shift work disorder, and the central hypersomnia disorder is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, and insufficient sleep syndrome.

[0444] Claim 10. The composition of claim 5 or the method of any one of claims 6-9, wherein the composition further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0445] Claim 11. The composition of claim 5 or the method of any one of claims 6 to 10, wherein the composition has a dosing regimen of about 1 to 2 times daily.

[0446] Claim 12. The composition of claim 5 or the method of any one of claims 6 to 11, wherein the composition has a dosing regimen of about once per day.

[0447] Claim 13. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof and instructions for use, wherein the compound is present in a unit dosage form, the unit dosage form being selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0448] 14. The kit of claim 13, further comprising an additional therapeutic compound, wherein the additional therapeutic compound is selected from the group consisting of amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, and combinations thereof.

[0449] Claim 15. The kit of claim 14, wherein the additional therapeutic compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0450] Claim 16. The kit of claim 15, wherein the compound of any one of claims 1 to 4 is present in a liquid dosage form and the further therapeutic compound is present in oral powder or sachet form.

[0451] Claim 17. The kit of claim 16, wherein the further therapeutic compound is added to a liquid dosage form of the compound prior to administration. In one embodiment of the invention, the instructions for use of the kit of claims 13-17 comprise instructions for administration of at least one of the compounds of claims 1-11, the further therapeutic compound, and / or a salt thereof, or a combination thereof.

[0452] Claim 18. An oral formulation comprising a therapeutically effective dose of a compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0453] Claim 19. The oral formulation of claim 18, wherein the oral formulation further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0454] Claim 20. The oral formulation of claim 18 or claim 19, wherein the therapeutically effective dose is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, and a buccal tablet.

[0455] Claim 21. The oral formulation of any one of claims 18 to 20, wherein the oral formulation has a dosing regimen of about 1 to 2 times per day.

[0456] Claim 22. The oral formulation of any one of claims 18-21, wherein the oral formulation has a dosing regimen that is about once per day, and wherein the oral formulation is orally administered to a human or animal subject.

[0457] Paragraph claim set D: Paragraphs [0458-0479]

[0458] Claim 1. In one embodiment of the present invention, a compound of formula V: [ka] (wherein M is hydrogen, 1,4-butanediol, 2-hydroxytetrahydrofuran, gamma-hydroxybutyrate, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, gamma-aminobutyric acid, phosphate, sulfate, sulfamate, alkenyl, alkenyl Aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, aryla ammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, thiol, amino acid, peptide, salts thereof,and combinations thereof), or a pharma- ceutically acceptable salt thereof.

[0459] Claim 2. The compound of claim 1, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and salts thereof.

[0460] Claim 3. The compound of claim 1 or 2, wherein the peptide is a dipeptide or a tripeptide.

[0461] Claim 4. The compound, [ka] 2. The compound of claim 1, selected from the group consisting of:

[0462] Claim 5. A composition comprising a compound according to claims 1 to 4 or a pharma- ceutically acceptable salt of said compound, wherein said pharma-ceutically acceptable salt is acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate. , sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, spiritol ... nitrate, dichloroacetate, edentate, ethyl sulfate, furanate, fusidate, galactate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophos The composition is selected from the group consisting of phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and mixtures thereof.

[0463] Claim 6. A method for preventing or treating a sleep disorder or syndrome in a subject in need thereof, comprising administering to the subject a composition comprising the composition of claim 5.

[0464] Claim 7. The method of claim 6, wherein the sleep disorder is a symptom of a neurodegenerative disease or disorder and / or a side effect of treatment of a neurodegenerative disease or disorder with a drug or therapeutic compound, and the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.

[0465] 8. The method of any one of claims 6-7, wherein the composition further comprises amantadine, aplindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, or a combination thereof.

[0466] Claim 9. The method of any one of claims 6 to 8, wherein the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea, or shift work disorder, and the central hypersomnia disorder is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a psychiatric condition, and insufficient sleep syndrome.

[0467] Claim 10. The composition of claim 5 or the method of any one of claims 6-9, wherein the composition further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0468] Claim 11. The composition of claim 5 or the method of any one of claims 6 to 10, wherein the composition has a dosing regimen of about 1 to 2 times daily.

[0469] Claim 12. The composition of claim 5 or the method of any one of claims 6 to 11, wherein the composition has a dosing regimen of about once per day, and the composition is orally administered to a human or animal subject.

[0470] Claim 13. A kit comprising a therapeutically effective amount of the compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, and instructions for use thereof, wherein the compound is present in a unit dosage form, and further wherein the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, an oral tablet, and a suppository.

[0471] 14. The kit of claim 13, further comprising an additional therapeutic compound, wherein the additional therapeutic compound is selected from the group consisting of amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, solriamfetol, and combinations thereof.

[0472] Claim 15. The kit of claim 14, wherein the additional therapeutic compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0473] Claim 16. The kit of claim 15, wherein the compound of any one of claims 1 to 4 is present in a liquid dosage form and the further therapeutic compound is present in oral powder or sachet form.

[0474] Claim 17. The kit of claim 16, wherein the further therapeutic compound is added to a liquid dosage form of the compound prior to administration. In another aspect of the invention, the instructions of the kit of claims 13-17 comprise instructions for administration of at least one of the compounds of claims 1-4, the further therapeutic compound, and / or a salt thereof, or a combination thereof.

[0475] Claim 18. An oral formulation comprising a therapeutically effective dose of a compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0476] Claim 19. The oral formulation of claim 18, wherein the oral formulation further comprises one or more additives selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0477] Claim 20. The oral formulation of claim 18 or claim 19, wherein the therapeutically effective dose is present in a unit dosage form, and the unit dosage form is selected from the group consisting of a sublingual tablet, a gummy, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a liquid, a thin strip, an orally disintegrating film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, and a buccal tablet.

[0478] Claim 21. The oral formulation of any one of claims 18 to 20, wherein the oral formulation has a dosing regimen of about 1 to 2 times per day.

[0479] Claim 22. The oral formulation of any one of claims 18-21, wherein the oral formulation has a dosing regimen that is about once per day, and wherein the oral formulation is orally administered to a human or animal subject.

[0480] In another embodiment of the invention, there is provided a method for preventing or treating a sleep disorder or syndrome in a subject in need thereof, comprising: [ka] or a pharma- ceutically acceptable salt of said compound.

[0481] In one alternative of this method, the sleep disorder is a symptom of neurodegenerative disease or disorder and / or a side effect of treating neurodegenerative disease or disorder with a drug or therapeutic compound.In one alternative of this method, the neurodegenerative disease or disorder can be selected from the group consisting of Parkinson's disease, primary parkinsonism, paralysis agitans, and idiopathic parkinsonism.In one alternative of this method, the sleep disorder can be selected from the group consisting of central hypersomnia, obstructive sleep apnea, or excessive daytime sleepiness associated with shift work disorder.In one alternative of this method, the central hypersomnia disorder can be selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Lewin syndrome, hypersomnia due to medical conditions, hypersomnia due to drugs or substances, hypersomnia due to mental conditions, and insufficient sleep syndrome. The compositions of the method may further comprise one or more of the following (active ingredients or compounds) such as amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samerisant, celdexmethylphenidate, and solriamfetol, or combinations thereof. In some alternatives of this method, the composition of this method may further comprise one or more additives, where the additives may be selected from the group consisting of anti-adhesive agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof. In some alternatives of this method, the composition of this method may further comprise one or more of the above-mentioned additional active ingredients / compounds with one or more of the above-mentioned additives.

[0482] In one embodiment of the above method of preventing or treating a sleep disorder or syndrome in a subject in need thereof, the composition has a dosing regimen that is about twice a day or less, more preferably, 1-2 times a day. In another embodiment, the composition has a dosing regimen that is about once a day. The composition may be administered to the subject (the subject being an animal or human) via oral, intranasal, intradermal, intramuscular, depot injection, subcutaneous, or intravenous means. In one alternative method, the composition is administered orally to the human or animal subject.

[0483] In another embodiment of the above technology, a kit is provided that includes a therapeutically effective amount of the composition of the present invention or a pharma- ceutically acceptable salt thereof (or a kit for a method of preventing or treating sleep disorders or syndromes in a subject in need of such prevention or treatment, comprising a therapeutically effective amount of the composition of the present invention), wherein the composition is in a unit dosage form.The unit dosage form may be selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast-dissolving tablets, tablets, capsules, caplets, troches, lozenges, oral powders, waters, liquids, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, oral tablets, and suppositories.Such a kit may further include one or more additional therapeutic compounds. The one or more additional therapeutic compounds may be selected from the group consisting of amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, pitolisant, reboxetine, samelisant, celdexmethylphenidate, solriamfetol, and combinations thereof. The one or more additional therapeutic compounds may be provided in a unit dosage form, where the unit dosage form is selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, troches, lozenges, oral powders, solutions, liquids, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, buccal tablets, and suppositories. In another aspect of the invention, such kits further comprise instructions for use, where the instructions comprise instructions for administration of at least one of the at least one composition, the additional therapeutic compound, and / or its (pharmaceutically acceptable) salt(s), or combinations thereof.

[0484] In any one or more of the methods or kits of paragraphs 243-246 above, the pharma- ceutically acceptable salt is selected from the group consisting of acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, Bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, Dichloroacetate, edentate, ethyl sulfate, furanate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophos The salts are selected from the group consisting of phosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrofenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and mixtures thereof.In another embodiment of the present invention, the pharma- ceutically acceptable salt may also be selected from the group further comprising salts of amphetamines (such as, for example, amphetaminonium), methylphenidate, and celdexmethylphenidate.

[0485] While the present invention has been described in conjunction with its detailed description, it will be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Formula I: 【Chemical 77】 (wherein L is selected from the group consisting of hydroxyl, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amino acids, peptides, salts thereof, and combinations thereof; M stands for hydrogen, gamma-hydroxybutyrate, gamma-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohol, ethylene glycol, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boremitol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglycitol, phosphat, sulfate, sulfamate, alkenyl, alkenylamino Carbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammo Nium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, nitro, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, thiol, amino acids, peptides, salts of these,Compounds having the structure (selected from the group consisting of combinations thereof) or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and salts thereof.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the peptide is a dipeptide or a tripeptide.

4. The aforementioned compound, 【Transformation 78】 【Chemistry 79】 【Chemistry 80】 【Chemistry 81】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

5. A composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt of said compound, wherein the pharmaceutically acceptable salt is acetate, L-aspartate, besilate, bicarbonate, carbonate, D-camsilate, L-camsilate, citrate, edisilate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphat, succinate To, sulfate, bisulfate, D-tartolate, L-tartolate, D,L-tartolate, meso-tartolate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stealtholate, tosylate, thiocyanate, acephyllinate, acetulate, aminosalicylate, ascorbat, volate, butyrate, cannolarate, cannolacarbonate, decanoate, hexanoate, colate, sipi Onate, dichloroacetate, edentate, ethylsulfate, flute, fucidate, galactalate, galacturonate, galart, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hipplat, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristoate, napadisylate, oleate, oxalate, palmitate, picrate, pivarate, propionate, pyrofoate A composition selected from the group consisting of sulfate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalilate, tribrophenate, valveate, valproate, adipate, 4-acetamidobenzoate, camsilate, octanoate, estrate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, corinate, lysinium, ammonium, troetamine, and mixtures thereof.

6. The composition according to claim 5 for preventing or treating sleep disorders or sleep syndromes in subjects requiring prevention or treatment of sleep disorders or sleep syndromes.

7. The composition according to claim 6, wherein the sleep disorder is a sign of a neurodegenerative disease or disorder, and / or a side effect of treatment of a neurodegenerative disease or disorder with a drug or therapeutic compound, and the neurodegenerative disease or disorder is selected from the group consisting of Parkinson's disease, primary parkinsonism, tremor paralysis, and idiopathic parkinsonism.

8. The composition according to claim 6, wherein the composition further comprises amantadine, aprindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, phenoldopam, istradefylline, levodopa (L-dopa), opicapon, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, almodafinil, caffeine, mazindol, modafinil, pitrisant, leboxetine, sameliant, soluriamfetol, or a combination thereof.

9. The composition according to claim 6, wherein the sleep disorder is excessive daytime sleepiness associated with central hypersomnia, obstructive sleep apnea, or shift work disorder, and the central hypersomnia is selected from the group consisting of narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical condition, hypersomnia due to a drug or substance, hypersomnia due to a mental state, and insufficient sleep syndrome.

10. The composition according to claim 5, wherein the composition further comprises one or more additives, the additives being selected from the group consisting of anti-adhesion agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, flow promoters, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, and combinations thereof.

11. The composition according to claim 5, wherein the composition is administered in a regimen of about 1 to 2 times a day.

12. The composition according to claim 5, wherein the composition has an administration regimen of approximately once a day, and the composition is administered orally to a human or animal subject.

13. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and instructions for use, wherein the compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast-dissolving tablets, tablets, capsules, caplets, lozenges, oral powders, liquids, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, oral tablets, and suppositories.

14. The kit according to claim 13, wherein the kit further comprises a further therapeutic compound, the further therapeutic compound being selected from the group consisting of amantadine, aprindol, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, phenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, trihexyphenidyl, amphetamine, almodafinil, caffeine, mazindol, modafinil, pitrisant, leboxetine, sameliant, soluriamfetol, and combinations thereof.

15. The kit according to claim 14, wherein the further therapeutic compound is present in a unit dosage form, and the unit dosage form is selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast-dissolving tablets, tablets, capsules, caplets, lozenges, oral powders, liquids, solutions, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, oral tablets, and suppositories.

16. The kit according to claim 15, wherein the compound is present in a liquid dosage form and the further therapeutic compound is present in an oral powder form or a sachet form.

17. The kit according to claim 16, wherein the further therapeutic compound is added to the liquid dosage form of the compound before administration.

18. An oral formulation comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in a therapeutically effective dose.

19. The oral formulation according to claim 18, wherein the oral formulation further comprises one or more additives, the additive being selected from the group consisting of anti-adhesion agents, binders, coatings, disintegrants, fillers, flavorings, dyes, pigments, flow promoters, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, and combinations thereof.

20. The oral formulation according to claim 18, wherein the therapeutically effective dose is present in a unit dosage form, and the unit dosage form is selected from the group consisting of sublingual tablets, gummies, chewable tablets, fast-dissolving tablets, tablets, capsules, caplets, lozenges, oral powders, liquids, solutions, thin strips, orally disintegrating films (OTFs), oral strips, syrups, suspensions, slurries, sachets, and oral tablets.

21. The oral preparation according to claim 18, wherein the oral preparation has an administration regimen in which it is administered about once or twice a day.

22. The oral preparation according to claim 18, wherein the oral preparation has an administration regimen of approximately once a day, and the oral preparation is administered orally to a human or animal subject.

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