Gamma-hydroxybutyrate delivery compounds and methods of making and using same

Abstract

Disclosed are one or more compounds comprising a chemically modified gamma-hydroxybutyrate (GHB), 2-hydroxytetrahydrofuran, and / or 1, 4-butanediol, and salts of such compounds (GHB delivery compounds and salts thereof). Also disclosed are compositions comprising at least one GHB delivery compound or salt thereof, methods of making such compounds, and methods of using such GHB delivery compounds and compositions. Methods of treatment using the compounds are also disclosed. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 333,391, filed on April 21, 2022, which is incorporated herein by reference in its entirety.

[0003] background

[0004] Gamma-hydroxybutyrate (or γ-hydroxybutyrate, "GHB") is a rapidly acting CNS (central nervous system) depressant and naturally occurring neurotransmitter. and mixed calcium, magnesium, potassium, and sodium oxybate ) has been approved by the US FDA for the treatment of narcolepsy and idiopathic hypersomnia.

[0005] Although not wishing to be bound by any particular theory, it is believed that these pharmaceutical products work primarily by producing sedation and improving sleep consolidation, thereby achieving better nighttime rest and less daytime sleepiness. However, due in part to suboptimal pharmacokinetics and oral bioavailability, high doses of the drug are required. Therefore, currently approved drugs require patients to administer the drug in two doses. The first dose is taken before bedtime, and the second dose is usually taken about 2.5 to about 4 hours later. Therefore, there is a need for treatment options with improved pharmacokinetics, including, for example, higher oral bioavailability and / or longer duration of action.

[0006] Brief Overview

[0007] The present technology provides one or more compounds for delivering GHB to human or animal subjects. In some aspects, these compounds have increased bioavailability or longer duration of action, or both, compared to sodium oxybate (NaGHB). In other aspects, based on its improved bioavailability, the compounds of the present technology can be administered to human or animal subjects at lower molar doses with therapeutic equivalence compared to NaGHB. These GHB delivery compounds are prodrugs or precursors of γ-hydroxybutyrate, salts of such compounds, and combinations thereof. In some aspects, the GHB prodrugs 2-hydroxytetrahydrofuran (2-OH-THF) and 1,4-butanediol (BD) of the present invention / currently described technology provide similar or improved oral bioavailability of GHB, similar or extended release of GHB, and / or reduced or zero sodium content compared to NaGHB. When administered as intended, the compounds of the currently described and claimed technology provide therapeutic plasma concentrations of GHB in human or animal subjects.

[0008] In at least one aspect of the present technology, there is provided a compound having a structure as shown in Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof; wherein L is selected from hydroxy, γ-hydroxybutyrate, γ-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, a salt thereof, and a combination thereof; and wherein M is selected from hydrogen, γ-hydroxybutyrate , γ-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptyl alcohol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglucitol, phosphate, sulfate, sulfamate, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkyl carbonyloxy, 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, cycloalkene alkyl, cycloheteroalkyl, 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.

[0011] Another aspect of the present technology includes compounds having the structure as shown in Formula II:

[0012]

[0013] or a pharmaceutically acceptable salt thereof; wherein G is S or O, and R is selected from 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, aryl wherein R is alkyl, alkyl, alkylsulfonylamino, 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; and wherein R 1 is an amino acid or a peptide (eg, a dipeptide or a tripeptide).

[0014] Another aspect of the present technology includes compounds having the structure of Formula III:

[0015]

[0016] or a pharmaceutically acceptable salt thereof; wherein Z is selected from the group consisting of γ-hydroxybutyrate, γ-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, salt thereof, and combination thereof.

[0017] Another aspect of the present technology includes compounds having the structure of Formula IV:

[0018]

[0019] where Y 1 and Y 2independently selected from hydroxy, γ-hydroxybutyrate, γ-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, aryl alkyl, cycloheteroalkyl, 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 combination thereof.

[0020] Another aspect of the present technology includes compounds having the structure of Formula V:

[0021]

[0022] or a pharmaceutically acceptable salt thereof; wherein M is selected from hydrogen, 1,4-butanediol, 2-hydroxytetrahydrofuran, γ-hydroxybutyrate, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptyl alcohol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglucitol, γ-aminobutyric acid, phosphate, sulfate, aminosulfonate, 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, aryl alkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl alkyl, 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.

[0023] In certain aspects of the presently described technology, the amino acids in Formula IV are selected from 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 certain aspects, the peptide can be a dipeptide or a tripeptide.

[0024] In certain aspects, at least one compound of the presently described technology having a structure of Formula I is selected from

[0025]

[0026]

[0027] In certain aspects, at least one compound of the presently described technology having a structure of Formula II is selected from

[0028]

[0029]

[0030] In certain further aspects, one or more compounds of the presently described technology having a structure of Formula III are selected from

[0031]

[0032]

[0033] In certain further aspects, at least one compound of the presently described technology having a structure of Formula IV is selected from

[0034]

[0035] In certain further aspects, one or more compounds of the presently described technology having a structure of Formula V are selected from

[0036]

[0037]

[0038] Another aspect of the present technology includes at least one composition comprising at least one of the disclosed GHB delivery compounds or compositions, or a pharmaceutically acceptable salt of said compound or composition. It will be appreciated by those skilled in the art that in another aspect of the present technology, compositions comprising unmodified GHB / NaGHB in combination with one or more of the presently described and claimed GHB delivery compounds are also contemplated.

[0039] In another aspect of the present technology, at least one method of preventing or treating a sleep disorder in a subject in need thereof is provided, the method comprising administering to the subject a composition comprising any of the disclosed GHB delivery compounds or a pharmaceutically acceptable salt of a compound thereof. In certain aspects, the sleep disorder is a symptom of a degenerative neurological disease or disorder and / or a side effect of treating a degenerative neurological disease or disorder with a drug or therapeutic compound. In another aspect, the degenerative neurological disease or disorder is selected from Parkinson's disease, idiopathic Parkinson's disease, Parkinson's disease, and / or idiopathic Parkinson's disease.

[0040] In some aspects of at least one method 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, tilolisan, reboxetine, samelisant, serdexmethylphenidate and solriamfetol or a combination thereof.

[0041] In another aspect, the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea, or shift work disorder. In another aspect, the central hypersomnia disorder is selected from narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to medical conditions, hypersomnia due to drugs or substances, hypersomnia associated with psychiatric conditions, and / or insufficient sleep syndrome.

[0042] In certain aspects, one or more compositions of the present technology further comprise one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof and / or combinations thereof.

[0043] In certain aspects, the compositions of the present technology have a dosing regimen of once a day. In other aspects, the compositions of the present technology have a dosing regimen of about twice a day.

[0044] In certain aspects, compositions of the present technology are administered orally to a human or animal subject.

[0045] 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 a pharmaceutically acceptable salt thereof and instructions for use, wherein the compound is in unit dosage form.

[0046] In certain aspects, the unit dosage form is selected from sublingual tablets, gummy tablets, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, tablets, lozenges, oral powders, solutions, liquids, thin strips, oral thin films (OTF), oral strips, syrups, suspensions, slurries, sachets, buccal tablets and / or suppositories. In further aspects, the unit dosage form is selected from transdermal patches, nasal sprays, intramuscular injections, depot injections, subcutaneous injections and / or intravenous injections. In one aspect, the unit dosage form can be packaged as a blister pack or similar unit dose delivery package or system.

[0047] In another aspect, one or more kits of the present technology further include other therapeutic compounds. In some aspects, the other therapeutic compounds are selected from amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, benzhexol, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, tilolisan, reboxetine, samelisant, serdexmethylphenidate and / or solriamfetol and combinations thereof. In another aspect, the other therapeutic compounds are in unit dosage form. In yet another aspect, the unit dosage form is a sublingual tablet, a soft candy tablet, 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 oral thin film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet and / or a suppository.

[0048] In certain aspects, the GHB delivery compound is in a liquid dosage form and the additional therapeutic compound is in an oral powder form or sachet form. In other aspects, the GHB delivery compound and the additional therapeutic compound may be in different combined dosage forms, including, but not limited to, capsules and films, or liquids and tablets.

[0049] In a further aspect, the additional therapeutic compound is added to the liquid dosage form of the GHB delivery compound prior to administration.

[0050] In certain aspects, the kit comprises instructions for use. In other aspects, the instructions for use include instructions for administering at least one GHB delivery compound, administering at least one additional therapeutic compound and / or salt thereof, or a combination thereof.

[0051] Another aspect of the present technology is an oral formulation comprising a therapeutically effective dose (eg, for the treatment of sleep disorders) of any of the disclosed GHB delivery compounds or a pharmaceutically acceptable salt thereof.

[0052] In certain aspects, the oral formulation further comprises one or more excipients, wherein the excipient is an anti-adherent, a binder, a coating agent, a disintegrant, a filler, a flavoring agent, a dye, a colorant, a glidant, a lubricant, a preservative, a sorbent, a sweetener, a derivative thereof, and / or a combination thereof. In another aspect, the therapeutically effective dose is in unit dosage form. In another aspect, the unit dosage form is a sublingual tablet, a soft candy tablet, a chewable tablet, a fast-dissolving tablet, a tablet, a capsule, a caplet, a tablet, a lozenge, an oral powder, a solution, a liquid, a thin strip, an oral thin film (OTF), an oral strip, a syrup, a suspension, a slurry, and / or a buccal tablet.

[0053] In some aspects, the oral formulation has a dosing schedule of about 2 times a day. In some aspects, the oral formulation has a dosing schedule of about 1 time a day. In another aspect, the oral formulation is orally administered to a human or animal subject.

[0054] In certain aspects, the pharmaceutically acceptable salt is acetate, L-aspartate, benzenesulfonate, bicarbonate, carbonate, D-camphorsulfonate, L-camphorsulfonate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartaric acid salt, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acefyllinate, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate, cholate, cyclopentanepropionate, dichloroacetate, edentate , ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidenesulfonate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylic acid sulfate (salicyls The invention also includes but is not limited to benzoic acid, succinate, thiocyanate ...

[0055] In other embodiments and aspects of the present technology, the pharmaceutically acceptable salt may be amphetaminium or serdexmethylphenidate.

[0056] Another aspect of the present technology is at least one method of preventing or treating a sleep disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a GHB delivery compound or a pharmaceutically acceptable salt of the compound selected from:

[0057]

[0058] In certain aspects of the method, the sleep disturbance is a symptom of a degenerative neurological disease or disorder and / or is a side effect of treating a degenerative neurological disease or disorder with a drug or therapeutic compound. In another aspect, the degenerative neurological disease or disorder is Parkinson's disease, idiopathic Parkinson's disease, Parkinson's disease, and idiopathic Parkinson's disease.

[0059] In another aspect 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate and solriamfetol or a combination thereof.

[0060] In another aspect, the sleep disorder is excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea or shift work disorder. In another aspect, the central hypersomnia disorder is narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by medical conditions, hypersomnia caused by drugs or substances, hypersomnia associated with psychiatric conditions, insufficient sleep syndrome and / or a combination thereof.

[0061] In some aspects of the method, the composition further comprises one or more excipients, wherein the excipient is an antiadherent, a binder, a coating agent, a disintegrant, a filler, a flavoring agent, a dye, a colorant, a glidant, a lubricant, a preservative, a sorbent, a sweetener, a derivative thereof and / or a combination thereof. In another aspect, the composition has a dosing regimen of about 2 times a day. In another aspect, the composition has a dosing regimen of once a day. In some aspects, the composition is orally administered to a human or animal subject.

[0062] Another aspect of the present technology is a kit comprising any of the disclosed compositions of therapeutically effective amounts, wherein the composition is in unit dosage form. In one aspect, the unit dosage form is a sublingual tablet, a soft candy tablet, a chewable tablet, a fast dissolving tablet, a tablet, a capsule, a caplet, a tablet, a lozenge, an oral powder, a solution, a liquid, a thin strip, an oral thin film (OTF), an oral strip, a syrup, a suspension, a sachet, a slurry, a buccal tablet, and / or a suppository. In one aspect, the unit dosage form can be packaged as a blister pack or similar unit dose delivery package or system.

[0063] In yet another aspect, the kit further comprises other therapeutic compounds. In yet another aspect, the other therapeutic compounds are amantadine, aplindore, apomorphine, benztropine, bromocriptine, carbidopa, entacapone, fenoldopam, istradefylline, levodopa (L-dopa), opicapone, pramipexole, rasagiline, ropinirole, rotigotine, safinamide, tolcapone, benzhexol, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, tilolisan, reboxetine, samelisant, serdexmethylphenidate and / or solriamfetol and combinations thereof. In yet another aspect, the other therapeutic compounds are in unit dosage form.

[0064] In another aspect, the unit dosage form is a sublingual tablet, a soft candy tablet, 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 oral thin film (OTF), an oral strip, a syrup, a suspension, a sachet, a slurry, a buccal tablet and / or a suppository.

[0065] In another aspect, the pharmaceutically acceptable salt is acetate, L-aspartate, benzenesulfonate, 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, methanesulfonate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L -Tartrate, D,L-tartrate, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acephylline, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate, cholate, cyclopentanepropionate, dichloroacetate, edetic acid edentate, ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidenesulfonate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyro Phosphate, salicylate, salicylate sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camphorsulfonate, octanoate, etopoate, ethanesulfonate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline salt, lysinium salt, ammonium, troethamine and / or mixtures thereof.

[0066] In other embodiments, the pharmaceutically acceptable salt may be amphetaminium or serdexmethylphenidate. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Various aspects of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0069] Figure 1 The metabolic pathways of 2-hydroxytetrahydrofuran and 1,4-butanediol to γ-hydroxybutyrate are depicted.

[0070] Figure 2Shown are the pharmacokinetic properties of NaGHB relative to 3CPr O-(ethoxycarbonyl)-GHB (4a) following oral administration in rats (all doses are molar equivalents of 70 mg / kg NaGHB).

[0071] Figure 3 Shown are the pharmacokinetic properties of NaGHB relative to 3CPr O-(ethoxycarbonyl)-GHB (4a) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0072] Figure 4 The pharmacokinetic properties of NaGHB relative to 3CPr sulfamate (33) following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0073] Figure 5 The pharmacokinetic properties of NaGHB relative to (2-THF) salicylate (34b) following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0074] Figure 6 Shown are the pharmacokinetic properties of NaGHB relative to O-(2-THF)-glutaric acid (35) and bis(2-THF) malonate (41c) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0075] Figure 7 The pharmacokinetic properties of NaGHB relative to O-(2-THF)O-(ethoxycarbonyl)-GHB (38) and bis(2-THF) maleate (39) following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0076] Figure 8 Shown are the pharmacokinetic properties of NaGHB relative to bis(2-THF) glutarate (41a) and bis(2-THF) succinate (41b) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0077] Fig. 9 The pharmacokinetic properties of NaGHB relative to bis(2-THF) adipate (41d) following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0078] Fig.10The pharmacokinetic properties of NaGHB relative to O-(2-THF)-GHB (58) following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0079] Fig.11 Shown are the pharmacokinetic properties of NaGHB relative to 4-hydroxybutyl(O-ethoxycarbonyl)-GHB (63a) and 4-hydroxybutyl O-acetyl-GHB (63b) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0080] Fig.12 Shown are the pharmacokinetic properties of NaGHB relative to O-(2-THF)BD (66) following oral administration in rats (all doses are molar equivalents of 80 mg / kg NaGHB).

[0081] Fig.13 Shown are the pharmacokinetic properties of NaGHB relative to O-(2-THF)BD (66) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0082] Fig.14 Shown are the pharmacokinetic properties of NaGHB relative to tri-O-(2-THF) ether (69a) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0083] Fig.15 Shown are the pharmacokinetic properties of NaGHB relative to erythritol tetra-O-(2-THF)ether (69b) and xylitol penta-O-(2-THF)ether (69c) following oral administration in rats (all doses are molar equivalents of 100 mg / kg NaGHB).

[0084] Fig.16 The pharmacokinetic properties of NaGHB relative to 2-OH-THF following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0085] Fig.17 The pharmacokinetic properties of NaGHB relative to GBL and BD following oral administration in rats are shown (all doses are molar equivalents of 100 mg / kg NaGHB).

[0086] Fig.18 Shown are the pharmacokinetic properties of NaGHB relative to O-(ethoxycarbonyl)-GHB following oral administration in rats (all doses are molar equivalents of 80 mg / kg NaGHB).

[0087] Detailed Description

[0088] The present technology generally describes novel compounds and compositions for delivering gamma-hydroxybutyrate ("GHB") to human or animal subjects. In certain aspects, these compounds have increased bioavailability or longer duration of action, or both, compared to sodium gamma-hydroxybutyrate ("NaGHB"). In further aspects, due to their increased bioavailability, the compounds of the present technology can be administered to human or animal subjects at lower molar doses that are therapeutically equivalent to NaGHB. These GHB delivery compounds are prodrugs or precursors of gamma-hydroxybutyrate, salts thereof, other derivatives thereof, and combinations thereof. The present technology also generally relates to methods of preparing these novel compounds and compositions comprising GHB delivery compounds and kits thereof.

[0089] It will be appreciated by those skilled in the relevant art that the present disclosure is not limited to the specific methods, protocols and reagents described herein, and may vary accordingly. It will also be understood that the terminology used herein is only used for the purpose of describing specific embodiments, and is not intended to limit the scope of the present disclosure or the appended claims.

[0090] Unless defined otherwise, 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.

[0091] The singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. These articles mean one or more than one (i.e., at least one). The term "and / or" refers to any one or more of the list connected with "and / or". As an example, "x and / or y" refers to any element in the three-element set {(x), (y), (x, y)}. In other words, "x and / or y" refers to "one or both of x and y". As another example, "x, y and / or z" refers to any element in the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z)}. In other words, "x, y and / or z" refers to "one or more of x, y and z".

[0092] The term "about" used in connection with numerical values ​​in this specification and claims indicates an accuracy interval familiar and acceptable to those skilled in the art. Generally, such an accuracy interval is ±10%.

[0093] Where ranges are given, the endpoints are included. In addition, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges may assume any specific value or sub-range within the range in different embodiments of the present disclosure, accurate to one-tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0094] The term "exemplary" refers to a non-limiting example, instance or illustration. As used herein, the term "eg" and "for example" lists one or more non-limiting aspects, examples, instances or illustrations.

[0095] The use of the terms "gamma-hydroxybutyrate," "gamma-hydroxybutyric acid," or "GHB" are synonymous and include salt forms thereof.

[0096] The use of the term "GHB delivery compound" refers to a compound that is configured to deliver GHB to a human or animal subject. In certain aspects, following administration, these compounds will be converted into GHB in vivo.

[0097] In certain aspects, the GHB delivery compounds contain one or more chiral centers. In certain embodiments, these chiral centers are part of a ligand and / or linker that is attached to, for example, GHB, 2-OH-THF, or 1,4-butanediol to produce a chiral GHB delivery compound. In further aspects, compositions of these chiral GHB delivery compounds contain a racemic mixture. In other aspects, compositions containing GHB delivery compounds are not in a racemic mixture. In still further aspects, compositions containing one or more chiral GHB delivery compounds can be an optically active mixture, a racemic mixture, a single stereoisomer, a single enantiomer, a mixture of stereoisomers, a mixture of enantiomers, or a combination thereof.

[0098] The term "oxoacid" (i.e., oxyacids, oxo acids, oxy acids, oxiacids, oxacids) refers to a class of compounds that contain oxygen, at least one other element, and at least one hydrogen combined with the oxygen, and which generate a conjugate base by losing a positive hydrogen ion (proton).

[0099] "Amino acid" means an organic compound containing a carboxyl (-COOH) and an amino (-NH2) group and a variable side chain group. The amino acids that can be used in the present technology can be natural, standard, non-standard, uncommon, synthetic and / or essential amino acids, and can be L-amino acids or D-amino acids or combinations thereof. Examples of amino acids used to practice the present technology include, but are not limited to, 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, γ-aminobutyric acid, 6-aminocaproic acid, sarcosine, carnitine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthiol amino acid, 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-abrin, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-Hydroxy-L-tryptophan, 1-aminocyclopropyl-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-fluorophenyl Formic acid, alloisoleucine, tert-leucine, 3-phenylserine, isoserine, 3-aminovaleric acid, 2-amino-suberic 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).

[0100] As used herein, the term "prodrug" refers to a substance that is converted from an inactive form of a drug to an active drug by a chemical or biological reaction in vivo. In one aspect of the present technology, the prodrug is, for example, a conjugate of at least one drug, GHB, and at least one ligand. Thus, in one aspect of the present technology, the GHB delivery compound is a prodrug.

[0101] As used herein, the term "ligand" refers to a moiety in the structure of a GHB delivery compound that is not a component of GHB or a GHB precursor.

[0102] As used herein, the term "precursor" refers to a substance that is converted into another substance in vivo through a metabolic process or biological reaction. In one aspect of the present technology, the GHB delivery compound is, for example, a precursor, or a conjugate of a precursor and at least one ligand. Thus, in one aspect of the present technology, the GHB delivery compound is a prodrug of a precursor. In one aspect of the present technology, the precursor is converted into GHB in vivo ("GHB precursor"). In one aspect of the present technology, the precursor can be, for example, 2-hydroxytetrahydrofuran or 1,4-butanediol.

[0103] As used herein, "3CPr" refers to 3-carboxypropyl, "BD" refers to 1,4-butanediol or 1,4-dihydroxybutane, "2-THF" refers to tetrahydrofuran-2-yl or 2-tetrahydrofuranyl, "2-OH-THF" refers to 2-hydroxytetrahydrofuran, "Bn" refers to benzyl, "BOP" refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, "DCC" refers to N,N'-dicyclohexylcarbodiimide, "DCM" refers to dichloromethane, "DIPEA" refers to N,N-diisopropylethylamine, "DMAP" refers to 4-dimethylaminopyridine, "DMF" refers to dimethylformamide, and "HATU" refers to hexafluorophosphate azabenzotriazole tetramethyluronium "Hydroxybenzotriazole" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, and "TLC" refers to thin layer chromatography.

[0104] Prodrugs are often useful because in some aspects, they may be easier to use or process than the parent drug. For example, they may be more bioavailable by oral administration, while the parent drug is not. Compared with the parent drug, the prodrug can also have improved solubility and / or stability in the pharmaceutical composition. Although not wanting to be bound by any particular theory, it is foreseen that in at least one aspect, the GHB delivery compound is designed as a prodrug of a precursor, which is metabolized to GHB after release (or when available). In some aspects, after in vivo administration, the prodrug is chemically converted into a biologically, pharmaceutically or therapeutically more active form of the compound. In some aspects, the prodrug is enzymatically or chemically metabolized to a biologically, pharmaceutically or therapeutically more active form of the compound by one or more steps or processes. Again, not wanting to be bound by any particular theory, in order to produce a prodrug, the pharmaceutically active compound is modified so that the active compound will be released / available after in vivo administration. Prodrugs are designed to alter the metabolic, pharmacokinetic, or transport characteristics of a drug in some way to reduce side effects or toxicity, increase tolerance, improve tolerability, increase bioavailability and / or aqueous solubility, improve the flavor of the drug, or alter other characteristics or properties of the drug in other discrete aspects.

[0105] General structure

[0106] According to certain aspects, the present technology provides GHB in the form of a compound. More specifically, the GHB delivery compound comprises at least one organic compound covalently bonded or linked to GHB, 2-OH-THF and / or 1,4-butanediol. A general structure of the GHB delivery compound of the present technology can be represented by the following general formula I:

[0107]

[0108] Wherein L comprises at least one component selected from the following: hydroxyl, γ-hydroxybutyrate, γ-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 its salt.

[0109] In certain aspects, 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. Various combinations of L are obvious to the skilled person.

[0110] M comprises at least one component selected from the group consisting of hydrogen, γ-hydroxybutyrate, γ-aminobutyric acid, 1,4-butanediol, 2-hydroxytetrahydrofuran, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptyl alcohol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglucitol, 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, aryl amino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkane alkyl, cycloheteroalkyl, 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.

[0111] In certain aspects, M 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. Various combinations of M are obvious to the skilled person.

[0112] Specific compounds of formula I include, but are not limited to

[0113]

[0114]

[0115] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula II:

[0116]

[0117] Where G is S or O, and

[0118] R is selected from 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, aryl R is a cycloalkyl, cycloalkyl, 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; and R 1 It is an amino acid or a peptide.

[0119] Specific compounds of formula II include, but are not limited to

[0120]

[0121]

[0122] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula III:

[0123]

[0124] wherein Z comprises at least one component selected from the group consisting of γ-hydroxybutyrate, γ-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.

[0125] In certain aspects, Z 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. Various combinations of Z are obvious to the skilled person.

[0126] Specific compounds of formula III include, but are not limited to

[0127]

[0128]

[0129] Another general structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula IV:

[0130]

[0131] where Y 1 and Y 2independently selected at least one (1) to five (5) times from the following: hydroxy, 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, 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.

[0132] In some ways, each Y 1 and / or Y 2 Independently selected from the groups / components listed in the previous paragraph at least two to at least five times. Independent selection applies to each Y 1 or Y 2 and also applies to Y 1 and Y 2 In some respects, each Y 1 and / or Y 2 Containing 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, and others. 1 and Y 2 The various combinations of are obvious to the ordinary technician. For example, in one aspect, Y 1 Contains three components such as, for example, O-(2-THF)-GHB-GHB, and Y 2 Contains two components such as, for example, BD-GHB.

[0133] Specific compounds of formula IV include, but are not limited to

[0134]

[0135] Another structure of the GHB delivery compounds of the present technology can be represented by the following general structural formula V:

[0136]

[0137] wherein M is selected from hydrogen, 1,4-butanediol, 2-hydroxytetrahydrofuran, γ-hydroxybutyrate, sugar alcohol, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptyl alcohol, isomalt, lactitol, maltotriitol, maltotetraitol, polyglucitol, γ-aminobutyric acid, 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, aryl aminocarbonyl, 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, 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.

[0138] In certain aspects, 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, and others. Various combinations of M are obvious to those of ordinary skill.

[0139] In a further aspect, M comprises 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, and others.

[0140] Specific compounds of formula V include, but are not limited to

[0141]

[0142]

[0143] The GHB delivery compound may also exist in salt form. In certain aspects, the pharmaceutically acceptable salt of the GHB delivery compound is a single salt or a mixed salt, wherein one or more salts are selected from acetate, L-aspartate, benzenesulfonate, 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, methanesulfonate, pamoate, phosphate, succinate, tartrate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acephylline, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate, cholate, cyclopentyl propionate, dichloroacetate, edentate, ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidenesulfonate, oleate, oxalate, palmitate, picrate, pivalate salt, propionate, pyrophosphate, salicylate, salicylate sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camphorsulfonate, octanoate, etopoate, ethanesulfonate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline salt, lysinium salt, ammonium, troethamine and / or mixtures thereof.

[0144] In other embodiments, the pharmaceutically acceptable salt may be amphetaminium or serdexmethylphenidate.

[0145] The GHB delivery compounds of the present technology can be formulated into a composition for administration to humans or animals. The composition can further comprise one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof and / or combinations thereof.

[0146] Physiological benefits

[0147] Although not wishing to be bound by any particular theory, it is believed that the GHB delivery compounds defined above of the presently claimed and described technology can be administered orally and release active GHB or GHB precursors after hydrolysis in vivo following administration. Since many of the phosphate, ketoacid, amino acid and / or peptide components ("ligands") of the present invention are naturally occurring metabolites or mimetics thereof, or pharmaceutically active compounds, these GHB delivery compounds can be readily recognized by physiological systems, resulting in the hydrolysis and release of GHB. The claimed compounds themselves have no or limited pharmacological activity and therefore may follow a different metabolic pathway than the pharmaceutically active GHB drug. By selecting an appropriate ligand, the release of GHB or GHB precursors into the systemic circulation can be controlled even if the GHB delivery compound is administered by routes other than oral administration.

[0148] In at least one embodiment, the GHB delivery compound may release GHB or a GHB precursor similar to free or unmodified GHB / NaGHB or a GHB precursor. In other embodiments, the GHB delivery compound may release GHB or a GHB precursor in a controlled or sustained manner, or in an extended manner. In yet another embodiment, administration of an amount or portion of a dose of a GHB delivery compound to a human or animal subject may provide a rapid release of GHB or a GHB precursor, while administration of an amount or portion of the same dose of a GHB delivery compound to a human or animal subject may provide GHB or a GHB precursor in a controlled or sustained manner, or in an extended manner. This may be achieved, for example, by designing a GHB delivery compound that is readily absorbed and has some, but not complete, resistance to first-pass metabolism. Thus, an amount or portion of a dose of a GHB delivery compound administered to a human or animal subject will release GHB or a GHB precursor systemically prior to providing a rapid rise in blood concentrations of GHB or a GHB precursor, and an amount or portion of the same dose of a 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 a GHB precursor in a controlled, sustained or extended manner.

[0149] In another embodiment, compositions comprising GHB delivery compounds of the present technology comprise at least two different GHB delivery compounds, wherein at least one GHB delivery compound will release GHB or a GHB precursor similar to free or unmodified GHB / NaGHB or a GHB precursor, and at least one other GHB delivery compound will release GHB or a GHB precursor in a controlled or sustained manner or in an extended manner.

[0150] In yet another embodiment, a composition comprising GHB delivery compounds of the present technology comprises unmodified GHB / NaGHB and at least one GHB delivery compound, wherein the unmodified GHB / NaGHB will provide a rapid onset of GHB blood concentrations and the at least one GHB delivery compound will release GHB or a GHB precursor in a controlled or sustained manner or in an extended manner.

[0151] Although not wanting to be bound by any particular theory, in at least one further embodiment, it is believed that controlled release of GHB or a precursor of GHB can potentially alleviate certain side effects and improve the safety profile of the parent drug. These side effects may include, for example, anxiety, balance disorders, bruxism, confusional states, loss of appetite, low mood, depression, diarrhea, dizziness, dry mouth, enuresis, falls, fatigue, feeling drunk, headache, hyperhidrosis, insomnia, irritability, muscle cramps, nausea, parasomnias, paresthesias, snoring, drowsiness, tremors, vomiting, and weight loss. In addition, GHB is also prone to substance abuse.

[0152] When GHB or a GHB precursor is conjugated to certain ligands, a substantial portion, or at least a certain amount or portion, of the resulting GHB delivery compound ("prodrug") is stable after oral administration through a first-pass metabolic process in the liver. Again, without wishing to be bound by any particular theory, it is believed that in certain aspects, the GHB delivery compound subsequently releases the GHB or GHB precursor in a controlled, sustained or prolonged manner in the systemic circulation. In other aspects, GHB delivery compounds that may at least partially undergo first-pass metabolism have improved bioavailability and / or are preferentially absorbed by the brain compared to unmodified GHB / NaGHB. Thus, these GHB delivery compounds of the presently described and claimed technology may be administered at lower molar doses compared to unmodified GHB / NaGHB with equivalent therapeutic efficacy.

[0153] The disclosed GHB delivery compounds can be used to prevent or treat sleep disorders, particularly sleep disorders affecting subjects suffering from degenerative neurological diseases or disorders.

[0154] In addition, other GHB-related compounds may also be formulated into compositions and used to prevent or treat sleep disorders, such as those affecting subjects with degenerative neurological diseases or disorders. These GHB-related compounds may include, but are not limited to

[0155]

[0156] These sleep disorders include, but are not limited to, daytime sleepiness associated with central hypersomnia disorders, obstructive sleep apnea, or shift work disorder. Non-limiting examples of central hypersomnia disorders include narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical condition, hypersomnia due to medications or substances, hypersomnia associated with a psychiatric condition, and insufficient sleep syndrome.

[0157] Certain sleep disorders (including, for example, excessive daytime sleepiness, narcolepsy and hypersomnia) may be caused by the primary symptoms of a degenerative neurological disease or disorder, or may be the result of treatment of a degenerative neurological disease or disorder. Non-limiting examples of degenerative neurological diseases or disorders include Parkinson's disease, primary Parkinson's disease, Parkinson's disease and idiopathic Parkinson's disease.

[0158] In certain treatment regimens, the GHB delivery compound or GHB related compound is shown to be particularly useful for improving the sleep quality of subjects with nocturnal sleep disorders. Depending on the sleep disorder prevented or treated, the GHB delivery compound or GHB related compound can be used in combination with one or more therapeutic compounds that improve daytime wakefulness. In a non-limiting embodiment, these therapeutic compounds can be amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, tilolisan, reboxetine, samelisant, serdexmethylphenidate and solriamfetol or a combination thereof.

[0159] In some treatment regimens, the GHB delivery compound or GHB related compound is shown to be particularly useful for treating sleep disorders in subjects with Parkinson's disease, primary Parkinson's disease, Parkinson's paralysis and idiopathic Parkinson's disease. According to the sleep disorder prevented or treated, GHB delivery compound or GHB related compound can be used in combination with another therapeutic compound. In a non-limiting embodiment, the therapeutic compound can be 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, tilolisane, reboxetine, samelisant, serdexmethylphenidate and solriamfetol or a combination thereof.

[0160] In addition, according to the treatment method, the composition can be administered about twice a day, alternatively, at least about once a day. Although the composition can be formulated for oral administration, such as as an oral formulation, it should be understood by a person of ordinary skill in the relevant art that the composition can be formulated for any administration method, including, but not limited to, intravenous or intranasal administration.

[0161] The GHB delivery compound, GHB-related compound or composition can also be provided in the form of a kit, for example, a kit comprising a therapeutically effective amount of any of the disclosed GHB delivery compounds or GHB-related compounds. 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. Since a kit can contain one unit dosage form or multiple unit dosage forms, this makes administration easy. For example, if the GHB delivery compound in the kit is intended to be administered once a day for 30 days, the kit can contain 30 separate unit dosage forms. The unit dosage form can be, for example, a sublingual tablet, a soft candy tablet, a chewable tablet, a fast-dissolving tablet, a tablet, a capsule, a caplet, a tablet, a lozenge, an oral powder, a solution, a liquid, a thin strip, an oral thin film (OTF), an oral strip, a syrup, a suspension, a sachet, a slurry, a buccal tablet and / or a suppository. In one aspect, the unit dosage form can be packaged as a blister pack or a similar unit dose delivery package or system.

[0162] In some aspects, the kit may include additional therapeutic compounds. For example, if the kit is intended for use in treating sleep disorders affecting subjects with degenerative neurological diseases or disorders, the kit may further contain 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, tilolisane, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, or a combination thereof.

[0163] In one aspect, the GHB delivery compound or GHB related compound is in liquid dosage form and the additional therapeutic compound is in oral powder form or sachet form.

[0164] In certain aspects, the additional therapeutic compound is added to the liquid dosage form of the GHB delivery compound prior to administration. In certain aspects, the unit dose of the GHB delivery compound may be the maximum tolerated dose. The maximum tolerated dose is the highest dose of the GHB delivery compound that does not cause unacceptable side effects. In these aspects, the GHB delivery compound may 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 may then be added to the liquid dosage form, such as a bottle, and shaken to mix with the GHB delivery compound. The subject may then drink the combined dose in the liquid dosage form, or pour it into a glass, cup, or other delivery container.

[0165] In certain aspects, the GHB delivery compounds of the present technology are present in the composition in an amount that is molar equivalent to a dose of NaGHB in the range of about 0.1 g to about 18 g / day, alternatively about 1 g to about 14 g / day, alternatively about 2 g to about 10 g / day, or alternatively about 4.5 g to about 9 g / day. One skilled in the art will appreciate that the presently described technology and ranges include all subranges within the ranges (and subranges within those subranges) on a daily (i.e., 24 hour) basis and divided doses within that daily (24 hour) time period. For example, 0.1 g to 0.2 g, to 0.3 g, to 0.4 g, to 0.5 g, to 0.6 g, to 0.7 g, to 0.8 g, to 0.9 g, to 1.0 g, to 1.1 g, to 1.2 g, to 1.3 g, to 1.4 g, to 1.5 g, to 1.6 g, to 1.7 g, to 1.8 g, to 1.9 g, to 2.0 g, to 2.1 g, to 2.2 g, to 2.3 g, to 2.4 g, to 2.5 g, to 2.6 g, to 2.7 g, to 2.8 g, to 2.9 g, to 3.0 g, to 3.1 g, to 3.2 g, to 3.3 g, to 3.4g, to 3.5g, to 3.6g, to 3.7g, to 3.8g, to 3.9g, 4.0g, to 4.1g, to 4.2g, to 4.3g, to 4.4g, to 4.5g, to 4.6g, 4.7g, to 4.8g, to 4.9g, to 5.0g, to 5.1g, to 5.2g, to 5.3g, to 5.4g, to 5.5g, to 5.6g, to 5.7g, to 5.8g, to 5.9g, to 6.0g, to 6.1g, to 6.2g, to 6.3g, to 6.4g, to 6.5g, to 6.6g, to 6.7g g, to 6.8g, to 6.9g, to 7.0g to 7.1g, to 7.2g, to 7.3g, to 7.4g, to 7.5g, to 7.6g, to 7.7g, to 7.8g, to 7.9g, to 8.0g, to 8.1g, to 8.2g, to 8.3g, to 8.4g, to 8.5g, to 8.6g, to 8.7g, to 8.8g, to 8.9g, 9.0g, to 9.1g, to 9.2g, to 9.3g, to 9.4g, to 9.5g, to 9.6g, to 9.7g, to 9.8g, to 9.9g, to 10.0g, to 10.1g, to 10.2g, to 10.3g, to 10.4g, to 10.5g, to 10.6g, to 10.7g, to 10.8g, to 10.9g, to 11.0g, to 11.1g, to 11.2g, to 11.3g, to 11.4g, to 11.5g, to 11.6g, to 11.7g, to 11.8g, to 11.9g, to 12.0g, to 12.1g, to 12.2g, to 12.3g, to 12.4g, to 12.5g, to 12.6g, to 12.7g, to 12.8g, to 12.9g, to 13.0g, to 13.1g, to 13.2g, to 13.3g, to 13.4g, to 13.5g, to 13.6g, to 13.7g, to 13.8g, to 13.9g, to 14.0g, to 14.1g, to 14.2g, to 14.3g, to 14.4g, to 14.5g, to 14.6g, to 14.7g, to 14.8g, to 15.0g, to 15.1g, to 15.2g, to 15.3g, to 15.4g, to 15.5g, To 15.6g, to 15.7g, to 15.8g, to 15.9g, to 16.0g, to 16.1g, to 16.2g, to 16.3g, to 16.4g, to 16.5g, 16.6g, to 16.7g, to 16.8g, to 16.9g, to 17.0g, 17.1g, to 17.2g, to 17.3g, to 17.4g, to 17.5g, to 17.6g, to 17.7g, to 17.8g, to 17.9g, to 18.0g, and others. It should also be understood that the present technology can be administered in doses within an appropriate measurement range, such as milligrams, grams, etc., depending on the treatment needs. .

[0166] Synthesis scheme

[0167] Reference to the following synthesis schemes will better understand the technology described herein and its advantages. These schemes are provided to describe specific aspects of the present technology. By providing these specific schemes, the applicant does not limit the scope and spirit of the present technology.

[0168] Synthesis of Benzyl O-Benzyl GHB (2):

[0169]

[0170] Scheme 1. (a) TEA, DMAP, DCM; (b) BH3·Me2S, THF

[0171] O-Benzyl-succinic acid (1)

[0172] 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 reactant was diluted with 100 mL of DCM and further extracted with 5% NaHCO3 aqueous solution (3×50 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 obtain compound 1 (1.58 g, 76%) as a white solid.

[0173] O-Benzyl GHB(2)

[0174] To a stirred solution of succinic acid monobenzyl ester 1 (1 g, 4.8 mmol) in anhydrous THF (10 mL) was added borane dimethyl sulfide (0.471 g, 6.24 mmol) dropwise at -20 °C. The reaction was stirred at -20 °C for 1 h and then stirred at room temperature for another 5 h. The reaction was cooled by placing it over 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 obtain compound 2 (0.484 g, 52%) as a colorless viscous liquid.

[0175] Synthesis of 3CPrGHB conjugates (4a-b):

[0176]

[0177] 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 (cat), DCM

[0178] O-(Ethyloxycarbonyl)-GHB(3a):

[0179] A solution of ethyl chloroformate (0.615 mL, 6.42 mmol) in DCM (2 mL) was added to a solution of 4-hydroxy-butyric acid benzyl ester 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 hours. 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 produce benzyl O-(ethoxycarbonyl)-GHB (1.35 g, 99%) as an oil.

[0180] 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 passed through Filtered. The filter cake was washed with EtOH (2 x 10 mL). The combined filtrates were evaporated to dryness to give 3a as an oil in quantitative yield.

[0181] 3CPr O-(ethoxycarbonyl)-GHB(4a):

[0182] 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 hours. The precipitate was filtered and washed with DCM, and the combined filtrate was evaporated to dryness. The crude product was purified by preparative HPLC to produce O-benzyl-3CPr O-(ethoxycarbonyl)-GHB (0.75 g, 85%) as an oil.

[0183] 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 passed through Filter. The filter cake was washed with EtOH (2 x 5 mL). The combined filtrates were evaporated under reduced pressure and dried to give 4a as an oil (0.51 g, 92%)

[0184] O-Acetyl-GHB(3b):

[0185] 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 dropwise a solution of Ac2O (0.36 mL, 3.86 mmol) in DCM (2 mL) at 0-5°C. After addition, the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and the DCM was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 10% NH4Cl aqueous solution, brine, dried over anhydrous Na2SO4 and evaporated to dryness to yield benzyl O-acetyl-GHB (0.72 g, 98%) as an oil.

[0186] Compound 3b was synthesized in quantitative yield following the same procedure as described above for 3a.

[0187] 3CPr O-acetyl-GHB (4b):

[0188] 3CPr O -acetyl-GHB 4b was synthesized in 75% overall yield following the same synthetic procedure as 4a.

[0189] Synthesis of GHB-Gly-GHB-GHB (10):

[0190]

[0191] Scheme 3. (a) HATU, DIPEA, DMF; (b) Pd / C, H2, MeOH; (c) 4-benzyloxybutyric acid, HATU, DIPEA, DMF; (d) TFA, DCM; (e) 5, HATU, DIPEA, DMF; (f) Pd / C, H2, EtOH

[0192] Cbz-Gly-GHB- t Bu(6a)

[0193] 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 was added tert-butyl 4-hydroxybutyrate 5 (1.53 g, 9.56 mmol) dropwise at room temperature under argon atmosphere. After stirring for 12 hours, the reaction was quenched by pouring onto a 5% aqueous bicarbonate solution. The aqueous layer was extracted with 3×50 mL of EtOAc. The organic layer was washed with water and brine in sequence and dried over anhydrous Na2SO4. The organic layer was filtered and evaporated under vacuum, and the residue was purified on silica gel (EtOAc: hexane, 1:4) to produce compound 6a (2.64 g, 78%).

[0194] Gly-GHB- t Bu(6b)

[0195] A solution of 6a (2.64 g, 7.5 mmol) in anhydrous EtOH (30 mL) was stirred at room temperature under H2 in the presence of Pd / C (1 g). After stirring for 2 h, the reaction was passed through The mixture was filtered through a pad of Celite® and the filtrate was evaporated under vacuum to afford compound 6b as a colorless viscous liquid in quantitative yield.

[0196] O-Benzyl-GHB-Gly-GHB- t Bu(8a)

[0197] Compound 8a was obtained by adapting the procedure described for 6a. Yield: 38%.

[0198] O-Benzyl-GHB-Gly-GHB(8b)

[0199] Compound 8a was treated with 30% TFA in DCM at room temperature for 30 minutes. After the reaction was complete, 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.

[0200] O-Benzyl-GHB-Gly-GHB-GHB- t Bu(9)

[0201] Compound 9 was synthesized by adopting the procedure described above (for 6a).

[0202] GHB-Gly-GHB-GHB(10)

[0203] Compound 9 was first deprotected with 30% TFA in DCM, followed by catalytic hydrogenation to provide compound 10.

[0204] Synthesis of bis(3CPr) carbonate (13a-b):

[0205]

[0206] Scheme 4. (a) triphosgene, pyridine, toluene; (b) 2, N-methylimidazole; (c) 1,4-cyclohexadiene, Pd / C, MeOH; (d) NaHCO3, water / CH3CN

[0207] Benzyl O4-chlorocarbonyl-GHB(11)

[0208] A solution of triphosgene (3 g, 10.1 mmol) in toluene (10 mL) was cooled in an ice-water bath (0-5 ° C). Anhydrous pyridine (0.913 g, 11.6 mmol) was added dropwise thereto under an inert atmosphere. After stirring for 30 min, 4-hydroxybutyric acid benzyl ester (1.5 g, 7.7 mmol) was added dropwise to the reaction mixture. The ice-water bath was removed, and the reactant was stirred for another 1.5 hours. 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 obtain the chloroformate derivative 11 as a colorless oil, which was used in the next step without further purification.

[0209] Bis(O-benzyl-3CPr) carbonate (12)

[0210] A solution of 4-hydroxybutyric acid benzyl ester 2 (0.755 g, 3.89 mmol) in 3 mL of N-methylimidazole was cooled in an ice-water bath (0-5 ° C) under an inert atmosphere. A solution of chloroformate 11 (1 g, 3.89 mmol) in DCM (2 mL) was added dropwise thereto. The ice-water bath was removed and the reaction was run for another 2 hours. 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 obtain the desired product 12 (1.2 g, 74%) as a viscous liquid.

[0211] Bis(3CPr) Carbonate (13a)

[0212] To a stirred solution of dibenzyl 4,4'-(carbonylbis(oxy))dibutyrate 12 (1.03 g, 2.49 mmol) in 20 mL of anhydrous methanol was added 1,4-cyclohexadiene (2 g, 24.9 mmol, 10 equiv) and 10% Pd / C (2 g) under an inert atmosphere. The precursor was completely consumed within 90 min as determined by TLC analysis. The suspension was passed through Filtered through a pad of Celite and the filtrate evaporated under vacuum to give the desired compound 13a (0.54 g, 92%) as a waxy solid.

[0213] Bis(3CPr) Carbonate, Disodium(13b)

[0214] The acid 13a was converted to its sodium salt by treatment with 2 equivalents of NaHCO3 solution. The solution was lyophilized to yield the disodium salt 13b as a white solid. Yield: quantitative.

[0215] Synthesis of 3CPr carbonate:

[0216]

[0217] Scheme 5. (a) Glycerol, pyridine, CHCl3; (b) Pd / C, H2, EtOH; (c) 4-benzyloxybutanol, pyridine, DCM

[0218] Glycerol tri(O-benzyl-3CPr carbonate)(14)

[0219] 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 hours, quenched with water (a 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 yield carbonate derivative 14 (0.42 g, 56%) as an oil.

[0220] Glycerol tris(3CPr carbonate)(15):

[0221] 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 at room temperature under H2 (balloon) for 5 h. The reaction mixture was filtered, washed with MeOH (3×5 mL) and the combined filtrates were evaporated under reduced pressure to give the carbonate derivative 15 (0.22 g, 86%) as a viscous oil.

[0222] O-Benzyl-3CPr O-Benzyl-4-hydroxybutyl carbonate (16)

[0223] 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 hours. 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 yield carbonate derivative 16 (0.41 g, 68%) as an oil.

[0224] 3CPr4-Hydroxybutyl Carbonate (17)

[0225] A suspension of 16 (0.41 g, 1.02 mmol), Pd / C (0.4 g) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 4 h. The reaction mixture was filtered, washed with EtOH (2×5 mL) and the combined filtrates were evaporated under reduced pressure to give 4-hydroxybutyl 3CPr carbonate 17 (0.21 g, 93%) as an oil.

[0226] Synthesis of sulfonylcarbamic acid 3CPr esters (19a-j and 21):

[0227]

[0228] Scheme 6. DCM, 0-5°C; (b) TEA, benzyl protected amino acid, DCM, 0-5°C; (c) Pd / C, H2, EtOH; (d) NH3 / EtOH

[0229] O-Benzyl-(Val)-N-yl-sulfonylcarbamic acid O-benzyl-3CPr ester (18a)

[0230] 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 hour, 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 yield 18a (0.71, 90%) as an oil.

[0231] (Val)-N-sulfonylcarbamic acid 3CPr ester (19a)

[0232] A suspension of 18a (0.7 g, 1.38 mmol), Pd / C (0.65 g) in EtOH (25 mL) was stirred under H2 (balloon) at room temperature for 3 h. The reaction mixture was passed through Filtered, washed with EtOH (2 x 10 mL), the combined filtrates were evaporated under reduced pressure and dried to give 19a (0.43 g, 95%) as a white solid.

[0233] (Amino acid)-N-sulfonylcarbamic acid 3CPr ester (19b-j)

[0234] (Ala)-N-yl-sulfonylcarbamic acid 3CPr ester (19b), (β-Ala)-N-yl-sulfonylcarbamic acid 3CPr ester (19c), (Phe)-N-yl-sulfonylcarbamic acid 3CPr ester (19d), (Tyr)-N-yl-sulfonylcarbamic acid 3CPr ester (19e), (Ser)-N-yl-sulfonylcarbamic acid 3CPr ester (19f), (Lys)-N-yl-sulfonylcarbamic acid 3CPr ester (19g), (Asp)-N-yl-sulfonylcarbamic acid 3CPr ester (19h), (Gly)-N-yl-sulfonylcarbamic acid 3CPr ester (19i) and (Gly-Gly)-N-yl-sulfonylcarbamic acid 3CPr ester (19j) were synthesized according to the same synthetic procedure as described for 19a.

[0235] Ethoxysulfonylcarbamic acid O-benzyl-3CPr ester (20)

[0236] 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, an ethanolic solution of 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 yield 20 (0.24 g, 47%) as an oil.

[0237] Ethoxysulfonylcarbamic acid 3CPr ester (21)

[0238] Compound 20 was deprotected following the same procedure as described for 18a to give the title compound 21 as an oil.

[0239] Synthesis of acylcarbamic acid 3CPr ester (23a-b):

[0240]

[0241] Scheme 7. (a) Benzoyl isocyanate, DCM; (b) Ethoxycarbonyl isocyanate, DCM; (c) Pd / C, H2, EtOH

[0242] Benzoylcarbamic acid O-benzyl-3CPr ester (22a)

[0243] To a solution of benzyl 4-hydroxybutyrate 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 at 0-5 °C for another 1 h and then quenched with water (a 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 yield 22a (0.45 g, 88%) as an oil.

[0244] Benzoylcarbamic acid 3CPr ester (23a)

[0245] 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 hours. The reaction mixture was passed through Filtered. The filter cake was washed with EtOH (2 x 8 mL) and the combined filtrates were evaporated under reduced pressure to give 23a (0.32 g, 97%) as a white solid.

[0246] N-(Ethoxycarbonyl)carbamic acid 3CPr ester (23b)

[0247] Compound 23b was synthesized as a white solid in 71% overall yield following the same procedure as described for 23a.

[0248] Synthesis of N-(ethoxycarbonyl)thiocarbamic acid 3CPr ester (25):

[0249]

[0250] Scheme 8. (a) EtOC(O)NCS, TEA, DCM; (b) Pd / C, H2, EtOH

[0251] N-(Ethoxycarbonyl)thiocarbamic acid O-benzyl-3CPr ester (24)

[0252] To a solution of benzyl 4-hydroxybutyrate 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% NH4Cl aqueous solution (50 mL), brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to produce compound 24 (0.35 g, 29%) as an oil.

[0253] N-(Ethoxycarbonyl)thiocarbamic acid 3CPr ester (25)

[0254] 24 was deprotected under catalytic hydrogenation as described previously to provide compound 25 in 98% yield.

[0255] Synthesis of 3CPr benzenesulfonylcarbamate (27):

[0256]

[0257] Scheme 9. (a) PhC(O)NCO, DCM; (b) Pd / C, H2, EtOH

[0258] Benzenesulfonylcarbamic acid O-benzyl-3CPr ester (26)

[0259] To a solution of benzyl 4-hydroxybutyrate 2 (0.41 g, 2.1 mmol) in DCM (10 mL) was added a solution of benzyl 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 (a few drops) and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC to yield 26 (0.62 g, 78%) as an oil.

[0260] Benzenesulfonylcarbamic acid 3CPr ester (27)

[0261] 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 hours. The reaction mixture was passed through Filtered. The filter cake was washed with EtOH (2 x 8 mL) and the combined filtrates were evaporated under reduced pressure to give 27 (0.41 g, 89%) as a solid.

[0262] Synthesis of 3CPr phosphorylcarbamate (29a-c):

[0263]

[0264] Scheme 10. (a) dichlorophosphoryl isocyanate, DCM; (b) NaOEt, EtOH; (c) Gly-OEt.HCl, TEA, DCM; (d) 2, pyridine, DCM; (e) Pd / C, H2, EtOH

[0265] Diethoxyphosphorylcarbamic acid O-benzyl-3CPr ester (28a)

[0266] Dichlorophosphoryl isocyanate (0.142mL, 1.44mmol) was added to a solution of benzyl 4-hydroxybutyrate (0.28g, 1.44mmol) in DCM (10mL) at 0-5°C. The reaction mixture was stirred at 0-5°C for 1 hour. A solution of NaOEt in EtOH (1.5mL, 21% by weight) was added dropwise at 0-5°C. The mixture was stirred at 0-5°C for 3h and then quenched with 10% NH4Cl aqueous solution (10mL). DCM was removed under reduced pressure. The residue was distributed between EtOAc (80mL) and 10% NH4Cl aqueous solution (50mL). The EtOAc portion was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to produce 28a (0.36g, 67%) as an oil.

[0267] Diethoxyphosphorylcarbamic acid 3CPr ester (29a)

[0268] A suspension of 28a (0.36 g, 0.96 mmol), Pd / C (10% Pd, 0.16 g) in EtOH (12 mL) was stirred under H2 (balloon) for 1.5 h. The reaction mixture was passed through Filtration, washing with EtOH (2 x 4 mL) and evaporation of the combined filtrates under reduced pressure gave compound 29a as an oil in quantitative yield.

[0269] Bis(O-ethylglycine)-phosphorylcarbamate O-benzyl-3CPr ester (28b)

[0270] To a solution of benzyl 4-hydroxybutyrate 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 hours. 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 hours and then at room temperature for 1 hour. The reactants were quenched with water and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 10% NH4Cl aqueous solution and brine, dried over anhydrous Na2SO4 and evaporated to dryness. The product was purified by preparative HPLC to produce 28b (0.44 g, 65%) as an oil.

[0271] Bis(O-ethylglycine)-phosphorylcarbamate 3CPr ester (29b)

[0272] Compound 28b was deprotected following the same procedure as described for 27a to give compound 29b in 81% yield.

[0273] Bis(3CPr)-phosphorylcarbamate O-benzyl-3CPr ester (28c)

[0274] To a solution of 4-hydroxybutyric acid benzyl ester 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 hours and then at room temperature for 2 hours. The reactant was quenched with water and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with 10% NH4Cl aqueous solution (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and evaporated to dryness. The product was purified by preparative HPLC to produce 28c (0.43 g, 51%) as an oil.

[0275] Bis(3CPr)-phosphorylcarbamate 3CPr ester (29c)

[0276] Compound 28c was deprotected following the same procedure as described for 27a to give compound 29c in quantitative yield.

[0277] Synthesis of diethyl 3CPr phosphate (31):

[0278]

[0279] Scheme 11. (a) diethyl chlorophosphate, pyridine, DCM; (b) Pd / C, H2, EtOH

[0280] Diethyl O-benzyl-3CPr phosphate (30)

[0281] A solution of diethyl chlorophosphate (0.58 mL, 4 mmol) in DCM (3 mL) was added to a solution of benzyl 4-hydroxybutyrate 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 dissolved in EtOAc (100 mL), washed with 10% NH4Cl aqueous solution (50 mL), 5% NaHCO3 aqueous solution (50 mL) and brine, dried over anhydrous Na2SO4 and evaporated to dryness. The phosphate derivative was purified by preparative HPLC to produce diethyl phosphate O-benzyl-3CPr ester 30 (0.9 g, 85%) as an oil.

[0282] Diethyl 3CPr phosphate (31)

[0283] 30 was deprotected under catalytic hydrogenation as described previously to afford compound 31 as an oil in 96% yield.

[0284] Synthesis of 3CPr sulfamic acid ester:

[0285]

[0286] Scheme 12. (a) aminosulfonyl chloride, dimethylacetamide, 0-5°C; (b) Pd / C, H2, EtOH

[0287] O-Benzyl-3CPr Sulfamic Acid Ester (32)

[0288] To a solution of benzyl 4-hydroxybutyrate 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 hour and then poured into a 10% aqueous NaCl solution (975 mL). The aqueous solution was extracted with EtOAc (100 mL), and the extract was washed with a 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 yield 32 (1.41 g, 91%) as an oil.

[0289] Aminosulfonic acid 3CPr ester (33)

[0290] 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 passed through Filtered and the filter cake was washed with EtOH (2 x 10 mL).The combined filtrates were evaporated under reduced pressure to give 33 as a white solid in quantitative yield.

[0291] Synthesis of (2-THF) esters (34a-b and 35):

[0292]

[0293] Scheme 13. (a) PPTS, DCM; (b) Pd / C, H2, EtOH

[0294] Benzoic acid (2-THF) ester (34a)

[0295] 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 while stirring in an ice-water bath (0-5 ° C). 2,3-dihydrofuran (0.743 g, 10.6 mmol) was added dropwise to the mixture under an inert atmosphere. Once the addition was complete, the ice-water bath was removed. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution and brine solution. 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 produce 34a (1.1 g, 72%) as a colorless liquid.

[0296] Salicylic acid (2-THF) ester (34b)

[0297] (2-THF) salicylate (34b) was synthesized as a colorless liquid in 67% yield following the above procedure.

[0298] Benzyl (2-THF) glutarate (34c)

[0299] To a stirred solution of benzyl glutarate (0.5 g, 2.25 mmol) and 5 mg pyridinium p-toluenesulfonate (PPTS) (0.02 mmol) in anhydrous dichloromethane was added 2,3-dihydrofuran (0.205 g, 2.93 mmol) dropwise at 0 ° C under an inert atmosphere. The reaction mixture was slowly warmed to room temperature. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution 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 obtain the desired product 34c (0.570 g, 87%) as a colorless liquid.

[0300] O-(2-THF)-glutaric acid (35)

[0301] Benzyl (2-THF) glutarate 34c (0.57 g, 1.95 mmol) was dissolved in anhydrous tetrahydrofuran and stirred at room temperature under H2 in the presence of 10% Pd / C (0.6 g). After 3 h, the suspension was passed through The filtrate was removed under vacuum to give the desired product 35 (0.337 g, 86%) as a viscous liquid.

[0302] Synthesis of O-(2-THF)O-(ethoxycarbonyl)-GHB (38):

[0303]

[0304] Scheme 14. (a) Ethyl chloroformate, pyridine; (b) Pd / C, H2, THF; (c) PPTS, DCM

[0305] O-(Ethoxycarbonyl)-4-hydroxybutyric acid benzyl ester (36)

[0306] While stirring, ethyl chloroformate (0.805 g, 7.42 mmol) was added dropwise to a solution of 4-hydroxybutyric acid benzyl ester 2 (1.2 g, 6.18 mmol) in anhydrous pyridine (15 mL) at 0-5 ° C under an inert atmosphere. The reactant was slowly warmed to room temperature and stirred. After 2 h, the reaction was stopped and the volume was reduced under vacuum. The residue was dissolved in EtOAc and the organic layer was washed with saturated NH4Cl aqueous solution, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under vacuum. The residue was purified on silica gel (hexane: EtOAc, 9: 1) to obtain a carbonate derivative 36 as a viscous liquid.

[0307] O-(Ethoxycarbonyl)-GHB(37)

[0308] 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 The filtrate was evaporated under vacuum to give O-(ethoxycarbonyl)-GHB 37 as a viscous liquid. Yield: 0.45 g (65%).

[0309] O-(2-THF)O-(ethoxycarbonyl)-GHB(38)

[0310] 2,3-dihydrofuran (0.233g, 3.32mmol) was added dropwise to a stirred solution of compound 37 (0.45g, 2.55mmol) and 8mg p-toluene pyridinium sulfonate (0.03mmol) in anhydrous dichloromethane at 0°C under an inert atmosphere. The reaction mixture was slowly warmed to room temperature. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution 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 obtain the desired product 38 (0.385g, 61%) as a viscous liquid.

[0311] Synthesis of carboxylic acid bis(2-THF) esters (39, 40, 41a-d).

[0312]

[0313] Scheme 15. (a) PPTS, DCM

[0314] Bis(2-THF)maleate(39)

[0315] While 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 on an ice-water bath (0-5 ° C) under an inert atmosphere. Once the addition was complete, the ice-water bath was removed. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution 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 produce 39 (1.39 g, 85%) as a waxy solid.

[0316] Fumaric acid bis(2-THF) ester (40)

[0317] Fumaric acid bis(2-THF) ester (40) was synthesized in 75% yield as a viscous liquid following the above procedure (for 39).

[0318] Dicarboxylic acid bis(2-THF) ester (41a-d)

[0319] 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 yields of 61%, 67%, 53% and 73%, respectively.

[0320] Synthesis of di-O-(2-THF)ethers (42 and 43).

[0321]

[0322] Scheme 16. (a) PPTS, DCM

[0323] Bis-O-(2-THF)BD(42)

[0324] While 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 on an ice-water bath (0-5 ° C) under an inert atmosphere. Once the addition was complete, the ice-water bath was removed. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution 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 provide compound 42 (1.06 g, 84%) as a colorless oil.

[0325] Bis-O-(2-THF)1,3-dihydroxyacetone (43)

[0326] Bis-O-(2-THF)1,3-dihydroxyacetone (43) was synthesized as a colorless oil in 66% yield according to the same procedure as above.

[0327] Synthesis of coumaric acid conjugate (44) of (2-THF):

[0328]

[0329] Scheme 17. (a) PPTS, DCM

[0330] O-(2-THF) p-Coumaric acid (2-THF) ester (44)

[0331] While stirring, 2,3-dihydrofuran (0.194g, 2.77mmol) was added dropwise to a mixture of p-coumaric acid (0.35g, 2.13mmol) and p-toluene pyridinium sulfonate (0.005g, 0.02mmol) in anhydrous dichloromethane at 0°C under an inert atmosphere. The mixture was slowly warmed to room temperature. The reaction was monitored by TLC and stopped after completion. The reaction mixture was transferred into a separatory funnel, diluted with DCM, and the organic layer was washed with 5% NaHCO3 aqueous solution 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 obtain the desired product 44 (0.222g, 34%) as a viscous liquid.

[0332] Synthesis of O-acetyl-4-hydroxybutyl salicylate (45):

[0333]

[0334] Solution 18.

[0335] O-Acetyl-4-hydroxybutyl salicylate (45)

[0336] While 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 under vacuum and the residue was dissolved in EtOAc. The organic layer was washed with saturated NH4Cl solution, water and brine. The EtOAc layer was collected on anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum and the residue was purified on silica gel (hexane: EtOAc, 9: 1) to obtain the desired product 45 (0.297 g, 37%) as a viscous liquid.

[0337] Synthesis of GHB amide (47a-i):

[0338]

[0339] 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)

[0340] O-Benzyl-GHB-Phe-O-Benzyl (46a)

[0341] To a solution of 4-benzyloxybutyric acid (0.3 g, 1.5 mmol), HOBt (0.23 g, 1.6 mmol) in THF (10 mL) was added dropwise DCC (0.33 g, 1.6 mmol) in THF (3 mL) 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% NH4Cl aqueous solution (50 mL), 5% NaHCO3 aqueous solution (50 mL) and brine (25 mL), dried over Na2SO4 and evaporated to dryness. The crude product was purified on silica gel to yield O-benzyl-GHB-Phe 46a (0.61 g, 93%).

[0342] GHB-Phe(47a)

[0343] A suspension of 46a (0.61 g, 1.4 mmol), Pd / C (0.5 g, 10% Pd) in EtOH (15 mL) was stirred under H2 (balloon) at room temperature for 5 h. The reaction mixture was passed through Filtered and the filter cake was washed with EtOH (2 x 8 mL).The combined filtrates were evaporated under reduced pressure to give 47a (0.33 g, 94%) as a solid.

[0344] GHB-Tyr (47b), GHB-Lys (47c) and GHB-Pro (47d) were synthesized following the same procedure as described for 47a.

[0345] O-Benzyl-GHB-Leu-O-Benzyl (46e)

[0346] To a solution of 4-benzyloxybutyric 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 at room temperature for 6 h, the suspension was filtered and the filtrate was evaporated to dryness to provide 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) and washed with 5% NaHCO3 aqueous solution (50 mL) and brine (40 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified on silica gel to give amide 46e as an oil (0.54 g, 90%).

[0347] GHB-Leu(47e)

[0348] A suspension of (4-(benzyloxybutyryl))leucine benzyl ester (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 passed through Filtered and the filter cake was washed with EtOH (2 x 8 mL).The combined filtrates were evaporated under reduced pressure and dried to give 47e (0.29 g, 99%) as a white solid.

[0349] GHB-Val(47f) and GHB-Phe-Leu(47g)

[0350] GHB-Val (47f) and GHB-Phe-Leu (47g) were synthesized according to the above procedure.

[0351] O-Benzyl-GHB-Ala-O-Benzyl (46h)

[0352] While 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 onto 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 amount was purified using silica gel (EtOAc: hexane, 1:4) to provide 46h (1.3 g, 72%)

[0353] GHB-Ala (47h)

[0354] (4-(Benzyloxy)butyryl)alanine benzyl ester 46h (1.3 g, 3.7 mmol) was dissolved in anhydrous EtOH (20 mL) and hydrogenated in the presence of Pd / C (0.5 g, 10% Pd). The reaction was stopped after stirring for 3 h and then passed through The mixture was filtered through a pad of Celite® and the filtrate was evaporated in vacuo to give the desired amide 47h (0.61 g, 95%) as a waxy solid.

[0355] GHB-Asp(47i)

[0356] GHB-Asp(47i) was synthesized according to the above procedure.

[0357] Synthesis of GHB amide esters (52a-c):

[0358]

[0359] Scheme 20. (a) BOP, HOBt, DIPEA, DMF; (b) 4N HCl / dioxane; (c) HATU, DIPEA, DMF; (d) Pd / C, H2, EtOH

[0360] Boc-Ser-GHB-O-Benzyl(49a)

[0361] While stirring, benzyl 4-hydroxybutyrate (0.35 g, 1.8 mmol) and DIPEA (0.650 g, 4.8 mmol) were added to Boc-Ser( tInto a solution of 4-(4-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. After stirring for 12 h, the reaction was quenched by pouring on 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%).

[0362] Ser-GHB-O-Benzyl (50a)

[0363] Compound 49a (0.9 g, 2 mmol) was dissolved in 4(N) HCl / dioxane (12 mL) and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The residue was co-evaporated with isopropyl acetate to give deprotected compound 50a in quantitative yield.

[0364] O-Benzyl-GHB-Ser-GHB-O-Benzyl (51a)

[0365] While 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 reactant was quenched by pouring on a 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 produce 51a (0.61 g, 63%).

[0366] GHB-Ser-GHB(52a)

[0367] 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 H2 atmosphere. After stirring overnight, the reaction mixture was passed through Filter through a pad of Celite® and remove the filtrate under vacuum to give the desired product 52a (0.324 g, 97%) as a gummy solid.

[0368] GHB-Asp(GHB)-GHB(52b)

[0369] A similar procedure was used to synthesize GHB-Asp(GHB)-GHB (52b).

[0370] GHB-Ala-GHB(52c)

[0371] A similar procedure was used to synthesize GHB-Ala-GHB (52c).

[0372] Synthesis of di-O-(3CPr) lactate:

[0373]

[0374] Scheme 21. (a) Ac2O, DMAP, DCM; (b) Ethyl chloroformate, DMAP, DIPEA, DCM; (c) Pd / C, H2, EtOH, (d) 2, DCC, DMAP, DCM

[0375] O-Acetolactate (53a)

[0376] While 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 on an ice bath (0-5 °C). The ice bath was removed once the addition was complete and the reaction was stirred at room temperature for another 1.5 h. The reaction was quenched by pouring onto 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, which was used in the next step without further purification.

[0377] The acetate was hydrogenated in ethanol (25 mL) at room temperature in the presence of 10% Pd / C (0.2 g). After stirring for 1 h, the reaction was passed through The filtrate was evaporated under vacuum to give compound 53a (0.38 g, 55% in 2 steps) as a light yellow viscous oil.

[0378] O-Acetolactate 3CPr ester (54a)

[0379] While stirring, benzyl 4-hydroxybutyrate 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 slowly warmed to room temperature. After overnight stirring, 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 hydrogenated as described above to give O-acetolactate GHB ester 54a (0.25 g, 40% in 2 steps) as a pale yellow oil.

[0380] Di-O-(3CPr)O-acetolactate (56a)

[0381] Di-O-(3CPr)O-acetolactate (56a) was synthesized in 48% yield (starting from 54a) following the same synthetic procedure as described for 54a.

[0382] O-(Ethoxycarbonyl)lactic acid (53b)

[0383] While stirring, DIPEA (1.78 g, 13.7 mmol), ethyl chloroformate (0.746 g, 6.9 mmol) and a 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 reactants were quenched by pouring on water and extracted with 3×50 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 obtain an oily residue. The residue was purified on silica gel (hexane: EtOAc, 95: 5) to obtain an ethyl carbonate intermediate as a colorless oil.

[0384] The ethyl carbonate intermediate was hydrogenated in ethanol at room temperature in the presence of 10% Pd / C (0.25 g). After stirring for 1 h, the reaction was passed through The filtrate was evaporated in vacuo to give 53b (0.52 g, 62% in 2 steps) as a light yellow oil.

[0385] O-(Ethoxycarbonyl) lactic acid 3CPr ester (54b)

[0386] O-(Ethoxycarbonyl)lactate 3CPr (54b) was synthesized by adopting the above procedure.

[0387] Di-O-(3CPr)O-(ethoxycarbonyl) lactate (56b)

[0388] Di-O-(3CPr)O-(ethoxycarbonyl)lactate (56b) was synthesized by employing the same procedure as described for 54a.

[0389] Synthesis of O-(2-THF)-GHB(58)

[0390]

[0391] Scheme 22. (a) DCM, PPTS; (b) H2, Pd / C (10%), MeOH

[0392] Benzyl O-(2-THF)-GHB(57)

[0393] A solution of 4-hydroxybutyrate 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. 2,3-dihydrofuran (0.43 g, 6.2 mmol) was added dropwise to the mixture. The reaction mixture was slowly warmed to room temperature. After stirring for 3 h, the reaction mixture was diluted by adding 50 mL of DCM. The organic layer was transferred into 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 obtain a light yellow liquid. The crude product was purified on silica gel (hexane: EtOAc, 9: 1) to obtain 57 (1.18 g, 86%) as a colorless oil.

[0394] O-(2-THF)-GHB(58)

[0395] 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 at room temperature under H2. The reaction was stopped after 1 h and the mixture was passed through The filtrate was evaporated under vacuum to afford the desired compound 58 (0.69 g, 95%) as a colorless oil.

[0396] Synthesis of 4-hydroxybutyl O-(2-THF)-GHB (62):

[0397]

[0398] Scheme 23. (a) DCM, Et3N, DMAP; (b) BH3.Me2S, anhydrous THF; (c) 2,3-dihydrofuran, PPTS, DCM; (d) H2, 10% Pd / C, MeOH

[0399] O-Benzyl-4-hydroxybutyl succinate (59)

[0400] To a solution of 4-(benzyloxy)butane-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 overnight at room temperature, the reaction was transferred into a separatory funnel, diluted with DCM (70 mL), and extracted with 5% sodium bicarbonate solution. The bicarbonate layer was adjusted to pH 2 by adding 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-hydroxybutyl succinate 59 (2.41 g, 77%) as a waxy solid.

[0401] O-Benzyl-4-hydroxybutyl GHB(60)

[0402] A solution of compound 59 (1.58 g, 5.6 mmol) in anhydrous THF was cooled to -20 °C. A solution of BH3·Me2S (3.7 mL, 7.3 mmol) in THF was added dropwise thereto. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was quenched by adding 100 mL of ether and washed with 2% aqueous potassium carbonate solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under vacuum to obtain a light yellow viscous liquid. The crude product was purified on silica gel to obtain compound O-benzyl-4-hydroxybutyl GHB 60 (1.2 g, 80%) as a colorless oil.

[0403] O-Benzyl-4-hydroxybutyl O-(2-THF)-GHB(61)

[0404] 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. 2,3-dihydrofuran (0.58 g, 8.3 mmol) was added dropwise to the mixture. The reaction mixture was slowly warmed 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 obtain compound 61 (1.03 g, 48%) as a colorless oil.

[0405] 4-Hydroxybutyl O-(2-THF)-GHB(62)

[0406] A suspension of compound 61 (1.03 g, 3.0 mmol) and 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 passed through Filtered. The filtrate was evaporated under vacuum to give compound 62 (0.624 g, 84%) as a colorless oil.

[0407] Synthesis of 4-hydroxybutyl GHB ester (63a-b):

[0408]

[0409] Scheme 24: (a) 4-Benzyloxybutanol, DCC, DMAP, DCM; (b) Pd / C, H2, EtOH

[0410] O-Benzyl-4-hydroxybutyl O-(ethoxycarbonyl)-GHB

[0411] A solution of DCC (0.43 g, 2.1 mmol) in CH2Cl2 (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 CH2Cl2 (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 yield O-benzyl-4-hydroxybutyl O-(ethoxycarbonyl)-GHB (0.455 g, 67%) as an oil.

[0412] 4-Hydroxybutyl(O-ethoxycarbonyl)-GHB(63a)

[0413] 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 passed through Filtered and washed with EtOH (2 x 5 mL).The combined filtrates were evaporated under reduced pressure and dried to give 63a (0.3 g, 91%) as an oil.

[0414] 4-Hydroxybutyl O-acetyl-GHB(63b)

[0415] 4-Hydroxybutyl O-acetyl-GHB 63b was synthesized following the same synthetic procedure as 63a.

[0416] Synthesis of di-O-(3CPr)O-(ethoxycarbonyl)-GHB (64):

[0417]

[0418] Scheme 25: (a) 2, DCC, DMAP, DCM; (b) Pd / C, H2, EtOH

[0419] Di-O-(3CPr)O-(ethoxycarbonyl)-GHB(64)

[0420] Di-O-(3CPr)O-(ethoxycarbonyl)-GHB 64 was synthesized following the same synthetic procedure as described for 4a.

[0421] Synthesis of O-(2-THF)BD (66):

[0422]

[0423] Scheme 26: (a) PPTS, DCM; (b) Pd / C, H2, MeOH

[0424] O-(2-THF)O-Benzyl-BD(65)

[0425] While 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 slowly warmed to room temperature. After stirring for 2 h, the mixture was diluted by adding 50 mL of 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 obtain a light yellow liquid. The crude product was purified on silica gel (hexane: EtOAc, 9: 1) to obtain O-(2-THF)O-benzyl-BD 65 (0.82 g, 83%) as a colorless oil.

[0426] O-(2-THF)BD(66)

[0427] 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 H2 for 2 h. The reaction mixture was passed through Filtered, and the filtrate was removed under vacuum and dried to yield 66 (0.31 g, 58%) as a light yellow oil.

[0428] Synthesis of bis(3CPr)sulfite 68:

[0429]

[0430] Scheme 27: (a) SOCl2, pyridine, DCM; (b) Pd / C, H2, EtOH

[0431] Bis(O-benzyl-3CPr)sulfite(67)

[0432] 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 dropwise a solution of SOCl2 in DCM 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 reactant was quenched with water (a few drops) and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (80 mL) and washed with 10% NH4Cl aqueous solution (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 produce bis (O-benzyl-3CPr) sulfite 67 (0.43 g, 37%) as a colorless oil.

[0433] Bis(3CPr)sulfite(68)

[0434] A suspension of 67 (0.43 g, 1 mmol) and Pd / C (10% Pd, 0.3 g) in anhydrous ethanol (20 mL) was stirred under H2 for 2 h. The reaction mixture was passed through Filtered and the filtrate was evaporated to dryness.The residue was redissolved in EtOH and subjected to a second hydrogenation under the same conditions for 1 h to yield 68 (0.21 g, 82%) as a viscous oil.

[0435] Synthesis of sugar alcohol O-(2-THF) ethers 69a-d:

[0436]

[0437] Plan 28.

[0438] General synthetic procedure

[0439] PPTS (0.01 equivalent / hydroxyl group) was added to a solution of sugar alcohol (1 equivalent) and 2,3-dihydrofuran (1.5 equivalents / sugar alcohol hydroxyl groups). The reaction mixture was stirred at room temperature for 2-4 days. The reactant was quenched with 5% NaHCO3 aqueous solution (1-2mL) and most of the dioxane was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with 5% NaHCO3 aqueous solution and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness to produce 69a-d as a viscous oil. The crude product was purified on silica gel (EtOAc / hexane) to produce 69a-d in 85-90% yield.

[0440] Synthesis of ascorbyl tetra-O-(tetrahydrofuran-2-yl) ether (70):

[0441] Ascorbyl tetra-O-(tetrahydrofuran-2-yl) ether 70 was synthesized following the same general procedure described above for the alditol O-(2-THF) ether and obtained in 33% yield as a light yellow viscous oil.

[0442] Table 1. List of compounds

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452] Example

[0453] Pharmacokinetic properties of GHB delivery compounds

[0454] Studies were conducted in rats to evaluate the pharmacokinetics of various conjugated GHB delivery compounds. Table 2 shows the mean pharmacokinetic parameters of GHB in plasma following administration by oral gavage in Sprague-Dawley rats. Blood samples were collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, and 4 hours after administration of the GHB delivery compounds. The GHB delivery compounds were formulated into compositions containing water, PEG-400 / water (1:1), or PEG-400 / water (1:3). Unless otherwise stated, each dose administered was the molar equivalent of 100 mg / kg sodium oxybate (NaGHB).

[0455] Table 2. Mean pharmacokinetic parameters of GHB in plasma following administration by oral gavage in Sprague-Dawley rats

[0456]

[0457]

[0458] a The dose in this study was equivalent to 70 mg / kg NaGHB. The data shown were extrapolated to 100 mg / kg (assuming dose proportionality) to facilitate comparison with other studies.

[0459] b Vehicle = PEG-400 / water (1:1)

[0460] c Medium = Water

[0461] d Vehicle = PEG-400 / water (1:3)

[0462] e The dose in this study was equivalent to 80 mg / kg NaGHB. The data shown were extrapolated to 100 mg / kg (based on dose proportionality) to facilitate comparison with other studies.

[0463] The pharmacokinetic data from these studies were also used to assess the relative oral bioavailability of GHB following administration of the GHB delivery compound compared to sodium oxybate in Sprague-Dawley rats (Table 3). max or %AUC) equals mean conjugate PK parameter / mean comparator PK parameter.

[0464] Table 3. Relative oral bioavailability relative to study comparator (sodium oxybate) in Sprague-Dawley rats.

[0465] Conjugate <![CDATA[%C max ]]> <![CDATA[%AUC 0-4hr ]]> <![CDATA[3CPr O-(ethoxycarbonyl)-GHB(4a) a,b > 112％ 91％ <![CDATA[3CPr O-(ethoxycarbonyl)-GHB(4a) b > 145％ 75％ <![CDATA[3CPr ester of sulfamic acid (33) c > 102％ 109％ <![CDATA[(2-THF) Salicylic Acid Ester (34b) b > 339％ 116％ <![CDATA[O-(2-THF)-Glutaric acid (35) b > 261％ 174％ <![CDATA[O-(2-THF)O-(ethoxycarbonyl)-GHB(38) b > 250％ 170％ <![CDATA[Bis(2-THF) maleate (39) b > 395％ 237％ <![CDATA[Bis(2-THF) glutarate (41a) b > 181％ 157％ <![CDATA[Bis(2-THF) succinate (41b) b > 223％ 150％ <![CDATA[Bis(2-THF) malonate (41c) b > 195％ 101％ <![CDATA[Bis(2-THF) adipate (41d) d > 248％ 135％ <![CDATA[O-(2-THF)-GHB(58) b ]]> 199％ 201％ <![CDATA[4-Hydroxybutyl (O-ethoxycarbonyl)-GHB (63a) b > 120％ 73％ <![CDATA[4-Hydroxybutyl O-acetyl-GHB (63b) b > 215％ 149％ <![CDATA[O-(2-THF)BD(66) c,e ]]> 72％ 76％ <![CDATA[O-(2-THF)BD(66) b ]]> 200％ 137％ <![CDATA[Triglyceride-O-(2-THF) ether (69a) d > 46％ 34％ <![CDATA[Erythritol tetra - O-(2 - THF) ether (69b) d > 279％ 151％ <![CDATA[Xylitol penta - O-(2-THF) ether (69c) d > 129％ 68％ <![CDATA[2-OH-THF c ]]> 297％ 188％ <![CDATA[GBL c ]]> 70％ 27％ <![CDATA[BD c ]]> 82％ 86％ <![CDATA[O-(Ethoxycarbonyl)-GHB c,e > 51％ 54％

[0466] a The dose in this study was equivalent to 70 mg / kg NaGHB. The data shown were extrapolated to 100 mg / kg (assuming dose proportionality) to facilitate comparison with other studies.

[0467] b Vehicle = PEG-400 / water (1:1)

[0468] c Medium = Water

[0469] d Vehicle = PEG-400 / water (1:3)

[0470] e The dose in this study was equivalent to 80 mg / kg NaGHB. The data shown were extrapolated to 100 mg / kg (based on dose proportionality) to facilitate comparison with other studies.

[0471] All features disclosed in the specification (including 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.

[0472] Each feature disclosed in the specification (including claims, abstract and drawings) can be replaced by alternative features serving the same, equivalent or similar purpose, unless otherwise expressly stated. Therefore, unless otherwise expressly stated, each feature disclosed is only one example in a series of equivalent or similar features.

[0473] Paragraph claim collection: PCT publication paragraphs [0387-0410]

[0474] Claim 1. In one embodiment of the present invention, a compound having a structure of formula II is described:

[0475]

[0476] or a pharmaceutically acceptable salt thereof;

[0477] Where G is S or O, and

[0478] R is selected from 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, 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;

[0479] And R 1 It is an amino acid or a peptide.

[0480] Claim 2. In one embodiment of the present invention, a compound having a structure of formula IV is described:

[0481]

[0482] where Y 1 and Y 2 each of which is independently selected from the following groups at least one to five times: hydroxy, γ-hydroxybutyrate, γ-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, 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.

[0483] Claim 3. The compound of claim 1 or claim 2, wherein the amino acid is selected from 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.

[0484] Claim 4. The compound of claims 1 to 3, wherein the peptide is a dipeptide or a tripeptide.

[0485] Claim 5. The compound of claim 1, wherein the compound is selected from

[0486]

[0487]

[0488] 6. The compound of claim 2, wherein the compound is selected from

[0489]

[0490] Claim 7. A composition comprising a compound according to claims 1-6 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from acetate, L-aspartate, benzenesulfonate, bicarbonate, carbonate, D-camphorsulfonate, L-camphorsulfonate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonate , pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acephylline, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate salt, bile salt, cyclopentane propionate, dichloroacetate, edentate, ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidesylate, oleate, oxalate, palmitate, picrate , pivalate, propionate, pyrophosphate, salicylate, salicylate sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camphorsulfonate, octanoate, etopoate, ethanesulfonate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline salt, lysinium salt, ammonium, troethamine, and mixtures thereof.

[0491] Claim 8. A method for preventing or treating a sleep disorder or sleep syndrome in a subject in need thereof, the method comprising administering to the subject a composition comprising the composition of claim 7.

[0492] Claim 9. The method of claim 8, wherein the sleep disturbance is a symptom of a degenerative neurological disease or disorder and / or a side effect of treating a degenerative neurological disease or disorder with a drug or therapeutic compound, and wherein further the degenerative neurological disease or disorder is selected from Parkinson's disease, primary Parkinson's disease, Parkinson's disease and idiopathic Parkinson's disease.

[0493] Claim 10. The method of any one of claims 8 to 9, wherein 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, or a combination thereof.

[0494] Claim 11. The method of any one of claims 8 to 10, wherein the sleep disorder is excessive daytime sleepiness associated with a central hypersomnia disorder, obstructive sleep apnea, or shift work disorder, wherein the central hypersomnia disorder is selected from narcolepsy type 1 with cataplexy, narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical condition, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric condition, and insufficient sleep syndrome.

[0495] Claim 12. The composition of claim 7 or the method of any one of claims 8 to 11, wherein the composition further comprises one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0496] Claim 13. The composition of claim 7 or the method of any one of claims 8 to 12, wherein the composition has a dosing schedule of about 1 to 2 times per day.

[0497] Claim 14. The composition of claim 7 or the method of any one of claims 8 to 13, wherein the composition has a dosing regimen of about once a day.

[0498] Claim 15. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and instructions for use thereof, wherein the compound is in unit dosage form, wherein the unit dosage form is selected from sublingual tablets, soft candy tablets, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, tablets, lozenges, oral powders, solutions, liquids, thin strips, oral thin films (OTF), oral strips, syrups, suspensions, slurries, sachets, buccal tablets and suppositories.

[0499] Claim 16. The kit of claim 15, wherein the kit further comprises 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, and combinations thereof.

[0500] Claim 17. The kit of claim 16, wherein the additional therapeutic compound is in unit dosage form, wherein the unit dosage form is selected from the group consisting of a sublingual tablet, a soft candy tablet, 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 oral thin film (OTF), an oral strip, a syrup, a suspension, a slurry, a sachet, a buccal tablet, and a suppository.

[0501] Claim 18. A kit according to claim 17, wherein the compound of any one of claims 1 to 4 is in liquid dosage form and the additional therapeutic compound is in oral powder form or sachet form.

[0502] Claim 19. The kit of claim 18, wherein the additional therapeutic compound is added to the liquid dosage form of the compound prior to administration. In another aspect of the invention, a kit is provided as claimed in any one of claims 16 to 19, wherein the instructions for use include instructions for administering at least one of the compounds of claims 1 to 6, administering at least one additional therapeutic compound and / or a salt thereof, or a combination thereof.

[0503] Claim 20. An oral preparation comprising a therapeutically effective dose of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

[0504] Claim 21. The oral formulation of claim 20, wherein the oral formulation further comprises one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

[0505] Claim 22. The oral formulation of claim 20 or claim 21, wherein the therapeutically effective dose is in a unit dosage form, wherein the unit dosage form is selected from the group consisting of a sublingual tablet, a soft candy tablet, 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 oral thin film (OTF), an oral strip, a syrup, a suspension, a slurry, and a buccal tablet.

[0506] Claim 23. The oral formulation of any one of claims 20-22, wherein the oral formulation has a dosing regimen of about 1 to 2 times per day.

[0507] Claim 24. The oral formulation of any one of claims 20-23, wherein the oral formulation has a dosing regimen of about once a day, and wherein the oral formulation is further orally administered to a human or animal subject.

[0508] In another embodiment of the present invention, there is provided a method for preventing or treating a sleep disorder or sleep syndrome in a subject in need thereof, the method comprising administering to the subject a composition comprising a compound selected from the following or a pharmaceutically acceptable salt of the compound:

[0509]

[0510] In an alternative of the method, the sleep disorder is a symptom of a degenerative neurological disease or disorder and / or is a side effect of using a drug or therapeutic compound to treat a degenerative neurological disease or disorder. In an alternative of the method, the degenerative neurological disease or disorder can be selected from Parkinson's disease, primary Parkinson's disease, Parkinson's disease and idiopathic Parkinson's disease. In an alternative of the method, the sleep disorder can be selected from excessive daytime sleepiness associated with central hypersomnia disorder, obstructive sleep apnea or shift work disorder. In an alternative of the method, the central hypersomnia disorder can be selected from narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by medical conditions, hypersomnia caused by drugs or substances, hypersomnia associated with psychiatric conditions and sleep deprivation syndrome. The composition of the method may further include 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, trihexyphenidol, amphetamine, armodafinil, caffeine, mazindol, methylphenidate, modafinil, tilolisan, reboxetine, samelisant, serdexmethylphenidate and solriamfetol or a combination thereof. In some alternatives of the method, the composition of the method may further include one or more excipients, wherein the excipient is selected from anti-adhesives, adhesives, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof. In some alternatives of the method, the composition of the method may further comprise one or more of the additional active ingredients / compounds described above and one or more of the excipients described above.

[0511] In one embodiment of the method for preventing or treating a sleep disorder or sleep syndrome in a subject in need thereof, the composition has a dosing regimen of about 2 times a day or less and more preferably 1 to 2 times a day. In another embodiment, the composition has a dosing regimen of about 1 time a day. The composition can be administered to a subject by oral, intranasal, intradermal, intramuscular, depot injection, subcutaneous or intravenous means, wherein the subject is an animal or a human. In an alternative method, the composition is orally administered to a human or animal subject.

[0512] In another embodiment of the above technology, a kit is provided, comprising a therapeutically effective amount of a composition of the present invention (or alternatively a kit for preventing or treating a sleep disorder or sleep syndrome in a subject in need thereof, comprising a therapeutically effective amount of a composition of the present invention) or one or more pharmaceutically acceptable salts thereof, wherein the composition is in a unit dosage form. The unit dosage form may be selected from sublingual tablets, soft candy tablets, chewable tablets, fast-dissolving tablets, tablets, capsules, caplets, tablets, lozenges, oral powders, solutions, liquids, thin strips, oral thin films (OTF), oral strips, syrups, suspensions, slurries, sachets, buccal tablets, and suppositories. Such a kit may further additionally comprise one or more additional therapeutic compounds. The one or more additional therapeutic compounds can be selected from 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, and combinations thereof. One or more additional therapeutic compounds may be provided in a unit dosage form, wherein the unit dosage form is selected from sublingual tablets, soft sugar tablets, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, troches, oral powders, solutions, liquids, thin strips, oral thin films (OTF), oral strips, syrups, suspensions, slurries, sachets, buccal tablets and suppositories. In another aspect of the invention, such a kit further comprises instructions for use, wherein the instructions for use include instructions for administering at least one composition, administering at least one additional therapeutic compound and / or its (pharmaceutically acceptable) salt or a combination thereof.

[0513] In the method or kit of any one or more of paragraphs 243-246 of the above PCT publication, the pharmaceutically acceptable salt is selected from acetate, L-aspartate, benzenesulfonate, bicarbonate, carbonate, D-camphorsulfonate, L-camphorsulfonate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonate, pamoate, phosphate Salt, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acephylline, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate, cholate , cyclopentanepropionate, dichloroacetate, edentate, ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidenesulfonate, oleate, oxalate, palmitate, picrate, neopentanoate Valerate, propionate, pyrophosphate, salicylate, salicylic acid sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribromophenolate (tribrophenate), valerate, valproate, adipate, 4-acetamidobenzoate, camphorsulfonate, caprylate, etopoate, ethanesulfonate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, choline salt, lysinium salt, ammonium, tromethamine (troethamine), and mixtures thereof. In another aspect of the invention, the pharmaceutically acceptable salt can also be selected from the salt of amphetamine (for example amphetamine), methylphenidate and serdexmethylphenidate.

[0514] It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative only and not to limit the scope of the invention, which is defined by the scope of the following claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. A compound having a structure of formula II: or a pharmaceutically acceptable salt thereof; Where G is S or O, and R is selected from 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, 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; And R 1 It is an amino acid or a peptide.

2. Compounds having the structure of Formula IV: where Y 1 and Y 2 each of which is independently selected from the following groups at least one to five times: hydroxy, γ-hydroxybutyrate, γ-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, 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.

3. The compound of claim 1 or claim 2, wherein the amino acid is selected from 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.

4. The compound of claims 1 to 3, wherein the peptide is a dipeptide or a tripeptide.

5. The compound of claim 1, wherein the compound is selected from 6. The compound of claim 2, wherein the compound is selected from 7. A composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from acetate, L-aspartate, benzenesulfonate, bicarbonate, carbonate, D-camphorsulfonate, L-camphorsulfonate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonate, pamoate salt, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, glucoheptonate, D-glucuronate, hydroxybenzoate, isethionate, malonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, stearate, toluenesulfonate, thiocyanate, acephylline, acetylglycinate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, caproate, bile salt, cyclopentane propionate, dichloroacetate, edentate, ethylsulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, mesylate, myristate, napthylidenesulfonate, oleate, oxalate, palmitate, picrate, Pivalate, propionate, pyrophosphate, salicylate, salicylate sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camphorsulfonate, octanoate, etopoate, ethanesulfonate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline salt, lysinium salt, ammonium, troethamine, and mixtures thereof.

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

9. The method of claim 8, wherein the sleep disturbance is a symptom of a degenerative neurological disease or disorder and / or a side effect of treating a degenerative neurological disease or disorder with a drug or therapeutic compound, and wherein further the degenerative neurological disease or disorder is selected from Parkinson's disease, primary Parkinson's disease, Parkinson's disease and idiopathic Parkinson's disease.

10. The method of any one of claims 8 to 9, wherein 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, or a combination thereof.

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

12. The composition of claim 7 or the method of any one of claims 8 to 11, wherein the composition further comprises one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

13. The composition of claim 7 or the method of any one of claims 8 to 12, having a dosing regimen of about 1 to 2 times per day.

14. The composition of claim 7 or the method of any one of claims 8 to 13, wherein the composition has a dosing regimen of about once a day.

15. A kit comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and instructions for use, wherein the compound is in unit dosage form, wherein the unit dosage form is selected from sublingual tablets, soft candy tablets, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, troches, oral powders, solutions, liquids, thin strips, oral thin films (OTF), oral strips, syrups, suspensions, slurries, sachets, buccal tablets and suppositories.

16. The kit of claim 15, wherein the kit further comprises 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, tilolisen, reboxetine, samelisant, serdexmethylphenidate, solriamfetol, and combinations thereof.

17. The kit of claim 16, wherein the additional therapeutic compound is in unit dosage form, wherein the unit dosage form is selected from the group consisting of sublingual tablets, soft candy tablets, chewable tablets, fast dissolving tablets, tablets, capsules, caplets, troches, lozenges, oral powders, solutions, liquids, thin strips, oral thin films (OTF), buccal strips, syrups, suspensions, slurries, sachets, buccal tablets, and suppositories.

18. The kit of claim 17, wherein the compound of any one of claims 1 to 4 is in liquid dosage form and the additional therapeutic compound is in oral powder form or sachet form.

19. The kit of claim 18, wherein the additional therapeutic compound is added to a liquid dosage form of the compound prior to administration.

20. An oral formulation comprising a therapeutically effective dose of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

21. The oral formulation of claim 20, wherein the oral formulation further comprises one or more excipients, wherein the excipients are selected from anti-adherents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

22. The oral formulation of claim 20 or claim 21, wherein the therapeutically effective dose is in a unit dosage form, wherein the unit dosage form is selected from the group consisting of a sublingual tablet, a soft candy tablet, 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 oral thin film (OTF), an oral strip, a syrup, a suspension, a slurry, and a buccal tablet.

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

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

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