Ketone sugar esters and ketone based prodrug esters for improved bioavailability

Abstract

The present disclosure provides esters and amides between known pharmaceutical, supplements, nutritional sugars, or nutritional compounds and ketone bodies and ketone body precursors with an enhanced bioavailability to mitigate adverse effects such as liver and kidney stress, gastrointestinal irritation, skin irritation, ulcers, and bleeding.

Description

KETONE SUGAR ESTERS AND KETONE BASED PRODRUG ESTERS FOR IMPROVED BIOAVAILABILITYFIELD

[0001] The present disclosure provides pharmaceuticals (oral, injectable, IV and topical), dietary supplements, and food products, with enhanced bioavailability to mitigate adverse effects such as liver and kidney stress, gastrointestinal irritation, skin irritation, ulcers, and bleeding.BACKGROUND

[0002] Many pharmaceutical compounds, supplements, and nutritive sweeteners can have poor bioavailability. One approach to overcome poor bioavailability involves modifying these molecules through esterification, amidation, and other linkage strategies to form a prodrug that can enhance efficacy and reduce side effects. However, traditional esterification agents like ethanol can generate toxic metabolites. Thus, there remains a need in the art for novel compounds that enhance bioavailability without generating toxic or otherwise undesirable metabolites.BRIEF SUMMARY

[0003] The present disclosure provides esters and amides of known pharmaceuticals, supplements, nutritional sugars, or nutritional compounds with suitable ketone bodies and suitable ketone body precursors. For example, the present disclosure provides esters including, but not limited to, glucose esterified with P-hydroxybutyric acid (glucose-PHB ester), fructose esterified with P-hydroxybutyric acid (fructose-PHB ester), ibuprofen esterified with 1,3 -butanediol (ibuprofen-l,3-BD ester), and acetaminophen esterified with 1,3 -butanediol (acetaminophen- 1, 3 -BD ester). Without wishing to be bound by a particular theory, it is believed that these esters have enhanced bioavailability relative to the parent molecule, such that the esters described herein are better able to mitigate adverse effects associated with the parent molecule, such as liver and kidney stress, gastrointestinal irritation, skin irritation, ulcers, and bleeding.

[0004] In one aspect, present disclosure provides a compound of Formula I,OH or a pharmaceutically acceptable salt thereof, wherein:R1is

[0005] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a compound of Formula IA:

[0006] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a compound of Formula IB:

[0007] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a mixture of a compound of Formula IA and a compound of Formula IB.

[0008] In another aspect, the mixture of a compound of Formula IA and a compound of Formula IB is in a ratio ranging from about 1 :99 to about 99: 1.

[0009] In another aspect, the mixture of a compound of Formula IA and a compound of Formula IB is in a ratio ranging from about 51 :49 to about 99: 1.

[0010] In another aspect, the mixture of a compound of Formula IB and a compound of Formula IA is in a ratio ranging from about 51 :49 to about 99: 1.

[0011] In one aspect, the present disclosure provides a compound of Formula II,pharmaceutically acceptable salt thereof, wherein:A is a double bond or single bond; provided that when A is a single bond R3is O and R4is H, and when A is a double bond R3is O and R4is absent.

[0012] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIA:YY°'OH OR2IIA

[0013] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIB:

[0014] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIC:YY%!OH 0 lie

[0015] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a mixture of a compound of Formula IIB and a compound of Formula IIC.

[0016] In another aspect, the mixture of a compound of Formula IIB and a compound of Formula IIC is in a ratio ranging from about 1:99 to about 99:1.

[0017] In another aspect, the mixture of a compound of Formula IIB and a compound of Formula IIC is in a ratio ranging from about 51:49 to about 99:1.

[0018] In another aspect, the mixture of a compound of Formula IIC and a compound of Formula IIB is in a ratio ranging from about 51:49 to about 99:1.

[0019] In one aspect, the present disclosure provides a composition comprising a compound selected from a group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate, (S)-3 -hydroxybutyl N- carbamimidoyl-N-methylglycinate, and combinations thereof;(R)-3 -hydroxybutyl 4-aminobutanoate, (S)-3 -hydroxybutyl 4-aminobutanoate, and combinations thereof;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, (S)-3- hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, and combinations thereof;(R)-3 -hydroxybutyl 2-acetoxybenzoate, (S)-3 -hydroxybutyl 2-acetoxybenzoate, and combinations thereof;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, (R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, and combinations thereof;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate, (S)-3 -hydroxybutyl(2S)-2-amino-6-diazo-5-oxohexanoate, and combinations thereof; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex-l-ene-l -carboxylate, (S)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5- amino-3 -(pentan-3 -yloxy)cyclohex-l-ene-l -carboxylate, and combinations thereof; and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0020] In another aspect, the composition comprises a compound selected from the group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate;(R)-3 -hydroxybutyl 4-aminobutanoate;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;(R)-3 -hydroxybutyl 2-acetoxybenzoate;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex- 1 -ene- 1 -carboxylate; and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0021] In one aspect, the present disclosure provides a composition comprising a compound selected from a group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;(3 S,4R, 5R)-3 ,4, 5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium, 3 -carbamoyl- 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((S)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium, and combinations thereof;4-acetamidophenyl (R)-3-hydroxybutanoate, 4-acetamidophenyl (S)-3- hydroxybutanoate, and combinations thereof;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate, (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3-hydroxybutanoate, and combinations thereof;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate, (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3-hydroxybutanoate, and combinations thereof; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hydroxybutanoate, (2S,3 S,4R)- 2,3,4-trihydroxy-5-oxopentyl (S)-3-hydroxybutanoate, and combinations thereof; and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0022] In another aspect, the composition comprises a compound selected from the group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl (R)-3 -hy droxybutanoate;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate; and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0023] In one aspect, the present disclosure provides a composition comprising at least two compounds selected from a group consisting of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate; (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; (2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl (R)-3 -hy droxybutanoate;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and (2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate; and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0024] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the compounds are present in the composition in a weight ratio of about 3 : 1 to about 1:3.

[0025] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the composition further comprises D-glucose.

[0026] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In a particular aspect, the composition further comprises D-fructose.

[0027] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In still another aspect, the composition further comprises D-glucose and D-fructose.

[0028] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the compounds are present in the composition in a weight ratio of about 3 : 1 to about 1:3.

[0029] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the compounds are present in the composition in a weight ratio of about 3 : 1 to about 1:3.

[0030] In another aspect of the composition, the at least two compounds are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the compounds are present in the composition in a weight ratio of about 3 : 1 to about 1:3.

[0031] In one aspect, the present disclosure provides a method of enhancing the bioavailability of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate or a pharmaceutically acceptable salt thereof.

[0032] In one aspect, the present disclosure provides a method of enhancing the bioavailability of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof.

[0033] In one aspect, the present disclosure provides a method of enhancing the bioavailability of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

[0034] In one aspect, the present disclosure provides a method of enhancing the bioavailability of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-acetoxybenzoate.

[0035] In one aspect, the present disclosure provides a method of enhancing the bioavailability of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3- dihy droi sobenzofuran-5 -yl)hex-4-enoate .

[0036] In one aspect, the present disclosure provides a method of enhancing the bioavailability of 2-(4-isobutylphenyl)propanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (R)-2-(4- isobutylphenyljpropanoate, (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate, or combinations thereof.

[0037] In another aspect, the method of enhancing the bioavailability of 2-(4- isobutylphenyljpropanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

[0038] In one aspect, the present disclosure provides a method of enhancing the bioavailability of 6-diazo-5-oxo-norleucine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-amino-6-diazo-5-oxohexanoate or a pharmaceutically acceptable salt thereof.

[0039] In one aspect, the present disclosure provides a method of enhancing the bioavailability of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)-3-hydroxybutanoate or a pharmaceutically acceptable salt thereof.

[0040] In one aspect, the present disclosure provides a method of enhancing the bioavailability of D-glucose comprising administering to a subject in need thereof, an effective amount of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl jmethyl (R)-3 -hydroxybutanoate.

[0041] In one aspect, the present disclosure provides a method of enhancing the bioavailability of L-glucose comprising administering to a subject in need thereof, an effective amount of ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl jmethyl (R)-3 -hydroxybutanoate.

[0042] In one aspect, the present disclosure provides a method of enhancing the bioavailability of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate, or combinations thereof.

[0043] In one aspect, the present disclosure provides a method of enhancing the bioavailability of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium.

[0044] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl-N-m ethylglycinate or a pharmaceutically acceptable salt thereof.

[0045] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof.

[0046] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6- dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

[0047] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-acetoxybenzoate.

[0048] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3- dihy droi sobenzofuran-5 -yl)hex-4-enoate .

[0049] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of 2-(4-isobutylphenyl)propanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl(R)-2-(4-isobutylphenyl)propanoate, (R)-3 -hydroxybutyl (S)-2-(4- isobutylphenyl)propanoate, or combinations thereof.

[0050] In another aspect, the method of reducing gastrointestinal side effects of 2-(4- isobutylphenyl)propanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

[0051] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of 6-diazo-5-oxo-norleucine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-amino-6-diazo- 5 -oxohexanoate or a pharmaceutically acceptable salt thereof.

[0052] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)-3-hydroxybutanoate or a pharmaceutically acceptable salt thereof.

[0053] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of D-glucose comprising administering to a subject in need thereof, an effective amount of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran- 2-yl)m ethyl (R)-3 -hydroxybutanoate.

[0054] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of L-glucose comprising administering to a subject in need thereof, an effective amount of ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran- 2-yl)methyl (3R)-3-hydroxybutanoate.

[0055] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate.

[0056] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l-((2R,3R,4S,5R)-3,4- dihydroxy-5-((((R)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium or a pharmaceutically acceptable salt thereof.

[0057] In another aspect, the method comprises wherein the compound is administered via injection, intravenously, orally, or topically.

[0058] Additional aspects and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure.

[0059] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and do not restrict the scope of the claims.DETAILED DESCRIPTION

[0060] The headings provided herein are not limitations of the various aspects of the disclosure, which can be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0061] The present disclosure generally relates to compounds with improved bioavailability, minimized side effects, and optimized drug delivery as described herein.Definitions

[0062] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular aspects, and are not intended to limit the claimed technology, because the scope of the technology is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification will control.

[0063] The articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. As used herein, the use of "or" means "and / or" unless expressly stated or understood by one skilled in the art. In thecontext of a multiple dependent claim, the use of "or" refers back to more than one preceding independent or dependent claim.

[0064] As used herein, the term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, z.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 10% (e.g., up to 5%, or up to 1%) of a given value.

[0065] As used herein “ 1,3 -butanedi ol” (also known as 1,3-butylene glycol, butane-1,3- diol, 1,3 -dihydroxybutane, 1,3-BD, and 1,3-BDO) refers to racemic 1,3 -butanediol as well as mixtures of its component enantiomers comprising from about 1 :99 to about 99:1 of (R)- 1,3 -butanediol (also known in the art as D- 1,3 -butanediol) and (S)-l,3-butanediol (also known as L-l,3-butanediol). Unless otherwise specified herein, (R)- 1,3 -butanediol refers to enantiopure (R)- 1,3 -butanediol, and (S)-l,3-butanediol refers to enantiopure (S)- 1,3 -butanediol.

[0066] As used herein “P-hydroxybutyric acid” (also known as 3 -hydroxybutanoic acid, PHB, or BHB) refers to racemic P-hydroxybutyric acid as well as mixtures of its component enantiomers comprising from about 1 :99 to about 99: 1 of (R)-P- hydroxybutyric acid (also known in the art as D-P-hydroxybutyric acid) and (S)-P- hydroxybutyric acid (also known in the art as L-P-hydroxybutyric acid). Unless otherwise specified herein, (R)-P-hydroxybutyric acid refers to enantiopure (R)-P- hydroxybutyric acid, and (S)-P-hydroxybutyric acid refers to enantiopure (S)-P- hydroxybutyric acid.

[0067] As used herein “P-hydroxypentanoic acid” (also known as 3-hydroxypentanoic acid) refers to racemic P-hydroxypentanoic acid as well as mixtures of its component enantiomers comprising from about 1 :99 to about 99: 1 of (R)-P-hydroxypentanoic acid and (S)-P-hydroxypentanoic acid. Unless otherwise specified herein, (R)-P- hydroxypentanoic acid refers to enantiopure (R)-P-hydroxypentanoic acid, and (S)-P- hydroxypentanoic acid refers to enantiopure (S)-P-hydroxypentanoic acid.

[0068] As used herein, the term “nutritive sweetener” refers to a sweetener, such as sucrose, fructose, glucose, corn syrup, or high-fructose com syrup that provides caloric content and is generally regarded as safe by the Food and Drug Administration.

[0069] As used herein, the term “ketone body” refers to a water-soluble molecule or compound that contains a ketone group and is produced from fatty acid metabolism (ketogenesis) by the liver. Exemplary ketone bodies includes, but are not limited to, acetoacetic acid (acetoacetate), P-hydroxybutyric acid (P-hydroxybutyrate), and acetone. Alternate “ketone body” energy sources include P-hydroxypentanoic acid and P-ketopentanoic acid (also known as 3 -oxopentanoic acid). Ketone bodies can also be introduced into a subject in need thereof as a supplement from an exogenous source.

[0070] As used here, the term “ketone body salts” refers to a base-addition salt of a compound that contains both a ketone group and a carboxylic acid group. Exemplary ketone body salts, include, but are not limited to the sodium, potassium, calcium, and magnesium salts of PHB.

[0071] As used herein, the term “ketone body precursor” refers to a compound that is metabolized or converted to B-hydroxybutyric acid. Examples of ketone body precursors are Medium-chain Triglycerides (MCT-oil), fatty acids, ketogenic amino acids, ketone esters (e.g. (R)-3 -hydroxybutyl (R)-3-hydroxybutanoate), and 1,3 -butanediol.

[0072] As used herein, the terms “dietary supplements” and “supplements” include vitamins (such as multivitamins or individual vitamins like vitamin D and biotin); minerals (such as calcium, magnesium, and iron); botanicals or herbs (such as echinacea and ginger); botanical compounds (such as caffeine and curcumin); live microbials (commonly referred to as “probiotics”). Other non-limiting examples of dietary supplements and supplements include astaxanthin, quercetin, resveratrol, omega-3 fatty acids (EPA / DHA), kratom, coenzyme Q10 (CoQlO), creatine, P-alanine, L-carnitine, glucosamine, folic acid, fullerene (c60), nicotinamide riboside (NR), spermidine, epigallocatechin gallate, pterostilbene, theacrine, methylliberine, BCAAs (branched-chain amino acids), whey protein, glutamine, HMB (P-hydroxy P-methylbutyrate), arginine, betaine, CLA (conjugated linoleic acid), nitric oxide boosters (e.g., citrulline), DHEA (dehydroepiandrosterone), turkesterone, caffeine, thiamine, B-12, L-theanine, GABA, kanna, or combinations thereof.Compounds

[0073] The present disclosure provides novel esters or amides of commonly known drugs or compounds with a ketone body, ketone body precursor, or ketone ester. In some aspects the drug or compound can be modified, for example synthetically orenzymatically, to incorporate the proper functionality (e.g. a hydroxyl, carboxylic acid, or amine functional group) to allow for esterification, transesterification, or amidation. (See, March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 3rd edition, New York: Wiley, ISBN 9780471854722, OCLC 642506595; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition By Richard C. Larock (Iowa State University). John Wiley & Sons, New York, NY. 1999. 2583 pp.: ISBN 0-471-19031-4; and Greene's Protective Groups in Organic Synthesis. Fourth Edition. By Peter G. M. Wuts and Theodora W. Greene. John Wiley & Sons, Inc., Hoboken, NJ. 2006: ISBN 0-471-69754-0.)

[0074] Without wishing to be bound by a particular theory, the ester and amide compounds of the disclosure that incorporate ketone bodies or ketone body precursors are believed to be more lipophilic, which improves membrane permeability and systemic absorption. This can lead to significantly higher bioavailability compared to the starting compound (e.g. compound containing a carboxylic acid). The increased bioavailability permits lower drug loading and may lead to reduced side effects and better overall therapeutic outcomes. Again, without wishing to be bound by a particular theory, the compounds disclosed herein may permit a greater proportion of the administered dose to reach the target site of action.

[0075] In addition to providing enhanced bioavailability, the compounds disclosed herein will metabolize or breakdown into the pharmaceutical compound, supplement, or nutritive sweetener and a ketone body or ketone body precursor. The ketone body precursor will be converted or metabolized to a ketone body within the subject. Ketone bodies are particularly beneficial for supporting stable energy levels without excessive “jitters” and without a rapid energy crash following consumption. The brain can utilize ketone bodies as an energy source, and in many instances, ketone bodies are the preferred source of energy for brain cells. An increase in the proportion of the brain's energy demand met by ketone bodies, as opposed to glucose, beneficially provides a stable and relatively long-lasting energy source to fuel the brain. Ketone bodies can provide a fuel source without causing an insulin spike, as is common with rapid consumption of sugars.

[0076] Drugs suitable for use in preparing the novel esters and amides described herein include, but are not limited to:• antidepressants, including venlafaxine, duloxetine, sertraline, paroxetine, fluoxetine (prozac), ketamine, esketamine, brexanolone, tianeptine, desvenlafaxine, amphetamine, tramadol, clomipramine, or doxepin.• Nonsteroidal anti-inflammatories (NSAID(s)), including ibuprofen, preferably dexibuprofen, naproxen, diclofenac, meloxicam, aspirin, salicylic acid, celecoxib, ketorolac, diclofenac, or indomethacin.• Antifungals, including itraconazole, voriconazole, posaconazole, amphotericin b, isavuconazole, caspofungin, micafungin, anidulafungin, amphotericin b, flucytosine, or ketoconazole.• Antivirals, including acyclovir, valacyclovir, ganciclovir, oseltamivir, tenofovir disoproxil, biktarvy, ganciclovir, foscamet, cidofovir, remdesivir, acyclovir, valganciclovir, or entecavir.• Antidiabetics, including glipizide, glyburide, pioglitazone, rosiglitazone, metformin, exenatide, liraglutide, semaglutide, jardiance (empagliflozin), trulicity (dulaglutide), or farxiga (dapagliflozin).• Antihypertensives, including propranolol, metoprolol, atenolol, lisinopril, losartan, esmolol, nitroglycerin, nicardipine, enalaprilat, or labetalol• Antipsychotics, including olanzapine, risperidone, quetiapine, aripiprazole, clozapine, haloperidol, fluphenazine, or chlorpromazine.• Statins, include atorvastatin, simvastatin, lovastatin, rosuvastatin, or pravastatin.• Antiepileptics, including phenytoin, valproic acid, carbamazepine, lamotrigine, topiramate, fosphenytoin, valproate sodium, levetiracetam, lacosamide, or phenobarbital.• Antibiotics, including amoxicillin, ciprofloxacin, clindamycin, doxycycline, erythromycin, vancomycin, ertapenem, meropenem, tigecycline, or daptomycin.• Steroids, including prednisolone, dexamethasone, hydrocortisone, methylprednisolone, betamethasone, testosterone, nandrolone, trenbolone, or boldenone.• Cannabinoids, including cannabidiol (CBD), tetrahydrocannabinol (THC), Delta- 8-THC, or Delta-9-THC.• Opioids, including morphine, codeine, thebaine, hydromorphone, hydrocodone, oxymorphone, or oxycodone.• Psychoactive indole alkaloids, including ibogaine.• Neurodegenerative treatments, including L-DOPA (levodopa) and Parkinson’s disease treatments, Alzheimer’s disease treatments, and other treatments to maintain quality of life in subject suffering for neurodegenerative diseases.• Various additional drug, including loratadine, amlodipine, clopidogrel, omeprazole, tamsulosin, fexofenadine, doxazosin, montelukast, caffeine, theobromine, theophylline, nicotine, quinine, ephedrine, or amphetamines.

[0077] Suitable supplements including, but are not limited to astaxanthin, quercetin, resveratrol, omega-3 fatty acids (EPA / DHA), kratom, coenzyme Q10 (CoQlO), creatine, beta-alanine, L-carnitine, glucosamine, folic acid, fullerene (c60), nicotinamide riboside (NR), spermidine (through modification), epigallocatechin gallate, pterostilbene, theacrine, methylliberine, branched-chain amino acids (BCAAs), whey protein, glutamine, HMB (beta-hydroxy beta-methylbutyrate), arginine, betaine, conjugated linoleic acid (CLA), nitric oxide boosters (e.g., citrulline), dehydroepiandrosterone (DHEA), turkesterone, caffeine, thiamine, B 12, L-theanine, gamma-aminobutyric acid (GABA), kanna, or minerals (such as calcium, magnesium, and iron).

[0078] Suitable sweeteners include, but are not limited to nutritive sweeteners, including fructose, glucose, sucrose, maltose, lactose, ribose, galactose, mannose, allulose, tagatose, trehalose, xylitol, isomaltulose, sorbitol, mannitol, erythritol, maltitol, com syrup, and high-fructose com syrup. In certain aspects, the one or more sweeteners include nutritive sweeteners and non-nutritive natural and artificial or synthetic sweeteners. In certain aspects, suitable nutritive sweeteners include sucrose, fructose, glucose, corn syrup, and high-fructose com syrup. In certain aspects, suitable non-nutritive natural and artificial or synthetic sweeteners include, but not limited to, acesulfame-K, aspartame, advantame, cyclamate, neotame, alitame, saccharin, sucralose, steviol glycosides (including, but not limited to, stevioside, steviolbioside, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside H, rebaudioside I, rebaudioside N, rebaudioside K, rebaudioside J, rebaudioside O, rebaudioside M, dulcoside A, rubusoside, iso-steviol glycosides such as iso-rebaudioside A, and mixtures thereof), Lo Han Guo powder, thaumatin, neohesperidin dihydrochalcone, trilobatin, glycyrrhizin, phyllodulcin, hernandulcin, osladin, polypodoside A, baiyunoside, pterocaryoside, thaumatin, monellin, monatin, and mabinlins I and II. In another embodiment, the sugars can be in thebiologically stereospecific form, racemic forms, diasteromeric forms, or biologically inactive forms.In one aspect, present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

[0079] In some aspects, the compound of Formula I is:3 -hy droxybuty 1 N-carb amimi doy 1 -N -methylglycinate ;3 -hydroxybutyl 4-aminobutanoate;3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;3 -hydroxybutyl 2-acetoxybenzoate;3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate; and3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate.

[0080] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a compound of Formula IA:

[0081] In some aspects, the compound of Formula IA is:(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate;(R)-3 -hydroxybutyl 4-aminobutanoate;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;(R)-3 -hydroxybutyl 2-acetoxybenzoate;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate; and(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate.

[0082] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a compound of Formula IB:

[0083] In some aspects, the compound of Formula IB is:(S)-3 -hydroxybutyl N-carbamimidoyl-N-m ethylglycinate;(S)-3 -hydroxybutyl 4-aminobutanoate;(S)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;(S)-3 -hydroxybutyl 2-acetoxybenzoate;(S)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate; and(S)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate.

[0084] In another aspect, the compound of the disclosure is a compound of Formula I, wherein the compound is a mixture of a compound of Formula IA and a compound of Formula IB.

[0085] In another aspect, the mixture of a compound of Formula IA and a compound of Formula IB is in a ratio ranging from about 1 :99 to about 99: 1, about 5:95 to about 95:5, about 10:90 to about 90: 10, about 15:85 to about 85: 15, about 20:80 to about 80:20, about 25:75 to about 75:25, about 30:70 to about 70:30, about 35:65 to about 65:35, 40:60 to about 60:40, or about 45:55 to about 55:45.

[0086] In another aspect, the mixture of a compound of Formula IA and a compound of Formula IB is in a ratio ranging from about 51 :49 to about 99: 1.

[0087] In another aspect, the mixture of a compound of Formula IB and a compound of Formula IA is in a ratio ranging from about 51 :49 to about 99: 1.

[0088] In certain aspects, the compound of Formula I can be a compound as set forth in Table 1, below.Table 1 : Representative compounds of Formula ITable 2: Additional Non-limiting compounds.

[0089] In one aspect, the present disclosure provides a compound of Formula II,pharmaceutically acceptable salt thereof, wherein:R2isA is a double bond or single bond; provided that when A is a single bond R3is O and R4is H, and when A is a double bond R3is O and R4is absent.

[0090] In another aspect, the compound of Formula II is:4-acetamidophenyl 3 -hydroxybutanoate;((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl 3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methy 3- hydroxybutanoate;(3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3 -hydroxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl 3 -hydroxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3 -hydroxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl 3-hydroxybutanoate;(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl 3-hydroxybutanoate;4-acetamidophenyl 3-oxobutanoate;((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl 3- oxobutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methy 3- oxobutanoate;(3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3-oxobutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl 3-oxobutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((3- oxobutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3-oxobutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl 3-oxobutanoate; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl 3-oxobutanoate.

[0091] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIA:W °'R2OH OIIA

[0092] In some aspects, the compound of Formula IIA is:4-acetamidophenyl 3 -hydroxybutanoate;((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl 3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methy 3- hydroxybutanoate;(3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3-hydroxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl 3-hydroxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl 3-hydroxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl 3-hydroxybutanoate; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl 3-hydroxybutanoate.

[0093] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIB:

[0094] In some aspects, the compound of Formula IIB is:4-acetamidophenyl (R)-3 -hydroxybutanoate;((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methy (R)-3- hydroxybutanoate;(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hydroxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate; and (2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3 -hydroxybutanoate.

[0095] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a compound of Formula IIC:YY°v OH OIIC

[0096] In some aspects, the compound of Formula IIC is:4-acetamidophenyl (S)-3-hydroxybutanoate;((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methy (S)-3- hydroxybutanoate;(3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3 -hydroxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3 -hydroxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((S)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3-hydroxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3-hydroxybutanoate; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (S)-3-hydroxybutanoate.

[0097] In certain aspects, the compound of Formula II can be a compound as set forth in Table 3, below.Table 3: Representative compounds of Formula IITable 4: Additional Non-limiting compounds.

[0098] In another aspect, the compound of the disclosure is a compound of Formula II, wherein the compound is a mixture of a compound of Formula IIB and a compound of Formula IIC.

[0099] In another aspect, the mixture of a compound of Formula IIB and a compound of Formula IIC is in a ratio ranging from 1 :99 to 99: 1, about 5:95 to about 95:5, about 10:90 to about 90: 10, about 15:85 to about 85: 15, about 20:80 to about 80:20, about 25:75 to about 75:25, about 30:70 to about 70:30, about 35:65 to about 65:35, 40:60 to about 60:40, or about 45:55 to about 55:45.

[0100] In another aspect, the mixture of a compound of Formula IIB and a compound of Formula IIC is in a ratio ranging from 51 :49 to 99: 1.

[0101] In another aspect, the mixture of a compound of Formula IIC and a compound of Formula IIB is in a ratio ranging from 51 :49 to 99: 1.Compositions

[0102] In certain aspects, the compositions described herein can be pharmaceutical compositions, beverages, drinks, gel packs, energy bars, nutritional bars, powder, tablets, capsules, or microencapsulated.

[0103] In some aspects, the composition is a pharmaceutical composition comprising an active (e.g. (R)-3 -hydroxybutyl (R)-2-(4-isobutylphenyl)propanoate and / or (R)-3- hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate (ibuprofen derivatives) and one or more pharmaceutically acceptable vehicles, carriers, or excipients as described elsewhere herein.

[0104] In some aspects, the composition is a beverage comprising a compound of the disclosure (e.g. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl 3- hydroxybutanoate), one or more dietary supplements, one or more sweeteners, one or more sugars, one or more additives, and water.

[0105] In one aspect, the present disclosure provides a composition comprising a compound selected from a group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate, (S)-3 -hydroxybutyl N- carbamimidoyl-N-methylglycinate, and combinations thereof;(R)-3 -hydroxybutyl 4-aminobutanoate, (S)-3 -hydroxybutyl 4-aminobutanoate, and combinations thereof;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, (S)-3- hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, and combinations thereof;(R)-3 -hydroxybutyl 2-acetoxybenzoate, (S)-3 -hydroxybutyl 2-acetoxybenzoate, and combinations thereof;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, (S)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, and combinations thereof;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate, (S)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate, and combinations thereof; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex-l-ene-l -carboxylate, (S)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5- amino-3 -(pentan-3 -yloxy)cyclohex-l-ene-l -carboxylate, and combinations thereof;and one or more dietary supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0106] Suitable dietary supplements include, but are not limited to, vitamins, minerals, Echinacea, ginger, caffeine, curcumin, live microbials, astaxanthin, quercetin, resveratrol, omega-3 fatty acids (EPA / DHA), kratom, coenzyme Q10 (CoQlO), creatine, b-alanine, L-carnitine, glucosamine, folic acid, fullerene (c60), nicotinamide riboside, spermidine, epigallocatechin gallate, pterostilbene, theacrine, methylliberine, BCAAs, whey protein, glutamine, P-hydroxy P -methylbutyrate, arginine, betaine, CLA, nitric oxide boosters, DHEA, turkesterone, thiamine, B-12, L-theanine, GABA, kanna, or minerals (such as calcium, magnesium, and iron). In certain aspects, the dietary supplement is magnesium. In certain aspects, the magnesium dietary supplement is magnesium citrate, magnesium PHB salt, magnesium lactate, magnesium aspartate, magnesium bisglycinate, magnesium chelate, magnesium malate, magnesium orotate, magnesium taurate, Sucrosomial® Magnesium, magnesium chloride, or combinations thereof. In certain aspects, the magnesium dietary supplement is magnesium (R / S)-PHB salt, magnesium (R)-PHB salt, or magnesium (S)-PHB salt. In certain aspects, the magnesium dietary supplement is magnesium (R)-PHB salt, magnesium (S)-PHB salt, or combinations thereof. In certain aspects, the magnesium dietary supplement is magnesium (R)-PHB salt. In certain aspects, the magnesium dietary supplement is magnesium (S)-PHB salt. In certain aspects, the magnesium dietary supplement is used to improve sleep.

[0107] In certain aspects, the additives include, but not limited to, acids and preservatives. In certain aspects, suitable acids include phosphoric acid, sorbic acid, benzoic acid, citric acid, tartaric acid, propionic acid, butyric acid, acetic acid, succinic acid, glutaric acid, maleic acid, malic acid, valeric acid, caproic acid, malonic acid, aconitic acid, and combinations thereof. In certain aspects, suitable preservatives include sodium benzoate, calcium benzoate, potassium benzoate, sodium sorbate, calcium sorbate, potassium sorbate, sodium citrate, potassium citrate, and combinations thereof.

[0108] In another aspect, the composition comprises a compound selected from the group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate;(R)-3 -hydroxybutyl 4-aminobutanoate;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;(R)-3 -hydroxybutyl 2-acetoxybenzoate;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex- 1 -ene- 1 -carboxylate; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0109] In one aspect, the present disclosure provides a composition comprising a compound selected from a group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;(3 S,4R, 5R)-3 ,4, 5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium, 3 -carbarn oyl-1- ((2R,3R,4S,5R)-3,4-dihydroxy-5-((((S)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran- 2-yl)pyridin-l-ium, and combinations thereof;4-acetamidophenyl (R)-3 -hydroxybutanoate, 4-acetamidophenyl (S)-3- hydroxybutanoate, and combinations thereof;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate, (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3-hydroxybutanoate, and combinations thereof;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate, (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3-hydroxybutanoate, and combinations thereof; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hydroxybutanoate, (2S,3 S,4R)- 2,3,4-trihydroxy-5-oxopentyl (S)-3-hydroxybutanoate, and combinations thereof; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0110] In another aspect, the composition comprises a compound selected from the group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl 3 -hy droxybutanoate;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.[OHl] In one aspect, the present disclosure provides a composition comprising at least two compounds selected from a group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate; (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; (2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl 3 -hy droxybutanoate; (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate; (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and (2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

[0112] In another aspect, the at least two compounds present in the composition are ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate. In particular aspects, the compounds are present in a weight ratio of about 20: 1; about 19: 1; about 18: 1; about 17: 1; about 16: 1 about 15: 1; about 14: 1; about 13: 1; about 12: 1; about 11 : 1; about 10: 1; about 9: 1; about 8: 1; about 7:1; about 6: 1; about 5: 1; about 4: 1; about 3: 1; about 2: 1; about 1 :1; about 1 :2; about 1 :3; about 1 :4; about 1 :5; about 1 :6; about 1 :7; about 1 :8; about 1 :9; about 1 : 10; about 1 : 11; about 1 : 12; about 1 : 13; about 1 : 14; about 1 : 15; about 1 : 16; about 1 : 17; about 1 : 18; about 1 : 19; or about 1 :20.

[0113] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-glucose. In another aspect, the composition further comprises about 0.01% to about 10 %; about 0.1 % to about 5%; from about 1 % to about 3 %; about 0.01 % to about 1 %; about 0.1 % to about 1 %; about 0.1 % to about 2 %; or about 2 % to about 5 % of D-glucose. In another aspect, the composition further comprises about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-glucose.

[0114] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-fructose. In another aspect, the composition further comprises about 0.01% to about 10 %; about 0.1 % to about 5%; from about 1 % to about 3 %; about 0.01 % to about 1 %; about 0.1 % to about 1 %; about 0.1 % to about2 %; or about 2 % to about 5 % of D-fructose. In another aspect, the composition further comprises about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-fructose.

[0115] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises R-PHB. In another aspect, the composition further comprises about 0.01% to about 10 %; about 0.1 % to about 5%; from about 1 % to about3 %; about 0.01 % to about 1 %; about 0.1 % to about 1 %; about 0.1 % to about 2 %; or about 2 % to about 5 % of R-PHB. In another aspect, the composition further comprises about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of R-PHB.

[0116] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-glucose, D-fructose, R-PHB, or combinations thereof.

[0117] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-glucose and D-fructose. In another aspect, the composition further comprises about 0.01% to about 10 %; about 0.1 % to about 5%; from about 1 % to about 3 %; about 0.01 % to about 1 %; about 0.1 % to about 1 %; about 0.1 % to about 2 %; or about 2 % to about 5 % of D-glucose and about 0.01% to about 10 %; about 0.1 % to about 5%; from about 1 % to about 3 %; about 0.01 % to about 1 %; about 0.1 % to about 1 %; about 0.1 % to about 2 %; or about 2 % to about 5 % of D-fructose. In another aspect, the composition further comprises about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-glucose and about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-fructose.

[0118] In another aspect, the composition comprising at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-glucose, D-fructose, and one or more ketonebodies, one or more ketone body salts, one or more ketone body precursors, or combinations thereof. In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3 S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises D-glucose, D-fructose, and R-PHB.

[0119] In another aspect, the composition comprising the at least two compounds (i.e. ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate and (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate) further comprises about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-glucose, about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of D-fructose, and about 0.01 %; about 0.05 %; about 0.1 %; about 0.15 %; about 0.20 %; about 0.25 %; about 0.30 %; about 0.35 %; about 0.40 %; about 0.45 %; about 0.50 %; about 0.55%; about 0.60%; about 0.65 %; about 0.70 %; about 0.75%; about 0.80 %; about 0.85%; about 0.90 %; about 0.95%; about 1.0 %; about 1.5 %; about 2.0 %; about 2.5 %; about 3.0 %; about 3.5 %; about 4.0 %; about 4.5 %; about 5.0 %; about 5.5 %; about 6.0 %; about 6.5 %; about 7.0 %; about 7.5 %; about 8.0 %; about 8.5 %; about 9.0%; about 9.5 %; or about 10.0 % of R-PHB.

[0120] In another aspect, the composition at least two compounds are ((2R,3S,4S,5R)- 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 20: 1; about 19: 1; about 18: 1; about17:1; about 16:1 about 15:1; about 14:1; about 13:1; about 12:1; about 11:1; about 10:1; about 9:1; about 8:1; about 7:1; about 6:1; about 5:1; about 4:1; about 3:1; about 2:1; about 1:1; about 1:2; about 1:3; about 1:4; about 1:5; about 1:6; about 1:7; about 1:8; about 1:9; about 1:10; about 1:11; about 1:12; about 1:13; about 1:14; about 1:15; about 1:16; about 1:17; about 1:18; about 1:19; or about 1:20.

[0121] In another aspect, the composition at least two compounds are ((2R,3S,4S,5R)- 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 20: 1; about 19:1; about 18:1; about 17:1; about 16:1 about 15:1; about 14:1; about 13:1; about 12:1; about 11:1; about 10:1; about 9:1; about 8:1; about 7:1; about 6:1; about 5:1; about 4:1; about 3:1; about 2:1; about 1:1; about 1:2; about 1:3; about 1:4; about 1:5; about 1:6; about 1:7; about 1:8; about 1:9; about 1:10; about 1:11; about 1:12; about 1:13; about 1:14; about 1:15; about 1:16; about 1:17; about 1:18; about 1:19; or about 1:20.

[0122] In another aspect, the composition at least two compounds are ((2R,3S,4S,5R)- 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 20: 1; about 19:1; about 18:1; about 17:1; about 16:1 about 15:1; about 14:1; about 13:1; about 12:1; about 11:1; about 10:1; about 9:1; about 8:1; about 7:1; about 6:1; about 5:1; about 4:1; about 3:1; about 2:1; about 1:1; about 1:2; about 1:3; about 1:4; about 1:5; about 1:6; about 1:7; about 1:8; about 1:9; about 1:10; about 1:11; about 1:12; about 1:13; about 1:14; about 1:15; about 1:16; about 1:17; about 1:18; about 1:19; or about 1:20.Methods

[0123] In one aspect, the present disclosure provides a method of enhancing the bioavailability of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate or a pharmaceutically acceptable salt thereof.

[0124] In one aspect, the present disclosure provides a method of enhancing the bioavailability of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof. In another aspect, the method of administering to a subject inneed thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof further comprises the administration of one or more ketone bodies, ketone body precursors, ketone esters, or combinations thereof. In another aspect, the method of administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof further comprises the administration of (R)- 1,3 -butanediol. In another aspect, (R)- 3 -hydroxybutyl 4-aminobutanoate can be administered to increase passage of GABA through the blood brain barrier (BBB). GABA has long been thought to be unable to cross the blood-brain barrier. However, there are various accounts regarding GABA's BBB permeability with some indication that small amounts of GABA cross the BBB.

[0125] In one aspect, the present disclosure provides a method of enhancing the bioavailability of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

[0126] In one aspect, the present disclosure provides a method of enhancing the bioavailability of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-acetoxybenzoate.

[0127] In one aspect, the present disclosure provides a method of enhancing the bioavailability of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3- dihy droi sobenzofuran-5 -yl)hex-4-enoate .

[0128] In one aspect, the present disclosure provides a method of enhancing the bioavailability of 2-(4-isobutylphenyl)propanoic acid (Ibuprofen) comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (R)-2-(4-isobutylphenyl)propanoate, (R)-3 -hydroxybutyl (S)-2-(4- isobutylphenyljpropanoate, or combinations thereof.

[0129] In another aspect, the method of enhancing the bioavailability of 2-(4- isobutylphenyljpropanoic acid comprises administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

[0130] In one aspect, the present disclosure provides a method of enhancing the bioavailability of 6-diazo-5-oxo-norleucine comprising administering to a subject in needthereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-amino-6-diazo-5-oxohexanoate or a pharmaceutically acceptable salt thereof.

[0131] In one aspect, the present disclosure provides a method of enhancing the bioavailability of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)-3-hydroxybutanoate or a pharmaceutically acceptable salt thereof. In another aspect, 4-acetamidophenyl (R)-3-hydroxybutanoate can be administered to prevent or reduce acetaminophen poisoning and the reduction of liver glutathione that causes liver damage and toxicity.

[0132] In certain aspects, for athletic performance, a ketone sugar ester can improve stability and solubility of the sugar. For example, D-glucose esterified with R-PHB (e,g, ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate) and D-Fructose esterified with R-PHB (e.g. (3S,4R,5R)-3,4,5,6- tetrahydroxy-2-oxohexyl (R)3-hydroxybutanoate) can provide a steady energy supply during prolonged activities. These ketone sugar esters can also offer sustained energy release and prevent spikes and crashes in blood sugar levels, while delivering sugar over a longer period of time. As used herein, sugars (e.g. glucose and fructose) and the ketone sugar esters of the disclosure can exist in the closed-ring form (e.g. closed pyran ring) or open-chain form. If the ratio of sugar to ketone bodies or ketone body precursors is not optimal based on the ketone sugar-ester of the disclosure, the ketone sugar-ester can further be co-administered with one or more nutritive sugars, one or more ketone bodies, ketone body precursors, ketone esters, ketone body salts, or combinations thereof.

[0133] In another aspect, drugs suitable for use in preparing the novel esters and amides described herein can be co-administered with ketone bodies, ketone body precursors, ketone esters, and / or ketone body salts. For example, L-DOPA used in the treatment of Parkinson’s disease can be co-administered with ketone bodies, ketone body precursors, ketone esters, and / or ketone body salts resulting in improved efficacy for a given subject, relative to treatment with just L-DOPA alone. Additionally, Alzheimer and medications to prevent cardiac events can also be co-administered with ketone bodies, ketone body precursors, ketone esters, and ketone body salts.

[0134] A typical person has internal stores of the carbohydrates (or sugars), namely glucose and fructose, to supply the needed energy for normal daily activity and light exercising that does not last more than an hour. Additionally, a typical person can ingestabout 60 g of glucose hourly or about 90 g of a mixture of glucose and fructose without causing gastrointestinal issues. This increased exogenous carbohydrate consumption through combined glucose-fructose ingestion can be utilized because glucose and fructose are transported across the gut and into the blood using different transport proteins. Athletes or a person exercising for longer than an hour may need to consume more carbohydrates (e.g. glucose and fructose) to maintain a certain performance level.However, a typical person can train their gastrointestinal system to accommodate the ingestion of more than 60 g, 90 g, 120 g, and up to about 200 g of carbohydrates.Accordingly, and in some aspects, glucose or fructose can be co-administered with ketone sugar esters, ketone bodies, ketone body, and / or a ketone ester (e.g. (R)-3 -hydroxybutyl (R)-3-hydroxybutanoate). In another aspect, the glucose can be D-glucose, L-glucose, or a combination thereof. In another aspect, the fructose can be D-fructose, L-fructose, or a combination thereof. In another aspect, glucose can be co-administered with a ketone sugar ester. In another aspect, the co-administration of glucose and a ketone sugar ester can increase the amount of glucose that can be ingested from about 60 g / hour to about 200 g / hour; about 60 g / hour to about 150 g / hour; about 60 g / hour to about 120 g / hour; about 70 g / hour to about 120 g / hour; about 80 g / hour to about 110 g / hour; about 90 g / hour to about 100 g / hour; about 70 g / hour to about 90 g / hour; about 90 g / hour to about 110 g / hour; about 100 g / hour to about 120 g / hour; about 60 g / hour to about 100 g / hour; and about 65 g / hour to about 100 g / hour. In another aspect, the co-administration of glucose and a ketone sugar ester can increase the amount of glucose that can be ingested to about 60 g / hour; about 70 g / hour; about 80 g / hour; about 90 g / hour; about 100 g / hour; about 110 g / hour; about 120 g / hour; about 130 g / hour; about 140 g / hour; about 150 g / hour; about 160 g / hour; about 170 g / hour; about 180 g / hour; about 190 g / hour; or about 200 g / hour. In another aspect, the co-administration of glucose and a ketone ester can increase the amount of glucose that can be ingested by about 5%; about 10%; about 15%; about 20%; about 25%; about 30%; about 35%; about 40%; about 45%; about 50%; about 55%; about 60%; about 65%; about 70%; about 75%; about 80%; about 85%; about 90%; about 95%; about 100%; about 150%; about 200%; or about 230%. In another aspect, glucose and fructose can be in a mixture in a ratio of about 10 to about 1; about 9 to about 1; about 8 to about 1; about 7 to about 1; about 6 to about 1; about 5 to about 1; about 4 to about 1; about 3 to about 1; about 2 to about ; or about 1 to about 1.

[0135] In another aspect, fructose can be co-administered with a ketone sugar ester. In another aspect, glucose can be co-administered with fructose and a ketone ester. In another aspect, the co-administration of glucose, fructose, and a ketone ester can increase the amount of glucose that can be ingested from about 60 g / hour to about 200 g / hour; about 60 g / hour to about 150 g / hour; about 60 g / hour to about 120 g / hour; about 70 g / hour to about 120 g / hour; about 80 g / hour to about 110 g / hour; about 90 g / hour to about 100 g / hour; about 70 g / hour to about 90 g / hour; about 90 g / hour to about 110 g / hour; about 100 g / hour to about 120 g / hour; about 60 g / hour to about 100 g / hour; and about 65 g / hour to about 100 g / hour. In another aspect, the co-administration of glucose, fructose, and a ketone ester can increase the amount of glucose that can be ingested to about 60 g / hour; about 70 g / hour; about 80 g / hour; about 90 g / hour; about 100 g / hour; about 110 g / hour; about 120 g / hour; about 130 g / hour; about 140 g / hour; about 150 g / hour; about 160 g / hour; about 170 g / hour; about 180 g / hour; about 190 g / hour; or about 200 g / hour. In another aspect, the co-administration of glucose, fructose, and a ketone ester can increase the amount of glucose that can be ingested by about 5%; about 10%; about 15%; about 20%; about 25%; about 30%; about 35%; about 40%; about 45%; about 50%; about 55%; about 60%; about 65%; about 70%; about 75%; about 80%; about 85%; about 90%; about 95%; about 100%; about 150%; about 200%; or about 230%. In another aspect, glucose and fructose can be in a mixture in a ratio of about 10 to about 1; about 9 to about 1; about 8 to about 1; about 7 to about 1; about 6 to about 1; about 5 to about 1; about 4 to about 1; about 3 to about 1; about 2 to about 1; or about 1 to about 1.

[0136] In another aspect, the co-administration of glucose, fructose, and a ketone sugar ester can increase the amount of fructose that can be ingested from about 20 g / hour to about 100 g / hour; about 30 g / hour to about 70 g / hour; or about 40 g / hour to about 60 g / hour. In another aspect, the co-administration of fructose and a ketone ester can increase the amount of fructose that can be ingested to about about 20 g / hour; about 25 g / hour; about 30 g / hour; about 35 g / hour; about 40 g / hour; about 45 g / hour; about 50 g / hour; about 55 g / hour; about 60 g / hour; about 65 g / hour; about 70 g / hour; about 75 g / hour; about 80 g / hour; about 85 g / hour; about 90 g / hour; about 95 g / hour; or about 100 g / hour.

[0137] In certain aspects, the sugars, for example but not limited, are D-glucose ((3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol), L-glucose((3S,4R,5R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol), D-fructose ((3S,4R,5R)-l,3,4,5,6-pentahydroxyhexan-2-one), and L-fructose ((3R,4S,5S)-1,3,4,5,6- pentahydroxyhexan-2-one) can be esterified with PHB at any for the sugar hydroxyl groups and in any combination of the sugar hydroxyl group. For example, D-glucose can be esterified with PHB at 1 of the 5 D-glucose hydroxyl groups, at 2 of the 5 D-glucose hydroxyl groups, at 3 of the 5 D-glucose hydroxyl groups, at 4 of the 5 D-glucose hydroxyl groups, or at 5 of the 5 D-glucose hydroxyl groups.

[0138] In one aspect, the present disclosure provides a method of enhancing the bioavailability of D-glucose comprising administering to a subject in need thereof, an effective amount of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl jmethyl (R)-3 -hydroxybutanoate.

[0139] In one aspect, the present disclosure provides a method of enhancing the bioavailability of L-glucose comprising administering to a subject in need thereof, an effective amount of ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl jmethyl (R)-3 -hydroxybutanoate.

[0140] In one aspect, the present disclosure provides a method of enhancing the bioavailability of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, or combinations thereof.

[0141] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, or combinations thereof further comprises the administration of D-glucose.

[0142] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, or combinations thereof further comprises the administration of D-fructose.

[0143] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate,or combinations thereof further comprises the administration of D-glucose and D- fructose.

[0144] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate, or combinations thereof further comprises the administration of one or more ketone bodies, ketone body precursors, ketone body salts, ketone body esters, or combinations thereof.

[0145] In one aspect, the present disclosure provides a method of enhancing the bioavailability of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium.

[0146] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl-N-m ethylglycinate or a pharmaceutically acceptable salt thereof.

[0147] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof.

[0148] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6- dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

[0149] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-acetoxybenzoate.

[0150] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3- dihy droi sobenzofuran-5 -yl)hex-4-enoate .

[0151] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of 2-(4-isobutylphenyl)propanoic acid (Ibuprofen) comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2- (4-isobutylphenyl)propanoate.

[0152] In another aspect, the method of reducing gastrointestinal side effects of 2-(4- isobutylphenyl)propanoic acid (Ibuprofen) comprises administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

[0153] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of 6-diazo-5-oxo-norleucine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)-2-amino-6-diazo- 5 -oxohexanoate or a pharmaceutically acceptable salt thereof.

[0154] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)-3-hydroxybutanoate or a pharmaceutically acceptable salt thereof.

[0155] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of D-glucose ((3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro- 2H-pyran-2,3,4,5-tetraol) comprising administering to a subject in need thereof, an effective amount of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl)methyl (R)-3 -hydroxybutanoate.

[0156] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of L-glucose ((3S,4R,5R,6S)-6-(hydroxymethyl)tetrahydro- 2H-pyran-2,3,4,5-tetraol) comprising administering to a subject in need thereof, an effective amount of ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2- yl)methyl (3R)-3 -hydroxybutanoate.

[0157] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate.

[0158] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate. In a particular aspect, the method further comprises the administration of D-glucose.

[0159] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate. In a particular aspect, the method further comprises the administration of D-fructose.

[0160] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate. In still another aspect, the method further comprises the administration of D-glucose and D-fructose.

[0161] In another aspect, the method of administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3- hydroxybutanoate, (3 S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate further comprises the administration of one or more ketone bodies, ketone body precursors, ketone body salts, ketone body esters, or combinations thereof.

[0162] In one aspect, the present disclosure provides a method of reducing gastrointestinal side effects of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l-((2R,3R,4S,5R)-3,4- dihydroxy-5-((((R)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium or a pharmaceutically acceptable salt thereof.

[0163] In another aspect, the compound is administered via injection, intravenously, orally, or topically. In certain aspects, formulations are prepared for storage and use by combining a compound of the present disclosure with a pharmaceutically acceptable vehicle (e.g. carrier, excipient) (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000). Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight polypeptides (e.g. less than about 10amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and non-ionic surfactants such as TWEEN or polyethylene glycol (PEG).

[0164] In certain aspects, the pharmaceutical compositions of the present disclosure can be administered in any number of ways for either local or systemic treatment.Administration can be topical (such as to mucous membranes including vaginal and rectal delivery) such as transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal); oral; or parenteral including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration.EXAMPLES

[0165] The examples presented below are provided for the purpose of illustration only and the aspects described herein should in no way be construed as being limited to these examples. Rather, the aspects should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Example 1 : Synthesis of 4-acetamidophenyl 3-hydroxybutanoate

[0166] A mixture of N-(4-hydroxyphenyl)acetamide (1 eq), 3 -hydroxybutanoic acid (1 eq), and N,N'-Dicyclohexylcarbodiimide (DCC) in tetrahydrofuran (THF) is stirred overnight. The mixture is filtered and solvent is removed under vacuum. The residue is slurried in 35 ml. of acetone, and the insoluble urea is separated by filtration. The acetone solution is treated with acetic acid and allowed to stand to remove excessdicyclohexylcarbodiimide. The mixture is extracted with methylene chloride. The methylene chloride is extracted with saturated aqueous sodium bicarbonate. The methylene chloride layer is dried over magnesium sulfate and concentrated to an oil. The residue is chromatographed on silica gel. The appropriate fractions are concentrated to give 4-acetamidophenyl 3-hydroxybutanoate. The stereoisomers are either isolated through chromatographic methods know in the art or are prepared through the above preparation starting with either (R)-3 -hydroxybutanoic acid or (S)-3-hydroxybutanoic acid.Example 2: Method of enhancing bioavailability of acetaminophen

[0167] A mixture of 250 parts of 4-acetamidophenyl 3-hydroxybutanoate, 200 parts of maize starch and 30 parts of alginic acid are mixed with a sufficient quantity of 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.

[0168] The 4-acetamidophenyl 3-hydroxybutanoate tablets are administered orally to a subject. The 4-acetamidophenyl 3-hydroxybutanoate demonstrates enhanced solubility and bioavailability over acetaminophen with fewer side effects while maintaining analgesic effect.Example 3: Synthesis of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate, (R)-3- hydroxybutyl (R)-2-(4-isobutylphenyl)propanoate, (R)-4-hydroxybutan-2-yl (S)-2-(4- isobutylphenyl)propanoate, and / or (R)-4-hydroxybutan-2-yl (R)-2-(4- isobutylphenyl)propanoate

[0169] Ibuprofen (1.26 g) was dissolved in (R)-l,3-butanediol (15.0 g) followed by the addition of Novozyme 435 immobilized enzyme (0.5 g) (Novonesis). The reactionmixture was stirred at room temperature for 48 hours. After 48 hours, the reaction mixture was filtered to remove the Novozyme 435 immobilized enzyme. GC / MS analysis identified two product peaks at 21.90 min. and 21.95 min. Both peaks display mass ion at m / z = 278 corresponding to two or more of (R)-3 -hydroxybutyl (S)-2-(4- isobutylphenyl)propanoate, (R)-3 -hydroxybutyl (R)-2-(4-isobutylphenyl)propanoate, (R)-4-hydroxybutan-2-yl (S)-2-(4-isobutylphenyl)propanoate, (R)-4-hydroxybutan-2-yl (R)-2-(4-isobutylphenyl)propanoate.Example 4: Synthesis of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate and / or (R)-4-hydroxybutan-2-yl (S)-2-(4-isobutylphenyl)propanoate

[0170] (S)-Ibuprofen (0.33 g) was dissolved in (R)- 1,3 -butanediol (11.2 g) followed by the addition of Novozyme 435 immobilized enzyme (0.5 g) (Novonesis). The reaction mixture was stirred at room temperature for 96 hours. After 96 hours, the reaction mixture was filtered to remove the Novozyme 435 immobilized enzyme. GC / MS analysis identified a product peak at 22 min. The peak displayed a mass ion at m / z = 278 corresponding to one or both of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate (3) and (R)-4-hydroxybutan-2-yl (S)-2-(4-isobutylphenyl)propanoate.

[0171] The foregoing description of the specific aspects will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0172] The breadth and scope of the present invention should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein:R1is2. The compound of Formula I according to claim 1, wherein the compound is a compound of Formula I A:

3. The compound of Formula I according to claim 1, wherein the compound is a compound of Formula IB:

4. The compound of Formula I according to claim 1, wherein the compound is a mixture of a compound of Formula IA and a compound of Formula IB.

5. The compound of claim 4, wherein the compound of Formula IA and the compound of Formula IB are present in a ratio ranging from about 1 : 99 to about 99: 1.

6. The compound of claim 5, wherein the compound of Formula IA and the compound ofFormula IB are present in a ratio ranging from about 51 :49 to about 99: 1.

7. The compound of claim 5, wherein the compound of Formula IB and the compound ofFormula IA are present in a ratio ranging from about 51 :49 to about 99: 1.

8. A compound of Formula II,or a pharmaceutically acceptable salt thereof, wherein:A is a double bond or single bond; provided that when A is a single bond R3is O and R4is H, and when A is a double bond R3is O and R4is absent.

9. The compound of Formula II according to claim 8, wherein the compound is a compound of Formula II A:

10. The compound of Formula II according to claim 9, wherein the compound is a compound of Formula IIB:

11. The compound of Formula II according to claim 9, wherein the compound is a compound of Formula IIC:

12. The compound of Formula II according to claim 9, wherein the compound is a mixture of a compound of Formula IIB and a compound of Formula IIC.

13. The compound of claim 12, wherein the compound of Formula IIB and the compound of Formula IIC are present in a ratio ranging from about 1 : 99 to about 99: 1.

14. The compound of claim 12, wherein the compound of Formula IIB and the compound of Formula IIC are present in a ratio ranging from about 51 :49 to about 99: 1.

15. The compound of claim 12, wherein the compound of Formula IIC and the compound of Formula IIB are present in a ratio ranging from about 51 :49 to about 99: 1.

16. A composition comprising a compound selected from a group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate, (S)-3 -hydroxybutyl N- carbamimidoyl-N-methylglycinate, and combinations thereof;(R)-3 -hydroxybutyl 4-aminobutanoate, (S)-3 -hydroxybutyl 4-aminobutanoate, and combinations thereof;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, (S)-3- hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, and combinations thereof;(R)-3 -hydroxybutyl 2-acetoxybenzoate, (S)-3 -hydroxybutyl 2-acetoxybenzoate, and combinations thereof;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, (S)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate, and combinations thereof;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate, (S)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate, and combinations thereof; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex-l-ene-l -carboxylate, (S)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5- amino-3 -(pentan-3 -yloxy)cyclohex-l-ene-l -carboxylate, and combinations thereof; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

17. The composition according to claim 16 wherein the compound is selected from the group consisting of(R)-3 -hydroxybutyl N-carbamimidoyl-N-methylglycinate;(R)-3 -hydroxybutyl 4-aminobutanoate;(R)-3 -hydroxybutyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;(R)-3 -hydroxybutyl 2-acetoxybenzoate;(R)-3 -hydroxybutyl (E)-4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4- enoate;(R)-3 -hydroxybutyl (2S)-2-amino-6-diazo-5-oxohexanoate; and(R)-3 -hydroxybutyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3- yloxy)cyclohex- 1 -ene- 1 -carboxylate; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

8. A composition comprising a compound selected from the group consisting of ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate, ((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (S)-3-hydroxybutanoate, and combinations thereof;(3 S,4R, 5R)-3 ,4, 5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-l-ium, 3 -carbarn oyl-1- ((2R,3R,4S,5R)-3,4-dihydroxy-5-((((S)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran- 2-yl)pyridin-l-ium, and combinations thereof;4-acetamidophenyl (R)-3 -hydroxybutanoate, 4-acetamidophenyl (S)-3- hydroxybutanoate, and combinations thereof;(3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3 -hydroxybutanoate, (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3 -hydroxybutanoate, (2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (S)-3 -hydroxybutanoate, and combinations thereof; and(2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3 -hydroxybutanoate, (2S,3 S,4R)- 2,3,4-trihydroxy-5-oxopentyl (S)-3 -hydroxybutanoate, and combinations thereof; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

19. The composition according to claim 18 wherein the compound is selected from the group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate; (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl 3 -hy droxybutanoate; (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and (2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate; and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

20. A composition comprising at least two compounds selected from the group consisting of((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;((2S,3R,4R,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3- hydroxybutanoate;(3 S,4R, 5R)-3 ,4, 5 ,6-tetrahy droxy-2-oxohexyl (R)-3 -hy droxybutanoate; (2R,3R,4S)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexyl (R)-3-hy droxybutanoate;3-carbamoyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3- hydroxybutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin- 1 -ium;4-acetamidophenyl 3 -hy droxybutanoate; (3R,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3-hy droxybutanoate;(2R,3R,4R)-2,3,4,6-tetrahydroxy-5-oxohexyl (R)-3-hy droxybutanoate; and (2S,3 S,4R)-2,3,4-trihydroxy-5-oxopentyl (R)-3-hy droxybutanoate;and one or more supplements, one or more sweeteners, one or more additives, water, or combinations thereof.

21. The composition of claim 20 wherein the two compounds are ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (3S,4R,5R)-3.4.5.6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of 3 : 1 or 1:3.

22. The composition of claim 21 further comprising D-glucose.

23. The composition of claim 21 further comprising D-fructose.

24. The composition of claim 21 further comprising D-glucose and D-fructose.

25. The composition of claim 20 wherein the two compounds are ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (2R,3R,4S)-2.3.4.6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 3 : 1 or about 1 :3.

26. The composition of claim 20 wherein the two compounds are ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (3R,4R,5R)-3.4.5.6-tetrahydroxy-2-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 3 : 1 or about 1 :3.

27. The composition of claim 20 wherein the two compounds are ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate and (2R,3R,4R)-2.3.4.6-tetrahydroxy-5-oxohexyl (R)-3-hydroxybutanoate and wherein the compounds are present in a weight ratio of about 3 : 1 or about 1 :3.

28. A method of enhancing the bioavailability of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl-N- methylglycinate or a pharmaceutically acceptable salt thereof.

29. A method of enhancing the bioavailability of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof.

30. A method of enhancing the bioavailability of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6- dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

31. A method of enhancing the bioavailability of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2- acetoxybenzoate.

32. A method of enhancing the bioavailability of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)- 4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4-enoate.

33. A method of enhancing the bioavailability of 2-(4-isobutylphenyl)propanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3- hydroxybutyl (R)-2-(4-isobutylphenyl)propanoate, (R)-3 -hydroxybutyl (S)-2-(4- isobutylphenyljpropanoate, or combinations thereof.

34. The method of claim 33, wherein the method comprises administering an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

35. A method of enhancing the bioavailability of 6-diazo-5-oxo-norleucine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (S)- 2-amino-6-diazo-5-oxohexanoate or a pharmaceutically acceptable salt thereof.

36. A method of enhancing the bioavailability of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)-3- hydroxybutanoate or a pharmaceutically acceptable salt thereof.

37. A method of enhancing the bioavailability of D-glucose comprising administering to a subject in need thereof, an effective amount of ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate.

38. A method of enhancing the bioavailability of L-glucose comprising administering to a subject in need thereof, an effective amount of ((2S, 3R,4R,5S)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (3R)-3-hydroxybutanoate.

39. A method of enhancing the bioavailability of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5- oxohexyl (R)-3-hydroxybutanoate, (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate, or combinations thereof..

40. A method of enhancing the bioavailability of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l- ((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran- 2-yl)pyridin- 1 -ium .

41. A method of reducing gastrointestinal side effects of creatine comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl N-carbamimidoyl- N-methylglycinate or a pharmaceutically acceptable salt thereof.

42. A method of reducing gastrointestinal side effects of GABA comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 4-aminobutanoate or a pharmaceutically acceptable salt thereof.

43. A method of reducing gastrointestinal side effects of diclofenac comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2-(2-((2,6- dichlorophenyl)amino)phenyl)acetate or a pharmaceutically acceptable salt thereof.

44. A method of reducing gastrointestinal side effects of acetylsalicylic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl 2- acetoxybenzoate.

45. A method of reducing gastrointestinal side effects of mycophenolic acid comprising administering to a subject in need thereof, an effective amount of (R)-3 -hydroxybutyl (E)- 4-methyl-6-(3-oxo-l,3-dihydroisobenzofuran-5-yl)hex-4-enoate.

46. A method of reducing gastrointestinal side effects of 2-(4-isobutylphenyl)propanoic acid comprising administering to a subject in need thereof, an effective amount of (R)-3- hydroxybutyl 2-(4-isobutylphenyl)propanoate.

47. The method of claim 46, wherein the method comprises administering an effective amount of (R)-3 -hydroxybutyl (S)-2-(4-isobutylphenyl)propanoate.

48. A method of reducing gastrointestinal side effects of 6-diazo-5-oxo-norleucine comprising administering to a subject in need thereof, an effective amount of (R)-3- hydroxybutyl (S)-2-amino-6-diazo-5-oxohexanoate or a pharmaceutically acceptable salt thereof.

49. A method of reducing gastrointestinal side effects of acetaminophen comprising administering to a subject in need thereof, an effective amount of 4-acetamidophenyl (R)- 3-hydroxybutanoate or a pharmaceutically acceptable salt thereof.

50. A method of reducing gastrointestinal side effects of D-glucose comprising administering to a subject in need thereof, an effective amount of ((2R,3 S,4S,5R)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (R)-3-hydroxybutanoate.

51. A method of reducing gastrointestinal side effects of L-glucose comprising administering to a subject in need thereof, an effective amount of ((2S, 3R,4R,5S)-3, 4,5,6- tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (3R)-3-hydroxybutanoate.

52. A method of reducing gastrointestinal side effects of fructose comprising administering to a subject in need thereof, an effective amount of 4-(2R,3R,4S)-2,3,4,6-tetrahydroxy-5- oxohexyl (R)-3-hydroxybutanoate, (3S,4R,5R)-3,4,5,6-tetrahydroxy-2-oxohexyl (R)-3- hydroxybutanoate.

53. A method of reducing gastrointestinal side effects of nicotinamide riboside comprising administering to a subject in need thereof, an effective amount of 3-carbamoyl-l- ((2R,3R,4S,5R)-3,4-dihydroxy-5-((((R)-3-hydroxybutanoyl)oxy)methyl)tetrahydrofuran- 2-yl)pyridin-l-ium or a pharmaceutically acceptable salt thereof.

54. The method of claims 25-53, wherein the compound is administered via injection, suppository, intravenously, orally, or topically.

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