Coq10 repletion using 4-hma

Abstract

The present invention relates to methods for alleviating symptoms selected from the group consisting of fatigue and frailty associated with aging, skin aging, muscle weakness, statin-associated muscle symptoms, cardiovascular diseases, kidney diseases, and CoQ10 depletion and mitochondrial failure associated with adult neurodegenerative diseases. The present invention further relates to methods for improving mitochondrial function in the end organs.

Description

Attorney Docket No.243735.000398 COQ10 REPLETION USING 4-HMA CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 627,321, filedJanuary 31, 2024, and U.S. Provisional Application No.63 / 612,679, filed December 20, 2023, the disclosure of each of which is incorporated by reference herein in its entirety. STATEMENT AS TO FEDERALLY FUNDED RESEARCH

[0002] This invention was made with government support under R35 GM147119 awarded bythe National Institutes of Health. The government has certain rights in the invention. FIELD OF INVENTION

[0003] The present invention relates to CoQ10 repletion using 4-HMA.BACKGROUND OF THE INVENTION

[0004] Coenzyme Q10 (CoQ10) is an endogenously synthesized antioxidant. CoQ10 consistsof a lipid tail (hydrophobic isoprenoid tail) and a quinone headgroup. The quinone accepts and donates electrons. CoQ10 is found in every biological membrane and serves both as an antioxidant and as an electron carrier in the mitochondrial electron transport chain.

[0005] Coenzyme Q10 (CoQ10) is the sole endogenously-synthesized, lipid soluble single-electron carrier in cells. This antioxidant is critical for the function of the electron transport chain required for mitochondrial energy production and for quenching of reactive oxygen species in membranes. CoQ10 is commonly taken as a supplement, in spite of its low bioavailability (<5% enters the plasma following oral dosing, and <1% enters the brain). The market is anticipated to grow by 10% between 2023 and 2032 and the anticipated market size in 2022 is $614.2 million. The low bioavailability of CoQ10 likely explains the poor response of patients with defects in CoQ10 synthesis (primary and secondary CoQ10 deficiencies) to CoQ10 supplementation. In particular, the encephalopathy, seizures, and other neurological symptoms of primary CoQ10 deficiencies do not respond to CoQ10 supplementation, likely because of the inability of CoQ10 to cross the blood-brain barrier.

[0006] Accordingly, there is a strong, unmet need for methods that increase the levels ofCoQ10.Attorney Docket No.243735.000398 SUMMARY OF THE INVENTION

[0007] Various non-limiting aspects and embodiments of the invention are described below.

[0008] In one aspect, the present disclosure provides a method of alleviating symptomsselected from the group consisting of fatigue and frailty associated with aging, skin aging, muscle weakness, statin-associated muscle symptoms, cardiovascular diseases, kidney diseases, and CoQ10 depletion and mitochondrial failure associated with adult neurodegenerative diseases, in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): , wherein:R1is selected from the group ; R2is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H ; or a compound of Formula (II):, wherein:n is 0 or 1; R1ais selected from the group ;Attorney Docket No.243735.000398 R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3 alkyl; and R4a is selected from the group consisting of H and ; andR5ais selected from the group consisting of H , or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present disclosure provides a method for improvingmitochondrial function in the end organs, in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): , wherein:R1 is selected from the group ; R2is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; and R4is selected from the group consisting of H ; or a compound of Formula (II):, wherein:n is 0 or 1;Attorney Docket No.243735.000398 R1a is selected from the group ; R2ais selected from the groupR3a is selected from the group and R4a is selected from the group consisting of H and ; andR5ais selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a method for alleviating symptomsassociated with recovery following myocardial infarction, recovery following ischemic brain injury, recovery following ischemic spinal cord injury, recovery following traumatic brain injury, or recovery following traumatic spinal cord injury, in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): ,R1is selected from the group ; R2 is selected from the groupR3is selected from the group consisting of H and C1-C3alkyl; and R4is selected from the group consisting of H ; or a compound of Formula (II):Attorney Docket No.243735.000398 , wherein:n is 0 or 1; R1ais selected from the group ; R2ais selected from the groupR3a is selected from the group and R4a is selected from the group consisting of H and ; andR5ais selected from the group consisting of H , or a pharmaceutically acceptable salt thereof.

[0011] In a further aspect, the present disclosure provides a method for treatment of an injuryselected form the group consisting of brain injury and spinal cord injury, in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): , wherein:R1 is selected from the group ; R2is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; andAttorney Docket No.243735.000398 R4 is selected from the group consisting of H and ; or a compound of Formula (II):,R3ais selected from the group consisting of H and C1-C3alkyl; and R4a is selected from the group consisting of H ; andR5a is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof.

[0012] These and other aspects of the present invention will become apparent to those skilledin the art after a reading of the following detailed description of the invention, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The patent or application file contains at least one drawing executed in color. Copiesof this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0014] Figure 1 shows that 13C6-4-hydroxymandelic acid (4-HMA) and 4-hydroxybenzoate(4-HB) were incorporated into CoQ9 (the mouse equivalent of CoQ10) in the brains of Hpdl+ / +, Hpdl+ / -, and Hpdl- / - mice, as demonstrated by high levels of m6 CoQ9 (red bars). Mice predominantly synthesize CoQ9instead of CoQ10, the dominant CoQ isoform in humans.Attorney Docket No.243735.000398 Fractional labeling data was measured due to difficulties normalizing CoQ9signal to tissue cellularity.

[0015] Figure 2 shows that supplementation of wild-type human fibroblasts with 13C6-4-HMAincreases total CoQ10pools. Nearly all of the increase in the CoQ10pool was labeled, m6 and m7 CoQ10 that arises from exogenous,13C6-4-HMA.

[0016] Figures 3A-3C show the incorporation of orally administered mammalian CoenzymeQ (CoQ) headgroup precursors into CoQ9in mice. Figure 3A is a schematic of the incorporation of13C from13C6-4-HMA and13C6-4-HB into mouse CoQ9. Figure 3B shows fractional labeling of bulk brain CoQ9 showing contributions of 4-HMA and 4-HB.13C6-4-HMA and13C6-4-HB were incorporated into13C6-CoQ9in Hpdl- / - mice. Figure 3C shows fractional labeling of bulk CoQ9showing contributions of 4-HMA and 4-HB in extracranial organs.13C6-4-HMA and13C6-4-HB were incorporated into13C6-CoQ9 in all tested tissues of all mice tested.

[0017] Figures 4A-4B show that treatment with 4-HMA increases the Rotarod latency (timeon the Rotarod) in 1-year-old, middle-aged mice. Figure 4A is the initial timepoint after one month of treatment. Figure 4B shows continued improvement in Rotarod latency after 3 months of treatment.

[0018] Figure 5 shows that treatment with 4-HMA increases normalized 4-paw grip strengthin 1-year-old, middle-aged mice. DETAILED DESCRIPTION

[0019] To facilitate an understanding of the principles and features of the various embodimentsof the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0020] As used herein, the terms “about” or “approximately” for any numerical values orranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” orAttorney Docket No.243735.000398 “approximately” may refer to the range of values ±20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.

[0021] As used herein, the term “alkyl” is given its ordinary meaning in the art and can includesaturated aliphatic groups, including straight-chain alkyl groups, and branched-chain alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 1–20 carbon atoms in its backbone (e.g., C1-20 for straight chain, C2-20 for branched chain), and alternatively, about 1– 10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1–4 carbon atoms (e.g., C1-4 for straight chain lower alkyls).

[0022] As described herein, in certain embodiments, certain compounds of the disclosure canbe indicated to comprise “optionally substituted” moieties. When indicated, in general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0023] As used herein, a substituent, e.g., -B, can be represented , wheredenotes a point of attachment.

[0024] Unless otherwise stated, structures depicted herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure.Attorney Docket No.243735.000398

[0025] The present application also includes pharmaceutically acceptable salts of thecompounds described herein. The “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. By way of an example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable anion selected from F−, Cl−, Br−, I−, OH−,−BF4, CF3SO3−, monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO3−, PF6−, NO2−, carboxylate, CeFfSO3−, (where e=2-10 and f=2e+1), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, oxalate, palmitate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide. By way of another example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0026] The term “prodrug” as used herein includes a chemical which may be transformed invivo to a pharmacologically active drug. The term “metabolite” as used herein includes a chemical that a given agent is transformed into in vivo.

[0027] The enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage ofthe major enantiomer less the percentage of the minor enantiomer. A “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee.Attorney Docket No.243735.000398

[0028] The term “enantiomerically enriched” or “enantioenriched” as used herein includescompounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and <100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer.

[0029] The term “enantiomerically pure” or “enantiopure” as used herein includes compoundswhere the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only.

[0030] The term “sample” as used herein includes any biological specimen obtained from asubject or patient. Samples that can be used in the methods of the present disclosure include, without limitation, tumor sample, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells), ductal lavage fluid, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by random periareolar fine needle aspiration), any other bodily fluid, a tissue sample such as a biopsy (e.g., needle biopsy), and cellular extracts thereof. In some embodiments, when the subject is a pregnant female, the sample may be a fetal DNA sample (e.g., cell-free fetal DNA (cffDNA)).

[0031] As used herein, the term “subject” or “patient” refers to mammals and includes, withoutlimitation, human and veterinary animals. In a preferred embodiment, the subject is human.

[0032] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventingor delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0033] An “effective amount” of a compound described herein refers to an amount sufficientto elicit the desired biological response, i.e., treating the state, disorder or condition. As will beAttorney Docket No.243735.000398 appreciated by those of ordinary skill in this art, the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0034] A “therapeutically effective amount” of a compound described herein is an amountsufficient to provide a therapeutic benefit in the treatment of a state, disorder or condition or to delay or minimize one or more symptoms associated with the state, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0035] It must also be noted that, as used in the specification and the appended claims, thesingular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named. In other words, the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.

[0036] Also, in describing the exemplary embodiments, terminology will be resorted to for thesake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

[0037] It is also to be understood that the mention of one or more method steps does notpreclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a composition does not preclude the presence of additional components than those expressly identified.

[0038] The materials described hereinafter as making up the various elements of the presentinvention are intended to be illustrative and not restrictive. Many suitable materials that wouldAttorney Docket No.243735.000398 perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the invention. Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention. Compounds of the Disclosure

[0039] In one aspect, provided herein is a compound having the structure of Formula (I):, whereR1is selected from the group ; R2 is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the compound of Formula (I) is provided as a racemic mixture ofthe R- and the S-enantiomers.

[0041] In another embodiment, the compound of Formula (I) is provided as an enantioenrichedmixture of the R-enantiomer. In one embodiment, the compound of Formula (I) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0042] In one embodiment, the compound of Formula (I) is present with an enantiomericexcess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least aboutAttorney Docket No.243735.000398 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0043] In another embodiment, the compound of Formula (I) is provided as the enantiopureR-enantiomer.

[0044] In another embodiment, the compound of Formula (I) is provided as an enantioenrichedmixture of the S-enantiomer. In one embodiment, the compound of Formula (I) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0045] In one embodiment, the compound of Formula (I) is present with an enantiomericexcess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0046] In another embodiment, the compound of Formula (I) is provided as the enantiopure S-enantiomer.

[0047] In some embodiments, R1 is H.

[0048] In some .

[0049] In some

[0050] In some embodiments, R2 is H.

[0051] In some embodiments, R3 is H.

[0052] In some embodiments, R3 is methyl.

[0053] In some embodiments, R4 is H.

[0054] In some .

[0055] In someof Formula (I) has the structure according toFormula (Ia):Attorney Docket No.243735.000398 O R1O or a pharmaceuticallyR1is selected from the groupR4is selected from the group consisting of H and .

[0056] In some embodiments, the(I) has the structure according toFormula (Ib): Me O or a pharmaceuticallyR1is selected from the groupR4is selected from the group consisting of H .

[0057] In some embodiments, thethe structure of Formula (I) is selectedfrom the group consisting of:Attorney Docket No.243735.000398 , or a

[0058] In some embodiments, the compound having the structure of Formula (I) is selectedfrom the group consisting of: a

[0059] In one aspect, provided herein is a compound having the structure of Formula (II):,Attorney Docket No.243735.000398 R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3 alkyl; and R4a is selected from the group consisting of H and ; andR5ais selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the compound of Formula (II) is provided as a racemic mixture ofthe R- and the S-enantiomers.

[0061] In another embodiment, the compound of Formula (II) is provided as anenantioenriched mixture of the R-enantiomer. In one embodiment, the compound of Formula (II) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0062] In one embodiment, the compound of Formula (II) is present with an enantiomericexcess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0063] In another embodiment, the compound of Formula (II) is provided as the enantiopureR-enantiomer.

[0064] In another embodiment, the compound of Formula (II) is provided as anenantioenriched mixture of the S-enantiomer. In one embodiment, the compound of Formula (II) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0065] In one embodiment, the compound of Formula (II) is present with an enantiomericexcess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least aboutAttorney Docket No.243735.000398 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0066] In another embodiment, the compound of Formula (II) is provided as the enantiopureS-enantiomer.

[0067] In some embodiments, the compound of Formula (II) has the structure according toFormula (IIa): , or a pharmaceuticallyR1a is selected from the group ; R2ais selected from the groupR3a is selected from the group consisting of H and C1-C3 alkyl; R4a is selected from the group consisting of H , andR5ais selected from the group consisting of H .

[0068] In some embodiments, the(II) has the structure according toFormula (IIb): or a pharmaceuticallyR1a is selected from the group ; R2ais selected from the groupR3a is selected from the group consisting of H and C1-C3 alkyl;Attorney Docket No.243735.000398 R4ais selected from the group consisting of H and , andR5a is selected from the group consisting of H and .

[0069] In some embodiments, the(II) has the structure:.

[0071] In some .

[0072] In some

[0073] In some embodiments, R2a is H.

[0074] In some embodiments, R3a is H.

[0075] In some embodiments, R3a is methyl.

[0076] In some embodiments, R4a is H.

[0077] In some .

[0078] In some

[0079] In some .

[0080] In somehaving the structure of Formula (II) is selectedfrom the group consisting of:Attorney Docket No.243735.000398

[0081] In some embodiments, the compound having the structure of Formula (II) is selectedfrom the group consisting of: ,

[0082] In some embodiments, the compound having the structure of Formula (II) is selectedfrom the group consisting of:Attorney Docket No.243735.000398 , ora pharmaceutically acceptable salt thereof.the structure of Formula (II) is selectedfrom the group consisting of: , ,Attorney Docket No.243735.000398 O O O oracid (also known as 4-hydroxymandelic acid (4-HMA)): , or a pharmaceuticallyco-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0085] In one embodiment, 4-HMA is provided as a racemic mixture of the R- and the S-enantiomers of 4-HMA, depicted below: .

[0086] Inmixture of the R-enantiomer, i.e., (R)-4-HMA. In one embodiment, the (R)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.Attorney Docket No.243735.000398

[0087] In one embodiment, the (R)-4-HMA is present with an enantiomeric excess (ee) of atleast about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0088] In another embodiment, 4-HMA is provided as the enantiopure R-enantiomer (R)-4-HMA.

[0089] In another embodiment, 4-HMA is provided as an enantioenriched mixture of the S-enantiomer, i.e., (S)-4-HMA. In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0090] In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of atleast about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0091] In another embodiment, 4-HMA is provided as the enantiopure S-enantiomer (S)-4-HMA.

[0092] In one aspect, provided herein is 4-hydroxybenzoate (4-HB):or a pharmaceuticallyco-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0093] In one embodiment, 4-HB is provided as a racemic mixture of the R- and the S-enantiomers of 4-HB.Attorney Docket No.243735.000398

[0094] In another embodiment, 4- HB is provided as an enantioenriched mixture of the R-enantiomer, i.e., (R)-4- HB. In one embodiment, the (R)-4- HB is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0095] In one embodiment, the (R)-4- HB is present with an enantiomeric excess (ee) of atleast about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0096] In another embodiment, 4- HB is provided as the enantiopure R-enantiomer (R)-4- HB.

[0097] In another embodiment, 4-HB is provided as an enantioenriched mixture of the S-enantiomer, i.e., (S)-4-HB. In one embodiment, the (S)-4-HB is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0098] In one embodiment, the (S)-4-HB is present with an enantiomeric excess (ee) of at leastabout 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0099] In another embodiment, 4-HB is provided as the enantiopure S-enantiomer (S)-4-HB.Pharmaceutical Compositions and Administration

[0100] The present invention also provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, R2, R3, R4, R1a, R2a, R3a, R4a, and R5a are as defined above.

[0101] The present invention also provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,Attorney Docket No.243735.000398 co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

[0102] Pharmaceutical compositions described herein can be prepared by any method knownin the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound(s) described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0103] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as asingle unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0104] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient,and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0105] Pharmaceutically acceptable excipients used in the manufacture of providedpharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0106] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate,dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0107] Exemplary granulating and / or dispersing agents include potato starch, corn starch,tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate,Attorney Docket No.243735.000398 silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0108] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g.,acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0109] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin,sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose,Attorney Docket No.243735.000398 hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0110] Exemplary preservatives include antioxidants, chelating agents, antimicrobialpreservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0111] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0112] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and saltsand hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0113] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethylparaben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0114] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol,phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0115] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.Attorney Docket No.243735.000398

[0116] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0117] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions,phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0118] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearicacid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0119] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot,black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethylAttorney Docket No.243735.000398 sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0120] Liquid dosage forms for oral and parenteral administration include pharmaceuticallyacceptable emulsions, microemulsions, dispersion, solutions, suspensions, gel, slurry, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0121] Injectable preparations, for example, sterile injectable aqueous or oleaginoussuspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0122] The injectable formulations can be sterilized, for example, by filtration through abacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0123] In order to prolong the effect of a drug, it is often desirable to slow the absorption ofthe drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate ofAttorney Docket No.243735.000398 absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0124] Compositions for rectal or vaginal administration are typically suppositories whichcan be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0125] Solid dosage forms for oral administration include capsules, tablets, pills,effervescent formulation, lyophilized formulation, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0126] Solid compositions of a similar type can be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using suchAttorney Docket No.243735.000398 excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0127] The active ingredient can be in a micro-encapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0128] Dosage forms for topical and / or transdermal administration of a compound of thisinvention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0129] Suitable devices for use in delivering intradermal pharmaceutical compositionsdescribed herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas toAttorney Docket No.243735.000398 accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0130] Formulations suitable for topical administration include, but are not limited to, liquidand / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0131] A pharmaceutical composition of the invention can be prepared, packaged, and / orsold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0132] Low boiling propellants generally include liquid propellants having a boiling point ofbelow 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non- ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0133] Pharmaceutical compositions of the invention formulated for pulmonary delivery mayprovide the active ingredient in the form of droplets of a solution and / or suspension. SuchAttorney Docket No.243735.000398 formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0134] Formulations described herein as being useful for pulmonary delivery are useful forintranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0135] Formulations for nasal administration may, for example, comprise from about as littleas 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the invention can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0136] A pharmaceutical composition of the invention can be prepared, packaged, and / orsold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 / 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients describedAttorney Docket No.243735.000398 herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are contemplated as being within the scope of this invention.

[0137] Although the descriptions of pharmaceutical compositions provided herein areprincipally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0138] Compounds provided herein are typically formulated in dosage unit form for ease ofadministration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0139] The compounds and compositions provided herein can be administered by any route,including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature ofAttorney Docket No.243735.000398 the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0140] The exact amount of a compound required to achieve an effective amount will varyfrom subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0141] The effective amount of the compound in the composition that may be used inaccordance with the present disclosure may vary from about 0.0001 mg / kg to about 1000 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, and from about 10.0 mg / kg to about 150 mg / kg.

[0142] The compounds and compositions provided herein can be administered to a subjectonce a day, twice a day, three times a day, or four or more times a day. Alternatively, the compounds and compositions provided herein can be administered to a subject once a week, twice a week, three times a week, or four or more times a week. The compounds and compositions provided herein can also be administered to a subject once every two weeks, once every three weeks, once a month, once every two month, once every three month, once every four month, once every five month, once every six month, once every seven month, once every eight month, once every nine month, once every ten month, once every eleven month, once a year, or once every two years.

[0143] The compounds and compositions provided herein can be administered to a subjectfor about a week, about two weeks, about three weeks, about four weeks, about a month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months,Attorney Docket No.243735.000398 about one year, about two years, about three years, about four years, about five years, about six or more years, about ten or more years, or about twenty or more years.

[0144] The compounds and compositions provided herein can be administered to a subjectuntil the subject reaches the age of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 5 years, about 6 years, about 10 years, about 12 years, about 16 years, about 18 years, about 21 years, about 25 years, or about 30 years.

[0145] In certain embodiments, an effective amount of a compound for administration one ormore times a day to a 70 kg adult human may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 20000 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 100000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form. For example, about 0.0001 g, about 0.001 g, about 0.01 g, about 0.1 g, about 1 g, about 2 g, about 3Attorney Docket No.243735.000398 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 15 g, or about 20 g.

[0146] In certain embodiments, an effective amount of a compound for administration one ormore times a day to a 30 kg child may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 20000 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 100000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form. For example, about 0.0001 g, about 0.001 g, about 0.01 g, about 0.1 g, about 0.2 g, about 0.3 g, about 0.4 g, about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 15 g, or about 20 g.

[0147] In certain embodiments, the compounds described herein may be at dosage levelssufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg toAttorney Docket No.243735.000398 about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect.

[0148] In certain embodiments, the compounds described herein may be administered at aconcentration of about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, or about 20 mg / mL.

[0149] It will be appreciated that dose ranges as described herein provide guidance for theadministration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0150] It will be also appreciated that a compound or composition, as described herein, canbe administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents).

[0151] The compound or composition can be administered concurrently with, prior to, orsubsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Methods of Uses

[0152] As shown in the present disclosure, 4-HMA supplementation has shown to increaseendogenous CoQ10 pools. It was discovered that 4-hydroxymandelate (4-HMA) is made by HPDLAttorney Docket No.243735.000398 (4-hydrophenylpyruvate dioxygenase-like) and that this step is the first committed step in the synthesis of 4-hydroxybenzoate (4-HB), the immediate precursor of the CoQ10 headgroup.

[0153] The present disclosure provides methods of using the compound(s) or pharmaceuticalcompositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, a compound of Formula (I), or a compound of Formula (II), for alleviating symptoms selected from the group consisting of fatigue and frailty associated with aging, skin aging, muscle weakness, statin-associated muscle symptoms, cardiovascular diseases, kidney diseases, and CoQ10 depletion and mitochondrial failure associated with adult neurodegenerative diseases, in a subject in need thereof.

[0154] In some embodiments, the cardiovascular disease is due to low levels of CoQ10 orinadequate CoQ10 synthesis.

[0155] In some embodiments, the cardiovascular disease is selected from the group consistingof heart failure, atrial fibrillation, myocardial infarction, coronary arterial disease, endothelial dysfunction, hypertension, and atherosclerosis.

[0156] In some embodiments, the kidney disease is an acute kidney injury and a chronic kidneydisease.

[0157] In some embodiments, the statin-associated muscle symptom is statin-associatedmyopathy, statin-associated myositis, statin-associated myalgia, statin-associated myonecrosis, or statin-associated clinical rhabdomyolysis.

[0158] In some embodiments, the CoQ10 depletion and mitochondrial failure associated withadult neurodegenerative diseases is the CoQ10 depletion and mitochondrial failure associated with Parkinson’s Disease, Alzheimer’s Disease, frontotemporal dementia, chronic traumatic encephalopathy, or amyotrophic lateral sclerosis (ALS).

[0159] The present invention provides methods of using the compound(s) or pharmaceuticalcompositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, a compound of Formula (I), or a compound of Formula (II), for improving mitochondrial function in the end organs, in a subject in need thereof.

[0160] In some embodiments, the end organ is selected from heart and muscles.

[0161] The present invention provides methods of using the compound(s) or pharmaceuticalcompositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, a compound of Formula (I), or a compound of Formula (II), for alleviating symptomsAttorney Docket No.243735.000398 associated with recovery following myocardial infarction, recovery following ischemic brain injury, recovery following ischemic spinal cord injury, recovery following traumatic brain injury, or recovery following traumatic spinal cord injury, in a subject in need thereof.

[0162] The present invention also provides methods of using the compound(s) orpharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, a compound of Formula (I), or a compound of Formula (II), for treatment of an injury selected form the group consisting of brain injury and spinal cord injury, in a subject in need thereof.

[0163] In some embodiments, the brain injury is an ischemic brain injury or a traumatic braininjury.

[0164] In some embodiments, the spinal cord injury is an ischemic spinal cord injury or atraumatic spinal cord injury.

[0165] According to the present disclosure, the subject is a mammal and includes human andveterinary animals. In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject is an elderly adult. In some embodiments,the subject is 55 years or older, 60 years or older, 65 years or older, 70 years or older ̧or 75 yearsor older. EXAMPLES

[0166] The following examples illustrate specific aspects of the instant description. Theexamples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects. Example 1.4-HMA Supplementation Increased CoQ Pools

[0167] CoQ10 is widely taken as a supplement to relieve statin-induced muscle symptoms,but also to improve mitochondrial function in the end organs such as the heart and muscles as a supplement during aging. It is also widely used in consumer products. CoQ10 is poorly bioavailable, with absorption of 1-4% of the orally administered dose. By identifying precursors of CoQ10that have improved bioavailability and supplementing with these molecules, cells will be able to make their own CoQ10.

[0168] As a supplement, 4-HMA, 4-HB, or more soluble and bioavailable derivatives couldreplace or augment CoQ10. As therapies, 4-HMA, 4-HB, or more soluble and bioavailableAttorney Docket No.243735.000398 derivatives could be used to treat statin-associated myositis, heart failure, or any of the cardiovascular diseases that can potentially be treated with CoQ10.4-HMA, 4-HB, or more soluble and bioavailable derivatives could also be used to treat CoQ10 depletion and mitochondrial failure that occurs in adult neurodegenerative diseases, such as Parkinson’s Disease, Alzheimer’s Disease, and ALS. Finally, because CoQ10 pools in nearly every organ decline with age, 4-HMA, 4-HB, or more soluble and bioavailable derivatives could be used to treat the fatigue and frailty that occurs during aging.

[0169] Both 4-HMA and 4-HB were found to enter the brains of wild-type, Hpdl+ / -, and Hpdl- / - mice and were incorporated into CoQ10 (Figure 1). The prior work had showed that 4-HMA supplementation did not increase levels of CoQ10in cancer cells, and that loss of HPDL did not decrease CoQ10pools (Banh et al., “The Polar Oxy-Metabolome Reveals the 4-Hydroxymandelate CoQ10 Synthesis Pathway,” Nature 597:420-425 (2021), which is hereby incorporated by reference in its entirety).

[0170] Surprisingly, wild-type fibroblasts supplemented with 4-HMA had higher CoQ10 poolsfollowing 4-HMA treatment (Figure 2). These data suggest that 4-HMA or other CoQ10 headgroup precursors such as 4-HB or derivatives can boost endogenous CoQ10 levels more efficiently than CoQ10supplementation in non-cancerous cells, and could do so in organs such as the brain that are not accessible to CoQ10.

[0171] The mammalian CoQ10 headgroup synthesis pathway was not undefined until 2021. Itwas discovered that the dioxygenase 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) makes a metabolite called 4-hydroxymandelate (4-HMA), which is the precursor of 4-hydroxybenzoate (4-HB), the immediate precursor of the CoQ10 headgroup.

[0172] The invention has been tested in Hpdl wild-type, heterozygote, and null animals(Figures 3B-3C). Oral supplementation of isotopically labeled 4-HMA or 4-HB in mice (Figure 3A) demonstrated that both compounds were incorporated into mouse CoQ9, the mouse equivalent of CoQ10, and that this incorporation took place in multiple mouse organs, including the brain (Figures 3B-3C). Wild-type animals made just under 10% of CoQ9from supplemented 4-HMA or 4-HB (Figures 3B-3C). Example 2.4-HMA Supplementation Increased Exercise Tolerance

[0173] 1 year-old mice (equivalent to middle-aged humans) were treated with 4-HMA at 10mg / kg in the water for 3-4 weeks. Their latency time on the Rotarod (a test of balance, strength,Attorney Docket No.243735.000398 motor coordination, and striatal function) was tested. Middle-aged animals treated with 4-HMA demonstrated increased time on the Rotarod in comparison to a control group that was not treated (Figures 4A-4B). One-year-old, middle-aged mice treated with 4-HMA also demonstrated stable to improved 4-paw grip strength in comparison to untreated mice (Figure 5).

[0174] 4-HMA supplementation will be tested in a cohort of aged mice to determine if 4-HMAsupplementation increases total CoQ pools, metabolic parameters, and exercise tolerance. * * *

[0175] As various changes can be made in the above-described subject matter withoutdeparting from the scope and spirit of the present invention, it is intended that all subject matter contained in the above description, or defined in the appended claims, be interpreted as descriptive and illustrative of the present invention. Many modifications and variations of the present invention are possible considering the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variances which fall within the scope of the appended claims.

[0176] All patents, applications, publications, test methods, literature, and other materials citedherein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

Attorney Docket No.243735.000398 WHAT IS CLAIMED IS:

1. A method of alleviating symptoms selected from the group consisting of fatigue and frailtyassociated with aging, skin aging, muscle weakness, statin-associated muscle symptoms, cardiovascular diseases, kidney diseases, and CoQ10 depletion and mitochondrial failure associated with adult neurodegenerative diseases, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): ,R1 is selected from the group ; R2is selected from the groupR3is selected from the group consisting of H and C1-C3alkyl; and R4is selected from the group consisting of H and ; or a compound of Formula (II): ,R3ais selected from the group consisting of H and C1-C3alkyl; andAttorney Docket No.243735.000398 R4a is selected from the group consisting of H and ; andR5ais selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the cardiovascular disease is due to low levels of CoQ10 orinadequate CoQ10 synthesis.

3. The method of claim 2, wherein the cardiovascular disease is selected from the groupconsisting of heart failure, atrial fibrillation, myocardial infarction, coronary arterial disease, endothelial dysfunction, hypertension, and atherosclerosis.

4. The method of claim 1, wherein the statin-associated muscle symptom is statin-associatedmyopathy, statin-associated myositis, statin-associated myalgia, statin-associated myonecrosis, or statin-associated clinical rhabdomyolysis.

5. The method of claim 1, wherein the CoQ10 depletion and mitochondrial failure associatedwith adult neurodegenerative diseases is the CoQ10 depletion and mitochondrial failure associated with Parkinson’s Disease, Alzheimer’s Disease, frontotemporal dementia, chronic traumatic encephalopathy, or amyotrophic lateral sclerosis (ALS).

6. The method of claim 1, wherein the kidney disease is an acute kidney injury or a chronickidney disease.

7. A method for improving mitochondrial function in the end organs, in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of 4- hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): ,Attorney Docket No.243735.000398 wherein: R1is selected from the group ; R2 is selected from the groupR3 is selected from the group and R4 is selected from the group consisting of H and ; or a compound of Formula (II):, wherein:n is 0 or 1; R1ais selected from the group ; R2a is selected from the groupR3ais selected from the group consisting of H and C1-C3alkyl; and R4a is selected from the group consisting of H ; andR5ais selected from the group consisting of H , or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the end organ is selected from heart and muscles.

9. A method for alleviating symptoms associated with recovery following myocardial infarction,recovery following ischemic brain injury, recovery following ischemic spinal cord injury, recovery following traumatic brain injury, or recovery following traumatic spinal cord injury,Attorney Docket No.243735.000398 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I): , wherein:R1is selected from the group ; R2 is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H ; or a compound of Formula (II):, wherein:n is 0 or 1; R1ais selected from the group ; R2a is selected from the groupR3a is selected from the group consisting of H and C1-C3 alkyl; and R4a is selected from the group consisting of H ; andR5ais selected from the group consisting of H and , orAttorney Docket No.243735.000398 a pharmaceutically acceptable salt thereof.

10. A method for treatment of an injury selected form the group consisting of brain injury andspinal cord injury, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), a compound of Formula (I): , wherein:R1is selected from the group ; R2is selected from the groupR3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H ; or a compound of Formula (II):, wherein:n is 0 or 1; R1ais selected from the group ; R2a is selected from the groupR3a is selected from the group consisting of H and C1-C3 alkyl; and R4a is selected from the group consisting of H ; andAttorney Docket No.243735.000398 R5a is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the brain injury is an ischemic brain injury or a traumaticbrain injury.

12. The method of claim 10, wherein the spinal cord injury is an ischemic spinal cord injury or atraumatic spinal cord injury.

13. The method of any one of claims 1-8, wherein 4-hydroxymandelic acid (4-HMA) orpharmaceutically acceptable salt thereof is administered to the subject.

14. The method of any one of claims 1-13, wherein the 4-HMA is enantioenriched (R)-4-HMA.

15. The method of claim 14, wherein the enantioenriched (R)-4-HMA has enantiomeric excess(ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

16. The method of any one of claims 1-15, wherein the 4-HMA is enantiopure (R)-4-HMA.

17. The method of any one of claims 1-8, wherein 4-hydroxybenzoate (4-HB) or pharmaceuticallyacceptable salt thereof is administered to the subject.

18. The method of any one of claims 1-8 or 17, wherein the 4-HB is enantioenriched (R)-4-HB.

19. The method of claims 18, wherein the enantioenriched (R)-4-HB has enantiomeric excess (ee)of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.Attorney Docket No.243735.00039820. The method of any one of claims 1-8, or 17-19, wherein the 4-HB is enantiopure (R)-4-HB.

21. The method of any one of claims 1-8, wherein a compound of Formula (I) orpharmaceutically acceptable salt thereof is administered to the subject.

22. The method of any one of claims 1-8 or 21, wherein the compound of Formula (I) isenantioentriched (R)-compound of Formula (I).

23. The method of claim 22, wherein the enantioentriched (R)-compound of Formula (I) hasenantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

24. The method of any one of claims 1-8 or 21-23, the wherein the compound of Formula (I) isenantiopure (R)-compound of Formula (I).

25. The method of any one of claims 1-12 or 21-24, wherein R1 is H.

26. The method of any one of claims 1-12 or 21-24, .

27. The method of any one of claims 1-12 or 21-26, wherein R2 is methyl.

28. The method of any one of claims 1-12 or 21-26, wherein R2 is H.

29. The method of any one of claims 1-12 or 21-28, wherein R3 is H.

30. The method of any one of claims 1-8 or 21-28, wherein R3 is methyl.Attorney Docket No.243735.00039831. The method of any one of claims 1-8 or 21-30, wherein R4 is H.

32. The method of any one of claims 1-8 or 21-30, wherein R4 is .

33. The method of any one of claims 1-8 or 21-32, wherein the compound of Formula (I) has thestructure according to Formula (Ia): O R1O or a pharmaceuticallyR1 is selected from the groupR4 is selected from the group consisting of H .

34. The method of any one of claims 1-8 or 21-32, wherein the compound of Formula (I) has thestructure according to Formula (Ib): Me O or a pharmaceuticallyR1 is selected from the groupR4 is selected from the group consisting of H .Attorney Docket No.243735.00039835. The method of any one of claims 1-8 or 21-32, wherein the compound having the structure ofFormula (I) is selected from the group consisting of: , or a36. The method of any one of claims 1-8 or 21-32, wherein the compound having the structure ofFormula (I) is selected from the group consisting of: , or a37. The method of any one of claims 1-8, wherein a compound of Formula (II) orpharmaceutically acceptable salt thereof is administered to the subject.

38. The method of any one of claims 1-12 or 37, wherein the compound of Formula (II) isenantioenriched (R)-compound of Formula (II).Attorney Docket No.243735.00039839. The method of claim 38, wherein the enantioenriched (R)-compound of Formula (II) hasenantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

40. The method of any one of claims 1-8 or 37-39, wherein the compound of Formula (II) isenantiopure (R)-compound of Formula (II).

41. The method of any one of claims 1-8 or 37-40, wherein the compound of Formula (II) has thestructure according to Formula (IIa): , or a pharmaceuticallyR1ais selected from the group ; R2a is selected from the groupR3ais selected from the group consisting of H and C1-C3alkyl; R4ais selected from the group consisting of H , andR5a is selected from the group consisting of H .

42. The method of any one of claims 1-8 or 37-40, wherein the compound of Formula (II) has thestructure according to Formula (IIb):Attorney Docket No.243735.000398 or a pharmaceuticallyR1a is selected from the group ; R2ais selected from the groupR3a is selected from the group R4a is selected from the group consisting of H and , andR5ais selected from the group consisting of H .

43. The method of any one of claims 1-8 or 37-40, wherein the compound of Formula (II) has thestructure:

44. The method of any one of claims 1-8 or 37-43, wherein R1a is H.

45. The method of any one of claims 1-8 or 37-43, .Attorney Docket No.243735.00039846. The method of any one of claims 1-8 or 37-45, wherein R2a is methyl.

47. The method of any one of claims 1-8 or 37-45, wherein R2a is H.

48. The method of any one of claims 1-8 or 37-47, wherein R3a is H.

49. The method of any one of claims 1-8 or 37-47, wherein R3a is methyl.

50. The method of any one of claims 1-8 or 37-49, wherein R4a is H.

51. The method of any one of claims 1-12 or 37-49, wherein R4a is .

52. The method of any one of claims 1-8 or 37-51, wherein R5a is H.

53. The method of any one of claims 1-12 or 37-51, wherein R5a .

54. The method of any one of claims 1-8 or 37-53, wherein the compound having the structure ofFormula (II) is selected from the group consisting of: O O ,Attorney Docket No.243735.000398 or55. The method of any one of claims 1-8 or 37-53, wherein the compound having the structure ofFormula (II) is selected from the group consisting of: ,or56. The method of any one of claims 1-8 or 37-53, wherein the compound having the structure ofFormula (II) is selected from the group consisting of:Attorney Docket No.243735.000398 , or57. The method of any one of claims 1-8 or 37-53, wherein the compound having the structure ofFormula (II) is selected from the group consisting of: , ,Attorney Docket No.243735.000398 or58. The method of any one of claims 1-57, wherein the subject is a mammal.

59. The method of claim 58, wherein the subject is a human.

60. The method of claim 59, wherein the subject is an adult.

61. The method of claim 59, wherein the subject is an elderly adult.

62. The method of claim 59, wherein the subject is 65 years or older.

63. The method of any one of claims 1-62, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

64. The method of any one of claims 1-63, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered orally.

65. The method of claim 64, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered as a liquid dosage form.Attorney Docket No.243735.00039866. The method of claim 65, wherein the liquid dosage form is selected from the group consistingof dispersion, solution, gel, syrup, elixir, slurry, and suspension.

67. The method of any one of claims 64, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered as a solid dosage form.

68. The method of claim 67, wherein the solid oral dosage form is selected from the groupconsisting of tablet, powder, pill, dragee, capsule, effervescent formulation, and lyophilized formulation.

69. The method of any one of claims 64, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered as a suspension.

70. The method of any one of claims 1-69, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at an amount from about 1mg to about 20g.

71. The method of any one of claims 1-69, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at an amount from about 100mg to about 10g.

72. The method of any one of claims 1-69, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at an amount from about 1g to about 5g.Attorney Docket No.243735.00039873. The method of any one of claims 1-69, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at an amount of about 3g.

74. The method of any one of claims 1-69, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), a compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at a concentration of about 10 mg / mL.

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