COQ10 headgroup repletion in the treatment of niemann-pick disease and other diseases

Abstract

The present invention relates to methods for treating Niemann-Pick disease, Rett syndrome, Leigh syndrome, Multiple System Atrophy, spinomuscular atrophy, Freidrich's Ataxia, or stroke.

Description

COQ10 HEADGROUP REPLETION IN THE TREATMENT OF NIEMANN-PICK DISEASE AND OTHER DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 697,726, filed September 23, 2024, and U.S. Provisional Application No. 63 / 762,496, filed February 24, 2025, 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 by the National Institutes of Health. The government has certain rights in the invention. FIELD OF INVENTION

[0003] The present invention relates to CoQ10 headgroup repletion in the treatment of Niemann-Pick disease, Rett syndrome, Leigh syndrome, Multiple System Atrophy, spinomuscular atrophy, Freidrich's Ataxia, neurodegenerative diseases including Alzheimer’s disease, stroke, and other diseases. BACKGROUND OF THE INVENTION

[0004] CoQ10 is the only endogenously synthesized lipophilic antioxidant capable of accepting single electrons. Delivery of CoQ10 to cells is difficult due to the poor absorption and trafficking of this molecule. Delivery of the CoQ10 precursors, particularly the headgroups that appear to be rate-limiting for CoQ10 synthesis in some circumstances, would enable local synthesis of CoQ10 at the organ and cellular sites where it is needed. There are a number of diseases whose symptoms might be attenuated by increased CoQ10 levels, particularly in the brain: Leigh syndrome (Complex I deficiency), ALS (particulalry SOD1-variant ALS), Alzheimer's disease including early-onset or famililal Alzheimer’s disease, Parkinson’s disease, Multiple System Atrophy, Frontotemporal dementia, spinomuscular atrophy, Freidrich's ataxia, aging, Niemann-Pick disease type C (NPDC), Rett syndrome, and insulin resistance / Type 2 DM.

[0005] Rett syndrome is a rare genetic disease driven by variants in the MECP2 gene. The overwhelming majority of cases are found in women. The disease presents with hand clasping,motor dysfunction, hypoactivity, and loss of developmental milestones. Apart from trofenitide there are no treatments for Rett syndrome.

[0006] Niemann-Pick disease type C (NPDC) is a progressive, lethal neurodevelopmental disorder caused by variants in the NPC1 and NPC2 genes, both of which are classically thought to transport and process cholesterol and the lipoproteins that carry it. There are no treatments for Neimann-Pick disease type C.

[0007] Accordingly, there is a strong, unmet need to develop treatment for Niemann-Pick disease, Rett syndrome, and other diseases. SUMMARY OF THE INVENTION

[0008] Various non-limiting aspects and embodiments of the invention are described below.

[0009] In one aspect, the present disclosure provides a method for treating Niemann-Pick disease, Rett syndrome, Leigh syndrome, Multiple System Atrophy, spinomuscular atrophy, Freidrich's Ataxia, or stroke 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): I), wherein:R1is selected from the group consisting of H and ; R2is selected from the group consisting of H and C1-C3alkyl; R3is selected from the group consisting of H and C1-C3alkyl; and R4is selected from the group consisting of H an ; or a compound of Formula (II):(II), wherein: n is 0 or 1; R1ais selected from the group consisting of H and ; R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3alkyl; and R4a is selected from the group consisting of H and ; and R5ais selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

[0010] These and other aspects of the present invention will become apparent to those skilled in the art after a reading of the following detailed description of the invention, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIGS. 1A-1C show the Barnes Maze data (FIG. 1A), latency data (FIG. 1B), and contextual fear conditioning data (FIG. 1C) for 5xFAD mice treated with 4-HMA.

[0012] FIG. 2 shows survival curves for the mice treated with 4-HB or 4-HMA. DETAILED DESCRIPTION

[0013] To facilitate an understanding of the principles and features of the various embodiments of 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 thedetails 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.

[0014] As used herein, the terms “about” or “approximately” for any numerical values or ranges 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” or “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%.

[0015] As used herein, the term “alkyl” is given its ordinary meaning in the art and can include saturated 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., C1-20for straight chain, C2-20for 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., C1-4for straight chain lower alkyls).

[0016] As described herein, in certain embodiments, certain compounds of the disclosure can be 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.

[0017] As used herein, a substituent, e.g., -B, can be represented as a or , where denotes a point of attachment.

[0018] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (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.

[0019] The present application also includes pharmaceutically acceptable salts of the compounds 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.

[0020] The term “prodrug” as used herein includes a chemical which may be transformed in vivo to a pharmacologically active drug. The term “metabolite” as used herein includes a chemical that a given agent is transformed into in vivo.

[0021] The enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage of the 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.

[0022] The term “enantiomerically enriched” or “enantioenriched” as used herein includes compounds 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.

[0023] The term “enantiomerically pure” or “enantiopure” as used herein includes compounds where 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.

[0024] The term “sample” as used herein includes any biological specimen obtained from a subject 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)).

[0025] As used herein, the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human.

[0026] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or 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) orat 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.

[0027] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the state, disorder or condition. As will be 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.

[0028] A “therapeutically effective amount” of a compound described herein is an amount sufficient 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.

[0029] It must also be noted that, as used in the specification and the appended claims, the singular 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.

[0030] Also, in describing the exemplary embodiments, terminology will be resorted to for the sake 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.

[0031] It is also to be understood that the mention of one or more method steps does not preclude 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.

[0032] The materials described hereinafter as making up the various elements of the present invention are intended to be illustrative and not restrictive. Many suitable materials that would 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

[0033] In one aspect, provided herein is a compound having the structure of Formula (I): (I), where R1is selected from the group consisting of H and ; R2is selected from the group consisting of H and C1-C3alkyl; R3is selected from the group consisting of H and C1-C3alkyl; and R4is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the compound of Formula (I) is provided as a racemic mixture of the R- and the S-enantiomers.

[0035] In another embodiment, the compound of Formula (I) is provided as an enantioenriched mixture of the R-enantiomer. In one embodiment, the compound of Formula (I) is present with anenantiomeric 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.

[0036] In one embodiment, the compound of Formula (I) is present with an 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%.

[0037] In another embodiment, the compound of Formula (I) is provided as the enantiopure R-enantiomer.

[0038] In another embodiment, the compound of Formula (I) is provided as an enantioenriched mixture 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.

[0039] In one embodiment, the compound of Formula (I) is present with an 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%.

[0040] In another embodiment, the compound of Formula (I) is provided as the enantiopure S- enantiomer.

[0041] In some embodiments, R1is H.

[0042] In some embodiments, R1is .

[0043] In some embodiments, R2is methyl.

[0044] In some embodiments, R2is H.

[0045] In some embodiments, R3is H.

[0046] In some embodiments, R3is methyl.

[0047] In some embodiments, R4is H.

[0048] In some embodiments, R4is .

[0049] In some embodiments, the compound of Formula (I) has the structure according to Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H and , and R4is selected from the group consisting of H and .

[0050] In some embodiments, the compound of Formula (I) has the structure according to Formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H and , and R4is selected from the group consisting of H and .

[0051] In some embodiments, the compound having the structure of Formula (I) is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the compound having the structure of Formula (I) is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.

[0053] In one aspect, provided herein is a compound having the structure of Formula (II): (II), where n is 0 or 1; R1a is selected from the group consisting of H and ;R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3alkyl; 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.

[0054] In one embodiment, the compound of Formula (II) is provided as a racemic mixture of the R- and the S-enantiomers.

[0055] In another embodiment, the compound of Formula (II) is provided as an enantioenriched 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.

[0056] In one embodiment, the compound of Formula (II) is present with an 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%.

[0057] In another embodiment, the compound of Formula (II) is provided as the enantiopure R-enantiomer.

[0058] In another embodiment, the compound of Formula (II) is provided as an enantioenriched 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.

[0059] In one embodiment, the compound of Formula (II) is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about50%, 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%.

[0060] In another embodiment, the compound of Formula (II) is provided as the enantiopure S-enantiomer.

[0061] In some embodiments, the compound of Formula (II) has the structure according to Formula (IIa): (IIa), or a pharmaceutically acceptable salt thereof, wherein: R1ais selected from the group consisting of H and ; R2a is selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3alkyl; R4a is selected from the group consisting of H and , and R5ais selected from the group consisting of H and .

[0062] In some embodiments, the compound of Formula (II) has the structure according to Formula (IIb): (IIb) or a pharmaceutically acceptable salt thereof, wherein: R1ais selected from the group consisting of H and ; R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3alkyl;R4ais selected from the group consisting of H and , and R5ais selected from the group consisting of H and .

[0063] In some embodiments, the compound of Formula (II) has the structure: or .

[0064] In some embodiments, R1ais H.

[0065] In some embodiments, R1ais .

[0066] In some embodiments, R2ais methyl.

[0067] In some embodiments, R2a is H.

[0068] In some embodiments, R3a is H.

[0069] In some embodiments, R3ais methyl.

[0070] In some embodiments, R4a is H.

[0071] In some embodiments, R4ais .

[0072] In some embodiments, R5ais H.

[0073] In some embodiments, R5ais .

[0074] In some embodiments, the compound having the structure of Formula (II) is selected from the group consisting of:, , , , , and , or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound having the structure of Formula (II) is selected from the group consisting of: , , , or , or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compound having the structure of Formula (II) is selected from the group consisting of:, or , or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound having the structure of Formula (II) is selected from the group consisting of: , , ,, , or .

[0078] In one aspect, the present invention provides 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (also known as 4-hydroxymandelic acid (4-HMA)): (4-HMA), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0079] In one embodiment, 4-HMA is provided as a racemic mixture of the R- and the S- enantiomers of 4-HMA, depicted below: and .

[0080] In another embodiment, 4-HMA is provided as an enantioenriched mixture 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.

[0081] In one embodiment, the (R)-4-HMA is present with an 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%.

[0082] In another embodiment, 4-HMA is provided as the enantiopure R-enantiomer (R)-4- HMA.

[0083] 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.

[0084] In one embodiment, the (S)-4-HMA is present with an 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%.

[0085] In another embodiment, 4-HMA is provided as the enantiopure S-enantiomer (S)-4- HMA.

[0086] In one aspect, provided herein is 4-hydroxybenzoate (4-HB): or a pharmaceutically acceptabe sa t, so vate, ydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0087] In one embodiment, 4-HB is provided as a racemic mixture of the R- and the S- enantiomers of 4-HB.

[0088] 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 enantiomericexcess (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.

[0089] In one embodiment, the (R)-4- HB is present with an 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%.

[0090] In another embodiment, 4- HB is provided as the enantiopure R-enantiomer (R)-4- HB.

[0091] 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.

[0092] In one embodiment, the (S)-4-HB is present with an 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%.

[0093] In another embodiment, 4-HB is provided as the enantiopure S-enantiomer (S)-4-HB. Pharmaceutical Compositions and Administration

[0094] The present invention also provides pharmaceutical compositions comprising a compound 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 R5aare as defined above.

[0095] The present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

[0096] Pharmaceutical compositions described herein can be prepared by any method known in 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.

[0097] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single 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.

[0098] 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.

[0099] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical 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.

[0100] 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.

[0101] 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, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodiumcarboxymethyl 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.

[0102] 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.

[0103] 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, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminumsilicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0104] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, 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.

[0105] 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.

[0106] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and 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.

[0107] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0108] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0109] 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.

[0110] 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, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0111] 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.

[0112] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, 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.

[0113] 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, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0114] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, dispersion, solutions, suspensions, gel, slurry, syrups andelixirs. 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.

[0115] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions 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.

[0116] The injectable formulations can be sterilized, for example, by filtration through a bacterial-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.

[0117] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the 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 of 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.

[0118] Compositions for rectal or vaginal administration are typically suppositories which can 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.

[0119] 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.

[0120] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin 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 such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0121] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, andgranules 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.

[0122] Dosage forms for topical and / or transdermal administration of a compound of this invention 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.

[0123] Suitable devices for use in delivering intradermal pharmaceutical compositions described 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 to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0124] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oilemulsions 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.

[0125] A pharmaceutical composition of the invention can be prepared, packaged, and / or sold 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.

[0126] Low boiling propellants generally include liquid propellants having a boiling point of below 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).

[0127] Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such 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 suchas 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.

[0128] Formulations described herein as being useful for pulmonary delivery are useful for intranasal 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.

[0129] Formulations for nasal administration may, for example, comprise from about as little as 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.

[0130] A pharmaceutical composition of the invention can be prepared, packaged, and / or sold 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 described 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.

[0131] Although the descriptions of pharmaceutical compositions provided herein are principally 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.

[0132] Compounds provided herein are typically formulated in dosage unit form for ease of administration 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.

[0133] 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 of 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).

[0134] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of asubject, 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).

[0135] The effective amount of the compound in the composition that may be used in accordance 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.

[0136] The compounds and compositions provided herein can be administered to a subject once 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.

[0137] The compounds and compositions provided herein can be administered to a subject for 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, 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.

[0138] The compounds and compositions provided herein can be administered to a subject until 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, about10 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.

[0139] In certain embodiments, an effective amount of a compound for administration one or more 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 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.

[0140] In certain embodiments, an effective amount of a compound for administration one or more 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 0.0001mg 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.

[0141] In certain embodiments, the compounds described herein may be at dosage levels sufficient 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 to 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.

[0142] In certain embodiments, the compounds described herein may be administered at a concentration 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.

[0143] It will be appreciated that dose ranges as described herein provide guidance for the administration 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.

[0144] It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents).

[0145] The compound or composition can be administered concurrently with, prior to, or subsequent 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 Use

[0146] The present disclosure provides methods of using the compound(s) or pharmaceutical 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 treating Niemann-Pick disease, Rett syndrome, Leigh syndrome, Multiple System Atrophy, spinomuscular atrophy, Freidrich's Ataxia, or stroke. Niemann-Pick disease

[0147] Niemann–Pick disease, also known as acid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. Niemann–Pick types A, A / B,and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM).

[0148] Niemann-Pick disease type C (NPDC) is a progressive, lethal neurodevelopmental disorder caused by variants in the NPC1 and NPC2 genes, both of which are classically thought to transport and process cholesterol and the lipoproteins that carry it.

[0149] Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen (splenomegaly) may also cause low levels of platelets in the blood (thrombocytopenia).

[0150] Accumulation of sphingomyelin in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk, and face (dystonia). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causing dementia and seizures.

[0151] Bones also may be affected, with the disease causing enlarged bone marrow cavities, thinned cortical bone, or a distortion of the hip bone called coxa vara. Sleep-related disorders also occur in Niemann-Pick disease, such as sleep inversion, sleepiness during the day and wakefulness at night. Gelastic cataplexy, the sudden loss of muscle tone when the affected patient laughs, is also seen.

[0152] In some embodiments, the Niemann-Pick disease is Niemann-Pick disease type A. In some embodiments, the Niemann-Pick disease is Niemann-Pick disease type B. In other embodiments, the Niemann-Pick disease is Niemann-Pick disease type C. Rett Syndrome

[0153] Rett syndrome is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in girls. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems. The severity of the condition is variable.

[0154] Rett syndrome is due to a genetic mutation in the MECP2 gene on the X chromosome. It almost always occurs as a new mutation, with less than one percent of cases being inherited. It occurs almost exclusively in girls; boys who have a similar mutation typically die shortly after birth. Diagnosis is based on the symptoms and can be confirmed with genetic testing.

[0155] There is no known cure for Rett syndrome. Treatment is directed at improving symptoms. Anticonvulsants may be used to help with seizures. Special education, physiotherapy, and leg braces may also be useful depending on the needs of the child. Many of those with the condition live into middle age. The condition affects about 1 in 8,500 females.

[0156] In some embodiments, the Rett syndrome is a classic Rett syndrome. In other embodiments, the Rett syndrome is an atypical Rett syndrome. In one embodiment, the subject is female. In one embodiment, the subject is a pediatric subject under 18 years of age. In one embodiment, the subject is a pediatric subject 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years, or 7 years, or 8 years, or 9 years, or 10 years, or 11 years, or 12 years, or 13 years, or 14 years, or 15 years, or 16 years, or 17 years, or 18 years of age. Leigh Syndrome

[0157] Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

[0158] The symptoms of Leigh syndrome were classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.

[0159] Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen, with reported prevalence of seizures in Leigh syndrome that ranges from 40% to 79%. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.

[0160] As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.

[0161] Respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.

[0162] Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.

[0163] In some embodiments, the Leigh syndrome is a Complex I deficiency. Multiple System Atrophy

[0164] Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum. MSA was first described in 1960 by Milton Shy and Glen Drager and was then known as Shy–Drager syndrome.

[0165] Many people affected by MSA experience dysfunction of the autonomic nervous system, which commonly manifests as orthostatic hypotension, impotence, loss of sweating, dry mouth and urinary retention and incontinence. Palsy of the vocal cords is an important and sometimes initial clinical manifestation of the disorder.

[0166] A prion of the alpha-synuclein protein within affected neurons may cause MSA. About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50–60 years. MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine agonists used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor.

[0167] MSA is distinct from multisystem proteinopathy, a more common muscle-wasting syndrome. MSA is also different from multiple organ dysfunction syndrome, sometimes referred to as multiple organ failure, and from multiple organ system failures, an often-fatal complication of septic shock and other severe illnesses or injuries.

[0168] MSA is characterized by the following: Autonomic and at least one Motor (clinically established MSA criteria 2022): • autonomic dysfunction: Post-void urinary residual volume ≥100 mL (usually by ultrasound); Unexplained urinary urge incontinence; or Neurogenic orthostatic hypotension (≥20 / 10 mmHg blood pressure drop) within 3 minutes (usually by head‐up tilt) • parkinsonism (muscle rigidity + / tremor and slow movement: MSA-P) • cerebellar ataxia (Poor coordination / unsteady walking: MSA-C)

[0169] A variant with combined features of MSA and dementia with Lewy bodies may also exist. There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.

[0170] In some embodiments, the Multiple System Atrophy is parkinsonian. In other embodiments, the Multiple System Atrophy is cerebellar.

[0171] According to the present disclosure, the subject is a mammal and includes human and veterinary 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

[0172] The following examples illustrate specific aspects of the instant description. The examples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects. Example 1. Treatment of Alzheimer’s Disease with CoQ10 Headgroup Intermediates

[0173] The 5xFAD mice were treated with 4-HMA. Each group consisted of at least 9 mice. Both male and female mice were tested. Mice were 4-4.5 months old at the beginning of the experiment. The 4-HMA groups were treated with 100 mg / kg / day 4-HMA provided in the drinking water for 2 months prior to the test.

[0174] The Barnes Maze tests spatial learning and memory in rodents. It consists of a circular platform with a number of holes around its circumference, beneath one of which is an escape box that rodents like to find because of their aversion to open spaces. The platform is placed in a box with visual cues that allow the mice to orient themselves. On day 1, the mice were placed in the center of the platform and led to the hole with the escape box to teach them where it was. The X- axis represents testing days. Each day represents a subsequent day of testing. All of the mice were then placed in the center of the platform and allowed to find the escape hole. Four trials were conducted each day. The Y-axis represents the fraction of times the mouse found the escape hole. The higher the fraction of times the mouse finds the escape hole, the better its spatial learning and memory and its coordination. At day 3, 4-HMA increases the fraction of times the mouse found the escape hole from ~0.5 (the mouse finds the escape hole about half the time) to ~0.8 (the mouse finds the hole about 80% of the time) (FIG. 1A). This increase is statistically significant. Wild- type mice found the escape hole ~90% of the time regardless of 4-HMA treatment. These differences are statistically significantly different from the untreated 5xFAD mice.

[0175] The Barnes Maze test also measures latency, which is the time required for the mouse to find the escape hole (FIG. 1B). The shorter the latency, the faster the mouse finds the escape hole and the better its spatial learning and memory, and its coordination. The wild-type mice had the shortest latency regardless of 4-HMA treatment. By day 3, 4-HMA treatment improved the latency of the 5xFAD mice to near-wild-type treated with 4-HMA (45 sec. vs. 41 sec.). Untreated 5xFAD mice have a latency of 62 sec.; untreated wild-type mice have a latency of 31 sec. Although the Day 3 differences are not statistically significant, there was a decrease in latency in the treated mice.

[0176] FIG. 1C depicts contextual fear conditioning data for 5xFAD mice treated with 4- HMA. In the contextual fear conditioning test, each animal is placed in a novel environment and provided with an aversive stimulus. When the animal is returned to that environment, it will freeze. Freezing is defined as absence of movement except for respiration. The higher the fraction of animals that freeze, the better the animals’ memory of the environment. Each group has at least 9 animals. Both male and female animals were tested. There were no statistically significant differences due to 4-HMA treatment in either wild-type or 5xFAD animals, but there was a trend to increased freezing in the 5xFAD mice treated with 4-HMA. However, there was a significant interaction term in the ANOVA, potentially consistent with effect of the compound. Example 2. Treatment of Rett Syndrome with CoQ10 Headgroup Intermediates

[0177] The current standard of care for Rett syndrome is trofinetide (Tropea et al., “Partial Reversal of Rett Syndrome-Like Symptoms in MeCP2 Mutant Mice,” Proc. Natl. Acad. Sci. PNAS 106(6):2029-2034 (2009), which is hereby incorporated by reference in its entirety), which extends the lifespan of Mecp2+ / - mice to ~100 days. This drug is given from P15 in mice. Trofenitide is administered by daily IP injection in mice, and is orally administered in humans. It improves patient symptoms and caregiver perceptions of the ability to communicate.

[0178] Mice were treated at P35 with 400 mg / kg sodium 4-HB, 200 mg / kg sodium 4-HB, or 400 mg / kg 4-HMA. The results showed improvement in the survival of mice to just under 50% at 70-115 days, which was comparable to trofenitide initiated at P15. The survival curves for the mice are shown in the FIG. 2. Example 3. Treatment of Niemann-Pick Disease with CoQ10 Headgroup Intermediates

[0179] Niemann-Pick disease type C (NPDC) is a progressive, lethal neurodevelopmental disorder caused by variants in the NPC1 and NPC2 genes, both of which are classically thought to transport and process cholesterol and the lipoproteins that carry it. There are no treatments for Neimann-Pick disease type C.

[0180] Coenzyme Q (CoQ) is a naturally occurring electron carrier and one of the main roles of CoQ is to produce energy through the electron transport chain in mitochondria. In addition, CoQ functions outside the mitochondria as an antioxidant. Mammalian cells can synthesize CoQ de novo, but can also take it from food or supplements. The pathway of CoQ synthesis in bacteria hasbeen studied extensively, but the pathway in mammalian cells remains elusive. Recently, one of the components of the pathway, HPDL, was discovered. HPDL is an iron-dependent dioxygenase that can produce a CoQ headgroup intermediate. There are still many gaps in the knowledge of CoQ synthesis and uptake from the external environment in mammals.

[0181] A CRISPR screen was developed to identify essential factors for the CoQ uptake and trafficking pathway. COQ2KO pancreatic cancer cell lines, which are unable to synthesize CoQ endogenously and are basically dependent on exogenous CoQ, were generated. COQ2KO cells produce more mitochondrial reactive oxygen species (ROS), which can be detected by MitoSOX Red dye, than control cells. However, supplementation of exogenous CoQ can quench mitochondrial ROS, suggesting that exogenous CoQ can properly reach the mitochondria.

[0182] Two conditions were used to perform CRISPR screening, with or without CoQ. Tofind important factors for the CoQ uptake and trafficking pathway, cells that showed 10% highest signal of MitoSOX Red in both conditions were sorted. In theory, if candidate genes are knocked out in the condition with CoQ, MitoSOX Red signal will be higher, and if the genes are knocked out in the condition without CoQ, the MitoSOX Red signal will not change. The strategy that was used for this screening was to narrow down the candidate genes by picking up the genes which show higher signal of MitoSOX Red in the condition with CoQ and no change of signal in the condition without CoQ.

[0183] In the screen, a lot of mitochondrial complex I genes were enriched in the condition with CoQ, indicating that the screening worked well. Interestingly, STARD7, which was recently identified as a CoQ binding protein and responsible for transporting CoQ from mitochondria to plasma membrane, was also enriched in the same condition. It was found that NPC1 and NPC2 were the highest hits thatfit our criteria explained above which were except mitochondrial complex I genes. NPC1 and NPC2 are localized at lysosomes and are well known as lysosomal cholesterol trafficking proteins. They are also known as the genes that, when mutated, results in Niemann- Pick disease type C (NPDC), which is characterized by progressive neurodegeneration and cholesterol deposition in visceral organs. According to the function of NPC1 and NPC2, it was hypothesized that the proteins would transport CoQ into the lysosome. NPC1 or NPC2 knockout in COQ2 KO cells showed lower oxygen consumption rate and more mitochondrial ROS in when CoQ is supplemented, suggesting that CoQ trafficking from lysosome to mitochondria wasinhibited. Recombinant NPC2 bound CoQ10, which also supports NPC2 is a carrier protein for CoQ10 in lysosome.

[0184] The next question is whether or not CoQ accumulates in NPC1 and NPC2 KO cells ven if cells retain the de novo CoQ synthesis pathway. To address this question, cells were labeled with heavy tyrosine to measure the total pool of CoQ and how much CoQ was synthesized in 24 hours. The total pool of CoQ was increased in NPC1 and NPC2 KO cancer cells, but the rate of synthesis didn’t change and the unlabeled fraction of CoQ accumulated. The same experiment was performed with NPC1 patientfibroblasts. Thefibroblasts didn’t change the total pool of CoQ, but the unlabeled fraction was increased.

[0185] These results support that CoQ accumulated in the lysosome in the KO cells. According to the current knowledge, the pathology of NPDC is described by lysosomal cholesterol accumulation. However, several cellular consequences, such as mitochondrial dysfunction, are difficult to explain by lysosomal cholesterol deposition alone. Based on the above data, it was hypothesized that impairment of CoQ distribution and lysosomal deposition of CoQ would be another cause of NPDC. In this scenario, CoQ accumulation in the lysosome would cause CoQ deficiency in the mitochondria, resulting in mitochondrial dysfunction.

[0186] Npc1- / - mice will be supplemented with the precursor of the CoQ headgroup to determine whether or not neurological symptoms and survival are recovered. If the mice are recovered with the treatment, NPDC is not just a lysosomal storage disease but also a metabolic disorder with the problems in energy production. * * *

[0187] As various changes can be made in the above-described subject matter without departing 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.

[0188] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

WHAT IS CLAIMED IS:

1. A method for treating Niemann-Pick disease, Rett syndrome, Leigh syndrome, Multiple System Atrophy, spinomuscular atrophy, Freidrich's Ataxia, or stroke 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): (I), wherein: R1is selected from the group consisting of H and ; R2is selected from the group consisting of H and C1-C3alkyl; R3is 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): (II), wherein: n is 0 or 1; R1ais selected from the group consisting of H and ; R2ais selected from the group consisting of H and C1-C3alkyl; R3a is selected from the group consisting of H and C1-C3alkyl; and R4a is selected from the group consisting of H and ; andR5a is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the Leigh syndrome is a Complex I deficiency.

3. The method of claim 1, wherein the Niemann-Pick disease is Niemann-Pick disease type C.

4. The method of any one of claims 1-3, wherein 4-hydroxymandelic acid (4-HMA) or pharmaceutically acceptable salt thereof is administered to the subject.

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

6. The method of claim 5, 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%.

7. The method of any one of claims 1-6, wherein the 4-HMA is enantiopure (R)-4-HMA.

8. The method of any one of claims 1-3, wherein 4-hydroxybenzoate (4-HB) or pharmaceutically acceptable salt thereof is administered to the subject.

9. The method of any one of claims 1-3 or 8, wherein the 4-HB is enantioenriched (R)-4-HB.

10. The method of claims 9, 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%.

11. The method of any one of claims 1-3 or 8-10, wherein the 4-HB is enantiopure (R)-4-HB.

12. The method of any one of claims 1-3, wherein a compound of Formula (I) or pharmaceutically acceptable salt thereof is administered to the subject.

13. The method of any one of claims 1-3 or 12, wherein the compound of Formula (I) is enantioentriched (R)-compound of Formula (I).

14. The method of claim 13, wherein the enantioentriched (R)-compound of Formula (I) 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%.

15. The method of any one of claims 1-3 or 12-14, the wherein the compound of Formula (I) is enantiopure (R)-compound of Formula (I).

16. The method of any one of claims 1-3 or 12-15, wherein R1is H.

17. The method of any one of claims 1-3 or 12-15, wherein R1is .

18. The method of any one of claims 1-3 or 12-17, wherein R2is methyl.

19. The method of any one of claims 1-3 or 12-17, wherein R2is H.

20. The method of any one of claims 1-3 or 12-19, wherein R3is H.

21. The method of any one of claims 1-3 or 12-19, wherein R3is methyl.

22. The method of any one of claims 1-3 or 12-21, wherein R4is H.

23. The method of any one of claims 1-3 or 12-21, wherein R4is .

24. The method of any one of claims 1-3 or 12-23, wherein the compound of Formula (I) has the structure according to Formula (Ia): O R1N O O Ia) or a pharmaceutically accendR4is selected from the group consisting of H an .

25. The method of any one of claims 1-3 or 12-23, wherein the compound of Formula (I) has the structure according to Formula (Ib): Me O R O b) or a pharmaceutically acceR1is selected from the group consistin ndR4is selected from the group consisting of H an .

26. The method of any one of claims 1-3 or 12-23, wherein the compound having the structure of Formula (I) is selected from the group consisting of:, or a pharmaceutic27. The method of any one of claims 1-3 or 12-23, wherein the compound having the structure of Formula (I) is selected from the group consisting of: , or ap a aceu ca y accep a e sa e eo .

28. The method of any one of claims 1-3, wherein a compound of Formula (II) or pharmaceutically acceptable salt thereof is administered to the subject.

29. The method of any one of claims 1-3 or 28, wherein the compound of Formula (II) is enantioenriched (R)-compound of Formula (II).

30. The method of claim 29, wherein the enantioenriched (R)-compound of Formula (II) has enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, orat 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%.

31. The method of any one of claims 1-3 or 28-30, wherein the compound of Formula (II) is enantiopure (R)-compound of Formula (II).

32. The method of any one of claims 1-3 or 28-31, wherein the compound of Formula (II) has the structure according to Formula (IIa): a), or a pharmaceuticallyR1a is selected from the group consistin ; R2ais selected from the group consistinR3ais selected from the group consisting of H and C1-C3alkyl; R4a is selected from the group consisting of H and , and.

33. The method of any one of claims 1-3 or 28-31, wherein the compound of Formula (II) has the structure according to Formula (IIb): b)or a pharmaceutically acceptable salt thereof, wherein: R1a is selected from the group consistin ; R2a is selected from the group consistin ; R3ais selected from the group consistingof H and C1-C3alkyl; R4ais selected from the group consisting of H and , and R5a is selected from the group consisting of H and .

34. The method of any one of claims 1-3 or 28-31, wherein the compound of Formula (II) has the structure: or35. The method of any one of claims 1-3 or 28-34, wherein R1ais H.

36. The method of any one of claims 1-3 or 28-34, wherei .

37. The method of any one of claims 1-3 or 28-36, wherein R2ais methyl.

38. The method of any one of claims 1-3 or 28-36, wherein R2a is H.

39. The method of any one of claims 1-3 or 28-38, wherein R3a is H.

40. The method of any one of claims 1-3 or 28-38, wherein R3ais methyl.

41. The method of any one of claims 1-3 or 28-40, whereinR4a is H.

42. The method of any one of claims 1-3 or 28-40, wherein R4ais .

43. The method of any one of claims 1-3 or 28-42, wherein R5a is H.

44. The method of any one of claims 1-3 or 28-42, wherein R5ais .

45. The method of any one of claims 1-3 or 28-44, wherein the compound having the structure of Formula (II) is selected from the group consisting of: O O H2,nd or46. The method of any one of claims 1-3 or 28-44, wherein the compound having the structure of Formula (II) is selected from the group consisting of: , ora pharmaceutically acceptable salt thereof.

47. The method of any one of claims 1-3 or 28-44, wherein the compound having the structure of Formula (II) is selected from the group consisting of:,or salt48. The method of any one of claims 1-3 or 28-44, wherein the compound having the structure of Formula (II) is selected from the group consisting of: , ,or49. The method of any one of claims 1-48, wherein the subject is a mammal.

50. The method of claim 49, wherein the subject is a human.

51. The method of claim 50, wherein the subject is an adult.

52. The method of claim 50, wherein the subject is an elderly adult.

53. The method of claim 50, wherein the subject is 65 years or older.

54. The method of any one of claims 1-53, 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.

55. The method of any one of claims 1-54, 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.

56. The method of claim 55, 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.

57. The method of claim 56, wherein the liquid dosage form is selected from the group consisting of dispersion, solution, gel, syrup, elixir, slurry, and suspension.

58. The method of any one of claims 55, 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.

59. The method of claim 58, wherein the solid oral dosage form is selected from the group consisting of tablet, powder, pill, dragee, capsule, effervescent formulation, and lyophilized formulation.

60. The method of any one of claims 55, 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.

61. The method of any one of claims 1-60, 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.

62. The method of any one of claims 1-60, 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.

63. The method of any one of claims 1-60, 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.

64. The method of any one of claims 1-60, 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.

65. The method of any one of claims 1-60, 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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