Leucine, acetyl leucine, and related analogs for treating disease

Abstract

To provide methods of treating diseases, disorders, conditions, or syndromes, e.g., traumatic brain injury, in a patient.SOLUTION: The present disclosure provides methods involving administering a therapeutically effective amount of DL-leucine, or a pharmaceutically acceptable salt thereof, L-leucine, or a pharmaceutically acceptable salt thereof, D-leucine, or a pharmaceutically acceptable salt thereof, L-leucine ethyl ester, or a pharmaceutically acceptable salt thereof, acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, acetyl-D-leucine, or a pharmaceutically acceptable salt thereof, or acetyl-L-leucine, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 49

Description

[Technical field]

[0001] BACKGROUND OF THEINVENTION FIELD OF THEINVENTION The present disclosure relates to DL-leucine or a pharma- ceutical acceptable salt thereof, D-leucine or a pharma- ceutical acceptable salt thereof, L-leucine or a pharma- ceutical acceptable salt thereof, L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof, acetyl-DL-leucine or acetyl-D-leucine or a pharma- ceutically acceptable salt thereof; a therapeutically effective amount of a salt thereof, or acetyl-L-leucine or a pharma- ceutically acceptable salt thereof. By doing so, a patient in need thereof may be treated with a method for treating a disease, disorder, illness, or syndrome, such as A method for treating traumatic brain injury is provided. [Background technology]

[0002] (background) Acetyl-DL-leucine was first developed in France in 1957 to treat acute vertigo. It has been used since 2000. FDG-μPET study in a rat model of acute unilateral labyrinthectomy (Zwert et al., 2011). Gal et al. (2016) Brain Struct Funct; 221(1): 159-70) reported that the activation and posterior Effects of the L-enantiomer, N-acetyl-L-leucine, on postural compensation via inactivation of the lateral thalamus The effect was significant (Gunther et al. (2015) PLoS One; 10(3): e0120891). Acetyl-DL - Improvement of symptoms of cerebellar ataxia with leucine has been shown in a case series of cerebellar patients (Strupp et al. (2013) J Neurol; 260(10): 2556-61). Another case series showed no benefit. (Pelz et al. (2015) J Neurol; 262(5): 1373-5). Quantitative gait analysis showed that Acetyl-DL-leucine improves episodic gait variability in patients with cerebellar ataxia (Schniepp et al., 2015, Cerebellum; 3:8). Niemann-Pick disease type C (NPC) A one-month study involving 12 patients with ataxia showed improvement in symptoms of ataxia. (Bremova et al. (2015) Neurology; 85(16): 1368-75). PET studies in patients with ataxia receiving cin have shown that responders have increased the midbrain and lower brain showed increased metabolism in the trunk (Becker-Bense et al., 2015 Abstract EAN).

[0003] WO 2018 / 029657 and WO 2018 / 029658 disclose a method for treating certain neurodegenerative diseases, such as Alzheimer's disease. Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) and leucine and acetyl-leucine for treating certain lysosomal storage diseases (LSDs) In WO 2018 / 029658, the use of In a mouse model, the brain of NPC1 mice showed accumulation of LC3-II and was upregulated by administration of acetyl-DL-leucine. It was shown that administration of rituximab was accompanied by a decrease in LC3-II, indicating a partial restoration of autophagic flux.

[0004] It is caused by the production of pro-inflammatory cytokines, e.g., IL-1β and chemokines. Inflammation is the basis of a variety of neurodegenerative, neuroinflammatory, mitochondrial, and other diseases. See, for example, Chakrabarti et al., Curr Alzheimer Res. 15(10):894- 904 (2018); Cherry et al., Journal of Neuroinflammation 11:98 (2014); Inacio et al. References, Journal of Neuroinflammation 12:211(2015); References, Lappalainen et al., Am J Resp ir Cell Mol Biol 32:311-318(2005); Coccia et al., J. Exp. Med. 209;1595-1609(20 12); Ray, Journal of the American College of Cardiology 63:1735-1438 (2014) Ren et al., Brain Res Rev. 60(1):57-64(2009); Frank-Cannon et al., Molecula r Neurodegeneration 4:47(2009); DiSabato et al., J Neurochem 139(Suppl 2):136-1 53(2016); Amor et al., Immunology 142:151-166(2013); Chen et al., Molecular Mechanics 142:151-166(2013). dicine Reports 13:3391-3396(2016); Tuttolomondo et al., Drug Design, Development t and Therapy 8:2221-2239(2014); Hong et al., Int Neurourol J 20 Suppl 1:S2-7( 2016); Gu et al., Journal of Biological Regulators & Homeostatic Agents 29:787 -791(2015); Belarbi et al., Journal of Neuroinflammation 9:23(2012); Abdulkhale In the article by q et al., Veterinary World, EISSN: 2231-0916 (www.veterinaryworld.org / Vol.11 / May -2018 / 9.pdf); Frankola et al., CNS Neurol Disord Drug Targets 10(3): 391-403(2011); Habbas et al., Cell 163:1730-1741(2015); Debray et al., Current Opinion in Pediatrics 20:471-482(2008); Niyazov et al., Mol Syndromol 7:122-13 Please refer to 7(2016).

[0005] For example, traumatic brain injury ("TBI") is a devastating illness associated with significant morbidity and mortality. Given the increase in population and the increase in injury-related events such as traffic accidents, the incidence of TBI is expected to increase. Other emergencies such as natural disasters, sports injuries, falls, assaults, and military conflicts also contribute to TB. In the United States alone, it is estimated that over 1.5 million people suffer TBI each year. TBI can vary in severity from mild to moderate to severe and can be focal or diffuse. Possibly. A focal injury occurs in a specific location, whereas a diffuse injury is potentially widespread. This is accompanied by significant axonal dysfunction and vascular damage.

[0006] Brain injury from TBI occurs in two stages. The first stage is the head trauma event itself. It is irreversible and only preventative measures can be taken to minimize the extent of the damage. There is then a continuous second phase that begins at the time of injury and continues for several days afterwards. This secondary phase lasts for several weeks to years. It restores homeostasis to the injured tissue. It induces a variety of physiological, cellular, and molecular responses aimed at promoting This can lead to secondary brain damage.

[0007] There is a need for pharmaceutical agents to treat diseases that respond to modulation of proinflammatory mediator expression. There is a need in the art. Summary of the Invention

[0008] (Summary of the invention) Applicant has demonstrated that acetyl-L-leucine is a potent anti-inflammatory agent in mice treated with controlled cortical impact (CCI) traumatic brain injury. We found that IL-1 regulates the expression of pro-inflammatory mediators in IL-1. In one aspect, the present disclosure provides a method for treating a disease in which modulation of one or more pro-inflammatory mediators would be beneficial. Methods for treating diseases, disorders, illnesses, or syndromes are disclosed. The most prominent syndromes are neuroinflammatory, neurological, autoimmune, and neurodegenerative tumors. psychiatric, psychiatric, and mitochondrial diseases, disorders, illnesses, or syndromes .

[0009] Without wishing to be bound by any particular theory, it is believed that leucine, acetyl-DL- Leucine, acetyl-D-leucine, and acetyl-L-leucine have been shown to be effective in treating neuroinflammatory and other diseases. Neuroinflammation is a pathway that counteracts molecular cascades that contribute to a disease, disorder, illness, or syndrome. For example, secondary brain injury in TBI patients is thought to modulate the hyperreactive response. In some cases, the condition is characterized by an increased risk of developing cardiovascular disease, in which excess pro-inflammatory cytokines play a role in maintaining and promoting brain function. These cytokines play a role in repair after TBI. Head trauma-induced brain injury is In particular, excessive and / or excessive levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α This can trigger uncontrolled release of these hormones, which can result in serious brain damage. Proinflammatory cytokines play a key role in the pathophysiology of neurodegenerative diseases such as AD, MS, PD, and ALS. It has been reported to play a role in cancer biology (Wei-Wei et al., Mol. Med. Rep. 2016; 13(4):3391-3396), hallmarks of genetic neurodegenerative disorders such as GM1 and GM2 gangliodystrophy. It has been confirmed that (Jeyakumar et al., Brain 2003; 126(Pt 4):974-87). Furthermore, disruption of normal lysosomal function in lysosomal storage diseases (LSDs) may be associated with abnormalities in inflammation, e.g. For example, it has been associated with abnormal increases in proinflammatory cytokines (Simonaro, 2002; al of Inborn Errors of Metabolism & Screening, Vol. 4: 1-8(2016)).

[0010] Also, without wishing to be bound by any particular theory, the present disclosure suggests that DL -Leucine, L-leucine, D-leucine, L-leucine ethyl ester, acetyl-DL-leucine The researchers found that acetylcholine, acetyl-D-leucine, and acetyl-L-leucine are potential markers of TBI. The tubule-associated protein tau (which is an autophagy substrate) and / or the microtubule-associated protein Regulates protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) LC3-II is a marker for autophagosome formation, and the level of LC3-II Increased autophagosome clearance may reflect impaired clearance of autophagic vacuoles. Autophagy is impaired in AD, and AD brains have a higher number of LCs than do LCs. 3-II levels are shown.

[0011] In one aspect, the present disclosure provides a method for treating a disease, disorder, illness, or condition in a subject in need thereof. A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. A method of treating a group of conditions comprising administering to said subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, illness, or syndrome is listed in Tables 1-17 (see below). The compounds of the present disclosure are any one or more of the diseases that , DL-Leucine ("DLL"), L-Leucine ("LL"), D-Leucine ("DL"), L-Leucine ethyl ester ("LLE" or "LEE"), acetyl-DL-leucine ("ADLL"), acetyl-D-lo acetyl-L-leucine ("ADL"), or acetyl-L-leucine ("ALL", "NAL", or "NALL"), The term "aryl amines" collectively refers to the compounds and pharma- ceutical acceptable salts thereof.

[0012] In another aspect, the present disclosure provides a method for treating or preventing TBI in a subject in need thereof. A method of treating symptoms of TBI in a subject in need thereof, comprising administering to said subject the therapeutic properties of a compound of the present disclosure. administering to the subject an effective amount.

[0013] In another aspect, the present disclosure provides a method for treating a disease, disorder, illness or condition in a subject in need thereof. for use in treating a disease, disorder, or syndrome in a subject in need thereof Provided are compounds of the disclosure for use in treating a symptom of a disease or syndrome, wherein The disease, disorder, illness, or syndrome may be any of those listed in Tables 1-17 (see below). Any one or more of the following:

[0014] In another aspect, the present disclosure provides a method for treating TBI in a subject in need thereof. For use in treating or treating symptoms of TBI in a subject in need thereof The disclosed compounds are provided.

[0015] In another aspect, the present disclosure provides a method for treating a disease, disorder, illness or condition in a subject in need thereof. for the manufacture of a medicament for treating a syndrome or a disease in a subject in need thereof, A compound of the present disclosure for the manufacture of a medicament for treating a symptom of a disorder, disease, or syndrome. wherein the disease, disorder, condition, or syndrome is selected from the group consisting of those listed in Tables 1-17 (see below). Any one or more of the diseases listed.

[0016] In another aspect, the present disclosure provides a pharmaceutical agent for treating TBI in a subject in need thereof. or for the manufacture of a medicament for treating TBI in a subject in need thereof. The present invention provides the use of the compounds of the present disclosure for the treatment of

[0017] In another aspect, the present disclosure provides a method for treating a disease, disorder, illness or condition in a subject in need thereof. for the manufacture of a medicament for treating a syndrome or a disease in a subject in need thereof, A compound of the present disclosure for the manufacture of a medicament for treating a symptom of a disorder, disease, or syndrome. and a pharma- ceutical composition comprising a medicament for treating the disease, disorder, or illness, ... carrier, or syndrome is any one or more of the disorders listed in Tables 1-17 (see below). It is a number.

[0018] In another aspect, the present disclosure provides a method for treating a subject with a pro-inflammatory mediator in a subject in need thereof, For example, a method for modulating the expression of proinflammatory cytokines and proinflammatory chemokines. and administering to the subject a therapeutically effective amount of a compound of the present disclosure. In an embodiment, the proinflammatory mediators include NOS2, IL-18, IFNb, IL-1β, TNFα, These include, but are not limited to, NOX2, NLRP3, SOCS3, ARG1, IL-10, IL-4ra, and / or YM1. Not determined.

[0019] Both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the invention as claimed. It should be understood that this is not a limitation of the claimed invention. [Brief description of the drawings]

[0020] Detailed Description of the Drawings [Figure 1] 1 is a schematic diagram showing the experimental design of NAL administration and cortical impact-induced TBI model. Mice were orally fed NAL and cortical tissues were harvested for biochemical analysis at 1, 3, and 7 days after TBI.

[0021] [Diagram 2] FIG. 2 is a bar graph showing the weight change in mice 7 days after NAL (N-acetyl-L-leucine or acetyl-L-leucine) treatment following TBI.

[0022] [Diagram 3] FIG. 3 is a bar graph showing spatial memory assessment in mice 7 days after NAL treatment following TBI using the Y-maze test.

[0023] [Figure 4]FIG. 4 is a bar graph showing IL-16 expression in mice 3 days after NAL treatment following CCI.

[0024] [Diagram 5] FIG. 5 is a bar graph showing IL-1β expression in mice 3 days after NAL treatment following CCI.

[0025] [Figure 6] FIG. 6 is a bar graph showing INFb expression in mice 3 days after NAL treatment following CCI.

[0026] [Figure 7] FIG. 7 is a bar graph showing Arg1 expression in mice 3 days after NAL treatment following CCI.

[0027] [Figure 8] FIG. 8 is a bar graph showing SOCS3 expression in mice 3 days after NAL treatment following CCI.

[0028] [Figure 9] FIG. 9 is a bar graph showing TNF expression in mice 3 days after NAL treatment following CCI.

[0029] [Figure 10] FIG. 10 is a bar graph showing IL-18 expression in mice 3 days after NAL treatment following CCI.

[0030] [Figure 11] FIG. 11 is a Western blot analysis evaluation of autophagy and cell death following NAL treatment after CCI.

[0031] [Figure 12] FIG. 12 is a bar graph showing fodrin / b-actin levels following NAL treatment after CCI.

[0032] [Figure 13]FIG. 13 is a bar graph showing LC3-II / b-actin levels after NAL treatment following CCI.

[0033] [Figure 14] FIG. 14 is a histogram of the ratio of LC3-II expression to βIII-tubulin in the cerebellum of 9-12 week old mouse NPC1 brains treated with ADLL, ALL, ADL, DLL, LL, DL, LLE, and miglustat (miglu.) for 3 weeks compared to untreated NPC1 cerebella (n=4, mean±SEM).

[0034] [Figure 15] FIG. 15 is a histogram of the ratio of APP-CTF:full-length APP expression in the cerebella of 9-12 week old mouse NPC1 brains treated with ADLL, ALL, ADL, DLL, LL, DL, LLE, and miglustat (miglu.) for 3 weeks compared to untreated NPC1 cerebella (n=4, mean±SEM).

[0035] [Figure 16] FIG. 16 is a histogram of the ratio of APP-CTF-6:full-length APP expression in the cerebella of 9-12 week old mouse NPC1 brains treated with ADLL, ALL, ADL, DLL, LL, DL, and LLE for 3 weeks compared to untreated NPC1 cerebella.

[0036] [Figure 17] FIG. 17 is a histogram of the ratio of APP-CTF-7:full-length APP expression in the cerebella of 9-12 week old mouse NPC1 brains treated with ADLL, ALL, ADL, DLL, LL, DL, and LLE for 3 weeks compared to untreated NPC1 cerebella (n=4, mean±SEM).

[0037] [Figure 18]FIG. 18 is a histogram of the ratio of LC3-II normalized to βIII tubulin in rat primary cortical neurons treated with U18666A (2 μg / ml, 24 h) in the absence or presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 24 h) (expressed as a percentage of untreated (n=1)).

[0038] [Figure 19] FIG. 19 is a histogram of the ratios of APP-CTF-6 and -7 normalized to their respective CTFs in untreated cells in rat primary cortical neurons treated with U18666A (2 μg / ml, 24 h) in the absence or presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 24 h) (expressed as percentage of untreated (n=1)).

[0039] [Figure 20] FIG. 20 is a Western blot of tau (5E2), synaptophysin, and βIII-tubulin in rat primary cortical neurons (neuron-enriched (NE) and neuron-glia (NG) cultures) in the absence and presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 5 days).

[0040] [Figure 21] FIG. 21 is a histogram of the ratio of full length tau normalized to βIII-tubulin in DIV14 NE cultures in the absence and presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 5 days).

[0041] [Figure 22] FIG. 22 is a histogram of the ratio of truncated tau (clone 5E2) normalized to βIII-tubulin in DIV14 NG medium cultures in the absence and presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 5 days).

[0042] [Diagram 23] FIG. 23 is a histogram of the ratio of synaptophysin normalized to βIII-tubulin in DIV14 NE media cultures in the absence and presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 5 days) (expressed as a percentage of untreated control lysates; n=4, mean±SEM).

[0043] [Figure 24] FIG. 24 is a histogram of the ratio of synaptophysin normalized to βIII-tubulin in DIV14 NG medium cultures in the absence and presence of ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 5 days) (expressed as a percentage of untreated control lysates; n=4, mean±SEM).

[0044] [Diagram 25] FIG. 25 is a bar graph showing lysosomal volume in wild-type and NPC1 null Chinese hamster ovary cells treated with ALL for 7 days at the indicated concentrations (n=4).

[0045] [Figure 26] FIG. 26 is a bar graph showing lysosomal volume in wild-type and NPC1 null Chinese hamster ovary cells treated with LEE at the indicated concentrations for 7 days (n=4).

[0046] [Figure 27] FIG. 27 is a bar graph showing lysosomal volume in wild-type and NPC1 null Chinese hamster ovary cells treated with LL at the indicated concentrations for 7 days (n=4).

[0047] [Figure 28] FIG. 28. Western blot analysis assessment of cortical tissue lysates from sham and TBI mice fed NALL or vehicle to detect α-fodrin breakdown products.

[0048] [Figure 29] Figure 29 is a bar graph showing densitometric analysis of α-fodrin relative to actin. Data are presented as mean ± SEM. n=5, **p<0.01 (2-way ANOVA with Bonferroni post-hoc test).

[0049] [Diagram 30] Figure 30 is a series of four images of vehicle or NALL-fed TBI mouse cortical brain sections stained for TUNEL. Data are presented as mean ± SEM. n=3 for vehicle-fed TBI mice and n=4 for NALL-fed TBI mice.

[0050] [Diagram 31] Figure 31 is a bar graph showing area quantification of TBI mouse cortical brain sections stained for TUNEL. Data are presented as mean ± SEM. n=3 for vehicle-fed TBI mice and n=4 for NALL-fed TBI mice.

[0051] [Diagram 32] Figure 32 is a bar graph showing cell quantification of TBI mouse cortical brain sections stained for TUNEL. Data are presented as mean ± SEM. n=3 for vehicle-fed TBI mice and n=4 for NALL-fed TBI mice.

[0052] [Diagram 33] FIG. 33 is a Western blot analysis assessment of cortical tissue lysates from sham and TBI mice fed NALL or vehicle for the autophagosomal marker LC3 and the autophagy cargo protein p62 / SQSTM1.

[0053] [Diagram 34]Figure 34 is a bar graph showing densitometry analysis of LC3-II relative to actin. Data are presented as mean ± SEM. n=5, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0054] [Diagram 35] Figure 35 is a bar graph showing densitometric analysis of p62 relative to actin. Data are presented as mean ± SEM. n=5, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0055] [Diagram 36] Figure 36 is a bar graph showing relative NOS2 mRNA levels in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0056] [Figure 37] Figure 37 is a bar graph showing the relative mRNA levels of NLRP3 in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0057] [Figure 38] Figure 38 is a bar graph showing relative IL-1β mRNA levels in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0058] [Figure 39]Figure 39 is a bar graph showing relative TNF-α mRNA levels in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0059] [Diagram 40] Figure 40 is a bar graph showing relative IFN-β mRNA levels in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0060] [Diagram 41] Figure 41 is a bar graph showing the relative mRNA levels of NOX2 in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0061] [Diagram 42] Figure 42 is a bar graph showing relative mRNA levels of SOCS3 in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0062] [Diagram 43] Figure 43 is a bar graph showing relative YM-1 mRNA levels in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0063] [Diagram 44]Figure 44 is a bar graph showing relative mRNA levels of IL-4ra in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0064] [Diagram 45] Figure 45 is a bar graph showing relative mRNA levels of Arg-1 in the cortex of sham and TBI mice fed NALL or vehicle. Data are presented as mean ± SEM. n=5, ***p<0.001, *p<0.05 (2-way ANOVA with Bonferroni post-hoc test).

[0065] [Diagram 46] Figure 46 shows images of cerebellar Purkinje cell loss and microglial activation progressing from anterior to posterior lobes in untreated Npc1- / - mice and Npc1- / - mice treated with ADLL, ALL, and ADL. Cerebellum was stained with calbindin-b (Purkinje cells) or CD68 (activated microglia).

[0066] [Figure 47] FIG. 47 is a scatter plot showing Purkinje cell survival at 59 days of age in untreated Npc1− / − mice and Npc1− / − mice treated with ADLL, ALL, and ADL.

[0067] [Figure 48] Figure 48 is a scatter plot showing the frequency of CD68-positive activated microglia in untreated Npc1- / - mice and Npc1- / - mice treated with ADLL, ALL, and ADL at 59 days of age. CD68 cell density was measured in the cerebellum. n=5 animals per group. Mean±SD, ***p<0.0009 (One-way ANOVA).

[0068] [Figure 49]FIG. 49 is a line graph showing motor function (beamwalk) outcomes in a controlled cortical impact TBI model using mice treated with NAL.

[0069] [Figure 50] FIG. 50 is a bar graph showing spatial memory (Y-maze) results in a controlled cortical impact TBI model using mice treated with NAL.

[0070] [Figure 51] FIG. 51 is a bar graph showing novel object recognition (NOR) results in a controlled cortical impact TBI model using mice treated with NAL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] Detailed Description of the Invention As used herein, a "subject" can be a vertebrate, a mammal, or a domestic animal. Thus, the compositions according to the present disclosure can be used in any mammal, including livestock (e.g., horses, cattle, sheep, or pigs), pets (e.g. cats, dogs, rabbits, or guinea pigs) can be used to treat laboratory animals (e.g., mice or rats) In one embodiment, the subject is a human. "Subject" and "patient" are used interchangeably.

[0072] As used herein, the singular forms "a," "an," and "the" are used interchangeably. " includes plural referents.

[0073] The terms "approximately" and "about" are used taking into account the nature or precision of the measurements. The degree of error to be tolerated for the quantity measured by the method is included in the standard number or value. It means they are the same.

[0074] As used herein, the terms "approximately" and "about" mean It should be understood that this typically encompasses ±20% of a given amount, frequency, or value. Quantities given in this document are approximate unless otherwise stated and may vary unless expressly stated. In some cases, the term "about" or "approximately" can be inferred. means...

[0075] As used herein, the terms "administer," "administration," or "administering" refer to (1) The compounds disclosed herein are administered orally by or through a health professional or his / her authorized agent. and (2) providing, donating, administering, and / or prescribing a compound of the disclosure. Refers to the taking, ingestion, or consumption of a substance by a patient or person (male or female) "Leucine", "Acetyl-DL-leucine" and "Acetyl-L-leucine" or Any reference to any other compounds disclosed herein is to be construed as being indicative unless expressly stated. The term "compounds" includes pharma- ceutical acceptable salts thereof.

[0076] Unless otherwise indicated, the term "leucine" refers to L-leucine.

[0077] The "pharmaceutical acceptable salts" referred to herein are suitable for use in pharmaceutical applications. Any salt preparation. Pharmaceutically acceptable salts include amine salts, e.g., N,N'-diamine salts. Benzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, proline Caine, N-benzylphenethylamine, 1-para-chloro-benzyl-2-pyrrolidine-1'-ylamine Benzimidazole, diethylamine, and other alkylamines, piperazine, triethylamine, (hydroxymethyl)aminomethane, etc.; alkali metal salts, for example, lithium, potassium , sodium, etc.; alkaline earth metal salts, e.g., barium, calcium, magnesium etc.; transition metal salts, e.g., zinc, aluminum, etc.; other metal salts, e.g., dihydrogen phosphate sodium, disodium phosphate, etc.; mineral acids, e.g., hydrochlorides, sulfates, etc.; and organic acids Salts of, for example, lactate, malate, tartrate, citrate, ascorbate, amber These include, but are not limited to, acid salts, butyrates, valerates, fumarates and the like.

[0078] The compounds of the present disclosure can be formulated and administered to a subject according to teachings known in the art. For example, DL-leucine, L-leucine, D-leucine, L-leucine ethyl ester, Acetyl-DL-leucine, acetyl-D-leucine, or acetyl-L-leucine is a compound of The pharmaceutical composition can be formulated as DL-leucine, L-leucine, D-leucine. , L-leucine ethyl ester, acetyl-DL-leucine, acetyl-D-leucine, or acetyl- The pharmaceutical composition may include leucine, leucine, and a pharma- ceutical acceptable carrier. Reference is made to the active agent only, i.e., DL-leucine, L-leucine, D-leucine, L-leucine. ethyl ester, acetyl-DL-leucine, acetyl-D-leucine, or acetyl-L- leucine, or in the form of a pharmaceutical composition.

[0079] Pharmaceutical compositions can be in a number of different forms, depending in particular on the method in which they are to be used. Thus, it may be in any form, for example, a powder, a tablet, a capsule, a liquid, Ointments, creams, gels, hydrogels, aerosols, sprays, micellar solutions, transdermal patches, In the form of a liposomal suspension or any other form that can be administered to a human or animal in need of treatment. The composition may be in any suitable form.

[0080] The term "pharmaceutical acceptable carrier" as used herein refers to a compound that is used in the formulation of a pharmaceutical composition. Any known compound or combination of known compounds known in the art to be useful. The carrier of a pharmaceutical composition is a substance that is suitable for the subject to which it is administered. It will be understood that the effects should therefore be tolerable.

[0081] In one embodiment, the pharma- ceutically acceptable carrier may be a solid and the composition may be It may be in powder or tablet form. Pharmaceutically acceptable solid carriers include: Flavoring agents, buffering agents, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, colorants, fillers agents, lubricants, compression aids, inert binders, sweeteners, preservatives, dyes, coating agents, or tableting agents. One or more substances that may also act as disintegrants may include, but are not limited to, The carrier may also be an encapsulating material. In the powder, the carrier is a finely divided powder according to the invention. In tablets, the active agent may be a finely divided solid mixed with the active agent. The agent is mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. The powders and tablets, for example, may contain up to 99% of the active agent. Examples of solid carriers include calcium phosphate, magnesium stearate, talc, sugars, and the like. , lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine In another embodiment, the pharmaceutical agent is a medicament. The acceptable carrier may be a gel, and the composition may be in the form of a cream, etc. This is also fine.

[0082] A carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, etc. starch, sodium starch glycolate, calcium hydrogen phosphate, stearin Examples of suitable antibacterial agents include magnesium oxide, talcum, and colloidal silicon dioxide.

[0083] In another embodiment, the pharma- ceutically acceptable carrier may be a liquid. In this embodiment, the pharmaceutical composition is in the form of a solution. The liquid carrier may be a solution, suspension, emulsion, or the like. In the preparation of infusions, syrups, elixirs and pressurized compositions, The compound may be dissolved in a pharma- ceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or The liquid carrier may be dissolved or suspended in a pharma- ceutically acceptable fat or oil. Suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspensions, It may contain a clouding agent, a thickening agent, a coloring agent, a viscosity adjusting agent, a stabilizer, or an osmolality adjusting agent. Suitable examples of liquid carriers for parenteral administration include water (containing additives such as those described above, e.g., cereals, vegetables, and the like). Some of them contain cellulose derivatives, for example sodium carboxymethylcellulose solution. alcohols (including monohydric and polyhydric alcohols, e.g., glycols); and its derivatives, as well as oils (e.g., coconut oil and peanut oil). For this purpose, the carrier may also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions may be halogenated hydrocarbons or other pharma- ceutically acceptable liquids. The propellant may be a propellant.

[0084] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered, for example, intramuscularly, intrathecally, epidurally, intraperitoneally, It can be administered by intravenous, intravenous, and subcutaneous injection. The active agent is dissolved in sterile water, saline, or the like. It can be dissolved or suspended at the time of administration using water or another appropriate sterile injectable medium. The composition may also be prepared as a sterile solid composition.

[0085] The composition may contain other solutes or suspending agents (e.g., enough saline or other aqueous solutions to make the solution isotonic). glucose), bile salts, gum arabic, gelatin, sorbitan monooleate, polyisobutene Sorbate 80 (oleic acid ester of sorbitol and its copolymer with ethylene oxide) The composition can be administered orally in the form of a sterile solution or suspension containing, for example, an anhydrous form. It can also be administered orally in either liquid or solid composition form. Compositions include solid forms such as pills, capsules, granules, tablets, and powders, as well as solutions, Liquid forms such as syrups, elixirs, and suspensions are included. Forms useful for parenteral administration Forms include sterile solutions, emulsions, and suspensions.

[0086] The compositions may alternatively be administered by inhalation (e.g., intranasally). The composition may also be formulated for topical use, for example by applying a cream or ointment to the skin. good.

[0087] The compounds of the present disclosure can be incorporated into sustained or delayed release devices. The device can be inserted, for example, cutaneously or subcutaneously, and the medicine can be delivered for weeks or months. Such devices can be used in accordance with the present disclosure. Long-term treatment with the compound is required, which requires frequent administration (e.g., at least daily). This may be advantageous when a patient may require administration of

[0088] In one embodiment, the pharmaceutical composition is a solid oral dosage form, such as a tablet. The active agent is mixed in a vehicle such as a pharma- ceutical acceptable carrier in suitable proportions and having the requisite compression properties. The tablet may be mixed with 100% glycerin and compressed into the desired shape and size. It may contain an active agent.

[0089] The pharmaceutical compositions in solid oral dosage forms, such as tablets, can be formulated by any method known in the art of pharmacy. Pharmaceutical compositions can be prepared by combining an active agent with a conventional pharma- ceutical acceptable carrier. It is prepared by mixing with

[0090] Tablets can be formulated as known in the art. For example, Tanganil® (brand name) wheat starch, pregelatinized maize (corn) starch The excipients include calcium carbonate, magnesium stearate, and the like. or similar excipients may be utilized with the present disclosure.

[0091] The composition of each 700 mg Tanganil® tablet is as follows: 500 mg Acetyl-DL- leucine, 88 mg wheat starch, 88 mg pregelatinized maize (corn (cor n) starch, 13 mg calcium carbonate, and 11 mg magnesium stearate. Tablets can be utilized in the methods of the present disclosure.

[0092] As discussed above, the compounds of the present disclosure can be administered as pharmaceutical compositions in any of a number of different forms. For example, the compounds of the present disclosure may be formulated and administered as a medicament, such as a medicament for crossing the blood-brain barrier. The compound can be formulated as a pharmaceutical composition to facilitate its delivery to the patient. By way of example, the compounds of the present disclosure can be formulated as pharmaceutical compositions to bypass the blood-brain barrier. in a manner that facilitates delivery across or bypasses the blood-brain barrier. The leucine (acetylated (not including the above) can be prepared and administered.

[0093] In one embodiment, for example, a pharmaceutical composition comprising acetyl-L-leucine or a salt thereof is They are formulated for nano-delivery, such as colloidal drug carrier systems. Suitable examples include liposomes, Nanoparticles (e.g., polymeric, lipid and inorganic nanoparticles), nanogels, dendrimers, micelles, These include polymersomes, nanoemulsions, polymersomes, exosomes, and quantum dots. For example, see, but are not limited to, Patel et al., Crossing the Blood-Brain Barrier: Drug Delivery to the Brain. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery ug Delivery to the Brain," CNS Drugs 31:109-133 (2017); Kabanov et al., "Blood New Technologies for Drug Delivery across the Brain Barrier the Blood-Brain Barrier,” Curr Pharm Des., 10(12):1355-1363 (2004); Cheng et al. The article, "High-performance liquid chromatography-enhanced ELISA using an in vitro blood-brain barrier model and Alzheimer's disease Tg2576 mice" Highly Stabilized Curcumin Nanoparticles Tested in an I n Vitro Blood-Brain Barrier Model and in Alzheimer's Disease Tg2576 Mice)'', The AAPS Journal, vol. 15, no. 2, pp. 324-336(2013); Lahde et al., "Aerosol Production of L-leucine nanoparticles under various conditions using the Row reactor method -Leucine Nanoparticles under Various Conditions Using an Aerosol Flow Reactor Me thod), Journal of Nanomaterials, vol. 2008, article ID 680897(2008) sea ​​bream.

[0094] In one embodiment, for example, a pharmaceutical composition comprising acetyl-L-leucine or a salt thereof is For example, the drug is formulated for direct delivery to the central nervous system (CNS) by injection or infusion. Formulations for and methods of direct delivery to the CNS are known in the art. See, U.S. Patent No. 9,283,181. Examples of such administration include intranasal, intraventricular, These include, but are not limited to, intrathecal, intracranial, and nasal mucosal implant delivery. Not determined.

[0095] In one embodiment, the pharmaceutical composition is formulated for intranasal delivery (and For example, Hanson et al., "Intranasal delivery bypasses the blood-brain barrier. , targeting therapeutic agents to the central nervous system to treat neurodegenerative diseases (Intranasal delivery bypass ses the blood-brain barrier to target therapeutic agents to the central nervous system 9(Suppl 3):S5(2008) In one embodiment, the pharmaceutical composition is formulated for nasal mucosal implantation ( In one embodiment, the pharmaceutical composition is administered by intracerebroventricular injection. The compound is formulated for injection or infusion (and administered by intracerebroventricular injection or infusion). In some embodiments, the pharmaceutical composition is formulated for intrathecal injection or infusion (and In one embodiment, the pharmaceutical composition is administered by intrathecal lumbar injection. It is formulated for injection or infusion (and administered by intrathecal lumbar injection or infusion).

[0096] Such techniques include, but are not limited to, burr hole puncture, cisternal puncture, or lumbar puncture, as known in the art. A variety of techniques can be used, including injection via a catheter or other device. whether internal (contained) or external, e.g. pumps, catheters, reservoirs, etc. A variety of devices can be used for delivery as known in the art. The administration interval is once every two weeks.

[0097] In one embodiment, the dosing interval is once a month. In one embodiment, the administration interval is twice a month. In one embodiment, the administration interval is once a week. In one embodiment, the administration interval is every day. In some cases, the administration is continuous, for example, by continuous infusion.

[0098] In one embodiment, a dose or amount equivalent to a compound of the present disclosure is administered to a subject in need of such treatment for its direct delivery to the CNS. The delivery of the drug can be tailored to account for either its delivery to the brain or across the blood-brain barrier. .

[0099] The present disclosure provides methods for treating a variety of diseases, disorders, illnesses, and syndromes in subjects in need thereof. The present disclosure describes compounds of the present invention, including pharmaceutical compositions thereof, for use in treating or preventing osteoarthritis of the spinal cord.

[0100] As used herein, a "traumatic brain injury" refers to at least one traumatic head event (i.e., That is, objects penetrating the brain and / or moving the brain rapidly and / or unnaturally within the subject's skull. The initial stage consists of the initial stage (stress or force applied to the brain) and the physiological and cellular stages resulting from the head trauma. This refers to any injury to the brain that has a subsequent second stage involving cerebrovascular accidents and / or molecular damage. Examples of wounds include, for example, objects penetrating the skull, such as bullets, arrows, and objects passing through the skull. and other physical objects penetrating the brain; shock loads applied to the head or other parts of the patient's body. or force; surgically induced trauma; shaking caused by explosion; non-explosive means, e.g., sports injuries These include injuries, automobile accidents, building collapses, and shaking caused by earthquakes. The injury may be of various types, and all forms of TBI are within the scope of this disclosure. For example, TBI can range in severity from brief changes in mental status or consciousness to prolonged unconsciousness or memory loss. In one embodiment, the TBI is caused by a concussion. In one embodiment, the TBI is caused by a contusion injury. In another embodiment, the TBI is caused by an open head injury. In another embodiment, the TBI is caused by a closed head injury. In one embodiment, the TBI is caused by a localized injury. In another embodiment, the TBI is caused by a localized injury. In one embodiment, the form of TBI is mild TBI. In one embodiment, the form of TBI is moderate TBI. In another embodiment, the form of TBI is , severe TBI.

[0101] As used herein, a "subject in need thereof" refers to a subject suffering from a disease, disorder, illness, or condition. A group, for example, a disease, disorder, condition, or syndrome provided in any one of Tables 1-17. The subject may be any subject. The subject may be any subject who has been diagnosed with the disease, disorder, illness, or syndrome. For example, a subject may have a diagnosis (clinical or non-clinical) of TBI. The subject may not yet have, but may have, one or more symptoms of TBI. or other similarly identifiable markers.

[0102] A "therapeutically effective amount" of a compound of the present disclosure is an amount that, when administered to a subject, has therapeutic effect for the purposes of the present disclosure. and / or in any amount that will be the amount needed to produce the desired effect, which may be prophylactic. The dose will depend on the particular compound of the disclosure used; the age of the subject being treated; Depending on various parameters such as age, weight, and condition; route of administration; and the required regimen. A physician can determine the required route of administration for any particular subject. For example, the daily dose can be about 10 to about 225 mg / kg body weight, about 10 to about It may be 150 mg / kg body weight, or from about 10 to about 100 mg / kg body weight.

[0103] As used herein, "treating" or "treatment" refers to, for example, remission; Preventing, reducing, inhibiting or eliminating any of the above symptoms; or to make a condition, disorder, disease, or condition more tolerable to the patient; or slowing the progression of the syndrome; or improving the physical or mental health of a subject in need thereof. The present invention relates to a method for treating a disease of a subject, including any objective or subjective parameter, such as improving mental health. , a disorder, disease, or syndrome, such as a disease, disorder, or syndrome provided in any one of Tables 1-17. Preventing, arresting, or ameliorating a disease, disorder, or syndrome of interest, and / or A disease, disorder, illness, or syndrome, such as any of the diseases, disorders, illnesses, or syndromes provided in any one of Tables 1-17. or success in preventing, halting, or ameliorating any one or more symptoms of the syndrome. Refers to any manifestation of merit.

[0104] The term "treating" or "treatment" refers to, for example, a disease, disorder, illness, or syndrome. For example, the term "inhibition, regression, or induction of equilibrium of the TBI" may be used to refer to a condition requiring treatment for TBI. Treatment of a patient or subject suffering from a TBI may include reducing symptoms of the TBI in the subject, inducing a clinical response, or and inhibiting or reducing the progression of TBI or inhibiting or reducing complications of TBI. Includes:

[0105] Prevent, arrest, or ameliorate the damage or pathological condition of a disease, disorder, illness, or syndrome For example, preventing, reducing, inhibiting one or more symptoms of a disease, disorder, illness, or syndrome. The introduction or elimination of the substance may be based, for example, on the results of a physical, neurological, and / or psychiatric examination. The evaluation can be based on objective and / or subjective parameters, including the results of Successful treatment of a particular disease, such as TBI, may be achieved, for example, by treatment with a compound of the present disclosure. The severity of the disease (e.g., objective and / or subjective parameters of TBI) before the onset of the disease was assessed in accordance with the present invention. 4. Objective and / or subjective parameters of the disease (e.g., TBI) following initiation of treatment with the indicated compounds. For example, the severity of a TBI can be measured or assessed by comparing it with the severity of a The evaluation may be performed using a scale, index, rating, or score. In such cases, the treatments described herein may involve such assessment as determining whether a particular symptomatic subject has a particular condition. In one embodiment, the subject's blood glucose level is improved from a level or degree characteristic of a symptom-free subject to a level or degree characteristic of a subject asymptomatic. In one embodiment, the treatments described herein improve such assessments compared to baseline. The baseline may be, for example, a time period before or after starting any treatment for a disease, e.g., TBI. The condition may be the state of the subject prior to initiating treatment of the disease with the disclosed compounds. A baseline may be, for example, the state of a subject a certain time after starting treatment for a disease. In one embodiment, treatment with the compounds disclosed herein reduces baseline and comparing the subject's assessment (e.g., scales, indices, etc. of objective and / or subjective parameters). At least 10%, at least 20%, at least 30%, or In one embodiment, the evaluation improves by at least 60%, or at least 40%, or at least 50%. %, at least 70%, at least 80%, at least 90%, or 100% improved.

[0106] For example, in one embodiment, the severity of a subject's disorder, e.g., TBI, is assessed using the Glasgow College of Cardiology (GGCCA) method. The GCS can be quantified by the GCS, which is a set of three areas of investigation: eye, language, For the eye examination, patients were asked to rate their scores from 1 to 4 as follows: The scores are: 1- Eyes do not open in response to any stimulus, 2- Eyes open only in response to pain, 3- For the language test, the patient was asked to The responses are rated from 1 to 5, such as: 1- no audio response, 2- unintelligible audio, 3- inappropriate language. For the motor test, patients were scored as follows: 1- Confused, 4- Oriented, and 5- Oriented. The motor response is graded from 1 to 6: 1- no motor response, 2- extension to pain, 3- abnormal to pain. 3-flex to pain, 4-retract to pain, 5-locate to pain, and 6-respond to command The GCS score is the sum of the three scores received for eye, speech, and motor responses. Generally, TBI is classified as mild, severe, or severe based on the Glasgow Coma Scale. Classified as moderate or severe: mild: GCS>13, moderate: GCS 9-12, and severe: GCS<8. The level of recovery in TBI patients is quantified by the Glasgow Outcome Scale (GOS). The Glasgow Outcome Scale is a 5-level score: 1- death , 2 - vegetative state, 3 - severe impairment, 4 - moderate impairment, and 5 - good recovery. GOS is often , "favorable" outcomes (moderate injury and good recovery) and "unfavorable" outcomes (death, plant condition, and severe disability).

[0107] A "symptom" of a disease, disorder, illness, or syndrome is a condition that is associated with that disease, disorder, illness, or syndrome. Any clinical or experimental signs of disease that are not limited to those that can be sensed or observed by the subject. For example, symptoms of certain diseases listed in Tables 1-17, such as TBI, may include fainting, confusion, anxiety, agitation, disorientation, memory loss, headache, lightheadedness, dizziness, blurred vision or tired eyes, fatigue or lethargy, changes in sleep patterns, behavioral or mood changes, memory, concentration, Problems with attention and / or thinking, nausea or repeated vomiting, convulsions or seizures, difficulty sleeping Inability to wake up, slurred speech, weakness or numbness in the limbs, and loss of coordination These include, but are not limited to:

[0108] In one embodiment, the compounds of the present disclosure are administered, optionally by solid or liquid oral route: For example, in the range of about 500 mg to about 30 g or in the range of about 500 mg to about 15 g per day, for example, The compounds of the present disclosure can be administered in doses ranging from about 1.5 g to about 10 g. Tanganil (registered) is prescribed for adults at a dose of 1.5 g to 2 g per day, 3 to 4 tablets administered twice a day at night and at night. The dosage can be administered according to the dosage prescribed by the manufacturer (trademark).

[0109] The single enantiomers, i.e., L-leucine, acetyl-D-leucine, or acetyl- If L-leucine is administered, the dose can be reduced accordingly. When only L-leucine or only acetyl-D-leucine is administered, the dose is about 2 In the range of 50 mg to about 15 g, in the range of about 250 mg to about 10 g per day, or in the range of about 250 mg to about 5 g per day The dosage may be within a range, for example, from about 0.75 g to about 5 g per day.

[0110] In one embodiment, the dose administered is from about 1 g to about 30 g per day, from about 1 g to about 1 5g, about 1g to about 10g per day, or about 1.5g to about 7g per day, 15.1g to about 30g per day, 16g to 30g per day, 17g to 30g per day, 18g to 30g per day, 19g to 30g per day or in the range of 20 g to about 30 g per day. This is about 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, or 14 g to about 15 g per day. , 8, or 9 g to about 10 g per day. , 23, 24, 25, 27, 28, or 29 g to about 30 g. This is more than about 1.5 g per day. However, it may be less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 grams per day. In one embodiment, the dosage ranges from about 4 g to about 6 g per day. The dosage ranges from about 4 g to about 5 g per day. In one embodiment, the dosage ranges from about In one embodiment, the dosage is about 5 g per day. , the dose is about 1g per day, about 2g per day, about 3g per day, about 4g per day, about About 5g, About 6g per day, About 7g per day, About 8g per day, About 9g per day, About 10g per day , about 11 g per day, about 12 g per day, about 13 g per day, about 14 g per day, or about In another embodiment, the dosage is about 16 g per day, about 17 g per day, about 18 g per day, about 20 g per day, about 22 g per day, about 24 g per day, about 26 g per day, about 28 g per day, about 29 g per day, about 30 g per day, about 31 g per day, about 32 g per day, about 33 g per day, about 34 g per day, about 35 g per day, In another embodiment, the dosage is about 18 g per day, about 19 g per day, or about 20 g per day. About 21g per day, about 22g per day, about 23g per day, about 24g per day, about 2 5g, about 26g per day, about 27g per day, about 28g per day, about 29g per day, or about In one embodiment, these doses are administered in solid oral dosage forms, in particular tablets. In another embodiment, these doses are administered in the amount of acetylated ... The enantiomeric excess is for acetyl-leucine. The dose for the drug is lower, for example about 50% lower. The recited dosage ranges are also expressly encompassed by this disclosure.

[0111] In one embodiment, the total daily dose can be spread over multiple administrations. That is, administration can be two or more times a day to achieve the total daily dose. The amount of tablets required to provide a total daily dose of the compound of the present disclosure may be two doses (e.g., morning and night). The dose can be divided into three doses (e.g., morning, midday, and evening) or split across three doses (e.g., morning, midday, and evening). The dose may be suitably administered with or without food. acetyl-L-leucine or acetyl-DL-leucine about 1 or about 2 hours before a meal, e.g. At least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about It may be administered 1 hour, or about 1, about 2, or about 3 hours after a meal, e.g., at least 1 hour after a meal. at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least Alternatively, the dose may be administered at least about 2 hours after the initial administration, or at least about 2.5 hours after the initial administration. For example, a daily dose of 4.5 g may be administered at least about 2 hours after the initial administration. The subjects were administered three doses of Tanganil® before breakfast, with breakfast, or after breakfast. (or equivalent) tablet, three additional tablets before, with, or after lunch, and dinner It may also be administered as three additional tablets before, with, or after dinner.

[0112] In one embodiment, with respect to TBI, administration of a compound of the present disclosure according to the present disclosure is In one embodiment, administration begins at or around (e.g., within 24 hours) the time of administration of It begins a period of time (e.g., days, weeks, months, or years) after the trauma. In embodiments, administration occurs after the subject has been diagnosed (clinically or non-clinically) with TBI. In one embodiment, administration is initiated when the subject has a Glasgow Coma Scale (GCS In one embodiment, the subject is administered 13 In another embodiment, the subject had a GCS score of 9 to 12. In another embodiment, the subject had a GCS score of 3 to 8. The injury occurred before the head injury (or after a subsequent head injury if one or more head injuries have already occurred). In one embodiment, administration is initiated to a subject at risk of suffering a TBI (prior to Elephants have been found to have biochemical or other similar identifiable markers of TBI. In one embodiment, administration is initiated at, around, or after the subject has one or more episodes of TBI. It begins when, around, or after the symptoms above are experienced.

[0113] The duration of treatment for any of the diseases listed in Tables 1 to 17 is, for example, about 7 days or more, about 2 weeks or more, about 3 weeks or more, about 1 month or more, about 6 weeks or more, about 7 weeks or more, or about 2 months or more In one embodiment, it may be for about 3 months or more, about 4 months or more, about 5 months or more, or The duration of treatment is about 6 months or more. The duration of treatment is about 1 year or more, about 2 years or more, about 4 years or more, about 5 years or more or for about 10 years or more. The duration of treatment may be for the lifetime of the subject.

[0114] Any and all combinations of dosage forms, dosage amounts, administration schedules, and duration of treatment are contemplated by the present disclosure. In one embodiment, the dosage is about 4 g to about 10 g per day. and should be taken 1, 2, or 3 times per day for a treatment duration of at least about 2 months. In another embodiment, the dosage is greater than 4 g but not greater than 5 g per day for about 6 months. The drug is administered 1, 2, or 3 times per day for the duration of treatment. It may be a solid oral dosage form, in particular a tablet.

[0115] The compounds of the present disclosure can be used to treat a disease, disorder, illness, or syndrome in a subject, for example, any of the diseases, disorders, conditions, or syndromes listed in Tables 1-17. Monotherapy (e.g., active ingredient) for treating a disease, disorder, illness, or syndrome provided in combination with one other agent Alternatively, the compounds of the present disclosure can be used as therapeutic agents for treating diseases, disorders, , disease, or syndrome, e.g., a disease, disorder, condition, or syndrome provided in any one of Tables 1-17. or as an adjunct to or in combination with other known therapies for treating the syndrome. can be used.

[0116] Also disclosed are methods for treating a disease, disorder, illness, or syndrome in a subject, such as any of Tables 1-17. 1. A kit for treating a disease, disorder, illness, or syndrome, comprising: The method comprises the steps of: diagnosing the disease, disorder, illness, or syndrome; A kit comprising a means for determining the prognosis of a disease and a compound of the disclosure.

[0117] The kit may further comprise a buffer or an aqueous solution. Thus, instructions for using the compounds of the present disclosure may further be included.

[0118] All of the features described herein (including any accompanying claims, abstract and drawings) ), and / or any method steps so disclosed. Except for combinations in which at least some of the features and / or steps are mutually exclusive, Any of the above may be combined in any combination.

[0119] "A disease, disorder, illness, or condition in which modulation of one or more proinflammatory mediators would be beneficial." The term "symptoms" and similar terms refer to (i) a syndrome in which one or more proinflammatory mediators are present, e.g., Is important or necessary for the onset, progression, or manifestation of the disease, disorder, condition, or syndrome or (ii) a disease, disorder, condition, or syndrome that is responsive to modulation of proinflammatory mediators. These terms refer to diseases, disorders, illnesses, or syndromes that are known to cause These include neuroinflammatory diseases, neurological diseases, autoimmune diseases, neurodegenerative protein diseases, and psychiatric diseases. Medical disorders, including, but not limited to, depression, and mitochondrial disorders. Proinflammatory mediators are well known in the art. "Really Essential Medical Immunology", 2nd edition, Rabson, Roitt, Delves (Bl Exemplary, non-limiting pro-inflammatory mediators include sarcolemmal inflammatory mediators, such as sarcolemmal inflammatory mediators, ... and sarcolemmal inflammatory mediators. Inhibitors, e.g., interleukin (IL)-1β, IL-8, tumor necrosis factor alpha (TNF-α) , IL-6, and IL-12, chemokines, and growth factors.

[0120] In one embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or condition in a subject in need thereof. or to treat a disease, disorder, illness, or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 1. , disease, or syndrome. Table 1 [Table 1] TIFF2024170602000003.tif238170TIFF2024170602000004.tif239170TIFF2024170602000005.tif238170TIFF2024170602000006.tif28170

[0121] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is any of the diseases, disorders, conditions, or syndromes provided in Table 2. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 2 [Table 2] TIFF2024170602000008.tif134170

[0122] In one embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or condition in a subject in need thereof. or to treat a disease, disorder, illness, or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 3. , disease, or syndrome. Table 3 [Table 3] TIFF2024170602000010.tif240170TIFF2024170602000011.tif118170

[0123] In another embodiment, the present disclosure provides a method for treating a neuroinflammatory disease, disorder in a subject in need thereof. Neuroinflammatory disease in a subject in need thereof, or for treating a disease or syndrome. A method for treating a symptom of a disease, disorder, or syndrome comprising administering to a subject the therapeutic effect of a compound of the present disclosure. administering to the subject an effective amount.

[0124] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 4. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 4 [Table 4] TIFF2024170602000013.tif237170TIFF2024170602000014.tif98170

[0125] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 5. The present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... In an aspect, the disclosure provides a method of treating traumatic brain injury. Table 5 [Table 5] TIFF2024170602000016.tif219170

[0126] In another embodiment, the present disclosure provides a method for treating a neurological disease, disorder, or Treating a disease, disorder, or syndrome in a subject in need thereof A method for treating a symptom of an injury, disease, or syndrome comprising administering a therapeutically effective amount of a compound of the present disclosure to a patient. to the subject.

[0127] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 6. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 6 [Table 6] TIFF2024170602000018.tif240170TIFF2024170602000019.tif240170TIFF2024170602000020.tif78170

[0128] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 7. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 7 [Table 7] TIFF2024170602000022.tif240170TIFF2024170602000023.tif240170TIFF2024170602000024.tif32170

[0129] In another embodiment, the present disclosure provides a method for treating an autoimmune disease, disorder, or condition in a subject in need thereof. To treat an autoimmune disease, disorder, or syndrome in a subject in need thereof A method for treating a symptom of an injury, disease, or syndrome comprising administering a therapeutically effective amount of a compound of the present disclosure to a patient. to the subject.

[0130] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 8. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 8 [Table 8]

[0131] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 9. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 9 [Table 9]

[0132] In another embodiment, the present disclosure provides a method for treating a neurodegenerative proteinopathy in a subject in need thereof. Treating or providing medical care to a person in need of a sexual illness, disorder, disease, or syndrome A method for treating a symptom of a transproteinopathy disease, disorder, condition, or syndrome, comprising: administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0133] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 10. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 10 [Table 10] TIFF2024170602000028.tif242170TIFF2024170602000029.tif98170

[0134] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 11. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 11 [Table 11] TIFF2024170602000031.tif242170TIFF2024170602000032.tif159170

[0135] In another embodiment, the present disclosure provides a method for treating a psychiatric disease, disorder, or the like in a subject in need thereof. psychiatric disorders, diseases, or syndromes in subjects in need thereof A method for treating a symptom of a disease, disorder, or syndrome comprising administering to a subject the therapeutic effect of a compound of the present disclosure. administering to the subject an effective amount.

[0136] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 12. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 12 [Table 12]

[0137] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is any of the diseases, disorders, conditions, or syndromes provided in Table 13. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 13 [Table 13]

[0138] In another embodiment, the present disclosure provides a method for treating a mitochondrial disease in a subject in need thereof. Treating a disorder, disease, or syndrome, or targeting mitochondria in a subject in need thereof A method for treating a symptom of a human disease, disorder, illness, or syndrome comprising administering to said patient a compound of the present disclosure. to the subject.

[0139] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 14. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 14 [Table 14]

[0140] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 15. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 15 [Table 15]

[0141] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is any of the diseases, disorders, conditions, or syndromes provided in Table 16. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 16 [Table 16]

[0142] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or to treat a disease, disorder, illness or syndrome in a subject in need thereof. A method for treating a symptom of the syndrome comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 17. In one embodiment, the present invention provides a method for treating a disease, injury, disease, or syndrome, comprising administering to a subject a therapeutically effective amount of the ... Table 17 [Table 17]

[0143] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. The method of treating a group of conditions comprises administering to a subject from about 1 g to about 30 g of the disclosed In another embodiment, the method comprises administering from about 2 g to about 15 g of the compound. The compound of the present disclosure is administered to the subject per day. In another embodiment, about 3 g to about 10 g The compound of the present disclosure is administered to the subject per day. In another embodiment, about 4 g to about 8 g The compound of the present disclosure is administered to the subject per day. In another embodiment, about 4 g to about 5 g The compound of the present disclosure is administered to the subject per day. In another embodiment, about 15.1 g to about 30 g of a compound of the present disclosure is administered to a subject per day. The indicated compound is administered to the subject per day.

[0144] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. The method of treating a group of conditions comprises administering DL-leucine or a medicament thereof to a subject. In another embodiment, the method comprises administering a therapeutically effective amount of an acceptable salt of the compound. A therapeutically effective amount of DL-leucine or a pharma- ceutical acceptable salt thereof is used to treat a disease, disorder, illness, or is administered to the subject to treat the syndrome. A therapeutically effective amount of a pharma- ceutically acceptable salt thereof is an amount that is sufficient to treat the symptoms of a disease, disorder, illness, or syndrome. The compound is administered to a subject to treat the subject.

[0145] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. The method of treating a group of conditions comprises administering to a subject L-leucine or a pharma- ceutically acceptable salt thereof. In another embodiment, a method is provided that comprises administering a therapeutically effective amount of a salt thereof, A therapeutically effective amount of L-leucine or a pharma- ceutical acceptable salt thereof is a therapeutically effective amount for treating a disease, disorder, illness, or condition. In another embodiment, L-leucine or its analogues are administered to a subject to treat a disorder. A therapeutically effective amount of a pharma- ceutically acceptable salt is an amount that is effective to treat a symptom of a disease, disorder, illness, or syndrome. The compound is administered to a subject to

[0146] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. The method of treating a group of conditions comprises administering to a subject D-leucine or a pharma- ceutically acceptable salt thereof. In another embodiment, a method is provided that comprises administering a therapeutically effective amount of a salt thereof, A therapeutically effective amount of D-leucine or a pharma- ceutical acceptable salt thereof is a therapeutically effective amount for treating a disease, disorder, illness, or condition. In another embodiment, D-leucine or its analogues are administered to a subject to treat a disorder. A therapeutically effective amount of a pharma- ceutically acceptable salt is an amount that is effective to treat a symptom of a disease, disorder, illness, or syndrome. The compound is administered to a subject to

[0147] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. The method of treating a group of conditions comprises administering to a subject L-leucine ethyl ester or its The method includes administering a therapeutically effective amount of a pharma- ceutically acceptable salt. In an embodiment, a therapeutically effective amount of L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof. is administered to a subject to treat a disease, disorder, illness, or syndrome. In the present invention, a therapeutically effective amount of L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof is The compound is administered to a subject to treat a symptom of the disease, disorder, condition, or syndrome.

[0148] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. A method for treating a group of conditions comprising administering acetyl-DL-leucine or a pharmaceutical agent thereof to a subject. In another embodiment, the method comprises administering to the patient a therapeutically effective amount of an acceptable salt thereof. In the present invention, a therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is In another embodiment, the compound is administered to a subject to treat a disorder, disease, or syndrome. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is The compound is administered to a subject to treat a symptom of the disease or syndrome.

[0149] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. A method for treating a group of conditions comprising administering acetyl-D-leucine or a pharmaceutical agent thereof to a subject. In another embodiment, the method comprises administering to the patient a therapeutically effective amount of an acceptable salt thereof. In the present invention, a therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is In another embodiment, the compound is administered to a subject to treat a disorder, disease, or syndrome. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is The compound is administered to a subject to treat a symptom of the disease or syndrome.

[0150] In another embodiment, the present disclosure provides a method for treating a disease, disorder, illness, or the like in a subject in need thereof. or a syndrome, e.g., a disease, disorder, illness, or condition provided in any one of Tables 1-17, or A disease, disorder, illness, or symptom in a subject in need thereof, or for whom the disease is to be treated. A method for treating a group of conditions comprising administering acetyl-L-leucine or a pharmaceutical agent thereof to a subject. In another embodiment, the method comprises administering to the patient a therapeutically effective amount of an acceptable salt thereof. In the present invention, a therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is In another embodiment, the compound is administered to a subject to treat a disorder, disease, or syndrome. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is The compound is administered to a subject to treat a symptom of the disease or syndrome.

[0151] In another embodiment, the present disclosure provides a method for treating one or more inflammatory conditions in a subject in need thereof. expression of inflammatory mediators, such as proinflammatory cytokines and chemokines; A method of modulating the function of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In another embodiment, the proinflammatory mediator is selected from the group consisting of NOS2, IL-18, IFNb, and the like. , IL-1β, TNFα, NOX2, NLRP3, SOCS3, ARG1, IL-10, IL-4ra, or YM1 is plural.

[0152] In another embodiment, administration of a compound of the present disclosure reduces neuritis in a subject in need thereof. In another embodiment, the reduced or inhibited neuroinflammation is due to excessive In another embodiment, neuroinflammation is a neuroinflammation disorder characterized by the following: A disease, disorder, illness, or syndrome to which a disclosed compound is not administered, such as those listed in Tables 1-17. Any one of the diseases, disorders, illnesses, or syndromes provided herein, e.g., in subjects suffering from TBI. Inhibited or reduced relative to neuroinflammation.

[0153] In another embodiment, administration of a compound of the present disclosure to a subject in need of treatment for TBI. Microtubule-associated protein tau and / or microtubule-associated protein 1A / 1B-light chain 3-phosphatase The present invention modulates the increase in the level of tidylethanolamine conjugate (LC3-II). In the present invention, an increase in the levels of tau protein and / or LC3-II is observed after administration of a compound of the present disclosure. Any disease, disorder, condition, or syndrome not listed above, such as those provided in any one of Tables 1-17. Tau protein in subjects suffering from a disease, disorder, illness, or syndrome, such as TBI. and / or is regulated relative to elevated levels of LC3-II.

[0154] In another embodiment, administration of a compound of the present disclosure improves the recovery of a subject in need thereof. In another embodiment, the improvement is effective to improve Any disease, disorder, illness, or syndrome not present in the present invention, such as any disease, disorder, illness, or syndrome provided in any one of Tables 1-17. The recovery of a subject suffering from a disease, disorder, illness, or syndrome, e.g., TBI, is improved compared to that of a subject suffering from a disease, disorder, illness, or syndrome, e.g., TBI .

[0155] In another embodiment, recovery is assessed using the Glasgow Outcome Scale (GOS). In one embodiment, leucine, acetyl-leucine, or any of the amino acids of the present disclosure are used. or pharma- ceutical acceptable salts thereof are not considered to be "preferred" for GOS. " The percentage of subjects with results is compared to baseline, e.g., leucine, Patients suffering from TBI who have not been administered acetyl-leucine or a pharma- ceutical acceptable salt thereof At least 10%, at least 20%, at least 30% %, at least 50%, or at least 70%. In another embodiment, the subject is evaluated using the GOS 3 months after the injury. In another embodiment, the subject is evaluated using the GOS 6 months after the injury. Subjects are assessed using the GOS at least 12 months after suffering their injury.

[0156] In another embodiment, administration of the disclosed compounds improves cognitive function in a subject in need thereof. In another embodiment, cognitive function is effective in improving cognitive function when a compound of the present disclosure is administered. Any disease, disorder, illness, or syndrome not listed in Tables 1-17, for example, and comparing the cognitive function of a subject suffering from a disease, disorder, illness, or syndrome, such as TBI. In one embodiment, the cognitive function is memory. In another embodiment, the cognitive function is learning. In the present study, the cognitive function is spatial navigation.

[0157] In another embodiment, administration of the disclosed compounds is to treat a disease in a subject in need thereof, A disorder, disease, or syndrome, such as a disease, disorder, or syndrome provided in any one of Tables 1-17. In another embodiment, the method further comprises administering to the subject a therapeutically effective amount of the compound, which reduces or inhibits at least one symptom of a tumor, or syndrome, such as TBI. In one embodiment, at least one symptom is a disease, disorder, or condition that does not occur in the setting of administration of a compound of the present disclosure. A disease, disorder, illness, or syndrome, such as a disease, disorder, illness, or syndrome provided in any one of Tables 1-17. The symptoms are reduced or inhibited as compared to the symptoms in a subject suffering from a traumatic brain injury, e.g., TBI. In the method, the disease is TBI, and at least one symptom of TBI is confusion, dizziness, disorientation, etc. , loss of coordination, memory loss, inability to form new memories, sleep disorders, behavioral or mood changes, increased agitation, depression, convulsions, and / or seizures.

[0158] In another embodiment, administration of a compound of the present disclosure is directed to treating a disease, disorder, illness, or syndrome, e.g. For example, a disease, disorder, illness, or syndrome provided in any one of Tables 1-17, e.g., TBI The severity of at least one symptom of Diseases and disorders for which chiru-leucine or a pharma- ceutical acceptable salt thereof is not administered , disease, or syndrome, such as a disease, disorder, illness, or syndrome provided in any one of Tables 1-17. is at least 10%, at least 20%, At least 30%, at least 40%, at least 50%, at least 70%, at least 90%, Or reduce it by 100%.

[0159] In another embodiment, administration of a compound of the present disclosure improves the physical and / or mental activity of the subject. In another embodiment, the recovery is effective to improve the levels of Any disease, disorder, illness, or syndrome not listed in Tables 1-17, for example, The improvement is compared to recovery in a subject suffering from a disease, disorder, illness, or syndrome, e.g., TBI. It will be improved.

[0160] In another embodiment, administration of the disclosed compounds is effective to treat encephalitis. In one embodiment, the encephalitis is infectious encephalitis. In another embodiment, the encephalitis is autologous. Symptoms of encephalitis include headache, mild flu-like symptoms (pain, fatigue, etc.) fatigue, mild fever), hypersensitivity to light, stiff neck, drowsiness or fatigue, increased irritability, seizures, Altered alertness, confusion or hallucinations, decreased energy, loss of appetite, unsteady gait, nausea and vomiting These include, but are not limited to, personality changes, and difficulty speaking and / or changes in speech. In some embodiments, symptoms of encephalitis include abnormal movements (chorea, loss of coordination), non-muscle pain, and muscle spasms. Typical motor symptoms, such as ataxia or hemiparesis, or seizures.

[0161] In some embodiments, the encephalitis is characterized by an upper respiratory tract infection, diarrhea, nausea, and vomiting in a subject. Vomiting-causing diseases, measles, mumps, rubella, chickenpox, herpes simplex virus, Nile virus, rabies, Lyme disease, tuberculosis, syphilis, and infections caused by parasites , for example, caused by toxoplasmosis, or an autoimmune reaction. In some embodiments, the present disclosure provides a method for preventing encephalitis in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure. wherein the subject is suffering from an upper respiratory tract infection, a disease causing diarrhea, nausea, and vomiting, measles, Gastrointestinal parotitis, rubella, chickenpox, herpes simplex virus, West Nile virus, rabies, Lyme disease malaria, tuberculosis, syphilis, infectious diseases caused by parasites, e.g. toxoplasmosis, has an autoimmune reaction.

[0162] In another embodiment, administration of the disclosed compounds is directed to treating sleep disorders associated with traumatic brain injury, For example, problems falling asleep and / or staying asleep, fatigue, somnolence, sleep apnea, narcolepsy, and / or are effective in treating sleepiness, eg, excessive daytime sleepiness.

[0163] In another embodiment, administration of a compound of the present disclosure is effective to treat a metabolic disorder of the CNS. In another embodiment, administration of the disclosed compounds is for treating diseases associated with metabolic abnormalities of the CNS. In another embodiment, the metabolic disorder is effective to treat glucoregulatory symptoms and / or diseases. In another embodiment, the metabolic abnormality is an imbalance in glucose metabolism in the cerebellum. In another embodiment, administration of the compounds of the present disclosure is an imbalance in, for example, the cerebellum. , increasing glucose metabolism in the CNS.

[0164] The present disclosure also provides the following specific embodiments.

[0165] Embodiment I: For use in a method of treating traumatic brain injury (TBI) in a subject in need thereof. Leucine, acetyl-leucine, or a pharma- ceutical acceptable salt thereof for the purpose of

[0166] Embodiment II: The method according to embodiment I, further comprising administering to the subject leucine, acetyl-leucine, or is used in a method comprising administering a therapeutically effective amount of a pharma- ceutical acceptable salt thereof. Leucine, acetyl-leucine, or a pharma- ceutically acceptable salt thereof for the treatment of

[0167] Embodiment III: Leucine is DL-leucine or acetyl-leucine is acetyl-DL-leucine. leucine, amyloid, leucine, Cetyl-leucine, or a pharma- ceutical acceptable salt thereof.

[0168] Embodiment IV: Leucine or acetyl-leucine is an enantiomeric excess of the L-enantiomer or For use in the method according to any of embodiments I and II, , leucine, acetyl-leucine, or a pharma- ceutically acceptable salt thereof.

[0169] Embodiment V: A method according to any of embodiments I-IV, comprising: For those in need, about 1g to about 15g per day, about 1g to about 10g per day, about 1.5g per day 2. The amount of the active ingredient in the composition of the present invention is about 4 to about 6 g per day, or about 4 to about 5 g per day. 2. A pharmaceutical composition comprising leucine, acetyl-leucine, or a pharmaceutical thereof for use in a method comprising the steps of: and acceptable salts.

[0170] Embodiment VI: Inhibiting or alleviating one or more symptoms of traumatic brain injury (TBI) in a subject in need thereof. The method of the present invention comprises the step of administering leucine, acetyl-leucine, or a pharma- ceutically acceptable salt thereof to a subject. administering to the subject a therapeutically effective amount of a salt thereof.

[0171] Embodiment VII: The leucine is DL-leucine and the acetyl-leucine is acetyl-DL-leucine. The method according to embodiment VI,

[0172] Embodiment VIII: Leucine or acetyl-leucine is an enantiomeric excess of the L-enantiomer or the D-enantiomer.

[0173] Embodiment IX: The therapeutically effective amount is from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, from about 1.5 g to about 7 g per day, about 4 g to about 6 g per day, or about 4 g to about 5 g per day. Either way.

[0174] The present disclosure also provides the following specific embodiments.

[0175] Embodiment 1. For treating a disease, disorder, illness, or syndrome in a subject in need thereof or to treat the symptoms of a disease, disorder, illness, or syndrome in a subject in need thereof. wherein the disease, disorder, condition, or syndrome is a disease provided in Table 1. , a disorder, disease, or syndrome.

[0176] Embodiment 2. The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 2. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0177] Embodiment 3. The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 3. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0178] Embodiment 4. The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 4. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0179] Embodiment 5. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 5. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0180] Embodiment 6. The method of embodiment 1, wherein the disease, disorder, condition, or syndrome is traumatic brain injury. The compounds of the present disclosure.

[0181] Embodiment 7. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 6. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0182] Embodiment 8. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 7. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0183] Embodiment 9. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 8. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0184] Embodiment 10. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 9. The compound of the present disclosure for use in embodiment 1, wherein said compound is any one or more of the following syndromes:

[0185] Embodiment 11. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 10. is any one or more of the syndromes. .

[0186] Embodiment 12. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 11. is any one or more of the syndromes. .

[0187] Embodiment 13. The disease, disorder, condition, or syndrome is any of the diseases, disorders, conditions, or syndromes provided in Table 12. is any one or more of the syndromes. .

[0188] Embodiment 14. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 13. is any one or more of the syndromes. .

[0189] Embodiment 15. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 14. is any one or more of the syndromes. .

[0190] Embodiment 16. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 15. is any one or more of the syndromes. .

[0191] Embodiment 17. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 16. is any one or more of the syndromes. .

[0192] Embodiment 18. About 1 g to about 30 g of a compound of the present disclosure is administered to a subject per day. 17. A compound of the present disclosure for use according to any one of claims 1 to 17.

[0193] Embodiment 19. About 2 g to about 15 g of a compound of the present disclosure is administered to a subject per day. The compounds of the present disclosure for use in

[0194] Embodiment 20. About 3 g to about 10 g of a compound of the present disclosure is administered to a subject per day. The compounds of the present disclosure for use in

[0195] Embodiment 21. The method of embodiment 20, wherein about 4 g to about 8 g of a compound of the present disclosure is administered to a subject per day. Compounds of the present disclosure for use.

[0196] Embodiment 22. The method of embodiment 21, wherein about 4 g to about 5 g of a compound of the present disclosure is administered to a subject per day. Compounds of the present disclosure for use.

[0197] Embodiment 23. The method of use of embodiment 22, wherein about 5 g of the compound of the present disclosure is administered to the subject per day. The compounds of the present disclosure for

[0198] Embodiment 24. A therapeutically effective amount of leucine or a pharma- ceutically acceptable salt thereof is administered to a subject. , a compound of the present disclosure for use according to any one of embodiments 1 to 23.

[0199] Embodiment 25. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease, disorder, or condition. The method of the present disclosure for use in embodiment 24, wherein the method is administered to a subject to treat a disease, illness, or syndrome. compound.

[0200] 26. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease, disorder, or condition. The present invention for use according to embodiment 24, wherein the compound is administered to a subject to treat a symptom of a disease or syndrome. Disclosed compounds.

[0201] Embodiment 27. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject The compound of the present disclosure for use according to any one of embodiments 1 to 23, wherein the compound is administered to

[0202] Embodiment 28. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is For use according to embodiment 27, the compound is administered to a subject to treat a disease, disorder, illness, or syndrome. The compounds of the present disclosure.

[0203] Embodiment 29. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The use of embodiment 27, wherein the compound is administered to a subject to treat a symptom of a disease, disorder, illness, or syndrome. The compounds of the present disclosure for use in

[0204] Embodiment 30. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject. The compound of the present disclosure for use according to any one of embodiments 1 to 23, wherein the compound is administered.

[0205] Embodiment 31. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is 31. For use according to embodiment 30, which is administered to a subject to treat a disorder, disease, or syndrome. The compound of the present disclosure.

[0206] Embodiment 32. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. 31. The use of embodiment 30, wherein the compound is administered to a subject to treat a symptom of a disorder, disease, or syndrome. The compounds of the present disclosure for

[0207] A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject A compound of the present disclosure for use according to any one of embodiments 1 to 23, wherein the compound is administered to an elephant.

[0208] Embodiment 32B. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutically acceptable salt thereof is The use of embodiment 32A, wherein the compound is administered to a subject to treat a disease, disorder, illness, or syndrome. The compounds of the present disclosure for

[0209] A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The compound of embodiment 32A is administered to a subject to treat a symptom of a disease, disorder, illness, or syndrome. Compounds of the present disclosure for use.

[0210] 33. Treating a disease, disorder, illness, or syndrome in a subject in need thereof for the manufacture of a medicament for treating or treating a disease, disorder, illness or condition in a subject in need thereof and the use of a compound of the present disclosure for the manufacture of a medicament for treating a symptom of the syndrome, The disease, disorder, illness, or syndrome is one of the diseases, disorders, illnesses, or syndromes provided in Table 1. Use of any one or more of the following:

[0211] Embodiment 34. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 2. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0212] Embodiment 35. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 3. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0213] Embodiment 36. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 4. Any disease, disorder, illness, or syndrome that is any one or more of the following: The use of embodiment 33, wherein the use is one or more of the following:

[0214] Embodiment 37. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 5. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0215] Embodiment 38. The use of embodiment 37, wherein the disease, disorder, condition, or syndrome is traumatic brain injury.

[0216] Embodiment 39. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 6. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0217] Embodiment 40. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 7. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0218] Embodiment 41. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 8. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0219] Embodiment 42. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 9. The use of embodiment 33, wherein the condition is any one or more of the following syndromes:

[0220] Embodiment 43. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 10. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0221] Embodiment 44. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 11. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0222] Embodiment 45. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 12. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0223] Embodiment 46. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 13. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0224] Embodiment 47. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 14. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0225] Embodiment 48. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 15. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0226] Embodiment 49. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 16. The use of embodiment 33, wherein said syndrome is any one or more of the following:

[0227] Embodiment 50. About 1 g to about 30 g of a compound of the present disclosure is administered to a subject per day. Use any one of ~49.

[0228] Embodiment 51. About 2 g to about 15 g of a compound of the present disclosure is administered to a subject per day. Use of.

[0229] Embodiment 52. About 3 g to about 10 g of a compound of the present disclosure is administered to a subject per day. Use of.

[0230] Embodiment 53. The method of embodiment 52, wherein about 4 g to about 8 g of a compound of the present disclosure is administered to a subject per day. use.

[0231] Embodiment 54. The method of embodiment 53, wherein about 4 g to about 5 g of a compound of the present disclosure is administered to a subject per day. use.

[0232] Embodiment 55. The use of embodiment 54, wherein about 5 g of a compound of the present disclosure is administered to the subject per day.

[0233] Embodiment 56. A therapeutically effective amount of leucine or a pharma- ceutically acceptable salt thereof is administered to a subject. , Use of any one of embodiments 33 to 55.

[0234] Embodiment 57. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is a therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof for treating a disease, disorder, or illness. The use of embodiment 56, wherein the compound is administered to the subject to treat a disease, illness, or syndrome.

[0235] 58. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease, disorder, or condition. The use of embodiment 56, wherein the compound is administered to the subject to treat a symptom of a disease or syndrome.

[0236] Embodiment 59. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject The use of any one of embodiments 33 to 55, wherein the patient is administered

[0237] Embodiment 60. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is The use of embodiment 59, wherein the compound is administered to a subject to treat a disease, disorder, illness, or syndrome.

[0238] Embodiment 61. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The use of embodiment 59, wherein the compound is administered to a subject to treat a symptom of a disease, disorder, condition, or syndrome. For.

[0239] Embodiment 62. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject. The use of any one of embodiments 33 to 55, wherein

[0240] Embodiment 63. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is The use of embodiment 62, wherein the compound is administered to a subject to treat a disorder, disease, or syndrome.

[0241] 64. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. 63. The use of embodiment 62, wherein the compound is administered to a subject to treat a symptom of a disorder, disease, or syndrome. .

[0242] Embodiment 64A. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutically acceptable salt thereof is administered to a subject. The use of any one of embodiments 33 to 55, wherein the patient is administered

[0243] Embodiment 64B. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is The use of embodiment 64A, administered to a subject to treat a disease, disorder, illness, or syndrome.

[0244] A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The compound of embodiment 64A is administered to a subject to treat a symptom of a disease, disorder, illness, or syndrome. use.

[0245] 65. Treating a disease, disorder, illness, or syndrome in a subject in need thereof For use in treating or in the treatment of a disease, disorder, illness, or condition in a subject in need thereof. Compounds of the present disclosure and pharma- ceutically acceptable carriers for use in treating a range of conditions. wherein the disease, disorder, condition, or syndrome is a disease provided in Table 1. , a disorder, disease, or syndrome.

[0246] Embodiment 66. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 2. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0247] Embodiment 67. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 3. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0248] Embodiment 68. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 4. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0249] Embodiment 69. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 5. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0250] Embodiment 70. The use of embodiment 65, wherein the disease, disorder, condition, or syndrome is traumatic brain injury. A pharmaceutical composition for use in treating

[0251] Embodiment 71. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 6. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0252] Embodiment 72. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 7. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0253] Embodiment 73. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 8. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0254] Embodiment 74. The disease, disorder, condition, or syndrome is a disease, disorder, condition, or syndrome provided in Table 9. The pharmaceutical composition for use according to embodiment 65, wherein the pharmaceutical composition is any one or more of the following syndromes:

[0255] Embodiment 75. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 10. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0256] Embodiment 76. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 11. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0257] Embodiment 77. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 12. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0258] Embodiment 78. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 13. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0259] Embodiment 79. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 14. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0260] Embodiment 80. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 15. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0261] Embodiment 81. The disease, disorder, illness, or syndrome is any of the diseases, disorders, illnesses, or syndromes provided in Table 16. 66. The pharmaceutical composition for use according to embodiment 65, wherein said syndrome is any one or more of the following:

[0262] Embodiment 82. About 1 g to about 30 g of a compound of the present disclosure is administered to a subject per day. A pharmaceutical composition for use in any one of claims 1 to 81.

[0263] Embodiment 83. About 2 g to about 15 g of a compound of the present disclosure is administered to a subject per day. A pharmaceutical composition for use in

[0264] Embodiment 84. About 3 g to about 10 g of a compound of the present disclosure is administered to a subject per day. A pharmaceutical composition for use in

[0265] Embodiment 85. The method of embodiment 84, wherein about 4 g to about 8 g of a compound of the present disclosure is administered to a subject per day. Pharmaceutical compositions for use.

[0266] Embodiment 86. The method of embodiment 85, wherein about 4 g to about 5 g of a compound of the present disclosure is administered to a subject per day. Pharmaceutical compositions for use.

[0267] Embodiment 87. The use of embodiment 86, wherein about 5 g of a compound of the present disclosure is administered to the subject per day. A pharmaceutical composition for use in treating

[0268] Embodiment 88. A therapeutically effective amount of leucine or a pharma- ceutically acceptable salt thereof is administered to a subject. , A pharmaceutical composition for use according to any one of embodiments 65 to 87.

[0269] Embodiment 89. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is a therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof for treating a disease, disorder, or illness. 89. The pharmaceutical composition for use according to embodiment 88, which is administered to a subject to treat a disease or syndrome. thing.

[0270] Embodiment 90. A therapeutically effective amount of leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease, disorder, or condition. 89. The pharmaceutical composition for use according to embodiment 88, which is administered to a subject to treat a symptom of a disease or syndrome. Pharmaceutical composition.

[0271] Embodiment 91. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject The pharmaceutical composition for use according to any one of embodiments 65 to 87, wherein the composition is administered to

[0272] Embodiment 92. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is For use according to embodiment 91, the compound is administered to a subject to treat a disease, disorder, illness, or syndrome. A pharmaceutical composition for the treatment of

[0273] Embodiment 93. A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The use of embodiment 91, wherein the compound is administered to a subject to treat a symptom of a disease, disorder, condition, or syndrome. A pharmaceutical composition for use.

[0274] Embodiment 94. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject. The pharmaceutical composition for use according to any one of embodiments 65 to 87, wherein the composition is administered.

[0275] Embodiment 95. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is 95. For use according to embodiment 94, which is administered to a subject to treat a disorder, disease, or syndrome. A pharmaceutical composition comprising:

[0276] Embodiment 96. A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. 95. The use of embodiment 94, wherein the compound is administered to a subject to treat a symptom of a disorder, disease, or syndrome. A pharmaceutical composition for

[0277] Embodiment 96A. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to a subject The pharmaceutical composition for use according to any one of embodiments 65 to 87, wherein the composition is administered to

[0278] Embodiment 96B. A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutically acceptable salt thereof is The use of embodiment 96A, wherein the compound is administered to a subject to treat a disease, disorder, illness, or syndrome. A pharmaceutical composition for use in treating

[0279] A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to treat a disease. The compound of embodiment 96A is administered to a subject to treat a symptom of a disease, disorder, illness, or syndrome. Pharmaceutical compositions for use. EXAMPLES

[0280] (Example) Example 1 Male patients suffering from traumatic brain injury were given a dose of 3 g per day for the first week, followed by Acetyl-DL-leucine was administered at a dose of 5 g per day. Patient care specialists and nurses reported that patients exhibited more active behavior after treatment with acetyl-DL-leucine. The medication was subsequently stopped and the patient's activity level improved with treatment with acetyl-DL-leucine. returned to its original level before

[0281] Example 2 Efficacy of N-acetyl-L-leucine in a CCI mouse model of TBI (Controlled Cortical Impact Model) Controlled cortical impact (CCI)-induced TBI was performed in male C57BL6 / J mice (20–25 g). After a 10-mm midline incision was made across the skull, the skin and fascia were wrapped, and a 4-mm craniotomy was performed. The rats were placed under surgical anesthesia (2–3% isoflurane in 70% N 2 O and 30% O 2 Evaporation in a gas mixture containing The impact velocity was 6 m / s and the deformation depth was 2 mm. Custom microprocessor controlled and pneumatically driven pneumatic tip with 3.5mm diameter tip Moderate injury was induced in the exposed brain with a quinpactor.

[0282] (NAL treatment) N-acetyl-L-leucine ("NAL" or "NALL") was dissolved in ethanol to give a 50 mg / ml solution. A solution was prepared, which was then dissolved in water to give a 10 mg / ml solution. The solution (10 mg / ml) was administered by oral gavage daily for 4 days after CCI-induced TBI at a dose of 10 mg / kg (2. Mice were orally administered 5 mg NAL / 25 g mouse. Mice were also given 100 mg NAL mixed with diet gel. NAL was fed in powdered diet at 0.5 mg / kg for up to 7 days after injury. See Figure 1. No significant difference in food intake was observed between the control and TBI mice fed NALL ( (Data not shown). A slight decrease in body weight was detected in vehicle-treated TBI mice, No obvious changes in body weight were observed in NALL-treated TBI mice (data not shown).

[0283] (Cell death after TBI) α-Fodori in the cortex of NALL-treated, vehicle-treated sham, and TBI mice The levels of cleavage products were determined by Western blot analysis and using the TUNEL assay. , we assessed whether NALL treatment reduces cortical cell death after TBI.

[0284] (Western blot analysis) Approximately 5 mm of tissue from the ipsilateral cortex surrounding the injury site from TBI mice or the same cortex from sham mice The same volume of corresponding tissue from the surrounding area was dissected and processed. Tissue lysates were diluted in 4-20% SDS-PA. The samples were resolved using GE gel (Bio-Rad, 5671095) and then transferred to a semi-dry transfer tube (Bio-Rad) for PVD. The cells were transferred to a membrane (Millipore, IPVH00010) and placed in Tris-buffered saline (TBST) containing 0.05% Tween 20. ) and then proteolyzed overnight at 4°C with primary antibodies in TBST containing 1% BSA. The antibodies were incubated with HRP-conjugated secondary antibodies (KPL, 474-1506, 474-1806, 14-16-06, and 14- 13-06) in blocking solution at room temperature for 1 hour. The strands were detected using a chemiluminescence kit (Pierce, 34076) and the Chemi-doc system (Bio-Rad). The band intensities were analyzed using Image Lab software (Bio-Rad) and visualized using the Primary antibody: LC3 (1:1000; Novus, NB100- 2220), p62 / SQSTM1 (1:1000; BD Bioscience, 610832), β-actin / ACTB (1:10,000; A1 978), and fodrin / spectrin (1:5000; Enzo Life Science International, BML-F G6090).

[0285] (TUNEL assay) Vehicle or NAL-fed sham and TBI mice fixed in 4% paraformaldehyde (PFA, pH 7.4) Cryosections (20 μm) were cut from mouse brains and preserved in 30% sucrose. The ApopTag in situ apoptosis detection kit (Millipore, S7165) was used as described by Coll. TUNEL assays were performed on frozen brain sections using a fluorescent Nikon Ti-E inverted microscope at 20X magnification (CFI Photon Fluorescence). Images after TUNEL assay were obtained using a lan APO VC 20X NA 0.75WD 1mm.

[0286] TBI inhibits the catabolism of α-fodrin, which produces fragments of 145–150 kDa and 150–120 kDa, respectively. Induce both insulin- and caspase-mediated cleavage. Vehicle fed after TBI Lower levels of 145-150 in the cortex of NALL-fed mice compared to the cortex of non-native mice. A 20 kDa α-fodrin fragment was observed, indicating a protective benefit of NALL in preventing cortical cell death. See Figures 28 and 29. NALL in fed compared to vehicle-fed TBI mice. Lower levels of TUNEL-positive cells were also detected in brain sections of injured mice after TBI. The protective role of NALL in reducing cell death was demonstrated. See Figures 30, 31, and 32.

[0287] (Autophagic flux after TBI) Autophagy is a lysosome-dependent cell pathway that is disrupted by lysosomal injury following TBI Degradation processes. See, e.g., Sarkar et al., Autophagy 10:2208-2222 (2014); See the article by K. et al., Autophagy, 1-20 (2019). Cells after NALL treatment in TBI mice We assessed whether the attenuation of death was mediated by restoration of autophagic flux. The results are shown in Figures 11 to 13 and 33 to 35.

[0288] Cortical tissue lysates prepared from vehicle- and NAL-fed naïve and TBI mice. The levels of LC3-II and p62 / SQSTM1 in mice were determined by Western blot analysis. LC3-II in the brains of NALL-fed mice compared to vehicle-treated mice 1 day after TBI We detected a decrease in the levels of α-amyloid in vehicle-treated mice after TBI. See Figures 33 and 34. We also observed a decrease in p62 / SQSTM1 levels in the cortex of NALL-fed mice compared with control mice. See Figures 33 and 35. These results indicate that NALL improves autophagic flux. We demonstrated that the IL-11 receptor agonist, IL-11, enhances the IL-11 receptor signaling pathway and thereby restores its neuroprotective function in the mouse cortex after TBI. is doing.

[0289] (Inflammatory cytokines in the brains of TBI mice) M1-type proinflammatory markers Nos2, Nlrp3, and IL-1β in the perilesional cortical region of TBI mice The expression levels of TNF, IFNβ, and Nox2 were determined by real-time rt-PCR. The expression levels of M2 markers Socs3, YM-1, IL4ra, and Arg-1 in the 14.1-HT2B1 cells were also determined. , presented in Figures 2-10 and 36-45.

[0290] (Real-time PCR) Total RNA was isolated from the ipsilateral cortex using the miRNeasy Mini kit (Qiagen, Cat No. 217004). The cDNA was prepared by the High Capacity RNA to cDNA Kit (Applied Biosystems, Cat. No. 131111) according to the manufacturer's instructions. The following mouse genes were used: Gapdh (Mm99 999915_g1), NLRP3 (Mm00840904_m1), NOX2 (Mm01287743_m1), iNOS (Mm00440502_m1), TNF α(Mm00443258_m1), IFnβ1(Mm00439552_s1), IL-10(Mm01288386_m1), IL1b(Mm00434228_ m1), Arg1 (Mm00475988_m1), SOCS3 (Mm00545913_s1), YM-1 (Mm00657889_mH), and IL-4ra ( Mm01275139_m1) (Applied Biosystems), 20x TaqMan® Gene Expression Assay cDNA was synthesized using TaqMan® Universal Master Mix II (Applied Biosystems). Quantitative labeling was performed using a ELISA kit (Digicel Biosystems, Cat. No. 4440040) as previously described. The reaction mixture was amplified using a 7900HT Fast Real-Time PCR System and Quantification was performed using the comparative Ct method and the corresponding software (Applied Biosystems). Relative gene expression normalized to pdh was calculated.

[0291] Increased levels of all M1-type pro-inflammatory markers were observed, regardless of treatment. In all TBI mouse cortices, the increase began on day 1 after injury and peaked on day 3. 41 However, the cortex of NAL-fed mice compared to that of vehicle-fed TBI mice Decreased levels of IFNβ and Nox2 mRNA in the cortex of mice were observed.

[0292] Similar to M1 markers, high expression of M2 markers Socs3, YM-1, IL4ra, and Arg-1 was observed in pseudo This was observed in the cortical tissue of all TBI mice compared to control animals. See Figures 42-45. Among these markers, NAL treatment significantly reduced injury when compared to vehicle-fed TBI mice. The levels of Arg-1, Socs3, YM-1, and IL-4ra in the mouse cortex were decreased. remained unchanged in NAL-fed mouse cortex when compared with sham mice.

[0293] These results indicate that NAL reduces the expression of several inflammatory markers. , thus indicating an overall reduction in neuroinflammation after TBI in mice.

[0294] (statistics) All data are presented as mean ± standard error of the mean (SEM). After that, appropriate post-hoc tests (Tukey's test) were performed as specified in the figure legends. For data with only two groups, a two-sample Student's t-test with equal variances was used. A p-value of ≤0.05 was considered statistically significant.

[0295] Example 3 (EAL flux in NPC mice) Amyloid-β deposition and accumulation of autophagic vacuoles are key drivers of Alzheimer's disease (AD) pathology. The biological characteristics of endosomal endothelial cells are as follows: Dysregulation of the endophagy-lysosome (EAL) pathway is one of the early changes in AD. Xu and Ren Annu Rev Physiol. 77:57-80 (2015). Lysosomal storage diseases such as NPC are also caused by dystrophic encephalomyelitis. The neurotrophic neurites, ectopic dendrites, neurofibrillary tangles, and amyloid aggregates seen in AD The autophagy dysfunction is accompanied by pathological changes reminiscent of the characteristic features. Journal of Biological Chemistry 285: 37415-37426 (2010).

[0296] ADLL, ALL, ADL, DLL, LL, and DL in attenuating impaired EAL flux in NPC1 mice The efficacy of acetyl DL-leucine (ADLL) and ethyl ester of L-leucine was investigated. LLE restores autophagic flux by reducing LC3-II levels However, the LC3-II levels induced by ADLL and LLE were not significantly increased in the control group (Fig. 14). The decrease in APP-CTFs was not accompanied by a concomitant decrease in APP-CTFs, particularly CTF-6 and -7 (Figure 15). While not wishing to be bound by theory, ADL and LLE probably act by activating mTOR Autophagy vacuoles constructed by inhibiting autophagosome formation through C1 Despite its ability to reduce AV accumulation, it may have been a The inability of ADL and LLE to reduce elevated levels of P-CTFs suggests that ADL and LLE inhibit lysosomal digestion. Surprisingly, L-leucine did not improve the performance of NPC1 mice. In addition, acetyl L-leucine (ALL), acetyl L-leucine (ACE), and acetyl L-leucine (ACE) reduced CTF-6 accumulation in the pulmonary arteries (Figure 16). D-leucine (ADL) and L-leucine (LL) down-regulate CTF-7 expression and lysosomal protein The effect of NF-κB on CTF-7 clearance in NPC1 mice was slightly improved (Figure 17). The positive effects of Cetyl D-Leucine, Acetyl L-Leucine, and D-Leucine are , endosome-lysosome clearance without affecting autophagosome-lysosome clearance This suggests that it may promote lysosomal fusion.

[0297] Example 4 (Lysosomal fusion in primary cortical neurons) Neurons contain a heterogeneous population of organelles belonging to the EAL pathway, extending from the cell body to distal neurites. These are autophagosomes, endosomes, and amphisomes ( U18666A contains the NPC1 protein. By inhibiting endosome-lysosome fusion, NPC1-like expression in cells was suppressed. U18666A-mediated autophagosome-lysosome fusion and endophagocytosis Inhibition of endothelial-lysosome fusion leads to an increase in LC3-II and APP-CTF-1-5, whereas , which blocks the production of CTF-6 and -7. Boland et al., The Journal of Biological Chemistry 285: 37415-37426(2010).

[0298] U18666A-mediated autophagosome-lysosome fusion and endosomal lysosome We investigated the efficacy of ADLL, ALL, ADL, DLL, LL, DL, and LLE in alleviating the impairment of endothelial fusion. In this cell-based assay of EAL flux impairment, basal levels of APP CTF-6 and -7 were The reappearance of Bell provided indications of enhanced endosome-lysosome fusion.

[0299] Primary rat cortical neurons (DIV14) treated with U18666A (2 μg / mL, 24 h) upregulated CTF-6 and and 7 were completely absent (Figure 18). Treatment with U18666A for 24 hours induced an increase in LC3-II accumulation. No (Figure 18).

[0300] Neurons were treated with U1866 along with ADLL, ALL, ADL, DLL, LL, DL, and LLE (1 mM, 24 hours). The reappearance of basal levels of CTF-6 and -7 in these cells was evident. Apparently, all co-treated neuronal cultures showed no endosome-lysosome fusion. ADLL, ALL, and ADL showed signs of increased LC3-II levels above basal levels (Figure 18). This indicates that these three compounds significantly reduced the autoimmune responses in primary cortical neurons. Enhancement of both thophagosome-lysosome fusion and endosome-lysosome fusion This suggests that...

[0301] Example 5 (Truncated tau in neuron-glia co-cultures) ADLL, ALL, in reducing truncated tau levels in neuron-glia (NG) cultures The effectiveness of ADL, DLL, LL, DL, and LLE was examined. The results of this study are provided in Figures 20-24. One purpose of this study is to determine whether ADLL, ALL, ADL, DLL, LL, DL, and LLE are cytopathic. Do they confer endogenous neuroprotection by sustaining neuronal function under conditions of proliferation? We will determine whether they act indirectly through non-autonomous regulation of glial cells. The aim of the study was to determine whether these compounds act directly or indirectly on neurons. By preventing the production of truncated forms of tau, whether they act directly or indirectly, the researchers hope to improve the integrity of neurons. Beneficial effects on sexuality are conferred.

[0302] Cultures were treated with 1 mM ADLL, ALL, ADL, DLL, LL, DL, or LLE for 5 days (DIV 9-14). , and then several neuron-specific Target markers: βIII-tubulin, full-length tau, truncated tau (antibody 5E2), and synaptophysin Consistent detection across untreated (control) and drug-treated samples was assessed. As evidenced by equivalent levels of synaptophysin and βIII-tubulin in ALL, ADL, DLL, LL, DL, and LLE were well tolerated in NE and NG cultures (Figure 2 0, 23, and 24). ADLL, ALL, ADL, DLL, LL, DL, and LLE were all derived from NG cultures at DIV14. These findings suggest that tau suppression by tau suppression did not reduce basal levels of truncated tau in mice (Figures 20 and 22). ADLL, ALL, ADL, DLL, LL, DL, and LLE are involved in the accumulation of substrates in the EAL network. It has been suggested that it may be particularly useful in treating degenerative conditions.

[0303] Example 6 (Lysosomal volume measured by flow cytometry) Wild-type and NPC1 null Chinese hamster ovary (CHO) cells were grown in T75 culture flasks. Before extraction, N-acetyl-L-leucine (ALL), L-leucine ethyl ester hydrochloride (LEE) The cells were treated with trypsin, ethanol, or L-leucine (1 or 5 mM, purchased from Sigma-Aldrich) for 7 days. The cells were treated with PBS, centrifuged (270 × g, 5 min), washed twice with 1 × PBS, centrifuged again, and diluted with 100 mL of PBS. The cells were stained with 20 nM LysoTracker-green DND-26 (Invitrogen) at room temperature for 20 minutes. After centrifugation, the cells were centrifuged (800 × g, 5 min) and diluted with 0.5 ml of FACS buffer (0.1% BSA in 1 × PBS). , 0.02M NaN3) and analyzed by flow cytometry (BD Biosciences FACSCanto II or Accuri C6 Plus) were kept on ice. Cytometer Setup and Tracking The cytometer was calibrated using BD FACSDiva beads and run prior to the assay. Lysotracker or iodine probes were analyzed using BD software or BD Accuri C6 Plus software (BD). Correction was performed using cells stained with pygm. Experiments and analysis were performed using 10,000 recorded cells. The median values ​​were obtained for further statistical analysis. The results are shown in Figures 25-27. There are.

[0304] Example 7 (Purkinje cell survival) Npc1- / - mice exhibit cerebellar pull syndrome that progresses from the anterior to the posterior lobes, accompanied by microglial activation. The mice showed progressive neurodegeneration accompanied by loss of kinje cells (Figure 46). ADLL treatment significantly increased the number of Npc1- / - mice compared to untreated Npc1- / - littermates. Prolonged Purkinje cell survival at 59 days of age compared to offspring: 133% more Purkinje cells in lobule I and II (p = 0.0027), and 402% more Purkinje cells were present in lobule III (p = 0.0108). No other treatments improved Purkinje cell survival in any of the cerebellar lobules (Npc1- Compared with / -UT, Npc1- / - ALL lobules I-II p=0.107, lobules III p=0.157, lobules IV-V p=0.53 3; Npc1- / -ADL Lobules I-II p=0.60, Lobules III p=0.11, Lobules IV-V p=0.766) (Figures 46 and 47). Furthermore, ALL treatment reduced the frequency of CD68-positive activated microglia (20%, p=0.0177). Other treatments had no effect (p=0.1 for Npc1- / -ADLL compared to Npc1- / -UT). 353, p=0.0553 for Npc1- / - ADL) (Figures 46 and 48). ADL mediates long-term neuroprotective effects. The combination of increased neuronal survival and reduced inflammatory environment in the brain was not shown to be associated with any clinical benefit in human subjects. It was possible to improve brain function and quality of life in the setting of cardiovascular disease and slow the progression of the disease.

[0305] Example 8 (Controlled Cortical Impact Model) Mice were subjected to moderate controlled cortical impact TBI or sham surgery. After initial postoperative recovery, The administration of the mice was started (by oral gavage, daily for 4 days) and continued for the duration of the experiment (in the diet, fed ad libitum). Preparative: NAL mice were treated with oral NAL. Vehicle mice received the same gavage vehicle. After administration of le, they were fed with standard chow. Groups: Sham + Vehicle = 5 mice: Sham + NAL = 4 mice; TBI+vehicle = 10 mice; and TBA+NAL = 9 mice. Functional outcomes were analyzed by beamwalk. (motor function), Y-maze (spatial memory), and novel object recognition (NOR, non-spatial memory) were assessed 28 days after surgery. The results are provided in Figures 49, 50, and 51, respectively.

[0306] The foregoing embodiments and examples are not intended to be limiting in any respect as to the scope of the present disclosure. It is not intended, and the claims presented herein are not to be construed as limiting the scope of the invention as expressly presented herein. It should be understood that all embodiments and examples are encompassed, regardless of whether they are specifically described or not. It is.

[0307] All patents and publications cited herein are hereby fully incorporated by reference in their entirety. is incorporated into. The present application provides the following aspects of the invention. (Aspect 1) Treating or preventing a disease, disorder, illness, or syndrome in a subject in need thereof A method of treating a symptom of a disease, disorder, illness, or syndrome in a subject in need thereof. Acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl-D-leucine or a pharma- ceutical acceptable salt thereof; acetyl-L-leucine or a pharma- ceutical acceptable salt thereof; or a pharma- ceutical acceptable salt thereof, or a therapeutic agent comprising L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof. administering to the subject a therapeutically effective amount of any one or more of the diseases, disorders, illnesses, or syndromes provided in Table 1. How to write. (Aspect 2) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 2. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 3) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 3. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 4) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 4. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 5) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 5. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 6) The method of embodiment 5, wherein said disease, disorder, condition, or syndrome is traumatic brain injury. (Aspect 7) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 6. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 8) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 7. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 9) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 8. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 10) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 9. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 11) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 10. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 12) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 11. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 13) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 12. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 14) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 13. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 15) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 14. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 16) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 15. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 17) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 16. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 18) The disease, disorder, illness, or syndrome is a disease, disorder, illness, or syndrome provided in Table 17. The method of embodiment 1, wherein the compound is any one or more of the group: (Aspect 19) About 1 g to about 30 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl- D-leucine or a pharma- ceutical acceptable salt thereof, acetyl-L-leucine or a pharma- ceutical acceptable salt thereof A pharma- ceutically acceptable salt thereof, or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof The method according to any one of embodiments 1 to 18, wherein the salt is administered to the subject per day. (Aspect 20) About 2 g to about 15 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl- D-leucine or a pharma- ceutical acceptable salt thereof, acetyl-L-leucine or a pharma- ceutical acceptable salt thereof A pharma- ceutically acceptable salt thereof, or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof The method of embodiment 19, wherein the salt is administered to the subject per day. (Aspect 21) About 3 g to about 10 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl- D-leucine or a pharma- ceutical acceptable salt thereof, acetyl-L-leucine or a pharma- ceutical acceptable salt thereof A pharma- ceutically acceptable salt thereof, or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof The method of embodiment 20, wherein the salt is administered to the subject per day. (Aspect 22) About 4 g to about 8 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl-D -Leucine or a pharma- ceutically acceptable salt thereof, or acetyl-L-leucine or a pharma- ceutically acceptable salt thereof A pharma- ceutically acceptable salt thereof, or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof The method of embodiment 21, wherein the salt is administered to the subject per day. (Aspect 23) About 4 g to about 5 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl-D -Leucine or a pharma- ceutically acceptable salt thereof, acetyl-L-leucine or a pharma- ceutically acceptable salt thereof or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof. The method of embodiment 22, wherein the salt is administered to the subject per day. (Aspect 24) Approximately 5 g of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl-D-leucine acetyl-L-leucine or a pharma- ceutically acceptable salt thereof; or L-leucine ethyl ester or a pharma- ceutically acceptable salt thereof. The method of embodiment 23, wherein the compound is administered to the subject per day. (Aspect 25) A therapeutically effective amount of L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof is administered to the subject. The method of any one of embodiments 1 to 24, wherein the (Aspect 26) A therapeutically effective amount of L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases. 26. The method of embodiment 25, wherein the compound is administered to the subject to treat a disorder, disease, or syndrome. (Aspect 27) A therapeutically effective amount of L-leucine ethyl ester or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases. 26. The method of claim 25, wherein the compound is administered to the subject to treat a symptom of a disorder, disease, or syndrome. method. (Aspect 28) A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to the subject. The method according to any one of embodiments 1 to 24, (Aspect 29) A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. The method of embodiment 28, wherein the compound is administered to the subject to treat an injury, disease, or syndrome. (Aspect 30) A therapeutically effective amount of acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. The method of embodiment 28, wherein the compound is administered to the subject to treat an injury, disease, or syndrome. (Aspect 31) A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutically acceptable salt thereof is administered to the subject. The method according to any one of embodiments 1 to 24, (Aspect 32) A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. The method of embodiment 31, wherein the compound is administered to the subject to treat an injury, disease, or syndrome. (Aspect 33) A therapeutically effective amount of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. 32. The method of claim 31, wherein the compound is administered to the subject to treat a symptom of the injury, disease, or syndrome. . (Aspect 34) A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to the subject. The method according to any one of embodiments 1 to 24, (Aspect 35) A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. The method of embodiment 34, wherein the compound is administered to the subject to treat an injury, disease, or syndrome. (Aspect 36) A therapeutically effective amount of acetyl-D-leucine or a pharma- ceutical acceptable salt thereof is administered to treat the above-mentioned diseases, disorders, and the like. 35. The method of claim 34, wherein the compound is administered to the subject to treat a symptom of the injury, disease, or syndrome. . (Aspect 37) The present invention relates to a method for determining the expression of one or more proinflammatory mediators in a subject in need thereof. The method for isolating acetyl-DL-leucine or a pharma- ceutical acceptable salt thereof, acetyl-D-leucine or a pharma- ceutical acceptable salt thereof, or acetyl-L-leucine or comprising administering to said subject a therapeutically effective amount of a pharma- ceutical acceptable salt thereof. (Aspect 38) The one or more proinflammatory mediators are NOS2, IL-18, IFNb, IL-1β, TNFα, NOX2, N The method of embodiment 37, wherein the gene is LRP3, SOCS3, ARG1, IL-10, IL-4ra, or YM1.

Claims

1. In treating a traumatic brain injury in a subject or treating symptoms of a traumatic brain injury in a subject COMPOSITION COMPRISING ACETYL-L-LEUCINE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF FOR USE - Patent application thing.

2. About 1 g to about 30 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered. The pharmaceutical composition according to claim 1, which is used for administration to a subject.

3. About 2 g to about 15 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered. The pharmaceutical composition according to claim 2, which is used for administration to a subject.

4. About 3 g to about 10 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered. The pharmaceutical composition according to claim 3, which is administered to a subject.

5. About 4 g to about 8 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered. The pharmaceutical composition according to claim 4, which is used for administration to a subject.

6. About 4 g to about 5 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered. The pharmaceutical composition according to claim 5, which is used for administration to a subject.

7. Approximately 5 g of acetyl-L-leucine or a pharma- ceutical acceptable salt thereof per day is administered to the subject. The pharmaceutical composition according to claim 6, which is used for administration.

8. A pharmaceutical composition according to any one of claims 1 to 7 for use in the treatment of traumatic brain injury. Composition.

9. A composition according to any one of claims 1 to 7 for use in the treatment of symptoms of traumatic brain injury. Pharmaceutical compositions.

10. Reduce the expression of one or more pro-inflammatory mediators in subjects with traumatic brain injury 2. The method of claim 1, wherein the acetylglucosamine salt is acetylglucosamine or a pharma- ceutical acceptable salt thereof .... wherein the one or more proinflammatory mediators are IFNb, IL-1β, NOX2 and / or ARG1.

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