Human aminosterol ENT-03 compound, related compositions containing same, and methods of using same

Abstract

The present invention relates generally to novel aminosterol compounds, compositions containing same, and methods of making and using the novel aminosterol compounds and compositions.

Description

[Technical Field]

[0001] This application claims the benefit of priority under 35 U.S.C. § 119 to U.S. Provisional Application No. 62 / 882,358, filed August 2, 2019, and U.S. Provisional Application No. 63 / 041,031, filed June 18, 2020, the entire contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION This application relates generally to aminosterol compounds for the treatment of human diseases. [Background technology]

[0003] Aminosterols are amino derivatives of sterols. Squalamine is the most abundant member of the large aminosterol family, which includes at least 12 related compounds (Rao et al., 2000).

[0004] [ka]

[0005] The discovery of squalamine (the structure of which is shown above) was reported by Michael Zasloff in 1993 (US Pat. No. 5,192,756).

[0006] Exemplary aminosterols also include ENT-02, trodusquemine, and MSI1436, also known as aminosterol 1436. These aminosterols (U.S. Patent No. 5,192,756) exhibit diverse pharmacological activities in mammalian systems. Aminosterol 1436 causes weight loss and adipose tissue mobilization in vertebrates (Zasloff et al., 2001).

[0007] [ka]

[0008] Aminosterol 1436 acts within hypothalamic nuclei involved in appetite and energy balance and has been shown to reverse insulin resistance in both diet-induced and genetic models in mice and rats. The compound has been shown to inhibit PTP1B, a phosphatase that turns off activated insulin receptors, with in vivo evidence of its activity against hypothalamic insulin receptors. Phase 1 human clinical trials using intravenous administration of aminosterol 1436 in obese subjects demonstrated improvement in insulin sensitivity.

[0009] Recognizing that aminosterol 1436 exhibits PTP1B inhibition in vivo, numerous studies have been conducted, including amelioration of metabolic syndrome in a mouse model of hypothalamic insulin resistance, reversal of atherosclerosis in LDL receptor knockout mice, suppression of malignant tumor growth, promotion of tail and myocardial regeneration in zebrafish, stem cell mobilization for regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice, reduction of stress-induced anxiety in mice by targeting mGluR5 receptors in the limbic system, behavioral reversal and prevention of neuronal loss in Alzheimer's disease models via a neuronal PTP1B-dependent mechanism, reduction of in vitro toxicity of β-amyloid aggregates in a C. elegans model of Alzheimer's disease (Limbocker et al., 2019), and reduction of toxic α-synuclein aggregate formation and lifespan extension in a C. elegans model of Parkinson's disease (Perni et al., 2018).

[0010] Several clinical trials have been conducted regarding the use of aminosterol 1436, including: (1) ClinicalTrials.gov Identifier NCT00509132, "A Phase I, Double-Blind, Randomized, Placebo-Controlled, Ascending Intravenous Single-Dose Tolerance and Pharmacokinetic Study of Trodusquemine in Healthy Volunteers," by Genera Corp.; (2) ClinicalTrials.gov Identifier NCT00606112, "A Single-Dose, Tolerability and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteers," by Genera Corp.; (3) ClinicalTrials.gov Identifier NCT00806338, "A Multiple-Ascending Dose, Tolerability and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteers," by Genera Corp.; and (4) ClinicalTrials.gov NCT00806338, "A Multiple-Ascending Dose, Tolerability and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteers," by DepEd Med. "Safety and Tolerability of MSI1436C in Metastatic Breast Cancer" by Inc.

[0011] There is a need in the art for novel aminosterol compounds and methods of their use. The present disclosure fulfills these needs. Summary of the Invention

[0012] In one aspect, aminosterol compounds are provided having the formula:

[0013] [ka]

[0014] In the formula, R 1 is H or D, and R 2 is H or D, but all R 1 is H and all R 2 is H, or all R 1 and R 2 is H, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0015] In one embodiment, the aminosterol compound has the formula:

[0016] [ka]

[0017] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0018] In one embodiment, the aminosterol has the formula:

[0019] [ka]

[0020] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0021] In one embodiment, the aminosterol has the formula:

[0022] [ka]

[0023] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0024] In one embodiment, the aminosterol has the formula:

[0025] [ka]

[0026] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0027] In another aspect, an aminosterol compound having the formula:

[0028] [ka]

[0029] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof is provided.

[0030] In one embodiment, the aminosterol compound has the formula:

[0031] [ka]

[0032] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0033] In one aspect, an aminosterol compound having the formula:

[0034] [ka]

[0035] Pharmaceutically acceptable salts, solvates, prodrugs, or derivatives are provided.

[0036] In one embodiment, the aminosterol compound has the formula:

[0037] [ka]

[0038] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0039] In another aspect, an aminosterol compound having the formula:

[0040] [ka]

[0041] In the formula, R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C-C aryl, optionally substituted C-C alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, and optionally substituted C-C alkenyl; and R 2 is H or -C(O)R 3 where R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C-C alkyl, optionally substituted C-C alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, or optionally substituted C-C alkenyl, with the proviso that R 1 and R 2 At least one of is not H; or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof; is provided.

[0042] In one embodiment, the aminosterol compound has the formula:

[0043] [ka]

[0044] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0045] In another aspect, an aminosterol compound having the formula:

[0046] [ka]

[0047] In the formula, R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C-C aryl, optionally substituted C-C alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, or optionally substituted C-C alkenyl; and R 2 is H or -C(O)R 3 where R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C-C alkyl, optionally substituted C-C alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, or optionally substituted C-C alkenyl, with the proviso that R 1 and R 2 at least one of which is not H; or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof; is provided.

[0048] In some embodiments, the aminosterol has the formula:

[0049] [ka]

[0050] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0051] In another aspect, an aminosterol compound having the formula:

[0052] [ka]

[0053] is provided. In the formula, R 1is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C-C alkyl, optionally substituted C-C alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, and optionally substituted C-C alkenyl; and R 2 is H or -C(O)R 3 and R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 1 alkynyl, optionally substituted heterocyclyl, optionally substituted C-C cycloalkyl, or optionally substituted C-C alkenyl; provided that R 1 and R 2 At least one of is not H; or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0054] In one embodiment, the aminosterol compound has the formula:

[0055] [ka]

[0056] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0057] In some embodiments, the aminosterol is formulated as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a phosphate salt.

[0058] In one aspect, a composition comprising an aminosterol compound according to any of the embodiments herein is provided, wherein the composition comprises at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises one or more of (a) an aqueous carrier, (b) a buffer, (c) a sugar, and / or (d) a polyol compound. In some embodiments, the composition comprises at least one additional active agent.

[0059] In some embodiments, the composition is administered via (a) oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, spray, inhalation, ophthalmic, otic, topical, buccal, nasal, and topical routes. (for external use) (b) into a dosage form selected from the group consisting of a liquid dispersion, a gel, an aerosol, an ointment, a cream, a lyophilized formulation, a tablet, and a capsule; and (c) into a dosage form selected from the group consisting of a liquid dispersion, a gel, an aerosol, an ointment, a cream, a lyophilized formulation, a tablet, and a capsule. Controlled-release formulations , fast melt formulations, delayed release formulations, sustained release sex formulations, pulsatile release formulations, and Mixing immediate-release and controlled-release formulations or (d) any combination of (a), (b), and (c).

[0060] In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated as an oral tablet or capsule. In some embodiments, the composition is formulated for intranasal administration.

[0061] In one aspect, a method of treating a subject in need thereof is provided, wherein the subject has a condition amenable to treatment with an aminosterol, the method comprising administering to the subject a composition according to any embodiment herein. In some embodiments, the condition is correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

[0062] In another aspect, there is provided a method of treating, preventing, and / or delaying the onset or progression of a condition or disorder correlated with aberrant alpha-synuclein pathology and / or dopaminergic dysfunction, or associated symptoms, in a subject in need thereof, comprising administering a therapeutically effective amount of a composition according to any embodiment herein.

[0063] In some embodiments, (a) the symptom is selected from the group consisting of constipation, hallucinations, cognitive impairment, and inflammation; and (b) the symptom is Synucleinopathy , a neurodegenerative disease, a neurological disease or disorder, a psychological and / or behavioral disorder, or a cerebral or systemic ischemic disorder or condition; and (c) the condition or disorder is Synucleinopathy (d) the condition or disorder is a psychological and / or behavioral disorder; or (e) the condition or disorder is a cerebral or systemic ischemic disorder or condition.

[0064] In some embodiments, (a) Synucleinopathy , neurodegenerative diseases, or neurological diseases or disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, multiple system atrophy, dementia with Lewy bodies, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich's ataxia, Vascular dementia, spinal muscular atrophy, (b) the psychological or behavioral disorder is selected from the group consisting of supranuclear palsy, progressive nuclear palsy, frontotemporal dementia, progressive nuclear palsy, Guadroitin Parkinsonism, spinocerebellar ataxia, parkinsonism, traumatic brain injury, age-related degenerative processes, and dementia of senility; autism spectrum disorders, Down's syndrome, Gaucher's disease, Krabbe's disease, lysosomal conditions affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delusions, memory loss, apathy, bipolar disorder, disinhibition, abnormal movements and obsessive-compulsive behaviors, addiction, cerebral palsy, epilepsy, major depressive disorder, REM sleep behavior disorder (RBD), sleep fragmentation, REM behavior disorder, circadian rhythm disorders, sleep apnea, and cognitive disorders; or (c) brain or whole body Ischemic damage of too Or the condition , slight Small vessel disease, intrapartum cerebral ischemia, During / after cardiac arrest or resuscitation cerebral ischemia, cerebral ischemia due to intraoperative problems, Cerebral ischemia during carotid artery surgery, brain fart Chronic cerebral ischemia caused by narrowing of the blood supply arteries cerebral sinus thrombosis or cerebral venous thrombosis, Cerebrovascular malformations, diabetic retinopathy, high cholesterol, myocardial infarction, Cardiac insufficiency, cardiac failure , congestive heart failure, myocarditis, pericarditis, Pericardial inflammation, Coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, malaria-associated thrombosis, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, Erectile dysfunction, cardiac conduction disorders, high blood pressure, low blood pressure, pulmonary edema.

[0065] In another aspect, there is provided a method of treating, preventing, and / or delaying the onset or progression of cerebral or systemic ischemic damage and / or associated symptoms correlated with aberrant alpha-synuclein pathology and / or dopaminergic dysfunction in a subject in need thereof, comprising administering a therapeutically effective amount of a composition according to any embodiment herein.

[0066] In one embodiment, the brain or whole body Ischemic disorders and / or related conditions include microangiopathy, intrapartum cerebral ischemia, cerebral ischemia during / after cardiac arrest or cardiac resuscitation, cerebral ischemia due to intraoperative problems, Cerebral ischemia during carotid artery surgery, brain fart Chronic cerebral ischemia caused by narrowing of the blood supply arteries cerebral sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, high blood pressure, low blood pressure, High cholesterol, myocardial infarction, Cardiac insufficiency, cardiac failure , congestive heart failure, myocarditis, pericarditis, Pericardial inflammation, Coronary heart disease, angina, congenital heart disease, Shock, limb ischemia, renal artery stenosis, diabetic retinopathy, malaria-associated thrombosis, artificial heart valves, anemia 、 hypersplenism syndrome, emphysema, The condition is selected from the group consisting of pulmonary fibrosis, erectile dysfunction, cardiac conduction disorders (CCD) and / or related conditions, and pulmonary edema.

[0067] In one aspect, a method of inhibiting a regulatory phosphatase (e.g., protein tyrosine phosphatase 1B (PTP1B)) in a subject is provided, comprising administering to the subject a therapeutically effective amount of a composition according to any embodiment herein. Other regulatory phosphatases inhibited by the aminosterols described herein are also detailed herein. In some embodiments, inhibition of one or more regulatory phosphatases is selected from about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, and about 90% to about 100%.

[0068] In another aspect, there is provided a method of inhibiting, preventing, and / or delaying the onset or progression of appetite or weight gain, and / or one or more associated symptoms, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition according to any embodiment herein.

[0069] In another aspect, there is provided a method of increasing gene transcription in the intestine of a subject, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any embodiment herein, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0070] In some embodiments, the increased gene transcription is related to caspase 14, collagen type XVII alpha 1, corneodesmosin, corniferin, cystatin E / M, delmokin, desmocollin 1, desmoglein 1 beta, filaggrin, gap junction protein beta 4, gap junction protein beta 6, H19 imprinted maternally expressed transcript, hornerin, kallikrein-related-peptidase 7 chymotryptic stratum, keratin 1, keratin 10, keratinocyte differentiation-associated protein, proline-rich keratinocyte, late cornified envelope 1A1, late cornified envelope 1A2, late cornified envelope 1B, late cornified envelope 1C , Late keratinizing envelope 1E, Late keratinizing envelope 1F, Late keratinizing envelope 1G, Late keratinizing envelope 1H, late keratinization envelope 1I, late keratinized envelope 1J, late Keratinization Envelope 1L, late model Keratinization Envelope 1M, late Keratinization Envelope 3C, late model Keratinization Envelope 3E, late Keratinization Envelope 3F, galactose-binding soluble lectin 7, loricrin, Shierin, Myoglobin, myosin bond Joint Project Protein C slow type, myosin heavy chain Polypeptide 1 skeletal muscle, myosin heavy chain Polypeptide 8 skeletal muscle , myosin light chain phosphorylable fast skeletal muscle , myosin light chain polypeptide 3, myozenin 1, myozenin 2, and titin cap.

[0071] In some embodiments, the method comprises detecting a protein selected from the group consisting of caspase 14, collagen type XVII alpha 1, corneodesmosin, corniferin, cystatin E / M, delmokin, desmocollin 1, desmoglein 1 beta, filaggrin, gap junction protein beta 4, gap junction protein beta 6, H19 imprinted maternally expressed transcript, hornerin, kallikrein-related-peptidase 7 chymotryptic stratum, keratin 1, keratin 10, keratinocyte differentiation-associated protein, proline-enriched keratinocyte, late cornified envelope 1A1, late cornified envelope 1A2, late cornified envelope 1B, late cornified envelope 1C, late cornified envelope 1E, late cornified envelope 1F, late cornified envelope 1G, late cornified envelope 1H, late keratinization envelope 1I, late keratinized envelope 1J, late Keratinization Envelope 1L, late model Keratinization Envelope 1M, late Keratinization Envelope 3C, late model Keratinization Envelope 3E, late Keratinization Envelope 3F, galactose-binding soluble lectin 7, loricrin, Shierin, Myoglobin, myosin-binding protein C slow type, myosin heavy chain Polypeptide 1 skeletal muscle, myosin heavy chain Polypeptide 8 skeletal muscle , myosin light chain phosphorylable fast skeletal muscle The method further comprises administering to the subject one or more non-aminosterol compounds that upregulate or downregulate one or more genes selected from myosin light chain polypeptide 3, myozenin 1, myozenin 2, and titin cap. The non-aminosterol compound may be any compound known in the art to regulate any of the aforementioned genes.

[0072] In some embodiments, the increase in gene transcription is between about 1% and about 10%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 50%, between about 50% and about 60%, between about 60% and about 70%, between about 70% and about 80%, between about 80% and about 90%, between about 90% and about 100%, between about 100% and about 125%, between about 125% and about 150%, between about 150% and about 175%, between about 180% and about 200%, between about 210% and about 225%, between about 230% and about 240%, between about 250% and about 260%, between about 260% and about 280%, between about 280% and about 300%, between about 310% and about 320%, between about 320% and about 330%, between about 330% and about 340%, between about 340% and about 350%, between about 350% and about 360%, between about 360% and about 370%, between about 370% and about 400%, between about 380% and about 410%, between about 380% and about 420%, between about 390% and about 430%, between about 440% and about 450%, between about 450% and about 460%, between about 460% and about 470%, between about 470% and about 480%, between about 480% and about 500%, between about 490% and about 510%, between about 510% and about 520%, between about 520% ​​and about 530%, between about The increase in gene transcription can be measured, for example, by qualitatively or quantitatively measuring the increase in expression of a protein that correlates with the transcription of the relevant gene, or by using a clinically validated scale or tool.

[0073] In one aspect, there is included a method for inhibiting one or more regulatory phosphatases to achieve a therapeutic or prophylactic benefit, comprising administering a therapeutically effective amount of an aminosterol compound or a composition comprising the same, as described herein.

[0074] In some embodiments, the method of administration comprises oral, nasal, pulmonary, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intraventricular, transdermal, or any combination thereof, hi some embodiments, the method of administration is nasal administration, oral administration, or a combination thereof.

[0075] In some embodiments, the therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof comprises: (a) about 0.1 to about 20 mg / kg body weight of the subject; (b) about 0.1 to about 15 mg / kg body weight of the subject; (c) about 0.1 to about 10 mg / kg body weight of the subject; (d) about 0.1 to about 5 mg / kg body weight of the subject; or (e) about 0.1 to about 2.5 mg / kg body weight of the subject.

[0076] In some embodiments, the therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof comprises: (a) about 0.001 to about 500 mg / day; (b) about 0.001 to about 250 mg / day; (c) about 0.001 to about 125 mg / day; (d) about 0.001 to about 50 mg / day; (e) about 0.001 to about 25 mg / day; (f) about 0.001 to about 10 mg / day; (g) about 0.001 to about 6 mg / day; (h) about 0.001 to about 4 mg / day; or (i) about 0.001 to about 2 mg / day.

[0077] In some embodiments, the method of administration comprises oral administration, and the therapeutically effective amount of the aminosterol compound, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, comprises: (a) about 1 to about 300 mg / day; or (b) about 25 to about 500 mg / day.

[0078] In some embodiments, the aminosterol compound or its pharmaceutically acceptable salt, solvate, prodrug or derivative is administered in combination with at least one additional active agent to achieve either additive or synergistic effects. In some embodiments, the additional active agent is administered via a method selected from the group consisting of: (a) concomitantly; (b) as a mixture; (c) separately and simultaneously or concurrently; and (d) separately and sequentially. In some embodiments, the additional active agent is a second aminosterol having a different structure from the aminosterol administered in any of the embodiments herein.

[0079] In some embodiments, administering the composition comprises administering onto an empty stomach, optionally within 2 hours of the subject waking up, hi certain embodiments, no food is consumed by the subject for about 60 to about 90 minutes after administering the composition.

[0080] In some embodiments, the aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, is of pharmaceutically acceptable grade. In some embodiments, a phosphate salt of the aminosterol is administered. In some embodiments, the subject is a human.

[0081] In some embodiments, the method further comprises (a) determining a dose of an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, or derivative for the subject, wherein the aminosterol dose is determined based on the effectiveness of the aminosterol dose in improving or eliminating the symptom being evaluated; and (b) subsequently: constant administering to a subject a composition comprising a dose of an aminosterol for a period of time comprising: (i) identifying a condition to be evaluated; (ii) identifying a starting dose of the aminosterol for the subject; and (iii) identifying an effective dose for the condition being evaluated. , constant administering incremental doses of an aminosterol to the subject over a period of time, where an effective dose is the aminosterol dose at which symptomatic improvement or resolution is observed, and fixing the aminosterol dose at that level for that particular symptom in that particular subject. In some embodiments, symptomatic improvement or resolution is measured using a clinically validated scale or tool.

[0082] In some embodiments, the composition is administered orally, and (a) the starting aminosterol dosage ranges from about 10 mg to about 150 mg / day; (b) the aminosterol dosage for the subject after titration is fixed in the range of about 25 mg to about 500 mg / day; and / or (c) the aminosterol, or salt or derivative thereof, dosage is titrated in increments of about 25 mg.

[0083] In some embodiments, the composition is administered intranasally, and (a) the starting aminosterol dosage ranges from about 0.001 mg to about 3 mg / day; (b) the aminosterol dosage for the subject after titration is fixed in the range of about 0.001 mg to about 6 mg / day; and (c) the aminosterol dosage for the subject after titration is a subtherapeutic dosage when given orally or by injection; and / or (c) the dosage of the aminosterol is titrated in increments of about 0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 mg.

[0084] In some embodiments, the aminosterol dosage is titrated up every about 3 to about 5 days. In some embodiments, the starting aminosterol dosage is higher if the symptoms being evaluated are severe.

[0085] In some embodiments, the symptoms are correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction. In some embodiments, the symptoms to be evaluated include (a) cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, characteristic of dopamine dysregulation syndrome; sleep disorders, (b) at least one non-motor aspect of daily living experience as defined by Part I of the Unified Parkinson's Disease Rating Scale selected from the group consisting of daytime sleepiness, pain, urinary problems, constipation problems, orthostatic dizziness, and fatigue; (b) speech, saliva and drooling, feeding and swallowing tasks; meal, Dressing, hygiene, handwriting, turning over, tremors, bed , car, or getting out of a deep chair , gait and balance 、 and at least one motor aspect of daily living experience as defined by Part II of the Unified Parkinson's Disease Rating Scale selected from the group consisting of: speech, facial expression, rigidity, Finger tapping, hand movements, Hand pronation - Supination, toe tapping, foot agility, chair lift Standing up, gait, freezing of gait, postural stability, posture, slowness of body movements, postural tremor in the hands, Motor tremors in the hands, at least one motor symptom identified on Part III of the Unified Parkinson's Disease Rating Scale selected from the group consisting of rest tremor, and rest tremor permanence; (d) time spent with movement disorder, functional impact of movement disorder, time spent in off-state, functional impact of motor fluctuations, complexity of motor fluctuations, and Painful off-state dystonia At least one motor activity identified in Part IV of the Unified Parkinson's Disease Rating Scale selected from the group consisting of complications (e) constipation, (f) depression, (g) cognitive impairment, (h) sleep disturbances, sleep problems (i) circadian rhythm dysfunction, (j) hallucinations, (k) fatigue, (l) REM sleep disorder, (m) REM behavior disorder, (n) erectile dysfunction, (o) apnea, (p) postural hypotension, (q) correction of blood pressure or orthostatic hypotension, (r) nocturnal hypertension, (s) regulation of body temperature, (t) improvement of breathing or apnea, (u) correction of cardiac conduction defects, (v) improvement of pain, (w) restoration of bladder sensation and voiding, (x) urinary incontinence, and / or (y) control of nocturia.

[0086] In some embodiments, the symptom being evaluated is constipation, characterized by: (a) a fixed, titrated aminosterol dose for constipation is defined as an aminosterol dose that results in complete spontaneous bowel movements (CSBM) within 24 hours of administration on at least two out of three days at a given dose; (b) if the average complete spontaneous bowel movements (CSBM) or average spontaneous bowel movements (SBM) is greater than or equal to one per week, the starting aminosterol dose before escalation is 75 mg / day; and / or (c) if the average CSBM or SBM is less than one per week, the starting aminosterol dose before escalation is 150 mg / day.

[0087] In one aspect, an aminosterol of the formula:

[0088] [ka]

[0089] is provided, which method stimulates the addition of spermine to compound Ia.

[0090] [ka]

[0091] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0092] In another aspect, an aminosterol of the formula

[0093] [ka]

[0094] is provided, which method comprises inhibiting the addition of spermine to compound Ia.

[0095] [ka]

[0096] In some embodiments, (a) the addition of spermine to Compound Ia is inhibited in vivo in a subject; or (b) the addition of spermine to Compound Ia is inhibited in vitro.

[0097] In some embodiments, compound Ia has the formula:

[0098] [ka]

[0099] and ENT-03 (Compound III) has the formula:

[0100] [ka]

[0101] In another aspect, a method for producing an aminosterol of the formula:

[0102] [ka]

[0103] is provided, the method comprising stimulating the addition of spermine to compound Ia.

[0104] [ka]

[0105] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0106] In another aspect, an aminosterol of the formula

[0107] [ka]

[0108] is provided a method of inhibiting the formation of the compound Ia, the method comprising inhibiting the addition of spermine to compound Ia.

[0109] [ka]

[0110] In some embodiments, (a) the addition of spermine to Compound Ia is inhibited in vivo in a subject; or (b) the addition of spermine to Compound Ia is inhibited in vitro.

[0111] In some embodiments, compound Ia has the formula:

[0112] [ka]

[0113] Compound IV has the formula:

[0114] [ka]

[0115] In another aspect, an aminosterol of the formula

[0116] [ka]

[0117] The method comprises stimulating the addition of spermine to compound Ia.

[0118] [ka]

[0119] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0120] In another aspect, an aminosterol of the formula

[0121] [ka]

[0122] is provided a method of inhibiting the formation of the compound Ia, the method comprising inhibiting the addition of spermine to compound Ia.

[0123] [ka]

[0124] In some embodiments, (a) the addition of spermine to Compound Ia is inhibited in vivo in a subject; or (b) the addition of spermine to Compound Ia is inhibited in vitro.

[0125] In some embodiments, compound Ia has the formula:

[0126] [ka]

[0127] Compound V has the formula:

[0128] [ka]

[0129] The foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the present disclosure and are not to be construed as limiting. Other objects, advantages, and novel features will become readily apparent to those skilled in the art from the following detailed description of the present disclosure. [Brief explanation of the drawings]

[0130] [Figure 1] Figures 1A and 1B show the percent weight loss over time in mice treated with ENT-02 (MSI1436) (circles) or ENT-03 (compound III; squares). Figure 1C shows that intraperitoneal administration of ENT-03 once weekly for 6 weeks resulted in dose-dependent weight loss in C57bl / 6 male mice. [Figure 2]

[0023] Figure 1 shows the results of administering ENT-03 (Compound III) and ENT-02 (MSI1436) to growing mice. While both compounds affected weight gain, ENT-02 had a more profound effect, suppressing growth and inducing body fat consumption. In contrast, animals treated with ENT-03 continued to grow normally, but they "slimmed down," suggesting that ENT-03 reestablished a new optimal weight "set point." [Figure 3] FIG. 3B shows images of the mucosal layer of a stomach showing a reduction in the mucosal layer in a 78-week-old stomach (FIG. 3B) versus a younger 20-week-old stomach (FIG. 3A). [Figure 4] 4A and 4B show IC50 curves for PTP1B inhibition by three aminosterols tested according to Example 1: ENT-02 (MSI1436), ENT-03 (Compound III), and D-1436 (FIG. 4A); and a control PTP1B inhibitor (FIG. 4B). [Figure 5] FIG. 5 shows that PTP1B inhibition with ENT-03 ameliorates cognitive impairment in hAPP-J20 (FIGS. 5A-5D) and PS19 (FIGS. 5E-5H) mice. [Figure 6] Volcano plots showing the magnitude (log2-transformed fold change) versus significance (as negative log10-transformed FDR-adjusted p-values) of differentially expressed genes in three contrasts: (Figure 6A) Aged mice compared to young mice; (Figure 6C) ENT-03-treated aged mice compared to vehicle-treated aged mice; (Figure 6B) ENT-03-treated young mice compared to vehicle-treated young mice. Genes identified as having different levels between groups are represented as red (upregulated) or blue (downregulated) dots, while non-significant genes are represented as black dots. The horizontal red line represents the applied p-value threshold. [Figure 7] 7A and 7B show chromatograms for LC / MS / MS analysis of brain extracts from elderly humans for ENT-03, where Figure 7A is a chromatogram of the brain extract and Figure 7B is a quality control sample of synthetic ENT-03. [Figure 8]8A and 8B show chromatograms for LC / MS / MS analysis of mouse pup brain extracts (FIG. 8A) and liver extracts (FIG. 8B). [Figure 9] FIG. 1 shows the approximate concentrations of ENT-03 measured in the brain and liver of neonatal mice over the first 3 weeks of life. [Figure 10] 10A-10D) or ileum (FIGS. 10D-10F) gene expression profiles of young and old mice treated with ENT-03 or control. [Figure 11] Figure 11 shows a series of heatmaps examining the overlap of differentially expressed genes between pairwise contrasts. The values ​​in the plots represent the number of cross-expressed genes (adjusted p-value < 0.05) between a particular pairwise contrast. The color of the boxes represents the Jaccard index (an index of gene crossover and linkage) and represents the contrast along the x- and y-axes. (Figure 11A) Differentially expressed genes in both directions; (Figure 11B) Up-regulated genes; (Figure 11C) Down-regulated genes; (Figure 11D) Up-regulated genes in one contrast and Down-regulated genes in the other contrast. Note that the numbers in the gray boxes represent the total number of selected differentially expressed genes for a particular contrast. [Figure 12] FIG. 1 shows the results regarding weight gain in mice after administration of ENT-03 compared to administration of the deuterated form of ENT-03, ENT-03D3. [Figure 13] Representative chromatograms of ENT-03 in 4-day-old mouse brain extracts. Figure 13A: MRM 619.6 / 545.5, top trace: endogenous ENT-03 in extract; MRM 623.6 / 549.5, bottom trace: extract + 2.2ng ENT-03-d4 / g brain tissue; Figure 13B: MRM 619.6 / 474.5, top trace: endogenous ENT-03 in extract; MRM 623.6 / 478.5, bottom trace: extract + 2.2ng ENT-03-d4 / g brain tissue. [Figure 14] 1 is a graph showing the weight loss results of male C57bl6 / j (N=5 / group) mice administered various doses of ENT-03 or vehicle by oral gavage every 3 days. [Figure 15] Venn diagram of transcripts downregulated in aging and upregulated in ENT-03. Plot showing the number of overlapping and non-overlapping differentially expressed genes between the two sets of transcripts downregulated in old versus young mice and upregulated with treatment compared to control. Number of features is shown from treatment with ENT-02 (MSI1436) and ENT-03. [Figure 16] Scatter plot of significant genes in ENT-02 (MSI1436) vs. control (young) compared with ENT-03 vs. untreated (young). Genes are represented by dots. The color of the dots indicates which set the gene is assigned to. For each gene, the log2(fold change) of ENT-02 (MSI1436) vs. control (young) contrast (y-axis) and the log2(fold change) of ENT-03 vs. untreated (young) contrast (x-axis) are shown. [Figure 17] Figure 12 shows the significant gene upset plot from Example 12. Plot showing the interactions between sets of up-regulated and down-regulated genes. The leftmost bar shows the size of each set used as input. The top bar shows the exclusive size of each set (i.e., each gene is counted only once in this bar). The central dot plot shows the interacting sets in each case. [Figure 18] Figure 18A: Venn diagram of overlapping genes in MSI1436 (aminosterol 1436) versus ENT-03 versus control (young) versus untreated (young) - all versus all. Figure 18B shows a Venn diagram of overlapping genes in MSI1436 versus control (young) versus ENT-03 versus untreated (young) - up versus up. Figure 18C shows a Venn diagram of overlapping genes in MSI1436 versus control (young) versus ENT-03 versus untreated (young) - down versus down. Figure 18D shows a Venn diagram of overlapping genes in MSI1436 versus control (young) versus ENT-03 versus untreated (young) - up versus down. Figure 18E shows a Venn diagram of overlapping genes in MSI1436 versus control (young) versus ENT-03 versus untreated (young) - down versus up. [Figure 19]Scatter plot of significant genes in MSI1436 (aminosterol 1436) vs. control (aged) compared with ENT-03 vs. untreated (aged). Genes are represented by dots. The color of the dots indicates which set the gene is assigned to. For each gene, the log2(fold change) of the MSI1436 vs. control (aged) contrast (y-axis) and the log2(fold change) of the ENT-03 vs. untreated (aged) contrast (x-axis) are shown. [Figure 20] Figure 1 shows a significant gene upset plot from Example 12. Plot showing the interaction between sets of up-regulated and down-regulated genes. The leftmost bar shows the size of each set used as input. The top bar shows the exclusive size of each set (i.e., each gene is counted only once in this bar). The central dot plot shows the interacting sets in each case. [Figure 21] Figure 21A shows a Venn diagram of overlapping genes for ENT-03 vs. untreated (aged) - all vs. all in ENT-02 (MSI1436) vs. control (aged). Figure 21B shows a Venn diagram of overlapping genes for ENT-03 vs. untreated (aged) - up vs. up in ENT-02 (MSI1436) vs. control (aged). Figure 21C shows a Venn diagram of overlapping genes for ENT-03 vs. untreated (aged) - down vs. down in ENT-02 (MSI1436) vs. control (aged). Figure 21D shows a Venn diagram of overlapping genes for ENT-03 vs. untreated (aged) - up vs. down in ENT-02 (MSI1436) vs. control (aged). Figure 21E shows a Venn diagram of overlapping genes for ENT-03 vs. untreated (aged) - down vs. up in ENT-02 (MSI1436) vs. control (aged). [Figure 22] Scatter plots are shown comparing significant genes in old vs. young (control) with significant genes in old vs. young (untreated). Genes are represented by dots. The color of the dots indicates which set the gene is assigned to. For each gene, the log2(fold change) in the old vs. young (control) contrast (y-axis) and the log2(fold change) in the old vs. young (untreated) contrast (x-axis) are shown. [Figure 23] Figure 1 shows a significant gene upset plot from Example 12. Plot showing the interaction between sets of up-regulated and down-regulated genes. The leftmost bar shows the size of each set used as input. The top bar shows the exclusive size of each set (i.e., each gene is counted only once in this bar). The central dot plot shows the interacting sets in each case. [Figure 24] Figure 24A shows a Venn diagram of overlapping genes in old vs. young (untreated) versus old vs. young (control) (all vs. all). Figure 24B shows a diagram comparing the overlap of old and young genes (control) with the overlap of old and young genes (untreated). Figure 24C shows a Venn diagram of overlapping genes in old vs. young (control) versus old vs. young (untreated) - down vs. down. Figure 24D shows a diagram comparing the overlap of old and young genes (control) with the overlap of old and young genes (untreated). Figure 24E shows a diagram comparing the overlap of old and young genes (control) with the overlap of old and young genes (untreated). [Figure 25] Scatter plot of significant genes in old vs. young (ENT-02; MSI1436) compared with old vs. young (ENT-03). Genes are represented by dots. The color of the dots indicates which set the gene is assigned to. For each gene, the log2(fold change) in the old vs. young (ENT-02; MSI1436) contrast (y-axis) and the log2(fold change) in the old vs. young (ENT-03) contrast (x-axis) are shown. [Figure 26] Figure 1 shows a significant gene upset plot from Example 12. Plot showing the interaction between sets of up-regulated and down-regulated genes. The leftmost bar shows the size of each set used as input. The top bar shows the exclusive size of each set (i.e., each gene is counted only once in this bar). The central dot plot shows the interacting sets in each case. [Figure 27]Figure 27A shows a Venn diagram of overlapping genes in old vs. young (MSI1436) versus old vs. young (ENT-03) (-all vs. all). Figure 27B shows a Venn diagram of overlapping genes in old vs. young (MSI1436) versus old vs. young (ENT-03) - up vs. up. Figure 27C shows a Venn diagram of overlapping genes in old vs. young (MSI1436) versus old vs. young (ENT-03) - down vs. down. Figure 27D shows a Venn diagram of overlapping genes in old vs. young (MSI1436) versus old vs. young (ENT-03) - up vs. down. Figure 27E shows a Venn diagram of overlapping genes in old vs. young (MSI1436) versus old vs. young (ENT-03) - down vs. up. [Figure 28] Heatmap of overlap between contrasts: A plot showing the number of overlapping selected genes between the contrasts performed. Note that the numbers on the diagonal represent the total number of selected genes found for each contrast. The color of the squares represents the Jaccard index (intersection on the union) of the contrast on the x-axis and the contrast on the y-axis. Figure 28A: Heatmap of overlap of up- and down-regulated (y-axis) vs. up- and down-regulated (x-axis) selected genes for each contrast. Figure 28B: Heatmap of overlap for each contrast of up-regulated (y-axis) vs. up-regulated (x-axis) selected genes. Figure 28C: Heatmap of overlap of down-regulated (y-axis) vs. down-regulated (x-axis) selected genes for each contrast. Figure 28D: Heatmap of overlap of up-regulated (y-axis) vs. down-regulated (x-axis) selected genes for each contrast. DETAILED DESCRIPTION OF THE INVENTION

[0131] I. Overview The pharmacological activity of aminosterols requires a highly specific chemical structure, which suggests that shark molecules are utilized by physiological circuits that exist to accommodate similar compounds produced by mammals.To date, such compounds have not been discovered or hypothesized to exist.The present disclosure provides such compounds, their modifications, and their methods of use.Therefore, in some embodiments, the present technology relates to compound III, or its pharmaceutically acceptable salts, solvates, prodrugs, or derivatives, methods for preparing such compounds, compositions comprising one or more of compound III or its derivatives, and methods for using them.

[0132] A. Summary of the Chemical Content of the Disclosure Since the 1980s, it has been known that 3-oxocholenic acid, with a specific chemical structure, can be isolated from humans under certain circumstances. In particular, fluids collected from chronic subdural hematomas have been shown to contain high concentrations of bile acid compound I, the function of which is unknown.

[0133] [ka]

[0134] This same compound was subsequently found to be present in high concentrations in cerebrospinal fluid (CSF) after subarachnoid hemorrhage and in low concentrations in the CSF of healthy adults. 12 Compound I, which has a hydroxyl group at the 27-position, has also been found in both amniotic fluid and urine of healthy newborn humans. The function of compound I and its related metabolic variants remains enigmatic. It is likely produced by the alternative bile acid pathway, which converts cholesterol first to 27-hydroxycholesterol and then to compound I. The role of this alternative pathway is still unknown, and it is responsible for approximately 5% of the bile acids produced in humans. Products of this "acidic" pathway are not thought to play a significant role in fat emulsification, the primary function of bile acids in human physiology.

[0135] Although not identical, the structure of Compound I is reminiscent of squalane aminosterols, including those shown and discussed herein. Both steroid scaffolds are substantially flat due to the steric constraints imposed between the A and B rings. In the case of Compound I, the 4-ene double bond imparts flatness. In the shark molecule, flatness is imposed by the 5-α hydrogen. The carboxyl moiety of Compound I is the C of the shark molecule. 24 Similar in spatial location to the sulfate salt above, both structures exhibit a negative charge in the same general spatial location relative to the steroid scaffold. Based on this spatial arrangement, ENT-03 (compound III) was synthesized by coupling the polyamine, spermine, with compound I, as shown below.

[0136] As detailed in the Examples, Applicant discovered that ENT-03 (Compound III) is found in subdural hematoma fluid in human and mouse pup brains. Compound III can be synthesized in the brain by condensation of spermine and Compound I. Compound I is thought to arise from the metabolism of 27-hydroxycholesterol (also known as (25R)26-dihydroxycholesterol), a biologically active oxysterol released into the circulation from many tissues, including vascular endothelium and macrophages (Griffiths et al., 2019; Bjorkhem et al., 2002; Javitt et al., 2002). In the brain, 27-hydroxycholesterol is metabolized sequentially by CYP27A1, CYP7B1, and HSD-3B7, likely in that order (Meaney et al., 2019). (Celotti et al., 2007). Synthesis of ENT-03 (compound III) requires three additional biosynthetic steps: reduction of the double bond in the cholesterol A ring to generate the 5α hydrogen; condensation with the 3-oxo group of spermine to form an imine; and subsequent reduction of the imine. The first step would be catalyzed by brain steroid 5α-reductase (Celotti et al., 1992). The missing biosynthetic linkage is the enzyme that conjugates spermine with bile acids.

[0137] [ka]

[0138] ENT-03 (Compound III) contains a 5-α hydrogen atom, which, like shark-derived ENT-02, provides greater chemical stability relative to 4-enes such as those of Compound I (Compound III), and, as discussed below and demonstrated by the Examples, reduces food intake and promotes weight loss in animal models. Confirming that ENT-03 (Compound III; 3-β-spermino-7α-hydroxy-5α-chlorstanoic acid) has the same pharmacological activity known to be associated with shark-derived ENT-02 (MSI1436) can validate the utility of ENT-03 (Compound III) in other applications for which ENT-02, as well as other aminosterols, are known to be useful.

[0139] ENT-03 contains a 5α-hydrogen rather than a 4-ene because the former is more chemically stable than the latter. Because the C24 sulfated hydroxyl on ENT-02 is replaced by a C27 ​​carboxylic acid in ENT-03, ENT-03 undergoes metabolism in a manner common to all bile acids, namely, via progressive cleavage of the cholesterol side chain. The difference in pharmacology is likely due, in part, to differences in metabolic handling of the two compounds.

[0140] ENT-03 (Compound III) is also shown in Example 1 to be a protein tyrosine phosphatase 1B (PTP1B) inhibitor. PTP1B is a validated target for the treatment of both type 2 diabetes and obesity; however, targeting PTP1B for drug discovery is challenging due to its highly conserved, positively charged active site pocket. PTP1B is a negative regulator of insulin and leptin signaling and a highly validated therapeutic target for diabetes and obesity. While traditional approaches to drug development have produced potent and specific PTP1B inhibitors, previous publications have reported that these inhibitors lack oral bioavailability, as it was believed that drugs must be absorbed into the bloodstream to produce a pharmacological effect (Krishnan et al., 2018).

[0141] As further described in the Examples, ENT-03 and trodusquemine have been shown to have similar pharmacological activity, therapeutic action in conditions such as Alzheimer's disease, and reversing the aging phenotype of the gastrointestinal tract.

[0142] B. ENT-03 (Compound III) suppresses appetite Example 2 of the present disclosure demonstrates that ENT-03 (Compound III) shares appetite-suppressing and weight-loss-promoting properties with shark-derived ENT-02 (MSI1436). While appetite suppression itself is a utility of aminosterols, it is believed that ENT-03 (Compound III) may also have efficacy against the same brain-gut disorders that shark-derived aminosterols have recently demonstrated (data not shown; see, e.g., ClinicalTrials.gov Identifier NCT03047629, "Evaluation of the Safety and Tolerability of ENT-01 for the Treatment of Parkinson's Disease-Associated Constipation (RASMET)"; and ClinicalTrials.gov Identifier NCT03781791, "Orally Administered ENT-01 for Parkinson's Disease-Associated Constipation (KARMET)"). ENT-01 is squalamine phosphate. Additionally, the activity of ENT-03 (Compound III) and its derivatives may span a variety of conditions characterized by αS pathology and / or dopaminergic dysfunction, as detailed herein.

[0143] Obesity is defined as a body mass index (BMI) of 30.0 or higher, while a BMI between 25.0 and 30 is defined as being in the overweight range. BMI is calculated by dividing a person's mass (in kilograms) by the square of their height (in meters). Contributing factors to obesity include poor diet (high calories), a sedentary lifestyle, lack of sleep, genetics, aging, and pregnancy. Fewer than 5% of adults participate in 30 minutes of physical activity daily, and only one in three children is physically active daily. Various conditions can also lead to obesity by causing weight gain and excessive hunger and food intake. Finally, more than 5% of the population may suffer from food addiction.

[0144] Mortality associated with weight gain or obesity is often the result of secondary conditions caused by excess weight: fatty liver, type 2 diabetes, heart disease, stroke, high blood pressure, gallbladder disease, gout, sleep apnea, osteoarthritis, high LDL cholesterol, low HDL cholesterol, high triglyceride levels (dyslipidemia), endometrial cancer, breast cancer, colon cancer, kidney cancer, gallbladder cancer, and liver cancer. Obesity also contributes to joint damage and osteoarthritis. Increased fat content is also thought to promote inflammation, further damaging joints.

[0145] Shark-derived ENT-02 (MSI1436) is known to have pharmacological activity in suppressing appetite and causing weight loss. The following examples show that ENT-03 (Compound III) also exhibits this same activity (Example 2). The examples also show that ENT-03 (Compound III), like shark-derived ENT-02 (MSI1436), is an inhibitor of regulatory phosphatases such as protein tyrosine phosphatase 1B (PTP1B) (Example 1). Because ENT-03 (Compound III) and shark-derived ENT-02 share the same appetite-suppressing and weight-loss-promoting properties, share a pharmacophore, and have similar chemical structures, it is believed that ENT-03 (Compound III) and its deuterated derivatives may be useful in treating indications for which other aminosterols are known to be useful.

[0146] C. ENT-02 (MSI1436 or Aminosterol 1436) and Disease Without being bound by theory, it is believed that aminosterols act by targeting neurotoxic aggregates of α-synuclein (αS) in the gastrointestinal tract, restoring enteric neuronal function and thereby treating and / or preventing the brain-gut disorders described herein. Based on this theory, several clinical trials using squalamine for the treatment of Parkinson's disease are underway or have been completed. For example, (1) ClinicalTrials.gov Identifier: NCT03047629: "A Multicenter, Single-Dose, Multiple-Dose, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered ENT-01 for the Treatment of Parkinson's Disease-Associated Constipation," 50 participants (study completion date: June 14, 2018); (2) ClinicalTrials.gov Identifier: NCT03781791: "A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability, and Efficacy of Orally Administered ENT-01 for the Treatment of Parkinson's Disease-Associated Constipation (KARMET)," 72 participants (estimated study completion date: June 2019); and (3) ClinicalTrials.gov Please refer to Identifier: NCT03938922: "A multicenter, randomized, double-blind study to investigate the tolerability and efficacy of oral ENT-01 for the treatment of Parkinson's disease dementia," targeting 40 participants (estimated study start date June 3, 2019, estimated study end date February 2020).

[0147] This effect of aminosterols is highly unexpected, given that aminosterols have very low bioavailability; for example, ENT-02 and ENT-03 appear to act locally rather than via absorption into the bloodstream. Currently functioning enteric neurons prevent retrograde transport of proteins such as αS to the brain. In addition to restoring GI function, this effect is thought to slow and possibly reverse disease progression in brain-gut disorders such as Parkinson's disease (PD), as well as other related brain-gut diseases and conditions described herein.

[0148] Targeting neurotoxic aggregates of αS in the gut represents a novel approach to the treatment of brain-gut disorders such as PD and other neurological diseases and conditions described herein, potentially restoring enteric neuronal function and preventing retrograde transport to the brain. In addition to restoring gut function, such actions may slow the progression of brain-gut disorders. Therefore, without being bound by theory, it is expected that the methods described herein using novel ENT-03 (compound III) or its pharmaceutically acceptable salts, solvates, prodrugs, or derivatives, as well as compositions comprising them, may be applicable to the treatment and / or prevention of any of the brain-gut disorders and conditions described herein.

[0149] PD correlates with the formation of toxic α-synuclein (αS) aggregates within the enteric nervous system (ENS) (Braak et al., 2003(a); Braak et al., 2003(b)). αS is a member of the synuclein family of soluble proteins (αS, β-synuclein, and γ-synuclein) commonly present in the vertebrate central nervous system (CNS). αS is expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum, and its primary location within presynaptic terminals of neurons is in both membrane-bound and cytoplasmic-free forms. Presynaptic terminals release chemical messengers called neurotransmitters from compartments known as synaptic vesicles. Neurotransmitter release relays signals between neurons and is important for normal brain function. αS is found in glia and melanocytes and is highly expressed in neuronal mitochondria in the olfactory bulb, hippocampus, striatum, and thalamus.

[0150] In pathological conditions characterized by Lewy bodies, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), αS aggregates to form insoluble fibrils. These disorders are known as synucleinopathies. αS pathology is observed in both sporadic and familial cases of AD. Thus, the formation of αS aggregates is one indicator of αS pathology.

[0151] At the molecular level, protein misfolding, accumulation, aggregation, and subsequent formation of amyloid deposits are common features in many neurological disorders, including Alzheimer's disease (AD) and PD, and neurodegenerative diseases are sometimes referred to as proteinopathies. The existence of common mechanisms suggests that neurodegenerative diseases likely share a common trigger and that the nature of the pathology is determined by the type of aggregated protein and the localization of the affected cells.

[0152] Following the discovery of a genetic link between αS and PD risk and the identification of aggregated αS as a major protein component of Lewy pathology, αS has emerged as a key therapeutic target in PD and related synucleinopathies (Brundin et al., 2017). The α-synuclein abnormalities typically seen in PD are thought to be responsible for the apparent catecholamine deficiency (dopamine is a catecholamine that shares metabolic pathways with other catecholamines) (Frisina et al., 2009).

[0153] Examples of conditions associated with abnormal αS pathology, also referred to as "gut-brain" disorders, and / or dopaminergic dysfunction include synucleinopathies (S-synucleinopathy). blood These include, but are not limited to, neurological disorders, psychological and / or behavioral disorders, cerebral and systemic ischemic disorders, and / or conditions. blood Examples of neurodegenerative and / or neurological diseases include, for example, AD, PD, Lewy body disease (LBD) or dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), schizophrenia, Friedreich's ataxia, vascular dementia, spinal muscular atrophy (SMA), progressive nuclear palsy, supranuclear palsy, frontotemporal dementia (FTD), progressive supranuclear palsy, Guadeloupe parkinsonism, parkinsonism, spinocerebellar ataxia, stroke, traumatic brain injury,Examples of psychological or behavioral disorders include, for example, depression, autism, Down's syndrome, Gaucher disease (GD), Krabbe disease (KD), lysosomal conditions affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delusions, amnesia, apathy, bipolar disorder, disinhibition, abnormal movements and obsessive-compulsive behaviors, addiction, cerebral palsy, epilepsy, major depressive disorder, and sleep disorders such as REM sleep behavior disorder (RBD), sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, and cognitive impairment. Whole body Examples of ischemic or cerebral ischemic disorders include, for example, microangiopathy, intrapartum cerebral ischemia, cerebral ischemia during / after cardiac arrest or cardiac resuscitation, cerebral ischemia due to intraoperative problems, Cerebral ischemia during carotid artery surgery, brain fart Chronic cerebral ischemia caused by narrowing of the blood supply arteries cerebral sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, High blood pressure, high cholesterol, myocardial infarction, Cardiac insufficiency, cardiac failure , congestive heart failure, myocarditis, pericarditis, Pericardial inflammation, Coronary heart disease, angina, congenital heart disease, Shock, limb ischemia, renal artery stenosis, diabetic retinopathy, malaria-associated thrombosis, artificial heart valves, anemia, hypersplenism syndrome, emphysema, These include pulmonary fibrosis, erectile dysfunction, cardiac conduction disorders, hypertension, hypotension, and pulmonary edema.

[0154] To the extent that constipation is suspected to correlate with the formation of toxic αS aggregates within the enteric nervous system (ENS), it serves as an early indicator of many neurological disorders, including PD (Braak et al., 2003b). Normal transport of αS aggregates from the ENS to the central nervous system (CNS) via afferent nerves such as the vagus nerve (Holmqvist et al., 2014; Svensson et al., 2015) results in the progressive accumulation of neurotoxic aggregates within the brainstem and more rostral structures. Therefore, inhibiting αS aggregation in the ENS may reduce ongoing neurological disease processes in both the ENS and CNS (Phillips et al., 2008). This relationship between the ENS and CNS is sometimes referred to herein as the "brain-gut" relationship, in reference to a class of disorders or axis of aminosterol activity.

[0155] Without being bound by theory, aminosterols are thought to improve intestinal function by acting locally on the gastrointestinal tract (supported by their low oral bioavailability, e.g., less than approximately 0.3%). Orally administered aminosterols, such as ENT-02, stimulate gastrointestinal motility in mice with constipation due to overexpression of human αS (West et al., manuscript in preparation). Perfusion of aminosterols through the lumen of isolated intestinal segments from PD mouse models excites IPANs (intrinsic primary afferent neurons), the main sensory neurons of the ENS, increasing the frequency of propulsive peristaltic contractions and enhancing neural signals projecting to the afferent arm of the vagus nerve.

[0156] It is theorized that nerve impulses initiated in the ENS after administration of aminosterols such as compound III increase afferent neuronal signaling to the CNS. This may stimulate clearance of αS aggregates within the afferent neurons themselves, as well as rostrally projecting second- and third-order neurons within the CNS, given that neuronal autophagic activity is known to increase with nerve stimulation (Shehata et al., 2012). After cessation of aminosterol administration, CNS neurons may gradually re-accumulate their αS load, either locally or via transport from αS reaggregates in the intestine.

[0157] Disruptions to circadian rhythms have been described in neurological disorders such as PD both clinically and in animal models and may play a role in the abnormal sleep architecture, dementia, mood, and autonomic dysfunction associated with neurological disorders such as PD (Breen et al., 2014; Videnovic et al., 2017; Antonio-Rubio et al., 2015; Madrid-Navarro et al., 2018). The circadian cycle of wrist skin temperature has been shown to correlate with the sleep-wake cycle, reflecting the effect of nocturnal heat dissipation from the skin on the decline in core temperature and the onset of sleep (Sarabia et al., 2008; Ortiz-Tudela et al., 2014). Administration of ENT-03 (Compound III) appears to have a significant positive effect on circadian rhythms in patients. Without being bound by theory, it is believed that Compound III affects neural circuits involving the master clock (suprachiasmatic nucleus) and its autonomic projections, opening up the possibility of therapeutic correction of circadian dysfunction.

[0158] In one aspect, aminosterol dosing can be patient-specific, as the therapeutically effective dose of ENT-03 (Compound III) can be related to the degree of neuronal damage, with greater neuronal damage correlating with the need for higher ENT-03 (Compound III) doses to achieve the desired therapeutic outcome. As described in more detail herein, the dosage of ENT-03 (Compound III) can range from about 0.01 to about 500 mg / day, with dosage determinations described in more detail below. However, the present disclosure is not limited to methods for determining patient-specific ENT-03 (Compound III) doses, as non-patient-specific therapeutic ENT-03 (Compound III) doses are also described herein.

[0159] D. Experimental Results (1) Detection of ENT-03 in human and mouse fetal brains In 1992, Nagata et al. identified high concentrations of the bile acid, 7-α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), in human chronic subdural hematoma fluid (Figure 1C) (Nagata et al., 1992) and subsequent acute subarachnoid hemorrhage (Nagata et al., 1995). In 1997, Zhang et al. reported that rat brain cells could metabolize 27-hydroxycholesterol to 7-HOCA (Zhang et al., 1997). Subsequently, Björkhem, Sjovall, Griffiths, and their colleagues identified 7-HOCA as the most abundant bile acid in human cerebrospinal fluid (Ogundare et al., 2010; Meaney et al., 2007; Saeed et al., 2014; Saeed et al., 2014). 7-HOCA did not appear to be a biologically active bile acid in that it did not activate any of the FXR, LXR, or RXR / NURR1 receptors, for which bile acids and oxysterols are known ligands (Ogundare et al., 2010). Bjorkhem proposed that the brain metabolizes 27-hydroxycholesterol that enters 7-HOCA from the periphery, facilitating the retrograde flow of oxysterols into the circulation (Meaney et al., 2007).

[0160] This study suggests that the presence of ENT-03 in subdural hematoma fluid reflects its possible role in the development of this structure. Following head injury, typically in elderly individuals and rarely in infants, a highly vascularized gallbladder-like "organ" develops, originating on one side from the dura mater ("external") and on the other from the subarachnoid space ("internal") (Yamashima et al., 2000). High concentrations of numerous growth factors, including VEGF, accumulate within the fluid (Edlmann et al., 2017). This study suggests that ENT-03 appears within subdural hematomas in an attempt to repair intracranial injury. In this context, one might speculate as to why healthy newborns who experience intracranial trauma and develop subdural and parenchymal hemorrhage after passing through the birth canal generally recover asymptomatically (Looney et al., 2007).

[0161] Due to known high concentrations of compound Ia (7-HOCA) in chronic subdural hematoma fluid, drained fluid from three elderly patients with chronic subdural hematoma was analyzed for the presence of ENT-03 via LC / MS / MS. Brain extracts were analyzed for ENT-03 via LC / MS / MS. Figure 7A shows the presence of ENT-03 in the brain extracts. Figure 7B shows a reference sample of synthetic ENT-03.

[0162] Based on these data, brain, liver, and kidney extracts from neonatal mice over the first two weeks of life were analyzed for the presence of ENT-03. 3-oxo-bile acids constitute 18–40% of the unconjugated bile acids in amniotic fluid during the last trimester of human fetal development (Nakagawa et al., 1990) and are present as a significant percentage of bile acids in the urine of healthy newborns, gradually decreasing during the first postnatal month (Wahlen et al., 1989 and Kimura et al., 1999). Given the abundance of 3-oxo-bile acids during the neonatal period, we focused our search for putative polyamine-bile acid molecules in neonatal mice. Brain and liver extracts were prepared from mice between day 1 and day 24 using a protocol designed to capture ENT-03 based on its physical properties (see Example 7).

[0163] Experimental results showed that ENT-03 was detectable in the brain and liver of neonatal mice (Figures 8A and 8B, respectively). The identity of endogenous ENT-03 was confirmed by its retention time, mass ([M + H +The peak mass of ENT-03 was established by MS / MS MRM of the 5-α conformation (m / z = 619.6) and characteristic fragments at masses 545.57 (Figure 13A) and 474.39 (Figure 13B). The approximate concentrations of ENT-03 measured in the brain and liver of neonatal mice over the first 3 weeks of life are shown in Figure 9. Both brain and liver showed peak concentrations at birth, followed by a gradual decline over the next 3 weeks. To determine the concentration of endogenous ENT-03 present in the chromatographed samples, the synthetic centroid ENT-03-d4 (-C2D2, -C4D2) was used as an internal standard. The identical retention times of the endogenous and synthetic molecules (Figures 13A and 13B) support the tentative assignment of the 5-α configuration based on the significant difference in retention times that characterize the "flat" (5α) and "kinked" (5β) conformers of the synthetic steroid precursor of ENT-03.

[0164] (2) Inhibition of regulatory phosphatases In one aspect, there is included a method of inhibiting one or more regulatory phosphatases to achieve a therapeutic or prophylactic benefit, comprising administering a therapeutically effective amount of an aminosterol compound or a composition comprising same, as described herein.

[0165] Many cellular processes involved in health and disease are regulated by phosphorylation. Protein kinases are responsible for the phosphorylation of cellular targets. Phosphatases reverse the action of kinases. There are two broad classes of regulatory phosphatases. The first group are tyrosine-specific PTPs, which dephosphorylate protein substrates on tyrosine. Tyrosine-specific PTPs include receptor-like PTPs and non-transmembrane PTPs. The second group are DSPs (dual specificity phosphatases), which dephosphorylate protein substrates on tyrosine, serine, and threonine residues, as well as lipid substrates. The focus of the present invention is on the first group of phosphatases.

[0166] While considerable effort has been directed toward developing therapeutic agents that inhibit protein kinases, success in developing inhibitors has been slow. The active sites of most phosphatases are organized as deep wells, the bottom of which is composed of positively charged residues. Corresponding inhibitors must bear negative charges or other hydrogen-bond-accepting functionality to dock within the base of the well and must be sufficiently elongated to extend into the well. Because large, highly charged molecules generally have limited cell permeability, compounds that demonstrate activity in in vitro enzymatic assays often exhibit little exoviduct activity when evaluated in cell culture or in vivo.

[0167] The phosphatases targeted by the present invention include several that regulate important cellular and physiological functions. These include PTP1B, which downregulates many receptor tyrosine kinases, such as insulin and IGF receptors; growth factor receptors such as VEGF, PDGF, EGF, and FGF; and stat proteins in the leptin pathway. PTPN11(E76K) is recognized as an oncogene that drives numerous human malignancies. PTPRC / CD45 has been extensively studied in lymphocytes and has been shown to act as a signaling gatekeeper in T cells after antigen stimulation. PTPN7 / LC-PTP inactivates MAPKs, attenuating processes such as neuronal signaling and growth factor stimulation. PTPN12 / PTP-PEST plays a key role in cytoskeletal rearrangements, which affect processes such as cell migration, cell spreading, and cell division.

[0168] ENT-03 is an inhibitor of regulatory phosphatases with the highest specificity for PTP1B. Furthermore, it exhibits the expected pharmacological activity in mice, i.e., reduced food intake and weight loss. The aminosterols described herein are various derivatives of ENT-03 that exhibit inhibitory activity against regulatory phosphatases in vitro and in vivo.

[0169] Example 1 shows that ENT-03 (compound III) is an inhibitor of regulatory phosphatases, such as protein tyrosine phosphatase 1B (PTP1B). PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, particularly for the treatment of type 2 diabetes (Combs et al., 2010). Gene knockout studies conducted in mouse models have provided substantial evidence for the role of PTP1B in the regulation of insulin signaling and the development of obesity (Elchebly et al., 1999).

[0170] ENT-03 (Compound III) and ENT-02 (MSI1436) were tested at 10 doses IC starting at 100 μM and serially diluted 3-fold in singlets. 50 The enzyme activity was monitored by measuring fluorescence. As can be seen in Table 2, the IC of ENT-02 (MSI1436, aminostrol 1436), which is already known to inhibit PTP1B, was 0.01. 50 was 2.89 μM, and the IC of ENT-03 (compound III) 50 The half-maximal inhibitory concentration, or IC 50 is a measure of the potency of a substance to inhibit a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half. Thus, the IC of ENT-03 (Compound III) 50 is less than half that of ENT-02 (MSI1436), making ENT-03 (compound III) significantly more potent than aminosterol 1436.

[0171] As detailed in Example 1, ENT-02 (MSI1436) is described as a PTP1B inhibitor, but both, like ENT-03 (compound III), exhibit comparable inhibitory activity against other phosphatases involved in cell signaling. Notably, both are active against full-length PTPN11 / SHP2. SHP2 (SH2 domain-containing phosphatase 2) is a protein tyrosine phosphatase involved in multiple cell signaling processes and directly linked to both human genetic diseases and cancer (Zheng et al., 2018; Chen et al., 2016). Furthermore, both compounds potently inhibit the gain-of-function PTPN11(E76K) mutant, which is recognized as an oncogene driving numerous human malignancies. Neither compound inhibits the closely related phosphatase PTPN6 / SHP1, which plays a functionally distinct role in biological pathways. Both compounds target PTPRC / CD45, PTPN7 / LC-PTP, and PTPN12 / PTP-PEST. PTPRC / CD45 has been extensively studied in lymphocytes and has been shown to act as a signaling gatekeeper in T cells after antigen stimulation. PTPN7 / LC-PTP inactivates MAPKs, attenuating processes such as neuronal signaling and growth factor stimulation (Fukunaga et al., 1998; Eswaran et al., 2006). PTPN12 / PTP-PEST plays a key role in cytoskeletal rearrangements that affect processes such as cell migration, cell spreading, and cell division.

[0172] Example 2 describes the activity of ENT-03 (Compound III) as a weight loss agent in mice. Mice were treated with either ENT-03 (Compound III) or ENT-02 (MSI1436) on days 0, 2, 4, 6, 8, and 10 while allowed to eat ad libitum. As can be seen in Figure 2, administration of both compounds resulted in a loss of body weight.

[0173] These data demonstrate that ENT-03 (Compound III) exhibits pharmacological responses in terms of appetite and body weight similar to ENT-02 (MSI1436) and suggest that ENT-03 (Compound III) may have utility in all therapeutic applications known to be associated with shark-derived aminosterol 1436, including neurodegenerative or neurological diseases (such as PD), psychological or behavioral disorders, and systemic or cerebral ischemic disorders.

[0174] ENT-03 (compound III) inhibits PTP1B, but along with ENT-02, ENT-03 (compound III) also inhibits PTP1B with similar K i We have also shown that ENT-03 (Compound III) inhibits several other phosphatases. Of particular interest is the proto-oncogene PTPN11, also known as SHP2, a ubiquitously expressed non-receptor protein tyrosine phosphatase utilized by hormones such as insulin, leptin, and numerous growth factors, along with PTP1B, PI3K / Akt, Ras / Raf / Erk, and JAK / STAT signaling pathways (Pulido et al., 2013). In contrast to PTP1B, which acts primarily as a negative regulator of hypothalamic leptin signaling in the mouse forebrain, neuronal SHP2 appears to enhance leptin signaling in the hypothalamus (Zhang et al., 2004). Thus, by targeting two phosphatases that regulate two major intracellular pathways downstream of leptin in opposite directions, gains in the leptin pathway can be controlled.

[0175] Finally, Example 9 details the evaluation of ENT-05's activity in vivo. This example demonstrates that modification of ENT-03 (compound III) to generate ENT-05 results in a compound with specificity for PTPN11 (E76K) and possibly other undescribed phosphatases. Its in vivo pharmacological effect on tadpoles is inhibition of sodium reabsorption, most likely in the kidney. The likely target is the sodium-potassium chloride cotransporter type 2 (NKCC2). Currently, little is known about the phosphatases that regulate the activity of NKCC2 in renal tubules.

[0176] This example teaches that ENT-05 identified a phosphatase that activates the NKCC2 transporter, a pathway that can be inhibited by ENT-05. ENT-05 may be useful in treating hypertension, as well as increased intracranial pressure and increased intraocular pressure (glaucoma), in a manner similar to furosemide, which inhibits NKCC2 in the kidney by a mechanism that does not involve inhibition of phosphatase activity.

[0177] (3) Intestinal rejuvenation Example 3 demonstrates that squalamine is effective in increasing the transcriptome in aged mice. As discussed in Section IA, shark-derived aminosterols such as ENT-03 (Compound III) and squalamine share similar structures and spatial locations of functional groups. Therefore, it is believed that the activity of squalamine extends to ENT-03 (Compound III).

[0178] Aging involves a decrease in intestinal gene expression, as evidenced by a decrease in the intestinal RNA transcriptome in old versus young mice. Example 3 evaluated the effects of oral administration of ENT-01 (squalamine phosphate) to old mice. After two weeks of administration, the animals were euthanized, and the gastrointestinal tract was sectioned into the stomach, duodenum, jejunum, ileum, cecum, colon, and rectum. Gastric tissue was then subjected to histological examination, and the transcriptome was analyzed by RNA-Seq.

[0179] The mRNA levels of all genes in Table 4 in the Examples showed significant increases after treatment with ENT-01 (squalamine phosphate) (see, e.g., Table 5A). This suggests that squalamine has a rejuvenating effect on the aged intestine, and this activity is believed to extend to ENT-03 (Compound III) and its salts, solvates, derivatives, and prodrugs. Furthermore, when oral administration of ENT-03 (Compound III) was examined, the transcriptional response in tissues was blunted in both cases in young animals compared with old animals (Figures 6A-6C). For example, 13 genes were differentially expressed in the stomach of treated young animals, compared with 63 in the old group. Similarly, in the jejunum, 42 genes were differentially expressed in the young group and 382 genes in the aged group upon treatment. In the ileum, 80 genes were differentially expressed in young animals and 1,162 genes in the old group upon treatment with ENT-03 (Compound III).

[0180] The differentially expressed gene sets (DEGs) with aging were compared with those differentially expressed in treated old or young animals. Analysis of overlapping DEGs between controls revealed, for example, that 37 gastric genes downregulated with aging (old vs. young) significantly overlapped with genes upregulated by ENT-03 treatment of old mice. In contrast, the only significant overlap between gastric aging genes and those in young ENT-03-treated stomachs was the 12 genes that were further downregulated in the aging direction.

[0181] The "aging" genes that ENT-03 (Compound III) most significantly complements in the stomach are listed in Table 5B. Notably, in the stomach, "restored" aging genes include genes involved in tissue renewal (fibroblast growth factor 2; zinc finger protein 383; forkhead box C2); neuronal differentiation (neural cell adhesion molecule 2); immunity (toll-like receptors 9 and 12; interleukin-2 receptor, beta chain), neurotransmitter synthesis and uptake (choline and serotonin transporters), and mitochondrial respiration (cytochrome c oxidase subunit 6B2).

[0182] Genes whose expression changed significantly between young and old mice were identified (Figure 6A). With aging, the expression of 75 genes in the stomach significantly decreased, while the expression of 11 genes significantly increased (Figure 6A). However, fewer differences were observed between the gene expression profiles of the jejunum (Figures 10A-10D) or ileum (Figures 10D-10F) of young and old mice. In the jejunum, expression of five genes decreased and expression of two genes increased with age. Meanwhile, in the ileum, expression of 19 genes decreased and expression of nine genes increased. These results are consistent with the recognized decreased regenerative capacity of the aging rodent stomach (Fukunaga et al., 1998) and the resilience of the small intestine with aging (Eswaran et al., 2006).

[0183] Oral administration of ENT-03 (Compound III) to young mice (20 weeks) induced a response of 13 gastric genes, all of which were transcriptionally repressed by ENT-03 treatment (Figure 6B). For both young and old mice, the expression of no more than two genes was significantly altered in response to ENT-03 exposure in the jejunum and ileum.

[0184] In contrast, a more robust effect on gene expression in the stomach was observed in aged animals (78 weeks) treated with ENT-03 (Compound III). 63 genes were transcriptionally induced (Figure 6C). Interestingly, 36 of the genes whose expression increased upon ENT-03 (Compound III) treatment of aged mice were the same genes whose expression decreased with age. These genes include those involved in tissue renewal (fibrolast growth factor 2 (Fgf2), zinc finger protein 382 (Zfp382), and forkhead box C2 (Fox2)), neural differentiation (neural cell adhesion molecule 2 (Ncam2)), immunity (Toll-like receptors 9 and 12 (Tlr9, Tlr12), interleukin receptor chain (Il2rb) and beta chain (CD300 (CD300ld))), neurotransmitter synthesis and uptake (choline and serotonin transporters (Slc5a7, Slc6a4)), and mitochondrial acid oxidative subunit 6B2 (Cox6b2)). These data support the hypothesis that oral administration of ENT-03 (Compound III) to aged mice can reverse some of the changes in gene expression associated with aging in the GI tract.

[0185] (4) Compound III and Alzheimer's Treatment Example 6 details data supporting the use of ENT-03 (Compound III) in the treatment of neurological disorders such as Alzheimer's disease. A PTP1B-dependent mechanism has been exploited to reverse memory impairment, normalize behavior, and reduce neuronal loss in a beta-amyloid and tau mouse model of Alzheimer's disease (Ricke, Cruz, et al., 2020). Other studies have demonstrated the reduction of beta-amyloid aggregate toxicity by ENT-02 in vitro and in a Ceregan model of Alzheimer's disease (Limbocker, Chia, et al., 2019).

[0186] ENT-02 (MSI1436) reverses several age-related conditions (in mice), including metabolic syndrome, Alzheimer's disease, atherosclerosis, cancer, and impaired regenerative repair. The data in Example 6 demonstrate that ENT-03 can treat Alzheimer's disease in a mouse model that is an acceptable animal model of human Alzheimer's disease.

[0187] Using the Morris water maze, we tested the effects of ENT-03 (compound III) on spatial learning and memory deficits in two mouse models of familial Alzheimer's disease: hAPP-J20 mice expressing a double mutant of the human amyloid precursor protein (Mucke et al., 2000), and PS19 mice expressing the P301S mutant of the human microtubule-associated protein tau (Yoshiyama et al., 2007). In both disease models, one with amyloidopathy and the other with tauopathy, learning during the training phase (Figures 5A and 5E) and probe day memory (Figures 5B, 5C, 5F, and 5G) was improved with ENT-03 treatment compared with vehicle-treated hAPP-J20 or PS19 littermate control mice (Figure 5). The effects on preventing cognitive decline are similar to those observed with the related compound ENT-02 and hAPP-J20 and PS19 mice (Ricke et al., 2020).

[0188] (5) Method for synthesizing ENT-03 (compound III) Synthetic methods for preparing the aminosterols described herein, including ENT-03 (Compound III), are described in the Examples. In particular, the synthetic methods first involve preparing bdg-5 from BDG-4:

[0189] [ka]

[0190] BDG-5: 1H NMR(500 MHz, CDCl3) δ 3.93 (m,4H), 3.82 (br s, 1H), 3.66 (s, 3H), 2.4-2.2 (m, 2H),1.9-1.2 (m, 24H), 0.92 (d,3H, J = 7 Hz), 0.81 (s, 3H), 0.66 (s, 3H); 13 C NMR (CDCl3)δ 177,109, 67.9, 64.2, 64.1, 55.8, 51.4, 50.5, 45.6, 42.6, 39.5, 39.4, 37.5,36.3, 36.1, 35.7, 35.5, 35.4, 31.2, 31.0, 30.9, 28.0, 23.6, 20.9, 18.3, 11.8,10.4.

[0191] Next, prepare BDG-6 from BDG-5:

[0192] [ka]

[0193] BDG-6: 1 H NMR(500 MHz, CDCl3)δ 3.93 (m, 4H), 3.82 (br s, 1H), 3.61 (m, 2H), 1.97-1.84 (m, 4H), 1.7-1.0 (m,22H), 0.93 (d, 3H, J = 7 Hz), 0.81 (s, 3H), 0.66 (s, 3H); 13 C NMR (CDCl3) δ 109.3, 67.9,64.15, 64.13, 63.5, 56.0, 50.6, 45.6, 42.6, 39.51, 39.48, 37.5, 36.3, 36.1,35.7, 35.6, 35.5, 31.8, 31.2, 29.4, 28.2, 23.6, 20.9, 18.6, 11.8, 10.4.

[0194] Next, BDG-6 to BDG-7 are prepared:

[0195]

change

[0196] BDG-7: 1 H NMR(500 MHz, CDCl3)δ 8.07 (d, 2H, J = 8 Hz), 8.00 (d, 2H, J = 8 Hz), 7.57 (t, 1H, J = 8 Hz), 7.53(t, 1H, J = 8 Hz), 7.47 (t, 2H, J = 8 Hz), 7.41 (t, 2H, J = 8Hz), 5.16 (br s,1H), 4.25 (m, 2H), 3.87 (m, 4H), 2.02-1.85 (m, 2H), 1.8-1.1 (m, 22H), 0.95 (d,3H, J = 7 Hz), 0.88 (s, 3H), 0.68 (s, 3H); 13 C NMR (CDCl3)δ 166.7, 166.0, 132.8,131.1, 130.5, 129.7, 129.5, 128.4, 128.3, 109.0, 71.9,65.5, 64.2, 64.1, 55.8, 50.7, 47.2, 42.8, 39.5, 38.6, 37.4, 37.2, 35.7, 35.5,35.3, 33.3, 32.0, 31.2, 28.0, 25.2, 23.6, 21.1, 18.6, 11.8, 10.5.

[0197] Second time, BDG-7 and BDG-8 modulation:

[0198]

change

[0199] BDG-8: 17.24 kg, 93.3%). 1H NMR (500 MHz, CDCl3) δ 8.07 (d, 2H, J = 8 Hz), 7.57 (t, 1H, J = 7 Hz), 7.48 (t, 2H, J = 7 Hz), 5.15 (br s, 1H), 3.88 (m, 4H), 3.56 (br s, 2H), 2.02-1.84 (m, 2H), 1.75-0.98 (m, 24 H), 0.92 (d, 3H, J = 6.5Hz), 0.88 (s, 3H), 0.67 (s, 3H). 13 CNMR (CDCl3) δ 166.0, 132.7, 131.0, 129.7, 128.4, 109.0, 71.9, 64.2,64.1, 63.5, 55.8, 50.7, 47.2, 42.7, 39.5, 38.6, 37.3, 37.2 35.7, 35.5, 33.3,31.7, 31.3, 29.3, 28.0, 23.6, 21.1, 18.6, 11.8, 10.5.

[0200] Next, compound 1 and BDG-8 are prepared:

[0201]

change

[0202] Compound 1: 1 H NMR(500 MHz, CDCl3) δ 9.72 (s, 1H), 8.07 (d,2H, J = 7 Hz), 7.59 (t, 1H, J = 7 Hz), 7.49 (t, 2H, J = 7 Hz), 5.16 (br s, 1H), 3.88 (m, 4H), 2.45-2.27 (m, 2H), 2.00-1.85 (m, 2H), 1.78-1.17 (m, 22H), 0.913(d, 3H, J = Hz), 0.88 (s, 3H), 0.68 (s, 3H). 13C NMR(CDCl3) δ 203, 166,132.8, 131.0, 129.8, 128.4, 109, 72.0, 64.17, 64.11, 55.7, 50.7, 47.2, 42.8,40.8, 39.5, 38.6, 37.3, 37.2, 35.7, 35.5, 35.4, 33.3, 31.2, 27.9, 27.8, 23.7,21.1, 18.3, 11.7, 10.5.

[0203] Next, compound 1 and compound 2 are prepared:

[0204]

change

[0205] Compound 2: 1 H NMR (CDCl3, 300 MHz) δ8.10 - 8.07 (m, 2H), 7.60 - 7.57 (m, 1H), 7.52 - 7.47 (m, 2H), 6.7, 5.9(t, 1H), 5.17 (m, 1H), 4.21 - 4.12 (m, 2H), 3.92 - 3.88 (m, 4H), 2.06 (s, 3H), 2.2 - 1.0 (m, 29 H), 0.95 (d, 3H, J = 7 Hz), 0.90 (s, 3H), 0.69 (s, 3H); MS(ES+) 485.45 (M-C7H7O2+H).

[0206] Next, compound 2 and compound 3 are prepared:

[0207]

change

[0208] Compound 3: 1H NMR (CDCl3, 300 MHz) δ8.09 - 8.06 (m, 2H), 7.58 - 7.56 (m, 1H), 7.55 - 7.45 (m, 2H), 5.16 (m,1H), 4.12 - 4.05 (m, 2H), 3.90 - 3.85 (m, 4H), 2.39 - 2.36 (m, 1H), 2.0-1.0 (m,35 H), 1.11 (d, 3H, J = 7Hz), 0.88 (s, 3H), 0.67 (s, 3H); MS (ES+) 487.46 (M-C7H7O2+H).

[0209] Next, compound 4 and compound 3 are prepared:

[0210]

change

[0211] Compound 4: 1 H NMR(CDCl3, 300 MHz)δ 8.05 - 8.02 (m, 2H), 7.60- 7.57 (m, 1H), 7.51 - 7.45 (m, 2H), 5.21 (m, 1H), 2.4-1.0 (m, 32 H), 1.15 (d,3H, J = 7 Hz), 1.09 (s, 3H), 0.91 (d, 3H, J = 7 Hz), 0.67 (s, 3H); MS (ES+)415.52 (M-C7H7O2+H).

[0212] Next, compound 4 and compound 5 are prepared:

[0213]

change

[0214] Compound 5: 1H NMR(CD3OD, 300 MHz) δ 8.05 - 8.02 (m, 2H), 7.66- 7.60 (m, 1H), 7.54 - 7.49 (m, 2H), 5.17 (m, 1H), 3.36 - 3.04 (m, 13H), 2.37(m, MS (ES+) 723.78 (M+H).

[0215] ENT-03 (compound III) is then prepared from compound 5:

[0216] [ka]

[0217] Compound III (ENT-03) as the tetrahydrochloride salt: 1 H NMR(CD3OD, 300 MHz) δ 3.80 (br s, 1H), 3.20 -3.05 (m, 13H), 2.37 (m, 1H), 2.2-1.0 (m, 36 H), 1.13 (d, 3H, J = 7 Hz), 0.93(d, 3H, J = 7 Hz), 0.87 (s, 3H), 0.69 (s, 3H); MS (ES+) 619.31 (M+H).

[0218] Exemplary synthetic methods for preparing deuterated ENT-03 (ENT-03-d3 and ENT-03-d4) are also described in the Examples below.

[0219] II. Compounds In one aspect, an aminosterol compound having the formula:

[0220] [ka]

[0221] In the formula, R 1is H or D, and R 2 is H or D, but all R 1 is H and all R 2 is H or all R 1 and R 2 is H, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof. is provided.

[0222] In one embodiment, an aminosterol compound of the formula:

[0223] [ka]

[0224] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is provided.

[0225] In one embodiment, the aminosterol has the formula:

[0226] [ka]

[0227] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0228] In one embodiment, the aminosterol has the formula:

[0229] [ka]

[0230] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0231] In one embodiment, the aminosterol has the formula:

[0232] [ka]

[0233] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0234] In one aspect, an aminosterol having the formula:

[0235] [ka]

[0236] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof is provided.

[0237] In one embodiment, the aminosterol has the formula:

[0238] [ka]

[0239] or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0240] In another aspect, an aminosterol compound having the formula:

[0241] [ka]

[0242] Pharmaceutically acceptable salts, solvates, prodrugs, or derivatives are provided.

[0243] In some embodiments, the aminosterol compound has the formula:

[0244] [ka]

[0245] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0246] In one embodiment, the prodrug comprises a compound of the formula:

[0247] [ka]

[0248] In the formula, R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkenyl; and R 2 is H or -C(O)R 3 where R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkenyl, with the proviso that R 1 and R 2 At least one of them is not H; or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0249] In one embodiment, the prodrug comprises a compound of the formula:

[0250] [ka]

[0251] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0252] In one aspect, the prodrug comprises a compound having the formula:

[0253] [ka]

[0254] In the formula, R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkenyl; and R 2 is H or -C(O)R 3 where R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkenyl, with the proviso that R 1 and R 2 At least one of them is not H; or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0255] In one embodiment, the prodrug comprises a compound of the formula:

[0256] [ka]

[0257] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0258] In another aspect, an aminosterol compound having the formula:

[0259] [ka]

[0260] In the formula, R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkenyl; and R 2 is H or -C(O)R 3 where R 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted heterocyclyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkenyl, with the proviso that R 1 and R 2 At least one of them is not H; or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0261] In one embodiment, the aminosterol compound has the formula:

[0262] [ka]

[0263] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0264] Exemplary structures proposed herein include:

[0265] [ka]

[0266] RH or OH,

[0267] [ka]

[0268] R3-CH3, isopropyl, H.

[0269] The aminosterols of the present disclosure may contain asymmetric carbon atoms. As such, the aminosterols of the present disclosure may exist as either individual enantiomers or mixtures of the above. The present disclosure encompasses both mixtures at C25 and the natural R-orientation of the compounds. Thus, the aminosterols of the present disclosure may include both racemic mixtures and individual individual stereoisomers that are substantially free of other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means that less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of other stereoisomers, or less than "about X"% of other stereoisomers (X is a number between 0 and 100).

[0270] In some embodiments, the aminosterol is a derivative of any of the aminosterols disclosed herein, or a derivative of Compound III (ENT-03), modified by medicinal chemistry to improve biodistribution, ease of administration, metabolic stability, or any combination thereof. In some embodiments, Compound III or a derivative aminosterol is modified to include one or more of the following: (1) replacement of the carboxylate with a sulfonate, phosphate, or other anionic moiety selected to avoid metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of the hydroxyl group with a non-metabolizable polar substituent, such as a fluorine atom, to prevent metabolic oxidation or conjugation; and / or (3) replacement of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system.

[0271] The present technology also provides the salts, solvates and hydrates of aminosterols disclosed herein.The salts of aminosterols of this technology are formed between the acid and basic groups of aminosterols, such as amino functional groups, or between the base and acidic groups of aminosterols, such as carboxyl functional groups.In another embodiment, the aminosterol is a pharmaceutically acceptable acid addition salt.Examples of pharmaceutically acceptable salts include, but are not limited to, hydrochloride, sodium salt, sulfate, acetate, phosphate or diphosphate, chloride, potassium salt, maleate, calcium salt, citrate, mesylate, nitrate, tartrate, aluminum salt and gluconate salt.

[0272] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, bumarate, butyne-1,4-dioate, hexyne-1,6-diol, and the like. Included are oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In certain embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid, and phosphoric acid.

[0273] III. Methods for Producing the Aminosterol Compounds of the Present Disclosure In one aspect, an aminosterol of the formula:

[0274] [ka]

[0275] The present invention provides a method for producing the compound Ia, which comprises stimulating the addition of spermine to ENT Ia (compound Ia).

[0276] [ka]

[0277] In one aspect, a method for inhibiting the formation of an aminosterol of the formula:

[0278] [ka]

[0279] The present invention provides a method for inhibiting the formation of ENT-01a (compound Ia), the method comprising inhibiting the addition of spermine to ENT-01a (compound Ia).

[0280] [ka]

[0281] In some embodiments, ENT-01a (compound Ia) has the formula:

[0282] [ka]

[0283] ENT-03 (Compound III) has the formula:

[0284] [ka]

[0285] In one aspect, an aminosterol of the formula:

[0286] [ka]

[0287] The method comprises stimulating the addition of spermine to compound Ia (ENT-01a).

[0288] [ka]

[0289] In one aspect, an aminosterol of the formula:

[0290] [ka]

[0291] is provided a method of inhibiting the formation of the compound Ia, the method comprising inhibiting the addition of spermine to compound Ia.

[0292] [ka]

[0293] In some embodiments, compound Ia has the formula:

[0294] [ka]

[0295] and compound IV has the formula:

[0296] [ka]

[0297] In another aspect, an aminosterol of the formula:

[0298] [ka]

[0299] The method comprises stimulating the addition of spermine to compound Ia.

[0300] [ka]

[0301] In another aspect, an aminosterol of the formula:

[0302] [ka]

[0303] is provided a method of inhibiting the formation of the compound Ia, the method comprising inhibiting the addition of spermine to compound Ia.

[0304] [ka]

[0305] In some embodiments, compound Ia has the formula:

[0306] [ka]

[0307] Compound V has the formula:

[0308] [ka]

[0309] In some embodiments, the aminosterol is produced in vivo in a subject. In some embodiments, the aminosterol is produced in vitro.

[0310] In some embodiments, the addition of spermine to Compound I is inhibited in vivo in a subject. In some embodiments, the addition of spermine to Compound I is inhibited in vitro. In some embodiments, the addition of spermine to Compound Ia is inhibited in vivo in a subject. In some embodiments, the addition of spermine to Compound Ia is inhibited in vitro.

[0311] In some embodiments, stimulating the addition of spermine to compound Ia comprises contacting a matrix containing spermine and compound Ia with an agent that promotes the addition of spermine to compound Ia. In some embodiments, stimulating the addition of spermine to compound Ia comprises contacting cells containing spermine and compound Ia with a reagent that promotes the addition of spermine to compound Ia. In some embodiments, the aminosterol is produced in vivo in a subject, and stimulating the addition of spermine to compound Ia comprises administering to the subject an effective amount of an agent that promotes the addition of spermine to compound Ia, and administration of the agent can include administration by any of the same routes discussed herein for administering aminosterols.

[0312] In some embodiments, the agent that promotes the addition of spermine to compound Ia comprises a promoter or effector. The effector may comprise an enzyme activator, an enzyme inducer, a protein, a small molecule, or a nucleic acid. In some embodiments, the agent may comprise any agent that activates or catalyzes the addition of spermine to compound Ia. In certain embodiments, the agent comprises one or more enzymes that catalyze the addition of spermine to compound Ia. In some embodiments, the agent comprises one or more polynucleotides encoding enzymes that catalyze the addition of spermine to compound Ia, or one or more polynucleotides encoding peptide effectors. The one or more polynucleotides may comprise recombinant DNA and / or RNA. In some embodiments, the agent may comprise a vector comprising one or more polynucleotides.

[0313] In some embodiments, the spermine addition is enzymatic reductive amination. In some embodiments, the spermine addition is synthetic reductive amination. In some embodiments, the subject is a human. In some embodiments, the subject includes humans and non-human animals, including mammals, and immature and mature animals, including human children and adults. The human subject may be an infant, a toddler, a school-age child, a teenager, a young adult, an adult, or an elderly patient.

[0314] IV. Composition In another aspect, provided herein are compositions comprising an aminosterol compound disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, and one or more pharmaceutically acceptable carriers and / or excipients. Administration of an aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, can include administration of the composition.

[0315] A. Pharmaceutical Carriers While it is possible for an aminosterol, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to be administered alone, it is preferable to administer it together with one or more pharmaceutically acceptable carriers as a pharmaceutical formulation. The carrier must be "acceptable" in the sense of being compatible with the aminosterol, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and not deleterious to the recipient thereof.

[0316] Generally, preparation is prepared by uniformly and intimately contacting the aminosterol described herein or its pharmaceutically acceptable salt, solvate, prodrug or derivative with liquid carrier or finely divided solid carrier, or both.Then, if necessary, product is shaped into desired formulation.Non-aqueous media such as solidified oil and ethyl oleate are also useful, as well as liposome.

[0317] Carriers suitably contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability. Such materials are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, succinate, acetate, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides, e.g., polyarginine or tripeptides; proteins such as gelatin, serum albumin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates, including cellulose or its derivatives, glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as polysolvates, poloxamers, or PEG.

[0318] When aerosol administration is appropriate, the aminosterols described herein, or their pharmaceutically acceptable salts, solvates or prodrugs, can be formulated as aerosols using standard procedures.The term "aerosol" includes any gas-suspended phase of the compounds described herein that can be inhaled into bronchioles or nasal cavity, including dry powder and aqueous aerosols, as well as lung and nasal aerosols.Specifically, aerosols include the gas-borne suspension of droplets of the compounds described herein, such as can be produced by metered dose inhalers or nebulizers, or mist sprayers.Aerosols also include the dry powder composition of the composition of the present technology suspended in air or other carrier gas, which can be delivered, for example, by inhalation from an inhaler device. See Ganderton & Jones, "Drug Delivery to the Respiratory Tract" (Ellis Horwood, 1987); Ganderton, Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313 (1990); and Raeburn et al., Pharmacol. Toxicol. Methods, 27:143-159 (1992).

[0319] B. Dosage form Aminosterol composition can be conveniently provided in unit dosage form and can be prepared by any method well known in the field of pharmacy.Exemplary aminosterol dosage forms include but are not limited to oral, intranasal and injectable (IP, IV or IM).Preferably, aminosterol preparation is administered orally, intranasally or a combination thereof.In yet another embodiment, administration comprises parenteral administration.

[0320] The formulations or compositions of the present technology can be packaged with instructions for use or a package insert, or can be included in a kit. A "pharmaceutically acceptable carrier" refers to any type of non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary.

[0321] Pharmaceutical compositions according to the present technology may also include one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients, such excipients being known in the art.

[0322] Examples of fillers include lactose monohydrate, lactose anhydrous, and various starches, and examples of binders include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC™).

[0323] Suitable lubricants, including agents that affect the flowability of the powder being compressed, can include colloidal silicon dioxide such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.

[0324] Examples of sweeteners include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame. Examples of flavoring agents include Magnasweet® (a trademark of MAFCO), bubble gum flavor, and fruit flavor.

[0325] Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl ethyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

[0326] Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars, and / or any mixtures thereof. Examples of diluents include microcrystalline cellulose such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®, mannitol, starch, sorbitol, sucrose, and glucose.

[0327] Suitable disintegrants include lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof.

[0328] C. Dosage and Administration Period Doses of the aminosterols described herein can range from about 1 to about 500 mg / day, or any amount between these two values. In some embodiments, a subject is administered a therapeutically effective amount of an aminosterol described herein. A therapeutically effective amount of at least one aminosterol, or a salt or derivative thereof, in the methods of the present disclosure can be, for example, about 0.1 to about 20 mg / kg, about 0.1 to about 15 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 5 mg / kg, or about 0.1 to about 2.5 mg / kg of body weight of the subject. In another aspect, the therapeutically effective amount of at least one aminosterol, or a salt or derivative thereof, in the methods of the present disclosure can be, for example, about 0.001 to about 500 mg / day, about 0.001 to about 250 mg / day, about 0.001 to about 125 mg / day, about 0.001 to about 50 mg / day, about 0.001 to about 25 mg / day, or about 0.001 to about 10 mg / day.

[0329] Oral dosages of the aminosterols described herein can range from about 1 to about 500 mg / day, or any amount between these two values. In one embodiment, the method of administration comprises oral administration, and the therapeutically effective amount of the aminosterol comprises: (i) about 1 to about 300 mg / day; (ii) about 25 to about 300 mg / day; (iii) about 50 to about 300 mg / day; or (iv) about 75 to about 300 mg / day. Other exemplary doses of orally administered aminosterols are about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 25 5, about 260, about 265, about 270, about 275, about 280, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395 about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, or about 500 mg / day.

[0330] Intranasal doses of aminosterols are much lower than oral doses of aminosterols. Examples of such low intranasal aminosterol doses include, but are not limited to, about 0.001 to about 6 mg / day, or any amount between these two values. In some embodiments, the method of administration includes intranasal administration, and the therapeutically effective amount of aminosterol includes (i) about 0.001 to about 6 mg / day; (ii) about 0.001 to about 4 mg / day; or (iii) about 0.001 to about 2 mg / day. For example, a low dose of an aminosterol administered intranasally may be about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about The dose may be about 0.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6 mg / day.

[0331] For intranasal (IN) administration, it is contemplated that the aminosterol dosage may be selected so that it does not provide any pharmacological effect and, furthermore, does not produce any negative effects when the same dosage is administered by any other route (e.g., a "subtherapeutic" dosage). For example, as described herein, Compound III (ENT-03) has the pharmacological effect of reducing food intake and weight loss. Thus, in certain embodiments of the IN method of the present disclosure, when the aminosterol can be Compound III (ENT-03) or a salt, solvate, prodrug, or derivative thereof, the same IN Compound III dosage does not produce a significant reduction in food intake or significant weight loss when administered via another route (e.g., oral, IP, or IV). Similarly, some aminosterols are known to produce the pharmacological effects of nausea, vomiting, and / or hypotension. Thus, in certain embodiments of the present disclosure, when an aminosterol is administered IN, it has this effect, but when the same IN aminosterol dosage is administered via another route, such as orally, IP, or IV, the aminosterol dosage does not cause significant nausea, vomiting, and / or a drop in blood pressure. In some embodiments, intranasal administration includes delivery of aminosterol to the brain. Suitable exemplary aminosterol dosages are described above.

[0332] Regardless of the dosage of aminosterol, if undesirable side effects such as diarrhea, vomiting, nausea, etc. persist, the dosage of aminosterol can be tapered (reduced). In another embodiment, the dosage of aminosterol can be varied by plus or minus a specified amount to allow for a moderate reduction in dosage to eliminate adverse events, or a moderate increase in dosage when clinical results suggest this is desirable (e.g., no or minimal adverse events and potential increased efficacy with a moderate increase in dosage). For example, in one embodiment, the aminosterol dosage can be increased or decreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0333] The pharmaceutical composition comprising aminosterol or its derivative, salt, solvate or prodrug can be administered for any suitable period, including long-term maintenance dose.Dosage can be carried out as needed using any pharmaceutically acceptable dosing regimen.Aminosterol can be administered once a day or less, once every other day, once every three days, once every four days, once every five days, once every six days, once a week, or divided into multiple periods during a given day (for example, twice a day).In an exemplary embodiment, administration is 1x / day.

[0334] In other embodiments, the compositions are administered (1) as a single dose or as multiple doses over a period of time; (2) at a maintenance dose for an indefinite period of time; (3) once, twice, or more times; (4) daily, every other day, every third day, weekly, or monthly; (5) at a dose of about 1, about 2, about 3, about 2, about 1, about 3, about 4 weeks, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, about 1 year, about 1.5 years, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9 , about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5, about 22, about 22.5, about 23, about 23.5, about 24, about 24.5, or about 25 years, or (6) any combination of these parameters, e.g., 6 months of daily administration, 1 year or more of daily administration.

[0335] Yet another exemplary dosing regimen includes regular dosing, where an effective dose can be delivered once every about 1, about 2, about 3, about 4, about 5, about 6 days, or once a week.

[0336] In a preferred embodiment, the aminosterol dose is taken in the morning, i.e., on an empty stomach, preferably within about 2 hours of waking, which may be followed by a food-free period, e.g., about 60 to about 90 minutes. In other embodiments, the aminosterol dose is taken within about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, or about 4 hours during waking. In yet further embodiments, the aminosterol dose follows a food-free period, which is at least about 30 minutes, about 45 minutes, about 60 minutes, about 1.25 hours, about 1.5 hours, about 1.75 hours, or about 2 hours.

[0337] Without being bound by theory, it is believed that aminosterols, possibly due to their ENS signaling, affect circadian rhythms, and taking an aminosterol dose in the morning allows for synchronization of all autonomic neurophysiological functions that occur during the day. In other embodiments of the present disclosure, the aminosterol dose is taken within about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, or about 4 hours of waking up. Additionally, in other embodiments of the present disclosure, after aminosterol administration, the subject has a period of about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, or about 3 hours during which the subject does not consume food.

[0338] D. "Fixed Dose Aminosterols" In one aspect, the present application relates to the discovery of a method for determining a "fixed dose" of an aminosterol (i.e., not age-, size-, or weight-dependent, but rather individually calibrated) as described herein. The "fixed dose" obtained by this method provides highly effective results in treating the condition for which the "fixed dose" was determined, related symptoms along the "brain-gut" axis, and the underlying disease. Furthermore, methods utilizing this same "fixed dose" method for methods of preventing underlying diseases are contemplated herein. The present disclosure is not limited to methods in which a fixed aminosterol dosage is determined for a particular patient.

[0339] A therapeutically effective "fixed aminosterol dose" (also referred to herein as a "fixed titrated aminosterol dose") is determined for each patient by establishing a starting dose of the aminosterol composition and a threshold for improvement of a specific symptom, which is used as a tool or marker for assessing the effectiveness of the aminosterol dose. After determining the starting aminosterol dose for a particular patient, the aminosterol dose is titrated up by consistent amounts over time intervals until the desired improvement is achieved, and this aminosterol dose is the "fixed titrated aminosterol dose" for that particular patient for that specific symptom. In an exemplary embodiment, the orally administered aminosterol dose is titrated up by about 25 mg every 3 to 5 days until the desired improvement is achieved. Symptoms assessed with tools for measuring symptom improvement include, but are not limited to, constipation, hallucinations, sleep disorders (e.g., REM sleep disorder or circadian rhythm dysfunction), cognitive impairment, depression, or α-synuclein aggregation, as specifically described below.

[0340] This therapeutically effective "fixed dose" is then maintained throughout treatment and / or prophylaxis. Thus, even if a patient "goes off the drug" and stops taking the aminosterol composition, the same "fixed dose" is taken without a ramp-up period after reinitiating aminosterol treatment. Without being bound by theory, it is believed that the aminosterol dose depends on the severity of the neurological damage associated with the condition, which establishes a "fixed dose" threshold - for example, for constipation, the dose may be related to the degree of neurological damage in the patient's gastrointestinal tract.

[0341] Dose increase: When determining the "fixed dose of aminosterol" for a particular patient, start with a lower dose and then increase until the evaluation subject's symptoms show a positive result.An exemplary symptom to be evaluated can be constipation, but any symptom related to the disease or disorder to be treated can be used as a marker for evaluating aminosterol dosage.If undesirable side effects such as diarrhea, vomiting, nausea, etc. persist regardless of the dosage of aminosterol, the dose of aminosterol can also be tapered (reduced).

[0342] The starting dose of aminosterol depends on the severity of symptoms - for example, for patients experiencing severe constipation, defined as having less than one spontaneous bowel movement (SBM) per week, the starting dose of oral aminosterol may be about 150 mg / day or more.In contrast, for patients with moderate constipation (defined as having one or more SBMs per week), the starting oral aminosterol dose may be about 75 mg / day.Thus, for example, patients experiencing moderate constipation can start with an oral aminosterol dose of about 75 mg / day, while patients experiencing severe constipation can start with an oral aminosterol dose of about 150 mg / day.

[0343] In other embodiments, patients experiencing moderate symptoms (for the symptoms used to calculate the fixed, incremental aminosterol dose) may be started on an oral aminosterol dose of about 10 mg / day to about 75 mg / day, or any amount between these values. For example, the starting oral aminosterol dosage for moderate symptoms may be about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 60, about 65, about 70, or about 75 mg / day.

[0344] In yet a further embodiment, if a patient is experiencing severe symptoms (for the symptoms used to calculate the fixed, titrated aminosterol dose), the patient may be started on an oral aminosterol dose ranging from about 75 to about 175 mg / day, or any amount between these two values. For example, the starting oral aminosterol dosage for severe symptoms may be about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, or about 175 mg / day.

[0345] In some embodiments, the starting oral aminosterol dose may be about 125 mg or about 175 mg / day, again depending on the severity of symptoms such as constipation.

[0346] The starting intranasal (IN) aminosterol dosage before dose escalation can be, for example, about 0.001 mg / day to about 3 mg / day, or any amount between these two values. For example, the starting aminosterol dose for IN administration before dose escalation can be, for example, about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.7, about 0.8, about 0.9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 1.0, about 1.1, about 1.25, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.75, about 1.8, about 1.9, about 2.0, about 2.1, about 2.25, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.75, about 2.8, about 2.9, or about 3 mg / day.

[0347] In exemplary embodiments, aminosterol dosage is given periodically as needed.For example, aminosterol dosage can be administered once a day.Aminosterol dosage can be given every other day, twice, three, four or five times a week, once a week or twice a week.In another embodiment, aminosterol dosage can be given every other week, or can be given for several weeks, followed by skipping a few weeks (because the effect persists after treatment), and then resume aminosterol treatment.

[0348] When calculating a fixed, titrated aminosterol dose, the dose may be titrated after any suitable period. In one embodiment, the aminosterol dose is increased by approximately the specified amount every 3 to 7 days until the desired improvement is achieved. For example, if the symptom being treated / measured is constipation, the threshold improvement may be an increase of 1 SBM per week or at least 3 total bowel movements per week. In other embodiments, the aminosterol dose may be increased every about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days. In other embodiments, the aminosterol dose may be titrated about 1x / week, about 2x / week, about every other week, or about 1x / month.

[0349] During dose escalation, the aminosterol dose can be increased by a specified amount. For example, if the aminosterol is administered orally, the dose can be increased by about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg. When the aminosterol is administered intranasally, the dosage can be increased in increments of, for example, about 0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 mg.

[0350] Other symptoms that can be used as endpoints for determining the aminosterol dosage for a given patient for a given increased aminosterol dosage are any symptoms known to be associated with the disease, disorder, or condition intended to be treated. For example, neurological symptoms described herein include, but are not limited to, (a) cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep disorders, (b) at least one non-motor aspect of daily living experience as defined by Part I of the Unified Parkinson's Disease Rating Scale (UPDRS), such as daytime sleepiness, pain, urinary problems, constipation problems, orthostatic dizziness, and fatigue; (c) at least one non-motor aspect of daily living experience as defined by Part I of the Unified Parkinson's Disease Rating Scale (UPDRS), such as speech, saliva and drooling, feeding and swallowing tasks, meal, Dressing, hygiene, handwriting, turning over, tremors, bed , car, or deep chair to get out , walk Lines and Balance 、 and still like UP DR (c) at least one motor aspect of daily living experience as defined in Part II of S; e.g., speech, facial expression, rigidity, Finger tapping, hand movements, Hand pronation-supination, toe tap, foot agility, chair lift Standing up , gait, freezing of gait, postural stability, posture, slowness of body movements, postural tremor in the hands, Motor tremors in the hands, (d) at least one motor symptom identified in Part III of the UPDRS, such as rest tremor and permanence of rest tremor; (e) time spent with movement disorder, functional impact of movement disorder, time spent in off-state, functional impact of motor fluctuations, complexity of motor fluctuations, and Painful off-state dystonia Like UPDRS Part IV At least one exercise identified in complications (e) constipation, (f) depression, (g) cognitive impairment, (h) sleep disturbance, (i) circadian rhythm dysfunction, (j) hallucinations, (k) fatigue, (l) REM sleep disorder, (m) REM behavior disorder, (n) erectile dysfunction, (o) apnea, (p) postural hypotension 、(q) correction of blood pressure or orthostatic hypotension, (r) nocturnal hypertension, (s) regulation of body temperature, (t) improvement in breathing or apnea, (u) correction of cardiac conduction defects, (v) improvement in pain, (w) restoration of bladder sensation and voiding, (x) urinary incontinence, and / or (y) control of nocturia.

[0351] V. Methods of Treatment and / or Prevention Aspects of the present disclosure relate to methods of treating certain conditions and / or diseases associated with one or more of these conditions by administering a therapeutically effective amount of an aminosterol disclosed herein (e.g., ENT-03 (Compound III) or another aminosterol described herein), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, optionally in one or more pharmaceutically acceptable carriers, to treat and / or prevent diseases or disorders associated with one or more of these conditions. A therapeutically effective amount can be as described herein, including, but not limited to, a "fixed aminosterol dosage" determined as described herein.

[0352] In one embodiment, the symptoms, diseases, and / or disorders generally correlate with abnormal αS pathology and / or dopaminergic dysfunction, which means that they are amenable to treatment with the aminosterols described herein. The compositions of the present technology can be administered using any pharmaceutically acceptable method, including, but not limited to, oral, pulmonary, nasal, and aerosol administration. In yet another embodiment, administration includes parenteral administration.

[0353] In some embodiments, provided herein are methods for treating a subject in need thereof having a condition or symptom susceptible to treatment with an aminosterol, the methods comprising administering to the subject a therapeutically effective amount of an aminosterol described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, provided herein are methods for treating a subject in need thereof having a condition susceptible to treatment with an aminosterol, the methods comprising administering to the subject a therapeutically effective amount of a composition comprising, or consisting essentially of, an aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0354] Non-limiting examples of conditions amenable to treatment with aminosterols include, but are not limited to, constipation, hallucinations, sleep disorders, cognitive impairment, depression, and inflammation.

[0355] Examples of diseases amenable to treatment with aminosterols are described herein and include those described herein, e.g., PD, AD, MSA, SchizophreniaNeurological disorders include, but are not limited to, neurological disorders such as Huntington's disease (HD), progressive supranuclear palsy, frontotemporal dementia (FTD), vascular dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy (SMA), and Friedreich's ataxia. In another embodiment, the aminosterols described herein and compositions comprising the same may be used in methods for treating, preventing, and / or delaying the onset or progression of psychological and / or behavioral disorders. In one embodiment, the psychological and / or behavioral disorder may be, for example, depression, anxiety, delirium, irritability, confusion and hallucinations, amnesia, autism, apathy, bipolar disorder, disinhibition, abnormal movements and obsessive-compulsive behavior, sleep disorders, sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, and cognitive impairment. In another embodiment, a method is provided for treating, preventing, and / or delaying the onset or progression of cerebral or systemic ischemic disorders and / or associated symptoms in a subject in need thereof. Cerebral or systemic ischemic disorders include, for example, microvascular disorders, intrapartum cerebral ischemia, cerebral ischemia during / after cardiac arrest or cardiac resuscitation, cerebral ischemia due to intraoperative problems, Cerebral ischemia during carotid artery surgery, brain fart Chronic cerebral ischemia caused by narrowing of the blood supply arteries cerebral sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, High blood pressure, high cholesterol, myocardial infarction, Cardiac insufficiency, cardiac failure, Congestive heart failure, myocarditis, pericarditis, Pericardial inflammation, Coronary heart disease, angina, congenital heart disease, Shock, limb ischemia, renal artery stenosis, diabetic retinopathy, malaria-associated thrombosis, artificial heart valves, anemia, hypersplenism syndrome, emphysema, There may be pulmonary fibrosis, erectile dysfunction, and pulmonary edema.

[0356] In one embodiment, a method of inhibiting protein tyrosine phosphatase 1B (PTP1B) is provided, comprising contacting PTP1B with at least one aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0357] Applicant demonstrated in Example 3 that squalamine can increase transcription in the intestine of aged mice, thus having a rejuvenating effect on the intestine. This activity is believed to extend to ENT-03 (compound III) and its derivatives. Thus, in another aspect, a method for increasing transcription in the intestine of a subject is provided, comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any of the embodiments herein, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0358] A. Illustrative Symptoms Correlating with Aberrant αS Pathology and / or Dopaminergic Dysfunction and Indications for Aminosterol Treatment (1) Constipation In one embodiment, there is provided a method of treating, preventing, and / or delaying the onset or progression of constipation and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0359] Constipation is a common problem worldwide, affecting 2%–27% of the population, with most estimates ranging from 12%–20%. The prevalence of constipation increases to 30–40% in people over 65 years of age, with women disproportionately affected. In North America, 63 million people meet the Rome IV criteria for constipation, and in the United States alone, constipation accounts for more than 2 million physician visits each year. Laxatives are prescribed to 2–3 million patients each year, and in the majority of patients, the condition is chronic, requiring lifelong treatment.

[0360] Constipation is far more prevalent in PD patients than in the general population. Approximately 1 million people in the United States have PD, and approximately 60% of them, or 600,000 people, suffer from chronic constipation. In most cases, this condition is chronic, severe, and unresponsive to standard treatments. This represents an economic burden for individuals with PD and for the healthcare system. According to the April 2016 Federal Supply Schedule, available at fss.gsa.gov, the average 30-day reimbursement price for a basket of orally administered medications for constipation is approximately $260 or $3,120 per year. This equates to approximately $1.8 billion in laxatives prescribed exclusively to PD patients.

[0361] Constipation is defined as having fewer bowel movements than normal over a period of time (e.g., less than three times per week). Although often dismissed as a strictly gastrointestinal symptom, constipation is believed to be an early indicator of neurodegenerative disease, to the extent that ENS degeneration may be an indicator of later CNS degeneration. In fact, without being bound by theory, constipation is believed to be one of the earliest indicators of PD pathology. Therefore, embodiments of the methods disclosed herein relate to the treatment of constipation, or the treatment and / or prevention of underlying conditions associated with constipation.

[0362] Constipation is common in PD, often manifesting several years before the onset of motor dysfunction and subsequent PD diagnosis. Substantial evidence indicates that the neurodegenerative process associated with PD, namely the accumulation of toxic α-synuclein aggregates, occurs within the enteric nervous system several years before they appear in the brain. The enteric nervous system (ENS) has a large surface area and is thought to be vulnerable to continuous damage from infectious and toxic agents. Although the function of α-synuclein is unknown, inflammation within the nervous system leads to increased intracellular levels. In PD patients, increased α-synuclein leads to the formation of neurotoxic aggregates, likely due to an inability of neurons (due to genetic factors) to process them effectively. The α-synuclein aggregates are then transported along the vagus nerve to the dorsal motor nucleus in the brainstem and from there to more rostral structures.

[0363] PD patients suffer from a form of constipation thought to be primarily caused by delayed colonic transit. Furthermore, defecation is often impaired by dysfunction of the recto-anal reflex in PD subjects. For many individuals, bowel problems are a significant adverse effect on quality of life. Failure to effectively manage this problem can also lead to bowel obstruction, especially as the end-stage of PD approaches. A limited number of treatments are undergoing clinical trials, including agents that increase the fluid content of stool by either blocking fluid absorption or increasing the osmotic load in the intestine.

[0364] The pathophysiology of gastrointestinal dysfunction in PD involves the deposition of αS in the ENS as well as in the brainstem. αS, a protein normally produced in neurons, forms neurotoxic intracellular aggregates in PD for unknown reasons. Numerous studies suggest that αS aggregate formation begins in the ENS of PD individuals many years before the onset of motor symptoms. As a result of normal retrograde neuronal transport within the vagus nerve, toxic αS aggregates are transported from ENS neurons to the dorsal motor nucleus of the vagus nerve and subsequently to areas of the brain involved in physical movement and balance. Constipation differs from other forms of this condition because it is primarily acquired and neurodegenerative in nature.

[0365] Examples of tools that can be used to measure and evaluate the effect of aminosterol treatment on constipation include, for example, (1) the Rome-IV criteria for constipation (seven criteria, requiring a constipation diagnosis of two or more of the following: (i) straining during at least 25% of bowel movements; (ii) sensation of incomplete evacuation during at least 25% of bowel movements; (iv) anorectal obstruction / blockage for at least 25% of bowel movements; (v) manual manipulations to facilitate at least 25% of bowel movements; and (vi) less than three times per week. (vi) absence of loose stools without laxative use; (2) the Constipation-Relief Scale (1 to 7, where 1 is incontinent, 4 is normal, and 7 is manual emptying); (3) the Bristol Stool Chart, a patient-friendly means of classifying stool characteristics (stool consistency ratings are a valid proxy for bowel motility) and a stool diary; (4) the Unified Parkinson's Disease Rating Scale (UPSRS), section 1.11; (5) Patient Assessment of Constipation Symptoms (PAC-SYM); and (5) Patient Assessment of Constipation Quality of Life (PAC-QOL).

[0366] Examples of constipation characteristics that can be positively affected by aminosterol treatment include, but are not limited to, frequency of constipation, duration of constipation symptoms, stool frequency, stool consistency, abdominal pain, abdominal bloating, incomplete defecation, unsuccessful attempts at defecation, pain associated with defecation, and straining associated with defecation. Potentially, all of these characteristics can be positively affected by the methods of the present disclosure. Furthermore, assessments of these characteristics, such as spontaneous bowel movements (SBM) per week, stool consistency (Bristol Stool Form Scale) (Lewis and Heaton 1997; Heaton et al., 1992), ease of passage (Ease of Evacuation Scale) (Andresen et al., 2007), rescue medication use, and bowel function-related symptoms and quality of life (PAC-SYM (Frank et al., 1999) and PAC-QOL (Marquis et al., 2005)), are known in the art.

[0367] Methods of using a therapeutically effective amount of an aminosterol composition according to the present disclosure to treat and / or prevent constipation preferably result in an increase in the number of spontaneous bowel movements per week and / or other improvement in stool condition, which may be, for example, an increase of about 1 to about 3 spontaneous bowel movements per week, or optionally, complete restoration of regular bowel function.

[0368] In one embodiment of the present disclosure, in the methods described herein, treating a subject with constipation with an aminosterol results in an improvement in one or more characteristics of constipation. The improvement can be, for example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 325, about 350, about 375, or about 400%. Examples of constipation characteristics that can be improved by the disclosed methods include, but are not limited to, frequency of constipation, duration of constipation symptoms, stool frequency, stool consistency, abdominal pain, abdominal bloating, incomplete defecation, unsuccessful attempts to defecate, pain with defecation, and straining with defecation. Measurement of constipation characteristics can be performed using any clinically recognized scale or tool.

[0369] In one embodiment, the dose of aminosterol required to positively affect the symptom being evaluated, referred to herein as a "fixed, incremental aminosterol dose," is patient-specific as described herein. In another embodiment, it is theorized that the severity of constipation correlates with a higher required "fixed, incremental aminosterol dose," and that the aminosterol dose required to achieve a positive effect in a subject for the symptom being evaluated correlates with the degree of neuronal damage. Therefore, it is theorized that greater neuronal damage correlates with a higher required aminosterol dose to achieve a positive effect in a subject for the symptom being evaluated. The observation that the aminosterol dose required to achieve a desired response increases with the severity of constipation supports the hypothesis that the greater the load on αS that interferes with neuronal function, the higher the dose of aminosterol required to restore normal intestinal function. It has also been hypothesized that gastrointestinal motility disorders in PD are due to the progressive accumulation of αS in the ENS, and that aminosterol treatment can restore neuronal function by replacing αS and stimulating enteric neurons. These results demonstrate that the ENS in PD is not irreversibly damaged and can be restored to normal function.

[0370] In calibrating a fixed aminosterol dose for a particular patient, the starting dose varies based on the severity of the constipation. Thus, for subjects with severe constipation (e.g., subjects with less than one CSBM or SBM per week), oral aminosterol dosing is initiated at about 100 to about 150 mg / day or more (or any amount between these values, as described herein). For patients with less severe constipation, e.g., more than one CSBM or SBM per week, oral aminosterol administration is initiated at about 25 to about 75 mg / day (or any amount between these values, as described herein). Thereafter, the dose is increased by a specified amount over a specified period until a consistent incremental dose is identified for the patient. If undesirable side effects, such as diarrhea, vomiting, or nausea, persist regardless of the aminosterol dose, the aminosterol dose can be tapered (decreased).

[0371] For example, for a patient with severe constipation, the starting oral aminosterol dosage can be from 75 mg to about 300 mg / day, or any amount between these two values. In other embodiments, the starting oral aminosterol dosage for a patient with severe constipation can be, for example, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 185, about 186, about 187, about 188, about 189, about 190, about 200, about 2010, about 2011, about 2012, about 2013, about 2014, about 2015, about 2016, about 2017, about 2018, about 2020, about 2021, about 2022, about 2023, about 2024, about 2025, about 2026, about 2027, about 2028, about 2029, about 2100, about 2111, about 2112, about 2113, about 2114, about 2115, about 2116, about 2117, about 2118, about 2119, about 2219, about 2220, about 2221, about 2222, about 2223, about 2224, about 2225, about 2226, about 2227 The oral aminosterol dose may be about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 1

[0372] For patients with less severe constipation, oral aminosterol dosage is initiated at about 10 to about 75 mg / day, or any amount between these two values ​​as described herein. For example, the starting oral aminosterol dosage for patients with moderate to mild constipation can be about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75 mg / day or less. The constant incremental oral aminosterol dose for patients with mild or moderate constipation can range from about 5 mg to about 350 mg / day, or any amount between these two values ​​as described herein.

[0373] (2) Hallucinations In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of hallucinations and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0374] Hallucinations are sensory impressions or perceptions of objects or events in any of the five senses (sight, touch, sound, smell, or taste) that are not based on external stimuli. Hallucinations can have debilitating effects on a subject's health and life by making it difficult for them to function normally in everyday situations and by causing sleep disturbances, leading to harm to themselves or others. Examples of hallucinations include "seeing" someone who is not there (visual hallucinations), "hearing voices that others do not hear" (auditory hallucinations), "feeling" something (tactile hallucinations), "smelling" (olfactory hallucinations), and "tasting" (gustatory hallucinations). Other examples of types of hallucinations include hypnagogic hallucinations (vivid, dream-like hallucinations that occur during sleep onset), hypnopompic hallucinations (vivid, dream-like hallucinations that occur during awakening), kinesthetic hallucinations (hallucinations involving sensations of bodily movement), and somatic hallucinations (hallucinations involving perceptions of bodily experiences occurring within the body).

[0375] Hallucinations can be the result of a psychiatric condition or correlate with a medical condition, such as a neurological disorder. Hallucinations, particularly auditory hallucinations, are characteristic of certain psychiatric conditions, such as schizophrenia, occurring in up to 70–80% of subjects. They also occur in 30–50% of individuals with borderline personality disorder. Auditory hallucinations can control behavior or actions, trigger violent defensive behavior, or lead to self-harm. They can also occur in postpartum psychosis. Auditory hallucinations may also be less common in severely depressed or manic individuals. Substance abuse can also be associated with visual hallucinations. Alcoholism or abstinence, post-traumatic stress disorder (PTSD), and bereavement can also be associated with visual hallucinations.

[0376] In some cases, hallucinations are the result of mental or neurological disorders.Aminosterol compositions can, for example, reverse the dysfunction of mental or neurological disorders and treat hallucinations.For example, mental disorders can be selected from the group consisting of bipolar disorder, borderline personality disorder, depression (mixed type), dissociative identity disorder, generalized anxiety disorder, major depression, obsessive-compulsive disorder, post-traumatic stress disorder, psychosis (NOS), schizoaffective disorder, and schizophrenia.For example, neurodegenerative disorders can be PD, supranuclear palsy, multiple system atrophy, Parkinsonism, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, Friedreich's ataxia, multiple sclerosis (MS), dementia or disease with Lewy bodies, spinal muscular atrophy, frontotemporal dementia, progressive nuclear palsy, Guadeloupian Parkinsonism, spinocerebellar ataxia, or vascular dementia. In a preferred embodiment, the aminosterol composition of the present disclosure reverses the dysfunction of neurodegenerative disorders and treats hallucinations.Neurological disorders can be, for example, the result of (a) brain tumor, (b) sleep disorders such as narcolepsy, or (c) focal brain lesions such as occipital lobe lesions or temporal lobe lesions.In exemplary embodiments, temporal lobe lesions can be lesions in the uncinate gyrus, cerebral peduncle, or substantia nigra.Neurological disorders can be, for example, the result of (d) diffuse involvement of the cerebral cortex, such as caused by viral infection.

[0377] Diffuse lesions in the cerebral cortex may be the result of cerebral vasculitis, and viral infections may be, for example, acute metabolic encephalopathy, encephalitis, or meningitis. The pathology of cerebral vasculitis may be caused by autoimmune diseases, bacterial infections, viral infections, systemic vasculitis, etc. The autoimmune disease may be, for example, systemic lupus erythematosus (SLE).

[0378] Furthermore, sensory loss can also lead to hallucinations. Sensory loss can be, for example, visual, auditory, gustatory, tactile, or olfactory. In a preferred embodiment, the aminosterol composition of the present disclosure reverses the dysfunction of sensory loss and treats hallucinations. In another preferred embodiment, the aminosterol composition of the present disclosure reverses the dysfunction of the enteric nervous system and treats hallucinations.

[0379] The method of using a therapeutically effective amount of an aminosterol composition according to the present disclosure to treat and / or prevent hallucinations preferably results in a reduction in hallucinations. This reduction can be, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% reduction in the occurrence of hallucinations. The method of the present disclosure can also result in the subject being free from hallucinations. Hallucinations can include, for example, visual, auditory, tactile, gustatory, or olfactory hallucinations. Improvement can be measured using any clinically recognized assessment or tool.

[0380] Examples of tools to measure and assess the effect of aminosterol treatment on hallucinations include the University of Miami Parkinson's Disease Hallucinations Questionnaire (UM-PDHQ), the Unified Parkinson's Disease Rating Scale (UPSRS) - Section 1.2 (Hallucins and Psychosis), direct questionnaires, the Chicago Hallucinations Rating Scale (CHAT), the Psychotic Symptom Rating Scale (PSYRATS), the Auditory Hallucinations Rating Scale (AHRS), the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ), the Auditory Hallucinations Questionnaire (CAHQ), the National Institute of Mental Health Schedule for Perceptions of Unusual People (MUPS), the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Launay-Slade Hallucinations Scale (LSHS), the Cardiff Abnormal Perceptions Scale (CAPS), and the Structured Interview for the Assessment of Perception Abnormalities (SIAPA).

[0381] (3) Inflammation and / or dopaminergic dysfunction associated with abnormal αS pathology and indications for aminosterol treatment In one embodiment, a method is provided for treating, preventing, and / or delaying the onset or progression of inflammation and / or related symptoms associated with αS pathology in a subject, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0382] αS is a potent pro-inflammatory hormone. Inflammation can be blocked by one of two strategies. First, inflammation can be blocked by reducing or stopping αS production, thereby decreasing the tissue concentration of αS. Alternatively, inflammation can be blocked by interrupting signaling between αS and inflammatory cells expressing CD11b. The subject of the disclosed method can be any mammal, including humans.

[0383] The inflammatory disease or condition caused by overexpression of neuronal αS may be a neurodegenerative disease (NDD) such as α-synucleinopathy. Exemplary α-synucleinopathies include, but are not limited to, PD, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, or schizophrenia. In other embodiments, the inflammatory disease or condition caused by overexpression of neuronal alpha-synuclein may be an autoimmune disease, a chronic inflammatory disease, or an autoinflammatory disease. In other embodiments, the inflammatory disease or condition caused by overexpression of neural αS may be selected from the group consisting of asthma, chronic peptic ulcer disease, tuberculosis, chronic periodontitis, chronic sinusitis, chronic active hepatitis, psoriatic arthritis, acne vulgaris, osteoarthritis, rheumatoid arthritis, lupus, systemic lupus erythematosus, multiple sclerosis, ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis, allergy, inflammatory bowel disease, celiac disease, chronic prostatitis, diverticulitis, dermatomyositis, polymyositis, systemic sclerosis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, interstitial cystitis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, sarcoidosis, transplant rejection, and vasculitis.

[0384] In some embodiments of the present disclosure, patient populations that are particularly susceptible to excessive production or secretion of αS can benefit from the methods of the present disclosure, for example, can be targeted for treatment, including preventive treatment. For example, patient populations with αS mutants that result in increased amounts of αS in tissues can be treated using the methods of the present disclosure. Another example of a patient population that is susceptible to high levels of αS is a patient with a chronic inflammatory condition or disease. Yet another example is a patient population that has elevated levels of αS aggregation in enteric neurons, which manifests as constipation.

[0385] The disclosed methods can result in a reduction in the intensity of inflammation, blood levels of inflammatory markers, inflammatory markers in tissue, or the number of inflammatory cells in tissue, or a combination thereof, compared to a control or compared to qualitative or quantitative amounts from the same patient or subject before treatment. For example, the reduction can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. Improvement can be measured using any clinically recognized tool or assessment.

[0386] In some embodiments, the reduction is measured quantitatively or qualitatively by a method selected from the group consisting of high performance liquid chromatography, liquid chromatography mass spectrometry, enzyme-linked immunosorbent assay, protein immunoprecipitation, immunoelectrophoresis, Western blot, and protein immunostaining.

[0387] Furthermore, the present disclosure shows that individuals having inflammatory conditions suitable for treatment or prevention by the αS-targeting methods described herein can be identified by determining the tissue concentration of αS at the site of inflammation, with higher levels of αS compared to controls or healthy subjects correlating with patients suitable for treatment by the methods of the present disclosure.

[0388] It is theorized that administration of aminosterols reduces the formation of neurotoxic αS aggregates in vivo and stimulates gastrointestinal motility in patients with neurological disorders such as PD and constipation. It is also hypothesized that the greater the αS inhibitory burden on neuronal function, the higher the dose of aminosterols needed to address other symptoms of α-synuclein aggregation and restore normal gut function.

[0389] B. Exemplary Diseases or Disorders Correlated with Aberrant αS Pathology and / or Dopaminergic Dysfunction and Applicability of Aminosterol Treatment The aminosterols described herein (e.g., ENT-03 (Compound III)), including pharmaceutically acceptable salts, solvates, prodrugs, or derivatives thereof, can be used in methods of treating and / or preventing various diseases and disorders generally correlated with aberrant αS pathology and / or dopaminergic dysfunction, as described herein and below.

[0390] In one embodiment, a method is provided for treating, preventing, and / or delaying the onset or progression in a subject of a disease or disorder correlated with abnormal αS pathology and / or dopaminergic dysfunction and / or associated symptoms related to αS pathology, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0391] (1) Neurological or neurodegenerative disorders or diseases In one embodiment, there is provided a method of treating, preventing, and / or delaying the onset or progression of a neurodegenerative or neurological disease and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0392] The disclosed methods and aminosterol compositions can be used to treat and / or prevent neurological disorders or diseases as described herein, examples of which include, but are not limited to, AD, PD, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), schizophrenia, Friedreich's ataxia, vascular dementia, dementia or disease with Lewy bodies, spinal muscular atrophy, supranuclear palsy, frontotemporal dementia, progressive nuclear palsy, Guadeloupe Parkinsonism, spinocerebellar ataxia, and autism.

[0393] Various neuroimaging techniques can be useful for early diagnosis and / or monitoring the progression of neurodegenerative disorders. Examples of such techniques include, but are not limited to, neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI) (e.g., including diffusion tensor measurements of anatomical connectivity), [18F]fluorodeoxyglucose (FDG) PET, amyloid-labeling agents, [18F]F-dopa PET, radiotracer imaging, volumetric analysis of regional tissue loss, specific imaging markers of abnormal protein deposition (e.g., for AD progression), multimodal imaging, and biomarker analysis. Jon Stoessl, "Neuroimaging for Early Diagnosis of Neurodegenerative Disease," Transl. Neurodegener., 1:5 (2012). Combinations of these techniques can also be used to monitor disease progression.

[0394] The progression of neurodegeneration can be measured using well-known techniques. For example, electroencephalography (EEG) can be used as a biomarker for the presence and progression of neurodegenerative diseases (Morairty, 2013). MRI is another exemplary technique that can be used to measure the progression of neurodegeneration (Rocca et al., 2017). Alternatively, neurodegeneration can be measured by measuring the levels of one or more biomarkers known in the art to indicate neurodegeneration, for example, using an analytical technique selected from the group consisting of high-performance liquid chromatography, liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assay, protein immunoprecipitation, immunoelectrophoresis, Western blot, and protein immunostaining. Biomarkers indicative of neurodegeneration are known to those skilled in the art and may include, for example, any of those described in Beach et al., 2017 (the entire disclosure of which is incorporated herein by reference).

[0395] For example, structural MRI can be used to measure atrophy of the hippocampus and entorhinal cortex in AD, as well as lesions in the lateral parietal cortex, posterior superior temporal cortex, and medial posterior cingulate cortex. In frontotemporal dementia (FTD), structural MRI can show atrophy of the frontal or temporal poles. DTI can be used to show abnormal white matter in the parietal lobe of patients with dementia with Lewy bodies (DLB) compared to AD. Functional MRI can reveal reduced frontal but increased cerebellar activation during working memory tasks in FTD compared to AD. In another example, [18F]fluorodeoxyglucose (FDG) PET can show decreased glucose metabolism in the parietotemporal cortex in AD. Id.

[0396] In one embodiment of the present disclosure, the progression or onset of a neurodegenerative disorder is delayed or prevented for a specified period of time after administration of a therapeutically effective amount of an aminosterol according to the present disclosure to a subject in need thereof, as measured by a medically recognized technique. For example, the progression or onset of a neurodegenerative disorder can be slowed by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0397] The period over which the progression or onset of a neurodegenerative disorder is measured can be, for example, one month or more or one year or more, e.g., about 6 months, about 1 year, about 18 months, about 2 years, about 36 months, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 years, or any value between about 6 months and about 20 years or more.

[0398] In another embodiment, a neurodegenerative disorder can be positively affected by administration of a therapeutically effective amount of an aminosterol according to the present disclosure. "Positively affecting" includes, for example, slowing the progression of the condition, ameliorating one or more symptoms, etc.

[0399] (i) Parkinson's disease In one embodiment, provided is a method for treating, preventing, and / or delaying the onset, prevention, and / or progression of Parkinson's disease (PD) and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0400] PD is a progressive neurodegenerative disease caused by the accumulation of the protein αS in the peripheral and central nervous systems (CNS), including the enteric nervous system (ENS), autonomic nervous system, and brain (Braak et al. 2003(a) and (b)). While motor symptoms remain necessary for the diagnosis of PD (Hughes et al. 1992), non-motor symptoms present a greater therapeutic challenge (Zahodne et al. 2012). These symptoms include constipation (Ondo et al. 2012; Lin et al. 2014), disturbances in sleep architecture (Ondo et al. 2001; Gjerstad et al. 2006), cognitive dysfunction (Auyeung et al. 2012), hallucinations (Friederich et al. 2016; Diederich et al. 2009), rapid eye movement disorder (REM) behavior disorder (RBD), and depression (Aarsland et al. 2007), all of which result from dysfunction of neural pathways that are not reversed by dopamine replacement. Indeed, prolonged institutionalization, caregiver burden, and reduced life expectancy correlate significantly more significantly with the severity of these symptoms than with motor symptoms (Goetz et al., 1995). In 2003, Braak proposed that PD begins in the gastrointestinal tract due to neurotoxic aggregates of αS-type endothelial cells (ENS), a finding clinically evidenced by the appearance of constipation in the majority of PD patients many years before the onset of motor symptoms (Braak et al., 2003(a) and (b)). Recent studies in rats have demonstrated the translocation of αS aggregates from the ENS to the CNS via the vagus nerve and other afferent nerves. Neurotoxic aggregates gradually accumulated in the brainstem, then dispersed rostrally to structures within the diencephalon, eventually reaching the cerebral hemispheres.

[0401] PD is defined as a synucleinopathy, with synuclein deposition being the primary diagnostic determinant. Furthermore, patients with dementia and Lewy bodies are considered to have PD if they meet the clinical disease criteria. Imaging modalities (e.g., MRI, single photon emission computed tomography [SPECT], and positron emission tomography [PET]) allow in vivo brain imaging of structural, functional, and molecular changes in PD patients.

[0402] Over the past few years, research has been conducted to identify specific markers or combinations of markers that can be used to probabilistically estimate prodromal PD. Researchers have identified a timeline of symptoms indicative of prodromal PD that predict PD. The presence of each contributes to the estimation of the likelihood of prodromal PD. Some have been employed to identify prodromal PD. Other studies have used a combination of symptoms and imaging tests (e.g., hyposmia combined with dopamine receptor imaging has been shown to have a high predictive value). In another example, REM sleep behavior disorder (SBD), constipation, and hyposmia were found to be individually common but rarely co-occur in individuals without PD, leading to a high predictive value for PD.

[0403] PD can also be assessed using the UPDRS, which consists of 42 items on the following four subscales: (1) Part I, Non-Motor Aspects of Daily Living Experience (nM-EDL); dementia (item 1.1), hallucinations / psychosis (item 1.2), depressed mood (item 1.3), anxious mood (item 1.4), blunted affect (item 1.5), features of dopamine dysregulation syndrome (item 1.6), sleep problems (item 1.7), daytime sleepiness (item 1.8), pain / other sensations (item 1.9), urinary problems (item 1.10), constipation problems (item 1.11), and lightheadedness (item 1.12). and Fatigue (section 1.13), (2) Part II, Motor Aspects of Daily Living Experiences (M-EDL); Speech (section 2.1), Saliva and drooling (Section 2.2), feeding and swallowing (Section 2.3), meal (section 2.4), changing clothes (section 2.5), hygiene (section 2.6), handwriting (2.7), Hobbies and other activities (2.8), Turning over (2.9), Tremor (2.10), Bed , car, or getting out of a deep chair (Section 2.11), Walking and balance (section 2.12), and Freezing of gait (section 2.13); Part III, motor examination; speech (section 3.1); facial expression (Section 3.2), rigidity (Section 3.3), finger tapping (Section 3.4), hand movement (Section 3.5), hand pronation and supination (Section 3.6), toe tapping (Section 3.7), foot agility (Section 3.8), Standing up from a chair(3.9), Gait (3.10), Freezing of Gait (3.11), Postural Stability (3.12), posture (Section 3.13), general spontaneity of movement (bradykinesia) (Section 3.14), postural tremor of the hand (Section 3.15), hand movement time Tremor (section 3.16), at rest Tremor (Section 3.17), and resting tremor permanent Sex (section 3.18); Part IV, Exercise complications : time spent in motor impairment (Section 4.1), functional impact of motor impairment (Section 4.2), time spent in the off state (Section 4.3), functional impact of fluctuations (Section 4.4), complexity of motor fluctuations (Section 4.5), and Painful off-state dystonia (Section 4.6).

[0404] Additionally, symptom-based endpoints can be assessed using known scales. For example, (1) depression can be assessed using the Beck Depression Inventory (BDI-II) (Steer et al., 2000), dementia can be assessed using the Mini-Mental State Examination (MMSE) (Palsetia et al., 2018), sleep and REM behavior disorders (RBD) can be assessed using a diary and the RBD Questionnaire (RBDQ) (Stiasny-Kolster et al., 2007), and hallucinations can be assessed using the PD Hallucinations Questionnaire (PDHQ) (Papapetropoulos et al., 2008) and direct questioning. Circadian system status can also be assessed by continuous monitoring of wrist skin temperature (Thermochron iButton DS1921H; Maxim, Dallas) according to published procedures (Sarabia et al., 2008).

[0405] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition described herein to a PD patient results in an improvement in one or more symptoms of PD, or an improvement in one or more clinically accepted evaluation metrics, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. Improvement can be measured using any clinically recognized tool or assessment.

[0406] The progression and treatment of PD are particularly challenging, considering that patients develop resistance to dopamine, which then requires gradually increasing the dose until no response is elicited. Without being bound by theory, it is believed that pre- or co-administration of an aminosterol composition according to the present disclosure (e.g., ENT-03 (Compound III)) can reduce the dopamine dose required to elicit a therapeutic effect on Parkinson's symptoms and / or increase the period during which the patient is sensitive to dopamine. It is also theorized that pre- or co-administration of an aminosterol composition according to the present disclosure can delay the period during which the patient is advised to begin dopamine therapy. This is important because patients are currently encouraged to delay the initiation of dopamine treatment as long as possible, even after a period of time during which the subject has become resistant to dopamine.

[0407] (ii) Alzheimer's disease In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of Alzheimer's disease (AD) and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0408] Alzheimer's disease (AD) is a chronic neurodegenerative disorder that usually begins slowly and worsens over time. It accounts for 60–70% of dementia cases. As the disease progresses, symptoms may include speech impairment, disorientation, mood swings, loss of motivation, and behavioral problems rather than managing self-care. As a person's condition deteriorates, they often withdraw from their family and society. Gradually, physical function is lost, ultimately leading to death. While the rate of progression varies, the typical life expectancy after diagnosis is 3–9 years. In 2015, the global population of AD was approximately 29.8 million. While AD most commonly occurs in people aged 65 or older, early-onset Alzheimer's disease accounts for 4–5% of cases. It affects approximately 6% of people aged 65 or older. In 2015, there were approximately 1.9 million deaths due to dementia.

[0409] Symptoms of Alzheimer's disease are primarily cognitive impairment, including memory loss, language impairment, and visuospatial skills; functional impairment, which may extend to occupational and social problems (e.g., activities of daily living); and behavioral symptoms, including depression, anxiety, aggression, and psychosis, may also emerge as the severity of the disease progresses.

[0410] Currently, a definitive diagnosis of AD requires clinical findings of cognitive impairment consistent with AD and postmortem identification of brain pathology consistent with AD. The term AD dementia is used to describe dementia due to AD pathophysiology. The term "probable Alzheimer's disease" is used in a subject's life when the subject exhibits clinical features of AD and other possible biological causes of dementia (e.g., PD or stroke) have been excluded. Currently, there are various art-accepted methods for diagnosing probable AD. Typically, these methods are used in combination and involve determining an individual's ability to perform daily activities and identifying changes in behavior and personality. AD-type dementia is also typically characterized by amnesic symptoms (memory impairment) or impairments in language, visuospatial, or executive function. Cognitive ability / impairment may be determined by art-accepted methods, including, but not limited to, validated instruments assessing global cognition (e.g., the modified Mini-Mental State Examination (3MS-E)), as well as specific domains such as visual and verbal memory (e.g., the Brief Visual-Spatial Memory Test-Revised (BVMT-R) and the Hopkins Verbal Learning Test-Revised (HVLT-R)), language (e.g., the Generative Verbal Fluency Test (GVFT)), and executive function and attention (e.g., the Digit Span Test (DST)). Dementia due to AD is also defined by an insidious onset and a history of worsening cognitive abilities.

[0411] Criteria for "probable AD" are described by the National Institute of Aging-Alzheimer's Association workgroup (McKhann et al., 2011). According to this workgroup, for individuals who initially exhibit core clinical features of AD dementia, evidence of disease-related biomarkers may increase diagnostic certainty.

[0412] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to a patient with AD results in an improvement in one or more symptoms of AD, or an improvement in one or more clinically accepted evaluation metrics, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0413] (iii) Multiple system atrophy In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of multiple system atrophy (MSA) and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0414] Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by a combination of symptoms affecting both the autonomic nervous system (the part of the nervous system that controls involuntary movements such as blood pressure and digestion) and movement. MSA, also known as Shy-Drager syndrome, is a neurodegenerative disorder characterized by tremor, bradykinesia, muscle rigidity, postural instability due to autonomic nervous system dysfunction (collectively known as parkinsonism), and ataxia. It is caused by the progressive degeneration of neurons in several parts of the brain, including the substantia nigra, striatum, inferior olivary nucleus, and cerebellum. There is no known cure for MSA, and management is primarily supportive.

[0415] The progression of neurodegeneration can be measured using well-known techniques. For example, electroencephalography (EEG) can be used as a biomarker for the presence and progression of neurodegenerative diseases (Morairty, 2013). MRI is another exemplary technique that can be used to measure the progression of neurodegeneration (Rocca et al., 2017).

[0416] Various neuroimaging techniques may be useful for early diagnosis and / or monitoring the progression of MSA. Examples of such techniques include, but are not limited to, neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI) (e.g., including diffusion tensor measurements of anatomical connectivity), [18F]fluorodeoxyglucose (FDG) PET, amyloid-labeling agents, [18F]F-dopa PET, radiotracer imaging, volumetric analysis of regional tissue loss, specific imaging markers of abnormal protein deposition (e.g., for MSA progression), multimodal imaging, and biomarker analysis (Stoessl, 2012). Combinations of these techniques may also be used to monitor disease progression.

[0417] For example, structural MRI can be used to measure atrophy of the hippocampus and entorhinal cortex in MSA, as well as lesions in the lateral parietal cortex, posterior superior temporal cortex, and medial posterior cingulate cortex. In frontotemporal dementia (FTD), structural MRI can show atrophy of the frontal or temporal poles.

[0418] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to a patient with MSA results in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in one or more symptoms of MSA. Improvement can be measured using any clinically recognized tool or assessment.

[0419] (iv) Schizophrenia In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of schizophrenia (SZ) and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)) or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0420] Schizophrenia is a chronic, progressive disease that originates from structural changes in both white and gray matter in the brain. These changes likely begin before the onset of clinical symptoms in cortical regions, particularly those related to language processing, and can then be detected by progressive ventricular enlargement. Current magnetic resonance imaging (MRI) techniques can provide a valuable tool for detecting early changes in cortical atrophy and language processing abnormalities that may lead to the development of schizophrenia.

[0421] A 2013 study of schizophrenia subjects documented brain changes seen in MRI scans of more than 200 patients, beginning with their first episode and continuing at regular intervals for up to 15 years. The scans showed that at the onset of the disease, the brain had less tissue than healthy controls. This finding suggests that something is affecting people with schizophrenia before they show outward signs of the illness.

[0422] The mainstay of treatment is antipsychotic medication, along with counseling, vocational training, and social rehabilitation. However, a 2013 study found that, in general, the higher the dose of antipsychotics, the greater the loss of brain tissue.

[0423] Approximately 0.3–0.7% of people will develop schizophrenia in their lifetime. In 2013, there were an estimated 23.6 million cases worldwide. Men are more likely to be affected, and symptoms are more severe on average. Approximately 20% of people remain healthy, and some fully recover. Approximately 50% have lifelong disabilities. Social problems such as long-term unemployment, poverty, and homelessness are common. Life expectancy for people with this illness is 10–25 years shorter than that of the general population. This is the result of increased physical health problems and a high suicide rate (approximately 5%). In 2015, an estimated 17,000 people worldwide died from behaviors related to or caused by schizophrenia.

[0424] Without wishing to be bound by theory, it is theorized that administering a therapeutically effective amount of aminosterol composition to schizophrenia patients can treat and / or prevent schizophrenia or any one or more symptoms thereof.In some embodiments, administration can be oral, resulting in absorption in ENS.In some embodiments, administration can be intranasal, resulting in stimulation of neurogenesis, which has a positive effect on the loss of brain tissue characteristic of schizophrenia patients.

[0425] In one embodiment of the present disclosure, administration of a therapeutically effective amount of an aminosterol composition to a patient with schizophrenia results in improvement of one or more symptoms as determined by a clinically validated psychiatric symptom rating scale, such as the Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), Quality of Life Scale (QLS), Schizophrenia Cognition Scale (SCoRS), Medication Attitude Inventory (DAI), and Aberrant Involuntary Behaviors Scale (AIMS).

[0426] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to a patient suffering from schizophrenia improves one or more symptoms by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% as determined by a clinically validated psychotic symptom rating scale. Improvement can be measured using any clinically recognized tool or assessment.

[0427] (v) Other neurological disorders The methods and compositions of the present disclosure may also be useful in treating and / or preventing various other neurological diseases.In one embodiment, a method is provided for treating, preventing, and / or delaying the onset, prevention, and / or progression of the neurological diseases and / or associated symptoms described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol (e.g., ENT-03 (Compound III)) disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.Examples of exemplary neurological diseases are described below and herein.

[0428] Huntington's disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It impairs a person's physical and mental abilities during the first year of work and is incurable. Full-time care is required in the later stages of the disease. Symptoms of Huntington's disease become evident between the ages of 35 and 44, but they can develop at any age, from infancy to old age. The most distinctive early physical symptom is jerky, random, uncontrollable movements called chorea. Suicide is the cause of death in approximately 9% of cases. Death typically occurs 15 to 20 years after the disease is first detected.

[0429] Progressive supranuclear palsy, also known as Steele-Richardson-Olszewski syndrome, is a brain disorder that causes significant problems with walking, balance, and eye movements. The disorder is caused by the deterioration of cells in areas of the brain that control body movement and thought. There is no known cure for PSP, and management is primarily supportive.

[0430] Frontotemporal dementia (FTD) is a group of related conditions resulting from progressive degeneration of the temporal and frontal lobes of the brain. These areas of the brain play important roles in decision-making, behavioral control, emotion, and language. Frontotemporal dementia (FTD) encompasses six types of dementia involving the frontal or temporal lobe: behavioral variant of FTD, semantic variant primary progressive aphasia, non-fluent agrammatic variant primary progressive aphasia, corticobasal syndrome, progressive supranuclear palsy, and FTD associated with motor neuron disease. Currently, there is no cure for FTD.

[0431] Vascular dementia, also known as multi-infarct dementia (MID) and vascular cognitive impairment (VCI), is a form of dementia caused by problems with blood supply to the brain, typically a series of minor strokes, leading to progressively worsening cognitive decline. Risk factors for vascular dementia include age, hypertension, smoking, hypercholesterolemia, diabetes, cardiovascular disease, and cerebrovascular disease. Other risk factors include geographic origin, genetic predisposition, and prior stroke.

[0432] Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a unique disorder that causes the death of nerves that control voluntary muscles. ALS is characterized by gradually worsening muscle weakness due to muscle stiffness, muscle spasms, and muscle shrinkage. This results in difficulty speaking, swallowing, and ultimately breathing. The cause is unknown in 90% to 95% of cases. The remaining 5 to 10% of cases are hereditary. The underlying mechanism involves damage to both upper and lower motor neurons. There is no known cure for ALS. The disease can affect people of any age, but onset usually occurs around age 60, and in hereditary cases, around age 50. The average survival time from onset to death is 2 to 4 years, with approximately 10% surviving for more than 10 years.

[0433] Multiple sclerosis (MS) is a demyelinating disease that damages the protective layer of nerve cells in the brain and spinal cord. This damage disrupts the ability of different parts of the nervous system to communicate, resulting in a variety of signs and symptoms, including physical, mental, and sometimes psychiatric problems. There are several forms of MS, and new symptoms can occur either in isolated attacks (relapsing) or worsen over time (progressive). There is no known cure for MS, and life expectancy is 5 to 10 years lower than in the unaffected population.

[0434] Spinal muscular atrophy (SMA) is a genetic neuromuscular disease characterized by motor neuron loss and progressive muscle wasting, often leading to premature death. The disease is caused by a genetic deficiency in the SMN1 gene, which encodes SMN, a protein required for motor neuron survival. Low levels of this protein result in loss of function of neuronal cells in the anterior horn of the spinal cord, followed by atrophy throughout the skeletal muscle system. SMA is the most common genetic cause of infant death. In December 2016, nusinersen was the first approved drug for the treatment of SMA, but several other compounds are currently in clinical trials.

[0435] Friedreich's ataxia is an autosomal recessive genetic disorder that causes progressive damage to the nervous system. It manifests initially with impaired coordination, including gait disturbances; it can also lead to scoliosis, heart disease, and diabetes, but does not affect cognitive function. Friedreich's ataxia is caused by degeneration of nerve tissue in the spinal cord, particularly sensory neurons (through connections to the cerebellum) that are essential for directing muscle movement in the arms and legs. The spinal cord thins, and nerve cells lose some of their myelin sheath (the covering that covers some nerve cells and helps conduct nerve impulses).

[0436] (2) psychological or behavioral disorders and / or related symptoms In one embodiment, there is provided a method for treating, preventing, and / or delaying the onset or progression of a psychological or behavioral disorder and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof. In one embodiment, the psychological or behavioral disorder is depression, anxiety, delirium, irritability, illusions and delusions, amnesia, autism, apathy, bipolar disorder, disinhibition, abnormal movements and obsessive-compulsive behavior, sleep disorder, sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, or cognitive impairment.

[0437] (i) Depression In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of depression and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0438] Clinical depression is characterized by a sad, blue mood that goes beyond normal sadness or sadness. One in ten people will suffer from depression in their lifetime. Doctors diagnose depression clinically; there are no laboratory or x-ray tests for depression.

[0439] Research has shown that the hippocampus is smaller in some people with depression. For example, in one fMRI study published in The Journal of Neuroscience, researchers studied 24 women with a history of depression. The hippocampus was, on average, 9% to 13% smaller in depressed women compared to women without depression. The more bouts of depression a woman had, the smaller her hippocampus was. Stress may be a key factor in playing a role in depression, as experts believe that stress can inhibit the production of new neurons (nerve cells) in the hippocampus.

[0440] Researchers are exploring a possible link between sluggish production of new neurons in the hippocampus and poor mood. An interesting fact about antidepressants supports this theory. Taking these drugs immediately increases levels of chemical messengers (neurotransmitters) in the brain. However, people typically don't begin to feel better for several weeks or more. Experts have long wondered why people don't immediately feel better once neurotransmitter levels increase, even if depression is primarily the result of low neurotransmitters. The answer may be that mood improves only as neurons grow and form new connections. This process takes several weeks. In fact, animal studies have shown that antidepressants stimulate the growth and branching of neurons in the hippocampus. So, this theory suggests, the true value of these medications may lie in creating new neurons (a process called neurogenesis), strengthening neuronal connections, and improving communication between neural circuits.

[0441] Thus, one embodiment of the present disclosure encompasses a method for treating and / or preventing depression, comprising administering a therapeutically effective amount of an aminosterol composition according to the present disclosure. Without wishing to be bound by theory, it is theorized that the aminosterol composition of the present disclosure induces neurogenesis, which functions to combat depression.

[0442] In some embodiments, the method of the present disclosure results in an improvement in clinical depression in a subject. The improvement in a subject's depression can be measured using any clinically recognized measurement. For example, the improvement can be measured using a depression rating scale. In one embodiment of the present disclosure, after treatment, the subject experiences about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100% improvement. The improvement can be measured using any clinically recognized tool or assessment.

[0443] Examples of tools that can be used to assess depression and / or mood and improvement after aminosterol treatment include, for example, (1) the Beck Depression Inventory (BDI-II); (2) UPDRS, sections 1.3 (depressed mood), 1.4 (anxious mood), 1.5 (blunted affect), and 1.13 (fatigue); and (3) the Parkinson's Disease Fatigue Scale (PFS-16). In some embodiments, improvement can be measured using one or more medically approved techniques selected from the group consisting of the Patient Health Questionnaire-9 (PHQ-9); Zung Self-Rating Depression Scale; Center for Epidemiological Studies Depression Scale (CES-D); and Hamilton Rating Scale for Depression (HRSD).

[0444] (ii) Cognitive impairment In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of cognitive impairment and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0445] Cognitive impairment, including mild cognitive impairment (MCI), is characterized by increased memory or thinking problems compared with normal subjects of the same age. Approximately 15–20% of people aged 65 and older have MCI. MCI is particularly associated with neurodegenerative diseases such as AD and synucleinopathies such as PD. In 2002, it was estimated that approximately 5.4 million people (22%) aged 70 and older in the United States had cognitive impairment without dementia (Plassman et al., 2009).

[0446] Cognitive impairment can involve memory problems, including subtle but significant and measurable declines in cognitive abilities, including memory and thinking skills. Individuals with amnestic MCI may forget information that would previously have been easily recalled, such as appointments, conversations, or recent events. When MCI primarily affects thinking skills other than memory, it is known as "non-amnestic MCI." Individuals with non-amnestic MCI may, for example, have a reduced ability to make sound decisions, judge the time or sequence of steps required to complete a complex task, or perform visual perception.

[0447] Mild cognitive impairment is a clinical diagnosis. A thorough assessment of cognitive impairment involves a combination of cognitive testing and information from those who frequently contact the subject. The medical workup includes a physician evaluation of the subject's medical history (including current symptoms, previous illnesses, and family history), an assessment of independent function and daily activities, a mental status assessment using brief tests to evaluate memory, planning, judgment, visual information, and other critical thinking skills, neurological testing to evaluate neural and reflex function, movement, coordination, balance, and sensation, mood assessment, brain imaging, or neuropsychological testing. Diagnostic guidelines for MCI have been developed by various groups, including the Alzheimer's Association, affiliated with the National Institute on Aging (NIA), an agency of the National Institutes of Health (NIH). Jack et al., 2011; McKhann et al., 2011; Albert et al., 2011. Recommendations for screening for cognitive impairment have been issued by the U.S. Preventive Services Task Force. Screening for Cognitive Impairment in Older Adults, U.S. Preventive Services Task Force (March 2014), https: / / www.uspreventiveservicestaskforce.org / Home / GetFileByID / 1882. For example, the Mini-Mental State Examination (MMSE) can be used. Palsetia et al. (2018); Kirkevold, O. & Selbaek, G. (2015). On the MMSE, a score of 24 or higher (out of 30) may indicate normal cognition, while lower scores indicate severe (≤9), moderate (10-18), or mild (19-23) cognitive impairment. Another screening tool is the Informant Questionnaire on Cognitive Decline in Elderly (IQCODE); an average score of 3 indicates no cognitive decline, while scores above 3 indicate some degree of decline. Jorm, AF2004.The 7-minute screener, also known as the Mental Test Score (AMTS), Cambridge Cognitive Assessment for Gender (CAMCOG), Generalized Clock Drawing Test (GPCOG), Mini-Cog, Memory Impairment Screening Score (MIS), Montreal Cognitive Assessment (RUDA), Rowland Universal Dementia Assessment (RUDA), Self-Administered Genetic Test (SAGE), Short and Sweet Screening Instrument (SAS-SI), Short Blessed Test (SBT), St. Louis Mental State Assessment (SLUMS), Short Portable Mental State Questionnaire (SPMSQ), Short Mental State Questionnaire (STMS), or Time and Change Test (T&C), is frequently used, particularly in clinical and research settings (Cordell et al., 2013). Because no single tool is recognized as the "gold standard," numerous tests are often used. While improvement in scores on any standardized test indicates successful treatment of cognitive impairment, achieving scores comparable to those of a non-disordered population indicates overall recovery.

[0448] In some embodiments, administration of a therapeutically effective amount of an aminosterol composition to a patient in need thereof results in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in cognitive impairment as determined by a clinically validated rating scale. Improvement can be measured using any clinically recognized tool or assessment.

[0449] Examples of tools that can be used to assess cognitive impairment and improvement after aminosterol treatment include, for example, (1) the Mini-Mental State Examination (MMSE), (2) the Trail Making Test (TMT) Parts A and B, and (3) the UPDRS, Section 1.1 (cognitive impairment).

[0450] (iii) sleep disorders / problems (e.g., REM sleep disorder or circadian rhythm dysfunction) In one embodiment, there is provided a method for the treatment, prevention, and / or progression of insomnia, sleep disorders, circadian rhythm disorders, and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof).

[0451] The alternating pattern of sleep and wakefulness that occurs every 24 hours is known as the circadian rhythm. The rhythm is set by the "zeitgeber" (time-setter), an entity known as the suprachiasmatic nucleus (SCN), located in the hypothalamus. The SCN is normally "entrained" or synchronized by the external light-dark cycle. The circadian sleep-wake cycle can also shift in response to changes in the external light-dark cycle, such as the desynchronization that occurs during movement from one time zone to another (jet lag). Under these circumstances, gradual adjustments occur until the SCN is resynchronized with the external light-dark cycle. Similar "phase shifts" and adjustments occur in night-shift workers.

[0452] Certain diseases and conditions can disrupt the normal function of the circadian clock. These conditions can be reversible, such as desynchronization resulting from jet lag, night shift work, hunger, or conditions that are easily improved by adaptation or food intake. In contrast, damage to the nerves that carry light-dark-related information from the retina to the SCN (a condition that can lead to blindness) or damage to the enteric nerves and neural structures that relay messages from the gut to the SCN (a condition that can lead to neurodegenerative disorders) can cause permanent dysfunction of the circadian rhythm and abnormal sleep behavior.

[0453] Circadian rhythm dysfunction manifests first and most prematurely through abnormal sleep patterns. These abnormalities are typically mild at onset and progressively worsen over time. A common symptom of sleep disorders is delayed sleep onset. This delay can last for several hours, and individuals may not be able to fall asleep until the early hours of the morning. Another common symptom is sleep fragmentation, which means that individuals awaken several times throughout the night. Once awakened, individuals are unable to return to sleep, with each awakening fragment lasting more than an hour, further reducing "total sleep time," which is calculated by subtracting the total time spent in bed from the total time spent in bed. Total sleep time also decreases with age, from approximately 14–16 hours per day in newborns to approximately 12 hours by 1 year of age, approximately 7–8 hours in young adults, and gradually decreasing to approximately 5–6 hours in older adults. Total sleep time can be used to calculate an individual's "sleep age," which can then be compared to their age. A significant discrepancy between sleep age and chronological age reflects the severity of the sleep disorder. "Sleep efficiency" is another metric that can be used to assess the severity of a sleep disorder. It is defined as the percentage of time spent in bed asleep. Sleep efficiency is said to be abnormal if the percentage is less than about 70%.

[0454] Sleep disorders and / or sleep disorders include, but are not limited to, REM behavior disorders, circadian rhythm disorders ("circadian rhythm dysfunction"), delayed sleep onset, sleep fragmentation, REM behavior disorder (RBD), and hallucinations. Other sleep disorders or disorders that can be treated and / or prevented in accordance with the disclosed methods include hypersomnia (i.e., daytime sleepiness), parasomnias (nightmares, night terrors , dream terrors, sleepwalking, and confusional awakenings), periodic limb movement disorders (such as restless leg syndrome), jet lag, narcolepsy, progressive sleep phase disorder, and non-24 hour sleep-wake syndrome.

[0455] A "normal" or "restful" sleep period is defined as a period of sleep uninterrupted by awakenings. Alternatively, the period can be defined by the recommended or appropriate amount of sleep for a subject's age category, such as: (i) 0-3 months = about 11 to about 19 hours; (ii) infants = about 4 to about 11 months = about 12 to about 18 hours; (iii) toddlers = about 1 to about 2 years = about 9 to about 16 hours; (iv) preschool children = about 3 to about 5 years = about 10 to about 14 hours; (v) school-age children = about 6 to about 13 years = about 7 to about 12 hours; (v) teenagers = about 14 to about 17 years = about 7 to about 11 hours; (vi) young adults = about 18 to about 25 years = about 6 to about 64 years = about 6 to about 10 hours; and (viii) older adults > 65 years = about 5 to about 9 hours. Thus, for treating a sleep disorder in a subject, the treatment can result in a period of restful sleep of at least about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours.

[0456] [Table 1]

[0457] There are several scientifically acceptable methods for measuring periods of sleep uninterrupted by wakefulness. First, electrodes attached to the subject's head can measure electrical activity in the brain via electroencephalography (EEG). This measure is used because EEG signals associated with wakefulness differ from those seen during sleep. Second, muscle tone also differs between wakefulness and sleep, so electromyography (EMG) can be used to measure muscle activity. Third, eye movements during sleep can be measured using electrooculography (EOG). This is a highly specialized measurement that helps identify rapid eye movement (REM) sleep. Any of these methods, or a combination of them, can be used to determine whether a subject achieves periods of restful sleep after administering at least one aminosterol or its salt or derivative to the subject.

[0458] Additionally, circadian rhythm regulation can be monitored in a variety of ways, including but not limited to, monitoring wrist skin temperature, as described in Sarabia et al., 2008. Similarly, RBD symptoms can be monitored using daily diaries and RBD questionnaires (Stiasny-Kolster et al., 2007).

[0459] In some embodiments, administration of a therapeutically effective amount of an aminosterol composition to a patient with disturbed sleep results in an improvement in the frequency of normal or restful sleep by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% as determined by a clinically validated rating scale for one or more types of sleep regulation disorders. Improvement can be measured using any clinically recognized tool or assessment.

[0460] Examples of tools that can be used to measure and evaluate the effects of aminosterol treatment on sleep include (1) sleep diaries (participants completed a sleep diary daily throughout the study, including bedtime and sleep duration, as well as nighttime wakefulness duration and duration) and (2) I-Button temperature assessment. The I-Button is a small, rugged, self-contained system that measures temperature and records the results in a protected memory section. A Thermochron I-Button DS1921H (Maxim Integrated, Dallas, TX) was used for skin temperature measurements. The I-Button was programmed to sample every 10 minutes and attached to a double-sided cotton sports wristband using Velcro, with the sensor surface of the I-Button positioned on the inside of the wrist over the radial artery of the dominant hand. Subjects removed and replaced the data logger as needed (i.e., to have a bath or shower). The value of skin temperature assessment in sleep studies is that endogenous skin warming resulting from increased skin blood flow is functionally related to sleep propensity. From the collected data, mesophase, amplitude, acrophase (time of peak temperature), Rayleight test (an index of interday stability), and mean waveform were calculated; (3) UPDRS, section 1.7 (sleep disturbance), section 1.8 (daytime sleepiness), and 1.13 (fatigue); (4) Parkinson's Disease Fatigue Scale (PFS‐16); (5) REM Sleep Behavior Disorder Screening Questionnaire; and (6) Parkinson's Disease Sleepiness Scale.

[0461] (iv) Autism In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of autism spectrum disorder (ASD) and / or associated symptoms, comprising administering to a subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0462] Autism, or autism spectrum disorder, refers to a range of conditions characterized by challenges with social skills, repetitive behaviors, and verbal and nonverbal communication, as well as unique intensities and variations. There are many different types of autism, each caused by a different combination of genetic and environmental influences. The most obvious signs of autism tend to appear between the ages of 2 and 3; in some cases, a diagnosis can be made as early as 18 months. Some developmental delays associated with autism can be identified and addressed even earlier.

[0463] The Centers for Disease Control and Prevention (CDC) estimates the prevalence of autism at 1 in 59 children in the United States, including 1 in 37 boys and 1 in 151 girls. Approximately one-third of people with autism remain nonverbal, and approximately one-third of people with autism have an intellectual disability. Autism is often associated with certain medical and mental health problems, including gastrointestinal (GI) disorders, seizures, sleep disorders, attention-deficit hyperactivity disorder (ADHD), anxiety, and phobias.

[0464] Experts are still unsure of the causes of autism. In all likelihood, there are multiple causes. Various circumstances, including environmental, biological, and genetic factors, appear to determine the stage of autism and predispose a child to the condition. Genetics likely plays a major role in the development of autism. Identical twins are more likely to be affected than syngeneic twins (who are not genetically identical). Families with one autistic child have about a 5% chance of having another child with autism, which is much higher than the general population. Research has also shown that emotional disorders, such as bipolar disorder, are more frequent in families of autistic children.

[0465] At least one group of researchers has found a link between abnormal genes and autism. A gene may be just one of three to five or more genes that interact in some way to cause the condition. Scientists suspect that a defective gene or genes may predispose individuals to autism, along with other factors, such as chemical imbalances at birth, viruses or chemicals, or oxygen deprivation at birth. Other potential causes of autism are environmental toxins, including pesticides and heavy metals (e.g., mercury). Heavy metals are certainly more commonly encountered in today's environment than in the past. Individuals with autism or those at high risk of developing autism may be more sensitive to these toxins than others.

[0466] Recent brain tissue studies suggest that children with autism have an excess of synapses, or connections between brain cells. This excess is due to a slowdown of the normal pruning process that occurs during brain development. Normal brain development involves a burst of synapse formation during early childhood. This is particularly evident in the cortex, the brain's central nervous system, responsible for thinking and processing information from the senses. However, by late adolescence, pruning eliminates approximately half of these cortical synapses. Furthermore, many genes associated with autism are known to affect the development and function of brain synapses. The study also revealed that brain cells in autistic individuals are filled with damaged parts and exhibit signs of a normal degradation pathway called "autophagy" (Tang et al., 2014).

[0467] Therefore, one embodiment of the present disclosure is directed to a method for treating autism, comprising administering a therapeutically effective amount of the aminosterol composition of the present disclosure.In one embodiment, treatment leads to the improvement of one or more characteristics of autism.Such characteristics can be, for example, communication skills, social interaction, sensory sensitivity, and behavior.Improvement can be measured using any clinically recognized tool or assessment.

[0468] For example, the methods of the present disclosure can show improvement in one or more characteristics of autism, such as behavior, communication, mood, etc., as measured by a medically validated scale. The improvement can be, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0469] (3) Cerebral or systemic ischemic injury and / or related symptoms In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of cerebral or systemic ischemic injury and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0470] In one embodiment, the cerebral or systemic ischemic injury is a microangiopathy, intrapartum cerebral ischemia, cerebral ischemia during / after cardiac arrest or cardiac resuscitation, cerebral ischemia due to intraoperative problems, Cerebral ischemia during carotid artery surgery, brain fart Chronic cerebral ischemia caused by narrowing of the blood supply arteries cerebral sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, High blood pressure, high cholesterol, myocardial infarction, Cardiac insufficiency, cardiac failure , congestive heart failure, myocarditis, pericarditis, Pericardial inflammation, Coronary heart disease, angina, congenital heart disease, Shock, limb ischemia, renal artery stenosis, diabetic retinopathy, malaria-associated thrombosis, artificial heart valves, anemia, hypersplenism syndrome, emphysema, Selected from pulmonary fibrosis, erectile dysfunction or pulmonary edema.

[0471] For example, the disclosed methods may show an improvement in one or more characteristics of cerebral or systemic ischemic damage as measured by a medically recognized scale. The improvement may be, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0472] Medically validated measures or techniques for measuring improvement include, for example, cholesterol testing, high-sensitivity C-reactive protein testing, lipoprotein(a), plasma ceramides, natriuretic peptides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, electrocardiogram (EKG), Holter monitor, stress test, echocardiogram, positron emission tomography (PET), thallium scan, myocardial perfusion scan, implantable loop recorder, tilt table test, electrophysiology test, coronary angiography, magnetic resonance angiography, cardiac CT scan, and event recorder.

[0473] (i) Erectile dysfunction In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of erectile dysfunction (ED) and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0474] Erectile dysfunction can be a symptom of a physical or psychological condition. It can cause stress, relationship strain, and low self-confidence. The main symptom is the inability to get or maintain an erection firm enough for intercourse. ED can manifest through different mechanisms. Based on its mechanism, ED can be classified as psychogenic, neurogenic (inability to initiate an erection), arteriogenic (failure of the penis to fill with blood), or cavernous (failure of the vascular system that keeps blood in the penis once filled) (Dean et al. 2005).

[0475] Many neurological disorders that cause ED, such as PD, are suspected to correlate with the formation of toxic αS aggregates within the enteric nervous system (ENS) (Braak et al., 2003(a) and (b)). ED has been reported to affect 60–79% of men with PD, whereas the prevalence of ED in non-Parkinsonian men is only approximately 37.5% (Papatsoris, 2006). Normal transport of αS aggregates from the ENS to the central nervous system (CNS) via afferent nerves such as the vagus nerve (Holmqvist et al., 2014; Svensson et al., 2015) results in the progressive accumulation of neurotoxic aggregates within the brainstem and more rostral structures. Inhibiting αS aggregation in the ENS may reduce the ongoing neurological disease process in both the ENS and CNS (Phillips et al., 2008), thereby potentially positively impacting ED associated with abnormal αS pathology.

[0476] Central dopamine is known to be an important neurotransmitter in the regulation of sexual function, including erectile dysfunction (Giuliano et al., 2001). Dopamine deficiency is thought to be the cause of erectile dysfunction, which is frequently observed in PD patients (Palma et al., 2014). In PD patients, αS-related pathology is expressed in serotonergic and cholinergic neurons, paralleling that seen in nigral dopamine neurons. Thus, regulation of αS may play a role in ED in PD through dopaminergic dysfunction.

[0477] In one embodiment, the method reduces the number of times the subject is unable to achieve an erection, and reducing the number of times the subject is unable to achieve an erection comprises reducing the number of times the subject is unable to achieve an erection over a defined period of time. In another aspect, the method results in a reduction in the severity of ED over a defined period of time, wherein the reduction in the severity of ED is measured by a medically recognized technique selected from the group consisting of bone compression erect length (BPEL) measurement, girth measurement, orthodontic hardness scale (EHS), and International Index of Orthodontic Function (IIEF).

[0478] (ii) Blood pressure In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of hypertension (HBP) or hypotension (LBP) and / or related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0479] Hypertension (HBP), also known as high blood pressure, is a long-term medical condition characterized by persistently elevated blood pressure in the arteries. Long-term hypertension is a major risk factor for coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, vision impairment, chronic kidney disease, and dementia. HBP can be characterized as (a) systolic blood pressure (BP) ≥ 120 and diastolic BP < 80; or (b) systolic blood pressure (BP) ≥ 130 or diastolic BP ≥ 80; whereas hypotension (LBP) can be characterized as (a) systolic blood pressure ≤ 80; or (b) diastolic blood pressure ≤ 50).

[0480] Low blood pressure (LBP), also called hypotension, is generally classified as a systolic blood pressure below 90 millimeters of mercury (mmHg) or a diastolic blood pressure below 60 mmHg. Primary symptoms include lightheadedness, vertigo, and fainting. Severely low blood pressure can deprive the brain and other vital organs of oxygen and nutrients, leading to a life-threatening condition called shock. For athletic and physically fit individuals, low blood pressure is a sign of good health and fitness. For many individuals, excessively low blood pressure can cause dizziness and fainting, or indicate serious cardiac, endocrine, or neurological disorders.

[0481] Blood pressure (BP) and αS pathology: Many neurological disorders that cause HBP or LBP, such as PD, are suspected to correlate with the formation of toxic αS aggregates within the enteric nervous system (ENS) (Braak et al. 2003(a) and (b)). In a study of 11.55 million physician visits in PD patients in the United States, hypertension was the most commonly recorded comorbidity, accounting for 37.8% of visits (Lingala et al. 2017). Orthostatic hypotension (OH) is one of the common non-motor symptoms in patients with idiopathic Parkinson's disease (IPD) (Fereshtehnejad et al. 2014).

[0482] Examples of conditions associated with abnormal αS pathology and / or dopaminergic dysfunction that correlate with HBP or LBP include, but are not limited to, synucleopathies, neurological diseases, psychological and / or behavioral disorders, and cerebral and systemic ischemic disorders, examples of which are described herein.

[0483] In one embodiment, in a subject with HBP, the method reduces systolic blood pressure and / or diastolic blood pressure by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%, as measured using a clinically validated scale or tool.

[0484] In one embodiment, in a subject with LBP, the method increases systolic and / or diastolic blood pressure by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%, as measured using a clinically validated scale or tool.

[0485] In one embodiment, the clinically validated scale or tool is selected from the group consisting of blood pressure measurement, arterial perfusion, arterial pulsation, accelerometry, oscillometry, continuous non-invasive arterial pressure (CNAP), pulse wave velocity, and ambulatory monitoring.

[0486] (iii) cardiac conduction defects In one embodiment, provided is a method for treating, preventing, and / or delaying the onset or progression of cardiac conduction disorder (CCD) and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0487] Cardiac conduction defects (CCDs) involve abnormalities in how electrical impulses travel to and through the heart. The cardiac conduction system, normally responsible for transmitting electrical signals generated by the sinoatrial node, triggers myocardial contractions. Cardiac conduction defects (CCDs) are serious and potentially life-threatening conditions. They belong to a group of conditions involving altered cardiac conduction through the atrioventricular (AV) node, a His-Purkinje system with right or left bundle branch block, and a widened QRS complex on the electrocardiogram (EKG). Originally, CCDs were considered structural diseases of the heart, involving anatomical changes in the conduction system underlying abnormal impulse propagation. However, a significant number of cases have been demonstrated in which conduction defects occur in the absence of anatomical abnormalities. In these cases, functional rather than structural changes appear to underlie the conduction defects. These functional defects have been termed "primary electrical diseases of the heart." While the pathophysiological mechanisms underlying CCDs are diverse, the most common form is the degenerative form, also known as Lenegre-Lev disease (idiopathic bipedicular fibrosis). Today, Lesna-Graves disease is the leading cause of pacemaker implantation worldwide.

[0488] In one embodiment, the CCD is evaluated for the presence of: (a) a QT interval (QTc) > 440 ms; (b) syncope; (c) the presence of delta waves in an electrocardiogram (EKG); (d) pseudonormal bundle branch block in an EKG; (e) ST elevation in V1-V3 in an EKG; (f) a QRS complex > 100 ms in an EKG; (g) a PR interval < 120 ms in an EKG; (h) a heart rate greater than 100 beats per minute (BPM); (i) a heart rate less than 60 BPM; (j) a PR interval > 200 ms in an EKG; (k) a QRS not following a p wave in an EKG; (l) no repeating relationship between p waves and QRS complexes in an EKG; (m) discrepancy in atrial and ventricular rates; (n) a QS or rS complex in lead V1 in an EKG; (o) a notched (M-shaped) R wave in lead V6; (p) discrepancy in T waves in an EKG; (q) (r) qR pattern (small q, high R) in lateral limb I and aVL during EKG; (s) rS pattern (small r, deep s) in anterior limb II, III and aVF during EKG; (t) delayed intrinsic deflection (>0.045 s) in lead aVL during EKG; (u) frontal plane axis between 90° and 180° during EKG; (v) rS pattern in lead i and aVL during EKG; (w) qR pattern in lead III and aVF during EKG; (x) chest pain; (y) dyspnea; (aa) rapid breathing; (bb) nausea; (cc) fatigue; (dd) sleep disturbance or disturbance; (ee) constipation; and (ff) cognitive impairment.

[0489] In one embodiment, the progression or onset of CCD, as measured by a medically approved technique, is slowed, stopped, or reversed over a specified period of time after administration of a fixed, incremental dose of an aminosterol or its salt or derivative. Furthermore, CCD can be positively influenced by a fixed, incremental dose of an aminosterol or its salt or derivative, as measured by a medically approved technique. The positive influence and / or progression of CCD can be quantitatively or qualitatively measured by one or more techniques selected from the group consisting of echocardiography, electrocardiography (ECG or EKG), magnetic resonance imaging (MRI), positron emission tomography (PET); coronary catheterization, intravascular ultrasound, Holter monitoring, stress testing, computed tomography angiography (CTA), and coronary CT calcium scan. Additionally, the progression or onset of CCD can be slowed, stopped, or reversed by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% as measured by medically recognized techniques.

[0490] In another embodiment, the aminosterol or its salt or derivative reverses the dysfunction caused by CCD and treats, prevents, improves, and / or eliminates the symptoms being evaluated. The improvement or resolution of CCD symptoms is measured using a clinically validated scale or tool. Furthermore, the improvement of CCD symptoms can be, for example, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%, when measured using the above-mentioned techniques.

[0491] C. Appetite suppression / obesity treatment In one embodiment, provided is a method for suppressing, preventing, and / or delaying the onset or progression of appetite and / or one or more associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0492] In one embodiment, the subject suffers from an increased appetite condition, and the increased appetite is compared to the subject's appetite before the increased appetite condition was suffered from. The increased appetite can be measured using a clinical scale or tool.

[0493] In one embodiment, the method causes a decrease in the subject's appetite over a defined period of time, wherein the decrease in appetite is compared to the subject's appetite before administration of the aminosterol (e.g., V) or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof. The decrease in the subject's appetite can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as measured by a clinical appetite scale or tool. In one embodiment, the clinical appetite scale or tool is selected from the group consisting of self-assessment of appetite, subjective assessment of appetite, visual analog scale (VAS), Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score, and Anorexia Questionnaire (AQ).

[0494] In one embodiment, the appetite-increasing condition is selected from the group consisting of stress, anxiety, depression, premenstrual syndrome, pregnancy, bulimia, hyperthyroidism, leptin resistance, Grave's disease, hypoglycemia, diabetes, Prader-Willi syndrome (PWS), bulimia nervosa (BED), obesity, drug withdrawal, and drug consumption.

[0495] In one embodiment, the one or more associated appetite symptoms are selected from the group consisting of borborygmi (rumbling stomach); fainting, dizziness, or lightheadedness; headache; irritability; cognitive impairment; and nausea. Performing the method may result in a reduction or elimination of one or more of the associated symptoms.

[0496] In one embodiment, (a) the method results in a reduction in the severity of the subject's syncope, dizziness, or lightheadedness over a period of time as measured by a clinically validated syncope, dizziness, or lightheadedness scale or tool; (b) the method results in a reduction in severity selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, and up to about 100%, as measured by a clinically validated syncope, dizziness, or lightheadedness scale or tool; and / or (c) the method results in the subject becoming free of syncope, dizziness, or lightheadedness.

[0497] In one embodiment, the clinically validated syncope, dizziness, or lightheadedness scale or tool is selected from the group consisting of the Ehmer Dizziness Diagnostic Scale (ADDS), Dizziness Symptom Scale, Dizziness Handicap Inventory, Vestibular Disorders of Daily Living Scale, Activities-specific Balance Confidence, Dizziness Handicap Questionnaire, Dizziness-Vertigo-Imbalance Questionnaire, UCLA Dizziness Questionnaire, Dizziness Factor Inventory, European Vertigo Rating, and Meniere's Disease Patient-Derived Severity Index.

[0498] In one embodiment, (a) the method results in a reduction in the subject's headache over a period of time as measured by one or more clinically recognized headache rating scales; (b) the method results in a reduction in the subject's headache over a period of time as measured by one or more clinically recognized headache rating scales, where the reduction is measured in one or more headache types selected from the group consisting of tension headache, cluster headache, migraine, hypertensive headache, and hypotensive headache; and / or (c) the method results in a reduction in the subject's headache over a period of time as measured by one or more clinically recognized headache rating scales, where the reduction is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, and about 100%.

[0499] In one embodiment, the one or more clinically recognized headache rating scales are selected from the group consisting of ID-Migraine, Visual Aura Rating Scale (VARS), Migraine Disability Assessment Questionnaire (MIDAS), Migraine-Specific Quality of Life Survey (MSQ 2.1), and Headache Under Treatment Response (HURT) questionnaire.

[0500] In one embodiment, (a) the method results in an improvement in the subject's cognitive impairment over a defined period of time as measured by one or more clinically validated cognitive assessment scales, and (b) the method results in an improvement in the subject's cognitive impairment over a defined period of time as measured by one or more clinically validated cognitive assessment scales, wherein the improvement is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100%.

[0501] In one embodiment, the one or more clinically recognized cognitive assessment scales are selected from the group consisting of ADASCog, Woodcock-Johnson Cognitive Abilities Test, Miller International Performance Scale, Raven's Progressive Matrices, Wonderlic Personnel Test, IQ test, Unified Parkinson's Disease Scale (UPDRS), Mini Mental Parkinson (MMP), Informant Questionnaire on Cognition in the Elderly (IQCODE), The 7-Minute Screen, Abbreviated Mental Performance Score (AMTS), Cambridge Cognitive Test (CAMCOG), Clock Drawing Test (CDT), General Practitioner Assessment Memory Impairment Screening (MIS), Montreal Cognitive Assessment (RUDA), Self-Administered Gerocognitive Examination (SAGE), Short and Sweet Screening Instrument (SBT), St. Louis Mental Status (SLUMS), Short Portable Mental Status Questionnaire (SPMSQ), Short Tests included the State of Mind (STMS), Time and Change Test (T&C test), Test of Memory (TYM), Addenbrooke's Cognitive Test-Revised (ACER); and computerized tests selected from Cantab Mobile, Cognigram, Cognivue, Cognision, and the Automated Neuropsychological Assessment Metric Cognitive Performance Test (CPT).

[0502] In one embodiment, provided is a method for reversing, preventing, and / or delaying the onset or progression of weight gain and / or associated symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0503] In one embodiment, a method for reducing weight in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of an aminosterol disclosed herein (e.g., ENT-03 (Compound III)), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0504] In some embodiments, the methods result in a subject losing about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% weight over a defined period of time.

[0505] In some embodiments, the method results in a reduction in calorie consumption by the subject over a defined period of time, where the reduction is compared to the calories consumed by the subject during a period prior to administration of the aminosterol (e.g., ENT-03 (Compound III)) or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof. The defined period and the period can be of the same length of time. Furthermore, the reduction in calorie consumption can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0506] In some embodiments, the method results in a reduction in food mass consumption by the subject over a specified period of time relative to the food mass consumed by the subject during a period prior to administration of the aminosterol or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein the specified period and the period are the same length of time, and wherein the reduction in food mass consumption is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0507] In some embodiments, the method results in a reduction in the subject's body weight over a specified period of time, wherein the weight reduction is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the subject's body weight prior to administration of the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof.

[0508] In some embodiments, each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

[0509] In some embodiments, the subject suffers from and / or is at risk for one or more conditions selected from the group consisting of obesity, fatty liver disease, type 2 diabetes, heart disease, stroke, high blood pressure, gallbladder disease, gout, sleep apnea, osteoarthritis, high LDL cholesterol, low HDL cholesterol, high levels of triglycerides (dyslipidemia), endometrial cancer, breast cancer, colon cancer, kidney cancer, gallbladder cancer, and liver cancer.

[0510] D. Antibiotic Treatment (1) Microbial infection In one aspect, the aminosterols described herein can be administered to the subject who needs to treat microbial infection.In some embodiments, the subject who needs to treat microbial infection has a condition selected from the group consisting of viral infection, microbial infection, bacterial infection, such as gram-negative and / or gram-positive bacterial infection, mycobacterial infection, fungal infection, and / or protozoal infection.

[0511] In some embodiments, the viral infection is caused by a virus selected from the group consisting of yellow fever, cytomegalovirus, eastern equine encephalitis virus, hepatitis B virus, hepatitis delta virus, dengue virus, and human immunodeficiency virus. In some embodiments, the condition to be treated is caused by a virus selected from the group consisting of "African swine fever virus", Arboviridae, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Chiroviridae, Coronaviridae, Cystoviridae, Dengueviridae, EBV, HIV family, Deltaviridae, Filoviridae, Flaviviridae, Hepadnaviridae (hepatitis), Herpesviridae (e.g., Cytomegalovirus, Herpes Simplex, Herpes Zoster), Iridoviridae, Mononegaviridae (e.g., Paramyxoviridae, Morbilliviridae, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., Influenza A, Influenza B, Parainfluenza), Papillomaviruses, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Picomaviridae (e.g., Rhinovirus, Poliovirus) In some embodiments, the condition being treated is a viral infection selected from the group consisting of viruses causing herpes, smallpox, papilloma, corona, influenza, hepatitis, Sendai, Sindbis, vaccinia virus, West Nile, hanta, and the common cold, and any combination thereof. In some embodiments, the condition being treated is selected from the group consisting of AIDS, viral meningitis, dengue fever, EBV, hepatitis, chronic diseases suspected of viral origin, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, cardiomyopathy, Kawasaki disease, aplastic anemia, and any combination thereof.

[0512] In some embodiments, the method further comprises administering one or more antiviral agents.

[0513] (2) Coronavirus infection In one aspect, a method of treating or preventing infection by a coronavirus in a subject is provided, comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any embodiment herein or a composition of any embodiment herein.

[0514] In some embodiments, the coronavirus is an alphacoronavirus; a coracovirus such as bat coronavirus CDPHE15; bat coronavirus HKU10; or Rhinolophus ferrumcinum Decaviruses like alpha coronavirus HuB-2013 Cow Rus; Dubinavirus, such as human coronavirus 229E; Lucien Rn rat coronavirus stomach Luccia like Luz Cow rus; ferret coronavirus or mink coronavirus 1 Minakoviruses like; Miniopetersubatcoronavirus 1 Or a minuna like Miniopetrus bat coronavirus HKU8 Kou Myotakoviruses such as Myotisrichetti alphacoronavirus Sax-2011; Nyctalus velutinus alphacoronavirus SC-2013 Kou viruses; pedacoviruses such as Porcine Epidemic Deere Virus or Scott Phillips Bat Coronavirus 512; rhinacoviruses such as Rhinolophus Bat Coronavirus HKU2; human coronaviruses stomach Setrachoviruses, such as brucei NL63 or the NL63-related bat coronavirus strain BtKYNL63-9b; tega, such as alphacoronavirus 1; Cow Rus; β Corona stomach Russ; β Corona stomach Rus1, Human coronavirus OC43, Chinese rat coronavirus S H KU24、 Envecoviruses such as human coronavirus HKU1 or murine coronavirus; bat Hp-β coronavirus stomach Hipekou such as Ruszejian 2013 stomach Rus; Hejehokkoronau stomach Rus1, Middle East Respiratory Syndrome-associated Coronavirus (MERS-CoV), Pipistereus Bat Coronavirus H KU5 also Ha Ironictebatkoronau stomach Melbe such as Russ HKU4 Cow Rus;RosetusBat CoronavirusGCCDC 1 , Rosetus Bat coronavirus Nobeko such as HKU9 stomach sarcoids, such as severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) stomach rus; delta coronavirus; andecoviruses such as Wigeon coronavirus HKU20; Bulbul coronavirus HKU11 、 Polshin Coronau stomach Russ HKU15, Munia Coronau stomach Russ HKU13 or White Eye Corona stomach Russ HKU16 Like Burde Coronavirus Night Heron Coronation stomach Herdecoviruses such as Rus HKU19; Common Moochen Coronavirus stomach Moodecorona such as Russ HKU21 stomach γ-coronavirus; Beluga whale coronavirus SW1 and other Sega coronaviruses stomach Rus; Apian coronavirus and other flu viruses stomach The compound is selected from the group consisting of:

[0515] In some embodiments, the coronavirus is encoded by a polynucleotide comprising a sequence of SARS-CoV-2 or a polynucleotide having at least 80% sequence identity to a polynucleotide comprising a sequence of SARS-CoV-2. In some embodiments, the coronavirus comprises or is characteristic of human coronavirus 229E, human coronavirus OC43, SARS-CoV, HCoV NL63, HKU1, MERS-CoV, or SARS-CoV-2. In some embodiments, the coronavirus comprises or is characteristic of SARS-CoV-2.

[0516] In some embodiments, the subject is considered to be at risk for severe disease and / or serious complications from coronavirus infection. In some embodiments, the subject is about 50 years of age or older, about 55 years of age or older, about 60 years of age or older, or about 65 years of age or older. In some embodiments, the subject suffers from one or more pre-existing conditions selected from the group consisting of diabetes, asthma, respiratory disorders, hypertension, and heart disease. In some embodiments, the subject is immunocompromised. In some embodiments, the subject is immunocompromised due to AIDS, cancer, cancer treatment, hepatitis, autoimmune disease, steroid administration, immunosenescence, or any combination thereof.

[0517] In some embodiments, administration increases the subject's chance of survival after exposure to coronavirus, hi some embodiments, the chance of survival is increased by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, as measured using any clinically validated technique.

[0518] In some embodiments, the subject is exposed to or anticipates exposure to an individual who is contagious to coronavirus. In some embodiments, the individual who is contagious to coronavirus has one or more symptoms selected from the group consisting of fever, cough, shortness of breath, diarrhea, sneezing, runny nose, and sore throat. In some embodiments, the subject is 60 years of age or older, a healthcare worker, a frequent traveler, a military member, a caregiver, or a subject with a pre-existing condition that poses an increased risk of death from infection.

[0519] In some embodiments, the method further comprises administering one or more antiviral agents, in some embodiments, the one or more antiviral agents are selected from the group consisting of chloroquine, hydroxychloroquine, darunavir, galidesivir, interferon beta, lopinavir, ritonavir, remdesivir, and / or triazavirin.

[0520] In some embodiments, administration reduces the risk of coronavirus transmission. In some embodiments, the reduction in risk of transmission is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, as measured using any clinically validated technique. In some embodiments, the medically validated technique includes PCR (polymerase chain reaction) or immunoassay.

[0521] VI. Patient Population The disclosed aminosterols and compositions containing them can be used to treat a range of subjects, including humans and non-human animals, including mammals, and immature and mature animals, including human children and adults. The human subject to be treated can be an infant, a toddler, a school-age child, a teenager, a young adult, an adult, or a geriatric patient.

[0522] In embodiments disclosed herein relating to prevention, certain patient populations may be selected based on being "at risk" for developing any of the conditions disclosed herein. For example, genetic markers of a condition or family history can be used as indicators to identify subjects who are likely to develop a particular condition. Thus, in some embodiments, prevention may first involve identifying a patient population at risk for developing a condition. Alternatively, certain symptoms may be considered early signs of a particular disease. Thus, in some embodiments, patient populations may be selected for being "at risk" for developing a condition based on age and experiencing symptoms associated with the condition. Additional genetic or genetic indicators may be used to refine the patient population.

[0523] VII. Kit The aminosterol preparation or composition of the present disclosure can be packaged together with instructions or a package insert in a kit or can be included in a kit. Such instructions or a package insert can address the recommended storage conditions, such as time, temperature, and light, considering the shelf life of the aminosterol or its derivative or salt. Such instructions or a package insert can also address the specific advantages of the aminosterol or its derivative or salt, such as the ease of storage for preparations that may need to be used on-site, other than in a controlled hospital, clinic, or office environment.

[0524] The present disclosure also provides pharmaceutical packs or kits comprising one or more containers filled with one or more aminosterol pharmaceutical compositions disclosed herein.The kit may, for example, comprise a container filled with an appropriate amount of aminosterol pharmaceutical composition, either as a powder to be dissolved, a tablet, or a sterile solution.Associated with such container is a notice in the form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals or biological products, and such notice indicates the fact that the government has approved the manufacture, use, or sale for human administration.In addition, aminosterols or their derivatives or salts can be used in conjunction with other therapeutic compounds.

[0525] In another aspect, disclosed is a kit comprising the nasal spray device as described herein.In one aspect, kit can comprise one or more devices as disclosed herein, comprising the disclosed low-dose aminosterol composition, wherein the device is sealed in a container sufficient to protect the device from atmospheric influence.The container can be, for example, foil or plastic pouch, particularly foil pouch or heat-sealed foil pouch.The appropriate container sufficient to adequately protect the device will be easily understood by those skilled in the art.

[0526] In one embodiment, a kit can include one or more devices as disclosed herein, and the device can be sealed in a first protective packaging, a second protective packaging, or a third protective packaging that protects the physical integrity of the product. One or more of the first, second, or third protective packaging can include a foil pouch. The kit can further include instructions for use of the device. In one embodiment, the kit includes two or more devices.

[0527] In one aspect, a kit can include a device as disclosed herein and can further include instructions for use. In one embodiment, the instructions can include visual aids / pictorial and / or written instructions to the person administering the device.

[0528] VIII. Combination Therapy In the methods of the present disclosure, the aminosterol composition can be administered alone or in combination with one or more other therapeutic agents, examples of which are known to treat the condition for which the aminosterol is being administered to treat.

[0529] For example, in the method of treating, preventing, and / or delaying the onset or progression of PD and / or related symptoms, the aminosterol composition can be combined with drugs commonly prescribed for treating PD or related symptoms, such as levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists, and MAO-B inhibitors. Exemplary dopa decarboxylase inhibitors are carbidopa and benserazide. Exemplary COMT inhibitors are tolcapone and entacapone. Dopamine agonists include, for example, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, and rotigotine. MAO-B inhibitors include, for example, selegiline and rasagiline. Other medications commonly used to treat PD include amantadine, anticholinergics, clozapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.

[0530] In methods for treating, preventing, and / or delaying the onset, prevention, and / or progression of AD or associated symptoms, the aminosterol composition can be co-administered or combined with drugs commonly prescribed to treat AD or associated symptoms, such as glutamate, antipsychotics, Huperzine A, acetylcholinesterase inhibitors, and NMDA receptor antagonists such as memantine (Akatinol®, Axura®, Ebixa® / Abixa®, Memox®, and Namenda®). Examples of acetylcholinesterase inhibitors are donepezil (Aricept®), galantamine (Razadyne®), and rivastigmine (Exelon®).

[0531] In methods for treating, preventing, and / or slowing the progression of diabetes, including both type 1 and type 2 diabetes, and / or related symptoms associated with diabetes, or diabetic neuropathy, the aminosterol composition can be co-administered in combination with drugs commonly prescribed to treat diabetes, or insulin (NPH insulin or synthetic insulin analogs) (e.g., Humulin®, Novolin®) and oral hypoglycemic agents. Oral antihyperglycemic agents include (1) biguanides, such as metformin (Glucophage®); (2) sulfonylguanides, such as acetohexamide, chlorpropamide (Diabinese®), glimepiride (Amaryl®), glipizide (Glucotrol®), tolazamide, tolbutamide, and glyburide (Diabeta®, Micronase®); (3) meglitinides, such as repaglinide (Prandin®) and nateglinide (Starlix®); and (4) rosiglita. (5) alpha-glucosidase inhibitors, such as acarbose (Precose®) and miglitol (Glyset®); (6) dipeptidyl peptidase-4 inhibitors, such as sitagliptin (Januvia®); (7) glucagon-like peptide agonists, such as exenatide (Byetta®); and (8) amylin analogs, such as pramlintide (Symlin®).

[0532] In methods of treating, preventing, and / or delaying the onset or progression of HD or Huntington's disease or disease-related symptoms, the aminosterol compositions can be co-administered or used in combination with drugs commonly prescribed to treat Huntington's disease or related symptoms, such as drugs prescribed to help control Huntington's disease or related emotional and movement problems. Such drugs include (1) antipsychotics such as haloperidol and clonazepam; (2) drugs used to treat dystonia (e.g., acetylcholine modulators (trihexyphenidyl, benztropine (Cogentin®), and procyclidine HCl); GABA modulators (diazepam (Valium®), lorazepam (Ativan®), clonazepam (Klonopin®), and baclofen (Lioresal®)); dopamine modulators (levothyroxine (Levofen®)); and steroid modulators (e.g., steroids). (3) Drugs used to treat depression (fluoxetine, sertraline, and nortriptyline). Other drugs commonly used to treat HD include, but are not limited to, vodopa / carbidopa (Sinemet®), bromocriptine (Palodel), reserpine, tetrabenzyne; anticonvulsants (carbamazepine (Tegretol®) and botulinum toxin (Botox®)); and (4) drugs used to treat depression (fluoxetine, sertraline, and nortriptyline). Other drugs commonly used to treat HD include amantadine, tetrabenazine, dopamine blockers, and coenzyme Q. 10 Includes:

[0533] In methods for treating, preventing, and / or delaying the onset or progression of peripheral sensory neuropathy or related symptoms associated with peripheral sensory neuropathy, aminosterol compositions can be co-administered or used in combination with drugs commonly prescribed to treat peripheral sensory neuropathy or related symptoms. Peripheral sensory neuropathy refers to damage to nerves in the peripheral nervous system, which can be caused by either neurological disease, trauma, or the side effect of a systemic illness. Drugs commonly used to treat this condition include, but are not limited to, neurotrophin-3, tricyclic antidepressants (e.g., amitriptyline), antiepileptic therapies (e.g., gabapentin or sodium valproate), synthetic cannabinoids (nabilone) and inhaled cannabis, opiate derivatives, and pregabalin (Lyrica®).

[0534] In methods for treating, preventing, and / or slowing the onset or progression of traumatic head and / or spinal cord injuries associated with traumatic head and / or spinal cord injury, the aminosterol compositions can be co-administered or used in combination with medications commonly prescribed to treat associated symptoms such as traumatic head and / or spinal cord injuries, or analgesics (acetaminophen, NSAIDs, salicylates, and opioid medications such as morphine and opium) and paralytic medications.

[0535] In methods for treating, preventing, and / or delaying the onset or progression of stroke or associated symptoms related to stroke, the aminosterol compositions can be co-administered or used in combination with drugs commonly prescribed to treat stroke or associated symptoms, such as aspirin, clopidogrel, dipyridamole, tissue plasminogen activator (tPA), and anticoagulants (e.g., alteplase, warfarin, dabigatran).

[0536] In methods of treating, preventing, and / or delaying the onset or progression of ALS or related symptoms associated with ALS, the aminosterol compositions can be co-administered or combined with drugs commonly prescribed to treat amyotrophic lateral sclerosis or related symptoms, such as riluzole (Rilutek®), KNS-760704 (an enantiomer of pramipexole), olesoxime (TRO19622), talampanel, arimoclomol, drugs that help relieve fatigue, drugs that help relieve muscle spasms, drugs that help control spasticity, drugs that help reduce excess saliva and phlegm, to control pain, depression, sleep disorders, swallowing disorders, and constipation.

[0537] In methods of treating, preventing, and / or delaying the onset or progression of MS or related symptoms associated with multiple sclerosis, the aminosterol composition may be used in combination with corticosteroids (e.g., methylprednisolone), plasmapheresis, fingolimod (Gilenya®), interferon beta-1a (Avonex®, CinnoVex®, ReciGen®, and Rebif®), interferon beta-1b (Betaseron® and Betaferon®), glatiramer acetate (Co It may be co-administered or combined with drugs commonly prescribed to treat multiple sclerosis or related conditions, such as paxone®), mitoxantrone, natalizumab (Tysabri®), alemtuzumab (Campath®), daclizumab (Zenapax®), rituximab, zircotide, BHT-3009, cladribine, dimethyl fumarate, estriol, fingolimod, laquinimod, minocycline, statins, temsirolimus, teriflunomide, naltrexone, and vitamin D analogs.

[0538] In methods for treating, preventing, and / or delaying the onset or progression of cerebral palsy or associated symptoms related to cerebral palsy, the aminosterol composition can be co-administered or used in combination with drugs commonly prescribed to treat cerebral palsy or associated symptoms, such as botulinum toxin A injections.

[0539] In a method of preventing, preventing, and / or delaying the onset, prevention, and / or progression of epilepsy or associated symptoms related to epilepsy, the aminosterol composition can be administered in combination with an antiepileptic drug (e.g., carbamazepine (Tegretol®), clorazepate (Tranxene®), clorazepam (Klonopin®), clonazepam (Zarontin®), felbamate (Felbatol®), fosphenytoin (Cerebyx®), gabapentin (Neurontin®), lacosamide (Vimpat®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), phenobarbital (Luminal®), phenytoin (Dilantin®), pregabalin ( Lyrica®), primidone (Mysoline®), tiagabine (Gabitril®), topiramate (Topamax®), (Vimpat®), valproate hemisodium (Depakote®), valproic acid (Depakene®), and zonisamide (Zonegran®), clobazam (Frisium®), vigabatrin (Sabril®), retigabine, brivaracetam, seletracetam, diazepam (Valium® and Diastat®), lovazetam (Ativan®), paraldehyde (Paral®), midazolam (Versed®), pentobarbital (Nembutal®), acetazolamide (Diamox®), It can be co-administered or used in combination with drugs commonly prescribed to treat epilepsy or related conditions, such as progesterone, adrenocorticosteroid hormones (ACTH and Acthar®), various corticotropic steroid hormones (prednisone), and bromide.

[0540] In methods of treating, preventing, and / or delaying the onset or progression of cognitive impairment or associated symptoms related to cognitive impairment, the aminosterol compositions can be co-administered or combined with drugs commonly prescribed to treat cognitive impairment, such as donepezil (Aricept®), galantamine (Razadyne®), rivastigmine (Exelon®); and stimulants such as caffeine, amphetamine (Adderall®), lisdexamfetamine (Vyvanse®), and methylphenidate (Ritalin®); NMDA antagonists such as memantine (Nameda®); supplements such as ginkgo biloba, L-theanine, piracetam, oxiracetam, aniracetam, tolcapone, atomoxetine, ginseng, and salvia officinalis.

[0541] In the method for treating, preventing and / or delaying the onset or progression of malignant tumors or related symptoms associated with malignant tumors, the aminosterol composition can be co-administered or combined with drugs commonly used to treat malignant tumors.These include all known cancer drugs, such as (but not limited to) those listed at http: / / www.cancer.gov / cancertopics / druginfo / αlist as of May 5, 2014, which are incorporated herein by reference.In one embodiment, the drugs commonly used to treat malignant tumors include actinomycin-D, alkeran, ara-C, anastrozole, bicalutamide, BiCNU, bicalutamide, bleomycin, busulfan, capecitabine, carboplatin, carboplatinum, carmustine, CCNU, chlorambacil, cisplatin, cladribine, CPT-11, cyclophosphamide, cytosine arabinoside, Cytarabine, Cytoxan, Dacarbazine, Dactinomycin, Daunorubicin, Dexarazoxane, Docetaxel, Doxorubicin, DTIC, Epirubicin, Ethyleneimine, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Fotemustine, Gemcitabine, Hexamethylamine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Mechlorethamine to Melf Alan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, oxaliplatin, pasiritaxel, pamidronate, bentostatin, plicamycin, procarbazine, steroids, streptozocin, STI-571, tamoxifen, temozolomide, teniposide, tetrazine, thioguanine, thiotepa, tomudex, tomotecan, treosulfan, trimetrexate, vinbrain vincristine, vindesine, vinorelbine, VP-16, Xeloda, asparaginase, AIN-457, bapineuzumab, belimumab, brentuximab, briakinumab, canakinumab, cetuximab, dalotuzumab, denosumab, epratuzumab, estafenatox, faretuzumab, figitumumab, galiximab, gemtuzumab, girentuzumab (WX-G250), herceptin, ibritumomab,Inotuzumab, ipilimumab, mepolizumab, muromonab-CD3, naptumomab, necitumomab, nimotuzumab, ocrelizumab, ofatumumab, otelizumab, ozogamicin, pasivaximab, panitumumab, pertuzumab, ramucirumab, reslizumab, rituximab, REGN88, solanezumab, tanezumab, teplizumab, tiuxetan, tositumomab, trastuzumab, tremelimumab, vedolizumab, zalutumumab, zanolimumab, 5FC, Accutane, Hoffmann-LaRoche, AEE788, Novartis, AMG-102, antineoplastons, AQ4N (banoxantrone), AVANDIA (Rosiglitazone Maleate), Avastin (Bevacizumab) Genetech, BCNU, biCNU Carmustine, CCI-779, CCNU, CCNU Lomustine, Celecoxib (Systemic), Chloroquine, Cilengitide (EMD 121974), CPT-11 (CAMPTOSAR, irinotecan), dasatinib (BMS-354825, Sprycel), dendritic cell therapy, etoposide (Eposin, Etopophos, Vepesid), GDC-0449, Glevec (imatinib mesylate), hydroxychloroquine, Gliadwafer, IL-13, IMC-3G3, immunotherapy, Iressa (ZD-1839), lavatinib (GW572016), methotrexate for cancer (Systemic), Novocure, OSI-774, PCV, RAD001 novartis (mTOR inhibitor), rapamycin (Rapamune, Sirolimus), RMP-7, RTA 744, simvastatin, sirolimus, sorafenib, SU-101, SU5416 Sugen, sulfasalazine (Azulfidine), stent (Pfizer), TARCEVA (erlotinib HCl), Taxol, TEMODAR schering-plow, TGF-B antisense, Thalomid (thalidomide), Ptecan (Systemic), VEGF trap, VEGF-trap, vorinostat (SAHA), X765, XL184, XL765, Zarnestra (tipifarnib), ZOCOR (simvastatin), cyclophosphamide (Cytoxan), (Alkeran),Chlorambucil (Leukeran), thiopeta (Thioplex), busulfan (Myleran), procarbazine (Matulane), dacarbazine (DTIC), altretamine (Hexalen), chlorambucil, cisplatin (Platinol), ifosfamide, methotrexate (MTX), 6-thiopurine (mercaptopurine [6-MP], thioguanine [6-TG]), mercaptopurine (Purinethol), fludarabine phosphate (Leustatin), flurouracil (5-FU), cytarabine (ara-C), azacitidine, vinblastine (Velban), vincristine (Oncovin), podophyllotoxin (etoposide {VP-16} and teniposide {VM-26}), camptothecin (topotecan and irinotecan), texans such as paclitaxel (Taxol) and docetaxel (Taxotere), (Adriamycin, Rubex, Doxil), dactinomycin (Cosmegen), plicamycin (Mithramycin), mitomycin (Mutamycin), bleomycin (Blenoxane), estrogen and androgen inhibitors (Tamoxifen), gonadotropin-releasing hormone agonists (Leuprolide and Goserelin (Zoladex)), aromatase inhibitors (Aminoglutethimide and Anastrozole (Arimidex)), amsacrine, asparaginase (El-spar), mitoxantrone (Novantrone), mitotane (Lysodren), retinoic acid derivatives, myeloid growth factors (sargramostim and filgrastim), amifostine, pemetrexed, decitabine, iniparib, olaparib, veliparib, everolimus, vorinostat, entinostat (SNDX-275), mocetinostat (MGCD103), panobinostat (LBH589), romidepsin, valproic acid, flavopiridol, olomoucine, roscovitine, Kenpaullone, AG-024322 (Pfizer), fascapridine, lubidin, pavalonol A, NU2058, BML-259, SU9516, PD-0332991, P276-00, geldanamycin,Tanespimycin, alvespimycin, radicicol, deguelin, BIIB021, cis-imidazoline, benzodiazepinedione, spiro-oxindole, isoquinolinone, thiophene, 5-deazaflavin, tryptamine, aminopyrimidine, diaminopyrimidine, pyridoisoquinoline, pyrrolopyrazole, indolocarbazole, pyrrolopyrimidine, dianilinopyrimidine, benzamide, phthalazinone, tricyclic indole, benzimidazole, indazole, pyrrolocarbazole, isoindolinone, mono The compound is selected from the group consisting of sulfolinyl anthracyclines, maytansinoids, dusarmycin, auristatins, calicheamicin (DNA damaging agents), α-amanitin (RNA polymerase II inhibitors), centanamycin, pyrrolobenzodiazepines, streptonigtin, nitrogen mustards, nitrosoureas, alkanesulfonates, pyrimidine analogs, purine analogs, antimetabolites, folic acid analogs, anthracyclines, taxanes, vinca alkaloids, topoisomerase inhibitors, hormonal agents, and any combination thereof.

[0542] In methods for treating, preventing, and / or delaying the onset or progression of depression or related symptoms associated with depression, the aminosterol composition can be co-administered or combined with drugs commonly used to treat depression, including citalopram (Celexa®, Celexa®), escitalopram (Lexapro®, Cipralex®), paroxetine (Paxil®, Seroxat®), fluocetine (Prozac®), fluvoxamine (Luvox®, Faverin®), sertraline (Zoloft®, Lustral®), indalpine (Upstene®), zimeldine (Normud®, Z). selective serotonin reuptake inhibitors (SSRIs) such as elmid®; serotonin-norpinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine (Pristiq®), duloxetine (Cymbalta®), levomilnacipran (Fetzima®), milnacipran (Ixel®, avella®), and venlafaxine (Effexor®); serotonin modulators and stimulants (SMS) such as vortioxetine (Trintellix®); serotonin antagonists and reuptake inhibitors such as nephadzone (Dutonin®, Nefadar®, Serzone®), trazodone (Desyrel®), etoperidone; norepinephrine reuptake inhibitors (NRIs) such as reboxetine (Edronax®), teniloxathine (Lucelan®, Metatone®), viloxazine (Vivalan®), atomoxetine (Strattera®); bupropion (Wellbutrin®), amineptine (Survector®, Maneon®), nomifensine (Merital®, Alival®), methylphenidate (Ritalin®, Concerta®),Norepinephrine-dopamine reuptake inhibitors such as lisdexamfetamine (Vyvanse®); asamitriptyline (Elavil®, Endep®), amitriptyline oxide (Amioxid®, Ambivalon®, Equilibrin (registered trademark), colomipramine (Anafranil (registered trademark), desipramine (Norpramin (registered trademark), Pertofrane (registered trademark)), dibenzepine (Noveril (registered trademark), Victoril (registered trademark)), dimetacrine (Istonil (registered trademark)), doslevin (Prothiaden (registered trademark)), doxepin (Adapin (registered trademark), Sinequan (registered trademark)), imipramine (Tofranil (registered trademark)), lofepramine (Lomont (registered trademark), Gamanil (registered trademark)), melitracen (Dixeran (registered trademark), Melixeran (registered trademark), Trausabun (registered trademark)), troxazepine (Sintamil (registered trademark)), nortriptyline (Pamelor (registered trademark), Aventyl (registered trademark)), Xyptiline (Agedal®, Elronon®, Nogedal®), opipramol (Insidon®), piprofezin (Azafen® / Azaphen®), protriptyline (Vivactil®), tripipramine (Surmontil®), butyriptyline (Evadyne®), demexiptyline (Deparon®, Tinoran®), fluacizine (Phtorazidine®), fluoxetine (Fentanyl ... sin®), imipramine (Imiprex®, Elepsin®), ibrindol (Prondol®, Galatur®, Tertran®), metapramine (Timaxel®), propizepine (Depressin®, Vagran®), quinupramine (Kinupril®, Kevopril®), thiazesim (Altinil®), tofenacin (Elamol®,tricyclic antidepressants such as Tofacine®, aminepsin (Survector®, Maneon®), tianeptine (Stablon®, Coaxil®); amoxapine (Asendin®), maprotiline (Ludiomil®), mianserin (Bolvidon®, Norval®, Tolvon®), mirtazapine (Remeron®), setiptiline (Tecipul®), mianserin, mirtazapine tetracyclic antidepressants such as benzodiazepine, setiptiline; isocarboxazid (Marplan®), phenelzine (Nardil®), tranylcypromine (Parnate®), benmoxine (Neuralex®), iproclozide (Sursum®), iproazide (Marsilid®), mevanazine (Actomol®), nialamide (Niamid®), octanoxine (Ximaol®), pheniprazine (Catron®), phenoxyethanol Propazine (Drazine®), pibhydrazine (Tersavid®), safradine (Safra®), selegiline (Eldepryl®, Zelapar®, Emsam®), caroxazone (Surodil®, Timostenil®), metralindole (Inkazan®), moclobemide (Aurorix®, Manerix®), pirlindole (Pirazidol®), toloxatone (Humory®), monoamine oxidase inhibitors (MAOIs) such as amisulpride (Solian®), lurasidone (Latuda®), quetiapine (Seroquel®); and ketamine (Ketalar®), an N-methyl-D-aspartate (NMDA) antagonist.

[0543] In methods for treating and / or preventing obesity, the aminosterol compositions can be co-administered or combined with drugs commonly prescribed to treat obesity, including, but not limited to, orlistat (Xenical), lorcaserin (Belviq), phentermine-topiramate (Qsymia), naltrexone-bupropion (Contrave), liraglutide (Saxenda), phentermine, benzphetamine, diethylpropion, and phendimetrazine.

[0544] The combination can be administered simultaneously, for example, as a mixture, separately but simultaneously, or simultaneously; or sequentially.This includes the procedure in which the combined drugs are administered together as a therapeutic mixture, and the procedure in which the combined drugs are administered separately but simultaneously, for example, through separate intravenous lines to the same individual.Administering "in combination" also includes the separate administration of one compound or drug administered first, followed by the separate administration of the second compound or drug.The selected regimen can be administered simultaneously, because the activation of aminosterol-induced response does not require the systemic absorption of aminosterol into the bloodstream, thus eliminating concerns about the potential drug-drug interaction between aminosterol and the administered drug.

[0545] IX.Definitions The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0546] Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. Any suitable materials and / or methods known to those skilled in the art can be utilized in carrying out the methods described herein.

[0547] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition, aminosterol, or agent provided herein refers to a non-toxic but sufficient amount of the composition, aminosterol, or agent to provide the desired response. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug used, the mode of administration, and the like. An appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein. Exemplary doses are provided herein merely for convenience. Those skilled in the art can adjust such amounts according to the methods disclosed herein to treat a particular subject suffering from a particular symptom or disease. The therapeutically effective amount may vary based on the route of administration and dosage form.

[0548] As used herein, the term "comprising" is intended to mean that compounds, compositions, and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compounds, compositions, and methods, is intended to mean excluding other elements that are essential to the combination. Thus, a composition consisting essentially of the elements defined herein does not exclude trace contaminants, e.g., from isolation and purification methods, pharmaceutically acceptable carriers, preservatives, etc. "Consisting of" means excluding trace elements or more other components. Embodiments defined by each of the transition terms are within the scope of the present technology.

[0549] All numerical designations, such as mass, temperature, time, and concentration, including ranges, are approximations (+) or (-) varied by 1%, 5%, or 10% increments. It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about."

[0550] The term "about" is understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to those skilled in the art given the context in which it is used, "about" means up to plus or minus 10% of the particular term. For example, in some embodiments, it means plus or minus 5% of the particular term. In this specification, certain ranges are set forth and preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that precedes it, as well as a number that is close to or approximately the number that the term precedes. When determining whether a number is close to or approximately a specifically recited number, the number that is close to or approximately the unimplied number may be a number that is substantially equivalent to the specifically recited number in the context in which it is presented.

[0551] "Optionally" or "optionally" means that the situation described below may or may not occur, and thus the specification includes both cases where the situation occurs and cases where it does not occur.

[0552] A "pharmaceutically acceptable excipient or carrier" refers to an excipient that may optionally be included in a composition of the present disclosure and that causes no significant adverse toxicological effects in a patient.

[0553] "Substantially" or "essentially" means nearly completely or entirely, e.g., 95% or more of a given amount. In some embodiments, "substantially" or "essentially" means 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0554] As used in the description of this disclosure and the appended claims, the singular forms "a," "an," and "the" are used interchangeably and are intended to include and encompass the plural forms as well, unless the context clearly dictates otherwise. Also, as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0555] As used in the description of this disclosure and the appended claims, the singular forms "a," "an," and "the" are used interchangeably and are intended to include and encompass the plural forms as well, unless the context clearly dictates otherwise. Also, as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0556] As used herein, the term "aminosterol" refers to an amino derivative of a sterol. Non-limiting examples of suitable aminosterols for use in the compositions and methods disclosed herein include ENT-03 (Compound III).

[0557] As used herein, the term "administering" includes formulation for administration as well as actual administration, including physical administration by the subject being treated or another subject.

[0558] As used herein, "regulatory phosphatase" or "phosphatase" refers to an enzyme known to those skilled in the art that removes a phosphate group from a phosphorylated amino acid residue of its substrate protein. Non-limiting examples include type 1 (PP1) and type 2 (PP2, i.e., PP2A, PP2C, and PP2B), such as PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP3CA, PPP3CB, PPP3CC, PPP4C, PPP5C, and PPP6C; class I Cys-based protein tyrosine phosphatases (PTPs); class III Cys-based PTPs; class IV Cys-based DSPs (dual specificity phosphatases); PTPs, such as PTP1B, CDC14 (CDC14A, CDC14B, CDC14C, CDKN3); phosphatase and tensin homologs, e.g., PTEN; Slingshot, e.g., SSH1, SSH2, SSH3; DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19, DUSP21, DUSP22, DUSP33, DUSP34, DUSP35, DUSP36, DUSP37, DUSP38, DUSP39, DUSP40, DUSP41, DUSP42, DUSP43, DUSP44, DUSP45, DUSP46, DUSP47, DUSP48, DUSP49, DUSP50, DUSP51, DUSP52, DUSP53, DUSP54, DUSP55, DUSP56, DUSP57, DUSP58 ...8, DUSP51, DUSP51, DUSP52, DUSP53, DUSP54, Dual specificity phosphatases such as SP23, DUSP26, DUSP27, DUSP28, etc.; and CTDP1, CTDSP1, CTDSP2, CTDSPL, DULLARD, EPM2A, ILKAP, MDSP, PGAM5, PHLPP1, PHPLPP2, PPEF1, PPEF2, PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPTC7, PT These include protein Ser / Thr phosphatases including PMT1, SSU72, UBLCP1, PP1B, PP1A, PP2α / PP2R1A complex, PTPN6 / SHP1, PTPRC / CD45, DUSP22 / MKPX, PTPN2 / TC-PTP, PTPN7 / LC-PTP, PTPN12 / PTP-PEST, PTPN1 / PTP1B-CD, PTPN11 / SHP2, PTPN11 / SHP2-FL, and PTPN11 / SHP2-FL(E76K).

[0559] As used herein, "subject," "patient," or "individual" refers to any subject, patient, or individual, and these terms are used interchangeably herein. In this regard, the terms "subject," "patient," and "individual" include mammals, particularly humans. When used in conjunction with "in need thereof," the term "subject," "patient," or "individual" refers to any subject, patient, or individual who has or is at risk for a particular condition or disease.

[0560] The terms "treatment," "treating," or any variation thereof, include reducing, ameliorating, or eliminating (i) one or more specific symptoms and / or (ii) one or more symptoms or effects of a specific disease. The terms "preventing," "preventing," or any variation thereof, include reducing, ameliorating, or eliminating the risk of developing (i) one or more specific symptoms and / or (ii) one or more symptoms or effects of a specific disease.

[0561] A "prodrug" is a drug or compound that, after administration, is metabolized (i.e., converted within the body) to a pharmacologically active drug, such as ENT-03 (Compound III). In some embodiments, the prodrug includes a derivative of ENT-03 (Compound III) in which the alcohol and / or carboxylate are esterified.

[0562] "Optionally substituted" refers to a group selected from the group and substituted forms of that group. A "substituted" group refers to a group substituted with a chemical substituent, for example, replacement of a C-H bond with a bond between the C and the substituent. In one embodiment, the substituents are, for example, CF3, OCF3, halo, haloaryl, C1-C6 alkoxy, acyl, propionyl, butyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, carboxyl ester, carboxyl ester amino, (carboxyl ester)oxy, haloalkyl, aryloxy, haloalkoxy, hydroxyl, thiol, dihydroxy, aminohydroxy, carboxy, amido, sulfoxy, sulfonyl, haloaryloxy, aryl, benzyl, benzyloxy, heteroaryl, nitrile, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkynyl, C3-C6 halocycloalkyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C 10 Heterocyclyl, C1-C 10 It is selected from heteroaryl, -N3, nitro, -CO2H or its C1-C6 alkyl esters, and combinations thereof.

[0563] As used herein, "derivative" refers to, for example, compounds III, III-P, IV, and IV-P, or salts or solvates thereof. A "derivative" of ENT-03 (compound III) can also refer to deuterated derivatives of ENT-03 (compound III), such as ENT-03-d4 and ENT-03-d3, disclosed herein. [Example]

[0564] X. Working Example Example 1: Activity of ENT-03 (Compound III) as an inhibitor of protein tyrosine phosphatase 1B (PTP1B) This example examines the PTP1B inhibitory activity of ENT-03 (Compound III) and ENT-02 (MSI-1436), and also includes comparative data on the inhibitory activity of D7-1436 (D-1436), an aminosterol derivative with the same structure.

[0565] [ka]

[0566] ENT-02 (MSI-1436), ENT-03 (compound III), and D-1436 were dissolved in dimethyl sulfoxide (DMSO) to a stock concentration of 10 mM. A known PTP1B inhibitor, 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethyl-benzofuran-6-sulfonic acid-(4-(thiazol-2-ylsulfamyl)-phenyl)-amide (Wiesmann et al., 2004), was used as a control. Compounds were administered at 10 doses of IC10 in a 3-fold serial dilution in singlets, starting at 100 μM. 50 The enzyme was a human truncated form (1-321) and recombinantly produced in E. coli. Enzyme activity was monitored by measuring fluorescence. Phosphatase activity was monitored as a time course measurement of the increase in fluorescent signal from a fluorescent substrate, and the initial linear portion of the slope (signal / min) was analyzed. No compounds exhibited fluorescent background that could interfere with the evaluation.

[0567] IC for the three aminosterols tested (Figure 4A) and the control compound (Figure 4B) 50 Curves were constructed and curve fitting was performed if the activity at the highest concentration of the compound was less than 65%.

[0568] As shown in Table 2, ENT-02 (MSI-1436), which is already known to inhibit PTP1B, IC of 2.89 μM 50 and ENT-03 (compound III) showed an IC of 1.03 μM. 50 D‐1436 showed an IC of 2.09 μM 50 and a control PTP1B compound with an IC of 2.47 μM50 showed.

[0569] [Table 2]

[0570] The activity of ENT-03 and ENT-06 against a number of other phosphatases was also investigated. Both compounds were evaluated in vitro against human phosphatases (Tables 2B and 2C). The two compounds exhibited similar activity compared to their corresponding IC 50 These compounds showed very similar phosphatase "fingerprints" for ENT-03 and trozusquemine. These results strongly support the hypothesis that ENT-03 and trozusquemine are phylogenetically chemical orthologs. The compounds were inactive against PP1A, PP1B, PP2Aα, PTPN6, and PTPN2.

[0571] [Table 3]

[0572] [Table 4]

[0573] These data demonstrate that ENT-03 (Compound III) is a potent inhibitor of PTP1B and has potential therapeutic utilities known to be associated with PTP1B inhibitors.

[0574] Example 2: ENT-03 (Compound III) as a weight loss agent in mice This example demonstrates the promotion of weight loss by ENT-03 (Compound III) in mice.

[0575] ENT-02 (MSI-1436) is known to induce weight loss through a mechanism involving specific brain circuits that control appetite. Trodusquemine, when administered systemically to mice, causes weight loss and alterations in lipid oxidation. The pharmacological target appears to be within the hypothalamus, including the arcuate nucleus, median eminence, and paraventricular nucleus, based on the localization of radioactive trodusquemine and c-Fos activation after intracerebroventricular administration (Ahima et al., 2002).

[0576] Structure-activity relationship studies of ENT-02 for weight loss demonstrated the high degree of structural specificity required for this pharmacological effect (Zasloff et al., 2001). For example, altering the chirality of spermine at C-3, the hydroxyl at C-7, or the methyl at C-21 eliminated weight loss. Activity was lost when spermine was replaced with spermidine or when the terminal amino group of spermine was methylated. In contrast, both stereoisomers of the sulfate at C-24 were equally active, demonstrating that spatial constraints are relaxed around the anionic moiety, consistent with the activity observed for ENT-03.

[0577] To determine whether ENT-03 (Compound III) showed similar activity, previously ad libitum fed male Swiss Webster mice (approximately 50 grams, N=3 for each group) were treated intraperitoneally with five doses of either ENT-02 (MSI-1436) or ENT-03 (Compound III) at 10 mg / kg every other day, e.g., on days 0, 2, 4, 6, 8, and 10. Food was provided ad libitum.

[0578] As seen in Figures 1A, 1B, and 2, ENT-03 administration results in weight loss with kinetics similar to that seen after ENT-02 administration. Administration of both compounds resulted in weight loss, with a nadir at approximately day 16, followed by a gradual recovery to starting weight by approximately day 45. The initial loss in weight was similar for both compounds, but by approximately day 10, the effects differed, with ENT-02 causing a more severe loss. By day 27, both sets of treated mice had lost approximately 10% of their starting weight.

[0579] These data demonstrate that ENT-03 (Compound III) exhibits a pharmacological response with respect to body weight similar to ENT-02 (MSI-1436) and suggest that ENT-03 (Compound III) may have utility in all therapeutic applications known to be associated with ENT-02 (MSI-1436) as well as other aminosterols.

[0580] In a second experiment, growing male mice (approximately 25 grams) were administered either compound according to a similar dosing regimen. As in the previous experiment, both compounds affected weight gain (see Figure 2). However, in growing mice, ENT-02 had a more profound effect, inhibiting growth and inducing body fat consumption. While animals treated with ENT-03 continued to grow normally, they "slimmed down," suggesting that ENT-03 reestablished a new optimal weight "set point."

[0581] In a third experiment, ENT-03 administered intraperitoneally once weekly for 6 weeks to C57bl / 6 male mice induced a dose-dependent weight loss, as shown in Figure 1C. Other than the weight loss, the treated animals appeared clinically normal.

[0582] Finally, in a fourth experiment, weekly intraperitoneal administration of ENT-03 (3 mg / kg, 5 mg / kg, 10 mg / kg, or vehicle) to C57bl / 6 male mice for two weeks caused a dose-dependent weight loss, as seen in Figure 14. Other than the weight loss, animals in the treated groups appeared clinically normal.

[0583] These studies demonstrate that ENT-03 (compound III), like ENT-02, exhibits potent pharmacological activity in mice.

[0584] Example 3: Rejuvenation of the RNA transcriptome in the intestinal tract The purpose of this example was to evaluate the effect of oral administration of ENT-02 and ENT-03 (Compound III) on aged intestinal tissue.

[0585] Aging is associated with a depletion of gene expression in the gastrointestinal tract. Comparing images of the gastric mucosal tissues of young (20-week-old, Figure 3A) and old (78-week-old, Figure 3B) mice reveals a decrease in the thickness of the mucosal layer in the old specimens. This decrease in mucosa correlates with a decrease in the RNA transcriptome in the stomachs of old (78-week-old) versus young (20-week-old) mice. See Table 3 below. This example evaluated the effects of oral administration of ENT-01 and ENT-02 on old mice.

[0586] The dosing schedules used to determine the effects of orally administered squalamine and ENT-02 on the GI tract of young and aged mice were as follows: 20- and 78-week-old male C57B1 / 6 mice were obtained from Jackson labs. Animals were exposed to a 12-hour light / dark cycle and provided with Teklad standard mouse chow and water ad libitum. Animals were assigned to treatment groups as shown in Table 3.

[0587] [Table 5]

[0588] Animals were dosed once daily by oral gavage in the morning for a total of 14 days. Animals were fasted for 3-4 hours before dosing and at least 1 hour after dosing, but fasting did not exceed 6 hours. Test substances were dissolved in 0.5% hydroxypropyl cellulose in water. On day 15, animals were euthanized by CO2 asphyxiation, necropsied, and tissues were prepared for histology and RNA sequencing analysis.

[0589] The animals' digestive tracts were sectioned into stomach, duodenum, jejunum, ileum, cecum, colon, and rectum. The tissues were then sent for histological examination, and the transcriptome was analyzed by RNA sequencing. Table 4 shows the mRNA abundance of each component in the stomach of young and aged mice.

[0590] As shown in Table 5A below, mRNA levels of all genes in the table showed significant increases after treatment with squalamine (ENT-01). Also noteworthy is that ENT-03 stimulates the induction of the transcriptome in these segments of the digestive tract in old mice, while exerting only a minimal effect in young animals, corresponding to minimal repression or induction of specific genes not associated with aging. Presumably, ENT-03 complements defects in old mice that are not present in young animals. This suggests that squalamine (ENT-01), and by extension, structurally related aminosterols, such as ENT-03 (compound III) and its derivatives, have rejuvenating effects in the intestine.

[0591] [Table 6]

[0592] [Table 7]

[0593] [Table 8]

[0594] [Table 9]

[0595] Applicants also examined transcriptome changes within each segment of the GI tract. Oral administration to aged mice increased the abundance of gene transcripts that decrease with age in the stomach, jejunum, and ileum, in some cases to levels observed in young individuals, as shown in Figures 6A-6C.

[0596] Young (20 weeks) and old (80 weeks) C57BL / 6 male mice were administered ENT-03 (40 mg / kg) or vehicle (water) by oral gavage daily for 2 weeks. Clinical findings, as well as gross and microscopic examinations of the gastrointestinal tract, were unremarkable during this period. The transcriptomes of the stomach, jejunum, and ileum were analyzed using RNA sequencing. Comparative analysis of transcripts from untreated animals identified numerous transcripts whose abundance differed between corresponding tissues in old and young individuals. Differential patterns were observed for 86 gastric transcripts (p(adj)<0.05): 70 decreased and 16 increased with age; in the jejunum, over 400 transcripts decreased and 200 increased with age; and in the ileum, 700 transcripts decreased, while 400 increased with age. Thus, aging is associated with transcriptome changes within these three distinct regions of the mouse GI tract.

[0597] When we examined the effects of oral ENT-03 administration on the tissue transcriptome, we observed a blunted transcriptional response in young animals compared to old animals in all cases (Figures 6A-6C). For example, in the stomach of treated young animals, 13 genes were differentially expressed (p(adj)<0.05) compared to 63 in the old group. Similarly, in the jejunum, 42 genes were differentially expressed in the young group and 382 genes in the old group upon treatment. In the ileum, 80 genes were differentially expressed in young animals compared to 1,162 genes in the old group upon treatment with ENT-03.

[0598] Next, we compared the differentially expressed gene sets (DEGs) with age with those differentially expressed in treated old or young animals. For example, 37 gastric genes downregulated with aging (old vs. young) significantly overlapped with genes upregulated by ENT-03 treatment in old mice (P < 0.0001, hypergeometric test). In contrast, the only significant overlap between gastric aging genes and those in young ENT-03-treated stomachs was the 12 genes that were further downregulated in the aging direction.

[0599] The "aging" genes that ENT-03 appears to most significantly complement in the stomach are listed in Table 5B. Notably, in the stomach, "restored" aging genes include genes involved in tissue renewal (fibroblast growth factor 2; zinc finger protein 383; forkhead box C2); neuronal differentiation (neural cell adhesion molecule 2); immunity (toll-like receptors 9 and 12; interleukin-2 receptor, beta chain), neurotransmitter synthesis and uptake (choline and serotonin transporters), and mitochondrial respiration (cytochrome c oxidase subunit 6B2).

[0600] [Table 10]

[0601] First, we identified genes whose expression significantly changed between young and old mice (FDR-adjusted p-value <0.05) (Figure 6A). With aging, the expression of 75 genes in the stomach significantly decreased, while the expression of 11 genes significantly increased (Figure 6A). Meanwhile, fewer differences were observed between the gene expression profiles of the jejunum (Figures 10A-10D) or ileum (Figures 10D-10F) of young and old mice. In the jejunum, expression of five genes decreased and expression of two genes increased with age. Meanwhile, in the ileum, expression of 19 genes decreased and expression of nine genes increased. These results are consistent with the recognized decreased regenerative capacity of the aging rodent stomach (Fukunaga et al., 1998) and the resilience of the small intestine with aging (Eswaran et al., 2006).

[0602] Oral administration of ENT-03 to young mice (20 weeks) induced a response of 13 gastric genes, all of which were transcriptionally repressed by ENT-03 treatment (Figure 6B). For both young and old mice, the expression of no more than two genes was significantly altered in response to ENT-03 exposure in the jejunum and ileum.

[0603] In contrast, a more robust effect on gene expression in the stomach was observed in aged animals (78 weeks) treated with ENT-03. 63 genes were transcriptionally induced (FDR-adjusted p<0.05) (Figure 6C). Interestingly, 36 of the genes whose expression increased with ENT-03 treatment in aged mice were the same genes whose expression decreased with aging. These genes include those involved in tissue renewal (fibrolast growth factor 2 (Fgf2), zinc finger protein 382 (Zfp382), and forkhead box C2 (Foxc2)), neural differentiation (neural cell adhesion molecule 2 (Ncam2)); immunity (Toll-like receptors 9 and 12 (Tlr9, Tlr12); interleukin receptor chain (Il2rb) and beta chain (CD300 (CD300ld)); neurotransmitter synthesis and uptake (choline and serotonin transporters (Slc5a7, Slc6a4)); and mitochondrial respiration (cytochrome oxidase c subunit 6B2 (Cox6b2)).

[0604] Statistical analysis of RNA sequencing data was performed using the R programming language. Transcripts with read counts less than 1 per million reads were removed across all samples from each tissue. Sample raw count data were then normalized using a trimmed mean of M-value...

Claims

1. An aminosterol compound having the formula: 【Chemistry 1】 In the formula, R １ is H or D, and R ２ is H or D, provided that all R １ is H or all R ２ is H or all R １ and R ２ is H, or a pharmaceutically acceptable salt or solvate thereof.

2. The aminosterol compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, (a) an aminosterol compound having the formula: 【Chemistry 2】 ENT-03 (Compound III) or a pharmaceutically acceptable salt or solvate thereof, or (b) an aminosterol compound having the formula: 【Transformation 3】 C ２５ (R)ENT-03 (Compound III) or a pharmaceutically acceptable salt or solvate thereof, or, (c) an aminosterol compound having the formula: 【Chemistry 4】 ENT-03-d4 or a pharmaceutically acceptable salt or solvate thereof, or (d) an aminosterol compound having the formula: 【Transformation 5】 ENT-03-d3 or a pharmaceutically acceptable salt or solvate thereof. (a) an aminosterol compound having the formula: 【Transformation 6】 Compound IV (Δ5 ENT-03) or a pharmaceutically acceptable salt or solvate thereof, or (b) an aminosterol compound having the formula: 【Transformation 7】 Compound V (Δ4 ENT-03) or a pharmaceutically acceptable salt or solvate thereof, or (c) an aminosterol compound having the formula: 【Transformation 8】 Compound IV-P In the formula, R １ is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ Cycloalkyl, and optionally substituted C ２ -C ６ alkenyl; and R ２ is H or -C(O)R ３ where R ３ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ６ alkenyl, where R １ and R ２ at least one of is not H; or a pharmaceutically acceptable salt or solvate thereof, or (d) an aminosterol compound having the formula: 【Chemistry 9】 Compound V-P In the formula, R １ is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ Cycloalkyl, and optionally substituted C ２ -C ６ alkenyl; and R ２ is H or -C(O)R ３ where R ３ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ６ alkenyl, where R １ and R ２ at least one of is not H; or a pharmaceutically acceptable salt or solvate thereof, or (e) an aminosterol compound having the formula: 【Chemistry 10】 Compound III-P In the formula, R １ is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ６ alkenyl; and R ２ is H or -C(O)R ３ where R ３ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted heterocyclyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ２ -C ６ alkenyl, where R １ and R ２ at least one of is not H; or a pharmaceutically acceptable salt or solvate thereof.

4. The aminosterol compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, (a) an aminosterol compound having the formula: 【Chemistry 11】 C ２５ (R) Compound IV (Δ5 ENT-03) or a pharmaceutically acceptable salt or solvate thereof, or (b) an aminosterol compound having the formula: 【Chemistry 12】 C ２５ (R) Compound V (Δ4 ENT-03) or a pharmaceutically acceptable salt or solvate thereof, or (c) an aminosterol compound having the formula: 【Chemistry 13】 C ２５ (R) compound IV-P or a pharmaceutically acceptable salt or solvate thereof, or (d) an aminosterol compound having the formula: 【Chemistry 14】 C ２５ (R) compound V-P or a pharmaceutically acceptable salt or solvate thereof, or (e) an aminosterol compound having the formula: 【Chemistry 15】 C ２５ (R) Compound III-P or a pharmaceutically acceptable salt or solvate thereof.

5. (a) formulated as a pharmaceutically acceptable salt, or (b) formulated as a phosphate salt, which is a pharmaceutically acceptable salt; or (c) the aminosterol compound, or a pharmaceutically acceptable salt or solvate thereof, is of pharmaceutically acceptable grade; The aminosterol compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof.

6. A composition comprising the aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier or excipient.

7. The composition of claim 6 , comprising one or more of an aqueous carrier, a buffer, a sugar, and / or a polyol compound.

8. The composition of claim 6 or 7, wherein the composition further comprises at least one additional active agent.

9. 9. The composition of any one of claims 6 to 8, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, spray, inhalation, ophthalmic, otic, topical, buccal, nasal, and local (external) administration.

10. 10. The composition of any one of claims 6 to 9, wherein the composition is formulated as a dosage form selected from the group consisting of a liquid dispersion, a gel, an aerosol, an ointment, a cream, a lyophilized formulation, a tablet, and a capsule.

11. 11. The composition of any one of claims 6 to 10, wherein the composition is formulated into a dosage form selected from the group consisting of a controlled release formulation, a fast dissolving formulation, a delayed release formulation, a sustained release formulation, a pulsatile release formulation, and a mixture of immediate release and controlled release formulations.

12. The composition of any one of claims 6 to 11, wherein the composition is formulated for oral administration.

13. The composition of any one of claims 6 to 12, wherein the composition is formulated as an oral tablet or capsule.

14. The composition of any one of claims 6 to 11, wherein the composition is formulated for intranasal administration.

15. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for treating a subject in need thereof having a condition susceptible to treatment with an aminosterol.

16. 16. The use according to claim 15, wherein the condition is correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

17. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for treating, preventing, and / or delaying the onset or progression of a condition or disorder correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction, or associated symptoms, in a subject in need thereof.

18. 18. The use of claim 17, wherein the associated symptoms are selected from the group consisting of constipation, hallucinations, cognitive impairment, and inflammation.

19. 18. The use of claim 17, wherein the associated condition is correlated with a synucleinopathy, a neurodegenerative disease, a neurological disease or disorder, a psychological and / or behavioral disorder, or a cerebral or whole-body ischemic disease or condition.

20. 18. The use of claim 17, wherein the condition or disorder is a synucleinopathy, a neurodegenerative disease, or a neurological disease or disorder.

21. 18. The use according to claim 17, wherein the condition or disorder is a psychological and / or behavioral disorder.

22. 18. The use according to claim 17, wherein the condition or disorder is a cerebral or systemic ischemic disease or condition.

23. 18. The use of claim 17, wherein the associated symptoms are correlated with a synucleinopathy, a neurodegenerative disease, or a neurological disease or disorder, and the synucleinopathy, neurodegenerative disease, or neurological disease or disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, schizophrenia, multiple system atrophy, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich's ataxia, vascular dementia, spinal muscular atrophy, supranuclear palsy, progressive nuclear palsy, frontotemporal dementia, Guadeloupian parkinsonism, spinocerebellar ataxia, parkinsonism, traumatic brain injury, age-related degenerative processes, and age-related dementia.

24. 18. The use of claim 17, wherein the associated symptoms are correlated with psychological and / or behavioral disorders, and the psychological or behavioral disorders are selected from the group consisting of depression, autism, autism spectrum disorders, Down's syndrome, Gaucher's disease, Krabbe's disease, lysosomal conditions affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delusions, memory loss, apathy, bipolar disorder, disinhibition, abnormal movements and obsessive-compulsive behavior, addiction, cerebral palsy, epilepsy, major depressive disorder, and sleep disorders.

25. 18. The use of claim 17, wherein the associated symptoms are correlated with a cerebral or systemic ischemic disorder or condition, and the cerebral or systemic ischemic disorder or condition is selected from the group consisting of microangiopathy, intrapartum cerebral ischemia, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to intraoperative problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying blood to the brain, cerebral venous sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, high cholesterol, myocardial infarction, cardiac insufficiency, cardiac failure, congestive heart failure, myocarditis, pericarditis, pericardiitis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, thrombosis associated with malaria, prosthetic heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction disorders, hypertension, hypotension, and pulmonary edema.

26. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for treating, preventing, and / or delaying the onset or progression of cerebral or systemic ischemic damage and / or related symptoms correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction in a subject in need thereof.

27. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for inhibiting one or more regulatory phosphatases in a subject.

28. 28. The use of claim 27, wherein the regulatory phosphatase comprises a protein Ser / Thr phosphatase, including type 1 (PP1) and type 2 (PP2, i.e., PP2A, PP2C, and PP2B); Class I Cys-based protein tyrosine phosphatase (PTP); Class II Cys-based PTP; Class III Cys-based PTP; Class IV Cys-based DSP (dual specificity phosphatase); PTP; phosphatase and tensin homolog; slingshot; dual specificity phosphatase; wherein the regulatory phosphatase optionally comprises protein tyrosine phosphatase 1B (PTP1B).

29. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for suppressing, preventing, and / or delaying the onset or progression of appetite or weight gain, and / or one or more associated symptoms, in a subject in need thereof.

30. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for increasing gene transcription in the intestine of a subject.

31. Increased gene transcription was observed for caspase 14, collagen type XVIIα1, corneodesmosin, corniferin, cystatin E / M, delmokin, desmocollin 1, desmoglein 1β, filaggrin, gap junction protein β4, gap junction protein β6, H19 imprinted maternally expressed transcript, hornerin, kallikrein-related peptidase 7 chymotryptic stratum, keratin 1, keratin 10, keratinocyte differentiation-associated protein, proline-rich keratinocyte, late cornified envelope 1A1, late cornified envelope 1A2, late cornified envelope 1B, late cornified envelope 1C, late cornified envelope 1E, late cornified envelope 1F, The use of claim 30, which is for one or more genes selected from the group consisting of late cornified envelope 1G, late cornified envelope 1H, late cornified envelope 1I, late cornified envelope 1J, late cornified envelope 1L, late cornified envelope 1M, late cornified envelope 3C, late cornified envelope 3E, late cornified envelope 3F, lectin galactose-binding soluble 7, loricrin, sheerin, myoglobin, myosin-binding protein C slow type, myosin heavy chain polypeptide 1 skeletal muscle, myosin heavy chain polypeptide 8 skeletal muscle, myosin light chain phosphorylatable fast skeletal muscle, myosin light chain polypeptide 3, myozenin 1, myozenin 2, and titin cap.

32. The use according to claim 30 or 31, wherein the increase in gene transcription is between 1% and 450%.

33. The use described in claim 30 or 31, wherein the increase in gene transcription is between 500% and 1500%.

34. 10. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical composition for inhibiting one or more regulatory phosphatases to achieve a therapeutic or prophylactic benefit.

35. 35. The use of any one of claims 15 to 34, wherein the pharmaceutical composition is formulated for oral, nasal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intraventricular, transdermal administration, or any combination thereof.

36. The use according to any one of claims 15 to 35, wherein the pharmaceutical composition is formulated for nasal administration, oral administration, or a combination thereof.

37. The use of any one of claims 15 to 36, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt or solvate thereof comprises 0.1 to 20 mg / kg of body weight of the subject.

38. The use of any one of claims 15 to 36, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt or solvate thereof comprises 0.001 to 500 mg / day.

39. 37. The use of any one of claims 15 to 36, wherein the pharmaceutical composition is formulated for oral administration and the therapeutically effective amount of the aminosterol compound, or a pharmaceutically acceptable salt or solvate thereof, comprises 1 to 300 mg / day.

40. The use of any one of claims 15 to 36, wherein the pharmaceutical composition is formulated for oral administration and the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt or solvate thereof comprises 25 to 500 mg / day.

41. 41. The use according to any one of claims 15 to 40, wherein the aminosterol compound or a pharmaceutically acceptable salt or solvate thereof is administered in combination with at least one additional active agent to achieve either an additive or a synergistic effect.

42. 42. The use according to any one of claims 15 to 41, wherein the administration of the pharmaceutical composition comprises administration onto an empty stomach, optionally within 2 hours of the subject waking up.

43. The use described in any one of claims 15 to 42, wherein no food is consumed by the subject 60 to 90 minutes after administration of the pharmaceutical composition.

44. Use according to any one of claims 15 to 34, further comprising: (a) determining a dose of an aminosterol or a pharmaceutically acceptable salt or solvate thereof for the subject, wherein the dose of the aminosterol is determined based on the effectiveness of the dose of the aminosterol in improving or eliminating the symptoms to be evaluated; (b) subsequently administering to the subject a pharmaceutical composition comprising a dose of an aminosterol for a period of time; Wherein the uses include: (i) identifying the condition to be evaluated, wherein the condition is susceptible to treatment with an aminosterol; (ii) identifying a starting dose of the aminosterol for the subject; (iii) administering increasing doses of an aminosterol to the subject over a period of time until an effective dose for the symptom being evaluated is identified, wherein said effective dose is the aminosterol dose at which improvement or elimination of the symptom is observed, and fixing the aminosterol dose at that level for that particular symptom in that particular subject; and (c) Optionally, improvement or resolution of said symptoms is measured using a clinically validated scale or tool.

45. the pharmaceutical composition is administered orally; (i) the starting dose of aminosterols ranges from 10 mg to 150 mg per day; (ii) the aminosterol dose for the subject after titration is fixed in the range of 25 mg to 500 mg per day; and / or (iii) The use according to claim 44, wherein the dose of the aminosterol or its salt or solvate is titrated up in increments of 25 mg.

46. 45. The use of claim 44, wherein the pharmaceutical composition is administered intranasally and the starting dose of aminosterol ranges from 0.001 mg to 3 mg per day.

47. The use of claim 44, wherein the pharmaceutical composition is administered intranasally and the dose of aminosterol to the subject after titration is fixed in the range of 0.001 mg to 6 mg per day.

48. The use of claim 44, wherein the pharmaceutical composition is administered intranasally and the dose of aminosterol to the subject after titration is a subtherapeutic dose when administered orally or by injection.

49. The use of claim 44, wherein the pharmaceutical composition is administered intranasally and the dose of aminosterol is gradually increased in increments of 0.1 to 2 mg.

50. 45. The use according to claim 44, wherein the dose of aminosterol is titrated up every 3 to 5 days.

51. 45. The use of claim 44, wherein the starting dose of the aminosterol is higher if the symptoms being evaluated are severe.

52. 45. The use of claim 44, wherein the condition is correlated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

53. 45. The use of claim 44, wherein the symptom to be evaluated is selected from the group consisting of: (i) at least one non-motor aspect of daily living experience as defined by Part I of the Unified Parkinson's Disease Rating Scale selected from the group consisting of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, lethargy, features of dopamine dysregulation syndrome, sleep disturbances, daytime sleepiness, pain, urinary problems, constipation problems, orthostatic dizziness, and fatigue; (ii) at least one motor aspect of daily living experience as defined by Part II of the Unified Parkinson's Disease Rating Scale selected from the group consisting of speech, saliva and drooling, feeding and swallowing tasks, eating, dressing, hygiene, handwriting, turning over, tremor, getting out of bed, car, or deep chair, gait and balance, and immobility; (iii) at least one motor symptom as defined by Part III of the Unified Parkinson's Disease Rating Scale selected from the group consisting of speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination, toe tapping, foot agility, chair rise, gait, freezing of gait, postural stability, posture, bradykinesia, postural tremor of the hand, kinetic tremor of the hand, rest tremor, and rest tremor permanence; (iv) at least one motor comorbidity as defined in Part IV of the Unified Parkinson's Disease Rating Scale selected from the group consisting of time spent with movement disorder, functional impact of movement disorder, time spent in off-state, functional impact of motor fluctuations, complexity of motor fluctuations, and painful dystonia in off-state; (v) constipation; (vi) depression; (vii) cognitive impairment; (viii) sleep disorders or problems; (ix) circadian rhythm dysfunction; (x) hallucinations; (xi) fatigue; (xii) REM sleep disorder; (xiii) REM behavior disorder; (xiv) erectile dysfunction; (xv) Apnea; (xvi) orthostatic hypotension; (xvii) improvement of blood pressure and orthostatic hypotension; (xviii) nocturnal hypertension; (xix) temperature regulation; (xx) improvement in breathing or apnea; (xxi) correction of cardiac conduction disorders; (xxii) improvement in pain; (xxiii) restoration of bladder sensation and micturition; (xxiv) urinary incontinence; and / or (xxv) Control of nocturia.

54. The symptom to be evaluated is constipation, where (i) A fixed incremental dose of an aminosterol for constipation is defined as a dose of an aminosterol that results in complete spontaneous bowel movements (CSBM) within 24 hours of administration on at least two out of three days at a given dose; (ii) if the average complete spontaneous bowel movements (CSBM) or average spontaneous bowel movements (SBM) is ≥ 1 per week, the starting dose of aminosterol before escalation is 75 mg / day; and / or (iii) If the average CSBM or SBM is less than once a week, the starting dose of aminosterol before escalation is 150 mg / day.

55. A method for producing an aminosterol of the formula: comprising stimulating the addition of spermine to compound Ia of the formula: 【Chemistry 16】 【Chemistry 17】 wherein stimulating the addition of spermine to compound Ia comprises contacting a matrix comprising spermine and compound Ia with an agent that promotes the addition of spermine to compound Ia, said agent comprising an agent that activates or catalyzes the addition of spermine to compound Ia.

56. A method for producing an aminosterol of the formula: comprising stimulating the addition of spermine to compound Ia of the formula: [Chemistry 18] 【Chemistry 19】 wherein stimulating the addition of spermine to compound Ia comprises contacting a matrix comprising spermine and compound Ia with an agent that promotes the addition of spermine to compound Ia, said agent comprising an agent that activates or catalyzes the addition of spermine to compound Ia.

57. A method for producing an aminosterol of the formula: comprising stimulating the addition of spermine to compound Ia of the formula: 【Chemistry 20】 【Chemistry 21】 wherein stimulating the addition of spermine to compound Ia comprises contacting a matrix comprising spermine and compound Ia with an agent that promotes the addition of spermine to compound Ia, said agent comprising an agent that activates or catalyzes the addition of spermine to compound Ia.

58. 58. The method of any one of claims 55 to 57, wherein the aminosterol is produced in vitro.

59. Compound Ia has the formula: 【Chemistry 22】 56. The method of claim 55, wherein ENT-03 (compound III) has the formula: 【Chemistry 23】

60. Compound Ia has the formula: 【Chemistry 24】 57. The method of claim 56, wherein compound IV has the formula: 【Chemistry 25】

61. Compound Ia has the formula: 【Chemistry 26】 58. The method of claim 57, wherein compound V has the formula: 【Chemistry 27】

62. An aminosterol compound having the formula: 【Chemistry 28】 or 【Chemistry 29】 or a pharmaceutically acceptable salt or solvate thereof.

63. 63. The ENT-05 aminosterol compound, or a pharmaceutically acceptable salt or solvate thereof, of claim 62 for use in a method for treating hypertension.

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