Aminosterol ENT-03 compounds, related compositions containing the same, and methods of use thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 USC §119 to U.S. Provisional Application No. 62 / 882,358, filed on August 2, 2019, and U.S. Provisional Application No. 63 / 041,031, filed on June 18, 2020, the entire contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application generally relates to aminosterol compounds useful for treating human disease. Background Art

[0004] Aminosterols are amino derivatives of sterols. Squalamine is the most abundant member of a larger aminosterol family that includes at least 12 related compounds (Rao et al., 2000).

[0005]

[0006] Squalamine

[0007] The discovery of squalamine, whose structure is shown above, was reported by Michael Zasloff in 1993 (US Pat. No. 5,192,756).

[0008] Exemplary aminosterols also include ENT-02, also known as aminosterol 1436, trodusquemine and MSI-1436. These aminosterols (U.S. Pat. No. 5,192,756) exhibit different pharmacological activities in mammalian systems. Aminosterol 1436 causes weight loss and adipose tissue mobilization in vertebrates (Zasloff et al., 2001).

[0009]

[0010] Aminosterol 1436

[0011] Aminosterol 1436 has been shown to act in hypothalamic nuclei involved in appetite and energy balance and 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 evidence that it is active on hypothalamic insulin receptors in vivo. A Phase 1 human clinical trial of intravenous administration of aminosterol 1436 in obese subjects demonstrated improvements in insulin sensitivity.

[0012] Recognizing that aminosterol 1436 exhibits PTP1B inhibition in vivo, a number of studies have been conducted. They include: improving metabolic syndrome in a mouse model of hypothalamic insulin resistance; reversing atherosclerosis in LDL receptor knockout mice; inhibiting malignant tumor growth; stimulating regeneration of zebrafish tail and myocardium; repairing myocardial infarction and traumatic limb muscle injury by mobilizing stem cells in adult mice for regeneration; alleviating stress-induced anxiety in mice by targeting mGluR5 receptors in the limbic system; reversing memory impairment and normalizing behavior and reducing neuronal loss in the amyloid-β and tau mouse models of Alzheimer's disease through a neuronal PTP1B-dependent mechanism; reducing the toxicity of amyloid-β aggregates in vitro and in the C. elegans model of Alzheimer's disease (Limbocker et al., 2019); and reducing the formation of toxic α-synuclein aggregates and increasing lifespan in the C. elegans model of Parkinson's disease (Perni et al., 2018).

[0013] Several clinical trials related to the use of aminosterol 1436 have been conducted, including: (1) ClinicalTrials.gov identifier NCT00509132, “A Phase I, Double-Blind, Randomized, Placebo-Controlled Ascending IV Single-Dose Tolerance and Pharmacokinetic Study of Trodusquemine in Healthy Volunteers” by Genaera Corp.; (2) ClinicalTrials.gov identifier NCT00606112, “A Single Dose, Tolerance and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteer” by Genaera Corp.; and (3) ClinicalTrials.gov identifier NCT00806338, “An Ascending Multi-Dose, Tolerance and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteer” by Genaera Corp. Volunteers”; and (4) ClinicalTrials.gov identifier: NCT02524951, “Safety and Tolerability of MSI-1436C in Metastatic Breast Cancer” by DepyMed Inc.

[0014] There is a need in the art for novel aminosterol compounds and methods of using the same. The present disclosure meets these needs. Summary of the invention

[0015] In one aspect, an aminosterol compound having the formula:

[0016]

[0017] Where: R 1 is H or D; and R 2 is H or D; the condition is that all R 1 All H, all R 2 All H, or all R 1 and R 2 All are H, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

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

[0019]

[0020] ENT-03 (Compound III),

[0021] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0022] In one embodiment, the aminosterol has the formula:

[0023]

[0024] C 25 (R)ENT-03(C 25 (R) compound III),

[0025] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0026] In one embodiment, the aminosterol has the formula:

[0027]

[0028] ENT-03-d4 (compound III-d4),

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

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

[0031]

[0032] ENT-03-d3 (compound III-d3),

[0033] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0034] In another aspect, an aminosterol compound having the formula:

[0035]

[0036] Compound IV (Δ5ENT-03),

[0037] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0038] In one embodiment, the aminosterol compound has the formula:

[0039]

[0040] C 25 (R) Compound IV (Δ5ENT-03),

[0041] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0042] In one aspect, an aminosterol compound having the formula:

[0043]

[0044] Compound V (Δ4ENT-03),

[0045] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0046] In one embodiment, the aminosterol compound has the formula:

[0047]

[0048] C 25 (R) Compound V (Δ4ENT-03),

[0049] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0050] In another aspect, an aminosterol compound having the formula:

[0051]

[0052] Compound IV-P,

[0053] Where: R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl and optionally substituted C 1 -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 1 -C 6alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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]

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

[0057] In another aspect, an aminosterol compound having the formula:

[0058]

[0059] ENT-03-P (Compound III-P),

[0060] Where: R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -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 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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.

[0061] In some embodiments, the aminosterol has the formula:

[0062]

[0063] C 25 (R)ENT-03-P(C 25 (R) Compound III-P),

[0064] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0065] In another aspect, an aminosterol compound having the formula:

[0066]

[0067] Compound VP,

[0068] Where: R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl and optionally substituted C 1 -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 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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.

[0069] In one embodiment, the aminosterol compound has the formula:

[0070]

[0071] C 25 (R) Compound VP,

[0072] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0073] In some embodiments, the aminosterol is formulated as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a phosphate salt.

[0074] In one aspect, a composition comprising an aminosterol compound according to any embodiment of the present invention is provided, the composition comprising at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises one or more of the following: (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.

[0075] In some embodiments, the composition is formulated (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, nebulization, inhalation, ophthalmic, otic, topical, buccal, nasal, and external administration; (b) in a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) in a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate and controlled release formulations; or (d) any combination of (a), (b), and (c).

[0076] 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.

[0077] In one aspect, a method of treating a subject in need thereof, the subject having a condition susceptible to aminosterol treatment, the method comprising administering to the subject a composition according to any embodiment of the present invention. In some embodiments, the condition is associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction.

[0078] In another aspect, provided is a method of treating, preventing and / or slowing the onset or progression of a condition or disorder associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction or associated symptoms in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition according to any embodiment herein.

[0079] In some embodiments, (a) the symptoms are selected from constipation, hallucinations, cognitive impairment, and inflammation; (b) the symptoms are associated with synucleinopathy, a neurodegenerative disease, a neurological disease or disorder, a psychological and / or behavioral disorder, or a cerebral or systemic ischemic disorder or condition; (c) the disorder or condition is a synucleinopathy, a neurodegenerative disease, or a neurological disease or disorder; (d) the disorder or condition is a psychological and / or behavioral disorder; or (e) the disorder or condition is a cerebral or systemic ischemic disorder or condition.

[0080] In some embodiments, (a) the synucleinopathy, neurodegenerative disease, or nervous system disease or disorder is selected from 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, supranuclear palsy, progressive nuclear palsy, frontotemporal dementia, progressive nuclear palsy, Guadeloupe Parkinson's disease, spinocerebellar syndrome, (b) the mental or behavioral disorder is selected from depression, autism, autism spectrum disorder, Down syndrome, Gaucher disease, Krabbe disease, lysosomal disorders affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delusions, amnesia, apathy, bipolar disorder, disinhibition, abnormal movements and compulsive behaviors, addiction, cerebral palsy, epilepsy, major depressive disorder, and sleep apnea. or (c) the cerebral or systemic ischemic disorder or condition is selected from microangiopathy, cerebral ischemia during childbirth, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to problems during surgery, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, high cholesterol, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, hypertension, hypotension, and pulmonary edema.

[0081] In another aspect, provided is a method for treating, preventing and / or slowing the onset or progression of cerebral or systemic ischemic disorders and / or related symptoms associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition according to any embodiment herein.

[0082] In one embodiment, the cerebral or systemic ischemic disorder and / or related symptoms are selected from microangiopathy, cerebral ischemia during delivery, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to problems during surgery, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypertension, hypotension, high cholesterol, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects (CCD) and / or related symptoms, and pulmonary edema.

[0083] On the one hand, a method of inhibiting a subject's regulatory phosphatase such as protein tyrosine phosphatase 1B (PTP1B) is adopted, the method comprising administering to the subject a therapeutically effective amount of a composition according to any embodiment of the present invention. Other regulatory phosphatases inhibited by aminosterols are also described in detail herein. In some embodiments, the 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%.

[0084] In another aspect, provided is a method of inhibiting, preventing and / or slowing the onset or progression of appetite or weight gain and / or one or more related symptoms in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition according to any embodiment herein.

[0085] In another aspect, provided is 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 according to any embodiment herein, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0086] In some embodiments, the increase in gene transcription is for one or more genes selected from the group consisting of caspase 14, type XVII collagen alpha 1, corneodesmosin, cornifelin, cystatin E / M, dermokine, desmocollin 1, desmoglein 1β, filaggrin, connexin β4, connexin β6, H19 imprinted maternally expressed transcript, hornerin, kallikrein-related peptidase 7 chymotrypsin layer, keratin 1, keratin 10, keratinocyte differentiation-associated protein, keratinocyte-expressed proline-rich late cornified envelope 1A1, late cornified envelope 1A2, advanced cornified envelope 1B, advanced cornified envelope 1C, advanced cornified envelope 1E, advanced cornified envelope 1F, advanced cornified envelope 1G, advanced cornified envelope 1H, advanced cornified envelope 1I, advanced cornified envelope 1J, advanced cornified envelope 1L, advanced cornified envelope 1M, advanced cornified envelope 3C, advanced cornified envelope 3E, advanced cornified envelope 3F, soluble galactose-binding lectin 7, loricrin, sciellin, myoglobin, slow myosin binding protein C, myosin heavy polypeptide 1 skeletal muscle, myosin heavy polypeptide 8 skeletal muscle, myosin light chain phosphorylatable fast ske, myosin light polypeptide 3, myozenin 1, myozenin 2, and titin-cap.

[0087] In some embodiments, the method further comprises administering to the subject one or more non-aminosterol compounds that upregulate or downregulate one or more genes selected from the group consisting of caspase 14, type XVII collagen alpha 1, corneal desmosin, keratin, cystatin E / M, skin factor, desmocollin 1, desmocollin 1β, filaggrin, connexin β4, connexin β6, H19 imprinted maternally expressed transcript, keratin, kallikrein-related peptidase 7 chymotrypsin layer, keratin 1, keratin 10, keratinocyte differentiation-associated protein, keratinocyte-expressed proline-rich late cornified envelope 1A1, late cornified envelope 1A2, late cornified envelope 1B, Advanced cornified envelope 1C, advanced cornified envelope 1E, advanced cornified envelope 1F, advanced cornified envelope 1G, advanced cornified envelope 1H, advanced cornified envelope 1I, advanced cornified envelope 1J, advanced cornified envelope 1L, advanced cornified envelope 1M, advanced cornified envelope 3C, advanced cornified envelope 3E, advanced cornified envelope 3F, soluble galactose binding lectin 7, loricrin, cornified envelope precursor protein, myoglobin, slow myosin binding protein C, myosin heavy polypeptide 1 skeletal muscle, myosin heavy polypeptide 8 skeletal muscle, myosin light chain phosphorylated fast ske, myosin light polypeptide 3, myomodulin 1, myomodulin 2, and titin-cap. The non-aminosterol compound can be any compound known in the art to regulate any of the above genes.

[0088] In some embodiments, the increase in gene transcription 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%, about 90% to about 100%, about 100% to about 125%, about 125% to about 150%, about 150% to about 1 %. 1500% to 1800%; 1500% to 2000%; 1500% to 3000%; 1500% to 4000%; 1500% to 5000%; 1500% to 6000%; 1500% to 7000%; 1500% to 8000%; 1500% to 9000%; 1500% to 180 ...2000%; 1500% to 2000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 1500% to 3000%; 15

[0089] In one aspect, methods of inhibiting one or more regulatory phosphatases for therapeutic or prophylactic benefit are contemplated, the methods comprising administering a therapeutically effective amount of an aminosterol compound or a composition comprising the same, as described herein.

[0090] In some embodiments, the administration method comprises oral, nasal, pulmonary, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intracerebroventricular, transdermal, or any combination thereof. In some embodiments, the administration method comprises nasal administration, oral administration, or a combination thereof.

[0091] In some embodiments, a 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 of the subject's body weight; (b) about 0.1 to about 15 mg / kg of the subject's body weight; (c) about 0.1 to about 10 mg / kg of the subject's body weight; (d) about 0.1 to about 5 mg / kg of the subject's body weight; or (e) about 0.1 to about 2.5 mg / kg of the subject's body weight.

[0092] In some embodiments, a 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.

[0093] 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.

[0094] 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 additive or synergistic effects. In some embodiments, the additional active agent is administered by a method selected from the following: (a) concomitantly; (b) as a mixture; (c) individually and simultaneously or in parallel; and (d) individually and sequentially. In some embodiments, the additional active agent is a second aminosterol having a different structure from the aminosterol administered in any embodiment herein.

[0095] In some embodiments, the administration of the composition comprises administration on an empty stomach, optionally within two hours after the subject wakes up. In some embodiments, the subject does not consume food after about 60 to about 90 minutes from the administration of the composition.

[0096] 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.

[0097] In some embodiments, the method further comprises (a) determining the dose of the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative 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 regressing the symptoms evaluated, (b) then administering to the subject a composition comprising the dose of the aminosterol for a period of time, wherein the method comprises: (i) identifying a symptom to be evaluated, wherein the symptom is susceptible to aminosterol treatment; (ii) identifying the starting dose of the aminosterol for the subject; (iii) administering to the subject increasing doses of the aminosterol over a period of time until an effective dose for the evaluated symptom is identified, wherein the effective dose is the dose of the aminosterol at which improvement or regression of the symptom is observed, and the dose of the aminosterol is fixed at the level for the specific symptom of the specific subject. In some embodiments, the improvement or regression of the symptom is measured using a clinically recognized scale or tool.

[0098] In some embodiments, the composition is administered orally and: (a) the initial aminosterol dose ranges from about 10 mg to about 150 mg / day; (b) the aminosterol dose for the subject after escalation is fixed within the range of from about 25 mg to about 500 mg / day; and / or (c) the dose of the aminosterol or its salt or derivative is increased in increments of about 25 mg.

[0099] In some embodiments, the composition is administered intranasally and: (a) the initial aminosterol dose ranges from about 0.001 mg to about 3 mg / day; (b) the aminosterol dose for the subject after escalation is fixed at from about 0.001 mg to about 6 mg / day; (c) the aminosterol dose for the subject after escalation is a subtherapeutic dose when administered orally or by injection; and / or (c) the dose of the aminosterol 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.

[0100] In some embodiments, the aminosterol dose is increased every about 3 to about 5 days. In some embodiments, if the assessed symptoms are severe, the initial aminosterol dose is higher.

[0101] In some embodiments, the symptoms are associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction. In some embodiments, the symptoms to be evaluated are selected from: (a) selected from the following as measured by the Unified Parkinson's Disease Rating Scale (UPRS) (a) at least one non-motor aspect of daily living experience as defined by Part I of the Unified Parkinson's Disease Rating Scale: cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness on standing, and fatigue; (b) 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 following: speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, turning over in bed, tremors, getting out of bed, car, or deep chair, walking and balance, and rigidity; (c) at least one motor symptom identified in Part III of the Unified Parkinson's Disease Rating Scale selected from the following: speech, facial expressions, rigidity, finger tapping, hand movements, pronation-supination movements of the hands, toe tapping, leg agility, rising from a chair, gait, gait rigidity, postural stability, posture, slowed body movements, postural tremor of the hands, (d) at least one motor complication selected from the group consisting of duration of dyskinesia, functional impact of dyskinesia, time in the off state, functional impact of fluctuations, complexity of motor fluctuations, and painful off-state dystonia; (e) constipation; (f) depression; (g) cognitive impairment; (h) sleep problems or sleep disturbances; (i) circadian rhythm dysfunction ; (j) hallucinations; (k) fatigue; (l) REM sleep disturbances; (m) REM behavior disorder; (n) erectile dysfunction; (o) apnea; (p) postural hypotension; (q) correction of blood pressure or orthostatic hypotension; (r) nocturnal hypertension; (s) temperature regulation; (t) improvement in breathing or apnea; (u) correction of cardiac conduction defects; (v) improvement in pain; (w) restoration of bladder sensation and urination; (x) urinary incontinence; and / or (y) control of nocturia.

[0102] In some embodiments, the symptom to be evaluated is constipation, and wherein: (a) the fixed ascending aminosterol dose for constipation is defined as the aminosterol dose that results in a complete spontaneous bowel movement (CSBM) within 24 hours of administration on at least 2 of 3 days at a given dose; (b) if the average complete spontaneous bowel movement (CSBM) or average spontaneous bowel movement (SBM) is greater than or equal to 1 time / week, the initial aminosterol dose before ascending is 75 mg / day; and / or (c) if the average CSBM or SBM is less than 1 time / week, the initial aminosterol dose before ascending is 150 mg / day.

[0103] In one aspect, a method of making an aminosterol having the formula:

[0104]

[0105] ENT-03 (Compound III),

[0106] The method comprises stimulating the addition of spermine to compound Ia:

[0107]

[0108] Compound Ia.

[0109] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0110] In another aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0111]

[0112] ENT-03 (Compound III),

[0113] The method comprises inhibiting the addition of spermine to compound Ia:

[0114]

[0115] Compound Ia.

[0116] 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.

[0117] In some embodiments, Compound Ia has the formula:

[0118]

[0119] ENT-01 (Compound 1);

[0120] And ENT-03 (Compound III) has the following formula:

[0121]

[0122] C 25 (R)ENT-03(C 25 (R) Compound III).

[0123] In another aspect, a method of making an aminosterol having the formula:

[0124]

[0125] Compound IV,

[0126] The method comprises stimulating the addition of spermine to compound Ia:

[0127]

[0128] Compound Ia.

[0129] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0130] In another aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0131]

[0132] Compound IV,

[0133] The method comprises inhibiting the addition of spermine to compound Ia:

[0134]

[0135] Compound Ia.

[0136] 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.

[0137] In some embodiments, Compound Ia has the formula:

[0138]

[0139] (Compound 1; ENT-01),

[0140] And compound IV has the following formula:

[0141]

[0142] (C 25 (R) Compound IV).

[0143] In another aspect, a method of producing an aminosterol having the formula:

[0144]

[0145] Compound V,

[0146] The method comprises stimulating the addition of spermine to compound Ia:

[0147]

[0148] Compound Ia.

[0149] In some embodiments, (a) the aminosterol is produced in vivo in a subject; or (b) the aminosterol is produced in vitro.

[0150] In another aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0151]

[0152] Compound V,

[0153] The method comprises inhibiting the addition of spermine to compound Ia:

[0154]

[0155] Compound Ia.

[0156] 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.

[0157] In some embodiments, Compound Ia has the formula:

[0158]

[0159] Compound I; ENT-01,

[0160] And compound V has the following formula:

[0161]

[0162] C 25 (R) Compound V.

[0163] The foregoing summary of the invention and the following description of the drawings and the specific embodiments are both exemplary and illustrative. They are intended to provide further details of the present disclosure, but should not be construed as limiting. Other purposes, advantages and novel features of the present disclosure will be apparent to those skilled in the art from the following specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0164] Figure 1A and Figure 1B Shown is the percent body weight loss over time for mice administered ENT-02 (MSI-1436) (circles) or ENT-03 (Compound III; squares). Figure 1CIt is shown that intraperitoneal administration of ENT-03 once a week to C57bl / 6 male mice over 6 weeks resulted in a dose-dependent weight loss.

[0165] Figure 2 Results of administering ENT-03 (Compound III) and ENT-02 (MSI-1436) to growing mice are shown. While both compounds affected weight gain, ENT-02 had a more pronounced effect, inhibiting growth and inducing loss of body fat. In contrast, animals treated with ENT-03 continued to grow normally, although they were "emaciated," suggesting that ENT-03 reestablished a new optimal weight "set point."

[0166] Figure 3 An image of the gastric mucosal layer is shown, showing a difference from a younger 20-week-old stomach ( Figure 3 A) compared with 78 weeks of age ( Figure 3 B) The mucosal layer is reduced.

[0167] FIG4 shows the three aminosterols ENT-02 (MSI-1436), ENT-03 (Compound III) and D-1436 ( Figure 4A ) and a control PTP1B inhibitor according to Example 1 ( Figure 4B )Inhibition of PTP1B IC 50 curve.

[0168] Figures 5A-H show that inhibition of PTP1B by ENT-03 improves cognitive impairment in hAPP-J20 (Figures 5A-5D) and PS19 (Figures 5E-5H) mice.

[0169] Figures 6A-6C A volcano plot is shown showing the significance (as negative log 10 The FDR-adjusted p-value was transformed and the magnitude of differentially expressed genes (log 2 The relationship between the fold change of conversion is: Fig. 6A ) Old mice vs young mice, ( Figure 6C )ENT-03 treated old mice vs vehicle treated old mice, ( Figure 6B ) ENT-03 treated young mice vs. vehicle treated young mice. Genes identified as having different levels between groups are represented as red (upregulated) or blue (downregulated) dots, and non-significant genes are represented as black dots. The horizontal red line represents the applied p-value threshold.

[0170] Fig. 7A and Figure 7B Shown is a chromatogram of LC / MS / MS analysis of elderly human brain extract for ENT-03. Fig. 7Ais the chromatogram of a brain extract, and Figure 7B It is the quality control sample for the synthesis of ENT-03.

[0171] Fig. 8A and Figure 8B Mouse pup brain extracts ( Fig. 8A ) and liver extract ( Figure 8B ) is a chromatogram of LC / MS / MS analysis.

[0172] Fig. 9 Shown are the approximate concentrations of ENT-03 measured in the brain and liver of newborn mice during the first 3 weeks of life.

[0173] FIG. 10 shows gene expression profiles of the jejunum ( FIGS. 10A-10D ) or ileum ( FIGS. 10D-10F ) of young and old mice treated with ENT-03 or control.

[0174] Fig.11 A set of heat maps is shown, investigating the overlap of differentially expressed genes between pairs of comparisons. The values ​​in the figure represent the number of differentially expressed genes that intersect between a particular pair of comparisons (adjusted p-value < 0.05). The color of the square represents the Jaccard index (the quotient of the intersection and union of genes) for the comparisons on the x-axis and y-axis: Fig.11 A) Differentially expressed genes in both directions, ( Fig.11 B) Upregulated genes, ( Fig.11 C) down-regulate genes, and ( Fig.11 D) Genes that are upregulated in one comparison and downregulated in another comparison. Note that the numbers in the grey squares represent the total number of selected differentially expressed genes for a particular comparison.

[0175] Fig.12 The results are shown for the administration of a deuterated form of ENT-03 (ENT-03D 3 ) compared with the results of body weight gain in mice after administration of ENT-03.

[0176] Fig.13A and Fig. 13B Representative chromatograms of ENT-03 in 4-day-old mouse brain extracts are shown. Fig.13A : MRM 619.6 / 545.5, upper trace: endogenous ENT-03 in the extract; MRM 623.6 / 549.5 lower trace: extract + 2.2ng ENT-03-d 4 / g brain tissue; Fig. 13B : MRM 619.6 / 474.5, upper trace: endogenous ENT-03 in the extract; MRM 623.6 / 478.5 lower trace: extract + 2.2ng ENT-03-d 4 / g brain tissue.

[0177] Fig.14 Shown are graphs representing the results of body weight loss in male C57bl6 / j (N=5 / group) mice administered ENT-03 at different doses or vehicle by oral gavage every 3 days.

[0178] Fig.15 A Venn diagram of transcripts that are downregulated in aging and upregulated by ENT-03 is shown. The figure shows the number of overlapping and non-overlapping differentially expressed genes between the two sets of transcripts, which are downregulated in old mice compared to young mice and upregulated after treatment compared to controls. The number of signatures from the treatments of ENT-02 (MSI-1436) and ENT-03 is shown.

[0179] Fig.16 A scatter plot comparing the significant genes in ENT-02 (MSI-1436) vs. control (young) vs. ENT-03 vs. untreated (young) is shown. Genes are represented by dots. The color of the dots indicates to which set the gene is assigned. For each gene, the log2 (fold change) in ENT-02 (MSI-1436) vs. control (young) (y-axis) and the log2 (fold change) in ENT-03 vs. untreated (young) (x-axis) are shown.

[0180] Fig.17 The upset diagram of significant genes according to embodiment 12 is shown. The diagram shows the interaction between the up-regulated gene set and the down-regulated gene set. The bar graph on the far left shows the size of each set used as input. The bar graph at the top shows the unique size of each set (that is, each gene is only calculated once in this bar graph). The dot graph at the center shows the interactive set in each case.

[0181] Fig.18 A-18E: Fig.18 A: Venn diagram of overlapping genes in MSI-1436 (aminosterol 1436) vs. control (young) and ENT-03 vs. untreated (young) - all vs. all. Fig.18 B shows a Venn diagram of overlapping genes in MSI-1436 vs. control (young) and ENT-03 vs. untreated (young) - top vs. top. Fig.18 C shows a Venn diagram of overlapping genes in MSI-1436 vs. control (young) and ENT-03 vs. untreated (young) - bottom to bottom. Fig.18 D shows a Venn diagram of overlapping genes in MSI-1436 vs. control (young) and ENT-03 vs. untreated (young) - top vs. bottom. Fig.18E shows a Venn diagram of overlapping genes in MSI-1436 vs. control (young) and ENT-03 vs. untreated (young) - bottom vs. top.

[0182] Fig.19 A scatter plot comparing the significant genes in MSI-1436 (aminosterol 1436) vs. control (old) vs. ENT-03 vs. untreated (old) is shown. The genes are represented by dots. The color of the dots indicates to which set the gene is assigned. For each gene, the log2 (fold change) in the MSI-1436 vs. control (old) comparison (y-axis) and the log2 (fold change) in the ENT-03 vs. untreated (old) comparison (x-axis) are shown.

[0183] Fig. 20 The Upset diagram of the significant gene according to embodiment 12 is shown. The diagram shows the interaction between the up-regulated gene set and the down-regulated gene set. The bar graph on the far left shows the size of each set used as input. The bar graph at the top shows the unique size of each set (that is, each gene is only calculated once in this bar graph). The dot graph at the center shows the interactive set in each case.

[0184] Fig.21 A-21E: Fig.21 A shows a Venn diagram of overlapping genes in ENT-02 (MSI-1436) vs. Control (Aged) and ENT-03 vs. Untreated (Aged) - all vs. all. Fig.21 B shows a Venn diagram of overlapping genes in ENT-02 (MSI-1436) vs. Control (Aged) and ENT-03 vs. Untreated (Aged) - top vs. top. Fig.21 C shows a Venn diagram of overlapping genes in ENT-02 (MSI-1436) vs. Control (Aged) and ENT-03 vs. Untreated (Aged) - bottom to bottom. Fig.21 D shows a Venn diagram of overlapping genes in ENT-02 (MSI-1436) vs. Control (Aged) and ENT-03 vs. Untreated (Aged) - top vs. bottom. Fig.21 E shows a Venn diagram of overlapping genes in ENT-02 (MSI-1436) vs. Control (Aged) and ENT-03 vs. Untreated (Aged) - bottom vs. top.

[0185] Fig. 22 Scatter plots comparing significant genes in old vs. young (control) and old vs. young (untreated) are shown. Genes are represented by dots. The color of the dots indicates to which set the gene is assigned. For each gene, the log2 (fold change) in the old vs. young (control) comparison (y-axis) and the log2 (fold change) in the old vs. young (untreated) comparison (x-axis) are shown.

[0186] Fig.23 The Upset diagram of the significant gene according to embodiment 12 is shown. The diagram shows the interaction between the up-regulated gene set and the down-regulated gene set. The bar graph on the far left shows the size of each set used as input. The bar graph at the top shows the unique size of each set (that is, each gene is only calculated once in this bar graph). The dot graph at the center shows the interactive set in each case.

[0187] Fig.24 A-24E: Fig.24 A shows a Venn diagram of overlapping genes in old vs. young (control) and old vs. young (untreated) - all vs. all. Fig.24 B shows a Venn diagram of overlapping genes in old vs. young (control) and old vs. young (untreated) - top vs. top. Fig.24 C shows a Venn diagram of overlapping genes in old vs. young (control) and old vs. young (untreated) - bottom to bottom. Fig.24 D shows a Venn diagram of overlapping genes in old vs. young (control) and old vs. young (untreated) - top vs. bottom. Fig.24 E shows a Venn diagram of overlapping genes in old vs. young (control) and old vs. young (untreated) - bottom vs. top.

[0188] Fig.25 A scatter plot comparing significant genes in old vs. young (ENT-02; MSI-1436) and old vs. young (ENT-03) is shown. 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; MSI-1436) comparison (y-axis) and the log2 (fold change) in the old vs. young (ENT-03) comparison (x-axis) are shown.

[0189] Fig.26 The Upset diagram of the significant gene according to embodiment 12 is shown. The diagram shows the interaction between the up-regulated gene set and the down-regulated gene set. The bar graph on the far left shows the size of each set used as input. The bar graph at the top shows the unique size of each set (that is, each gene is only calculated once in this bar graph). The dot graph at the center shows the interactive set in each case.

[0190] Fig. 27 A-27E: Fig. 27 A shows a Venn diagram of overlapping genes in old vs. young (MSI-1436) and old vs. young (ENT-03) - all vs. all. Fig. 27 B shows a Venn diagram of overlapping genes in old vs. young (MSI-1436) and old vs. young (ENT-03) - top to top. Fig. 27 C shows a Venn diagram of overlapping genes in old vs. young (MSI-1436) and old vs. young (ENT-03) - bottom to bottom. Fig. 27 D shows a Venn diagram of overlapping genes in old vs. young (MSI-1436) and old vs. young (ENT-03) - top vs. bottom. Fig. 27 E shows a Venn diagram of overlapping genes in old vs. young (MSI-1436) and old vs. young (ENT-03) - bottom vs. top.

[0191] Figure 28: Heatmap of overlap between contrasts: A graph showing the number of selected genes that overlap between 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 Jacquard index (intersection over union) for the contrast on the x-axis versus the contrast on the y-axis. Fig.28A : Overlay heatmap of up-regulated and down-regulated (y-axis) and up-regulated and down-regulated (x-axis) selected genes for each comparison. Fig.28B : Overlay heatmap of upregulated (y-axis) and downregulated (x-axis) selected genes for each comparison. Fig.28C : Overlay heatmap of upregulated (y-axis) and downregulated (x-axis) selected genes for each comparison. Fig.28D : Overlay heatmap of upregulated (y-axis) and downregulated (x-axis) selected genes for each comparison. DETAILED DESCRIPTION

[0192] I. Overview

[0193] The pharmacological activity of aminosterols requires a highly specific chemical structure, suggesting that shark molecules are exploited by existing physiological circuits to accommodate similar compounds made by mammals. To date, no such compounds have been discovered, or even hypothesized to exist. The present disclosure provides such compounds, modified forms thereof, and methods of using them. Thus, in some embodiments, the present technology relates to Compound III or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof; methods of preparing such compounds; compositions comprising one or more Compound III or a derivative thereof; and uses thereof.

[0194] A. Overview of the Chemistry of the Disclosure

[0195] It has been known since the 1980s that 3-oxocholenic acid with a specific chemical structure can be isolated from the human body under certain circumstances. In particular, fluid drawn from chronic subdural hematomas was shown to contain high concentrations of bile acid compound I, whose function was unknown.

[0196]

[0197] Compound I

[0198] (Detected in humans)

[0199] Later, this same compound was found to be present in high concentrations in cerebrospinal fluid (CSF) after subarachnoid hemorrhage and in low concentrations in the CSF of healthy adults. Compound I was also found in both the amniotic fluid and urine of healthy humans in newborns, where it was 12 The function of Compound I and its related metabolic variants remains a mystery. It appears to be produced by a minor bile acid pathway that first converts cholesterol to 27-hydroxycholesterol and then to Compound I. The role of this minor pathway remains unknown and is responsible for approximately 5% of bile acids produced in humans. It is believed that the products of this "acidic" pathway do not play a significant role in fat emulsification, which is the primary function of bile acids in human physiology.

[0200] Although not identical, the structure of Compound I is reminiscent of Squalus aminosterols, including those shown and discussed herein. Both steroid scaffolds are essentially flat due to the steric constraints imposed between the A and B rings. In the case of Compound I, the flatness is imparted by the 4-olefinic double bond. In the shark molecule, the flatness is imposed by the 5-alpha hydrogen. The spatial positioning of the carboxyl moiety of Compound I is similar to the C of the shark molecule. 24 The sulfate ester on the steroid scaffold is shown in Figure 1, wherein both structures present negative charges in the same general position in space relative to the steroid scaffold. Based on this spatial positioning, ENT-03 (Compound III) was synthesized by coupling a polyamine (spermine) to Compound I, as shown below.

[0201] As described in detail in the examples, the applicant found that ENT-03 (Compound III) is present in subdural hematoma fluid in the brain of human and mouse pups. Compound III can be synthesized in the brain by the condensation of spermine and compound I. Compound I is believed to be derived from the metabolism of 27-hydroxycholesterol (also known as (25R) 26-dihydroxycholesterol), which is 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 subjected to continuous metabolism by CYP27A1, CYP7B1 and HSD-3B7, possibly in this order (Meaney et al., 2007). The synthesis of Ent-03 (Compound III) will require three additional biosynthetic steps: reduction of the double bond in the cholesterol A ring to produce 5α hydrogen; spermine condenses with 3-oxo groups to form imines; and subsequent imine reduction. The first step is probably catalyzed by brain steroid 5α-reductase (Celotti et al., 1992). The missing biosynthetic link is the enzyme that couples spermine to bile acid.

[0202]

[0203] ENT-03 (Compound III) contains a 5-alpha hydrogen, providing greater chemical stability compared to 4-enes such as Compound I. Like shark-derived ENT-02, ENT-03 (Compound III) reduces food intake and promotes weight loss in animal models, as discussed below and demonstrated by the following examples. By confirming that ENT-03 (Compound III; 3-β-spermine-7α-hydroxy-5α-cholestanoic acid) has the same pharmacological activity associated with shark-derived ENT-02 (MSI-1436), the usefulness of ENT-03 (Compound III) in other applications where ENT-02 and other aminosterols are known to be useful can be validated.

[0204] ENT-03 contains a 5α hydrogen rather than a 4-ene because the chemical stability of the former is greater than that of the latter. Since the C24 sulfated hydroxyl group on ENT-02 is replaced by a C27 ​​carboxylic acid in ENT-03, ENT-03 will be metabolized in a manner common to all bile acids, i.e., by stepwise cleavage of the cholesterol side chain. The pharmacological differences may be due in part to differences in the metabolic processing of the two compounds.

[0205] ENT-03 (Compound III) is also shown in Example 1 as a protein tyrosine phosphatase 1B (PTP1B) inhibitor. PTP1B is a valid target for the treatment of both type 2 diabetes and obesity; however, targeting PTP1B is challenging for drug discovery due to the highly conserved and positively charged active site pocket. PTP1B is a negative regulator of insulin and leptin signaling and is a highly validated therapeutic target for diabetes and obesity. Conventional drug development approaches have produced potent and specific PTP1B inhibitors, but previous publications have reported that these inhibitors lack oral bioavailability, "which limits their drug development potential" because it is believed that the drug must be absorbed into the blood to produce a pharmacological effect (Krishnan et al., 2018).

[0206] As further described in the Examples, ENT-03 and trodoquimine have been shown to have similar pharmacological activities, therapeutic effects in conditions such as Alzheimer's disease, and to reverse the aging phenotype of the gastrointestinal tract.

[0207] B. ENT-03 (Compound III) suppresses appetite

[0208] Example 2 of the present disclosure demonstrates that ENT-03 (Compound III) shares the properties of suppressing appetite and promoting weight loss with shark-derived ENT-02 (MSI-1436). Although appetite suppression itself is an effect of aminosterols, it is believed that ENT-03 (Compound III) may also have the same efficacy against brain-gut disorders that shark-derived aminosterols have recently been shown to have (data not shown; see, e.g., ClinicalTrials.gov Identifier NCT03047629for "Evaluation of Safety and Tolerability of ENT-01for the Treatment of Parkinson's Disease-Related Constipation (RASMET)"; and ClinicalTrials.gov Identifier NCT03781791for "Orally Administered ENT-01for Parkinson's Disease-Related Constipation (KARMET)"). ENT-01 is a squalamine phosphate. Furthermore, the activity of ENT-03 (Compound III) and its derivatives may extend to a variety of conditions marked by αS pathology and / or dopaminergic dysfunction, as detailed herein.

[0209] Obesity is defined as a body mass index (BMI) of 30.0 or higher, while 25.0 to <30 is defined as the overweight range. BMI provides a calculation of a person's mass (in kg) divided by the square of their height in meters. Factors that contribute to obesity include poor diet (high in calories), a sedentary lifestyle, lack of sleep, genetics, aging, and pregnancy. Less than 5% of adults participate in 30 minutes of physical activity every day and only one-third of children are physically active every day. Various medical conditions may also cause obesity by causing weight gain and excessive hunger or food consumption. Finally, more than 5% of the population may suffer from food addiction.

[0210] Mortality associated with weight gain or obesity is often the result of secondary conditions caused by excess weight. These conditions include 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. Obesity also leads to joint damage and osteoarthritis. Increased fat content is also thought to promote inflammation and further damage the joints.

[0211] Shark-derived ENT-02 (MSI-1436) is known to have pharmacological activity, resulting in appetite suppression and weight loss. The following examples show that ENT-03 (Compound III) also exhibits the same activity (Example 2). The following examples also show that, like shark-derived ENT-02 (MSI-1436), ENT-03 (Compound III) is an inhibitor of regulatory phosphatases such as protein tyrosine phosphatase 1B (PTP1B) (Example 1). Since ENT-03 (Compound III) and shark-derived ENT-02 share the same appetite suppression and weight loss promoting properties and have similar chemical structures that may share pharmacophores, it is believed that ENT-03 (Compound III) and its deuterated derivatives can be used to treat indications for which other aminosterols are known to be useful.

[0212] C.ENT-02 (MSI-1436 or aminosterol 1436) and disease

[0213] Without being bound by theory, it is believed that aminosterols act by targeting neurotoxic aggregates of alpha-synuclein (αS) in the gastrointestinal tract to restore the function of enteric nerve cells, thereby treating and / or preventing the brain-gut disorders described herein. Based on this theory, several clinical trials using squalamine to treat Parkinson's disease are ongoing or completed. See, e.g., (1) ClinicalTrials.gov Identifier: NCT03047629, “A Multi-Center, Single-Dose, Multiple-Dose, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Orally Administered ENT-01for the Treatment of Parkinson's Disease Related Constipation,” with 50 participants (study completed June 14, 2018); (2) ClinicalTrials.gov Identifier: NCT03781791, “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate Safety, Tolerability and Efficacy of Orally Administered ENT-01for the Treatment of Parkinson's Disease-Related Constipation (KARMET)” with 72 participants (estimated study completion date June 2019); and (3) ClinicalTrials.gov identifier: NCT03938922, “A Multicenter, Randomized, Double Blind Study to Evaluate Tolerability and Efficacy of Orally Administered ENT-01for the Treatment of Parkinson's Disease Dementia” with a target of 40 participants (estimated study start date June 3, 2019, and estimated study completion date February 2020).

[0214] Given that aminosterols have very low bioavailability, for example, ENT-02 and ENT-03 appear to act locally rather than by absorption into the bloodstream, this effect of aminosterols is very unexpected. Now functional enteric neurons prevent proteins (such as αS) from retrograde transport to the brain. In addition to restoring GI function, this effect is thought to slow down and possibly reverse the progression of brain-gut disorders such as Parkinson's disease (PD) and other related brain-gut diseases and conditions as described herein.

[0215] The strategy of targeting neurotoxic aggregates of αS in the gastrointestinal tract represents a new approach to treating brain-gut disorders such as PD and other neurological diseases and disorders described herein, and it can restore the function of enteric nerve cells and prevent retrograde transport to the brain. In addition to restoring gastrointestinal function, such activities may potentially slow the progression of brain-gut diseases. Therefore, but not being bound by theory, the methods described herein using novel ENT-03 (Compound III) or its pharmaceutically acceptable salts, solvates, prodrugs or derivatives and compositions comprising the same are expected to be useful for treating and / or preventing any of the brain-gut diseases and symptoms described herein.

[0216] PD is associated with the formation of toxic α-synuclein (αS) aggregates in 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), which are commonly found in the vertebrate central nervous system (CNS). αS is expressed in the neocortex, hippocampus, substantia nigra, thalamus and cerebellum, with the main location in the presynaptic terminals of neurons, both in membrane-bound and cytoplasmic free forms. The presynaptic terminals release chemical messengers called neurotransmitters from compartments called synaptic vesicles. The release of neurotransmitters transmits signals between neurons and is essential for normal brain function. αS can be seen in glial cells and melanocytes, and is highly expressed in neuronal mitochondria in the olfactory bulb, hippocampus, striatum and thalamus.

[0217] αS aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). These disorders are known as synucleinopathies. αS pathology has also been found in both sporadic and familial AD cases. Therefore, one indicator of αS pathology is the formation of αS aggregates.

[0218] At the molecular level, protein misfolding, accumulation, aggregation, and subsequent formation of amyloid deposits are common features of many neurological disorders, including Alzheimer's disease (AD) and PD. Therefore, neurodegenerative diseases are sometimes referred to as proteinopathies. The presence of common mechanisms suggests that neurodegenerative disorders may have common triggers, and the nature of the pathology is determined by the type of aggregated protein and the localization of the affected cells.

[0219] Since the discovery of the genetic link between αS and PD risk two decades ago and the identification of aggregated αS as the major protein component of Lewy pathology, αS has become a major therapeutic target for PD and related synucleinopathies (Brundin et al., 2017). It is believed that the α-synuclein abnormalities typically found in PD are responsible for the apparent catecholamine deficiency (dopamine is a catecholamine that shares metabolic pathways with other catecholamines) (Frisina et al., 2009).

[0220] Examples of disorders associated with abnormal αS pathology and / or dopaminergic dysfunction (also referred to as "brain-gut" disorders) include, but are not limited to, synucleinopathies, neurological diseases, psychological and / or behavioral disorders, cerebral and systemic ischemic disorders, and / or disorders or disorders. Examples of synucleinopathies, neurodegenerative diseases, and / or nervous system diseases include, for example, AD, PD, dementia with Lewy bodies (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 Parkinson's disease, Parkinson's disease, spinocerebellar ataxia, stroke, traumatic brain injury, degenerative processes associated with aging, and senile dementia. Examples of psychological or behavioral disorders include, for example, depression, autism, Down syndrome, Gaucher disease (GD), Krabbe disease (KD), lysosomal disorders affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, delusions and hallucinations, amnesia, apathy, bipolar disorder, disinhibition, abnormal movements and 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. Examples of general ischemic or cerebral ischemic disorders include, for example, microangiopathy, cerebral ischemia during labor, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to problems during surgery, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypertension, high cholesterol, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, hypertension, hypotension, and pulmonary edema.

[0221] To the extent that constipation is suspected to be related to the formation of toxic αS aggregates in the enteric nervous system (ENS), constipation is used as an early indicator of many neurological diseases (such as PD) (Braak et al. 2003 (b)). Since αS aggregates are normally transported to the central nervous system (CNS) (Holmqvist et al. 2014; Svensson et al. 2015) from ENS via afferent nerves such as the vagus nerve, neurotoxic aggregates gradually accumulate in brainstem and more rostral structures. Therefore, inhibiting the αS aggregation in ENS may reduce the neurological disease process (Phillips et al. 2008) that persists in both ENS and CNS. This relationship between ENS and CNS is sometimes described in this article as "brain gut" associated with a class of obstacles or aminosterol activity axis.

[0222] Without being bound by theory, it is believed that aminosterols improve intestinal function by acting locally on the gastrointestinal tract (as supported by low oral bioavailability (e.g., less than about 0.3%)). Orally administered aminosterols such as ENT-02 stimulate gastrointestinal motility in mice constipated by overexpression of human αS (West et al., manuscript in preparation). Infusion of aminosterols through the lumen of isolated intestinal segments of PD mouse models results in the excitation of IPANs (intrinsic primary afferent neurons), the main sensory neurons of the ENS that communicate with the myenteric plexus, thereby increasing the frequency of propulsive peristaltic contractions and strengthening neural signals projecting to the afferent arm of the vagus nerve.

[0223] In theory, the nerve impulses starting from the ENS after the administration of aminosterols (such as compound III) strengthen the afferent nerve signaling to the CNS. This may stimulate the removal of αS aggregates in the afferent neurons themselves and in the secondary and tertiary neurons projected rostrally in the CNS, because it is known that nerve stimulation is accompanied by an increase in neuronal autophagic activity (Shehata et al. 2012). It is believed that after the administration of aminosterols is stopped, the neurons of the CNS gradually re-accumulate αS load locally or through the transport of αS re-aggregation in the intestine.

[0224] Circadian rhythm disturbances in neurological diseases such as PD have been described both clinically and in animal models, and may play a role in abnormal sleep architecture, dementia, mood, and autonomic dysfunction associated with neurological diseases such as PD (Breen et al. 2014; Videnovic et al. 2017; Antonio-Rubio et al. 2015; Madrid-Navarro et al. 2018). The diurnal cycle of wrist skin temperature has been shown to be associated with the sleep-wake cycle, reflecting the effect of nocturnal skin heat dissipation on core temperature reduction and sleep onset (Sarabia et al. 2008; Ortiz-Tudela et al. 2014). It is believed that the administration of ENT-03 (Compound III) will have a significant positive effect on the patient's circadian rhythm. Without being bound by theory, it is believed that Compound III can affect neuronal circuits involving the master clock (suprachiasmatic nucleus) and its autonomic projections, and open the possibility of therapeutic correction of circadian rhythm dysfunction.

[0225] In one aspect, the aminosterol dosage can be patient-specific, because the therapeutically effective dosage of ENT-03 (Compound III) may be related to the degree of neuronal damage, with greater neuronal damage being associated with the need for a higher ENT-03 (Compound III) dosage to obtain the desired therapeutic outcome. As described in more detail herein, the dosage range of ENT-03 (Compound III) can be from about 0.01 to about 500 mg / day, and dosage determination will be described in more detail below. However, the present disclosure is not limited to methods for determining patient-specific ENT-03 (Compound III) dosages, as non-patient-specific therapeutic ENT-03 (Compound III) dosages are also described herein.

[0226] D. Experimental results

[0227] (1) Detection of ENT-03 in the brains of humans and mouse pups

[0228] In 1992, Nagata et al. identified high concentrations of the bile acid 7-α-hydroxy-3-oxo-4-cholesterol (7-HOCA) in human chronic subdural hematoma fluid and later in acute subarachnoid hemorrhage (Nagata et al., 1995) Figure 1C )(Nagata et al., 1992). In 1997, Zhang et al. reported that rat brain cells can metabolize 27-hydroxycholesterol to 7-HOCA (Zhang et al., 1997). Subsequently, Griffiths and collaborators 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 does not appear to be a biologically active bile acid as it does not activate the FXR, LXR, or RXR / NURR1 receptors for which bile acids and oxysterols are known ligands (Ogundare et al., 2010). It is proposed that the brain metabolizes 27-hydroxycholesterol entering from the periphery to 7-HOCA to facilitate the return of oxysterols to the circulation (Meaney et al., 2007).

[0229] The disclosure shows that the presence of ENT-03 in subdural hematoma fluid reflects its possible role in the development of this structure. After head injury, usually in older people and rarely in infants, a highly vascularized cystic "organ" is formed, one side of which is derived from the dura mater ("external membrane"), and the other side is from the subarachnoid space ("endomembrane") (Yamashima et al., 2000). High concentrations of multiple growth factors, including VEGF, accumulate in body fluids (Edlmann et al., 2017). The disclosure shows that ENT-03 appears in subdural hematoma in an attempt to repair intracranial damage. In this context, people may wish to speculate why (very common) healthy newborns who experience intracranial trauma after passing through the birth canal cause subdural and parenchymal hemorrhage to usually recover asymptomatically (Looney et al., 2007).

[0230] Fluid drained from three elderly patients with chronic subdural hematomas was analyzed by LC / MS / MS for the presence of ENT-03 due to the known high concentration of compound Ia (7-HOCA) in chronic subdural hematoma fluid. Brain extracts were analyzed by LC / MS / MS for ENT-03. Fig. 7A The presence of ENT-03 in brain extracts is shown. Figure 7B A reference sample of synthetic ENT-03 is shown.

[0231] Based on these data, the presence of ENT-03 in the extracts of brain, liver and kidney of newborn mice in the first two weeks after birth was analyzed. 3-oxo-bile acid includes unconjugated bile acid between 18%-40% in the amniotic fluid during the last three phases of human fetal development (Nakagawa et al. 1990) and accounts for a significant percentage in the bile acid in the urine of healthy newborns, which gradually decreases during the first month after birth (Wahlen et al., 1989 and Kimura et al., 1999). Due to the abundance of 3-oxo-bile acid in the neonatal period, the search for the putative polyamine-bile acid molecules is focused on newborn mice. Brain and liver extracts (see Example 7) were prepared from mice aged from the 1st day to the 24th day using a scheme designed to capture ENT-03 based on its physical properties.

[0232] The results showed that ENT-03 could be detected in the brain and liver of newborn mice (respectively Fig. 8A and Figure 8B The identity of endogenous ENT-03 was determined by its retention time, mass ([M+H + ]m / z=619.6) and MS / MS MRM characteristic fragment mass 545.57 ( Fig.13A ) and 474.39( Fig. 13B ) to build. Fig. 9 The approximate concentrations of ENT-03 measured in the brain and liver of newborn mice during the first 3 weeks of life are presented in Figure 1. In the brain and liver, the highest concentrations are seen at birth and gradually decrease over the next 3 weeks. 4 (-C2D 2 , -C4D 2 ) was used as an internal standard to determine the concentration of endogenous ENT-03 present in the chromatographic samples. Based on the significant differences in the retention times of the "flat" (5α) and "twisted" (5β) conformers that characterize the synthetic steroid precursor of ENT-03, the same retention times ( Fig.13A and Fig. 13B ) supports the tentative assignment of the 5-α configuration.

[0233] (2) Inhibition of regulatory phosphatases

[0234] In one aspect, methods of inhibiting one or more regulatory phosphatases for therapeutic or prophylactic benefit are contemplated, the methods comprising administering a therapeutically effective amount of an aminosterol compound or a composition comprising the same, as described herein.

[0235] Many cellular processes involved in health and disease are regulated by phosphorylation. Protein kinases are involved in the phosphorylation of cellular targets. Phosphatases reverse the action of kinases. There are two major classes of regulatory phosphatases. The first group is the tyrosine-specific PTPs, which dephosphorylate protein substrates on tyrosine. Tyrosine-specific PTPs include receptor-like PTPs and non-transmembrane PTPs. The second group is the DSPs (dual-specific 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.

[0236] Although significant efforts have been made in the development of therapeutic agents that inhibit protein kinases, comparable success has lagged in the development of inhibitors. The active sites of most phosphatases are configured as deep wells, at the bottom of which are positively charged residues. The corresponding inhibitors must carry negative charges or other hydrogen bond accepting functional groups to dock at the base of the well, and must be sufficiently slender to extend into the well. Because large, strongly charged molecules generally have limited cell permeability, few compounds that exhibit activity in in vitro enzyme assays also exhibit activity when assayed in cell culture or in vivo.

[0237] The phosphatases targeted by the present invention include several phosphatases that regulate vital cellular and physiological functions. They include: PTP1B, which downregulates many receptor tyrosine kinases, such as insulin and IGF receptors; growth factor receptors, such as VEGF, PDGF, EGF, FGF; stat proteins in the EGF leptin pathway. PTPN11 (E76K) is considered to be an oncogene that drives many human malignancies. PTPRC / CD45 has been extensively studied in lymphocytes and has been shown to act as a signaling gatekeeper in T cells after antigenic stimulation. PTPN7 / LC-PTP inactivates MAPK, inhibiting processes such as neuronal signaling and growth factor stimulation. PTPN12 / PTP-PEST plays a major role in cytoskeletal rearrangements that affect processes such as cell migration, cell extension, and cell division.

[0238] ENT-03 is a regulatory phosphatase inhibitor with the highest specificity for PTP1B. In addition, it exhibits the expected pharmacological activity in mice, namely reduced food intake and body weight. The aminosterols described herein are various derivatives of ENT-03 that exhibit inhibitory activity against regulatory phosphatases in vitro and in vivo.

[0239] 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). Knockout studies in mouse models provide a lot of evidence for the role of PTP1B in regulating insulin signaling and the development of obesity (Elchebly et al., 1999).

[0240] ENT-03 (Compound III) and ENT-02 (MSI-1436) were diluted in 10 doses of 3-fold serial dilution starting from 100 μM. 50 The fluorescence was measured to monitor the enzyme activity. As shown in Table 2, ENT-02 (MSI-1436, aminosterol 1436), which is known to inhibit PTP1B, exhibited an IC of 2.89 μM. 50 ; ENT-03 (Compound III) exhibited an IC of 1.03 μM 50 Half maximal inhibitory concentration or IC 50 It is a measure of the potency of a substance in inhibiting 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. Therefore, ENT-03 (Compound III) is significantly more potent than aminosterol 1436 because the IC of ENT-03 (Compound III) is 50 It is less than half of ENT-02 (MSI-1436).

[0241] As detailed in Example 1, although ENT-02 (MSI-1436) is described as a PTP1B inhibitor, it and ENT-03 (Compound III) exhibit comparable inhibitory activity against other phosphatases involved in cell signaling. In particular, both are active against full-length PTPN11 / SHP2. SHP2 (phosphatase 2 containing SH2 domain) is a protein tyrosine phosphatase that is involved in a variety of cell signaling processes and is directly related to both human genetic disorders and cancer (Zheng et al., 2018; Chen et al., 2016). In addition, both compounds effectively inhibit the gain-of-function PTPN11 (E76K) variant, which is considered to be an oncogene driving many human malignancies. Neither of these two compounds inhibits the closely related phosphatase PTPN6 / SHP1, which plays a functionally different role in biological pathways. Both also 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 following antigenic stimulation. PTPN7 / LC-PTP inactivates MAPK, inhibiting processes such as neuronal signaling and growth factor stimulation (Fukunaga et al., 1998; Eswaran et al., 2006). PTPN12 / PTP-PEST plays a major role in cytoskeletal rearrangements that affect processes such as cell migration, cell extension, and cell division.

[0242] Example 2 describes the activity of ENT-03 (Compound III) as a weight loss agent in mice. Mice were treated with ENT-03 (Compound III) or ENT-02 (MSI-1436) on days 0, 2, 4, 6, 8, and 10, while food was provided ad libitum. Figure 2 As can be seen, administration of both compounds resulted in a decrease in body weight.

[0243] These data demonstrate that ENT-03 (Compound III) exhibits similar pharmacological responses to ENT-02 (MSI-1436) in terms of appetite and body weight, and suggest that ENT-03 (Compound III) may be used for 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.

[0244] Although ENT-03 (Compound III) inhibits PTP1B, it was also shown that together with ENT-02, ENT-03 (Compound III) also inhibits iSeveral other phosphatases. Of particular interest is the proto-oncogene PTPN11, also known as SHP2, which is a ubiquitously expressed non-receptor protein tyrosine phosphatase that, together with PTP1B, regulates the PI3K / Akt, Ras / Raf / Erk and JAK / STAT signaling pathways utilized by hormones such as insulin, leptin and various growth factors (Pulido et al., 2013). In the mouse forebrain, neuronal SHP2 appears to enhance leptin signaling in the hypothalamus, while PTP1B instead primarily acts as a negative regulator of hypothalamic leptin signaling (Zhang et al., 2004). Therefore, by targeting two phosphatases that regulate the two main intracellular pathways downstream of leptin in opposite directions, ENT-03 (Compound III) can control the increase in the leptin circuit.

[0245] Finally, Example 9 evaluates the in vivo activity of ENT-05 in detail. The example demonstrates that modification of ENT-03 (Compound III) to produce ENT-05 produces a compound that is specific for PTPN11 (E76K) and possibly other phosphatases not yet described. The in vivo pharmacological effect on tadpoles is an inhibitory effect on sodium reabsorption, most likely in the kidney. A possible target is the type 2 sodium-potassium-chloride cotransporter (NKCC2). Little is known about the phosphatases that regulate the activity of NKCC2 in the renal tubules.

[0246] The Examples teach that ENT-05 has identified a phosphatase that activates the NKCC2 transporter of a channel that can be inhibited by ENT-05. ENT-05 clearly has potential utility in treating hypertension, similar to the drug furosemide, which inhibits renal NKCC2 by a mechanism that does not involve inhibition of phosphatase activity, as well as intracranial hypertension (increased intracranial pressure) and intraocular hypertension (glaucoma).

[0247] (3) Intestinal rejuvenation

[0248] Example 3 shows that squalamine effectively increases the transcriptome of aged mice. As discussed in Section IA, ENT-03 (Compound III) and shark-derived aminosterols such as squalamine share similar structures and spatial positioning of functional groups. Therefore, the activity of squalamine is believed to extend to ENT-03 (Compound III).

[0249] Aging involves a loss of gene expression in the intestine, which is demonstrated by a reduction in the RNA transcriptome in the intestine of old mice compared to young mice. Example 3 evaluates the effect of oral administration of ENT-01 (squalamine phosphate) on old mice. After 2 weeks of administration, the animals were euthanized and the gastrointestinal tract was segmented into stomach, duodenum, jejunum, ileum, cecum, colon and rectum. The stomach tissue was then sent for histological examination and the transcriptome was analyzed by RNAseq.

[0250] The mRNA levels of all genes in Table 4 of the Examples showed a significant increase after treatment with ENT-01 (squalamine phosphate) (see, e.g., Table 5A). This suggests that squalamine has a rejuvenating effect in the aged intestine, and this activity would be expected to extend to ENT-03 (Compound III) and its salts, solvates, derivatives and prodrugs. In addition, when the effects of oral administration of ENT-03 (Compound III) on the transcriptome of the tissue were examined, in each case it was observed that the transcriptional response of young animals was attenuated compared to that of old animals ( Figures 6A-6C ). For example, in the stomach of the treated young animals, 13 genes were differentially expressed, while in the old group it was 63 genes. Similarly, for the jejunum, 42 genes were differentially expressed in the young group, and 382 genes in the treated old group. In the ileum, 80 genes were differentially expressed in young animals treated with ENT-03 (Compound III), and 1162 genes were differentially expressed in old animals.

[0251] The set of genes (DEGs) differentially expressed with aging was compared to the set of genes differentially expressed in the old animals treated or the young animals treated. Analysis of overlapping DEGs between contrasts revealed that, for example, in the stomach, 37 genes (old vs. young) that were downregulated in aging significantly overlapped with genes upregulated by ENT-03 treatment in old mice. In contrast, the only significant overlap between the gastric aging genes and the genes in the young ENT-03 treated stomach was 12 genes, which were further downregulated in the aging direction.

[0252] The "senescent" genes that ENT-03 (Compound III) appears to most significantly replenish in the stomach are listed in Table 5B. Notably, in the stomach, the "restored" senescent genes include genes involved in tissue renewal (fibroblast growth factor 2; zinc finger protein 383; forkhead box C2); genes involved in neuronal differentiation (neural cell adhesion molecule 2); genes involved in immunity (toll-like receptors 9 and 12; interleukin 2 receptor beta chain), genes involved in neurotransmitter synthesis and uptake (choline and serotonin transporters), and genes involved in mitochondrial respiration (cytochrome c oxidase subunit 6B2).

[0253] Identified genes whose expression significantly changed between young and old mice ( Fig. 6A ). With aging, the expression of 75 genes in the stomach was significantly decreased, and the expression of 11 genes was significantly increased ( Fig. 6A). Meanwhile, smaller 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 5 genes decreased and expression of 2 genes increased with aging. In the ileum, expression of 19 genes decreased and expression of 9 genes increased. These results are consistent with the well-established reduced regenerative capacity of the stomach in aging rodents (Fukunaga et al., 1998) and the ability of the small intestine to recover with aging (Eswaran et al., 2006).

[0254] After oral administration of ENT-03 (Compound III) to young mice (20 weeks), 13 gastric genes responded, and all genes were transcriptionally repressed by ENT-03 treatment ( Figure 6B ). For both young and old mice, the expression of no more than 2 genes changed significantly in response to ENT-03 exposure in the jejunum and ileum.

[0255] In contrast, more robust effects on gene expression in the stomach were observed in older animals (78 weeks) treated with ENT-03 (Compound III). 63 genes were transcriptionally induced ( Figure 6C Interestingly, the 36 genes whose expression increased after treatment of old mice with ENT-03 (Compound III) were the same genes whose expression decreased with aging. These included genes involved in tissue renewal (fibroblast growth factor 2 (Fgf2); zinc finger protein 382 (Zfp382), and forkhead box C2 (Foxc2)); genes involved in neuronal differentiation (neural cell adhesion molecule 2 (Ncam2)); genes involved in immunity (toll-like receptors 9 and 12 (Tlr9, Tlr12), interleukin 2 receptor beta chain (Il2rb), and CD300 (Cd300ld)); genes involved in neurotransmitter synthesis and uptake (choline and serotonin transporters (Slc5a7, Slc6a4)) and genes involved in mitochondrial respiration (cytochrome c oxidase 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 gastrointestinal tract.

[0256] (4) Compound III and Alzheimer's disease treatment

[0257] Example 6 details data supporting the use of ENT-03 (Compound III) to treat neurological diseases such as Alzheimer's disease. PTP1B-dependent mechanisms have been used to reverse memory impairment in the amyloid-β and tau mouse models of Alzheimer's disease and normalize behavior and reduce neuronal loss (Ricke, Cruz et al. 2020). Other studies have shown that the toxicity of amyloid-β aggregates in vitro and in the Caenorhabditis elegans model of Alzheimer's disease is reduced by ENT-02 (Limbocker, Chia et al., 2019).

[0258] ENT-02 (MSI-1436) reverses several conditions associated with aging (in mice), such as metabolic syndrome, Alzheimer's disease, atherosclerosis, cancer, and decreased regenerative repair capacity. The data in Example 6 demonstrate that ENT-03 can treat Alzheimer's disease in a mouse model, which is an acceptable animal model for human Alzheimer's disease.

[0259] The Morris water maze was used to test the effects of ENT-03 (Compound III) on spatial learning and memory deficits in two familial Alzheimer's disease mouse models (hAPP-J20 mice expressing a double mutant of human amyloid precursor protein (Mucke et al., 2000) and PS19 mice expressing a P301S mutant of human microtubule-associated tau protein (Yoshiyama et al., 2007)). In both disease models (one with amyloidosis and the other with tauopathy), learning ( Figure 5A and Figure 5E ) and memory on the probe day ( Figure 5B , 5C, 5F, and 5G) were improved under ENT-03 treatment compared to vehicle-treated hAPP-J20 or PS19 littermate control mice (Figure 5). The effect of preventing cognitive decline is similar to that observed with the related compound ENT-02 and hAPP-J20 and PS19 mice (Ricke et al., 2020).

[0260] (5) Synthesis method for preparing ENT-03 (Compound III)

[0261] The examples describe synthetic methods for preparing the aminosterols described herein, including ENT-03 (Compound III). In particular, the synthetic method includes first preparing BDG-5 from BDG-4:

[0262]

[0263] BDG-5: 1 H NMR (500 MHz, CDCl 3)δ3.93(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=7Hz),0.81(s,3H),0.66(s,3H); 13 C NMR (CDCl 3 )δ177,109,67.9,64.2,64.1,55.8,51.4,50.5,45.6,42.6,39.5,39.4,37.5,36 .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.

[0264] Next, BDG-6 was prepared from BDG-5:

[0265]

[0266] BDG-6: 1 H NMR (500 MHz, CDCl 3 )δ3.93(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=7Hz),0.81(s,3H),0.66(s,3H); 13 C NMR (CDCl 3 )δ109.3,67.9,64.15,64.13,63.5,56.0,50.6,45.6,42.6,39.51,39.48,37.5,3 6.3,36.1,35.7,35.6,35.5,31.8,31.2,29.4,28.2,23.6,20.9,18.6,11.8,10.4.

[0267] Next, BDG-7 was prepared from BDG-6:

[0268]

[0269] BDG-7: 1 H NMR (500 MHz, CDCl 3)δ8.07(d,2H,J=8Hz),8.00(d,2H,J=8Hz),7.57(t,1H,J=8Hz),7.53(t,1H,J=8Hz),7.47(t,2H,J=8Hz),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=7Hz),0.88(s,3H),0.68(s,3H); 13 C NMR (CDCl 3 )δ166.7,166.0,132.8,131.1,130.5,129.7,129.5,128.4,128.3,109.0,71.9,65.5,64.2,64.1,55.8,50.7,4 7.2,42.8,39.5,38.6,37.4,37.2,35.7,35.5,35.3,33.3,32.0,31.2,28.0,25.2,23.6,21.1,18.6,11.8,10.5.

[0270] Next, BDG-8 was prepared from BDG-7:

[0271]

[0272] BDG-8: 17.24kg, 93.3%). 1 H NMR (500 MHz, CDCl 3 )δ8.07(d,2H,J=8Hz),7.57(t,1H,J=7Hz),7.48(t,2H,J=7Hz),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,24H),0.92(d,3H,J=6.5Hz),0.88(s,3H),0.67(s,3H). 13 C NMR (CDCl 3 )δ166.0,132.7,131.0,129.7,128.4,109.0,71.9,64.2,64.1,63.5,55.8,50.7,47.2,42.7,39.5,38.6,37.3,37.2 35.7,35.5,33.3,31.7,31.3,29.3,28.0,23.6,21.1,18.6,11.8,10.5.

[0273] Next, compound 1 was prepared from BDG-8:

[0274]

[0275] Compound 1: 1 H NMR (500 MHz, CDCl 3 )δ9.72(s,1H),8.07(d,2H,J=7Hz),7.59(t,1H,J=7Hz),7.49(t,2H,J=7Hz),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). 13 C NMR (CDCl 3 )δ203,166,132.8,131.0,129.8,128.4,109,72.0,64.17,64.11,55.7,50.7,47.2,42.8,40.8, 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.

[0276] Next, compound 2 was prepared from compound 1:

[0277]

[0278] Compound 2: 1 H NMR (CDCl 3 ,300MHz)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,29H),0.95(d,3H,J=7Hz),0.90(s,3H),0.69(s,3H);MS(ES+)485.45(MC 7 H 7 O 2 +H).

[0279] Next, compound 3 was prepared from compound 2:

[0280]

[0281] Compound 3: 1 H NMR (CDCl 3 ,300MHz)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,35H),1.11(d,3H,J=7Hz),0.88(s,3H),0.67(s,3H); MS(ES+)487.46(MC 7 H 7 O 2 +H).

[0282] Next, compound 4 was prepared from compound 3:

[0283]

[0284] Compound 4: 1 H NMR (CDCl 3 ,300MHz)δ8.05-8.02(m,2H),7.60-7.57(m,1H),7.51-7.45(m,2H),5.21(m,1H),2.4-1.0(m ,32H),1.15(d,3H,J=7Hz),1.09(s,3H),0.91(d,3H,J=7Hz),0.67(s,3H); MS(ES+)415.52(MC 7 H 7 O 2 +H).

[0285] Next, compound 5 was prepared from compound 4:

[0286]

[0287] Compound 5: 1 H NMR (CD 3 OD,300MHz)δ8.05-8.02(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, 1H), 2.1-1.0 (m, 39H), 1.10 (d, 3H, J = 7Hz), 0.95 (m, 6H), 0.74 (s, 3H); MS (ES+) 723.78 (M+H).

[0288] Next, ENT-03 (Compound III) was prepared from Compound 5:

[0289]

[0290] Compound III (ENT-03) as tetra-HCl salt: 1 H NMR (CD 3 OD,300MHz)δ3.80(br s,1H),3.20-3.05(m,13H),2.37(m,1H),2.2-1.0(m,36H),1.13(d,3H,J=7 Hz), 0.93 (d, 3H, J = 7Hz), 0.87 (s, 3H), 0.69 (s, 3H); MS (ES+) 619.31 (M+H).

[0291] Exemplary synthetic methods for preparing deuterated ENT-03 (ENT-03-d3 and ENT-03-d4) are also described in the following examples.

[0292] II. Compound

[0293] In one aspect, an aminosterol compound having the formula:

[0294]

[0295] Where: R 1 is H or D; and R 2 is H or D; the condition is that all R 1 All H, all R 2 All H, or all R 1 and R 2 All are H, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0296] In one embodiment, the aminosterol compound has the formula:

[0297]

[0298] Compound III (ENT-03),

[0299] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0300] In one embodiment, the aminosterol has the formula:

[0301]

[0302] C 25 (R) Compound III (ENT-03),

[0303] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0304] In one embodiment, the aminosterol has the formula:

[0305]

[0306] Compound III (ENT-03-d4),

[0307] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0308] In one embodiment, the aminosterol has the formula:

[0309]

[0310] Compound III(ENT-03-d3),

[0311] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0312] In one aspect, an aminosterol having the formula:

[0313]

[0314] (Compound IV),

[0315] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0316] In one embodiment, the aminosterol has the formula:

[0317]

[0318] (C 25 (R) Compound IV) (Δ5ENT-03),

[0319] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0320] In another aspect, an aminosterol compound having the formula:

[0321]

[0322] Compound V (Δ4ENT-03),

[0323] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0324] In some embodiments, the aminosterol compound has the formula:

[0325]

[0326] C 25 (R) Compound V (Δ4ENT-03),

[0327] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0328] In one embodiment, the prodrug comprises a compound of the formula:

[0329]

[0330] (Compound III-P),

[0331] in:

[0332] R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 alkenyl; and

[0333] 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 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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.

[0334] In one embodiment, the prodrug comprises a compound of the formula:

[0335]

[0336] (C 25 (R) Compound III-P),

[0337] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0338] In one aspect, the prodrug comprises a compound having the formula:

[0339]

[0340] (Compound IV-P),

[0341] in:

[0342] R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl and optionally substituted C 1 -C 6 alkenyl; and

[0343] 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 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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.

[0344] In one embodiment, the prodrug comprises a compound of the formula:

[0345]

[0346] (C 25 (R) Compound IV-P),

[0347] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0348] In another aspect, an aminosterol compound having the formula:

[0349]

[0350] Compound VP,

[0351] Where: R 1 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl and optionally substituted C 1 -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 1 -C 6 alkynyl, optionally substituted heterocyclyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 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.

[0352] In one embodiment, the aminosterol compound has the formula:

[0353]

[0354] C 25 (R) Compound VP,

[0355] or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0356] The exemplary structures proposed in this paper include:

[0357]

[0358] R 1 H or OH

[0359] R 3 -CH 3 , isopropyl, H

[0360] The aminosterols of the present disclosure may contain asymmetric carbon atoms. Therefore, the aminosterols of the present disclosure may exist as a single enantiomer or the mixture described above. The present disclosure covers both the natural R-orientation of C25 mixtures and compounds. Therefore, the aminosterols of the present disclosure may include two racemic mixtures and also substantially free of the single corresponding stereoisomers of another possible stereoisomer. As used herein, the term "substantially free of other stereoisomers" means that there are 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 (wherein X is a number between 0 and 100, including endpoints).

[0361] In some embodiments, the aminosterol is a derivative of any aminosterol disclosed herein or a derivative of compound III (ENT-03) modified by medical chemistry to improve biodistribution, ease of administration, metabolic stability, or any combination thereof. In some embodiments, compound III or derivative aminosterols include one or more of the following: (1) substitution of carboxylates with selected sulfonates, phosphates, or other anionic moieties to circumvent metabolic removal of sulfate moieties and oxidation of cholesterol side chains; (2) substitution of hydroxyl groups with non-metabolizable polar substituents such as fluorine atoms to prevent their metabolic oxidation or conjugation; and / or (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system.

[0362] The present technology also provides salts, solvates and hydrates of aminosterols disclosed herein. The salts of aminosterols of this technology are formed between the acid and basic groups (such as amino functional groups) of aminosterols or the base and acidic groups (such as carboxyl functional groups) of aminosterols. According to another embodiment, aminosterols are pharmaceutically acceptable acid addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, hydrochloride, sodium, sulfate, acetate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, tartrate, aluminum and gluconate.

[0363] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, dihydrotartaric 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, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid; and related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, Pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid, and phosphoric acid.

[0364] III. Methods for producing aminosterol compounds of the present disclosure

[0365] In one aspect, a method of producing an aminosterol having the formula:

[0366]

[0367] ENT-03 (Compound III),

[0368] The method comprises stimulating the addition of spermine to ENT 1a (Compound 1a):

[0369]

[0370] ENT-01a (Compound Ia).

[0371] In one aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0372]

[0373] ENT-03 (Compound III),

[0374] The method comprises inhibiting the addition of spermine to ENT-01a (Compound Ia):

[0375]

[0376] ENT-01a (Compound 1a).

[0377] In some embodiments, ENT-01a (Compound Ia) has the formula:

[0378]

[0379] ENT-01 (Compound I),

[0380] And ENT-03 (Compound III) has the following formula:

[0381]

[0382] C 25 (R)ENT-03(C 25 (R) Compound III).

[0383] In one aspect, a method of producing an aminosterol having the formula:

[0384]

[0385] (Compound IV),

[0386] The method comprises stimulating the addition of spermine to Compound Ia (ENT-01a):

[0387]

[0388] (Compound Ia).

[0389] In one aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0390]

[0391] (Compound IV)

[0392] The method comprises inhibiting the addition of spermine to compound Ia:

[0393]

[0394] (Compound Ia).

[0395] In some embodiments, Compound Ia has the formula:

[0396]

[0397] (Compound 1; ENT-01)

[0398] And compound IV has the following formula:

[0399]

[0400] (C 25 (R) Compound IV).

[0401] In another aspect, a method of producing an aminosterol having the formula:

[0402]

[0403] (Compound V),

[0404] The method comprises stimulating the addition of spermine to compound Ia:

[0405]

[0406] ENT-01a (Compound Ia).

[0407] In another aspect, a method of inhibiting the formation of an aminosterol of the formula:

[0408]

[0409] (Compound V),

[0410] The method comprises inhibiting the addition of spermine to compound Ia:

[0411]

[0412] ENT-01a (Compound Ia).

[0413] In some embodiments, Compound Ia has the formula:

[0414]

[0415] ENT-01 (Compound I,

[0416] And compound V has the following formula:

[0417]

[0418] (C 25 (R) Compound V).

[0419] In some embodiments, the aminosterol is produced in vivo in a subject. In some embodiments, the aminosterol is produced in vitro.

[0420] 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.

[0421] In some embodiments, 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. In some embodiments, stimulating the addition of spermine to compound Ia comprises contacting a cell comprising spermine and compound Ia with an agent that promotes the addition of spermine to compound Ia. In some embodiments, aminosterols are produced 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. Administration of the agent may include administration by any of the same routes discussed herein for administering aminosterols.

[0422] In some embodiments, the agent that promotes the addition of spermine to compound Ia comprises a promoter or an effector. The effector may include an enzyme activator, an enzyme inducer, a protein, a small molecule, or a nucleic acid. In some embodiments, the agent may include any agent that activates or catalyzes the addition of spermine to compound Ia. In some embodiments, the agent includes one or more enzymes that catalyze the addition of spermine to compound Ia. In some embodiments, the agent includes one or more polynucleotides encoding an enzyme that catalyzes the addition of spermine to compound Ia or one or more polynucleotides encoding peptide effectors. The one or more polynucleotides may include recombinant DNA and / or RNA. In some embodiments, the agent may include a vector of one or more polynucleotides.

[0423] In some embodiments, the addition of spermine is an enzymatic reductive amination. In some embodiments, the addition of spermine is a 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 can be an infant, toddler, school-age child, teenager, young adult, adult, or elderly patient.

[0424] IV. Composition

[0425] In another aspect, provided herein is a composition 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 may include administration of the composition.

[0426] A. Drug carrier

[0427] Although the aminosterol or its pharmaceutically acceptable salt, solvate or prodrug can be administered alone, it is preferably administered as a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers. The one or more carriers must be "acceptable" in the sense of being compatible with the aminosterol or its pharmaceutically acceptable salt, solvate or prodrug and not deleterious to the recipient thereof.

[0428] Typically, the formulation is prepared by uniformly and intimately contacting the aminosterol described herein or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof with a liquid carrier or a finely divided solid carrier or both. The product is then, if necessary, shaped into the desired formulation. Non-aqueous carriers such as fixed oils and ethyl oleate and liposomes can also be used herein.

[0429] The carrier suitably contains a small amount of additives, such as substances that enhance isotonicity and chemical stability. Such materials are nontoxic to the recipient at the dosage and concentration used, and include buffers such as phosphates, citrates, succinates, acetic acid and other organic acids or salts thereof; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, such as 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 dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as polysorbates, poloxamers or PEGs.

[0430] In the case of suitable aerosol administration, the aminosterols described herein or their pharmaceutically acceptable salts, solvates or prodrugs can be formulated into aerosols using standard procedures. The term "aerosol" includes any airborne suspension phase of the compounds described herein, which can be inhaled into the bronchioles or nasal passages, and includes dry powders and aqueous aerosols as well as pulmonary and nasal aerosols. Specifically, aerosols include airborne suspensions of droplets of the compounds described herein, which can be produced in a metered dose inhaler or nebulizer or in a sprayer. Aerosols also include dry powder compositions of the present technology compositions suspended in air or other carrier gases, which can be delivered, for example, by blowing from an inhaler device. See Ganderton & Jones, Drug Delivery to the Respiratory Tract (Ellis Horwood, 1987); Gonda, Critical Reviews in therapeutic Drug Carrier Systems, 6:273-313 (1990); and Raeburn et al. Pharmacol. Toxicol. Methods, 27:143-159 (1992).

[0431] B. Dosage Form

[0432] The aminosterol composition can be conveniently presented in unit dosage form and can be prepared by any method well-known in the pharmaceutical field. Exemplary aminosterol dosage forms include but are not limited to oral, intranasal and injection (IP, IV or IM). Preferably, the aminosterol formulation is administered orally, intranasally or a combination thereof. In another embodiment, administration includes parenteral administration.

[0433] The formulations or compositions of the present technology can be packaged together with instructions or package inserts or included in a kit therewith. "Pharmaceutically acceptable carrier" refers to any type of non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary.

[0434] The pharmaceutical composition 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 are known in the art.

[0435] Examples of fillers include lactose monohydrate, anhydrous lactose and various starches; examples of binders include various celluloses and cross-linked polyvinyl pyrrolidone, microcrystalline cellulose such as PH101 and PH102 microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC TM ).

[0436] Suitable lubricants, including agents that affect the flow properties of the powder to be compressed, may include colloidal silicon dioxide, such as 200, talc, stearic acid, magnesium stearate, calcium stearate and silica gel.

[0437] Examples of sweeteners may include any natural or artificial sweeteners such as sucrose, xylitol, saccharin sodium, sodium cyclamate, aspartame, and acesulfame potassium. Examples of flavoring agents are (a trademark of MAFCO), bubble gum flavoring and fruit flavoring, etc.

[0438] Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parabens such as butylparaben, alcohols such as ethanol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

[0439] Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, calcium hydrogen phosphate, sugars and / or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as PH101 and PH102; lactose, such as lactose monohydrate, anhydrous lactose and DCL21; calcium hydrogen phosphate, such as mannitol; starch; sorbitol; sucrose; and glucose.

[0440] Suitable disintegrants include lightly cross-linked polyvinyl pyrrolidone, corn starch, potato starch, corn starch and modified starches, cross-linked sodium carboxymethylcellulose, crospovidone, sodium starch glycolate, and mixtures thereof.

[0441] C. Dosage and Administration Period

[0442] The dosage range of aminosterol described herein can be from about 1 to about 500mg / day or any amount between these two values. In some embodiments, the aminosterol described herein of therapeutically effective dose is applied to the subject. The therapeutically effective amount of at least one aminosterol or its salt or derivative in the method of the present disclosure can be, for example, about 0.1 to about 20mg / kg, about 0.1 to about 15mg / kg, about 0.1 to about 10mg / kg, about 0.1 to about 5mg / kg or about 0.1 to about 2.5mg / kg subject body weight. On the other hand, the therapeutically effective amount of at least one aminosterol or its salt or derivative in the method of the present disclosure can be, for example, about 0.001 to about 500mg / day, about 0.001 to about 250mg / day, about 0.001 to about 125mg / day, about 0.001 to about 50mg / day, about 0.001 to about 25mg / day or about 0.001 to about 10mg / day.

[0443] The oral dosage range of aminosterols described herein can be from about 1 to about 500 mg / day or any amount between these two values. In one embodiment, the method of administration includes oral administration, and the therapeutically effective amount of aminosterols includes (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 dosages for oral administration of aminosterols include, but are not limited to, 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 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, 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 3 about 470, about 475, about 480, about 485, about 490, about 495, or about 500 mg / day.

[0444] The intranasal dose of aminosterol is much lower than the oral dose of aminosterol. Examples of such intranasal low doses of aminosterol 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 nasal 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 can 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 2.1, about 2. 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.

[0445] For intranasal (IN) administration, it is contemplated that the aminosterol dose can be selected so that the same dose will not provide any pharmacological effect if administered by any other route - e.g., a "sub-therapeutic" dose, and in addition, will not have a negative effect. For example, as described herein, Compound III (ENT-03) has a pharmacological effect of reducing food intake and weight loss. Therefore, in certain embodiments of the intranasal method of the present disclosure, if the aminosterol can be Compound III (ENT-03) or a salt, solvate, prodrug or derivative thereof, then if the same intranasal Compound III dose is administered via another route such as oral, intraperitoneal or intravenous, the Compound III dose will not result in a significant reduction in food intake or significant weight loss. Similarly, some aminosterols are known to produce pharmacological effects of nausea, vomiting and / or hypotension. Therefore, in certain embodiments of the intranasal method of the present disclosure, if the aminosterol has this effect when administered intranasally, then if the same intranasal aminosterol dose is administered via another route such as oral, intraperitoneal or intravenous, the aminosterol dose will not result in a significant reduction in food intake or significant weight loss. In some embodiments, intranasal administration comprises delivering the aminosterol to the brain. Suitable exemplary aminosterol dosages are described above.

[0446] If any given aminosterol causes a continuous undesirable side effect, such as diarrhea, vomiting or nausea, then the aminosterol dosage can be decreased (reduced). In another embodiment, the dosage of aminosterol can be changed by adding or subtracting a limit amount, so that the dosage can be appropriately reduced to eliminate adverse events, or if the clinical results show that this is desirable-for example, no or minimal adverse events and appropriate increase in dosage potentially increase efficacy, then appropriate increase in dosage. For example, in one embodiment, the aminosterol dosage can increase or decrease 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%.

[0447] The pharmaceutical composition comprising aminosterol or its derivative, salt, solvate or prodrug can be used in any suitable time period, including as a maintenance dose in the extended time period. Any pharmaceutically acceptable dosage regimen can be used for administration on the basis of needs. The aminosterol administration can be no more than once a day, 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 time periods (for example, twice a day) in a given day. In an exemplary embodiment, the dosage is 1 time / day.

[0448] In other embodiments, the composition can be administered as follows: (1) as a single dose or as multiple doses over a certain period of time; (2) as a maintenance dose for an indefinite period of time; (3) once, twice, or more times; (4) daily, every other day, every 3 days, weekly, or monthly; (5) for a certain period of time, such as about 1, about 2, about 3, or about 4 weeks, about 1, 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, such as daily administration for 6 months, weekly administration for 1 year or more, and so on.

[0449] Yet another exemplary dosing regimen includes periodic dosing, wherein an effective dose may be delivered once every about 1, about 2, about 3, about 4, about 5, about 6 days, or once a week.

[0450] In a preferred embodiment, the aminosterol dosage is taken in the morning, i.e. preferably taken on an empty stomach within about two hours after waking up, and can then fast for a certain period of time, such as, for example, about 60 to about 90 minutes. In other embodiments, the aminosterol dosage is taken within about 15min, about 30min, about 45min, about 1hr, about 1.25h, about 1.5h, about 1.75h, about 2h, about 2.25h, about 2.5h, about 2.75h, about 3h, about 3.25h, about 3.5h, about 3.75h or about 4h after waking up. In a further embodiment, fasting for about a period of time after the aminosterol dosage, wherein the period of time is at least about 30min, about 45min, about 60min, about 1.25h, about 1.5h, about 1.75h or about 2h.

[0451] Not bound by theory, it is believed that due to aminosterols, circadian rhythm is affected, it may be due to its ENS signal conduction, and taking aminosterol dosage in the morning can synchronize all autonomous physiological functions occurring during the day. In other embodiments of the present disclosure, aminosterol dosage is taken in about 15min, about 30min, about 45min, about 1 hour, about 1.25h, about 1.5h, about 1.75h, about 2h, about 2.25h, about 2.5h, about 2.75h, about 3h, about 3.25h, about 3.5h, about 3.75h or about 4h after waking up. In addition, in other embodiments of the present disclosure, after aminosterol dosage, subject fasts about 15min, about 30min, about 45min, about 1 hour, about 1.25h, about 1.5h, about 1.75h, about 2h, about 2.25h, about 2.5h, about 2.75h ​​or about 3 hours of time period.

[0452] D. "Fixed aminosterol dose"

[0453] On the one hand, the application relates to a method for determining a "fixed dose" of aminosterols described herein that is independent of age, size or weight, but is individually calibrated. The "fixed dose" obtained by this method has produced very effective results in treating one or more symptoms based on which the "fixed dose" is determined, related symptoms along the "brain-gut" axis, and potential obstacles. In addition, methods for fully using this same "fixed dose" method for methods of preventing potential obstacles are contemplated herein. The present disclosure is not limited to methods for determining a fixed aminosterol dose for a specific patient thereby.

[0454] The "fixed aminosterol dose" that will be effective for treatment is determined for each patient by establishing the starting dose of the aminosterol composition and the threshold value for improving specific symptoms, which is also referred to herein as the "fixed increasing aminosterol dose", and the threshold value is used as a tool or marker for evaluating the effectiveness of the aminosterol dose. After determining the starting aminosterol dose for a specific patient, the aminosterol dose is then gradually increased in a consistent amount at consistent time intervals until the desired improvement is achieved; this aminosterol dose is the "fixed increasing aminosterol dose" for this specific symptom of the specific patient. In an exemplary embodiment, the orally administered aminosterol dose is increased by about 25 mg every about 3 to about 5 days until the desired improvement is achieved. The symptoms evaluated and the tools for measuring symptom improvement may be described in detail below, including but not limited to constipation, hallucinations, sleep disorders (e.g., REM disordered sleep or circadian rhythm dysfunction), cognitive impairment, depression, or alpha-synuclein aggregation.

[0455] This therapeutically effective "fixed dose" is then maintained throughout the course of treatment and / or prevention. Thus, even if a patient goes "off" and stops taking the aminosterol composition, upon re-initiation of aminosterol therapy, the same "fixed dose" is taken without a ramp-up period. Without being bound by theory, it is believed that the aminosterol dose depends on the severity of the neurological damage associated with the symptom for which a "fixed dose" threshold is established - for example, for constipation, the dose may be related to the degree of damage to the patient's enteric nervous system.

[0456] Dose escalation: When a "fixed aminosterol dose" is determined for a particular patient, the patient starts at a lower dose, and then the dose is increased until a positive result for the evaluated symptom is observed. An exemplary symptom to be evaluated may be constipation, but any symptom associated with the disease or disorder to be treated may be used as a marker for evaluating the aminosterol dose. If any given aminosterol causes persistent undesirable side effects, such as diarrhea, vomiting, or nausea, the aminosterol dose may also be decremented (reduced).

[0457] The starting aminosterol dose depends on the severity of the symptoms - for example, for patients experiencing severe constipation (defined as less than one spontaneous bowel movement (SBM) per week), the starting oral aminosterol dose can be about 150 mg / day or higher. In contrast, for patients suffering from moderate constipation (e.g., defined as having more than one SBM per week), the starting oral aminosterol dose can 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.

[0458] In other embodiments, the patient who experiences moderate symptoms (calculating the symptoms of fixed increasing aminosterol dosage) can start with an oral aminosterol dosage from about 10 mg / day to about 75 mg / day or any amount between these values. For example, the initial oral aminosterol dosage for moderate symptoms can 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.

[0459] In a further embodiment, when the patient is experiencing severe symptoms (symptoms for calculating fixed incremental aminosterol doses), the patient can start with an oral aminosterol dose in the range of from about 75 to about 175 mg / day or any amount between these two values. For example, the initial oral aminosterol dose for severe symptoms can 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.

[0460] In some embodiments, the initial oral aminosterol dose may be about 125 mg or about 175 mg / day; again depending on the severity of symptoms such as constipation.

[0461] The initial intranasal (IN) aminosterol dose prior to dose escalation can be, for example, about 0.001 mg to about 3 mg / day or any amount between these two values. For example, the initial aminosterol dose for intranasal administration prior to 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 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.

[0462] In an exemplary embodiment, the aminosterol dosage is regularly given as needed. For example, the aminosterol dosage can be given once a day. The aminosterol dosage can also be given every other day, 2,3,4 or 5 times / week, once / week, or 2 times / week. In another embodiment, the aminosterol dosage can be given every other week, or it can be given for a few weeks, then skip a few weeks (because the effect persists after treatment), and then restart the aminosterol treatment.

[0463] When calculating the fixed increasing aminosterol dosage, can be increasing dosage after any suitable time period.In one embodiment, the aminosterol dosage increases progressively the amount of about restriction every about 3 to about 7 days, until reaching desired improvement.For example, when the symptom of institute's treatment / measurement is constipation, the threshold value improvement can be an increase of SBM / week or at least three defecation / week in total.In other embodiments, the aminosterol dosage can increase progressively 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 dosage can increase progressively about 1 time / week, about 2 times / week, about every other week, or about 1 time / month.

[0464] During the dose escalation, the aminosterol dosage can increase the amount of limitation. For example, when the aminosterol is administered orally, the dosage can be increased progressively with the increment of 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 progressively with the increment of about 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.

[0465] Other symptoms that can be used as endpoints for determining fixed escalating aminosterol doses for a patient are any symptom known to be associated with the disease, disorder or condition to be treated. For example, neurological disease symptoms are described herein and include, but are not limited to (a) at least one non-motor aspect of daily life experience as defined by the Unified Parkinson's Disease Rating Scale (UPDRS) Part I, such as, for example, cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness on standing, and fatigue; (b) at least one motor aspect of daily life experience as defined by UPDRS Part II, such as, for example, speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, turning over in bed, tremors, getting out of bed, car or deep chair, walking and balance, and rigidity; (c) at least one motor symptom identified in UPDRS Part III, such as, for example, speech, facial expressions, rigidity, finger tapping, hand movements, pronation-supination movements of the hands, toe tapping, leg agility, getting up from a chair, gait, gait rigidity, postural stability, posture, etc. (d) at least one motor complication identified in UPDRS Part IV, such as dyskinesia, functional impact of dyskinesia, time spent in the off state, functional impact of fluctuations, complexity of movement fluctuations, and painful off-state dystonia; (e) constipation; (f) depression; (g) cognitive impairment; (h) sleep problems or sleep disturbances; (i) circadian rhythm dysfunction; (ii) (j) hallucinations; (k) fatigue; (l) REM sleep disturbances; (m) REM behavior disorder; (n) erectile dysfunction; (o) apnea; (p) postural hypotension; (q) correction of blood pressure or orthostatic hypotension; (r) nocturnal hypertension; (s) temperature regulation; (t) improvement in breathing or apnea; (u) correction of cardiac conduction defects; (v) improvement in pain; (w) restoration of bladder sensation and urination; (x) urinary incontinence; and / or (y) control of nocturia.

[0466] V. Treatment and / or prevention methods

[0467] Aspects of the present disclosure relate to methods of treating certain symptoms and / or methods of treating and / or preventing diseases or disorders associated with one or more of these symptoms 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. The therapeutically effective amount can be as described herein, including but not limited to a "fixed aminosterol dose" determined as described herein.

[0468] In one embodiment, symptoms, diseases and / or disorders are generally associated with abnormal αS pathology and / or dopaminergic dysfunction, which means that they are amenable to treatment with amino solids as 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 non-oral administration.

[0469] In some embodiments, provided herein are methods for treating a subject in need having a condition or symptom susceptible to aminosterol treatment, the method 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 having a condition susceptible to aminosterol treatment, the method 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.

[0470] Non-limiting examples of symptoms amenable to aminosterol treatment include, but are not limited to, constipation, hallucinations, sleep disturbances, cognitive impairment, depression, and inflammation.

[0471] Examples of diseases amenable to aminosterol treatment are described herein and include, but are not limited to, those described herein, such as neurological diseases, e.g., PD, AD, MSA, schizophrenia, Huntington's disease (HD), progressive supranuclear palsy, frontotemporal dementia (FTD), vascular dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy (SMA), Friedreich's ataxia. In another embodiment, aminosterols described herein and compositions comprising them are provided for treating, preventing and / or slowing down the onset or progression of psychological or behavioral disorders and / or associated symptoms in subjects in need thereof, in one embodiment, psychological or behavioral disorders may be, for example, depression, anxiety, delirium, irritability, illusions and delusions, amnesia, autism, apathy, bipolar disorder, disinhibition, abnormal movements and compulsive behaviors, sleep disorders, sleep fragmentation, REM behavior disorders, circadian rhythm dysfunction, sleep apnea, and cognitive impairment. In another embodiment, a method for treating, preventing and / or slowing down the onset or progression of cerebral or systemic ischemic disorders and / or related symptoms in a subject in need thereof is provided. The cerebral or systemic ischemic disorder can be, for example, microangiopathy, cerebral ischemia during childbirth, cerebral ischemia during cardiac arrest or resuscitation / after, cerebral ischemia due to problems during surgery, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypertension, high cholesterol, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, and pulmonary edema.

[0472] In one embodiment, a method of inhibiting protein tyrosine phosphatase 1B (PTP1B) is provided, the method comprising contacting PTP1B with at least one aminosterol disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0473] Applicants have shown in Example 3 that squalamine can increase transcription in the intestine of aged mice, thereby having a rejuvenating effect on the intestine. It is believed that this activity extends to ENT-03 (Compound III) and its derivatives. Therefore, in another aspect, a method of increasing transcription in the intestine of a subject is provided, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any embodiment of the present invention or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0474] A. Exemplary symptoms associated with aberrant αS pathology and / or dopaminergic dysfunction and amenable to aminosterol treatment

[0475] (1) Constipation

[0476] In one embodiment, a method of treating, preventing and / or reducing the onset or progression of constipation and / or related symptoms in a subject in need thereof is provided, the method 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.

[0477] Constipation is a common problem worldwide, affecting 2% to 27% of the population, with most estimates varying from 12% to 20%. In people aged >65, the prevalence of constipation increases to 30%-40%, and women are disproportionately affected. In North America, 63 million people meet the Rome IV criteria for constipation, and in the United States alone, constipation causes more than 2 million doctor visits each year. Laxatives are prescribed for 2-3 million patients each year, and in addition, in most patients, the condition is chronic, requiring lifelong treatment.

[0478] Constipation is more common in PD patients than in the general population. There are 1 million people with PD in the United States, of which about 60% or 600,000 people suffer from chronic constipation, and in most cases, the condition is chronic, severe and unresponsive to standard therapy. This represents an economic burden for individuals with PD and the healthcare system. According to the Federal Supply Schedule of April 2016, which can be accessed on fss.gsa.gov, the average 30-day reimbursement price for a basket of oral constipation drugs is about $260 or $3120 per year. This represents about $1.8 billion in prescription laxatives for patients with PD alone.

[0479] Constipation is defined as a lower frequency of bowel movements than normal (e.g., less than 3 bowel movements / week) within a fixed time. Although often strictly excluded as a gastrointestinal symptom, constipation is considered to be an early indicator of neurodegenerative diseases to the extent that ENS degeneration may indicate late CNS degeneration. Indeed, without being bound by theory, constipation is considered to be one of the earliest indicators of PD pathology. Therefore, the method embodiments disclosed herein relate to the treatment of constipation or the treatment and / or prevention of potential obstacles associated with constipation.

[0480] Constipation is common in PD, and symptoms usually appear several years before the onset of motor dysfunction and subsequent PD diagnosis. There is a lot of evidence that the neurodegenerative process associated with PD, i.e. the accumulation of toxic aggregates of alpha-synuclein, occurs in the enteric nervous system several years before they appear in the brain. It is believed that the enteric nervous system (ENS) (its surface area is huge) is subject to continuous infringement by infectious agents and toxic substances. Although the function of alpha-synuclein is unknown, inflammation in the nervous system can lead to an increase in its intracellular level. In individuals with PD, the increase of alpha-synuclein leads to the formation of neurotoxic aggregates, probably because neurons fail to effectively process them (due to genetic factors). Then, the aggregates of alpha-synuclein are transported to the dorsal motor nucleus in the brainstem along the vagus nerve, and from there reach more rostral structures.

[0481] Individuals with PD suffer from a form of constipation that is thought to be primarily caused by delayed transit through the colon. In addition, dysfunction of the anorectal reflex in PD subjects often impairs defecation. For many individuals, bowel problems represent a significant impairment of quality of life. Failure to effectively manage this problem may also lead to intestinal obstruction, especially as the end stage of PD approaches. A limited number of therapies have been tested in clinical trials, and they include agents that increase the fluid content of the stool by blocking fluid reabsorption or increasing the osmotic load in the intestine.

[0482] The pathophysiology of GI dysfunction in PD involves αS deposition in both the ENS and the brainstem. Due to still unknown reasons, the protein αS, which is usually produced in neurons, forms neurotoxic intracellular aggregates in PD. A large number of studies have shown that the formation of αS aggregates begins in the ENS of PD individuals many years before the onset of motor symptoms. Due to the normal retrograde neuronal transport that occurs in the vagus nerve, toxic αS aggregates are transported from the neurons of the ENS to the dorsal motor nucleus of the vagus nerve, and then gradually transported to the parts of the brain involved in body movement and balance. Because constipation fundamentally has acquired neurodegenerative properties, it is different from other forms of this disease.

[0483] Examples of tools that can be used to measure and evaluate the effects of aminosterol therapy on constipation include, for example: (1) Rome-IV criteria for constipation (7 criteria, where a diagnosis of constipation requires two or more of the following: (i) straining during at least 25% of bowel movements, (ii) lumpy or hard stool in at least 25% of bowel movements, (iii) sensation of incomplete emptying for at least 25% of bowel movements, (iv) sensation of anorectal obstruction / blockage for at least 25% of bowel movements; (v) manual strategies to facilitate at least 25% of bowel movements; (vi) fewer than 3 bowel movements / week; and (vii) infrequent presence of loose stools without the use of laxatives); (2) Constipation-Ease of Evacuation Scale (from 1-7, where 7=incontinence, 4=normal, and 1=manual disimpaction); (3) Bristol Stool Chart (Bristol Stool Chart). Chart, a patient-friendly means of categorizing stool characteristics (stool consistency assessment is a validated surrogate for bowel motility) and a stool diary; (4) Unified Parkinson's Disease Rating Scale (UPSRS), section 1.11 (Constipation Problems); (5) Patient Assessment of Constipation Symptoms (PAC-SYM); and (5) Patient Assessment of Constipation Quality of Life (PAC-QOL).

[0484] The example of the characteristic of constipation that can produce positive impact by aminosterol treatment includes but is not limited to the frequency of constipation, the duration of constipation symptoms, defecation frequency, stool consistency, abdominal pain, abdominal distention, incomplete emptying, unsuccessful emptying attempts, pain during emptying and tension during emptying. Potentially, all these characteristics can be positively affected by the method of the present disclosure. In addition, the assessment of these characteristics is known in the art, such as spontaneous defecation (SBM) / week, stool consistency (Bristol stool chart) (Lewis and Heaton 1997; Heaton et al. 1992), easy passing (emptying ease scale) (Andresen et al. 2007), the use of emergency medicine and the symptoms and quality of life (PAC-SYM (Frank et al. 1999) and PAC-QOL (Marquis et al. 2005)) related to intestinal function.

[0485] The method of treating and / or preventing constipation using a therapeutically effective dose of an aminosterol composition according to the present disclosure preferably results in an increase in the number of spontaneous bowel movements / week and / or improvements in other stool conditions. For example, the increase can be an increase in spontaneous bowel movements between about 1 and about 3 times per week, or optionally, complete restoration of normal intestinal function.

[0486] In one embodiment of the present disclosure, treating a subject with constipation with an aminosterol in the methods described herein results in an improvement in one or more features of the 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 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, about 500%, about 51 ... 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%. The example of constipation characteristics that can be improved by the method of the present disclosure includes but is not limited to the frequency of constipation, the duration of constipation symptoms, defecation frequency, stool consistency, abdominal pain, bloating, incomplete emptying, unsuccessful emptying attempts, pain during emptying, and tension during emptying. The measurement of constipation characteristics can be completed using any clinically recognized scale or tool.

[0487] In one embodiment, the dose of aminosterol required for the positive effect on the evaluated symptom, referred to herein as "fixed ascending aminosterol dose", is patient-specific, as described herein. In another embodiment, the severity of constipation is associated with a higher required "fixed ascending aminosterol dose". In theory, the dose of aminosterol required to obtain a positive effect on the evaluated symptom in the subject is associated with the degree of neuronal damage. Therefore, in theory, greater neuronal damage is associated with a higher dose of aminosterol required for the positive effect of the evaluated symptom in the subject. The observation that the dose of aminosterol required to achieve the desired response increases with the severity of constipation supports the following hypothesis: the greater the burden of αS hindering neuronal function, the higher the dose of aminosterol required to restore normal intestinal function. It is also assumed that gastrointestinal dysmotility in PD is caused by the progressive accumulation of αS in the ENS, and aminosterol treatment can restore neuronal function by replacing αS and stimulating enteric neurons. These results prove that the ENS in PD is not irreversibly damaged and can be restored to normal function.

[0488] When fixing aminosterol dosage for specific patient calibration, initial dose changes based on the severity of constipation.Therefore, for the experimenter suffering from severe constipation, for example 1 or less experimenter of CSBM or SMB / week, oral aminosterol dosage starts at about 100 to about 150mg / day or more (or any amount between these values ​​as described herein).For the experimenter of constipation not too serious (for example, more than 1 CSBM or SBM / week), oral aminosterol dosage starts at about 25 to about 75 / day mg (or any amount between these values ​​as described herein).Then in the time period limited, the amount of two patients' dosage increments limited, until identifying the patient's fixed incremental dose.If any given aminosterol causes lasting undesirable side effect, such as diarrhoea, vomiting or nausea, then can also decrease (reduce) aminosterol dosage.

[0489] For example, for a patient with severe constipation, the initial oral aminosterol dosage may be from 75 mg to about 300 mg / day or any amount therebetween. In other embodiments, the starting oral aminosterol dose for patients 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 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 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, or about 300 mg / day. "Fixed-escalation" oral aminosterol dosages for patients with severe constipation may range from about 75 mg up to about 500 mg / day.

[0490] For patients with less severe constipation, oral aminosterol dosage starts at about 10 to about 75 / day mg or any amount between these two values ​​as described herein. For example, the initial oral aminosterol dosage for patients suffering from 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, up to less than or equal to about 75mg / day. For patients with mild to moderate constipation, the fixed incremental oral aminosterol dosage can be in the range of from about 5mg to about 350mg / day or any amount between these two values ​​as described herein.

[0491] (2) Hallucinations

[0492] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of hallucinations and / or related symptoms in a subject in need thereof is provided, the method 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.

[0493] A hallucination is a sensory impression or perception of an object or event in any of the five senses (sight, touch, sound, smell, or taste) that has no basis in external stimulation. Hallucinations can have a debilitating effect on the subject's health and life by causing harm to oneself or others, making it difficult for the subject to function normally in everyday situations, and causing sleep disruption. Examples of hallucinations include "seeing" people who are not there (visual hallucinations), "hearing" voices that others do not hear (auditory hallucinations), "feeling" something crawling up your legs (tactile hallucinations), "smelling" (olfaction), and "tasting" (gustatory). Other examples of types of hallucinations include hypnagogic hallucinations (vivid dream-like hallucinations that occur while falling asleep), wakeful hallucinations (vivid dream-like hallucinations that occur while awake), kinesthetic hallucinations (hallucinations involving the sense of body movement), and somatic hallucinations, which are hallucinations involving the perception of physical sensations occurring within the body.

[0494] Hallucinations may be the result of psychiatric disorders or be associated with diseases such as neurological diseases. Hallucinations, especially auditory hallucinations, are features of certain psychiatric disorders 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 actions or behaviors and induce violent defensive behaviors or alternatively lead to self-harming behaviors. They may also occur in postpartum psychosis. Auditory hallucinations may less often occur in severely depressed patients or even mania. Drug abuse may also be associated with visual hallucinations. Alcoholism or withdrawal, post-traumatic stress disorder (PTSD) and bereavement may also be associated with visual hallucinations.

[0495] In some cases, hallucinations are the result of psychiatric or nervous system disorders. For example, aminosterol compositions reverse the functional impairment of psychiatric or nervous system disorders and treat hallucinations. For example, psychiatric disorders can be selected from 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. Neurodegenerative disorders can be, for example, PD, supranuclear palsy, multiple system atrophy, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, Friedreich's ataxia, multiple sclerosis (MS), Lewy body dementia or disease, spinal muscular atrophy, frontotemporal dementia, progressive nuclear palsy, Guadeloupe Parkinson's disease, spinocerebellar ataxia or vascular dementia. In a preferred embodiment, the aminosterol compositions of the present disclosure reverse the functional impairment of neurodegenerative disorders and treat hallucinations. For example, the neurological disorder can also be the result of: (a) a brain tumor, (b) a sleep disorder such as narcolepsy, or (c) a focal brain lesion, such as an occipital lobe lesion or a temporal lobe lesion. In an exemplary embodiment, the temporal lobe lesion can be a lesion of the uncus, cerebral peduncle, or substantia nigra. For example, the neurological disorder can be the result of: (d) a diffuse involvement of the cerebral cortex, such as a diffuse involvement of the cerebral cortex caused by a viral infectious disease.

[0496] Diffuse involvement of the cerebral cortex may be the result of cerebral vasculitis conditions, and viral infections may be, for example, acute metabolic encephalopathy, encephalitis, or meningitis. Cerebral vasculitis conditions may be caused by autoimmune disorders, bacterial or viral infections, or systemic vasculitis. Autoimmune disorders may be, for example, systemic lupus erythematosus (SLE).

[0497] In addition, hallucinations may be caused by sensory loss. Sensory loss can be, for example, visual, auditory, taste, 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.

[0498] The method for treating and / or preventing hallucination using the aminosterol composition according to the present disclosure of a therapeutically effective amount preferably results in a reduction in hallucination. Reduction can be, for example, a reduction in hallucination 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%. The method of the present disclosure may also result in the experimenter not having hallucinations. Hallucinations may include, for example, visual, auditory, tactile, taste or olfactory hallucinations. Any clinically approved assessment or tool may be used to measure improvement.

[0499] Examples of tools that can be used to measure and evaluate the effects of aminosterol treatment on hallucinations include, for example, the University of Miami Parkinson's Disease Hallucinations Questionnaire (UM-PDHQ), the Unified Parkinson's Disease Rating Scale (UPSRS) - Section 1.2 (Hallucinations and Psychosis), Direct Questioning, the Chicago Hallucination Assessment Tool (CHAT), the Psychotic Symptom Rating Scales (PSYRATS), the Auditory Hallucinations Rating Scale (AHRS), the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ), the Characteristics of Auditory Hallucinations Questionnaire (CAHQ), the Mental Health Research Institute Unusual Perception Schedule (MUPS), the Positive and Negative Syndrome Scale (PNS), and the Psychotic Symptom Rating Scale (PSYRATS). The PANSS scale was used to measure the degree of hallucinations in the brain, the SAPS scale was used to measure the degree of hallucinations in the brain, the LSHS scale was used to measure the degree of hallucinations in the brain, the PANSS scale was used to measure the degree of hallucinations in the brain, the LSHS scale was used to measure the degree of hallucinations in the brain, and the LSHS scale was used to measure the degree of hallucinations in the brain.

[0500] (3) Inflammation associated with abnormal αS pathology and / or dopaminergic dysfunction and amenable to aminosterol treatment

[0501] In one embodiment, a method for treating, preventing and / or slowing down the onset or progression of inflammation and / or related symptoms associated with αS pathology in a subject is provided. The method comprises 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.

[0502] αS is a potent pro-inflammatory hormone. Inflammation can be blocked by either of two strategies. First, inflammation can be blocked by reducing the tissue concentration of αS by reducing or stopping the production of αS. Alternatively, inflammation can be blocked by interrupting the signaling between αS and inflammatory cells expressing CD11b. The subject of the method of the present disclosure can be any mammal, including humans.

[0503] Inflammatory diseases or conditions caused by overexpression of neuronal αS can be neurodegenerative disorders (NDDs), such as α-synuclein diseases. Exemplary α-synuclein diseases include, but are not limited to, PD, Lewy body dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, or schizophrenia. In other embodiments, inflammatory diseases or conditions caused by overexpression of neuronal α-synuclein can be autoimmune diseases, chronic inflammatory diseases, or autoinflammatory diseases. In other embodiments, the inflammatory disease or disorder caused by overexpression of neuronal αS can be selected from asthma, chronic peptic ulcer, tuberculosis, chronic periodontitis, chronic sinusitis, chronic active hepatitis, psoriatic arthritis, gouty 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.

[0504] In some embodiments of the present disclosure, a patient population that is particularly susceptible to overproduction or secretion of αS can benefit from the methods of the present disclosure and is the target of therapy (including, for example, preventive therapy). For example, a patient population with a mutant form of αS that causes an increase in the amount of αS in a tissue can be treated using the methods of the present disclosure. Another example of a patient population susceptible to the effects of high levels of αS is a patient with a chronic inflammatory condition or disease. A further example is a patient population with elevated levels of αS aggregation (manifested as constipation) in their enteric neurons.

[0505] Compared with the qualitative amount or quantitative amount from the same patient or experimenter before treatment, the method of the present disclosure can lead to the reduction of the number of inflammatory cells in the blood level of inflammation markers, inflammation markers in tissues or tissues or its combination. 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%. Any clinically recognized tool or assessment can be used to measure improvement.

[0506] 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 blotting, and protein immunostaining.

[0507] Additionally, it is derived from the present disclosure that individuals suffering from inflammatory disorders suitable for treatment or prevention using the methods targeting αS described herein are identified by determining the tissue concentration of αS at the site of inflammation, wherein high levels of αS compared to controls or healthy subjects are associated with patients suitable for treatment using the methods of the present disclosure.

[0508] In theory, administration of aminosterols reduces the formation of neurotoxic αS aggregates in vivo and stimulates gastrointestinal motility in patients with neurological diseases such as PD and constipation. It is also hypothesized that the greater the burden of αS impeding neuronal function, the higher the dose of aminosterol required to restore normal intestinal function and resolve other symptoms of α-synuclein aggregation. B. Exemplary diseases or disorders associated with abnormal αS pathology and / or dopaminergic dysfunction and amenable to aminosterol treatment

[0509] The aminosterols described herein (e.g., ENT-03 (Compound III)), including pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof, can be used in methods for treating and / or preventing a variety of diseases and disorders that are generally associated with abnormal αS pathology and / or dopaminergic dysfunction, as described herein and as described below.

[0510] In one embodiment, a method for treating, preventing and / or slowing down the onset or progression of a disease or disorder associated with abnormal αS pathology and / or dopaminergic dysfunction and / or related symptoms associated with αS pathology in a subject is provided. The method comprises 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.

[0511] (1) Nervous system or neurodegenerative disorders or diseases

[0512] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of a neurodegenerative disease or a neurological disease and / or related symptoms in a subject in need thereof is provided, the method 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.

[0513] The methods and aminosterol compositions of the present disclosure can be used to treat and / or prevent neurological disorders or diseases, such as those 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, Lewy body dementia or disease, spinal muscular atrophy, supranuclear palsy, frontotemporal dementia, progressive nuclear palsy, Guadeloupe Parkinson's disease, spinocerebellar ataxia, and autism.

[0514] A variety of neuroimaging techniques can be used for early diagnosis and / or measurement of the progression of neurodegenerative disorders. Examples of such techniques include, but are not limited to, neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI) (including, for example, diffusion tensor measurements of anatomical connectivity), [18F] fluorodeoxyglucose (FDG) PET, agents labeled amyloid, [18F] F-DOPA PET, radiotracer imaging, volume 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 in the early diagnosis of neurodegenerative disease," Transl. Neurodegener., 1: 5 (2012). The combination of these techniques can also be used to measure disease progression.

[0515] The progress of neurodegeneration can be measured using well-known techniques. For example, electroencephalogram (EEG) can be used as a biomarker for the presence and progress of neurodegenerative diseases (Morairty, 2013). Another exemplary technique that can be used to measure the progress of MRI neurodegeneration (Rocca et al., 2017). Alternatively, neurodegeneration can be measured by measuring the level of one or more biomarkers of neurodegeneration known in the art using analytical techniques selected from, for example, high performance liquid chromatography, liquid chromatography mass spectrometry, enzyme-linked immunosorbent assay, protein immunoprecipitation, immunoelectrophoresis, western blotting and protein immunostaining. Biomarkers indicating neurodegeneration are known to those skilled in the art and can include, for example, any of those in Beach et al. 2017, and the entire disclosure of the document is hereby incorporated by reference.

[0516] For example, structural MRI can be used to measure atrophy of the hippocampus and entorhinal cortex as well as involvement of the lateral parietal cortex, posterior superior temporal cortex, and medial posterior cingulate cortex in AD. In frontotemporal dementia (FTD), structural MRI can show atrophy in 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 lobe activation 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.

[0517] In one embodiment of the present disclosure, the progression or onset of a neurodegenerative disorder is slowed or prevented within a defined time period after administering a therapeutically effective amount of an aminosterol according to the present disclosure to a subject in need thereof, as measured by medically recognized techniques. For example, the progression or onset of a neurodegenerative disorder may 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%.

[0518] The time period over which progression or onset of a neurodegenerative disorder is measured can be, for example, one or more months or one or more years, such as 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 amount of months or years between values ​​of about 6 months to about 20 years or more.

[0519] In another embodiment, a neurodegenerative disorder can be positively affected by administering a therapeutically effective amount of an aminosterol according to the present disclosure."Positively affect" includes, for example, slowing the progression of the disorder, ameliorating one or more symptoms, and the like.

[0520] (i) Parkinson's disease

[0521] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of Parkinson's disease (PD) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0522] PD is a progressive neurodegenerative disorder caused by the accumulation of the protein αS in the periphery and central nervous system (CNS), including the enteric nervous system (ENS), autonomic nerves, and brain (Braak et al. 2003(a) and (b)). Although motor symptoms are still required for the diagnosis of PD (Hughes et al. 1992), non-motor symptoms represent a greater therapeutic challenge (Zahodne et al. 2012). These symptoms include constipation (Ondo et al. 2012; Lin et al. 2014), sleep architecture disturbances (Ondo et al. 2001; Gjerstad et al. 2006), cognitive dysfunction (Auyeung et al. 2012), hallucinations (Friedman et al. 2016; Diederich et al. 2009), REM behavior disorder (RBD), and depression (Aarsland et al. 2007), all of which are due to damage to the function of neural pathways that cannot be restored by dopamine replacement. In fact, compared with motor symptoms, long-term hospitalization, caregiver burden and life expectancy reduction are more significantly related to the severity of these symptoms (Goetz et al. 1995). In 2003, Braak proposed that PD starts in the gastrointestinal tract, when the neurotoxic aggregates of αS are formed in the ENS, it is caused, and this is clinically proved by most people with PD that constipation occurs many years before the motor symptoms begin (Braak et al., 2003 (a) and (b)). Recent studies in rats have proved that αS aggregates move to CNS from ENS via vagus nerve and other afferent nerves. Neurotoxic aggregates gradually accumulate in the brainstem, and then disperse to the structure in the diencephalon to the mouth, and finally reach the cerebral hemisphere.

[0523] PD is defined as a synucleinopathy, and synuclein deposition remains the main final marker for diagnosis. In addition, patients with dementia and Lewy bodies are considered to have PD if they meet clinical disease criteria. Imaging (eg, MRI, single-photon emission computed tomography [SPECT], and positron emission tomography [PET]) allows in vivo brain imaging of structural, functional, and molecular changes in patients with PD.

[0524] In the past few years, studies have identified specific markers or combinations of markers for the probability estimation of prodromal PD. Researchers have identified a timeline of symptoms that indicate prodromal PD and predict PD. The presence of each helps to estimate the possibility of prodromal PD. Some have been used to identify prodromal PD. Other studies use a combination of symptoms and imaging (for example, a combination of hyposmia and dopamine receptor imaging has been found to have a high predictive value). In another example, it was found that REM sleep behavior disorder (SBD), constipation, and hyposmia were common in individuals but rarely co-occurred in individuals without PD, resulting in a high predictive value for PD.

[0525] PD can also be assessed using the UPDRS, which consists of 42 items in four subscales: (1) Part I, Non-Motor Aspects of Experiences of Daily Living (nM-EDL): cognitive impairment (Part 1.1), hallucinations and psychosis (Part 1.2), depressed mood (Part 1.3), anxious mood (Part 1.4), apathy (Part 1.5), features of dopamine dysregulation syndrome (Part 1.6), sleep problems (Part 1.7), daytime sleepiness (Part 1.8), pain and other sensations (Part 1.9), urinary problems (Part 1.10), constipation problems (Part 1.11), mild dizziness when standing up (Part 1.12), and fatigue (Part 1.13); (2) Part II, Motor Aspects of Experiences of Daily Living (nM-EDL): cognitive impairment (Part 1.1), hallucinations and psychosis (Part 1.2), depressed mood (Part 1.3), anxious mood (Part 1.4), apathy (Part 1.5), features of dopamine dysregulation syndrome (Part 1.6), sleep problems (Part 1.7), daytime sleepiness (Part 1.8), pain and other sensations (Part 1.9), urinary problems (Part 1.10), constipation problems (Part 1.11), mild dizziness when standing up (Part 1.12), and fatigue (Part 1.13); DailyLiving) (M-EDL): Speech (Part 2.1), Saliva and drooling (Part 2.2), Chewing and swallowing (Part 2.3), Feeding tasks (Part 2.4), Dressing (Part 2.5), Hygiene (Part 2.6), Handwriting (Part 2.7), Hobbies and other activities (Part 2.8), Turning over in bed (Part 2.9), Tremor (Part 2.10), Getting out of bed, car, or deep chair (Part 2.11), Walking and balance (Part 2.12), and Freeze (Part 2.13); Part III, Motor Examination: speech (Part 3.1), facial expressions (Part 3.2), rigidity (Part 3.3), finger tapping (Part 3.4), hand movements (Part 3.5), pronation-supination movements of the hand (Part 3.6), toe tapping (Part 3.7), leg agility (Part 3.8), rising from a chair (Part 3.9), gait (Part 3.10), gait freezing (Part 3.11), postural stability (Part 3.12), posture (Part 3.13), global spontaneity of movement (bradykinesia) (Part 3.14), postural tremor of the hand (Part 3.15), kinetic tremor of the hand (Part 3.16), resting tremor amplitude (Part 3.17), and resting tremor persistence (Part 3.18); Part IV, Motor complications Complications: duration of dyskinesia (Section 4.1), functional effects of dyskinesia (Section 4.2), time in the off state (Section 4.3), the functional effects of fluctuations (Section 4.4), the complexity of motor fluctuations (Section 4.5), and painful off-dystonia (Section 4.6).

[0526] In addition, 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), cognition can be assessed using the Mini Mental State Examination (MMSE) (Palsetia et al. 2018), sleep and REM behavior disorder (RBD) can be assessed using a daily diary and the RBD Questionnaire (RBDQ) (Stiasny-Kolster et al. 2007), and hallucinations can be assessed using the PD Hallucination Questionnaire (PDHQ) (Papapetropoulos et al. 2008) and direct questionnaires. Circadian system status can also be assessed by continuously monitoring wrist skin temperature (Thermochron iButton DS1921H; Maxim, Dallas) (Sarabia et al. 2008) according to published procedures.

[0527] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition described herein to a PD patient results in an improvement 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% in one or more symptoms or one or more clinically acceptable scoring indicators of PD. The improvement can be measured using any clinically recognized tool or assessment.

[0528] In view of the resistance of patients to dopamine and the subsequent dose escalation until no response can be elicited, the progression and treatment of PD are particularly difficult. Without being bound by theory, it is believed that the pre- or co-administration of an aminosterol composition (e.g., ENT-03 (Compound III)) according to the present disclosure can reduce the dopamine dose required for the therapeutic effect on Parkinson's symptoms and / or increase the time period during which the patient is sensitive to dopamine. It is also theoretically possible that the pre- or co-administration of an aminosterol composition according to the present disclosure can delay the time period during which it is recommended that the patient start dopamine therapy. This is important because patients are currently encouraged to delay the start of dopamine therapy for as long as possible because the subject develops resistance to dopamine after a certain period of time.

[0529] (ii) Alzheimer's disease

[0530] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of Alzheimer's disease (AD) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0531] Alzheimer's disease (AD) is a chronic neurodegenerative disease that usually starts slowly and worsens over time. It is the cause of 60%-70% of dementia cases. As the disease progresses, symptoms may include language problems, disorientation, mood swings, loss of motivation, inability to manage oneself, and behavioral problems. As a person's condition declines, they typically withdraw from family and society. Gradually, physical function is lost, eventually leading to death. Although the rate of progression can vary, the typical life expectancy after diagnosis is 3 to 9 years. In 2015, approximately 29.8 million people worldwide had AD. It is most common in people over the age of 65, although 4% to 5% of cases are early-onset Alzheimer's disease. It affects about 6% of people aged 65 and over. In 2015, dementia caused about 1.9 million deaths.

[0532] Symptoms of Alzheimer's disease are primarily characterized by cognitive deficits, including impairment of memory, language dysfunction, and visuospatial skills; functional impairment (e.g., activities of daily living) that may involve occupational and social problems; and, as disease severity progresses, behavioral symptoms, including depression, anxiety, aggression, and psychosis, may also appear.

[0533] At this point, a clear diagnosis of AD requires clinical findings consistent with AD and autopsy identification of brain lesions consistent with AD. The term AD dementia is used to describe dementia caused by the pathophysiology of AD. When the subject exhibits clinical features of AD and when other possible biological causes of dementia (e.g., PD or stroke) are excluded, the term "possible Alzheimer's disease" is used in life. There are currently a variety of methods accepted in the art for diagnosing possible AD. Typically, these methods are used in combination and include determining the ability of an individual to carry out daily activities and identifying changes in behavior and personality. The typical features of AD dementia are also amnesia (memory deficits) or language, visual space or executive function deficits. 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)) and specific domains such as visual and verbal memory (e.g., the Brief Visuospatial Memory Test (Revised) (BVMT-R) and the Hopkins Verbal Learning Test (Revised) (HVLT-R), respectively), 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 as insidious onset and a history of worsening cognitive performance.

[0534] The criteria for "probable AD" are described in the National Institute of Aging-Alzheimer's Association Working Group (McKhann et al. 2011). According to this working group, for a person who first presents with the core clinical features of AD dementia, evidence of biomarkers associated with the disease may increase the certainty of the diagnosis.

[0535] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to an AD patient results in an improvement 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% in one or more symptoms or one or more clinically acceptable scoring indicators of AD.

[0536] (iii) Multiple system atrophy

[0537] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of multiple system atrophy (MSA) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0538] Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by a combination of symptoms that affect both the autonomic nervous system (the part of the nervous system that controls involuntary actions such as blood pressure or digestion) and movement. MSA, also known as Shy-Drager syndrome, is a neurodegenerative disorder characterized by tremors, slow movements, muscle stiffness, and postural instability (collectively known as Parkinson's disease) due to autonomic nervous system dysfunction and ataxia. This 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.

[0539] 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). Another exemplary technique that can be used to measure the progression of neurodegeneration is MRI. Rocca et al. 2017.

[0540] A variety of neuroimaging techniques can be used for early diagnosis and / or measurement of the progression of MSA. Examples of such techniques include, but are not limited to, neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI) (including, for example, diffusion tensor measurements of anatomical connectivity), [18F] fluorodeoxyglucose (FDG) PET, agents labeled amyloid, [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 can also be used to measure disease progression.

[0541] For example, structural MRI can be used to measure atrophy of the hippocampus and entorhinal cortex in MSA as well as involvement of the lateral parietal cortex, posterior superior temporal cortex, and medial posterior cingulate cortex. In frontotemporal dementia (FTD), structural MRI can show atrophy in the frontal or temporal poles.

[0542] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to a patient with MSA results in an improvement in one or more symptoms of MSA 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%. The improvement can be measured using any clinically recognized tool or assessment.

[0543] (iv) Schizophrenia

[0544] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of schizophrenia (SZ) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0545] Schizophrenia is a chronic progressive disorder with structural brain changes in both white and gray matter at its root. These changes are likely to begin before clinical symptoms begin in cortical areas, particularly those related to language processing. Later, they can be detected by progressive ventricular enlargement. Current magnetic resonance imaging (MRI) technology can provide valuable tools for detecting early changes in cortical atrophy and abnormal language processing that can predict who will develop schizophrenia.

[0546] A 2013 study of schizophrenia patients documented brain changes seen in MRI scans of more than 200 patients, starting with their first episode and continuing at regular intervals for up to 15 years. The scans showed that people had less brain tissue than healthy individuals at the time of their first episode. The findings suggest that people with schizophrenia are affected by something before they show outward signs of the illness.

[0547] The mainstay of treatment is antipsychotic drugs, along with counseling, vocational training and social rehabilitation. However, a 2013 study found that, in general, the higher the dose of antipsychotic drugs, the greater the loss of brain tissue.

[0548] About 0.3%-0.7% of people are affected by schizophrenia in their lifetime. In 2013, there were an estimated 23.6 million cases worldwide. Men are more susceptible and experience more severe symptoms on average. About 20% of people do well, and a few recover completely. About 50% of people have lifelong impairment. Social problems such as long-term unemployment, poverty and homelessness are common. The average life expectancy of people with the disorder is ten to twenty-five years less than the general population. This is a result of increased physical health problems and a higher suicide rate (about 5%). In 2015, an estimated 17,000 people died worldwide from behaviors related to or caused by schizophrenia.

[0549] Although not wishing to be bound by theory, in theory, administering a therapeutically effective amount of an aminosterol composition to a schizophrenia patient can treat and / or prevent schizophrenia or any one or more of its symptoms. In some embodiments, administration can be oral, resulting in absorption in the ENS. In some embodiments, administration can be intranasal, resulting in stimulation of neurogenesis, which has a positive impact on the loss of brain tissue characteristics of schizophrenia subjects.

[0550] In one embodiment of the present disclosure, administration of a therapeutically effective amount of an aminosterol composition to a schizophrenia patient results in an improvement in one or more symptoms as determined by a clinically recognized psychiatric symptom rating scale. Examples of such rating scales include, for example, the Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scales (PSYRATS), Quality of Life Scale (QLS), Schizophrenia Cognition Rating Scale (SCoRS), Drug Attitude Inventory (DAI), and Abnormal Involuntary Movement Scale (AIMS).

[0551] In another embodiment, administration of a therapeutically effective amount of an aminosterol composition to a schizophrenia patient results in an improvement 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% in one or more symptoms as determined by a clinically recognized psychiatric symptom rating scale. The improvement can be measured using any clinically recognized tool or assessment.

[0552] (v) Other neurological diseases

[0553] The methods and compositions of the present disclosure can also be used to treat and / or prevent a variety of other neurological diseases. In one embodiment, a method for treating, preventing and / or slowing down the onset or progression of a neurological disease and / or related symptoms described herein in a subject in need is provided, the method 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. Examples of exemplary neurological diseases are described below and herein.

[0554] Huntington's disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person's physical and mental abilities during their prime working years and there is no cure. Full-time care is required in the later stages of the disease. Symptoms of Huntington's disease most often become apparent between the ages of 35 and 44, but they can begin at any age from infancy to old age. The most characteristic initial physical symptom is jerky, random and uncontrollable movements called chorea. In about 9% of cases, suicide is the cause of death. Death typically occurs 15 to 20 years from when the disease is first detected.

[0555] Progressive supranuclear palsy, also known as Steele-Richardson-Olszewski syndrome, is a brain disorder that causes severe problems with walking, balance, and eye movement. The disorder is caused by the degeneration of cells in an area of ​​the brain that controls body movement and thinking. There is no known cure for PSP, and management is primarily supportive.

[0556] Frontotemporal dementia (FTD) is a group of related conditions caused by progressive degeneration of the temporal and frontal lobes of the brain. These areas of the brain play a significant role in decision-making, behavioral control, emotions, and language. Frontotemporal dementia (FTD) covers six types of dementia involving the frontal or temporal lobes. They are: behavioral variant of FTD, semantic variant primary progressive aphasia, nonfluent grammatical variant primary progressive aphasia, corticobasal syndrome, progressive supranuclear palsy, and FTD associated with motor neuron disease. Currently, there is no cure for FTD.

[0557] Vascular dementia, also known as multi-infarct dementia (MID) and vascular cognitive impairment (VCI), is a dementia caused by problems with blood supply to the brain, typically a series of minor strokes, leading to a progressive worsening of cognitive decline. Risk factors for vascular dementia include age, high blood pressure, smoking, high cholesterol, diabetes, cardiovascular disease, and cerebrovascular disease. Other risk factors include geographic origin, genetic predisposition, and previous stroke.

[0558] Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a specific disease that causes the death of neurons that control voluntary muscles. ALS is characterized by muscle stiffness, muscle twitching, and weakness that gradually worsens due to reduced muscle size. This can lead to difficulty speaking, swallowing, and ultimately breathing. In 90% to 95% of cases, the cause is unknown. The remaining 5%-10% of cases are hereditary. The underlying mechanism involves damage to both upper motor neurons and lower motor neurons. There is no known cure for ALS. The disease can affect people of any age, but usually starts around the age of 60 and hereditary cases start around the age of 50. The average survival period from onset to death is 2 to 4 years, although about 10% survive longer than 10 years.

[0559] Multiple sclerosis (MS) is a demyelinating disease in which the insulating covering of nerve cells in the brain and spinal cord is damaged. This damage disrupts the ability of parts of the nervous system to communicate, leading to a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. There are several forms of MS, in which new symptoms occur in isolated attacks (relapsing forms) or accumulate over time (progressive forms). There is no known cure for MS. Life expectancy is, on average, 5 to 10 years lower than in unaffected populations.

[0560] Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by motor neuron loss and progressive muscle atrophy, often leading to premature death. The disorder is caused by a genetic defect in the SMN1 gene that encodes SMN, a protein essential for motor neuron survival. Lower levels of the protein lead to loss of neuronal cell function in the anterior horn of the spinal cord and subsequent system-wide skeletal muscle atrophy. SMA is the most common inherited cause of death in infants. In December 2016, nusinersen became the first drug approved to treat SMA, while several other compounds are still in clinical trials.

[0561] Friedreich's ataxia is an autosomal recessive genetic disease that causes progressive damage to the nervous system. It manifests as initial symptoms of poor coordination such as gait disturbance; it may also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The ataxia of Friedreich's ataxia is caused by the degeneration of nerve tissue in the spinal cord, especially the sensory neurons (through connections to the cerebellum) necessary for directing arm and leg muscle movement. The spinal cord becomes thinner, and nerve cells lose some of their myelin (the insulating covering on some nerve cells that helps conduct nerve impulses).

[0562] (2) Psychological or behavioral disorders and / or related symptoms

[0563] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of a psychological or behavioral disorder and / or related symptoms in a subject in need thereof is provided, the method 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 compulsive behaviors, sleep disorders, sleep fragmentation, REM behavior disorders, circadian rhythm dysfunction, sleep apnea, or cognitive impairment.

[0564] (i) Depression

[0565] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of depression and / or related symptoms in a subject in need thereof is provided, the method 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.

[0566] Clinical depression is characterized by sad, gloomy moods that are above and beyond normal sadness or grief. One in 10 people will develop depression in their lifetime. Doctors diagnose depression clinically; there are no lab tests or X-rays for depression.

[0567] Studies have shown that some people with depression have smaller hippocampi. For example, in an fMRI study published in The Journal of Neuroscience, researchers studied 24 women with a history of depression. The depressed women had an average of 9 to 13 percent smaller hippocampi compared to women who were not depressed. The more episodes of depression a woman had, the smaller her hippocampus was. Stress, which plays a role in depression, may be a key factor, as experts believe that stress can inhibit the creation of new neurons (nerve cells) in the hippocampus.

[0568] Researchers are exploring a possible link between slow growth of new neurons in the hippocampus and low mood. Interesting facts about antidepressants support this theory. These drugs immediately increase the concentration of chemical messengers (neurotransmitters) in the brain. However, people typically don't start to feel better for a few weeks or longer. Experts have long wondered why people don't feel better sooner when neurotransmitter levels increase, if depression is primarily the result of low neurotransmitter levels. The answer may be that mood improves only as nerves grow and form new connections, a process that takes weeks. In fact, animal studies show that antidepressants do stimulate the growth and enhanced branching of nerve cells in the hippocampus. Therefore, the theory goes, the real value of these drugs may be in the generation of new neurons (a process called neurogenesis), the strengthening of nerve cell connections, and the improvement of information exchange between neural circuits.

[0569] Therefore, in one embodiment of the present disclosure, a method for treating and / or preventing depression is contemplated, the method comprising administering a therapeutically effective amount of an aminosterol composition according to the present disclosure. Although not wishing to be bound by theory, in theory, the aminosterol composition of the present disclosure triggers neurogenesis, which functions to combat depression.

[0570] In some embodiments, the method of the present disclosure produces an improvement in the clinical depression of the subject. Any clinically approved measurement can be used to measure the improvement of the subject's depression. For example, the improvement can be measured using a depression rating scale. In one embodiment of the present disclosure, after treatment, the subject undergoes an improvement 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%. Any clinically approved tool or assessment can be used to measure the improvement.

[0571] Examples of tools that can be used to assess depression and / or mood and improvement following aminosterol treatment include: (1) the Beck Depression Inventory (BDI-II); (2) UPDRS, sections 1.3 (depressed mood), 1.4 (anxious mood), 1.5 (apathy), and 1.13 (fatigue); and (3) Parkinson's Disease Fatigue Scale (PFS-16). In some embodiments, improvement can be measured by one or more medically approved techniques selected from the group consisting of the Patient Health Questionnaire-9 (PHQ-9); the Zung Self-Rating Depression Scale; the Center for Epidemiologic Studies-Depression Scale (CES-D); and the Hamilton Rating Scale for Depression (HRSD).

[0572] (ii) Cognitive impairment

[0573] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of cognitive impairment and / or related symptoms in a subject in need thereof is provided, the method 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.

[0574] Cognitive impairment, including mild cognitive impairment (MCI), is characterized by increased memory or thinking problems exhibited by subjects compared to normal subjects of the same age. Approximately 15% to 20% of people aged 65 or older have MCI, and MCI is particularly associated with neurodegenerative disorders such as AD and synucleinopathies such as PD. In 2002, an estimated 5.4 million people (22%) over 70 years old in the United States suffered from cognitive impairment without dementia. Plassman et al. 2009.

[0575] Cognitive impairment may involve memory problems, including a slight but significant and measurable decline in cognitive abilities (including memory and thinking skills). When MCI primarily affects memory, it is referred to as "amnestic MCI". People with amnestic MCI may forget information that was easy to recall before, such as, for example, appointments, conversations, or recent events. When MCI primarily affects thinking skills other than memory, it is referred to as "non-amnestic MCI". For example, people with non-amnestic MCI may have reduced ability to make correct decisions, judge the time or sequence of steps required to complete a complex task, or visual perception.

[0576] Mild cognitive impairment is a clinical diagnosis. Cognitive impairment is fully assessed using a combination of cognitive tests and information from people who have frequent contact with the subject. Medical examinations include one or more of the following: a physician's assessment of the subject's medical history (including current symptoms, past medical conditions, and family history); an assessment of independent functioning and daily activities; an assessment of mental status using brief tests that assess memory, planning, judgment, ability to comprehend visual information, and other key thinking skills; a neurologic examination that assesses nerve and reflex function, movement, coordination, balance, and sensation; an assessment of mood; brain imaging; or neuropsychological testing. Guidelines for the diagnosis of MCI have been developed by multiple groups, including the Alzheimer's Association in collaboration with the National Institute on Aging (NIA), an agency of the US National Institutes of Health (NIH). Jack et al. 2011; McKhann et al. 2011; Albert et al. 2011. The US Preventive Services Task Force has issued recommendations for screening for cognitive impairment. Screening for Cognitive Impairment in Older Adults, US 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). With respect to the MMSE, a score of 24 or higher (out of 30) can indicate normal cognition, and lower scores indicate severe (less than or equal to 9 points), moderate (10-18 points), or mild (19-23 points) cognitive impairment. Other screening tools include the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), in which an average score of 3 indicates no cognitive decline, and a score above 3 indicates a certain degree of decline. Jorm, AF 2004.Alternatively, the 7-Minute Screener, Abbreviated Mental Test Score (AMTS), Cambridge Cognitive Examination (CAMCOG), Clock Drawing Test (CDT), General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), Rowland Universal Dementia Assessment (RUDA), Self-Administered Gerocognitive Examination (SAGE), Short and Sweet Screening Instrument (SAS-SI), Short Blessed Test (SBT), St. Louis Mental Status (SLUMS), Short Portable Mental Status Questionnaire (SPMQ), and the Memory Impairment Screen (MIS) are often used in clinical and research settings. The Cognitive Status Questionnaire (SPMSQ), the Short Test of Mental Status (STMS), or the Time and Change Test (T&C), etc. Cordell et al. 2013. Many tests can be used, as no single tool is considered the "gold standard" and an improvement in the score on any standardized test indicates successful treatment of cognitive impairment, while obtaining a score comparable to a non-impaired group indicates complete recovery.

[0577] In some embodiments, administration of a therapeutically effective amount of an aminosterol composition to a patient in need thereof results in an improvement in cognitive impairment as determined by a clinically recognized assessment scale 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.

[0578] Examples of instruments that can be used to assess cognitive impairment and improvement following aminosterol treatment include: (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).

[0579] (iii) Sleep disturbances / problems (e.g., REM sleep disorder or circadian rhythm dysfunction)

[0580] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of sleep disturbances, sleep problems, sleep disorders, circadian rhythm dysfunction and / or related symptoms in a subject in need thereof is provided, the method 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.

[0581] The alternating pattern of sleep and wakefulness that occurs every 24 hours is called the circadian rhythm. The rhythm is set by a "zeitgeber" (time setter), which is an entity called the suprachiasmatic nucleus (SCN) and located in the hypothalamus. The SCN is usually "entrained" or synchronized by an external light-dark cycle. The circadian rhythm sleep-wake cycle can also be transformed in response to changes in the external light-dark cycle, such as the asynchrony (jet lag) that occurs during travel from one time zone to another. In this case, progressive regulation occurs until the SCN resynchronizes with the external light-dark cycle. Similar "phase-shift" and regulation occur in night shift workers.

[0582] Certain diseases and conditions may impair the normal function of the "timing factor" or circadian clock. These conditions may be reversible, such as asynchrony caused by jet lag, night shift work, or hunger, and the conditions are easily corrected by adaptation or food intake. In contrast, damage to the nerves that transmit light and dark related information from the retina to the SCN (a condition that may lead to blindness) or damage to the enteric nerves and neural structures that transmit information from the intestine to the SCN (a condition that may lead to neurodegenerative disorders) may cause permanent dysfunction of the circadian rhythm and abnormal sleep behavior.

[0583] Circadian rhythm dysfunction first and foremost manifests itself as an abnormal sleep pattern. Such abnormalities are typically mild at the beginning and gradually worsen over time. A common symptom of sleep disorders is delayed falling asleep. This delay may be as long as several hours, and the individual may not be able to fall asleep until several hours in the morning. Another common symptom is sleep fragmentation, which means that the individual wakes up several times during the night. Once awakened, the individual may not be able to return to sleep, and each awake segment may last for an hour or more, further reducing the "total sleep time", which is calculated by subtracting the total time of the awake segments from the total time spent in bed. Total sleep time also decreases with aging, from about 14 to about 16 hours per day for newborns, to about 12 hours at one year old, to about 7 to about 8 hours for young adults, and gradually decreases to about 5 to about 6 hours for elderly individuals. Total sleep time can be used to calculate the "sleep age" of an individual and compare it with their chronological age. The significant difference between sleep age and chronological age reflects the severity of the sleep disorder. "Sleep efficiency", defined as the percentage of time spent sleeping in bed, is another indicator that can be used to determine the severity of sleep disorders. When the percentage falls below about 70%, sleep efficiency is considered abnormal.

[0584] Sleep disorders and / or sleep disturbances include, but are not limited to, REM-behavior disorder, circadian rhythm disturbances ("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 according to the disclosed methods include, but are not limited to, hypersomnia (i.e., daytime sleepiness), parasomnias (such as nightmares, night terrors, sleepwalking, and confusion), periodic limb movement disorders (such as restless legs syndrome), jet lag, narcolepsy, advanced sleep phase disorder, and non-24-hour sleep-wake syndrome.

[0585] A "normal" or "restless" sleep period is defined as a sleep period that is not interrupted by awakening. Alternatively, the period can be defined by the recommended or appropriate amount of sleep for the subject's age category, for example, (i) infants 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) preschoolers about 3 to about 5 years = about 10 to about 14 hours; (v) school children about 6 to about 13 years = about 7 to about 12 hours; (v) adolescents 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 11 hours; (vii) adults about 26 to about 64 years = about 6 to about 10 hours; and (viii) older adults ≥ 65 years = about 5 to about 9 hours. Thus, to treat a sleep disorder in a subject, treatment may result in a restful sleep period of at least about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours.

[0586]

[0587]

[0588] There are several different scientifically acceptable methods to measure sleep periods that are not interrupted by wakefulness. First, electrodes attached to the subject's head can measure electrical activity in the brain through an electroencephalogram (EEG). This measurement is used because the EEG signals associated with wakefulness are different from the EEG signals found during sleep. Secondly, electromyography (EMG) can be used to measure muscle activity because the muscle tone between wakefulness and sleep is also different. Third, electrooculography (EOG) can be used to measure eye movements during sleep. This is a very specific measurement that helps identify rapid eye movement or REM sleep. Any one of these methods or a combination thereof can be used to determine whether a subject obtains a restful sleep period after administering at least one aminosterol or a salt or derivative thereof to the subject.

[0589] Additionally, circadian rhythm regulation can be monitored by a variety of means including, but not limited to, monitoring wrist skin temperature as described by Sarabia et al. 2008. Similarly, symptoms of RBD can be monitored using daily diaries and RBD questionnaires (Stiasny-Kolster et al. 2007).

[0590] In some embodiments, administration of a therapeutically effective amount of an aminosterol composition to a patient with a disorder results in an improvement in the frequency of normal or restful sleep as determined by a clinically recognized assessment scale for one or more types of sleep disorders 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%. The improvement can be measured using any clinically recognized tool or assessment.

[0591] Examples of tools that can be used to measure and evaluate the effects of aminosterol treatment on sleep include: (1) Sleep diaries (participants completed sleep diaries daily throughout the study. The diaries included bedtime and estimated sleep onset time as well as wake-up time and nighttime duration); (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. The Thermochron I-Button DS1921H (Maxim Integrated, Dallas, Texas) was used for skin temperature measurements. The I-Button was programmed to sample every 10 min and was attached to a double-sided cotton sports wristband using Velcro, with the sensor side of the I-Button placed on the inside of the wrist, over the radial artery of the dominant hand. Subjects removed and replaced the data logger when necessary (i.e., to bathe or shower). The value of skin temperature assessment in sleep studies is that endogenous skin warming caused by increased skin blood flow is functionally related to sleep propensity. From the collected data, median values, amplitude, peak phase (time to peak temperature), Rayleigh test (index of daytime stability), average waveform) were calculated; (3) UPDRS, section 1.7 (sleep problems), section 1.8 (daytime sleepiness), and section 1.13 (fatigue); (4) Parkinson's Disease Fatigue Scale (PFS-16); (5) REM Sleep Behavior Disorder Screening Questionnaire; and (6) Parkinson's Disease Sleep Scale.

[0592] (iv) Autism

[0593] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of autism spectrum disorder (ASD) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0594] Autism or autism spectrum disorder refers to a series of diseases characterized by challenges in social skills, repetitive behaviors, speech and nonverbal communication, and unique strengths and differences. There are many types of autism, caused by different combinations of genetic and environmental influences. The most obvious signs of autism tend to appear between the ages of 2 and 3. In some cases, it can be diagnosed as early as 18 months. Some developmental delays associated with autism can be identified and addressed even earlier.

[0595] The Centers for Disease Control and Prevention (CDC) estimates the prevalence of autism in the United States to be 1 in 59 children. This includes 1 in 37 boys and 1 in 151 girls. About one-third of people with autism remain nonverbal, and about one-third of individuals with autism have intellectual disabilities. Certain medical and mental health problems often accompany autism. They include gastrointestinal (GI) disorders, epilepsy, sleep disorders, attention deficit and hyperactivity disorder (ADHD), anxiety, and phobias.

[0596] Experts are still unsure of the cause of autism. There are likely multiple causes. It appears that many different circumstances, including environmental, biological, and genetic factors, lay the foundation for autism and make children more likely to develop the disorder. Genetics may play an important role in the development of autism. Identical twins are more likely to be affected than fraternal twins (genetically different). In a family with one child with autism, the chance of having another child with autism is about 5%, which is much higher than the normal population. Studies have also found that some mood disorders (such as manic depression) are more common in families with autistic children.

[0597] At least one group of researchers has found a link between abnormal genes and autism. The gene may be just one of 3-5 or more genes that interact in some way to cause the condition. Scientists suspect that one or more defective genes may make a person more likely to develop autism when there are other factors such as chemical imbalances, viruses or chemicals, or lack of oxygen at birth. Other potential causes of autism are environmental toxins, including pesticides and heavy metals, such as mercury. Heavy metals in the environment are indeed more common now than in the past. People with autism or those who are at higher risk of autism may be more sensitive to these toxins than others.

[0598] Recent studies of brain tissue suggest that children affected by autism have an excess of synapses, or connections between brain cells. The excess is due to a slowing of the normal pruning process that occurs during brain development. During normal brain development, a burst of synapse formation occurs during infancy. This is particularly evident in the cortex, which is the center for thinking and processing sensory information. However, by late adolescence, pruning eliminates about half of these cortical synapses. Additionally, many of the genes associated with autism are known to affect the development or function of brain synapses. Studies have also found that brain cells of individuals with autism are filled with damaged parts and lack signs of a normal breakdown pathway called "autophagy." Tang et al. 2014.

[0599] Therefore, one embodiment of the present disclosure relates to a method for treating self-closing disease, and the method comprises administering the aminosterol composition according to the present disclosure of a therapeutically effective amount. In one embodiment, treatment causes one or more characteristics of self-closing disease to improve. For example, such characteristics can be communication skills, social interaction, sensory sensitivity and behavior. Any clinically approved tool or assessment can be used to measure improvement.

[0600] For example, the method of the present disclosure can show improvement of one or more features of autism (such as behavior, communication, emotion, etc.), as measured by a medically approved 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%.

[0601] (3) Cerebral or systemic ischemic disorder and / or related symptoms

[0602] In one embodiment, a method for treating, preventing and / or slowing the onset or progression of a cerebral or systemic ischemic disorder and / or related symptoms in a subject in need thereof is provided, the method 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.

[0603] In one embodiment, the cerebral or systemic ischemic disorder is selected from microangiopathy, cerebral ischemia during delivery, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to problems during surgery, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypertension, high cholesterol, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, or pulmonary edema.

[0604] For example, the method of the present disclosure can show the improvement of one or more features of brain or systemic ischemic disorder, as measured by a medically recognized 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%.

[0605] Medically accepted scales or techniques for measuring improvement include, for example, cholesterol tests, high sensitivity C-reactive protein tests, lipoprotein(a), plasma ceramides, natriuretic peptides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, electrocardiogram (EKG), Holter monitor, stress testing, echocardiogram, positron emission tomography (PET), thallium scan, myocardial perfusion scan, implantable loop recorder, tilt table testing, electrophysiology studies, coronary angiography, magnetic resonance imaging, magnetic resonance angiography, cardiac CT scan, and event recorder.

[0606] (i) Erectile dysfunction

[0607] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of erectile dysfunction (ED) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0608] Erectile dysfunction can be a sign of a physical or psychological condition. It can cause stress, relationship strain, and low self-confidence. The main symptom is the inability of a man to get or keep an erection strong enough for sexual intercourse. ED can manifest through different mechanisms. Depending on its mechanism, ED can be classified as psychogenic, neurogenic (inability to initiate an erection), arterial (inability of the penis to fill with blood), and cavernous (inability of the vascular system to retain blood in the penis once filled) (Dean et al. 2005).

[0609] Many neurological diseases that cause ED, such as PD, are suspected to be associated with the formation of toxic αS aggregates in the enteric nervous system (ENS) (Braak et al. 2003 (a) and (b)). It is reported that ED affects men with PD in the range of 60%-79%, while the prevalence of ED in non-Parkinson men is only about 37.5% (Papatsoris, 2006). Since αS aggregates are normally transported 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), neurotoxic aggregates gradually accumulate in the brainstem and more rostral structures. Therefore, inhibiting αS aggregation in the ENS may reduce the ongoing neurological disease process in both the ENS and the CNS (Phillips et al. 2008) and thereby have a positive effect on ED associated with abnormal αS pathology.

[0610] Central dopamine is known to be a key neurotransmitter in the control of sexual function, including erection (Giuliano et al. 2001). It is said that dopamine deficiency may be responsible for the erectile dysfunction frequently observed in PD patients (Palma et al. 2014). In patients with PD, the development of αS-related pathology in serotonergic and cholinergic neurons parallels that seen in substantia nigra dopamine neurons. Therefore, regulation of αS may play a role in ED in PD through dopaminergic dysfunction.

[0611] In one embodiment, the method results in a reduction in the number of instances in which the subject is unable to have an erection, and the reduction in the number of instances in which the subject is unable to have an erection includes a reduction in the number of instances in which the subject is unable to have an erection within a defined period of time. In another aspect, the method results in a reduction in the severity of ED within a defined period of time, wherein the reduction in the severity of ED is measured by a medically accepted technique selected from the group consisting of bone pressurized erectile length (BPEL) measurement, circumference measurement, Erection Hardness Scale (EHS), and International Index of Erectile Function (IIEF).

[0612] (ii) Blood pressure

[0613] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of high blood pressure (HBP) or low blood pressure (LBP) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0614] Hypertension (HBP), also known as hypertension, is a long-term medical condition in which arterial blood pressure is persistently elevated. Chronic hypertension is a major risk factor for coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, vision loss, 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; while low blood pressure (LBP) can be characterized as (a) systolic blood pressure ≤80; or (b) diastolic blood pressure ≤50.

[0615] Low blood pressure (LBP), also called hypotension, is generally classified as a systolic blood pressure of less than 90 millimeters of mercury (mm Hg) or a diastolic blood pressure of less than 60 mm Hg. Major symptoms include dizziness, vertigo, and fainting. Severe low blood pressure can deprive the brain and other vital organs of oxygen and nutrients, leading to a life-threatening condition called shock. For some people who exercise and are in good physical condition, low blood pressure is a sign of good health and fitness. For many people, low blood pressure can cause dizziness and fainting, or indicate a serious heart, endocrine, or nervous system disorder.

[0616] Blood pressure (BP) and αS pathology: Many neurological diseases that cause HBP or LBP, such as PD, are suspected to be associated 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 PD patient visits in the United States, the most commonly documented comorbidity was hypertension, accounting for 37.8% of visits (Lingala et al. 2017). Orthostatic hypotension (OH) is one of the non-motor symptoms commonly seen in patients with idiopathic Parkinson's disease (IPD) (Fereshtehnejad et al. 2014).

[0617] Examples of disorders associated with abnormal αS pathology and / or dopaminergic dysfunction associated with HBP or LBP include, but are not limited to, synucleinopathies, neurological diseases, psychological and / or behavioral disorders, cerebral and systemic ischemic disorders, examples of which are described herein.

[0618] In one embodiment, the method reduces 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% in a subject with HBP as measured using a clinically accepted scale or tool.

[0619] In one embodiment, 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% in a subject with LBP as measured using a clinically accepted scale or tool.

[0620] In one embodiment, the clinically accepted scale or tool measures selected from the group consisting of sphygmomanometery, arterial penetration, palpitations, auscultation, oscillometric measurement, continuous non-invasive arterial pressure (CNAP), pulse wave velocity, and ambulatory monitoring.

[0621] (iii) Cardiac conduction defects

[0622] In one embodiment, a method of treating, preventing and / or slowing the onset or progression of cardiac conduction defects (CCD) and / or related symptoms in a subject in need thereof is provided, the method 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.

[0623] Cardiac conduction defects (CCD) involve abnormalities in how electrical impulses reach and pass through the heart. The cardiac conduction system transmits electrical signals, normally generated by the sinoatrial node, to cause the heart muscle to contract. Cardiac conduction defects (CCD) are serious and potentially life-threatening disorders. It belongs to a group of pathologies that alter cardiac conduction through the atrioventricular (AV) node, the His-Purkinje system with right or left bundle branch block, and widening of the QRS complex in the electrocardiogram (EKG). Initially, CCD was considered a structural disease of the heart in which anatomical changes in the conduction system were the root cause of abnormal impulse propagation. However, in a considerable number of cases, conduction disturbances are found to occur in the absence of anatomical abnormalities. In these cases, functional rather than structural changes appear to be the root cause of the conduction disturbances. These functional defects are referred to as "primary electrical diseases of the heart". The underlying pathophysiological mechanisms of CCD are diverse, but the most common form of CCD is the degenerative form, also known as Lenègre-Lev disease (idiopathic bilateral bundle branch fibrosis). Today, Lenègre-Lev disease represents the leading cause of pacemaker implantation in the world.

[0624] In one embodiment, CCD includes or causes (a) QT interval (QTc) ≥ 440ms; (b) syncope; (c) presence of delta waves in electrocardiogram (EKG); (d) pseudo right bundle branch block in EKG; (e) ST elevation of V1-V3 in EKG; (f) QRS complex in EKG > 100ms; (g) PR interval in EKG < 120ms; (h) heart rate above 100 beats per minute (BPM); (i) heart rate below 60 BPM; (j) PR interval in EKG > 200ms; (k) QRS not followed by P wave in EKG; (l) The absence of a repetitive relationship between the P wave and the QRS complex; (m) different atrial and ventricular rates; (n) QS or rS complexes in lead V1 on the EKG; (o) notched ('M'-shaped) R waves in lead V6; (p) T wave discordance on the EKG; (q) left axis deviation between -45° and -60° on the EKG; (r) qR pattern (small q, tall R) in lateral limb leads I and aVL on the EKG; (s) rS pattern (small r, deep S) in inferior leads II, III, and aVF on the EKG; (t) delayed intrinsicoid tortuosity (intrinsicoid truncation) in lead aVL on the EKG. deflection) (>0.045s); (u) frontal plane axis between 90° and 180° in the EKG; (v) rS pattern in leads I and aVL in the EKG; (w) qR pattern in leads III and aVF in the EKG; (x) chest pain; (y) palpitations; (z) dyspnea; (aa) shortness of breath; (bb) nausea; (cc) fatigue; (dd) sleep problems, sleep disorders, or sleep disturbances; (ee) constipation; and (ff) cognitive impairment.

[0625] In one embodiment, the progression or onset of CCD is slowed, stopped or reversed within a defined time period following administration of a fixed ascending dose of an aminosterol or a salt or derivative thereof, as measured by medically recognized techniques. Additionally, CCD may be positively affected by a fixed ascending dose of an aminosterol or a salt or derivative thereof, as measured by medically recognized techniques. The positive effects and / or progression of CCD may be quantitatively or qualitatively measured by one or more techniques selected from the group consisting of: echocardiography, electrocardiogram (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 accepted techniques.

[0626] In another embodiment, aminosterol or its salt or derivative reverses the dysfunction caused by CCD and treats, prevents, improves and / or disappears the symptoms evaluated. Use clinically recognized scale or tool to measure the improvement or disappearance of CCD symptoms. In addition, the improvement of CCD symptoms can be 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 for example above-mentioned technology.

[0627] C. Appetite Suppression / Obesity Treatment

[0628] In one embodiment, a method of inhibiting, preventing and / or reducing the onset or progression of appetite and / or one or more related symptoms in a subject in need thereof is provided, the method 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.

[0629] In one embodiment, the subject suffers from a disorder of increased appetite, and the increase in appetite is related to the subject's appetite prior to suffering from the disorder of increased appetite.The increase in appetite can be measured using a clinical scale or tool.

[0630] In one embodiment, the method causes a decrease in the appetite of the subject over a defined period of time, wherein the decrease in appetite is related to the appetite of the subject before administration of an aminosterol (e.g., v) or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof. The increase 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 self-assessment of appetite, subjective assessment of appetite, a visual analogue scale (VAS), the Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score, and the Anorexia Questionnaire (AQ).

[0631] In one embodiment, the appetite increased disorder is selected from stress, anxiety, depression, premenstrual syndrome, pregnancy, bulimia, hyperthyroidism, leptin resistance, Grave's disease, hypoglycemia, diabetes, Prader-Willi syndrome (PWS), binge eating disorder (BED), obesity, drug withdrawal, and drug consumption.

[0632] In one embodiment, the one or more appetite-related symptoms are selected from borborygmi (stomach growling); fainting, dizziness or lightheadedness; headache; irritability; cognitive impairment; and nausea. Execution of the method may result in a reduction or elimination of one or more associated symptoms.

[0633] In one embodiment, (a) the method results in a reduction in the severity of syncope, dizziness or lightheadedness in a subject over a defined time period, as measured by a clinically recognized syncope, dizziness or lightheadedness scale or tool; (b) the method results in a reduction in the severity of syncope, dizziness or lightheadedness over a defined time period, wherein the reduction in severity is selected from a reduction 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% and about 100%, as measured by a clinically recognized syncope, dizziness or lightheadedness scale or tool; and / or (c) the method results in the absence of syncope, dizziness or lightheadedness in the subject.

[0634] In one embodiment, the syncope, dizziness or lightheadedness scale or tool recognized clinically is selected from the group consisting of Amer Dizziness Diagnostic Scale (ADDS), Vertigo Symptom Scale, Dizziness Handicap Inventory, Vestibular Disorders of Daily Living Scale, Activities-specific Balance Confidence, Vertigo Handicap Questionnaire, Vertigo, Dizziness, Imbalance Questionnaire, UCLA Dizziness Questionnaire, Dizzy Factor Inventory, European Evaluation of Vertigo, and Meniere's Disease Patients-Oriented Severity Index.

[0635] In one embodiment, (a) the method results in a reduction in headache for a defined period of time in the subject as measured by one or more clinically recognized headache rating scales; (b) the method results in a reduction in headache for a defined period of time in the subject as measured by one or more clinically recognized headache rating scales, and the reduction is one or more types of headache 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 headache for a defined period of time in the subject as measured by one or more clinically recognized headache rating scales, and the subject's headache is reduced 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%.

[0636] In one embodiment, the one or more clinically recognized headache rating scales are selected from ID-Migraine, Visual Aura Rating Scale (VARS), Migraine Disability Assessment Questionnaire (MIDAS), Migraine-Specific Quality of Life Survey (MSQ 2.1), and Headache Under-Response to Treatment (HURT) questionnaire.

[0637] 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 recognized cognitive rating scales; (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 recognized cognitive rating scales, and 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%.

[0638] In one embodiment, the one or more clinically recognized cognitive rating scales are selected from ADASCog, Woodcock-Johnson Tests of Cognitive Abilities, Leiter International Performance Scale, Miller Analogies Test, Raven's Progressive Matrices, Wonderlic Personnel Test, IQ test, Unified Parkinson's Disease Rating Scale (UPDRS), Mini Mental State Examination (MMSE), Mini Mental Parkinson's Disease Rating Scale (MMSE), Mini Mental Parkinson's Disease Rating Scale (MPRS), Mini Mental State Examination ...MPS), Mini Mental State Examination (MPS), Mini Mental State Examination (MPS), Mini Mental State Examination (MPS), Mini Mental State Examination (MPS), Mini Mental State Examination (MPS Parkinson) (MMP), Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE), 7-Minute Screener, Brief Mental Test Score (AMTS), Cambridge Cognitive Examination (CAMCOG), General Practitioner Cognitive Assessment (GPCOG), Mini-Cog, Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), Roland Universal Dementia Assessment (RUDA), Self-Administered Geriatric Cognitive Examination (SAGE), Brief Summary Screening Instrument (SAS-SI), Short Blessings Test (SBT), St. Louis Mental Status (SLUMS), Brief Portable Mental Status Questionnaire (SPMSQ), Short Test of Mental Status (STMS), Time and Change Test (T&C), Test Your Memory (TYM) Test, Addenbrooke's Cognitive Examination-Revised (ACER); and computer tests selected from the following: Cantab Mobile, Cognigram, Cognivue, Cognision, and Automated Neuropsychological Assessment Index Cognitive Performance Test (CPT).

[0639] In one embodiment, a method of reversing, preventing and / or slowing the onset or progression of weight gain and / or related symptoms in a subject in need thereof is provided, the method 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.

[0640] In one embodiment, a method of reducing body 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.

[0641] In some embodiments, the methods result in a loss 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% weight in a subject over a defined period of time.

[0642] In some embodiments, the method results in a reduction in calorie consumption in a subject within a defined time period, wherein the reduction is relative to the calories consumed by the subject within a time span prior to administration of an aminosterol (e.g., ENT-03 (Compound III)) or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof. The defined time period and the time span may be the same length of time. In addition, the reduction in calorie consumption may 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%.

[0643] In some embodiments, the method results in a reduction in the mass of food consumed by the subject over a defined time period relative to the mass of food consumed by the subject over a time span prior to administration of the aminosterol or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein the defined time period and the time span are the same length of time and wherein the mass of food consumed is reduced 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%.

[0644] In some embodiments, the method results in a reduction in body weight in a subject over a defined period of time, wherein the reduction in body weight 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.

[0645] In some embodiments, each defined period of time is independently selected from 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 about greater than 12 months.

[0646] In some embodiments, the subject has and / or is at risk for having one or more conditions selected from 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.

[0647] D. Antimicrobial therapy

[0648] (1) Microbial infection

[0649] In one aspect, the aminosterols described herein can be administered to a subject in need thereof to treat a microbial infection. In some embodiments, the subject in need thereof suffers from a condition selected from the group consisting of a viral infection, a microbial infection, a bacterial infection (e.g., a Gram-negative and / or Gram-positive bacterial infection, a Mycobacterium infection), a fungal infection, and / or a protist infection.

[0650] In some embodiments, the viral infection is caused by a virus selected from the group consisting of Yellow Fever Virus, Cytomegalovirus, Eastern Equine Encephalitis Virus, Hepatitis B Virus, Hepatitis D Virus, Dengue Virus, and Human Immunodeficiency Virus. In some embodiments, the condition to be treated is a viral infection caused by a virus selected from the group consisting of: African Swine Fever Virus, Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Cauliviridae Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Dengue, EBV, HIV, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Hepadnaviridae (hepatitis), Herpesviridae (such as Cytomegalovirus, Herpes simplex) Simplex, Herpes Zoster), Iridoviridae, Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., influenza A, influenza B, and parainfluenza viruses), Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Picomaviridae (e.g.,Rhinovirus, Poliovirus), Poxviridae (such as smallpox or cowpox), Potyviridae, Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), Rhabdoviridae, Tectiviridae, Togaviridae (e.g., Rubivirus), herpes, pox, papilloma, coronavirus, influenza, hepatitis, Sendai virus, sindbis, vaccinia virus, West Nile virus, hanta, viruses that cause the common cold, and any combination thereof. In some embodiments, the condition to be treated is selected from AIDS, viral meningitis, dengue fever, EBV, hepatitis, chronic diseases suspected of being of viral origin, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, cardiomyopathy, Kawasaki disease, aplastic anemia, and any combination thereof.

[0651] In some embodiments, the method further comprises administering one or more antiviral drugs.

[0652] (2) Coronavirus infection

[0653] In one aspect, a method of treating or preventing a coronavirus infection in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any embodiment herein or a composition of any embodiment herein.

[0654] In some embodiments, the coronavirus comprises a virus selected from the group consisting of an alpha coronavirus; a colacovirus, such as bat coronavirus CDPHE15; a decacovirus, such as bat coronavirus HKU10 or Rhinolophus ferrumequinum alpha coronavirus HuB-2013; a duvinacovirus, such as human coronavirus 229E; a luchacovirus, such as Lucheng Rn bat coronavirus; a minacovirus, such as ferret coronavirus or mink coronavirus 1; a minunacovirus, such as Miniopterus bat coronavirus 1 or Long-fingered bat coronavirus HKU8; a myotacovirus, such as Myotis ricketti alpha coronavirus Sax-2011; a nyctacovirus, such as Nyctalus sphenotype. velutinus) alpha coronavirus SC-2013; Pedacovirus, such as porcine epidemic diarrhea virus or Scotophilus bat coronavirus 512; Rhinacovirus, such as Rhinolophus bat coronavirus HKU2; Setracovirus, such as human coronavirus NL63 or NL63-related bat coronavirus strain BtKYNL63-9b; Tegacovirus, such as alpha coronavirus 1; Beta coronavirus; Embecovirus, such as Beta coronavirus 1, human coronavirus OC43, China rat coronavirus OC43, Rattus) coronavirus HKU24, human coronavirus HKU1 or mouse coronavirus; Hibecovirus, such as bat Hp-β coronavirus Zhejiang 2013; Merbecovirus, such as hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5 or Tylonycteris bat coronavirus HKU4; Nobecovirus, such as Rousettus bat coronavirus GCCDC1 or fruit bat coronavirus HKU9, Sarbecovirus, such as severe acute respiratory syndrome-related coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19); Delta coronavirus; Andecovirus, such as wild duck coronavirus HKU20; Buldecovirus, such as nightingale coronavirus HKU11, porcine coronavirus HKU15, munia coronavirus HKU13 or white-eye coronavirus HKU16;Herdecovirus, such as night heron coronavirus HKU19; Moordecovirus, such as Common moorhen coronavirus HKU21; Gammacoronavirus; Cegacovirus, such as Beluga coronavirus SW1; and Igacovirus, such as avian coronavirus. ;

[0655] In some embodiments, the coronavirus is encoded by a polynucleotide comprising a SARS-CoV-2 sequence or a polynucleotide having at least 80% sequence identity to a polynucleotide comprising a SARS-CoV-2 sequence. In some embodiments, the coronavirus comprises human coronavirus 229E, human coronavirus OC43, SARS-CoV, HCoV NL63, HKU1, MERS-CoV, or SARS-CoV-2 or has features thereof. In some embodiments, the coronavirus comprises SARS-CoV-2 or has features thereof.

[0656] In some embodiments, the subject is considered to have a risk of severe illness and / or severe complications of coronavirus infection. In some embodiments, the subject is about 50 years old or older, about 55 years old or older, about 60 years old or older, or about 65 years old or older. In some embodiments, the subject suffers from one or more pre-existing conditions selected from 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 acceptance, immunosenescence or any combination thereof.

[0657] In some embodiments, administration increases the probability of survival of a subject after exposure to a coronavirus. In some embodiments, the probability 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 recognized technique.

[0658] In some embodiments, the subject is exposed to or expected to be exposed to an individual with coronavirus infectiousness. In some embodiments, the individual with coronavirus infectiousness has one or more symptoms selected from fever, cough, shortness of breath, diarrhea, sneezing, runny nose and sore throat. In some embodiments, the subject is a healthcare worker, frequent traveler, military personnel, caregiver, or a subject with a pre-existing condition that increases the risk of death from infection, who is 60 years of age or older.

[0659] In some embodiments, the method further comprises administering one or more antiviral drugs. In some embodiments, the one or more antiviral drugs are selected from chloroquine, hydroxychloroquine, darunavir, galidesivir, interferon beta, lopinavir, ritonavir, remdesivir and / or triazole riboside.

[0660] In some embodiments, administration reduces the risk of coronavirus transmission. In some embodiments, the risk of transmission is reduced 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 recognized technique. In some embodiments, medically recognized techniques include PCR (polymerase chain reaction) or immunoassays.

[0661] VI. Patient population

[0662] The disclosed aminosterols and compositions comprising the same 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, toddler, school-age child, teenager, young adult, adult or elderly patient.

[0663] In the embodiments disclosed herein related to prevention, a specific patient population can be selected based on being "at risk" of developing any of the conditions disclosed herein. For example, genetic markers of a condition or family history can be used as markers to identify subjects who may develop a specific condition. Therefore, in some embodiments, prevention may involve first identifying a patient population at risk of developing a condition. Alternatively, certain symptoms are considered early markers of a specific disorder. Therefore, in some embodiments, a patient population at "risk" of developing a condition can be selected based on age and experiencing symptoms associated with the condition. Further genes or genetic markers can be used to refine the patient population.

[0664] VII. Reagent test kit

[0665] The aminosterol formulations or compositions of the present disclosure may be packaged with instructions or package inserts or included in a kit with them. Such instructions or package inserts may describe recommended storage conditions, such as time, temperature, and light, in view of the shelf life of the aminosterol or its derivatives or salts. Such instructions or package inserts may also describe specific advantages of the aminosterol or its derivatives or salts, such as the easy storage of the formulations that may need to be used in locations outside of controlled hospital, clinic or office conditions.

[0666] The present disclosure also provides a kind of pharmaceutical packaging or test kit, it comprises one or more containers, and the one or more containers are filled with one or more aminosterol pharmaceutical compositions disclosed herein.The test kit can comprise, for example, a container filled with an appropriate amount of aminosterol pharmaceutical composition, the aminosterol pharmaceutical composition as a powder to be dissolved, a tablet, or as a sterile solution.Related to one or more such containers can be a notice in the form of a government agency regulation of the manufacture, use or sale of a drug or biological product, the notice reflecting the approval of manufacture, use or sales agencies for human administration.In addition, aminosterol or its derivatives or salts can be used in combination with other therapeutic compounds.

[0667] In other aspects, a kit is disclosed comprising a nasal spray device as described herein. In one aspect, the kit may 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 influences. The container may be, for example, a foil or plastic bag, particularly a foil bag or a heat-sealed foil bag. One skilled in the art will readily appreciate suitable containers sufficient to adequately protect the device.

[0668] In one aspect, the kit may comprise one or more devices as disclosed herein, wherein the device may be sealed within 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 may include a foil bag. The kit may further comprise instructions for use of the device. In one aspect, the kit contains two or more devices.

[0669] In one aspect, the kit may comprise a device as disclosed herein, and may further comprise instructions for use. In one aspect, the instructions may include visual aids / illustrations and / or written instructions for an administrator of the device.

[0670] VIII. Combination therapy

[0671] In the methods of the present disclosure, the aminosterol compositions may be administered alone or in combination with one or more additional therapeutic agents. Examples of additional therapeutic agents are known therapeutic agents useful for treating the condition for which the aminosterol is being administered.

[0672] For example, in the method for treating, preventing and / or slowing down the onset or progression of PD and / or related symptoms, the aminosterol composition can be co-administered or combined with drugs such as levodopa (usually in combination with a dopa decarboxylase inhibitor or a COMT inhibitor), dopamine agonists and MAO-B inhibitors that are usually prescribed for the treatment of PD or related symptoms. Exemplary dopa decarboxylase inhibitors are carbidopa and benserazide. Exemplary COMT inhibitors are tolcapone and entocapone. 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 drugs commonly used in the treatment of PD include, for example, amantadine, anticholinergics, clozapine for psychosis, cholinesterase inhibitors for dementia and modafinil for daytime sleepiness.

[0673] In methods of treating, preventing and / or slowing the onset or progression of AD or related symptoms associated with AD, the aminosterol compositions can be combined with drugs commonly prescribed for the treatment of AD or related symptoms such as glutamate, antipsychotics, huperzine A, acetylcholinesterase inhibitors and NMDA receptor antagonists such as memantine. and co-administered or combined. Examples of acetylcholinesterase inhibitors are donepezil Galantamine Rivastigmine

[0674] In methods of treating, preventing and / or slowing the onset or progression of diabetes or related symptoms associated with diabetes and / or diabetes mellitus (including type 1 and type 2 diabetes or diabetic neuropathy), the aminosterol compositions can be used with drugs commonly prescribed for the treatment of diabetes or related symptoms such as insulin (NPH insulin or synthetic insulin analogs) (e.g., ) and oral anti-hyperglycemic drugs are co-administered or combined. Oral anti-hyperglycemic drugs include but are not limited to (1) biguanides, such as metformin (2) Sulfonylureas, such as acetophenonesulfonylcyclohexylurea and chlorpropamide Glimepiride Glipizide Tolbutamide, tolbutamide, and glyburide (3) Meglitinides, such as repaglinide and nateglinide (4) Thiazolidinediones, such as rosiglitazone and pioglitazone (5) α-glucosidase inhibitors, such as acarbose Miglitol (6) Dipeptidyl peptidase-4 inhibitors, such as sitagliptin (7) Glucagon-like peptide agonists, such as exenatide and (8) amylin analogs, such as pramlintide

[0675] In methods of treating, preventing and / or slowing the onset or progression of HD or related symptoms associated with Huntington's disease or disease, the aminosterol composition may be co-administered or combined with medications typically prescribed for the treatment of Huntington's disease or related symptoms, such as medications prescribed to help control mood and movement problems associated with Huntington's disease. Such medications include, but are not limited to, (1) antipsychotics, such as haloperidol and clonazepam; (2) medications used to treat dystonia, such as acetylcholine modulating drugs (benzhexol, benztropine); and procyclidine hydrochloride); GABA modulating drugs (diazepam Lorazepam Clonazepam and baclofen ); dopamine modulators (levodopa / carbidopa Bromocriptine (parlodel), reserpine, tetrabenazine); anticonvulsants (carbamazepine and botulinum toxin ); and (3) 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 .

[0676] In methods for treating, preventing and / or slowing the onset or progression of peripheral sensory neuropathy or related symptoms associated with peripheral sensory neuropathy, the aminosterol composition can be co-administered or combined with a drug commonly prescribed for the treatment of peripheral sensory neuropathy or related symptoms. Peripheral sensory neuropathy refers to damage to the nerves of the peripheral nervous system, which may be caused by a neurological disease or neurotrauma or a 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), anti-epileptic therapies (e.g., gabapentin or sodium valproate), synthetic cannabinoids (Nabilone) and inhaled cannabis, opium derivatives, and pregabalin.

[0677] In methods of treating, preventing and / or slowing the onset or progression of traumatic head and / or spinal injury or related symptoms associated with traumatic head and / or spinal injury, the aminosterol compositions can be co-administered or combined with medications commonly prescribed for the treatment of traumatic head and / or spinal injury or related symptoms, such as analgesics (acetaminophen, NSAIDs, salicylates, and opioids, such as morphine and opium) and paralytics.

[0678] In methods of treating, preventing and / or slowing the onset or progression of stroke or related symptoms associated with stroke, the aminosterol compositions can be co-administered or combined with drugs commonly prescribed for the treatment of stroke or related symptoms such as aspirin, clopidogrel, dipyridamole, tissue plasminogen activator (tPA), and anticoagulants (e.g., alteplase, warfarin, dabigatran).

[0679] In methods of treating, preventing and / or slowing the onset or progression of ALS or related symptoms associated with ALS, the aminosterol compositions can be used in combination with drugs commonly prescribed for the treatment of amyotrophic lateral sclerosis or related symptoms, such as riluzole. KNS-760704 (enantiomer of pramipexole), olesoxime (TRO19622), talampanel, arimoclomol, drugs that help reduce fatigue, relieve muscle spasms, control spasticity, reduce excessive salivation and phlegm, control pain, depression, sleep disorders, difficulty swallowing and constipation are co-administered or combined.

[0680] In methods of treating, preventing and / or slowing the onset or progression of MS or related symptoms associated with multiple sclerosis, the aminosterol compositions can be used with drugs commonly prescribed for the treatment of multiple sclerosis or related symptoms such as corticosteroids (e.g., methylprednisolone), plasmapheresis, fingolimod, Interferon beta-1a and Interferon beta-1b and Glatiramer acetate Mitoxantrone, natalizumab Alemtuzumab Daclizumab Rituximab, dirucotide, BHT-3009, cladribine, dimethyl fumarate, estriol, fingolimod, laquinimod, minocycline, statins, temsirolimus teriflunomide, naltrexone, and vitamin D analogs are co-administered or combined.

[0681] In methods of treating, preventing and / or slowing the onset or progression of cerebral palsy or related symptoms associated with cerebral palsy, the aminosterol compositions may be co-administered or combined with medications commonly prescribed for the treatment of cerebral palsy or related symptoms, such as botulinum toxin type A injection.

[0682] In methods of treating, preventing and / or slowing the onset or progression of epilepsy or related symptoms associated with epilepsy, the aminosterol compositions can be used in combination with drugs commonly prescribed for the treatment of epilepsy or related symptoms such as anticonvulsants (e.g., carbamazepine, Chlordiazepoxide Clonazepam Ethosuximide Felbamate Fosphenytoin Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Phenobarbital Phenytoin Pregabalin Primidone Tiagabine Topiramate Valproate hemisodium Valproic acid and zonisamide Clobazam Vigabatrin Retigabine, brivaracetam, seletracetam, diazepam and Lorazepam Paraldehyde Midazolam Pentobarbital Acetazolamide Progesterone, adrenocorticotropic hormone (ACTH and ), various adrenocorticotropic steroids (prednisone) and bromides co-administered or combined.

[0683] In methods of treating, preventing and / or slowing the onset or progression of cognitive impairment or associated symptoms associated with cognitive impairment, the aminosterol compositions can be used with drugs commonly prescribed for the treatment of cognitive impairment, such as donepezil. Galantamine Rivastigmine and stimulants, such as caffeine, amphetamines Lisdexamfetamine and methylphenidate NMDA antagonists, such as memantine Supplements such as Ginkgo, L-theanine, piracetam, oxiracitam, aniracetam, tolcapone, atomoxetine, ginseng, and sage are co-administered or combined.

[0684] In the method of treating, preventing and / or slowing down 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 anticancer drugs, such as but not limited to those listed in http: / / www.cancer.gov / cancertopics / druginfo / alphalist as of May 5, 2014, which are specifically incorporated by reference. In one embodiment, drugs commonly used to treat malignant tumors can be selected from actinomycin-D, melphalan, arabinoside (ara-C), anastrozole, BiCNU, bicalutamide, bleomycin, busulfan, capecitabine, carboplatin, carboplatinum, carmustine, CCNU, chlorambucil, cisplatin, cladribine, CPT-11, cyclophosphamide, cytarabine, cytosine arabinoside, cyclophosphamide, dacarbazine, dactinomycin, daunorubicin, dexrazoxane , docetaxel, doxorubicin, DTIC, epirubicin, ethyleneimine, etoposide, floxuridine, fludarabine, fluorouracil, flutamide, fomostine, gemcitabine, hexamethylolamine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, procarbazine, steroids, streptozotocin, S TI-571, tamoxifen, temozolomide, teniposide, tetrazine, thioguanine, thiotepa, tomudex, topotecan, treosulphan, trimetrexate, vinblastine, vincristine, vindesine, vinorelbine, VP-16, xeloda, asparaginase, AIN-457, bapineuzumab, belimumab, brentuximab, briakinumab, canakinumab, dalo tuzumab), denosumab, epratuzumab, estafenatox, farletuzumab, figitumumab, galiximab, gemtuzumab, girentuximab (WX-G250), Herceptin, ibritumomab, inotuzumab, ipilimumab,mepolizumab, muromonab-CD3, naptumomab, necitumumab, nimotuzumab, ocrelizumab, ofatumumab, otelixizumab, ozogamicin, pagibaximab, panitumumab, pertuzumab, ramucirumab, reslizumab, rituximab, REGN88, solanezumab, tanezumab, teplizumab, tiuxetan, tositumomab, trastuzumab, tremelimumab, vedolizumab, zalutumumab, zanolimumab, 5FC, accutane hoffmann-la roche), AEE788 Novartis, AMG-102, antineoplastic agents, 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, Gleevec (imatinib mesylate), Gliadel implant (gliadel wafer), hydroxychloroquine, IL-13, IMC-3G3, immunotherapy, Iressa (ZD-1839), lapatinib (GW572016), methotrexate (systemic) for cancer, novocure, OSI-774, PCV, RAD001 Novartis (mTOR inhibitor), rapamune (Sirolimus), RMP-7, RTA 744,Simvastatin, sirolimus, sorafenib, SU-101, SU5416 sugen, sulfasalazine (Azulfidine), sutent (Pfizer), TARCEVA (erlotinib hydrochloride), paclitaxel, temozolomide (TEMODAR) schering-plough, TGF-B antisense, thalomid (thalidomide), topotecan (systemic), VEGF trap, VEGF-trap, vorinostat (SAHA), XL 765, XL184, XL765, zarnestra (tipifarnib), ZOCOR (simvastatin), cyclophosphamide (Cytoxan), melphalan, chlorambucil (Leukeran), thiotepa (Thioplex), busulfan (Myleran), procarbazine (Matulane), dacarbazine (DTIC), altretamine (Hexalen), phenylbutamol (Phenylbutamol) Clorambucil, cisplatin (Platinol), ifosfamide, methotrexate (MTX), 6-thiopurine (mercaptopurine [6-MP], thioguanine [6-TG]), mercaptopurine (Purinethol), fludarabine phosphate, (Leustatin), 5-fluorouracil (5-FU), cytarabine (ara-C), azacitidine, vinblastine (Velban), vincristine (Oncovin), podophyllotoxin (etoposide) glycosides {VP-16} and teniposide {VM-26}), camptothecins (topotecan and irinotecan), taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere), (doxorubicin, Rubex, Doxil), dactinomycin (Cosmegen), plicamycin (mithramycin), mitomycin: (mutamycin), bleomycin (Blenoxane), estrogen and androgen inhibitors (Tamoxifen), gonadotropin-releasing hormone agonists (leuprore lin and goserelin (Zoladex), aromatase inhibitors (aminoglutethimide and (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 (MGCD0103), panobinostat (LBH589), romidepsin, valproic acid, flavopiridol, olomoucine, roscovitine, kenpaullone, AG-024322 (Pfizer), fascaplysin, ryuvidine, purvalanol A, NU2058, BML-259, SU 9516, PD-0332991, P276-00, geldanamycin, tanespimycin, alvespimycin, radicicol, deguelin, BIIB021, cis-imidazoline, benzodiazepine dione, spirooxindole, isoquinolinone, thiophene, 5-deazaflavin, tryptamine, aminopyridine, diaminopyrimidine, pyridoisoquinoline, pyrrolopyrazole, indolecarbazole, pyrrolo Pyrimidine, diphenylamine pyrimidine, benzamide, phthalazinone, tricyclic indole, benzimidazole, indazole, pyrrolocarbazole, isoindolinone, morpholino anthracycline, maytansinoid, ducarmycin, auristatin, calicheamicin (DNA damaging agent), α-amanitin (RNA polymerase II inhibitor), centanamycin, pyrrolobenzodiazepine, streptonigtin, nitrogen mustard, nitrosourea, alkyl sulfonate, pyrimidine analog, purine analog, antimetabolite, folic acid analog, anthracycline, taxane, vinca alkaloid, topoisomerase inhibitor, hormonal agent and any combination thereof.

[0685] In methods of treating, preventing and / or slowing the onset or progression of depression or related symptoms associated with depression, the aminosterol compositions may be co-administered or combined with drugs commonly used to treat depression. These include selective serotonin reuptake inhibitors (SSRIs), such as citalopram Escitalopram Paroxetine Fluoxetine Fluvoxamine Sertraline Indapamine Zimelidine Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine Duloxetine Levomilnacipran Milnacipran Venlafaxine Serotonin modulators and stimulators (SMS), such as vilazodone Vortioxetine Serotonin antagonists and reuptake inhibitors, such as nefazodone Trazodone Etoperidone; norepinephrine reuptake inhibitors (NRIs), such as reboxetine Teniloxazine Viloxazine Norepinephrine-dopamine reuptake inhibitors, such as bupropion Amiheptanoic acid Nomifensine Methylphenidate Lysine Tricyclic antidepressants, such as amitriptyline Amitriptylinoxide Clomipramine De-Isocyanate Dibenzepine Dimetholine doxepin Doxepin Imipramine Lofepramine Melitracen nitroxazepine Noramitriptyline Nocitriptyline Opipramol Pipofilazine Protriptyline Trimipramine Butriptyline Fluacizine Oxymipramine Metapramine Propirazepam Thiazepam Tofenacin amineptine Tianeptine Tetracyclic antidepressants, such as amoxapine Maprotiline Mianserin Mirtazapine Sputiline Mianserin, mirtazapine, setiline; monoamine oxidase inhibitors (MAOIs), such as isocarboxazid Phenelzine Tranylcypromine Benmoxin Iproclorazepam Iprohydrazide Mebanazone Niacinamide Octamoxin Phenylprohydrazine Phenoxyproline Pivalohydrazine Salvador Selegiline Caroxazone Metraindole Moclobemide Pyrindole Toloxatone Ipelbemide Minaprin Difemelane Atypical antipsychotics, such as amisulpride Lurasidone Quetiapine and N-methyl D-aspartate (NMDA) antagonists, such as ketamine

[0686] In methods of treating and / or preventing obesity, the aminosterol compositions can be co-administered or combined with drugs commonly prescribed for the treatment of obesity, including but not limited to orlistat (Xenical), lorcaserin (Belviq), phentermine-topiramate (Qsymia), naltrexone-bupropion (Contrave), liraglutide (Saxenda), phentermine, benzphetamine, diethylpropion, and phendimetrazine.

[0687] The combination can be administered concomitantly (e.g., as a mixture), separately but simultaneously or in parallel; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also procedures in which the combined agents are administered separately but simultaneously, e.g., through separate intravenous lines into the same individual. "Combination" administration further includes separate administration, first administering one of the compounds or agents, then the second. The selected regimen can be administered in parallel, because the activation of the aminosterol-induced response does not require systemic absorption of the aminosterol into the bloodstream, and thus eliminates concerns about the possibility of systemic drug-drug interactions between the aminosterol and the administered drug.

[0688] IX. definition

[0689] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0690] Unless defined otherwise, technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art.The methods described herein can be implemented using any suitable materials and / or methods known to one of ordinary skill in the art.

[0691] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition, aminosterol or medicament as provided herein refers to an amount of a composition, aminosterol or medicament that is nontoxic but sufficient 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, one or more specific drugs used, the mode of administration, etc. The appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experiments based on the information provided herein. Exemplary dosages are provided herein only for convenience. Those skilled in the art can adjust such amounts according to the methods disclosed herein to treat specific subjects suffering from specific symptoms or disorders. The therapeutically effective amount can vary based on the route of administration and dosage form.

[0692] As used herein, the term "comprising" is intended to mean that compounds, compositions, and methods include the listed elements, but do not exclude other elements. When used to define compounds, compositions, and methods, "consisting essentially of" is intended to exclude other elements that have any significance to the combination. Thus, a composition consisting essentially of elements as defined herein will not exclude trace contaminants, for example, contaminants from separation and purification methods and pharmaceutically acceptable carriers, preservatives, etc. "Consisting of" should mean excluding not only trace elements but also other ingredients. Embodiments defined by each of these transition terms are within the scope of the present technology.

[0693] All numerical designations, such as mass, temperature, time and concentration (including ranges), are approximate values ​​with variations (+) or (-) in increments of 1%, 5% or 10%. It should be understood, although not always explicitly stated, that all numerical expressions are preceded by the term "about".

[0694] The term "about" should be understood by those of ordinary skill in the art, and will vary to some extent according to the context in which it is used. If the use of the term is unclear for those of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of a particular term. For example, in some embodiments, it will mean plus or minus 5% of a particular term. Certain ranges are presented herein by numerical values ​​preceded by the term "about". The term "about" is used herein to provide textual support for the exact numerical value thereafter and the numerical value after approaching or approximating the term. When determining whether a number is close to or approximating a specific enumerated number, the close or approximate unenumerated number can be a number that provides a substantially equivalent form of a specific enumerated number in the context in which it is presented.

[0695] "Optional" or "optionally" means that the subsequently described event may or may not occur, so that the description includes instances where the event occurs and instances where it does not.

[0696] "Pharmaceutically acceptable excipient or carrier" refers to an excipient that may be optionally included in the compositions of the present disclosure and that does not cause significant adverse toxicological effects to patients.

[0697] "Significantly" or "substantially" means almost all or completely, for example, 95% or more of a given amount. In some embodiments, "significantly" or "substantially" means 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9%.

[0698] As used in the present disclosure and the appended claims, the singular forms "a", "an", and "the" are used interchangeably and are intended to include the plural forms as well and fall within each meaning unless the context clearly indicates otherwise. In addition, 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 a combination when interpreted as an alternative ("or").

[0699] 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).

[0700] As used herein, the term "administering" includes prescribing for administration as well as actual administration, and includes physical administration by the subject being treated or by another person.

[0701] As used herein, "regulatory phosphatase" or "phosphatase" refers to an enzyme known to those of ordinary skill in the art that removes a phosphate group from a phosphorylated amino acid residue of its substrate protein. Non-limiting examples include protein Ser / Thr phosphatases, including type 1 (PP1) and type 2 (PP2, i.e., PP2A, PP2C, and PP2B), such as PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP2CB, PPP3CA, PPP3CB, PPP3CC, PPP4C ... PPP5C and PPP6C; class I Cys-based protein tyrosine phosphatases (PTPs); class II Cys-based PTPs; class III Cys-based PTPs; class IV Cys-based DSPs (dual specificity phosphatases); PTPs such as PTP1B, CDC14 (CDC14A, CDC14B, CDC14C, CDKN3); phosphatases and tensin homologs such as PTEN; slingshots such as SSH1, SSH2, and SSH3; dual specificity phosphatases such as DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUSP10, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19, DUSP21, DUSP22, DUSP23, DUSP26, DUSP27, and DUSP28; and others Phosphatases such as CTDP1, CTDSP1, CTDSP2, CTDSPL, DULLARD, EPM2A, ILKAP, MDSP, PGAM5, PHLPP1, PHPLPP2, PPEF1, PPE F2, PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPTC7, PTPMT1, S SU72, UBLCP1, PP1B, PP1A, PP2Aα / 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).

[0702] As used herein, "subject," "patient," or "individual" refers to any subject, patient, or individual, and the terms are used interchangeably herein. In this regard, the terms "subject," "patient," and "individual" include mammals and particularly humans. When used in conjunction with "in need thereof," the terms "subject," "patient," or "individual" refer to any subject, patient, or individual having a particular symptom or disorder or being at risk of a particular symptom or disorder.

[0703] 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 disorder. The terms "prevention", "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 disorder.

[0704] "Prodrugs" are drugs or compounds that are metabolized (i.e., converted in vivo) to pharmacologically active drugs (e.g., ENT-03 (Compound III)) after administration. In some embodiments, prodrugs include derivatives of ENT-03 (Compound III) in which alcohols and / or carboxylic acid esters have been esterified.

[0705] "Optionally substituted" refers to a group selected from the group and substituted forms of the group. A "substituted" group refers to a group substituted with a chemical substituent, such as replacing a CH bond with a bond between C and the substituent. In one embodiment, the substituent is selected from, for example, CF 3 、OCF 3 , halogen, halogenated aryl, C 1 -C 6 alkoxy, acyl, propionyl, butyryl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, carboxy ester, carboxy esteramino, (carboxy ester)oxy, haloalkyl, aryloxy, haloalkoxy, hydroxy, thiol, dihydroxy, aminohydroxy, carboxyl, amide, sulfoxy, sulfonyl, haloaryloxy, aryl, benzyl, benzyloxy, heteroaryl, nitrile, C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, C1 -C 6 Halogenated alkenyl, C 1 -C 6 Haloalkynyl, C 3 -C 6 Halogenated cycloalkyl, C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl, C 2 -C 10 Heterocyclic group, C 1 -C 10 Heteroaryl, -N 3 , nitro, -CO 2 H or its C 1 -C 6 Alkyl esters, and combinations thereof.

[0706] As used herein, "derivatives" refers to, for example, compounds III, III-P, IV and IV-P or salts or solvates thereof. "Derivatives" of ENT-03 (Compound III) may also refer to deuterated derivatives of ENT-03 (Compound III), such as ENT-03-d4 and ENT-03-d3 disclosed herein.

[0707] X. Example

[0708] Example 1: Activity of ENT-03 (Compound III) as an inhibitor of protein tyrosine phosphatase 1B (PTP1B)

[0709] This example tests the PTP1B inhibitory activity of ENT-03 (Compound III) and ENT-02 (MSI-1436). Also included are aminosterols D having the following structure: 7 Comparative data of the inhibitory activity of -1436 (D-1436):

[0710]

[0711] ENT-02 (MSI-1436), ENT-03 (Compound III) and D-1436 were dissolved in dimethyl sulfoxide (DMSO) to a stock concentration of 10 mM. The known PTP1B inhibitor 3-(3,5-dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonic acid-(4-(thiazol-2-ylsulfamoyl)-phenyl)-amide (Wiesmann et al., 2004) was used as a control. The compounds were diluted in 10 doses of IC in a single 3-fold serial dilution starting from 100 μM. 50The phosphatase activity was measured as a time-course measurement of the increase in the fluorescent signal from the fluorescent substrate, and the initial linear part of the slope (signal / min) was analyzed. No compound exhibited a fluorescent background that could interfere with the determination.

[0712] For the three tested aminosterols ( Figure 4A ) and control compound ( Figure 4B )Generate IC 50 When the activity of the highest concentration of the compound was less than 65%, curve fitting was performed.

[0713] As shown in Table 2, ENT-02 (MSI-1436), which is known to inhibit PTP1B, exhibited an IC of 2.89 μM. 50 ; ENT-03 (Compound III) exhibited an IC of 1.03 μM 50 ; D-1436 exhibited an IC of 2.09 μM 50 ; and the control PTP1B compound showed an IC of 2.47 μM 50 .

[0714]

[0715] The activity of ENT-03 and ENT-06 against a number of other phosphatases was also investigated. Both compounds were assayed in vitro against human phosphatases (Table 2B and Table 2C). The two compounds were 50 The compounds were found to be inactive against PP1A, PP1B, PP2Aα, PTPN6 and PTPN2.

[0716]

[0717] These data demonstrate that ENT-03 (Compound III) is a potent PTP1B inhibitor and has potential therapeutic utility known to be associated with PTP1B inhibitors.

[0718] Example 2: ENT-03 (Compound III) as a Weight Loss Agent in Mice

[0719] This example demonstrates that ENT-03 (Compound III) promotes weight loss in mice.

[0720] ENT-02 (MSI-1436) is known to induce weight loss through a mechanism involving certain brain circuits that control appetite. Trodoquiline causes weight loss and a switch to lipid oxidation when systemically administered to mice. The pharmacological target appears to be located in the hypothalamus, including the arcuate nucleus, median eminence, and paraventricular nucleus based on the localization of radioactive trodoquiline and cFos activation after intracerebroventricular administration (Ahima et al., 2002).

[0721] Studies of the structure activity relationship of ENT-02 for weight loss demonstrate the high degree of structural specificity required for this pharmacological action (Zasloff et al., 2001). For example, changing the chirality of spermine at C-3, the hydroxyl group at C-7, or the methyl group at C-21 abolishes weight loss. Activity is lost if spermine is replaced by spermidine or if the terminal amino group of spermine is methylated. In contrast, the two stereoisomers of sulfuric acid at C-24 are equally active, demonstrating a loose steric restriction around the anionic moiety, consistent with the activity observed for ENT-03.

[0722] To determine whether ENT-03 (Compound III) exhibits similar activity, male Swiss Webster mice (approximately 50 g, N=3 per group) previously fed ad libitum were treated intraperitoneally with 5 doses of ENT-02 (MSI-1436) or ENT-03 (Compound III) every other day at 10 mg / kg, e.g., on days 0, 2, 4, 6, 8, and 10. Food was provided ad libitum.

[0723] like Figure 1A , Figure 1B and Figure 2 As can be seen in the Figure 1, administration of ENT-03 resulted in weight loss with kinetics similar to that seen following administration of ENT-02. Administration of both compounds resulted in a decrease in body weight that reached a nadir at approximately day 16, followed by a gradual return to starting weight by approximately day 45. Although initial weight loss was similar for both compounds, by approximately day 10, the effects diverged, with ENT-02 causing a more severe decline. By day 27, both groups of treated mice had lost approximately 10% of their starting body weight.

[0724] These data demonstrate that ENT-03 (Compound III) exhibits similar pharmacological responses in terms of body weight as ENT-02 (MSI-1436) and suggest that ENT-03 (Compound III) may be useful for all known therapeutic applications associated with ENT-02 (MSI-1436) as well as other aminosterols.

[0725] In a second experiment, either compound was administered to approximately 25 gram growing male mice according to a similar dosing regimen. As in the previous experiments, both compounds affected body weight gain. Figure 2In the case of growing mice, however, ENT-02 had a more pronounced effect, inhibiting growth and inducing a loss of body fat. While animals treated with ENT-03 continued to grow normally, they “wasted away,” suggesting that ENT-03 reestablished a new optimal “set point” for body weight.

[0726] In the third experiment, Figure 1C As seen, intraperitoneal administration of ENT-03 to C57bl / 6 male mice once a week for 6 weeks resulted in a dose-dependent weight loss. Apart from the weight loss, the treated animals appeared clinically normal.

[0727] Finally, in the fourth experiment, Fig.14 As seen, intraperitoneal administration of ENT-03 (3 mg / kg, 5 mg / kg, 10 mg / kg or vehicle) once a week to C57bl / 6 male mice over 2 weeks caused a dose-dependent weight loss. Except for the weight loss, the treated animals appeared clinically normal.

[0728] These studies demonstrated that ENT-03 (Compound III) exhibited similarly potent pharmacological activity as ENT-02 in mice.

[0729] Example 3: Rejuvenation of the RNA transcriptome in the intestine

[0730] The purpose of this example was to evaluate the effects of oral administration of ENT-02 and ENT-03 (Compound III) on young and aged intestinal tissue.

[0731] Aging involves loss of gene expression in the intestine. Young mice (20 weeks, Figure 3 A) and old mice (78 weeks, Figure 3 Comparison of the images of mucosal tissue in the stomach of 78 weeks and 20 weeks of age shows that the thickness of the mucosal layer is reduced in the older samples. This reduction in mucosa is associated with a reduction in the RNA transcriptome in the stomach of old mice (78 weeks) versus young mice (20 weeks), see Table 3 below. This example evaluates the effects of oral administration of ENT-01 and ENT-02 on old mice.

[0732] The dosing regimen for determining the effects of oral administration of squalamine and ENT-02 on the gastrointestinal tract of young and old mice is as follows. Male C57Bl / 6 mice aged 20 and 78 weeks were obtained from Jackson labs. Animals were exposed to a 12h light-dark cycle and provided with Teklad standard mouse diet and free drinking water. Animals were assigned to the treatment groups shown in Table 3.

[0733]

[0734] Animals were dosed once daily by oral gavage in the morning for a total of 14 days. Animals were fasted 3-4 hours before and at least 1 hour after dosing, and not to exceed 6 hours. The test article was dissolved in 0.5% hydroxypropylcellulose in water. On day 15, the test article was administered by CO 2 Animals were euthanized by asphyxiation, necropsied, and tissues prepared for histology and RNAseq analysis.

[0735] The gastrointestinal tract of the animals was segmented into stomach, duodenum, jejunum, ileum, cecum, colon and rectum. The tissues were then sent for histological examination and the transcriptome was analyzed by RNAseq. Table 4 shows the corresponding mRNA amounts in the stomach of young and old mice.

[0736] As shown in Table 5A below, the mRNA levels of all genes in the table showed a significant increase after treatment with squalamine (ENT-01). It is also noteworthy that while ENT-03 stimulates the induction of the transcriptome of these segments of the gastrointestinal tract of older mice, it has minimal effects in younger animals, corresponding to slight inhibition or induction of certain genes not associated with aging. Perhaps, ENT-03 is supplementing deficiencies in older mice that are not present in younger animals. This suggests that squalamine (ENT-01) and, by extension, structurally related aminosterols such as ENT-03 (Compound III) and its derivatives have a rejuvenating effect in the intestine.

[0737]

[0738]

[0739]

[0740] Applicants also investigated transcriptome changes within various segments of the gastrointestinal tract. Following oral administration to aged mice, the abundance of transcripts for genes that decrease with aging increased in the stomach, jejunum, and ileum, in some cases reaching levels observed in younger individuals, such as Figures 6A-6C shown.

[0741] 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. During this time period, clinical observations were not obvious, as were gross and microscopic examinations of the gastrointestinal tract. The transcriptomes of the stomach, jejunum, and ileum were analyzed by RNAseq technology. Comparative analysis of transcripts from untreated animals identified many transcripts that differed in abundance between the corresponding tissues from old and young individuals. Differential expression of 86 gastric transcripts was observed (p(adj)<0.05): 70 decreased and 16 increased with aging; in the case of the jejunum, more than 400 transcripts decreased and 200 increased with aging; and for the ileum, 700 transcripts decreased and 400 increased with aging. Therefore, in these three different regions of the mouse gastrointestinal tract, aging is associated with changes in the transcriptome.

[0742] When the effects of oral administration of ENT-03 on the transcriptome of tissues were examined, in each case a blunted transcriptional response was observed in young animals compared to that in aged animals ( Figures 6A-6C ). For example, in the stomach of young animals treated, 13 genes were differentially expressed (p(adj)<0.05), while in the old group it was 63 genes. Similarly, for the jejunum, 42 genes were differentially expressed in the young group, and 382 genes in the treated old group. In the ileum, 80 genes were differentially expressed in young animals treated with ENT-03, and 1162 genes were differentially expressed in old animals.

[0743] Next, the set of genes (DEGs) differentially expressed with aging was compared with the set of genes differentially expressed in the old animals or young animals of treatment. The analysis of overlapping DEGs between contrasts revealed that, for example, in the stomach, 37 genes (old to young) that were downregulated in aging significantly overlapped with genes upregulated by ENT-03 treatment in old mice (P < 0.0001, hypergeometric test). In contrast, the only significant overlap between the genes in the stomach of gastric aging genes and young ENT-03 treatment was 12 genes, which were further downregulated in the aging direction.

[0744] The "senescent" genes that ENT-03 appears to most significantly replenish in the stomach are listed in Table 5B. Notably, in the stomach, the "restored" senescent genes include genes involved in tissue renewal (fibroblast growth factor 2; zinc finger protein 383; forkhead box C2); genes involved in neuronal differentiation (neural cell adhesion molecule 2); genes involved in immunity (toll-like receptors 9 and 12; interleukin 2 receptor beta chain), genes involved in neurotransmitter synthesis and uptake (choline and serotonin transporters), and genes involved in mitochondrial respiration (cytochrome c oxidase subunit 6B2).

[0745]

[0746] First, genes whose expression was significantly changed between young and old mice (FDR-adjusted p-value < 0.05) were identified ( Fig. 6A ). With aging, the expression of 75 genes in the stomach was significantly decreased, and the expression of 11 genes was significantly increased ( Fig. 6A ). Meanwhile, smaller 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 5 genes decreased and expression of 2 genes increased with aging. In the ileum, expression of 19 genes decreased and expression of 9 genes increased. These results are consistent with the well-established reduced regenerative capacity of the stomach in aging rodents (Fukunaga et al., 1998) and the ability of the small intestine to recover with aging (Eswaran et al., 2006).

[0747] After oral administration of ENT-03 to young mice (20 weeks), 13 gastric genes responded, and all genes were transcriptionally repressed by ENT-03 treatment ( Figure 6B ). For both young and old mice, the expression of no more than 2 genes changed significantly in response to ENT-03 exposure in the jejunum and ileum.

[0748] In contrast, more robust effects on gene expression in the stomach were observed in older animals (78 weeks) treated with ENT-03. 63 genes were transcriptionally induced (FDR adjusted p < 0.05) ( Figure 6CInterestingly, the 36 genes whose expression increased after ENT-03 treatment of old mice were the same genes whose expression decreased with aging. These included genes involved in tissue turnover (fibroblast growth factor 2 (Fgf2); zinc finger protein 382 (Zfp382), and forkhead box C2 (Foxc2)); genes involved in neuronal differentiation (neural cell adhesion molecule 2 (Ncam2)); genes involved in immunity (toll-like receptors 9 and 12 (Tlr9, Tlr12), interleukin 2 receptor beta chain (Il2rb), and CD300 (Cd300ld)); genes involved in neurotransmitter synthesis and uptake (choline and serotonin transporters (Slc5a7, Slc6a4)) and genes involved in mitochondrial respiration (cytochrome c oxidase subunit 6B2 (Cox6b2)).

[0749] Statistical analysis of RNA sequencing data was performed using the R programming language. Transcripts with less than one read count per million reads were removed from all samples of each tissue. The raw count data of the samples were then normalized using the trimmed mean of the M value normalization and transformed using voom (Law et al., 2014) to obtain logarithmic squares with associated precision weights. 2 Counts per million are converted. Normalized data provide input for statistical hypothesis testing, wherein genes significantly different between sample groups are identified. Statistical comparisons are performed using linear modeling, as implemented in Bioconductor package limma (Ritchie et al., 2015). The significance values ​​(p-values) of multiple tests are adjusted using the Benjamini-Hochberg program (Benjamini et al., 1995). For each comparison (e.g., group A vs. group B), the positive log2 conversion fold change indicates that group A is upregulated relative to group B.

[0750] In order to study the overlap between contrasts, the number of differentially expressed genes overlapping between all paired combinations compared was counted (defined using adjusted p-value < 0.05). For each comparison, the Jacquard index (defined as intersection ratio union) measures the similarity between the two contrasts considered. Under the assumption that contrast and gene are independent, the p-value is calculated using a hypergeometric test taking into account the size of the universe.

[0751] Fig.11 A set of heatmaps investigating the overlap of differentially expressed genes between pairs of alignments is shown.

[0752] These data support the hypothesis that oral administration of ENT-03 to aged mice can reverse some of the changes in gene expression associated with aging within the gastrointestinal tract.

[0753] Example 4: Pharmacokinetic study of ENT-03 (Compound III) by intravenous and oral administration

[0754] The purpose of this example was to determine the pharmacokinetic characteristics of ENT-03 (Compound III) in male SD rats by intravenous and oral administration.

[0755] The study groups are shown in Table 6 below.

[0756]

[0757] *: A salt factor of 1.177 was used for the formulation preparation of Compound III.

[0758] Animal feeding control: Animals were fasted overnight before dosing and fed 4 hours after administration with free access to water.

[0759] Dose Formulation Handling During Dosing: The dose formulation was kept under stirring at room temperature and used within 2 hours.

[0760]

[0761]

[0762] NOTE: Unscheduled clinical observations (cage-side or detailed) were also performed as needed.

[0763]

[0764] PK sample analysis: LC-MS / MS method was used to analyze the concentration of ENT-03 (Compound III) in plasma and dose samples. WinNonlin (Phoenix TM , Version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated from the data of the relationship between plasma concentration and time as much as possible.

[0765] Intravenous push administration: T 1 / 2 , C 0 , AUC 最后 , AUC inf , MRT inf ,Cl,Vss,number of points used for regression.

[0766] Oral administration: F, T 1 / 2 , C max 、T max , AUC inf , AUC 最后 , MRT inf , the number of points used for regression.

[0767] Descriptive statistics such as mean and standard deviation were used to describe the pharmacokinetic data. After testing, all remaining biological samples were stored in a refrigerator (-75°C ± 15°C) for a period of 6 months. The results are listed in Table 14 below.

[0768]

[0769] Example 5: Synthetic method for preparing ENT-03

[0770] This example describes...

Claims

1. An aminosterol compound having the formula: in: R 1 is H or D; and R 2 is H or D; All R 1 All H or All R 2 They are all H. or a pharmaceutically acceptable salt thereof.

2. The aminosterol compound according to claim 1, which has the following formula: or a pharmaceutically acceptable salt thereof.

3. The aminosterol compound according to claim 1, which has the following formula: or a pharmaceutically acceptable salt thereof.

4. The aminosterol compound according to claim 1, which has the following formula: or a pharmaceutically acceptable salt thereof.

5. The aminosterol compound according to claim 1, which has the following formula: or a pharmaceutically acceptable salt thereof.

6. An aminosterol compound having the formula: in: R 1 is H, aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkynyl, heterocyclyl, C3-C8 cycloalkyl or C1-C6 alkenyl; and R 2 is H or -C(O)R 3 , where R 3 is aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkynyl, heterocyclyl, C3-C8 cycloalkyl or C1-C6 alkenyl; The condition is R 1 and R 2 At least one of them is not H, or a pharmaceutically acceptable salt thereof.

7. The aminosterol compound according to claim 6, which has the following formula: or a pharmaceutically acceptable salt thereof.

8. The aminosterol compound according to claim 7, which is a phosphate.

9. A composition comprising the aminosterol compound according to any one of claims 1 to 7 and at least one pharmaceutically acceptable carrier or excipient.

10. The composition according to claim 9, comprising one or more of the following: (a) an aqueous carrier; (b) a buffer; (c) sugar; and / or (d) Polyol compounds.

11. The composition of claim 9, wherein the composition further comprises at least one additional active agent.

12. The composition according to claim 9, wherein the composition is formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, aerosol, inhalation, ocular, otic, topical, buccal, nasal and external administration; (b) in 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; (c) in a dosage form selected from the group consisting of a controlled release formulation, a fast melt formulation, a delayed release formulation, an extended release formulation, a pulsatile release formulation, and a mixed immediate and controlled release formulation; or (d) Any combination of (a), (b) and (c).

13. The composition of claim 12, formulated for oral administration.

14. The composition according to claim 13, formulated as an oral tablet or capsule.

15. The composition of claim 12, formulated for intranasal administration.

16. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for treating a condition susceptible to aminosterol treatment.

17. Use according to claim 16, wherein the condition is associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction.

18. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for treating, preventing and / or slowing the onset or progression of a condition or disorder or associated symptoms associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction in a subject in need thereof.

19. The use according to claim 18, wherein (a) the symptom is selected from constipation, hallucinations, cognitive impairment and inflammation; (b) the symptoms are associated with synucleinopathy, a neurodegenerative disease, a nervous system disease or disorder, a psychological and / or behavioral disorder, or a cerebral or systemic ischemic disorder or condition; or (c) the condition or disorder is a synucleinopathy, a neurodegenerative disease, or a disease or disorder of the nervous system; (d) the condition or disorder is a psychological and / or behavioural disorder; or (e) The condition or disorder is a cerebral or systemic ischemic disorder or condition.

20. The use according to claim 19, wherein (a) the synucleinopathy, neurodegenerative disease, or nervous system disease or disorder is selected from 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, Guadeloupe Parkinson's disease, spinocerebellar ataxia, and traumatic brain injury; (b) the mental or behavioral disorder is selected from depression, autism spectrum disorder, Down syndrome, Gaucher disease, Krabbe disease, lysosomal disorders affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delusions, amnesia, apathy, bipolar disorder, disinhibition, abnormal movements and compulsive behaviors, addiction, cerebral palsy, epilepsy, major depressive disorder, and a sleep disorder selected from REM sleep behavior disorder, sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, and cognitive impairment; or (c) the cerebral or systemic ischemic disorder or condition is selected from microangiopathy, cerebral ischemia during labor, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia due to problems during surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, high cholesterol, myocardial infarction, heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, hypertension, hypotension, and pulmonary edema.

21. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for treating, preventing and / or slowing the onset or progression of cerebral or systemic ischemic disorders and / or related symptoms associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction in a subject in need thereof.

22. The method of claim 21, wherein the cerebral or systemic ischemic disorder and / or related symptoms are selected from microangiopathy, cerebral ischemia during labor, cerebral ischemia during cardiac arrest or resuscitation / after, cerebral ischemia due to problems during surgery, chronic cerebral ischemia due to stenosis of the arteries supplying the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypertension, hypotension, high cholesterol, myocardial infarction, heart failure, myocarditis, pericarditis, pericardial myocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, thrombosis associated with malaria, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, and pulmonary edema.

23. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for inhibiting one or more regulatory phosphatases, wherein the one or more regulatory phosphatases include PTP1B, PTPRC / CD45, DUSP22 / MKPX, PTPN7 / LC-PTP, PTPN12 / PTP-PEST, PTPN1 / PTP1B-CD, PTPN11 / SHP2, PTPN11 / SHP2-FL, or PTPN11 / SHP2-FL with E76K mutation.

24. The use according to claim 23, wherein the regulatory phosphatase comprises PTP1B.

25. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for inhibiting, preventing and / or slowing the onset or progression of appetite or weight gain and / or one or more related symptoms in a subject in need thereof.

26. The use of claim 16, wherein the medicament is formulated for oral administration, nasal administration, sublingual administration, buccal administration, rectal administration, vaginal administration, intravenous administration, intraarterial administration, intradermal administration, intraperitoneal administration, intrathecal administration, intramuscular administration, epidural administration, intracerebral administration, intracerebroventricular administration, transdermal administration, or any combination thereof.

27. The use according to claim 26, wherein the medicament is formulated for nasal administration, oral administration or a combination thereof.

28. The use according to claim 16, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt thereof comprises: (a) 0.1 to 20 mg / kg of the subject's body weight; (b) 0.1 to 15 mg / kg of the subject's body weight; (c) 0.1 to 10 mg / kg of the subject's body weight; (d) 0.1 to 5 mg / kg body weight of the subject; or (e) 0.1 to 2.5 mg / kg body weight of the subject.

29. The use according to claim 16, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt thereof comprises: (a) 0.001 to 500 mg / day; (b) 0.001 to 250 mg / day; (c) 0.001 to 125 mg / day; (d) 0.001 to 50 mg / day; (e) 0.001 to 25 mg / day; (f) 0.001 to 10 mg / day; (g) 0.001 to 6 mg / day; (h) 0.001 to 4 mg / day; or (i) 0.001 to 2 mg / day.

30. The use according to claim 16, wherein the medicament is formulated for oral administration, and wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt thereof comprises: (a) 1 to 300 mg / day; or (b) 25 to 500 mg / day.

31. The use according to claim 16, wherein the aminosterol compound or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional active agent to achieve an additive or synergistic effect.

32. The use according to claim 31, wherein the additional active agent is administered by a method selected from one of the following: (a) the accompanying land; (b) as a mixture; (c) individually and simultaneously or concurrently; and (d) Individually and sequentially.

33. The use according to claim 31, wherein the additional active agent is a second aminosterol having a different structure than the aminosterol administered in the use according to claim 16.

34. The use according to claim 16, wherein the administration of the medicament comprises administration on an empty stomach.

35. The use according to claim 34, wherein the administration of the drug is administered within two hours after the subject wakes up.

36. The use according to claim 16, wherein the subject does not consume food after 60 to 90 minutes from administration of the medicament.

37. The use according to claim 16, wherein the aminosterol or a pharmaceutically acceptable salt thereof is of pharmaceutically acceptable grade.

38. Use according to claim 37, wherein the phosphate salt of the aminosterol is administered.

39. The use according to claim 16, further comprising: (a) determining a dose of the aminosterol or a pharmaceutically acceptable salt 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 resolving the evaluated symptom, (b) then administering to the subject a composition comprising said dose of said aminosterol for a period of time, wherein said use comprises: (i) identifying symptoms to be evaluated, wherein the symptoms are susceptible to aminosterol treatment; (ii) identifying a starting dose of an aminosterol for said subject; (iii) administering increasing doses of the aminosterol to the subject over a period of time until an effective dose for the evaluated symptom is identified, wherein the effective dose is the dose of the aminosterol at which improvement or regression of the symptom is observed, and fixing the dose of the aminosterol at that level for the particular symptom for the particular subject.

40. The use according to claim 39, wherein the improvement or regression of the symptoms is measured using a clinically accepted scale or tool.

41. The use according to claim 39, wherein the composition is administered orally and: (a) the initial aminosterol dose ranges from 10 mg to 150 mg / day; (b) the aminosterol dose for the subject after escalation is fixed within the range of from 25 mg to 500 mg / day; and / or (c) The dose of the aminosterol or its salt or derivative is increased in increments of 25 mg.

42. The use according to claim 39, wherein the composition is administered intranasally and: (a) the initial aminosterol dose ranges from 0.001 mg to 3 mg / day; (b) the aminosterol dose for the subject is fixed at from 0.001 mg to 6 mg / day after escalation; (c) the escalated aminosterol dose to the subject is subtherapeutic when administered orally or by injection; and / or (d) the dose of the aminosterol is increased in increments of 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mg.

43. The use according to claim 39, wherein the dose of the aminosterol is increased every 3 to 5 days.

44. The use according to claim 39, wherein the symptoms are associated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

45. The use according to claim 39, wherein the symptom to be evaluated is selected from: (a) 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 following: cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, pain, urinary problems, constipation problems, dizziness on standing, and fatigue; (b) at least one motor aspect of the experience of daily living as defined by Part II of the Unified Parkinson's Disease Rating Scale selected from the following: speech, saliva and drooling, chewing and swallowing, feeding tasks, dressing, hygiene, handwriting, turning over in bed, tremors, getting out of bed, car, or deep chair, walking and balance, and freezing; (c) at least one motor symptom identified in Part III of the Unified Parkinson's Disease Rating Scale selected from the following: speech, facial expression, rigidity, hand movement, toe tapping, leg agility, rising from a chair, gait, gait stiffness, posture, bradykinesia, resting tremor amplitude, and persistence of resting tremor; (d) at least one motor complication identified in Part IV of the Unified Parkinson's Disease Rating Scale selected from the following: duration of dyskinesias, functional impact of dyskinesias, time in the off state, functional impact of fluctuations, complexity of movement fluctuations, and painful off-state dystonia; (e) Constipation; (f) depression; (g) cognitive impairment; (h) Sleep problems or sleep disturbances; (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) Temperature regulation; (t) Improvement of breathing or apnea; (u) Correction of cardiac conduction defects; (v) improvement in pain; (w) restoration of bladder sensation and urination; (x) urinary incontinence; and / or (y) Control of nocturia.

46. ​​The use according to claim 45, wherein the symptom to be assessed is constipation, and wherein: (a) a fixed ascending aminosterol dose for constipation is defined as the aminosterol dose that results in complete spontaneous defecation within 24 hours of administration on at least 2 of 3 days at a given dose; (b) if mean complete spontaneous bowel movements or mean spontaneous bowel movements are greater than or equal to 1 / week, the initial aminosterol dose prior to titration is 75 mg / day; and / or (c) If mean complete spontaneous bowel movements or mean spontaneous bowel movements are less than 1 / week, the initial aminosterol dose before titration is 150 mg / day.

47. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1 to 7 for the preparation of a medicament for increasing gene transcription in the intestine of a subject.

48. The use according to claim 47, wherein the increase in gene transcription is for one or more genes selected from the group consisting of caspase 14, type XVII collagen alpha 1, corneal desmosin, keratin, cystatin E / M, skin factor, desmocollin 1, desmocollin 1β, filaggrin, connexin β4, connexin β6, H19 imprinted maternally expressed transcript, keratin, kallikrein-related peptidase 7 chymotrypsin layer, keratin 1, keratin 10, keratinocyte differentiation-associated protein, proline-rich expressed by keratinocytes, advanced cornified envelope 1A1, advanced cornified envelope 1A2, advanced cornified envelope 1B, advanced cornified envelope 1C, late cornified envelope 1E, late cornified envelope 1F, 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, soluble galactose-binding lectin 7, loricrin, cornified envelope precursor protein, myoglobin, slow myosin binding protein C, myosin heavy polypeptide 1 skeletal muscle, myosin heavy polypeptide 8 skeletal muscle, myosin light chain phosphorylated fast ske, myosin light polypeptide 3, myomodulin 1, myomodulin 2, and titin-cap.

49. The use according to claim 47, wherein the increase in gene transcription is selected from 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 100%, 100% to 125%, 125% to 150%, 150% to 160%, 170% to 200%, 180% to 210%, 180% to 220%, 180% to 230%, 180% to 240%, 180% to 250%, 180% to 260%, 180% to 270%, 180% to 280%, 180% to 290%, 190% to 200%, 200% to 210%, 200% to 220%, 200% to 250%, 200% to 260%, 200% to 270%, 200% to 280%, 200% to 290%, 0% to 175%, 175% to 200%, 200% to 250%, 250% to 300%, 300% to 350%, 350% to 400%, 400% to 450%, 500% to 600%, 600% to 700%, 700% to 800%, 800% to 900%, 900% to 1000%, or 1000% to 1500%.

50. Use of a therapeutically effective amount of an aminosterol compound according to any one of claims 1-7 for the preparation of a medicament for inhibiting one or more regulatory phosphatases to achieve therapeutic or prophylactic benefit, wherein the one or more regulatory phosphatases include PTP1B, PTPRC / CD45, DUSP22 / MKPX, PTPN7 / LC-PTP, PTPN12 / PTP-PEST, PTPN1 / PTP1B-CD, PTPN11 / SHP2, PTPN11 / SHP2-FL, or PTPN11 / SHP2-FL with an E76K mutation.

51. A method for producing an aminosterol of the formula: The method comprises stimulating the addition of spermine to compound Ia:

52. The method of claim 51, wherein (a) the aminosterol is produced in the subject; or (b) The aminosterol is produced in vitro.

53. A method of inhibiting the formation of an aminosterol of the formula: The method comprises inhibiting the addition of spermine to compound Ia:

54. The method of claim 53, wherein (a) inhibiting the addition of spermine to Compound Ia in a subject; or (b) Inhibition of spermine addition to compound Ia in vitro.

55. The method of any one of claims 51-54, wherein compound Ia has the formula: And ENT-03 has the following formula:

56. A method for producing an aminosterol of the formula: The method comprises stimulating the addition of spermine to compound Ia:

57. The method of claim 56, wherein (a) the aminosterol is produced in the subject; (b) The aminosterol is produced in vitro.

58. A method of inhibiting the formation of an aminosterol of the formula: The method comprises inhibiting the addition of spermine to compound Ia:

59. The method of claim 58, wherein (a) inhibiting the addition of spermine to Compound Ia in a subject; or (b) Inhibition of spermine addition to compound Ia in vitro.

60. The method of any one of claims 56-59, wherein compound Ia has the formula: And compound IV has the following formula:

61. A method for producing an aminosterol of the formula: The method comprises stimulating the addition of spermine to compound Ia:

62. The method of claim 61, wherein (a) the aminosterol is produced in the subject; or (b) The aminosterol is produced in vitro.

63. A method of inhibiting the formation of an aminosterol of the formula: The method comprises inhibiting the addition of spermine to compound Ia:

64. The method of claim 63, wherein (a) inhibiting the addition of spermine to Compound Ia in a subject; or (b) Inhibition of spermine addition to compound Ia in vitro.

65. The method of any one of claims 61-64, wherein compound Ia has the formula: And compound V has the following formula:

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