Aminosterol compounds, aminosterol-cyclodextrin formulations, and methods of using same

Abstract

Novel aminosterol compounds and additional aminosterol-cyclodextrin formulations suitable for injection administration are described, as well as methods of using the same.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 356,910 filed on June 29, 2022; U.S. Provisional Application No. 63 / 459,107 filed on April 13, 2023; and U.S. Provisional Application No. 63 / 461,875 filed on April 25, 2023, the contents of which are specifically incorporated by reference. Technical Field

[0002] The present application relates generally to novel aminosterol compounds, aminosterol-cyclodextrin compositions, and methods of treatment using these compounds and compositions. Background Art

[0003] Aminosterols are amino derivatives of sterols. Exemplary aminosterols include squalamine (ENT-01) and aminosterol 1436 (ENT-02) (also known as trodusquemine and MSI-1436). These aminosterols were discovered by Michael Zasloff in the spiny dogfish shark Squalus acanthias (U.S. Patent No. 5,192,756), and they exhibit multiple pharmacological activities in mammalian systems. Aminosterol 1436 exhibits pharmacological effects in vertebrates, causing weight loss and adipose tissue mobilization (Zasloff et al., 2001). Squalamine has antiviral, antibiotic, antifungal and anticancer activities, and inhibits the aggregation of α-synuclein, which is unique in Parkinson's disease.

[0004] Other recently described aminosterols include (1) ENT-03 and ENT-05 (US-2023 / 0123701), (2) ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, and ENT-11 (US2023 / 0125585), and (3) ENT-06 (US2022 / 0372066).

[0005] It is well known that the stereochemical purity of drugs is important in certain therapeutic agents, and single enantiomers or compounds with stereodefinition at key carbon centers may provide greater selectivity for their biological targets, improved therapeutic index and / or better pharmacokinetics compared to isomeric mixtures.

[0006] There is a need in the art for new aminosterol compounds, as these compounds are useful in treating a variety of human diseases. There is also a need in the art for new pharmaceutical formulations of aminosterols, as aminosterol compounds are useful in treating a variety of human diseases. The present invention satisfies these needs. Summary of the invention

[0007] In one aspect, disclosed are compounds designated as ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also referred to as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, ENT-22, ENT-22S, ENT-22R, ENT-22 mixed isomers, ENT-23, ENT-24, ENT-25 -24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, aminosterol compound A, aminosterol compound B and aminosterol compound C or their pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives, the structure of each compound is shown below: as well as

[0008] In another aspect, an aminosterol compound having the following chemical structure (Formula (I)) is disclosed: in: R 1 is optionally substituted C1-C8 alkyl, optionally substituted 2 to 8-membered heteroalkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; R 2 H or -C(O)R 5 , where R 5is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; and R 3 and R 4 are each independently H or optionally substituted 2 to 14-membered heteroalkyl; or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof; Wherein the compound is not: (1) (24R)-3β-({3-[(3-aminopropyl)amino]propyl}amino)-7α-hydroxycholestane-24-yl hydrosulfate (squalamine); (2) (3R,6R)-6-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptyl-3-hydrogen sulfate (aminosterol 1436); (3) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (ENT-03); (4) (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-03); (5) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptyl-2,3,3-d3 acid (ENT-03d3); (6) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-(benzoyl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (7) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (8) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (9) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (10) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (11) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (12) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2-d-ol; (13) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (14) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (15) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (16) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (17) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (18) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (19) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (20) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (21) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylhept-2-enoic acid; (22) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (23) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (24) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-hydroxy-2-methylheptanoic acid; (25) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (26) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (27) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (28) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (29) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)heptan-3-one; (30) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (31) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (32) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (33) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (34) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (35) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (36) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (37) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (38) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (39) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (40) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (41) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (42) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (43) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (44) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (45) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (46) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (47) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2,3-diol; (48) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2,3-diol; (49) (3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylheptane-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (50) (3S, 5R, 7R, 10S, 13R, 17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylhept-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (51) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-05); (52) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-06); (53) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-ammoniopropyl)ammonio)butyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoate-2,3-d2; (54) (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-03); (55) (2R,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (56) (2S,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (57) (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-06); (59) (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-06); (60) (6R)-6-((3S,5R,7R,10S,13R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-squalamine); (61) (3R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthran-17-yl)-2-methylheptane-3-yl hydrosulfate-3-d (24-D1-squalamine); or (62) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-1436).

[0009] In another aspect, the aminosterol has a structure of formula (I), wherein R 1 Selected from

[0010] In another aspect, the aminosterol has a structure of formula (I), wherein R 2 For H.

[0011] In another aspect, the aminosterol has a structure of formula (I), wherein R 3 and R 4 Independently selected from H,

[0012] In another aspect, the aminosterol has a structure of formula (I), wherein R 3 is H, and R 4 Independently selected from

[0013] In some embodiments, the compounds disclosed herein are 25 The carbon has a diastereomeric excess (de) of about 80% to about 90%, about 90% to about 95%, about 95% to about 99%, about 99% to about 99.9%, or about 100%.

[0014] In another aspect, deuterated aminosterol compounds are described, wherein at least one hydrogen of the aminosterol compounds described herein is replaced with deuterium.

[0015] In one aspect, a composition is provided, comprising an aminosterol compound disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises one or more of the following: an aqueous carrier; a buffer; a sugar; and / or a polyol compound. In some embodiments, the composition comprises at least one additional active agent.

[0016] In some embodiments, the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is of pharmaceutically acceptable grade.

[0017] In some embodiments, the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is in the form of a phosphate, hydrochloride or sodium salt.

[0018] In some embodiments, the composition is formulated for: (a) 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) a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, and capsules; (c) a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, and mixed immediate and controlled release formulations; or (d) any combination of (a), (b), and / or (c).

[0019] 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.

[0020] In another aspect of the present disclosure, an aqueous aminosterol formulation is contemplated, comprising: (a) an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, or derivative thereof; and (b) a cyclodextrin, wherein the formulation is buffered to a pH of about 4 to 9, and wherein the cyclodextrin reversibly binds to a molecule of the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof to form a cyclodextrin-aminosterol complex. The cyclodextrin may be, for example, β-cyclodextrin (such as unmodified β-cyclodextrin) or γ-cyclodextrin (such as unmodified γ-cyclodextrin). In other aspects, the cyclodextrin may be sulfobutyl ether-β-cyclodextrin (SBE-β-CD).

[0021] In another aspect of the present disclosure, the pH may be from about 5 to about 8 or from about 7 to about 8. In one embodiment, the pH may be from about 7.3 to about 7.5, such as 7.4.

[0022] In one embodiment of the present disclosure, the buffer may be selected from the following: acetate buffer, phosphate buffer, citrate buffer, histidine buffer, tris(hydroxymethyl)aminomethane (TRIS), sodium phosphate, citric acid, acetic acid, KH2PO4, CHES, borate, tromethamine, gluconic acid, lactic acid, tartaric acid, aspartic acid, glutamic acid, citric acid cycle intermediates, [tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), N-[tris(hydroxymethyl)methyl] Glycine (Tricine), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TABSO), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]amino]ethanesulfonic acid (TES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES), dimethylarsonic acid (Cacadylate) and 2-(N-morpholino)ethanesulfonic acid (MES). In one aspect, the aqueous aminosterol preparation is buffered with phosphate. In another aspect, the aqueous aminosterol preparation can be buffered with tris(hydroxymethyl)aminomethane (Tris).

[0023] In another embodiment of the present disclosure, the cyclodextrin may be present in an amount of about 10% to about 40%, about 15% to about 30%, about 18% to about 25%, or about 20% to about 25%. In addition, the cyclodextrin may be present in an amount of about 20% to about 25%.

[0024] In another embodiment of the present disclosure, the aminosterol can be present in an amount of about 20 mg / ml to about 75 mg / ml. In another aspect, the aminosterol can be present in an amount of about 30 mg / ml to about 65 mg / ml, about 40 mg / ml to about 55 mg / ml, or about 50 mg / ml.

[0025] In another aspect of the present disclosure, the ratio of the concentration (in mg / ml) of the aminosterol to the cyclodextrin may be about 0.1 to about 0.75. In addition, the ratio of the concentration (in mg / ml) of the aminosterol to the cyclodextrin may be about 0.15 to about 0.5, or the ratio of the concentration (in mg / ml) of the aminosterol to the cyclodextrin may be about 0.20.

[0026] In another aspect of the present disclosure, the aqueous aminosterol formulation is for intravenous, subcutaneous or intramuscular administration.

[0027] In another embodiment of the present disclosure, the aminosterol is any aminosterol as described herein, including but not limited to ENT-01, squalamine phosphate, ENT-02 (aminosterol 1436), ENT-03, ENT-03S (C 25 (S)ENT-03)、ENT-03R(C 25 (R)ENT-03), ENT-03 mixed isomers, ENT-04, ENT-05, ENT-06, ENT-07, ENT-08, ENT-09, ENT-10, ENT-11, ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also known as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, ENT-22, ENT-23, ENT-24 T-22S, ENT-22R, ENT-22 mixed isomers, ENT-23, ENT-24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, aminosterol compound A, aminosterol compound B and aminosterol compound C, or one of their pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives, the structure of each compound being shown below: as well as

[0028] In one embodiment of the present disclosure, the aminosterol is ENT-03S. In another aspect, the aminosterol may be ENT-03R. In another aspect, the aminosterol is racemic ENT-03.

[0029] In another aspect of the present disclosure, the aqueous aminosterol formulation comprises 50 mg / ml of any aminosterol compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, and about 20 to about 23% SBE-β-CD, buffered with Tris to pH 7.3-7.5.

[0030] In another aspect of the present disclosure, the aqueous aminosterol formulation comprises 50 mg / ml ENT-03R and about 20 to about 25% 2HPβ-CD, buffered to pH 7.3-7.5 with phosphate. In another aspect of the present disclosure, the aqueous aminosterol formulation comprises 50 mg / ml ENT-03S and about 20 to about 25% 2HP-β-CD, buffered to pH 7.3-7.5 with phosphate.

[0031] In another aspect of the present disclosure, the aqueous aminosterol formulation comprises 50 mg / ml of a racemic aminosterol compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.5.

[0032] In another aspect, the aqueous aminosterol formulation includes 50 mg / ml racemic ENT-03 and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.5.

[0033] The cyclodextrin formulations may also include deuterated aminosterol compounds, wherein at least one hydrogen of the aminosterol compound as described herein is replaced with deuterium.

[0034] In one aspect, a method of treating a subject in need thereof suffering from a condition susceptible to aminosterol treatment is provided, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug or derivative or composition thereof, including but not limited to the aminosterol-cyclodextrin compositions described herein.

[0035] In some embodiments, the condition is associated with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction. In another aspect, the condition is associated with protein misfolding. For example, the misfolded protein may be alpha-synuclein, tau, and / or amyloid-β.

[0036] In one aspect, a method for treating, preventing and / or slowing down the occurrence or progression of a condition or disorder or associated symptoms associated with abnormal α-synuclein pathology, dopaminergic dysfunction and / or protein misfolding in a subject in need thereof is provided. The method comprises administering a therapeutically effective amount of an aminosterol compound or composition described herein, including but not limited to an aminosterol-cyclodextrin composition. In some embodiments, the associated symptoms: (a) are selected from the following: constipation, hallucinations, cognitive impairment, and inflammation; and / or (b) are associated with a neurosynaptic disease, a neurodegenerative disease, a neurological disease or disorder, a psychological and / or behavioral disorder, or a brain or systemic ischemic condition or disorder; and / or (c) the condition or disorder may be a neurosynaptic disease, a neurodegenerative disease, a neurological disease or disorder, a psychological and / or behavioral disorder, or a brain or systemic ischemic condition or condition.

[0037] In some embodiments, (a) the neurosynaptic disease, neurodegenerative disease, or nervous system disease or disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, schizophrenia, multiple system atrophy, Lewy body dementia, Lewy body dementia, 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, Guadeloupian Parkinsonism, spinocerebellar ataxia, parkinsonism, traumatic brain injury, degenerative processes associated with aging, and Alzheimer's disease; and (b) the psychological or behavioral disorder is selected from the group consisting of depression, autism, autism spectrum disorder, Down syndrome, Gaucher's disease, disease), Krabbe's disease, lysosomal disorders affecting glycosphingolipid metabolism, ADHD, ADD, agitation, anxiety, delirium, irritability, hallucinations and delusions, 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 disorder, sleep apnea, and cognitive impairment; or (c) the cerebral or systemic ischemic disorder or condition is selected from the following: microangiopathy, cerebral ischemia during delivery, cerebral ischemia during / after cardiac arrest or resuscitation, intraoperative problems Cerebral ischemia caused by arterial stenosis, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia caused by stenosis of cerebral blood supply arteries, 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, acromial ischemia, renal artery stenosis, diabetic retinopathy, malaria-related thrombosis, artificial heart valves, anemia, hypersplenism, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, hypertension, hypotension and pulmonary edema.

[0038] In one aspect, a method of 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, dopaminergic dysfunction and / or protein misfolding in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of an aminosterol compound or composition disclosed herein, including but not limited to an aminosterol-cyclodextrin composition.

[0039] In one aspect, a method of inhibiting one or more regulatory phosphatases in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound or composition disclosed herein. In some embodiments, the regulatory phosphatases include one or more of 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; cofilin phosphatases (slingshots) such as SSH1, SS H2 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 Other phosphatases such as CTDP1, CTDSP1, CTDSP2, CTDSPL, DULLARD, EPM2A, ILKAP, MDSP, PGAM5, PHLPP1, PHPLPP2, PPEF1, PPEF2, PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPTC7, PTPMT1, SSU72, UBLCP1, PP1B, P1A, PP2α / PP2R1A complex, PTPN6 / SHP1, PTPRC / CD45, DUSP22 / MKPX, PTPN2 / TC-PTP, PTPN7 / LC-PTP, PTPN12 / PTP-PEST, PTPN1 / PTP1B-CD, PTPN11 / SHP2, PTPN11 / SHP2-FL and / or PTPN11 / SHP2-FL(E76K). In some embodiments, the regulatory phosphatase comprises protein tyrosine phosphatase 1B (PTP1B).

[0040] In one aspect, a method of inhibiting, preventing and / or slowing the onset or progression of appetite or weight gain (including but not limited to obesity) 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 an aminosterol compound or composition disclosed herein, including but not limited to an aminosterol-cyclodextrin composition.

[0041] In another aspect, a method of improving or eliminating impaired reproductive function, impaired fertility and / or impaired reproductive behavior in a subject in need thereof is provided. The method comprises administering to the subject a therapeutically effective amount of an aminosterol compound or composition disclosed herein, including but not limited to an aminosterol-cyclodextrin composition.

[0042] In another aspect, a method for treating, preventing and / or ameliorating diabetes in a subject in need thereof is provided, wherein the diabetes may be type 1 or type 2 diabetes. The method comprises administering to the subject a therapeutically effective amount of an aminosterol compound or composition disclosed herein, including but not limited to an aminosterol-cyclodextrin composition.

[0043] In some embodiments, (a) the administration method comprises oral, nasal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracisternal, transdermal or any combination thereof; and / or (b) the administration method is nasal administration, oral administration or a combination thereof.

[0044] In some embodiments, the therapeutically effective amount of the aminosterol compound, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, comprises: (a) about 0.1 to about 20 mg / kg body weight of the subject; (b) about 0.1 to about 15 mg / kg body weight of the subject; (c) about 0.1 to about 10 mg / kg body weight of the subject; (d) about 0.1 to about 5 mg / kg body weight of the subject; or (e) about 0.1 to about 2.5 mg / kg body weight of the subject.

[0045] In some embodiments, the therapeutically effective amount of the 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.

[0046] In some embodiments, the method of administration comprises oral administration, and wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof comprises: about 1 to about 300 mg / day; or about 25 to about 500 mg / day.

[0047] In some embodiments, the aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is administered in combination with at least one additional active agent or therapeutic agent to achieve an additive or synergistic effect. In some embodiments, the additional active agent or therapeutic agent is administered by a method selected from the group consisting of: (a) concomitantly; (b) as a mixture; (c) separately and simultaneously (simultaneously) or concurrently (concurrently); and (d) separately and sequentially. In some embodiments, the additional active agent or therapeutic agent is a second aminosterol having a different structure from the aminosterol administered as described in the above paragraphs.

[0048] In some embodiments, administration of the composition comprises administration on an empty stomach, optionally within two hours after the subject wakes up; and / or the subject does not consume food for about 60 to about 90 minutes after administration of the composition.

[0049] 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 eliminating the symptoms evaluated, and (b) then administering a composition comprising the dose of the aminosterol to the subject for a period of time, wherein the method comprises: (i) confirming the symptoms to be evaluated, wherein the symptoms are susceptible to aminosterol treatment; (ii) confirming the starting dose of the aminosterol for the subject; (iii) administering increasing doses of the aminosterol to the subject over a period of time until an effective dose for the symptoms evaluated is confirmed, wherein the effective dose is the dose of the aminosterol at which the symptom is improved or eliminated, and the dose of the aminosterol is fixed at this level for the specific symptom in the specific subject. In some embodiments, a clinically recognized scale or tool is used to measure the improvement or elimination of the symptoms.

[0050] In some embodiments: (a) the composition is administered orally and: (i) the initial aminosterol dose range is about 10 mg to about 150 mg / day; (ii) the aminosterol dose for the subject after escalation is fixed at about 25 mg to about 500 mg / day; and / or (iii) the dose of the aminosterol or its salt or derivative is increased in increments of about 25 mg; or (b) the composition is administered intranasally and: (i) the initial aminosterol dose range is about 0.001 mg to about 3 mg / day; (ii) the aminosterol dose for the subject after escalation is fixed at about 0.001 mg to about 6 mg / day. g / day; (iii) the dose of the aminosterol for the subject after the escalation is a subtherapeutic dose when administered orally or by injection; and / or (iv) the dose of the aminosterol is increased 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.

[0051] In some embodiments: (a) the dose of the aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, is increased every about 3 to about 5 days; and / or (b) if the symptoms evaluated are severe, the initial aminosterol dose is higher; and / or (c) the symptoms are associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction.

[0052] In some embodiments, the symptoms to be evaluated are selected from the following: (a) at least one non-motor aspect of daily life experience as defined in 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, daytime sleepiness, pain, urinary system problems, constipation problems, dizziness on standing, and fatigue; (b) at least one motor aspect of daily life experience as defined in Part II of the Unified Parkinson's Disease Rating Scale, selected from the following: speech, saliva and drooling, chewing and swallowing, eating, dressing, hygiene, writing, turning over in bed, trembling, getting out of bed, car or deep chair, walking and balance, and freezing; (c) at least one motor symptom as 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, getting up from a chair, gait, freezing of gait, postural stability, posture, body (d) at least one motor complication identified on the Unified Parkinson's Disease Rating Scale Part IV selected from the group consisting of: duration of movement disorder, functional impact of movement disorder, duration of resting state, functional impact of fluctuations, complexity of movement fluctuations, and painful non-status dystonia; (e) constipation; (f) depression; (g) cognitive impairment; (h) sleep problems or sleep disturbances ; (i) circadian rhythm disturbances; (j) hallucinations; (k) fatigue; (l) REM disturbed sleep; (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) pain relief; (w) restoration of bladder sensation and urination; (x) urinary incontinence; and / or (y) control of nocturia.

[0053] 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 after dosing on at least 2 of the 3 days of a given dose; (b) if the average complete spontaneous bowel movement (CSBM) or average spontaneous bowel movement (SBM) is greater than or equal to once per week, the initial aminosterol dose before ascending is 75 mg / day; and / or (c) if the average CSBM or SBM is less than once per week, the initial aminosterol dose before ascending is 150 mg / day.

[0054] In one aspect, a method of increasing gene transcription in the intestine of a subject is provided, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound or composition disclosed herein. In some embodiments, the increase in gene transcription is directed to one or more genes selected from the group consisting of caspase 14, collagen type XVII alpha 1, corneal adhesion protein, keratin, cystatin E / M, dermokine, desmoglein 1, desmoglein 1β, filaggrin, connexin β4, connexin β6, H19 imprinted maternally expressed transcript, hornerin, kallikrein related-peptidase 7, chymotryptic stratum, keratin 1, keratin 10, keratinocyte differentiation-related protein, keratinocyte expressed proline-rich protein proline-rich), late cornified coat protein 1A1, late cornified coat protein 1A2, late cornified coat protein 1B, late cornified coat protein 1C, late cornified coat protein 1E, late cornified coat protein 1F, late cornified coat protein 1G, late cornified coat protein 1H, late cornified coat protein 1I, late cornified coat protein 1J, late cornified coat protein 1L, late cornified coat protein 1M, late cornified coat protein 3C, late cornified coat protein 3E, late cornified coat protein 3F, galactoside-binding lectin 7, loricrin, sciellin, myoglobin, myosin binding protein C slow type, skeletal muscle myosin heavy polypeptide 1, skeletal muscle myosin heavy polypeptide 8, rapidly phosphorylated myosin light chain, myosin light polypeptide 3, myomodulin 1, myomodulin 2 2) and titin-cap.

[0055] 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 175%, about 175% to about 200%, about 200% to about 250%, about 250% to about 300%, about 300% to about 350%, about 350% to about 400%, about 400% to about 450%, about 500% to about 600%, about 600% to about 700%, about 700% to about 800%, about 800% to about 900%, about 900% to about 1000%, or about 1000% to about 1500%.

[0056] In one aspect, a method of inhibiting one or more regulatory phosphatases for therapeutic or prophylactic benefit is provided, the method comprising administering to a subject a therapeutically effective amount of an aminosterol compound disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug or derivative or composition thereof.

[0057] In all methods described herein, the subject can be a human.

[0058] The above content and the following description of the drawings and specific embodiments are exemplary and explanatory. They are intended to provide further details of the present disclosure, but should not be interpreted as limiting. Through the following specific embodiments of the present disclosure, other objects, advantages and novel features will be readily apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 XIC chromatogram showing full MS / ddMS2 scan of ENT-03S in rat plasma sample.

[0060] Figure 2 XIC chromatogram showing full MS / ddMS2 scan of ENT-03S in rat urine sample.

[0061] Figure 3 The MS / MS fragmentation spectrum of ENT-03S is shown.

[0062] Figure 4 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M1-PU) is shown.

[0063] Figure 5 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M2-PU) is shown.

[0064] Figure 6 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M4-PU) is shown.

[0065] Figure 7 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M5-PU) is shown.

[0066] Figure 8 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M6-PU) is shown.

[0067] Fig. 9 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M7-PU) is shown.

[0068] Fig.10 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M8-PU) is shown.

[0069] Fig.11 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M9-PU) is shown.

[0070] Fig.12 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M10-PU) is shown.

[0071] Fig.13 The metabolic pathway of ENT-03S in rat plasma and urine samples is shown.

[0072] Fig.14 The chromatogram of ENT-19 is shown.

[0073] Fig.15 XIC chromatogram showing full MS / ddMS2 scan of ENT-03S in rat bile sample.

[0074] Fig.16 The MS / MS fragmentation spectrum of ENT-03S is shown.

[0075] Fig.17 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M1-RB) is shown.

[0076] Fig.18 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M2-RB) is shown.

[0077] Fig.19 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M3-RB) is shown.

[0078] Fig. 20The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M4-RB) is shown.

[0079] Fig.21 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M5-RB) is shown.

[0080] Fig. 22 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M6-RB) is shown.

[0081] Fig.23 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M8-RB) is shown.

[0082] Fig.24 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M9-RB) is shown.

[0083] Fig.25 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M10-RB) is shown.

[0084] Fig.26 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated ENT-25S) (M11-RB) is shown.

[0085] Fig. 27 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M12-RB) is shown.

[0086] Fig.28 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M13-RB) is shown.

[0087] Fig.29 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M14-RB) is shown.

[0088] Fig.30 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M15-RB) is shown.

[0089] Fig.31 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M16-RB) is shown.

[0090] Fig.32 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M17-RB) is shown.

[0091] Fig.33 The possible metabolic pathways of ENT-03S from rat bile samples are shown.

[0092] Fig.34 The mean plasma concentration versus time curve of aminosterol ENT-03S formulated with cyclodextrin in male SD rats after subcutaneous injection at 10 mg / kg.

[0093] Fig.35 Shown are the mean plasma concentration versus time curves of the aminosterol ENT-03S in male SD rats following subcutaneous injection of 10 mg / kg in a formulation without cyclodextrin. DETAILED DESCRIPTION I. Overview of the Invention

[0094] The present invention relates to aminosterol compositions for use in methods of treating human diseases. Specific compounds disclosed include the aminosterol compounds named as follows: ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also known as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, ENT-22, ENT-22S, ENT-22R, ENT-22 mixed isomers, ENT-22 isomers, ENT-23, ENT-24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, aminosterol compound A, aminosterol compound B and aminosterol compound C, or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof.

[0095] Inhibition of protein tyrosine phosphatase 1B (PTP1B) by aminosterol 1436 has been found both in vitro and in vivo. When administered to obese mice, aminosterol 1436 reduced food intake, adiposity and body weight, corrected insulin resistance and reversed fatty liver disease. In early human clinical trials, it showed dose-dependent weight loss and improved insulin sensitivity.

[0096] Since aminosterol 1436 exhibits pharmacological activity in many vertebrate species, it is theoretically believed that functional analogs exist in higher vertebrates. Aminosterol 1436 contains sulfated planar ("flat") bile alcohols attached to spermine. Although similar compounds have not been isolated from any mammalian source so far, planar C-26 bile acids, such as 7-α-hydroxy-3-oxo-4-cholesterol acid (7-HOCA), are one of the most abundant bile acids present in the cerebrospinal fluid of mice and humans. Based on this information and additional studies, ENT-03 is confirmed and described in WO 2021 / 025973.

[0097] ENT-03 was detected in the brain, liver, kidney and digestive tract (GI tract) of newborn mice. The highest concentration was detected in the brain. ENT-03 isolated from the brain exists as two diastereoisomers, R and S, at the chiral C25 center, at a ratio of about 60% and 40%, respectively. Brain concentrations are low at birth, reach peak concentrations in the first week after birth, and decline rapidly as the animals age. The low concentrations of ENT-03 in the digestive tract indicate that milk is not the source of this compound.

[0098] ENT-03 was tested in vitro with a commercially available phosphatase library. PTP1B was the most effectively inhibited of the phosphatases measured. The inhibitory "fingerprint" of ENT-03 is similar to that of aminosterol 1436. The properties of ENT-03 include improving insulin sensitivity as a centrally active PTP1B inhibitor, as well as long-term reductions in food intake and body weight after peripheral and central administration to lean rodents. In short, ENT-03 causes reduced food consumption and thus weight loss. In addition, ENT-03 reduces hepatic steatosis and acutely increases insulin sensitivity. In addition, after chronic intranasal administration, ENT-03 maintains its effects on metabolism.

[0099] Based on the identified properties of ENT-03, novel metabolites of ENT-3 were identified. Throughout this application, the term "PU" refers to compounds isolated from rat plasma and urine, and "RB" refers to compounds isolated from rat bile.

[0100] In addition, the present disclosure relates to the preparation of aminosterol compounds delivered to subjects for the treatment of diseases. The specific compound under consideration is an aminosterol related to mammal polyamine-bile acid, including its pharmaceutically acceptable salt, solvate, prodrug or derivative. This aspect of the present disclosure covers novel aminosterols described in detail herein and aminosterols described in the prior art, such as squalamine (ENT-01), squalamine phosphate, aminosterol 1436 (ENT-02) (also known as Trodusquemine (trodusquemine) and MSI-1436), ENT-03, ENT-05 (US-2023 / 0123701), ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, ENT-11 (US2023 / 0125585) and ENT-06 (US 2022 / 0372066).

[0101] The aminosterols described herein have biophysical properties that are incompatible with subcutaneous administration. In particular, the chemical structure of aminosterols predicts that at physiological pH, the molecule will be highly water-soluble, amphipathic and cationic. When injected into animal tissues, membrane-active or membrane-destructive aminosterol solutions destroy tissues by dissolution. The degree of tissue damage is directly proportional to the concentration of aminosterols. When applied, tissue damage is associated with severe pain, making aminosterol compounds unsuitable and undesirable for injection therapy purposes (subcutaneous, intramuscular, intravenous, etc.). In addition, due to the positive charge and the tissue damage caused, the bioavailability of subcutaneously administered aminosterols is impaired. In short, as a result of detergency, aminosterols cannot be administered subcutaneously (or IM, IV, etc.) at concentrations required to achieve therapeutic effects.

[0102] The present disclosure details a method for preparing a parenteral formulation of an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof using cyclodextrins. The novel formulation surprisingly results in painless subcutaneous administration and further exhibits acceptable bioavailability.

[0103] Based on pharmacological studies in rodents, the possible dose of aminosterols that must be administered to a 75 kg human is between about 10 and about 50 mg. Since the maximum volume of a subcutaneous dose is about 1 ml, aminosterol concentrations between 10 and 50 mg / ml should be administered. At such concentrations, administration of aminosterols will cause severe burning pain, similar to a bee sting, and cause tissue necrosis at the injection site.

[0104] The present disclosure relates to the discovery of ideal formulations of aminosterols, or pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof, which are painless upon injection and allow for rapid diffusion of the drug from the injection site into the bloodstream.

[0105] In another aspect of the present disclosure, the preparation of aminosterol or its pharmaceutically acceptable salt, solvate or derivative contains at least about 50 mg / ml of aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative. In another aspect, the preparation is a homogeneous aqueous solution that can be sterilized by filtration. In another aspect of the present disclosure, the aminosterol preparation includes minimal excipients and exhibits the necessary chemical and physical stability required for a pharmaceutical product.

[0106] Since the aminosterol-cyclodextrin formulations described herein are used for injection administration, e.g., intravenous, subcutaneous or intramuscular injection, it is preferred that the formulations be buffered to an appropriate pH. Suitable pH for intravenous and intramuscular injections is 2-11, and suitable pH for subcutaneous injection is 4-9. In one aspect, the formulation is used for subcutaneous administration and the pH is about 7-8. In other aspects, the pH of the buffered aqueous aminosterol cyclodextrin formulation is between about 7 and 8 or about 7.2 to 7.5 or about 7.4.

[0107] The pH can be controlled in the ideal range of pH 5-8 by buffers such as acetate, phosphate, citrate, histidine, tris(hydroxymethyl)aminomethane (TRIS), etc. Commonly used buffers include, for example, sodium phosphate, citric acid, acetic acid, KH2PO4, CHES, borate, tromethamine, histidine, gluconic acid, lactic acid, tartaric acid, aspartic acid, glutamic acid, citric acid cycle intermediates, [tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), N-[tris(hydroxymethyl)methyl]glycine (Tricine), 3-[N-tris(hydroxymethyl)methyl]

[0063] The following are some examples of the compounds: 1,2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES), dimethylarsonic acid (Cacadylate), and 2-(N-morpholino)ethanesulfonic acid (MES).

[0108] In one aspect of the present disclosure, the aminosterol cyclodextrin formulation comprises the following at a pH of 7.4: 50 mg / ml ENT-03 (active ingredient), 25% 2-hydroxypropyl-β-cyclodextrin, and 80 mM phosphate.

[0109] In another aspect of the present disclosure, the aminosterol cyclodextrin formulation comprises the following at a pH of 7.3: II. Novel aminosterols

[0110] The novel aminosterol compounds disclosed herein are designated as ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also known as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, ENT-22, ENT-22S, ENT-22R, ENT-22 mixed isomers, ENT -23, ENT-24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, aminosterol compound A, aminosterol compound B and aminosterol compound C or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof, the structure of each compound is shown below: as well as

[0111] The present invention encompasses all enantiomers (R and S) and racemic mixtures of all aminosterol compounds disclosed herein.

[0112] In another aspect, an aminosterol compound having the following chemical structure (Formula (I)) is disclosed: in: R 1is optionally substituted C1-C8 alkyl, optionally substituted 2 to 8-membered heteroalkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; R 2 H or -C(O)R 5 , where R 5 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; and R 3 and R 4 are each independently H or optionally substituted 2 to 14-membered heteroalkyl; or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof; Wherein the compound is not: (1) (24R)-3β-({3-[(3-aminopropyl)amino]propyl}amino)-7α-hydroxycholestane-24-yl hydrosulfate (squalamine); (2) (3R,6R)-6-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptyl-3-hydrogen sulfate (aminosterol 1436); (3) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (ENT-03); (4) (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-03); (5) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptyl-2,3,3-d3 acid (ENT-03d3); (6) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-(benzoyl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (7) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (8) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (9) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (10) (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (11) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (12) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2-d-ol; (13) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (14) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (15) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (16) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (17) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (18) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (19) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (20) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (21) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylhept-2-enoic acid; (22) (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (23) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (24) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-hydroxy-2-methylheptanoic acid; (25) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (26) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (27) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (28) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (29) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)heptan-3-one; (30) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (31) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (32) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (33) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (34) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (35) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (36) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (37) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (38) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (39) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (40) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (41) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (42) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (43) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (44) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (45) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (46) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (47) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2,3-diol; (48) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2,3-diol; (49) (3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylheptane-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (50) (3S, 5R, 7R, 10S, 13R, 17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylhept-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (51) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-05); (52) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-06); (53) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-ammoniopropyl)ammonio)butyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoate-2,3-d2; (54) (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-03); (55) (2R,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (56) (2S,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (57) (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-06); (59) (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-06); (60) (6R)-6-((3S,5R,7R,10S,13R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-squalamine); (61) (3R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthran-17-yl)-2-methylheptane-3-yl hydrosulfate-3-d (24-D1-squalamine); or (62) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-1436).

[0113] In another aspect, the aminosterol has a structure of formula (I), wherein R 1 Selected from

[0114] In another aspect, the aminosterol has a structure of formula (I), wherein R 2 For H.

[0115] In another aspect, the aminosterol has a structure of formula (I), wherein R 3 and R 4 Independently selected from H,

[0116] In another aspect, the aminosterol has a structure of formula (I), wherein R 3 is H, and R 4 Independently selected from

[0117] In some embodiments, the compounds disclosed herein are 25 The carbon has a diastereomeric excess (de) of about 80% to about 90%, about 90% to about 95%, about 95% to about 99%, about 99% to about 99.9%, or about 100%.

[0118] Given the chemical structure, the aminosterol compounds described herein can be prepared using standard chemical synthesis methods. For example, US-2023 / 0123701 describes the coupling of polyamines to 3-ketosterols and the control of C25 stereochemistry. The preparation of the described aminosterol molecules can also be completed by synthesizing the required polyamines and 3-ketosterols by standard methods in the art. III. Deuterated aminosterol compounds

[0119] In another aspect of the present disclosure, deuterated aminosterol compounds are described, wherein at least one hydrogen of the aminosterol compounds described herein is replaced with deuterium. Deuterated forms of aminosterols may have improved safety, better tolerability, and / or enhanced efficacy. Deuterium is a naturally occurring, stable, non-radioactive isotope of hydrogen. The aminosterol may be any compound described herein, including but not limited to ENT-01, squalamine phosphate, ENT-02 (aminosterol 1436), ENT-03, ENT-03S (C 25 (S)ENT-03)、ENT-03R(C 25ENT-03), ENT-03 mixed isomers, ENT-04, ENT-05, ENT-06, ENT-07, ENT-08, ENT-09, ENT-10, ENT-11, ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also known as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, E NT-22, ENT-22S, ENT-22R, ENT-22 mixed isomers, ENT-23, ENT-24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, aminosterol compound A, aminosterol compound B and aminosterol compound C or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof.

[0120] Deuterated aminosterols, in which one or more hydrogen atoms contained in the aminosterol molecule have been replaced with the heavier stable isotope deuterium, are expected to have a lower metabolic rate and therefore a longer half-life and / or reduced or less frequent dosing to obtain the desired therapeutic effect. Deuterium-carbon bonds are generally about 6 to 10 times more stable than corresponding hydrogen-carbon bonds. These stronger bonds are more difficult to break, which can slow the rate of bond cleavage. This effect on rate is called the kinetic isotope effect (KIE).

[0121] Deuteration of aminosterols can produce compounds with improved pharmacokinetic and / or toxicological properties (such as improved safety, efficacy, and / or tolerability) compared to unmodified aminosterols because the stronger deuterium-carbon bond alters the metabolism of the aminosterol.

[0122] In another aspect, for the aminosterol compounds described herein, any atom not designated as deuterium is present at its natural isotopic abundance. In another embodiment, the deuterium incorporation at each designated deuterium atom is at least about 90%, at least about 95%, or at least about 97%.

[0123] In another embodiment, the deuterated aminosterol compounds of the invention have an isotopic enrichment factor selected from the group consisting of at least about 3500, at least about 4000, at least about 4500, at least about 5000, at least about 5500, at least about 6000, at least about 6333.3, at least about 6466.7, at least about 6600, and at least about 6633.3. In one embodiment, the compounds of the invention have an isotopic enrichment factor of at least 3500 for one deuterium at a single position in the compound.

[0124] In one embodiment, the deuterated aminosterol compound of the invention is a pharmaceutically acceptable salt, such as a phosphate salt.

[0125] In one embodiment, the deuterated aminosterol compounds of the invention have a longer half-life compared to the non-deuterated form of the same aminosterol. For example, the half-life may be increased 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%.

[0126] In one aspect of the methods of the invention, the deuterated aminosterol compound has an improved safety profile as measured by a reduction in the incidence of one or more adverse events as assessed using a clinically recognized scale or tool, compared to the same aminosterol compound that is not deuterated. For example, the safety profile may be improved 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%.

[0127] In another aspect of the method of the present invention, the deuterated aminosterol compound has improved efficacy compared to the same aminosterol compound without deuteration. For example, the improved efficacy can be measured by the improvement of one or more disease symptoms evaluated using a clinically recognized scale or tool. For example, the efficacy improvement 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%.

[0128] In another aspect of the methods of the invention, the deuterated aminosterol compound has improved tolerability as measured using a clinically recognized scale or tool compared to the same compound without deuteration. For example, the tolerability may be improved 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%.

[0129] In another aspect of the method of the present invention, the deuterated aminosterol compound has a reduced required dosage and / or dosing frequency compared to the same aminosterol compound without deuteration to obtain the same or improved desired therapeutic effect measured using a clinically recognized scale or tool. For example, the deuterated aminosterol composition according to the present invention may have a dosage of about 5% less than the same but unmodified aminosterol to obtain the same therapeutic effect. In another embodiment, the dosage is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% less than the same but unmodified aminosterol to obtain the same or improved therapeutic effect. IV. Aminosterol-cyclodextrin preparations

[0130] In one aspect, the present disclosure describes a method of "masking" an aminosterol in a manner that eliminates its membrane-disrupting properties during residence at the injection site, thereby eliminating local pain, tissue damage, and improving bioavailability. The "masking" of the aminosterol is achieved by mixing an aqueous solution of the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof with an aqueous solution of a suitably configured cyclodextrin. After mixing, the cyclodextrin molecules will reversibly bind to the aminosterol molecules or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof to form a cyclodextrin-aminosterol complex.

[0131] As is well known in the art, cyclodextrin has a three-dimensional cup-shaped structure, which allows them to encapsulate (capture) smaller organic compounds. The biophysical properties of the resulting complex are usually determined by the biophysical properties of cyclodextrin. Cyclodextrin is formed by end-to-end connection of glucose molecules to form a ring structure. Therefore, they show the characteristics of oligosaccharides, i.e. high water solubility and excellent tissue compatibility. Therefore, cyclodextrin is widely used in the pharmaceutical industry to solubilize compounds with poor water solubility.

[0132] In the present disclosure, cyclodextrin is used to "mask" the detergency of the aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative at the injection site. In order to achieve this result, the cyclodextrin concentration in the formulation must be increased to drive the equilibrium to move in the direction of all complexation of the aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative. Since the complex between cyclodextrin and aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative is non-covalent, the components exist in the form of free molecules and complex equilibrium, and the equilibrium is determined by the stability of the complex and the concentration of free molecules. When the complex diffuses from the injection site and enters the systemic circulation, the concentration of cyclodextrin decreases and the complex dissociates, releasing the aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative.

[0133] Cyclodextrins exist in three size classes based on their number of glucose units: α, 6; β, 7; and γ, 8. The "cup" size of cyclodextrins increases with the number of glucose units. In addition, cyclodextrins can be chemically modified with substituents such as alkylhydroxyl groups, anionic and cationic groups, which can further affect complex formation with desirable ligands.

[0134] Many methods have been described to determine the extent of complex formation, using methods such as isothermal calorimetry and NMR. In the present disclosure, the optimal cyclodextrin concentration required to completely mask the aminosterol or its pharmaceutically acceptable salt, solvate, prodrug or derivative can be approximated by titrating the cyclodextrin solution into the aminosterol aqueous solution to a concentration at which the solution no longer bubbles when agitated. Since "bubbling" reflects a reduction in surface tension, and aminosterols have detergent properties, when the concentration of free aminosterols is below a few μg / ml, the strong "bubbling" disappears. The cyclodextrin concentration is then further adjusted based on the clinical response of the subject to the injection of the aminosterol formulation. If subcutaneous injection is painful, the concentration of cyclodextrin can be increased.

[0135] The high concentrations of aminosterols that must be formulated require cyclodextrins with high water solubility. Furthermore, at these high concentrations, the selected cyclodextrins must not exhibit aggregation in solution, a property typically observed with native cyclodextrins. Only very specific chemically modified cyclodextrins can serve as satisfactory carriers.

[0136] An exemplary cyclodextrin is 2-hydroxypropyl β-cyclodextrin (2HP-β-CD). 2HP-β-CD is β-CD chemically modified with a hydroxypropyl moiety. The "cup size" is large enough to accommodate the ENT-03 molecule or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof. The stability provided by the hydrophobic interactions allows the formation of complexes at cyclodextrin concentrations. Upon dilution into tissue fluids, the hydrophobic bonds are weak enough to allow dissociation, which is further promoted by the binding of aminosterols to plasma proteins. 2HP-β-CD is water soluble, up to concentrations of over 60%, allowing the formulation of high concentrations of aminosterols.

[0137] Other exemplary cyclodextrins include, but are not limited to, chemically modified or unmodified β and γ cyclodextrins. Alpha cyclodextrins may not be suitable because of their small "cup" size. Exemplary chemically modified or unmodified β and γ cyclodextrins include, for example, β cyclodextrin, γ cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, random methylated-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and polymerized cyclodextrins such as epichlorohydrin-β-cyclodextrin and carboxymethyl epichlorohydrin β-cyclodextrin. In one aspect of the present disclosure, the cyclodextrins used in the aminosterol formulations are cited in the FDA's list of inactive pharmaceutical ingredients and / or are classified in the FDA's generally recognized as safe (GRAS) list.

[0138] Any aminosterol described in the present disclosure and aminosterols disclosed in WO 2021 / 025973 and US 2023 / 0123701 (both related to "human aminosterol ENT-03 compounds, related compositions containing them and methods of using them"), WO 2021 / 025974 and US2022 / 0372066 (both related to "human squalamine derivatives, including their related compositions and methods of using them") and US2023 / 0125585 (related to "Protocols and Regimens for aminosterol treatment") (all of which are specifically incorporated by reference), and pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof that can be used in the described cyclodextrin formulations. The aminosterols may also be present in a racemic mixture.

[0139] Exemplary aminosterols that can be used in the formulations herein also include, but are not limited to, ENT-01, squalamine phosphate, ENT-02 (aminosterol 1436), ENT-03, ENT-03S (C 25 (S)ENT-03)、ENT-03R(C 25ENT-03), ENT-03 mixed isomers, ENT-04, ENT-05, ENT-06, ENT-07, ENT-08, ENT-09, ENT-10, ENT-11, ENT-12, ENT-13, ENT-14, ENT-14S, ENT-14R, ENT-15, ENT-16, ENT-17 (also known as M1-PU), ENT-18, ENT-18S, ENT-18R, ENT-19 (ENT-19 is the racemic form of M10-PU), ENT-19S, ENT-20, ENT-21, ENT-21S, ENT-21R, ENT-21 mixed isomers, ENT-22, ENT -22S, ENT-22R, ENT-22 mixed isomers, ENT-23, ENT-24, ENT-25, ENT-25R, ENT-25S (also known as M11-RB), ENT-25 mixed isomers, ENT-26, ENT-27, ENT-28, ENT-29, ENT-30, ENT-31, ENT-32, ENT-33, M10-PU / M14-RB, M2-RB, M3-RB, M8-RB, M5-RB, M16-RB, any one of aminosterol compound A, aminosterol compound B and aminosterol compound C or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, the structure of each compound is shown below: as well as V. Composition A. Drug carrier

[0140] In another aspect, compositions are provided herein, which include aminosterol compounds disclosed herein or pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof, and one or more pharmaceutically acceptable carriers and / or excipients. The composition does not require the presence of cyclodextrin. The administration of the aminosterols disclosed herein or pharmaceutically acceptable salts, solvates or prodrugs thereof may include the administration of the composition. Although the aminosterols or pharmaceutically acceptable salts, solvates or prodrugs thereof may be administered alone, it is preferably administered as a pharmaceutical preparation together with one or more pharmaceutically acceptable carriers. The carrier must be "acceptable", i.e., compatible with the aminosterols or pharmaceutically acceptable salts, solvates or prodrugs thereof, and harmless to the recipient thereof.

[0141] Where aerosol administration is appropriate, the aminosterols described herein or their pharmaceutically acceptable salts, solvates or prodrugs can be formulated as aerosols using standard procedures. The term "aerosol" includes any airborne suspension of the compounds described herein that can be inhaled into the bronchioles or nasal passages, and includes dry powders and aqueous aerosols, as well as pulmonary and nasal aerosols. In particular, aerosols include airborne suspensions of droplets of the compounds described herein, which can be generated in a metered dose inhaler or nebulizer or in a sprayer. Aerosols also include dry powder compositions of the compositions of the present technology suspended in air or other carrier gas, which can be delivered by, for example, insufflation from an inhaler device, e.g., 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). B. Dosage Form

[0142] The aminosterol composition can be conveniently present in the form of a unit dosage form and can be prepared by any known method 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 preparation can be administered orally, intranasally or in combination thereof. In another embodiment, administration includes non-oral administration.

[0143] The formulations or compositions according to the present technology can be packaged together with instructions or package inserts or included in a kit with instructions or package inserts. "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or any type of formulation auxiliary.

[0144] 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. These excipients are known in the art. 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 Suitable lubricants, including agents that affect the flowability of the powder to be compressed, may include colloidal silicon dioxide, such as 200, talc, stearic acid, magnesium stearate, calcium stearate and silica gel. 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. Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other parabens such as butylparaben, alcohols such as ethanol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Suitable diluents include pharmaceutically acceptable fillers such as microcrystalline cellulose, lactose, dibasic calcium 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; dibasic calcium phosphate such as Mannitol; starch; sorbitol; sucrose; and glucose. Suitable disintegrants include lightly cross-linked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, cross-linked sodium carboxymethylcellulose, cross-linked povidone, sodium carboxymethyl starch, and mixtures thereof. C. Dosage & Dosing Cycle

[0145] The dosage range of aminosterols described herein may be from about 1 to about 500 mg / day or any amount between these two values. In some embodiments, a therapeutically effective dose of aminosterols described herein is administered to a subject. The therapeutically effective amount of at least one aminosterol or its salt or derivative described in the method of the present disclosure may be, for example, from about 0.1 to about 20 mg / kg, from about 0.1 to about 15 mg / kg, from about 0.1 to about 10 mg / kg, from about 0.1 to about 5 mg / kg, or from about 0.1 to about 2.5 mg / kg of the subject's body weight. In another aspect, the therapeutically effective amount of at least one aminosterol or its salt or derivative in the method of the present disclosure may be, for example, from about 0.001 to about 500 mg / day, from about 0.001 to about 250 mg / day, from about 0.001 to about 125 mg / day, from about 0.001 to about 50 mg / day, from about 0.001 to about 25 mg / day, or from about 0.001 to about 10 mg / day.

[0146] The oral dosage range of the aminosterols described herein can be from about 1 to about 500 mg / day or any amount between these two values. In one embodiment, the administration method comprises oral administration and the therapeutically effective amount of the aminosterol comprises (i) from about 1 to about 300 mg / day; (ii) from about 25 to about 300 mg / day; (iii) from about 50 to about 300 mg / day; or (iv) from about 75 to about 300 mg / day. Other exemplary dosages of orally administered 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 about 470, about 475, about 480, about 485, about 490, about 495, or about 500 mg / day.

[0147] The intranasal dose of aminosterol is much lower than the oral dose of the aminosterol. Examples of such low doses of intranasal 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 the 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 for intranasal administration 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.

[0148] For intranasal (IN) administration, it can be contemplated to select an aminosterol dose such that if administered by any other route, such as a "subtherapeutic" dose, the same dose will not provide any pharmacological effect, and in addition, will not result in negative effects. 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 IN method of the present disclosure, if the aminosterol may be Compound III (ENT-03) or a salt, solvate, prodrug or derivative thereof, if the same IN Compound III dose is administered via another route (such as oral, IP or IV), the Compound III dose will not result in a significant reduction in food intake or significant weight loss. Similarly, some aminosterol compounds are known to produce pharmacological effects of nausea, vomiting and / or lowering blood pressure. Therefore, in certain embodiments of the IN method of the present disclosure, if the aminosterol has this effect when administered IN, if the same IN aminosterol dose is administered via another route (such as oral, IP or IV), the aminosterol dose will not result in significant nausea, vomiting and / or lowering of blood pressure. In some embodiments, intranasal administration includes delivering the aminosterol to the brain. Suitable exemplary aminosterol dosages are described above.

[0149] If any given aminosterol dose causes persistent adverse side effects, such as diarrhea, vomiting, or nausea, the aminosterol dose may be decremented (reduced). In another embodiment, the dose of the aminosterol may be varied, increasing or decreasing a defined amount so that the dose is appropriately reduced to eliminate adverse events, or if clinical results indicate that this is desirable (e.g., no or minimal adverse events, and with a moderate increase in dose with potential improved efficacy), the dose may be appropriately increased. For example, in one embodiment, the aminosterol dose may be increased or decreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0150] The pharmaceutical composition comprising aminosterol or its derivative, salt, solvate or prodrug can be administered in any suitable time period, including as a maintenance dose for an extended time period. Any pharmaceutically acceptable dosing regimen can be used as needed. The aminosterol administration may not exceed 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 (e.g., twice a day) during a given day. In an exemplary embodiment, administration is 1 time / day.

[0151] In other embodiments, the composition can be administered: (1) as a single dose or as multiple doses over a period of time; (2) indefinitely at a maintenance dose; (3) once, twice, or more times; (4) daily, every other day, every three days, weekly, or monthly; (5) for a 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 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 8.5, about 9 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, etc. However, another exemplary dosing regimen includes periodic dosing, wherein the effective dose can be delivered once every about 1, about 2, about 3, about 4, about 5, about 6 days, or once a week.

[0152] In a preferred embodiment, the aminosterol dose is taken in the morning, i.e., preferably within about two hours after waking up, on an empty stomach, and may be followed by a period of time without food, such as, for example, about 60 to about 90 minutes. In other embodiments, the aminosterol dose is taken within about 15 min, about 30 min, about 45 min, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, or about 4 hours after waking up. In a further embodiment, the aminosterol dose may be taken after about a period of time without food, wherein the time is at least about 30 min, about 45 min, about 60 min, about 1.25 hours, about 1.5 hours, about 1.75 hours, or about 2 hours.

[0153] Without being bound by theory, it is believed that aminosterols have an impact on circadian rhythms, possibly due to their ENS signaling, taking aminosterol dosages in the morning synchronizes all autonomous physiological functions that occur during the day. In other embodiments of the present disclosure, the aminosterol dosage is taken within about 15min, about 30min, about 45min, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours or about 4 hours after waking up. In addition, in other embodiments of the present disclosure, after taking the aminosterol dosage, the subject has a time period of about 15min, about 30min, about 45min, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours or about 3 hours without eating. D. "Fixed aminosterol dose"

[0154] In one aspect, the present application relates to a method for determining a "fixed dose" of an aminosterol described herein that is independent of age, size, or weight, but is individually calibrated. The "fixed dose" obtained by this method produces very effective results in treating the symptoms (one or more) on which the "fixed dose" is based, related symptoms along the "brain-gut" axis, and underlying conditions. In addition, methods for preventing underlying conditions utilizing this same "fixed dose" method are contemplated herein. The present disclosure is not limited to methods for determining a fixed aminosterol dose for a particular patient.

[0155] "Fixed aminosterol dose" is also referred to herein as "fixed ascending aminosterol dose", the therapeutic effect of which is determined for each patient by establishing a starting dose of an aminosterol composition and a threshold for improving a specific symptom, which is used as a tool or marker for evaluating the effectiveness of the aminosterol dose. After determining the starting aminosterol dose for a particular patient, the aminosterol dose is then gradually increased by a consistent amount at consistent time intervals until the expected improvement is achieved; this aminosterol dose is the "fixed ascending aminosterol dose" for the particular patient for the particular symptom. In an exemplary embodiment, the orally administered aminosterol dose is increased by about 25 mg every about 3 to about 5 days until the expected improvement is achieved. The symptoms evaluated and the tools used to measure symptom improvement can be described in detail below, including but not limited to constipation, hallucinations, sleep disorders (e.g., REM disturbed sleep or circadian rhythm disorders), cognitive disorders, depression, or alpha-synuclein aggregation.

[0156] This therapeutically effective "fixed dose" is then maintained throughout the treatment and / or prevention. Thus, even if a patient goes "off" and stops taking the aminosterol composition, upon re-starting aminosterol therapy, the same "fixed dose" would need to be taken without a step-up period. Without being bound by theory, it is believed that the aminosterol dose depends on the severity of the nerve damage associated with the symptom to establish a "fixed dose" threshold - for example, for constipation, the dose may be related to the extent of the nervous system damage in the patient's gut.

[0157] Dose escalation: When a "fixed aminosterol dose" is determined for a particular patient, the patient is started at a lower dose and the dose is subsequently escalated until a positive result is observed for the symptom being evaluated. An exemplary symptom to be evaluated may be constipation, but any symptom associated with the disease or condition to be treated may be used as a marker for evaluating the aminosterol dose. The aminosterol dose may also be decremented (reduced) if any given aminosterol dose causes persistent adverse side effects, such as diarrhea, vomiting, or nausea.

[0158] 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 may be about 150 mg / day or higher. In contrast, for patients suffering from moderate constipation, for example, defined as having more than one SBM per week, the starting oral aminosterol dose may be about 75 mg / day. Thus, as an example, a patient experiencing moderate constipation may be started at an oral aminosterol dose of about 75 mg / day, while a patient experiencing severe constipation may be started at an oral aminosterol dose of about 150 mg / day.

[0159] In other embodiments, patients experiencing moderate symptoms (for which fixed ascending aminosterol doses are calculated) can start from about 10 mg / day to about 75 mg / day, or any amount between these values. For example, the starting oral aminosterol dose 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.

[0160] In further embodiments, when a patient is experiencing severe symptoms (for symptoms used to calculate fixed ascending aminosterol doses), the patient can start with an oral aminosterol dose ranging from about 75 to about 175 mg / day, or any amount between these two values. For example, the starting oral aminosterol 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.

[0161] 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).

[0162] Before dose escalation, the starting intranasal (IN) aminosterol dose can be, for example, about 0.001 mg to about 3 mg / day or any amount between these two values. For example, before dose escalation, the starting aminosterol dose for IN administration can be, for example, about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, About 0.65, 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.

[0163] In an exemplary embodiment, the aminosterol dose can be administered regularly as needed. For example, the aminosterol dose can be administered once a day. The aminosterol dose can also be administered every other day, 2, 3, 4 or 5 times per week, once / week or 2 times / week. In another embodiment, the aminosterol dose can be administered every other week, or it can be administered continuously for a few weeks, then skip a few weeks (because the effect persists after treatment), and then restart aminosterol treatment.

[0164] When calculating the fixed increasing aminosterol dosage, the dosage can be increased after any suitable time period. In one embodiment, the aminosterol dosage is increased progressively with an amount of about limitation every about 3 to about 7 days, until the desired improvement is reached. For example, when the symptom of treatment / measurement is constipation, the threshold improvement can be to increase SBM once a week or defecate at least three times a week in total. In other embodiments, the aminosterol dosage can be increased 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 be increased progressively by about 1 time / week, about 2 times / week, about every other week or about 1 time / month.

[0165] During the dose escalation, the aminosterol dosage can be increased by a limited amount. For example, when the aminosterol is administered orally, the dosage can be increased by about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg. When the aminosterol is administered intranasally, the dosage can be 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.

[0166] Other symptoms that can be used as endpoints for determining the fixed ascending aminosterol dose for a patient are any symptom known to be associated with the disease, disorder or condition to be treated. For example, the neurological disease symptoms described herein include, but are not limited to, (a) at least one non-motor aspect of daily life experience as defined in Part I of the Unified Parkinson's Disease Rating Scale (UPDRS), 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 system problems, constipation problems, dizziness and fatigue when standing up; (b) at least one motor aspect of daily life experience as defined in Part II of the UPDRS, such as, for example, speech, saliva and drooling, chewing and swallowing, eating, dressing, hygiene, writing, turning over in bed, trembling, getting out of bed, car or deep chair, walking and balance and freezing; (c) at least one motor symptom as identified in Part III of the UPDRS, 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 freezing, postural stability , posture, bradykinesia, postural tremor of the hands, kinetic tremor of the hands, resting tremor amplitude, and constancy of resting tremor; (d) at least one motor complication identified in UPDRS Part IV, such as, for example, movement disorder, functional impact of movement disorder, time in resting state, functional impact of fluctuations, complexity of movement fluctuations, and painful non-status dystonia; (e) constipation; (f) depression; (g) cognitive impairment; (h) sleep problems or sleep disturbances; (i) circadian rhythm disturbances; (j) hallucinations; (k) fatigue; (l) REM disturbed sleep; (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) pain relief; (w) restoration of bladder sensation and urination; (x) urinary incontinence; and / or (y) control of nocturia. VI. Methods of treatment and / or prevention

[0167] Aspects of the present disclosure relate to methods for treating certain symptoms and / or methods for treating and / or preventing diseases or conditions associated with one or more of these symptoms by administering a therapeutically effective amount of an aminosterol disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof and / or an aminosterol composition, optionally in one or more pharmaceutically acceptable carriers. In one aspect, the aminosterol composition comprises a cyclodextrin as described in detail herein.

[0168] In one embodiment, the symptoms, diseases and / or conditions are generally associated with abnormal αS pathology, dopaminergic dysfunction and / or protein misfolding (including but not limited to abnormal tau pathology, abnormal amyloid β pathology, abnormal αS pathology and / or dopaminergic dysfunction), which means that they can be treated with aminosterols described herein. The composition of the present technology can be administered using any pharmaceutically acceptable method, including but not limited to oral, pulmonary, nasal and aerosol administration. In another embodiment, administration includes non-oral administration. The administration of the aminosterol cyclodextrin preparation can be by injection, for example, intravenous, subcutaneous, intramuscular, etc. In one embodiment, administration includes non-oral administration.

[0169] In some embodiments, provided herein are methods for treating a subject in need of a condition or symptom susceptible to treatment with an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, comprising administering to the subject a therapeutically effective amount of an aminosterol or a pharmaceutically acceptable salt, solvate or prodrug thereof or an aminosterol composition as described herein. In some embodiments, provided herein are methods for treating a subject in need of a condition susceptible to treatment with an aminosterol, comprising administering to the subject a therapeutically effective amount of a composition comprising an aminosterol or a pharmaceutically acceptable salt, solvate or prodrug thereof disclosed herein, and one or more pharmaceutically acceptable carriers and / or excipients or consisting essentially of the same. The aminosterol composition may be a cyclodextrin composition.

[0170] Non-limiting examples of symptoms suitable for treatment with an aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, include, but are not limited to, constipation, hallucinations, sleep disorders, cognitive impairment, depression, and inflammation.

[0171] Examples of diseases suitable for treatment with aminosterols or pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof are described herein, including, but not limited to, nervous system or neurodegenerative disorders or diseases. Nervous system or neurodegenerative disorders or diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), schizophrenia, Huntington's disease (HD), progressive supranuclear palsy, progressive nuclear palsy, supranuclear palsy, frontotemporal dementia (FTD), vascular dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body dementia or disease, Guadeloupian Parkinsonism, spinocerebellar ataxia, and autism. In other embodiments, the aminosterols described herein and compositions comprising the same can be used for methods of treating, preventing and / or slowing down the occurrence or progression of a psychological or behavioral disorder and / or associated symptoms in a subject in need thereof. In one embodiment, the psychological or behavioral disorder can be, for example, depression, anxiety, delirium, irritability, hallucinations and delusions, amnesia, autism, apathy, bipolar disorder, disinhibition, abnormal movements and compulsive behaviors, sleep disorders, sleep fragmentation, REM behavior disorders, circadian rhythm disorders, sleep apnea, and cognitive disorders.

[0172] In one embodiment, a method for treating, preventing and / or mitigating the occurrence 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 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. The aminosterol composition may be a cyclodextrin composition.

[0173] In another embodiment, neurodegenerative diseases can be positively affected by administering a therapeutically effective amount of an aminosterol according to the present disclosure."Positively affecting" includes, for example, slowing disease progression, improving one or more symptoms, and the like.

[0174] In another embodiment, a method for treating, preventing and / or slowing down the occurrence or progression of cerebral or systemic ischemic diseases and / or related symptoms in a subject in need thereof is provided. The cerebral or systemic ischemic diseases may be, for example, microangiopathy, cerebral ischemia during childbirth, cerebral ischemia during cardiac arrest or resuscitation / after, cerebral ischemia caused by intraoperative problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia caused by stenosis of the cerebral artery 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, acral ischemia, renal artery stenosis, diabetic retinopathy, malaria-related thrombosis, artificial heart valves, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction and pulmonary edema.

[0175] Examples of diseases suitable for treatment with aminosterols or pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof are described herein, including but not limited to fertility and reproductive function and behavior. Thus, one aspect contemplated is a method of improving or eliminating impaired reproductive function, impaired fertility function and / or impaired reproductive behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an aminosterol compound disclosed herein or a composition comprising the aminosterol.

[0176] Also contemplated are methods of inhibiting, preventing and / or slowing the onset or progression of appetite or weight gain and / or one or more related symptoms (including but not limited to obesity) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an aminosterol compound disclosed herein or a composition comprising the aminosterol.

[0177] In addition, methods of inhibiting, preventing and / or slowing the development or progression of diabetes (type 1 and / or type 2) and / or one or more related symptoms in a subject in need thereof are also contemplated, comprising administering to the subject a therapeutically effective amount of an aminosterol compound disclosed herein or a composition comprising the aminosterol.

[0178] In one embodiment, a method of inhibiting protein tyrosine phosphatase 1B (PTP1B) is provided, comprising contacting PTP1B with at least one aminosterol disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0179] Exemplary symptoms associated with abnormal αS pathology, dopaminergic dysfunction and / or protein misfolding and suitable for aminosterol treatment include, for example, constipation, hallucinations, and other symptoms described herein. In one embodiment, a method for treating, preventing and / or mitigating the occurrence 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 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0180] Also contemplated are methods of treating and / or preventing a psychological or behavioral disorder or any symptom associated with these diseases or conditions. In one embodiment, the psychological or behavioral disorder is depression, anxiety, delirium, irritability, hallucinations and delusions, amnesia, autism, apathy, bipolar disorder, disinhibition, abnormal movements and compulsive behaviors, sleep disorders, sleep fragmentation, REM behavior disorder, circadian rhythm disorder, sleep apnea, or cognitive impairment.

[0181] In another embodiment, psychological or behavioral disorders or any symptoms associated with these diseases or conditions can be positively affected by administering a therapeutically effective amount of an aminosterol according to the present disclosure."Positively affected" includes, for example, slowing the progression of a condition, improving one or more symptoms, etc.

[0182] In one aspect, the aminosterols described herein can be administered to a subject in need of treatment for a microbial infection. In some embodiments, the subject in need 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 mycobacterial infection, a fungal infection, and / or a protozoan infection. In some embodiments, the method further comprises administering one or more antiviral agents.

[0183] In some embodiments, the viral infection is caused by a virus selected from the group consisting of: yellow fever, cytomegalovirus, eastern equine encephalitis virus, hepatitis B virus, hepatitis 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, caulimoviridae, circoviridae, coronaviridae, cystovviridae, iridae), dengue, EBV, HIV, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Hepadnaviridae (hepatitis), Herpesviridae (e.g., cytomegalovirus, herpes simplex virus, herpes zoster virus), Iridoviridae, Mononegavirus (e.g., Paramyxoviridae, Morbilliviridae, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., Influenza A virus), A), Influenza B and parainfluenza viruses), Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Picomaviridae (e.g., rhinovirus, poliovirus), Poxviridae (such as smallpox or vaccinia), Potyviridae, Reoviridae (e.g., rotavirus), Retroviridae (HTLV-I, HTLV-II, lentivirus), Rhabdoviridae, Tectiviridae, Togaviridae (e.g., rubella virus), Herpes virus, Pox virus, Papilloma virus, Corona virus, Influenza virus, Hepatitis virus, Sendai virus, Sindbis virus, Vaccinia virus, West Nile virus, Hanta virus, viruses that cause the common cold, and any combination thereof. In some embodiments, the condition to be treated is selected from the group consisting of AIDS, viral meningitis, dengue fever, EBV, hepatitis, chronic diseases of suspected viral origin, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, cardiomyopathy, Kawaski disease, aplastic anemia, and any combination thereof.

[0184] In one aspect, a method of treating or preventing an infection caused by a coronavirus in a subject is provided, comprising administering to the subject a therapeutically effective amount of an aminosterol compound of any embodiment herein or a composition of any embodiment herein.

[0185] In some embodiments, the coronavirus comprises a virus selected from the group consisting of: alphacoronavirus; Colacovirus such as bat coronavirus CDPHE15; Decacovirus such as bat coronavirus HKU10 or horseshoe bat alphacoronavirus HuB-2013; Duvinacovirus such as human coronavirus 229E; Luchacovirus such as Lucheng Rn rat coronavirus; Minacovirus such as ferret coronavirus or mink coronavirus 1; Minunacovirus such as Miniopterus bat coronavirus 1 or Miniopterus bat coronavirus HKU8; Myotacovirus such as Myotis ricketti alphacoronavirus Sax-2011; Nyctacovirus such as Nyctalus velutinus alphacoronavirus SC-2013; 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 HKU24 (China Rattus coronavirus HKU24), human coronavirus HKU1 or rat coronavirus; Hibecovirus such as bat beta coronavirus Zhejiang 2013 (BatHp-betacoronavirus Zhejiang2013); Merbecovirus such as hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5 (Pipistrellus bat coronavirus HKU5) or Tylonycteris bat coronavirus HKU4 (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); Deltacoronavirus; Andecovirus such as Wigeon coronavirus HKU20; Buldecovirus such as Bulbul coronavirus HKU11, Porcine coronavirus HKU15, Munia coronavirus HKU13 or White-eye coronavirus HKU16; Herdecovirus such as Night heron coronavirus HKU19; Moordecovirus such as Commonmoorhen coronavirus HKU19 HKU21); gamma coronavirus; Cegacovirus such as Belugawhale coronavirus SW1; and Igacovirus such as avian coronavirus. ;

[0186] In some embodiments, the coronavirus is encoded by a polynucleotide comprising a SARS-CoV-2 sequence or having at least 80% sequence identity to a polynucleotide comprising a SARS-CoV-2 sequence. In some embodiments, the coronavirus includes or has features of human coronavirus 229E, human coronavirus OC43, SARS-CoV, HCoV NL63, HKU1, MERS-CoV, or SARS-CoV-2. In some embodiments, the coronavirus includes or has features of SARS-CoV-2. VII. Patient population

[0187] The disclosed aminosterol compounds and compositions comprising them include, but are not limited to, aminosterol-cyclodextrin compositions, which can be used to treat a variety 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.

[0188] In the embodiments disclosed herein related to prevention, a specific patient population can be selected based on being "at risk" for the development of any of the conditions disclosed herein. For example, a genetic marker or family history of a condition can be used as a marker to identify that a subject is likely to develop a specific condition. Thus, in some embodiments, prevention can involve first identifying a patient population at risk of developing the condition. Alternatively, certain symptoms are considered to be early signs of a particular condition. Thus, in some embodiments, a patient population at "risk" of developing the condition can be selected based on age and experiencing symptoms associated with the condition. Further genes or genetic signs can be used to refine the patient population.

[0189] In some embodiments, the subject suffers from and / or is at risk for suffering from one or more conditions selected from the group consisting of obesity, fatty liver disease, type 2 diabetes, heart disease, stroke, high blood pressure, gallbladder disease, gout, sleep apnea, osteoarthritis, high LDL cholesterol, low HDL cholesterol, high levels of triglycerides (dyslipidemia), endometrial cancer, breast cancer, colon cancer, kidney cancer, gallbladder cancer, and liver cancer. VIII. Reagent test kit

[0190] The aminosterol formulations or compositions of the present disclosure may be packaged with instructions or package inserts or included in a kit with instructions or package inserts. These instructions or package inserts may describe recommended storage conditions, such as time, temperature, and illumination, taking into account the shelf life of the aminosterol or its derivative or salt. These instructions or package inserts may also describe specific advantages of the aminosterol or its derivative or salt, such as the ease of storage of the formulation, which may need to be used on-site, outside of controlled hospital, clinic, or office conditions.

[0191] The present disclosure also provides a pharmaceutical package or kit, which includes one or more containers filled with one or more aminosterol pharmaceutical compositions disclosed herein. The kit may include, for example, a container filled with an appropriate amount of aminosterol pharmaceutical composition (either as a powder to be dissolved, a tablet or as a sterile solution). Associated with the container may be a notification form prescribed by a government agency that regulates the preparation, use or sale of drugs or biological products, which reflects the preparation, use or sale approved by the agency for human administration. In addition, the aminosterol or its derivative or salt thereof may be used in combination with other therapeutic compounds.

[0192] In other aspects, a kit comprising a nasal spray device as described herein is disclosed. In one aspect, the kit may include one or more devices as disclosed herein, including a disclosed low-dose aminosterol composition, wherein the device is sealed in a container sufficient to protect the device from the atmosphere. 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.

[0193] In one aspect, the kit may include one or more devices as disclosed herein, wherein the device may be sealed in a first protective package, or in a second protective package, or in a third protective package to protect the physical integrity of the product. One or more of the first, second, or third protective packages may include a foil bag. The kit may further include instructions for use of the device. In one aspect, the kit contains two or more devices.

[0194] In one aspect, the kit may include a device as disclosed herein, and may further include instructions for use. In one aspect, the instructions may include visual aids / images and / or written instructions to a user of the device. IX. Combination therapy

[0195] In the methods of the present disclosure, the aminosterol composition can be administered alone or in combination with one or more other therapeutic agents. An example of an additional therapeutic agent is one known to treat the condition for which the aminosterol is administered.

[0196] The combination can be administered simultaneously, for example, as a mixture, separately but simultaneously or concurrently; or sequentially. This includes presentations where the combined agents are administered together as a therapeutic mixture, and also includes procedures where the combined agents are administered separately but simultaneously, for example, through separate intravenous lines into the same individual. "Combination" administration also includes first administering one of the administered compounds or agents separately, followed by administration of the second. The selected regimen allows for concurrent administration because the reaction caused by the activation of the aminosterol does not require systemic absorption of the aminosterol into the blood, and thus eliminates concerns about the possibility of systemic drug-drug interactions between the aminosterol and the administered drug. X. definition

[0197] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0198] Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art.Any suitable materials and / or methods known to one of ordinary skill in the art can be used to perform the methods described herein.

[0199] As used in the specification of the present invention and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" can be used interchangeably and are also intended to include the plural forms and belong to each meaning. 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 excluding combinations when interpreted as an alternative ("or").

[0200] As used herein, the phrase "therapeutically effective amount" means a dose of an aminosterol or a salt or derivative thereof that provides a specific pharmacological effect (for which one or more compounds are administered). It should be emphasized that a therapeutically effective amount is not always effective in achieving the desired effect in a given subject, even if such a dose is considered a therapeutically effective amount by a person skilled in the art. Exemplary doses are provided herein only for convenience. Those skilled in the art may adjust these amounts according to standard practices required for treating a particular subject. A therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and / or the severity of the subject's condition. For example, a person skilled in the art will understand that a therapeutically effective amount for treating a small individual may be different from a therapeutically effective amount for treating a large individual.

[0201] As used herein, the term "administering" includes prescription for administration as well as actual administration, and includes physical administration by the subject being treated or another person.

[0202] As used herein, "subject" or "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.

[0203] "Derivatives" of the aminosterols described herein may have one or more chemical modifications that do not change, drastically reduce, or improve the activity of the aminosterol. The "activity" may include pharmacological targets and affinities, and thus include variations in affinity for different subtypes of specific receptor targets. "Derivatives" of aminosterols may introduce modifications well known in the field of medicinal chemistry to "mimic" the original spatial and charge characteristics of a portion of the original structure to improve the therapeutic properties of the aminosterol. Generally speaking, such modifications are introduced to affect metabolism, ease of administration, biodistribution, or any combination thereof. Examples of these variants or derivatives include, but are not limited to, (1) substitution of sulfate or carboxylic acid moieties by sulfonates, sulfates, phosphates, carboxylates, or other selected anionic moieties to avoid metabolic removal of sulfate moieties and oxidation of cholesterol side chains; (2) replacement of hydroxyl groups by non-metabolizable polar substituents (such as fluorine atoms) to prevent their metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the sterol ring system. Other derivatives include replacement of one or more hydrogens of the aminosterol with deuterium or unsaturation of any one or more CC single bonds of the aminosterol. The pharmaceutical composition may include one or more pharmaceutically acceptable carriers or excipients.

[0204] As used herein, the terms "comprising" or "comprises" are intended to indicate that the compositions and methods include the elements, but do not exclude other elements. When used to define compositions and methods, "essentially consisting of" indicates the exclusion of other elements that have any essential meaning to the combination for the purpose. Thus, a composition consisting essentially of the elements defined herein will not exclude other materials or steps that have no substantial effect on the basic and novel features of the claimed invention. "Consisting of" means not only excluding trace elements but also excluding other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention. When an embodiment is defined by one of these terms (e.g., "comprising"), it should be understood that the disclosure also includes optional embodiments, such as "essentially consisting of" and "consisting of" for the embodiment.

[0205] "Substantially" or "essentially" means nearly all or completely, such as 95%, 96%, 97%, 98%, 99% or more of a given quantity.

[0206] The term "about" will be understood by those of ordinary skill in the art and will vary to a certain extent depending on the context in which it is used. If certain usages of the term are unclear to those of ordinary skill in the art given the context in which the term is used, "about" will mean an increase or decrease of up to 10% of the particular term. For example, in some embodiments, it will mean an increase or decrease of 5% of the particular term. Certain ranges present herein are preceded by the term "about". The term "about" used herein provides literal support for the exact numerical value preceding it and for the numerical value approaching or approximating the numerical value preceding the term. When determining whether a number is approaching or approximating a specifically quoted numerical value, the approaching or approximate unquoted numerical value can be a numerical value that provides a substantial equivalent of the numerical value specifically quoted in the context in which it exists.

[0207] Where a numerical range is provided, it is understood that unless the context clearly indicates otherwise, any values ​​between the upper and lower limits of the range and any other stated or intervening values ​​within the range, up to one-tenth of the unit of the lower limit, are encompassed within the present invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the present invention, subject to any explicitly excluded limits in the stated range. If the stated range includes one or both of the stated limits, ranges excluding either or both of those included limits are also encompassed within the present disclosure.

[0208] As used herein, the term "treatment" or "treating" means any treatment of a disease or condition or related disorder in a patient. Inhibiting or preventing the disease or condition, i.e., preventing or inhibiting the development of clinical symptoms (such as neurological deficits caused by cerebral ischemia), providing neuroprotection and / or alleviating the disease or condition, i.e., causing the elimination of clinical symptoms (e.g., improving nervous system function or reducing nervous system deficits) are also included in "treatment".

[0209] In some embodiments, "treating" encompasses "providing neuroprotection" to the subject. "Treating" and "providing neuroprotection" may include administering a therapeutic agent(s) or composition disclosed herein.

[0210] "Pharmaceutically acceptable salt" refers to a salt of a compound that is suitable for pharmaceutical use and is derived from various organic and inorganic counterions well known in the art. When the compound contains an acidic functional group, pharmaceutically acceptable salts include, by way of example only, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and tetraalkylammonium salts. When the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Stahl and Wermuth, ed., "Handbook of Pharmaceutically Acceptable Salts," (2002), Verlag Helvetica Chimica Acta, Zürich, Switzerland), the teachings of which are associated with pharmaceutically acceptable salts are incorporated herein by reference, discussing various pharmaceutical salts, their selection, preparation, and use.

[0211] As used herein, "reductive amination" refers to a synthetic method in which a ketone or aldehyde reacts with an amine to form an imine or iminium ion, which is subsequently reduced to form an amine. Methods and processes for effecting reductive amination are known to those of ordinary skill in the art. See, for example, Dangerfield et al., J. Org. Chem., 2010, 75, 5470-5477; Taibakhsh et al., Synthesis, 2011, 490-496; and Abdel-Magid et al., J. Org. Chem., 1996, 61, 3849-3862; the entire disclosures of which are incorporated herein by reference.

[0212] It is understood that in any aminosterol or steroid compound disclosed herein, the stereochemical configurations of carbon 17 and carbon 20 are identically represented as depicted by the two steroid nucleus examples shown below, i.e., as shown below, the stereochemical configurations of carbon 17 and carbon 20 are identical:

[0213] In any of the embodiments herein, where the ring carbons of the aminosterol (or the corresponding carbons of the synthetic intermediates corresponding to Compound IR or -S) marked with the exclamation mark below are not stereodefined, embodiments where these carbons are defined as shown in Formula II are within the scope of the invention:

[0214] The embodiments described herein are further illustrated by, but not limited to, the following working examples. Example Example 1: Identification of metabolites of ENT-03 in rat plasma and urine samples

[0215] The purpose of this example was to identify potential metabolites of ENT-03S and predict the possible metabolic pathways of ENT-03S in rat plasma and urine samples.

[0216] Equal amounts of rat urine (50 μL) were obtained from different animals at different time points after administration of ENT-03S. For plasma samples, Hamilton pooling was used. After pooling, 50 μL of matrix was mixed with 200 μL of methanol (containing 0.1% formic acid), vortexed for 100 seconds and then centrifuged at 16,000 g for 10 minutes at 4°C to precipitate protein. 100 μL of supernatant was transferred to a new tube and the supernatant was diluted with 100 μL of pure water, mixed and analyzed using UPLC-MS / MS.

[0217] A total of 9 ENT-03S metabolites were detected in rat plasma and urine samples. The metabolite forms of ENT-03S in rat plasma and urine samples are listed in Table 2. All metabolites observed were less than 5% of the drug-related substances in male rat plasma samples. The peak areas of metabolites and parent drugs in rat urine samples were very low, and no major metabolites were observed. Note: Relative peak areas were determined from extracted ion chromatograms of rat plasma and urine samples. The m / z values ​​were obtained from the MS full scan spectra of rat plasma and urine samples. “-”: Not observed.

[0218] Materials and Instrument Information: ENT-03S, which has a molecular weight of 618.98 g / mol (free base), and a molecular weight of 764.82 g / mol, and an HPLC purity of 97.37%, was used for this experiment. ENT-03S was stored at 2-8°C.

[0219] After ENT-03S at a dose of 10 mg / kg was subcutaneously administered to male SD rats with bile duct cannulated, plasma and urine samples were obtained from male rats at different time points, as detailed in Table 3. Before use, the samples were transferred to dry ice and stored at -80°C.

[0220] Other chemicals and materials: All inorganic reagents, organic solvents and water must be at least of analytical laboratory grade, see Table 4 for details.

[0221] Instrument information: The instruments used in this example are detailed in Table 5.

[0222] Study design: After administration of ENT-03S, the same number of rat urine samples (50 μL) were obtained from different animals at different time points in study No. PH-DMPK-ETR-21-001. For plasma samples, Hamiltonian pooling method was used. The specific sampling volume at each time point is shown in Table 6 below:

[0223] Sample preparation: For urine and bile samples, after each set of samples was administered, the same volume of samples (50 μL) was obtained from different animals at different time points, and the same set of samples was thoroughly mixed. After pooling, 50 μL of matrix and 200 μL of methanol (containing 0.1% formic acid) were mixed, vortexed for 100 seconds and then centrifuged at 16,000 g for 10 minutes at 4°C to precipitate proteins. 100 μL of supernatant was transferred to a new tube and the supernatant was diluted with 100 μL of pure water and mixed. The samples were then analyzed using UPLC-MS / MS.

[0224] Data Analysis: UPLC-MS / MS was used for sample analysis and was performed using a Dionex UltiMate 3000 / Vanquish UHPLC system. For mass spectrometry (MS), all analyses were performed using a Q-Exactive instrument (Thermo Fisher). Full MS scans were used to trigger data-dependent acquisition (DDA) of MS / MS scan spectra. Compound-related parameters were optimized using ENT-03S. DDA settings were used to trigger the acquisition of MS for the top 5 ions in terms of intensity among all ions. 2 Spectrum, excluding impurity ions (m / z 149.02332, m / z 279.15909, m / z 391.28429 and m / z 445.12003), appeared 3 times, lasted 10s. Dynamic exclusion setting: automatically exclude acquired ions. The parameters of the biological analysis samples are shown in Table 7. Table 7 Table 7 Table 7

[0225] Data analysis: Data were acquired and processed using Xcalibur v4.1 software (Thermo Fisher Scientific) and CompoundDiscoverer 3.1 (Thermo Fisher Scientific) and Excel (Microsoft 2016).

[0226] Research results: The metabolite information of ENT-03S is shown in Table 8. Note: Relative peak areas were determined from extracted ion chromatograms of rat plasma and urine samples. “-”: Not observed. The m / z values ​​were obtained from the MS full scan spectra of rat plasma and urine samples.

[0227] XIC chromatograms of full MS / ddMS2 scans of ENT-03S in rat plasma and urine samples are shown in Figure 2. Figure 1 – Figure 2 The MS / MS spectra of ENT-03S and its metabolites are shown in Figure 3 – Fig.12 The possible metabolic pathways of ENT-03S in rat plasma and urine samples are shown in Fig.13 shown.

[0228] In particular, the XIC chromatogram of rat plasma sample is as follows Figure 1 As shown, and the XIC chromatogram of rat urine sample is as follows Figure 2 shown. Figure 3 The MS / MS fragmentation spectrum of ENT-03S is shown. Figure 4 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M1-PU) is shown. Figure 5 The fragmentation spectrum of the ENT-03S derivative (designated M2-PU) is shown. Figure 6 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M4-PU) is shown. Figure 7 The fragmentation spectrum of the ENT-03S derivative (designated M5-PU) is shown. Figure 8 The fragmentation spectrum of the ENT-03S derivative (designated M6-PU) is shown. Fig. 9 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M7-PU) is shown. Fig.10 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M8-PU) is shown. Fig.11 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M9-PU) is shown. Fig.12 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M10-PU) is shown. Example 2: Identification of metabolites of ENT-03 in rat bile samples

[0229] The purpose of this example is to identify potential metabolites of ENT-03S and predict the possible metabolic pathways of ENT-03S in rat bile samples.

[0230] After administration of ENT-03S, the same volume of rat bile samples (50 μL) were obtained from different animals at different time points. 50 μL of matrix and 200 μL of methanol (containing 0.1% formic acid) were mixed, vortexed for 100 seconds and then centrifuged at 16,000g for 10 minutes at 4°C to precipitate proteins. 100 μL of supernatant was transferred to a new tube and the supernatant was diluted with 100 μL of pure water, mixed and analyzed using UPLC-MS / MS.

[0231] A total of 16 ENT-03S metabolites were detected in rat bile samples. The metabolite information of ENT-03S in rat bile samples is listed in Table 9. The peak area percentages of the parent drug and each metabolite were determined by semi-quantitative estimation using the extracted ion chromatogram peak areas of all drug-related substances detected in the samples. Metabolites with peak area percentages ≥10% were considered to be the major metabolites of ENT-03S. Dealkylated and oxidized metabolite M1 and dealkylated, oxidized and dehydrogenated metabolite M4 were the major metabolites in male rat bile samples, with peak area percentages of 21.50% and 15.28%. Note: Relative peak areas were determined from extracted ion chromatograms of rat bile samples. The m / z values ​​were obtained from the MS full scan spectrum of rat bile samples. “-”: Not observed.

[0232] Materials and Instrument Information: ENT-03S, which has a molecular weight of 618.98 g / mol (free base), and a molecular weight of 764.82 g / mol, and an HPLC purity of 97.37%, was used for this experiment. ENT-03S was stored at 2-8°C.

[0233] After ENT-03S at a dose of 10 mg / kg was subcutaneously administered to male SD rats with bile duct cannulated, bile samples were obtained from male rats at different time points, as detailed in Table 10. Before use, the samples were transferred to dry ice and stored at -80°C.

[0234] Other chemicals and materials: All inorganic reagents, organic solvents and water must be at least of analytical laboratory reagent grade and are detailed in Table 11.

[0235] Instrument information: The instruments used in this example are detailed in Table 12.

[0236] Study design: After administration of ENT-03S, equal volumes of rat bile samples (50 μL) were obtained from different animals at different time points in study No. PH-DMPK-ETR-21-001. 50 μL of matrix and 200 μL of methanol (containing 0.1% formic acid) were mixed, vortexed for 100 seconds and then centrifuged at 16,000 g for 10 minutes at 4°C to precipitate proteins. 100 μL of supernatant was transferred to a new tube and diluted with 100 μL of purified water, mixed and analyzed using UPLC-MS / MS.

[0237] Sample preparation: For bile samples, the same volume of samples (50 μL) were obtained from different animals at different time points after administration of each group of samples, and the samples in the same group were thoroughly mixed.

[0238] Data Analysis: UPLC-MS / MS was used for sample analysis and was performed using a Dionex UltiMate 3000 / Vanquish UHPLC system. For mass spectrometry (MS), all analyses were performed using a Q-Exactive instrument (Thermo Fisher). Full MS scans were used to trigger data-dependent acquisition (DDA) of MS / MS scan spectra. Compound-related parameters were optimized using ENT-03S. DDA settings were used to trigger the acquisition of MS for the top 5 ions in terms of intensity among all ions. 2 Spectrum, excluding impurity ions (m / z 149.02332, m / z 279.15909, m / z 391.28429 and m / z 445.12003), appeared 3 times, lasted 10s. Dynamic exclusion setting: automatically exclude acquired ions. The parameters of the biological analysis samples are shown in Table 13. Table 13 Table 13

[0239] Data Analysis: The analysis was performed using a Thermo Fisher Q-Exactive instrument. Full MS scans were used to trigger data-dependent acquisition (DDA) of MS / MS scan spectra. Compound-dependent parameters were optimized using ENT-03S. DDA settings were used to trigger MS acquisition of the top 5 intensities of all ions. 2Spectra, excluding impurity ions (m / z 149.02332, m / z 279.15909, m / z 391.28429 and m / z 445.12003), appeared 3 times and lasted for 10 s. Data were collected and processed using Xcalibur v4.1 software (Thermo Fisher Scientific) and Compound Discoverer 3.1 (Thermo Fisher Scientific) and Excel (Microsoft 2016).

[0240] Research results: The metabolite information of ENT-03S is shown in Table 14. Note: Relative peak areas were determined from extracted ion chromatograms of rat plasma and urine samples. “-”: Not observed. The m / z values ​​were obtained from the MS full scan spectra of rat plasma and urine samples.

[0241] Full MS / ddMS of ENT-03S in bile samples 2 The scanned XIC chromatogram is as follows Fig.15 The MS / MS spectra of ENT-03S and metabolites are shown in Fig.16 – Fig.32 The possible metabolic pathways of ENT-03S from bile samples are shown in Fig.33 shown.

[0242] In particular, the XIC chromatogram from rat bile sample is as follows Fig.15 As shown, Fig.16 The MS / MS fragmentation spectrum of ENT-03S is shown. Fig.17 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M1-RB) is shown. Fig.18 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M2-RB) is shown. Fig.19 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M3-RB) is shown. Fig. 20 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M4-RB) is shown. Fig.21 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M5-RB) is shown. Fig. 22 The full MS spectrum of the ENT-03S derivative (designated M6-RB) is shown. Fig.23 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M8-RB) is shown. Fig.24 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M9-RB) is shown. Fig.25 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M10-RB) is shown. Fig.26 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated ENT-25S) (M11-RB) is shown. Fig. 27 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M12-RB) is shown. Fig.28 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M13-RB) is shown. Fig.29 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M14-RB) is shown. Fig.30 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M15-RB) is shown. Fig.31 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M16-RB) is shown. Fig.32 The MS / MS fragmentation spectrum of the ENT-03S derivative (designated M17-RB) is shown. Example 3

[0243] The purpose of this example was to further characterize the novel aminosterol designated ENT-19.

[0244] The novel aminosterol 3-((aminopropyl)amino)butyric acid-7α-hydroxy-25[R,S]-cholestanoic acid HCl salt, named ENT-19, has the following chemical structure:

[0245] The compound has a molecular weight of 649.78 (576.86) and a C 34 H 60 The chemical formula of N2O5-2HCl.

[0246] The purity of ENT-19 was found to be higher than 95% (95.27%) by HPCL, and the compound was confirmed to be structurally consistent by LC-MS (Shimadzu LCMS 2020). The test parameters are shown in Table 15 below. Table 15

[0247] The chromatogram of the compound is Fig.14 The characteristics of peaks 1-5 are shown in Table 16. Table 16 peak Retention time (min) area high Peak area percentage 1 12.385 50032 9073 1.002 2 12.555 4757714 681512 95.266 3 12.915 31229 5452 0.625 4 13.104 99850 14337 1.999 5 13.993 55321 14468 1.108 Example 4: Preparation of aminosterol subcutaneous preparation

[0248] The purpose of this example is to describe the preparation of a subcutaneous formulation of aminosterol ENT-03S. The structure of ENT-03S is shown below:

[0249] Preparation of a 10 ml formulation sample includes the following steps: First, 2.51 grams of 2-HPβ cyclodextrin powder and 0.5 grams of ENT-03S (free base sodium salt) powder are added to a container and the powders are thoroughly mixed. 7.5 ml of distilled water is added to the container and the mixture is stirred or shaken to obtain a transparent solution containing a small amount of undissolved solids. The solution is heated to 40°C until all particles are dissolved. The solution is adjusted to pH 7.3 by adding 1M H3PO4 and left at room temperature for 24 hours, during which time the pH rises to about 7.6. Then an additional 1M H3PO4 is added to bring the pH to 7.4-7.5. The solution volume is adjusted to 10 ml with distilled water. The solution is sterile filtered through a 0.2μm cellulose acetate membrane and then stored at room temperature.

[0250] The final composition consisted of: ENT-03S 50mg / ml (active ingredient) 2-Hydroxypropyl β-cyclodextrin 25% (w / v) Phosphate, about 80 mM pH 7.4-7.6.

[0251] This example demonstrates the successful preparation of an aminosterol cyclodextrin formulation suitable for subcutaneous administration. Example 5: Evaluation of the subcutaneous aminosterol cyclodextrin formulation of Example 4

[0252] The purpose of this example is to evaluate the aminosterol cyclodextrin preparation prepared in Example 4.

[0253] An insulin syringe was filled with 1 ml of the subcutaneous formulation of ENT-03S prepared in Example 4. The contents of the syringe were injected subcutaneously into the abdominal area of ​​a human subject, causing significant swelling. There was a slight stinging sensation that disappeared after a few minutes. After one hour, the swelling disappeared.

[0254] This example demonstrates that aminosterol cyclodextrin formulations can be administered subcutaneously with little or no side effects, such as pain upon administration. Example 6: Pharmacokinetic Evaluation of the Aminosterol Cyclodextrin Formulation of Example 4

[0255] The purpose of this example was to evaluate the pharmacological properties of the aminosterol cyclodextrin formulation as prepared in Example 1.

[0256] In this example, ENT-03S was formulated with unmodified β-cyclodextrin at a concentration of 25 mg / ml ENT-03 and 20% β-cyclodextrin, buffered with phosphate to pH 7.5.

[0257] Male Sprague-Dawley rats were subcutaneously administered ENT-03-cyclodextrin formulation at a dose of 10 mg / kg. Blood samples were taken from the tail vein at different times to determine the concentration of ENT-03 and determine the PK parameters.

[0258] As shown in Table 17 and Fig.34 As shown, ENT-03 diffused rapidly from the subcutaneous administration site into the blood, reaching a peak concentration at 2 hours and gradually decreasing within 72 hours. Table 17

[0259] T 1 / 2 , T max , C max , AUC last , AUC inf And additional pharmacokinetic parameters are shown in Table 18 below. Table 18 Summary of ENT-03S SC plasma pharmacokinetic parameters SC dose 10 mg / kg PK parameters unit Rat 1 Rat 2 Rat 3 Mean SD CV(%) <![CDATA[T 1 / 2 ]]> h 19.4 27.5 20.3 22.4 4.4 19.8 <![CDATA[T max ]]> h 2.00 2.00 2.00 2.00 0.00 0.000 <![CDATA[C max ]]> ng / mL 31300 32700 33300 32433 1026 3.16 <![CDATA[AUC last ]]> h*ng / mL 715608 944488 811185 823760 114957 14.0 <![CDATA[AUC Inf ]]> h*ng / mL 767327 1110949 882526 920267 174892 19.0 <![CDATA[AUC_ ％Ex trap _obs]]> ％ 6.74 15.0 8.08 9.9 4.4 44.5 <![CDATA[MRT Inf _obs]]> h 24.3 36.3 27.2 29.3 6.3 21.4 <![CDATA[AUC last / D]]> h*mg / mL 71561 94449 81119 82376 11496 14.0 F ％ NA NA NA NA NA NA Example 7: Comparison with non-cyclodextrin aminosterol formulations

[0260] The benefits provided by the aminosterol cyclodextrin formulations disclosed herein can be appreciated by comparing the pharmacokinetics of an aqueous solution of ENT-03S without cyclodextrin at a concentration of 2 mg / ml ENT-03S at pH 7.4.

[0261] The dose selected was the maximum ENT-03S concentration that could be delivered to rats without causing significant local tissue necrosis.

[0262] Injection of 0.1 ml of this preparation into human subjects causes severe pain within seconds that lasts for hours, accompanied by local swelling, redness, and fever that lasts for days.

[0263] The experiment was conducted in male Sprague-Dawley rats using the same experimental protocol as described above. The formulation was administered subcutaneously at a dose of 10 mg / kg. The data obtained are shown in Tables 19 and 20 and Fig.35 shown. Table 19 Table 20 PK parameters unit Rat 1 Rat 2 Rat 3 Mean SD CV(%) <![CDATA[T 1 / 2 ]]> h NA NA NA NA NA NA <![CDATA[T max ]]> h 24.0 24.0 24.0 24.0 0.0 0.000 <![CDATA[C max ]]> ng / mL 43300 40000 54300 45867 7488 16.3 <![CDATA[AUC last ]]> h*ng / mL 675103 559927 749498 661509 95514 14.4 <![CDATA[AUC Inf ]]> h*ng / mL NA NA NA NA NA NA <![CDATA[AUC_ ％Ex trap _obs]]> ％ NA NA NA NA NA NA <![CDATA[MRT Inf _obs]]> h NA NA NA NA NA NA <![CDATA[AUC last / D]]> h*mg / mL 71561 94449 81119 82376 9552 14.4 F ％ NA NA NA NA NA NA

[0264] The pharmacokinetic properties of ENT-03S solution clearly indicate that the aminosterol compound enters the bloodstream slowly from the injection site. Fig.35 Maximum concentrations were not achieved within 72 hours. The slow entry of ENT-03 into the circulation may be due to binding to polyanionic proteoglycans present within the subcutaneous layer of the skin and local tissue damage. Example 8: Preparation of an Exemplary Cyclodextrin Formulation of ENT-03

[0265] The purpose of this example was to prepare an exemplary cyclodextrin formulation of ENT-03.

[0266] The resulting preparation consists of: 50mg / ml ENT-03 (active ingredient) 2HPβCD 25%(w / v) 40 mM sodium phosphate pH 7.4-7.5 Final volume: 12ml

[0267] During the preparation process, 840 mg ENT-03S HCl (70%) was added to the container. Next, 8 ml of water was added to the ENT-03S powder and the powder was completely dissolved. Next, 1800 mg of 2HPβCD (sigma #778966) was added to the ENT-03S solution and completely dissolved. Next, 0.960 ml of 0.5M Na2HPO4 (pH about 4.5) (about 480 micromolar) was added. 1M NaOH was titrated (about 1 ml / 1 millimole to give a final pH of 7.4-7.5). Water was added to give a final volume of 12 ml. Finally, the composition was sterile filtered through a 0.2 μm surfactant-free cellulose acetate membrane.

[0268] This example demonstrates that a cyclodextrin formulation of ENT-03 suitable for intravenous, subcutaneous, or intramuscular administration was successfully prepared. Example 9: Preparation of an Exemplary ENT-03 Cyclodextrin Formulation

[0269] The purpose of this example is to prepare an exemplary ENT-03 cyclodextrin formulation. The formulation method described in this example is for subcutaneous ENT-03S Na + Batch (e.g., for 402.5 mL batch size).

[0270] The final formulation consists of the following ingredients:

[0271] In the first step, 100.7 g of (2-hydroxypropyl)-β-cyclodextrin was added to a sterile 1 L glass bottle, and then 300 mL of accurately measured USP pure water was added to the container. The solution was mixed well with a magnetic stirring plate until it formed a clear solution.

[0272] Next, the (2-hydroxypropyl)-β-cyclodextrin solution was transferred to a solution containing 23 g ENT-03Na + The powder (API) was placed in a HDPE container. The solution was mixed manually and then transferred to a 37°C water bath on a magnetic stirring plate. The ingredients were then further mixed and the solids dissolved while heating until a complete solution was formed (pH>9). Undissolved particles were allowed to remain at this stage. The solution was then titrated with 1 M H3PO4 to adjust the pH to 7.5.

[0273] Next, while the solution was still in a 37°C water bath, the pH was adjusted to 7.3 (± 0.1) by slowly adding more 1 M H3PO4. The mixture was continued to be stirred to mix. The final volume (QS) was adjusted to 402.5 mL by adding ~102.5 mL USP purified water. The solution was then thoroughly mixed using a magnetic stirring plate until all particles were dissolved and the solution was still clear at 37°C.

[0274] The solution was transferred to room temperature (RT) and left at RT for ~24 hours. After 24 hours, the pH was measured and adjusted to pH 7.3. The solution was then filtered through a 0.2 μm filter membrane (PES) into a new sterile container (or the solution was filtered into a final sterile BDS container (bag) for a Microcell filling machine). The formulated DP solution was stored at RT and bottled within 24 hours of preparation. ***

[0275] While certain embodiments have been illustrated and described, it will be understood that changes and modifications may be made therein in accordance with ordinary skill in the art without departing from the broader aspects of the technology as defined in the following claims.

[0276] The embodiments described illustratively herein can be appropriately implemented without any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc. should be interpreted broadly without limitation. In addition, the terms and expressions used herein have been used as descriptive terms rather than limiting terms, and when using such terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications can be made within the scope of the claimed technology. In addition, the phrase "essentially consisting of..." will be understood to include those elements specifically enumerated and those additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any unspecified elements.

[0277] The present disclosure is not limited to the specific embodiments described in this application. Many modifications and variations can be made without departing from the spirit and scope thereof, which will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the present disclosure, in addition to those listed herein, will be apparent to those skilled in the art from the above description. These modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims and the full range of equivalents enjoyed by the claims. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds or compositions that can of course vary. It should also be understood that the terms used herein are only used for the purpose of describing specific embodiments and are not intended to be restrictive.

[0278] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0279] As will be appreciated by those skilled in the art, for any and all purposes, particularly in providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof, including endpoints. Any listed range can be easily identified as a full description, and the same range can be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily divided into a lower third, a middle third, and an upper third, etc. It will also be appreciated by those skilled in the art that all languages ​​such as "to", "at least", "higher than", "lower than", etc. include the stated quantities and refer to ranges that can subsequently be divided into subranges as discussed above. Finally, as will be appreciated by those skilled in the art, a range includes each individual member.

[0280] All publications, patent applications, issued patents, and other documents mentioned in this specification are incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0281] Other embodiments are listed in the following claims.

Claims

1. An aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof having a structure selected from the following:

2. An aminosterol compound of formula (I): in: R 1 is optionally substituted C1-C8 alkyl, optionally substituted 2 to 8-membered heteroalkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; R 2 H or -C(O)R 5 , where R 5 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl or optionally substituted C3-C8 cycloalkyl; and R 3 and R 4 Each is independently H or optionally substituted 2 to 14-membered heteroalkyl; or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof; Wherein the compound is not: (24R)-3β-({3-[(3-aminopropyl)amino]propyl}amino)-7α-hydroxycholestane-24-yl hydrosulfate (squalamine); (3R,6R)-6-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptyl-3-hydrogen sulfate (aminosterol 1436); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (ENT-03); (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-03); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptyl-2,3,3-d3 acid (ENT-03d3); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-(benzoyl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2-d-ol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2-d-ol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d-ol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2-d-ol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptanoic acid; (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-hydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-hydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)heptan-3-one; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)heptan-3-one; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)heptan-3-one; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid methyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid isopropyl ester; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,3-dihydroxy-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2,3-diol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2,3-diol; (3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylheptane-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylhept-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-7,12-diol; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7,12-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-05); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-ammoniobutyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoate (ENT-06); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-ammoniopropyl)ammonio)butyl)ammonio)propyl)ammonio)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-3-hydroxy-2-methylheptanoate-2,3-d2; (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-03); (2R,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (2S,6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (2R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (R)ENT-06); (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid (C 25 (S)ENT-06); (6R)-6-((3S,5R,7R,10S,13R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-squalamine); (3R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthran-17-yl)-2-methylheptane-3-yl hydrosulfate-3-d (24-D1-squalamine); or (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptane-3-yl hydrosulfate-1,1,1,2-d4 (D7-1436).

3. The aminosterol compound according to claim 2, wherein R 1 Selected from 4. The aminosterol compound according to claim 2, wherein R 2 For H.

5. The aminosterol compound according to claim 2, wherein R 3 and R 4 Independently selected from H, 6. The aminosterol compound according to claim 2, wherein R 3 H and R 4 Independently selected from 7. The aminosterol compound according to any one of claims 1 to 6, which is a hydrochloride salt.

8. The aminosterol compound according to any one of claims 1 to 6, which is a sodium salt.

9. The aminosterol compound according to any one of claims 1 to 6, wherein relative to C 25 The diastereomeric excess (de) of carbon is about 80% to about 90%, about 90% to about 95%, about 95% to about 99%, about 99% to about 99.9%, or about 100%.

10. The aminosterol compound according to any one of claims 1 to 9, wherein at least one hydrogen of the aminosterol compound is replaced with deuterium.

11. A composition comprising the aminosterol compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable carrier or excipient.

12. The composition according to claim 11, comprising: (a) one or more of: an aqueous carrier, a buffer, a sugar; and / or a polyol compound; and optionally (b) wherein the composition further comprises at least one additional active agent.

13. The composition according to any one of claims 11-12, wherein the composition is formulated as: (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) a dosage form selected from the group consisting of a liquid dispersion, a gel, an aerosol, an ointment, a cream, a lyophilized preparation, a tablet, and a capsule; (c) a dosage form selected from the group consisting of a controlled release formulation, a fast melt formulation, a delayed release formulation, a sustained release formulation, a pulsed release formulation, and a combination of immediate and controlled release formulations; (d) for oral administration; (e) As oral tablets or capsules; (f) for intranasal administration; or (g) Any combination of (a), (b), (c), (d), (e) and / or (f).

14. An aqueous aminosterol composition comprising: (a) an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof; and (b) cyclodextrin, wherein the formulation is buffered to a pH of about 4 to 9, and The cyclodextrin is reversibly bound to the aminosterol molecule or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof to form a cyclodextrin-aminosterol complex.

15. The aqueous aminosterol composition of claim 14, wherein the cyclodextrin is unmodified β-cyclodextrin or unmodified γ-cyclodextrin.

16. The aqueous aminosterol composition according to claim 14 or 15, wherein: (a) the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD); or (b) The cyclodextrin is sulfobutyl ether-β-cyclodextrin (SBE-β-CD).

17. The aqueous aminosterol composition according to any one of claims 14-16, wherein the pH: (a) from about 5 to about 8 or from about 7 to about 8; or (b) is from about 7.3 to about 7.

5.

18. The aqueous aminosterol composition according to any one of claims 14 to 17, wherein the buffer is selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, histidine buffer, tris(hydroxymethyl)aminomethane (TRIS), sodium phosphate, citric acid, acetic acid, KH2PO4, CHES, borate, tromethamine, gluconic acid, lactic acid, tartaric acid, aspartic acid, glutamic acid, citric acid cycle intermediates, [tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), N-[ Tris(hydroxymethyl)methyl]glycine (Tricine), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TABSO), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES), dimethylarsonic acid (Cacadylate), and 2-(N-morpholino)ethanesulfonic acid (MES).

19. The aqueous aminosterol composition of any one of claims 14-18, wherein the composition is buffered with: (a) phosphates; or (b) Tris(hydroxymethyl)aminomethane (Tris).

20. The aqueous aminosterol composition of any one of claims 14-19, wherein the cyclodextrin is present in the following amounts: (a) from about 10% to about 40%, from about 15% to about 30%, from about 18% to about 25%, or from about 20% to about 25%; or (b) from about 20% to about 25%.

21. The aqueous aminosterol composition of any one of claims 14-20, wherein the aminosterol is present in the following amounts: (a) from about 20 mg / ml to about 75 mg / ml; (b) from about 30 mg / ml to about 65 mg / ml; (c) from about 40 mg / ml to about 55 mg / ml; or (d) about 50 mg / ml.

22. The aqueous aminosterol composition according to any one of claims 14 to 21, wherein the ratio of the concentration (in mg / ml) of the aminosterol to the cyclodextrin is: (a) from about 0.1 to about 0.75; (b) from about 0.15 to about 0.5; or (c) About 0.

20.

23. An aqueous aminosterol composition according to any one of claims 14 to 22 for intravenous, subcutaneous or intramuscular administration.

24. The aqueous aminosterol composition of any one of claims 1-19, wherein the aminosterol is selected from the group consisting of:

25. The aqueous aminosterol composition according to any one of claims 14 to 24, wherein: (a) the aminosterol is ENT-03S, and optionally wherein the composition comprises 50 mg / ml ENT-03S and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.5; (b) the aminosterol is ENT-03R, and optionally wherein the composition comprises 50 mg / ml ENT-03R and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.5; (c) the aminosterol is racemic ENT-03, and optionally wherein the composition comprises 50 mg / ml racemic ENT-03R and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.5; (d) the aminosterol is a racemic aminosterol selected from the following: Racemic ENT-01, racemic squalamine phosphate, racemic ENT-02, racemic ENT-04, racemic ENT-05, racemic ENT-06, racemic ENT-07, racemic ENT-08, racemic ENT-09, racemic ENT-10, racemic ENT-11, racemic ENT-12, racemic ENT-13, racemic ENT-14, racemic ENT-15, racemic ENT-16, racemic ENT-17, racemic ENT-18, racemic ENT-19, racemic ENT-20, racemic ENT-21, racemic ENT-22, racemic ENT-23, racemic ENT-24, racemic ENT-25 racemic ENT-25, racemic ENT-26, racemic ENT-27, racemic ENT-28, racemic ENT-29, racemic ENT-30, racemic ENT-31, racemic ENT-32, racemic ENT-33, racemic M10-PU / M14-RB, racemic M2-RB, racemic M3-RB, racemic M8-RB, racemic M5-RB, racemic M16-RB, racemic aminosterol compound A, racemic aminosterol compound B, and racemic aminosterol compound C, and optionally wherein the composition comprises 50 mg / ml racemic aminosterol and about 20 to about 25% 2HP-β-CD, buffered with phosphate to pH 7.3-7.

5.

26. A method of treating a subject in need thereof suffering from a condition susceptible to aminosterol therapy, comprising administering to the subject a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition according to any one of claims 1 to 25.

27. The method of claim 26, wherein the condition is associated with abnormal αS pathology, dopaminergic dysfunction and / or protein misfolding, and optionally wherein the misfolded protein is α-synuclein, tau, huntingtin, TDP-43 and / or amyloid-β.

28. A method for treating, preventing and / or slowing the onset or progression of a condition or disorder associated with abnormal αS pathology, dopaminergic dysfunction and / or protein misfolding in a subject in need thereof, comprising administering a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof or an aminosterol composition according to any one of claims 1 to 25.

29. The method of claim 28, wherein: (a) the symptom is selected from the group consisting of constipation, hallucinations, cognitive impairment, and inflammation; (b) the symptoms are associated with a synaptic disorder, 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 synaptic disease, a neurodegenerative disease, or a nervous system disease or disorder; (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.

30. The method of claim 29, wherein: (a) the neurosynaptic disease, neurodegenerative disease or nervous system disease or disorder is selected from the group consisting of 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, Guadeloupian Parkinsonism, spinocerebellar ataxia, parkinsonism, traumatic brain injury, degenerative processes associated with aging and senile dementia; (b) the mental or behavioral disorder is selected from the group consisting of depression, autism, autism spectrum disorder, Down syndrome, Gaucher's disease, Krabbe's disease, lysosomal disorders affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, hallucinations and delusions, 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 disorders, sleep apnea, and cognitive impairment; or (c) the cerebral or systemic ischemic disorder or condition is selected from the following: microangiopathy, cerebral ischemia during delivery, cerebral ischemia during / after cardiac arrest or resuscitation, cerebral ischemia caused by intraoperative problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia caused by stenosis of the cerebral artery supplying blood, 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, acromial ischemia, renal artery stenosis, diabetic retinopathy, malaria-related thrombosis, artificial heart valves, anemia, hypersplenism, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction defects, hypertension, hypotension, diabetes and pulmonary edema.

31. A method of inhibiting, preventing and / or slowing the occurrence or progression of appetite or weight gain and / or one or more related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof or an aminosterol composition according to any one of claims 1 to 25.

32. A method for improving or eliminating impaired reproductive function, impaired fertility and / or impaired reproductive behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof or an aminosterol composition according to any one of claims 1-25.

33. A method for treating, preventing and / or ameliorating diabetes in a subject in need thereof, wherein the diabetes may be type 1 or type 2 diabetes, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition according to any one of claims 1 to 25.

34. The method according to any one of claims 26 to 33, wherein: (a) the method of administration includes oral, nasal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracisternal, transdermal or any combination thereof; and / or (b) The administration method is nasal administration, oral administration or a combination thereof.

35. The method of any one of claims 26-34, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof comprises: (a) from about 0.1 to about 20 mg / kg of subject body weight; (b) from about 0.1 to about 15 mg / kg of subject body weight; (c) from about 0.1 to about 10 mg / kg of subject body weight; (d) from about 0.1 to about 5 mg / kg of subject body weight; (e) from about 0.1 to about 2.5 mg / kg of subject body weight; (f) about 0.001 to about 500 mg / day; (g) from about 0.001 to about 250 mg / day; (h) from about 0.001 to about 125 mg / day; (i) from about 0.001 to about 50 mg / day; (j) about 0.001 to about 25 mg / day; (k) about 0.001 to about 10 mg / day; (l) from about 0.001 to about 6 mg / day; (m) from about 0.001 to about 4 mg / day; (n) about 0.001 to about 2 mg / day; (o) from about 1 to about 300 mg / day, wherein the administration is oral; or (p) from about 25 to about 500 mg / day, wherein the administration is oral.

36. The method of any one of claims 26-35, wherein the aminosterol compound or composition, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, is administered in combination with at least one additional active agent to achieve an additive or synergistic effect.

37. The method according to any one of claims 26 to 36, wherein: (a) administration of the composition comprises administration on an empty stomach, optionally within 2 hours of waking of the subject; and / or (b) the subject does not consume any food for about 60 to about 90 minutes after administration of the composition; and / or (c) the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is of a pharmaceutically acceptable grade; and / or (d) administering the hydrochloride salt of said aminosterol; and / or (e) administering the sodium salt of said aminosterol; and / or (f) The subject is a human.

38. The method according to any one of claims 26-37, further comprising: (a) determining a dose of an aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof for a subject, wherein the dose of the aminosterol is determined based on the effectiveness of the dose of the aminosterol in improving or eliminating the symptoms being evaluated, (b) then administering a composition comprising said amount of aminosterol to the subject for a period of time, wherein said method comprises: (i) identifying symptoms to be evaluated, wherein the symptoms are susceptible to aminosterol treatment; (ii) confirming the starting dose of aminosterol for the subject; (iii) administering increasing doses of an aminosterol to the subject over a period of time until an effective dose for the symptom being evaluated is identified, wherein the effective dose is the dose of the aminosterol at which improvement or elimination of the symptom is observed, and fixing the aminosterol dose at that level for that particular symptom in that particular subject.

39. The method of claim 38, wherein: (a) the composition is administered orally and: (i) an initial aminosterol dose ranging from about 10 mg to about 150 mg / day; (ii) the dose of the aminosterol for the subject after escalation is fixed in the range of about 25 mg to about 500 mg / day; and / or (iii) the dose of the aminosterol, or salt or derivative thereof, is increased in increments of about 25 mg; or (b) the composition is administered intranasally and: (i) an initial aminosterol dosage range of about 0.001 mg to about 3 mg / day; (ii) the dose of the aminosterol for the subject after escalation is fixed in the range of about 0.001 mg to about 6 mg / day; (iii) the dose of aminosterol administered to the subject after escalation is a subtherapeutic dose when administered orally or by injection; and / or (iv) the dose of the aminosterol is increased 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.

40. The method according to any one of claims 26 to 39, wherein: (a) the dosage of the aminosterol is increased every about 3 to about 5 days; and / or (b) if the assessed symptoms are severe, the initial aminosterol dose is higher; and / or (c) The symptoms are associated with abnormal α-synuclein pathology and / or dopaminergic dysfunction.

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