Aminosterol compound, aminosterol-cyclodextrin formulation and method of using the same

Abstract

Disclosed are novel amino steroid compounds, an amino steroid-cyclodextrin formulation more suitable for parenteral administration, and methods of using the same.

Description

Technical Field

[0001] · Cross-reference to Related Applications : This application claims the benefit of priority of U.S. Provisional Application No. 63 / 356,910, filed on Jun. 29, 2022, U.S. Provisional Application No. 63 / 459,107, filed on Apr. 13, 2023, and U.S. Provisional Application No. 63 / 461,875, filed on Apr. 25, 2023, the contents of which are hereby incorporated by reference in their entirety.

[0002] · Field of the Invention: This application generally relates to novel amino steroid compounds, amino steroid-cyclodextrin compositions, and methods of treatment using such compounds and compositions.

Background Art

[0003] Amino steroids are amino derivatives of steroids. Exemplary amino steroids include squalamine (ENT-01) and amino steroid 1436 (ENT-02) (also known as trodusquemine and MSI-1436). These amino steroids were discovered by Michael Zasloff from the spiny dogfish shark Squalus acanthias (U.S. Patent No. 5,192,756) and exhibit diverse pharmacological activities in mammalian systems. Amino steroid 1436 exhibits pharmacological effects that cause weight loss and adipose tissue mobilization in vertebrates (Zasloff et al., 2001). Squalamine has antiviral, antibiotic, antifungal, and anticancer activities and inhibits the aggregation of α-synuclein protein characteristic of Parkinson's disease.

[0004] Other recently disclosed amino steroids include (1) ENT-03 and ENT-05 (US Patent Publication No. 2023 / 0123701), (2) ENT-04, ENT-07, ENT-08, ENT-09, ENT-10 and ENT-11 (US Patent Publication No. 2023 / 0125585), and (3) ENT-06 (US Patent Publication No. 2022 / 0372066).

[0005] It is well understood that the stereochemical purity of a drug is important in certain treatments. Compounds with a single enantiomer or a stereostructure at the main carbon center have higher selectivity for biological targets, improved therapeutic indices, and better pharmacokinetics than mixtures of isomers.

[0006] Since such compounds are useful for the treatment of various human diseases, there is a need in the art for novel amino steroid compounds. Since amino steroid compounds are useful for the treatment of various human diseases, there is also a need in the art for novel pharmaceutical formulations of amino steroids. The present invention meets these needs. SUMMARY OF THE INVENTION

[0007] In one aspect, disclosed are 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 racemate 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, amino steroid compound A, amino steroid compound B, and amino steroid compound C or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, or derivatives thereof, and the structures of each compound are shown below: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chem.] [Chem.]

[0008] In another aspect, there is disclosed an amino steroid compound having the following chemical structure (Formula (I)) or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof: [Chem.] where R 1 is optionally substituted C1-C8 alkyl, optionally substituted 2-8 membered heteroalkyl, optionally substituted heterocyclyl, or optionally substituted C3-C8 cycloalkyl; R 2 is H or C(O)R 5 wherein 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 2-14 membered heteroalkyl; wherein the compound is not the following; (1) (24R)-3β-({3-[(3-aminopropyl)amino]propyl}amino)-7α-hydroxy cholestan-24-yl hydrogen sulfate (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-dimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl heptan-3-yl 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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptane-2,3,3-d3 acid (ENT-03 d3); (6)(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-Aminopropyl)amino)butyl)amino)propyl)amino)-7-(benzoyloxy)-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-d acid; (12) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-d acid; (13) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-d acid; (14) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-2-d acid; (15) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (35) Methyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; (36) Methyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (37) Methyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (38) Methyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (39) Isopropyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (40) Isopropyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (41) Isopropyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (42) Isopropyl (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (43) (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-methylheptan-2-yl)-10,13-dimethylhexadecahydro-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-methylheptan-2-yl)-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-hydroxy-2-methylheptane-2,3-d2 acid; (54) (2S,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-Aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadeca hydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadeca hydro-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-dimethylhexadeca hydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptan-3-yl-1,1,1,2-d4 hydrogen sulfate (D7-squalamine); (61)(3R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-3-yl-3-d hydrogen sulfate (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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(methyl-d3)heptan-3-yl-1,1,1,2-d4 hydrogen sulfate (D7-1436).

[0009] In another aspect, the aminosterol has the structure of formula (I), where R 1 is

Chemical formula

[0010] In another aspect, the amino steroid has the structure of formula (I), wherein R 2 is H.

[0011] In another aspect, the amino steroid has the structure of formula (I), wherein R 3 and R 4 are independently H, and

Chemical formula

[0012] In another aspect, the amino steroid has the structure of formula (I), wherein R 3 is H, R 4 is independently

Chemical formula

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

[0014] In a further aspect, deuterated amino steroid compounds are disclosed, wherein at least one hydrogen of the amino steroid compounds disclosed herein is replaced by deuterium.

[0015] In one aspect, there is provided a composition 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, intravesical, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, nebulization, inhalation, ocular, otic, topical, buccal, nasal and local administration; (b) a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) a dosage form selected from the group consisting of controlled release formulations, fast melting formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, and mixed formulations of immediate release and release control formulations; or (d) formulated in 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 nasal administration.

[0020] In another aspect of the disclosure, included is an aqueous amino steroid formulation comprising: (a) an amino steroid, 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 reversibly binds to the molecule of the amino steroid, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, to form a cyclodextrin-amino steroid complex. The cyclodextrin can be, for example, beta-cyclodextrin (such as unmodified beta-cyclodextrin) or gamma-cyclodextrin (such as unmodified gamma-cyclodextrin). In another aspect, the cyclodextrin can be sulfobutyl ether-beta-cyclodextrin (SBE-β-CD).

[0021] In another aspect of the disclosure, the pH can be from about 5 to about 8, or from about 7 to about 8. In one embodiment, the pH can 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 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 intermediate, [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), dimethylarsinate (Cacadylate), and 2-(N-morpholino)ethanesulfonic acid (MES). In certain embodiments, the aqueous amino steroid formulation is buffered with phosphate. In a further embodiment, the aqueous amino steroid formulation can be buffered with tris(hydroxymethyl)aminomethane (Tris).

[0023] In another embodiment of the present disclosure, 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%. Further, cyclodextrin may be present in an amount of about 20% to about 25%.

[0024] In one embodiment of the present disclosure, the amino steroid may be present in an amount of about 20 mg / ml to about 75 mg / ml. In another embodiment, the amino steroid may 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 of the amino steroid to the cyclodextrin (in mg / ml units) can be from about 0.1 to about 0.75. Further, the ratio of the concentration of the amino steroid to the cyclodextrin (in mg / ml units) can be from about 0.15 to about 0.5, or the ratio of the concentration of the amino steroid to the cyclodextrin (in mg / ml units) can be about 0.20.

[0026] In a further aspect of the present disclosure, the aqueous amino steroid formulation is for intravenous, subcutaneous or intramuscular administration.

[0027] In one embodiment of the present disclosure, the amino steroid is any amino steroid disclosed herein, including but not limited to ENT-01, squalamine phosphate, ENT-02 (amino steroid 1436), ENT-03, ENT-03S (C25 (S) ENT-03), ENT-03R (C25(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 racemate 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, amino steroid compound A, amino steroid compound B, and amino steroid compound C or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof. The structures of each compound are shown below: [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] One of these may be mentioned, but is not limited thereto.

[0028] In one embodiment of the present disclosure, the amino steroid is ENT-03S. In another embodiment, the amino steroid can be ENT-03R. In yet another embodiment, the amino steroid is racemic ENT-03.

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

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

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

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

[0033] The cyclodextrin formulation can also comprise a deuterated amino steroid compound, wherein at least one hydrogen of the amino steroid compound disclosed herein is replaced with deuterium.

[0034] In one aspect, there is provided a method of treating a subject having a condition treatable by an amino steroid and in need of treatment, the method comprising administering to the subject a composition comprising a therapeutically effective amount of an amino steroid compound disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, or an amino steroid-cyclodextrin composition, but not limited thereto.

[0035] In some embodiments, the condition correlates with abnormal α-synuclein pathology and / or dopaminergic dysfunction. In a further aspect, the condition correlates with protein misfolding. For example, the misfolded protein can be α-synuclein, tau, and / or amyloid-β.

[0036] In one aspect, there is provided a method of treating, preventing and / or delaying the onset or progression of a condition or disorder that correlates with abnormal α-synuclein pathology, dopaminergic dysfunction and / or protein misfolding, or related symptoms, in a subject in need thereof. The method comprises administering a therapeutically effective amount of an amino steroid compound or composition disclosed herein (including, but not limited to, an amino steroid-cyclodextrin composition). In some embodiments, the related symptoms are selected from the group consisting of (a) constipation, hallucinations, cognitive impairment, and inflammation, and / or (b) correlate with synovitis, neurodegenerative disease, neurological disease or disorder, psychological and / or behavioral disorder, or cerebral or systemic ischemia disorder or condition; and / or (c) the condition or disorder is synovitis, neurodegenerative disease, neurological disease or disorder, psychological and / or behavioral disorder, or cerebral or systemic ischemia disorder or condition.

[0037] In some embodiments, (a) the synovitis, neurodegenerative disease or neurological disease or disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, schizophrenia, multiple system atrophy, Lewy body dementia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich's ataxia, vascular dementia, spinal muscular atrophy, supranuclear palsy, progressive supranuclear palsy, frontotemporal dementia, progressive supranuclear palsy, Guadeloupean Parkinson's syndrome, spinocerebellar ataxia, Parkinson's syndrome, traumatic brain injury, age-related degenerative processes, and age-related dementia; (b) the psychological or behavioral disorder is selected from the group consisting of depression, autism, autism spectrum disorder, Down syndrome, Gaucher's disease, Krabbe disease, lysosomal conditions affecting glycosphingolipid metabolism, ADHD, ADD, agitation, anxiety, delirium, irritability, hallucinations and delusions, amnesia, apathy, bipolar disorder, disinhibition, abnormal motor behavior and compulsions, intoxication, cerebral palsy, epilepsy, major depressive disorder, and REM sleep behavior disorder (RBD), sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, sleep disorders such as cognitive impairment; or (c) the cerebral or systemic ischemia disorder or condition is selected from the group consisting of microangiopathy, intra-partum, cerebral ischemia, cardiac arrest or cerebral ischemia during / after resuscitation, cerebral ischemia due to intraoperative problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying blood to the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformations, diabetic retinopathy, hypercholesterolemia, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, perimyocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, limb ischemia, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valve, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction disorder, hypertension, hypotension, pulmonary edema.

[0038] In one aspect, there is provided a method of treating, preventing, and / or delaying the onset or progression of a cerebral ischemia disorder or a systemic ischemia disorder and / or related symptoms, in a subject in need thereof, which is correlated with abnormal α-synuclein pathology, dopaminergic dysfunction, and / or protein misfolding, the method comprising administering a therapeutically effective amount of an amino steroid compound or composition (including but not limited to amino steroid-cyclodextrin compositions) disclosed herein.

[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 phosphatase comprises 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 PTP; class III Cys-based PTP; class IV Cys-based DSP (dual specificity phosphatase); PTP, such as PTP1B, CDC14s (CDC14A, CDC14B, CDC14C, CDKN3); phosphatase and tensin homolog, such as PTEN; slingshot, such as SSH1, SSH2, SSH3; dual specificity phosphatase, 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, 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, PP1A, PP2Aα / PP2R1A complex, PTPN6 / SHP1, PTPRC / CD45, DUSP22 / MKPX, PTPN2 / TC-PTP, PTPN7 / LC-PTP, PTPN12 / PTP-PEST, PTPN1 / PTP1B-CD, PTPN11 / SHP2, PTPN11 / SHP2-FL, and / or PTPN11 / SHP2-FL(E76K). In some embodiments, the regulatory phosphatase comprises protein tyrosine phosphatase 1B (PTP1B).

[0040] In one aspect, there is provided a method for suppressing, preventing, and / or delaying 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, the method comprising administering to the subject a therapeutically effective amount of an amino steroid compound or composition disclosed herein (including but not limited to amino steroid-cyclodextrin compositions).

[0041] In another aspect, there is provided a method for improving or resolving a disorder of reproductive function, reproductive capacity, and / or reproductive behavior in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an amino steroid compound or composition disclosed herein (including but not limited to amino steroid-cyclodextrin compositions).

[0042] In a further aspect, there is provided a method for treating, preventing, and / or improving diabetes, which can be either type 1 diabetes or type 2 diabetes, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an amino steroid compound or composition disclosed herein (including but not limited to amino steroid-cyclodextrin compositions).

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

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

[0045] In some embodiments, a therapeutically effective amount of an amino-sterol 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 includes oral administration, and a therapeutically effective amount of an amino-sterol 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 amino-sterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is administered in combination with at least one additional active or therapeutic agent to achieve either an additive or synergistic effect. In some embodiments, the additional active or therapeutic agent is administered by a method selected from the group consisting of: (a) simultaneously, (b) as a mixture, (c) separately and simultaneously or in parallel, and (d) separately and sequentially. In some embodiments, the additional active or therapeutic agent is a second amino-sterol having a structure different from the amino-sterol administered as described in the above paragraph.

[0048] In some embodiments, administration of the composition comprises administration on an empty stomach, optionally within 2 hours after the subject wakes up; and / or the subject refrains from consuming food for about 60 to about 90 minutes after administration of the composition.

[0049] In some embodiments, the method further comprises: (a) determining a dosage of an amino steroid or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof for a subject, wherein the dosage of the amino steroid is determined based on the effectiveness of the dosage of the amino steroid in the improvement or resolution of the symptoms being evaluated; (b) then administering to the subject, for a period of time, a composition comprising the dosage of the amino steroid, and the method comprises: (i) identifying the symptoms being evaluated, wherein the symptoms are sensitive to treatment with the amino steroid; (ii) identifying an initial dosage of the amino steroid for the subject; (iii) increasing the dosage of the amino steroid for the subject over a period of time until an effective dosage for the symptoms being evaluated is identified, wherein the effective dosage is the dosage of the amino steroid at which improvement or resolution of the symptoms is observed, and fixing the dosage of the amino steroid for the particular symptoms in the particular subject at that level. In some embodiments, improvement or resolution of the symptoms is measured using clinically recognized scales or tools.

[0050] In some embodiments, (a) the composition is administered orally and (i) the initial dosage of the amino steroid ranges from about 10 mg to about 150 mg per day; (ii) the dosage of the amino steroid for the subject after titration is fixed in the range of about 25 mg to about 500 mg per day; and / or (iii) the dosage of the amino steroid or its salt or derivative is increased by about 25 mg each time; or (b) the composition is administered intranasally and (i) the initial dosage of the amino steroid ranges from about 0.001 mg to about 3 mg per day; (ii) the dosage of the amino steroid for the subject after titration is fixed in the range of about 0.001 mg to about 6 mg per day; (iii) the dosage of the amino steroid for the subject after titration is below the therapeutic dosage when administered orally or by injection; and / or (iv) the dosage of the amino steroid is increased by 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 each time.

[0051] In some embodiments, (a) the dosage of the amino steroid or its pharmaceutically acceptable salt, solvate, prodrug or derivative is increased every about 3 to about 5 days; and / or (b) if the symptoms to be evaluated are severe, the initial dosage of the amino steroid is increased; and / or (c) the symptoms correlate with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

[0052] In some embodiments, the symptoms to be evaluated are selected from the group consisting of: (a) at least one non-motor aspect of daily life experience as defined by Part I of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of cognitive impairment, hallucinations and psychosis, depressive mood, anxious mood, apathy, features of the dopamine dysregulation syndrome, sleep disorders, daytime sleepiness, pain, urinary disorders, constipation disorders, dizziness on standing, and fatigue; (b) at least one motor aspect of daily life experience as defined by Part II of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of speech, saliva and drooling, chewing and swallowing, eating movements, dressing, hygiene, writing, turning in bed, tremors, getting up from bed, car, or deep chair, walking, balance, and freezing; (c) motor symptoms as defined by Part III of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of speech, facial expression, rigidity, finger tapping, hand movement, pronation-supination movement of the hand, toe tapping, leg agility, getting up from a chair, walking, freezing gait, postural stability, posture, body bradykinesia, tremor at rest during hand posture, tremor during hand movement, amplitude of rest tremor, and constancy of rest tremor; (d) at least one motor complication as defined by Part IV of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of time with dyskinesia, functional impact of dyskinesia, time spent in the off state, functional impact of fluctuations, complexity of motor fluctuations, and painful off-state dystonia; (e) constipation; (f) depression; (g) cognitive impairment; (h) sleep problems or sleep disturbances; (i) circadian rhythm dysfunction; (j) hallucinations; (k) fatigue; (l) REM sleep disorder; (m) REM behavior disorder; (n) erectile dysfunction; (o) apnea; (p) orthostatic hypotension; (q) correction of blood pressure or orthostatic hypotension; (r) nocturnal hypertension; (s) thermoregulation; (t) improvement of respiration or apnea; (u) correction of cardiac conduction disorders; (v) improvement of pain; (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, where (a) the fixed escalating amino-sterol dosage for constipation is defined as the amino-sterol dosage that results in complete spontaneous bowel movement (CSBM) within 24 hours after administration for at least 2 out of 3 days at a given dosage, (b) when the average complete spontaneous bowel movement (CSBM) or average spontaneous bowel movement (SBM) is more than once a week, the starting amino-sterol dosage before escalation is 75 mg / day, and / or (c) when the average CSBM or SBM is less than once a week, the starting amino-sterol dosage before escalation is 150 mg / day.

[0054] In one aspect, provided is a method of increasing gene transcription in the intestine of a subject, the method comprising administering to the subject a therapeutically effective amount of an aminosterol compound or composition disclosed herein. In some embodiments, the increase in gene transcription is for one or more genes selected from the group consisting of caspase 14, collagen XVII alpha 1, corneodesmosin, corneifin, cystatin E / M, dermokine, desmocollin 1, desmoglein 1 beta, filaggrin, gap junction protein beta 4, gap junction protein beta 6, H19 imprinted maternally expressed transcript, hornerin, kallikrein-related peptidase 7 chymotrypsin-like, keratin 1, keratin 10, keratinocyte differentiation-related protein, keratinocyte-expressed proline-rich, late cornified envelope 1A1, late cornified envelope 1A2, late cornified envelope 1B, late cornified envelope 1C, late cornified envelope 1E, late cornified envelope 1F, late cornified envelope 1G, late cornified envelope 1H, late cornified envelope 1I, late cornified envelope 1J, late cornified envelope 1L, late cornified envelope 1M, late cornified envelope 3C, late cornified envelope 3E, late cornified envelope 3F, lectin galactose-binding soluble 7, loricrin, sciellin, myoglobin, myosin-binding protein C slow type, myosin heavy polypeptide 1 skeletal muscle, myosin heavy polypeptide 8 skeletal muscle, myosin light chain phosphorylatable fast ske, myosin light polypeptide 3, myosin 1, myosin 2, 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 to achieve a therapeutic or prophylactic benefit is provided, the method comprising administering to a subject a therapeutically effective amount of an aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, or a composition disclosed herein.

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

[0058] Both the foregoing summary and the following drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

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[0094] · Detailed Description I.Summary of the Invention The present invention relates to an amino steroid composition useful for treating human diseases. Specific compounds disclosed include 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 a racemate 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, amino steroid compound A, amino steroid compound B, and amino steroid compound C, or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof.

[0095] Amino steroid 1436 was found to inhibit protein tyrosine phosphatase 1B (PTP1B) both in vitro and in vivo. When administered to obese mice, amino steroid 1436 decreased food intake, fat percentage and body weight, improved insulin resistance and reversed fatty liver disease. In early-stage human clinical trials, it decreased body weight in a dose-dependent manner and increased insulin sensitivity.

[0096] Since aminosterol 1436 has shown pharmacological activity in many vertebrate species, it has been theorized that there are also functional analogs in higher vertebrates. Aminosterol 1436 is composed of a sulfated planar ("flat") bile alcohol conjugated to spermine. To date, no similar compounds have been isolated from mammals, but planar C-26 bile acids such as 7-alpha-hydroxy-3-oxo-4-cholesten-26-oic 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 research, ENT-03 was identified and disclosed in International Publication No. WO 2021 / 025973.

[0097] ENT-03 was detected in the brains, livers, kidneys, and gastrointestinal tracts of neonatal mice. The highest concentration was detected in the brain. ENT-03 isolated from the brain was represented by both R and S diastereomers at the chiral C25 center, with ratios of approximately 60% to 40%, respectively. Brain concentrations were low at birth, peaked at one week of age, and decreased rapidly with the aging of the animals. The low concentration of ENT-03 in the gastrointestinal tract suggested that the source of this compound was not milk.

[0098] ENT-03 was evaluated in vitro against a commercial phosphatase bank. PTP1B was the most potently inhibited of the phosphatases evaluated. The inhibition "fingerprint" of ENT-03 was similar to that of aminosterol 1436. The properties of ENT-03 are to increase insulin sensitivity as a centrally active PTP1B inhibitor and to induce a decrease in food intake and body weight for an extended period after administration to both the periphery and the center in lean rodents. In summary, ENT-03 causes a decrease in food intake, resulting in a decrease in body weight. Furthermore, ENT-03 reduces hepatic steatosis and rapidly increases insulin sensitivity. Additionally, ENT-03 maintains its metabolic effects even after chronic intranasal administration.

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

[0100] Furthermore, the present disclosure relates to the formulation of aminosteroid compounds for delivery to a subject for the treatment of diseases. Specific compounds contemplated are aminosteroids related to the class of mammalian polyamine bile acids and include pharmaceutically acceptable salts, solvates, prodrugs, or derivatives thereof. This aspect of the present disclosure includes aminosteroids described in the prior art such as squalamine (ENT-01), squalamine phosphate, aminosterol 1436 (ENT-02) (also known as trodusquemine and MSI-1436), ENT-03, ENT-05 (U.S. Patent Publication 2023 / 0123701), ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, ENT-11 (U.S. Patent Publication 2023 / 0125585), and ENT-06 (U.S. Patent Publication 2022 / 0372066), as well as novel aminosteroids detailed herein.

[0101] The aminosteroids disclosed herein share biophysical properties that are not compatible with subcutaneous administration. In particular, from the chemical structure of the aminosteroids, it is predicted that at physiological pH, the molecules are highly water-soluble, amphiphilic, and cationic. When injected into animal tissue, solutions of membrane-active or membrane-disruptive aminosteroids damage the tissue by solubilization. The degree of tissue damage is directly proportional to the aminosteroid concentration. Since this tissue damage correlates with intense pain upon administration, aminosteroid compounds are not suitable for therapeutic injection (subcutaneous, intramuscular, intravenous, etc.) and are undesirable. In addition, as a result of both the positive charge and the tissue damage incurred, the bioavailability of subcutaneously administered aminosteroids is impaired. In summary, as a result of detergency, aminosteroids cannot be administered subcutaneously (or intramuscularly, intravenously, etc.) at the concentrations required to achieve a therapeutic effect.

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

[0103] Based on pharmacological studies in rodents, the estimated amount of amino steroid that must be administered to a 75 kg human is about 10 to about 50 mg. Since the maximum volume for subcutaneous administration is about 1 ml, the concentration of amino steroid administered is 10 - 50 mg / ml. At these concentrations, when amino steroid is administered, intense burning pain like being stung by a bee occurs and the tissue at the injection site necroses.

[0104] The present disclosure is directed to the discovery of an ideal formulation of an amino steroid, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, that is painless upon injection and enables rapid diffusion of the drug from the injection site into the bloodstream.

[0105] In another aspect of the present disclosure, a formulation of an amino steroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof contains at least about 50 mg / ml of the amino steroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof. In another aspect, the formulation is a filter - sterilizable aqueous homogeneous solution. In a further aspect of the present disclosure, the amino steroid formulation contains minimal excipients and exhibits the necessary chemical and physical stability required for a pharmaceutical.

[0106] The amino steroid-cyclodextrin formulations disclosed herein are for parenteral administration, for example, for intravenous, subcutaneous or intramuscular administration. Therefore, it is preferred that the formulations are buffered to an appropriate pH. The appropriate pH for intravenous and intramuscular injection is 2-11, and the appropriate pH for subcutaneous injection is 4-9. In one embodiment, the formulation is for subcutaneous administration and the pH is about 7-8. In other embodiments, the pH of the buffered aqueous amino steroid cyclodextrin formulation is about 7-8, or about 7.2-7.5, or about 7.4.

[0107] The pH can be controlled to an ideal range of pH 5-8 by a buffer, for example, 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)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), dimethylarsinate (Cacadylate), 2-(N-morpholino)ethanesulfonic acid (MES).

[0108] In one embodiment of the present disclosure, the amino steroid cyclodextrin formulation has a pH of 7.4 and contains the following: 50 mg / ml ENT-03 (active), 25% 2-hydroxypropyl-beta-cyclodextrin and 80 mM phosphate.

[0109] In another aspect of the present disclosure, the amino steroid cyclodextrin formulation contains the following and has a pH of 7. [Table 1] II. Novel Amino Sterols

[0110] The novel amino steroid compounds disclosed herein are 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 racemate 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, amino steroid compound A, amino steroid compound B, and amino steroid compound C, or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, or derivatives thereof, and the structure of each compound is shown below: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula]

Chem.

Chem.

Chem.

Chem.

Chem.

[0111] All enantiomers (R and S), and racemic mixtures of all the aminosterol compounds disclosed in this specification are included in the present invention.

[0112] In another aspect, an aminosterol compound having the following chemical structure (Formula (I)) or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is disclosed:

Chem.

[0113] In another aspect, the aminosterol has the structure of formula (I), where R 1 is [Chemical formula] selected from.

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

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

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

[0117] In some embodiments, the compounds disclosed herein have 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% with respect to C 25 carbon.

[0118] In view of the chemical structure, the amino steroid compounds disclosed herein can be produced using standard chemical synthesis techniques. For example, the coupling of polyamines and 3-ketosteroids is described in US Patent Publication No. 2023 / 0123701, and C 25 Stereochemical control is also possible. The preparation of the disclosed amino steroid molecules can also be achieved by synthesizing the required polyamines and 3-ketosteroids by methods standard in the art. III. Deuterated Amino Sterol Compounds

[0119] In another aspect of the present disclosure, deuterated amino steroid compounds are disclosed in which at least one hydrogen of the amino steroid compounds disclosed herein is replaced by deuterium. The deuterated forms of amino steroids can have improved safety, better tolerability, and / or enhanced efficacy. Deuterium is a naturally occurring stable non-radioactive hydrogen isotope. The amino steroids are ENT-01, squalamine phosphate, ENT-02 (amino steroid 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 racemate 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, amino sterol compound A, amino sterol compound B, and amino sterol compound C, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, or derivative thereof, which may include, but is not limited to, any compound disclosed herein.

[0120] Deuterated amino sterols are those in which one or more of the hydrogen atoms contained in the amino sterol molecule are replaced with deuterium, a heavier stable isotope. They have a lower metabolic rate and, therefore, a longer half-life, and it is expected that the dosage required to obtain the desired therapeutic effect will be reduced or the dosing frequency will be decreased. The deuterium-carbon bond is generally about 6 to 10 times more stable than the corresponding hydrogen-carbon bond. Such strong bonds are difficult to break and can slow down the bond cleavage rate. This effect on the rate is called the kinetic isotope effect (KIE).

[0121] When amino sterols are deuterated, the deuterium-carbon bond becomes stronger and the metabolism of the amino sterol changes, resulting in compounds with improved pharmacokinetic and / or toxicological properties, such as improved safety, efficacy, and tolerability, compared to unmodified amino sterols.

[0122] In another aspect, for the deuterated aminosterol compounds disclosed herein, any atom not designated as deuterium is present in 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 yet 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 of the compound.

[0124] In one embodiment, the deuterated aminosterol compounds of the invention are pharmaceutically acceptable salts such as phosphates.

[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 can 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 method of the present invention, the deuterated aminosterol compound has an improved safety profile as measured by a decrease in the incidence of one or more adverse events evaluated using clinically recognized scales or tools compared to the same non-deuterated aminosterol compound. For example, the safety profile can 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 non-deuterated aminosterol compound. For example, the improved efficacy can be measured by improvement of one or more disease symptoms evaluated using clinically recognized scales or tools. For example, the improvement in efficacy 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 method of the present invention, the deuterated aminosterol compound has improved tolerability as measured using clinically recognized scales or tools compared to the same non-deuterated compound. For example, the tolerability can 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 non-deuterated same aminosterol compound in order to obtain the same or improved therapeutic effect as measured using clinically recognized scales or tools. For example, the deuterated aminosterol composition according to the present invention can reduce the dosage by about 5% compared to the same but unmodified aminosterol to obtain the same therapeutic effect. In other embodiments, 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 dosage of the same but unmodified aminosterol to obtain the same or improved therapeutic effect. IV. Amino Sterol-Cyclodextrin Formulations

[0130] In one aspect, the disclosed invention describes a method of "masking" an aminosteroid in such a way as to eliminate its membrane-disrupting properties while it remains at the injection site, thereby eliminating local pain, tissue damage, and improving bioavailability. "Masking" of the aminosteroid is achieved by mixing an aqueous solution of the aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof with an aqueous solution of a cyclodextrin of appropriate configuration. Upon mixing, the cyclodextrin molecules reversibly bind to the molecules of the aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, forming a cyclodextrin-aminosteroid complex.

[0131] As is well known in the art, cyclodextrins have a three-dimensional cup-shaped structure and can encapsulate (capture) smaller organic compounds. The biophysical properties of the resulting complex are usually governed by the biophysical properties of the cyclodextrin. Cyclodextrins are formed by linking glucose molecules end-to-end to form a cyclic structure. As such, they exhibit the properties expected of oligosaccharides, namely high water solubility and excellent tissue compatibility. For this reason, cyclodextrins are widely used in the pharmaceutical industry to solubilize poorly water-soluble compounds.

[0132] In the present disclosure, cyclodextrin serves to “mask” the washability of an aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof at the injection site. To achieve this result, it is necessary to increase the cyclodextrin concentration in the formulation and maintain an equilibrium towards complete complexation of the aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof. Since the complex between cyclodextrin and an aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof is non-covalent, the components exist as free molecules and complexes, and are in an equilibrium state determined by the stability of the complex and the concentration of free molecules. When the complex diffuses from the injection site into the systemic circulation, the concentration of cyclodextrin decreases and the complex dissociates, releasing the aminosteroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof.

[0133] Cyclodextrins are classified into the following three size classes according to the number of glucose units: alpha, 6; beta, 7; gamma, 8. The “cup” size of cyclodextrin increases as the number of glucose units increases. Furthermore, cyclodextrins can be chemically decorated with substituents such as alkyl hydroxy groups, anionic groups, cationic groups, etc., and can further influence the complex formation with the intended ligand.

[0134] Numerous methods for determining the degree of complex formation using procedures such as isothermal calorimetry and NMR have been described. In the present disclosure, the optimal cyclodextrin concentration required to completely mask an amino steroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof can be estimated by titrating a solution of cyclodextrin into an aqueous solution of the amino steroid and titrating until the solution no longer foams upon stirring. "Bubbling" reflects a decrease in surface tension, and since amino steroids have washing properties, strong "bubbling" disappears when the concentration of free amino steroid is below a few μg / ml. Further adjustment of the cyclodextrin concentration is based on the clinical response to injection of the amino steroid formulation into the subject. If subcutaneous injection is painful, the concentration of cyclodextrin can be increased.

[0135] Since it is necessary to formulate a high concentration of amino steroid, a high water solubility is required for cyclodextrin. Furthermore, at such high concentrations, the selected cyclodextrin should not exhibit aggregation in solution, which is a property commonly observed with natural cyclodextrins. Only very special chemically modified cyclodextrins function as satisfactory carriers.

[0136] An exemplary cyclodextrin is 2-hydroxypropyl β-cyclodextrin (2HP-β-CD). 2HP-β-CD is β-CD chemically decorated with hydroxypropyl groups. 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 hydrophobic interactions allows for complex formation at the concentration of cyclodextrin. When diluted in tissue fluid, the hydrophobic bond becomes sufficiently weak to allow dissociation, which is further facilitated by the binding of the amino steroid to plasma proteins. 2HP-β-CD is water-soluble at concentrations above 60% and enables the formulation of high concentrations of amino steroids.

[0137] Other exemplary cyclodextrins include, but are not limited to, chemically modified or unmodified beta and gamma cyclodextrins. Alpha cyclodextrin is not likely to be suitable because of its small "cup" size. Exemplary chemically modified or unmodified beta and gamma cyclodextrins include, for example, beta cyclodextrin, gamma cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, and polymeric cyclodextrins such as epichlorohydrin-beta-cyclodextrin and carboxymethylepichlorohydrin beta cyclodextrin. In one aspect of the present disclosure, the cyclodextrin utilized in the amino steroid formulation is cited in the FDA's list of inactive pharmaceutical ingredients and / or classified in the FDA's Generally Recognized as Safe (GRAS) list.

[0138] Any amino steroid described in the present disclosure, as well as International Publication No. 2021 / 025973 and U.S. Patent Publication No. 2023 / 0123701 (both regarding "Human Amino Steroid ENT-03 Compounds, Related Compositions Containing the Same, and Methods of Using the Same"), International Publication No. 2021 / 025974 and U.S. Patent Publication No. 2022 / 0372066 (both regarding "Human Squalamine Derivatives, Related Compositions Containing the Same, and Methods of Using the Same"), and U.S. Patent Publication No. 2023 / 0125585 ("Administration Protocols and Regimens for Amino Steroid Therapy") (all of which are specifically incorporated by reference), and their pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives can be utilized in the disclosed cyclodextrin formulations. The amino steroid can also be present as a racemic mixture.

[0139] Exemplary amino steroids that can be utilized in the formulations herein also include ENT-01, squalamine phosphate, ENT-02 (amino steroid 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 racemate 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, amino - steroid compound A, amino - steroid compound B, and amino - steroid compound C or any one of their pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives, but not limited thereto, and the structures of each compound are shown below:

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0140] In another aspect, provided herein is a composition comprising an aminosterol compound disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, and one or more pharmaceutically acceptable carriers and / or excipients. The composition does not require the presence of cyclodextrin. Administration of the aminosterol disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof may constitute administration of the composition. It is also possible to administer the aminosterol or a pharmaceutically acceptable salt, solvate or prodrug thereof alone, but it is preferably administered as a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers. The carrier must be "acceptable" in the sense that it is compatible with the aminosterol or a pharmaceutically acceptable salt, solvate or prodrug thereof and is not harmful to its receptor.

[0141] When aerosol administration is appropriate, the amino steroids or pharmaceutically acceptable salts, solvates or prodrugs thereof disclosed herein can be formulated as aerosols using standard procedures. The term "aerosol" includes any gaseous medium suspension phase of the compounds disclosed herein that can be inhaled into the bronchus or nasal cavity, including dry powder aerosols and aqueous aerosols, as well as pulmonary aerosols and nasal aerosols. Specifically, aerosols include gas medium suspensions of droplets of the compounds disclosed herein that can be produced by metered dose inhalers or nebulizers, or mist sprayers. Aerosols also include dry powder compositions of the compositions of the present technology suspended in air or other carrier gases, which can be delivered, for example, by insufflation from an inhalation device. See Ganderton & Jones, Drug Delivery to the Respiratory Tract (Ellis Horwood, 1987); Gonda, Critical Reviews in therapeutic Drug Carrier Systems, 6:273-313 (1990); and Raeburn et al., Pharmacol. Toxicol. Methods, 27:143-159 (1992). B. Dosage Forms

[0142] The amino steroid compositions can conveniently be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical arts. Exemplary amino steroid dosage forms include, but are not limited to, oral, nasal, and injectable (IP, IV, or IM) forms. Preferably, the amino steroid formulations are administered orally, intranasally, or in combination thereof. In yet another embodiment, administration includes parenteral administration.

[0143] The formulations or compositions of the present technology are packaged with instructions or package inserts, or are included in kits. The term "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or any type of formulation aid.

[0144] The pharmaceutical composition according to the present technology may also contain one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, foaming agents, and other excipients. Such 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 polyvinylpyrrolidone, microcrystalline cellulose such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose and siliconized microcrystalline cellulose (ProSolv SMCC®). Suitable lubricants (including agents that act on the fluidity of compressed powders) can include colloidal silicon dioxide such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners can include natural or artificial sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame. Examples of flavoring agents include Magnasweet® (a trademark of MAFCO), bubble gum flavor, fruit flavor, etc. Examples of preservatives include potassium sorbate, methyl paraben, propyl paraben, benzoic acid and its salts, other esters of p-hydroxybenzoic acid such as butyl paraben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Suitable diluents can include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or any mixture of the foregoing. Examples of diluents include microcrystalline cellulose such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.Suitable disintegrants include lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, corn starch, and modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. C. Dosage and Duration of Administration

[0145] The dosage of the amino steroid disclosed herein can be from about 1 to about 500 mg / day, or any amount within the range of these two values. In some embodiments, the subject is administered a therapeutically effective amount of the amino steroid disclosed herein. The therapeutically effective amount of at least one amino steroid or a salt or derivative thereof in the methods of the present disclosure can be, for example, about 0.1 to about 20 mg / kg, about 0.1 to about 15 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 5 mg / kg, or about 0.1 to about 2.5 mg / kg per kg of the subject's body weight. In another aspect, the therapeutically effective amount of at least one amino steroid or a salt or derivative thereof in the methods of the present disclosure can be, for example, about 0.001 to about 500 mg / day, about 0.001 to about 250 mg / day, about 0.001 to about 125 mg / day, about 0.001 to about 50 mg / day, about 0.001 to about 25 mg / day, or about 0.001 to about 10 mg / day.

[0146] The oral dosage of the amino steroid disclosed in this specification can be about 1 to about 500 mg / day, or any amount within the range between these two values. In one embodiment, the administration method includes oral administration, and a therapeutically effective amount of the amino steroid consists of (i) about 1 to about 300 mg / day; (ii) about 25 to about 300 mg / day; (iii) about 50 to about 300 mg / day; or (iv) about 75 to about 300 mg / day. Other exemplary dosages of the amino steroid administered orally 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 mg / day, about 380 mg / day, about 385 mg / day, about 390 mg / day, about 395 mg / day, about 400 mg / day, about 405 mg / day, about 410 mg / day, about 415 mg / day, about 420 mg / day, about 425 mg / day, about 430 mg / day, about 435 mg / day, about 440 mg / day, about 445 mg / day, about 450 mg / day, about 455 mg / day, about 460 mg / day, about 465 mg / day, about 470 mg / day, about 475 mg / day, about 480 mg / day, about 485 mg / day, about 490 mg / day, about 495 mg / day, or about 500 mg / day.

[0147] The intranasal dosage of the amino steroid is much lower than the oral dosage. Examples of such low intranasal amino steroid dosages include, but are not limited to, from about 0.001 to about 6 mg / day, or any amount in between these two values. In some embodiments, the administration method includes intranasal administration, and a therapeutically effective amount of the amino steroid includes (i) from about 0.001 to about 6 mg / day; (ii) from about 0.001 to about 4 mg / day; or (iii) from about 0.001 to about 2 mg / day. For example, the low dosage of the amino steroid administered intranasally can be about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6 mg / day.

[0148] In the case of intranasal (IN) administration, the dosage of the amino steroid can be selected to be, for example, a dosage "below the therapeutic dose" such that no pharmacological effect is obtained when the same dosage is administered by other routes, and further, it is contemplated that no negative effect will result. For example, as disclosed herein, Compound III (ENT-03) has the pharmacological effects of reducing food intake and weight loss. Thus, in certain embodiments of the IN method of the present disclosure, when the amino steroid is Compound III (ENT-03) or a salt, solvate, prodrug, or derivative thereof, the Compound III dosage by IN, when administered by another route such as orally, IP, or IV, does not result in a significant decrease in food intake or a significant weight loss. Similarly, some amino steroids are known to produce the pharmacological effects of nausea, vomiting, and / or a decrease in blood pressure. Thus, in certain embodiments of the IN method of the present disclosure, when the amino steroid has this effect upon IN administration, the dosage of the amino steroid at the same IN dosage, when administered by another route such as orally, IP, or IV, does not result in significant nausea, vomiting, and / or a decrease in blood pressure. In some embodiments, intranasal administration includes delivery of the amino steroid to the brain. Suitable exemplary amino steroid dosages are described above.

[0149] If undesirable side effects such as diarrhea, vomiting, and nausea are continuously induced, the dosage of the amino steroid can be reduced. In another embodiment, the dosage of the amino steroid can be varied plus or minus the specified amount to slightly reduce the dosage to eliminate adverse events or, if suggested by clinical results to be desirable (e.g., there are no or minimal adverse events and there is a possibility of improving efficacy by slightly increasing the dosage), the dosage can be slightly increased. For example, in one embodiment, the dosage of the amino steroid can be increased or decreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0150] A pharmaceutical composition comprising an amino steroid or a derivative, salt, solvate or prodrug thereof can be administered for any suitable period, such as as a maintenance dose over a long period. Administration can be carried out as necessary using any pharmaceutically acceptable dosage regimen. The amino steroid can be taken once or less per 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 within a given day (e.g., twice a day). In an exemplary embodiment, the administration is once a 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) as an intermittent maintenance dose; (3) once, twice or multiple times; (4) daily, every other day, every three days, weekly or monthly; (5) for 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, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5, about 22, about 22.5, about 23, about 23.5, about 24, about 24.5 or about 25 years, or (6) any combination of these parameters, such as daily administration for six months, weekly administration for more than one year, etc. Yet another exemplary dosage regimen includes regular administration that can deliver an effective amount 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 amino steroid dosage is taken in the morning, i.e., preferably on an empty stomach within about 2 hours after waking up, and then, for example, a period without food, such as about 60 to about 90 minutes, may follow. In other embodiments, the amino steroid dosage is taken within about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours or about 4 hours after waking up. In a further embodiment, the amino steroid dosage is taken during a period without food, and the period is at least about 30 minutes, about 45 minutes, about 60 minutes, about 1.25 hours, about 1.5 hours, about 1.75 hours or about 2 hours.

[0153] Without being bound by theory, since amino steroids affect the circadian rhythm, it is believed that by taking amino steroids in the morning, probably due to the signal transduction of its ENS, synchronization of all autonomic neurophysiological functions occurring during the day can be achieved. In other embodiments of the present disclosure, the amino steroid dosage is taken within about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, within about 2 hours, within 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 administration of the amino steroid, the subject has a period of not consuming food for about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours or about 3 hours. D. "Fixed Amino Sterol Dosage"

[0154] In one aspect, the present application relates to the discovery of a method for determining the "fixed dose" of an aminosterol disclosed herein, which is not dependent on age, build, or weight, but rather is individually calibrated. The "fixed dose" obtained by this method results in very effective outcomes in the treatment of the condition for which the "fixed dose" was determined, related conditions along the "brain-gut" axis, and underlying diseases. Further contemplated herein is a method of utilizing this same "fixed dose" method in a method of preventing underlying diseases. The present disclosure is not limited to methods of determining aminosterol dosages for a particular patient.

[0155] A therapeutically effective "fixed aminosterol dose" (also referred to herein as "fixed escalated aminosterol dose") is determined for each patient by setting a threshold for improvement of a particular symptom that is being tested as a tool or marker for evaluating the effectiveness of the aminosterol dosage, relative to the starting dosage of the aminosterol composition. After determining the starting aminosterol dosage for a particular patient, the aminosterol dosage is gradually increased in fixed amounts at regular time intervals until the desired improvement is achieved; this aminosterol dosage is the "fixed escalated aminosterol dosage" for a particular patient for a particular symptom. In an exemplary embodiment, the dosage of orally administered aminosterol is escalated by about 25 mg every about 3 to about 5 days until the desired improvement is reached. This includes, but is not limited to, constipation, hallucinations, sleep disorders (e.g., REM sleep disorder or circadian rhythm dysfunction), cognitive impairment, depression, or alpha-synuclein aggregation.

[0156] This therapeutically effective "fixed dose" is maintained during treatment and / or prophylaxis. Thus, even if the patient goes "off drug" and discontinues taking the amino-sterol composition, the same "fixed dose" is taken without a titration period after restarting amino-sterol treatment. Without being bound by theory, the dose of amino-sterol is thought to depend on the degree of nerve damage associated with the symptoms that set the "fixed dose" threshold. For example, in the case of constipation, the dose may be related to the degree of damage to the nervous system in the patient's intestine.

[0157] Dose titration: When determining the "fixed amino-sterol dose" for a particular patient, the patient starts at a low dose and titrates the dose upward until a positive result is observed for the symptoms being evaluated. An example of a symptom to be evaluated is constipation, but any symptom associated with the disease or disorder being treated can be used as a marker for evaluating the amino-sterol dose. Also, if a particular amino-sterol dose causes persistent undesirable side effects such as diarrhea, vomiting, or nausea, the amino-sterol dose can be titrated downward (decreased).

[0158] The starting dose of amino-sterol depends on the severity of the symptoms. For example, in the case of a patient experiencing severe constipation defined as less than one spontaneous bowel movement (SBM) per week, the starting oral dose of amino-sterol can be about 150 mg / day or more. In contrast, for a patient with moderate constipation, for example, defined as having more than one SBM per week, the starting oral dose of amino-sterol can be about 75 mg / day. Thus, as an example, a patient experiencing moderate constipation can start with an oral amino-sterol dose of about 75 mg / day, while a patient experiencing severe constipation can start with an oral amino-sterol dose of about 150 mg / day.

[0159] In other embodiments, patients experiencing moderate symptoms (for the symptoms used to calculate the fixed escalating amino-steroid dosage) can start with an oral amino-steroid dosage of from about 10 mg / day to about 75 mg / day or any amount in between these values. For example, the starting oral amino-steroid dosage for moderate symptoms can be about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 60, about 65, about 70, or about 75 mg / day.

[0160] In yet another embodiment, if a patient is experiencing severe symptoms (for the symptoms used to calculate the fixed escalating amino-steroid dosage), the patient can start with an oral amino-steroid dosage in the range of about 75 to about 175 mg / day or any amount in between these two values. For example, the starting oral amino-steroid dosage for severe symptoms can be about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 mg / day.

[0161] In some embodiments, the starting dosage of oral amino-steroid may be about 125 mg / day or about 175 mg / day, depending on the severity of symptoms such as constipation.

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

[0163] In an exemplary embodiment, the aminosteroid dosage is administered periodically as needed. For example, the aminosteroid dosage can be administered once a day. The aminosteroid dosage can also be administered every other day, two, three, four, or five times a week, once a week, or twice a week. In another embodiment, the aminosteroid dosage can be administered every other week or for several weeks, then skipped for several weeks (so that the effect persists after treatment), and then aminosteroid treatment can be resumed.

[0164] When calculating a fixed incremental amino-sterol dosage, the dosage can be incremented after any suitable period. In one embodiment, the amino-sterol dosage is incremented by a defined amount every about 3 to about 7 days until the desired improvement is reached. For example, if the symptom being treated / measured is constipation, the threshold improvement can be an increase in SBM once a week or at least a total of three bowel movements a week. In other embodiments, the amino-sterol dosage can be incremented every about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In other embodiments, the amino-sterol dosage can be incremented about once / week, about twice / week, every other week, or about once / month.

[0165] During dosage escalation, the dosage of the amino-sterol can be increased by a defined amount. For example, when administering the amino-sterol 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 each time. When administering the amino-sterol intranasally, the dosage can be increased, for example, by 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 each time.

[0166] Other symptoms that can be used as endpoints for determining a patient's fixed escalating amino steroid dosage are any symptoms known to be associated with the disease, disorder or condition for which treatment is intended. For example, neurological disease symptoms disclosed herein include, but are not limited to, (a) at least one non-motor aspect of daily life experience as defined by Part I of the Unified Parkinson's Disease Rating Scale (UPDRS), such as cognitive impairment, hallucinations and psychosis, depression, anxiety, apathy, characteristics of dopamine dysregulation syndrome, sleep disorders, daytime sleepiness, pain, urinary disorders, constipation disorders, orthostatic dizziness and fatigue when standing up, but not limited thereto; (b) at least one motor aspect of daily life experience as defined in Part II of the UPDRS (e.g., speech, saliva and drooling, chewing and swallowing, eating movements, dressing, hygiene, writing, turning in bed, tremors, getting out of bed, car or deep chair, walking and balance, cramps, etc.); (c) at least one motor symptom identified in Part III of the UPDRS, such as speech, expression, rigidity, finger tapping, hand movement, pronation-supination movement of the hand, toe tapping, leg agility, getting out of a chair, walking, cramped feet, postural stability, posture, bradykinesia of the body, tremors at rest during hand posture, tremors during hand movement, amplitude of rest tremors, constancy of rest tremors; (d) at least one motor complication identified in Part IV of the UPDRS (e.g., dyskinesia, functional effects of dyskinesia, time spent in the off state, functional effects of fluctuations, complexity of motor fluctuations, painful off-state dystonia, etc.), (e) constipation, (f) depression, (g) cognitive impairment, (h) sleep problems or sleep disturbances, (i) circadian rhythm dysfunction, (j) hallucinations, (k) fatigue; (l) REM sleep disorder; (m) REM behavior disorder; (n) erectile dysfunction; (o) apnea; (p) orthostatic hypotension; (q) correction of blood pressure or orthostatic hypotension; (r) nocturnal hypertension; (s) thermoregulation; (t) improvement of breathing or apnea, (u) correction of cardiac conduction disorders, (v) improvement of pain, (w) restoration of bladder sensation and urination, (x) urinary incontinence, and / or (y) suppression of nocturia. VI. Treatment and / or Prevention Methods

[0167] Aspects of the present disclosure relate to a method of treating and / or preventing a disease or disorder associated with one or more of these symptoms, in a therapeutically effective amount of an aminosterol and / or aminosterol composition disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, optionally present in one or more pharmaceutically acceptable carriers. In one aspect, the aminosterol composition includes cyclodextrin, as detailed herein.

[0168] In one embodiment, the symptoms, diseases, and / or disorders generally correlate with abnormal alpha-synuclein pathology, dopaminergic dysfunction, and / or protein misfolding, including but not limited to abnormal tau pathology, abnormal amyloid-beta pathology, abnormal alpha-synuclein pathology, and / or dopaminergic dysfunction, which means that treatment with the aminosterols disclosed herein is possible. The compositions of the present technology can be administered using any pharmaceutically acceptable method, including but not limited to oral administration, pulmonary administration, nasal administration, and nebulization administration. In yet another embodiment, the administration includes parenteral administration. Administration of the aminosterol cyclodextrin formulation is by injection, for example, intravenous, subcutaneous, intramuscular, etc. In one embodiment, the administration includes parenteral administration.

[0169] In some embodiments, provided herein is a method for treating a subject in need of treatment for a condition or symptom treatable by an aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof, the method comprising administering to the subject a therapeutically effective amount of an aminosterol or aminosterol composition disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, provided herein is a method for treating a subject in need of treatment for a condition treatable by an aminosterol, the method comprising administering to the subject a therapeutically effective amount of a composition comprising, or consisting essentially of, an aminosterol or a pharmaceutically acceptable salt, solvate or prodrug thereof disclosed herein, and one or more pharmaceutically acceptable carriers and / or excipients. The aminosterol composition can be a cyclodextrin composition.

[0170] Non-limiting examples of symptoms treatable by 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 treatable by an amino steroid or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof are disclosed herein and include, but are not limited to, neurological or neurodegenerative diseases or disorders. Examples of neurological or neurodegenerative diseases or disorders 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 disorder, guadrupole type Parkinsonian syndrome, spinocerebellar ataxia and autism. In another embodiment, the amino steroids and compositions containing them disclosed herein can be used in a method for treating, preventing and / or delaying the onset or progression of a psychological or behavioral disorder and / or related 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, lethargy, bipolar disorder, disinhibition, abnormal movements and compulsions, sleep disorders, sleep fragmentation, REM sleep behavior disorder, circadian rhythm dysfunction, sleep apnea, and cognitive impairment.

[0172] In one embodiment, a method is provided for treating, preventing and / or delaying the onset or progression of inflammation and / or related symptoms associated with αS pathology in a subject. The method comprises administering to the subject a therapeutically effective amount of at least one amino steroid or a pharmaceutically acceptable salt, solvate or prodrug thereof as disclosed herein, and one or more pharmaceutically acceptable carriers and / or excipients. The amino steroid composition can be a cyclodextrin composition.

[0173] In another embodiment, the neurodegenerative disease can be positively affected by administration of a therapeutically effective amount of an amino steroid according to the present disclosure. "Positive effect" includes, for example, delaying the progression of the condition, improving one or more symptoms, and the like.

[0174] In another embodiment, a method is provided for treating, preventing and / or delaying the onset or progression of cerebral ischemia disorder or systemic ischemia disorder and / or related symptoms in a subject in need thereof. Cerebral ischemia disorder or systemic ischemia disorder can be, for example, microangiopathy, intra-partum cerebral ischemia, cerebral ischemia during or after cardiac arrest or resuscitation, cerebral ischemia due to intraoperative problems, cerebral ischemia due to carotid artery problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of the arteries supplying blood to the brain, sinus thrombosis or cerebral venous thrombosis, cerebrovascular malformation, diabetic retinopathy, hypertension, hypercholesterolemia, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, myopericarditis, coronary artery disease, angina pectoris, congenital heart disease, shock, ischemia of the extremities, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valve, anemia, hypersplenism syndrome, pulmonary emphysema, pulmonary fibrosis, erectile dysfunction, pulmonary edema, etc.

[0175] Examples of diseases treatable with an amino steroid or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof are disclosed herein and include, but are not limited to, reproductive capacity, reproductive function, and reproductive behavior. Thus, in one aspect included is a method for improving or resolving a disorder of reproductive function, a disorder of reproductive capacity, and / or a disorder of reproductive behavior in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an amino steroid compound disclosed herein, or a composition comprising such an amino steroid.

[0176] Also included is a method for suppressing, preventing and / or delaying the onset or progression of one or more related symptoms including, but not limited to, appetite or weight gain, and / or obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an amino steroid compound disclosed herein, or a composition comprising such an amino steroid.

[0177] Furthermore, a method for suppressing, preventing and / or delaying the onset or progression of diabetes (type 1 and / or type 2), and / or one or more related symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an amino steroid compound disclosed herein or a composition comprising such an amino steroid is encompassed.

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

[0179] Exemplary conditions that correlate with abnormal αS pathology, dopaminergic dysfunction, and / or protein misfolding and are treatable with amino steroids include, for example, constipation, hallucinations, and other conditions disclosed herein. In one embodiment, a method for treating, preventing and / or delaying the onset or progression of inflammation and / or related symptoms in a subject associated with αS pathology is provided. The method comprises administering to the subject a therapeutically effective amount of at least one amino steroid disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0180] Also encompassed is a method for treating and / or preventing a psychological or behavioral disorder or any symptom associated with such a disease or condition. In one embodiment, the psychological or behavioral disorder is depression, anxiety, delirium, irritability, hallucinations and delusions, amnesia, autism, lethargy, bipolar disorder, disinhibition, abnormal motor behavior and compulsions, sleep disorders, sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, or cognitive impairment.

[0181] In another embodiment, any psychological or behavioral disorder or any symptom associated with such a disease or condition may be positively affected by administration of a therapeutically effective amount of an amino steroid according to the present disclosure. Positive effects include, for example, slowing the progression of the condition, improving one or more symptoms, and the like.

[0182] In one aspect, the amino steroids disclosed herein can be administered to a subject in need to treat a microbial infection. In some embodiments, the subject in need has a condition selected from the group consisting of a viral infection, a microbial infection, a bacterial infection, such as a gram-negative and / or gram-positive bacterial infection, a mycobacterial infection, a fungal infection, and / or a protozoal 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 delta virus, dengue virus, and human immunodeficiency virus. In some embodiments, the condition to be treated is "African Swine Fever Viruses", Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, bimaviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Dengueviridae, EBV, HIV, Deltaviridae, Filoviridae, Filoviridae, Flaviviridae, Hepadnaviridae (hepatitis), Herpesviridae (such as cytomegalovirus, herpes simplex, varicella zoster, etc.), Iridoviridae, Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., influenza A, influenza B, and parainfluenza), Papillomaviruses), 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., Rubivirus), herpes, pox, papilloma, corona, influenza, hepatitis, Sendai sindbis, vaccinia viruses, West Nile hanta, cold-causing viruses, and viral infections caused by viruses selected from the group consisting of 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 suspected of being virus-derived, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, cardiomyopathy, Kawasaki disease, aplastic anemia, and any combination thereof.

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

[0185] In some embodiments, the coronavirus is an Alphacoronavirus; a Colacovirus such as Bat coronavirus CDPHE15; a Decacovirus such as Bat coronavirus HKU10 or Rhinolophus ferrumequinum alphacoronavirus HuB-2013; a Duvinacovirus such as Human coronavirus 229E; a Luchacovirus such as Lucheng Rn rat coronavirus; a Minacovirus such as Ferret coronavirus or Mink coronavirus 1; a Minunacovirus such as Miniopterus bat coronavirus 1 or Miniopterus bat coronavirus HKU8; a Myotacovirus such as Myotis ricketti alphacoronavirus Sax-2011; a Nyctacovirus such as Nyctalus velutinus alphacoronavirus SC-2013; a Pedacovirus such as Porcine epidemic diarrhea virus or Scotophilus bat coronavirus 512;Rhinacoviruses such as Rhinolophus bat coronavirus HKU2; Setracoviruses such as Human coronavirus NL63 or NL63-related bat coronavirus strain BtKYNL63-9b; Tegacoviruses such as Alphacoronavirus 1; Betacoronaviruses; Embecoviruses such as Betacoronavirus 1, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1 or Murine coronavirus; Hibecoviruses such as Bat Hp-betacoronavirus Zhejiang2013; Merbecoviruses such as Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5, or Tylonycteris bat coronavirus HKU4; Nobecoviruses such as Rousettus bat coronavirus GCCDC1 or Rousettus bat coronavirus HKU9;Viruses selected from the group consisting of 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, White-eye coronavirus HKU16; Herdecovirus such as Night heron coronavirus HKU19; Moordecovirus such as Common moorhen coronavirus HKU21; Gammacoronavirus; Cegacovirus such as Beluga whale coronavirus SW1; and Igacovirus such as Avian coronavirus.;

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

[0187] The disclosed amino steroids and compositions containing them (including, but not limited to, amino steroid-cyclodextrin compositions) can be used to treat a variety of subjects, including humans and non-human animals, including mammals, and immature and mature animals, including human infants and adults. The human subject to be treated can be an infant, toddler, school-aged child, teenager, young adult, adult, or elderly patient.

[0188] In embodiments disclosed herein related to prevention, a particular patient population can be selected based on being "at risk" of developing any of the conditions disclosed herein. For example, gene markers or family history of a condition can be used as indicators to identify subjects who are likely to develop a particular condition. Thus, in some embodiments, prevention can include first identifying a patient population at risk of developing the condition. Alternatively, certain symptoms are considered early signs of a particular disorder. Thus, in some embodiments, a patient population may be selected as being "at risk" of developing a disease based on experiencing age- and disease-related symptoms. Additionally, genetic or hereditary indicators can be used to narrow down the patient population.

[0189] In some embodiments, the subject has and / or is at risk of having one or more diseases selected from the group consisting of obesity, fatty liver disease, type 2 diabetes, heart disease, stroke, hypertension, gallbladder disease, gout, sleep apnea syndrome, osteoarthritis, high LDL cholesterol, low HDL cholesterol, high triglyceride levels (dyslipidemia), endometrial cancer, breast cancer, colon cancer, kidney cancer, gallbladder cancer, and liver cancer. VIII. Kits

[0190] The amino steroid preparation or composition of the present disclosure may be packaged together with a kit, or included in a kit, together with an instruction manual or package insert. Such an instruction manual or package insert can address the recommended storage conditions such as time, temperature, and light, taking into account the shelf life of the amino steroid or its derivative or salt. Such an instruction manual or package insert can also mention the specific advantages of the amino steroid or derivative or its salt, such as the ease of storage of the preparation that requires on-site use outside the conditions of a regulated hospital, clinic, or office.

[0191] The present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the amino steroid pharmaceutical compositions disclosed herein. The kit can include, for example, containers filled with an appropriate amount of the amino steroid pharmaceutical composition as a dissolved powder, tablet, or sterile solution. Such containers can be accompanied by a notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals or biological products, and this notice reflects the approval by the government agency for manufacture, use, or sale for administration to humans. Further, the amino steroid or its derivative or salt can be used in combination with other therapeutic compounds.

[0192] In other aspects, kits are disclosed that include the nasal spray devices disclosed herein. In one aspect, the kit can include one or more devices as disclosed herein that include the disclosed low-dose aminosterol composition, and the devices are sealed within a container sufficient to protect the devices from the influence of the atmosphere. The container can be, for example, foil, or a plastic pouch, particularly a foil pouch, or a heat-sealed foil pouch. Appropriate containers sufficient to adequately protect the devices will be readily understood by those skilled in the art.

[0193] In one aspect, the kit can include one or more devices as disclosed herein, and the devices can be sealed within a first protective packaging, or a second protective packaging, or a third protective packaging that protects the physical integrity of the product. One or more of the first, second, or third protective packagings can include a foil pouch. The kit can further include instructions for use of the device. In one aspect, the kit includes two or more devices.

[0194] In one aspect, the kit can include a device as disclosed herein and can further include instructions for use. In one aspect, the instructions can include visual aids / diagrams and / or written instructions for the administrator of the device. IX. Combination Therapies

[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. Examples of additional therapeutic agents are those known to treat the condition for which the aminosterol is administered.

[0196] Combinations may be administered either concomitantly, e.g., as an admixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and procedures in which the combined agents are administered separately but simultaneously, e.g., through separate intravenous lines to the same individual. "Combination" administration further includes separately administering one of the compounds or agents to be administered first and then administering the second agent. Since activation of the amino-sterol-induced response does not require systemic absorption of the amino-sterol into the bloodstream, there are no systemic concerns regarding the potential for drug-drug interactions between the amino-sterol and the administered drug, and the selected regimen can be administered concomitantly. X. Definitions

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

[0198] Technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art unless otherwise defined. Any suitable materials and / or methodologies known to those of ordinary skill in the art can be utilized in practicing the methods disclosed herein.

[0199] As used in the description of the present invention and the appended claims, the singular forms "a", "an", and "the" are used interchangeably and are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and / or" refers to any and all possible combinations of one or more of the listed items, and, when alternatively construed ("or"), also includes the absence of a combination.

[0200] As used herein, the term "therapeutically effective amount" means the amount of an amino steroid or a salt or derivative thereof that produces a particular pharmacological effect of a compound or compounds being administered. It is emphasized that a therapeutically effective amount, even though it is an amount that would be considered a therapeutically effective amount by one of ordinary skill in the art, may not be effective to achieve the intended effect in a given subject. For convenience, exemplary dosages are provided herein. One of ordinary skill in the art can adjust such amounts as needed, according to standard practice, to treat a particular subject. A therapeutically effective amount can vary based on the route of administration and dosage form, the age and weight of the subject, and / or the severity of the condition of the subject. For example, one of ordinary skill in the art will understand that the therapeutically effective amount for treating a smaller individual may be different from the therapeutically effective amount for treating a larger individual.

[0201] As used herein, the term "administering" includes prescribing for administration as well as actually administering, and includes physically administering by the subject being treated or by another.

[0202] As used herein, the term "subject" or "patient" or "individual" refers to any subject, patient or individual, and these terms are used interchangeably herein. In this regard, the terms "subject", "patient" and "individual" include mammals, particularly humans.

[0203] The "derivative" of the aminosterol disclosed in this specification can have one or more chemical modifications that do not change the activity of the aminosterol, or that may dramatically reduce or improve it. Such "activity" includes pharmacological targets and the resulting affinities, including changes in affinity for different subtypes of specific receptor targets. The "derivative" of the aminosterol has modifications well known in the field of medicinal chemistry introduced to "mimic" the original steric and charge characteristics of part of the original structure, improving the therapeutic properties of the aminosterol. Generally, such modifications are introduced to affect metabolism, ease of administration, in vivo distribution, or combinations thereof. Examples of such variants or derivatives include (1) substituting a sulfate or carboxylic acid with a sulfonate, sulfate, phosphate, carboxylate, or other anionic moiety selected to avoid metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacing a hydroxyl group with a non-metabolizable polar substituent such as a fluorine atom to prevent metabolic oxidation or conjugation; and (3) substituting various ring hydrogen atoms to prevent oxidation or reductive metabolism of the steroid ring system, although not limited thereto. Other derivatives include substituting one or more hydrogens of the aminosterol with deuterium, or making one or more C-C single bonds of the aminosterol unsaturated. The pharmaceutical composition can include one or more pharmaceutically acceptable carriers or excipients.

[0204] As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. When used to define the compositions and methods, "consisting essentially of" means excluding other elements that have an essential meaning for the combination for the recited purpose. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding other components and substantial method steps in excess of trace elements. Embodiments defined by each of these transitional terms are within the scope of the present invention. It should be understood that when an embodiment is defined by one of these terms (e.g., "comprising"), the present disclosure also includes alternative embodiments such as "consisting essentially of" and "consisting of" for the embodiment.

[0205] "Substantially" or "essentially" means nearly completely or completely, e.g., 95%, 96%, 97%, 98%, 99% or more of a given amount.

[0206] The term "about" is understood by those skilled in the art and varies somewhat depending on the context in which it is used. When there is an unclear use for those skilled in the art from the context in which the term is used, "about" means plus or minus 10% of a particular term. For example, in some embodiments, it means plus or minus 5% of a particular term. In this specification, the term "about" is attached before a numerical value to indicate a particular range. The term "about" is used in this specification to provide a literal support for the exact numerical value that the term precedes, and for numerical values that are close to or nearly close to the numerical value that the term precedes. When determining whether a numerical value is close to or approximate to a specifically recited numerical value, the close or non-approximate numerical value may be a numerical value that provides substantial equivalence to the specifically recited numerical value in the context in which it is presented.

[0207] When a range of values is presented, unless clearly specified otherwise in the context, each intervening value between the upper and lower limits of that range, and other expressly recited values or intervening values within that range, is understood to be included in the present invention to within one tenth of the lower limit. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges, and are also included in the present invention, subject to any particular exclusions expressly recited within the recited range. When the recited range includes one or both of the limits, ranges excluding one or both of the included limits are also included in the disclosure.

[0208] As used herein, the terms "treatment" or "treating" mean any treatment of a disease or condition of a patient, or an associated disorder. Also included in "treatment" is the suppression or prevention of a disease or condition, i.e., preventing or suppressing the manifestation of clinical symptoms such as neurological deficits resulting from cerebral ischemia; and / or the alleviation of a disease or condition, i.e., causing regression of clinical symptoms (e.g., increasing neurological performance or decreasing neurological deficits).

[0209] In some embodiments, "treatment" includes "providing neuroprotection" to a subject. "Treatment" and "providing neuroprotection" can include administration of the therapeutic agent(s) or composition(s) disclosed herein.

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

[0211] As used herein, "reductive amination" refers to a synthetic procedure in which a ketone or aldehyde is reacted with an amine to form an imine or iminium, followed by reduction to form an amine. Methods and means for affecting reductive amination are known to those skilled 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 these are hereby incorporated by reference herein.

[0212] In any of the amino steroid or steroid compounds disclosed herein, the stereochemical configurations at carbons 17 and 20 are equivalently represented as depicted in the two exemplary steroid nuclei shown below, that is, it should be understood that the configurations at carbons 17 and 20 depicted below are the same:

Chemical formula

[0213] In any embodiment of the present specification, when the ring carbons of the amino steroid (or the corresponding carbons of the synthetic intermediate corresponding to Compound I-R or -S) marked with an exclamation mark below are not stereodefined, the embodiments in which these carbons are defined as shown in Formula II are within the scope of the present invention:

Chemical formula

[0214] The embodiments disclosed herein are further illustrated by the following examples, but are not limited thereto.

Examples

[0215] Example 1: Identification of ENT-03 Metabolites in Rat Plasma and Urine The purpose of this example was to identify potential metabolites of ENT-03S and predict the metabolic pathway of ENT-03S in rat plasma and urine samples.

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

[0217] A total of nine metabolites of ENT-03S were detected from rat plasma and urine. The metabolite information of ENT-03S in rat plasma and urine samples is shown in Table 2. All metabolites were less than 5% of the drug-related substances in male rat plasma samples. The peak areas of metabolites and the parent drug in rat urine samples were very low, and no major metabolites were observed. [Table 2]

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

[0219] After subcutaneous administration of 10 mg / kg of ENT-03S to male SD rats with bile duct cannulas inserted, plasma and urine samples were collected from male rats at various time points as detailed in Table 3. The samples were transferred to dry ice before use and stored at -80°C. [Table 3]

[0220] Other Chemicals and Materials : All inorganic reagents, organic solvents, and water were at least of analytical laboratory reagent grade and are detailed in Table 4. [Table 4]

[0221] Apparatus Information : Information on the equipment used in this example is detailed in Table 5. [Table 5]

[0222] Study Design : After the administration of ENT-03S, from the research number PH-DMPK-ETR-21-001, the same number of rat urine (50 μL) samples were collected from different animals at various time points. For plasma samples, the Hamilton pooling method was used. The specific sampling volumes at each time point are shown in Table 6 below.

Table 6

[0223] Sample Preparation : For urine and bile samples, after the administration of each sample group, equal amounts of samples (50 μL) were collected from different animals at various time points, and the same sample groups were mixed well. After pooling, 50 μL of the matrix was mixed with 200 μL of methanol (containing 0.1% formic acid), vortexed for 100 seconds, then centrifuged at 16,000 g at 4 °C for 10 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new tube, and the supernatant was diluted with 100 μL of pure water and mixed well. The samples were analyzed by 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 on a Q-Exactive instrument (Thermo Fisher). For the data-dependent acquisition (DDA) trigger of the MS / MS scan spectrum, a full MS scan was used. The compound-dependent parameters were optimized for ENT-03S. The DDA settings excluded impurity ions (m / z 149.02332, m / z 279.15909, m / z 391.28429, m / z 445.12003), and the MS 2 spectra of the top 5 ions in intensity were used as the trigger to be acquired 3 times in 10 seconds. The bioanalytical sample analysis parameters are shown in Table 7.

Table 7-1

Table 7-2

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

[0226] Study Results : Metabolite information of ENT-03S is shown in Table 8.

Table 8

[0227] XIC chromatograms of ENT-03S in rat plasma and urine samples by full MS / ddMS2 scan are shown in Figures 1 to 2. MS / MS spectra of ENT-03S and metabolites are shown in Figures 3 to 12. The metabolic pathway of ENT-03S from rat plasma and urine samples is shown in Figure 13.

[0228] Specifically, the XIC chromatogram of the rat plasma sample is shown in Figure 1, and the XIC chromatogram of the rat urine sample is shown in Figure 2. Figure 3 is the MS / MS fragmentation spectrum of ENT-03S. Figure 4 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M1-PU. Figure 5 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M2-PU. Figure 6 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M4-PU. Figure 7 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M5-PU. Figure 8 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M6-PU. Figure 9 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M7-PU. Figure 10 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M8-PU. Figure 11 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M9-PU. Figure 12 shows the MS / MS fragmentation spectrum of the ENT-03S derivative named M10-PU. Example 2: Identification of ENT-03 Metabolites in Rat Bile Samples

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

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

[0231] A total of 16 metabolites of ENT-03S were detected from rat bile samples. The metabolite information of ENT-03S in rat bile samples is shown in Table 9. The peak area ratios of the parent drug and each metabolite were determined by semi-quantitative estimation using the peak areas of the extracted ion chromatograms of all drug-related substances detected in the samples. Metabolites with a peak area ratio of 10% or more were proposed as the main metabolites of ENT-03S. The dealkylation-oxidation metabolite M1 and the dealkylation-oxidation-dehydrogenation metabolite M4 were the main metabolites in male rat bile samples, with peak area ratios of 21.50% and 15.28%, respectively.

Table 9

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

[0233] As detailed in Table 10, after subcutaneous administration of 10 mg / kg of ENT-03S to male SD rats inserted with bile duct cannulas, bile samples were obtained from male rats at various time points. The samples were transferred to dry ice and stored at -80°C before use.

Table 10

[0234] Other Chemicals and Materials : All inorganic reagents, organic solvents, and water were at least of analytical laboratory reagent grade and are detailed in Table 11.

Table 11

[0235] Apparatus Information : Information regarding the equipment used in this example is detailed in Table 12.

Table 12

[0236] Study Design : Equal amounts of rat bile samples (50 μL) were collected from different animals at various time points after administration of ENT-03S with test number: PH-DMPK-ETR-21-001. 50 μL of the matrix was mixed with 200 μL of methanol (containing 0.1% formic acid), vortexed for 100 seconds, and then centrifuged at 16,000 g at 4 °C for 10 minutes to precipitate the protein. 100 μL of the supernatant was transferred to a new tube, diluted with 100 μL of pure water, mixed well, and analyzed by UPLC-MS / MS.

[0237] Sample Preparation : Bile samples were collected in equal amounts (50 μL) from different animals at various time points after administration of each sample group, and the same sample group was 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 on a Q-Exactive instrument (Thermo Fisher). A full MS scan was used as the trigger for data-dependent acquisition (DDA) of the MS / MS scan spectrum. Compound-dependent parameters were optimized for ENT-03S. The DDA settings excluded impurity ions (m / z 149.02332, m / z 279.15909, m / z 391.28429, m / z 445.12003), and the MS 2 spectra of the top 5 ions in intensity were used as the trigger to be acquired after being generated 3 times in 10 seconds. The bioanalytical sample analysis parameters are shown in Table 13.

Table 13-1

Table 13-2

[0239] Data Analysis : The analysis was performed using a Thermo Fisher Scientific Q Exactive instrument. A full MS scan was used as the trigger for data-dependent acquisition (DDA) of the MS / MS scan spectra. The compound-dependent parameters were optimized with ENT-03S. The DDA settings excluded ions (m / z 149.02332, m / z 279.15909, m / z 391.28429, m / z 445.12003), and for the top 5 ions in intensity, the MS spectra of the ions entering the top 5 in intensity were used as the trigger to be acquired 3 times in 10 seconds. The data acquisition and processing were performed using Xcalibur v4.1 software (Thermo Fisher Scientific), Compound Discoverer 3.1 (Thermo Fisher Scientific), and Excel (Microsoft 2016). 2 The data acquisition and processing were performed using Xcalibur v4.1 software (Thermo Fisher Scientific), Compound Discoverer 3.1 (Thermo Fisher Scientific), and Excel (Microsoft 2016).

[0240] Study Results : The metabolite information of ENT-03S is shown in Table 14.

Table 14

[0241] The XIC chromatogram from the full MS / ddMS2 scan of ENT-03S in the bile sample is shown in Figure 15. The MS / MS spectra of ENT-03S and its metabolites are shown in Figures 16 to 32. The proposed metabolic pathway of ENT-03S from the bile sample is shown in Figure 33.

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

[0243] The objective of this example was to further clarify the characteristics of the novel aminosterol named ENT-19.

[0244] The novel aminosterol 3-((aminopropyl)amino)butanoic-7α-hydroxy-25[R,S]-cholestanate hydrochloride, named ENT-19, has the following chemical structure:

[0245] The molecular weight of this compound is 649.78 (576.86), and the chemical formula is C 34 H60N2O5·2HCl.

Chemical Structure

[0246] ENT-19 was confirmed to have a purity of 95% or more by HPCL (95.27%), and as confirmed by LC-MS (Shimadzu LCMS2020), the compound was in accordance with the structure. The test parameters are shown in Table 15.

Table 15

[0247] The chromatogram of this compound is shown in Figure 14. The characteristics of Peaks 1 - 5 are shown in Table 16.

Table 16

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

Chemical Structure

[0249] The preparation of the 10 ml formulation sample was carried out as follows: First, 2.51 g of 2-HP β-cyclodextrin as a powder and 0.5 g of ENT-03S (free basic sodium salt) as a powder were added to a container, and the powders were thoroughly mixed. 7.5 ml of distilled water was added to the container, and the mixture was stirred or shaken to obtain a clear solution containing a small amount of undissolved solid. The solution was warmed at 40 °C until all the fine particles were dissolved. The solution was adjusted to pH 7.3 by the addition of 1M H3PO4 and left at room temperature for 24 hours, during which the pH rose to about 7.6. Subsequently, further 1M H3PO4 was added to adjust the pH to 7.4 - 7.5. This solution was made up to 10 ml with distilled water. This solution was sterile filtered through a 0.2 μm cellulose acetate membrane and stored at room temperature.

[0250] The final composition was as follows: ·ENT-03S 50 mg / ml (active form) ·2-hydroxypropyl β-cyclodextrin 25% (w / v) ·Phosphate, approximately 80 mM ·pH 7.4 - 7.6.

[0251] This example shows that the preparation of an amino-steroid cyclodextrin formulation suitable for subcutaneous administration was successful. Example 5: Evaluation of the Amino Sterol Cyclodextrin Subcutaneous Administration Formulation of Example 4

[0252] The purpose of this example was to evaluate the amino-steroid cyclodextrin formulation prepared in Example 4.

[0253] A 1 ml subcutaneous formulation of ENT-03S prepared in Example 4 was loaded into an insulin syringe. The contents of the syringe were injected subcutaneously into the abdomen of a human subject, resulting in a visible swelling. A mild tingling sensation was observed, but this disappeared within a few minutes. The swelling disappeared over the course of 1 hour.

[0254] This example shows that even when the amino-steroid cyclodextrin formulation is administered subcutaneously, there are few or no side effects such as pain during administration. Example 6: Pharmacokinetic Evaluation of the Amino Sterol Cyclodextrin Formulation of Example 4

[0255] The objective of this example was to evaluate the pharmacokinetic properties of the amino steroid cyclodextrin formulation prepared in the same manner as in Example 1.

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

[0257] The ENT-03-cyclodextrin formulation was subcutaneously administered to male Sprague-Dawley rats at a dose of 10 mg / kg. Blood was collected from the tail vein at various times, the concentration of ENT-03 was measured, and PK parameters were determined.

[0258] As shown in Table 17 and Figure 34, ENT-03 rapidly diffused from the subcutaneous administration site into the blood, reached the peak concentration in 2 hours, and gradually decreased over 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.

Table 18

[0260] The advantages provided by the amino steroid-cyclodextrin formulations disclosed herein can be understood by comparing the pharmacokinetics of an ENT-03S aqueous solution at a concentration of 2 mg / ml of ENT-03S and pH 7.4 in the absence of cyclodextrin.

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

[0262] When 0.1 ml of this preparation was injected into human subjects, intense pain occurred within seconds, persisted for several hours, and was accompanied by local swelling, redness, and a feeling of warmth, which lasted for several days.

[0263] Experiments were conducted using male Sprague-Dawley rats according to the same protocol as above. The preparation was administered subcutaneously at a dose of 10 mg / kg. The data obtained are shown in Tables 19 and 20 and Figure 35 below.

Table 19

Table 20

[0264] The slow transfer of the amino steroid compound from the injection site to the bloodstream is evident from the pharmacokinetic properties of the ENT-03S solution. See also Figure 35. It takes 72 hours to reach the maximum concentration. The slow entry of ENT-03 into the circulation is thought to be due to both binding to polyanionic proteoglycans present in the subcutaneous layer of the skin and local tissue damage. Example 8: Preparation of an Exemplary ENT-03 Cyclodextrin Formulation

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

[0266] The preparation obtained was as follows: 50 mg / ml ENT-03 (active form) 2HPβCD 25% (w / v) Sodium phosphate 40 mM pH 7.4 - 7.5 Final volume: 12 ml

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

[0268] This example shows that the preparation of an ENT-03 cyclodextrin formulation suitable for intravenous, subcutaneous, or intramuscular administration was successful. Example 9: Preparation of an Exemplary ENT-03 Cyclodextrin Formulation

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

[0270] The final formulation consisted of the following components:

Table 21

[0271] As a first step, 100.7 g of (2-hydroxypropyl)-β-cyclodextrin was added to a sterilized IL glass bottle, followed by accurately measuring 300 mL of USP purified water into the container. This solution was mixed well using a magnetic stirring plate until it became a clear solution.

[0272] Next, the (2-hydroxypropyl)-β-cyclodextrin solution was transferred to an HDPE container containing 23 g of ENT-03 Na+ powder (API). The solution was mixed well by hand and immediately transferred to a 37 °C water bath on a magnetic stirring plate. Then, the contents were further mixed and the solid was dissolved while heating until dissolution was complete. (The pH was >9). There may be undissolved particles remaining at this stage. Then, the solution was titrated with IM H3PO4 to adjust the pH to 7.5.

[0273] Next, to adjust the pH to 7.3 (±0.1), while the solution was in the 37 °C water bath, IM H3PO4 was slowly added. The mixture was continuously stirred. The final volume (QS) was adjusted to 402.5 mL by adding ~102.5 mL of USP purified water. Then, while maintaining at 37 °C, the solution was mixed well using a magnetic stirring plate until all the particles were dissolved and the solution became clear.

[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. Then, the solution was filtered through a 0.2 μm filter (PES) and placed in a new sterile container (or it may be filtered into a final sterile BDS container (bag) for use in a microcell filler). The formulated DP solution is stored at room temperature and filled into vials within 24 hours after preparation.

[0275] Although specific embodiments have been illustrated and described, it is to be understood that changes and modifications can be made in accordance with the ordinary skills of those skilled in the art without departing from the broader aspects of the technology as defined in the following claims.

[0276] The embodiments illustratively described in this specification can be preferably implemented even in the absence of elements or elements, limitations or limitations not specifically disclosed herein. Therefore, for example, terms such as "comprising", "including", "containing", etc. shall be read expansively without limitation. Further, the terms and expressions adopted in this specification are used as terms of explanation and are not meant to be limiting. The use of such terms and expressions is not intended to exclude equivalents of the features shown and described or a part thereof, but it is recognized that various changes are possible within the scope of the claimed technology. Further, the expression "consisting essentially of" is understood to include specifically described elements and additional elements that do not substantially affect the basic and novel characteristics of the claimed technology. The expression "consisting of" excludes elements not specified.

[0277] The present disclosure is not limited from the perspective of the specific embodiments described in this application. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent methods and compositions within the scope of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be included within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims, together with the full scope of equivalents to which such claims are entitled. It should be understood that the present disclosure is not limited to a particular method, reagent, compound or composition. Also, it should be understood that the terms used in this specification are for the purpose of describing particular embodiments and are not intended to be limiting.

[0278] In addition, when features or aspects of the present disclosure are described from the perspective of a Markush group, one of ordinary skill in the art will recognize that the present disclosure is also described from the perspective of any individual member or subgroup of members of the Markush group.

[0279] As will be understood by one of ordinary skill in the art, for all purposes, particularly from the perspective of providing a written description, all ranges disclosed herein, including endpoints, include any and all possible subranges and combinations of those subranges. It can be readily recognized that any recited range sufficiently describes and enables the same range to be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily decomposed into lower thirds, middle thirds, and upper thirds, etc. Also, as will be understood by one of ordinary skill in the art, all language such as "up to", "at least", "greater than", "less than", etc. includes the recited number and refers to a range that can be subsequently decomposed into subranges as described above. Finally, as will be understood by one of ordinary skill in the art, ranges include individual members.

[0280] All publications, patent applications, issued patents, and other documents mentioned herein are incorporated herein 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 the incorporated by reference text are excluded to the extent they are inconsistent with the definitions in the present disclosure.

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

Claims

1. Aminosterol compounds having a structure selected from the group consisting of the following, or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, or derivatives thereof: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】

2. Aminosterol compounds of formula (I), or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, or derivatives thereof: 【Chemistry 12】 Here R １ is an arbitrarily substituted C １ ―C ８ Alkyl, optionally substituted 2- to 8-membered heteroalkyl, optionally substituted heterocyclyl, or optionally substituted C ３ -C ８ It is cycloalkyl; R ２ is H or C(O)R ５ where R ５ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C １ -C ６ alkyl, optionally substituted heterocyclyl, or optionally substituted C ３ -C ８ cycloalkyl; and R ３ and R ４ Each is independently a 2- to 14-membered heteroalkyl group, which is either H or optionally substituted; The aforementioned compound is not: (24R)-3β-({3-[(3-aminopropyl)amino]propyl}amino)-7α-hydroxycholestane-24-yl bisulfate (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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-3-yl bisulfate (aminosterol 1436); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2,3,3-d3 acid (ENT-03 d3); (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-(benzoyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptanoic acid; (6R)-6-((3R,5S,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptanoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptane-2-d acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-2-d acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-2-d acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-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-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-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-dimethylhexadecahydro-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)-7,12-dihydroxy-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhepta-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylhepta-2-enoic acid; (6R,E)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhepta-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylhepta-2-enoic acid; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoic acid; Methyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Methyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Methyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Methyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Isopropyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Isopropyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; Isopropyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methyl-3-oxoheptanoate; Isopropyl(6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxoheptanoate; (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-2,3-diol; (3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-17-((2R)-5,6-dihydroxy-6-methylheptan-2-yl)-10,13-dimethylhexadecahydro-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-methylheptan-2-yl)-10,13-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-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-dimethylhexadecahydro-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-dimethylhexadecahydro-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-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptan-3-yl-1,1,1,2-d4 bisulfate (D ７ - Squalamine); (3R,6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-aminobutyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-3-yl-3-d bisulfate (24-D １ - Squalamine); or (6R)-6-((3S,5R,7R,10S,13R,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(methyl-d3)heptan-3-yl-1,1,1,2-d4 bisulfate (D ７ -1436).

3. R １ but, 【Chemistry 13】 An aminosterol compound according to claim 2, selected from the above.

4. R ２ The aminosterol compound according to claim 2, wherein H is present.

5. R ３ and R ４ However, independently, H, and, 【Chemistry 14】 An aminosterol compound according to claim 2, selected from the above.

6. R ３ However, H is R ４ However, independently 【Chemistry 15】 An aminosterol compound according to claim 2, selected from the above.

7. The aminosterol compound according to claim 1 or 2, which is a hydrochloride salt.

8. The aminosterol compound according to claim 1 or 2, which is a sodium salt.

9. C ２５ The aminosterol compound according to claim 1 or 2, wherein the carbon-related diastereomer excess (de) 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 claim 1 or 2, wherein at least one hydrogen of the aminosterol compound is substituted with deuterium.

11. A composition comprising the aminosterol compound according to claim 1 or 2 and at least one pharmaceutically acceptable carrier or excipient.

12. The composition according to claim 11, comprising the following: (a) one or more of the following: aqueous carriers, buffers, sugars; and / or polyol compounds; and optionally (b) The composition further comprises at least one additional activator.

13. The composition is (a) For administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intravesical, vaginal, abdominal, intravenous, subcutaneous, intramuscular, nebulization, inhalation, ocular, ocular, local, buccal, nasal and topical administration; (b) in a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized preparations, tablets, and capsules; (c) A dosage form selected from the group consisting of controlled-release formulations, rapid-dissolving formulations, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, and mixed formulations of immediate-release formulations and controlled-release formulations; (d) For oral administration (e) In the form of oral tablets or capsules; (f) For intranasal administration; or The composition according to claim 11, formulated in any combination of (g)(a), (b), (c), (d), (e) and / or (f).

14. Aqueous aminosterol composition containing the following: (a) aminosterols or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers or derivatives thereof; and (b) Cyclodextrin Here, the formulation is buffered to a pH of approximately 4 to 9, and Here, the cyclodextrin is reversibly bound to a molecule of the aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, so that it forms a cyclodextrin-aminosterol complex.

15. The aqueous aminosterol composition according to claim 14, wherein the cyclodextrin is unmodified beta-cyclodextrin or unmodified gamma-cyclodextrin.

16. The aqueous aminosterol composition according to claim 14, 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 claim 14, wherein the pH is (a) about 5 to about 8, or about 7 to about 8; or (b) Approximately 7.3 to approximately 7.

5.

18. The buffers are acetate buffer, phosphate buffer, citrate buffer, histidine buffer, tris(hydroxymethyl)aminomethane (TRIS), sodium phosphate, citric acid, acetic acid, KH ２ PO ４ CHES, borate, tromethamine, gluconic acid, lactic acid, tartaric acid, aspartic acid, glutamic acid, citric acid cycle intermediate, [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) The aqueous aminosterol composition according to claim 14, selected from the group consisting of (Tyl)-1-piperazine ethanesulfonic 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), dimethylarsenate (Cacadylate), and 2-(N-morpholino)ethanesulfonic acid (MES).

19. The aqueous aminosterol composition according to claim 14, which is buffered as follows: (a) Phosphate; or (b) Tris(hydroxymethyl)aminomethane (Tris).

20. The aqueous aminosterol composition according to claim 14, wherein the cyclodextrin is present in the following amounts: (a) about 10% to about 40%, about 15% to about 30%, about 18% to about 25%, or about 20% to about 25%; or (b) Approximately 20% to 25%.

21. The aqueous aminosterol composition according to claim 14, wherein the aminosterol is present in the following amounts: (a) about 20 mg / ml to about 75 mg / ml; (b) about 30 mg / ml to about 65 mg / ml; (c) Approximately 40 mg / ml to approximately 55 mg / ml; or (d) about 50 mg / ml.

22. The aqueous aminosterol composition according to claim 14, wherein the ratio of the concentration (mg / ml) of the aminosterol to the cyclodextrin is as follows: (a) about 0.1 to about 0.75; (b) about 0.15 to about 0.5; or (c) about 0.

20.

23. The aqueous aminosterol composition according to claim 14, for administration intravenously, subcutaneously, or intramuscularly.

24. The aqueous aminosterol composition according to claim 14, wherein the aminosterol is selected from the group consisting of the following: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】

25. The aqueous aminosterol composition according to claim 24, wherein: (a) The aminosterol is ENT-03S, and optionally the composition contains 50 mg / ml of ENT-03S and about 20-25% of 2HP-β-CD, and is buffered with phosphate to pH 7.3-7.5; (b) The aminosterol is ENT-03R, and optionally the composition contains 50 mg / ml of ENT-03R and about 20-25% of 2HP-β-CD, buffered with phosphate to pH 7.3-7.5; (c) The aminosterol is racemic ENT-03, and optionally the composition contains 50 mg / ml of racemic ENT-03 and about 20-25% of 2HP-β-CD, buffered with phosphate to pH 7.3-7.5; (d) The aminosterols are 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 E NT-13, Race Semi ENT-14, Race Semi ENT-15, Race Semi ENT-16, Race Semi ENT-17, Race Semi ENT-18, Race Semi ENT-19, Race Semi ENT-20, Race Semi ENT-21, Race Semi ENT-22, Race Semi ENT-23, Race Semi ENT-24, Race Semi ENT-25, Race Semi ENT-26, Race Semi ENT- 27, a racemic aminosterol selected from the group consisting of 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, the composition contains 50 mg / ml of racemic aminosterol and about 20-25% of 2HP-β-CD, buffered with phosphate at pH 7.3-7.

5.

26. A method for treating a subject that is in a condition to be treated with aminosterols and is in need of treatment, comprising administering to the subject a therapeutically effective amount of the aminosterol compound described in claim 1, 2, or 14, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition.

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

28. A method for treating, preventing and / or delaying the onset or progression of abnormal αS pathology, dopaminergic dysfunction and / or conditions or disorders correlated with protein misfolding, or related symptoms, in a person in need, the method comprising administering a therapeutically effective amount of the aminosterol compound described in claim 1, 2, or 14, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition.

29. The method according to claim 28, wherein (a) The symptoms are selected from the group consisting of constipation, hallucinations, cognitive impairment, and inflammation; (b) The symptoms are associated with synovial disease, neurodegenerative disease, neurological disorder or impairment, psychological and / or behavioral disorder, or cerebral or systemic ischemic disorder or condition; or (c) The condition or disorder is synovial disease, neurodegenerative disease, or neurological disorder or disorder; (d) The condition or disorder is a psychological and / or behavioral disorder; or, (e) The condition or disorder is a cerebral or systemic ischemic disorder or condition.

30. The method according to claim 29, wherein (a) The synovial disease, neurodegenerative disease, or neurological disease or disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, schizophrenia, multiple system atrophy, Lewy body dementia, 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, Guadeloupean parkinsonian syndrome, spinocerebellar ataxia, Parkinsonian syndrome, traumatic brain injury, age-related degenerative processes, and age-related dementia; (b) The psychological or behavioral disorder is selected from the group consisting of depression, autism, autism spectrum disorder, Down syndrome, Gaucher disease, Krabbe disease, lysosomal storage disorders affecting glycosphingolipid metabolism, ADHD, agitation, anxiety, delirium, irritability, illusions and delirium, amnesia, apathy, bipolar disorder, disinhibition, abnormal motor behavior and obsessive-compulsive behavior, intoxication, cerebral palsy, epilepsy, major depressive disorder, and sleep disorders such as REM sleep behavior disorder (RBD), sleep fragmentation, REM behavior disorder, circadian rhythm dysfunction, sleep apnea, and cognitive impairment; (c) The cerebral or systemic ischemic disorder or condition is selected from the group consisting of microangiopathy, intrapartum, cerebral ischemia, cerebral ischemia during or after cardiac arrest or resuscitation, cerebral ischemia due to intraoperative problems, cerebral ischemia during carotid artery surgery, chronic cerebral ischemia due to stenosis of arteries supplying blood to the brain, sinus thrombosis or cerebral venous thrombosis, cerebral vascular malformation, diabetic retinopathy, hypercholesterolemia, myocardial infarction, heart failure, congestive heart failure, myocarditis, pericarditis, pericardiomyocarditis, coronary heart disease, angina pectoris, congenital heart disease, shock, ischemia of the limbs, renal artery stenosis, diabetic retinopathy, thrombosis associated with malaria, artificial heart valve, anemia, hypersplenism syndrome, emphysema, pulmonary fibrosis, erectile dysfunction, cardiac conduction disorder, hypertension, hypotension, diabetes mellitus, and pulmonary edema.

31. A method for suppressing, preventing, and / or delaying the onset or progression of appetite or weight gain, and / or one or more related symptoms, in a person in need. The method comprises administering a therapeutically effective amount of the aminosterol compound described in claim 1, 2, or 14, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition to a target.

32. A method for improving or resolving a disorder of reproductive function, a disorder of reproductive capacity and / or a disorder of reproductive behavior in a subject in need thereof, comprising administering a therapeutically effective amount of the aminosterol compound according to claim 1, 2, or 14, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition, to the subject.

33. A method for treating, preventing and / or improving diabetes, which may be either type 1 or type 2 diabetes, in a person who needs it, A method comprising administering a therapeutically effective amount of an aminosterol compound according to claim 1, 2, or 14, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer or derivative thereof, or an aminosterol composition.

34. The method according to claim 26, wherein (a) The method of administration includes oral, nasal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intraventricular, percutaneous, or a combination thereof; and / or (b) The method of administration is intranasal administration, oral administration, or a combination thereof.

35. The method according to claim 26, wherein the therapeutically effective amount of the aminosterol compound or a pharmaceutically acceptable salt, solvate, prodrug or derivative thereof comprises the following: (a) Approximately 0.1 to 20 mg per kg of body weight of the subject; (b) Approximately 0.1 to 15 mg / kg per kg of body weight of the subject; (c) Approximately 0.1 to 10 mg / kg per kg of body weight of the subject; (d) Approximately 0.1 to 5 mg / kg per kg of body weight of the subject; (e) Approximately 0.1 to 2.5 mg / kg per kg of body weight of the subject; (f) about 0.001 to about 500 mg / day; (g) about 0.001 to about 250 mg / day; (h) about 0.001 to about 125 mg / day; (i) 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) about 0.001 to about 6 mg / day; (m) about 0.001 to about 4 mg / day; (n) About 0.001 to about 2 mg / day (o) Approximately 1 to approximately 300 mg / day, administered orally; or (p) Approximately 25 to 500 mg / day, administered orally.

36. The method according to claim 26, 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 activator to achieve either an additive or synergistic effect.

37. The method according to claim 26, wherein (a) Administration of the composition includes, optionally, administration on an empty stomach, within two hours of the subject waking up; and / or (b) The subject does not ingest food approximately 60 to 90 minutes after administration of the composition; and / or (c) The aminosterol, or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, is of pharmaceutically acceptable grade; and / or (d) The hydrochloride salt of the aminosterol is administered; and / or (e) The sodium salt of the aminosterol is administered; and / or (f) The subject is human.

38. The method according to claim 26, further comprising the following steps: (a) A step of determining the dosage of the aminosterol or a pharmaceutically acceptable salt, solvate, prodrug or derivative to a subject, wherein the dosage of the aminosterol is determined based on the effectiveness of the dosage of the aminosterol in improving or resolving the symptoms being evaluated. (b) The method then includes administering to a subject a composition containing the aforementioned aminosterol dosage for a certain period of time, wherein the method includes the following: (i) A step of identifying a symptom to be evaluated, wherein the symptom is treatable with aminosterols; (ii) A step of determining the initial dose of the aminosterol for the subject; (iii) A step of gradually increasing the dose of aminosterols administered to a subject over a certain period of time until an effective dose for the symptoms to be evaluated is identified, wherein the effective dose is the dose of aminosterols at which improvement or resolution of the symptoms is observed, and fixing the dose of aminosterols for the specific symptoms in the specific subject at that level.

39. The method according to claim 38, wherein (a) The composition is administered orally. (i) The starting dose of the aminosterol is approximately 10 mg to approximately 150 mg / day; (ii) The dose of aminosterol administered to the subject after dose escalation is fixed in the range of approximately 25 mg to approximately 500 mg / day; and / or (iii) Increase the dose of the aminosterol or its salt or derivative by approximately 25 mg each; or (b) The composition is administered intranasally, and (i) The starting dose of the aminosterol is in the range of about 0.001 mg to about 3 mg / day; (ii) The dose of aminosterol administered to the subject after gradual increase is fixed in the range of approximately 0.001 mg to approximately 6 mg / day; (iii) The dose of aminosterol administered to the subject after escalation shall be less than or equal to the therapeutic dose when administered orally or by injection; and / or (iv) Increase the dose of aminosterol by approximately 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg.

40. The method according to claim 26, wherein (a) The dose of the aminosterol is gradually increased every 3 to 5 days; and / or (b) If the symptoms being evaluated are severe, the initial dose of aminosterol will be increased; and / or (c) The symptoms correlate with abnormal alpha-synuclein pathology and / or dopaminergic dysfunction.

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