Isotopically enriched 3-amino-1-propanesulfonic acid derivatives and uses thereof

Abstract

The present invention relates to the use of isotopically enriched compounds of general formula I and pharmaceutically acceptable salts or esters thereof, and pharmaceutical compositions comprising the same, for the prevention and treatment of inflammatory-related conditions or autoimmune diseases in humans or animals. R 1 R 2 X‑CR2‑CH2‑CH2‑SO3H(I).

Description

TECHNICAL FIELD

[0001] The present invention relates to the use of derivatives of 3-amino-1-propanesulfonic acid (3APS) and compositions thereof in the prevention and treatment of inflammatory related conditions or autoimmune diseases or conditions in humans or animals. BACKGROUND

[0002] Inflammation is a stress response of the body to infection or injury, which can help the body to recover as soon as possible, however, in some cases, the activation of the immune system can have a negative impact. Inflammation is usually divided into acute and chronic, inflammatory response can spread throughout the systemic circulation and into the central nervous system (Central Nervous System, "CNS"), inflammation plays a key role in many diseases of the central nervous system, and different immune mechanisms can dominate according to the stage of the disease. Inflammatory response in the central nervous system involves complex interactions between immune cells entering / migrating, resident and circulating immune cells, parenchymal cells, cellular components of the central nervous system microvascular system, and changes in immune cell function. The central nervous system can produce inflammatory mediators, such as pro-inflammatory cytokines, prostaglandins, free radicals, and complements, etc., in response to injury, infection and / or disease, wherein inflammatory mediators can induce chemotactic factors to recruit immune cells and activate glial cells. Chronic immune can affect all parts of the body and can be a secondary factor for many diseases, including multiple sclerosis, type I diabetes, etc.

[0003] Multiple sclerosis (MS) is a chronic inflammatory demyelination of the central nervous system with pathological features of alternating relapse and remission and gradual loss of neuronal myelin (Wan M, Ding L, Wang D, et al. Serotonin: A potent immune cell modulator in autoimmune diseases [J] Front Immunol 2020 11:186). The destruction of axonal myelin will disrupt the transmission of nerve impulses and lead to fatigue, ataxia, paralysis and cognitive impairment in patients (Wan M, Ding L, Wang D, et al. Serotonin: A potent immune cell modulator in autoimmune diseases [J] Front Immunol 2020 11:186).

[0004] ​W. Clinical implications of neuropathological findings in multiple sclerosis[J]. Journal of Neurology, 2005, 252(Suppl 3):iii10-iii4.). The occurrence of this type of inflammatory disease can, in some cases, significantly impact people's quality of life and create social and economic burdens. According to the "2020 Comprehensive Social Survey Report on Multiple Sclerosis Patients in China," in 2018, the average out-of-pocket medical expenses of multiple sclerosis patients exceeded 46,000 yuan, accounting for 45.18% of their family income. This exceeds the warning line pointed out by catastrophic medical care (i.e., out-of-pocket medical expenses account for 40% or more of the family's ability to pay), creating enormous pressure on their economic capacity and family relationships.

[0005] Gamma-aminobutyric acid (GABA) is a common neurotransmitter in the central nervous system, widely studied for its neurobiological activity in brain development. There are two types of GABA receptors (GABA-Rs), encoded by different gene families, and their activation is induced by different pathways. A -Rs are fast-acting chloride channels (RWOlsen et al., Molecular biology of GABAA receptors, 4FASEB J 1469-1480 (1990)). GABA B -Rs are slow-acting G protein-coupled receptors (B. Bettler et al., Molecular structure and physiological functions of GABA(B) receptors, PHYSIOL REV: 835-867 (2004).). Rodent and human T cells express GABA. A -Rs are functional expressions, but for GABA B -Rs-specific receptors do not respond (J. Tian et al., GABA(A)-receptors mediate inhibition of T cell responses, 96 J. NEUROIMMUNOL 21-28 (1999). Human T cells do not respond to GABA. A Receptor expression is mediated by GABA. A- R agonists and antagonists (Prud'homme, G. J. et al. GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone. Transplantation 96, 616-623.). GABA exerts therapeutic effects in type 1 diabetes patients by inhibiting the proliferative response of human peripheral blood mononuclear cells (PBMC) and the activation of nuclear factor (NF)-KB, while simultaneously suppressing the secretion of IL-6, TNF, IL-17A, CXCL10 / IP-10, CCL4, CCL20, and MCP-3.

[0006] Homotaurine, a GABAA-R specific agonist, has excellent safety profile and has been disclosed to limit inflammation in the CNS (WO2020081886). However, due to the safety profile of GABA and the problems of limiting autoimmunity in preclinical models, there is an urgent need to find safer and more effective therapeutic drugs. Therefore, there is still a need for a disease or disorder that can be effectively prevented or treated by inhibiting the specific ion transport of gamma-GABA(A)-R, particularly multiple sclerosis, which is an inflammatory-related disorder or autoimmune disease.

[0007] It is believed that the present invention meets this need by providing compounds and pharmaceutical compositions for preventing and / or treating inflammation and its complications. SUMMARY

[0008] Surprisingly, the inventors have found that isotopically enriched 3-amino-1- propanesulfonic acid (3APS) and its derivatives have a positive effect in inhibiting the specific ion transport activity of gamma-GABA(A)-R. It can be used in the preparation of a medicament for the treatment of inflammatory-related disorders or autoimmune diseases, including multiple sclerosis.

[0009] Therefore, in a first aspect, the present invention relates to the use of compounds of general formula (I), (II), (III), (IV), and (V) as detailed hereinafter, especially the compounds shown in Tables 1 to 4, and pharmaceutical compositions thereof, for the treatment or prevention of an inflammatory-related disorder or autoimmune disease in a human or animal.

[0010] In a second aspect, the present invention provides a compound of general formula I, or a pharmaceutically acceptable salt or ester thereof:

[0011] R 1 R 2 X-CR2-CH2-CH2-SO3H (I)

[0012] wherein R 1 and R 2 are independently a hydrogen of natural abundance or a protecting group of carbon or / and oxygen atom of natural abundance or isotopic enrichment, including but not limited to acyl (except acetyl), carbonyl, thiocarbonyl and aminoalkanoyl, etc.; X is a nitrogen atom of natural abundance or 15 N-enriched nitrogen atom 15 N); R is a hydrogen atom of natural abundance or deuterium isotopic enrichment (D); wherein X, R, R 1 and R 2 are not simultaneously atoms or groups of natural abundance, in other words, when R 1 and R 2 are atoms or groups of natural abundance, X and R cannot be simultaneously atoms of natural abundance; when R and X are simultaneously atoms of natural abundance, R 1 and R 2 are not or are not simultaneously atoms or groups of natural abundance; or, when the compound of general formula (I) does not contain isotopically enriched atoms, with the proviso that the compound (I) is not 3-amino-1 -propanesulfonic acid and N-acetyl-3-amino-1 -propanesulfonic acid.

[0013] In some embodiments, when R is a hydrogen atom of natural abundance, X is 15 N. In some embodiments, when R is D, X is a nitrogen atom of natural abundance. In some embodiments, when R is D, X is 15 N.

[0014] In one embodiment of the compound of general formula (I), R 1 is an amino acid acyl with or without isotopic enrichment and R 2 is a hydrogen atom of natural abundance; X is a nitrogen atom with or without isotopic enrichment and R is a hydrogen atom with or without isotopic enrichment. Or in the compound of general formula (I), R 2 is an amino acid acyl with or without isotopic enrichment and R 1 is a hydrogen atom of natural abundance; X is a nitrogen atom with or without isotopic enrichment and R is a hydrogen atom with or without isotopic enrichment.

[0015] An amino acid acyl is an organic compound group linked to a carbonyl carbon atom after removal of the hydroxyl group in the carboxyl group of an amino acid. The amino acid can be a natural amino acid or a non-natural amino acid, wherein the natural amino acid or the non-natural amino acid can be an L-amino acid, a D-amino acid, or an L- and D- mixed amino acid. In one embodiment, the amino acid acyl is an a-amino acid acyl. In another embodiment, the a-amino acid acyl has an L-configuration.

[0016] In a third aspect, the present invention provides compound II of general formula, or a pharmaceutically acceptable salt or ester thereof:

[0017] H2X-CR2-CH2-CH2-SO3H (II)

[0018] Where X is naturally abundant nitrogen or nitrogen atoms enriched by the N-15 isotope (also referred to in this invention as " 15 "N-enriched nitrogen atoms" or " 15 X is N”). R is hydrogen or deuterium (D) of natural abundance, wherein X and R exist only if they are not both naturally abundant atoms (in other words, when X is nitrogen of natural abundance, R is not hydrogen of natural abundance, or when X is nitrogen of natural abundance, R is D). In some embodiments, R is hydrogen of natural abundance and X is 15 N. In some embodiments, R is D and X is a naturally abundant nitrogen atom. In some embodiments, R is D and X is 15 N.

[0019] In a fourth aspect, the present invention provides compound III of general formula, or a pharmaceutically acceptable salt or ester thereof:

[0020]

[0021] Where X and R are defined as described above; Y is a naturally abundant carbon atom or 13 C-enriched carbon atoms ( 13 C); Z is the naturally abundant sulfur atom, the naturally abundant oxygen atom, or 18 O or 17 O-enriched oxygen atoms ( 18 O or 17 O); and R 3 Substituents include, but are not limited to, substituted or unsubstituted alkyl, aryl, aminoalkyl, aminoarylalkyl, heterocyclic, alkoxy, alkylthio, alkylamino, acyloxy, portions of natural or non-natural amino acids other than the carboxyl group, thioacyloxy, and other substituents.

[0022] In one embodiment of compound (III), R 3 Y and Z together form an amide-linked acyl group with X. In another embodiment, R 3 It is the part of an amino acid other than the carboxyl group, and R 3Y and Z together with X form an amino acid linked acyl group. In one aspect, the amino acid can be an L-amino acid, a D-amino acid, or a mixture of L- and D-amino acids. In another aspect, the amino acid can be a natural or unnatural amino acid. In some specific embodiments, the amino acid is an L-amino acid. In other embodiments, the amino acid is a naturally occurring L-amino acid.

[0023] In some embodiments, the present application provides compounds of general formula IV and V, or a pharmaceutically acceptable salt or ester thereof:

[0024]

[0025] wherein R 4 is the side chain of a natural or unnatural amino acid. O * is an isotopically enriched oxygen atom (e.g. 18 O or 17 O) or a combination thereof. C * is a carbon atom at natural abundance or 13 C an isotopically enriched carbon atom 13 C). The corresponding amino acid can be an L-amino acid, a D-amino acid, or a mixture of L- and D-amino acids. The corresponding amino acid can be a natural or unnatural amino acid.

[0026] In some embodiments, the compound is 3-amino-3,3-dideutero-l-propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof; or is 3- 15 N-amino)-l-propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof.

[0027] In some embodiments, the compound is 3-((L-valinyl)amino)-3,3-dideutero-l- propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof.

[0028] In some embodiments, the compound of general formula (I), (II), (III), (IV), or (V) is not N-acetyl-3-amino-l-propanesulfonic acid and 3-amino-l-propanesulfonic acid.

[0029] The compound of general formula (I), (II), (III), (IV), or (V) can comprise one or more atoms that are isotopically enriched. Any stable or pharmaceutically acceptable isotopic atom can be used in the isotopically enriched compounds of the present application. For example, the isotopically enriched compound can include D( 2 H), 13 C, 15 N, 17 O and / or 18 O.

[0030] In some embodiments, isotopically enriched compounds of general formula (I), (II), (III), (IV), or (V) (see Tables 1, 2, 3, or 4) can be a single compound or a pharmaceutically acceptable salt, ester, chelate, hydrate, solvate, and stereoisomer thereof, or different crystalline forms thereof.

[0031] Table 1. Examples of 3,3-dideuterium-3-amino-1-propanesulfonic acid and its derivatives

[0032]

[0033] Table 2. 15 Examples of N-3-amino-1-propanesulfonic acid and its derivatives

[0034]

[0035] Table 3. Examples of doubly isotopically labeled 3-amino-1-propanesulfonic acid derivatives and prodrug compounds

[0036]

[0037]

[0038] Table 4. Examples of cysteinyl derivatives of isotopically enriched 3-amino-1-propanesulfonic acid

[0039]

[0040] In one embodiment, the isotopically enriched compound is 3-(acylamino)-3,3-dideuterium-1-propanesulfonic acid or 3-(acyl- 15 N-amino)-1-propanesulfonic acid, or a pharmaceutically acceptable salt, ester, chelate, hydrate, solvate, stereoisomer, or different crystalline form thereof; wherein the acyl group comprises arginyl, asparaginyl, aspartamyl, cysteinyl, glutamyl, glutaminyl, glycyl, isoleucyl, leucyl, lysinyl, methionyl, prolinyl, selenocysteinyl, threonyl, tryptophanyl, tyrosyl, and 4-hydroxyisoleucyl.

[0041] In some embodiments, the compounds encompassed by the present application are in their original acid or base form, such as sulfamic acid. In other embodiments, the compounds encompassed by the present application include other pharmaceutically acceptable forms or the original form, such as inorganic salts, organic salts, esters, chelates, hydrates, or solvates. The present application also encompasses different polymorphs of the compounds of general formula (I) to (V) and the compounds shown in Tables 1 to 4.

[0042] In another aspect, the present application relates to a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), especially a compound as shown in Tables 1-4, or a pharmaceutically acceptable salt or ester thereof, wherein the compound is not N-acetyl-3-amino-l-propanesulfonic acid and 3-amino-l-propanesulfonic acid. In some embodiments, the pharmaceutical composition can comprise a pharmaceutically acceptable carrier. In some embodiments, the present application also relates to a formulation comprising the above-mentioned compound.

[0043] In a fifth aspect, the present application provides a method for preventing and / or treating an inflammatory-related disorder or an autoimmune disease in a human or an animal, comprising administering to a subject in need thereof an effective amount of a compound (or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition or a related formulation of the present application. The inflammatory-related disorder or autoimmune disease is caused by a decrease in the specific ion transport activity of γ-GABA(A)-R.

[0044] In some embodiments, the inflammatory-related disorder or autoimmune disease is selected from the group consisting of Type I diabetes, multiple sclerosis, neurodegenerative disease, amyotrophic lateral sclerosis, asthma, atherosclerosis, autism spectrum disorder, brain abscess, Crohn's disease, a harmful immune response to infection, encephalitis, hepatitis, inflammatory bowel disease, lupus, meningitis, migraine, neuroinflammation, neuropathic pain, obesity, paraneoplastic disease, periodontitis, rheumatoid arthritis, sarcoidosis, schizophrenia, traumatic brain injury, tuberculosis, ulcerative colitis, ulcer, and vasculitis.

[0045] In some embodiments, the inflammatory-related disorder or autoimmune disease is mediated by T cells, dendritic cells, monocytes or macrophages, granulocytes, mast cells, and the like immune cells.

[0046] In some embodiments, the disorder mediated by T cells is selected from the group consisting of Type I diabetes, multiple sclerosis, and rheumatoid arthritis.

[0047] Without being bound by theory, in the methods of the present application, it is generally believed that the isotopically enriched 3APS derivative and / or prodrug compounds encompassed by the present application can improve the therapeutic efficacy of 3APS by improving its biodistribution and / or pharmacokinetic profile. This can be achieved, for example, by increasing bioavailability, decreasing metabolism of the compound, increasing stability of the compound, and / or altering the rate of release of 3APS from the prodrug, and the like.

[0048] In another aspect, the methods of the present application can improve the therapeutic efficacy of 3APS. This includes administering to a subject, such as a subject, especially a subject patient, a therapeutically effective amount of an isotopically enriched 3APS derivative, or a prodrug compound, and a formulation thereof, so as to achieve the purpose of improving the release of isotopically enriched 3APS.

[0049] In some embodiments of the methods of the present application, the compound is a compound of any one of Formulae (I) to (V), or a pharmaceutically acceptable salt thereof. In some embodiments of the methods of the present application, the compound is a compound of any one of Formulae (I) to (V), or a pharmaceutically acceptable salt thereof, with the exception of N-acetyl-3-amino-l-propanesulfonic acid and 3-amino-l-propanesulfonic acid.

[0050] In one aspect, the compounds, compositions and formulations of the present application, when used in a subject, will produce or result in 3APS or isotopically enriched 3APS.

[0051] Also, in some embodiments, the compounds of Formulae (I) to (V) can improve or increase the therapeutic effect of 3APS in a subject, as compared to 3APS that is not isotopically enriched (i.e., 3APS in which all atoms are at their natural abundance). In some embodiments, the compounds of Formulae (I) to (V) can improve or increase the bioavailability of 3APS, the AUC value of 3APS, the amount and manner of distribution of 3APS in the brain and / or cerebrospinal fluid, the peak exposure of 3APS, the T max value of 3APS, the stability of 3APS, the therapeutic biodistribution of 3APS, and / or the bioabsorption of 3APS, as compared to 3APS that is not isotopically enriched. In some embodiments, the compounds of Formulae (I) to (V) can improve or increase the effective therapeutic level of 3APS in human tissues, such as the brain or cerebrospinal fluid, as compared to 3APS that is not isotopically enriched. In some embodiments, the compounds of Formulae (I) to (V) can delay the metabolism of 3APS in a subject, as compared to 3APS that is not isotopically enriched. In some embodiments, the compounds of Formulae (I) to (V) can reduce the side effects of 3APS in a subject, as compared to 3APS that is not isotopically enriched.

[0052] In some embodiments, the compounds of Formulae (I) to (V) can be used to prevent and / or treat inflammatory-related conditions or autoimmune diseases and various complications caused thereby, and diseases and conditions associated therewith, particularly multiple sclerosis and conditions associated therewith.

[0053] In another aspect, the present application provides a method for preventing and / or treating inflammatory-related conditions or autoimmune diseases and various complications caused thereby, in a human or animal, comprising administering to a subject in need thereof a compound (or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition and formulation of the present application, and, optionally, one or more additional components, such as an acid, a base, a buffer, an inorganic salt, a solvent, an antioxidant, a preservative, or a metal chelator.

[0054] In some embodiments, the method of the present invention for the prevention and / or treatment of inflammatory-related conditions or autoimmune diseases in humans or animals includes administering to a subject in need the compound 3-amino-3,3-dideuter-1-propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition or formulation thereof, and optionally one or more additional components, such as acids, bases, buffers, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.

[0055] In other embodiments, the method of the present invention for preventing and / or treating inflammatory-related conditions or autoimmune diseases in humans or animals includes administering compound 3-(of the present invention) to a subject in need. 15 N-amino)-1-propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition or formulation thereof, and optionally one or more additional components, such as acids, bases, buffers, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.

[0056] Furthermore, the method provided by the present invention for the prevention and / or treatment of inflammatory-related conditions or autoimmune diseases in humans or animals includes administering the compound of the present invention, 3-((L-valinel)amino)-3,3-dideuter-1-propanesulfonic acid, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition and formulation thereof, to a subject in need, and optionally one or more additional components, such as acids, bases, buffers, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.

[0057] The present invention also relates to the use of the compounds of the present invention in the preparation of corresponding kits; and related kits, as well as instructions for use of the methods described above. Attached Figure Description

[0058] Figure 1 The demyelination score is obtained according to Example 11 of the present invention.

[0059] Figure 2 The inflammatory infiltration score is obtained according to Example 11 of the present invention. Detailed Implementation

[0060] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. To better understand the present invention and more clearly demonstrate how to implement it, features of embodiments according to the present invention are now described by way of example and with reference to the accompanying drawings.

[0061] For convenience, the meanings of certain terms and phrases used in this invention are provided below. Unless otherwise specified, all technical and scientific terms used in this invention have the same meanings as commonly understood by one of ordinary skill in the art.

[0062] The use of the word "a" or "an" when used in conjunction with the term "comprising" can mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0063] The use of the word "including" (and any form of including) as used in the specification and claims, "having" (and any form of having), "including" and "containing" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0064] The term "about" or "approximately" is used to indicate that a value includes the error resulting from the instrument and method used to determine the value.

[0065] The term "derivative" as used herein is understood to be another compound that is structurally similar, differing in some subtle structural way.

[0066] The present specification refers to a number of chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0067] The term "alkyl" as used herein refers to saturated hydrocarbons having 1 to 12 carbon atoms, including straight chain, branched chain and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term alkyl includes unsubstituted alkyl groups and substituted alkyl groups. The term "C1-Cnalkyl" (where n is an integer from 2 to 12) refers to alkyl groups having from 1 to n carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl group can be substituted with a hydroxyl, amino, carboxyl, carboxylate, amide, carbamate, or aminoalkyl group, among others. n The term "alkyl" as used herein refers to saturated hydrocarbons having 1 to 12 carbon atoms, including straight chain, branched chain and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term alkyl includes unsubstituted alkyl groups and substituted alkyl groups. The term "C1-Cnalkyl" (where n is an integer from 2 to 12) refers to alkyl groups having from 1 to n carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl group can be substituted with a hydroxyl, amino, carboxyl, carboxylate, amide, carbamate, or aminoalkyl group, among others.

[0068] The term "acyclic" as used herein refers to an organic moiety that does not have a cyclic system. The term "aliphatic group" includes organic moieties characterized as straight-chained or branched, typically having from 1 to 15 carbon atoms. Aliphatic groups include acyclic alkyl, alkenyl, and alkynyl groups.

[0069] The term "alkenyl" as used herein refers to unsaturated hydrocarbons having 2 to 12 carbon atoms, including straight-chain, branched-chain and cyclic non-aromatic alkenyl groups, and containing one to six carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl 1,3-pentadien-5-yl, cyclopentenyl, cyclohexenyl, ethylcyclopentenyl, ethylcyclohexenyl, and the like. The term alkenyl includes unsubstituted alkenyl and substituted alkenyl. The term "C2-C12alkenyl" means an alkenyl group having 2 to 12 carbon atoms. n The term "alkenyl" as used herein refers to unsaturated hydrocarbons having 2 to 12 carbon atoms, including straight-chain, branched-chain and cyclic non-aromatic alkenyl groups, and containing one to six carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl 1,3-pentadien-5-yl, cyclopentenyl, cyclohexenyl, ethylcyclopentenyl, ethylcyclohexenyl, and the like. The term alkenyl includes unsubstituted alkenyl and substituted alkenyl. The term "C2-C12alkenyl" means an alkenyl group having 2 to 12 carbon atoms.

[0070] The term "alkynyl" as used herein refers to unsaturated hydrocarbons having 2 to 12 carbon atoms, including straight-chain, branched-chain and cyclic non-aromatic alkynyl groups, and containing one to six carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-5-yl, 1,3-pentadiyn-5-yl, and the like. The term alkynyl includes unsubstituted alkynyl and substituted alkynyl. The term "C2-C12alkynyl" means an alkynyl group having 2 to 12 carbon atoms. n The term "alkynyl" as used herein refers to unsaturated hydrocarbons having 2 to 12 carbon atoms, including straight-chain, branched-chain and cyclic non-aromatic alkynyl groups, and containing one to six carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-5-yl, 1,3-pentadiyn-5-yl, and the like. The term alkynyl includes unsubstituted alkynyl and substituted alkynyl. The term "C2-C12alkynyl" means an alkynyl group having 2 to 12 carbon atoms.

[0071] Unless otherwise indicated, "lower" in "lower aliphatic", "lower alkyl", "lower alkenyl" and "lower alkynyl" as used herein means that the moiety has at least one (two for alkenyl and alkynyl) and up to and including 6 carbon atoms.

[0072] The terms "cycloalkyl", "alicyclic", "ring carbon" and equivalent groups as used herein refer to carbocyclic ring systems containing saturated or partially unsaturated carbocyclic groups in a single spiro (sharing one atom) or fused (sharing at least one bond) ring, which system has 3 to 15 carbon atoms in the ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C3-C15cycloalkyl" means a cycloalkyl group having 3 to 15 carbon atoms in the ring structure. Unless otherwise indicated, "lower cycloalkyl" groups as used herein refer to cycloalkyl groups having at least 3 and up to and including 8 carbon atoms in their ring structure. n The term "cycloalkyl", "alicyclic", "ring carbon" and equivalent groups as used herein refer to carbocyclic ring systems containing saturated or partially unsaturated carbocyclic groups in a single spiro (sharing one atom) or fused (sharing at least one bond) ring, which system has 3 to 15 carbon atoms in the ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C3-C15cycloalkyl" means a cycloalkyl group having 3 to 15 carbon atoms in the ring structure. Unless otherwise indicated, "lower cycloalkyl" groups as used herein refer to cycloalkyl groups having at least 3 and up to and including 8 carbon atoms in their ring structure.

[0073] As used in this invention, cycloalkyl residues can be saturated groups or groups containing one or more double bonds within a ring. Specifically, they can be saturated cyclic groups or cyclic groups containing a single double bond within a ring. In unsaturated cycloalkyl residues, the double bond can be present in any suitable position. Monocycloalkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, or cyclotetradecyl, and may also be C14 or C24. 1-4 Alkyl substitution. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Examples of parent structures for bicyclic systems are norbornene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.1]octane.

[0074] As used in this invention, the term "heterocyclic alkyl" and its equivalent group refer to a group containing a saturated or partially unsaturated carbocyclic ring in a single spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic system, having three to fifteen carbon atoms, including one to six heteroatoms (e.g., N, O, S, P) or including heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). Heterocyclic alkyl groups may be linked to a C atom or to a heteroatom (e.g., via a nitrogen atom). Examples of heterocyclic alkyl groups include, but are not limited to, pyrrolyl, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxyl, piperazine, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, high-piperidinyl, oxacyclic heptyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dialkyl, 1,3-dioxolanecycloyl, pyrazolinyl, dithiaalkyl, dithiocyclic pentanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, 3H-indolyl, quinazinyl, and sugars, etc. The term heterocyclic alkyl includes both unsubstituted and substituted heterocyclic alkyl groups. The term "C3-C" is also used. 15 "Heterocyclic alkyl", where n is an integer from 4 to 15, refers to a heterocyclic alkyl group having 3 to the number of atoms shown as "n" in its ring structure, including at least one heterogroup or atom as defined above. Unless otherwise stated, "low heterocyclic alkyl" as used in this invention refers to a cyclic alkyl group having at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0075] The term "aryl" and "aryl ring" as used herein refers to aromatic groups having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic ring system, where n is an integer from 1 to 3, and having from 6 to 14 ring atoms. The polycyclic ring system includes at least one aromatic ring. The aryl group can be attached directly or through a C1-C3 alkyl group (also referred to as aralkyl). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthyl, fluorenyl, phenanthryl, anthryl, and the like. The term "aryl" includes unsubstituted aryl groups and substituted aryl groups. The term "C6-Ci2 aryl" refers to aryl groups having from 6 to 12 carbon atoms in the ring structure, including at least one heteroatom group or atom as defined above. n The term "aryl" (where n is an integer from 6 to 15) refers to aryl groups having from 6 to the indicated "n" number of carbon atoms in the ring structure, including at least one heteroatom group or atom as defined above.

[0076] The term "heteroaryl" and "heteroaryl ring" as used herein refers to aromatic groups having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic ring system, where n is an integer from 1 to 3, and including from one to six heteroatoms (e.g., N, O, S, P) or including heteroatom groups (e.g., NH, NRx(Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). The polycyclic ring system includes at least one heteroaromatic ring. The heteroaryl group can be attached directly or through a C1-C3 alkyl group (also referred to as heteroarylalkyl or heteroaralkyl). The heteroaryl group can be attached to a carbon or to a heteroatom (e.g., through a nitrogen atom). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, quinazolinyl, quinolinyl, quinolinonyl, isoquinolinonyl, quinoxalinyl, naphthyridinyl, furopyridinyl, carbazolyl, phenanthrolinyl, acridinyl, perylenyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, phenoxazinyl, diphenylfuranyl, and the like. The term heteroaryl includes unsubstituted heteroaryl groups and substituted heteroaryl groups. The term "C5-Ci2 heteroaryl" refers to heteroaryl groups having from 5 to 12 carbon atoms in the ring structure, including at least one heteroatom group or atom as defined above. 15 The term "heteroaryl" (where n is an integer from 6 to 15) refers to heteroaryl groups having from 5 to the indicated "n" number of atoms in the ring structure, including at least one heteroatom group or atom as defined above.

[0077] The term "heterocycle" or "heterocyclic" as used herein includes heterocycloalkyl and heteroaryl groups. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, 4alphaH-carbazolyl, carbolinyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolyl, pyrroyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, xanthenyl, and the like. The term "heterocycle" includes both unsubstituted heterocyclic groups and substituted heterocyclic groups.

[0078] The term "amine" or "amino" as used herein refers to the moiety -NR a R b where R a and R b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and R btogether with the nitrogen atom to which they are attached. The term amino refers to an amine group or moiety in which at least one carbon or heteroatom is covalently bonded to a nitrogen atom. Thus, the terms "alkylamino" and "dialkylamino" as used herein refer to an amine group having one and at least two C1-C6alkyl groups, respectively, attached to the nitrogen atom. The terms "arylaminos" and "diarylaminos" include groups having at least one or two aryl groups attached to the nitrogen atom. The term "amide" or "aminocarbonyl" refers to a structure in which the carbon of a carbonyl or thiocarbonyl group of a compound or moiety is attached to a nitrogen atom. The term "acylamino" refers to a structure in which an amino group is directly attached to an acyl group.

[0079] The term "nitro" as used herein refers to -NO2. The terms "halo" and "halogen" refer to a substituent of bromo, chloro, fluoro, or iodo. The term "thiol", "sulfhydryl" or "mercapto" refers to SH. The term "hydroxy" or "hydroxyl" refers to -OH. The term "alkylthio" refers to a structure in which an alkyl group is attached to a mercapto group. Suitable alkylthio groups include groups having from 1 to about 12 carbon atoms (preferably from 1 to about 6 carbon atoms). The term "alkylcarboxy" as used herein refers to a structure in which an alkyl group is attached to a carboxyl group.

[0080] The term "alkoxy" or "lower alkoxy" as used herein refers to a structure in which an alkyl group is attached to an oxygen atom. Representative alkoxy groups include groups having from 1 to about 6 carbon atoms, such as methoxy, ethoxy, propyloxy, t-butyloxy, and the like. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like. The term alkoxy includes unsubstituted or substituted alkoxy groups, as well as perhaloalkoxy groups, and the like.

[0081] The term "carbonyl" or "carboxyl" as used herein includes structures in which the carbon of a compound or moiety is attached to an oxygen atom through a double bond. Examples of moieties containing carbonyl groups include aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, and the like

[0082] The term "acyl" as used herein refers to a structure in which the carbon atom of a carbonyl group is attached to hydrogen (i.e., formyl), an aliphatic group (C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, such as acetyl), a cycloalkyl group (C3-C8cycloalkyl), a heterocyclyl group (C3-C8heterocycloalkyl and C5-C6heteroaryl), an aryl group (C6aryl, such as benzoyl). The acyl group can be unsubstituted or substituted acyl (e.g., salicyloyl).

[0083] It is understood that the term "substituted" or "substitution" as used herein includes the implicit proviso that such substitution is in accordance with permitted valence of the substituting atom and the substituent and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo rearrangement, cyclization, elimination, etc. The term "substituted" as used herein includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyl, amino (including alkylamino, arylamino, aralkylamino, and the like), aminocarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfonyl, sulfato, sulfonate, sulfamide, phosphato, phosphonate, imino, formyl, and the like. Any of the above substituents can further be substituted, e.g., with alkyl, aryl, or other groups, if permitted by the nature of the substituent.

[0084] The term "solvate" as used herein refers to a physical association between a compound and one or more solvent molecules (whether organic or inorganic). This physical association can include hydrogen bonding. In certain instances, the solvate can be isolated. "Solvate" includes solution-phase and isolatable solvates. Solvates include, but are not limited to, hydrates, ethanolates, methanolates, hemi-ethanolates, and the like.

[0085] A "pharmaceutically acceptable salt" of a compound refers to a salt of a compound that is pharmaceutically acceptable. Desirable salts include those that retain the biological effectiveness and properties of the parent compound and that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be prepared using Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). Included are salts of metabolic derivatives of the parent compound. Salts of other derivatives formed during product metabolism can also be included. Salts include, but are not limited to:

[0086] (1) salts formed by addition of an acid to a basic or positively charged functional group, inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, nitric, phosphoric, carbonic, and the like. Organic acids include acetic, propionic, lactic, oxalic, glycolic, new valeric, tertiary butyl acetic, beta-hydroxybutyric, valeric, hexanoic, cyclopentanepropionic, pyruvic, malonic, succinic, malic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, cyclohexylaminosulfonic, benzenesulfonic, sulfanilic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphorsulfonic, 3-phenylpropionic, lauryl sulfonic, lauryl sulfuric, oleic, palmitic, stearic, lauric, pamoic (embonic), pamoic, pantothenic, lactobionic, alginic, galactaric, galacturonic, gluconic, glucoheptonic, glutamic, naphthalene- 1 -sulfonic, hydroxynaphthoic, salicylic, ascorbic, stearic, muconic, and the like.

[0087] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, calcium, barium), or other metal ion such as aluminum, zinc, iron, and the like, or when a negatively charged functional group such as carboxylate, phosphate, sulfonate, sulfonamide, and the like, is replaced by a cationic or basic ion. Organic bases include, but are not limited to, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, and the like.

[0088] Pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared either by reacting the free acid or base forms of the compounds of the application with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. The salts can be prepared in situ during the final isolation and purification of the compounds. In addition, the purified compounds in the free acid or base form can be converted into the salt form using standard chemical techniques. Also included are zwitterionic forms of the compounds of the application, which are referred to as "inner salts". All acid, base and other ionic and non-ionic forms of the compounds of the application are intended to be included within the scope of the application. For example, if the compound of the application is an acid, its salt form is also intended to be included. Likewise, if the compound of the application is a salt, its free acid or base form is also intended to be included.

[0089] The term "AUC" as used herein is the area under the curve representing the concentration of a compound in a biological sample of a subject as a function of time after administration of the compound to the subject. Examples of biological samples include, without limitation, biological fluids such as plasma, blood, cerebrospinal fluid (CSF) and saliva, organ homogenates such as brain and liver homogenates and the like. The AUC can be determined by measuring the concentration of the compound in the biological sample at various time intervals using a method such as liquid chromatography-tandem mass spectrometry (LC / MS / MS) and calculating the area under the concentration versus time period. Methods for calculating AUC from drug concentration-time curves are well known and accepted in the art. In connection with the disclosure herein, the AUC of 3APS can be determined by measuring the concentration of 3APS in plasma, blood, CSF or brain homogenate of a subject after oral administration of a compound according to the disclosure to the subject.

[0090] The term "bioavailability" as used herein refers to the rate and extent of the drug or prodrug that becomes available to the general circulation of the subject after administration to the patient and can be determined by assessing, for example, the plasma or blood concentration of the compound versus time profile. Parameters used to characterize the plasma or blood concentration versus time curve include the area under the curve (AUC), the time of peak concentration (T max ), and the maximum drug concentration (C max ). The term "C max " refers to the maximum concentration of a compound in a biological sample of a subject after administration of a dose of the compound to the subject. The term "T max " refers to the time to the maximum concentration (C max ) of a compound in a biological sample of a subject after administration of a dose of the compound to the subject. Bioavailability is typically expressed as F (%) and refers to the percentage of the AUC of a compound after a particular mode of administration (e.g., oral) relative to the AUC of the compound after intravenous (iv) administration.

[0091] The term "bioequivalence" as used herein refers to the equivalence in the rate and extent of absorption of a pharmaceutical agent (e.g., a compound) after administration of the same dose to a patient. As used herein, two plasma or blood concentration profiles are bioequivalent if the 90% confidence interval for the ratio of the mean responses of the two profiles is within the limits of 0.8 and 1.25. The mean response includes at least one characteristic parameter of the profile, such as C max , T max , and AUC.

[0092] As used in this invention, the term "effective amount" refers to the quantity or dosage of a compound that provides the desired effect in a patient undergoing diagnosis or treatment after administration of a single or multiple doses. The effective amount can be readily determined by the attending physician or diagnostician using known techniques and by observing results obtained under similar conditions. In determining the effective amount or dosage of a compound, the attending physician or diagnostician considers many factors, including but not limited to: the patient's weight or size, age and general health, the specific disease involved, the extent or severity of the disease, the individual patient's response, the specific route of administration of the compound, the bioavailability characteristics of the administered formulation, the chosen dosing regimen, the use of concurrent drug therapy, and other relevant circumstances.

[0093] As used in this invention, the term "therapeutic biodistribution of 3APS" refers to one or more 3APS pharmacokinetic parameters that affect the therapeutic activity of 3APS. Examples of such pharmacokinetic (PK) parameters include, but are not limited to: 3APS bioavailability, 3APS AUC, 3APS brain levels, 3APS CSF levels, and 3APS C6 levels. max 3APS of T max And / or 3APS bioabsorption, etc.

[0094] In some embodiments, compared with non-isotope-enriched 3APS or its prodrugs, the drugs included in this invention can improve the therapeutic efficacy of 3APS by improving the therapeutic biodistribution of 3APS, improving the bioavailability of 3APS, improving the stability of 3APS, reducing the metabolism of 3APS, and / or improving other pharmacokinetic parameters of 3APS.

[0095] As used in this invention, the terms "enhanced (or similar terms, such as increased, improved, or improved) therapeutic efficacy / efficacy of 3APS" and "enhanced (or similar terms, such as enhanced, improved, or improved) therapeutic efficacy / efficacy of 3APS" refer to an increase in the efficacy of 3APS. This increase is measured, for example, by one or more parameters under the "therapeutic biodistribution of 3APS" described above, such as 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 125%, etc., or even more, such as 2 or 4 times, or even more (when the treated subject is, for example, an animal or human). This increase is relative to an equimolar dose of non-isotope-enriched 3APS. In some embodiments, this increase is achievable relative to the compounds disclosed in CN102793694B and the formulations in Table 3 of U.S. Patent Application Publication No. 2006-0079578, published April 13, 2016, administered orally at an equimolar dose of 3APS.

[0096] The term "reduction of the metabolism of 3APS" (or related terms, such as decrease, lessening, lower, reduced, etc.) as used herein refers to a reduction of the extent or amount of metabolism of 3APS in the gastrointestinal tract or in the liver. Such reduction, e.g. by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or even 100% is relative to an equimolar dose of non-isotopically enriched 3APS. In some embodiments, such reduction is achievable relative to oral administration of an equimolar dose of 3APS of the compound disclosed in CN102793694B and the formulations of Table 3 of U.S. Patent Application Publication No. 2006-0079578 published on April 13, 2016.

[0097] The term "reduction of the metabolism of 3APS" (or related terms, such as decrease, lessening, lower, reduced, etc.) as used herein also refers to a reduction of the extent or amount of metabolism of 3APS in the blood or in brain tissue or other organs. Such reduction, e.g. by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or even 100% is relative to an equimolar dose of non-isotopically enriched 3APS.

[0098] "Reduction of the metabolism of 3APS" can be characterized by quantitative or semi-quantitative detection of the amount of 3APS metabolites. A decrease in the amount of 3APS metabolites is indicative of a decrease in the rate of metabolism and a reduction of metabolism.

[0099] The term "reduction of side effects of 3APS" as used herein refers to a reduction of the amount or severity of one or more side effects of 3APS, e.g. by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9%, or even 100%. Such reduction of the amount or severity of side effects of 3APS is relative to an equimolar dose of non-isotopically enriched 3APS. In some embodiments, such reduction is achievable relative to oral administration of an equimolar dose of 3APS of the compound disclosed in CN102793694B and the formulations of Table 3 of U.S. Patent Application Publication No. 2006-0079578 published on April 13, 2016. More generally, the terms lessening or increasing in the context of the present invention can be a percentage, e.g. 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, etc., or even more, e.g. 2 or 4 fold, or even more.

[0100] In some embodiments, the compounds of the application improve the AUC of 3APS at least about 20% relative to an equimolar dose of non-isotopically enriched 3APS or prodrug. In some embodiments, the compounds of the application improve the AUC of 3APS at least about 20% relative to an oral equimolar dose of non-isotopically enriched 3APS or prodrug. In other embodiments, the AUC is improved at least about 5%, at least about 10%, at least about 25%, at least about 30% or at least about 40%.

[0101] The term "pharmaceutically acceptable" as used herein refers to drugs, drug products, inerts, etc. which are suitable for use with humans and lower animals with no undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, as well as the relative biological and medical considerations. It preferably refers to compounds, compositions, and formulations which are approved or approvable by a regulatory agency of the Federal or a state government or the United States Pharmacopeia or other recognized pharmacopeia for use in animals, more particularly in humans.

[0102] The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered.

[0103] The term "pharmaceutical composition" as used herein refers to at least one compound and at least one pharmaceutically acceptable carrier with which the compound is administered to a patient.

[0104] The term "prevent" as used herein means to decrease the likelihood (i.e., cause the cessation or reduction of development of at least one clinical symptom of a disease in a patient that can be exposed to or predisposed to a disease but does not yet experience or express symptoms of the disease) of acquiring a disease or disorder at least.

[0105] The term "treat" as used herein in some embodiments means to ameliorate at least one disease or disorder (i.e., to arrest or reduce the development of a disease or at least one clinical symptom thereof). In certain embodiments, "treat" means to ameliorate a physical parameter of a patient, which can or can not be discernible by the patient. In certain embodiments, "treat" means to inhibit the progress of a disease or disorder in an individual's body (e.g., stable a discernible symptom), in an individual's physiology (e.g., stable a physical parameter), or both. In certain embodiments, "treat" means to delay the onset of a disease or disorder. The term "treatment" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition including any objective or subjective parameter such as alleviation of symptoms, reduction of multiple sclerosis patient's neurological deficit resulting from inflammatory reactions in the brain, spinal cord, optic nerve, etc.

[0106] In some embodiments, the term "treatment" as used herein refers to any improvement in at least one disease or condition (i.e., halting or reducing the progression of the disease or at least one of its clinical symptoms) after the disease or condition has been treated, wherein such improvement is a pathological indicator.

[0107] The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a patient for treatment or prevention of a disease, is sufficient to effect such treatment or prevention of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated or prevented from the disease.

[0108] The term "prodrug" and equivalent expressions as used herein refer to a form of an agent that can be converted directly or indirectly to the active compound in vitro or in vivo (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs". 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards, XVIII, 1470 p. Springer). Prodrugs can be used to alter the biodistribution (e.g., to allow entry of an agent into a reaction site of a protease that it would not normally enter) or the pharmacokinetics of a particular agent. A wide variety of groups can be used to modify a compound to form a prodrug, such as esters, ethers, phosphates, and the like. When a prodrug is administered to a subject, the group is enzymatically or non-enzymatically cleaved, reduced, oxidized, or hydrolyzed, or otherwise released, to yield the active compound. As encompassed by the present application, "prodrugs" refer to pharmaceutically acceptable salts or pharmaceutically acceptable solvates of any of the above agents as well as any crystalline forms of any of the above agents. The prodrug is often, but not necessarily, pharmacologically inactive until it is converted to the parent drug.

[0109] The term "ester" as used herein refers to a compound that can be represented by the general formula RCOOR (carboxylic acid ester) or the general formula RS03R' (sulfonic acid ester), wherein the group R can be the 3-aminopropane segment of 3APS and the group R' can be another organic group. Typically, these compounds can be obtained by the reaction of a carboxylic acid or sulfonic acid with an alcohol, respectively, with the elimination of a molecule of water.

[0110] The term "amino acid" as used herein generally refers to an organic compound that contains both a carboxylic acid group and an amine group. The term "amino acid" includes "natural" and "non-natural" amino acids. In addition, the term amino acid includes O-alkylated or N-alkylated amino acids, as well as amino acids having side chains containing nitrogen, sulfur or oxygen (e.g., Lys, Cys or Ser), where the nitrogen, sulfur or oxygen atom can or can not be acylated or alkylated. The amino acid can be an L-amino acid, a D-amino acid or an L- and D-mixed amino acid, including but not limited to racemic mixtures.

[0111] The term "natural amino acid" and equivalent expressions as used herein refer to L-amino acids that are typically found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (lie), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gin), arginine (Arg), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-Ala) and γ-aminobutyric acid (GABA), among others.

[0112] The term "non-natural amino acid" as used herein refers to any derivative of a natural amino acid, including D-forms of amino acids and their derivatives, as well as alpha- and beta-amino acid derivatives. It is noted that certain non-natural amino acids (e.g., hydroxyproline) can occur in nature in certain biological tissues or in specific proteins. Amino acids with a number of different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available. In addition to the twenty most common natural amino acids, the following non-natural amino acids and amino acid derivatives (common abbreviations in parentheses) can be used according to the present application: 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminobutyric acid (β-Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminopentanoic acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta), aminooxyacetic acid (Aoa), 2-amino-tetrahydronaphthalene-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA), p-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-Cl-Tyr), p-benzoylphenylalanine (Bpa), t-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-Cl2-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), 2,3-diaminobutyric acid (Dab), 2,4-diaminobutyric acid (Dbu), 2,6-diaminohexanoic acid (Dha), 2,7-diaminoheptanoic acid (Dhe), 2,8-diaminooctanoic acid (Dho), 2,9-diaminononanoic acid (Dhn), 2,10-diaminodecanoic acid (Dda), 2,11-diaminoundecanoic acid (Ddu), 2,12-diaminododecanoic acid (Ddo), 2,13-diaminotridecanoic acid (Ddt), 2,14-diaminotetradecanoic acid (Ddt), 2,15-diaminopentadecanoic acid (Ddp), 2,16-diaminohexadecanoic acid (Ddh), 2,17-diaminoheptadecanoic acid (Ddi), 2,18-diaminooctadecanoic acid (Ddo), 2,19-diaminononadecanoic acid (Ddn), 2,20-diaminoeicosanoic acid (Dde), 2,21-diaminoheneicosanoic acid (Ddh), 2,22-diaminodocosanoic acid (Ddd), 2,23-diaminotricosanoic acid (Ddt), 2,24-diaminotetracosanoic acid (Ddt), 2,25-diaminopentacosanoic acid (Ddp), 2,26-diaminohexacosanoic acid (Ddh), 2,27-diaminohentacosanoic acid (Ddi), 2,28-diaminooctacosanoic acid (Ddo), 2,29-diaminononacosanoic acid (Ddn), 2,30-diaminoeicosanoic acid (Dde), 2,31-diaminoheneicosanoic acid (Ddh), 2,32-diaminodocosanoic acid (Ddd), 2,33-diaminotricosanoic acid (Ddt), 2,34-diaminotetracosanoic acid (Ddt), 2,35-diaminopentacosanoic acid (Ddp), 2,36-diaminohexacosanoic acid (Ddh), 2,37-diaminohentacosanoic acid (Ddi), 2,38-diaminooctacosanoic acid (Ddo), 2,39-diaminononacosanoic acid (Ddn), 2,40-diaminoeicosanoic acid (Dde), 2,41-diaminoheneicosanoic acid (Ddh), 2,42-diaminodocosanoic acid (Ddd), 2,43-diaminotricosanoic acid (Ddt), 2,44-diaminotetracosanoic acid (Ddt), 2,45-diaminopentacosanoic acid (Ddp), 2,46-diaminohexacosanoic acid (Ddh), 2,47-diaminohentacosanoic acid (Ddi), 2,48-diaminooctacosanoic acid (Ddo), 2,49-diaminononacosanoic acid (Ddn), 2,50-diaminoeicosanoic acid (Dde), 2,51-diaminoheneicosanoic acid (Ddh), 2,52-diaminodocosanoic acid (Ddd), 2,53-diaminotricosanoic acid (Ddt), 2,54-diaminotetracosanoic acid (Ddt), 2,55-diaminopentacosanoic acid (Ddp), 2,56-diaminohexacosanoic acid (Ddh), 2,57-diaminohentacosanoic acid (Ddi), 2,58-diaminooctacosanoic acid (Ddo), 2,59-diaminononacosanoic acid (Ddn), 2,60-diaminoeicosanoic acid (Dde), 2,61-diaminoheneicosanoic acid (Ddh), 2,62-diaminodocosanoic acid (Ddd), 2,63-diaminotricosanoic acid (Ddt), 2,64-diaminotetracosanoic acid (Ddt), 2,65-diaminopentacosanoic acid (Ddp), 2,66-diaminohexacosanoic acid (Ddh), 2,67-diaminohentacosanoic acid (Ddi), 2,68-diaminooctacosanoic acid (Ddo), 2,69-diaminononacosanoic acid (Ddn), 2,70-diaminoeicosanoic acid (Dde), 2,71-diaminoheneicosanoic acid (Ddh), 2,72-diaminodocosanoic acid (Ddd), 2,73-diaminotricosanoic acid (Ddt), 2,74-diaminotetracosanoic acid (Ddt), 2,75-diaminopentacosanoic acid (Ddp), 2,76-diaminohexacosanoic acid (Ddh), 2,77-diaminohentacosanoic acid (Ddi), 2,78-diaminooctacosanoic acid (Ddo), 2,79-diaminononacosanoic acid (Ddn), 2,80-diaminoeicosanoic acid (Dde), 2,81-diaminoheneicosanoic acid (Ddh), 2,82-diaminodocos5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine-isotyrosine (4-I-Tyr), dihydroindole-2-carboxylic acid (Idc), iso-idoxuridine (Ide), isoleucine (α-Ile), isoperidinic acid (Inp), N-methylisoleucine (Melle), N-methyllysine ( MeLys), m-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), leucine (Nle), valine (Nva), ornithine (Orn), 1-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid, penicillamine, pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), piperidine acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiazolidin-4-carboxylic acid (thioproline, Th).

[0113] As used in this invention, the term "the portion of an amino acid other than the carboxyl group" refers to the portion of an amino acid molecule that is attached to the carboxyl group, and the attachment point of this portion is the same site in the amino acid molecule where it is attached to the carboxyl group. For example, the "portion other than the carboxyl group" in phenylalanine is (1-amino-2-phenyl)ethyl (Ph-CH2(NH2)CH–); as another example, the "portion other than the carboxyl group" in γ-aminobutyric acid is 3-aminopropyl-1- or 3-amino-1-propyl (NH2CH2CH2–).

[0114] When multiple substituents are attached to the structure of a compound, it should be understood that the substituents can be the same or different. Therefore, for example, "any one, two, or three Rs..." q R with substituent group m " indicates R m Use 1, 2 or 3 Rs q Group-substituted, wherein R q The functional groups can be the same or different.

[0115] Isotope-enriched compounds

[0116] Isotope enrichment is the process of changing the relative abundance of isotopes of a given element, enriching (i.e., increasing) one particular isotope and correspondingly decreasing or depleting another. As used herein, the term "isotope-enriched" compound or derivative refers to a compound in which one or more particular isotopes is increased (i.e., one or more particular isotope elements is enriched or increased). Typically, in an isotope-enriched compound or derivative, a particular isotope element is enriched or increased at a particular position of the compound. However, it is understood that a compound can have two or more isotope elements enriched or increased, including different isotopes of the same element as well as respective isotopes of different elements. Moreover, an isotope-enriched compound can be a mixed form of isotope enrichment, i.e., containing multiple particular isotopes or elements or both.

[0117] Typically, deuterium (D or 2 H) (a stable isotope of hydrogen having about twice the mass of hydrogen), nitrogen-15 15 N), carbon-13 13 C), oxygen-18 18 O) and oxygen-17 17The natural abundance of 0) is 0.016%, 0.37%, 1.11%, 0.204%, and 0.037%, respectively. A "isotopically enriched" compound or derivative used in the present application has an isotopic level higher than this natural abundance. The level of isotopic enrichment depends on the natural abundance of the particular isotope itself. In some embodiments, the level of isotopic enrichment of a compound or element in a compound can be about 1 to about 100 mole percent (%), such as about 2%, about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 98%, and greater than about 98%, about 99%, or 100%. In one embodiment, the level of isotopic enrichment of an isotopically enriched compound of the present application (e.g., 3APS, a compound of any one of Formulae (I)-(V), etc.) is about 5% or greater, or about 10% or greater. In another embodiment, the level of isotopic enrichment of an isotopically enriched compound of the present application (e.g., 3APS, a compound of any one of Formulae (I)-(V), etc.) is about 20% or greater, or about 50% or greater. In another embodiment, the level of isotopic enrichment of an isotopically enriched compound of the present application (e.g., 3APS, a compound of any one of Formulae (I)-(V), etc.) is about 75% or greater, or about 90% or greater. In another embodiment, the level of isotopic enrichment of an isotopically enriched compound of the present application (e.g., 3APS, a compound of any one of Formulae (I)-(V), etc.) is about 95% or greater, 98% or greater, or 100%. It is noted that the level of isotopic enrichment of a particular compound or of a particular element in a compound will depend on several properties of the compound including chemistry, pharmacokinetics, and therapeutic efficacy, among others, in order to improve the therapeutic efficacy, therapeutic biodistribution, bioavailability, metabolism, stability, and / or pharmacokinetics of the compound.

[0118] The term "naturally abundant element" or "natural abundance element" used in the present application refers to the element that is most abundant in nature in terms of atomic mass. For example, the naturally abundant element of hydrogen is 1 H, the naturally abundant element of nitrogen is 14 N; the naturally abundant element of oxygen is 16 O, the naturally abundant element of carbon is 12 C, etc. A "non-isotopically enriched" compound is one in which all atoms or elements in the compound are of the naturally abundant isotope, i.e., all atoms or elements are of the atomic mass that is most abundant in nature. An isotopically enriched compound refers to one in which one or more particular elements are enriched in an isotope that is not the naturally abundant isotope.

[0119] The terms "compound of the invention", "compound encompassed by the invention" and equivalent expressions refer to the isotopically enriched compounds provided by the invention and useful for at least one purpose of the invention. Isotopically enriched compounds include any one of the compounds of the general formula (I)-(V), as well as the specific compounds mentioned in the invention (compounds in Tables 1-4), and acceptable salts, esters, chelates, hydrates, solvates, and different crystalline forms thereof.

[0120] The present invention does not include N-acetyl-3-amino-l-propanesulfonic acid and 3-amino-l-propanesulfonic acid.

[0121] As understood by one of ordinary skill in the art, "compound" includes salts, esters, solvates, hydrates, oxides, complexes, and any stereoisomeric or polymorphic forms of the compound, or mixtures of any proportion of any form of the compound. Thus, the compounds according to some embodiments of the invention (including in pharmaceutical compositions and methods of treatment) exist in salt form.

[0122] It is noted that the compounds described herein can contain one or more chiral centers and / or double bonds and therefore can exist as stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. The chemical structures disclosed herein include all possible enantiomeric and stereoisomeric forms of the illustrated compounds, including single stereoisomeric forms (e.g., geometrically pure, enantiomeric pure or diastereomeric pure) as well as mixtures of enantiomers and stereoisomers. Enantiomeric and stereoisomeric mixtures can be resolved into their respective single-configuration compounds using separation techniques well known to those skilled in the art or chiral synthesis techniques, and the desired isomer recovered by chiral salt or ester exchange or cleavage. Such techniques include, for example, chiral chromatography (e.g., chiral HPLC), immunoassay techniques, or separation of covalent (e.g., Mosher's ester) and non-covalent (e.g., chiral salt) bonded chiral reagents of mixtures of chiral enantiomers or stereoisomers by conventional methods such as chromatography, distillation, crystallization or sublimation. The compounds can also exist in several tautomeric forms, including enol and keto forms and mixtures thereof. The chemical structures disclosed herein can include all possible tautomeric forms of the illustrated compounds.

[0123] The compounds can exist in unsolvated forms as well as solvated forms, including hydrates. In general, the compounds can be in the form of a hydrate or solvate. Some compounds can exist in various crystalline or amorphous forms. In general, all physical forms are included in the present invention.

[0124] In the present invention, the compound 3-amino-1-propanesulfonic acid can be expressed as the term "3APS", and can also be expressed as Tramiprosate, tramiprosate, or Homotaurine, or 3-HT. All of these names refer to the compound having the structural formula H2NCH2CH2CH2SO3H and to the corresponding compounds in the form of salts thereof, such as the hydrochloride salt and the sodium salt. And the scope of use encompasses both natural abundance Homotaurine and Homotaurine containing one or more isotopically enriched atoms.

[0125] The compounds described in the present invention include, but are not limited to, optical isomers, racemic compounds and other mixtures thereof. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or chiral resolution. Resolution of racemates can be achieved, for example, by conventional methods, such as recrystallization from a resolving agent, or by chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, some compounds containing carbon-carbon double bonds have the Z- and E- (or cis- and trans-) configurations. Where the compounds described in the present invention exist in tautomeric forms, the term "compound" is meant to encompass all tautomeric forms of the compound. Such compounds also include crystal and chelate forms. Similarly, the term "salt" encompasses all tautomeric forms of the compound and crystal forms of the compound.

[0126] The configuration of any carbon-carbon double bond that appears in the present invention is merely for convenience of selection and is not intended to be a specific design. Thus, the compounds described in the present invention that contain carbon-carbon double bonds can be Z, E or a mixture of the two in any ratio.

[0127] In some embodiments, the present application relates to compounds also including salts, including pharmaceutically acceptable salts. Various salts (e.g., triethylamine salts, tetrazolium salts, sodium salts, potassium salts, etc.) are possible depending on the understanding of one skilled in the art, as are suitable salts known in the art that can be considered. The term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. For example, for compounds containing a basic nitrogen, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Pharmaceutically acceptable acids suitable for use in the present application include, but are not limited to, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. When the compound contains an acidic side chain, pharmaceutically acceptable bases suitable for use in the present application include, but are not limited to, metal salts such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts such as lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0128] Pharmaceutical compositions

[0129] In one embodiment, a pharmaceutical composition of a compound of the present application includes any of the compounds of the general formulae (I)-(V) and pharmaceutically acceptable salts, esters or solvates thereof, and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutical composition of a compound of the present application includes a specific compound mentioned in the present application (a compound in Tables 1-4), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical composition of a compound of the present application includes any of the compounds of the general formulae (I)-(V) and the specific compounds in Tables 1-4, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, with the proviso that the compound is not N-acetyl-3-amino-l-propanesulfonic acid and 3-amino-l-propanesulfonic acid.

[0130] The preparation of the pharmaceutical compositions can be effected in a manner known per se (see, e.g., Remington: The Science and Practice of Pharmacy, 20th Ed., Philadelphia, PA: Lippincott Williams & Wilkins, 2000). thEdition, 2000). For example, the therapeutic compound and / or composition is combined with one or more solid or liquid vehicle(s) and / or additive(s) (or auxiliary agent(s)) of a pharmaceutical carrier substance and / or other active compounds having therapeutic or prophylactic effects, if necessary, in a suitable administration form or dosage form, and then administered as a medicine in humans or animals. The preparation of the medicine can add many additives known in the art, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing osmotic pressure, coating agents, or antioxidants, etc.

[0131] The term "pharmaceutical composition" as used herein refers to a composition of the compounds described herein, in combination with at least one pharmaceutically acceptable carrier, vehicle, diluent, adjuvant, excipient or preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant and dispersant, as required by the administration form and dosage form.

[0132] The term "pharmaceutically acceptable carrier" as used herein is intended to mean any carrier, diluent, adjuvant, excipient or vehicle of the compounds described herein. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like, can also be added. Prolonged absorption of injectable pharmaceuticals can be achieved by the use of agents delaying absorption, such as aluminum monostearate and gelatin. Examples of suitable carriers, diluents, solvents or vehicle include water, ethanol, polyols, suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Examples of excipients include lactose, lactose monohydrate, sodium citrate, calcium carbonate and dicalcium phosphate. Examples of disintegrants include beta, alginic acid and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.

[0133] The term "pharmaceutically acceptable" as used herein means that which, within the scope of sound medical judgment, is suitable for use in contact with the cells of subjects, such as humans and animals, without an unreasonable toxicity, irritation, allergic response and with an appropriate benefit / risk ratio.

[0134] Pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, a carrier is suitable for parenteral administration, and can be suitable for intravenous, intraperitoneal, intramuscular, subcutaneous, or oral administration. In other embodiments, a carrier is suitable for topical administration or administration by inhalation. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders that can be used to reconstitute sterile injectable solutions or dispersions. Such media and agents for pharmaceutical active substances are known in the art. Except insofar as a conventional media or agent is incompatible with the active compound, such as by production of inapropriate reactions, its use in the pharmaceutical compositions of the present application is contemplated. Supplementary active compounds can also be incorporated into the compositions. For example, as described below, the pharmaceutical compositions of the present application can further incorporate at least one additional agent that elicits various complications that are initiated by the inflammatory-related conditions or autoimmune diseases in humans or animals.

[0135] The pharmaceutical compositions of the present application can be administered orally, for example, in the form of capsules, tablets, coated tablets, sugar coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic (or oily) solutions, syrups, emulsions or suspensions. Alternatively, they can be administered rectally, for example, in the form of suppositories. They can also be administered parenterally, for example, by injection or infusion, for subcutaneous, intramuscular or intravenous administration. Other suitable modes of administration are intradermal or transdermal, for example, in the form of ointments, creams, tinctures, sprays or transdermal therapeutic systems. Or in the form of nasal sprays or aerosol mixtures for inhalation. Or by means of microcapsules, implants or wafers.

[0136] In some embodiments, the pharmaceutical compositions of the present application are useful for oral administration. For example, the pharmaceutical compositions can be in the form of hard or soft gelatin capsules, cachets, pills, tablets, lozenges, powders, granules, pellets, pastilles or pastes, sugar-coated tablets, and the like. Alternatively, the pharmaceutical compositions can be in the form of solutions, aqueous liquid suspensions, non-aqueous liquid suspensions, oil-in-water liquid emulsions, water-in-oil liquid emulsions, elixirs or syrups, and the like. The pharmaceutical compositions can or can not be enteric-coated. In some embodiments, the pharmaceutical compositions are formulated as controlled release formulations, for example, delayed release or extended release formulations.

[0137] In further embodiments, the compounds and compositions thereof can be formulated in a multiple-dose form, i.e., in the form of a multi-particulate dosage form (e.g., a hard gelatin capsule or a conventional tablet prepared using a rotary tablet press), comprising one or more beads or mini-tablets for oral administration to a patient. The conventional tablet will rapidly disperse upon entry into the stomach. The one or more coated beads or mini-tablets can be compressed into a corresponding tablet with appropriate excipients (e.g., a binding agent, a diluent / filler, and a disintegrant for a conventional tablet, and the like).

[0138] The tablets, pills, beads or minitablets of a compound or composition thereof can be coated or otherwise compounded to provide a controlled drug release (including delayed release or extended release) or to protect it from the acidic medium in the stomach. For example, the tablets or pills can contain an inner dosage and an outer dosage component, the latter being in the form of a coating, which surrounds the former. The two components can be separated by a polymeric layer which controls the release of the inner dosage.

[0139] In certain embodiments, the layer can comprise at least one enteric polymer. In further embodiments, the layer can comprise a combination of at least one enteric polymer and at least one non-water soluble polymer. In further embodiments, the layer can comprise a combination of at least one enteric polymer and at least one water soluble polymer. In further embodiments, the layer can comprise a combination of at least one enteric polymer and a pore former.

[0140] In certain embodiments, the layer can comprise at least one non-water soluble polymer. In further embodiments, the layer can comprise a combination of at least one non-water soluble polymer and at least one water soluble polymer. In further embodiments, the layer can comprise a combination of at least one non-water soluble polymer and a pore former.

[0141] Representative examples of water soluble polymers include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene glycol, and the like.

[0142] Representative examples of enteric polymers include cellulose esters and their derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH sensitive methacrylic acid-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or as aqueous dispersions. Some commercially available materials include methacrylic acid copolymers manufactured by Rohm Pharma under the trademark Eudragit (LI 00, SI 00, L30D), Cellacefate (cellulose acetate phthalate) manufactured by Eastman Chemical Co., Aquateric (aqueous dispersion of cellulose acetate phthalate) manufactured by FMC Corp., and Aqoat (aqueous dispersion of hydroxypropyl methylcellulose acetate succinate) manufactured by Shin Etsu K.K.

[0143] Representative examples of non-water soluble polymers include ethyl cellulose, polyvinyl acetate (e.g., Kollicoat SR #30D manufactured by BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium salt groups, such as Eudragit NE, RS and RS 30D, RL or RL 30D, etc.

[0144] Any of the above polymers can be plasticized with one or more pharmaceutically acceptable plasticizers. Representative examples of plasticizers include compounds or mixtures thereof such as glyceryl triacetate, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides, etc. When plasticizers are used, the plasticizer can comprise about 3 to 30% by weight of the polymer, typically about 10 to 25% by weight. The type of plasticizer and its content depend on the nature of the polymer or polymers and the coating system (e.g., aqueous or solvent based, solution or dispersion based, and total solids, etc.).

[0145] The pharmaceutical compositions must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The solvent or dispersion medium can be, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating such as lecithin, by the maintenance of required particle size in the case of dispersion and by the use of surfactants. In many cases, the compositions can be preserved by the inclusion of excipients such as anti-oxidants, e.g., ascorbic acid, it is also possible to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by the inclusion in the composition of agents which delay absorption, for example, monostearate salts and gelatin. In addition, the compound can be prepared in a time release formulation, for example, by including in the composition a slow release polymer. The compound can be prepared in a carrier which prevents its rapid release, for example, a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic and polylactic, polyglycolic copolymers (PLG).

[0146] Many methods of preparing such formulations are known to those skilled in the art. Sterile injectable solutions can be prepared by incorporating the active compound, e.g., any one of the compounds of Formula (I)-(V), in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions can be prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the above-identified ingredients, hi preparing sterile powders, methods of the art that are conventional in the art are used, e.g., vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0147] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Dosage unit forms of the present application are desirably in sizes that can be used by humans and other mammals, and are governed by, and in direct proportion to, the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such therapeutic compounds for the prevention or treatment of inflammatory-related conditions or autoimmune diseases in humans or animals.

[0148] In some embodiments, the pharmaceutical composition includes an effective amount of the compound and / or composition and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutical composition for treating or preventing an inflammatory-related condition or autoimmune disease and the like in humans or animals, includes a compound or a pharmaceutically acceptable salt thereof according to the present application and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical composition for treating or preventing an inflammatory-related condition or autoimmune disease and the like in humans or animals, includes a compound or a pharmaceutically acceptable salt thereof according to the present application and a pharmaceutically acceptable carrier.

[0149] Methods of using the compounds and compositions

[0150] In another aspect, the present application relates to a method of preventing or treating an inflammatory-related condition or autoimmune disease in humans or animals, by administering to a subject an effective amount of a compound or composition according to the present application. In a related aspect, the present application relates to a method of preventing or treating an inflammatory-related condition or autoimmune disease in humans or animals, by administering to a subject an effective amount of a compound or composition according to the present application.

[0151] As used in this invention, the term "treated subject" includes those with inflammatory conditions or autoimmune diseases in humans or animals. Examples of treated subjects include humans, monkeys, cattle, rabbits, sheep, goats, pigs, dogs, cats, rats, mice, and their transgenic species. The term "treated subject" generally includes animals susceptible to inflammatory conditions or autoimmune diseases in humans or animals, such as mammals, primates, and humans. Animals may also include animal models suffering from this condition, such as transgenic mouse models, etc.

[0152] In some embodiments, the selected patient has a need for treatment and requires and is treated using the methods provided by this invention. Patients requiring treatment are recognized in the art, including individuals who have been identified as having a disease or condition or having symptoms of such a disease or condition, or are at risk of such a disease or condition, and who, based on a diagnosis, such as a medical diagnosis, are expected to benefit from treatment (e.g., cure, healing, prevention, relief, mitigation, alteration, remedy, improvement, or influence on the disease, or its symptoms or risk).

[0153] In some embodiments, when the compounds and treatment methods of the present invention are administered to the treated group, there is an acceptable difference between the treatment or prevention methods of the present invention and the placebo group or historical control group.

[0154] It should be understood that the choice of use of one or more active compounds and / or compositions and their dosage depends on the individual's basic circumstances (generally, the individual's condition should be optimized for the best effect). Dosing and administration regimens should be within the capabilities of a person skilled in the art, and appropriate dosages depend on many factors, including the knowledge and competence level of a general technical physician, veterinarian, or researcher (see Wells et al. eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000)). For example, dosing and administration can depend on the condition itself and its severity, as well as the sex, age, weight, and individual responsiveness of the person or animal being treated, the effective duration and half-life of the compound, whether the treatment is acute, chronic, or prophylactic, and / or whether other active compounds are administered in addition to the therapeutic molecule.

[0155] Therefore, the dosage of a compound or composition depends on a variety of factors, including but not limited to: the activity, biological and pharmacokinetic properties, and / or side effects of the compound used; the subject's age, weight, general health condition, sex, and diet; the timing and route of administration, excretion rate, and any applicable drug combinations; the physician's desired effect of the compound on the treated individual; the properties of the compound administered (e.g., bioavailability, stability, efficacy, toxicity, etc.); and the established rational dosage recognized in the art. When one or more compounds of the present invention are administered to a human, the physician may initially prescribe a relatively low dose, subsequently increasing the dose until an appropriate response is obtained.

[0156] There are no particular limitations on the dosage of each compound involved in the present invention used in the composition. Example dosages include milligrams or micrograms of the compound per kilogram of treated person or sample weight (e.g., about 50 micrograms per kilogram to about 500 milligrams per kilogram, about 1 milligram per kilogram to about 100 milligrams per kilogram, about 1 milligram per kilogram to about 50 milligrams per kilogram, about 1 milligram per kilogram to about 10 milligrams per kilogram, or about 3 milligrams per kilogram to about 5 milligrams per kilogram). Other example dosages include about 5-500 mg, about 25-300 mg, about 25-200 mg, about 50-150 mg, or about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg, 500 mg, for example, lower or higher doses, such as daily or twice daily.

[0157] In some embodiments, the oral dose for adults is typically 0.005 mg to 10 g / day. Formulations in tablet or other forms may conveniently contain an amount (such a dose or multiple thereof is an effective dose) of a compound (e.g., a compound of general formula (I) or (II), or a compound of general formula (III) to (V)). For example, containing 5 mg to 500 mg, typically about 10 mg to 200 mg. Dosage units of the compound (e.g., oral dosage units) may include, for example, 1-30 mg, 1-40 mg, 1-100 mg, 1-300 mg, 1-500 mg, 2-500 mg, 3-100 mg, 5-20 mg, 5-100 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 1...). 5mg, 16mg, 17mg, 18mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg or 500mg).

[0158] In some embodiments, the oral dosing of the compound is in the range of about 0.001 mg to about 2000 mg per kilogram of body weight. In some embodiments, the oral dose is 0.01 mg to 100 mg per kilogram of body weight, 0.1 mg to 50 mg per kilogram of body weight, 0.5 mg to 20 mg per kilogram of body weight, or 1 mg to 10 mg per kilogram of body weight. In some embodiments, the oral dose is 5 mg of compound per kilogram of body weight.

[0159] In other embodiments, the injectable dosing of the compound is in the range of about 0.001 mg to about 1000 mg per kilogram of body weight. In some embodiments, the oral dose is 0.01 mg to 100 mg per kilogram of body weight, 0.1 mg to 50 mg per kilogram of body weight, 0.5 mg to 20 mg per kilogram of body weight, or 1 mg to 10 mg per kilogram of body weight. In some embodiments, the injectable dose is 1 mg of compound per kilogram of body weight. In other embodiments, the injectable dose is 5 mg of compound per kilogram of body weight

[0160] In further embodiments, the dosage range (including all ranges and subranges thereof) is about 10-1000 mg, such as about 10-900 mg, about 10-800 mg, about 10-700 mg, about 10-600 mg, about 10-500 mg, about 10-400 mg, about 10-300 mg, about 10-250 mg, about 10-200 mg, about 10-150 mg, about 10-100 mg, about 10-50 mg, about 50-900 mg, about 50-800 mg, about 50-700 mg, about 50-600 mg, about 50-500 mg, about 50-400 mg, about 50-300 mg, about 50-250 mg, about 50-200 mg, about 50-150 mg, about 50-100 mg, about 100-900 mg, about 100-800 mg, about 100-700 mg, about 100-600 mg, about 100-500 mg, about 100-400 mg, about 100-300 mg, about 100-250 mg, about 100-200 mg, about 100-150 mg, about 150-200 mg, about 150-250 mg, about 150-300 mg, about 150-400 mg, about 150-500 mg, about 200-900 mg, about 200-800 mg, about 200-700 mg, about 200-600 mg, about 200-500 mg, about 200-400 mg, about 200-300 mg, about 200-250 mg, about 300-900 mg, about 300-800 mg, about 300-700 mg, about 300-600 mg, about 300-500 mg, about 300-400 mg, about 400-900 mg, about 400-800 mg, about 400-700 mg about 400-600 mg, about 400-500 mg, about 500-900 mg, about 500-800 mg, about 500-700 mg, about 500-600 mg, about 100-500 mg, about 100-400 mg, about 100-300 mg, or about 100-250 mg, etc. In one embodiment, the range is about 150-400 mg.

[0161] In further embodiments, the dosage is 10 mg, 25 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, etc.

[0162] The compounds and compositions of the present application are administered to a subject in dosages effective to achieve the desired goal over a period of time by known methods of sequence, dosage. The dosage regimen can be adjusted to best suit the needs of the subject. For example, the dosage can be divided into multiple administrations per day, or the dosage can be proportionally reduced in urgent care situations.

[0163] In some embodiments, the subject is prevented or treated for an inflammatory-related condition or autoimmune disease in a human or animal subject with an effective amount of the compound or composition. In addition, the compound or composition can be administered by any suitable route or means, such as, but not limited to, oral, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, topical, or intranasal administration, inhalation, and the like methods commonly used in the art.

[0164] The compounds and compositions contemplated by the present application can be administered once, twice, three times, or four times daily by any of the reasonable means described above. In addition, in certain embodiments, administration or treatment with any of the compounds described by the present application (depending on the structure of the compound) can continue for several weeks. For example, treatment can continue for at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or 104 weeks, etc. In additional embodiments, administration or treatment with any of the compounds described by the present application (depending on the structure of the compound) can continue for several months. For example, treatment can continue for at least 2 months, 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 20 months, or 24 months, etc. In additional embodiments, administration or treatment with any of the compounds described by the present application (depending on the structure of the compound) can continue indefinitely. In additional embodiments, administration or treatment with any of the compounds described by the present application (depending on the structure of the compound) can be long term. It is understood that the compounds and / or compositions contemplated by the present application can be used alone or in combination with other therapies.

[0165] Kit

[0166] The compounds and compositions contemplated by the present application can be packaged as part of a kit, which can include containers such as packages, boxes, vials, etc. The kits can be used commercially in accordance with the methods described by the present application, including instructions for these methods. Additional components of the kits can include acids, bases, buffers, inorganic salts, solvents, antioxidants, preservatives, or metal chelators, etc. Additional components of the kits can be present in the form of the pure composition, or in the form of an aqueous or organic solution incorporating one or more additional kit components. Any or all of the kit components can also include a buffer or / and diluent.

[0167] Examples

[0168] General Methods

[0169] Method A. Preparation and use of 3-amino-1-propanesulfonic acid sodium salt: 3-amino-1-propanesulfonic acid was supplied by the vendor, and 3-amino-2,2-dideuterio-1-propanesulfonic acid was synthesized in the laboratory. The above acid was dissolved in water, and an equimolar amount of sodium hydroxide was added, stirred at room temperature for 10 minutes, and the solvent was removed by rotary evaporation, and dried before use in the subsequent reaction.

[0170] Method B. Desalting by ion exchange resin: Dissolve the crude product containing sodium chloride in water (e.g., 2 mmol of crude in 10 mL of water), add clean Amberlite IR120 H-form resin (e.g., 2 mL), stir intermittently for 5 minutes, filter to remove the resin, wash the resin with water (e.g., 3 times, 2 mL each), and combine the filtrate and washings. Repeat the resin treatment twice more on the resulting solution. Concentrate the final solution on a rotary evaporator to remove the solvent, and dry to give the product.

[0171] Example 1: Synthesis of 3-amino-3,3-dideutero-l-propanesulfonic acid (1) and 3-amino-3,3-dideutero-l-propanesulfonic acid sodium salt (1s)

[0172] Slowly add a solution of 3-hydroxypropionitrile (26.0 g, 366 mmol, 1.0 eq.) in dry THF (50 mL) to a solution of LiAlD4(10.0 g, 238 mmol, 0.65 eq.) in dry THF (200 mL) and stir the reaction mixture at reflux overnight. After cooling the reaction to room temperature, quench by adding water (4.8 mL), 15% aqueous NaOH (4.8 mL), and water (14.4 mL) sequentially, and stir at room temperature for 2 h, then filter to remove the solid impurities. Concentrate the filtrate under reduced pressure and dry to give a red oily liquid which is used directly in the next step without further purification.

[0173] Dissolve the oily liquid (10.0 g, 128 mmol, 1.0 eq.) in 100 mL of chloroform and stir in an ice bath while slowly adding dichlorosulfoxide (18.2 g, 154 mmol, 1.2 eq.). Stir the reaction mixture at reflux overnight, spin off the solvent on a rotary evaporator, and concentrate to give a black mixture. Purify by column chromatography to give 3-chloro-l,l-dideutero-l-propanamine hydrochloride as a white solid (10.8 g, 64.4%).

[0174] Dissolve 3-chloro-l,l-dideutero-l-propanamine hydrochloride (10.0 g, 76.3 mmol, 1.0 eq.) in water (50 mL), stir, and add Na2SO3(9.61 g, 76.3 mmol, 1.0 eq.). Stir the mixture at reflux overnight, spin off the solvent on a rotary evaporator, and add concentrated hydrochloric acid to the white solid. Filter to remove the solid (sodium chloride), concentrate the filtrate under reduced pressure, and dry to give a white solid. Recrystallize from water-ethanol, dry, and obtain 3-amino-3,3-dideutero-l-propanesulfonic acid (1) as a white solid (9.5 g, 88.3%). 1 H NMR (500 MHz, D2O): δ ppm 2.15 (t, J = 7.5 Hz, 2H), 3.07 (t, J = 7.5 Hz, 2H); 13C NMR (125 MHz, D20): δ ppm 22.21, 37.74 (m, CD2), 47.87; m / z (ES - ) 140.0 (M-H).

[0175] 3-Amino-3,3-dideutro-l-propanesulfonic acid was dissolved in 10 mL of water and an equimolar amount of sodium hydroxide was added. The mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure to dryness. A white solid was obtained (1s) which was directly used in the next step. Example 2: Synthesis of 3-((L-alanyl)amino)-3,3-dideutro-l-propanesulfonic acid (2)

[0176] Compound 1s (0.30 g, 1.84 mmol, 1.0 eq.) and N-tert-butoxycarbonyl-L-alanine (0.37 g, 2.0 mmol, 1.1 eq.) were mixed in anhydrous DMF (10 mL). After the addition of N,N'-dicyclohexylcarbodiimide (DCC, 0.56 g, 2.7 mmol, 1.5 eq.) and 1-hydroxybenzotriazole (HOBt, 0.24 g, 1.80 mmol, 1.0 eq.) under ice-bath conditions, the mixture was stirred at room temperature overnight. After the addition of water (2 mL), stirring was continued for one hour and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a white solid as a crude product. The solid was dissolved in water (20 mL) and extracted twice with ethyl acetate. The aqueous phase was concentrated under reduced pressure and the residue was purified by column chromatography to obtain 3-((N-Boc-L-alanyl)amino)-3,3-dideutro-l-propanesulfonic acid sodium salt as a white solid (0.50 g, 81.3% yield). This white solid (0.50 g, 1.50 mmol, 1.0 eq.) was dissolved in 10 mL of 1 N HCI solution and stirred at 50 °C for 2 h. The solution was concentrated under reduced pressure. The solid was dissolved in water (5 mL) and stirred for 2 minutes after the addition of Amberlite IR120 H type ion exchange resin. The resin was removed by filtration. The ion exchange process was repeated and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from methanol and ethyl acetate, filtered and dried to obtain 3-((L-alanyl)amino)-3,3-dideutro-l-propanesulfonic acid (2) as a white solid (277 mg, 87.3%). 1 H NMR (500 MHz, D20): δ ppm 1.49 (d, J = 7.0 Hz, 3H), 1.92 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 3.97-4.07 (m, 1H), 8.34 (s, 1H); 13 C NMR (125 MHz, D20): δ ppm 16.47, 23.71, 48.30, 49.10, 170.69; m / z (ES - ) 210.8 (M-H).

[0177] Example 3: Preparation of 3-((L-Serineyl)amino)-3,3-dideuterio-1-propanesulfonic acid (3)

[0178] N-tert-butoxycarbonyl-L-serine 1.03 g (5 mmol, 1 eq.) and compound 1s (806 mg, 5 mmol, 1 eq.) were placed in a 25 mL single neck flask, DMF (7 mL) and triethylamine (0.77 mL) were added, and diphenylphosphoryl azide (DPPA) (1.51 g, 1 eq.) was added dropwise at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, the solvent was dried under reduced pressure. Column chromatography (methanol: dichloromethane, 1:5) was used to separate the product, and white solid 3-((N-tert-butoxycarbonyl-L-serineyl)amino)-3,3-dideuterio-1-propanesulfonic acid sodium salt (800 mg, 58%) was obtained. The solid obtained in the first step (250 mg, 0.71 mmol, 1 eq.) was added to 1 M aqueous HC1 (5 mL), and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, the solvent was dried under reduced pressure to obtain the crude product. The above crude product was dissolved in water (5 mL), and ion exchange resin (Amberlite IR120 H type, 1 mL) was added. After mixing for two minutes, the resin was removed by filtration. After washing with water (2 mL), the aqueous phase was collected. The same ion exchange process was repeated twice, and the aqueous phase was dried under reduced pressure to obtain white solid compound 3 (150 mg, 92.6%). 1 H NMR (500 MHz, D2O) δ ppm 1.84-1.94 (m, 2H), 2.78-2.94 (m, 2H), 3.83-3.98 (m, 2H), 4.08-4.14 (m, 1H); 13 C NMR (125 MHz, D2O) δ ppm 23.70, 37.80, 48.30, 54.57, 60.16, 167.59; m / z (ES + ) 228.9 (M+H).

[0179] Example 4: Synthesis of 3-((L-Valinyl)amino)-3,3-dideuterio-1-propanesulfonic acid (4)

[0180] 3-amino-3,3-dideutero-1-propanesulfonic acid sodium salt Is (1.63 g, 10.0 mmol, 1.0 eq.) and N-tert-butoxycarbonyl-L-valine (2.60 g, 12.0 mmol, 1.2 eq.) were dissolved in dry DMF (20 mL). After addition of DCC (2.47 g, 12.0 mmol, 1.2 eq.) and HOBt (1.35 g, 10.0 mmol, 1.0 eq.) at ice-bath conditions, stirring was continued overnight at room temperature. After addition of water (2 mL), stirring was continued for one hour, the insoluble solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a white solid crude. The solid was dissolved in water (20 mL) and extracted twice with ethyl acetate, the aqueous phase was concentrated under reduced pressure and the white solid 3-((N-tert-butoxycarbonyl-L-valyl)amino)-3,3-dideutero-1-propanesulfonic acid sodium salt (3.2 g, 88.3%) was obtained by column chromatography. The white solid (3.2 g, 8.83 mmol, 1.0 eq.) was dissolved in 1 N HCI solution (30 mL) and stirred at 50 °C for 2 h, concentrated under reduced pressure. The solid was dissolved in water (10 mL) and Amberlite IR120 H type ion exchange resin was added and stirred for 2 min, the resin was removed by filtration. The ion exchange process was repeated and the filtrate was concentrated under reduced pressure. The crude was recrystallized from methanol and ethyl acetate, filtered and dried to give the white solid 3-((L-valyl)amino)-3,3-dideutero-1-propanesulfonic acid (4) (1.87 g, 88.1%). 1 H NMR (500 MHz, D2O): δ ppm 0.92-1.06 (m, 6H) 1.98 (t, J=7.5 Hz, 2H), 2.17-2.21 (m, 1H), 2.95 (t, J=8.0 Hz, 2H), 3.76 (d, J=6.5 Hz, 1H); 13 C NMR (125 MHz, D2O): δ ppm 17.01, 17.57, 23.73, 29.80, 48.40, 58.78, 169.18; m / z (ES - ) 239.1 (M-H).

[0181] Example 5: Synthesis of 3-((L-phenylalanyl)amino)-3,3-dideutero-1-propanesulfonic acid (5)

[0182] 3-amino-3,3-dideutero-1-propanesulfonic acid sodium salt Is (815 mg, 5.0 mmol, 1.0 eq.) and N-tert-butoxycarbonyl-L-phenylalanine (1.59 g, 6.0 mmol, 1.2 eq.) were dissolved in 20 mL of dry DMF. After the addition of DCC (1.24 g, 6.0 mmol, 1.2 eq.) and HOBt (675 mg, 5.0 mmol, 1.0 eq.) at ice bath condition, it was stirred at room temperature overnight. After the addition of 2 mL of water, it was stirred for another hour, the insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give a white solid crude. The solid was dissolved in 20 mL of water, extracted with ethyl acetate twice, and the aqueous phase was concentrated under reduced pressure and then purified by column chromatography to give 3-((N-tert-butoxycarbonyl-L-phenylalaninyl)amino)-3,3-dideutero-1-propanesulfonic acid sodium 1.8 g, yield 87.7%. The white solid (1.80 g, 4.39 mmol, 1.0 eq.) was dissolved in 1 N HBr solution (20 mL) and stirred at 50 °C for 2 h, and concentrated under reduced pressure. The crude product was recrystallized from ethanol and water, filtered, and dried to give 3-((L-phenylalaninyl)amino)-3,3-dideutero-1-propanesulfonic acid (5) (1.07 g, 84.5%) as a white solid. 1 H NMR (500 MHz, D2O): δ ppm 1.67-1.80 (m, 2H), 2.54-2.68 (m, 2H), 3.05-3.28 (m, 2H), 4.14 (t, J = 6.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.34-7.47 (m, 3H); 13 C NMR (125 MHz, D2O): δ ppm 23.44, 36.87, 37.53 (m, CD2), 48.18, 54.64, 128.04, 129.17, 129.27, 133.86, 168.81; m / z (ES - ) 287.0 (M-H).

[0183] Example 6: Preparation of 3-((L-glycyl)amino)-3,3-dideutero-1-propanesulfonic acid hydrobromide (6)

[0184] 1.465 g (5.74 mmol, 1 eq.) of N-tert-butoxycarbonyl-L-histidine and 0.93 g (5.74 mmol, 1 eq.) of compound 1s were placed in a 100-mL single-necked flask, and DMF (10 mL) and triethylamine (0.88 mL, 1.1 eq.) were added. Diphenyl azide phosphate (DPPA) (1.739 g, 1.1 eq.) was added dropwise at room temperature. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The product was separated by column chromatography (methanol:dichloromethane, 1:3) to give a white solid, 3-((N-tert-butoxycarbonyl-L-histyl)amino)-3,3-dideuterium-1-propanesulfonate (1.4 g, 61%). The solid obtained in the first step was added to 20 mL of 1NHBr aqueous solution and reacted at room temperature for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dispersed in ethanol (30 mL). After stirring at room temperature for 1 hour, the solid was obtained by filtration. The solid was dissolved in water (5 mL), and then ethanol (30 mL) was added dropwise. After stirring at room temperature for 1 hour, the solid was obtained by filtration, and the filter cake was dried under vacuum to obtain a white solid product 3-((L-histyl)amino)-3,3-dideuterium-1-propanesulfonic acid hydrobromide (6) (1.25 g, 99%). 1 H NMR(500MHz,D2O)δppm 1.82(d,J=6.8Hz,2H),2.78(t,J=7.0Hz,2H),3.37(s,2H),4.21(d,J=6.0Hz,1H),7.44(s,1H),8.71(s,1H); 13 C NMR (125MHz, D2O) δppm 23.55, 25.99, 48.21, 52.30, 118.30, 125.91, 134.32, 167.69; m / z (ES + 278.9(M+H).

[0185] Example 7: 3-( 15 Synthesis of N-amino))-1-propanesulfonic acid (7)

[0186] Add to a 1,3-propanesulfonic acid lactone (0.61 g, 5.0 mmol, 1.0 eq.) methanol / water (1:1) solution 15 N-ammonium sulfate ( 15Nitrogen abundance, 98%; 1.0 g, 7.5 mmol, 1.5 eq.) and sodium hydroxide (0.5 g, 12.5 mmol, 2.5 eq.). The reaction was carried out overnight at 70 °C in a closed system. After cooling to room temperature, NaHCO3 (0.63 g, 7.5 mmol, 1.5 eq.) and di-tert-butyl dicarbonate (1.64 g, 7.5 mmol, 1.5 eq.) were added sequentially, and the reaction was carried out at 70 °C for 3 hours. The crude product was concentrated under reduced pressure to obtain a white solid, which was dissolved in methanol solution. The white solid was removed by filtration, and the filtrate was concentrated and subjected to column chromatography to obtain a white gel. This gel was dissolved in 1 N HBr solution (20 mL) and stirred at 50 °C for 2 hours, then concentrated under reduced pressure. The crude product was recrystallized from ethanol and water, filtered, and dried to obtain a white solid 3-( 15 N-amino)-1-propanesulfonic acid (7), 398 mg, 56.8%. 1 H NMR (500MHz, D2O): δppm 2.06-2.16 (m, 2H), 3.01 (t, J = 7.5Hz, 2H), 3.15 (t, J = 7.5Hz, 2H); 13 C NMR (125MHz, D2O): δ C (ppm)22.23,38.17(d,J=5.0Hz),47.82; m / z(ES + 140.8 (M+H).

[0187] Example 8: 3-(L-valine-( 15 Synthesis of N-amino))-1-propanesulfonic acid (10)

[0188] Add to a 1,3-propanesulfonic acid lactone (1.22 g, 10.0 mmol, 1.0 eq.) methanol / water (1:1) solution 15 N-labeled ammonium sulfate (2.0 g, 15.0 mmol, 1.5 eq.) and sodium hydroxide (1.0 g, 25 mmol, 2.5 eq.) were added. The reaction was carried out overnight at 70 °C in a closed system. After cooling to room temperature, triethylamine (1.51 g, 15.0 mmol, 1.5 eq.) and di-tert-butyl dicarbonate (3.27 g, 15.0 mmol, 1.5 eq.) were added sequentially, and the reaction was carried out at 70 °C for 3 hours. The product was concentrated under reduced pressure to obtain a white crude solid, which was dissolved in methanol solution. The white solid was removed by filtration, and the filtrate was concentrated and subjected to column chromatography to obtain a white gel. This gel was dissolved in 30 mL of 1 N HCl solution and stirred at 50 °C for 2 hours. The mixture was concentrated under reduced pressure and dried to obtain a white solid 3-( 15 N-amino)-1-propanesulfonic acid (7) can be used directly in the next step of the reaction without purification.

[0189] 3-( 15N-amino)-1-propanesulfonic acid was dissolved in water (10 mL) and an equimolar amount of sodium hydroxide was added. The mixture was stirred at room temperature for 10 minutes, then concentrated under reduced pressure and dried to obtain a white solid 3-( 15 Sodium N-amino)-1-propanesulfonate can be used directly in the next reaction without purification.

[0190] 3-( 15 Sodium N-amino(1-propanesulfonate) and N-tert-butoxycarbonyl-L-valine (3.26 g, 15.0 mmol, 1.5 eq.) were dissolved in 30 mL of anhydrous DMF. DCC (3.09 g, 15.0 mmol, 1.5 eq.) and HOBt (1.35 g, 10.0 mmol, 1.0 eq.) were added under ice bath conditions, and the mixture was stirred overnight at room temperature. 2 mL of water was added, and stirring continued for one hour. The insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a white crude solid. The solid was dissolved in 20 mL of water and extracted twice with ethyl acetate. The aqueous phase was concentrated under reduced pressure and then subjected to column chromatography to obtain a white gel-like solid. This crude solid was dissolved in 30 mL of 1 N HCl solution and stirred at 50 °C for 2 h, then concentrated under reduced pressure. The solid was dissolved in 10 mL of water, and Amberlite IR120 H-type ion exchange resin was added and stirred for 2 minutes. The resin was removed by filtration. The ion exchange process was repeated, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from ethanol and water, filtered, and dried to give a white solid 3-(L-valine-( 15 N-amino))-1-propanesulfonic acid (10) (1.23 g, 51.4%). 1 H NMR (500MHz, D2O): δppm 0.99-1.08 (m, 6H), 1.91-2.03 (m, 2H), 2.12-2.25 (m, 1H), 2.93 (t, J = 9.0 Hz, 2H), 3.32-3.45 (m, 2H), 3.74 (d, J = 6.0 Hz, 1H); 13 C NMR (125 MHz, D2O): δ C (ppm)16.97,17.54,23.88,29.77,38.03(d,J=8.8Hz),48.39,58.74(d,J=8.8Hz),169.13(d,J=17.5Hz); m / z(ES - 237.9 (MH).

[0191] Example 9: 3-(( 18 Preparation of OL-valine)amino)-3,3-dideuter-1-propanesulfonic acid (14)

[0192] Sodium 3-amino-3,3-dideuterio-1-propanesulfonate 1s (250 mg, 1.53 mmol, 1.0 eq.) and N-tert-butoxycarbonyl- 18 O-L-(1,1-di- 18 O)-valine p-nitrophenyl ester (624 mg, 1.84 mmol, 1.2 eq.) were dissolved in anhydrous DMF (20 mL). The reaction was stirred overnight at room temperature. After concentration under reduced pressure, the residue was purified by column chromatography to give the white solid sodium 3-((N-tert-butoxycarbonyl- 18 O-L-valyl)amino)-3,3-dideuterio-1-propanesulfonate (400 mg, 71.7%). The white solid was dissolved in 1N HCl solution (30 mL) and stirred at 50 °C for 2 h, then concentrated under reduced pressure. The solid was dissolved in water (5 mL), Amberlite IR120 H+ ion exchange resin was added and stirred for 2 minutes, and the resin was filtered off. The ion exchange process was repeated, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from ethanol and water, filtered, and dried to give the white solid 3-(( 18 O-L-valyl)amino)-3,3-dideuterio-Propane sulfonic acid (14) (283 mg, 89.8%). 1 H NMR (500 MHz, D2O): δ ppm 1.00 - 1.08 (m, 6H), 1.97 (t, J = 7.5 Hz, 2H), 2.16 - 2.26 (m, 1H), 2.94 (t, J = 8.0 Hz, 2H), 3.75 (d, J = 6.0 Hz, 1H), 8.48 (s, 1H); 13 C NMR (125 MHz, D2O): δ ppm 17.03, 17.59, 23.75, 29.81, 37.O59 (m, CD2), 48.42, 58.79, 169.16; m / z (ES - ) 240.9 (M-H).

[0193] Example 10: Synthesis of 3-((L-cysteinyl)amino)-3,3-dideuterio-1-propanesulfonic acid (18)<N / A> <N / A>

[0194] 3-amino-3,3-dideutero-l-propanesulfonic acid sodium salt Is (0.7 g, 4.3 mmol, 1.0 eq.) and N-tert-butoxycarbonyl-L-cysteine (1.4 g, 4.3 mmol, 1.0 eq.) were dissolved in dry DMF (15 mL). After addition of DCC (1.4 g, 6.5 mmol, 1.5 eq.) and HOBt (0.6 g, 4.6 mmol, 1.1 eq.) at ice-bath condition, it was stirred at room temperature overnight. After addition of water (2 mL), it was stirred for another hour, the insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give a white solid crude. The solid was dissolved in water (20 mL), extracted with ethyl acetate twice, and the aqueous phase was concentrated under reduced pressure and then purified by column chromatography to give 3-((N-tert-butoxycarbonyl-L-cysteinyl)amino)-3,3-dideutero-l-propanesulfonic acid sodium salt (1.2 g, 59.8%) as a white solid. The white solid (1.2 g, 2.57 mmol, 1.0 eq.) was dissolved in IN HCl solution (30 mL) and stirred at 50°C for 2 h, and then concentrated under reduced pressure. The solid was dissolved in water (5 mL), stirred for 2 min after addition of Amberlite IR120 H type ion exchange resin, and then the resin was removed by filtration. The ion exchange process was repeated, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from ethanol and water, filtered, and dried to give 3-((L-cysteinyl)amino)-3,3-dideutero-l-propanesulfonic acid (18) (0.57 g, 83.3%) as a white solid. 1 H NMR (500 MHz, D2O): δ ppm 1.97 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 3.01-3.13 (m, 2H), 4.16 (t, J = 6.0 Hz, 1H); 13 CNMR (125 MHz, D2O): δ ppm 23.70, 24.73, 48.34, 54.55, 167.83; m / z (ES + ) 244.9.

[0195] Example 11: Experimental evaluation of the efficacy of the compounds in the model of experimental autoimmune encephalomyelitis (EAE)

[0196] Preparation of solutions:

[0197] (1) Homotaurine was directly dissolved in drinking water to prepare a 0.25 mg / ml solution, with a molar concentration of 1.80 umol / ml;

[0198] (2) Compound 4 was directly dissolved in drinking water to prepare a 0.25 mg / ml solution, with a molar concentration of 1.04 umol / ml;

[0199] Model preparation:

[0200] EAE is an important experimental model for studying the pathogenesis and immunoregulation of CD4+TH1 / TH17-mediated tissue injury, and is also considered to be a relevant model for studying human immune-mediated demyelinating multiple sclerosis. Myelin oligodendrocyte glycoprotein (MOG) is an important glycoprotein in the process of nerve myelination in the central nervous system. In the experiment, C57BL / 6 mice were often immunized with MOG35-55 polypeptide to induce chronic EAE.

[0201] In the experiment, 32 mice were randomly divided into 4 groups according to body weight, 8 mice in each group, blank control group G1, model control group G2, positive drug control group G3, and compound 4 administration group G4. 7 to 9 weeks of C57BL / 6 female mice (Shanghai Jihui Experimental Animal Breeding Co., Ltd.) were placed in a 20-26°C pathogen-free experimental space, and myelin oligodendrocyte glycoprotein MOG35-55 (Jier Biochemical Co., Ltd. (Shanghai, China)) was used to induce mice to establish EAE model, the antigen MOG35-55 was diluted with normal saline to 2 mg / ml, 2 mg / mL of MOG 35-55 solution was mixed with equal volume of 4 mg / mL complete Freund's adjuvant, and the mixed solution was stirred on ice with a high-speed homogenizer at a speed of 30,000 rpm for 1.5 hours. 0.1 ml per mouse was subcutaneously injected at three points on both sides of the mouse spine, and 0.5 ml of pertussis toxin PTX (Sigma (St. Louis, MO, USA), Catalog No: P7208) (1400 ng per mouse) was injected intraperitoneally at 0h and 48h on the day of immunization. The day of animal immunization was considered as day 0, and all groups were orally administered with drinking water.

[0202] Pathological examination, the cervical thoracic lumbar three segments of the spinal cord of each mouse were embedded into the same wax block for sectioning, two sections were prepared and stained respectively, and the pathologist rated the stained sections, including one Luxol Fast Blue (LFA) staining (demyelination injury score) and one H&E staining (inflammatory infiltration score). Demyelination injury score: 0 points: normal tissue and cell morphology; 1 point: occasional or scattered vacuolar changes in gray matter or white matter in spinal cord tissue; 2 points: aggregated vacuolar changes distributed in gray matter or white matter in spinal cord tissue; 3 points: aggregated vacuolar changes distributed in gray matter and white matter in spinal cord tissue; 4 points: diffuse vacuoles in gray matter and white matter; 5 points: extensive vacuolar changes throughout the spinal cord. Inflammatory infiltration score standard: 0 points: no lesions, relatively normal; 1 point: a small amount of scattered inflammatory cells; 2 points: mild local aggregation of inflammatory cells; 3 points: moderate aggregation of inflammatory cells; 4 points: severe aggregation of inflammatory cells. The score results are shown in Table 5, Figure 1 and Figure 2 .

[0203] The experimental data are expressed as mean ± SEM. The data were analyzed by Graphpad Prism or SPSS using the appropriate statistical method. p<0.05, *; p<0.01, **; p<0.001, ***; p<0.05 are considered to be significant differences.

[0204] Table 5 Histopathology score

[0205]

[0206] From the data, it can be seen that, in the case of the molar ratio of the compound is not equal, that is, the molar concentration of compound 4 (1.04 umol / ml) is significantly lower than that of the positive control taurine (1.80 umol / ml), the demyelination score of compound 4 is significantly better than that of the model group, and compared with the control group, there is also a significant advantage difference. Under the same conditions, the inflammatory infiltration score of compound 4 is also significantly better than that of the model group and the control group. This shows that the compound provided by the present application has a significant advantage compared with taurine, even at a lower drug administration concentration. And the efficacy between the test drug treatment group and the positive control group is compared to evaluate the efficacy of the test drug. Through comparison, it can be seen that the compound 4 of the present application, even at a lower molar concentration, shows a more significant advantage in terms of incidence, mortality, average maximum clinical score, average score per group, duration of EAE, average onset time and area under the curve of clinical score, etc. relative to the positive control drug. In summary, the compound provided by the present application has good effect in the treatment of inflammatory-related diseases or autoimmune diseases such as multiple sclerosis.

[0207] Although the present application has been described in detail with reference to the embodiments thereof, the embodiments are provided for illustration purposes only and are not intended to limit the present application. Other embodiments that can be derived from the principles of the present application are within the scope of the claims of the present application.

Claims

1. Use of compounds of general formula I or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of multiple sclerosis in humans or animals: R 1 R 2 X-CR2-CH2-CH2-SO3H(I) in, R 1 and R 2 Hydrogen atoms are naturally abundant and exist independently. R is deuterium (D); X is a nitrogen atom of natural abundance; Where X, R, R 1 and R 2 The conditions for their existence are atoms or groups that are not simultaneously naturally abundant; or Compounds represented by formula I are compounds of formula IV, or pharmaceutically acceptable salts thereof: in, R 4 It is the side chain of a natural amino acid or the side chain of a non-natural amino acid; O * It is the natural abundance of oxygen atoms, 18 O or 17 O;C * It is naturally abundant carbon atoms or 13 C; X is a nitrogen atom that is naturally abundant.

2. The use according to claim 1, wherein, The compound is selected from compounds represented by the following formula, or pharmaceutically acceptable salts thereof:

3. The use according to claim 2, wherein the compound is 3-amino-3,3-dideuter-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof; or 3-((L-valinel)amino)-3,3-dideuter-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof.

4. The use according to any one of claims 1 to 3, wherein, The compound contains 5% or more of non-naturally abundant isotopes.

5. The use according to claim 4, wherein, The compound contains 10% or more of non-naturally abundant isotopes.

6. The use according to claim 4, wherein, The compound contains 20% or more of non-naturally abundant isotopes.

7. The use according to claim 4, wherein, The compound contains 50% or more of non-naturally abundant isotopes.

8. The use according to claim 4, wherein, The compound contains 75% or more of non-naturally abundant isotopes.

9. The use according to claim 4, wherein, The compound contains 90% or more of non-naturally abundant isotopes.

10. The use according to claim 4, wherein, The compound is enriched at a level of 95% or more for non-naturally abundant isotopes.

11. The use according to claim 4, wherein, The compound is enriched at a level of 98% or more for non-naturally abundant isotopes.

12. Use of the pharmaceutical composition in the preparation of a medicament for the treatment or prevention of multiple sclerosis in humans or animals, wherein, The pharmaceutical composition comprises a compound as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. The use according to claim 12, wherein, The pharmaceutical composition is administered orally or by injection.

14. The use according to claim 12, wherein, The oral form of the pharmaceutical composition is in the form of hard-shell gelatin capsules, soft-shell gelatin capsules, flat capsules, pills, tablets, powders, granules, lozenges, elixirs, or syrups.

15. The use according to claim 12, wherein, The oral form of the pharmaceutical composition is in the form of pellets or sugar-coated pills.

16. The use according to claim 12 or 13, wherein, The pharmaceutical composition is in the form of a solution, an aqueous suspension, a non-aqueous suspension, an oil-in-water emulsion, or an oil-in-water emulsion.

17. The use according to any one of claims 13 to 15, wherein, The oral pharmaceutical composition has an enteric coating and / or a controlled release formulation.

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