A thienylcarboxamide compound and use thereof

Abstract

Disclosed are thiophene carboxamide compounds shown in formula (I), or an isotopically labeled, optical isomer, pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, X1, X2, X3, X4, X5, j, k are defined in the specification. The present application provides the use of the compound, or an isotopically labeled, optical isomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a drug for preventing and / or treating Vanin-1 mediated diseases. The diseases are, for example, autoimmune diseases, inflammatory diseases, metabolic diseases, infection-based diseases, etc.

Description

Technical Field

[0001] This invention relates to a novel thiophene carboxamide compound having Vanin-1 inhibitory activity, as well as pharmaceutical compositions comprising the same and their pharmaceutical uses. Background Technology

[0002] Vanin-1 is a molecular chaperone encoded by the PTGES3 gene, a highly conserved protein widely distributed in eukaryotes. Vanin-1 binds to the Hsp90 protein, promoting the stability of Hsp90 protein aggregates with various biological functional molecules, such as estrogen receptors, androgen receptors, and telomerase. Studies have found that the substrate of Vanin-1 is panthenyl thioethylamine, which Vanin-1 catalyzes for hydrolysis to produce pantothenic acid and thioethylamine (Pitari G et al., Panthenase activity of membrane-bound vanin-1: lack of free cysteamine in tissues of vanin-1 dificientmice. FEBS Lett. 2000; 483:149-154). These products influence various biological processes. Pantothenic acid participates in the synthesis and metabolism of coenzyme A, and regulates the metabolism of fatty acid synthesis and pyruvate oxidation. Mercaptoethylamine affects cellular redox state, and its deficiency leads to resistance to oxidative tissue damage induced by gamma radiation or paraquat administration, and can prevent or eliminate tissue inflammation (Berruyer C et al., Vanin-1- / -mice exhibit a glutathione-mediated tissue resistance to oxidative stress. Mol Cell Biol. 2004; 24:7214-7224). Vanin-1 deficiency effectively resists IBD (including DSS (dextrose sulfate) and TNBS (trinitrobenzenesulfonate) colitis in mouse models (Berruyer C et al., Vanin-1 licenses inflammatory mediator production by gutepithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor γ activity. J Exp Med. 2006; 203:2817-2827). Existing technologies such as WO2018011681, WO2016193844, and WO2020114947 have disclosed a series of Vanin-1 inhibitors for the treatment of various diseases, such as Crohn's disease and ulcerative colitis. Furthermore, studies have found that Vanin-1 is highly expressed in various tumors, including lung cancer, prostate cancer, breast cancer, and leukemia. High expression of Vanin-1 can promote tumor cell migration, upregulate androgen receptor levels and biological activity, and promote tumorigenesis.

[0003] However, overall, there is still a lack of effective small molecule compounds that inhibit Vanin-1, as well as a lack of relatively mature related small molecule compound drugs.

[0004] The technical problem to be solved by the present invention is to provide novel uses of the thiothiophene formamide compound of formula (I) or its isotopic label, optical isomer, or pharmaceutically acceptable salt in the preparation of medicaments for the prevention and / or treatment of Vanin-1 mediated diseases. Summary of the Invention

[0005] This invention synthesizes a series of thiophene formamide compounds via chemical synthesis. Surprisingly, these compounds exhibit a high affinity for Vanin-1, effectively inhibiting the catalytic activity of Vanin-1 on panthenyl thioethylamine substrates and interfering with the synthesis and metabolism of panthenol and coenzyme A. Based on this pathway, these thiophene formamide compounds show therapeutic effects on Vanin-1-mediated diseases, particularly inflammatory diseases such as inflammatory bowel disease, and possess the potential for future development as drugs for treating inflammatory conditions.

[0006] On one hand, the present invention provides the use of a compound of formula (I), or an isotope label thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of Vanin-1 mediated diseases.

[0007]

[0008] in,

[0009] X1, X2, X3, and X4 are each independently selected from CR5 or N;

[0010] X5 is selected from O, S, or CH2;

[0011] R1 is selected from H or C. 1-6 alkyl;

[0012] R2 is selected from -(CH2). i -X6;

[0013] or,

[0014] R1, R2, together with the nitrogen atom they are attached to, form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally selected from C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbon cyclo group, C 6-14 Group substitution of aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0015] Each R3 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0016] Each R4 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0017] Each R5 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0018] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbonyl group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic; wherein the carbocyclic, aryl, heteroaryl, or heterocyclic group is optionally selected from C 6-14 Aryl groups, NR6R6 ’ Substitution of groups such as -C(O)NH2 and -S(O)2NH2;

[0019] R6 and R6' are each independently selected from H and C. 1-6 Alkyl groups, or R6, R6', together with the nitrogen atoms attached to them, form 5- or 6-membered heterocyclic groups;

[0020] i can be 0, 1, 2, 3, 4 or 5;

[0021] j is 2;

[0022] k is 0 or 1.

[0023] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) as described herein, an isotopic label thereof, an optical isomer, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0024] In another aspect, the present invention provides the use of compounds of general formula (I) described herein, or isotopic markers thereof, optical isomers, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention and / or treatment of Vanin-1 mediated diseases. Attached Figure Description

[0025] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention, but do not constitute a limitation thereof. In the drawings:

[0026] Figure 1 The acute phase body weight and DAI score of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention are shown.

[0027] Figure 2 The results of acute colon length measurement in mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention are shown.

[0028] Figure 3 The expression levels of acute-phase inflammatory factors IL-1β, TNF-α, IL-10, and IFN-γ in mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention are shown.

[0029] Figure 4 The results show the recovery body weight of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention. # represents a dead mouse, and each # represents one mouse.

[0030] Figure 5 A and Figure 5 B shows the colon length measurement results during the recovery period in mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention.

[0031] Figure 6 The expression levels of inflammatory factors IL-1β, IL-6, TNF-α, and IFN-γ in mice with DSS-induced inflammatory bowel disease during the recovery period after treatment with the compounds of this invention are shown.

[0032] Figure 7 The study shows a comparison of colon tissue repair and inflammatory status in mice with DSS-induced inflammatory bowel disease after treatment with the compounds of this invention. Detailed Implementation

[0033] definition

[0034] As used in the specification of this invention, the following words and phrases are generally considered to have the meanings set forth below, unless otherwise specified in the context in which they are used.

[0035] As used herein, the term "about" means an approximation of ±10% of the nominal value it refers to. In one embodiment, the term "about" means an approximation of ±5% of the nominal value it refers to. In another embodiment, the term "about" means an approximation of ±2% of the nominal value it refers to. This level of approximation is appropriate unless specifically stated that a more stringent range is required for the value.

[0036] As used herein, the term "alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon chain consisting only of carbon and hydrogen atoms. In one embodiment, the alkyl group comprises 1 to 6 carbon atoms. In another embodiment, the alkyl group comprises 1 to 4 carbon atoms. In a further embodiment, the alkyl group comprises 1 to 3 carbon atoms. The term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0037] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0038] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein the alkyl group is as defined herein. The term is illustrative of groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0039] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a 5- to 8-membered monocyclic saturated or partially unsaturated group having 5 to 8 carbon atoms as ring atoms. The carbocyclic or carbocyclic group can be saturated or partially unsaturated and can be fused with another saturated, partially unsaturated, or aromatic ring, provided that the ring atom attached to the target molecule is not an aromatic carbon. Examples of carbocyclic or carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, etc.

[0040] As used herein, the term "aryl" refers to an aromatic carbocyclic group having 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) of a monocyclic (e.g., phenyl) or polycyclic (e.g., biphenyl) or multiple fused (fused) rings (e.g., naphthyl, fluorenyl, and anthracene). The term is exemplified by groups such as phenyl, fluorenyl, naphthyl, anthracene, 1,2,3,4-tetrahydronaphthalene (if the linking point is through an aryl group), etc.

[0041] As used herein, the term "heteroaryl" refers to a monocyclic aromatic ring group comprising 5 to 6 ring atoms, wherein, in addition to a carbon atom, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Exemplary heteroaryls include, but are not limited to: pyridyl, pyrroleyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, and thiadiazolyl.

[0042] As used herein, the term "heterocyclic group" refers to a monocyclic saturated or partially unsaturated group having 5 to 6 ring atoms within a ring, wherein, in addition to a carbon atom, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, pyrrolylyl, tetrahydrothiophenyl, imidazoyl, oxazolyl, thiazoyl, morpholinyl, piperidinyl, piperazine, dihydropyridinyl, etc.

[0043] As used herein, the term "therapeutic effective amount" means, when administered to a mammal in need of such treatment, an amount sufficient, as defined below, to (i) prevent or treat a particular disease or condition, (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease or condition, or (iii) prevent or delay the onset of one or more symptoms of a disease or condition described herein. Therapeutic effective amounts as described herein include amounts sufficient to detectably modulate, inhibit, or reduce disease symptoms associated with Vanin-1 activity. Therapeutic effective amounts will vary depending on the subject and disease condition, the subject's weight and age, the severity of the disease condition, the route of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a given compound, and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be derived from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromicates, sulfates, nitrates, phosphates, metaphosphates, carbonates, bisulfates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, etc. Salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, p-toluenesulfonates, trifluoroacetates, gluconates, salicylates, ascorbic acid salts, glucuronates, aspartate salts, glutamate salts, stearates, p-hydroxybenzoates, phenylacetate salts, pantothenates, 2-hydroxyethanesulfonates, sulfanamide salts, alginates, camphorates, camphor sulfonates, nicotinate salts, palmitate salts, adipate salts, laurates, lactates, anthranilates, and dihydroxynaphthylcarbamates, among others.

[0045] As used herein, “optionally” means that an event or situation subsequently described may or may not occur, and the description includes both cases in which said event or situation occurs and cases in which it does not occur.

[0046] As used herein, the term “pharmaceutical acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or mammals treated with it.

[0047] Any general formula or structure given herein, including general formula I or any general formula disclosed herein, is also intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically labeled” or “isotopically enriched analogs.” Isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, but not limited to… 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes (e.g. 3 H, 13 C and 14 Those of type C). These compounds are synthesized using methods well-known in the field, such as by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0048] compound

[0049] In one embodiment, the present invention provides a compound of formula (I), or an isotopic label thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0050]

[0051] in,

[0052] X1, X2, X3, and X4 are each independently selected from CR4 or N;

[0053] X5 is selected from O or S;

[0054] R1 is selected from H or C. 1-6 alkyl;

[0055] R2 is selected from -(CH2). i -X6;

[0056] or,

[0057] R1, R2, together with the nitrogen atom they are attached to, form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally selected from: C 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbonyl group, C 6-14 Group substitution of aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0058] Each R3 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0059] Each R4 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0060] Each R5 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0061] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbonyl group, C 6-14 Aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the carbocyclic, aryl, heteroaryl, and heterocyclic group are optionally selected from C 6-14 Aryl groups, NR6R6 ’ Substitution of groups such as -C(O)NH2 and -S(O)2NH2;

[0062] R6 and R6' are each independently selected from H and C. 1-6 Alkyl groups, or R6, R6', together with the nitrogen atoms attached to them, form 5- or 6-membered heterocyclic groups;

[0063] i can be 0, 1, 2, 3, 4 or 5;

[0064] j is 2;

[0065] k is 0 or 1.

[0066] Preferably, X5 is selected from O or S.

[0067] Preferably, k is 1.

[0068] Preferably, R3 is H.

[0069] In one embodiment, the compound described herein has the structure shown in formula (II).

[0070]

[0071] Where X1 is selected from C or N;

[0072] l is 3 or 4;

[0073] R1 is selected from H or C. 1-6 alkyl;

[0074] R2 is selected from -(CH2).i -X6;

[0075] or,

[0076] R1, R2, together with the nitrogen atom they are attached to, form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally selected from C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbon cyclo group, C 6-14 Group substitution of aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0077] Each R3 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0078] Each R4 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0079] Each R5 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0080] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbon cyclo group, C 6-14 Aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the carbocyclic, aryl, heteroaryl, and heterocyclic group are optionally substituted with groups selected from the following: C 6-14 Aryl groups, NR6R6 ’ -C(O)NH2, -S(O)2NH2;

[0081] R6 and R6' are each independently selected from H and C. 1-6Alkyl groups, or R6, R6', together with the nitrogen atoms attached to them, form 5- or 6-membered heterocyclic groups;

[0082] i can be 0, 1, 2, 3, 4 or 5;

[0083] j is 2;

[0084] k is 1;

[0085] l is 3 or 4.

[0086] In one embodiment, the compound described herein is a compound of formula (II-A) or (II-B).

[0087]

[0088] Or its isotopic markers, optical isomers, or pharmaceutically acceptable salts.

[0089] in,

[0090] R1 is selected from H or C. 1-6 alkyl;

[0091] R2 is selected from -(CH2). i -X6;

[0092] or,

[0093] R1, R2, together with the nitrogen atom they are attached to, form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally selected from C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbon cyclo group, C 6-14 Group substitution of aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0094] Each R4 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0095] Each R5 is independently selected from H and C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0096] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 carbonyl group, C 6-14 Aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the carbocyclic, aryl, heteroaryl, and heterocyclic group are optionally selected from C 6-14 Aryl groups, NR6R6 ’ Substitution of groups such as -C(O)NH2 and -S(O)2NH2;

[0097] R6 and R6' are each independently selected from H and C. 1-6 Alkyl groups, or R6, R6', together with the nitrogen atoms attached to them, form 5- or 6-membered heterocyclic groups;

[0098] i can be 0, 1, 2, 3, 4 or 5.

[0099] In one embodiment, the compound described herein is a compound of formula (II-A) or (II-B), or an isotopic label thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0100] in,

[0101] R1 is selected from H;

[0102] R2 is selected from The aforementioned groups are optionally selected from C. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-6 Substitution of carbocyclic, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0103] i can be selected from 0, 1, 2, 3, 4 or 5.

[0104] In one embodiment, the compound described herein is a compound of formula (II-A) or (II-B), or an isotopic label thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0105] in,

[0106] R1, R2, and the nitrogen atoms they are attached to form... The aforementioned groups are optionally selected from C. 1-6 Alkyl, halogen, hydroxyl, C 1-6Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-6 Substitution of carbocyclic, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic groups;

[0107] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-6 Carbocyclic, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic; wherein the above groups are optionally selected from benzyl, NR6R6 ’ -C(O)NH2, -S(O)2NH2; R6, R6' are each independently selected from H or C. 1-6 Alkyl group substitution;

[0108] i can be selected from 0, 1, 2, 3, 4 or 5.

[0109] In one embodiment, the compound described herein, or its isotopic label, optical isomer, or pharmaceutically acceptable salt, wherein said compound has

[0110]

[0111] The structure shown.

[0112] Pharmaceutical composition and administration

[0113] The pharmaceutical compositions provided by this invention comprise the compounds of this invention or their isotopic markers, optical isomers, pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art and include diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, flow aids, emulsifiers, colorants, flavoring agents, sweeteners, etc. Depending on the route of administration, such as oral, parenteral, and rectal administration, the pharmaceutical compositions of this invention can be formulated in solid form (including but not limited to tablets, capsules, pills, granules, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) a lubricant, such as silica, talc, stearic acid, polyethylene glycol, etc.; c) a binder, such as magnesium aluminosilicate, gelatinized starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) a disintegrant, such as starch, alginic acid, agar, corn starch; e) a stabilizer, such as an antioxidant like ascorbic acid; f) a flow aid, such as silica; g) a flavoring agent, such as peppermint, methyl salicylate; and a sweetener, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerin, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0114] In one embodiment, the pharmaceutical composition of the present invention can be administered orally. Oral administration can be by swallowing, sublingual administration, or oral administration. In another embodiment, the compound of the present invention can be administered parenterally. Suitable methods of parenteral administration include, but are not limited to, intravenous, intra-arterial, intraperitoneal, intraventricular, intraurethral, ​​intracranial, intramuscular, and subcutaneous administration. In another embodiment, the compound of the present invention can also be administered topically. Suitable methods of topical administration include, but are not limited to, transdermal administration, intranasal inhalation, rectal administration, vaginal administration, ocular administration, and ocular administration.

[0115] The effective dosage of the pharmaceutical composition of the present invention depends on at least a number of factors, including the nature and severity of the condition being treated, the route of administration, the dosage form of the drug, and the patient's age, weight, and medical condition, which will be ultimately determined by the clinician. It is anticipated that the dosage of the compound of the present invention can be in the range of about 0.01 to about 100 mg per kilogram of body weight per day; typically about 0.1 to about 50 mg per kilogram of body weight per day; more typically, about 0.5 to about 30 mg per kilogram of body weight per day. In one embodiment, the daily dose of the compound of the present invention can be about 0.01 to about 10 mg per kilogram of body weight, or about 0.1 to about 10 mg per kilogram of body weight, or about 0.1 to about 5 mg per kilogram of body weight, or about 0.1 to about 1 mg per kilogram of body weight, or about 0.1 to about 0.5 mg per kilogram of body weight, and can be administered in single or multiple doses.

[0116] Indications

[0117] The compounds represented by general formula (I) of the present invention, or their isotopic markers, optical isomers, pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, are Vanin-1 inhibitors and may be used for the prevention and / or treatment of Vanin-1-related or Vanin-1-mediated diseases and / or conditions, including but not limited to the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, and infection-based diseases.

[0118] In one embodiment, the compound of general formula (I) of the present invention or its isotopic label, optical isomer, pharmaceutically acceptable salt, or pharmaceutical composition comprising the thereof may be used for the prevention and / or treatment of Crohn's disease, ulcerative colitis, atopic dermatitis, psoriasis, systemic sclerosis, non-alcoholic steatohepatitis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, cystic fibrosis, atherosclerosis, gingivitis, interstitial cystitis, pain associated with irritable bowel syndrome, acute lung injury, irritable bowel syndrome, inflammatory bowel disease, proctitis, celiac disease, eosinophilic gastroenteritis, allergic urticaria, angioedema, glomerular injury, spinal cord injury, graft-versus-host disease, hyperlipidemia, metabolic syndrome, etc.

[0119] Preferably, the compound represented by the pharmaceutical formula (I) of the present invention or its isotopic label, optical isomer, pharmaceutically acceptable salt, or pharmaceutical composition containing the thereof can be used for the prevention and / or treatment of Crohn's disease, ulcerative colitis, systemic sclerosis, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, scleroderma, etc.

[0120] More preferably, the compound represented by general formula (I) of the present invention or its isotopic label, optical isomer, pharmaceutically acceptable salt, or pharmaceutical composition comprising the thereof can be used for the prevention and / or treatment of Crohn's disease and / or ulcerative colitis.

[0121] General Synthesis Method

[0122] The compounds of the present invention can be prepared using the methods disclosed herein and their modifications, as well as methods well known in the art. Typical embodiments of the compounds according to the invention can be synthesized using the following general reaction procedure. It will be apparent from the description herein that different products can be obtained by using other materials having similar structures instead of the reactants. The reactants are typically obtained from commercial sources or synthesized using the disclosed methods.

[0123] Reaction process I

[0124]

[0125] The compound shown in formula (Ia) is coupled with the compound shown in formula (Ib) under suitable conditions, followed by hydrolysis under alkaline conditions to produce the compound shown in formula (Ic). For example, suitable conditions for the coupling reaction of the compound shown in formula (Ia) and the compound shown in formula (Ib) include, but are not limited to, the use of a palladium catalyst and a phosphine ligand compound, and alkaline conditions. The palladium catalyst is a commonly used palladium catalyst in Buchwald-Hartwig coupling reactions, including but not limited to tris(dibenzylacetone)dipalladium, 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, palladium acetate, tetra(triphenylphosphine)palladium, etc. The phosphine ligand compound includes, but is not limited to, 1,1'-bis(diphenylphosphine)ferrocene, tris(o-tolyl)phosphine, 2-(di-tert-butylphosphine)biphenyl, 2-(dicyclohexylphosphine)biphenyl, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, etc.; the hydrolysis reaction... The appropriate alkaline conditions include inorganic bases and / or organic bases, wherein inorganic bases include, but are not limited to, alkali metal or alkaline earth metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates or bicarbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, cesium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, etc.); organic bases include, but are not limited to, ammonia, dimethylamine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.

[0126] The variables X1, X2, X3, X4, X5, R1, R2, and n are as defined in this paper.

[0127] Reaction Process II

[0128]

[0129] The compound shown in formula (Ic) undergoes a condensation reaction with the compound shown in formula (Id) under suitable conditions. For example, the compounds shown in formulas (Ic) and (Id) are reacted with a condensing agent (e.g., 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethylurea-hexafluorophosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI HCl), ethyl 2-oxime cyanoacetate, etc.) and a base (e.g., N-methylmorpholine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, etc.) in a mixture of inert solvents (e.g., dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane) to give the compound shown in formula (I).

[0130] Example

[0131] The following examples are provided to illustrate the preparation of the compounds of the present invention, but are not intended to limit the invention in any way.

[0132] The abbreviations used in the embodiments of this invention have the following meanings:

[0133] BINAP 1,1'-Binaphthyl-2,2'-bis(diphenylphosphine) <![CDATA[Cs2CO3]]> cesium carbonate DCM dichloromethane DMAP 4-Dimethylaminopyridine DMSO Dimethyl sulfoxide EA Ethyl acetate EDC·HCl 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride HCl hydrogen chloride h Hour LiOH Lithium hydroxide MeOH methanol mg mg mL milliliters mmol millimole <![CDATA[Pd2(DBA)3]]> Tris(dibenzylacetone)dipalladium PE petroleum ether TLC Thin-layer chromatography THF Tetrahydrofuran

[0134] Example 1: Synthesis of Compound III-A

[0135]

[0136] 1. Preparation of intermediate 1-c

[0137] Under nitrogen protection, ethyl 5-bromothiophene-2-carboxylate (1-a, 3.11 g, 13.2 mmol), 3,4-dihydro-2H-benzo[b][1,4]thiazine (1-b, 1 g, 6.6 mmol), Cs₂CO₃ (3.23 g, 9.9 mmol), Pd₂(DBA)₃ (300 mg, 0.33 mmol), and BINAP (526 mg, 0.98 mmol) were dissolved in 20 mL of 1,4-dioxane and stirred at 100 °C for 12 h. TLC monitoring showed that most of the Ib reaction was complete. The solvent was removed by vacuum distillation, and the residue was separated by silica gel column chromatography (PE:EA = 6:1, V / V) to obtain a mixture of coupling reaction products, which was used directly in the next reaction without further purification. The obtained product mixture and LiOH (1.58 g, 66 mmol) were completely dissolved in 20 mL THF / 20 mL H₂O and reacted at 80 °C for 24 h. After the reaction was detected by TLC, the reaction solution was poured into 200 mL of 1N HCl, extracted twice with EA, the organic phases were combined, EA was removed by rotary evaporation, and the residue was separated by silica gel column chromatography (DCM:MeOH = 10:1, V / V) to give a pale yellow solid 5-(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)thiophene-2-carboxylic acid 1-c (1 g), with a two-step yield of 54.6%.

[0138] 1 H NMR(500MHz,DMSO)δ7.50(d,J=4.1Hz,1H),7.33(d,J=8.0Hz,1H),7.28–7.13(m,1H),7.09(dd,J=11 .1,4.1Hz,1H),7.02(t,J=7.5Hz,1H),6.55(d,J=4.1Hz,1H),4.16–3.62(m,2H),3.29–2.82(m,2H).

[0139] 13 C NMR (125MHz, DMSO) δ162.90,159.42,140.51,133.75,127.57,125.01,124.88,124.04,122.85,121.15,111.71,50.03,25.50.

[0140] 2. Preparation of Compound III-A

[0141] 1-C (1 g, 3.6 mmol), 2-(cyclohexyl-1-en-1-yl)ethylamine (1-D, 900 mg, 7.2 mmol), EDC·HCl (1.38 g, 7.2 mmol), and DMAP (878 mg, 7.2 mmol) were dissolved in 40 mL of DCM and stirred at room temperature for 12 h. The residue was separated by silica gel column chromatography (PE:EA = 2:1, V / V) to give a white solid 1 (1 g), yield 72.2%.

[0142] 1 H NMR (500MHz, CDCl3) δ7.22(t,J=10.5Hz,1H),7.19–7.08(m,2H),6.98(dd,J=11.1,4.0Hz,1H),6.90(t,J=7.4Hz,1H),6.44(d,J=4.0Hz,1H),5.88(s,1 H),5.51(s,1H),4.07–3.80(m,2H),3.45(dd,J=12.4,6.6Hz,2H),3.27–2.9 8(m,2H),2.20(t,J=6.7Hz,2H),1.98(d,J=28.1Hz,4H),1.71–1.48(m,4H).

[0143] 13 C NMR (125MHz, CDCl3) δ161.86,157.65,141.03,134.74,128.32,127.74,125.13,123.83,1 23.55,122.98,121.81,114.44,51.58,37.66,37.51,27.90,26.01,25.29,22.84,22.38.

[0144] Example 2 Preparation of compound III-B

[0145]

[0146] Compound III-B was prepared by replacing intermediate 1-b with 2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine using a method similar to that in Example 1.

[0147] Example 3 Preparation of Compound III-C

[0148]

[0149] Compound III-C was prepared by replacing intermediate 1-d with 1-benzylpiperidine-4-amine using a method similar to that in Example 1.

[0150] Example 4: Preparation of Compound III-D

[0151]

[0152] Compound 4 was prepared by replacing intermediate 1-d with 4-(aminomethyl)-N,N-dimethylaniline using a method similar to that in Example 1.

[0153] Example 5 Preparation of Compound III-E

[0154]

[0155] Compound III-E was prepared by replacing intermediate 1-d with 4-(aminomethyl)-N,N-dimethylaniline using a method similar to that in Example 1.

[0156] Example 6 Preparation of compound III-F

[0157]

[0158] Compound III-F was prepared by replacing intermediate 1-d with 1-phenylpiperazine using a method similar to that in Example 1.

[0159] Example 7 Preparation of Compound III-G

[0160]

[0161] Compound III-G was prepared by replacing intermediate 1-b with 7-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine and intermediate 1-d with benzylamine, using a method similar to that in Example 1.

[0162] Example 8 Preparation of compound III-H

[0163]

[0164] Compound III-G was prepared by replacing intermediate 1-d with cyclohexylamine using a method similar to that in Example 1.

[0165] Example 9 Preparation of Compound III-I

[0166]

[0167] Compound III-I was prepared by replacing intermediate 1-d with 4-(2-aminoethyl)benzylsulfonamide using a method similar to that in Example 1.

[0168] Example 10 Preparation of Compound III-J

[0169]

[0170] Compound III-J was prepared by replacing intermediate 1-d with aniline using a method similar to that in Example 1.

[0171] Bioactivity test

[0172] 1. Human recombinant Vanin-1 activity inhibition experiment

[0173] The panthenol of Vanin-1 was selected as its classic endogenous physiological substrate (final concentration 5 μM). The optimal concentration of recombinant human Vanin-1 protein was 80 ng / mL within its catalytic linear range. The incubation time was 30 min within the linear range. The concentrations of the test compound as an inhibitor were set between 0-1000 nM (5, 10, 20, 50, 100, 500, 1000 nM). The inhibition curve of the compound against Vanin-1 was fitted. The compound of this invention inhibits the Vanin-1-catalyzed hydrolysis of panthenol to VB5 and cysteine ​​in a concentration-dependent manner. The IC50 of the compound of this invention for inhibiting Vanin-1 is [not specified]. 50 The values ​​are shown in Table 1. The results show that the compounds of the present invention have a good inhibitory effect on Vanin-1.

[0174] Table 1

[0175] Example number <![CDATA[Human recombinant Vanin-1 IC 50 (nM)]]> 1 A 2 A 3 A 4 A 5 A 6 C 7 B 8 B 9 B 10 C RR6 B

[0176] Note: A≤50nM, 50nM <B≤500nM,500nM<C≤5000nM;

[0177] RR6 (CAS No.:1351758-37-6) is a competitive Vanin-1 inhibitor and is used as a positive control here.

[0178] 2. Pharmacodynamic evaluation of DSS-induced acute inflammatory bowel disease

[0179] 2.1 Materials

[0180] Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-22g each, were purchased from Liaoning Changsheng Biotechnology Co., Ltd. All mice were fed sterile water and standard feed and housed in an SPF laboratory. Sodium dextran sulfate (DSS) was purchased from Dalian Meilun Biotechnology Co., Ltd.

[0181] 2.2 Model Construction and Drug Administration

[0182] All mice were acclimatized for one week before the start of the experiment and randomly divided into a normal control group, a model control group, and a treatment group, with 6 mice in each group. Mice in the model and treatment groups were given free access to 3% DSS aqueous solution for 7 days to induce colitis. Mice in the treatment group were given free access to 3% DSS aqueous solution while simultaneously receiving compound III-A orally (10 mg / kg / day), while the normal and model control groups were given an equal volume of the solvent by gavage during the same period. Mouse body weight was monitored daily, and the fecal intestinal function index (DAI) was scored. Modeling and drug administration were terminated on day 7. Mice were euthanized the day after fasting, and physiological and biochemical indicators were collected to evaluate the pharmacodynamic efficacy of compound III-A in treating inflammatory bowel disease.

[0183] 2.3 Evaluation

[0184] from Figure 1 As can be seen, the weight change and DAI score of the treated mice during the modeling period were significantly lower than those of the model control group, revealing that compound III-A can effectively alleviate the physiological function and activity status of mice during inflammatory bowel disease. The colon length of the treated mice was measured, and the results are as follows: Figure 2 As shown, the colon length of the treated group mice was approximately 1.8 cm longer than that of the model group mice, almost approaching the colon length of the normal control group mice. The fecal morphology of the treated group mice was intact, revealing that compound III-A can significantly improve diarrhea and intestinal epithelial mucosal damage in mice during the course of inflammatory bowel disease. Further molecular mechanism results showed that multiple inflammatory factors, including IL-6, TNF-α, IL-10, and IFN-γ, were significantly lower in the colon of the treated group mice than in the model control group, indicating that the compound of this invention can significantly improve the inflammation level in the mouse colon, thereby reducing tissue damage caused by inflammatory factors during the course of inflammatory bowel disease. Figure 3 In summary, the compounds of this invention can significantly improve the levels of inflammatory factors in the colon during the course of inflammatory bowel disease, alleviate colonic tissue damage, and thus improve symptoms such as diarrhea in inflammatory bowel disease, demonstrating excellent therapeutic effects on inflammatory bowel disease.

[0185] 3. Pharmacodynamic evaluation of DSS-induced inflammatory bowel disease during the recovery period

[0186] 3.1 Materials

[0187] Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-24g each, were purchased from Liaoning Changsheng Biotechnology Co., Ltd. All mice were fed sterile water and standard feed and housed in an SPF laboratory. Sodium dextran sulfate (DSS) was purchased from Dalian Meilun Biotechnology Co., Ltd.

[0188] 3.2 Model Construction and Drug Administration

[0189] All mice were acclimatized for one week before the experiment and randomly divided into a normal control group, a model control group, and a treatment group, with 6 mice in each group. The recovery model involved inducing colitis first, followed by drug treatment, and the recovery of colitis in the mice under drug treatment was observed. Details are as follows: Mice in the model group and treatment group were given free access to 4% DSS aqueous solution for 7 days to induce colitis. Mice in the treatment group and model group were given normal drinking water starting on day 8; simultaneously, the treatment group was given compound III-A (10 mg / kg / day) starting on day 8, while the model group received a blank solvent in parallel. Recovery continued until day 15, with daily monitoring of mouse weight and activity, and recording of mortality. Finally, the mice were euthanized, and colonic tissue was collected. PCR was performed to detect the levels of inflammatory factors in the colonic tissue, and the colonic tissue was fixed for H&E and PAS staining for pathological analysis of the intestinal inflammation recovery.

[0190] 3.3 Evaluation

[0191] During the recovery period, the fur of mice in the treatment group gradually returned to normal, becoming dark and shiny. Compared to the lethargic state of the model control group, the mice in the treatment group had a significantly higher food intake. Furthermore, weight monitoring showed that after DSS removal, the weight of mice in the model control group continued to decrease, eventually averaging a 40% decrease, while the weight of mice in the treatment group gradually plateaued and then increased daily. In the model control group, one mouse died on the seventh and eighth days after DSS removal, while no mice in the treatment group died. Figure 4 The treatment group had a significantly longer colon than the model control group, and the ileocecal valve and fecal matter in the colon were almost identical to those in the normal control group, indicating a return to normal levels. Figure 5 A and Figure 5 B). This indicates that the compounds of the present invention have a significant therapeutic effect on mice in the recovery period of inflammatory bowel disease, and can accelerate the recovery and improve the condition of the mice. The results of the determination of inflammatory factors in colon tissue are as follows. Figure 6 As shown, in the treatment group, the levels of inflammatory factors IL-1β, IL-6, TNF-α, and IFN-γ in the mice returned to near-normal levels, while the colonic tissue in the model control group remained at a high level of inflammation. Histopathological sections also indicated that the colonic villi and morphology of the mice in the treatment group had returned to normal, with no obvious inflammatory infiltration. In contrast, the colonic villi of the model control group mice remained severely damaged, with significant inflammatory infiltration. Figure 7 A and Figure 7 B). The above results indicate that the compounds of the present invention can significantly improve colonic tissue repair and inflammatory status in patients with inflammatory bowel disease, and have a good therapeutic effect during the recovery period of the disease.

[0192] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0193] It should be noted that all the above embodiments belong to the same inventive concept, and the descriptions of each embodiment have different focuses. Where the description in a particular embodiment is not exhaustive, please refer to the description in other embodiments. The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of compounds III-A, III-B, III-C, III-D, III-E, III-G, III-H, or III-I, or their isotopic labels or pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of Vanin-1 mediated diseases. (III-A)、 (III-B)、 (III-C)、 (III-D)、 (III-E)、 (III-G)、 (III-H)、 (III-I)。 2. The use according to claim 1, wherein the Vanin-1 mediated disease is selected from inflammatory diseases, autoimmune diseases, metabolic diseases, or oxidative stress-related diseases.

3. The use according to claim 2, wherein the inflammatory disease is selected from inflammatory bowel disease, irritable bowel syndrome, rheumatoid arthritis, osteoarthritis, or juvenile idiopathic arthritis.

4. The use according to claim 3, wherein the inflammatory bowel disease is selected from Crohn's disease, ulcerative colitis, or proctitis.

5. The use according to claim 2, wherein the autoimmune disease is selected from systemic lupus erythematosus, scleroderma, multiple sclerosis, or allergic eczema.

6. The use according to claim 2, wherein the metabolic disease is selected from metabolic syndrome, diabetes, or obesity.

7. The use according to claim 2, wherein the oxidative stress-related disease is selected from cardiovascular diseases, neurodegenerative diseases, or kidney diseases.

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