A compound, a preparation method thereof, and a pharmaceutical composition and application thereof

Abstract

This invention provides a compound, its preparation method, a pharmaceutical composition, and its applications, relating to the field of pharmaceutical technology. The compound provided by this invention has the structure shown in Formula I. This compound can effectively relieve acute alcohol poisoning and protect the liver from damage. In vitro cell experiments show that this compound can accelerate the excretion of ethanol, acetaldehyde, and their metabolites in vivo, protect hepatocytes from acetaldehyde-induced lipid peroxidation, and prevent acetaldehyde-induced glutathione reduction. In a mouse model of acute alcohol poisoning, this compound can significantly delay the onset of intoxication and significantly accelerate the sobering-up time. Furthermore, the compound provided by this invention has low toxicity and good drug-like properties. This invention provides a method for preparing the compound with the structure shown in Formula I, which is simple to synthesize and has a high yield.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a compound, its preparation method, pharmaceutical composition, and applications. Background Technology

[0002] Alcohol abuse is one of the most serious social problems facing humanity, with complex contributing factors including physiological and genetic factors, as well as cultural and environmental influences. The most common disease caused by alcohol consumption is liver damage, and the mechanisms of ethanol-induced liver toxicity remain poorly understood. Research indicates that ethanol also alters the transmission of many neurotransmitters in the brain: such as stimulating dopamine transmission, interfering with serotonergic transmission, and interfering with glutamine transmission in the central nervous system. Long-term excessive alcohol consumption leads to neuropathological diseases.

[0003] Currently, metadoxine is the main drug used clinically to treat acute and chronic alcohol poisoning and alcoholic liver disease. Metadoxine is a water-soluble vitamin that can accelerate the excretion of ethanol and its metabolites from the body, thus showing good efficacy in treating alcoholic liver disease. However, the activity of metadoxine still needs improvement, mainly because after taking metadoxine, intoxication still occurs relatively quickly, and the sobering-up time (i.e., the duration of intoxication) is still relatively long. Therefore, new drugs for treating alcohol poisoning and alcohol-related diseases are still needed clinically. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a compound, a method for preparing the same, a pharmaceutical composition, and its applications. The compound provided by the present invention can significantly delay the onset of intoxication and accelerate the sobering-up time, and has excellent effects in detoxifying alcohol and protecting the liver.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a compound having the structure shown in Formula I, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof;

[0007]

[0008] In Formula I, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, halogen, hydroxyl, carboxyl, C 1～6 Acyl group, C 1～3 alkyl-carbonyl-C 1～3 Alkyl, C 1～6 Alkyl-aldehyde group, C 1～6 Alkyl-hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy groups.

[0009] Preferably, R1 and R2 are independently selected from hydrogen or C. 1～6 Alkyl group, wherein R3, R4, and R5 are independently selected from hydrogen, hydroxyl, C... 1～6 Alkyl or C 1～6 Alkyl-hydroxyl.

[0010] Preferably, the C 1～6 The alkyl group is methyl, ethyl, propyl or cyclopropyl.

[0011] Preferably, the C 1～6 The alkyl-hydroxy group is hydroxymethyl, hydroxyethyl, or hydroxypropyl.

[0012] Preferably, the compound having the structure shown in Formula I has any of the following structures:

[0013]

[0014] This invention provides a method for preparing compounds having the structure shown in Formula I as described in the above technical solutions, comprising the following steps:

[0015] The compounds shown in Formula II and Formula III are mixed with an inert solvent to carry out a salt-forming reaction, yielding a compound having the structure shown in Formula I;

[0016]

[0017] Preferably, the molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:1; the temperature of the salt formation reaction is 0–80°C, and the time is 0.1–60 h.

[0018] The present invention provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is a compound having the structure shown in Formula I as described in the above technical solutions, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a prodrug thereof.

[0019] This invention provides the use of compounds having the structure shown in Formula I, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, or pharmaceutical compositions described in the above technical solutions, in the preparation of medicaments for the prevention and / or treatment of related diseases, including acute alcohol poisoning, chronic alcohol poisoning, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases, or Fragile X syndrome.

[0020] Preferably, the central nervous system disease includes ADHD, anxiety disorder, depression, or schizophrenia.

[0021] This invention provides a compound having the structure shown in Formula I. The compound provided by this invention can effectively relieve acute alcohol poisoning and protect the liver from damage. In vitro cell experiments show that this compound can accelerate the excretion of ethanol, acetaldehyde, and their metabolites in vivo, protect hepatocytes from acetaldehyde-induced lipid peroxidation, and prevent acetaldehyde-induced glutathione reduction. In a mouse model of acute alcohol poisoning, this compound can significantly delay the onset of intoxication and significantly accelerate the sobering-up time. Furthermore, the compound provided by this invention has low toxicity and good drug-like properties.

[0022] This invention provides a method for preparing the compounds described in the above technical solutions, which is simple to synthesize and has a high yield. Attached Figure Description

[0023] Figure 1 The efficacy of each experimental group in a mouse alcohol intoxication model was measured. Figure 1 (a) shows the effect of the control compound metadoxine (MTD) and the test compound NBA05001 on the onset time of intoxication in mice, and (b) shows the effect of the control compound metadoxine (MTD) and the test compound NBA05001 on the duration of intoxication in mice.

[0024] Figure 2 The efficacy of the drugs in each experimental group in a mouse alcohol intoxication model was measured. Figure 2 (a) shows the effect of compounds NBA05001, NBA05100, and NBA05200 on the onset time of intoxication in mice, and (b) shows the effect of compounds NBA05001, NBA05100, and NBA05200 on the duration of intoxication in mice. Detailed Implementation

[0025] the term:

[0026] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0027] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0028] In the compounds of this invention, when any variable appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. It will be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or on different carbon atoms, as long as structural stability is achieved.

[0029] As used in this invention, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, "C 1～6 "C" in "alkyl" 1～6 The definition of "alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, such as cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc. The term "alkoxy" represents an alkyl-oxy group, where the definition of alkyl is as shown above. "Halogen" refers to chlorine, fluorine, bromine, and iodine. The term "haloalkyl" represents an alkyl group in which one or more hydrogen atoms are replaced by a halogen, where the definition of alkyl is as shown above. The term "haloalkoxy" represents an alkyl-oxy group in which one or more hydrogen atoms are replaced by a halogen, where the definition of alkyl is as shown above.

[0030] This invention provides a compound having the structure shown in Formula I, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof;

[0031]

[0032] In Formula I, R1, R2, R3, R4, and R5 are independently selected from: hydrogen, halogen, hydroxyl, carboxyl, C 1～6 Acyl group, C 1～3 alkyl-carbonyl-C 1～3 Alkyl, C 1～6 Alkyl-aldehyde group, C 1～6 Alkyl-hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy groups.

[0033] In this invention, the halogen is fluorine, chlorine, bromine, or iodine; the C 1～3 alkyl-carbonyl-C 1～3 Alkyl groups are preferably C 1～2 alkyl-carbonyl-C 1～2Alkyl; the C 1～6 The alkyl-aldehyde group is preferably C 1～3 Alkyl-aldehyde group; the C 1～6 Alkyl-hydroxyl groups are preferably C 1～3 Alkyl-hydroxy, more preferably hydroxymethyl, hydroxyethyl or hydroxypropyl; the C 1～6 Alkyl groups are preferably C 1～3 Alkyl, more preferably methyl, ethyl, propyl or cyclopropyl; the C 1～6 The alkyl halide is preferably C10. 1～3 Halogenated alkyl; the C 1～6 The preferred halogenated alkoxy group is C. 1～3 Halogenated alkoxy groups.

[0034] In this invention, R1 and R2 are preferably independently selected from hydrogen or C. 1～6 Alkyl, the C 1～6 Alkyl groups are preferably C 1～3 Alkyl, more preferably methyl, ethyl, propyl or cyclopropyl; wherein R3, R4 and R5 are independently selected from hydrogen, hydroxyl, C 1～6 Alkyl or C 1～6 alkyl-hydroxyl, the C 1～6 Alkyl groups are preferably C 1～3 Alkyl, more preferably methyl, ethyl, propyl or cyclopropyl, wherein the C 1～6 Alkyl-hydroxyl groups are preferably C 1～3 Alkyl-hydroxy, more preferably hydroxymethyl, hydroxyethyl or hydroxypropyl.

[0035] In this invention, the compound having the structure shown in Formula I preferably has any of the following structures:

[0036]

[0037] The compounds provided by this invention can significantly delay the onset of intoxication and accelerate the sobering-up time, effectively relieve acute alcohol poisoning, protect the liver, and have excellent alcohol-relieving and liver-protecting activities.

[0038] This invention provides a method for preparing compounds having the structure shown in Formula I as described in the above technical solutions, comprising the following steps:

[0039] The compounds shown in Formula II and Formula III are mixed with an inert solvent to carry out a salt-forming reaction, yielding a compound having the structure shown in Formula I;

[0040]

[0041] Unless otherwise specified, all raw materials involved in this invention are commercially available products or prepared in accordance with methods known to those skilled in the art.

[0042] In this invention, R1 and R2 in the compound shown in Formula II, and R3, R4 and R5 in the compound shown in Formula III are consistent with R1, R2, R3, R4 and R5 in Formula I, and will not be repeated here.

[0043] In this invention, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is preferably 1:1. In this invention, the inert solvent is preferably water; the amount of the inert solvent used is not particularly important, as long as the reaction proceeds smoothly. In this invention, the temperature of the salt-forming reaction is preferably 0–80°C, more preferably 0–50°C, and even more preferably room temperature (25°C); the time of the salt-forming reaction is preferably 0.1–60 h, more preferably 0.5–48 h; the salt-forming reaction is preferably carried out under nitrogen protection and stirring. In this invention, the salt-forming reaction involves the following reactions:

[0044]

[0045] In this invention, after the salt formation reaction is completed, the resulting reaction solution is preferably concentrated under reduced pressure, and the resulting concentrate is washed with acetone and dried in sequence to obtain a compound with the structure shown in Formula I.

[0046] The present invention provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier (or excipient), wherein the active ingredient is a compound having the structure shown in Formula I as described in the above technical solutions, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a prodrug thereof.

[0047] The present invention does not have any particular requirements for the preparation method of the pharmaceutical composition. Any preparation method of pharmaceutical composition known to those skilled in the art can be used. Specifically, the active ingredient and a pharmaceutically acceptable carrier can be mixed.

[0048] It should be understood that the active ingredients of the present invention also include the crystalline form, amorphous compound, chiral compound, and deuterated compound of the compound.

[0049] In this invention, "pharmaceutically acceptable salt" refers to a salt formed by the compounds of this invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed by the compounds of this invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharmaceutically acceptable amine salts, such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively).

[0050] In this invention, the prodrug refers to a compound having the structure shown in Formula I that, after being modified, becomes a compound having the structure shown in Formula I after entering the body.

[0051] In this invention, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances suitable for human use, and which must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of this invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0052] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. In the present invention, one dose of the pharmaceutical composition contains 1–3000 mg (active dose range 3–30 mg / kg) of the active ingredient, preferably 10–2000 mg of the active ingredient. "One dose" refers to one capsule or tablet or a single intravenous injection.

[0053] The present invention does not impose any particular limitation on the administration method of the compound or pharmaceutical composition, and representative administration methods include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0054] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert carrier (or excipient), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0055] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0056] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances. In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, agar, or mixtures thereof.

[0057] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0058] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.

[0059] The compounds or pharmaceutical compositions of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0060] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose, and for a person weighing 60 kg, the daily dose is typically 1–2000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0061] This invention provides the use of compounds having the structure shown in Formula I, their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, or the pharmaceutical compositions described in the above technical solutions, in the preparation of remedies for the prevention and / or treatment of related diseases, including acute alcohol poisoning, chronic alcohol poisoning, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases, or Fragile X syndrome. In this invention, the central nervous system diseases preferably include ADHD, anxiety disorders, depression, or schizophrenia. The compounds, their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, or the pharmaceutical compositions described in the above technical solutions provided by this invention can effectively detoxify alcohol and protect the liver. The compounds, their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, or the pharmaceutical compositions described in the above technical solutions provided by this invention can effectively prevent, treat, and / or alleviate related diseases.

[0062] To further illustrate the present invention, the compounds, their preparation methods, pharmaceutical compositions, and applications provided by the present invention are described in detail below with reference to examples, but these should not be construed as limiting the scope of protection of the present invention.

[0063] Example 1

[0064] The preparation method of compound NBA05001 is as follows:

[0065] (1) Step 1, the reaction formula is as follows:

[0066]

[0067] The specific procedure is as follows: Under nitrogen protection at -5℃, add 40wt% acetaldehyde solution (25g, 0.22mol, 1.1eq) to the compound SM solution (25g dissolved in 550mL water, 0.21mol, 1.0eq), and stir the mixture at room temperature for 1.5h.

[0068] After most of the compounds SM reacted completely, the mixture was concentrated and dried under reduced pressure by ¹H NMR analysis. Then, 100 mL of ethanol and 10 mL of water were added, and the mixture was stirred at room temperature for 16 hours. After filtration, the mixture was washed with 20 mL of ethanol and then dried under vacuum to obtain 26.8 g of product P1.

[0069] (2) Step two, the reaction formula is as follows:

[0070]

[0071] The specific procedure was as follows: Compound P1 (26.3 g, 0.18 mol, 1.0 eq), compound S1 (30.2 g, 0.18 mol, 1.0 eq), and water (360 mL) were mixed and stirred at 25 °C under nitrogen protection for 60 h. The mixture was then concentrated under reduced pressure, and 850 mL of acetone was added. The mixture was stirred at room temperature for another 16 h and concentrated under reduced pressure. The mixture was then washed three times with acetone, adding 30 mL of acetone each time, and concentrated under reduced pressure after each wash. Finally, it was dried under vacuum to obtain 39.2 g of NBA05001.

[0072] Product NMR data: 1 H-NMR(300MHz,DMSO-D6)δ8.07(s,1H),5.70-5.40(brs,1H),4.77(s,2H),4.78-4.69(m,0.5H),4.65(s,2H),4.60-4.50(m,0.5H),4.40 -4.30(m,0.5H),4.00-3.90(m,0.5H),3.35-3.25(m,1H),3.15-3.05(m,0.5H),3.04-2.91(m,0.5H),2.53(s,3H),1.52-1.45(m,2.6H).

[0073] It should be emphasized that although compounds P1 and S2 are known compounds, NBA05001 and its various chiral forms are novel compounds that have not been reported in the literature.

[0074] Example 2

[0075] The preparation of compound NBA04910 is carried out according to the following reaction formula:

[0076]

[0077] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P2 and compound S1 is replaced with compound S2. The rest is the same as step (2) of Example 1.

[0078] Example 3

[0079] The preparation of compound NBA04923 is carried out according to the following reaction formula:

[0080]

[0081] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P3 and compound S1 is replaced with compound S3, and the rest is the same as step (2) of Example 1.

[0082] Example 4

[0083] The preparation of compound NBA04928 is carried out according to the following reaction formula:

[0084]

[0085] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P4 and compound S1 is replaced with compound S4, and the rest is the same as step (2) of Example 1.

[0086] Example 5

[0087] The preparation of compound NBA04951 is carried out according to the following reaction formula:

[0088]

[0089] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P5 and compound S1 is replaced with compound S5, and the rest is the same as step (2) of Example 1.

[0090] Example 6

[0091] The preparation of compound NBA04955 is carried out according to the following reaction formula:

[0092]

[0093] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P6 and compound S1 is replaced with compound S6, and the rest is the same as step (2) of Example 1.

[0094] Example 7

[0095] The preparation of compound NBA04959 follows the reaction formula below:

[0096]

[0097] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P7 and compound S1 is replaced with compound S7, and the rest is the same as step (2) of Example 1.

[0098] Example 8

[0099] The preparation of compound NBA04962 is carried out according to the following reaction formula:

[0100]

[0101] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P8 and compound S1 is replaced with compound S8, and the rest is the same as step (2) of Example 1.

[0102] Example 9

[0103] The preparation of compound NBA04975 is carried out according to the following reaction formula:

[0104]

[0105] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P9 and compound S1 is replaced with compound S9. The rest is the same as step (2) of Example 1.

[0106] Example 10

[0107] The preparation of compound NBA04977 follows the reaction formula below:

[0108]

[0109] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P10 and compound S1 is replaced with compound S10. The rest is the same as step (2) of Example 1.

[0110] Example 11

[0111] The preparation of compound NBA04991 is carried out according to the following reaction formula:

[0112]

[0113] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P11 and compound S1 is replaced with compound S11. The rest is the same as step (2) of Example 1.

[0114] Example 12

[0115] The preparation of compound NBA04998 follows the reaction formula below:

[0116]

[0117] The preparation method is the same as step (2) of Example 1, except that compound P1 is replaced with compound P12 and compound S1 is replaced with compound S12. The rest is the same as step (2) of Example 1.

[0118] Test Example 1:

[0119] Effects of the compound on alcohol dehydrogenase and aldehyde dehydrogenase

[0120] 1. Experimental Methods

[0121] Thirty male KM mice (18–22 g, SPF grade) were randomly divided into three groups of 10 mice each after one week of acclimatization in the animal facility. After a 12-hour fast (but with unlimited water), the mice were administered the control compound metadoxine (MTD) and NBA05001 via gavage, while the placebo group received physiological saline. The concentrations of MTD and NBA05001 were 10 mg / mL. Thirty minutes after each group received the medication via gavage (0.2 mL), they were sequentially given 56% ABV liquor, while remaining fasted but with unlimited water. One hour after the liquor administration, blood samples were collected from each group, and the activities of alcohol dehydrogenase and aldehyde dehydrogenase were measured using an ELISA kit.

[0122] 2. Experimental Results

[0123] The results of the detection of alcohol dehydrogenase and aldehyde dehydrogenase activities in the plasma of mice in each experimental group are shown in Table 1 and Table 2.

[0124] Table 1. Results of alcohol dehydrogenase activity assay in plasma

[0125]

[0126] Table 2 Results of acetaldehyde dehydrogenase activity detection in plasma

[0127]

[0128] As shown in Tables 1 and 2, compared with placebo, both NBA05001 and metadoxine significantly increased the activities of alcohol dehydrogenase and aldehyde dehydrogenase in mouse plasma.

[0129] Test Example 2:

[0130] In vitro activity assay of compounds

[0131] 1. Experimental Methods

[0132] 1.1. Cell Preparation

[0133] HepG2 cells grown to 80%–90% confluence in 10cm cell culture dishes were digested with 0.25% trypsin for 2–3 minutes. After resuspending the cells, they were seeded into 15 6cm cell culture dishes, with 2 × 10⁶ cells per dish. 6 Incubate overnight in a CO2 incubator at 37°C.

[0134] 1.2. Cell Treatment

[0135] The final concentration of 40% acetaldehyde (0.39 mol / L) was 175 μM; the final concentration of the test sample (i.e., the test compound) was 50 μM; and the culture medium volume was 4 mL.

[0136] Discard the original culture medium, add the drug to the fresh culture medium and mix thoroughly, then slowly add it to each cell culture dish; incubate in a CO2 incubator at 37°C for 24 hours.

[0137] 1.3. Sample Preparation

[0138] 1.3.1. Cell lysis

[0139] (1) Discard the original culture medium, wash twice with PBS, and then add 1-2 mL of trypsin to digest for 4 min;

[0140] (2) Discard the trypsin, use PBS to blow the cells off, and centrifuge at 1200 rpm for 5 min;

[0141] (3) Discard the supernatant, add 300-500 μL of PBS, and resuspend;

[0142] (4) Repeat the freeze-thaw cycle 3 times to lyse the cells, centrifuge at 4℃, 10000rpm for 10min, and collect the supernatant;

[0143] (5) If subsequent samples need to be diluted, the diluent is PBS.

[0144] 1.4. Sample Testing

[0145] (1) BCA assay for protein concentration;

[0146] (2) MDA (malondialdehyde) was detected using an MDA lipid oxidation kit;

[0147] (3) Detect glutathione (GSH) using a GSH kit.

[0148] 2. Experimental Results

[0149] The experimental results are shown in Tables 3 and 4, with the saline treatment group serving as the control.

[0150] Table 3 shows the effect of the compounds in reducing acetaldehyde-induced increases in MDA levels in HepG2 cells.

[0151]

[0152]

[0153] As shown in Table 3, among the 12 compounds tested, NBA05001 was the most effective in reducing the acetaldehyde-induced increase in MDA levels compared to cells treated with saline (the smaller the p-value, the greater the difference between the test sample and the control, and the better the effect).

[0154] Table 4. Effects of the compounds on increasing acetaldehyde-induced GSH levels in HepG2 cells.

[0155]

[0156] As shown in Table 4, among the 12 compounds tested, NBA05001 was the most effective in increasing the reduction of GSH levels induced by acetaldehyde, compared to cells treated with saline.

[0157] Test Example 3:

[0158] Evaluation of the Anti-Alcohol Detoxification Efficacy of NBA05001 in Mice (Part 1)

[0159] 1. Experimental Methods

[0160] Seventy male KM mice (18–22 g, SPF grade) were randomly divided into seven groups of 10 mice each after a one-week acclimatization period in the animal facility. After a 12-hour fast with unlimited water, mice were administered the control compound metadoxine (MTD) and NBA05001 via gavage. The placebo was physiological saline. The high, medium, and low doses of MTD and NBA05001 were administered at concentrations of 100 mg / mL, 30 mg / mL, and 10 mg / mL, respectively. Thirty minutes after each group was administered the drug via gavage (0.2 mL), they were sequentially given 56% ABV liquor. The mice were kept on a fast but allowed unlimited water intake. Any abnormalities, including death, were observed within 24 hours. The onset of intoxication (time from administration of liquor to intoxication) and the duration of intoxication (sobering-up time) were recorded.

[0161] 2. Experimental Results

[0162] Experimental results are as follows Figure 1 As shown, Figure 1 The efficacy of each experimental group in a mouse alcohol intoxication model was measured. Figure 1 The middle control group is the placebo group. Figure 1 (a) shows the effect of the control compound metadoxine (MTD) and the test compound NBA05001 on the onset time of alcohol intoxication in mice. Figure 1(a) The time of intoxication is the onset of intoxication; (b) shows the effect of the control compound metadoxine (MTD) and the test compound NBA05001 on the duration of intoxication in mice. The results for each group of mice are the corresponding time ± 3 times the average.

[0163] NBA05001 Mouse Alcohol Detoxification Efficacy Evaluation II

[0164] 1. Experimental Methods

[0165] Seventy male KM mice (18–22 g, SPF grade) were randomly divided into seven groups of 10 mice each after a one-week acclimatization period in the animal facility. After a 12-hour fast (but with access to water), mice were administered compounds NBA05001, NBA05100 (MTCA, 2-methylthiazolidine-4-carboxylic acid), and NBA05200 (pyridoxine) via gavage. A placebo was administered saline. The high and low dose concentrations of NBA05001, NBA05100 (MTCA), and NBA05200 (pyridoxine) were 2 mg / mL and 0.5 mg / mL, respectively. Thirty minutes after each group was administered the compound via gavage (0.2 mL), mice were sequentially given 56% ABV liquor. The mice were kept on a fast but with access to water. Any abnormalities, including death, were observed within 24 hours. The time from administration of the liquor to intoxication and the duration of intoxication (sobering-up time) were recorded.

[0166] 2. Experimental Results

[0167] Experimental results are as follows Figure 2 As shown, Figure 2 The middle control group is the placebo group. Figure 2 The efficacy of the drugs in each experimental group in a mouse alcohol intoxication model was measured. Figure 2 (a) shows the effects of compounds NBA05001, NBA05100, and NBA05200 on alcohol intoxication in mice. Figure 2 (a) shows the intoxication time, which is the onset time of intoxication; (b) shows the effect of compounds NBA05001, NBA05100, and NBA05200 on the duration of intoxication in mice. The results for each group of mice are the corresponding time ± 3 times the average value.

[0168] Results of the in vivo drug efficacy experiment in mice in Test Example 3 ( Figures 1-2The results showed that, compared with the control group and the metadoxine group, compound NBA05001 significantly delayed the onset of intoxication in mice at three concentrations of 10 mg / mL, 30 mg / mL, and 100 mg / mL. Metadoxine and compound NBA05001 significantly reduced the duration of intoxication in mice at all three different doses, meaning that both metadoxine and compound NBA05001 caused mice to sober up earlier at different doses, and at low doses, the duration of intoxication in mice corresponding to compound NBA05001 was significantly shorter than that corresponding to metadoxine. Furthermore, under low concentration conditions (2 mg / mL, 0.5 mg / mL), NBA05001 at a concentration of 2 mg / mL significantly delayed the onset of intoxication in mice, while NBA05100 and NBA05200 at concentrations of 2 mg / mL and 0.5 mg / mL had no effect on delaying the duration of intoxication in mice. In addition, all three compounds, NBA05001, NBA05100, and NBA05200, could reduce the duration of intoxication in mice at a concentration of 2 mg / mL, but NBA05001 was clearly more effective.

[0169] Test Example 4:

[0170] NBA05001 Preliminary Acute Toxicity Test

[0171] Thirty male KM mice (18–22 g, SPF grade) were administered NBA05001 after a 12-hour fast with unlimited water intake. Five mice were divided into groups and administered 1x (300 mg / mL), 0.5x, 0.25x, 0.1x, 0.05x, and 0.01x doses, respectively, via gavage (0.2 mL). The mice were again kept on a fast with unlimited water intake, and observation was conducted for any abnormalities, including death, within 24 hours.

[0172] The results showed that none of the mice exhibited any abnormal reactions, and no organ abnormalities were found in the five mice that received the maximum concentration of 1x (300 mg / mL) after dissection. Therefore, NBA05001 is safe at a dosage concentration of 300 mg / mL.

[0173] Based on the above experimental results, compound NBA05001 can rapidly detoxify alcohol in mice and protect liver cells from damage. Therefore, this compound and compositions thereof have important clinical applications, including but not limited to detoxification and liver protection.

[0174] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A compound, its pharmaceutically acceptable salt or hydrate, said compound having any of the following structures: 。 2. The method for preparing the compound according to claim 1, characterized in that, Includes the following steps: The compound shown in Formula II and the compound shown in Formula III are mixed with an inert solvent to carry out a salt-forming reaction to obtain the compound of claim 1; Formula II, Formula III; R1 and R2 in the compound shown in Formula II and R3, R4 and R5 in the compound shown in Formula III correspond to the compound of claim 1.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:1; the temperature of the salt formation reaction is 0~80℃ and the time is 0.1~60h.

4. A pharmaceutical composition, characterized in that, It includes an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is the compound of claim 1, its pharmaceutically acceptable salt or hydrate.

5. The use of the compound of claim 1, its pharmaceutically acceptable salt or hydrate, or the pharmaceutical composition of claim 4 in the preparation of a medicament for the prevention and / or treatment of related diseases, including acute alcoholism, chronic alcoholism, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system disorders, or Fragile X syndrome.

6. The application according to claim 5, characterized in that, The central nervous system disorders mentioned include ADHD, anxiety, depression, or schizophrenia in children.

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