Compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides a compound, a preparation method thereof, a pharmaceutical composition and application, and relates to the technical field of medicines. The compound provided by the invention has a structure as shown in a formula I. The compound provided by the invention can efficiently relieve acute alcoholism and protect the liver from being damaged. In-vitro cell experiments show that the compound can accelerate in-vivo discharge of ethanol, acetaldehyde and metabolites thereof, protect liver cells from acetaldehyde-induced lipid peroxidation and prevent acetaldehyde-induced glutathione reduction. In an acute alcoholism mouse model, the compound can obviously delay the drunkenness starting time of a mouse and obviously accelerate the sobering time of the mouse. In addition, the compound provided by the invention is low in toxic and side effects and good in druggability. The invention provides the preparation method of the compound with the structure as shown in the formula I, the synthesis is simple, and the yield is higher. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a compound and a preparation method thereof, as well as a pharmaceutical composition and application thereof. Background Art

[0002] Alcoholism is one of the most serious social problems facing mankind. Its causes are complex, with physiological and genetic factors as well as cultural and environmental influences. The most common disease caused by drinking is liver damage, and the mechanism of liver toxicity caused by ethanol is still not very clear. Studies have shown that ethanol also changes the transmission of many brain neurotransmitters: such as stimulating the transmission of dopamine, interfering with the transmission of serotonin, and interfering with the transmission of glutamine in the central nervous system. Long-term excessive drinking leads to neuropathic diseases.

[0003] At present, the main drug used for the treatment of acute and chronic alcoholism and alcoholic liver disease clinically is metadoxine. Metadoxine is a water-soluble vitamin that can accelerate the excretion of ethanol and ethanol metabolites in the body, so it has a relatively good effect for the treatment of alcoholic liver disease. However, the activity of metadoxine still needs to be improved, mainly manifested in that after the human body takes metadoxine, drunkenness is still faster, and the sobering time (i.e., drunkenness duration) is still longer. Therefore, new drugs for the treatment of alcoholism 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 and a preparation method thereof, as well as a pharmaceutical composition and application thereof. The compound provided by the present invention can significantly delay the onset of drunkenness and accelerate the sobering time, and has excellent alcohol detoxification and liver protection effects.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a compound having a 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 the group consisting of hydrogen, halogen, hydroxyl, carboxyl, C 1～6 Acyl, C 1～3 Alkyl-carbonyl-C 1～3 Alkyl, C 1～6 Alkyl-aldehyde, C 1～6 Alkyl-hydroxyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy.

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

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

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

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

[0013]

[0014] The present invention provides a method for preparing the compound having the structure shown in Formula I described in the above technical scheme, comprising the following steps:

[0015] The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed to form a salt, thereby obtaining a compound having a structure represented by formula I;

[0016]

[0017] Preferably, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1; the temperature of the salt-forming reaction is 0 to 80° C., and the time is 0.1 to 60 hours.

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

[0019] The present invention provides a compound having a structure shown in Formula I as described in the above technical scheme, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or use of the pharmaceutical composition as described in the above technical scheme in the preparation of a drug for preventing and / or treating related diseases, wherein the related diseases include acute alcoholism, chronic alcoholism, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases, or fragile X syndrome.

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

[0021] The present invention provides a compound having a structure shown in Formula I. The compound provided by the present invention can effectively relieve acute alcohol poisoning and protect the liver from damage. In vitro cell experiments show that the compound can accelerate the excretion of ethanol, acetaldehyde and their metabolites in the body, protect liver cells from lipid peroxidation induced by acetaldehyde and prevent the reduction of glutathione induced by acetaldehyde. In an acute alcohol poisoning mouse model, the compound can significantly delay the onset of drunkenness in mice and significantly accelerate the sobering time of mice. In addition, the compound provided by the present invention has low toxicity and side effects and good drugability.

[0022] The present invention provides a method for preparing the compound described in the above technical solution, which has simple synthesis and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the drug efficacy of each test group in the mouse drunkenness model, Figure 1 (a) shows the effects of the control compound metadoxine (MTD) and the test compound NBA05001 on the onset time of drunkenness in mice, and (b) shows the effects of the control compound metadoxine (MTD) and the test compound NBA05001 on the duration of drunkenness in mice;

[0024] Figure 2 is the drug efficacy of each experimental group in the mouse drunkenness model, Figure 2 (a) shows the effects of compounds NBA05001, NBA05100, and NBA05200 on the onset time of drunkenness in mice, and (b) shows the effects of compounds NBA05001, NBA05100, and NBA05200 on the duration of drunkenness in mice. DETAILED DESCRIPTION

[0025] the term:

[0026] The terms "including" and "having" and any variations thereof of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, device, product or equipment comprising a series of steps is not limited to the listed steps or modules, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or equipment.

[0027] In the present invention, the term "multiple" refers to two or more than two. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0028] In the compounds of the present invention, when any variable occurs more than once in any component, its definition at each occurrence is independent of the definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations render the compound stable. It is understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0029] The term "alkyl" as used herein is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. 1～6 "C" in "alkyl" 1～6 " includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having 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, wherein the alkyl group is as defined above. "Halogen" is meant to include chlorine, fluorine, bromine and iodine. The term "haloalkyl" represents an alkyl group in which one or more hydrogen atoms are replaced by halogen, wherein the alkyl group is as defined above. The term "haloalkoxy" represents an alkyl-oxy group in which one or more hydrogen atoms are replaced by halogen, wherein the alkyl group is as defined above.

[0030] The present invention provides a compound having a 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 the group consisting of hydrogen, halogen, hydroxyl, carboxyl, C 1～6 Acyl, C 1～3 Alkyl-carbonyl-C 1～3 Alkyl, C 1～6 Alkyl-aldehyde, C 1～6 Alkyl-hydroxyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy.

[0033] In the present invention, the halogen is fluorine, chlorine, bromine or iodine; 1～3 Alkyl-carbonyl-C 1～3 The alkyl group is 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; said C 1～6 Alkyl-hydroxy is preferably C 1～3 Alkyl-hydroxyl, more preferably hydroxymethyl, hydroxyethyl or hydroxypropyl; the C 1～6 The alkyl group is preferably C 1～3 Alkyl, more preferably methyl, ethyl, propyl or cyclopropyl; the C 1～6 The haloalkyl group is preferably C 1～3 haloalkyl; said C 1～6 The haloalkoxy group is preferably C 1～3 Halogenated alkoxy.

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

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

[0036]

[0037] The compound provided by the present invention can significantly delay the onset of drunkenness and accelerate the sobering time, can effectively relieve acute alcohol poisoning, protect the liver, and has excellent alcohol sobering and liver protecting activity.

[0038] The present invention provides a method for preparing the compound having the structure shown in Formula I described in the above technical scheme, comprising the following steps:

[0039] The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed to form a salt, thereby obtaining a compound having a structure represented by formula I;

[0040]

[0041] In the present invention, unless otherwise specified, the raw materials involved are commercially available products or prepared according to methods well known to those skilled in the art.

[0042] In the present invention, R1 and R2 in the compound represented by formula II, and R3, R4 and R5 in the compound represented by formula III are respectively consistent with R1, R2, R3, R4 and R5 in formula I, and are not repeated here.

[0043] In the present invention, the molar ratio of the compound represented by formula II to the compound represented by formula III is preferably 1:1. In the present invention, the inert solvent is preferably water. The present invention has no special requirements for the amount of the inert solvent, as long as the reaction proceeds smoothly. In the present invention, the temperature of the salt-forming reaction is preferably 0 to 80°C, more preferably 0 to 50°C, and further preferably room temperature (25°C); the time of the salt-forming reaction is preferably 0.1 to 60h, more preferably 0.5 to 48h; the salt-forming reaction is preferably carried out under nitrogen protection and stirring. In the present invention, the reactions involved in the salt-forming reaction are as follows:

[0044]

[0045] In the present invention, after the salt-forming reaction is completed, the obtained reaction solution is preferably concentrated under reduced pressure, and the obtained concentrate is washed with acetone and dried in sequence to obtain a compound with a 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 a structure shown in Formula I as described in the above technical scheme, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0047] The present invention has no special requirements for the preparation method of the pharmaceutical composition, and the preparation method of the pharmaceutical composition well known to those skilled in the art can be adopted. Specifically, the active ingredient and the pharmaceutically acceptable carrier are mixed.

[0048] It should be understood that the active ingredient of the present invention also includes crystalline forms, amorphous compounds, chiral compounds, and deuterated compounds of the compound.

[0049] In the present invention, the "pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by the compound of the present invention and an acid. 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, 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, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts, such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively).

[0050] In the present invention, the prodrug refers to a compound having the structure shown in Formula I which has undergone certain modifications and becomes a compound having the structure shown in Formula I after entering the body.

[0051] In the present invention, the "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0052] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In the present invention, one dose of the pharmaceutical composition contains 1 to 3000 mg (active dose range 3 to 30 mg / kg) of active ingredient, preferably, 10 to 2000 mg of active ingredient, and the "one dose" is a capsule or tablet or a single in vivo injection.

[0053] The present invention has no particular limitation on the administration method of the compound or pharmaceutical composition. 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 the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0055] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

[0056] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent 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-butylene glycol, dimethylformamide and oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil or a mixture of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents and spices. In addition to the active ingredient, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum methylate, agar or a mixture of these substances.

[0057] Compositions for parenteral injection may include 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 inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0059] The compound or pharmaceutical composition of the present invention may 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 a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

[0061] The present invention provides the use of the compound having the structure shown in Formula I described in the above technical scheme, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or the pharmaceutical composition described in the above technical scheme in the preparation of a drug for preventing and / or treating related diseases, wherein the related diseases include acute alcoholism, chronic alcoholism, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases or fragile X syndrome. In the present invention, the central nervous system diseases preferably include childhood hyperactivity, anxiety, depression or schizophrenia. The compound provided by the present invention, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or the pharmaceutical composition described in the above technical scheme can effectively detoxify alcohol and protect the liver. The compound provided by the present invention, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or the pharmaceutical composition described in the above technical scheme can effectively prevent, treat and / or alleviate related diseases.

[0062] In order to further illustrate the present invention, the compounds and preparation methods thereof, as well as the pharmaceutical compositions and applications provided by the present invention are described in detail below in conjunction with examples, but they 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 operation is as follows: under nitrogen protection at -5°C, 40 wt% acetaldehyde solution (25 g, 0.22 mol, 1.1 eq) was added to the compound SM solution (25 g dissolved in 550 mL of water, 0.21 mol, 1.0 eq), and the mixture was stirred at room temperature for 1.5 h.

[0068] After HNMR detection showed that most of the compound SM had reacted, the mixture was concentrated and dried under reduced pressure. Then 100 mL of ethanol and 10 mL of water were added, and the mixture was stirred at room temperature for 16 hours, filtered, washed with 20 mL of ethanol, and then dried in vacuo to obtain 26.8 g of product P1.

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

[0070]

[0071] The specific operation is 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) are mixed, stirred at 25 ° C under nitrogen protection for 60 h; the mixture is concentrated under reduced pressure, and then 850 mL of acetone is added, and the mixture is stirred at room temperature for 16 h, and concentrated under reduced pressure. The mixture is then washed with acetone three times, adding 30 mL of acetone each time, and concentrated under reduced pressure after each washing. Finally, it is 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 here that, although compounds P1 and S2 are known compounds, NBA05001 and its various chiral forms are new compounds that have not been reported in the literature.

[0074] Example 2

[0075] The preparation of compound NBA04910, the reaction formula is as follows:

[0076]

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

[0078] Example 3

[0079] The preparation of compound NBA04923, the reaction formula is as follows:

[0080]

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

[0082] Example 4

[0083] The preparation of compound NBA04928, the reaction formula is as follows:

[0084]

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

[0086] Example 5

[0087] The preparation of compound NBA04951, the reaction formula is as follows:

[0088]

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

[0090] Example 6

[0091] The preparation of compound NBA04955, the reaction formula is as follows:

[0092]

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

[0094] Example 7

[0095] The preparation of compound NBA04959, the reaction formula is as follows:

[0096]

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

[0098] Example 8

[0099] The preparation of compound NBA04962, the reaction formula is as follows:

[0100]

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

[0102] Example 9

[0103] The preparation of compound NBA04975, the reaction formula is as follows:

[0104]

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

[0106] Example 10

[0107] The preparation of compound NBA04977, the reaction formula is as follows:

[0108]

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

[0110] Embodiment 11

[0111] The preparation of compound NBA04991, the reaction formula is as follows:

[0112]

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

[0114] Example 12

[0115] The preparation of compound NBA04998, the reaction formula is as follows:

[0116]

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

[0118] Test example 1:

[0119] Effects of compounds on alcohol dehydrogenase and acetaldehyde dehydrogenase

[0120] 1. Experimental Methods

[0121] 30 KM mice (male, 18-22g, SPF grade) were randomly divided into 3 groups, 10 mice / group, after one week of adaptation in the animal room. The control compound metadoxine (MTD) and NBA05001 were given by gavage after 12 hours of fasting but not water conservancy. The placebo group was given normal saline. The concentrations of MTD and NBA05001 were 10 mg / mL, respectively. After 30 minutes of gavage (0.2 mL) of each group of mice, 56-degree liquor was sequentially given, without fasting or water conservancy. One hour after gavage of liquor, blood was collected from each group of mice, and the activities of alcohol dehydrogenase and acetaldehyde dehydrogenase of each mouse were measured using ELISA kits.

[0122] 2. Experimental results

[0123] The results of the activity detection of alcohol dehydrogenase and acetaldehyde dehydrogenase in the plasma of mice in each experimental group are shown in Tables 1 and 2.

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

[0125]

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

[0127]

[0128] It can be seen from Tables 1 and 2 that, compared with placebo, NBA05001 and metadoxine can significantly increase the activities of alcohol dehydrogenase and acetaldehyde 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% to 90% in a 10 cm cell culture dish were digested with 0.25% trypsin for 2 to 3 min. After resuspending the cells, the cells were plated in 15 6 cm cell culture dishes, with 2 × 10 cells in each dish. 6 , and cultured 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 (ie, the test compound) was 50 μM, and the volume of the culture medium was 4 mL.

[0136] The original culture medium was discarded, the drug was added to the fresh culture medium and mixed thoroughly, then slowly added to each cell culture dish; the cells were cultured in a CO2 incubator at 37°C for 24 hours.

[0137] Sample processing

[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, blow off the cells with PBS, and centrifuge at 1200 rpm for 5 min;

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

[0142] (4) Repeat freezing and thawing three times to lyse the cells, centrifuge at 10,000 rpm for 10 min at 4°C, and collect the supernatant;

[0143] (5) If the sample needs to be diluted later, the diluent is PBS.

[0144] 1.4. Sample testing

[0145] (1) BCA detection of protein concentration;

[0146] (2) Detect MDA (malondialdehyde) using the 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 as the control.

[0150] Table 3 Effects of compounds on reducing the increase of MDA levels induced by acetaldehyde in HepG2 cells

[0151]

[0152]

[0153] As can be seen from Table 3, among the 12 compounds tested, NBA05001 had the best effect on reducing the increase in MDA levels induced by acetaldehyde compared with cells treated with normal saline (the smaller the p value, the greater the difference between the test sample and the control, the better the effect).

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

[0155]

[0156] As can be seen from Table 4, among the 12 compounds tested, NBA05001 had the best effect on increasing the reduction of GSH levels induced by acetaldehyde relative to cells treated with normal saline.

[0157] Test Example 3:

[0158] Evaluation of NBA05001's efficacy in detoxifying alcohol in mice

[0159] 1. Experimental Methods

[0160] 70 KM mice (male, 18-22g, SPF grade) were randomly divided into 7 groups, 10 mice / group, after one week of adaptation in the animal room. The control compound metadoxine (MTD) and NBA05001 were given by gavage after 12 hours of fasting but not water deprivation. The placebo was normal saline. The concentrations of MTD and NBA05001 at high, medium and low doses were 100mg / mL, 30mg / mL and 10mg / mL, respectively. After 30 minutes of gavage (0.2mL) of each group of mice, 56-degree liquor was sequentially given, without food or water deprivation. The mice were observed for any abnormalities including death within 24 hours, and their intoxication start time (time from gavage of liquor to intoxication) and intoxication duration (sobering time) were recorded.

[0161] 2. Experimental results

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

[0163] Evaluation of NBA05001 in mice for alcohol detoxification

[0164] 1. Experimental Methods

[0165] 70 KM mice (male, 18-22g, SPF grade) were randomly divided into 7 groups, 10 mice / group, after one week of adaptation in the animal room. After fasting but not water, compounds NBA05001, NBA05100 (MTCA, 2-methylthiazolidine-4-carboxylic acid), NBA05200 (pyridoxine) were given by gavage for 12 hours, and normal saline was used as placebo. The concentrations of high and low doses of NBA05001, NBA05100 (MTCA), and NBA05200 (pyridoxine) were 2mg / mL and 0.5mg / mL, respectively. After 30 minutes of gavage (0.2mL) of each group of mice, 56-degree liquor was sequentially given, without food or water. The mice were observed for any abnormalities including death within 24 hours, and their drunkenness time (time from gavage of liquor to drunkenness) and drunkenness duration (sobering time) were recorded.

[0166] 2. Experimental results

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

[0168] Results of the in vivo efficacy experiment in mice of Test Example 3 ( Figure 1-2) showed that compared with the control group and the metadoxine group, the compound NBA05001 at three concentrations of 10mg / mL, 30mg / mL, and 100mg / mL could significantly delay the onset of drunkenness in mice. Metadoxine and compound NBA05001 could significantly reduce the duration of drunkenness in mice at three different doses, that is, metadoxine and compound NBA05001 could sober up mice earlier at different doses, and at low doses, the duration of drunkenness in mice corresponding to compound NBA05001 was significantly lower than that of metadoxine. In addition, under low concentration conditions (2mg / mL, 0.5mg / mL), NBA05001 could significantly delay the onset of drunkenness in mice at a concentration of 2mg / mL, while NBA05100 and NBA05200 had no effect on delaying the drunkenness of mice at concentrations of 2mg / mL and 0.5mg / mL. In addition, the three compounds NBA05001, NBA05100, and NBA05200 can all reduce the duration of drunkenness in mice at a concentration of 2 mg / mL, but NBA05001 is obviously more effective.

[0169] Test Example 4:

[0170] NBA05001 Preliminary Acute Toxicity Test

[0171] 30 KM mice (male, 18-22g, SPF grade) were fasted for 12 hours but not water deprivation and then given NBA05001. Five mice in each group were given 1x (300mg / mL), 0.5x, 0.25x, 0.1x, 0.05x, 0.01x, 0.2mL by gavage. The mice were still fasted but not water deprivation, and observed for any abnormalities including death within 24 hours.

[0172] The results showed that all mice had no abnormal reactions, and no organ abnormalities were found in the autopsies of 5 mice that were given the maximum concentration of 1x (300 mg / mL). Therefore, NBA05001 is safe at a concentration of 300 mg / mL.

[0173] Based on the above experimental results, compound NBA05001 can quickly detoxify alcohol in mice and protect liver cells from damage. Therefore, the compound and the composition composed of it have important clinical application value, including but not limited to the effects of detoxifying alcohol and protecting the liver.

[0174] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A compound having a structure as shown in Formula I, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; In Formula I, R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carboxyl, C 1～6 Acyl, C 1～3 Alkyl-carbonyl-C 1～3 Alkyl, C 1～6 Alkyl-aldehyde, C 1～6 Alkyl-hydroxyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy.

2. The compound having the structure shown in Formula I according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, characterized in that: The R1 and R2 are independently selected from hydrogen or C 1～6 Alkyl, wherein R3, R4 and R5 are independently selected from hydrogen, hydroxyl, C 1～6 Alkyl or C 1～6 Alkyl-hydroxy.

3. The compound having the structure shown in Formula I according to claim 1 or 2, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, characterized in that: The C 1～6 The alkyl group is methyl, ethyl, propyl or cyclopropyl.

4. The compound having the structure shown in Formula I according to claim 1 or 2, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, characterized in that: The C 1～6 Alkyl-hydroxy is hydroxymethyl, hydroxyethyl or hydroxypropyl.

5. The compound having the structure shown in Formula I according to claim 1 or 2, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, characterized in that: The compound having the structure shown in formula I has any of the following structures:

6. A method for preparing a compound having a structure represented by formula I according to any one of claims 1 to 5, characterized in that: The following steps are involved: The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed to form a salt, thereby obtaining a compound having a structure represented by formula I; 7. The preparation method according to claim 6, characterized in that: The molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1; the temperature of the salt-forming reaction is 0 to 80° C., and the time is 0.1 to 60 hours.

8. A pharmaceutical composition, characterized in that It comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is a compound having a structure shown in formula I as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

9. Use of the compound having the structure represented by formula I according to any one of claims 1 to 5, its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating related diseases, wherein the related diseases include acute alcoholism, chronic alcoholism, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases or fragile X syndrome.

10. The use according to claim 9, characterized in that: The central nervous system diseases include ADHD, anxiety, depression or schizophrenia.

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