Sulfonyl-substituted aziridine compound with anti-inflammatory and liver-protecting activity as well as preparation and application of sulfonyl-substituted aziridine compound

Abstract

The invention belongs to the technical field of medicines, and discloses sulfonyl substituted aziridine compounds with anti-inflammatory and liver-protecting activity as well as a preparation method and application of the sulfonyl substituted aziridine compounds. Specifically, the invention discloses preparation of sulfonyl-substituted aziridine new compounds 1 and 2, pharmaceutically acceptable salts of the sulfonyl-substituted aziridine new compounds 1 and 2, and application of pharmaceutical compositions of the sulfonyl-substituted aziridine new compounds 1 and 2 in preparation of anti-inflammatory and liver-protecting drugs. Cellular level experiments prove that the compounds 1 and 2 have good anti-inflammatory and liver-protecting effects and are expected to become drugs for treating diseases related to liver injury.

Description

Technical Field

[0001] The present invention relates to a class of sulfonyl-substituted aziridine compounds and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing the compounds, and applications of the compounds in anti-inflammatory and liver protection, belonging to the field of medical technology. Background Art

[0002] The liver is one of the most important organs in the human body and is also the largest substantial organ in the human body. It has important functions such as biological transformation, detoxification, protein secretion, blood sugar regulation, and participation in blood coagulation. At the same time, the liver is also an organ that is often invaded by various pathogenic factors or diseases. Abnormal metabolism, drugs, microorganisms, etc. can all cause liver damage. In recent decades, liver disease has become one of the diseases with the highest mortality rate in the world, including acute hepatitis, liver cancer, etc., accounting for 4% of all deaths worldwide. [1] my country is a country with a high incidence of liver disease, with more than one-fifth of the population affected by some form of liver disease, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, cirrhosis, liver cancer, non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD) and drug-induced liver injury (DILI). [2] According to statistics, direct economic losses from chronic hepatitis (including cirrhosis and liver cancer in later stages) in my country reach 900 billion RMB annually. In recent years, the incidence of liver-related diseases has also been increasing year by year. Therefore, the development of new anti-inflammatory and liver-protecting drugs is urgent and has become one of the main research areas in the current drug research and development field.

[0003] As we all know, liver disease is a progressive disease. There is a variety of evidence suggesting that liver inflammation is seen in almost all causes of liver disease and often runs throughout the course of liver disease. In 2014, the Expert Consensus Committee on Liver Inflammation and Its Prevention and Treatment of the Infectious Diseases Branch of the Chinese Medical Association published the Expert Consensus on Liver Inflammation and Its Prevention and Treatment. [3] The "Consensus" points out: "Liver inflammation and the resulting liver fibrosis, cirrhosis and liver failure are the main pathophysiological and pathological histological basis of liver disease progression; anti-inflammatory and liver-protecting treatment is an important part of the comprehensive treatment of liver inflammation. For liver inflammation, regardless of whether there is an effective etiological treatment, anti-inflammatory and liver-protecting treatment should be considered; for some patients who lack effective etiological treatment or are temporarily unable to undergo etiological treatment, anti-inflammatory and liver-protecting treatment should be considered." Anti-inflammatory and liver-protecting drugs are a class of drugs that have the effects of improving liver function, promoting liver cell regeneration and / or enhancing liver detoxification function. They can reduce liver damage caused by pathogenic factors such as hepatitis viruses, drugs, toxins and alcohol, and are an important part of the comprehensive treatment of liver disease. However, for a long time, the progress in anti-inflammatory and liver-protecting treatment has not been ideal. The clinically available anti-inflammatory and liver-protecting drugs and means are limited, and the main varieties are limited to licorice products. [4] , silymarin[5] glutathione [6] and bicyclol [7] etc. There are less varieties of Chinese original or with Chinese independent intellectual property rights. Therefore, the development of new anti-inflammatory hepatoprotective drugs with our own intellectual property rights has important strategic significance and medical value in China.

[0004] References

[0005] [1] P. Byass, The global burden of liver disease: a challenge for methods and for public health. BMC Med, 2014, 12, 159.

[0006] [2] F.-S. Wang, J.-G. Fan, Z. Zhang, B. Gao, H.-Y. Wang, Hepatology. 2014, 60, 2099-2108.

[0007] [3] Li Lan-juan, Wang Yu-ming, Liver inflammation and its prevention and treatment expert consensus. Chin J Hepatol, 2014, 22, 94-103.

[0008] [4] X. Miao, Hepatoprotective treatment for liver injury induced by antituberculosis chemotherapy drug. Chin J Tuberculosis Resp Dis, 2013, 36, 729-731.

[0009] [5] S. Pradhan, C. Girish, Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res, 2006, 124, 491-504.

[0010] [6] G. Li, Z. Zhang, C. Yang, The Classification and function of common anti-inflammatory drugs. Chin Prac Med, 2012, 7, 236-238.

[0011] [7]W.Xie,G.Shi,H.Zhang,G.Zhao,Z.Yu,Z.Lang,H.Zhao,J.Yan,J.Cheng,Arandomized,multi-central,controlled study of patients with hepatitis B eantigen-positive chronic hepatitis B treated by adefovir dipivoxil oradefovir dipivoxil plus bicyclol.Hepatol Int,2012,6,441-448. Summary of the Invention

[0012] The technical problem solved by the present invention is to provide a class of sulfonyl-substituted aziridine compounds and pharmaceutically acceptable salts thereof, as well as the use of pharmaceutical compositions thereof in the preparation of anti-inflammatory and liver-protecting drugs.

[0013] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0014] The first aspect of the technical solution of the present invention is to provide compounds shown in the following group:

[0015]

[0016] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound described in the first aspect.

[0017]

[0018] 7-Methylbenzo[e][1,2,3]thiazine 2,2-dioxide 3 and dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 4 react in a formal [2+1] reaction under alkaline conditions to give ((1S,8bR)-6-methyl-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)(phenyl)methanone compound 1; benzo[e] [1,2,3]thiazine 2,2-dioxide 5 and (2-(2,5-dimethoxyphenyl)-2-oxoethyl)dimethylsulfonium bromide 6 undergo a formal [2+1] reaction under alkaline conditions to obtain (2,5-dimethoxyphenyl)((1S,8bR)-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)methanone compound 2.

[0019] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition containing compounds as shown in structures 1 and 2 and pharmaceutically acceptable salts thereof, wherein the pharmaceutical composition contains compounds as shown in compounds 1 and 2 included in the group and pharmaceutically acceptable salts thereof as active ingredients, and optionally contains a pharmaceutical carrier.

[0020] Typically, the pharmaceutical composition of the present invention contains 0.1-95% by weight of the compound of the present invention.

[0021] The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to prepare suitable administration forms or dosage forms that can be used as human or veterinary medicines.

[0022] The compound of the present invention or the pharmaceutical composition containing the same can be administered in unit dosage form. The administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum, etc., preferably oral.

[0023] The compound of the present invention or the pharmaceutical composition containing the same can be administered by injection, including intravenous injection, intramuscular injection, subcutaneous injection and intradermal injection.

[0024] The dosage form can be a liquid or solid dosage form. For example, liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and freeze-dried powder injections.

[0025] The extract or compound of the present invention can be made into common preparations, or can be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0026] In order to prepare unit dosage forms into tablets, a wide variety of carriers well known in the art can be used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders such as water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0027] For example, to prepare the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, gelucire, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.

[0028] For example, to prepare a dosing unit in the form of a capsule, the active ingredient extract or compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule. Alternatively, the active ingredient compound of the present invention may be formulated into microcapsules and suspended in an aqueous medium to form a suspension, which may be encapsulated in a hard capsule or formulated as an injection.

[0029] For example, the extracts or compounds of the present invention can be formulated into injectable formulations, such as solutions, suspension solutions, emulsions, or lyophilized powder injections. These formulations can be aqueous or non-aqueous and may contain one or more pharmacologically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. For example, diluents can be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulation. Conventional cosolvents, buffers, and pH adjusters can also be added. Cosolvents can include poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters can include phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators can include sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol or glucose can also be added as support agents.

[0030] In addition, if necessary, colorants, preservatives, perfumes, flavorings, sweeteners or other materials may be added to the pharmaceutical preparations.

[0031] To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0032] The fourth aspect of the technical solution of the present invention is to provide the use of the sulfonyl-substituted aziridine compounds 1 and 2 and pharmaceutically acceptable salts thereof in the preparation of anti-liver injury, anti-inflammatory and liver-protecting drugs.

[0033] When the sulfonyl-substituted aziridine derivatives and pharmaceutically acceptable salts thereof or the composition of the present invention are used to treat the above-mentioned diseases, the dosage thereof can refer to the dosage used when the sulfonyl-substituted aziridine derivatives are used for treatment.

[0034] The dosage of the compounds and pharmaceutical compositions of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, and the purpose of treatment. Therefore, the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical ingredients of the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of the drug contained in the final preparation of the compound composition of the present invention to achieve the requirements of its therapeutically effective amount and complete the prevention or treatment purpose of the present invention. The daily suitable dosage range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.01-100 mg / kg body weight, more preferably 0.01-60 mg / kg body weight, and most preferably 0.1-10 mg / kg body weight. The above dosage can be administered in a single dose form or divided into several, such as two, three or four dose forms. This is limited by the clinical experience of the administering physician and the administration regimen including the use of other treatment means.

[0035] The total dose required for each treatment can be divided into multiple doses or administered as a single dose. The compounds and compositions of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs with adjusted dosages.

[0036] The inventors have discovered that compounds 1 and 2 and their pharmaceutically acceptable salts have significant anti-inflammatory and hepatoprotective effects. Therefore, compounds 1 and 2 and their pharmaceutically acceptable salts also provide methods for treating and ameliorating diseases associated with liver damage. These methods comprise administering a therapeutically effective amount of compounds 1 and 2 or their pharmaceutically acceptable salts, or a pharmaceutical composition thereof, to a patient in need of treatment.

[0037] The present invention shows that compounds 1 and 2 have significant anti-inflammatory and hepatoprotective effects at the cellular level. There are no public reports on compounds 1 and 2 or their pharmaceutically acceptable salts, and there are no public reports on the anti-inflammatory and hepatoprotective activities of compounds 1 and 2.

[0038] Beneficial technical effects

[0039] During their research on aziridine compounds, the inventors of this invention chemically synthesized two novel sulfonyl-substituted aziridine compounds, 1 and 2. Using a classic cell model for evaluating hepatoprotective activity, the compounds were evaluated for their protective effects against paracetamol (APAP)-induced hepatocellular damage. The results demonstrated that compounds 1 and 2 possess significant anti-inflammatory and hepatoprotective activity. These compounds represent valuable new lead compounds in the development of anti-inflammatory and hepatoprotective drugs. DETAILED DESCRIPTION

[0040] The following examples further illustrate the present invention but are not intended to limit the present invention in any way.

[0041] Example 1: Preparation of ((1S,8bR)-6-methyl-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazin-1-yl)(phenyl)methanone compound (1)

[0042]

[0043] 7-Methylbenzo[e][1,2,3]thiazine 2,2-dioxide 3 (197 mg) and dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 4 (390 mg) were weighed and dissolved in 7.5 mL of dichloromethane. Triethylamine (202 mg) was added and reacted at room temperature for 1.5 hours. The organic solvent was removed under reduced pressure and column chromatography was performed to obtain a white solid ((1S,8bR)-6-methyl-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)(phenyl)methanone compound 1 (292 mg, 94%). Mp:192.4-192.9℃; IRνmax(film):3044,2924,1687,1599,1506,1450,1393,1194,1033,798,720cm -1 ; 1 H NMR (800MHz, CDCl3): δ = 8.09 (d, J = 7.2Hz, 2H), 7.67 (t, J = 7.2Hz, 1H), 7.54 (t, J = 7.6Hz, 2H), 7.39 (d, J = 7.2 Hz,1H),7.13(d,J=8.0Hz,1H),6.98(s,1H),4.67(d,J=3.2Hz,1H),4.24(d,J=3.2Hz,1H),2.39(s,3H)ppm; 13 C NMR (200MHz, CDCl3): δ = 189.4, 149.9, 141.9, 135.2, 134.9, 129.4, 129.3, 129.1, 127.9, 120.1, 114.9, 48.0, 45.4, 21.4ppm. HRMS (ESI) m / z: [M+H] + calcd for C 16 H 14 O4NS 316.0638; found:316.0638.

[0044] Example 2: Preparation of (2,5-dimethoxyphenyl)((1S,8bR)-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazin-1-yl)methanone (2)

[0045]

[0046] Benzo[e][1,2,3]thiazine 2,2-dioxide 5 (183 mg) and (2-(2,5-dimethoxyphenyl)-2-oxoethyl)dimethylsulfonium bromide 6 (480 mg) were weighed and dissolved in 7.5 mL of dichloromethane. Triethylamine (202 mg) was added and the mixture was reacted at room temperature for 1.5 hours. The organic solvent was removed under reduced pressure and the mixture was purified by column chromatography to obtain (2,5-dimethoxyphenyl)((1S,8bR)-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)methanone 2 (340 mg, 95%) as a white solid. Mp: 184.9-185.7°C; IRν max (film):3062,2951,2840,1672,1498,1390,1193,1033,821,760cm -1 ; 1 H NMR (CDCl3, 800MHz): δ = 7.45 (d, J = 36.0Hz, 2H), 7.30 (s, 2H), 7.13 (d, J = 8.0Hz, 2H ),6.92(d,J=5.6Hz,1H),4.91(s,1H),4.14(s,1H),3.81(s,3H),3.70(s,3H)ppm; 13 C NMR (CDCl3, 200MHz): δ=190.4,154.4,153.9,150.1,130.5,129.4,126.8,125.8,123.0,119 .6,119.0,113.88,113.4,56.3,56.1,49.44,48.62(d,J=12.0Hz)ppm; HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 O6NS 362.0693; found:362.0693.

[0047] Pharmacological experiments

[0048] Example 1. Evaluation of the protective effect of compounds 1 and 2 on APAP-induced hepatocellular damage in experimental cell lines

[0049] Human HepG2 hepatocellular carcinoma cells, which retain the characteristics of normal human hepatocytes, were grown in DMEM (100 U / ml penicillin and 100 μg / ml streptomycin) supplemented with 10% fetal bovine serum at 37°C, 5% CO2, and saturated humidity. They were digested and passaged using a solution containing 0.25% trypsin and 0.02% EDTA.

[0050] Experimental methods

[0051] (1) Effects of compounds on HepG2 cell proliferation

[0052] The MTT method was used. HepG2 cells were seeded in a 96-well cell culture plate and cultured for 24 hours. Different concentrations of the test compound were then added. A solvent control group was also established, with three parallel wells for each drug concentration. After 24 hours of drug exposure, the culture medium was discarded, and 100 μl of MTT (0.5 mg / ml) solution was added to each well. The cells were cultured for another 4 hours. The MTT solution was discarded, and 150 μl of DMSO was added to each well. The cells were mixed and shaken, and the absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (mean OD value of the treated cells / mean OD value of the solvent control cells) × 100%.

[0053] (2) Protective effect of the compound on paracetamol-induced hepatocyte damage in vitro

[0054] The MTT assay was used. HepG2 cells were seeded in a 96-well cell culture plate and cultured for 24 hours. Non-toxic concentrations of the test compound and paracetamol (APAP, final concentration 8 mM) were then added. A positive drug control group (glutathione GSH), a solvent blank control group, and a model group were also established. The cells were treated for a further 24 hours. The culture medium was discarded, and 100 μl of MTT (0.5 mg / ml) solution was added to each well. The cells were cultured for another 4 hours. The MTT solution was discarded, and 150 μl of DMSO was added to each well. The cells were mixed and shaken, and the absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (mean OD value of the drug group / mean OD value of the solvent control group) × 100%.

[0055] Experimental results

[0056] (1) Cytotoxicity

[0057] Compounds 1 and 2 had no significant cytotoxicity to HepG2 cells at a concentration of 10 μM for 24 h, and the cell survival rate was greater than 90%. They were used in subsequent experiments at a non-toxic concentration of 10 μM.

[0058] (2) Protective effect on APAP-induced hepatocellular damage

[0059] APAP 8mM treatment of HepG2 cells for 24 hours significantly damaged the cells, with cell survival significantly reduced (65.80%) compared to the blank control group. Under the current experimental protocol, compounds 1 and 2 at a concentration of 10μM showed significant protective effects against APAP-induced HepG2 cell damage. The experimental results are shown in Table 1.

[0060] Table 1. Hepatoprotective effects of compounds 1 and 2

[0061]

[0062] *** P < 0.001 compared with the blank group; # P<0.05, ### P<0.001, compared with the APAP model group.

Claims

1. A compound and a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following group:

2. A method for preparing the compound and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The preparation method of the compound is as follows: 7-Methylbenzo[e][1,2,3]thiazine 2,2-dioxide 3 and dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 4 react in a formal [2+1] reaction under alkaline conditions to give ((1S,8bR)-6-methyl-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)(phenyl)methanone compound 1; benzo[e] [1,2,3]thiazine 2,2-dioxide 5 and (2-(2,5-dimethoxyphenyl)-2-oxoethyl)dimethylsulfonium bromide 6 undergo a formal [2+1] reaction under alkaline conditions to obtain (2,5-dimethoxyphenyl)((1S,8bR)-3,3-dioxido-1,8b-dihydroaziridinyl[1,2-c]benzo[e][1,2,3]thiazine-1-yl)methanone compound 2.

3. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound shown in claim 1 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

4. Use of the compound according to claim 1 and its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 2 in the preparation of an anti-liver injury drug or an anti-inflammatory and hepatoprotective drug.

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