CN116925095A - Phenanthrene compound and preparation method and application thereof - Google Patents

Phenanthrene compound and preparation method and application thereof Download PDF

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Publication number
CN116925095A
CN116925095A CN202310894782.7A CN202310894782A CN116925095A CN 116925095 A CN116925095 A CN 116925095A CN 202310894782 A CN202310894782 A CN 202310894782A CN 116925095 A CN116925095 A CN 116925095A
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compound
formula
reaction
carbonate
phenanthrene compound
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季光
林国强
张莉
田平
高顶顶
李清华
操颖
赵骞
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Shanghai University of Traditional Chinese Medicine
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Shanghai University of Traditional Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Abstract

The invention provides a phenanthrene compound, a preparation method and application thereof, wherein the phenanthrene compound has a structure shown in a formula 1 or a formula 2, can obviously inhibit macrophage inflammation, can generate pharmacological reaction at a concentration of 0.001 mu mol, and has a good application prospect in preparing medicaments for treating non-alcoholic fatty liver.

Description

Phenanthrene compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a phenanthrene compound, and a preparation method and application thereof.
Background
Fructus Schisandrae, also called mountain fructus Zanthoxyli, caulis et folium Piperis Kadsurae, is a perennial entwining vine of Schisandra of Magnoliaceae, and is named because its fruit has 5 flavors of sweet, sour, pungent, bitter and salty. The Shennong Ben Cao Jing (Shennong's herbal medicine) has the Chinese magnoliavine fruit listed as the top grade, and the Ming Dynasty Lizhen Zhen in Ben Cao gang mu (compendium of materia Medica): sour and salty taste enters the liver to tonify the kidney, bitter and bitter enter the heart to tonify the lung, sweet enter the middle-jiao Gong Yi spleen and stomach. The traditional Chinese medicine considers that the traditional Chinese medicine has the effects of astringing lung and nourishing kidney, promoting the production of body fluid and arresting sweating, astringing essence and checking diarrhea, calming heart and soothing the nerves and the like, can be used for treating symptoms such as lung deficiency and asthma and cough, dry mouth with little body fluid, spontaneous sweat, night sweat, spermatorrhea, fatigue and emaciation, chronic diarrhea, amnesia, insomnia and the like, and is the most prominent one of the traditional Chinese medicines. Scientists report that the dried schisandra chinensis fruit extract has a stimulating effect on the central nervous system and can strengthen psychological and physiological physique in the 50 th century. At the beginning of the 70 s of the 20 th century, chinese magnoliavine fruit is found in clinical application in China to improve liver function and clinical symptoms of hepatitis B patients.
Lignans and triterpenes are main active ingredients of schisandraceae plants, and researches show that most lignans have a basic skeleton of dibenzocyclooctene (dibenzocyclooctene) and have wide biological activities, including the effects of resisting tumors, antagonizing PAF (platelet activating factor), antagonizing calcium, resisting oxidation, inhibiting central nerves, improving memory and the like; the triterpene component has anti-HIV and anti-tumor activities. Recent researches have found that various lignans and triterpenes in schisandra plants have remarkable anti-HIV and anti-Hepatitis B Virus (HBV) effects.
The pharmacological activities of the crude extracts of schisandra chinensis and 7 main lignans are intensively studied by the pharmaceutical institute of the national academy of medical science and the Beijing synergetic medical institute, and two new drugs of biphenyl diester (DDB) and bicyclol (bicyclol) for treating chronic viral hepatitis are developed according to the structural activity rules. DDB has good liver protection effect, and bicyclol has various pharmacological effects on the liver, is a novel multifunctional and multi-target drug, has the effects of resisting hepatitis virus, liver injury, liver fibrosis, alcoholic liver injury, fatty liver and the like, has the effect of chemoprevention on liver cancer, has multi-target action mechanism on the liver, can remove free radicals to maintain stability of liver cell membranes, protects liver cell mitochondria from injury, inhibits liver cell apoptosis caused by various signal transduction pathways, but has not proved the effect on liver inflammatory cell infiltration and the expression of inflammatory cytokines ("the drug effect of schisandrin for treating non-alcoholic fatty liver disease", dong Yanmin, chen Yanan, li Meifeng and the like, in Guangdong medical science 2016,37 (03): 349-351).
The study on the intervention of the schisandrin B on the macrophages in the abdominal cavity of the mice shows that the schisandrin B has obvious down-regulation effect on inflammatory cytokines IL-6, TNF-alpha and NO in the physiological concentration of the macrophages, but the effect of the drug in the inflammatory state is not clear ("the effect of the schisandrin B on the expression of the macrophage inflammation related medium", hu Zhonglian, meng Xianghui, chinese experimental diagnostics, 2014,18 (01): 25-27.); compounds of formula (I)The effect of (structure disclosed by CN101844970 a) and its derivatives was evaluated in a state of significant elevation of macrophage inflammatory cytokines, which was found to significantly down-regulate the mRNA expression of intracellular inflammatory cytokines IL-6, TNF- α and IL-1β and the level of secretion into the supernatant, defining the anti-inflammatory effect of the compounds.
Schisandrin B has obvious effect of inhibiting liver steatosis in a simple fatty liver mouse model, but has no confirmed effect on liver inflammatory cell infiltration and inflammatory cytokine expression (the drug effect of Schisandrin B for treating nonalcoholic fatty liver disease, dong Yanmin, chen Yanan, li Meifeng, etc., guangdong medical science, 2016,37 (03): 349-351). Compounds of formula (I)(the structure is disclosed by CN 101844970A) can obviously improve liver steatosis, reduce infiltration of liver inflammatory cells and inflammatory cytokine expression in a methionine choline deficiency diet-induced nonalcoholic steatohepatitis (NASH) model and a high-fat high-sugar diet-induced NASH mouse model, and shows that the compound is shown in the specification>Is a treatment of NASHPotential drugs for therapeutic use.
On the basis of patent WO2011144054, the compoundAnd the derivative development research thereof and find that the series of compounds can obviously improve liver steatosis, reduce infiltration of liver inflammatory cells and inflammatory cytokine expression in a methionine choline deficiency diet-induced non-alcoholic steatohepatitis (NASH) model and a high-fat high-sugar diet-induced NASH mouse model, but have poor effect on improving liver steatosis and liver fat content.
Because the medicament for treating the NASH prepared in the prior art needs to have pharmacological reaction at a higher concentration, has poor effect of inhibiting the expression of inflammatory cytokines and has no obvious effect of improving the liver fat transformation and the liver fat content, the development of the phenanthrene compound with pharmacological reaction at a lower concentration and obvious effect of improving the liver fat transformation and the liver fat content is very significant as the medicament for treating the NASH.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a phenanthrene compound, a preparation method and application thereof, wherein the phenanthrene compound can be used as a NASH medicament, can generate pharmacological reaction at the concentration of 0.001 mu mol, can inhibit macrophage inflammation, and can be applied to preparing medicaments for treating non-alcoholic fatty liver.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a phenanthrene compound having a structure as shown in formula 1 or formula 2:
wherein R is 1 、R 3 Each independently hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl (e.g., C1, C2, C3, C4, C5, C6 alkyl), C1-C6 alkoxy (e.g., C1, C2, C3, C4, C5, C6 alkoxy), each independently selected from keto,Amino or amido; r is R 2 、R 4 Each independently is hydrogen, a substituted or unsubstituted C1-C6 alkyl group (e.g., which may be C1, C2, C3, C4, C5, C6 alkyl), a C1-C6 alkoxy group (e.g., which may be C1, C2, C3, C4, C5, C6 alkoxy group), and each independently is selected from keto, amino, or amido.
Preferably, said R 1 、R 3 Each independently is hydrogen, hydroxy or methoxy.
Preferably, said R 2 、R 4 Each independently is hydrogen or methoxy.
Preferably, the phenanthrene compound has a structure as shown in any one of formula 3, formula 4 or formula 5:
in a second aspect, the present invention provides a method for preparing a phenanthrene compound according to the first aspect, wherein the phenanthrene compound has a structure shown in formula 1, and R is 1 Alkoxy of hydroxy or C1-C6, R 2 Alkoxy of C1-C6, said preparation method being method A comprising:
compound 1And mixing carbonate with C1-C6 iodinated alkane to react to obtain the structure shown in the formula 1.
The phenanthrene compound has a structure shown in a formula 3, and the preparation method is a method B, comprising the following steps:
compound 1Mixing carbonate and methanesulfonic acid, and reacting to obtain the structure shown in formula 3.
Preferably, in method a, said R 1 Is hydroxyl, the molar ratio of the compound 1 to the C1-C6 iodinated alkane is 1: (1-1.5), for example, may be 1:1. 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, and specific point values between the above point values, are limited to space and for reasons ofFor simplicity, the invention is not intended to be exhaustive of the specific point values encompassed by the range. The molar ratio of the compound 1 to the carbonate is 1: (4.5-5.5), for example, may be 1:4.5, 1:4.6, 1:4.8, 1:5. 1:5.2, 1:5.4, 1:5.5, and specific point values between the above point values, are limited in space and for brevity, the present invention is not intended to exhaustively list the specific point values included in the range.
Preferably, said R 1 For C1-C6 alkoxy, the molar ratio of compound 1 to C1-C6 iodinated alkane is 1: (2.5-3.5), for example, may be 1:2.5, 1:2.7, 1:2.9, 1:3. 1:3.2, 1:3.4, 1:3.5, and specific point values between the above point values, are limited in space and for brevity, the present invention is not intended to exhaustively list the specific point values included in the range. The molar ratio of the compound 1 to the carbonate is 1: (4.5-5.5), for example, may be 1:4.5, 1:4.6, 1:4.8, 1:5. 1:5.2, 1:5.4, 1:5.5, and specific point values between the above point values, are limited in space and for brevity, the present invention is not intended to exhaustively list the specific point values included in the range.
Preferably, the carbonate comprises cesium carbonate.
Preferably, the iodinated alkane comprises any one of methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentane iodide or hexane iodide.
Preferably, in method A, the temperature of the reaction is 70-90 ℃, for example, 70 ℃, 72 ℃,4 ℃,76 ℃, 78 ℃,80 ℃, 82 ℃, 84 ℃,86 ℃, 88 ℃, 90 ℃ and specific values between the above values are not exhaustive, for reasons of space and for reasons of simplicity.
Preferably, the reaction time is 10-14h, for example, 10h, 11h, 12h, 13h, 14h, and specific point values between the above point values, and the present invention is not exhaustive of the specific point values included in the range for reasons of space and for reasons of brevity.
Preferably, the reaction is carried out in the presence of a solvent.
Preferably, the solvent comprises acetonitrile.
Preferably, in method a, the post-reaction further comprises a post-treatment.
Preferably, the post-treatment comprises filtration, concentration, purification.
Preferably, the concentrating comprises distillation under reduced pressure.
Preferably, the purification comprises purification and isolation using column chromatography.
Preferably, in reaction B, the molar ratio of compound 1 to methanesulfonic acid is 1: (0.5-1.5), for example, can be 1:0.5, 1:0.6, 1:0.8, 1:1. 1:1.2, 1:1.4, 1:1.5, and specific point values between the above point values, are limited in space and for brevity, the present invention is not intended to exhaustively list the specific point values encompassed by the described range.
Preferably, the molar ratio of compound 1 to carbonate is 1: (4.5-5.5), for example, may be 1:4.5, 1:4.8, 1:5. 1:5.3, 1:5.5, and specific point values between the above point values, are limited in space and for brevity, the present invention is not intended to exhaustively list the specific point values included in the range.
Preferably, the temperature of the reaction is from-5 to 5 ℃, for example, -5 ℃, -3 ℃, -1 ℃,0 ℃,2 ℃,4 ℃,5 ℃, and specific point values between the above point values, are limited in space and for the sake of brevity, the invention is not exhaustive of the specific point values comprised in the range.
Preferably, the reaction time is 0.5-1.5h, and may be, for example, 0.5h, 0.7h, 0.9h, 1h, 1.2h, 1.4h, 1.5h, and specific point values between the above point values, although the invention is not exhaustive of the specific point values included in the range for reasons of brevity and conciseness.
Preferably, the carbonate salt comprises sodium bicarbonate.
Preferably, the reaction is carried out in the presence of a solvent.
Preferably, the solvent comprises dichloromethane.
Preferably, in method B, the post-reaction further comprises a post-treatment.
Preferably, the post-treatment comprises washing, drying, concentrating, purifying.
Preferably, the concentrating comprises distillation under reduced pressure.
Preferably, the purification comprises purification using column chromatography.
Column chromatography purification was performed on silica gel using (petroleum ether/ethyl acetate, PE/ea=2:1 or hexane/diethyl ether=5:1) as eluent.
The preparation method of the compound 1 specifically comprises the following steps:
reacting 1 equivalent of tetraalkylammonium fluoride with Zn, chiral monophosphine ligand and nickel complex catalyst in polar organic solvent at 75-80 ℃ for 6-7 hours to obtain a product, dissolving the product in polar solvent, adding 3 equivalents of LiAlH at 0-10 DEG C 4 Slowly heating to room temperature, reacting for 1-2 hr to obtain active test sample, dissolving the coupled product with tetrahydrofuran, adding into SmI at-78-70deg.C 2 In the solution, the reaction is carried out for 4 to 5 hours, and the compound 1 is obtained by purifying and separating through column chromatography.
In a third aspect, the present invention provides an application of the phenanthrene compound according to the first aspect in preparing a medicament for treating non-alcoholic fatty liver disease.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a phenanthrene compound which can obviously inhibit macrophage inflammation, can generate pharmacological reaction at the concentration of 0.001 mu mol and has better prospect in preparing medicaments for treating non-alcoholic fatty liver.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the structure shown in formula 1-1 prepared in preparation example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of the structure represented by formula 1-1 prepared in preparation example 1.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The instrument types and manufacturers used in the examples are shown in Table 1:
TABLE 1
Preparation example 1
The preparation example provides a compound with a structure shown as a formula 1-1;
the preparation method comprises the following steps:
freshly prepared samarium diiodide (0.5 mmol) in THF (3 mL) was cooled to-78 ℃ under nitrogen, 0.1mmol of diaryl dialdehyde was dissolved in 1.0mL of THF and slowly added dropwise to the solution, the reaction typically being completed within 15 minutes. The reaction mixture was taken up in 2mL of saturated Na 2 S 2 O 3 Quenching with water solution, extracting with ethyl acetate, purifying by column chromatography to obtain compound of formula 1-1 with 95% yield, nuclear magnetic resonance spectrum shown in figure 1, nuclear magnetic resonance spectrum shown in figure 2, 1 H NMR(600MHz,CDCl 3 )δ6.88(s,2H),6.07(d,J＝1.5Hz,2H),5.99(d,J＝1.5Hz,2H),4.50–4.50(m,2H),3.95(s,6H)；13C NMR(151MHz,CDCl3)δ145.0,143.0,135.5,130.6,105.5,104.8,101.5,73.8,56.6,40.9.；ESI-LRMS[M+H] + theoretical value C 18 H 16 NaO 8 383.0737, experimental value 383.0746, the structure shown in formula 1-1.
Example 1
The embodiment provides a phenanthrene compound, which has a structure shown in a formula 5, and the preparation method of the phenanthrene compound comprises the following steps:
under nitrogen, the compound (33 mg,0.09mmol, obtained in preparation 1), methyl iodide (MeI, 15mg,0.11mmol,1.2 eq.) and cesium carbonate (Cs 2 CO 3 150mg,0.45mmol,5.0 equiv.) and 4mL of acetonitrile are added to a 10mL dry sealed tube with a magnetic stirrer bar. The mixture was stirred at 80℃for 12h. The mixed solution was filtered through celite. The filtrate was concentrated by distillation under reduced pressure, and purified by column chromatography on silica gel using (petroleum ether/ethyl acetate, PE/ea=2:1) as eluent to give the product as a colorless oil having a structure shown in formula 5, 7.2mg, yield 21%. The nuclear magnetic spectrum was tested using Bruker nuclear magnetism, 1 H NMR(600MHz,CDCl 3 )δ6.79(s,1H),6.66(s,1H),6.04–6.01(m,4H),4.62–4.60(m,1H),4.15(d,J＝6.9Hz,1H),3.96(s,3H),3.94(s,3H),3.52(s,3H),2.35(s,1H).； 13 C NMR(151MHz,CDCl 3 ) Delta 152.1,151.8,146.5,134.4,134.1,133.9,130.7,122.4,122.1,104.0,103.7,101.8,86.0,80.6,57.0,56.1, which shows that the phenanthrene compound is a structure shown in formula 5.
Example 2
The embodiment provides a phenanthrene compound, which has a structure shown as a formula 4, and the preparation method of the phenanthrene compound comprises the following steps:
under nitrogen, the compound (44 mg,0.12mmol, obtained in preparation 1), methyl iodide (MeI, 50mg,0.36mmol,3.0 equiv), cesium carbonate (Cs) 2 CO 3 200mg,0.6mmol,5.0 equiv) and 4mL acetonitrile solution were added to a 10mL dry sealed tube with a magnetic stir bar. The mixture was stirred at 80℃for 12h. The mixed solution was filtered through celite. The filtrate was concentrated by distillation under reduced pressure, and purified by column chromatography on silica gel using (petroleum ether/ethyl acetate, PE/ea=2:1) as eluent to give the structural product represented by formula 4 as a colorless oil, 9.2mg, yield 20%. The nuclear magnetic spectrum was tested using Bruker nuclear magnetism, 1 H NMR(600MHz,CDCl 3 )δ6.60(s,2H),6.09(s,2H),5.99(s,2H),4.23(s,2H),3.96(s,6H),3.35(s,6H).； 13 C NMR(dept135,151MHz,CDCl 3 ) Delta 110.4,101.5,80.3,60.4,56.9,56.7,21.1,14.2, which shows that the phenanthrene compound is the structure shown in formula 4.
Example 3
The embodiment provides a phenanthrene compound, which has a structure shown as a formula 3, and the preparation method of the phenanthrene compound comprises the following steps:
methanesulfonic acid (10 mg,0.1 mmol,1.0 equiv.) was added dropwise to a dichloromethane (5 mL) solution of the compound (36 mg,0.1 mmol,1.0 equiv. Obtained in preparation 1) under nitrogen protection at 0deg.C. After stirring for 1 hour, 0.5mL of sodium bicarbonate (2.0M) solution was added, the organic phase was separated and washed with brine (5 mL), na 2 SO 4 Drying and concentrating under reduced pressure to obtain colorless oily substance; purification by silica gel column chromatography (hexane/diethyl ether=5/1, rf about 0.3) gave the product (26 mg,76% yield). The nuclear magnetic spectrum was tested using Bruker nuclear magnetism, 1 h NMR (600 MHz, deuterated acetone) δ9.04 (s, 1H), 7.53 (d, j=1.8 hz, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 6.16 (s, 2H), 6.08 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H) 13C NMR (150 MHz, deuterated acetone) δ 150.06,145.29,144.87,144.74,144.62,136.54,133.98,130.83,123.34,109.87,105.56,105.45,104.65,103.44,101.89,101.43,99.98,56.34. ESI-LRMS [ M+H ] using Agilent 1260 mass spectrometry] + Theoretical value C 18 H 14 O 7 342.3030, experimental value 343.0500, and shows that the phenanthrene compound is obtained as shown in formula 3.
Example 4
Comparative example 1
This comparative example provides a structure represented by the formula 1-1, i.e., the compound obtained in preparation example 1.
Comparative example 2
This comparative example provides a structure as shown in formulas 1-2, prepared in the same manner as CN101844970A.
Application example 1
The present application example aims at examining the anti-inflammatory effect of the phenanthrene compound of example 1-3 in the structure of formula 3-5 and the structures of comparative example 1-2 in the structures of formula 1-1 and formula 1-2.
The analysis results showed that endotoxin (LPS, 100 ng/mL) stimulated the mouse macrophage cell line Raw264.7 for 12h, combined with formula 1-2 (L-307, 50. Mu.M, 100. Mu.M), formula 1-1 (R-307,50. Mu.M, 100. Mu.M), formula 3 (0.001. Mu.M, 0.01. Mu.M, 0.1. Mu.M, 5. Mu.M, 20. Mu.M), formula 5 (0.001. Mu.M, 0.01. Mu.M, 0.1. Mu.M, 5. Mu.M, 20. Mu.M), formula (0.001. Mu.M, 0.01. Mu.M, 0.1. Mu.M, 5. Mu.M, 20. Mu.M) intervention, different concentrations of phenanthrene compound(s) intervention the inflammatory factor level of supernatant after Raw264.7 cellsn=3) as shown in table 2, cell mRNA levels after intervention of phenanthrene compounds at different concentrations into raw264.7 cells: the normal group was a conventional cultured mouse macrophage cell line Raw264.7 cell, the model control group stimulated Raw264.7 cell with endotoxin (LPS, 100 ng/mL) for 12h, and the model control group interfered with the model control group in combination with the model control groups of formulas 1-2 (L-307, 100. Mu.M, 50. Mu.M), formulas 1-1 (R-307,100. Mu.M, 50. Mu.M), formulas 3 (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.1. Mu.M, 0.001. Mu.M), formulas 5 (20. Mu.M, 10. Mu.M, 1. Mu.M, 0.01. Mu.M, 0.001. Mu.M), and formulas 4 (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.1. Mu.M, 0.01. Mu.M, 0.001. Mu.M), qRT-PCR detection of intracellular IL-6, IL-1β and TNF α mRNA expression levels, ELISA and qRT-PCR detection of inflammatory factors IL-6, IL-1β and TNF α content in cell supernatant and intracellular mRNA expression levels, respectively, with different concentrations of phenanthrene compounds interfering with Raw264.7 relative amounts of cytokine mRNA expression (>n=3) as shown in table 3, the supernatant inflammatory factor content after intervention of different concentrations of phenanthrene compound into raw264.7 cells: normal group is normal cultured mouse macrophage line Raw264.7 cell, model control groupStimulation of Raw264.7 cells with endotoxin (LPS, 100 ng/mL) for 12h combined with intervention of formulas 1-2 (L-307, 100. Mu.M, 50. Mu.M), formulas 1-1 (R-307,100. Mu.M, 50. Mu.M), formula 3 (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.01. Mu.M, 0.001. Mu.M), formula 5 (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.1. Mu.M, 0.001. Mu.M), formula 4 (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.1. Mu.M, 0.01. Mu.M), and TNF-. Alpha.) showed that the results of both formulas 1-1, 1-2 and 3, 4 and 5 significantly inhibited macrophage inflammation, and that the ELISA reactions were shown to occur at 0.001. Mu.mol concentrations.
TABLE 2
TABLE 3 Table 3
The phenanthrene compound provided by the invention can inhibit macrophage inflammation, can generate pharmacological reaction at the concentration of 0.001 mu M, and has good application prospect in preparing NASH medicaments. For an obese NASH mouse model, the phenanthrene compound provided by the invention can reduce infiltration of liver inflammatory cells, lower the levels of serum liver enzymes ALT and AST, lower the levels of serum inflammatory factors IL-1 beta and IL-6, and has an obvious improvement effect on symptoms of FPC diet-induced NASH mice.
The applicant states that the present invention is illustrated by the above examples as well as a preparation method and application thereof, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

Claims (10)

1. The phenanthrene compound is characterized by having a structure shown in formula 1 or formula 2:
wherein R is 1 、R 3 Each independently hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, each independently selected from keto, amino, or amido; r is R 2 、R 4 Each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, each independently selected from keto, amino, or amido.
2. Phenanthrene compound according to claim 1, wherein R 1 、R 3 Each independently is hydrogen, hydroxy or methoxy;
preferably, said R 2 、R 4 Each independently is hydrogen or methoxy.
3. The phenanthrene compound according to claim 1 or 2, wherein the phenanthrene compound has a structure as shown in any one of formula 3, formula 4 or formula 5:
4. a method for preparing a phenanthrene compound according to any one of claims 1 to 3, wherein the phenanthrene compound has a structure as shown in formula 1, and R is 1 Alkoxy of hydroxy or C1-C6, R 2 Alkoxy of C1-C6, said preparation method being method A comprising:
compound 1Mixing carbonate and C1-C6 iodinated alkane, and reacting to obtain a structure shown in formula 1;
the phenanthrene compound has a structure shown in a formula 3, and the preparation method is a method B, comprising the following steps:
compound 1Mixing carbonate and methanesulfonic acid, and reacting to obtain the structure shown in formula 3.
5. The process of claim 4, wherein in process A, R is 1 As hydroxyl groups, the molar ratio of compound 1 to C1-C6 iodinated alkane is 1: (1-1.5), the molar ratio of compound 1 to carbonate being 1: (4.5-5.5);
preferably, said R 1 For C1-C6 alkoxy, the molar ratio of compound 1 to C1-C6 iodinated alkane is 1: (2.5-3.5), the molar ratio of compound 1 to carbonate is 1: (4.5-5.5);
preferably, the carbonate comprises cesium carbonate;
preferably, the C1-C6 iodinated alkane comprises any one of methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentane iodide or hexane iodide.
6. The process according to claim 4 or 5, wherein in process a, the temperature of the reaction is 70-90 ℃;
preferably, the reaction time is 10-14 hours;
preferably, the reaction is carried out in the presence of a solvent;
preferably, the solvent comprises acetonitrile.
7. The process according to any one of claims 4 to 6, wherein in process a, the post-reaction further comprises a post-treatment;
preferably, the post-treatment comprises filtration, concentration, purification;
preferably, the concentrating comprises distillation under reduced pressure;
preferably, the purification comprises purification and isolation using column chromatography.
8. The process according to any one of claims 4 to 7, wherein in reaction B, the molar ratio of compound 1 to methanesulfonic acid is 1: (0.5-1.5);
preferably, the molar ratio of compound 1 to carbonate is 1: (4.5-5.5);
preferably, the temperature of the reaction is from-5 to 5 ℃;
preferably, the reaction time is 0.5-1.5h;
preferably, the carbonate comprises sodium bicarbonate;
preferably, the reaction is carried out in the presence of a solvent;
preferably, the solvent comprises dichloromethane.
9. The process according to any one of claims 4 to 8, wherein in process B, the post-reaction further comprises a post-treatment;
preferably, the post-treatment comprises washing, drying, concentrating, purifying;
preferably, the concentrating comprises distillation under reduced pressure;
preferably, the purification comprises purification using column chromatography.
10. Use of a phenanthrene compound according to any one of claims 1-3 in the preparation of a medicament for treating non-alcoholic fatty liver disease.
CN202310894782.7A 2023-07-20 2023-07-20 Phenanthrene compound and preparation method and application thereof Pending CN116925095A (en)

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