CN102391332A - Liver protecting compound and preparation method and use thereof - Google Patents
Liver protecting compound and preparation method and use thereof Download PDFInfo
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Abstract
The invention belongs to a liver protecting compound and a preparation method and use thereof, relating to the technical field of medicines. The preparation method comprises the following steps of: using (3R, 4S)-dihydroxy butyrolactone as a starting material, connecting substituent aralkyl through protection and deprotection nucleophilic substitution, then using lithium hexamethyldisilazide (LHMDS) to pull hydrogen, connecting one substituent aralkyl at the alpha position of carbonyl, further connecting D-glucosyl through trimethylsilyl trifluoromethanesulfonate (TMSOTf) glycosidation and finally conducting deprotection to obtain the liver protecting compound. The preparation method is simple and feasible and has a good repeatability. The compound provided by the invention has activities of suppressing the secretion and the reproduction of hepatitis B virus desoxyribonucleic acid, eliminating superoxide radicals, suppressing the generation of radical-induced lipid peroxide and protecting liver cells against rat in-vivo and in-vitro chemical-induced liver damages, and can be used for preparing drugs for preventing and curing virus B hepatitis, liver protecting drugs and healthcare products.
Description
Technical field:
The invention belongs to medical technical field, relate to hepatic anoectochilus roxburghii glycosides verivate, analogue, be specifically related to anoectochilus roxburghii glycosides verivate, analogue and preparation method thereof and its application in diseases such as treatment hepatitis B and hyperlipidemia.
Background technology:
Hepatitis B is caused, is served as main and can cause a kind of transmissible disease of multiple organ injury with the liver inflammatory lesion by hepatitis B virus (HBV).This disease is widely current in countries in the world, mainly invades children and person between twenty and fifty, and small number of patients can be converted into liver cirrhosis or liver cancer.Therefore, it has become the worldwide disease of serious threat human health, also is a kind of transmissible disease that China's current popular is the most extensive, hazardness is the most serious.Hepatitis B does not have certain popular phase, all can fall ill throughout the year, but distributes belong to more.The hepatitis B sickness rate is and obviously increases trend in recent years.A kind of worldwide disease.Developing country's sickness rate is high, and according to statistics, the asymptomatic hepatitis B virus carriers in the whole world (HBsAg carrier) surpasses 2.8 hundred million, and China accounts for 1.3 hundred million.Most asymptomatic, wherein 1/3 hepatic injury appears and clinical manifestation.There is hepatitis B patient 3,000 ten thousand in China at present.The characteristics of hepatitis B are that onset is more slow, and are more common with subclinical type and chronic type.Non-icteric type HBsAg lasting masculin person is prone to chronicity.This disease mainly contacts with property through blood, mother and baby and propagates.
Herba Anoectochili roxburghii (Herba Anoectochili) is opened the dry herb that lip epidendrum floral leaf opens lip orchid (Anoectochilus roxburghii) for the orchid family, is perennial rare herbal medicine.All there is its abundant herb resource in provinces such as Guangxi, China south, Guangdong, Hainan, Guizhou, Sichuan, Yunnan, and medication among the people is wider.Herba Anoectochili roxburghii is in laudatory titles such as among the people have " gold grass ", " refreshing medicine ", " black gensengs ", and in Zhejiang, the place of production of Fujian one band, its bright careless price is up to 360～500 yuan/kilogram.Herba Anoectochili roxburghii is popular in Taiwan fully, and among the people being referred to as " king of medicine " is used to treat difficult and complicated illness such as mellitus, hypertension, tumour.We are under the subsidy of state natural sciences fund (NSFC30400585) and State Administration of Traditional Chinese Medicine's traditional Chinese medicine research special fund (04-05ZQ03); Under the guidance of hypoglycemic activity; The hypoglycemic activeconstituents of Herba Anoectochili roxburghii has been carried out systematic research; Be separated to main active ingredient kinsenoside (4 (R)-β-D-Glucopyranose oxygen base-butyric acid (γ) lactone are called " anoectochilus roxburghii glycosides " in this patent).
Anoectochilus roxburghii glycosides
Summary of the invention:
We have carried out liver-protecting activity research to anoectochilus roxburghii glycosides; And design in view of the above and prepared the brand-new compound of a class formation, and it is caused rat hepatocytes damage body inner model and external model, rat primary hepatocyte injury protection activity, the ultra oxyradical of external removing, suppresses activity that the lipoperoxide of free yl induction generates, suppresses human body hepatitis B virus thymus nucleic acid HBVDNA activity and study tetracol phenixin.The present invention relates to the anoectochilus roxburghii glycosides analog derivative of one type of brand new; It has the activity that suppresses hepatitis B virus thymus nucleic acid secretion and replication activity, removing superoxide radical activity, suppresses the lipoperoxide generation of free yl induction; It is active that rat inside and outside chemistry is caused liver injury tool hepatocyte protection, can be used for preparation and prevent and treat hepatitis B medicine, liver protecting medicine and healthcare products.
Task of the present invention provides a kind of compound that protects the liver.
Realize that technical scheme of the present invention is:
This compound provided by the invention has with structure shown in the following formula (III):
Wherein
R
1, R
2, R
3, R4 and R5 can be identical or different, can be respectively, simultaneously or the alkoxyl group or the amino of the hydrogen of respectively doing for oneself, the alkyl that contains 1-8 carbon, halogen, nitro, a 1-8 carbon;
R
6, R
7, R
8, R
9And R
10Can be identical or different, can be respectively, simultaneously or the alkoxyl group or the amino of the hydrogen of respectively doing for oneself, the alkyl that contains 1-8 carbon, halogen, nitro, a 1-8 carbon;
M and n are the number of methylene radical, can be 1-4, can be identical or different.
Formula (III) compound can be optically pure compound, also can be the not purified mixture with same plane configuration.
The method for preparing compound according to the invention: be with (3R; 4S)-and dihydroxyl GBL (compound 1) is a starting raw material, connects substituted aralkyl through protection deprotection nucleophilic substitution, take off with LHMDS then and pull out hydrogen; Connect another substituted aralkyl at the carbonyl alpha position; Further connect the D-glucone with the TMSOTf glycosidation, last deprotection makes formula provided by the invention (III) compound, and its synthetic route is following:
This preparation method is simple, favorable reproducibility.Compound provided by the invention has the activity that suppresses hepatitis B virus thymus nucleic acid secretion and replication activity, removing superoxide radical activity, suppresses the lipoperoxide generation of free yl induction; It is active that rat inside and outside chemistry is caused liver injury tool hepatocyte protection, can be used for preparation and prevent and treat hepatitis B medicine, liver protecting medicine and healthcare products.
Description of drawings
Fig. 1: the structure iron with compound of hepatoprotective effect provided by the invention.
Embodiment
Embodiment 1: (4R, 5S)-preparation of 4-hydroxyl-5-(((4-methoxy-benzyl) oxygen) methyl) dihydrofuran--2 (3H)-ketone (I-1)
0.5g compound 1 is dissolved in the acetonitrile of 10ml, adds 0.75g to methoxy benzyl bromine, after the stirring and dissolving, adds the 0.8g triethylamine again, reflux 3-4 hour.After detection reaction is complete, adds 2N hydrochloric acid and regulate pH to 7, concentrate and remove acetonitrile, use ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, the silicagel column purifying gets white solid 0.98g.
1H?NMR(400MHz，CDCl
3)δ7.28-7.14(m，2H)，6.96-6.82(m，2H)，4.62-4.60(m，2H)，4.54-4.52(m，2H)，3.79(s，3H)，3.89-3.70(dd，2H)，2.63-2.57(dd，2H)
Embodiment 2: (4R, 5S)-preparation of 4-hydroxyl-5-(((3, the 4-dimethoxy-benzyl) oxygen) methyl) dihydrofuran--2 (3H)-ketone (I-2)
1H?NMR(400MHz，CDCl
3)δ6.95(s，1H)，6.81(d，J＝2.8Hz，2H)，4.61(m，2H)，4.59-4.57(m，2H)，3.89-3.70(d，2H)，3.85(d，6H)，3.10(m，1H)，2.63-2.57(dd，2H)
Embodiment 3:4-(((2S, 3R)-3-hydroxyl-5-oxygen THF-2-yl) methoxyl group)-1, the preparation of 2-diethylamino phenyl acid esters (I-3)
1H?NMR(400MHz，CDCl
3)δ7.34(m，1H)，7.24(m，1H)，7.11(m，1H)，4.74-4.72(dd，2H)，4.62-4.60(m，2H)，3.89-3.70(md，2H)，2.63-2.57(dd，2H)，2.27(s，3H)，2.22(s，3H)
Embodiment 4: (4R, 5S)-preparation of 4-hydroxyl-5-(((3,4,5-trimethoxy benzyl) oxygen) methyl) dihydrofuran--2 (3H)-ketone (I-4)
1H?NMR(500MHz，Chloroform)δ6.03(s，2H)，4.65-4.60(m，5H)，3.89-3.70(dd，2H)，3.84(s，6H)，3.81(s，3H)，2.63-2.57(dd，2H)
Embodiment 5: (4R; 5S)-4-hydroxyl-5-((benzene [d] [1; The preparation of dihydrofuran--2 (3H)-ketone (I-5) methyl 3] dioxy-5-base oxethyl)) (4R, 5S)-5-((benzo [d] [1,3] dioxol-5-ylmethoxy) methyl)-4-hydroxydihydrofuran-2 (3H)-one
1H?NMR(400MHz，CDCl
3)δ6.84(s，1H)，6.84-6.79(dd，2H)，5.93(s，2H)，4.65(m，1H)，4.60(m，1H)，3.87(m，2H)，3.87-3.80(m，2H)，3.10(m，1H)，2.86(m，2H)，2.63-2.57(dd，2H)
Embodiment 6: (4R, 5S)-preparation of 4-hydroxyl-5-((benzene [d] [1,3] dioxy-5-ylmethoxy) methyl) dihydrofuran--2 (3H)-ketone (I-6)
1H?NMR(400MHz，CDCl
3)δ7.01(s，1H)，6.87-6.83(dd，2H)，5.92(s，2H)，4.62-4.57(m，4H)，3.89-3.70(d，2H)，3.10(m，1H)，2.63-2.57(dd，2H)
Embodiment 7:4-(((4R, 5S)-4-hydroxyl-5-(((4-methoxybenzyl) oxygen) methyl)-2-oxygen THF-3-yl) methyl) phenylacetic acid ester (II-1)
1g compound I-1 is joined in the 10mL THF, be cooled to-20 ℃, keep temperature to add 20mL LHMDS solution, stirred 20 minutes, keep temperature again, add 1.2g, reacted 3-4 hour acetyl oxygen bromotoluene.After reaction finished, with the cancellation of 2N hydrochloric acid, with acetate acetic acid extraction three times, merging organic phase, drying reduced pressure and removes organic solvent, gets white solid 1.2g with chromatography column purifying gained mixture.
1H?NMR(400MHz，CDCl
3)δ7.53(m，2H)，7.23(m，2H)，6.95(m，2H)，6.87(m，2H)，4.68(m，1H)，4.54-4.52(d，2H)，4.20(m，1H)，3.89-3.87(dd，2H)，3.79(s，3H)，3.22(m，1H)，2.99-2.80(d，2H)，2.27(s，3H)
Embodiment 8:4-(((4R, 5S)-4-hydroxyl-5-(((3, the 4-veratryl) oxygen) methyl)-2-oxygen THF-3-yl) methyl) phenylacetic acid ester (II-2)
1H?NMR(400MHz，CDCl
3)δ7.53(m，2H)，6.95(m，3H)，6.80(m，2H)，4.68(m，1H)，4.59-4.57(d，2H)，4.20(m，1H)，3.89-3.87(dd，2H)，3.85(d，6H)，3.22(m，1H)，2.99-2.80(d，2H)，2.27(s，3H)
Embodiment 9:4-(((2S, 3R)-4-(4-acetyl oxygen benzyl)-3-hydroxyl-5-oxygen THF-2-yl) methoxyl group)-1, the preparation of 2-diethylamino phenyl acid esters (II-3)
1H?NMR(400MHz，CDCl
3)δ7.53(m，2H)，7.34(s，1H)，7.24(m，1H)，7.11(d，1H)，6.95(m，2H)，4.74-4.72(dd，2H)，4.68(m，1H)，4.20(m，1H)，3.89-3.87(dd，2H)，3.22(m，1H)，2.99-2.80(d，2H)，2.27(d，6H)，2.22(s，3H)
Embodiment 10:4-(((4R, 5S)-4-hydroxyl-5-(((3,4,5-trimethoxy benzyl) oxygen) methyl)-2-oxygen THF-3-yl) methyl) phenylacetic acid ester (II-4)
1H?NMR(400MHz，CDCl
3)δ7.53(d，2H)，6.95(d，2H)，6.03(s，2H)，4.68(m，1H)，4.65-4.63(d，2H)，4.20(m，1H)，3.89-3.87(dd，2H)，3.84(s，6H)，3.81(s，3H)，3.22(m，1H)，2.99-2.80(d，2H)，2.27(s，3H)
Embodiment 11:4-(the preparation of ((4R, 5S)-5 ((benzene [d] [1,3] dioxy-5-methoxyl group) methyl)-4-hydroxyl-2-oxygen THF-3-yl) methyl) phenylacetic acid ester (II-5)
1H?NMR(400MHz，CDCl
3)δ7.53(d，2H)，6.95(d，1H)，6.84(m，2H)，6.79(d，1H)，5.93(s，2H)，4.71(m，1H)，4.20(m，1H)，3.87(t，2H)，3.86-3.80(dd，2H)，3.22(m，1H)，2.99-2.80(dd，2H)，2.86(t，2H)，2.27(s，3H)
Embodiment 12:4-(the preparation of ((4R, 5S)-5 ((benzene [d] [1,3] dioxy-5-methoxyl group) methyl)-4-hydroxyl-2-oxygen THF-3-yl) methyl) phenylacetic acid ester (II-6)
1H?NMR(400MHz，CDCl
3)δ7.53(d，2H)，7.01(s，1H)，6.95(d，2H)，6.87-6.83(dd，2H)，5.92(s，2H)，4.68(m，1H)，4.59-4.57(d，2H)，4.20(m，1H)，3.89-3.87(dd，2H)，3.22(m，1H)，2.99-2.80(dd，2H)，2.27(s，3H)
Embodiment 13: (4R, 5S)-preparation of 4-D-glucone-5-(((4-methoxy-benzyl) oxygen) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-1)
Compound 1g II-1 is added in the 10mL anhydrous acetonitrile, and stirring and dissolving adds 0.8g4A molecular sieve and tetra-acetylated glucose three chlorimide ester 1.5g, is cooled to-40 ℃, is added dropwise to 0.2mL TMSOTf, keeps thermotonus 3-4 hour.After reacting completely, add 1mL triethylamine cancellation reaction, column chromatography obtains the glycosidation product.The glycosidation product is sloughed protection with the methanol solution of salt of wormwood, and with the neutralization of positively charged ion resin, column chromatography obtains white solid compound III-10.45g.
1H?NMR(400MHz，CDCl
3)δ7.23(d，2H)，7.11(d，2H)，6.87(d，2H)，6.78(d，2H)，4.97(d，1H)，4.60(m，1H)，4.54-4.52(dd，2H)，4.40(m，1H)，4.11-3.96(m，2H)，3.88-3.86(m，3H)，3.79(s，3H)，3.77(m，1H)，3.72(m，1H)，3.61(m，1H)，3.15(m，1H)，2.98-2.79(d，2H)
Embodiment 14: (4R, 5S)-preparation of 4-D-glucone-5-(((3, the 4-dimethoxy-benzyl) oxygen) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-2)
1H?NMR(400MHz，CDCl
3)δ7.11(m，2H)，6.95(m，1H)，6.81-6.78(m，4H)，4.97(d，1H)，4.60-4.57(m，3H)，4.40(m，1H)，4.11-3.96(dd，2H)，3.88-3.86(m，3H)，3.85(d，6H)，3.77(m，1H)，3.72(m，1H)，3.61(m，1H)，3.22(m，1H)，3.15(m，1H)，2.98-2.79(d，2H)
Embodiment 15: (4R, 5S)-preparation of 4-D-glucone-5-(((3, the 4-dihydroxy benzyl) oxygen) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-3)
1H?NMR(400MHz，CDCl
3)δ7.57(m，2H)，7.34(s，1H)，7.24(m，1H)，7.11(d，1H)，6.99(m，2H)，4.97(d，1H)，4.74-4.72(dd，2H)，4.60(m，1H)，4.40(m，1H)，4.11-3.96(m，2H)，3.88-3.86(dd，2H)，3.87(m，1H)，3.72(m，1H)，3.61(m，1H)，3.17(m，1H)，2.98-2.79(d，2H)
Embodiment 16: (4R, 5S)-preparation of 4-D-glucone-5-(((3,4,5-trimethoxy benzyl) oxygen) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-4)
1H?NMR(400MHz，CDCl
3)δ7.11(d，2H)，6.78(d，1H)，6.03(s，2H)，4.97(d，1H)，4.65-4.60(m，3H)，4.40(m，1H)，4.11-3.96(dd，2H)，3.88-3.86(m，3H)，3.84(s，6H)，3.81(s，3H)，3.77(m，1H)，3.72(m，1H)，3.61(m，1H)，3.15(m，1H)，2.98-2.79(d，2H)
Embodiment 17: (4R, 5S)-preparation of 4-D-glucone-5-((benzene [d] [1,3] dioxy-5-oxyethyl group) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-5)
1H?NMR(400MHz，CDCl
3)δ7.11(d，2H)，6.84(m，2H)，6.79-6.78(m，3H)，5.93(s，2H)，4.97(d，1H)，4.64(m，1H)，4.40(m，1H)，4.11-3.96(dd，2H)，3.87-3.85(m，4H)，3.77(m，1H)，3.72(m，1H)，3.61(m，1H)，3.15(m，1H)，2.98-2.79(d，2H)
Embodiment 18: (4R, 5S)-preparation of 4-D-glucone-5-((benzene [d] [1,3] dioxy-5-methoxyl group) methyl)-3-(4-hydroxybenzyl) dihydrofuran--2 (3H)-ketone (III-6)
1H?NMR(400MHz，CDCl
3)δ7.11(d，2H)，7.01(s，1H)，6.87-6.83(dd，2H)，6.78(d，2H)，5.92(s，2H)，4.97(d，1H)，4.60(m，1H)，4.59-4.57(m，2H)，4.40(m，1H)，4.11-3.96(dd，2H)，3.88-3.86(m，3H)，3.77(m，1H)，3.72(m，1H)，3.61(m，1H)，3.15(m，1H)，2.98-2.79(d，2H)
Embodiment 19: the protection of compound III-6 pair chmice acute carbon tetrachloride hepatic injury (liver injury model in the animal body) is active
The ICR mouse, complete male, 48.Be divided into normal group, model group, positive group, high, medium and low dosed administration group.Method intragastrically, mouse gave in advance in continuous 7 days III-6 (25,50,100mgkg
-1), the 7th Nikkei abdominal cavity single injection tetracol phenixin (CCL
4, 1mLkg
-1) bring out chemical damage.Measure serum transaminase (ALT, AST) level behind the 24h, oxidative stress medium mda (MDA) content, and hepatomicrosome superoxide-dismutase (SOD) activity.Observe the variation of liver organization pathology and hepatic necrosis scoring and rats death rate simultaneously.
The influence of table 1 compound III-6 couple chmice acute carbon tetrachloride hepatic injury ALT, AST, MDA and SOD
Experiment conclusion:
1. biochemical indicator (AST and ALT) detected result shows that all it is successful that tetracol phenixin causes the modeling of chmice acute liver injury model.
2. serum AST and ALT detected result show: reagent III-6 and positive drug can obviously reduce liver injury mice serum AST and ALT level under test dose; Wherein reagent height and middle dose groups can significantly reduce liver injury.
3. the pharmacology histology shows, reagent and positive drug group liver color do not have considerable change, and quality is soft, and the tissues observed cytopathy is lighter under the light microscopic, near normal liver tissue.Compound III-6 couple CCl
4The hepatocellular injury that causes mouse chemical damage model has the protection activity, and belonging to has certain active liver protecting compound.
Embodiment 20: compound III-6 pair tetracol phenixin causes the protection activity of the hepatocellular injury of rat primary hepatocyte damage body external model.
The normal rat primary hepatocyte cultivated 12 as a child, added the CCl of 8mmol/L
4Act on after 6 hours, add respectively the basic, normal, high dose groups of compound III-6 (25,50,100mgkg
-1) the test soup, establish solvent control group simultaneously.Continued to cultivate 48 as a child, centrifugal collection supernatant, MDA content in ALT level and the liver cell in the mensuration supernatant.
Table 2 compound III-6 pair tetracol phenixin causes the influence of rat primary hepatocyte damage ALT and MDA
| Group (n) | ALT(u·L -1) | MDA(nmol·mg -1) |
| Normal group (10) | 14.78±0.45 | 13.41±0.48 |
| Model group | 1502.21±37.4 | 257.48±3.74 |
| The positive drug group | 136.5±12.4 | 0.52±0.07 |
| III-6 is low | 1264.40±21.47 | 157.24±3.12 |
| Among the III-6 | 412.28±4.12 | 66.51±2.17 |
| III-6 is high | 61.45±3.15 | 0.47±0.14 |
Experiment conclusion: compound III-6 pair tetracol phenixin causes the hepatocellular injury protection activity of rat stem cell injuries external model, and belonging to has certain active liver protecting compound.
Embodiment 21: the restraining effect of compound III-6 pair hepatitis B virus thymus nucleic acid (HBV-DNA)
The HepG cell strain is inoculated in the DMEM nutrient solution, changes after 24 hours and contain the high, medium and low dose groups nutrient solution of reagent, continue to cultivate 24 hours, leave and take culture supernatant and prestore to be checked in-20 ℃.With under the similarity condition not the nutrient solution cultured cells of drug as positive control, use the same method and measure its restraining effect with lamivudine as contrast HBV.
The inhibiting rate (%) of table 3 compound III-6 pair HepG hepatitis B virus thymus nucleic acid (HBV-DNA) and the inhibiting rate (%) of the 12nd day cell growth
Experiment conclusion: it is active that the 4th day, the 8th day and the 12 day compound III-6 couple HBV-DNA all demonstrate certain inhibition, but than a little less than the inhibition activity of positive control drug lamivudine to HBV-DNA, belonging to has certain active HBV-DNA suppressor factor.
Embodiment 22: compound III-6LD
50Mensuration
Compound III-6LD
50Mensuration: 12 of regular grade kunming mices, 20 ± 2g, male and female half and half, flexibility are fed back fasting 12 hours, are assigned to the oral acute toxicity that high dose group is investigated III-6 immediately, every group of male and female half and half.Irritate stomach, observe the diet of animal in the week, activity, situation such as Mao Ze and living or death.Animal appearance and behavior are acted normally behind the gastric infusion, do not have any toxic reaction, and none is poisoned to death.The result does not have any toxic reaction when being illustrated in 40 times of effective reference dose, thinks that compound III-6 toxicity rank is very low or nontoxic, and oral safety no longer improves dosage and does toxicity test.
Therefore, compound III-6 toxicity rank is very low or nontoxic, oral safety.
Embodiment 23: compound III-6 tablet prepn and method
Main medicinal raw material comprises: active substance III-6, the thinner of medicinal tablets, tablet binder and disintegrating agent, lubricant.Thinner can be selected one or more in Microcrystalline Cellulose, starch, Sodium Hydroxymethyl Stalcs, the glycosides propylhomoserin; Tackiness agent can be selected a kind of in starch slurry, PVP rubber cement, the gelatine size; A kind of in the selectable talcum powder of lubricant, the Magnesium Stearate.Tablet stability is good, and the patient can be by doctor's advice, medicine is taken home taken, and guarantees the persistence of treatment.
Get III-65g, starch 35g, Microcrystalline Cellulose 35g, Sodium Hydroxymethyl Stalcs 6g; Glycocoll 20g is porphyrize respectively, crosses 80 mesh sieves, and the addition of equivalent mixes, and processes softwood with starch slurry (5%); Granulate with the filter of 30 mesh sieves, put drying under 70 ℃ of conditions, add Magnesium Stearate 0.3g with the whole grain of 40 mesh sieves filter back again, mix; Compressing tablet, packing promptly gets.
Claims (9)
1. the compound or its pharmaceutically useful salt that have structure shown in the formula (III),
Wherein
R
1, R
2, R
3, R4 and R5 can be identical or different, can be respectively, simultaneously or the alkoxyl group or the amino of the hydrogen of respectively doing for oneself, the alkyl that contains 1-8 carbon, halogen, nitro, a 1-8 carbon;
R
6, R
7, R
8, R
9And R
10Can be identical or different, can be respectively, simultaneously or the alkoxyl group or the amino of the hydrogen of respectively doing for oneself, the alkyl that contains 1-8 carbon, halogen, nitro, a 1-8 carbon;
M and n are the number of methylene radical, can be 1-4, can be identical or different.
2. compound according to claim 1 is characterized in that, compound can be optically pure compound shown in the formula (III), also can be the not purified mixture with same plane configuration.
3. claim 1 or 2 described compounds or its pharmaceutically useful salt application in the preparation hepatic.
4. a hepatic comprises the claim 1 or 2 described compounds or its pharmaceutically useful salt that use as activeconstituents.
5. a hepatic preparation is characterized in that, it contains as acceptable additive, excipient and/or carrier on the claim 1 of activeconstituents use or 2 described compounds or its pharmaceutically useful salt and the pharmaceutics.
6. hepatic preparation according to claim 5 is characterized in that, it is to be activeconstituents by the oral liquid of ordinary method preparation with each described compound in claim 1 or 2 or its pharmaceutically useful salt.
7. the pharmaceutical prepn that is used for reducing blood-fat according to claim 5 is characterized in that, it is to be the tablet of activeconstituents by the ordinary method preparation with claim 1 or 2 described compounds or its pharmaceutically useful salt.
8. the preparation method of claim 1 or 2 described compounds; It is so that (3R 4S)-the dihydroxyl GBL is a starting raw material, connects substituted aralkyl through protection deprotection nucleophilic substitution; Take off with LHMDS then and pull out hydrogen; Connect another substituted aralkyl at the carbonyl alpha position, further connect the D-glucone with the TMSOTf glycosidation, last deprotection makes.
9. the preparation method of claim 1 according to claim 8 or 2 described compounds is characterized in that, its synthetic route is:
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| WO2019024758A1 (en) * | 2017-08-02 | 2019-02-07 | 华中科技大学 | Application of glycoside compound in preparing drug for treating hepatic fibrosis |
| CN113209118A (en) * | 2020-01-21 | 2021-08-06 | 华中科技大学 | Medicine for treating non-alcoholic steatohepatitis |
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| CN102391332B (en) | 2014-09-24 |
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