CN101486650A - 2-hydroxyl phenylacetic acid derivative inhibiting HIV activity, and preparation and use thereof - Google Patents
2-hydroxyl phenylacetic acid derivative inhibiting HIV activity, and preparation and use thereof Download PDFInfo
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- CN101486650A CN101486650A CNA2009100091419A CN200910009141A CN101486650A CN 101486650 A CN101486650 A CN 101486650A CN A2009100091419 A CNA2009100091419 A CN A2009100091419A CN 200910009141 A CN200910009141 A CN 200910009141A CN 101486650 A CN101486650 A CN 101486650A
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- acetic acid
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- acid analog
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Abstract
The invention discloses a 2-hydroxyphenylacetic acid derivative which has HIV resisting activity. The invention also discloses a method for preparing the compound from entada phaseoloides in entada plants of pea family and an application of the compound on preparing medicaments for resisting HIV.
Description
Technical field:
The present invention relates to separate from beans section Ke rattan platymiscium Ke rattan a class 2-Hydroxyphenyl Acetic Acid analog derivative for preparing, its preparation contains their pharmaceutical composition and the application in the inverase composition thereof.
Technical background:
Medical science full name of acquired immune deficiency syndrome (AIDS) is that (Acquired Immune Deficiency Syndrome AIDS), is caused by human immunodeficiency virus (HIV claims hiv virus again) " acquired immune deficiency syndrome (AIDS) ".After American Studies personnel in 1981 found the first acquired immune deficiency syndrome (AIDS) case in the world, acquired immune deficiency syndrome (AIDS) is rapid spread in the world, becomes the important public health event and the hot spot of society that the whole world is paid close attention to gradually.Owing to still lack the anti-AIDS drug of high-efficiency low-toxicity so far, modern medicine has been absorbed in deadlock again preventing and treating on the acquired immune deficiency syndrome (AIDS), therefore, traditional medicine is prevented and treated acquired immune deficiency syndrome (AIDS) just naturally and understandably becomes a human focus of paying close attention to, and the HIV (human immunodeficiency virus)-resistant activity of seeking high-efficiency low-toxicity from nature especially has the plant of traditional pharmaceutical use becomes to be divided into one of direction of research and development inverase.
The Ke vine is the seed of beans section Ke rattan platymiscium Ke rattan (Entada phaseoloides (L.) Merr.), has another name called the glasses beans, resembles beans, is the Dai nationality's medicine commonly used.Ke vine puckery is sweet, and is flat, can treat have blood in stool, illnesss such as bloody flux, jaundice, prolapse of the anus, larynx numbness.The Ke vine is one of main composition of Dai Nationality medicine name side " Qi Wei Ke vine ball ", this side Dai Nationality name " Ya Shalimen moves ", be ten thousand to answer the meaning of piller, by 7 kinds of medicine (Ke vine benevolence, Semen Nigellae, pepper, Herba Crotonis tomentosi, Simpleleaf Shrub Chastetree Fruit, asafoetide, Yerbadetajo Herb grass juice factor) form, have relieve summer heat and in, relieving spasm to stop pain, remove full antidiarrheic effect, be one of only two medicine Cheng Fang of the Dai Nationality of recording of China's pharmacopeia, the stomachache that is used for clinically vomiting and diarrhoea, uncomfortable in chest, hypochondriac pain, illness such as have a headache and fever.
The chemical research of Ke vine starts from the 1950's, but because condition restriction was ended to 1991, and kind benevolence isolated compound is determined only 7 of structure, and wherein 2 compounds have anti-inflammatory activity, 2 compounds have anti-tumor activity.German scholar studies show that ， Ke vine is the Chinese medicine with potential edibleness, Jian Yu Ke vine in China south and South East Asia, South Asia one band extensively distribute, its aboundresources has certain exploitation and is worth.
Summary of the invention:
The present invention relates to a class 2-Hydroxyphenyl Acetic Acid analog derivative, the method that provides the 2-Hydroxyphenyl Acetic Acid analog derivative from beans section Ke rattan platymiscium Ke rattan, to separate preparation, and the application of this analog derivative in the preparation inverase.
The 2-Hydroxyphenyl Acetic Acid analog derivative has the structure of following general formula, wherein R
1And R
2Can be identical or different, be selected from hydrogen atom respectively, contain containing ring or not containing naphthenic hydrocarbon, contain alkene or do not contain ethylene linkage alkane of 1～8 carbon atom, C3～6 replaces or unsubstituted cycloalkyl; The acyl group of replacement or unsubstituted C1～6; the replacement or the unsubstituted glycosyl that contain 5～6 carbon atoms (comprise the alditol acidifying; the amination glycosyl; glycosyl quantity is 1～3; sugar chain can be straight or branched); replace or unsubstituted five yuan or hexa-atomic alicyclic ring, replace or unsubstituted five yuan or hexa-atomic aromatic nucleus.
The preparation method of 2-Hydroxyphenyl Acetic Acid analog derivative: making with Ke Calamus plant is raw material, with Ke rattan platymiscium Ke rattan planted and pulverize the back and remove degrease with the sherwood oil heating and refluxing extraction earlier; Extract with the finite concentration alcohol heating reflux again, obtain medicinal extract after extracting solution concentrated, concentrated extract is suspended in water, use chloroform successively, ethyl acetate, n-butanol extraction, respectively extracted the position after concentrating, with sherwood oil, chloroform, ethyl acetate, acetone, methyl alcohol, ethanol, common solvent such as water with single or various combination proportioning as eluent, use silica gel with one or many, polymeric amide, ODS, customary filler such as Sephadex-LH20 are as stationary phase, with sherwood oil, chloroform, ethyl acetate, acetone, methyl alcohol, ethanol, common solvent such as water, are separated and purifying prepares the 2-Hydroxyphenyl Acetic Acid analog derivative as the recrystallization solvent recrystallization with single or various combination proportioning.
The 2-Hydroxyphenyl Acetic Acid analog derivative can be used in the preparation inverase: the medicinal compositions of 2-Hydroxyphenyl Acetic Acid analog derivative and pharmacy acceptable salt, ester etc., comprise and the pharmaceutical carrier combination, be used to prepare the medicine that relative disease is infected in prevention or treatment and HIV.The medicinal compositions that contains 2-Hydroxyphenyl Acetic Acid analog derivative and pharmacy acceptable salt, ester etc. comprises and the pharmaceutical carrier combination, is used to prepare the medicine that relative disease is infected in prevention or treatment and HIV.2-Hydroxyphenyl Acetic Acid analog derivative and pharmacy acceptable salt, ester etc., or can be by oral, non-enteron aisle and topical routes with its medicinal compositions of forming as activeconstituents, form of administration can be pharmaceutically acceptable formulations such as tablet, capsule, solution, suspension, injection liquid, drip liquid, lyophilized powder.
Embodiment:
Below be the specific embodiment of the present invention, be to further describe, and do not mean that any limitation of the invention of the present invention.
Example 1:2, (ethyl 2,5-dihydroxy benzeneacetate, preparation EP03) for 5-dihydroxyphenyl acetic acid ethyl ester
1. sample source
The kind benevolence of beans section Ke rattan platymiscium Ke rattan (Entada phaseoloides (L.) Merr.).
2. extraction separation and purification process
The seed 11.5kg of Ke vine is broken up and will plant Renhe kind shell separation with iron hammer, plant and use the sherwood oil heating and refluxing extraction to remove degrease earlier after benevolence 7.2kg pulverizes; Extract with 95% alcohol heating reflux again, obtain medicinal extract 700g after extracting solution is concentrated.To plant benevolence medicinal extract and suspend in water, use chloroform, ethyl acetate, n-butanol extraction successively, respectively be extracted the position after concentrating.Chloroform extract 23.5g wherein, ethyl acetate extraction 23.3g, n-butanol extraction 200g, the about 200g of water layer.
Get ethyl acetate layer medicinal extract 20g, dissolve with methanol, 100～200 order silica gel mixed samples, volatilize solvent, carry out wash-out with chloroform and acetone different ratios solvent, collect chloroform: acetone=20: 1 wash-out parts, in Rotary Evaporators cryoconcentration evaporate to dryness, with dissolve with methanol evaporate to dryness part, by Sephadex-LH20, with chloroform: methyl alcohol=1: 2 wash-out, elutriant is separated out crystallization, ether is done recrystallization repeatedly, and purifying obtains compd E P03.
3. compound structure is identified
EP03: white needle (ether), C
10H
12O
4, be soluble in chloroform, methyl alcohol, ethyl acetate, acetone equal solvent, mp114～115 ℃.EI-MS?m/z(％)：196[M]+(18)，150(43)，123(41)，122(100)，94(38)，77(8)。Above data and document
[1]2 of report, 5-dihydroxyphenyl acetic acid ethyl ester (ethyl 2,5-dihydroxy benzeneacetate) unanimity.Shown in the following general formula of structural formula.
Example 2:2, (methyl 2,5-dihydroxy benzeneacetate, preparation EP04) for 5-dihydroxyphenyl acetic acid methyl esters
1. sample source
The kind benevolence of beans section Ke rattan platymiscium Ke rattan (Entada phaseoloides (L.) Merr.).
2. extraction separation and purification process
The 11.5kg that planted of Ke vine is broken up and will plant Renhe kind shell separation with iron hammer, plant and use the sherwood oil heating and refluxing extraction to remove degrease earlier after benevolence 7.2kg pulverizes; Slowly extract, obtain medicinal extract 700g after extracting solution is concentrated with 95% alcohol heating reflux.To plant benevolence medicinal extract and suspend in water, use chloroform, ethyl acetate, n-butanol extraction successively, respectively be extracted the position after concentrating.Chloroform extract 23.5g wherein, ethyl acetate extraction 23.3g, n-butanol extraction 200g, the about 200g of water layer.
Get ethyl acetate layer medicinal extract 20g, dissolve with methanol, 100～200 order silica gel mixed samples, volatilize solvent, carry out wash-out with chloroform and acetone different ratios solvent, collect chloroform: acetone=15: 1 wash-out parts, in Rotary Evaporators cryoconcentration evaporate to dryness, with dissolve with methanol evaporate to dryness part, by Sephadex-LH20, with chloroform: methyl alcohol=1: 2 wash-out, elutriant is separated out crystallization, ether is done recrystallization repeatedly, and purifying obtains compd E P04.
3. compound structure is identified
EP04: white needle (ether) is soluble in chloroform, methyl alcohol, ethyl acetate, acetone equal solvent, mp116～117 ℃.EI-MS?m/z(％)：182[M]
+(28)，150(48)，123(43)，122(100)，94(57)，77(8)。Above data and document
[2]2 of report, 5-dihydroxyphenyl acetic acid methyl esters (methyl2,5-dihydroxy benzeneacetate) unanimity.Shown in the following general formula of structural formula.
Example 3:2, (butyl 2,5-dihydroxy benzeneacetate, preparation EP16) for the positive butyl ester of 5-dihydroxyphenyl acetic acid
1. sample source
The kind benevolence of beans section Ke rattan platymiscium Ke rattan (Entada phaseoloides (L.) Merr.).
2. extraction separation and purification process
The seed 11.5kg of Ke vine is broken up and will plant Renhe kind shell separation with iron hammer, plant and use the sherwood oil heating and refluxing extraction to remove degrease earlier after benevolence 7.2kg pulverizes; Extract with 95% alcohol heating reflux again, obtain medicinal extract 700g after extracting solution is concentrated.To plant benevolence medicinal extract and suspend in water, use chloroform, ethyl acetate, n-butanol extraction successively, respectively be extracted the position after concentrating.Chloroform extract 23.5g wherein, ethyl acetate extraction 23.3g, n-butanol extraction 200g, the about 200g of water layer.
Get ethyl acetate layer medicinal extract 20g, dissolve with methanol, 100～200 order silica gel mixed samples, volatilize solvent, carry out wash-out with chloroform and acetone different ratios solvent, collect chloroform: acetone=10: 1 wash-out parts, in Rotary Evaporators cryoconcentration evaporate to dryness, with dissolve with methanol evaporate to dryness part, by Sephadex-LH20, with chloroform: methyl alcohol=1: 2 wash-out, elutriant is separated out crystallization, chloroform: methyl alcohol is done recrystallization repeatedly, and purifying obtains compd E P16.
3. compound structure is identified
EP16: white crystal (chloroform: methyl alcohol), mp69 ℃.EI-MS m/z (%): 224 (M
+, 10), 150 (74), 122 (100), 94 (49), 56 (30), 41 (59), point out this compd E P16 may have 2,5-dihydroxyphenyl acetic acid ester structure.
1There is the relevant characteristic signal of phenyl ring ABX coupling system among the H-NMR (see Table 1., collection of illustrative plates is seen accompanying drawing): δ 6.82 (1H, d, J=8.5Hz), 6.68 (1H, dd, J=3.0,8.5Hz), 6.61 (1H, d J=3.0Hz), has 1 among the prompting compd E P16,2,4-trisubstituted benzene loop systems, ownership is 3 respectively, 4,6 proton signals; δ 3.61 (2H, s) be methene proton signal in the typical phenylacetate, in the HMBC spectrum, this proton signal has long-range relevant with carbonyl carbon δ 174.8 (C8), oxygen aryl carbon 150.1 (C2) of company and aromatic carbon 117.1 (C6), further proved conclusively it and had 2,5-dihydroxyphenyl acetic acid ester structure skeleton.
1Also exist in the HNMR spectrum 3 methylene signals δ 4.14 (1H, t, J=6.5Hz), 1.64 (2H, m), 1.37 (2H, m) and a methyl signals δ 0.92 (3H, t J=7.5Hz), have n-butoxy to exist with reference to the prompting of HMBC spectrum.Analyze the HMBC spectrum, δ 4.14 (1H, t, J=6.5Hz) relevant with carbonyl carbon δ 174.8, the prompting n-butoxy links to each other with carbonyl, so the structure of compd E P16 is defined as 2, the positive butyl ester of 5 dihydroxyphenyl acetic acids (butyl 2,5-dihydroxy benzeneacetate) is a kind of new compound.Shown in the following general formula of structural formula.
Table 1.The
1HNMR (500MHz),
13CNMR (125MHz) and HMBC data of EP16 in CD
3OD
The test of example 4. HIV (human immunodeficiency virus)-resistant activity
1. material and method
Cell and compound H EK293 cell are available from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; Human embryonic kidney cell system (293), human lung carcinoma cell (A549) are all available from ATCC company; (zidovudine is AZT) available from Sigma-Aldrich company for zidovudine.(didanosine DDI) is so kind as to give by Dongbei Pharmaceutical General Factory to remove the hydroxyl glycosides.
(1) preparation of pseudovirus: preceding 1 day of transfection, inoculate 293 cells in the 100mm culture dish by cell count 2.2 * 106, calcium phosphate precipitation method cotransfection VSV-G plasmid 3 μ g and pNL4-3.1uc.R-E-or pNL4-3.GFP.R-E-(HIV-1 core gene with improvement, can form the HIV-1 core after the transfection separately) 8 μ g, 16h after the transfection, wash cell and renew bright substratum continuation cultivation 32h with PBS, collect supernatant liquor and, contain the VSVG/HIV pseudovirion in the supernatant liquor after the filtration through the membrane filtration of 0.45 μ m.Same quadrat method, cotransfection VSV-G plasmid 3 μ g, pHIT60 plasmid 8 μ g and pMX-EGFP 8 μ g obtain the VSVG/MLV pseudovirion.
(2) the infectious detection: infected preceding 1 day, and be inoculated on 24 orifice plates by cell count 6 * 104 holes, with VSVG/HIV and VSVG/MLV virion with different thinning ratios (VSVG/HIV-luc:1: 4,1: 8,1: 16,1: 32,1: 64,1: 128; VSVG/HIV-GFP:1: 1,1: 10,1: 100; VSVG/MLV-GFP:1: 2) infect corresponding cell.After infecting 48h, the every hole of the cell that VSVG/HIV-luc infects adds cell pyrolysis liquid (Promega) 50 μ l lysing cell, and luciferase substrate (Promega) 30 μ l are mixed the plain enzyme of cell fluorescence is measured in the back with FB15 fluorimetric detector (Sirius) relative reactivity with cell pyrolysis liquid 20 μ l; Observe the cell of VSVG/HIV-GFP or VSVG/MLV-GFP infection with inverted fluorescence microscope (Olympus), and count the per-cent of GFP positive cell with flow cytometer (Beckman).
2. the compound inhibition detects
Dissolve AZT and treat SCREENED COMPOUND with DMSO, 15min adds in the cell culture fluid before infecting, and makes blank with the DMSO solvent.The extent of dilution of VSVG/HIV-luc virion is 1: 8 during infection.
Experiment is carried out in 3 grades of (BSL-3) laboratories of Biosafety according to working specification, repeats twice.Calculate inhibiting rate and half-inhibition concentration.
3. the anti HIV-1 virus screening active ingredients result of compound
Application recombinant virus Dui separates 6 compounds that obtain and has carried out the pharmacologically active evaluation of cell levels Cong the Ke vine, the results are shown in Table 3.
The anti-HA of table 3 part of compounds (Viet)/HIV virus activity The selection result
*
From table 3 kind as can be seen, 2,5-dihydroxyphenyl acetic acid compounds EP03, EP04 and EP16 show to HA (Viet)/HIV virus and suppress active that further Mechanism Study confirms the inhibition of effect link for HIV-1 is duplicated of this inhibition.Thereafter, we have examined or check the dose-effect relationship of EP03, EP04, and they suppress the half-inhibition concentration that HIV-1 duplicates and are respectively 9.93 μ M and 11.7 μ M.
Reference:
1.Jinrui?Dai，Leonardus?B.S.Kardono，Soefjan?Tsauri，Kosasih?Padmawinata，John?M.Pezzuto，A.Douglas?Kinghorn.Phenylacetic?acid?derivatives?and?a?thioamide?glycoside?from?Entadaphaseoloides[J].phytochemistry，1991，30(11)：3749-3752
2. Wu Bin, Wu Lijun, Zhang Lei, Jin Zheshi.The research (I) [J] of Senecio cannabifolius antimicrobial chemical composition. Shenyang Pharmaceutical University's journal, 2004,21 (5): 341-345
Claims (6)
1. the 2-Hydroxyphenyl Acetic Acid analog derivative or its pharmacy acceptable salt or ester, the wherein R that have following general formula
1And R
2Can be identical or different, be selected from hydrogen atom respectively, contain containing ring or not containing naphthenic hydrocarbon, contain alkene or do not contain ethylene linkage alkane of 1～8 carbon atom, C3～6 replaces or unsubstituted cycloalkyl; Replace or the acyl group of unsubstituted C1～6, contain the replacement or the unsubstituted glycosyl of 5～6 carbon atoms, replace or unsubstituted five yuan or hexa-atomic alicyclic ring, replace or unsubstituted five yuan or hexa-atomic aromatic nucleus.
2. the 2-Hydroxyphenyl Acetic Acid analog derivative of claim 1 or its pharmacy acceptable salt or ester, wherein R
1Be CH
3, C
2H
5, C
3H
7, C
4H
9, C
5H
11Or C
6H
13R
2Be glucosyl group, rhamanopyranosyl, two glucosyl groups or glucal acidic group.
3. claim 1 or 2 2-Hydroxyphenyl Acetic Acid analog derivative or its pharmacy acceptable salt or ester, wherein R
1Be CH
3, C
2H
5, C
3H
7Or C
4H
9R
2Be glucosyl group, the glucal acidic group.
4. the preparation method of the 2-Hydroxyphenyl Acetic Acid analog derivative of claim 1 is characterized in that the seed of Ke rattan platymiscium Ke vine is pulverized the back removes degrease with the sherwood oil heating and refluxing extraction earlier; Extract with the finite concentration alcohol heating reflux again, obtain medicinal extract after extracting solution concentrated, concentrated extract is suspended in water, use chloroform successively, ethyl acetate, n-butanol extraction, respectively extracted the position after concentrating, with sherwood oil, chloroform, ethyl acetate, acetone, methyl alcohol, one of in the second alcohol and water or various combination as eluent, use silica gel with one or many, polymeric amide, ODS, Sephadex-LH20 is as stationary phase, with sherwood oil, chloroform, ethyl acetate, acetone, methyl alcohol, one of in the second alcohol and water or various combination as the recrystallization solvent recrystallization, separate and purifying prepares.
In the claim 1～3 arbitrary 2-Hydroxyphenyl Acetic Acid analog derivative or its pharmacy acceptable salt or ester in the catch purposes of shape or disease medicament of preparation prevention or treatment and HIV.
6. according to the purposes of claim 5, pharmaceutical dosage form wherein is tablet, capsule, solution, suspension, injection liquid, lyophilized powder or drip liquid etc.
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|---|---|---|---|
| CNA2009100091419A CN101486650A (en) | 2009-02-20 | 2009-02-20 | 2-hydroxyl phenylacetic acid derivative inhibiting HIV activity, and preparation and use thereof |
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2772480A1 (en) * | 2011-10-25 | 2014-09-03 | Shionogi & Co., Ltd. | Hiv replication inhibitor |
-
2009
- 2009-02-20 CN CNA2009100091419A patent/CN101486650A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2772480A1 (en) * | 2011-10-25 | 2014-09-03 | Shionogi & Co., Ltd. | Hiv replication inhibitor |
| EP2772480A4 (en) * | 2011-10-25 | 2015-04-22 | Shionogi & Co | Hiv replication inhibitor |
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Application publication date: 20090722 |