CN101492373A - Disubstituted fragrant acyl ethylene glycol compounds and medical use - Google Patents
Disubstituted fragrant acyl ethylene glycol compounds and medical use Download PDFInfo
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- CN101492373A CN101492373A CNA2008100624508A CN200810062450A CN101492373A CN 101492373 A CN101492373 A CN 101492373A CN A2008100624508 A CNA2008100624508 A CN A2008100624508A CN 200810062450 A CN200810062450 A CN 200810062450A CN 101492373 A CN101492373 A CN 101492373A
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Abstract
The invention relates to a bi-substituted aromatic acyl ethylene glycol compound indicated by Formula (I) and the pharmaceutical application. The invention also relates to a preparation method of the compounds and a drug composition containing the compounds. The compound in Formula (I) and the medicine salt thereof, as well as 1, 2-bi-oxygen-[3-(4-metoxybenzene) allyl acyl]-ethylene glycol, have the function of inhibiting HBsAg and display certain cytotoxicity to two-strain human tumor cells. The compound can be used for preparing the medicine for curing hepatitis B infectious diseases and tumor diseases in anticipation.
Description
Technical field
The present invention relates to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to disubstituted fragrant acyl ethylene glycol compounds and pharmacologically acceptable salt thereof and their preparation method and medicinal use, this compounds is found the function of inhibition hepatitis B virus surface antigen (HBsAg); Simultaneously two strain human body tumour cells are demonstrated certain cytotoxicity, can expect to be used to prepare the relevant hepatitis B virus infection disease of treatment and the pharmaceutical use of tumor disease.
Background technology
B virus type hepatitis (Hepatitis B) is the multiple and common heavy communicable disease of China, and its pathogenic agent is hepatitis B virus (HBV).The about 1.2 hundred million HBV carrier in the whole nation die from 150,000 philtrums of primary hepatocarcinoma every year, and are most relevant with hepatitis B infection.At present, treatment plan to the HBV sufferer can only reach inhibition hbv replication and secondary infection clinically, main medicine is still nucleoside medicine such as lamivudine (3-TC), Entecavir, Adefovir (ADV) etc., though they are disease controlling effectively, but fetch long price first, second life-time service all resistance can occur, and knock-on in various degree, and the 3rd, the comparatively tangible well-known undesirable action that the life-time service nucleoside medicine occurs.So find that from the medicine of national folk life-time service new non-nucleoside hepatitis B virus inhibitor has very big meaning, select the main judge index of lead compound to be that such novel non-nucleoside material must have the inhibition activity to hepatitis B virus thymus nucleic acid (HBVDNA) and/or hepatitis B surface antigen (HBsAg).
Chlorogenic acid in the natural product (chlorogenic acid) is by coffic acid (caffeic acid) and quinic acid (quinovic acid, quinic acid) the monobasic depside of Zu Chenging, for the main effective constituent of antibacterial and detoxicating, anti-inflammatory and choleretic in numerous medicinal materials (as Japanese Honeysuckle, oriental wormwood, the bark of eucommia) and the Chinese patent medicine (as Fuganning, honeysuckle injection liquid, acne oral liquid), be the important indicator of some Chinese medicine preparation quality control simultaneously.Chlorogenic acid is a kind of important biological material, have antibiotic, antiviral, increase effects such as white cell, hepatic cholagogic, antitumor, hypotensive, reducing blood-fat, removing free radical and stimulating central nervous system system, important use [Zhao Yu etc.: " caffetannic acid compounds progress " are especially arranged in the prevention and cure of viruses field, CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2006,31 (11), 869-874].
The three-dimensional arrangement of quinic acid is too complicated, need consider the mechanism problem of raw-material cost and three-dimensional location, protection and deprotection etc., is unfavorable for suitability for industrialized production.So scientist is devoted to streamline any further with simple five-ring or the six-ring ring-type system six-ring that this is complicated always.For example, be lead compound according to the quinic acid of transforming in the recent period, scientist has found new antiviral caffeoyl organic acid ester compound L-chicoric acid (chicoric acid) [Robinson, W.E.Jr.Infect Med.1998 successively from the feverfew witloof, 15,129-137].This lead compound has potent inhibition activity to HIV viral integrase enzyme (IN), and nontoxic scope is bigger simultaneously, helps developing into inverase.Many structure activity studies thereby carry out in succession, and prepare multiple L-chicoric acid derivative, wherein active compound suppresses the active IC of HIV-1 intergrase
50Value is about 0.8～1.1 μ M[King, P.J., Robinson, W.E.Jr. etc., J.Med.Chem.1999,42,497-509; Lin, Z., Bruke, T.R.Jr., J.Med.Chem.1999,42,1401-1414].Above-mentioned research report result points out: the pyrocatechol part in the caffeoyl structure plays considerable effect in the inhibition activity of whole molecule, yet too much phenolic hydroxyl group also can bring bigger toxicity.
Consider above factor, and caffetannic acid class and L-chicoric acid compound separate comparatively factor such as difficulty, scientists designs synthetic a series of change quinic acid parent nucleus again and still keeps its bioactive compound.By continuous simplification, obtained a series of higher bioactive chicoric acid analogue that has to linker in the chicoric acid; Comprising keeping a chicoric acid carboxyl; With two carboxyl alkyl or cycloalkyl alternate; That two carboxyls are directly removed and with connection chain between two hydroxyls increase etc. different series, hereinto between the most noticeable two caffeoyl ethylene glycol that surely belong to, it suppresses the IC of HIV-1 intergrase
50Value reaches 0.4 μ M, be 2-3 times of chicoric acid, but its toxicity is very big, so the purposes of its medical aspect is restricted.
On this basis, it is the alternative parent nucleus of quinic acid that the inventor selects to replace L-tartrate with ethylene glycol, as a linker two aromatic compounds is coupled together and forms an aromaticacyl radical glycol ester compounds.We transform this compound, reduce phenolic hydroxyl group to reduce the toxicity of whole molecule, substitute caffeoyl with the different phenylallene acyls that replace, and introduce halogen atom, add the furans ring system, and the hydroxyl etc. that replaces coffee acyl with alkoxyl group is as new trial.
High homology based on inverase and HBV medicine; the present invention has tested its inhibition activity to hepatitis B surface antigen HBsAg to the aromaticacyl radical glycol ester compounds that synthesizes, and more various can produce inhibiting L-witloof acids analogue to hepatitis B virus duplication in the hope of seeking.
In our this series compound of synthetic, I-e is reported compound [Lewis, Frederick D. etc., Journal of the American Chemical Society, 1986,108 (11), 3005-3015; Jiang, Xikui etc., Journal of the Chemical Society, ChemicalCommunications.1988,11,689-690], but its disclosed use of a compound be participate in the selectivity of the isomer of styracin in the photochemical reaction synthetic or with phenylallene acyl ethylene glycol as the raw material that forms macrocylc compound.Suppress the biological activity and the related application of compounds such as HIV-1 intergrase activity, inhibition hepatitis B surface antigen activity, cytotoxic activity does not then appear in the newspapers about phenylallene acyl ethylene glycol involved in the present invention.
In order to explore other physiologically actives of the aromaticacyl radical glycol ester compounds that the present invention prepares; we have also adopted MTT, and (3-(4; 5-dimethylthiazole-2)-2; 5-phenylbenzene tetrazole bromine salt) method has been carried out the growth inhibitory activity test to this compounds at two kinds of human tumor cultured cell in vitro strain [human cervical carcinoma cell (Hela) and human lung carcinoma cell (A549)], thereby finishes the present invention.
Summary of the invention
The object of the present invention is to provide a class to be used to prepare the compound of new hepatitis B virus resisting and cell toxicant series antineoplastic medicament, particularly, the invention provides the disubstituted fragrant acyl ethylene glycol compounds and the pharmacologically acceptable salt thereof of structure shown in the class formula (I):
Wherein: substituent R
1And R
2Can be identical or different, be selected from 2-furan nucleus-3-allyl acyl group respectively, 2 or 4 benzoyls that methoxyl group replaces, the benzoyl that an ortho position or a position or contraposition dimethoxy replace, the mono-substituted 3-benzene of methoxyl group or halogen allyl acyl group, or ortho position or a position or the dibasic 3-benzene of contraposition halogen allyl acyl group; Its condition is: R
1, R
2Can not be 3 the mono-substituted 3-benzene of methoxyl group allyl acyl groups simultaneously or be 4 the mono-substituted 3-benzene of methoxyl group allyl acyl groups simultaneously, can not be 4 the mono-substituted 3-benzene of fluorine allyl acyl groups simultaneously, R
1, R
2Can't be 3 simultaneously, the 4-dimethoxy replaces or is 2 simultaneously, the 3-benzene allyl acyl group that the 5-dimethoxy replaces.
Another object of the present invention has provided the preparation method of formula (I) compound.
Another purpose of the present invention has provided described fragrant acyl ethylene glycol compounds and pharmacologically acceptable salt is used for the pharmaceutical use that preparation suppresses hepatitis B virus surface antigen (HBsAg).
A further object of the present invention has provided the purposes that formula (I) compound and pharmacologically acceptable salt thereof are used to prepare the cell toxicant series antineoplastic medicament.
A further object of the present invention has provided a kind of pharmaceutical composition that is used for the hepatitis B virus resisting disease and/or cell toxicant series antineoplastic medicament that contains formula (I) compound.According to the present invention, can add various pharmaceutical excipients, additive and carrier in this pharmaceutical composition.
The preferred formula of the present invention (I) compound and pharmacologically acceptable salt thereof are listed below:
I-a.1-oxygen-[3-(4-anisole) acrylyl]-2-oxygen-4-methoxybenzoyl-ethylene glycol;
I-b.1,2-two-oxygen-[3-(4-chlorobenzene)-acrylyl]-ethylene glycol;
I-c.1,2-two-oxygen-[3-(2-furyl)-acrylyl]-ethylene glycol;
I-d.1,2-two-oxygen-[3-(2,4 dichloro benzene)-acrylyl]-ethylene glycol.
The present invention also provides compound 1, and 2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol (I-e) is used to prepare cell toxicant class anti-tumor drug purposes.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof is expressed hepatitis B surface antigen(HBsAg) (HBsAg) certain restraining effect, and it also has certain restraining effect to two kinds of human tumor cultured cell in vitro strain [human cervical carcinoma cell (Hela), human lung carcinoma cell (A549)].According to the present invention, such compound or pharmaceutically acceptable salt thereof can combine with auxiliary material or carrier pharmaceutically commonly used, prepares the pharmaceutical composition and/or the cell toxicant series antineoplastic medicament that can be used for the treatment of the viral hepatitis B disease-related.
Embodiment:
We are the alternative parent nucleus of quinic acid with ethylene glycol, as a linker two aromatic compounds are coupled together and form an aromaticacyl radical glycol ester compounds, and transform the synthesizing series derivative with the alternative caffeoyl of the different phenylallene acyls that replace.We carry out active testing to the serial aromaticacyl radical glycol ester compounds that the present invention is synthesized, and comprise the compound that is synthesized has been carried out testing to hepatitis B surface antigen HBsAg and to the inhibition growth activity of two kinds of human tumor cultured cell in vitro strain.
Further specify the present invention below by embodiment.Embodiment has provided the synthetic and dependency structure appraising datum of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: Compound I-a is the preparation of 1-oxygen-[3-(4-anisole) acrylyl]-2-oxygen-4-methoxybenzoyl-ethylene glycol
In reaction flask, add 3-(4-anisole) allyl acid (85 milligrams, 0.48 mmole), (73 milligrams of 4-methoxybenzoic acids, 0.48 mmole), dicyclohexylcarbodiimide (200 milligrams, 0.97 mmole), 10 milliliters of anhydrous methylene chlorides, at room temperature stirred 20 minutes, after white casse occurring, add ethylene glycol (20 milligrams, 0.32 mmole), 4-Dimethylamino pyridine (DMAP, 12 milligrams, 0.1 mmole), whole solution at room temperature reacted 2 days, suction filtration is removed insolubles, boil off solvent, precipitation obtains white solid, column chromatography purification (petrol ether/ethyl acetate=10: 1), separate obtaining 95 milligrams of white solids, productive rate is 83%.
Compound I-a: white solid, fusing point: 103～105 ℃ (chloroform); R
f(chloroform/methanol/formic acid=50: 2: 1): 0.48; Proton nmr spectra (400MHz, deuterated methanol): δ 3.86 (6H, unimodal, OCH
3), 4.53 (4H, multiplet, H-1,2), 6.43 (1H, bimodal, J=16.0Hz, H-2 '), 7.00 (4H, bimodal, J=8.4Hz, H-6 ', 8 ', 4 "; 6 "), 7.65 (2H, bimodal, J=8.4Hz, H-5 ', 9 '), 7.68 (1H, bimodal, J=16.0HZ, H-3 '), 7.99 (2H, bimodal, J=8.4HZ, H-3 ", 7 "); Electrospray ionization mass spectrum ESI-MS m/z374.04 ([M+H
2O]
+).
Prepare table one illustrated embodiment 2-4 compound according to embodiment 1 identical method:
Table one
List the physicochemical data of each compound in the table one below:
Compound I-b: white solid, R
f(chloroform/methanol/formic acid: 50/2/1): 0.42; Proton nmr spectra (
1HNMR) (400MHz, deuterated methanol): δ 4.50 (4H, multiplet, H-1,2), 6.40 (2H, bimodal, J=16.0Hz, H-2 ', 2 "); 7.21 (4H, bimodal, J=8.7Hz, H-6 ', 6 ", 8 ', 8 "), 7.25 (4H, bimodal, J=8.7Hz; H-5 ', 5 ", 9 ', 9 "), 7.66 (2H; bimodal, J=16.0Hz, H-3 ', 3 ").
Compound I-c: white solid, R
f(chloroform/methanol/formic acid: 50/2/1): 0.58; Proton nmr spectra (
1HNMR) (400MHz, deuterated methanol): δ 4.48 (4H, multiplet, H-1,2), 6.29 (2H, multiplet, H-6 ', 6 "), 6.38 (2H; bimodal, J=16.0Hz, H-2 ', 2 "), 6.72 (2H, multiplet, H-5 ', 5 "), 7.27 (2H; multiplet, H-7 ', 7 "), 7.56 (2H, bimodal, J=16.0Hz, H-3 ', 3 ").
Compound I-d: white solid, R
f(chloroform/methanol/formic acid: 50/2/1): 0.31; Proton nmr spectra (
1HNMR) (400MHz, deuterated methanol): δ 4.49 (4H, multiplet, H-1,2), 6.36 (2H, bimodal, J=16.0Hz, H-2 ', 2 "); 7.36 (2H, bimodal, J=8.6Hz, H-8 ', 8 "), 7.50 (2H, unimodal H-6 ', 6 "), 7.76 (2H; multiplet, H-9 ', 9 "), 7.58 (2H, bimodal, J=16.0Hz, H-3 ', 3 ").
Embodiment 5: Compound I-e is 1, the preparation of 2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol
In reaction flask, add (173 milligrams of 3-(4-anisole) allyl acid, 0.97 mmole), (200 milligrams of dicyclohexylcarbodiimide, 0.97 mmole), 10 milliliters of anhydrous methylene chlorides at room temperature stirred 20 minutes, after white casse occurring, add ethylene glycol (20 milligrams, 0.32 mmole), (12 milligrams of 4-Dimethylamino pyridines, 0.1 mmole), whole solution at room temperature reacted 2 days, and suction filtration is removed insolubles, boils off solvent, precipitation obtains white solid, column chromatography purification (petrol ether/ethyl acetate=10: 1) separates obtaining 73 milligrams of white solids, and productive rate is 60%.
Compound I-e: white solid, fusing point: 140～141 ℃ (chloroform); R
f(chloroform/methanol/formic acid=50: 2: 1): 0.6; Proton nmr spectra (400MHz, deuterated methanol): δ 3.84 (6H, unimodal, OCH
3), 4.48 (4H, unimodal, H-1,2), 6.35 (2H, bimodal, J=16.0Hz, H-2 ', 2 "); 6.90 (4H, bimodal, J=8.8Hz, H-6 ', 8 ', 6 ", 8 "), 7.48 (4H, bimodal, J=8.8Hz; H-5 ', 9 ', 5 ", 9 "), 7.68 (2H, bimodal, J=16.0Hz, H-3 ', 3 "); Electrospray ionization mass spectrum ESI-MS m/z:399.87 ([M+H
2O]
+).
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof has the function of inhibition hepatitis B virus surface antigen (HBsAg); Can be used to prepare the relevant hepatitis B virus infection disease medicament of treatment.This medicine can combine with auxiliary material or carrier pharmaceutically commonly used, has the pharmaceutical composition that antiviral activity can be used to prevent and treat the disease that virus causes thereby prepare with the routine techniques in the pharmacy field.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also utilize existing known technology to be prepared into its controlled release, slow release formulation and nanometer formulation, can also use the targeted drug preparation technique and be prepared into relative medicine formulation and administering mode.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof can wait with the treatment hepatitis B medicine that has now gone on the market such as lamivudine (lamivuding), Adefovir and two volt esters (adevovir/adevovirdipivoxil), Entecavir (entecavir), emtricitabine (emtricitabine), Ke Laifu fixed (clevudine), general former times network Wei (famciclovir), Lobucavir (lobucavir), Interferon, rabbit (IFN) unites use, prepares to have the medicine for the treatment of hepatitis B.Above-mentioned various kinds of drug composition all can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also utilize existing known technology to be prepared into its controlled release, slow release formulation and nanometer formulation, can also use the targeted drug preparation technique and be prepared into relative medicine formulation and administering mode.
In addition, formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and Compound I-e (promptly 1,2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol) or its pharmacologically acceptable salt have certain growth inhibitory activity for human cervical carcinoma cell (Hela) and human lung carcinoma cell (A549), can expect as control related neoplasms disease medicament purposes.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and Compound I-e (promptly 1,2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol) or its pharmacologically acceptable salt can combine with auxiliary material or carrier pharmaceutically commonly used, prepare pharmaceutical composition with anticancer usage.Aforementioned pharmaceutical compositions can adopt injection, tablet, capsule, paster, the subcutaneous formulations such as burying agent of planting, or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and Compound I-e (promptly 1,2-two-oxygen-[3-(4 anisole) acrylyl]-ethylene glycol) or its pharmacologically acceptable salt can with antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active Cytotoxic pharmaceutical composition, can be used for preparing the medicine of treatment kinds of tumors disease.
In order to understand essence of the present invention better, sketch formula (I) compound with the form of pharmacology embodiment respectively below, and 1, (Compound I-e) illustrates its purposes in antiviral and antitumor drug development field to the The pharmacological results of the growth-inhibiting of hepatitis B virus surface antigen (HBsAg) inhibition test and two strain human vitronectin culture of tumor cell strains to 2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol.Pharmacology embodiment has provided formula (I) compound and 1,2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol (part activity data of Compound I-e).Same mandatory declaration, pharmacology embodiment of the present invention is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Pharmacology embodiment 1: Compound I-a is to the restraining effect of hepatitis B virus surface antigen
1.1 cell cultures:
In containing 10% inactivated fetal bovine serum, 100U/ ml penicillin and 100 mcg/ml Streptomycin sulphates in the DMEM substratum of 100 mcg/ml G418, are put 37 ℃, 5% carbonic acid gas CO with the HepG2.2.15 cell cultures
2, cultivate in the incubator of 100% relative humidity.
Measure the restraining effect of Compound I-a 1.2 adopt mtt assay to the growth of HepG2.2.15 cell:
The HepG2.2.15 cell of taking the logarithm vegetative period becomes 1 * 10 with substratum with cell dilution
5Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres, at 37 ℃, 5%CO
2, cultivate the Compound I-a that adds after 24 hours with the substratum dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO
2Cultivate in the incubator of 100% relative humidity, cultivate after 72 hours, every hole adds 5 mg/ml MTT (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) reagent 10 microlitres, continue to cultivate 4 hours, discard substratum, every hole adds dimethyl sulfoxide (DMSO) DMSO 200 microlitres, with vibrator vibration 20 minutes, under the 570nm wavelength, measure the OD value with microplate reader.With the culture hole that only adds substratum is control wells.The experiment triplicate.
Inhibiting rate (%)=(control wells OD value-experimental group OD value)/control wells OD value * 100%.
1.3 measure the restraining effect of Compound I-a to hepatitis B surface antigen(HBsAg) (HBsAg):
The HepG2.2.15 cell of taking the logarithm vegetative period becomes 1 * 10 with substratum with cell dilution
5Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres are at the 5%CO of 100% relative humidity
2Cultivate the Compound I-a compound that adds after 24 hours with the substratum dilution for 37 ℃ in the incubator, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, and every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO
2, cultivate in the incubator of 100% relative humidity, changed the substratum that contains the same concentrations sample in per 4 days, with the substratum equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.With hepatitis B surface antigen(HBsAg) (HBsAg) concentration in the integrated enzyme reaction ELISA kit measurement substratum, represent with P/N; With the positive contrast of lamivudine (3-TC).
1.4 experimental result:
Experimental result as shown in Table 2, Compound I-a has the effect of significant inhibition hepatitis B surface antigen(HBsAg).Its growth to the HepG2.2.15 cell does not have obvious restraining effect, all is higher than lamivudine but the hepatitis B surface antigen(HBsAg) HBsAg of HepG2.2.15 emiocytosis is suppressed activity under high, medium and low dosage.
Table two Compound I-a is to HepG2.2.15 excretory hepatitis B surface antigen(HBsAg) inhibiting rate (%)
aExpression unrestraint activity.
1.5 presentation of results:
Hepatitis B surface antigen(HBsAg) (HBsAg) inhibiting rate is to judge hepatitis b virus infected important symbol, and effectively suppressing the HBsAg secretion and the HBsAg reaction is turned out cloudy is one of target of treatment hepatitis B.Compound I-a has significant inhibitory effect at the 8th day hepatitis B surface antigen(HBsAg) (HBsAg) to HepG2.2.15 emiocytosis, illustrates that this type of fragrant acyl ethylene glycol compounds can be expected to develop into the medicine that reduces hepatitis B surface antigen(HBsAg), control Type B viral hepatitis symptom.
Pharmacology embodiment 2: Compound I-d is to the restraining effect of hepatitis B virus surface antigen
2.1 cell cultures: with pharmacology embodiment 1.
Measure the restraining effect of Compound I-d to the growth of HepG2.2.15 cell 2.2 adopt mtt assay: the HepG2.2.15 cell in the vegetative period of taking the logarithm, method is with pharmacology embodiment 1.
2.3 measure the restraining effect of Compound I-d, with the positive contrast of lamivudine (3-TC) to hepatitis B surface antigen(HBsAg) (HBsAg).Concrete grammar is with pharmacology embodiment 1.
2.4 experimental result: experimental result as shown in Table 3, Compound I-d has the effect of significant inhibition hepatitis B surface antigen(HBsAg) (HBsAg).Its growth to the HepG2.2.15 cell does not have obvious restraining effect, all is higher than lamivudine but the hepatitis B surface antigen(HBsAg) HBsAg of HepG2.2.15 emiocytosis is suppressed activity under high, medium and low dosage.
Table three Compound I-d is to HepG2.2.15 excretory hepatitis B surface antigen(HBsAg) inhibiting rate (%)
aExpression unrestraint activity.
2.5 presentation of results: hepatitis B surface antigen(HBsAg) (HBsAg) inhibiting rate is to judge hepatitis b virus infected important symbol, and effectively suppressing the HBsAg secretion and the HBsAg reaction is turned out cloudy is one of target of treatment hepatitis B.Compound I-d has certain restraining effect at the 8th day hepatitis B surface antigen(HBsAg) (HBsAg) to HepG2.2.15 emiocytosis, illustrates that such fragrant acyl ethylene glycol compounds can be expected to develop into the medicine that reduces hepatitis B surface antigen(HBsAg), control Type B viral hepatitis symptom.
Pharmacology embodiment 3: compound is to the cytotoxic activity of human cervical carcinoma (Hela) cell
3.1 human cervical carcinoma (Hela) cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
3.2 the measuring method of cell survival rate: with the improvement mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the compound that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 microlitre methyl-sulphoxides in every hole, the MTT crystal first that the vibration dissolving generates
(formazan), formed first
With microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein compound is to the half-inhibition concentration (IC of Hela cell
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 4.As positive control, the positive control cis-platinum is to the IC of Hela cell with an antitumor line medication cis-platinum (DDP) in this test
50Be 19.6 μ M.
Each test compounds of table four is to the half-inhibition concentration (IC of Hela cell
50) (mcg/ml)
Compound I-a I-d I-e
Suppress active IC
50156.2 121.2 213.0
3.3 presentation of results: Compound I-a, I-d, I-e have certain restraining effect to the growth of Hela cell, illustrate that such disubstituted fragrant acyl ethylene glycol compounds is expected to develop into the medicine of cell toxicant class treatment human hela.
Pharmacology embodiment 4: compound is to the cytotoxic activity of people's lung cancer A549 cell
4.1 people's lung cancer (A549) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
4.2 the mensuration of cell survival rate: with improvement mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein compound is to the half-inhibition concentration (IC of A549 cell
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 5.And the positive control cis-platinum is to the IC of A549 cell
50Be 17.8 μ M.
Each test compounds of table five is to the half-inhibition concentration (IC of A549 cell
50) (mcg/ml)
Compound I-a I-d I-e
Suppress active IC
50125.3 140.8 262.7
4.3 presentation of results: Compound I-a, I-d, I-e have certain restraining effect to the growth of A549 cell, illustrate that such disubstituted fragrant acyl ethylene glycol compounds is expected to develop into the medicine of cell toxicant class treatment Human Lung Cancer.
When above-mentioned specification sheets elaboration was of the present invention, the purpose that embodiment and pharmacology embodiment are provided simultaneously was to illustrate actual mechanical process of the present invention and meaning of the present invention.In the time of in entering claim of the present invention and its equivalent scope, practical application of the present invention comprises all general variations, cooperates, or improves.
Claims (8)
1. a disubstituted fragrant acyl ethylene glycol compounds and pharmacologically acceptable salt thereof with structure shown in the formula (I):
Formula (I)
Wherein: substituent R
1And R
2Can be identical or different, be selected from 2-furan nucleus-3-allyl acyl group respectively, 2 or 4 benzoyls that methoxyl group replaces, the benzoyl that an ortho position or a position or contraposition dimethoxy replace, the mono-substituted 3-benzene of methoxyl group or halogen allyl acyl group, or ortho position or a position or the dibasic 3-benzene of contraposition halogen allyl acyl group; Its condition is: R
1, R
2Can not be 3 the mono-substituted 3-benzene of methoxyl group allyl acyl groups simultaneously or be 4 the mono-substituted 3-benzene of methoxyl group allyl acyl groups simultaneously, can not be 4 the mono-substituted 3-benzene of fluorine allyl acyl groups simultaneously, R
1, R
2Can't be 3 simultaneously, the 4-dimethoxy replaces or is 2 simultaneously, the 3-benzene allyl acyl group that the 5-dimethoxy replaces.
2. according to the described disubstituted fragrant acyl ethylene glycol compounds of claim 1, it is characterized by formula (I) compound and be selected from:
I-a.1-oxygen-[3-(4-anisole) acrylyl]-2-oxygen-4-methoxybenzoyl-ethylene glycol;
I-b.1,2-two-oxygen-[3-(4-chlorobenzene)-acrylyl]-ethylene glycol;
I-c.1,2-two-oxygen-[3-(2-furyl)-acrylyl]-ethylene glycol;
I-d.1,2-two-oxygen-[3-(2,4 dichloro benzene)-acrylyl]-ethylene glycol.
3. be used to prepare the purposes that suppresses the hepatitis B virus surface antigen medicine according to arbitrary described disubstituted fragrant acyl ethylene glycol compounds of claim 1～2 and pharmacologically acceptable salt thereof.
4. the purposes that is used to prepare the cell toxicant series antineoplastic medicament according to the arbitrary described disubstituted fragrant acyl ethylene glycol compounds of claim 1～2 and pharmacologically acceptable salt thereof.
5. compound 1-e and pharmacologically acceptable salt thereof are used to prepare the purposes of cell toxicant series antineoplastic medicament, and the title that it is characterized by compound 1-e is 1,2-two-oxygen-[3-(4-anisole) acrylyl]-ethylene glycol.
6. pharmaceutical composition that is used to reduce hepatitis B surface antigen, its contain the treatment significant quantity as activeconstituents according to claim 1,2 arbitrary described compound or their mixing, and their pharmacologically acceptable salt and pharmaceutically acceptable auxiliaries.
7. pharmaceutical composition that is used for the treatment of tumor disease, its contain the treatment significant quantity as activeconstituents according to the arbitrary described compound of claim 1～2, compound 1-e, or their mixing and their pharmacologically acceptable salt and pharmaceutically acceptable auxiliaries.
8. according to arbitrary described medicine of claim 3～7 and pharmaceutical composition, its formulation is injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, or its controlled release or slow release formulation or nanometer formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100624508A CN101492373A (en) | 2008-06-17 | 2008-06-17 | Disubstituted fragrant acyl ethylene glycol compounds and medical use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100624508A CN101492373A (en) | 2008-06-17 | 2008-06-17 | Disubstituted fragrant acyl ethylene glycol compounds and medical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101492373A true CN101492373A (en) | 2009-07-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100624508A Pending CN101492373A (en) | 2008-06-17 | 2008-06-17 | Disubstituted fragrant acyl ethylene glycol compounds and medical use |
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| Country | Link |
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Open date: 20090729 |