CN101548970A - Application of lignin flavanonol in preparation of antiviral drugs - Google Patents
Application of lignin flavanonol in preparation of antiviral drugs Download PDFInfo
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Abstract
The invention relates to application of lignin flavanonol in preparation of antiviral drugs, particularly, the invention relates to a chemical compound as formula (I), (+-)-2-[2,3-dihydro-2-(3,5-dimethoxy-4-hydroxy phenyl)-3-hydroxymethyl-1,4-benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-benzopyrone-4-ketone, or use of its medicinal salt used for preparing drugs for repressing herpes simplex virus and/or influenza virus. Pharmacological experiments in vitro shows that the chemical compound (I) can not only repress growth of herpes simplex virus HSV-1, HSV-2 obviously, and repress influenza virus effectively. And so it is expected to be develpoed as anti-infective agents for curing I/II type herpes simplex virus, or develpoed as viral influenza drugs infected by IV A virus.
Description
Technical field
The present invention relates to medical technical field, particularly, the present invention relates to a lignin flavanone 01 derivatives is formula (I) chemical compound, (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt are used to prepare the purposes that suppresses herpes simplex virus medicament or be used to prepare anti-influenza virus medicament.
Background technology
The herpes simplex virus diameter is about the 120-150 micron, the nuclear that contains DNA is positioned at middle, outwards form by peplos, body quilt, three kinds of concentric structures of capsid successively, the capsid surface is 3: 3: 2 axisymmetric 20 bodies that 162 shell microgranules are formed, can survive the several months damp and hot 50 ℃ and dry 90 ℃ of deactivations in 30 minutes at low temperatures.Herpes simplex virus can be divided into two kinds on I type and II type, I type herpesvirus (HSV-1) mainly infects the mucocutaneous and organ of waist with the upper part, HSV-1 is mainly by respiratory tract, skin and the close contact transmission of mucosa, the inflammation and the herpes of 99% lip mucosa, nasal vestibule, eye conjunctiva, bottleneck throat, a mouth and a mouthful herpes that takes place are on every side all caused by I type herpesvirus infection.II type herpesvirus (HSV-2) mainly is present in penis, urethra of women's cervix uteri, vagina, skin of vulva and male etc. to be located, and is the arch-criminal who causes genitals inflammation and herpes.
Oral ulcer is outbreak repeatedly easily, does not still have the specific treatment method at present, and main clinically treatment measure comprises topical therapeutic and whole body therapeutic, and western medical treatment is oral with iodine glycerol and vitamin B1, B2 and vitamin C with the part, and general curative effect is very unobvious.Seriously, obstinate oral ulcer then need take hormone drugs, antibiotics quasi drugs etc. orally, use this type of medicine to have bigger toxic and side effects again and easily make patient produce the weak point of drug resistance and dysbacteriosis.The Chinese medicine medicine for external use comprises external preparation such as XILEI SAN, BINGPENG SAN, but therapeutic effect is not very good; Oral medicine comprises cow-bezoar anti-toxic bolus, cow-bezoar bolus for clearing away heat of the upper part of the body etc., but this disease is not had significant specific aim.Many new buccal tablets class pharmaceutical preparation such as watermelon crystal buccal tablet, cydiodine and the lysozyme buccal tablet etc. that occur are progressive to some extent aspect mouthfeel, sterilization, antiinflammatory respectively in the recent period, but some is unsuitable for women breast-feeding their children, hyperthyroidism patient and iodine allergy person again.Therefore, the innovative medicine of use modern disease poison technology of science, excavating out the treatment oral ulcer is extremely urgent.
HSV-2 virus is after sexual organ's contact, hide about 2-20 days (average 6 days), HSV-2 infects and can be divided into former and recur two kinds in the genital herpes clinical manifestation cause, and disease sites has burn feeling earlier, very fast 3-10 red pimple in groups takes place on the erythema basis, with pruritus, pimple becomes phlysis very soon, becomes pustule after 3-5 days, forms large stretch of erosion and ulcer behind the ulceration, conscious pain, incrustation healing at last.Sustainable about 20 days of the whole course of disease.The male sends out in glans penis, coronary sulcus, urethral orifice, penis, scrotum, thigh and arm etc. well and locates.The good occurring in YIN part of the body lip of women, mons pubes, clitoris, crissum or vagina; About 90% patient, virus can be invaded cervix uteri simultaneously, occurs that vaginal secretions increases or lower abdominal pain, and can concurrent cervicitis and metritis.The enlargement of most of male and female patient bilateral inguinal lymph nodes.When the later stage inflammation involves urethra, bladder, dysuria, dysurea, frequent micturition, severe patient can occur phenomenons such as urine retention can take place.In addition, also have other symptom and occur simultaneously, incomplete as heating, general malaise, headache, stiffness of the neck, meningitis and sacrum portion nervous function.
Genital herpes virus is in close relations with genital malignant tumor, and the II type herpesvirus that causes genital herpes may be the potential cancerigenic factor of cervical cancer.Discover, the women who suffered from genital herpes did not get the dangerous big 5-10 times of cervical cancer than suffering from the person, and, in cervical cancer tissues, strip off cell or found II type herpesvirus specific antigen precancer in the cell, thereby show that II type herpesvirus has played important function in the generating process of cervical cancer.In addition, from carcinoma of penis patient's biopsy material, also observe herpes simplex virus sample granule.In addition, people notice that also the anemia of pregnant woman infects the seriousness of II type herpes in recent years: concerning the patient or asymptomatic toxin expelling of gestation, the most serious is to infect to give neonate, and the anemia of pregnant woman suffers from genital herpes can cause fetal anomaly, miscarriage, stillbirth.
HSV-2 is infected the viral disease that causes does not still have the specific treatment method at present, and main clinically treatment measure is antiviral drugs such as employing acyclovir.In addition, human leukocyte interferon also can suppress virus breeding, reduces the relapse rate of genital herpes.Yet use this type of hormone drugs, antibiotics quasi drugs medicine to have bigger toxic and side effects and easily make patient produce the weak point of drug resistance and dysbacteriosis.
The traditional Chinese medical science is called " erosion of vulva " with II type herpes-ness progenitalis infection disease, and its characteristic of disease belongs to heat syndrome, excess syndrome in early days, is damp and hot, poison fire retardance the liver pulse; Later stage is then with deficiency of the liver and kindey.The Chinese medicine medicine for external use comprises external 1% chlorine zinc oil, Radix Arnebiae (Radix Lithospermi) wet goods method, but therapeutic effect is not very good; Square medicine commonly used is that the sacred Tonga of detoxicating subtracts, cow-bezoar anti-toxic bolus, LIUWEI DIHUANG WAN plus-minus and Decoction of Gentiana for Purging the Liver-fire etc., but this disease is not had significant specific aim.
Therefore, use modern disease poison technology of science, utilize the Modern Pharmaceutical Chemistry means, seek the lead compound skeleton of novelty, develop that novel therapeutic II herpes simplex virus type that the side effect that can either avoid the ucleosides antiviral drugs can effectively suppress virus again infects and control genital herpes medicine is very necessary.
In addition, influenza virus has hyperinfection, thus very easily take place popular, or even worldwide being very popular.China also is the multiple ground of influenza, and 3 worldwide being very popular since nineteen fifty-seven are all originated from China.Influenza Virus orthomyxovirus section, Influenza Virus comprises first, second, the third three types, first type antigenic variability is the strongest, infects human and other animals, in causing, the severe disease, attacks all age group crowds, often causes worldwide being very popular.Because some restrictions that influenza virus vaccine is used, and this vaccine is to factors such as clinical influenza patient are invalid, and antiviral treatment still plays crucial effect in the control of influenza.Antiviral drugs can be divided into ion channel M2 blocker, neuraminidase inhibitor, influenza virus receptor blocking agent and resisiting influenza virus antisense oligonucleotide etc. according to them at the different links of virus replication.What enter clinical practice at present is mainly ion channel M2 blocker and neuraminidase inhibitor.Ion channel M2 blocker mainly contains two kinds: amantadine and rimantadine.They all can produce significant gastrointestinal tract, central nervous system's side reaction, as nervousness, anxiety, absent minded, headache, nausea and vomiting etc.These side effect are generally lighter, how to occur in several hours after medication, can rapidly disappear mostly after the drug withdrawal.Because it is active that ion channel M2 blocker lacks the Type B influenza virus, easily produce drug resistance, and toleration is poor, so they are not widely used.Neuraminidase inhibitor: the neuraminidase inhibitor that enters clinical practice at present has zanamivir and Oseltamivir, but does not find the specific medicament of treatment influenza infection disease up to now as yet.
In like manner, seeking from the natural drug template and optimize novel anti influenza lead compound also is very urgent task.With positive drug ribavirin (virazole) is contrast, and test compounds is the clear and definite and necessary means that screening suppresses the influenza virus lead compound to the protective effect of Testis et Pentis Canis passage cell (MDCK) influenza virus infection IVA (influenza A virus).
Flavanolignan's chemical compound belongs to weedtree quality class, is the natural product that is contained the C6-C3-C6-C3-C6 construction unit by a class of a part phenylpropyl alcohol element and a part flavone be combined into.Its representative compounds surely belongs to the lignin flavanonol silibinin in the seed that is present in the feverfew Herba Silybi mariani.Herba Silybi mariani is extensive use clinically, its commodity Legalon by name on market
TMGrand or the Flavobion of sharp liver
TMThis medical instrument of the clinical trial certificate of three more than ten years has definite curative effect and hypotoxicity (to consult people such as Flora K., Am.J.Gastroenterol, 1998,93,139-143; People such as Saller R., Drugs, 2001,61 (14), 2035-2063).Therefore, the flavanolignan's compounds that with the silibinin is representative has caused increasing concern, also have obvious antioxidation activity (Yang Leixiang, Zhao Yu etc. as the inventor in a series of silibinin analog derivatives of preparation in 2006 and report, " Synthesis and Antioxidant PropertiesEvaluation of Novel Silybin Analogues ", Journal of Enzyme Inhibition andMedicinal Chemistry, 2006,21 (4), 399-404).
The silibinin compounds has the definite multiple curative effect of the above, yet it comprises that in anti-virus aspect the new purposes that suppresses herpes simplex virus, suppresses influenza virus is effectively developed as yet, so we have prepared and the silibinin structure new derivant of difference to some extent, also promptly introduce a pair of horses going side by side and close the different dioxane substituent group in position, just formed the lignin flavanone alcohol compound of some novel structures thus at flavone parent B ring.Use at the antiviral that aforementioned silybin derivant is possible, we have tested its inhibition I herpes simplex virus type HSV-1, II herpes simplex virus type HSV-2 and have suppressed the pharmacologically active that influenza virus IVA (FM-1 strain) duplicates, in the hope of finally obtaining the chemical entities that can effectively suppress the independent intellectual property right of above-mentioned viral infection.Result of the test is found: the synthetic lignin flavanone alcohol compound that obtains is (±)-2-[2 among the present invention, 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone all has definite inhibition activity to HSV-1, HSV-2 and FM-1 Strain, can be used as the broad-spectrum antiviral medicament lead compound and continue exploitation, thereby finish the present invention.
Summary of the invention
The object of the present invention is to provide a lignin flavanone alcohol compound with formula (I) structure is (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt are prevented and treated by the viral infection of herpes simplex virus HSV-1 initiation and/or the purposes of stomatocace medicine in preparation.
A further object of the present invention has provided a kind of be used to the to prevent and treat viral infection that caused by herpes simplex virus HSV-1 and/or the medicine or the pharmaceutical composition of oral ulcer, and it contains the formula as active component (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable auxiliaries for the treatment of effective dose.According to the present invention, can add various pharmaceutically acceptable pharmaceutical excipient, additive and carriers in this pharmaceutical composition.
Another purpose of the present invention has provided formula (I) chemical compound and has been used to prepare the purposes of control by the genital herpes virus infection medicine of II herpes simplex virus type HSV-2 initiation.
Another object of the present invention has provided a kind of medicine or pharmaceutical composition that is used to prevent and treat the genital herpes that is caused by II herpes simplex virus type HSV-2, and it contains the formula as active component (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable auxiliaries for the treatment of effective dose.According to the present invention, can add various pharmaceutically acceptable pharmaceutical excipient, additive and carriers in this pharmaceutical composition.
A further object of the present invention has provided formula (I) chemical compound and has been used to prepare the purposes of control by the viral influenza medicine of influenza virus IVA initiation.
Another object of the present invention has provided a kind of viral influenza medicine or pharmaceutical composition that is used to prevent and treat by influenza virus IVA initiation, and it contains the formula as active component (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable auxiliaries for the treatment of effective dose.According to the present invention, can add various pharmaceutically acceptable pharmaceutical excipient, additive and carriers in this pharmaceutical composition.
Another purpose of the present invention has provided a kind of method by chemical synthesis process preparation formula (I) chemical compound.The synthesis route feature of this method is: with chemical compound 2,4,6-trimethoxy methoxyacetophenone (1) and 1,2-dimethoxy methoxybenzaldehyde (2) is an initiation material, condensation obtains chalcone derivative (3) in organic solvent and aqueous alkali, epoxidation obtains epoxy chalcone derivative (4) under the effect of alkaline hydrogen peroxide, (4) cyclization obtains flavanonol (±)-2-(2 in acid organic solvent, the 3-dihydroxy phenyl) 2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone (5); Under the catalyst silver catalyst, (5) with 3,5-dimethoxy-4 '-hydroxyl cinnamyl alcohol (6) carries out the free radical coupling reaction and generates chemical compound (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, idiographic flow is as follows:
Wherein, OMOM is meant the methoxy methoxy base.
Characteristics of the present invention are, prove through pharmacological evaluation: the complete synthesis lignin flavanone alcohol compound that obtains is formula (I) chemical compound (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone duplicates I herpes simplex virus type HSV-1, II herpes simplex virus type HSV-2 and influenza virus IVA (FM-1 strain) all definite inhibitory action, illustrates that this chemical compound is expected to develop into broad-spectrum antiviral medicament lead compound and medicine.
Usefulness of the present invention is: the structure optimization of natural product silibinin is obtained having inhibition HSV-1 virus, HSV-2 virus and the active formula of influenza FM-1 Strain (I) chemical compound, i.e. (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, suppressing viral innovative medicine for the exploitation wide spectrum provides new material base.This chemical compound can be got through synthetic transformation of several steps by simple raw material, and raw material sources conveniently are easy to get, and preparation process is easy, and cost is low, and productive rate is higher, is beneficial to industrialization.Therefore, the present invention has potential social benefit and economic benefit.
The specific embodiment
The lignin flavanone alcohol compound for preparing among the present invention is the conventional method of formula (I) compound or pharmaceutically acceptable salt thereof in the pharmaceutical field, in conjunction with in, conventional pharmaceutically acceptable auxiliaries in the Western medicine pharmacy, can make various pharmaceutical compositions, as injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, or controlled release or slow release formulation or nanometer formulation.These pharmaceutical compositions can be used to prevent and treat viral infection and/or the oral ulcer that is caused by herpes simplex virus HSV-1.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof can also with the associating of the common drug of the treatment herpes simplex infections that has now gone on the market, oral ulcer or the use that intersects, prepare and have the pharmaceutical composition or the compound preparation for the treatment of herpes simplex infections, oral ulcer.Medicament example capable of being combined comprises Ah former times's network Wei (ACV), valaciclovir (VCV), general former times network Wei (FCV), penciclovir (PCV), vidarabine (ara-T), bromine ethylene deoxidation guanosine (BVDU), phosphine formic acid (PFA), former times network Wei (GCV) etc. more.In addition, its can also with neuralgia analgesic and ntipyretic analgesic medicine drug combination.
The common drug associating or the use that intersects that formula of the present invention (I) compound or pharmaceutically acceptable salt thereof can also infect with the treatment herpes simplex virus HSV-2 that now gone on the market prepare and have the compositions or the compound preparation for the treatment of genital herpes.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof can combine with adjuvant or carrier pharmaceutically commonly used, prepares medicine and pharmaceutical composition with disease that prevention and treatment influenza virus cause.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof can also be united with the medicine of influenza virus inhibitor that has gone on the market or other treatment influenza associated conditions and crude drug thereof such as amantadine, rimantadine and/or neuraminidase inhibitor such as zanamivir and Oseltamivir etc. and used or intersects use, prepares to have pharmaceutical composition or the compound preparation of preventing and treating influenza infection.
Above-mentioned various kinds of drug compositions or compound preparation can adopt drug forms such as tablet, capsule, injection, aerosol, suppository, membrane, drop pill, comprise various slow release, controlled release form or nanometer formulation that the now generally acknowledged pharmaceutics general knowledge of employing gets via the routine preparation.
Further specify the present invention below by embodiment.Embodiment has provided the data of preparation and the purification process and the dependency structure evaluation thereof of formula (I) chemical compound.Mandatory declaration, preparation method described in the embodiment and isolation and purification method are to be used for explanation of the present invention rather than limitation of the present invention.
In order to understand essence of the present invention better, the present invention also passes through mode formula (I) chemical compound of embodiment to herpes simplex virus HSV-1, HSV-2 and the inhibiting The pharmacological results of influenza virus IVA (FM-1 strain).Same mandatory declaration, these pharmacology related embodiment of the present invention are still and are 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: formula (I) chemical compound (±)-2-[2,3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5, the preparation of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone
1.1 starting material A-2,4, the preparation of 6-trimethoxy methoxyacetophenone (1):
40 milliliters of DMF solution ice-water baths coolings with 2.6 sodium hydrides that restrain; Dropwise 5 .6 gram 2,4 under the nitrogen protection state, 60 milliliters of benzene of 6-trihydroxy-acetophenone and the mixed solution of 7.0 milliliters of DMF; the ice bath cooling drips 9.0 milliliters of chloromethyl ether solution down, stirs 24 hours under the room temperature.In 100 milliliter of 10% sodium hydrate aqueous solution of impouring, ether extraction 3 times, each 50 milliliters, the saturated sodium bicarbonate washing, anhydrous sodium sulfate drying, filter, concentrate, 40 grams, 200～300 order silica gel column chromatographies, 4: 1 eluting of petroleum ether/ethyl acetate, obtain 7.0 gram starting material A (2,4,6-trimethoxy methoxyacetophenone).Yellow oil.R
f(petroleum ether/ethyl acetate=3: 1): 0.30; Proton nmr spectra (400MHz, deuterochloroform): δ 2.52 (unimodal, 3H, CH
3), 3.50 (unimodal, 9H, OCH
3), 5.17 (unimodal, 6H, OCH
2O), 6.52 (unimodal, 2H, H-3,5).
1.2 starting material B-1, the preparation of 2-dimethoxy methoxybenzaldehyde (2):
2,3-4-dihydroxy benzaldehyde 4.8 grams are dissolved in 30 milliliters of acetone, stir to add potassium carbonate 17.5 grams after 10 minutes, drip 6 milliliters of chloromethyl ethers (MOMCl) again, and reflux 1 hour is filtered, and filtrate concentrating obtains yellow oil 7.0 grams, is directly used in next step reaction.
1.3 the preparation of intermediate chalcone derivative (3):
2.8 the gram potassium hydroxide dissolves in 30 ml methanol, stirring drips down 10 milliliters of the mixing methanol solutions of 1.4 gram starting material A and 1.3 gram starting material B, stirs 8 hours under the room temperature, removes solvent under reduced pressure, in residue, add 20 ml waters, ethyl acetate extraction (3 times, each 20 milliliters) merges organic layer, after removing solvent under reduced pressure, residue is through 30 grams, 200～300 order silica gel column chromatographies, and 3: 1 eluting of petroleum ether/ethyl acetate obtain 1.76 gram intermediate chalcone derivative.Yellow oil; R
f(petroleum ether/ethyl acetate=2: 1): 0.38; UV (methanol) λ max:209,300nm.Be used for next step reaction.
1.4 the preparation of epoxy chalcone derivative (4):
1.4 gram intermediate chalcone derivative is dissolved in 25 ml methanol, adds 1.6 milliliters of 2N potassium hydroxide aqueous solutions, adds 1.6 milliliter of 30% hydrogen peroxide solution again, stirring at room 2 hours.Add 25 ml waters, concentrating under reduced pressure, with ethyl acetate extraction (3 times, each 20 milliliters), merge organic layer, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure after, residue is through 20 grams, 200～300 order silica gel column chromatographies, 3: 1 eluting of petroleum ether/ethyl acetate obtain 1.1 gram intermediate epoxy chalcone derivative.Yellow oil; R
f(petroleum ether/ethyl acetate=2: 1): 0.33; UV (methanol) λ max:210,285nm.Be used for next step reaction.
1.5 flavanonol (±)-2-(2, the 3-dihydroxy phenyl) 2,3-dihydro-3,5, the preparation of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone (5):
1.0 gram intermediate epoxy chalcone derivative is dissolved in 15 ml methanol, add under the stirring in the 10 ml methanol solution that are dissolved with 1.5 milliliters of concentrated hydrochloric acid, heat up 60 ℃ and react half an hour, remove heating, remove solvent after the cooling under reduced pressure, in residue, add 50 ml waters, with ethyl acetate extraction (3 times, each 20 milliliters), merge organic layer, saturated common salt washing 2 times, anhydrous sodium sulfate drying filters, after removing solvent under reduced pressure, residue is through 20 grams, 200～300 order silica gel column chromatographies, and 3: 1 eluting of petrol ether/ethyl acetate obtain 97 milligrams (±)-2-(2, the 3-dihydroxy phenyl) 2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.Yellow oil.R
f(petroleum ether/ethyl acetate=2: 1): 0.29; Be directly used in next step reaction.
1.6 the preparation of formula (I) chemical compound:
In exsiccant reaction bulb, drop into Disilver carbonate 0.22 gram, add 20 milliliters of anhydrous benzene and 5 milliliters of anhydrous propanones, drip 90 milligrams (±)-2-(2 under the room temperature, the 3-dihydroxy phenyl) 2,3-dihydro-3,5,5 milliliters and 89 milligram 3 of the anhydrous benzene solution of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, 3 milliliters of the anhydrous propanone solution of 5-dimethoxy-4 '-hydroxyl cinnamyl alcohol (6), insulation reaction is 20 hours in the time of 55 ℃.Leave standstill after being chilled to room temperature, the elimination insoluble matter, the mother solution concentrating under reduced pressure gets yellow oil, and through 20 grams, 200～300 order silica gel column chromatographies, 10: 1 eluting of chloroform/methanol obtain 26 milligrams of formulas (I) chemical compound.
R
f(chloroform/methanol/ethyl acetate/acetone/acetic acid=11: 0.5: 1: 1: 0.1): 0.24; Proton nmr spectra
1H NMR (400MHz, deuterated acetone) δ: 3.92 (multiplet, 1H, H-23a), 4.22 (multiplet, 1H, H-23b), 4.78 (H-10), 4.95 is (bimodal for multiplet, 1H, J=11.2Hz, 1H, H-3), 5.51 (multiplet, 1H, H-11), 5.65 (bimodal, J=11.2Hz, 1H, H-2), 5.84 (bimodal, J=1.2Hz, 1H, H-6), 5.88 is (bimodal, J=1.2Hz, 1H, H-8), 6.78～6.93 (multiplet, 3H, H-14,18,22), 7.05 (bimodal, J=8.0Hz, 1H, H-15), 7.11 (bimodal, J=8.0Hz, 1H, H-13), 10.07 (wide unimodal, 1H, OH-20), 10.41 is (wide unimodal, 1H, OH-7), 12.33 (unimodal, 1H, 5-OH); Electrospray Mass Spectrometry ESI-MS:511 (M-1)
+
Because silver catalyst coupling reaction product down is based on anti-configuration, so the advantage product that the present invention obtains also is 11 of dioxane and 12 raceme products of anti-configuration each other.
Embodiment 2: adopt mtt assay to measure the cytotoxicity of formula (I) chemical compound, and suppress (CPE) method with micro-cytopathy and study its inhibitory action test HSV-1 to the Vero cell
2.1 experiment purpose
The Vero cell that infects with HSV-1 is a model, screens anti-HSV medicine, and wherein sample is from formula (I) compound sample of embodiment 1.
2.2 material
2.2.1 virus and cell
2.2.1.1 virus: HSV-1 is provided by pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department;
2.2.1.2 cell: the Vero cell is available from Shanghai RESEARCH ON CELL-BIOLOGY institute of the Chinese Academy of Sciences.
2.3 reagent
2.3.1RPMI 1640 culture medium: Gibco company product;
2.3.2L-glutamine: AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
2.3.3MTT:AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
2.3.4 hyclone: Gibco company product;
2.3.5 penicillin sodium: Jiangxi east wind Pharmaceutical limited company product;
2.3.6 streptomycin sulfate: Huabei Pharmaceutic Co., Ltd's product;
2.3.7 positive control drug: acyclovir (ACV), Hubei KeYi Pharmacentic Co., Ltd., 0.25g/ props up.
2.4 instrument
2.4.1CO
2Incubator: U.S. Shellab company product;
2.4.2XD-2 inverted microscope: Chongqing Optical ﹠ Electrical Instrument Co., Ltd.'s product;
2.4.3 Biohazard Safety Equipment: U.S. LABCONCO company product;
2.4.4Synergy HT microplate reader: U.S. BIO-TEK company product;
2.4.5LDZX-40BI the vertical automatic electric heating pressure steam sterilizer of type: Shenan Medical Appliances Factory, Shanghai's product.
2.5 cell culture and virus go down to posterity
The Vero cell culture in containing 10% deactivation calf serum, in the RPMI1640 culture medium of 100U/ ml penicillin and 100 mcg/ml, is put 37 ℃, and 5% carbon dioxide is cultivated in the incubator of 100% relative humidity.HSV-1 is added in the cell bottle of the long Vero that has, put 37 ℃, 5% carbon dioxide is cultivated in the incubator of 100% relative humidity, collects culture supernatant, puts under the low temperature and preserves.
2.6 experimental technique
2.6.1 adopt MTT[3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt] method measures the inhibitory action of formula (I) chemical compound to the growth of Vero cell:
(1) formula that testing drug: embodiment 1 prepares (I) chemical compound; The positive control drug of acyclovir (ACV).
(2) the take the logarithm Vero cell of trophophase becomes 1 * 10 with culture medium with cell dilution
5/ milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres, at 37 ℃, 5% carbon dioxide, cultivate formula (I) chemical compound that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml, 20 mcg/ml and 10 mcg/ml, place incubator to cultivate, cultivate after 72 hours, every hole adds MTT reagent 10 microlitres, continues to cultivate 4 hours, discard culture medium, every hole adds dimethyl sulfoxine 200 microlitres, with agitator vibration 20 minutes, measures the OD value with microplate reader under the 570nm wavelength.With the culture hole that only adds culture medium is control wells.Suppression ratio (%)=(control wells OD value-experimental group OD value)/control wells OD value * 100%.The experiment triplicate.According to the suppression ratio of cell growth under the variable concentrations, calculate the median toxic concentration (TD of cell growth
50).
2.6.2 with micro-cytopathic-effect inhibition assay working sample to the viral growth inhibitory action:
The take the logarithm Vero cell of trophophase becomes 1 * 10 with culture medium with cell dilution
5/ milliliter is inoculated in 96 porocyte culture plates, and 37 ℃, 5% carbon dioxide, 100% relative humidity was cultivated 24 hours, added 100TCID
50Virus 100 microlitres, inclining virus, adds formula (I) chemical compound of variable concentrations respectively, establishes the contrast of normal cell contrast and viral infection simultaneously, 37 ℃, 5% carbon dioxide, the cultivation of 100% relative humidity after 48 hours under inverted microscope the observation of cell pathological changes.With the Pyatyi standard as judging cytopathic standard ,-: cell no change, score value are 8 minutes; +: pathological changes appears in 25% following cell, and score value is 6 minutes; ++: pathological changes appears in 25%～50% cell, and score value is 4 minutes; Pathological changes appears in +++: 50%～75% cell, and score value is 2 minutes; ++ ++: pathological changes appears in 75% above cell, and score value is 0 minute.
2.6.3 experimental result:
Formula (I) chemical compound suppresses the percent inhibition that HSV-1 duplicates under 100 mcg/ml concentration be 25%, is 100% and positive control medicine Ah former times network Wei suppresses the percent inhibition that HSV-1 duplicates under 100 mcg/ml concentration.
2.6.4 conclusion:
Above-mentioned result of the test explanation, formula (I) chemical compound has certain inhibitory action to the I herpes simplex virus type, though its inhibition strength is lower than the positive control drug acyclovir, but it is the non-nucleosides compound that is derived from natural product, belong to the HSV-1 inhibitor that has positive effect in this compounds, thereby can expect that it is developed further into the medicine into inhibition HSV-1 virus and anti-treating dental ulcer, or can unite use with the treatment HSV-1 virus infective medicament that goes on the market.
Embodiment 3: micro-cytopathy suppresses the inhibitory action of (CPE) method research formula (I) chemical compound to HSV-2
3.1 experiment purpose
The Vero cell that infects with HSV-2 is a model, screens anti-HSV medicine, and wherein sample is from the formula that makes among the embodiment 1 (I) compound sample.
3.2 material
3.2.1 virus and cell
3.2.1.1 virus: HSV-2 is provided by pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department;
3.2.1.2 cell: the Vero cell is available from Shanghai RESEARCH ON CELL-BIOLOGY institute of the Chinese Academy of Sciences.
3.2.2 reagent
3.2.2.1RPMI 1640 culture medium: Gibco company product;
3.2.2.2L-glutamine: AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
3.2.2.3MTT:AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
3.2.2.4 hyclone: Gibco company product;
3.2.2.5 penicillin sodium: Jiangxi east wind Pharmaceutical limited company product;
3.2.2.6 streptomycin sulfate: Huabei Pharmaceutic Co., Ltd's product;
3.2.2.7 positive control drug: acyclovir (ACV), Hubei KeYi Pharmacentic Co., Ltd., 0.25g/ props up.
3.2.3 instrument
3.2.3.1CO
2Incubator: U.S. Shellab company product;
3.2.3.2XD-2 inverted microscope: Chongqing Optical ﹠ Electrical Instrument Co., Ltd.'s product;
3.2.3.3 Biohazard Safety Equipment: U.S. LABCONCO company product;
3.2.3.4Synergy HT microplate reader: U.S. BIO-TEK company product;
3.2.3.5LDZX-40BI the vertical automatic electric heating pressure steam sterilizer of type: Shenan Medical Appliances Factory, Shanghai's product.
3.3 method
3.3.1 virus virulence is measured: in growing up to the cell of monolayer, add the viral liquid of 10 times of continuous doubling dilutions, from 10
-1To 10
-9Deng totally 9 concentration, at 37 ℃, 5% carbon dioxide was cultivated 48 hours under the 100% relative humidity condition, used the mtt assay colorimetric then, measured the virulence of virus, with TCID
50Expression.
3.3.2 sample toxicity test: the medicine serial dilution is become 4 concentration (100 mcg/ml with culture medium, 10 mcg/ml, 1 mcg/ml), add cell respectively and grown up in 96 well culture plates of monolayer, every hole 200 microlitres place 37 ℃, 5% carbon dioxide, cultivate in the incubator of 100% relative humidity, cultivate the toxicity of using mtt assay working sample pair cell after 72 hours, calculate median toxic concentration (TD
50).
3.3.3 the cytopathic-effect inhibition assay working sample is to the viral growth inhibitory action: cell inoculation 96 well culture plates, 37 ℃, 5% carbon dioxide, 100% relative humidity was cultivated 24 hours, added 2 * 100TCID
50Virus 100 microlitres, adsorbed 2 hours, incline and virus, adding Cmax respectively is the variable concentrations sample of non-toxic concn, normal cell contrast and viral infection contrast are established, 37 ℃ simultaneously in every concentration 3 holes, 5% carbon dioxide, 100% relative humidity are cultivated after 72 hours observation of cell pathological changes under inverted microscope.With the Pyatyi standard as judging cytopathic standard ,-: cell no change, score value are 8 minutes; +: pathological changes appears in 25% following cell, and score value is 6 minutes; ++: pathological changes appears in 25%～50% cell, and score value is 4 minutes; Pathological changes appears in +++: 50%～75% cell, and score value is 2 minutes; ++ ++: pathological changes appears in 75% above cell, and score value is 0 minute.
3.4 result
Formula (I) chemical compound suppresses the percent inhibition that HSV-2 duplicates under 100 mcg/ml concentration be 35%, is 100% and positive control medicine Ah former times network Wei suppresses the percent inhibition that HSV-2 duplicates under 100 mcg/ml concentration.
3.5 conclusion
Above-mentioned result of the test explanation, formula (I) chemical compound has certain inhibitory action to the II herpes simplex virus type, though its inhibition strength is lower than the positive control drug acyclovir, but it is the non-nucleosides compound that is derived from natural product, belong to the HSV-2 inhibitor that has positive effect in this compounds, thereby can expect that it is developed further into the medicine into the control genital herpes, or unite use with the treatment HSV-2 virus infective medicament that goes on the market.
Embodiment 4: the resisiting influenza virus effect of formula (I) chemical compound that micro-cytopathy inhibition (CPE) method research embodiment 1 prepares
4.1 experiment purpose
The Vero cell that infects with influenza A virus (IVA) is a model, the screening anti-influenza virus medicament, and wherein sample is from embodiment 1 formula (I) compound sample.
4.2 material
4.2.1 virus and cell
4.2.1.1 virus: influenza A virus (IVA) is provided by pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department; Virus is inoculated in the chick embryo allantoic cavity of 9-11 age in days according to routine, cultivates 72 hours for 35 ℃, and 4 ℃ of refrigerator overnight are collected allantoic fluid.Carry out hemagglutination test (HA test), recorded virus titer 1: 1280.
4.2.1.2 cell: the Madin-Darby canine kidney(cell line) (MDCK) mdck cell is available from Shanghai RESEARCH ON CELL-BIOLOGY institute of the Chinese Academy of Sciences.
4.2.2 reagent
4.2.2.1RPMI 1640 culture medium: Gibco company product;
4.2.2.2L-glutamine: AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
4.2.2.3MTT:AMRESCO product, Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing;
4.2.2.4 hyclone: Gibco company product;
4.2.2.5 penicillin: Shijiazhuang Pharmaceutical Group Co Ltd's product;
4.2.2.6 streptomycin: Shijiazhuang Pharmaceutical Group Co Ltd's product;
4.2.2.7 positive control drug: ribavirin (RBV), Yangzhou Zhongbao Pharmaceutical Co., Ltd., 0.1 grams per milliliter.
4.2.3 instrument
4.2.3.1CO
2Incubator: U.S. Shellab company product;
4.2.3.2XD-2 inverted microscope: Chongqing Optical ﹠ Electrical Instrument Co., Ltd.'s product;
4.2.3.3 Biohazard Safety Equipment: U.S. LABCONCO company product;
4.2.3.4Synergy HT microplate reader: U.S. BIO-TEK company product;
4.2.3.5LDZX-40BI the vertical automatic electric heating pressure steam sterilizer of type: Shenan Medical Appliances Factory, Shanghai's product.
4.3 method
4.3.1 virus virulence is measured:
One bottle in the cell of trophophase 4.3.1.1 take the logarithm, the digestion back adds RPMI-1640, is inoculated in 96 porocyte culture plates, and every hole 100 microlitres, were cultivated 24 hours by 37 ℃;
4.3.1.2 take out 96 orifice plates next day, discard culture fluid after, use Hank ' s liquid to wash twice;
4.3.1.3 virus is taken out from cryogenic refrigerator, adds the viral liquid of 10 times of continuous doubling dilutions respectively, from 10
-1To 10
-9Deng totally 9 concentration, at 37 ℃, 5% carbon dioxide was cultivated 48 hours under the 100% relative humidity condition, and observation of cell pathological changes effect (CPE) is then measured the virulence of virus, and outcome record is: " ++ ++ " be 100% pathological changes; " +++" be 75% pathological changes; " ++ " is 50% pathological changes; "+" is 25% pathological changes, "-" negative result.
4.3.2 sample toxicity test:
One bottle in the cell of trophophase 4.3.2.1 take the logarithm, the digestion back adds RPMI-1640, is inoculated in 96 porocyte culture plates, and every hole 100 microlitres, were cultivated 24 hours by 37 ℃;
4.3.2.2 take out 96 orifice plates next day, discard culture fluid after, use Hank ' s liquid to wash twice;
4.3.2.3 the medicine serial dilution that will prepare with serum-free 1640 culture medium becomes 4 concentration (1000 mcg/ml, 100 mcg/ml, 10 mcg/ml, 1 mcg/ml), add cell respectively and grown up in 96 well culture plates of monolayer, every hole 100 microlitres, place 37 ℃, 5% carbon dioxide is cultivated in the incubator of 100% relative humidity, cultivates 72 hours;
4.3.2.4 under the 570nm wavelength, use the microplate reader colorimetric, calculate the suppression ratio under each concentration, the median toxic concentration (TD of calculation sample pair cell
50).
4.3.3 the cytopathic-effect inhibition assay working sample is to the viral growth inhibitory action:
One bottle in the cell of trophophase 4.3.3.1 take the logarithm, the digestion back adds RPMI-1640, is inoculated in 96 porocyte culture plates, and every hole 100 microlitres, were cultivated 24 hours by 37 ℃;
4.3.3.2 take out 96 orifice plates next day, discard culture fluid after, use Hank ' s liquid to wash twice;
Culture fluid in 96 orifice plates 4.3.3.3 incline, adding 1640 dilution back concentration is 100TCID
50Virus liquid 100 microlitres, 37 ℃, 5%CO
2Under adsorbed 2 hours.
4.3.3.4 adding formula (I) chemical compound maximal non-toxic concentration (TD
0=1600 mcg/ml) medicinal liquid is made 6 concentration of continuous 2 times of dilutions, every concentration 3 holes, 37 ℃, 5%CO
2Under cultivated 3 days.Add ribavirin (virazole) maximal non-toxic concentration (TD
0) medicinal liquid makes 6 concentration of continuous 2 times of dilutions, 37 ℃, 5%CO
2Under cultivated 3 days.Set up experimental drug and positive drug, cell contrast and virus control group respectively.Microscopically observation of cell pathological changes after 3 days, record lesion degree (CPE).Press the antiviral effect of Reed-Muench method difference calculating formula (I) chemical compound and ribavirin.
4.4 result of the test: the medium effective concentration IC of formula (I) chemical compound of measuring according to the CPE method
50=218 mcg/ml; Therapeutic index TI=TD
50/ IC
50=7.3; And medium effective concentration 5.0 mcg/ml of the ribavirin of positive control; Therapeutic index TI=253.0.
4.5 conclusion:
The explanation of above-mentioned result of the test, formula (I) chemical compound has certain inhibitory action to influenza A virus, can be developed further into the medicine into the control influenza A, or with the medication combined use of treatment influenza a virus infection of going on the market.
When above-mentioned description 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 (7)
1. chemical compound (±)-2-[2 of structure shown in the formula (I), 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt are used to prepare the purposes of the medicine of viral infection that treatment causes by I herpes simplex virus type HSV-1 and/or oral ulcer;
Wherein, the spatial configuration that formula (I) chemical compound is 11,12 is trans each other, also is that the two is R simultaneously or is the S configuration simultaneously.
2. chemical compound (±)-2-[2 of structure shown in the formula (I), 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt are used to prepare the purposes of treatment by the medicine of the genital herpes of II herpes simplex virus type HSV-2 initiation.
3. chemical compound (±)-2-[2 of structure shown in the formula (I), 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt are used to prepare the purposes of control by the medicine of the viral influenza of influenza virus IVA initiation.
4. one kind is used to prevent and treat by the viral infection of I herpes simplex virus type HSV-1 initiation and/or the medicine or the pharmaceutical composition of oral ulcer, it contains (±) as the active component-2-[2 that treats effective dose, 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt and pharmaceutically acceptable auxiliaries.
5. a medicine or pharmaceutical composition that is used to prevent and treat the genital herpes that causes by II herpes simplex virus type HSV-2, it contains (±) as the active component-2-[2 that treats effective dose, 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt and pharmaceutically acceptable auxiliaries.
6. a medicine or pharmaceutical composition that is used to prevent and treat the viral influenza that causes by influenza virus IVA, it contains (±) as the active component-2-[2 that treats effective dose, 3-dihydro-2-(3,5-dimethoxy-4 '-hydroxy phenyl)-3-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone or its officinal salt and pharmaceutically acceptable auxiliaries.
7. according to medicine or the pharmaceutical composition of claim 4～6 described in each, its dosage form is injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, or controlled release or slow release formulation or nanometer formulation.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014013503A1 (en) * | 2012-07-16 | 2014-01-23 | Bhaskara Rao Katragadda | Viral trappers |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014013503A1 (en) * | 2012-07-16 | 2014-01-23 | Bhaskara Rao Katragadda | Viral trappers |
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