CN103040810A - Preparation and medical application of substituted tetrahydro-pyran-4-yl ester compound - Google Patents
Preparation and medical application of substituted tetrahydro-pyran-4-yl ester compound Download PDFInfo
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Abstract
The invention relates to preparation and medical application of a substituted tetrahydro-pyran-4-yl ester compound and particularly discloses a compound [(3S,4R,6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-tetrahydro-pyran-4-yl] acrylate or pharmaceutically acceptable salts thereof and a preparation method and medicinal application thereof. The compound has the advantages that the compounding steps are simple and convenient, the preparation method is simple and feasible, the raw materials are conveniently and easily acquired, the cost is low, and the pollution is little. The compound has remarkable fungal growth inhibition activity, and the 80% inhibition concentration of the compound is 125 micrograms/milliliter. Shown by pharmacodynamic results, the compound or pharmaceutically acceptable salts thereof can be expected to be applied to preparation of drugs for prevention and treatment of diseases caused by fungal infection.
Description
Technical field
The present invention relates to medical technical field, particularly, the present invention relates to contain the substituted-tetrahydro pyrans of acrylic-4-base ester type compound [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-and the 2H-tetrahydropyran-4-base] application of acrylate in preparation anti-fungal infection medicine.
Background technology
Along with medical science applied development, being widely used of the medical procedure such as various novel drugs and new technique such as broad ectrum antibiotic, hormone, various intubation catheter technology, chemotherapy, transplanting, and HIV infects and tumor, the case increasing year by year that causes the human immunity system to be destroyed gradually, thus cause the sickness rate of deep mycosis more and more high; And on the other hand, along with being widely used of human abuse of antibiotics and clinical antifungal drug, cause traditional antibiotic can not resist effectively that some serious fungal infection and antibacterial infect, the drug resistance phenomenon of fungus is day by day serious.The antibiotic effect of tradition has met with remarkable bottleneck, and most of antibacterials, fungus have produced significant Drug resistance to common antibiotic; The concurrent fungal infections such as HIV sufferers, patient with severe symptoms, fire victim more make sufferer hang by a hair.Therefore, searching wide spectrum, antifungal new drug efficient, low toxicity have become the focus of drug research; Research to fastbacteria/intractable fungus is extremely urgent.
The disease that fungal infection causes can be divided into following four classes substantially: studies of invasive fungal infections and systemic mycosis (such as aspergillosis and candidiasis etc.), mucosal pattern mycosis (such as " thrush " etc.), shallow phenotype dermatomycosis (such as " tinea pedis " or " tinea capitis ", " tinea unguium " etc.) and anaphylactic type mycosis (such as asthma and chronic inflammatory disease etc.).In above four class mycosises, with the first kind mankind are endangered maximum, then three class mycosises are corresponding light.According to from external clinical statistics data, in dying from the crowd of infectious disease, have 4% to be to die from general aspergillosis mushroom fungal infection, about 2% people dies from the general monilial infection.The clinical statistics data shows that in a single day patient suffers from the general aspergillosis, and its mortality rate is up to 85%, as suffer from the blood candidiasis then its mortality rate can reach 40%.The existing antifungal drug treatment systemic mycosis of utilization or the mycotic effect of blood infection type so far still can't be satisfactory.Therefore, pharmacy circle is being sought the newtype drug that can suppress systemic infection.
At present, the antifungal drug of having developed listing both at home and abroad mainly contains four large classes, i.e. echinocandin (echinocandins) class (such as Caspofungin and Mi Kamin etc.) of polyenoid class (such as amphotericin B), triazole type (such as fluconazol, miconazole, econazole, Itraconazole and ketoconazole etc.), alkyl amine (such as terbinafine) and listing newly developed.Front three major types antifungal agent is the old medicine of 20th century exploitation listing, and the echinocandin class then is the new drug of exploitation listing at the beginning of 21 century.But in said medicine, only have a few can be used for the treatment of systemic fungal infection disease.Antifungal drug in triazole class is the first generation or the second filial generation is all to there being the fungus-caused systemic infection unsatisfactory curative effect of silk no matter, and echinocandin class antifungal new drug is then effective to this class disease.The greatest problem that present echinocandin faces is: there is no peroral dosage form, be only limited to injection (and only limiting to hospital's use), so patient uses rather inconvenience.Secondly, although echinocandin is pretty good to the sick fungal infection curative effect that waits of Candida spp, it is expensive, so limited the sales volume in they markets beyond developed country.As it is reported that on China market, the retail price of every Caspofungin injection (dosage is 50 milligrams) is 3148 yuan, and the Mi Kamin price that Japan produces is slightly low, but every (50 milligrams of dosage) also wants 650 yuan.China's hospital clinical at present the most frequently used general antifungal drug still is fluconazol and terbinafine.
The onset by lanosterol 14 demethylases in the Antifungi ergosterol biosynthesis such as the health azole of old kind such as fluconazol, itraconazole, voriconazole, posaconazole, this type of old brand triazole antifungal agent thing antimicrobial spectrum is narrower and drug resistance grows with each passing day.Metabolisming property and physicochemical property are not good though the new product antimicrobial spectrum enlarges, and water solublity is low, bioavailability is poor; The needs of patients high fat diet is in order to drug absorption, or take the extraordinary dosage form of high price can onset; Also bring larger threat to the renal insufficiency person for increasing cyclodextrin that water solublity adds etc.
In sum, seeking as early as possible new structure, differ from the in the past antifungal lead compound of medicine, is that many decades medicine workers need the promptly task of top priority of development from now on.In order to explore this field, the inventor is according to a large amount of literature surveies, structure activity relationship models coupling 3D-SAR evaluation work (Tripos database software) in conjunction with flood tide, design a class substituted-tetrahydro pyrans-4-base ester type compound, in the hope of the lead compound of discovery energy establishment conk, thereby even it is developed further into the new medicinal products with energy Antifungi growth killing fungus.We synthesize this compounds of preparing design thus, and have tested its growth inhibited effect to multiple fungal bacterial strain.Found that: [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-the trimethoxyphenyl)-2H-tetrahydropyran-4-base] acrylate shown in the formula (1) has significant antifungal activity, finishes thus the present invention.
Summary of the invention
The purpose of this invention is to provide as the formula (1) substituted-tetrahydro pyrans of a kind of structure-4-base ester type compound for the preparation of the purposes of antifungal drug:
The present invention also provides the method for a kind of preparation formula (1) chemical compound:
Wherein, OMe refers to methoxyl group; OEt refers to ethyoxyl.The name of formula (1) chemical compound is called [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-tetrahydropyran-4-base] acrylate.Synthesis condition and reagent: a) 3,4,5-Trimethoxybenzaldehyde, sodium hydride, n-BuLi, anhydrous tetrahydro furan; B) sodium borohydride, methanol; C) Lithium hydrate (1 mol/L), ethanol; D) hydrochloric acid, water; E) dicyclohexylcarbodiimide, pyridine, dichloromethane.
Use initial compounds I, in anhydrous tetrahydrofuran solution, in the presence of sodium hydride and the n-BuLi, obtain Compound I I with the 3,4,5-Trimethoxybenzaldehyde reaction.Compound III makes through sodium borohydride reduction by Compound I I, and compound III obtains sour IV through hydrolysis again.Compound IV makes ester V by molecule inner ring condensation again, and this step is at ambient temperature, and the effect by dicyclohexylcarbodiimide (DCC) and pyridine in the dichloromethane obtains.Target molecule (1) is formed by tetrahydropyrans ester V and organic acid condensation.
Another purpose of the present invention provides the substituted-tetrahydro pyrans shown in the formula (1)-4-base ester type compound or the application of its pharmaceutically useful salt in the medicine of preparation prevention and treatment candida albicans infection disease.
Drug excipient or carrier that another object of the present invention provides the substituted-tetrahydro pyrans that contains shown in the formula (1)-4-base ester type compound and pharmaceutically useful salt thereof and preparation permission are prepared into pharmaceutical composition, and prepared pharmaceutical composition can also contain other antibacteriums and/or antifungal drug.Described medicine can be made multiple dosage form by means known in the art, comprises varnish, membrane, unguentum, injection, transdermal patch, aerosol, controlled release or slow releasing agent, and nanometer formulation.
Through the detailed Literature Consult of the inventor, up to the present, there is no relevant this compounds for the preparation of the report of antifungal drug.This substituted-tetrahydro pyrans-4-base ester type compound belongs to beyond thought discovery for the potent inhibition of conk, and definite originality is arranged, and finishes accordingly the present invention.
Usefulness of the present invention is: the substituted-tetrahydro pyrans shown in the discoverable type (1)-4-base ester type compound has the patent medicine potentiality of Antifungi growth, preparation anti-fungal infection aspect first, provides new material base for exploitation becomes treatment fungal infection original new drug.Has potential huge Social benefit and economic benefit.
The specific embodiment
Further specify the present invention below by embodiment.Embodiment has provided chemical compound [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4, the 5-trimethoxyphenyl)-and the 2H-tetrahydropyran-4-base] preparation method and the part physicochemical data of acrylate, and the part pharmacologically active data of this substituted-tetrahydro pyrans-4-base ester type compound Antifungi growth.The following embodiment of mandatory declaration is for explanation 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:The preparation of [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-tetrahydropyran-4-base] acrylate
1.1 instrument and reagent
Fusing point is measured with micro-meldometer (production of Beijing Imtech), and temperature is not proofreaied and correct; Optically-active is produced Polax-2L type automatic polarimeter in Japan and is measured; Infrared spectrum IR is by Bruker Vector-22 determination of infrared spectroscopy, through the KBr tabletting; Ultraviolet spectra is measured with Shimadzu UV-240 ultraviolet spectrophotometer; Proton nmr spectra
1H NMR, carbon-13 nmr spectra
13C NMR and 2D NMR measure (tetramethylsilane ether TMS is interior mark) by INOVA type NMR spectrometer with superconducting magnet (VARIAN INOVA-400MHz); Electrospray Mass Spectrometry ESI-MS is measured by Bruker Esquire 3000+ mass spectrograph, and column chromatography is Haiyang Chemical Plant, Qingdao's product with silica gel (100-200,200-300 and 300-400 order) and thin layer chromatography with silica GF254 (10-40 order); Agents useful for same is analytical pure, and wherein the petroleum ether boiling range is 60-90 ° of C; Thin layer preparative chromatography (PTLC) the aluminium foil silica gel plate of Merck company; Column chromatography adopts Sweden Amersham Pharmacia Biotech AB company product with polydextran gel Sephadex LH-20; Thin plate (TLC) is surveyed the uviol lamp with 254nm and 365nm; Developer iodine vapor, 10% sulphuric acid-ethanol, phosphorus molybdenum acid solution.
1.2 synthetic and purification
1.2.1 Compound I I[2-methyl-3-oxo-5-hydroxyl-5-(3,4,5-trimethoxyphenyl)-ethyl valerate] synthetic
2.30 gram (95.8 mMs) sodium hydrides are joined in 140 milliliters of oxolanes, drip successively hexane solution (2.10 mol/L), 5.88 gram (30.0 mMs) 3 of 5.4 gram (37.5 mMs) Compound I [2-methyl-acetoacetic ester], 28 milliliters of n-BuLis under the cryosel bath condition, 4,10 milliliters of tetrahydrofuran solutions of 5-TMB, continue reaction 15 minutes, 30 milliliters of saturated ammonium chloride (NH of rear adding
4Cl) solution with 150 milliliters of extracted with diethyl ether three times, merges organic facies, anhydrous sodium sulfate (Na
2SO
4) drying, sucking filtration removes solvent under reduced pressure, crude product through silica gel column chromatography separate (eluent is petroleum ether: ethyl acetate=1:1), get product II[2-methyl-3-oxo-5-hydroxyl-5-(3,4,5-trimethoxyphenyl)-ethyl valerate]: colourless jelly, R
f(ethyl acetate: petroleum ether=1:1)=the 0.59. proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.27 (triplet, 3H, J=7.2Hz ,-OCH
2CH
3), 1.37 (bimodal, 3H, J=7.2Hz, CHCH
3), 3.02 (multiplet, 2H, H-4), 3.55 (quartet, 1H, J=7.2Hz, H-2), 3.83 (unimodal, 3H, 4 '-OCH
3), 3.87 (unimodal, 6H, 2 * OCH
3), 4.21 (multiplet, 2H ,-OCH
2CH
3), 5.14 (multiplet, 1H, H-5), 6.88 (multiplet, 2H, Ar-H).ESI-MS?m/z:341[M+H]
+。
1.2.2 compound III [2-methyl-3,5-dihydroxy-5-(3,4,5-trimethoxyphenyl)-ethyl valerate] is synthetic
3.36 gram (9.9 mMs) Compound I I are dissolved in the mixed solvent of 66 milliliters of oxolanes and 27 ml methanol, add 1.04 gram (27.0 mMs) sodium borohydrides, reaction is 30 minutes under the ice-water bath condition, adds 30 milliliters of saturated NH
4The Cl aqueous solution, 120 milliliters of extracted with diethyl ether three times merge organic facies, anhydrous Na
2SO
4Drying, sucking filtration removes solvent under reduced pressure, crude product through silica gel column chromatography separate (eluent is petroleum ether: ethyl acetate=1:1), get product III[2-methyl-3,5-dihydroxy-5-(3,4,5-trimethoxyphenyl)-ethyl valerate]: yellow oil, R
f(petroleum ether: ethyl acetate=1:1)=the 0.35. proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.22 (bimodal, 3H, J=7.2Hz ,-OCH
2CH
3), 1.37 (bimodal, 3H, J=7.2Hz, CHCH
3), 1.79 (multiplet, 2H, H-4), 2.103 (multiplet, 1H, H-2), 3.82 (unimodal, 3H, 4 '-OCH
3), 3.88 (unimodal, 6H, 2 * OCH
3), 4.17 (multiplet, 2H ,-OCH
2CH
3), 4.27 (multiplet, 1H, H-3), 4.96 (multiplet, 1H, H-5), 6.88 (multiplet, 2H, Ar-H); ESI-MSm/z:343[M+H]
+
1.2.3 compound IV [2-methyl-3,5-dihydroxy-5-(3,4,5-trimethoxyphenyl)-valeric acid] is synthetic
3.39 gram (9.9 mMs) compound III are dissolved in 72 milliliter of 95% ethanol, add 10 milliliters of Lithium hydrates (1 mol/L), stirred 1 hour.Remove ethanol under reduced pressure, add 50 ml waters, with 30 milliliters of ethyl acetate extractions three times.Water layer drips 15 milliliters of hydrochloric acid (1 mol/L), with ethyl acetate extraction repeatedly, merges organic facies, anhydrous Na
2SO
4Drying, sucking filtration removes solvent under reduced pressure, (eluent is petroleum ether to crude product: ethyl acetate=1:4), get compound IV [2-methyl-3,5-dihydroxy-5-(3 through the silica gel column chromatography separation, 4,5-trimethoxyphenyl)-and valeric acid]: yellow oil, proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.22 (bimodal, 3H, J=7.2Hz, CHCH
3), 1.76 (multiplet, 2H, H-4), 2.115 (multiplet, 1H, H-2), 3.82 (unimodal, 3H, 4 '-OCH
3), 3.88 (unimodal, 6H, 2 * OCH
3), 4.30 (multiplet, 1H, H-3), 4.97 (multiplet, 1H, H-5), 6.87 (multiplet, 3H, Ar-H); ESI-MS m/z:315[M+H]
+
1.2.4 chemical compound V[3-methyl-4-hydroxyl-6-(3,4,5-trimethoxyphenyl)-Pentamethylene oxide .-2-ketone] synthetic
2.81 gram (8.9 mMs) compound IV, 1.90 gram (9.0 mMs) dicyclohexylcarbodiimides (DCC) are dissolved in 120 milliliters of dichloromethane, then drip 0.74 milliliter of (9.0 mMs) pyridine.Stirring is spent the night, 30 milliliters of (15 milliliters * 2) distilled water washs, anhydrous Na
2SO
4Drying, sucking filtration removes solvent under reduced pressure, crude product through silica gel column chromatography separate (eluent is petroleum ether: ethyl acetate=2:1), get chemical compound V[3-methyl-4-hydroxyl-6-(3,4,5-trimethoxyphenyl)-Pentamethylene oxide .-2-ketone]: colourless jelly, R
f(petroleum ether: ethyl acetate=1:1)=the 0.35. proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.41 (bimodal, J=7.2Hz, 3H, 3-CH
3), 2.11 (multiplet, 1H, H-3), 2.25 (multiplet, 2H, H-5), 3.88 (unimodal, 3H, 4 '-OCH
3), 3.89 (unimodal, 6H, 2 * OCH
3), 4.28 (wide unimodal, 1H, H-4), 5.63 (multiplet, 1H, H-6), 6.88 (multiplet, 2H, Ar-H); ESI-MS m/z:297[M+H]
+
1.2.5 the preparation of formula (1) chemical compound
60 milligrams of midbody compound V are dissolved in 16 milliliters of dichloroethanes, add dicyclohexylcarbodiimide (DCC) 62 milligrams, 7.6 milligrams of DMAPs (DMAP), add at last 20 milligrams in acrylic acid, reacted 3 hours, filter, filtrate is concentrated that crude product separates through silica gel column chromatography that (eluent is petroleum ether: ethyl acetate=2:1), get product [(3S, 4R, 6R)-and 3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-tetrahydropyran-4-base] acrylate: colourless jelly; R
f(petroleum ether: ethyl acetate=2:1)=0.47; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.31 (bimodal, J=7.2Hz, 3H, 3-CH
3), 2.86 (multiplet, 1H, H-3), 2.55 (multiplet, 2H, H-5), 3.85 (unimodal, 3H, 4 '-OCH
3), 3.89 (unimodal, 6H, 2 * OCH
3), 3.86 (unimodal, 6H, 3 ', 5 '-OCH
3), 4.38 (wide unimodal, 1H, H-4), 5.52 (wide bimodal, 1H, J=8.4Hz, H-6), (5.66 wide bimodal, 1H, J=10Hz), 6.12(is bimodal, 1H, J=2.4Hz), 6.49 (double doublets, 2H, J=10Hz, 2.4Hz), 6.58 (unimodal, 2H, H-2', H-6'); ESI-MS m/z:351[M+H]
+The evaluation structure is as follows:
Embodiment 2:The activity test of formula (1) chemical compound Antifungi
Standardization antifungal sensitivity testing method with reference to standard committee of American National clinical laboratory (NCCLS) proposition, the formula that test implementation example 1 prepares (1) chemical compound [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-and the 2H-tetrahydropyran-4-base] extracorporeal antifungal activity of acrylate.
2.1 fungus type strain:
Candida albicans ATCC10231: Chongqing Center for Disease Control (CDC) provides;
Candida albicans ATCC76615: attached Long March hospital of The 2nd Army Medical College provides.
2.2 reagent:
2.2.1 sabouraud's agar (sabouraud dextrose agar): the triumphant microorganism in Guangdong Science and Technology Ltd. product.
2.2.2 yeast extract (yeast extract): the packing of worker's biotechnology Services Co., Ltd is given birth in the sea.
2.2.3 three morpholino nitrogen quinoline propane sulfonic acid (3-N-morpholinopropanesulfonicacid, MOPS).
2.2.4 testing drug: fluconazol (Fluconazole, FCZ), company of Yangzijiang Pharmaceutical Group; Formula (1) chemical compound.The doubling dilution liquid that testing drug is configured to the variable concentrations gradient is stand-by.
2.2.5 dimethyl sulfoxide (dimethyl sulfoxide, DMSO) and dimethyl formamide (dimethylformamide, DMF): Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing product.
2.3 instrument:
2.3.1 electronic balance JA1203N(AB204-5, METTLER TOLEDO): Shanghai exact science instrument company product.
2.3.2SW-CJ-2FD the double single face clean work station of type: Purifying Equipment Co., Ltd., Suzhou's product.
2.3.3 water isolation type constant incubator (GSP-9160MBE): Shanghai Yiheng Scientific Instruments Co., Ltd's product.
2.3.4 electro-heating standing-temperature cultivator (HZQ-F160A): Shanghai Yiheng Scientific Instruments Co., Ltd's product.
2.3.5 U.S. Pedicellus et Pericarpium Trapae electric refrigerator (BCD-221CHC): Hefei Meiling Co. Ltd.'s product.
2.3.6 micropipettor (Proline Pipette, DragonMed Pipette): Finland Lei Bo company product.
2.3.7 cell counting count board (96 well cell culture cluster): Shanghai refinement instrument company product.
2.3.8 ordinary optical microscope (Olympus): Japanese Olympus optical instrument Co., Ltd. product.
2.3.9 hot air oven (101A-2): Shanghai Chongming experimental apparatus company product.
2.3.10 vertical autoclave sterilizer (YXQ-LS-50S II): the rich industry company limited product of proving to be true after interrogation in Shanghai.
2.3.11 magnetic force heating stirrer (ARE): Italian VELP company product.
2.3.12 filter membrane, filter (0.22 μ m, Sartorius): Sartorius AG's product.
2.3.13 acidometer (PHSJ-4A): Lei Ci company of upper Nereid section product.
2.3.14 test tube oscillator (MS2): laboratory technique company of Guangzhou instrument section product.
2.3.15 constant-temperature shaking incubator (THZ-18AB): the permanent scientific instrument in Shanghai one company product.
2.3.16 cryogenic refrigerator (20 ℃, the dragon BCD-219WAK of section): dragon electrical equipment Co., Ltd of Guangdong section product.
2.3.1796 the flat microtest plate in hole: U.S. Corning Incorporated product.
2.4 experimental technique:
2.4.1 experimental procedure:
2.4.1.1RPMI-1640 the preparation of liquid: get 10.4 gram RPMI-1640 powder and (contain the L glutamine, do not contain sodium bicarbonate, GIBCO) be dissolved in 900 ml sterile waters, adding 34.53 grams, three morpholino nitrogen quinoline propane sulfonic acid (MOPS) to its endpoint concentrations is 0.165 mol/L, uses magnetic stirring apparatus mixing 2-3 hour under the room temperature, and it is fully dissolved, regulate pH value to 7.0(25 ° of C with sodium hydroxide (1 mol/L)), be settled to 1 liter with aquesterilisa, Entkeimung ,-20 ℃ save backup after the packing.
2.4.1.2 the preparation of storing solution: take by weighing 10 milligrams of fluconazol (FCZ) with electronic balance, and with 1 milliliter of dimethyl formamide (DMF) dissolving, be diluted to 1280 ug/ml with RPMI-1640 afterwards ,-70 ℃ save backup after the packing.
2.4.1.3 use the preparation of liquid: it is rare with RPMI-1640 liquid storing solution to be done to remake multiple proportions after 1:10 dilutes, and FCZ is the concentration that 128 ug/ml-0.25 ug/ml is made 10 series.
2.4.1.4 the preparation of micro-susceptibility culture plate: use disposable 96 orifice plates, the 1-10 row add respectively the application liquid of the testing drug of 10 Concentraton gradient, from the high concentration to the low concentration.The 11st row add RPMI-1640, every hole 100 microlitres, the 12nd row are as blank, it is for subsequent use to put into-20 ℃ of refrigerators, during use through-4 ° of C, 4 ° of C and room temperature each 1 hour.
2.4.1.5 the activation of candidiasis and dilution: with bacterial strain to be measured at YPD Agar culture medium (1% yeast extract, 1% peptone, 2% glucose) after activating twice on, bacteria suspension is made greater than a little mixing in 3 milliliters of physiological saline solution of bacterium colony of 1 millimeter in the cut-off footpath, get a little, with the bacterial cell number in four large grids of hemocyte technology plate counting, the X that averages, this moment, the bacterial cell number was X * 10
4The CFU/ milliliter, adjusting concentration with RPMI-1640 liquid is 3 * 10
4CFU/ milliliter (twice final concentration).
2.4.1.6 application of sample: add the candidiasis suspension at the above-mentioned culture plate that contains testing drug for preparing, every hole 100 microlitre blanks do not add, and concussion is put into 35 ° of C of wet box (prevent evaporating of micro plate and affect the concentration of medicine) behind the mixing and hatched observed result after 24-48 hour.
2.4.1.7 naked eyes judged result: take the growth control blank as foundation, suppressing with 80% (is MIC
80) for observing terminal point, growth obviously reduces, liquid is slightly muddy; Well-grown in the simultaneously positive growth, blank is limpid, without bacterial growth.The MIC value of Quality Control bacterial strain shows that experimental result is effective in the scope of U.S. Clinical microorganism laboratory standard CLSI M27-A2 scheme regulation.
2.5 experimental result: see Table 1.
Table 1 testing drug is to Candida albicans fungus inhibitory action (unit: ug/ml)
2.6 conclusion:
By adopting " Herbs By Broth Microdilution " Research-type (1) chemical compound to the antibacterial activity in vitro of two kinds of fungus reference cultures, experimental study shows: [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-and the 2H-tetrahydropyran-4-base] acrylate has clear and definite antifungal activity to 2 kinds of albicans strains.Illustrate that it is potential Antifungi growth activity material, have further exploitation and be worth.
Substituted-tetrahydro pyrans shown in the formula for preparing among the present invention (1)-4-base ester type compound can be combined with adjuvant or carrier pharmaceutically commonly used, prepares to have prevention and treatment by medicine and pharmaceutical composition or health product or the cosmetics of everyday use of the fungus-caused infection such as Candida albicans.The dosage form that above-mentioned various kinds of drug compositions, health product or cosmetics of everyday use can adopt comprises varnish, membrane, unguentum, injection, transdermal patch, aerosol, controlled release or slow releasing agent, and nanometer formulation.
Substituted-tetrahydro pyrans-4-base ester type compound as the formula (1) of the present invention can also with medicine and the crude drug thereof of the treatment fungal infection associated conditions that has now gone on the market, as: the polyenoid class (as, amphotericin B), triazole type (as, fluconazol, miconazole, econazole, Itraconazole and ketoconazole etc.), alkyl amine (as, terbinafine) and the kind such as the echinocandin of listing newly developed (echinocandins) unite use, prepare compositions or compound preparation with treatment fungal infection associated conditions effect activity, can expect becomes treatment fungal infection disease medicine/health product or cosmetics of everyday use.Above-mentioned various kinds of drug compositions, medicine/health product or cosmetics of everyday use can adopt the dosage forms such as varnish, membrane, unguentum, injection, transdermal patch, aerosol, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slow release, controlled release form or the nanometer formulation that gets.
When above-mentioned description elaboration was of the present invention, the purpose that embodiment is 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 (3)
1. chemical compound shown in the formula (1) or its pharmaceutically useful salt are for the preparation of the medicinal usage of anti-fungal infection, the name of this chemical compound is called [(3S, 4R, 6R)-3-methyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-and the 2H-tetrahydropyran-4-base] acrylate;
2. pharmaceutical composition that is used for the disease that the control fungal infection causes is characterized in that: the treatment effective dose according to claim 1 in formula (1) chemical compound or drug excipient or the carrier of its pharmaceutically useful salt and preparation permission be prepared into pharmaceutical composition.
3. according to claim 2 pharmaceutical composition, it is characterized in that: the dosage form of described pharmaceutical composition is varnish, membrane, unguentum, injection, transdermal patch, aerosol, controlled release or slow releasing agent.
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| CN111712487A (en) * | 2018-02-16 | 2020-09-25 | 捷恩智株式会社 | Polymerizable compound, polymerizable composition, polymer, and composition for photoresist |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1721416A (en) * | 2004-07-15 | 2006-01-18 | 浙江海正集团有限公司 | Substituted methylene pyrones derivatives and their preparing process and use |
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| CN1721416A (en) * | 2004-07-15 | 2006-01-18 | 浙江海正集团有限公司 | Substituted methylene pyrones derivatives and their preparing process and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111712487A (en) * | 2018-02-16 | 2020-09-25 | 捷恩智株式会社 | Polymerizable compound, polymerizable composition, polymer, and composition for photoresist |
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