CN103040801B - Preparation and medical application of aromatic ring substituted ethyl valerate - Google Patents
Preparation and medical application of aromatic ring substituted ethyl valerate Download PDFInfo
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Abstract
The invention relates to preparation and medical application of aromatic ring substituted ethyl valerate and particularly discloses a compound 2-methyl-3-oxo-5-hydroxy-5-(3,4-dimethoxyphenyl)-ethyl valerate 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 substituted ethyl valerate compound or pharmaceutically acceptable salts thereof can be expected to be applied to the 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 aromatic ring and replace ethyl valerate compounds 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate in the purposes of preparing aspect anti-fungal infection medicine.
Background technology
Along with medical science applied development, various novel drugs and new technique are widely used as the medical procedure 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 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 mankind's abuse of antibiotics and clinical antifungal drug, cause traditional antibiotic can not effectively resist 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 (as aspergillosis and candidiasis etc.), mucosal pattern mycosis (as " thrush " etc.), shallow phenotype dermatomycosis (as " tinea pedis " or " tinea capitis ", " tinea unguium " etc.) and anaphylactic type mycosis (as asthma and chronic inflammatory disease etc.).In above four class mycosises, with the first kind, the mankind are endangered to maximum, then three class mycosises are corresponding light.According to the clinical statistics data from external, 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 general monilial infection.Clinical statistics data shows, once patient suffers from general aspergillosis, its mortality rate is up to 85%, as suffer from blood candidiasis its mortality rate can reach 40%.Utilize existing antifungal drug treatment systemic mycosis or the mycotic effect of blood infection type so far still cannot be satisfactory.Therefore, pharmacy circle is being found 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 (as Caspofungin and meter Ka Min etc.) of polyenoid class (as amphotericin B), triazole type (as fluconazol, miconazole, econazole, Itraconazole and ketoconazole etc.), alkyl amine (as terbinafine) and listing newly developed.Front three major types antifungal agent is the old medicine of 20th century exploitation listing, and echinocandin class 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 effective to this class disease.The greatest problem that echinocandin faces is at present: there is no peroral dosage form, be only limited to injection (and only limiting to hospital's use), therefore 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, in China market, the retail price of every Caspofungin injection (dosage is 50 milligrams) is 3148 yuan, and the meter Ka Min price that Japan produces is slightly lower, but every (50 milligrams of dosage) also wants 650 yuan.China's hospital clinical at present the most frequently used general antifungal drug is still fluconazol and terbinafine.
The health azole of old kind is as the onset by lanosterol 14 demethylases in Antifungi ergosterol biosynthesis such as fluconazol, itraconazole, voriconazole, posaconazole, and this type of old brand triazole antifungal agent thing antimicrobial spectrum is compared with narrow and drug resistance grows with each passing day.Though new product antimicrobial spectrum expands, metabolisming property and physicochemical property are not good, and water solublity is low, bioavailability is poor; Needs of patients high fat diet is in order to drug absorption, or take the extraordinary dosage form of high price can onset; For increasing cyclodextrin that water solublity adds etc., also to renal insufficiency person, bring larger threat.
In sum, finding as early as possible new structure, differ from the antifungal lead compound of medicine in the past, 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 and replace ethyl valerate compounds, to finding the effectively lead compound of Antifungi growth, thereby even be 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: 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-the Dimethoxyphenyl)-ethyl valerate shown in formula (1) has significant antifungal activity, completes thus the present invention.
Summary of the invention
The object of this invention is to provide a kind of structure replacement ethyl valerate compounds as the formula (1) for the preparation of the purposes of antifungal drug:
The present invention also provides the method for a kind of preparation formula (1) compound:
Wherein, OMe refers to methoxyl group; OEt refers to ethyoxyl.The name of formula (1) compound is called 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate.Synthesis condition and reagent: a) iodomethane, sodium metal, ethanol; B) Veratraldehyde, sodium hydride, n-BuLi, oxolane.
Another object of the present invention is to provide the replacement ethyl valerate compounds shown in formula (1) or the application of its pharmaceutically useful salt in the medicine of preparation prevention and treatment candida albicans infection disease.
Another object of the present invention is to provide the drug excipient or the carrier that contain the replacement ethyl valerate compounds shown in formula (1) and pharmaceutically useful salt and preparation permission and is 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 replacement ethyl valerate ester type compound belongs to beyond thought discovery for the potent inhibition of conk, has definite originality, completes accordingly the present invention.
Usefulness of the present invention is: the replacement ethyl valerate compounds shown in discoverable type (1) has the patent medicine potentiality that Antifungi is grown, prepared anti-fungal infection aspect first, for exploitation becomes treatment fungal infection original new drug, provides new material base.Its preparation method is simple, and raw material sources are conveniently easy to get, and cost is low, it is little to pollute, be beneficial to the large-scale production under energy-saving and emission-reduction condition.Industrialization prospect is very clear and definite.There is potential huge Social benefit and economic benefit.
The specific embodiment
Below by embodiment, further illustrate the present invention.Embodiment has provided preparation method and the part physicochemical data of formula (1) compound 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate, and the part pharmacologically active data of this compound Antifungi growth.The following embodiment of mandatory declaration is for the present invention rather than limitation of the present invention are described.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the scope of protection of present invention.
embodiment 1:the preparation of 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate
1.1 instruments and reagent
Micro-meldometer for fusing point (production of Beijing Imtech) is measured, and temperature is not proofreaied and correct; Optically-active is produced on Polax-2L type automatic polarimeter and is measured in Japan; Infrared spectrum IR is by Bruker Vector-22 determination of infrared spectroscopy, through 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 Esquire3000+ mass spectrograph, silica gel for column chromatography (100-200,200-300 and 300-400 order) and for thin layer chromatography silica GF254 (10-40 order) be Haiyang Chemical Plant, Qingdao's product; Agents useful for same is analytical pure, and wherein petroleum ether boiling range is 60-90 ° of C; The aluminium foil silica gel plate of Merck company for thin layer preparative chromatography (PTLC); Column chromatography adopts Sweden Amersham PharmaciaBiotech AB company product with polydextran gel Sephadex LH-20; Thin plate (TLC) is surveyed the uviol lamp with 254nm and 365nm; Iodine vapor, 10% sulphuric acid-ethanol, phosphorus molybdenum acid solution for developer.
1.2 synthetic and purifications
According to following reaction process, the ethyl acetoacetate (I) of take is starting material, and through 2 step reactions (a, b), final purification obtains formula (1) compound;
A) preparation of 2-methyl-acetoacetic ester (Compound I I):
In 300 milliliters of ethanol, add 13.8 grams of sodium metals (0.6 mole), after dissolving completely, drip ethyl acetoacetate (I) 80 milliliters, heat up and reflux 1 hour, drip 50 milliliters of iodomethane, reflux two hours, be cooled to room temperature, rotary evaporation is removed ethanol, adds extracted with diethyl ether for water (5 * 50 milliliters), merges organic facies, anhydrous sodium sulfate drying, sucking filtration, rotary evaporation is removed ether, distilling under reduced pressure, collect 78-80 ℃ of (13mmHg) fraction, can obtain the colourless transparent liquid of Compound I I.
B) preparation of 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate:
Cryosel is bathed under cooling condition, in the oxolane suspension (140 milliliters) of 2.3 grams of sodium hydrides, drip 5.78 grams of 2-methyl-acetoacetic esters, then drip containing 28 milliliters of the hexane solutions of 2.5 moles of n-BuLis, after 10 minutes, drip containing 5.88 gram 3, the tetrahydrofuran solution of 4-dimethoxy benzaldehyde (10 milliliters), continue reaction 15 minutes, in reaction system, add saturated aqueous ammonium chloride (30 milliliters), with ether (3 * 50 milliliters), extract, merge organic facies, with saturated common salt water washing (3 * 20 milliliters), anhydrous sodium sulfate drying, sucking filtration, silica gel column chromatography (petrol ether/ethyl acetate: 2/1) obtain yellow oily liquid, Rf (ethyl acetate/petroleum ether: 1/1): 0.59, be target compound.Product structure warp
1h NMR and ESI-MS are accredited as 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate.
Proton nmr spectra
1h NMR (400MHz, deuterochloroform): δ 1.27 (triplet, J=7.2Hz, 3H, CH
2cH
3), 1.37 (bimodal, J=7.2Hz, 3H, CHCH
3), 2.86～3.17 (multiplet, 2H, H-4a, H-4b), 3.55 (quartet, J=7.2Hz, 1H, H-2), 3.83 (unimodal, 3H, 4 '-OMe), 3.87 (unimodal, 3H, 3 '-OMe), 4.21 (multiplet, 2H, CH
2cH
3), 5.14 (multiplet, 1H, H-5), 6.84～6.91 (multiplet, 3H, H-2 ', H-5 ', H-6 '); Mass spectrum ESI-MSMS:m/z311[M+H]
+.Evaluation structure is as follows:
embodiment 2:the activity test of formula (1) compound Antifungi
The standardization antifungal sensitivity testing method proposing with reference to standard committee of American National clinical laboratory (NCCLS), the extracorporeal antifungal activity of the formula that test implementation example 1 prepares (1) compound 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate.
2.1 fungus type strains:
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): Guangdong triumphant microorganism Science and Technology Ltd. product.
2.2.2 yeast extract (yeast extract): Hai Shenggong biotechnology Services Co., Ltd subpackage.
2.2.3 three morpholino nitrogen quinoline propane sulfonic acid (3-N-morpholinopropanesulfonicacid, MOPS).
2.2.4 testing drug: positive control is standard antifungal injection fluconazol (Fluconazole, FCZ), company of Yangzijiang Pharmaceutical Group; Formula (1) compound.The doubling dilution liquid that testing drug is configured to variable concentrations gradient is stand-by.
2.2.5 dimethyl sulfoxide (dimethylsulfoxide, DMSO) and dimethyl formamide (dimethylformamide, DMF): Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's subpackage product.
2.3 instruments:
2.3.1 electronic balance JA1203N(AB204-5, METTLER TOLEDO): Shanghai exact science instrument company product.
2.3.2SW-CJ-2FD the double one side 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 (96well 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): Shanghai Bo Xun Industrial Co., Ltd. product.
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): upper Nereid Ke Lei magnetic company product.
2.3.14 test tube oscillator (MS2): Guangzhou Yi Ke laboratory technique company product.
2.3.15 constant-temperature shaking incubator (THZ-18AB): Shanghai Yi Heng scientific instrument company product.
2.3.16 cryogenic refrigerator (20 ° of C, section dragon BCD-219WAK): Guangdong Ke Long electrical equipment Co., Ltd product.
2.3.1796 the flat microtest plate in hole: U.S. Corning Incorporated product.
2.4 experimental techniques:
2.4.1 experimental procedure:
2.4.1.1RPMI-1640 the preparation of liquid: get 10.4 grams of RPMI-1640 powder (containing L glutamine, not containing sodium bicarbonate, GIBCO) be dissolved in 900 ml sterile waters, adding 34.53 gram of three morpholino nitrogen quinoline propane sulfonic acid (MOPS) to its endpoint concentration is 0.165 mol/L, under room temperature, with magnetic stirring apparatus, mixes 2-3 hour, and it is fully dissolved, with sodium hydroxide (1 mol/L), regulate pH value to 7.0(25 ° of C), with aquesterilisa, be settled to 1 liter, Entkeimung, after subpackage ,-20 ° of C save backup.
2.4.1.2 the preparation of storing solution: take 10 milligrams of fluconazol (FCZ) with electronic balance, and dissolve with 1 milliliter of dimethyl formamide (DMF), be diluted to 1280 mcg/ml afterwards with RPMI-1640, after subpackage ,-70 ° of C save backup.
2.4.1.3 apply the preparation of liquid: with RPMI-1640 liquid, storing solution is done to after 1:10 dilutes, remake multiple proportions rare, FCZ is that 128 mcg/ml-0.25 mcg/ml are made 10 serial concentration.
2.4.1.4 the preparation of micro-susceptibility culture plate: use disposable 96 orifice plates, 1-10 row add respectively the application liquid of the testing drug of 10 Concentraton gradient, from high concentration to low concentration.The 11st row add RPMI-1640, every hole 100 microlitres, the 12nd row, as blank, are put into-20 ° of C refrigerators standby, 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: by bacterial strain to be measured at YPD Agar culture medium (1% yeast extract, 1% peptone, 2% glucose) upper activation after twice, cut-off footpath be greater than 1 millimeter bacterium colony a little in 3 milliliters of physiological saline solution, mix and make bacteria suspension, get a little, with the bacterial cell number in four large grids of hemocyte technology plate counting, the X that averages, now bacterial cell number is X * 10
4cFU/ milliliter, with RPMI-1640 liquid, adjusting concentration is 3 * 10
4cFU/ milliliter (twice final concentration).
2.4.1.6 application of sample: add candidiasis suspension on the above-mentioned culture plate that contains testing drug 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) after mixing and hatched observed result after 24-48 hour.
2.4.1.7 naked eyes judged result: take growth control blank as foundation, (is MIC with 80% inhibition
80) for observing terminal, growth obviously reduces, liquid is slightly muddy; Well-grown in positive growth simultaneously, blank is limpid, without bacterial growth.In the scope of Quality Control bacterial strain ZhiMICZhi U.S. Clinical microorganism laboratory standard CLSI M27-A2 scheme regulation, show that experimental result is effective.
2.5 experimental results: in Table 1.
Table 1 testing drug is to Candida albicans fungus inhibitory action (unit: mcg/ml)
2.6 conclusions:
By adopting the antibacterial activity in vitro of " Herbs By Broth Microdilution " Research-type (1) compound to two kinds of fungus reference cultures, experimental study shows: 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate has clear and definite antifungal activity to 2 kinds of albicans strains.Illustrate that it is potential Antifungi growth activity material, there is further exploitation and be worth.
Replacement ethyl valerate compounds shown in the formula preparing in the present invention (1) can be combined with pharmaceutically conventional adjuvant or carrier, prepares and has prevention and treat medicine and pharmaceutical composition or health product or the cosmetics of everyday use by 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.
Replacement ethyl valerate compounds as the formula (1) of the present invention can also with medicine and the crude drug thereof of the treatment fungal infection associated conditions now having gone on the market, as: 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) combine use, prepare compositions or the compound preparation with treatment fungal infection associated conditions effect activity, can expect and become 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 now conventional preparation of generally acknowledged pharmaceutics general knowledge of employing and various slow release, controlled release form or nanometer formulation.
When above-mentioned description elaboration is of the present invention, the object that embodiment is provided is simultaneously to illustrate actual mechanical process of the present invention and meaning of the present invention.In the time of within the scope of entering the claims in the present invention and its equivalent, practical application of the present invention comprises all general variations, cooperation, or improves.
Claims (1)
1. the application of formula (1) compound or pharmaceutically acceptable salt thereof in the medicine of preparation prevention or treatment fungal infection; It is characterized by, the name of formula (1) compound is called 2-methyl-3-oxygen-5-hydroxyl-5-(3,4-Dimethoxyphenyl)-ethyl valerate;
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990478A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | 6-aryl-3-substituted methylene pyranone compounds, preparation process and use thereof |
| CN101092414A (en) * | 2006-06-23 | 2007-12-26 | 赵昱 | Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation |
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2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990478A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | 6-aryl-3-substituted methylene pyranone compounds, preparation process and use thereof |
| CN101092414A (en) * | 2006-06-23 | 2007-12-26 | 赵昱 | Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation |
Non-Patent Citations (3)
| Title |
|---|
| BIODIVERSITY》.2005,第2卷第557-567页. * |
| Xiangrui Jiang et.al.Design,Synthesis,and Biological Evaluation of New Territrem B Analogues.《CHEMISTRY & BIODIVERSITY》.2005,第2卷第557-567页. |
| Xiangrui Jiang et.al.Design,Synthesis,and Biological Evaluation of New Territrem B Analogues.《CHEMISTRY & * |
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