CN103044375B - A kind of dihydropyrane ketone compound and preparation method thereof and pharmaceutical use - Google Patents
A kind of dihydropyrane ketone compound and preparation method thereof and pharmaceutical use Download PDFInfo
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Abstract
The present invention relates to a kind of dihydropyrane ketone compound and preparation method thereof and pharmaceutical use, specifically, the invention discloses compound (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone or its pharmaceutically useful salt and preparation method thereof and medicinal use.The synthesis step of this compound is easy, preparation method is simple, raw material sources are conveniently easy to get, cost is low, it is little to pollute.This compound has significant fungal growth inhibition activity, and its 80% inhibition concentration is 125 mcg/ml.Pharmacodynamic result shows that this substituted-dihydro pyranone compounds or its pharmaceutically useful salt can be expected as the pharmaceutical use preparing the disease that control fungi infestation causes.
Description
Technical field
The present invention relates to medical art, specifically, the present invention relates to substituted-dihydro pyrone compound (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone preparation method and preparing the application in anti-fungal infection medicine.
Background technology
Along with medical science applied development, various novel drugs and new technology widely using as medical procedure such as Broad spectrum antibiotics, hormone, various intubation catheter technology, chemotherapy, transplanting, and HIV and tumour, cause human immune system to be increased year by year by the case destroyed gradually, thus cause the sickness rate of deep mycosis more and more high; And on the other hand, along with widely using of mankind's abuse of antibiotics and clinical antifungal drug, cause conventional antibiotic can not effectively resist some serious fungal infections and bacteriological infection, fungi resistance phenomenon day by day serious.The effect of conventional antibiotic has met with remarkable bottleneck, and most of bacterium, fungi create significant resistance to common microbiotic; The concurrent fungal infections such as AIDS patient, patient with severe symptoms, fire victim more make sufferer hang by a hair.Therefore, find wide spectrum, antimycotic new drug that is efficient, low toxicity has become the focus of drug research; Extremely urgent to the research of resistant organism/intractable fungi.
The disease that fungi infestation causes can be divided into following four classes substantially: studies of invasive fungal infections and systemic mycosis (as aspergillosis and moniliosis etc.), mucosal pattern mycosis (as " white mouth " etc.), shallow phenotype tinea (as " tinea pedis " or " tinea capitis ", " tinea unguium " etc.) and anaphylactic type mycosis (as asthma and chronic inflammatory diseases etc.).In above four class mycosises, endanger maximum with the first kind to the mankind, then three class mycosises are corresponding comparatively light.According to from external clinical statistics data, in the crowd dying from infectious diseases, have 4% to be die from the fungi infestation of general aspergillus mushroom, the people of about 2% dies from systemic Candida infections.Clinical statistics data shows, patient once suffer from general aspergillosis, its mortality ratio up to 85%, as suffer from blood borne moniliosis then its mortality ratio can reach 40%.Utilizing existing antifungal drug to treat systemic mycosis or the mycotic effect of blood infection type so far still cannot be satisfactory.Therefore, pharmacy circle is finding the newtype drug that can suppress systemic infection.
At present, the antifungal drug having developed both at home and abroad listing mainly contains four large classes, i.e. echinocandin (echinocandins) class (as Caspofungin and meter Ka Min etc.) of polyenoid class (as amphotericin B), triazole species (as fluconazole, miconazole, econazole, itraconazole and KETOKONAZOL etc.), alkyl amine (as Terbinafine) and listing newly developed.Front three major types antifungal drug is the old medicine of 20th century exploitation listing, and echinocandin class is then develop the new drug of 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.The antifungal drug in triazole class no matter first-generation or the s-generation is all to there being the fungus-caused systemic infection unsatisfactory curative effect of silk, the antimycotic new drug of echinocandin class is then effective to this kind of disease.The greatest problem that current echinocandin faces is: there is no oral dosage form, be only limited to injection (and being only limitted to hospital's use), therefore patient uses rather inconvenience.Secondly, although echinocandin waits fungal infection curative effect pretty good to Candida spp disease, it is expensive, so limit the sales volume in their market beyond developed country.As it is reported, in China market, the retail price of often propping up Caspofungin injection (dosage is 50 milligrams) is 3148 yuan, and the meter Ka Min price that Japan produces is slightly lower, but often props up (dosage 50 milligrams) and also want 650 yuan.The most frequently used at present systemic antifungal medicine of China's hospital clinical is still fluconazole and Terbinafine.
The health azole of old kind is as the onset by lanosterol 14 demethylase in the biosynthesizing of Antifungi ergosterol such as fluconazole, itraconazole, voriconazole, posaconazole, and this type of old brand triazole antifungal agent thing antimicrobial spectrum is narrower and resistance grows with each passing day.Though new product antimicrobial spectrum expand metabolisming property and physicochemical property not good, water-soluble low, bioavailability is poor; Needs of patients high fat diet is in order to drug absorption, or the extraordinary dosage form taking high price can onset; For increasing water-soluble and the cyclodextrin that adds etc. also bring larger threat to renal insufficiency person.
In sum, finding novel texture as early as possible, differ from the antimycotic lead compound of medicine in the past, is that many decades medicine workers will need the task of top priority of promptly development from now on.In order to explore this field, the present inventor is according to a large amount of literature surveies, in conjunction with the structure activity relationship models coupling 3D-SAR evaluation work (Tripos database software) of flood tide, design a class substituted-dihydro pyranone compounds, to find can the lead compound of effective Antifungi growth, even thus be developed further into and have and can grow the new medicinal products of killing fungus by Antifungi.We prepare this compounds of design at synthesis thus, and test its growth-inhibiting effect to multiple fungal bacterial strain.Found that: (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5, the 6-dihydropyrane-2-ketone shown in formula (1) has significant anti-mycotic activity, completes the present invention thus.
Summary of the invention
The object of this invention is to provide the purposes of a kind of structure substituted-dihydro pyranone compounds as the formula (1) for the preparation of antifungal drug:
Present invention also offers the method for a kind of preparation formula (1) compound, it is characterized in that: aromatic ring formaldehyde and 2-methyl-acetoacetic ester obtain target compound through reacting as follows: the first step, and under cooling conditions, 2-methyl-acetoacetic ester is through sodium hydride effect; Second step, the tetrahydrofuran solution dripping n-Butyl Lithium under-10 ~-40 ° of C low temperature reacts 10 ~ 20 minutes, continues reaction 20 ~ 60 minutes after adding Veratraldehyde; 3rd step, adds the tetrahydrofuran solution of sodium hydroxide, reacts 10 ~ 30 minutes under cooling conditions; 4th step, with hydrochloric acid soln cancellation.
Wherein, OMe refers to methoxyl group; OEt refers to oxyethyl group.The name of formula (1) compound is called (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone.Synthesis condition and reagent: 1) sodium hydride; 2) n-Butyl Lithium, tetrahydrofuran (THF), low temperature; 3) sodium hydroxide, tetrahydrofuran (THF); 4) hydrochloric acid.
Another object of the present invention is to provide the substituted-dihydro pyranone compounds shown in formula (1) or its application of pharmaceutically useful salt in the medicine preparing prevention and therapy candida albicans infection disease.
Another object of the present invention is to provide the drug excipient that allows containing the substituted-dihydro pyranone compounds shown in formula (1) and pharmaceutically useful salt thereof and preparation or carrier is prepared into pharmaceutical composition, and prepared pharmaceutical composition can also contain other antibacteriums and/or antifungal drug.Described medicine can make multiple formulation by means known in the art, comprises paint, film, paste, injection, transdermal patch, aerosol, controlled release or sustained release dosage, and nanometer formulation.
Through the Literature Consult that the present inventor is detailed, up to the present, there is no about this compounds is for the preparation of the report of antifungal drug.This substituted-dihydro pyranone compounds belongs to beyond thought discovery for the potent suppression of fungal growth, has definite originality, completes the present invention accordingly.
Usefulness of the present invention is: the substituted-dihydro pyranone compounds shown in Late Cambrian formula (1) has Antifungi growth, prepares the potentiality of anti-fungal infection medicine, provides new basic substance for exploitation becomes treatment fungi infestation original new drug.There is potential huge Social benefit and economic benefit.A present invention again feature is: the synthesis initiator convenient sources of the present invention, synthetic method is simple, and cost is low, pollutes little, is beneficial to the scale operation under energy-saving and emission-reduction condition.Industrialization prospect is very clear and definite.
Embodiment
The present invention is further illustrated below by embodiment.Embodiment gives formula (1) compound (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5, the preparation method of 6-dihydropyrane-2-ketone and part physicochemical data, and the part pharmacologically active data of this compound Antifungi growth.The following embodiment of mandatory declaration is for illustration of the present invention instead of 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:(R) preparation of-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone
1.1 instruments and reagent
Fusing point micro-meldometer (production of Beijing Imtech) measures, and temperature does not correct; Optically-active is produced on Polax-2L type automatic polarimeter in Japan and is measured; Infrared spectra IR by Bruker Vector-22 determination of infrared spectroscopy, through KBr compressing tablet; UV spectrum Shimadzu UV-240 ultraviolet spectrophotometer measures; Proton nmr spectra
1h NMR, carbon-13 nmr spectra
13c NMR and 2D NMR measures (tetramethylsilane ether TMS is interior mark) by INOVA type NMR spectrometer with superconducting magnet (VARIAN INOVA-400MHz); Electrospray ionization mass spectrum ESI-MS is measured by Bruker Esquire 3000+ mass spectrograph, and column chromatography silica gel (100-200,200-300 and 300-400 order) and thin-layer chromatography silica GF254 (10-40 order) are Haiyang Chemical Plant, Qingdao's product; Agents useful for same is analytical pure, and wherein sherwood oil boiling range is 60-90 ° of C; Thin layer preparative chromatography (PTLC) the aluminium foil silica-gel plate of Merck company; Column chromatography dextrane gel Sephadex LH-20 adopts Sweden Amersham Pharmacia Biotech AB Products; The ultraviolet lamp of thin plate (TLC) survey 254nm and 365nm; Developer iodine vapor, 10% sulfuric acid-ethanol, phosphorus molybdenum acid solution.
The synthesis of 1.2 formulas (1) compound and purification
Under cryosel bath cooling conditions, to in the tetrahydrofuran (THF) suspension liquid (140 milliliters) of 2.3 grams of sodium hydrides, drip 2-methyl-acetoacetic ester 5.78 grams, then under-20 ° of C low temperature, drip the hexane solution 28 milliliters containing 2.5 moles of n-Butyl Lithiums, drip after 10 minutes containing 5.88 gram 3, the tetrahydrofuran solution (10 milliliters) of 4-dimethoxy benzaldehyde, continue reaction 30 minutes, the tetrahydrofuran solution 20 milliliters containing 2 molar sodium hydroxides is added in reaction system, under cryosel bath cooling conditions, reaction is after 20 minutes, with 1 mole hydrochloride aqueous solution cancellation reaction, concentrating under reduced pressure, volatilize organic solvent.Water liquid ether (3 × 50 milliliters) extracts, merge organic phase, with saturated common salt water washing (3 × 20 milliliters), anhydrous sodium sulfate drying, suction filtration, (petrol ether/ethyl acetate: 2/1) obtain yellow oily liquid, is formula (1) compound (R)-6-(3 to silica gel column chromatography, 4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone: Rf (ethyl acetate/petroleum ether: 1/1): 0.48; Proton nmr spectra
1h NMR (400MHz, deuterochloroform, δ ppm): 2.38 (unimodal, 3H, 3-CH
3), 2.52 (multiplet, 1H, H-5a), 2.66 (bimodal, 1H, J=7.8Hz, H-5b), 5.32 (wide bimodal, 1H, J=8.2Hz, H-6), 3.83 (unimodal, 3H, OCH
3), 3.85 (unimodal, 3H, OCH
3), 6.83(is bimodal, 1H, J=1.8Hz, H-6'), 6.89 (double doublet, 1H, J=8.3Hz, 1.7Hz, H-5'), 6.98 (bimodal, 1H, J=1.8Hz H-2'); ESI-MS m/z:265.2 [M+H]
+.Qualification structure is as follows:
embodiment 2:formula (1) shownschematically substituted-dihydro pyranone compounds Antifungi activity test
With reference to the antimycotic sensitivity testing method of stdn that the American National Clinical Laboratory Standard council (NCCLS) proposes, formula (1) compound (the R)-6-(3 that testing example 1 prepares, 4-Dimethoxyphenyl) extracorporeal antifungal activity of-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone.
2.1 fungi type strains:
Candida albicans ATCC10231: Chongqing Center for Disease Control 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 Science and Technology Ltd. in Guangdong product.
2.2.2 yeast extract (yeast extract): Hai Shenggong biotechnology Services Co., Ltd packing.
2.2.3 three morpholino nitrogen quinolines propanesulfonic acid (3-N-morpholinopropanesulfonicacid, MOPS)
2.2.4 testing drug: positive control is standard anti-fungal injection liquid fluconazole (Fluconazole, FCZ), company of Yangzijiang Pharmaceutical Group; Formula (1) compound.Doubling dilution liquid testing drug being configured to different concns gradient is stand-by.
2.2.5 dimethyl sulfoxide (DMSO) (dimethylsulfoxide, DMSO) and dimethyl formamide (dimethylformamide, DMF): Shanghai Sangon Biological Engineering Technology And Service Co., Ltd's packing product.
2.3 instruments:
2.3.1 electronic balance JA1203N(AB204-5, METTLER TOLEDO): Shanghai precision scientific instrument company.
2.3.2SW-CJ-2FD the double one side clean work station of type: Purifying Equipment Co., Ltd., Suzhou.
2.3.3 water isolation type constant incubator (GSP-9160MBE): Shanghai Yiheng Scientific Instruments Co., Ltd.
2.3.4 electro-heating standing-temperature cultivator (HZQ-F160A): Shanghai Yiheng Scientific Instruments Co., Ltd.
2.3.5 U.S. water chestnut refrigerator (BCD-221CHC): Hefei Meiling Co. Ltd..
2.3.6 micropipet (Proline Pipette, DragonMed Pipette): Lei Bo company of Finland.
2.3.7 cell counting count board (96well cell culture cluster): Shanghai refinement instrument company.
2.3.8 ordinary optical microscope (Olympus): Japanese Olympus opticinstrument Co., Ltd..
2.3.9 hot air drying oven (101A-2): Shanghai Chongming laboratory apparatus company.
2.3.10 vertical autoclave sterilizer (YXQ-LS-50S II): Shanghai Bo Xun Industrial Co., Ltd..
2.3.11 magnetic force heating stirrer (ARE): Italian VELP company.
2.3.12 filter membrane, filter (0.22 μm, Sartorius): Sartorius AG.
2.3.13 acidometer (PHSJ-4A): upper Nereid Ke Lei magnetic company.
2.3.14 test tube oscillator (MS2): Guangzhou Yi Ke laboratory technique company.
2.3.15 constant-temperature shaking incubator (THZ-18AB): the permanent Scientific Instruments Corporation in Shanghai one.
2.3.16 cryogenic refrigerator (-20 DEG C, section dragon BCD-219WAK): Guangdong Ke Long electrical equipment limited liability company.
2.3.17 96 hole flat-bottom microplates: Corning Incorporated company of the U.S..
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 propanesulfonic acid (MOPS) is 0.165 mol/L to its endpoint concentration, with magnetic stirring apparatus mixing 2-3 hour under room temperature, makes it fully dissolve, by sodium hydroxide (1 mol/L) adjust ph to 7.0(25 ° of C), be settled to 1 liter with aqua sterilisa, Entkeimung, after packing ,-20 ° of C save backup.
2.4.1.2 the preparation of storing solution: take fluconazole (FCZ) 10 milligrams with electronic balance, and dissolve with 1 milliliter of dimethyl formamide (DMF), be diluted to 1280 mcg/ml with RPMI-1640 afterwards, after packing ,-70 ° of C save backup.
2.4.1.3 apply the preparation of liquid: remake multiple proportions after storing solution being done 1:10 dilution with RPMI-1640 liquid rare, FCZ is that 128 mcg/ml-0.25 mcg/ml make 10 serial concentration.
2.4.1.4 the preparation of micro-susceptibility culture plate: use disposable 96 orifice plates, 1-10 row add the application liquid of the testing drug of 10 concentration gradients respectively, from high density to lower concentration.11st row add RPMI-1640, every hole 100 microlitre, and the 12nd row, as blank, put into-20 ° of C refrigerators for subsequent use, each 1 hour of warp-4 ° of C, 4 ° of C and room temperatures during use.
2.4.1.5 the activation of candidiasis and dilution: by bacterial strain to be measured at YPD Agar substratum (1% yeast extract, 1% peptone, 2% glucose) after upper activation twice, the bacterium colony that cut-off footpath is greater than 1 millimeter a little in 3 milliliters of stroke-physiological saline solution mixing make bacteria suspension, get a little, count the mycetocyte number in four block plaid with hemocyte technology plate, average X, and now mycetocyte number is X × 10
4cFU/ milliliter is 3 × 10 by RPMI-1640 liquid adjustment concentration
4cFU/ milliliter (twice final concentration).
2.4.1.6 application of sample: add candidiasis suspension on the above-mentioned culture plate containing testing drug prepared, every hole 100 microlitre blank does not add, and puts into wet box (prevent evaporating of micro plate and affect the concentration of medicine) 35 ° of C and hatch observations after 24-48 hour after concussion mixing.
2.4.1.7 naked eyes judged result: blank for foundation with growth control, suppresses (i.e. MIC with 80%
80) for observing terminal, growth obviously reduces, liquid little cloudy; Well-grown in Growth positive simultaneously, blank is limpid, without bacterial growth.The MIC value of Quality-control strains is in the scope of U.S. clinical Microbiological Lab standard C LSI M27-A2 scheme prescribes, and display experimental result is effective.
2.5 experimental results: in table 1.
Table 1 testing drug is to Candida albicans fungi restraining effect (unit: mcg/ml)
2.6 conclusions:
By adopting " Herbs By Broth Microdilution " Research-type (1) compound to the antibacterial activity in vitro of two kinds of fungi reference cultures, experimental study shows: (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone has clear and definite anti-mycotic activity to 2 kinds of albicans strains.Illustrate that it is potential Antifungi growth activity material, there is further Development volue.
The substituted-dihydro pyranone compounds shown in formula (1) prepared in the present invention can be combined with pharmaceutically conventional auxiliary material or carrier, prepares and has prevention and therapy by the medicine of the fungus-caused infection such as Candida albicans and pharmaceutical composition or healthcare products or cosmetics of everyday use.The dosage form that above-mentioned various kinds of drug composition, healthcare products or cosmetics of everyday use can adopt comprises paint, film, paste, injection, transdermal patch, aerosol, controlled release or sustained release dosage, and nanometer formulation.
Substituted-dihydro pyranone compounds as the formula (1) of the present invention can also with the medicine of the treatment fungi infestation associated conditions now gone on the market and bulk drug thereof, as: polyenoid class (as, amphotericin B), triazole species (as, fluconazole, miconazole, econazole, itraconazole and KETOKONAZOL etc.), alkyl amine (as, Terbinafine) and the kind conbined usage such as echinocandin (echinocandins) of listing newly developed, prepare the composition or compound preparation with treatment fungi infestation associated conditions effect activity, can expect and become treatment fungal infection disease medicine/healthcare products or cosmetics of everyday use.Above-mentioned various kinds of drug composition, medicine/healthcare products or cosmetics of everyday use can adopt the formulations such as paint, film, paste, injection, transdermal patch, aerosol, comprise the preparation of pharmaceutics general knowledge routine and the various slowly-releasings, controlled release form or the nanometer formulation that obtain that employing now generally acknowledged.
When above-mentioned specification sheets is set forth of the present invention, the object simultaneously providing embodiment illustrates actual mechanical process of the present invention and meaning of the present invention.When entering in the claims in the present invention and its equivalency range, practical application of the present invention comprises all general changes, cooperation, or improves.
Claims (5)
1. one kind such as formula (1) shownschematically substituted-dihydro pyrone compound or its pharmacologically acceptable salt; It is characterized by, the name of formula (1) compound is called (R)-6-(3,4-Dimethoxyphenyl)-4-hydroxy-3-methyl-5,6-dihydropyrane-2-ketone:
2. prepare a method for formula according to claim 1 (1) shownschematically substituted-dihydro pyrone compound, it is characterized in that: Veratraldehyde and 2-methyl-acetoacetic ester obtain target compound through four-step reaction; Wherein: the first step, under cooling conditions 2-methyl-acetoacetic ester through sodium hydride effect; Second step, the tetrahydrofuran solution dripping n-Butyl Lithium under-10 ~-40 DEG C of low temperature reacts 10 ~ 20 minutes, continues reaction 20 ~ 60 minutes after adding Veratraldehyde; 3rd step, adds the tetrahydrofuran solution of sodium hydroxide, reacts 10 ~ 30 minutes under cooling conditions; 4th step, with hydrochloric acid soln cancellation.
3. the application of formula according to claim 1 (1) compound or pharmaceutically acceptable salt thereof in the medicine preparing the disease that prevention and therapy fungi infestation causes, is characterized in that: described fungi refers to Candida albicans.
4. for preventing and treating a pharmaceutical composition for the disease that fungi infestation causes, it is characterized in that: the drug excipient that formula according to claim 1 (1) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity and preparation allow or carrier are prepared into pharmaceutical composition; Described fungi refers to Candida albicans.
5. pharmaceutical composition according to claim 4, is characterized in that: the dosage form of described pharmaceutical composition is paint, film, paste, injection, transdermal patch, aerosol, controlled release or sustained release dosage.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1085554A (en) * | 1992-09-10 | 1994-04-20 | 拜尔公司 | The 3-aryl-pyrone derivatives |
| CN1090279A (en) * | 1992-11-13 | 1994-08-03 | 厄普约翰公司 | Be used for the treatment of HIV and other retroviral pyran-2-ones and 5,6-dihydropyrane-2-ketone |
| CN101010306A (en) * | 2004-07-05 | 2007-08-01 | 拜尔农作物科学股份公司 | Phenyl-substituted [1.2] -oxazine-3, 5-dione and dihydropyrone derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003040711A (en) * | 2001-07-25 | 2003-02-13 | Sumitomo Chem Co Ltd | Antibacterial agent |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1085554A (en) * | 1992-09-10 | 1994-04-20 | 拜尔公司 | The 3-aryl-pyrone derivatives |
| CN1090279A (en) * | 1992-11-13 | 1994-08-03 | 厄普约翰公司 | Be used for the treatment of HIV and other retroviral pyran-2-ones and 5,6-dihydropyrane-2-ketone |
| CN101010306A (en) * | 2004-07-05 | 2007-08-01 | 拜尔农作物科学股份公司 | Phenyl-substituted [1.2] -oxazine-3, 5-dione and dihydropyrone derivatives |
Non-Patent Citations (2)
| Title |
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| J. Antonio Rocha-Valadez,等.6-Pentyl-a-Pyrone Production by Trichoderma harzianum: The Influence of Energy Dissipation Rate and Its Implications on Fungal Physiology.《BIOTECHNOLOGY AND BIOENGINEERING》.2005,第91卷(第1期), * |
| 周庆发,等.2-吡喃酮衍生物合成研究进展.《有机化学》.2010,第30卷(第11期), * |
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