CN101024637A - Sesquiterplactone in dandelion and its use of resisting Gram's positive bacteria - Google Patents
Sesquiterplactone in dandelion and its use of resisting Gram's positive bacteria Download PDFInfo
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Abstract
The invention relates to a faked guaiane sesquiterpene lactone compound-Morgan blowball lactone A and the medicinable salt. The chemical name is 1-ketone-11(R)-hydroxyl-3, 5, 1(10)-trienin-faked lignum benedictum-8 alpha, 12-lactone. The compound could make medicine vehicle or medicine medicinal preparation with medicinable salt. The medicine contains other antibacterial druy. The preparation includes tablet, granule, capsule, oral liquid, drop pills, injection, skin penetrating agent, aerosol, etc. the compound could be used in medicine to prevent and cure anti gram positive fungus.
Description
Technical field
The present invention relates to medical technical field, obtain a pseudo-guainane sesquiterpene lactones and pharmacologically acceptable salt thereof in particular to from taraxacum, separating, contain the pharmaceutical composition of these compounds and the purposes in anti-infectives thereof.
Technical background
Streptococcus aureus (Staphylococcus aureus) is the Gram-positive coccus, the streptococcus aureus (MRSA) in anti-methyl XiLin is the bacterial strain that begins to occur the eighties in 20th century, it is the epiphytotics main pathogeny of microorganism in the hospital and clinically, the main infection that causes the people has furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, mazoitis, urocystitis, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, pharyngitis, trachelitis, pelvic inflammatory disease, and muscle, skin, urodeum, the abscess of central nervous system.So be that HUMAN HEALTH is influenced great pathogenic species.Suis (Streptococcus species) is into catenation, amphimicrobian Gram-positive bacillus.Medically common pathogenic suis major part belongs to β haemolysis type.They are present on people's the mucous membrane of skin, respiratory tract, digestive tube and urodeum, can cause diseases such as skin, respiratory tract and soft tissue infection such as pneumonia, microbemia, endocarditis, meningitis, urinary tract inflammation and sacroiliitis.
Chinese traditional medicine is a resourceful treasure-house.Wherein many medicinal plants all contain the effect of good restraining streptococcus aureus (being called for short " golden Portugal bacterium ") and beta hemolytic streptococcus.Taraxacum is feverfew taraxacum (Taraxacum mongolicum Hand-Mazz also claims Mongolian taraxacum) or the dry herb that belongs to several plants together, is heat-clearing and detoxifying herb, and the function of heat-clearing, detoxifcation, diuresis, dissipating bind is arranged; Cure mainly acute mastitis, furunculosis, hot eyes, pharyngalgia, jaundice due to damp-heat and heat and drench puckery pain etc.Be usually used in treating diseases such as acute mastitis, lymphadenitis, malignant boil carbuncle toxin, acute conjunctivitis, cold, fever, acute tonsillitis, acute bronchitis, hepatitis, swollen capsulitis and urinary tract infections clinically.Taraxacum mainly contains triterpenes, phytosterol, sesquiterpene lactones class, coumarins, flavonoid, phenolic acid compound, carotenoid and fatty acid compound.Its pharmacological action has antisepsis and anti-inflammation, anti-oxidant, hepatic cholagogic, immunomodulatory and antitumor etc.At present, injection, tablet and the granule etc. that utilize the taraxacum single medicinal material to make are widely used in clinical, treat various diseases associated with inflammation and have obtained curative effect preferably.
Taraxacum has stronger heat-clearing toxin-expelling functions, have higher research and development and be worth, but domestic research to taraxacum mainly rests on its crude extract, especially lacks the effective substance correlative study.Domestic correlative study report and patent generally all are to use with the compound form, rare from taraxacum extracting effective components and the report studied at its bacteriostatic activity.More comprehensive abroad to the chemical constitution study of common dandelion (Taraxacumofficinale), find that it mainly contains sesquiterpene, triterpene and flavones ingredient, the pharmacologically active report is less, and does not see the chemical constitution study report at Mongolian taraxacum (T.mongolicum).Domestic chemical constitution study report to the Dandelion plant is very few, quotes the chemical ingredients of common dandelion Taraxacum officinale more, and the seminar that finds by retrieval at present to reach the clouds has carried out the research report to the chemical ingredients of Mongolian taraxacum and [reached the clouds, Bao Yanyan, Zhu Lili, Zheng Junhua, Cai Shaoqing, Xiao Yue, the taraxacum The Chemical Constituents, Chinese Pharmaceutical Journal, 1997,32,584-586; Reach the clouds Bao Yanyan, Zhang Yonglin, Cai Shaoqing, Zheng Junhua, taraxacum The Chemical Constituents, the Navy General Hospital journal, 1998,11,167-169], be divided into 5 compounds: β-Gu Zaichun, Quercetin, coffic acid, chlorogenic acid and luteolin-7-O-glucoside, and other chemical ingredients it be not immediately clear.For understanding the chemical constitution of each polar fraction of T.mongolicum, the applicant has carried out the fitochemical studies of system to it.Result of study shows that flavonoid compound and polyphenolic compound are its main chemical compositions, and low polar fraction is in the majority with phytosterin compound.
Summary of the invention
The purpose of this invention is to provide a kind of pseudo-guainane sesquiterpene lactones compound and pharmaceutically useful salt thereof that from composite family taraxacum plant, obtains; Pseudo-guainane sesquiterpene lactones compound provided by the invention is to extract to prepare from the feverfew taraxacum, and chemistry is by name: 1-ketone-11 (R)-hydroxyl-3,5, and 1 (10)-triolefin-pseudo-pockwood-8 α, the 12-lactone has following structural:
Mongolia taraxacum lactone A
Pseudo-guainane type sesquiterpene lactone compound is called Mongolian taraxacum lactone A again.
Another object of the present invention provides and contains pseudo-guainane sesquiterpene lactones compounds and pharmaceutically useful salt becomes pharmaceutical composition with preparation allowable pharmaceutical excipients or preparing carriers, and drug prepared also contains other antibacterials.
Described medicine can be made multiple formulation by this formulation art currently known methods, and dosage form mainly comprises tablet, granule, capsule, oral liquid, dripping pill, injection, transdermal patch, aerosol, controlled release or sustained release dosage or nanometer formulation.
Another purpose of the present invention provides pseudo-guainane sesquiterpene lactones compounds and pharmaceutically useful salt thereof in the preparation prevention with treat in the medicine of anti-gram-positive bacteria and use.Mainly preparing prevention and treating in the medicine that infects the disease that causes by streptococcus aureus and/or beta hemolytic streptococcus and use.
Mongolia taraxacum lactone A is a unique pseudo-guainane type sesquiterpene (Pseudoguaianolide) of assigning to from the ethyl acetate extraction position of Mongolian taraxacum (Taraxacum mongolicum).
Pseudo-guainane type sesquiterpene lactone compound is mainly derived from each position of feverfew taraxacum, preferably from taraxacum (claiming Mongolian taraxacum again) (Taraxacum mongolicumHand-Mazz), alkali ground taraxacum (claiming magnificent taraxacum again) (Taraxacum sinicumKitag), hot river taraxacum (claiming white edge taraxacum again) (Taraxacum platypecidum Diels), Herba Taraxaci ohwiani (Taraxacumohwianum Kitag), anti-luxuriant taraxacum (Taraxacum grypodon Dahlst), common taraxacum medicinal material rhizome on the Xingan taraxacum Chinese drug markets such as (Taraxacum falcilobum Kitag), leaf, flower comprises preparing in its dry product and the bright product and getting.The herb part of preferred taraxacum (claim not only Mongolian taraxacum) (Taraxacum mongolicum Hand-Mazz) and/or alkali ground taraxacum (but also claiming magnificent taraxacum) (Taraxacum sinicum Kitag).
Characteristics of the present invention are: from feverfew taraxacum rhizome, leaf, flower separates its efficient part of purifying in the position, and therefrom obtain a monomeric compound, through the chemical assay structure is pseudo-guainane type sesquiterpene lactone compound, and find that it has very strong inhibition streptococcus aureus and beta hemolytic streptococcus effect, provide and to have expected to be used to prepare to cause or relevant physiological change or treatment of diseases medicine and prevention and health care product with gram-positive bacteria especially streptococcus aureus and beta hemolytic streptococcus, include but not limited to furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, trachelitis, and muscle, skin, urodeum, the abscess of central nervous system.
Embodiment
Further specify the present invention below by embodiment.The following embodiment of mandatory declaration is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Plant is in the past discovered and is contained triterpenes, coumarins, phenolic acids (flavonoid that comprises phenolic hydroxy group), sesquiterpenoids, phytosterol, carotenoid and long-chain fat acid compounds in the taraxacum plant.The inventor is to the high polarity position of this plant milk extract, obtain this by multiple positive and negative phase chromatography means and effectively suppress streptococcus aureus and active two active compounds of beta hemolytic streptococcus, and derive the pseudo-guainane type sesquiterpene lactone compound Mongolia taraxacum lactone A (compound 1) that its chemical structure was not reported for forefathers through integration analysis such as infrared, mass spectrum, ultraviolet and NMR (Nuclear Magnetic Resonance) spectrum.
Compound 1 is the unique pseudo-guainane type sesquiterpene (Pseudoguaianolide) that we assign to from the ethyl acetate extraction position of taraxacum (Taraxacum mongolicum).From the Dandelion plant, separate the sesquiterpenoids that obtains and be generally germacrane type, eudesmane-type and guainane type sesquiterpene, and isolating pseudo-guainane type sesquiterpene has only one piece of bibliographical information [VUAhmad etc. so far from the Taraxacum platymiscium, Taraxacin, a new duaianol ide from Taraxacum wallichii, Journalof Natural Products, 2000,63,1010-1011], this paper has then reported the structure evaluation of a new pseudo-guainane type sesquiterpene lactone.
Medicinal material among the present invention can be the arbitrary position of home-made Dandelion plant in any one, promptly can be taraxacum (claiming Mongolian taraxacum again) (Taraxacum mongolicum Hand-Mazz), alkali ground taraxacum (claiming magnificent taraxacum again) (Taraxacum sinicum Kitag), hot river taraxacum (claiming white edge taraxacum again) (Taraxacum platypecidum Diels), Herba Taraxaci ohwiani (Taraxacumohwianum Kitag), anti-luxuriant taraxacum (Taraxacum grypodon Dahlst), common taraxacum medicinal material on the Xingan taraxacum Chinese drug markets such as (Taraxacum falcilobum Kitag), can be dry product or bright product, it can be the root of taraxacum medicinal material plant, stem, leaf, flower, seed, skin, fruit also can be their mixture.Preferred herb.The more preferably herb part of taraxacum (claim not only Mongolian taraxacum) (Taraxacum mongolicum Hand-Mazz) and/or alkali ground taraxacum (but also claiming magnificent taraxacum) (Taraxacum sinicum Kitag).All be called for short taraxacum in the present invention's the specification sheets.
The separation of embodiment 1 Mongolian taraxacum lactone A:
1.1 instrument and reagent
Fusing point is measured with micro-fusing point instrument (production of Beijing Imtech), and temperature is not proofreaied and correct; Optically-active is produced on the automatic polarimeter of Polax-2L type in Japan and is measured; Infrared spectra IR is by Bruker Vector-22 determination of infrared spectroscopy, through the KBr compressing tablet; UV spectrum 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-400 MHz); Electrospray ionization mass spectrum ESI-MS is measured by Bruker Esquire 3000+ mass spectrograph, and column chromatography is produced by Haiyang Chemical Plant, Qingdao with silica GF254 (10-40 order) with silica gel (100-200,200-300 and 300-400 order) and thin-layer chromatography; Agents useful for same is analytical pure, and wherein the sherwood oil boiling range is 60-90 ℃; Thin layer preparative chromatography (PTLC) the aluminium foil silica-gel plate of Merck company; Column chromatography adopts the biochemical plastic molding and processing plant of Taizhou, Zhejiang Province city road and bridge tetramethyl product with polymeric amide (14-30 order and 100-200 order); Dextrane gel Sephadex LH-20 adopts Sweden Amersham Pharmacia Biotech AB company product; Reverse phase silica gel RP-18 adopts the Chromatorex product of Japanese FujiSilysia Chemical company; MCI is a Mitsubishi chemical company product, and thin plate (TLC) detects the ultraviolet lamp with 254 nm and 365 nm; Developer iodine vapor, 10% sulfuric acid-ethanol, 2% iron trichloride-methanol solution, phospho-molybdic acid and tetrabromo-mcresolsulfonphthalein solution.
Liquid phase: Waters series of high efficiency liquid chromatograph comprises 2695 separation systems (quaternary pump, column oven and automatic sampler), 2996 ultraviolet diode matrix detectors, Empower chromatographic run software.
1.2 plant origin and evaluation
Purchase in the Haozhou, Anhui August calendar year 2001 with the taraxacum medicinal material for extracting, be accredited as the herb of Mongolian taraxacum (Taraxacum mongolicum Hand.-Mazz.) by pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department.Use taraxacum (Mongolian taraxacum) (Taraxacum mongolicumHand.-Mazz) for comparing content, alkali ground taraxacum (magnificent taraxacum) (Taraxacum sinicum Kitag), hot river taraxacum (white edge taraxacum) (Taraxacum platypecidum Diels), Herba Taraxaci ohwiani (Taraxacum ohwianum Kitag), anti-luxuriant taraxacum (Taraxacum grypodon Dahlst), each 20 gram of Xingan taraxacum (Taraxacum falcilobum Kitag) dry product are assisted to gather and identify by the Peng Hua of Kunming plant institute of Chinese Academy of Sciences professor in August, 2003～2004 year July., identify than gathering from the Tian Mu Shan Mountain, Zhejiang Province for fresh and dried product content by pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department than taraxacum (Mongolian taraxacum) (Taraxacum mongolicum Hand.-Mazz) and each 100 gram of the bright product of alkali ground taraxacum (magnificent taraxacum) (Taraxacum sinicum Kitag).
1.3 extract and separate
Sample shines dry grinding (5.0 kilograms of dry weights) back and carries twice with heat under the 75% industrial spirit boiling water, and extracting solution cooling back merges, and gets the thick crude extract of 462 gram browns through concentrating under reduced pressure.With the crude extract dissolve with methanol, the D-101 macroporous resin is mixed sample, methyl alcohol is removed in decompression on Rotary Evaporators, with the discolour silica gel is siccative, 40 ℃ of vacuum-dryings are spent the night, and application of sample is collected 50% methanol-water wash-out position in the good D-101 post of water balance, elutriant is concentrated into dried, makes behind the suspension with distilled water again and distribute extraction with sherwood oil, ethyl acetate, propyl carbinol successively.Get 3 grams after each organic layer evaporated under reduced pressure respectively, 32 grams, 127 gram medicinal extract, surplus is the water position.
1.4 the separation and purification of ethyl acetate
Get ethyl acetate extract medicinal extract 82 gram silica gel (200-300 order) posts (900 gram), with chloroform-methanol (1: 0 → 0: 1) is the eluent gradient elution, be divided into 6 positions (F1-F6) according to thin-layer chromatography TLC situation, wherein F2 (4 gram) crosses silicagel column (100 gram), with petroleum ether-ethyl acetate (8: 1 → 0: 1) wash-out, check that through thin-layer chromatography TLC petroleum ether-ethyl acetate (4: 1) wash-out person is contained same composition, obtains Mongolian taraxacum lactone A (25.2 milligrams) through recrystallization.
1.5 structure is identified
The structure of Mongolia taraxacum lactone A is identified: compound 1 be a white, needle-shaped crystals, and it is 260 that ESI-MS provides molecular ion peak m/z, is C15H1604 in conjunction with the molecular formula of hydrogen spectrum and carbon spectrum release compound 1, and 8 degrees of unsaturation are arranged in the molecule.Show that compound has three absorption peaks [246nm (15800) in the UV spectrum, 259nm (15500), 312nm (8200)] in conjunction with the absorption peak 3276 in the IR spectrum, 1770,1690,1625,1605,990 and 868cm-1 explanation compound 1 in have hydroxyl, saturated lactonic ring, pentacyclic conjugation ketone carbonyl group and double bond structure.Investigate the 13C-NMR and the DEPT spectrum of compound 1: have lactone structure in the tertiary carbon signal prompt molecule of the quaternary carbon signal of δ 178.4 and δ 74.9; There is the beta-unsaturated ketone structure in the quaternary carbon signal indicating molecule of δ 194.6; Also there are three two keys (δ 162.9,146.5,139.5,131.2,126.8,118.3) in the molecule; Provided three methyl signals [δ 2.37 (3H, unimodal), 2.19 (3H, unimodal), 1.31 (3H, unimodal)] in the 1H-NMR spectrum, inferred that according to above information compound may be pseudo-guainane type sesquiterpene.The hydrogen spectrum of this compound and data very alike [VU Ahmad etc., Taraxacin, a new duaianolide from Taraxacumwallichii of carbon spectrum data and compound Taraxacin, Journal of Natural Products, 2000,63,1010-1011].
Yet (δ 154.7 for the two key signals in the compound Taraxacin carbon spectrum between C-7 and the C-11,124.3) in the carbon spectrum of compound 1, disappeared, the carbon at compound 1 is correspondingly replaced by a company's oxygen quaternary carbon (δ 74.8) and a methyne (δ 52.8) in composing.Above information shows that compound 1 is 7,11 pseudo-guainane derivatives that go two keys and 11 hydroxyl replacements of Taraxacin.Concern that from source of students 11 is beta configuration; Connect in the 1H-NMR of compound 1 spectrum simultaneously oxygen signal [δ 4.39 (and 1H, triple bimodal, J=9.6,9.6,4.8Hz, H-8)] demonstration C-7,8 trans condensed lactonic rings, promptly 8 hydrogen are beta configuration [YL Liu etc., Sesquiterpene lactones from Artemisiafrigida, Journal of Natural Products, 1981,44,722-728], and if 8 hydrogen stiff molecule model then overtension and can't build when being α-configuration; The relative configuration of 13 methyl is derived as α-configuration [W Zhang etc. by the chemical shift contrast with known compound, Menverins A-D, new highly oxygenated guaiane lactones from Hainan Gorgonian Menellaverrucosa (BRUNDIN), Helvetica Chimica Acta, 2004,87,2919-2925; JMAguilar etc., Sesquiterpene lactones from Artemisia lanata, Phytochemistry, 1988,27,2229-2233; OA Konovalova etc., Sesquiterpenelactones from Artemisia caucasica, Khimiya Prirodnykh Soedinenii, 1971,7,741-744].And in the NOESY spectrogram, 13-CH3 and H-8 do not have correlation effect and have the yet provable above deduction of correlation effect with H-7, are Mongolian taraxacum lactone A as shown in the figure so determine compound 1.
Mongolia taraxacum lactone A (compound 1): white needle; C
15H
16O
4Fusing point m.p.:272-274 ℃; UV λ max (methyl alcohol): 246,259,312nm; Infrared IRv
Max KBr(cm
-1): 3276,1690,1625,1605,990,868; ESI-MS m/z:261[M+H]
+Proton nmr spectra
1H-NMR (DMSO-d
6, 400 MHz) δ 6.16 (1H, unimodal, H-3), 6.04 (1H, bimodal, J=2.4Hz, H-6), 4.39 (1H, triple bimodal, J=9.6,9.6,4.8Hz, H-8), 3.20 (1H, bimodal, J=11.2Hz, H-9a), 3.01 (1H, bimodal, J=11.2Hz, H-9b), 2.99 (1H, double doublets, J=9.6,2.4Hz, H-7), 2.37 (3H, unimodal, H-14), 2.19 (3H, unimodal, H-15), 1.31 (3H, unimodal, H-13); Carbon-13 nmr spectra
13C-NMR (DMSO-d
6, 100MHz) δ 194.6 (s, C-2), 178.4 (s, C-12), 162.9 (s, C-5), 146.5 (s, C-4), 139.5 (s, C-10), 131.2 (d, C-3), 126.8 (s, C-1), 118.3 (d, C-6), 74.9 (d, C-8), 74.8 (s, C-11), 52.8 (d, C-7), 43.9 (t, C-9), 21.1 (q, C-14), 18.8 (q, C-13), 14.1 (q, C-15).
Embodiment 2: pseudo-guainane type sesquiterpene lactone compound suppresses the gram-positive bacteria ability and detects
2.1 principle:
Adopt the antibacterial activity in vitro of " cup-plate method " research trial medicine, be to utilize the trial drug that is added in the cup of Oxford to be diffused into inoculation to have in the substratum of test organisms, thereby suppress the growth of bacterium, come the anti-microbial activity of confirmed test medicine by the diameter that detects the inhibition zone that around the cup of Oxford, forms.
2.2 detect bacterium:
Streptococcus aureus 26003-23 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Beta hemolytic streptococcus 32210 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
2.3 trial drug:
The DMSO:DMSO solvent control;
Norfloxicin: 1.25mg/ml;
Mongolia taraxacum lactone A (compound 1): 5.0mg/ml; Dissolve with DMSO.
2.4 method and step:
2.4.1, the preparation of M-H agar, M-H meat soup and test organisms liquid.
2.4.2, the preparation of two dish:
(1), M-H agar bottom: get sterilization M-H agar liquid naturally cooling and solidify.
(2), M-H agar bacterium layer: get bacterium liquid 150 μ l and 30mlM-H agar mixing.Get about 5ml and contain bacterium liquid agar, evenly spread out cloth in plate with M-H agar bottom.
2.4.3, treat culture medium solidifying after, in each plate, evenly put the upright test soup Oxford cup of filling it up with.
2.4.4, put 37 ℃ and cultivated 24 hours.
2.4.5, use the vernier caliper measurement antibacterial circle diameter.
Table 2: Mongolian taraxacum lactone A (compound 1) is to the antibacterial circle diameter (mm) of standard pathogenic bacterium
| Bacterial classification | The experiment medicine | ||
| DMSO | Compound 1 (5.0mg/ml) | Norfloxicin (2.5mg/ml) | |
| Streptococcus aureus-26003 beta hemolytic streptococcus-10102 | Unrestraint 9.56 | 12.87 13.56 | 30.1 28.65 |
2.5 experiment conclusion:
By adopting the antibacterial activity in vitro of " micro-dilution method " research 1 pair of streptococcus aureus of compound and beta hemolytic streptococcus.The result shows: 1 pair of streptococcus aureus of compound and beta hemolytic streptococcus have better antibacterial activity.Illustrate that it is that potential suppresses the gram-positive bacteria active substance, has further exploitation and is worth.
This puppet guainane type sesquiterpene lactone composition that the present invention obtains has the function that suppresses streptococcus aureus and beta hemolytic streptococcus growth; Can be used to prevent and treat furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, the trachelitis that causes by streptococcus aureus and beta hemolytic streptococcus, and the abscess and medicine or the healthcare products purposes relevant with above-mentioned symptom or disease of muscle, skin, urodeum, central nervous system.
The sesquiterpene lactones Mongolia taraxacum lactone A that finds in the taraxacum of the present invention can combine with auxiliary material or carrier pharmaceutically commonly used, prepares the medicine and pharmaceutical composition or the healthcare products that have prevention and treat the infection that is caused by streptococcus aureus and/or beta hemolytic streptococcus.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Sesquiterpene of the present invention Mongolia taraxacum lactone A can also infect the medicine of associated conditions and bulk drug thereof such as cephalosporin, Macrolide and sulfamido such as husky magnitude types of drugs with the similar gram-positive bacteria of the streptococcus aureus that has now gone on the market, beta hemolytic streptococcus inhibitor and/or other treatment and unite use, prepare and have the treatment gram-positive bacteria and infect active composition of associated conditions effect or compound preparation, can expect becomes treatment gram-positive bacteria catch medicine or healthcare products.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as tablet, capsule, injection, aerosol, suppository, film, pill, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slowly-releasings, controlled release form or the nanometer formulation that gets.
This puppet guainane type sesquiterpene lactone composition that the present invention obtains has the function that suppresses streptococcus aureus and beta hemolytic streptococcus growth; Can be used to prevent and treat furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, the trachelitis that causes by streptococcus aureus and beta hemolytic streptococcus, and the abscess and medicine or the healthcare products purposes relevant with above-mentioned symptom or disease of muscle, skin, urodeum, central nervous system; Thereby may develop the anti-infection drug composition.
The comparison of compound 1 in 3: five kinds of Dandelion plant roots and stems of embodiment and the over-ground part cauline leaf
Taraxacum (Mongolian taraxacum) (Taraxacum mongolicum Hand-Mazz), alkali ground taraxacum (magnificent taraxacum) (Taraxacum sinicum Kitag), hot river taraxacum (white edge taraxacum) (Taraxacum platypecidum Diels), Herba Taraxaci ohwiani (Taraxacum ohwianumKitag), anti-luxuriant taraxacum (Taraxacum grypodon Dahlst), each 20 gram of Xingan taraxacum (Taraxacumfalcilobum Kitag) dry product are gathered by professor Peng Hua of Kunming plant institute of the Chinese Academy of Sciences and are identified.
With this high performance liquid chromatography of water (Waters HPLC, 2695 separation systems comprise quaternary pump, column oven automatic sampler; 2996 ultraviolet diode matrix detectors, Empower chromatographic run software and WatersSymmetry
RP-18 4.6mm * 250mm, 5 μ m chromatography columns) compound 1 has been carried out content detection.
Handle for test agent: the sample that dries in the shade after pulverizing respectively takes by weighing 0.5 gram (± 0.1 milligram), puts 25 milliliters of volumetric flasks, adds 20 ml methanol, 25～30 ℃ ultrasonic 60 minutes down, add methyl alcohol to scale, filter with 0.45 μ m filter membrane.
The preparation of standardized solution: accurately take by weighing 110.0 milligrams of compounds, add 8 ml methanol ultrasonic dissolutions respectively, add the standard reserving solution that methyl alcohol is made into 0.5 mg/ml again., 1: 10,1: 50, be mixed with standardized solution, refrigerate standby at 1: 100 according to 1: 1 with methyl alcohol.Prepare the standardized solution of compound 1 separately with method.Reagent: methyl alcohol is HPLC level (Merk production), and water is redistilled water.Chromatographic condition: use Symmetry
The RP-18 chromatographic column (4.6mm * 250mm), 5 μ m, 30 ℃ of column temperatures detect wavelength: 254nm, flow velocity: 0.8 ml/min, sample size: 20 μ l.Shown in the moving phase table composed as follows:
Table 3 is measured the efficient liquid chromatography condition of Mongolian taraxacum glycosides A and Mongolian taraxacum glycosides B
| Time (minute) | Methyl alcohol (%) | 0.1% acetic acid (%) |
| 0 | 22 | 78 |
| 30 | 22 | 78 |
| 31 | 35 | 65 |
| 55 | 35 | 65 |
| 56 | 40 | 60 |
| 80 | 40 | 60 |
Content measuring: with extraction solvent, standard solution, confession test agent difference sample introduction, record color atlas.With the corresponding concentration of standard solution curve plotting of peak area, calculate linearity range, relation conefficient 〉=0.998.Calculate the content of compound 1 from typical curve.
Discovery content is as shown in table 4:
Mongolian taraxacum lactone A (compound 1) content in the common taraxacum of table 4
| Compound 1 content (%) | |
| Mongolia's taraxacum (taraxacum) rhizome part | 0.036 |
| Mongolia's taraxacum (taraxacum) over-ground part cauline leaf | 0.045 |
| Alkali ground taraxacum (magnificent taraxacum) herb | 0.049 |
| Hot river taraxacum (white edge taraxacum) herb | 0.076 |
| The Herba Taraxaci ohwiani herb | 0.061 |
| Anti-luxuriant taraxacum herb | 0.018 |
| Xingan's taraxacum herb | 0.039 |
The result shows: Mongolian taraxacum rhizome and over-ground part all contain compound of the present invention, and alkali ground taraxacum, hot river taraxacum, Herba Taraxaci ohwiani, anti-luxuriant taraxacum, the compound 1 that all contains different content in the Xingan taraxacum, illustrate that Mongolian taraxacum lactone A is the characteristic chemical constituent in the composite family Dandelion plant, is not limited to Mongolian taraxacum so use this platymiscium to comprise, alkali ground taraxacum, hot river taraxacum, Herba Taraxaci ohwiani, anti-luxuriant taraxacum, Xingan taraxacum etc. can prepare the anti-gram-positive bacteria medicine that contains Mongolian taraxacum lactone A of the presently claimed invention.
The comparison of 4: two kinds of Dandelion plant stem-leafs of embodiment (in bright product and the dry product) compound 1
Taraxacum (Mongolian taraxacum) (Taraxacum mongolicum Hand-Mazz), each 100 gram of the bright product of alkali ground taraxacum (magnificent taraxacum) (Taraxacum sinicum Kitag) are identified by professor Chen Liurong of Zhejiang University.
With this high performance liquid chromatography of water (Waters HPLC, 2695 separation systems comprise quaternary pump, column oven automatic sampler; 2996 ultraviolet diode matrix detectors, Empower chromatographic run software and WatersSymmetry
RP-18 4.6mm * 250mm, 5 μ m chromatography columns) compound 1 has been carried out content detection.
Content measuring: with extraction solvent, standard solution, confession test agent difference sample introduction, record color atlas.With the corresponding concentration of standard solution curve plotting of peak area, calculate linearity range, relation conefficient 〉=0.998.Calculate the content of compound 1 respectively from typical curve.Concrete operations are with embodiment 3.
Mongolian taraxacum lactone A (compound 1) content contrast in two kinds of taraxacum dry products of table 5 and the bright product
| Compound 1 content (%) | |
| The bright product of Mongolia taraxacum (taraxacum) | 0.055 |
| Mongolia's taraxacum (taraxacum) dry product | 0.045 |
| The bright product of alkali ground taraxacum (magnificent taraxacum) | 0.051 |
| Alkali ground taraxacum (magnificent taraxacum) dry product | 0.049 |
The result shows: all contain the compound 1 of different content in dry product of Mongolian taraxacum and alkali ground taraxacum and the bright product, content there is no big difference.Illustrate that Mongolian taraxacum lactone A exists and content is comparatively stable in composite family Dandelion plant, so use dry product of this platymiscium and bright product can prepare the anti-gram-positive bacteria medicine that contains Mongolian taraxacum lactone A of the presently claimed invention.
Claims (7)
1. a pseudo-guainane type sesquiterpene lactone compound is to extract to prepare from the feverfew taraxacum, is called Mongolian taraxacum lactone A, chemistry is by name: 1-ketone-11 (R)-hydroxyl-3,5,1 (10)-triolefin-pseudo-pockwood-8 α, the 12-lactone is characterized in that having following array structure:
2. pseudo-guainane type sesquiterpene lactone compound according to claim 1, it is characterized in that: described compound comprises its pharmaceutically useful salt.
3. pseudo-guainane type sesquiterpene lactone compound according to claim 1 and 2, it is characterized in that: described compound and pharmaceutically useful salt thereof become pharmaceutical composition with preparation allowable pharmaceutical excipients or preparing carriers.
4. pseudo-guainane type sesquiterpene lactone compound according to claim 3, it is characterized in that: drug prepared also contains other antibacterials.
5. according to claim 3 or 4 described pseudo-guainane type sesquiterpene lactone compounds, it is characterized in that: the dosage form of described medicine comprises tablet, granule, capsule, oral liquid, dripping pill, injection, transdermal patch, aerosol, controlled release or sustained release dosage or nanometer formulation.
6. pseudo-guainane type sesquiterpene lactone compound according to claim 1 and 2 is in preparation prevention and treat anti-gram-positive bacteria and infect in the medicine of the disease that causes and use.
7. the purposes of pseudo-guainane type sesquiterpene lactone compound according to claim 5 is characterized in that: preparing prevention and treating in the medicine that is infected the disease that causes by streptococcus aureus and/or beta hemolytic streptococcus and use.
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| CN102499916A (en) * | 2011-11-29 | 2012-06-20 | 中国人民解放军第二军医大学 | Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis |
| CN104016952A (en) * | 2013-02-28 | 2014-09-03 | 东北林业大学 | Novel sesquiterpene active ingredient and preparation method and application thereof |
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| CN102250106A (en) * | 2011-05-19 | 2011-11-23 | 华东理工大学 | Extraction method of sesquiterpene lactone compound from Chinese mugwort leaf and application thereof |
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| CN102499916A (en) * | 2011-11-29 | 2012-06-20 | 中国人民解放军第二军医大学 | Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis |
| CN104016952A (en) * | 2013-02-28 | 2014-09-03 | 东北林业大学 | Novel sesquiterpene active ingredient and preparation method and application thereof |
| CN104016952B (en) * | 2013-02-28 | 2016-05-18 | 东北林业大学 | A kind of sequiterpene active component and preparation method thereof and application |
| CN112876439A (en) * | 2021-01-15 | 2021-06-01 | 宁波大学 | Nano-docetaxel type sesquiterpenoids, preparation method and application thereof |
| CN112876439B (en) * | 2021-01-15 | 2022-06-21 | 宁波大学 | Nano-docetaxel type sesquiterpenoids, preparation method and application thereof |
| CN113318106A (en) * | 2021-03-15 | 2021-08-31 | 沈阳伟嘉生物技术有限公司 | Long-acting compound amoxicillin oil suspension injection for livestock and preparation method thereof |
| CN113318106B (en) * | 2021-03-15 | 2022-05-06 | 沈阳伟嘉生物技术有限公司 | Long-acting compound amoxicillin oil suspension injection for animals and preparation method thereof |
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