CN105949157A - Medicinal composition of dihydroartemisinin and application of medicinal composition of dihydroartemisinin in biological medicine - Google Patents

Medicinal composition of dihydroartemisinin and application of medicinal composition of dihydroartemisinin in biological medicine Download PDF

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Publication number
CN105949157A
CN105949157A CN201610487517.7A CN201610487517A CN105949157A CN 105949157 A CN105949157 A CN 105949157A CN 201610487517 A CN201610487517 A CN 201610487517A CN 105949157 A CN105949157 A CN 105949157A
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compound
dihydroartemisinin
dihydroarteannuin
preparation
medicinal composition
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陈露
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a medicinal composition of dihydroartemisinin and an application of the medicinal composition of dihydroartemisinin in a biological medicine. The medicinal composition of dihydroartemisinin provided by the invention comprises dihydroartemisinin and a natural product with a novel structure, namely a compound (I), when each of dihydroartemisinin and the compound (I) acts independently, a therapeutic effect on emphysema is generated; when dihydroartemisinin and the compound (I) are in combined action, the therapeutic effect on the emphysema can be further improved, so that dihydroartemisinin and the compound (I) can be developed into the medicine for treating the emphysema. Compared with the prior art, the medicinal composition of dihydroartemisinin and the application of dihydroartemisinin in the biological medicine have prominent substantive features and obvious progress.

Description

The pharmaceutical composition of dihydroarteannuin and the application in biological medicine thereof
Technical field
The invention belongs to biomedicine field, relate to the new application of dihydroarteannuin, be specifically related to the drug regimen of dihydroarteannuin Thing and the application in biological medicine thereof.
Background technology
Dihydroarteannuin is the derivant of arteannuin, has powerful and quick killing action to Blood-stage Plasmodium, can control rapidly Clinical episodes and symptom.The mechanism of action of arteannuin is the most fully aware of, mainly disturbs plasmodial pellicle one mitochondrial function. Arteannuin is by affecting the ultrastructure of Blood-stage Plasmodium so that it is film structure changes.Due to the effect to food vacuolar membrane, Block plasmodial nutrition intake, when plasmodium large losses endochylema and nutrient substance, and can not get supplementing, quickly dead.
Up to now, there is not yet dihydroarteannuin and pharmaceutical composition thereof to report with emophysematous dependency.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of dihydroarteannuin, containing dihydroarteannuin in this pharmaceutical composition Can be with Synergistic treatment emphysema with the natural product of a kind of novel structure, dihydroarteannuin and this natural product.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition of dihydroarteannuin, including dihydroarteannuin, compound as claimed in claim 1 (I) and Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder, Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: Radix Glehniae is pulverized by (a), with 85～95% second Alcohol circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes Thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then with 12 column volumes of 90% ethanol elution, collects 90% eluent, concentrating under reduced pressure obtains 90% ethanol elution concentrate；C in () step (b), 90% ethanol elution concentrate is with just Phase silica gel separates, and obtains 4 with the methylene chloride-methanol gradient elution that volume ratio is 120:1,60:1,30:1 and 15:1 successively Component；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1,30:1 and 10:1 by volume ratio successively Methylene chloride-methanol gradient elution obtain 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti- Phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collects 14～18 column volume eluents, Eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
The above-claimed cpd (I) application in emophysematous medicine is treated in preparation.
The application in emophysematous medicine is treated in preparation of the pharmaceutical composition of above-mentioned dihydroarteannuin.
Advantages of the present invention: new containing dihydroarteannuin and a kind of structure in the pharmaceutical composition of the dihydroarteannuin that the present invention provides Emphysema, when dihydroarteannuin, compound (I) independent role, are had therapeutical effect by the natural product of grain husk；Double hydrogen Herba Artemisiae Annuaes When element and compound (I) synergy, therapeutic effect improves further, can develop into the emophysematous medicine for the treatment of.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Radix Glehniae (2kg) is pulverized by (a), extracts (15L × 3 time) with 90% alcohol heat reflux, and merging carries Take liquid, be concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturation N-butyl alcohol (3L × 3 time) extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) Acetic acid ethyl ester extract D101 type macroporous resin remove impurity in step (a), first with 8 column volumes of 35% ethanol elution, then uses 90% ethanol elution 12 column volume, collects 90% eluent, and concentrating under reduced pressure obtains 90% ethanol elution concentrate；(c) step B in (), 90% ethanol elution concentrate purification on normal-phase silica gel separates, be 120:1 (11 column volumes), 60:1 by volume ratio successively The methylene chloride-methanol gradient elution of (9 column volumes), 30:1 (9 column volumes) and 15:1 (8 column volumes) obtains 4 Individual component；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1 (6 cylinders by volume ratio successively Long-pending), the methylene chloride-methanol gradient elution of 30:1 (8 column volumes) and 10:1 (6 column volumes) obtain 3 components；(e) The reverse phase silica gel that in step (d), component 2 is bonded by octadecylsilane separates, water-soluble with the methanol that concentration expressed in percentage by volume is 85% Liquid isocratic elution, collects 14～18 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I) (HPLC normalizing Change purity more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 377.2289, can obtain molecular formula in conjunction with nuclear-magnetism feature is C22H32O5, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, pyridine-d5, 500MHz): H-1 (5.37, Dd, J=4.3,10.1Hz), H-2a (3.32, m), H-2b (3.08, m), H-3 (6.82, m), H-5a (3.23, D, J=15.6Hz), H-5b (2.98, dd, J=15.6,9.3Hz), H-6 (5.06, dd, J=9.3,1.4Hz), H-7 (1.87, m), H-8 (1.94, m), H-9a (2.06, dd, J=16.1,2.6Hz), H-9b (1.64, dd, J=16.1, 7.3Hz), and H-11 (1.80, m), H-12 (0.93, d, J=5.7Hz), H-13 (1.13, d, J=5.7Hz), H-14 (1.78, s), H-2 ' (2.77, m), H-3 ' (5.26, m), H-4 ' (1.23, d, J=6.3Hz), H-5 ' (1.09, D, J=7.1Hz), H-2 " (1.97, s)；Carbon-13 nmr spectra data δC(ppm, pyridine-d5, 125MHz): 126.2 (CH, 1-C), 29.4 (CH2, 2-C) and 131.3 (CH, 3-C), 132.2 (C, 4-C), 28.3 (CH2, 5-C), 77.4 (CH, 6-C), 41.3 (CH, 7-C), 37.9 (CH, 8-C), 32.5 (CH2, 9-C), 143.1 (C, 10-C), 26.4 (CH, 11-C), 22.1 (CH3, 12-C), 23.8 (CH3, 13-C), 22.6 (CH3, 14-C), 171.2 (C, 15-C), 217.8 (C, 1 '-C), 48.4 (CH, 2 '-C), 72.4 (CH, 3 '-C), 17.3 (CH3, 4 '-C), 12.7 (CH3, 5 '-C), 170.3 (C, 1 "-C), 21.4 (CH3, 2 " and-C).1756cm in infrared spectrum-1 236nm absorption band during absorption band is composed with UV shows that this compound contains α, β-unsaturated lactone structure, in infrared spectrum 1715cm-1With 1680cm-1Absorption band shows to there is ketone group and double bond fragment in structure.13C-NMR, DEPT and hsqc spectrum In show 22 carbon signals, including six methyl, three methylene, eight methines (two even oxygen carbon and two alkene carbon), And five quaternary carbons (three carbonyl carbon and two alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is Twin nuclei.1H-NMR spectrum combines hsqc spectrum and shows five methyl proton signal δH0.93 (3H, d, J=5.7Hz), 1.13 (3H, d, J=5.7Hz), 1.78 (3H, s), 1.23 (3H, d, J=6.3Hz), 1.09 (3H, d, J=7.1Hz), One acetylmethyl proton signal δH1.97 (3H, s), two olefinic proton signals δH5.37 (1H, dd, J=4.3,10.1Hz) With 6.82 (1H, m), two even oxygen methine proton signal δH5.06 (1H, dd, J=9.3,1.4Hz) and 5.26 (1H, m)。1H-1There is H-1/H in H COSY spectrum2-2/H-3、H2-5/H-6/H-7/H-8/H2-9、H-7/H-11/H3-12、H-11/H3-13 Coherent signal, the H of display in composing in conjunction with HMBC2-2 and H2-9 and C-1, H2-2、H2-5 and H-6 Yu C-4 coherent signals Germacrane sesquiterpene skeleton can be built.And1H-1H in H COSY spectrum3-5’/H-2’/H-3’/H3-4 ' coherent signal and HMBC H-2 ' and C-1 ', C-3 ' and C-5 ' in spectrum, H-3 ' and C-2 ', C-4 ' and C-1 " and H-2 " and C-1 " coherent signal can be with structure Build another part fragment, and present in this part-structure, acetyl group is connected with C-3 ' by oxygen atom, simultaneously HMBC spectrum H-8 with C-1 ' coherent signal shows the position that this fragment is connected with germacrane sesquiterpene skeleton.Additionally HMBC spectrum H-3, H2A lactonic ring structure is there is between-5 and H-6 and C-15 coherent signal hint C-6 and C-15.In NOESY spectrum, H-8 For beta comfiguration, therefore, O-3 '-O-acetyl group-2 '-espeleton base should be α configuration.In addition there is coherent signal in H-9b Yu H-8, So H-9a Yu H-2a and H-9a Yu H-5a coherent signal can determine whether to judge that H-2a, H-5a, H-9a are all α configuration, with Time H-2a and H-5a coherent signal show Δ3(4)Double bond is E.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, And document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration passes through ECD further Test determines, theoretical value is basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment use trachea once injects elastoser 750UkgBW and prepares emphysema in rats model, observes medicine and improves The pulmonary emphysema against function of the aspects such as animal lung total capacity (TVL), average alveolar area, fiber cross section are long-pending.
1, materials and methods
1.1 animal
8～10 week old SD rats, male and female half and half, body weight 170～190g.Carried by institute of lab animals of Sichuan Academy of Medical Sciences Supply.Laboratory Animal Facility condition: animal observation ward of pharmaceutical college of Chengdu University of Traditional Chinese Medicine.
1.2 reagent and sample
Dihydroarteannuin is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
1.3 instrument
With IEICa Q500MC type image analyzer (Leica company, Germany).
Prepared by 1.4 rat packets and model
Rat divides 5 groups at random, often group 12, respectively Normal group, model control group, dihydroarteannuin group (80mg kg-1)、 Compound (I) group (80mg kg-1), dihydroarteannuin and compound (I) compositions group [40mg kg-1Dihydroarteannuin +40mg·kg-1Compound (I)].Normal group saline injection 1ml, remaining group once injects elastin laminin through trachea Enzyme 750U/kg BW.Modeling after adapting to environment 1 week, continuous gastric infusion 7d, Normal group and model control group rat Gavage gives purified water.
1.5 pathologic finding experiments
Last the 2nd day be administered, after rat anesthesia, dislocation is put to death, and opens breast and dissociates trachea, takes out lungs, at 25cm H2O Under pressure when trachea no longer increases to volume with 10% neutral formalin perfusion lungs, survey total lung capacity, TLC with drainage (TVL).Bottom right lung maximum longitudinal section is drawn materials, and HE dyes, and average alveolar area is surveyed in graphical analysis.
1.6 diaphram fiber kenel observation experiments
Last the 2nd day be administered, the section of Qu Leige district diaphram fiber cross sections, thick 10 μm, alkalescence ATP enzyme dyeing. With IEICaQ500MC type image analyzer to fast ballism (FT) fiber, the quantitative determination of slow ballism (ST) fibre transections area.
1.7 statistical method
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carry out one factor analysis of variance and T checks, statistically significant for difference with P ＜ 0.05.
2, experimental result
2.1 on Model of Emphysema induced lung total capacity, the impact of average alveolar area
With Normal group ratio, model control group total lung capacity, TLC, average alveolar area significantly increase (P ＜ 0.01)；With model pair According to group ratio, dihydroarteannuin and compound (I) compositions group total capacity, average alveolar area are substantially reduced (P ＜ 0.01)； With model control group ratio, dihydroarteannuin group, compound (I) group total capacity, average alveolar area reduce (P ＜ 0.05). It is shown in Table 1.
2.2 impacts long-pending on Model of Emphysema diaphragm in rats fiber cross section
Comparing with Normal group, the FT of model control group rat substantially reduces, ST significantly raised (P ＜ 0.01).With model Matched group compares, and dihydroarteannuin is significantly raised with compound (I) compositions group FT, ST substantially reduces (P ＜ 0.01)； Comparing with model control group, dihydroarteannuin group, compound (I) group FT raises, ST reduces (P ＜ 0.05).It is shown in Table 1.
The impact that table 1 is long-pending on Model of Emphysema induced lung total capacity, average alveolar area and diaphram fiber cross section
Elastoser causes induced lung edema due to disorder of QI solution to model to cut open, physiological characteristics changes consistent with mankind's emphysema, is to observe lung qi The ideal model that time swollen, respiratory muscle changes.That there are no significant is poor to emphysema group and control animals body weight, diaphragm weight for this laboratory observation Different, the impact of trophic factor can be got rid of, emphysema group ST fiber cross section is long-pending to be significantly increased, and FT fiber is without significantly changing.ST Fiber is mainly derived from oxidative phosphorylation process rich in Myoglobin, gland plastochondria and oxidase, ATP, and contraction time is long, is difficult to Tired.Emphysema diaphram ST fiber cross section is long-pending to be significantly increased, and is the material base of emphysema diaphram anti-fatigue ability enhancing. It is regarded as the compensatory change of diaphram load down.Respiratory muscle energy supply is that musculotonic key factor is breathed in impact, In the chronic course of disease of COPD, owing to airway resistance increase and lung are excessively inflated, respiratory muscle acting substantially increases, energy matter consumption, Muscle protein decomposes energy supply, and causing weight loss, Diaphragmatic muscle atrophy is the main cause that its muscular strength declines.
The above results shows, when dihydroarteannuin, compound (I) independent role, emphysema is had therapeutical effect；Double hydrogen When arteannuin and compound (I) synergy, therapeutic effect improves further, can develop into the emophysematous medicine for the treatment of.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this. It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off Essence and protection domain from technical solution of the present invention.

Claims (8)

1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a dihydroarteannuin, it is characterised in that: include dihydroarteannuin, as claimed in claim 1 Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of dihydroarteannuin the most according to claim 2, it is characterised in that: pharmaceutically acceptable carries Body includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, suction Appendix body or lubricant.
The pharmaceutical composition of dihydroarteannuin the most according to claim 2, it is characterised in that: described dosage form include tablet, Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) By Radix Glehniae pulverize, with 85～95% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, second Acetoacetic ester and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract； B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then use 90% second 12 column volumes of alcohol eluting, collect 90% eluent, and concentrating under reduced pressure obtains 90% ethanol elution concentrate；In (c) step (b) 90% ethanol elution concentrate purification on normal-phase silica gel separates, and is the dichloromethane of 120:1,60:1,30:1 and 15:1 by volume ratio successively -methanol elution gradient obtains 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, use volume successively 3 components are obtained than the methylene chloride-methanol gradient elution for 40:1,30:1 and 10:1；Component 2 in (e) step (d) Separate with the reverse phase silica gel of octadecylsilane bonding, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collect 14～18 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101 Type macroporous adsorbent resin.
7. the application in emophysematous medicine is treated in preparation of the compound (I) described in claim 1.
8. pharmaceutical composition the answering in emophysematous medicine is treated in preparation of the arbitrary described dihydroarteannuin of claim 2～4 With.
CN201610487517.7A 2016-06-24 2016-06-24 Medicinal composition of dihydroartemisinin and application of medicinal composition of dihydroartemisinin in biological medicine Withdrawn CN105949157A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106074501A (en) * 2016-07-21 2016-11-09 范瑶飞 Compound, nifedipine pharmaceutical composition preparation treatment hemolytic anemia medicine in application
CN106214676A (en) * 2016-07-21 2016-12-14 范瑶飞 The pharmaceutical composition of nifedipine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106074501A (en) * 2016-07-21 2016-11-09 范瑶飞 Compound, nifedipine pharmaceutical composition preparation treatment hemolytic anemia medicine in application
CN106214676A (en) * 2016-07-21 2016-12-14 范瑶飞 The pharmaceutical composition of nifedipine

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