CN108503678A - A kind of iridoid and its preparation method and application - Google Patents
A kind of iridoid and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of iridoids and its preparation method and application.Preparation method：(1) herb ethanol water refluxing extraction recycles ethyl alcohol, staticly settles, and filters, obtains filtered fluid；(2) filtered fluid uses chloroform, ethyl acetate extraction, water layer liquid after must extracting successively.(3) water layer liquid is concentrated to dryness, the chromatographies column separating purification such as silica gel, Sephadex LH 20, and crystallization obtains the compounds of this invention.Compound of the present invention has the function of good analgesic activity and eliminates acute inflammatory reaction.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to the iridoid compound extracted from plant and its preparation side
Method and application.
Background technology
Rubiaceae plants of Hedyotis has more than 50 kinds in China, and more than 20 kinds medicinal, is mostly antipyretic and antidotal type Chinese medicine, is used for
Treatment flu, inflammation and cancer.Goldhair Hedyotis Herb (Herba hedyotids chrysotrichae) also known as Herba Salviae Chinensis are used
In treatment virus hepatitis, traumatic injury, infantile acute nephritis, rheumatic arthritis, the swelling and pain of sore malignant boil and various cancers.
Invention content
The present invention extracts biologically active iridoid from plant, and provides it and controlled in preparation
Treat the application in the drug of pain or acute inflammation.Specifically, the present invention provides iridoid, structure is such as
Shown in Formulas I：
Formulas I
Or its officinal salt
Wherein：
R2For COOR5, R3Can be C for hydroxyl or alkoxy1-C6Alkoxy, such as C1-C4Alkoxy or C1-C3Alkoxy, and
R4For R6-OH；
Or R2、R3It is combined into lactone, can be that there is the lactone of 5-7 annular atom, such as with 5,6 or 7 annular atoms
Lactone, and R4For C1-C6Alkylidene OC (O) R7, alkylidene therein such as C1、C2、C3、C4、C5、C6Alkylidene, such as methylene；
R1For glycosyl, preferably glycosyl is selected from glucosyl group, galactosyl, mannose group, aralino, xylosyl, ribose
Base, lysol glycosyl and husband's glycosyl or other polyol groups；
R5For C1-C6Alkyl, such as C1-C4Alkyl or C1-C3Alkyl, such as methyl；R6For C1-C6Alkylidene, sub- heterocycle or sub- benzene
Base, the alkylidene such as C1、C2、C3、C4、C5、C6Alkylidene, such as methylene；R7For C1-C6Alkyl or C6-C10Aryl, it is described
Alkyl such as C1-C4Alkyl or C1-C3Alkyl, such as methyl, the aryl such as phenyl, naphthalene.
The compound is for example：
Compound 1
Compound 2
In one embodiment, the compound is compound 1 and/or compound 2.
In another embodiment, the compound is the compound of formula I other than compound 1 and/or compound 2.
The present invention also provides the preparation methods of above compound, include the following steps：
(1) Goldhair Hedyotis Herb whole herb with root or active component can be cut into 1-2cm segments, use ethanol water such as root, stem, leaf
Refluxing extraction, such as measure 95% ethanol water refluxing extraction 2 times with 10 times, such as 2 h every time, merge extracting solution, second is recycled in filtering
Alcohol, such as recycling ethyl alcohol measure medicinal material volume or so to 0.5-1 times, staticly settle, and filter, obtain filtered fluid；
(2) filtered fluid uses chloroform, ethyl acetate extraction successively, such as extracts 3 times, such as each 100ml, merges identical
Extract liquor, water layer liquid after must extracting.
(3) water layer liquid is concentrated to dryness, and methanol is added to dissolve, silica gel mixed sample, volatilization methanol to dry, upper silica gel chromatograph post separation,
Chloroform-methanol elution gradient is collected and is merged the fraction containing main component, such as can be collected with every 50ml respectively, collects
Merge fraction 12-25（Containing compound 1）, 29-42（Containing compound 2）, recycling design to dry, methanol dissolve respectively after on
Sephadex LH-20 column purifications, are eluted with methanol, collect merge the fraction containing main component respectively, such as can be received with every 50ml
Collection is collected and merges fraction 4-7, during collecting fraction, can carry out TLC test to the fraction of collection（Solvent
Can be chloroform-methanol（4∶1）, vanillic aldehyde-sulphate reagent colour developing）, subsequent crystallisation, such as can be blown to nitrogen few
Volume is measured, crystallization can be refrigerated at 4 DEG C, is filtered, methanol cleaning crystallization；Crystallization multiplexing methanol dissolving, recrystallization, such as nitrogen can be used
Air-blowing can be recrystallized to a small amount of volume at 4 DEG C, and filtering, methanol rinses, dry, obtain compound, including compound 1 and be changed
Close object 2.Gained compound can carry out further structural modification and conversion, obtain the similar derivative of structure.
Inventor by physicochemical property and Modern spectroscopy learn to do section (UV, IR, MS,1H-NMR、13C-NMR and 2D-NMR
) Structural Identification has been carried out to isolated compound, it was demonstrated that it is structure iridoid compound shown in formula I.
It is another object of the present invention to provide compounds shown in a kind of Formulas I to prepare answering in treating pain medication
With.The pain such as Acute Pain, subacute pain, neuropathic pain, systemic pain；The pain is for example drawn by inflammation
It rises.
It is another object of the present invention to provide compounds shown in a kind of Formulas I to prepare treatment or eliminate acute inflammation medicine
Application in object.Acute inflammation such as serous inflammation, fibrinous inflammation, suppurative inflammation and hemorrhagic inflammation.
It is yet a further object of the present invention to provide a kind of pharmaceutical compositions, including compound shown in above-mentioned Formulas I.
The present invention also provides a kind of pharmaceutical compositions treated pain or treatment or eliminate acute inflammation, contain treatment
A effective amount of above-mentioned compound of formula I and one or more pharmaceutically acceptable carriers.
In one embodiment, the drug or composition are lived without other treatments in addition to the compound of formula I
Property ingredient.
In one embodiment, the drug or composition are without the yellow hair of others in addition to the compound of formula I
Auricled Hedyotis Herb ingredient.
Description of the drawings
Fig. 1 is the mass spectrum of compound 1；
Fig. 2 is the hydrogen spectrum of compound 1；
Fig. 3 is the carbon spectrum of compound 1；
Fig. 4 is the mass spectrum of compound 2；
Fig. 5 is the hydrogen spectrum of compound 2；
Fig. 6 is the carbon spectrum of compound 2.
Specific implementation mode
In order to make those skilled in the art more fully understand technical scheme of the present invention, with reference to specific embodiment pair
The present invention is described in further detail.
The preparation of 1 the compounds of this invention of embodiment
(1) dry Goldhair Hedyotis Herb whole herb with root, is cut into 1-2cm segments, 10 times of 95% ethanol water refluxing extractions of amount 2 times, and every time 2
H merges extracting solution, filtering；Recycling ethyl alcohol measures medicinal material volume or so to 0.5-1 times, staticly settles, and filters, obtains filtered fluid；
(2) filtered fluid uses chloroform, ethyl acetate extraction successively, extracts 3 times, each 100ml merges identical extract liquor, obtains
Water layer liquid after extraction；
(3) water layer liquid is concentrated to dryness, and methanol is added to dissolve, silica gel mixed sample, volatilization methanol to dry, upper silica gel chromatograph post separation, trichlorine
The fraction containing main component is collected and merged to methane-methanol gradient elution respectively, is collected per 50ml, collects and merge fraction 12-25
（Containing compound 1）, 29-42（Containing compound 2）, for recycling design to doing, it is pure that methanol goes up Sephadex LH-20 columns after dissolving respectively
Change, eluted with methanol, collect merge the fraction containing main component respectively, is collected per 50ml, collect and merge fraction 4-7, collecting
During fraction, TLC test is carried out to the fraction of collection（Solvent is chloroform-methanol（4∶1）, vanillic aldehyde-
Sulphate reagent develops the color）；Nitrogen is blown to a small amount of volume, 4 DEG C of refrigeration crystallizations, filtering, methanol cleaning crystallization；Crystallization is multiplexed a little methanol
Dissolving, nitrogen are blown to a small amount of volume, and 4 DEG C of recrystallizations, filtering, methanol rinses, dry, obtains compound, including compound 1 and chemical combination
Object 2.
The Structural Identification of 2 the compounds of this invention of embodiment
Compound 1：ESI-MSm/z: 437.1059 [M+Na]+。1H-NMR (500 MHz, CD30D)δ:7.30 ( 1H, d
, J=2.05 Hz, H-3), 5.95(1H, d, J=1.05Hz , H-1), 5.73(1H, s, H-7), 5.56(1H, d,
J=6.6Hz, H-6), 4.79( 1H, dd, J=1.0, 14.3Hz, H-l′), 4.68-4.64(2H, t, H-10a,
10b), 3.92( 1H, dd, J=2.1, 11.85Hz, H-6′a), 3.68-3.65(2H, m, H- 6′b, 5),
3.39-3.17(5H, m, H-3′, 5′, 4′, 9, 2′), 2.07(3H, s, CH3COO); 13C-NMR(500MHz,
CD30D) δ:172.56(C-11),172.23(CH3CO),150.27(C-3),144.29(C-8),128.93(C-7),
106.18(C-4),100.02(C-1′),93.31(C-1),86.30(C-6),78.38(C-3′),77.889(C-5′),74.65
(C-2′),71.60(C-4′),62.80(C-6′), 61.91(C-10),45.27(C-9),37.45(C-5),20.62(CH3)。
High resolution mass spectrum molecular weight is analyzed, and 1 molecular weight of compound is 414.1059, molecular formula C18H22O11, similarity
99.14%.Through looking into noval chemical compound 1 and compound Asperuloside（Asperuloside）Have identical13C chemical shifts,13C chemistry
Displacement similarity 100%,13C chemical shift datas are shown in Table 1.In conjunction with1H-NMR is composed, and determines that compound 1 is Asperuloside（Vehicle
Leaf grass glycosides）.
1 compound 1 of table and Asperuloside（Asperuloside）13C Chemical shift comparisons
1 Asperuloside of compound（Asperuloside）
Compound 2:ESI-MSm/z: 427.1213 [M+Na]+。1H-NMR (500 MHz,CD30D) δ: 7.54(1H, s,
H-3), 5.83(1H, s , H-7), 5.22(1H, d, J=6.0Hz, H-1), 4.70(1H, d, J=8.0Hz, H-
1′), 4.58(1H, t, J=1.0Hz, H-6), 4.37(1H, d , J=15.2Hz , H-10a) , 4.22(1H, d,
J=15.0Hz, H-10), 3.90(1H, d, J=11.0Hz, H-6′a), 3.66(1H, dd, J=5.0, 11.0Hz ,
H-6′b), 3.78(3H, s, OCH3), 3.22~3.41 (4H, m, H-2 ', 3 ', 4 ', 5 '), 3.01~3.08
(2H, m, H-5,9); 13C-NMR (500 MHz,CD30D) δ:170.301(C-11), 153.848(C-3), 147.518
(C-8), 130.147(C-7), 110.836(C-4), 100.335(C-1′), 98.367(C-1), 82.302(C-6),
78.424(C-3′), 77.902(C-5′), 74.801(C-2′), 71.555(C-4′), 62.708(C-6′), 61.046
(C-10), 52.042(OCH3), 47.164(C-9), 45.637(C-5)。
High resolution mass spectrum molecular weight is analyzed, and 2 molecular weight of compound is 404, molecular formula C17H24O11, similarity 99.83%.
Through looking into new discovery Scandoside methyl ester（Scandoside methyl ester）Have with compound 2 identical13C chemical shifts,
Similarity is 100%,13C chemical shift datas are shown in Table 2.In conjunction with1H-NMR is composed, and determines that compound 2 is Scandoside methyl
ester（Scandoside methyl ester）.
2 compound 2 and Scandoside methyl ester of table（Scandoside methyl ester）13C Chemical shift comparisons
2 Scandoside methyl ester of compound（Scandoside methyl ester）
3 the compounds of this invention of embodiment treats pain medication detection
The standard step of embryo collection：The breeding of zebrafish embryo is carried out in a manner of natural paired cross.Mating prepares 4 every time
~ 5 pairs of Adult Zebrafishs, it is averagely each pair of to produce 200 ~ 300 embryos.In after fertilization 6 hours（That is 6 hpf）With 24 hpf
Embryo is cleared up（Remove dead embryo）, and suitable embryo is selected according to the stage of development of embryo（Kimmel et
al. 1995）.Under the conditions of 28 DEG C embryo is incubated with fish culture water（Fish culture water water quality：It is added 200 in per 1L reverse osmosis waters
Mg Instant Oceans, conductivity are 480 ~ 510 μ S/cm；PH is 6.9 ~ 7.2；Hardness is 53.7 ~ 71.6 mg/L CaCO3）.Cause
Nutriment can be obtained from the yolk bag of itself for embryo, so in after fertilization 9 days（9 dpf）Feeding is not needed.
Over-exposure processing is carried out to the zebra fish of each stage of development with tricaine methanesulfonic acid, is put to death to anaesthetize zebra fish, fiber crops
The operating procedure of liquor-saturated execution meets American Veterinary association（AVMA）The code requirement that Animal Anesthesia is put to death.
1. determining the maximal tolerable concentration of compound（MTC）
Zebra fish strain：Wild type AB systems；
Normal group：The normal zebra fish of fish culture water processing；
Model control group：Zebra fish is handled with glacial acetic acid, establishes zebra fish pain model；
Test sample group：Five initial detecting concentration of test sample are respectively：1,10,100,250 and 500 μ g/mL；Test sample with
It is water-soluble to handle pain model zebra fish to sample loading mode；
Each experimental group is 30 tail zebra fish, is incubated in 28 DEG C of incubators；
Test sample after treatment counts the zebra fish The dead quantity and toxicity profile of each experimental group, determines the maximum of test sample
Tolerable concentration（MTC）；
If MTC cannot be obtained in initial Concentration Testing experiment, the detectable concentration range of test sample is will be enlarged by, the upper limit is
2000 μ g/mL or test sample maxima solubility, lower limit are 0.1 μ g/mL.
Required zebra fish number：At least need 210 tail zebra fish
As a result：The results show that 100,250 and 500 μ g/mL can obviously reduce zebra fish abnormal motion caused by glacial acetic acid.
2. evaluating the analgesic activity of compound
Zebra fish strain：Wild type AB strains；
Normal group：The normal zebra fish of fish culture water processing；
Model control group：Zebra fish is handled with glacial acetic acid, establishes zebra fish pain model；
Test sample group：According to 1. experimental result, chooses 3 concentration and evaluated（Usually 1/9 MTC, 1/3 MTC and
MTC）；Test sample handles pain model zebra fish with water-soluble to sample loading mode；
Positive drug control group：Aspirin；
Each experimental group handles 30 tail zebra fish, is incubated in 28 DEG C of incubators；
If test sample has analgesic effect, the pain caused caused zebra fish abnormal motion number of glacial acetic acid can be slowed down and increased.For
Test product after treatment detects the times of exercise of zebra fish using zebra fish behavioural analysis instrument（N）, evaluate the analgesia work of test sample
With, statistical procedures result withIt indicates；
Test sample is as follows to pain relief effect calculation formula：
Statistical analysis is examined using variance analysis and Dunnett ' s T-, p<0.05 is significant difference；p<0.01 is pole
Significant difference.
3. result
In the pain caused caused zebra fish abnormal motion number experiment of glacial acetic acid, compared with model control group, 1 He of compound
Zebra fish has apparent inhibiting effect caused by 2 middle and high dosage are pain caused to glacial acetic acid.Model control group, positive control drug
The zebra fish glacial acetic acid abnormal motion experimental result of group, compound 1 and 2 low, middle and high dose groups is shown in Table 3：
Inhibiting rate（%）=（Medication group abnormal motion mean-model group abnormal motion mean）/ model group abnormal motion mean.
Influence of 3. compound of table to zebra fish pain（, n=10）
Compared with model control group, * p<0.05, **p<0.01.
4. conclusion
This experiment establishes zebra fish pain model, the middle and high dosage group of the compounds of this invention is to ice to handle zebra fish with glacial acetic acid
Acetic acid causes zebra fish pain to significantly inhibit.The compounds of this invention shows apparent analgesic activity.It is described
Pain such as Acute Pain, subacute pain, neuropathic pain, systemic pain；The pain is for example caused by inflammation.
The present invention is using zebra fish as experimental subjects, and zebra fish abnormal motion number is evaluated caused by glacial acetic acid is pain caused
The analgesic activity of test sample can be the above is only a preferred embodiment of the present invention experiment pair with mouse, rat etc.
As the animal model pharmacological activity that eases pain to it for causing pain by chemical stimulation and thermostimulation is studied.It is prepared by the present invention
Iridoid compound can be combined with commercially available or common carrier in obtained plants of Hedyotis, be used to prepare prevent, treat,
The drug of synergistic treatment pain.The drug can be the forms such as micro emulsion, injection, tablet, capsule, suppository, oral solution.
4 the compounds of this invention of embodiment eliminates acute inflammatory reaction drug test
1. the effect of paraxylene induced mice auricle edema inflammatory model
SPF grades of kunming mices, 18~22 g of weight, half male and half female, this experiment use sc administering modes, experiment basic, normal, high
3 dose concentrations are respectively set to 25,50,100 mg/kg.Kunming mouse 80, is randomly divided into according to weight and gender
8 groups：Model control group, hydrocortisone positive controls（25 mg/kg）Group, 1 low, middle and high dose groups of compound, compound 2
Low, middle and high dose groups, every group 10.Daily administration 1 time, 5 d of successive administration.After 40 min of last time administration,
10 μ L dimethylbenzene are uniformly applied to outside, the distilled water that left ear is coated with same volume in mouse right ear and compare.Weight after 40 min
It is multiple primary, neck execution mouse is taken off after 40 min, ears are cut along auricle baseline, is distinguished with the card punch of 8 mm of diameter
Round auricle is laid at the same position of two ears, electronic balance scale quality, every mouse right ear piece is used to subtract left auricle quality i.e. rapidly
For auricle inflammation swelling, ear swelling rate and ear swelling inhibiting rate are calculated.
Ear swelling rate=（Auris dextra tablet quality-left auricle quality）/ left auricle quality
Ear swelling inhibiting rate=（Control group swelling rate-the administration group that is averaged is averaged swelling rate）/ control group is averaged swelling rate
2. result
Compared with model control group, hydrocortisone positive controls, compound 1 50,100mg/kg groups, compound 2
50,100mg/kg groups paraxylene induced mice auricle edema significantly inhibits（ p<0.05 is poor for conspicuousness
It is different；p<0.01 is pole significant difference.）, showing 1 and change 2 can dose-dependent improvement dimethylbenzene induced mice auricles
Swelling the results are shown in Table 4.
4. compound paraxylene induced mice auricle edema of table antagonism (, n = 10)
Compared with model control group, * p<0.05, **p<0.01.
3. conclusion
Using chmice acute inflammatory model as research object, the compound 1 of 50,100 mg/kg and 2 paraxylene cause for this experiment
The acute inflammation of mice auricle swelling all have apparent inhibiting effect, inhibiting rate is respectively 26.3%, 51.5%；24.3%,
44.5%.The compounds of this invention has good inhibiting effect for acute inflammation model.Acute inflammation such as serous inflammation, fiber
Disposition inflammation, suppurative inflammation and hemorrhagic inflammation.
The present invention is using zebra fish as experimental subjects, and zebra fish abnormal motion number is evaluated caused by glacial acetic acid is pain caused
The analgesic activity of test sample is only the preferred embodiment of the present invention, can be with mouse, rat etc. for experimental subjects, passing through
Stimulate and the animal model of thermostimulation initiation pain eases pain to it, and pharmacological activity is studied.This experiment is with caused by dimethylbenzene
The acute inflammation model of mice auricle swelling evaluates the acute inflammation elimination effect of test sample for research object, is only the present invention
Preferred embodiment.
Iridoid compound can be combined with commercially available or common carrier in the plants of Hedyotis that the present invention is prepared,
Be used to prepare prevent, treat, the drug of the drug of synergistic treatment pain or acute inflammation.The drug can be micro emulsion, injection
The forms such as agent, tablet, capsule, suppository, oral solution.Prepared drug can be administered by conventional route.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, several improvement can also be made
Or supplement, these are improved or supplement also should be regarded as protection scope of the present invention.
Although term is used more herein, it does not preclude the possibility of using other terms.Use these terms
It is only for the convenience of describing and explaining the nature of the invention；Be construed as any one of the additional limitations all and be with
What spirit of that invention was disagreed.
Claims (10)
1. a kind of iridoid, structure are shown in formula I：
Formulas I
Or its officinal salt
Wherein：
R2For COOR5, R5For C1-C6Alkyl, R3For hydroxyl or C1-C6Alkoxy, and R4For R6- OH, R6For C1-C6Alkylidene, Asia are miscellaneous
Ring group or phenylene；
Or R2、R3It is combined into the lactone with 5-7 annular atom, and R4For C1-C6Alkylidene OC (O) R7, R7For C1-C6Alkyl
Or C6-C10Aryl；
R1For glycosyl, preferably glycosyl be selected from glucosyl group, galactosyl, mannose group, aralino, xylosyl, ribosyl,
Lysol glycosyl and husband's glycosyl or other polyol groups.
2. according to the compound described in claim 1, R5For C1-C4Alkyl；R3For C1-C4Alkoxy；Wherein R5+R3Carbochain
Sum is 3 ~ 7.
3. according to the compound described in claim 1, R7For C1-C3Alkyl.
4. the preparation method of compound described in claim 1, which is characterized in that include the following steps：
(1) Goldhair Hedyotis Herb whole herb with root or active component, as root, stem, leaf merge extraction with ethanol water refluxing extraction
Liquid, filtering are recycled ethyl alcohol, are staticly settled, and filter, obtain filtered fluid；
(2) filtered fluid uses chloroform, ethyl acetate extraction successively, merges identical extract liquor, water layer liquid after must extracting；
(3) water layer liquid is concentrated to dryness, and methanol is added to dissolve, silica gel mixed sample, volatilization methanol to dry, upper silica gel chromatograph post separation, trichlorine
Methane-methanol gradient elution, collects and merges the fraction containing main component respectively, and recycling design is to dry, after methanol dissolves respectively
Upper Sephadex LH-20 column purifications, are eluted with methanol, collect merge the fraction containing main component respectively, crystallize, filtering, methanol
Cleaning crystallization；Crystallization multiplexing methanol dissolving, recrystallizes, filtering, methanol rinses, dry, compound is obtained, including compound 1
With compound 2：
Compound 1；
Compound 2.
5. preparation method according to claim 4, which is characterized in that step (1) ethanol water is 0-100% ethanol waters
Solution.
6. application of the compound described in claim 1 in the drug for preparing treatment pain.
7. application of the compound described in claim 1 in preparing treatment or eliminating acute inflammation drug.
8. a kind of pharmaceutical composition, which is characterized in that include compound described in claim 1.
9. one kind is for treating pain medication composition, which is characterized in that chemical combination described in the claim 1 containing therapeutically effective amount
Object and pharmaceutically acceptable carrier.
10. one kind is for treating or eliminating acute inflammation pharmaceutical composition, which is characterized in that the right containing therapeutically effective amount is wanted
Ask 1 compound and pharmaceutically acceptable carrier.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710103107.2A CN108503678A (en) | 2017-02-24 | 2017-02-24 | A kind of iridoid and its preparation method and application |
| PCT/CN2018/076529 WO2018153310A1 (en) | 2017-02-24 | 2018-02-12 | Iridoids, and preparation method and use thereof |
Applications Claiming Priority (1)
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Cited By (3)
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| CN109796511A (en) * | 2019-03-05 | 2019-05-24 | 山东省药学科学院 | A kind of new iridoid and preparation method thereof and medical usage |
| CN113072604A (en) * | 2021-04-02 | 2021-07-06 | 中南大学 | Preparation method of iridoid glycoside in herba Hedyotidis Diffusae and application of iridoid glycoside in preparing antiinflammatory medicine |
| CN113354539A (en) * | 2021-05-12 | 2021-09-07 | 广州中医药大学(广州中医药研究院) | Morinda officinalis iridoid compound with anti-inflammatory activity and preparation method and application thereof |
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| WO2018153310A1 (en) | 2018-08-30 |
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