CN107827940A - Yncaria stem with hooks acid amides A and its pharmaceutical composition and application - Google Patents
Yncaria stem with hooks acid amides A and its pharmaceutical composition and application Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 150000001408 amides Chemical class 0.000 title claims abstract description 13
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 102000001419 Melatonin receptor Human genes 0.000 claims abstract description 26
- 108050009605 Melatonin receptor Proteins 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 20
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- 239000012190 activator Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000010828 elution Methods 0.000 claims description 11
- 239000000284 extract Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 241000345998 Calamus manan Species 0.000 claims description 5
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- DAXYUDFNWXHGBE-VKCGGMIFSA-N Isorhynchophylline Chemical compound O=C1NC2=CC=CC=C2[C@]11CCN2C[C@H](CC)[C@@H](\C(=C/OC)C(=O)OC)C[C@H]21 DAXYUDFNWXHGBE-VKCGGMIFSA-N 0.000 description 1
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- DAXYUDFNWXHGBE-KAXDATADSA-N Rhynchophylline Chemical compound O=C1NC2=CC=CC=C2[C@@]11CCN2C[C@H](CC)[C@@H](\C(=C/OC)C(=O)OC)C[C@H]21 DAXYUDFNWXHGBE-KAXDATADSA-N 0.000 description 1
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- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
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- 229960003987 melatonin Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a new glucosides of indole alkaloid three shown in structure formula (I), yncaria stem with hooks acid amides A (1), the pharmaceutical composition formed with the compound 1 and pharmaceutical acceptable carrier or excipients of therapeutically effective amount, the preparation method of compound 1 and its pharmaceutical composition, and melatonin receptors activator is used as, and its application in preparing treatment or improving the medicine of the central nervous system disease related to melatonin receptors.
Description
Technical field：
The invention belongs to technical field of pharmaceuticals.In particular it relates to a new glucosides of indole alkaloid three, yncaria stem with hooks acid amides A
(1), the pharmaceutical composition with compound 1 for active ingredient, it is as the application in melatonin receptors activator, and its is preparing
Treatment improves application in the medicine of the central nervous system disease related to melatonin receptors.
Background technology：
Epiphysin (melatonin, MT) is the endogenous hormone secreted by mammal pineal body, and it, which is secreted, has substantially
Round the clock with seasonal oscillation, there is important adjustment effect to the circadian rhythm of organism, reproduction, aging etc..Epiphysin exists
Played a role in vivo by activating specific melatonin receptors, having improves the lifes such as sleep, anti-aging and raising immunity of organisms
Reason activity, also has adjustment effect to depression and anxiety and pain in addition.Human body melatonin receptors include MT1And MT2Two kinds of hypotypes,
Belong to g protein coupled receptor, share 7 transmembrane segments, there is high-affinity to epiphysin, be the main function of epiphysin in human body
Site.MT1And MT2Acceptor has widely distributed in human central nervous system and peripheral tissues, mainly divides in central nervous system
It is distributed in SCN, hypophysis, olfactory bulb, midbrain, hypothalamus etc.；Cardiovascular system, spleen, chest are distributed mainly in peripheral tissues
Gland, lymph node, sexual gland, intestines and stomach, kidney etc..After melatonin receptors are activated, reacted, mediated by a series of signal transductory cascade
Intracellular Ca2+, NO, cyclic guanosine monophosphate (cGMP), the message level such as CAMP (cGMP), activate MEK/ERK signal paths,
And then play the biological effects such as sleep wakefulness, immunological regulation, cardiovascular system regulation.Now there are some researches show activate MT1Acceptor
The release of the Neural spike train and prolactin of SCN can be suppressed, promote sleep and vasoconstrictor activity to have with epiphysin
Close；Activate MT2Acceptor can cause Spleen cell proliferation and coronary artery diastole, have with epiphysin circadian rhythm and blood vessel dilatation function
Close.Melatonin receptors activator is the study hotspot of current new antidepression and hypnotic sedative agent, can be avoided because acting on GABA
The side effect such as drug dependence caused by acceptor and opiate receptor etc..From 1980s successful clone MT1And MT2By
Since body, people have synthesized multiple MT receptor stimulating agents, and which part activator as antidepression and improves sleep medicine
Thing lists, and such as agomelatine, auspicious U.S. is for high, Ta Simeiqiong.
As people go deep into Natural products research, increasing natural small molecule causes the emerging of Pharmaceutical Chemist
Interest.Particularly traditional Chinese medicine is the important sources for finding natural activity molecule.Rubiaceae Rubiaceae wild gambiers Uncaria plants
Thing yncaria stem with hooks U.rhynchophylla is the important Original plant of traditional Chinese medicine yncaria stem with hooks.Its cold nature is sweet, Return liver, pericardium channel, tool
There are dispelling wind and relieving convulsion, The flat liver of heat-clearing and other effects, be clinically used for treating liver wind agitation, twitch, hyperpyretic convulsion, dysphoric cold, small
Youngster's crying with fear, pre-eclampsia, dizziness of having a headache etc., now have become clinical hypotensive and treatment the nervous system disease conventional Chinese medicine.It is existing
Show for pharmacological research, yncaria stem with hooks has hypotensive, calmness, anticonvulsion, Ca2+ overloading, removing free radical, neuroprotection isoreactivity.Hook
It is Chinese medicine yncaria stem with hooks that the compositions such as indole alkaloid, flavones, triterpene, organic acid, particularly indole alkaloid are mainly contained in rattan plant
Study hotspot.The hypotensive activity of Chinese medicine yncaria stem with hooks is still current research emphasis, and research shows that rhynchophyllin and isorhynchophylline are
Yncaria stem with hooks plays the main active of antihypertensive effect.
So far, report of the prior art without yncaria stem with hooks acid amides A (1), also without medicines of the yncaria stem with hooks acid amides A (1) as active ingredient
The report of compositions, also without yncaria stem with hooks acid amides A (1) and its pharmaceutical composition as melatonin receptors activator, and treatment or
Improve the application report of the central nervous system disease related to melatonin receptors.
The content of the invention：
It is an object of the invention to provide the new indoles biology of one shown in a kind of new formula (I) with medical value
The glucosides of alkali three, yncaria stem with hooks acid amides A (1), the yncaria stem with hooks acid amides A (1) of effective dose is used as melatonin receptors activator, with yncaria stem with hooks acid amides A
And its application of the pharmaceutical composition in treating or improving the central nervous system disease related to melatonin receptors (1).
In order to realize the above-mentioned purpose of the present invention, the invention provides following technical scheme：
Compound yncaria stem with hooks acid amides A (1) shown in structure formula (I),
Application of the compound 1 of described formula (I) in melatonin receptors activator is prepared.
Application of the compound 1 of described formula (I) in preparing treatment or improving the medicine of central nervous system disease.
Apply as mentioned, wherein described disease is the central nervous system disease related to melatonin receptors.
The present invention additionally provides formula (I) compound 1 containing therapeutically effective amount and pharmaceutically acceptable carrier simultaneously
Pharmaceutical composition.
Application of the described pharmaceutical composition in melatonin receptors activator is prepared.
Application of the described pharmaceutical composition in the medicine for treating or preventing central nervous system disease is prepared.
Apply as mentioned, wherein described disease is the central nervous system disease related to melatonin receptors.
The present invention still further provides the method for preparing described formula (I) compound 1, the drying buckle stem branch of hook taking rattan,
Crush, with the extraction of 70% alcohol reflux twice, 3 hours every time, merge ethanol extract, ethanol is recovered under reduced pressure and obtains medicinal extract.Medicinal extract is with 5
Amount water dissolving again, utilizes D101 macroporous resin column chromatographies, alcohol-water gradient elution.Merge 50% alcohol elution, concentrate,
Methanol dissolves, and is adsorbed on silica gel, and room temperature, which is placed, volatilizes solvent, grinds after sieving through silica gel column chromatography, chloroform-methanol-water (7：
3：0.3) elute, obtain 4 flow point A-D.Flow point C, which is continued on through, to be suppressed standby in MCI CHP-20P gel columns, methanol-water gradient is washed
De- (1：9~9：1) 5 flow points, C-1~C-5, are obtained.Flow point C-2 purifies through HPLC, utilizes Rp-C18Post, acetonitrile-water gradient are washed
De- (1：9~3：7) target compound 1, is obtained.
It is raw material with compound 1 that the method for preparing the pharmaceutical composition containing compound 1, which is, adds pharmaceutical acceptable carrier or tax
Shape agent.Described pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine system
Product assistant agent.
When the compounds of this invention 1 is used as melatonin receptors activator or medicine, can directly it use, or with drug regimen
The form of thing uses.The pharmaceutical composition contains 0.1~99%, preferably 0.5~90% compound 1, and remaining is materia medica
Upper acceptable, nontoxic to humans and animals and inert pharmaceutical acceptable carrier and/or excipient.By the present invention pharmaceutical composition with
The form of per weight dose uses.The medicine of the present invention can be administered through injecting (intravenous, intramuscular injection) and oral two kinds of forms.
Brief description of the drawings：
Fig. 1 is the structural formula of the compounds of this invention 1；
Fig. 2 is the melatonin receptors excitement rate of the compounds of this invention 1, is set to the maximum exciting rate of epiphysin (MT)
100%, the test concentrations of compound are 1.0mM, and exciting rate is Mean ± SD (n=3).
Embodiment：
Essence for a better understanding of the present invention, below in conjunction with the accompanying drawings, entered with the test example and embodiment of the present invention
One step illustrates the compounds of this invention yncaria stem with hooks acid amides A (1) preparation method, Structural Identification, pharmacological action, and the preparation of the present invention
Method and medicine composition, but the present invention is not limited with this test example and embodiment.
Embodiment 1：
The preparation of compound 1：
The drying buckle stem branch of hook taking rattan, crush, with the extraction of 70% alcohol reflux twice, 3 hours every time, merge ethanol and carry
Liquid, ethanol is recovered under reduced pressure and obtains medicinal extract.Medicinal extract is dissolved with 5 times of amount water, and using D101 macroporous resin column chromatographies, alcohol-water gradient is washed
It is de-.Merge 50% alcohol elution, concentrate, methanol dissolving, be adsorbed on silica gel, room temperature, which is placed, volatilizes solvent, grinds sieving
By silica gel column chromatography, chloroform-methanol-water (7: 3: 0.3) elution, 4 flow point A-D are obtained.Flow point C continues on through MCI CHP-
Suppress standby in 20P gel columns, methanol-water gradient elution (1: 9~9: 1), obtain 5 flow points, C-1~C-5.Flow point C-2 is passed through
HPLC is purified, and utilizes Rp-C18Post, acetonitrile-water gradient (1: 9~3: 7), obtains target compound 1.
The Structural Identification of compound 1：
Optically-active is determined by the polarimeters of Jasco model 1020 (Horiba, Tokyo, Japan)；Infrared spectrum (IR) uses
KBr pressed disc methods, determined by Bio-Rad FTS-135 types infrared spectrometers (Hercules, California, USA)；Ultraviolet spectra
Determined by UV-2401PC types ultraviolet spectrometer (Shimadzu, Kyoto, Japan)；ECD is composed by Applied Photophysics
Circular dichroism spectrometer (Agilent, Santa Clara, United States) is determined, and nuclear magnetic resoance spectrum (1D and 2D NMR) is used
AVANCE III-600 types NMR spectrometer with superconducting magnet (Bruker, Bremerhaven, Germany) determines, using deuterated water as molten
Agent；High resolution mass spectrum (HRMS) is determined with LCMS-IT-TOF types mass spectrograph (Shimadzu, Kyoto, Japan)；Thin-layer chromatography silicon
Glue, column chromatography silica gel (200-300 mesh) are purchased from the U.S. high and Qingdao Haiyang Chemical Group Co., Ltd in Qingdao.CHP20P MCI gels
Purchased from Mitsubishi Chemical Corporation (Tokyo, Japan).
Compound 1
Molecular formula：C38H50N2O19
Molecular weight：838.30
Character：White powder
HRESIMS(+)m/z:839.3081([M+H]+,0mDa)。
HRESIMS(–)m/z:883.2983([M+HCOO]-,–0.7mDa)
IR(KBr)vmax:3420,2924,1613,1519,1446,1384,1284,1073,592cm-1。
UV/Vis (methanol) λmax(logε):206(4.76),279(4.06)nm。
1H-NMR and13C-NMR data are shown in Table 1.
[α]D 23=-45.5 (c 0.13, methanol).
The compound 1 of table 1.1H-NMR (600MHz) and13C-NMR (150MHz) data (D2O)
Embodiment 2：
Compound 1 is to melatonin receptors MT1And MT2The agonist activity of acceptor.
1 material and method
1.1 material：
Melatonin receptors MT1And MT2The cell line of agonist activity Select to use corresponds to human body renal epithelial cell respectively
HEK293-MT1And HEK293-MT2；Cell culture medium (Dulbecco's Modified Eagle containing 10% hyclone
Medium,DMEM)；Disposable calcium current kit.
1.2 instrument：CO2Constant incubator Thermo Forma 3310 (U.S.)；Inverted biologic microscope XD-101 types
(Nanjing)；Flexstation 3Benchtop Multi-Mode Microplate Reader(Molecular Devices,
Sunnyvale,California,USA)。
1.3 experimentation
96 hole Hei Bi are revealed the exact details into Tissue Culture Plate using matrix BD Matrigel coatings, in 37 DEG C of constant incubator 1h, inhaled
Supernatant is taken, with 4 × 104The density in/hole, corresponding HEK293 cells are inoculated in 96 hole Hei Bi and revealed the exact details in Tissue Culture Plate, in
CO216~24h is cultivated in 37 DEG C of constant incubators that concentration is 5%；Former culture medium is discarded, adds the μ of dye liquor 100 of fresh configuration
L/ holes, 60min is incubated in 37 DEG C of lucifuges.The preparation of testing sample：Prepare the testing sample of various concentrations.By treating for designated volume
Test sample product are added in cell, and addition sample volume is 50 μ l/ holes, and sample is determined using the multi-function microplate readers of Flexstation 3
Agonism of the product to melatonin receptors.Experimental result is analyzed using the softwares of Graphpad prism 5.
2. result：
Compound 1 is under 1.0mM concentration, to MT1And MT2The exciting rate of acceptor is respectively 79.6 and 46.3% (see Fig. 2ization
Compound 1 is to MT1And MT2The exciting rate of acceptor, 100% is set to the maximum exciting rate of epiphysin (MT), the test concentrations of compound
For 1.0mM, exciting rate is Mean ± SD (n=3)).
3rd, conclusion：
Experimental result shows that compound 1 is to MT1And MT2Acceptor shows preferable agonism, under 1.0mM concentration,
To MT1And MT2The exciting rate of acceptor is respectively 79.6 and 46.3%.Result above shows that compound 1 can be as new epiphysin
Receptor stimulating agent, and can treat or improve the central nervous system disease related to melatonin receptors.
Embodiment 3：
Example of formulations：
1. compound 1 is prepared as described in Example 1, after a small amount of DMSO dissolvings, routinely add water for injection,
Parenteral solution is made in refined filtration, embedding sterilizing.
2. compound 1 is prepared as described in Example 1, after a small amount of DMSO dissolvings, aseptic injection is dissolved in
With in water, it is stirred to dissolve, is filtered with sterile suction funnel, then sterile refined filtration, it is sub-packed in ampoule, nothing after frozen drying
Bacterium seals to obtain powder-injection.
It is 9 by itself and excipient weight ratio 3. compound 1 is first prepared as described in Example 1:1 ratio adds
Excipient, pulvis is made.
It is 5 by itself and excipient weight ratio 4. compound 1 is first prepared as described in Example 1:1 ratio adds
Excipient, pelletizing press sheet.
5. compound 1 is first prepared as described in Example 1, routinely oral liquid is made in oral liquid preparation method.
It is 5 by itself and excipient weight ratio 6. compound 1 is first prepared as described in Example 1:1 ratio adds
Excipient, capsule is made.
It is 3 by itself and excipient weight ratio 7. compound 1 is first made as described in Example 1:1 ratio adds figuration
Agent, capsule is made.
It is 5 by itself and excipient weight ratio 8. compound 1 is first prepared as described in Example 1:1 ratio adds
Excipient, granule is made.
Claims (10)
1. the compound yncaria stem with hooks acid amides A (1) shown in structure formula (I),
2. application of the compound 1 of the formula (I) described in claim 1 in melatonin receptors activator is prepared.
3. the compound 1 of the formula (I) described in claim 1 is in preparing treatment or improving the medicine of central nervous system disease
Using.
4. application as claimed in claim 3, wherein described disease is the central nervous system disease related to melatonin receptors
Disease.
5. preparing the method for formula (I) compound 1 described in claim 1, the drying buckle stem branch of hook taking rattan, crush, with 70%
Alcohol reflux extracts twice, 3 hours every time, merges ethanol extract, ethanol is recovered under reduced pressure and obtains medicinal extract.Medicinal extract is dissolved with 5 times of amount water,
Utilize D101 macroporous resin column chromatographies, alcohol-water gradient elution.Merge 50% alcohol elution, concentrate, methanol dissolving, inhale
Invest on silica gel, room temperature, which is placed, volatilizes solvent, elutes, obtains through silica gel column chromatography, chloroform-methanol-water 7: 3: 0.3 after grinding sieving
To 4 flow point A-D, flow point C, which is continued on through, to be suppressed standby in MCI CHP-20P gel columns, methanol-water gradient elution 1: 9~9: 1, obtained
Purified to 5 flow points, C-1~C-5, flow point C-2 through HPLC, utilize Rp-C18Post, acetonitrile-water gradient 1: 9~3: 7, is obtained
Target compound 1.
6. the medicine group of formula (I) compound 1 and pharmaceutically acceptable carrier described in the claim 1 containing therapeutically effective amount
Compound.
7. application of the pharmaceutical composition in melatonin receptors activator is prepared described in claim 6.
8. the answering in the medicine for treating or preventing central nervous system disease is prepared of the pharmaceutical composition described in claim 6
With.
9. application as claimed in claim 8, wherein described disease is the central nervous system disease related to melatonin receptors
Disease.
10. preparing the method for the pharmaceutical composition described in claim 6, the drying buckle stem branch of hook taking rattan, crush, with 70% second
Alcohol reflux extracts twice, 3 hours every time, merges ethanol extract, ethanol is recovered under reduced pressure and obtains medicinal extract.Medicinal extract is dissolved with 5 times of amount water, profit
With D101 macroporous resin column chromatographies, alcohol-water gradient elution.Merge 50% alcohol elution, concentrate, methanol dissolving, absorption
In on silica gel, room temperature placement volatilizes solvent, elutes, obtains through silica gel column chromatography, chloroform-methanol-water 7: 3: 0.3 after grinding sieving
4 flow point A-D, flow point C, which are continued on through, to be suppressed standby in MCI CHP-20P gel columns, methanol-water gradient elution 1: 9~9: 1, obtain 5
Individual flow point, C-1~C-5, flow point C-2 purify through HPLC, utilize Rp-C18Post, acetonitrile-water gradient 1: 9~3: 7, obtains mesh
Compound 1 is marked, then a certain proportion of pharmaceutical acceptable carrier or excipient are added for raw material with compound 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110105421A (en) * | 2019-06-12 | 2019-08-09 | 扬州工业职业技术学院 | A kind of oxidation uncaria indoles diterpene alkaloid and the preparation method and application thereof |
| CN113149857A (en) * | 2021-05-10 | 2021-07-23 | 山东中医药大学 | Amide compound and preparation method and application thereof |
| CN113717190A (en) * | 2021-10-08 | 2021-11-30 | 中国科学院昆明植物研究所 | Indole alkaloid, pharmaceutical composition thereof, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58154571A (en) * | 1982-03-08 | 1983-09-14 | Nippon Shinyaku Co Ltd | Novel tannin |
| CN101491610A (en) * | 2007-04-18 | 2009-07-29 | 北京和润创新医药科技发展有限公司 | Method for separating hooked uncaria total alkaloids from hooked uncaria extract |
| CN107056790A (en) * | 2016-12-22 | 2017-08-18 | 中国科学院昆明植物研究所 | (±) UncarilinsA and B and its pharmaceutical composition and application |
-
2017
- 2017-11-20 CN CN201711159741.4A patent/CN107827940B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58154571A (en) * | 1982-03-08 | 1983-09-14 | Nippon Shinyaku Co Ltd | Novel tannin |
| CN101491610A (en) * | 2007-04-18 | 2009-07-29 | 北京和润创新医药科技发展有限公司 | Method for separating hooked uncaria total alkaloids from hooked uncaria extract |
| CN107056790A (en) * | 2016-12-22 | 2017-08-18 | 中国科学院昆明植物研究所 | (±) UncarilinsA and B and its pharmaceutical composition and application |
Non-Patent Citations (1)
| Title |
|---|
| BIN MA: "Three New Alkaloids from the Leaves of Uncaria rhynchophylla", 《HELVETICA CHIMICA ACTA》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110105421A (en) * | 2019-06-12 | 2019-08-09 | 扬州工业职业技术学院 | A kind of oxidation uncaria indoles diterpene alkaloid and the preparation method and application thereof |
| CN110105421B (en) * | 2019-06-12 | 2020-03-24 | 扬州工业职业技术学院 | Oxidation uncaria indoxyl diterpenoid alkaloid and preparation method and application thereof |
| CN113149857A (en) * | 2021-05-10 | 2021-07-23 | 山东中医药大学 | Amide compound and preparation method and application thereof |
| CN113149857B (en) * | 2021-05-10 | 2021-10-29 | 山东中医药大学 | Amide compound and preparation method and application thereof |
| CN113717190A (en) * | 2021-10-08 | 2021-11-30 | 中国科学院昆明植物研究所 | Indole alkaloid, pharmaceutical composition thereof, preparation method and application thereof |
| CN113717190B (en) * | 2021-10-08 | 2023-06-13 | 中国科学院昆明植物研究所 | Indole alkaloid and pharmaceutical composition thereof, and preparation method and application thereof |
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