CN108129295A - A kind of Diterpene derivative and its pharmaceutical composition and purposes - Google Patents
A kind of Diterpene derivative and its pharmaceutical composition and purposes Download PDFInfo
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- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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Abstract
Diterpene derivative (1 9) as shown in structure formula (I), the pharmaceutical composition of compound 19 and pharmaceutical carrier composition containing therapeutically effective amount, the preparation method of the Diterpene derivative (1-9) and its pharmaceutical composition, and its application in the drug for preparing treatment human diseases, particularly in spleen tyrosine kinase (the Spleen tyrosine kinase of alternatively property, SYK) inhibitor and the application in the drug of various diseases for the treatment of SYK mediations is prepared.
Description
Technical field：
It is effective containing it specifically, being related to a kind of Diterpene derivative the invention belongs to technical field of pharmaceuticals
The pharmaceutical composition of the treatment rheumatoid arthritis of ingredient, alternatively preparation method and the spleen tyrosine kinase of property
(Spleen tyrosine kinase, SYK) inhibitor prepares treatment by the application in the drug of the SYK various diseases mediated.
Background technology：
Spleen tyrosine kinase (Spleen tyrosine kinase, SYK) is a kind of nonreceptor tyrosine kinase, in human body
Various Tissues in generally express.SYK is most important for function of immune system, particularly in lymphatic system development and B cell
Receptors signal transduction process plays a significant role.A variety of diseases such as SYK dysfunctions and autoimmune disease and B cell lymphoma
The occurrence and development of disease are closely related.Rheumatoid arthritis (Rheumatoid Arthrtis, RA) is a kind of chronic autoimmunity
Property disease, according to statistics, the illness rate of global RA is 0.5-1%, is 0.3-0.4% in China.RA is mainly due to arthrosynovitis
Arthralgia, deformity or even function is caused to be lost, seriously affects the quality of life of patient.
The drug for the treatment of RA mainly includes non-steroidal anti-inflammatory drugs, alclometasone diproionate, the biological agent for targeting Inflammatory Pathway at present
With protein tyrosine kinase JAK inhibitor etc..Non-steroidal anti-inflammatory drugs and steroid medicine can temporarily mitigate arthralgia and swell
It is swollen, but progression of disease can not be controlled, and easily cause a variety of adverse reactions.The biological agent of targeting Inflammatory Pathway mainly includes
The monoclonal antibody of antagonism inflammatory factor such as tumor necrosis factor (TNF), il-1 (IL-1) and interleukin-6 (IL-6).It is single
Antiradiation drug can effectively alleviate RA progression of the disease, be the choice drug treated RA active stages.But biological agent is due to expensive,
It at present can not be in clinical large-scale application.Protein tyrosine kinase JAK micromolecular inhibitors can be led to by regulating and controlling JAK-STAT
Suppression of autoimmune responses and inflammation are come in road, are presently available for the RA treatment invalid to TNF monoclonal antibodies.But JAK is in immune response
Wide participation in journey causes JAK inhibitor to have higher adverse reaction risk.Therefore, it studies more safely and effectively novel
Drug is for the treatment important in inhibiting of RA.SYK is the modulation for treating rheumatoid arthritis, has multiple SYK at present
Inhibitor enters clinical test.Research finds the SYK for having activation in RA synovial tissues, so as to cause downstream inflammatory reaction.SYK
Inhibitor can be by blocking the B cell signal that SYK is mediated to turn, B cell being hindered to develop so as to inhibit immune response, so as to alleviate class
Rheumathritis.In addition, the indication of SYK inhibitor further includes systemic loupus erythematosus, thrombocytopenic purpura, chronic leaching
Bar leukaemia and other B cell lymphomas.
There are long Study of Medicinal Herbs and application tradition in China, and natural products is important drug molecule source.It is purple
Pearl is used to treat a variety of diseases such as inflammation, rheumatism, allergy, haemorrhage as the distinctive plant of China civil.It is but anti-inflammatory to its
The research of effective component and anti-inflammatory target is still insufficient.
So far, the report in the prior art without such abietane forskolin (1-9 shown in Formulas I), also without its conduct
The report of the pharmaceutical composition of active ingredient, also without such abietane forskolin (1-9 shown in Formulas I) and its pharmaceutical composition
Application report of the object in preparing SYK inhibitor and treating the drug for the disease that SYK is mediated.
Invention content：
The purpose of the present invention is to provide the abietane forskolins shown in a new class of formula (I) with medical value
(1-9), containing can inhibit SYK activity and treat SYK mediation a effective amount of abietane forskolin of various diseases (1-9)
(I) and pharmaceutical carrier or excipient as SYK inhibitor and treat SYK mediations disease pharmaceutical composition, abietane two
The preparation method of triterpene derivative (1-9) and its pharmaceutical composition, such compound or its pharmaceutical composition are preparing SYK inhibitor
And treat the application in the various diseases of SYK mediations.
In order to realize the above-mentioned purpose of the present invention, the present invention provides following technical solutions：
Diterpene derivative (1-9) shown in structure formula (I),
Invention also provides a kind of formula (I) Diterpene derivative (1-9) containing therapeutically effective amount is any
Kind appoints several and pharmaceutically acceptable carrier pharmaceutical compositions.
And a kind of spleen tyrosine kinase SYK inhibitor, wherein the formula described in claim 1 containing therapeutically effective amount
(I) Diterpene derivative (1-9) is any or appoints several and pharmaceutically acceptable carrier.
It is any or appoint and several controlled in preparation that the present invention still further provides formula (I) Diterpene derivative (1-9)
Treat the application in human diseases or the drug of illness.
Formula (I) Diterpene derivative (1-9) is any as mentioned or appoints several in preparation treatment human diseases
Or the application in the drug of illness, wherein the disease or illness is the various diseases mediated by SYK.
It is any or appoint and several preparing spleen tyrosine kinase to additionally provide formula (I) Diterpene derivative (1-9)
Application in SYK inhibitor.
And formula (I) Diterpene derivative (1-9) is any or appoints several in preparation treatment rheumatoid arthrosis
Inflammation, systemic loupus erythematosus, thrombocytopenic purpura, chronic lymphocytic leukemia and other B cell lymphomas drug in
Application.
Meanwhile additionally provide application of the pharmaceutical composition in the drug for the treatment of human diseases or illness is prepared.
Application of the pharmaceutical composition in the drug for the treatment of human diseases or illness is prepared as mentioned, wherein the disease
Disease or illness are the various diseases mediated by SYK.
Present invention further provides the methods for preparing formula (I) Diterpene derivative (1-9), take Japanses beauty-berry
(Callicarpa bodinieri) leaf branch part, dry, pulverize, and be extracted at room temperature 3 times with 85% ethyl alcohol, merges ethyl alcohol and carries
Liquid filters, and is concentrated under reduced pressure；The extracting solution is suspended in aqueous solution, successively with petroleum ether, ethyl acetate and extracting n-butyl alcohol,
After ethyl acetate extraction part is concentrated under reduced pressure, it is adsorbed on silica gel with chloroform dissolving, is placed at room temperature for and volatilizes solvent, ground, through silicon
Plastic column chromatography, with 1:0→0:1 chloroform/acetone gradient elution obtains five parts of A-E；Wherein D parts silica gel column chromatography,
With 50:1→1:1 chloroform/acetone affords tri- parts of D1-D3.Wherein D1 uses sephadex chromatography column in part successively
Compound 2 is obtained with C18 chromatographies.D3 parts preparative high performance liquid chromatography chromatography, using silicagel column and 9: 2
Ethyl acetate/acetone eluant, obtain compound Isosorbide-5-Nitrae, 5,6 and 9.E parts C18 column chromatographies, through 1:9→1:0
Methanol/water solution affords tetra- parts of E1-E4, E2 parts silica gel column chromatography, respectively with 10:1,9:2,8:3 and 6:4
Chloroform/methanol gradient elution obtains compound 3,7 and 8.
The method for preparing the pharmaceutical composition of derivative containing Diterpene (1-9) is with Diterpene derivative
(1-9) is raw material, adds in pharmaceutical acceptable carrier or excipient.
When the compounds of this invention is used as drug, it can directly use or be used in the form of pharmaceutical composition.The drug
Composition contains 0.1-99%, preferably 0.5-90% the compounds of this invention, remaining is pharmaceutically acceptable, to people and
The nontoxic and inert pharmaceutical acceptable carrier of animal and/or excipient.
The pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine
Tetramune adjuvant.The pharmaceutical composition of the present invention is used in the form of per weight dose.The drug of the present invention can be through note
Penetrate (intravenous, intramuscular injection) and oral two kinds of forms administration.
Description of the drawings：
Fig. 1 is the structure diagram of Diterpene derivative (1-9) of the present invention.
Specific embodiment：
To better understand the essence of the present invention, it will illustrate formula (I) pine with the test example of the present invention below
The pharmacological action of fragrant alkane type forskolin (1-9) with this test example as a result, but do not limit the present invention.
Test example 1：
Formula (I) Diterpene derivative (1-9) is to the inhibiting effect of SYK：
1 material and method
1.1 material:Diterpene derivative (I, 1-9)；SYK (Carna), staurosporin
(Staurosporine)(Carna)；DMSO(Sigma)；N-2- hydroxyethyl piperazine-N'-2- ethanesulfonic acids (HEPES) (Sigma)；
Brij-35(Sigma)；EDTA(Sigma)；Coating Reagent#3(Caliper).
1.2 buffer：1) Brij-35 that 0.0015% is added in the HEPES of 50mM pH7.5 forms substrate buffering
Liquid；2) 0.015% Brij-35,0.2% Coating Reagent#3 is added in the HEPES of 100mM pH7.5,50mM's
EDTAp is made into stop buffer.
1.3 instrument：Micro flow control chip capillary electrophoresis enzyme kinetics plate reader LabChip EZ Reader (Caliper).
1.4 experimentation：With 100% DMSO by compound dissolved dilution to 5mM, the 100 μ l solution are moved into 96 holes
Plate (96 orifice plate #1) adds in 100% DMSO, respectively as no compound control in other two blank well of same plate
It is compareed with no enzyme.20 μ l compound solutions are shifted from 96 orifice plate #1 to another piece of 96 orifice plate (96 orifice plate #2), then in 96 holes
180 μ l kinases substrate buffer solutions, concussion mixing 10min are added in each hole of plate #2.From each hole of 96 orifice plate #2
5 μ l are shifted to 384 orifice plates, and are repeated once.SYK is added in substrate buffer solution and is made into kinase solution, in substrate buffer solution
The polypeptide and ATP for adding in FAM labels are made into polypeptide solution.10 μ l kinase solutions, room temperature are added in each hole of 384 orifice plates
10 μ l polypeptide solutions are added in after lower incubation 10min.1h is incubated at 28 DEG C, 25 μ l stop buffers is added in and terminates reaction.With
Caliper programs collect data and carry out curve fitting.The positive control of the experiment is staurosporin
(Staurosporine), concentration gradient carries out three times gradient dilution for 100 μM of startings, totally 10 concentration points.
2. result：Conversion is conversion values, is provided automatically by Caliper programs.Max be DMSO blank controls, min
For positive control.
Inhibiting rate=(max-conversion)/(max-min) × 100%
The inhibiting rate of 10 concentration points is fitted with the XLFit plug-in units in Excel, obtains IC50Value, fit equation is such as
Under：
Y=Bottom+ (Top-Bottom)/(1+ (IC50/X)HillSlope)
Bottom is minimum inhibiting rate, and Top is maximal percentage inhibition
Concrete outcome is shown in Table 1：
1 Diterpene derivative (1-9) (I) of table is in vitro to SYK inhibitions (unit μM)
* staurosporin Staurosporine
3rd, conclusion：
Experimental result shows that 5 Diterpene derivatives (2,3,5,6,9) in vitro have SYK activity notable
Inhibiting effect, IC50Value is between 7.2-85.3 μM.
Below in conjunction with attached drawing, it is made up of, and not come the preparation method and drug that the present invention is furture elucidated embodiment
The present invention is limited with this.
Embodiment 1：
The preparation of Diterpene derivative (1-9) (I)：
The extraction separation of Diterpene derivative (1-9) (I)：
It is Agilent 1260 and Zorbax SB-C18 (9.4mm × 25cm) that half used in experiment, which prepares efficient liquid phase,
Chromatographic column；Thin-layer chromatography silica gel, column chromatography silica gel (100-200 mesh and 200-300 mesh) are purchased from Qingdao Makall Group Co., Ltd.；
Reversed C18 silica gel is Lichroprep RP-18gel (40-63 μm, Merck, Darmstadt, Germany), sephadex
For Sephadex LH-20 (Pharmacia).
Japanses beauty-berry (Callicarpa bodinieri) leaf branch part is acquired, dry, pulverize, carried at room temperature with 85% ethyl alcohol
It takes 3 times, merges ethanol extract, filter, be concentrated under reduced pressure；The extracting solution is suspended in aqueous solution, successively with petroleum ether, acetic acid second
Ester and extracting n-butyl alcohol after ethyl acetate extraction part is concentrated under reduced pressure, is adsorbed on silica gel with chloroform dissolving, is placed at room temperature for and volatilizes
Solvent is ground, through silica gel column chromatography, with 1:0→0:1 chloroform/acetone gradient elution obtains five parts of A-E；Wherein D portions
Divide and use silica gel column chromatography, with 50:1→1:1 chloroform/acetone affords tri- parts of D1-D3.Wherein D1 uses Portugal in part successively
Polysaccharide gel chromatographic column and C18 chromatographies obtain compound 2.D3 parts preparative high performance liquid chromatography chromatography,
Using silicagel column and 9: 2 ethyl acetate/acetone eluant, compound Isosorbide-5-Nitrae is obtained, 5,6 and 9.E parts C18 chromatographic column layers
Analysis, through 1:9→1:0 methanol/water solution affords tetra- parts of E1-E4, E2 parts silica gel column chromatography, respectively with 10:
1,9:2,8:3 and 6:4 chloroform/methanol gradient elution, obtains compound 3,7 and 8.The structure of more than compound passes through1H,13C
NMR, IR, UV and mass spectrometric data are determined.
The structured data of Diterpene derivative (1-9)：
Optically-active is measured by SEPA-300 and 1020 polarimeters of Jascomodel (Horiba, Tokyo, Japan)；Infrared light
(IR) is composed using KBr pressed disc methods, by 27 type infrared spectrometers of Tenor；Ultraviolet spectra is by UV-2401A type ultraviolet spectrometers
(Shimadzu) it measures；Nuclear magnetic resoance spectrum (NMR) Brucker AM-400 types and DRX-500 types NMR spectrometer with superconducting magnet are surveyed
Fixed, using acetone as solvent, TMS (tetramethylsilane) makees internal standard；High resolution mass spectrum (HREI-MS) API Qstar Pulsar
Mass spectrograph measures.The NMR data of compound is as shown in table 2 and table 3；Diterpene backbone carbon atoms number following structural formula
It is shown.
2 Diterpene derivative (1-9) (I) of table1H NMR spectras attribution data (600MHz, acetone) (δ:ppm,
J:Hz)
3 Diterpene derivative (1-9) (I) of table13C NMR spectras attribution data (600MHz, acetone) (δ:ppm,
J:Hz)
Compound 1
Molecular formula：C19H24O4
Molecular weight：316.40
Character：Unformed colourless powder
Optically-active(c=0.52mg cm–3, methanol)
IR(KBr)vmax:3430,2962,2935,1680,1603,1415,1383,1271,1189,1064cm–1。
UV/Vis(MeOH)λmax(logε):210(4.31),258(4.12)nm。
ESIMS(–)m/z:315[M-H]-。
HRESIMS[M+Na]+m/z:Experiment value 339.1568, calculated value 339.1572.
Compound 2
Molecular formula：C20H28O3
Molecular weight：316.44
Character：White powder
Optically-active(c=0.10mg cm–3, MeOH)
IR(KBr)vmax:3423,2960,2933,1700,1498,1459,1189,1025cm-1。
UV/Vis(MeOH)λmax(logε):202(4.13),213(3.96),255(3.04)nm。
EIMS m/z:339[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 339.1931, calculated value 339.1934.
Compound 3
Molecular formula：C20H26O3
Molecular weight：314.43
Character：Colourless powder
Optically-active(c=0.10mg cm–3, MeOH)
IR(KBr)vmax:3390,2963,2936,1700,1499,1451,1376,1227,1189,1071,1025cm-1。
UV/Vis(MeOH)λmax(logε):211(4.39),250(4.08)nm。
EIMS m/z:337[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 337.1774, calculated value 339.1775.
Compound 4
Molecular formula：C22H30O5
Molecular weight：374.48
Character：Colourless needles
Optically-active(c=0.28mg cm–3, MeOH)
IR(KBr)vmax:3427,2970,2935,1746,1702,1379,1237,1039cm-1。
UV/Vis(MeOH)λmax(logε):201(4.33),212(4.11),268(2.99)nm。
EIMS m/z:397[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 397.1983, calculated value 397.1983.
Compound 5
Molecular formula：C22H28O5
Molecular weight：372.46
Character：Unformed colourless powder
Optically-active(c=0.10mg cm–3, MeOH)
IR(KBr)vmax:3390,2963,2936,1700,1499,1451,1376,1227,1189,1071,1025cm-1。
UV/Vis(MeOH)λmax(logε):211(4.39),250(4.08)nm。
EIMS m/z:337[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 337.1774, calculated value 337.1775.
Compound 6
Molecular formula：C22H28O4
Molecular weight：356.46
Character：Unformed colourless powder
Optically-active(c=0.13mg cm–3, MeOH)
IR(KBr)vmax:3420,2963,2937,1742,1454,1441,1379,1235,1039cm-1。
UV/Vis(MeOH)λmax(logε):211(4.37),250(4.05)nm。
EIMS m/z:379[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 379.1880, calculated value 379.1879.
Compound 7
Molecular formula：C19H24O5
Molecular weight：332.40
Character：Unformed colourless powder
Optically-active(c=0.10mg cm–3, MeOH)
IR(KBr)vmax:3420,2960,2937,1714,1611,1500,1442,1381,1243,1041cm-1。
UV/Vis(MeOH)λmax(logε):203(4.46),216(4.06),280(3.46)nm。
EIMS m/z:355[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 355.1516, calculated value 355.1518.
Compound 8
Molecular formula：C21H26O5
Molecular weight：358.43
Character：White micro-crystals
Optically-active(c=0.42mg cm–3, MeOH)
IR(KBr)vmax:2916,2938,1741,1604,1363,1237,1039cm-1。
UV/Vis(MeOH)λmax(logε):207(4.17),257(3.95)nm。
EIMS m/z:381[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 381.1674, calculated value 381.1678.
Compound 9
Molecular formula：C22H30O4
Molecular weight：358.48
Character：Unformed colourless powder
Optically-active(c=0.10mg cm–3, MeOH)
IR(KBr)vmax:3429,2960,2933,2873,1742,1498,1461,1381,1237,1039cm-1。
UV/Vis(MeOH)λmax(logε):204 (4.37), 210 (4.20), 254 (3.31) nm
EIMS m/z:381[M+Na]+。
HRESIMS[M+Na]+m/z:Experiment value 381.2036, calculated value 381.2035.
Embodiment 2：
Diterpene derivative (1-9) is first made as described in Example 1, after being dissolved respectively with a small amount of DMSO,
Routinely plus parenteral solution is made in water for injection, refined filtration, embedding sterilizing.
Embodiment 3：
Diterpene derivative (1-9) is first made as described in Example 1, after being dissolved respectively with a small amount of DMSO,
It is dissolved in sterile water for injection, is stirred to dissolve, filtered, then sterile refined filtration, be sub-packed in ampoule with sterile suction funnel,
It is sterile after frozen drying to seal to obtain powder-injection.
Embodiment 4：
It is respectively 9 by itself and excipient weight ratio by separated obtained Diterpene derivative (1-9):1 ratio
Example adds in excipient, and pulvis is made.
Embodiment 5：
Diterpene derivative (1-9) is first made as described in Example 1, is by itself and excipient weight ratio respectively
5:1 ratio adds in excipient, pelletizing press sheet.
Embodiment 6：
Diterpene derivative (1-9) is first made as described in Example 1, routinely oral liquid preparation method is made respectively
Oral liquid.
Embodiment 7：
Diterpene derivative (1-9) is first made as described in Example 1, is by itself and excipient weight ratio respectively
5:1 ratio adds in excipient, and capsule is made.
Embodiment 8：
Diterpene derivative (1-9) is first made as described in Example 1, is by itself and excipient weight ratio respectively
3:1 ratio adds in excipient, and capsule is made.
Claims (10)
1. the Diterpene derivative (1-9) shown in structure formula (I),
2. formula described in claim 1 (I) the Diterpene derivative (1-9) containing therapeutically effective amount is any or appoints several
The pharmaceutical composition of kind and pharmaceutically acceptable carrier.
3. spleen tyrosine kinase SYK inhibitor, wherein formula described in claim 1 (I) abietane-type containing therapeutically effective amount
Forskolin (1-9) is any or appoints several and pharmaceutically acceptable carrier.
4. (I) the Diterpene derivative of formula described in claim 1 (1-9) is any or appoints several in preparation treatment mankind's disease
Application in the drug of disease or illness.
5. formula (I) Diterpene derivative (1-9) as claimed in claim 4 is any or appoints several in preparation treatment people
Application in the drug of class disease or illness, it is characterised in that the disease or illness is the various diseases mediated by SYK.
6. (I) the Diterpene derivative of formula described in claim 1 (1-9) is any or appoints and several swashs preparing spleen tyrosine
Application in enzyme SYK inhibitor.
7. (I) the Diterpene derivative of formula described in claim 1 (1-9) is any or appoints several in preparation treatment rheumatoid
Arthritis, systemic loupus erythematosus, thrombocytopenic purpura, chronic lymphocytic leukemia and other B cell lymphomas medicine
Application in object.
8. application of the pharmaceutical composition in the drug for the treatment of human diseases or illness is prepared described in claim 2.
9. application of the pharmaceutical composition as claimed in claim 8 in the drug for the treatment of human diseases or illness is prepared, special
Sign is that the disease or illness are the various diseases mediated by SYK.
10. prepare the method for formula (I) Diterpene derivative (1-9) described in claim 1, it is characterised in that take folium callicarpae pedunculatae
Branch part, dry, pulverize, extracted at room temperature 3 times with 85% ethyl alcohol, merge ethanol extract, filter, and be concentrated under reduced pressure；This is carried
Liquid is taken to be suspended in aqueous solution, successively with petroleum ether, ethyl acetate and extracting n-butyl alcohol, ethyl acetate extraction part reduced pressure
Afterwards, it is adsorbed on silica gel with chloroform dissolving, room temperature is put to solvent and volatilized, and grinds, through silica gel column chromatography, with 1:0→0:1 chlorine
Imitative/acetone gradient elution, obtains five parts of A-E；Wherein D parts silica gel column chromatography, with 50:1→1:1 chloroform/acetone
Tri- parts of D1-D3 are afforded, wherein D1 parts obtain chemical combination with sephadex chromatography column and C18 chromatographies successively
Object 2；D3 parts are with preparative high performance liquid chromatography chromatography, using silicagel column and 9: 2 ethyl acetate/acetone eluant,
Obtain compound Isosorbide-5-Nitrae, 5,6 and 9；E parts C18 column chromatographies, through 1:9→1:0 methanol/water solution affords E1-
Tetra- parts of E4, E2 parts silica gel column chromatography, respectively with 10:1,9:2,8:3 and 6:4 chloroform/methanol gradient elution, obtains
Compound 3,7 and 8.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530281A (en) * | 2018-06-11 | 2018-09-14 | 云南大学 | A kind of isopimarane type forskolin, medical composition and its use |
| CN110698443A (en) * | 2019-10-28 | 2020-01-17 | 成都中医药大学 | SHP2 small-molecule selective inhibitor and application thereof in preparation of anti-lung cancer drugs |
| CN114044734A (en) * | 2021-09-08 | 2022-02-15 | 新疆维吾尔自治区中药民族药研究所 | Abietane diterpene and preparation method and application thereof |
| CN115448827A (en) * | 2022-10-20 | 2022-12-09 | 杭州师范大学 | Abietane diterpenoid compound containing terminal double bond and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
| KR100575253B1 (en) * | 2004-11-04 | 2006-05-02 | 한국생명공학연구원 | Novel abietane diterpenoid compounds for prevention and treatment of cardiovascular disease and the composition comprising the same |
| CN101397241A (en) * | 2007-09-27 | 2009-04-01 | 中国科学院上海药物研究所 | Ent-abieta diterpenoid largeleaf rabdosia leaf I and J, preparation method and use thereof |
| CN103613490A (en) * | 2013-12-11 | 2014-03-05 | 中国科学院烟台海岸带研究所 | Drop diterpenoid type compound as well as preparation method and application thereof |
-
2018
- 2018-01-12 CN CN201810028568.2A patent/CN108129295B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
| KR100575253B1 (en) * | 2004-11-04 | 2006-05-02 | 한국생명공학연구원 | Novel abietane diterpenoid compounds for prevention and treatment of cardiovascular disease and the composition comprising the same |
| CN101397241A (en) * | 2007-09-27 | 2009-04-01 | 中国科学院上海药物研究所 | Ent-abieta diterpenoid largeleaf rabdosia leaf I and J, preparation method and use thereof |
| CN103613490A (en) * | 2013-12-11 | 2014-03-05 | 中国科学院烟台海岸带研究所 | Drop diterpenoid type compound as well as preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| OH J, ET AL.: "Syk/Src pathway-targeted inhibition of skin inflammatory responses by carnosic acid", 《MEDIATORS OF INFLAMMATION》 * |
| WANG Z H, ET AL: "Three New Abietane-Type Diterpenoids from Callicarpa macrophylla Vahl", 《MOLECULES》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530281A (en) * | 2018-06-11 | 2018-09-14 | 云南大学 | A kind of isopimarane type forskolin, medical composition and its use |
| CN108530281B (en) * | 2018-06-11 | 2021-02-02 | 云南大学 | Isopimarane diterpene derivative, pharmaceutical composition and application thereof |
| CN110698443A (en) * | 2019-10-28 | 2020-01-17 | 成都中医药大学 | SHP2 small-molecule selective inhibitor and application thereof in preparation of anti-lung cancer drugs |
| CN114044734A (en) * | 2021-09-08 | 2022-02-15 | 新疆维吾尔自治区中药民族药研究所 | Abietane diterpene and preparation method and application thereof |
| CN114044734B (en) * | 2021-09-08 | 2023-08-29 | 新疆维吾尔自治区中药民族药研究所 | Rosin alkane diterpene and preparation method and application thereof |
| CN115448827A (en) * | 2022-10-20 | 2022-12-09 | 杭州师范大学 | Abietane diterpenoid compound containing terminal double bond and preparation method and application thereof |
| CN115448827B (en) * | 2022-10-20 | 2024-01-30 | 杭州师范大学 | Abietane diterpenoid compound containing terminal double bond, and preparation method and application thereof |
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