CN106749496A - New triptolide derivative and its preparation and use - Google Patents
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- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
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Abstract
The present invention relates to a class formula(I)Shown triptolide derivative, and its optical isomer and its pharmaceutically acceptable salt and hydrate, and it is related to its application in treatment tumour and immune correlated disease medicine.
Description
Technical field
The present invention relates to a class similar to triptolide new triptolide analog derivative, and preparation method thereof
And the application in antitumor, immunosuppressant medicine is prepared.
Background technology
Celastraceae plant thunder godvine(Tripterygium wilfordii Hook.F.), SOUTHERN CHINA is distributed mainly on,
Including Zhejiang, Hunan, Anhui, Yunnan, Fujian and Taiwan and other places.Research in recent years finds that thunder godvine has anti-inflammatory, immune suppression
The pharmacological action such as system, antitumor, is widely used to treatment rheumatoid arthritis, ephritis, lupus erythematosus and various skins at present
Skin disease.Commercialized product is Glucosidorum Tripterygll Totorum, and antineoplaston curative effect is undesirable.
In the various composition of thunder godvine, diterpene-kind compound drug effect is most strong, diterpene compound contained by tripterygium plant,
Category abietane-type, majority has unsaturated lactone structure.Diterpene-kind compound mainly includes triptolide
(triptolide), NSC-163063(tripdiolide), Triptolide triol(triptriolide), tripterygone
(triptonide)Deng.Wherein triptolide(Triptolide), it is the principal active component of thunder godvine.Clinically,
Antitumor, immunosupress is can apply to, while can be additionally used in rheumatic arthritis, rheumatoid arthritis, lupus erythematosus etc.
The treatment of the aspects such as disease treatment.
Triptolide has obvious antitumor activity.Triptolide can induce the cell that caspase 3 is relied on to wither
Die.Research shows that with the increase of the activity and time of triptolide caspase 3 is sheared activation, and cell enters
Apoptosis program.Triptolide suppresses NF-kB activity and suppresses HSP70.NF-kB is important transcription factor, participates in inflammation, swells
The regulation and control of the extensive pathological processes such as knurl, immune, cell propagation and apoptosis.HSP70 crosses table in people's malignant mela noma
Reach, suppress HSP70 and be beneficial to suppress tumor cell proliferation.Triptolide can suppress HCT116(Human colon cancer cell
System), and the constantly level of reduction B cell lymphoma and the GAP-associated protein GAP of leukaemia -2 Bcl-2, suppress many leukaemia related
Cell line.There are some researches show triptolide is to the breast carcinoma cell strains such as MCF-7, BT-20, MKN-45, MKN-7, stomach cancer cell
Strain cell propagation is inhibited.Cancer of pancreas be it is a kind of especially there is aggressive and destructive disease, 5 annual survival rates less than
5%.Currently without the survival rate active drug that can effectively extend patient.It is thin that triptolide can suppress the cancers of pancreas such as Aspc-1
Born of the same parents' strain propagation.Triptolide is also an effective angiogenesis inhibitor.Domestic and international experimental data shows, thunder godvine
A prime is effective to treatment breast cancer, colorectal cancer, cancer of pancreas, glioma, prostate cancer, malignant mela noma.
Triptolide has immunosuppressive action and antiinflammatory action.Triptolide can suppress T cell early activation
The expression of factor CD69, CD25 etc..Can be with inducing T cell hybridoma, Jurkat cell in addition to suppressing T cell and breeding
With the apoptosis of unactivated T cell.Other triptolide can also suppress the propagation of B cell.Because triptolide has suppression
The effect of immune cell propagation processed, can apply to panimmunity system related disorders, including systemic lupus erythematosus.Thunder
Public rattan A prime can suppress the expression of the inflammatory factors such as COX-2 protease and IL-2, and this is also relevant with NF-kB is suppressed, Ke Yiying
For anti-inflammatory treatment, hence it is evident that reduce the generation of mouse arthritis.
Triptolide has various pharmacological activity, but triptolide poorly water-soluble, and half-life period is shorter, according to the study table
Bright, about 38 minutes or so its half-life period, toxicity is big, is unfavorable for clinical application, hinders further research and development.It is necessary
Triptolide is chemically modified, increases water-soluble, improve physicochemical property, be conducive to being made appropriate preparation.Into salt
It is water-soluble that triptolide derivative will substantially improve it.
The content of the invention
The present invention devises a class Triptolide for the purpose of reducing toxicity, increase water-soluble, raising bioavilability
The new triptolide analog derivative of alcohol.The synthetic method craft of compound of the present invention it is scientific and reasonable it is simple, quality can
Control, suitable for production.
It is an object of the present invention to provide the new triptolide derivative of a class.
It is a further object to provide a kind of preparation method of such triptolide derivative.
Prepared for treating tumour, immune suppression it is still another object of the present invention to provide such triptolide derivative
Application in pharmacy thing.
A further object of the present invention is to provide one kind to treat tumour, immunosuppressant pharmaceutical composition, and it includes one kind
Or the of the invention new triptolide derivative and pharmaceutically acceptable auxiliary material of various therapeutically effective amounts.
The invention provides formula(I)Shown triptolide derivative, its optical isomer and its can pharmaceutically connect
The salt and hydrate received:
(I)
Formula(I)In:
Wherein:
R1For-CONRR ';
R, R ' form the 5-8 circle heterocycles containing 1-2 N, O, S together, the heterocycle has 0-3 substituent R ' ', R ' ' be fluorine, chlorine, bromine,
Iodine, hydroxyl, methoxyl group or be XY;
In XY, X is the 0-2 aliphatic chain of carbon composition, and Y is to contain the 1-3 5-8 circle heterocycles of hetero atom N, O, S;
R2It is hydrogen, hydroxyl;
R3For hydrogen, formoxyl, acetyl group, propiono, benzoyl, to chlorobenzene formacyl, a chlorobenzene formacyl;
C18With R4Between, C3And C18Between, C3And C4Between, C4And C19Between "" singly-bound or double bond are represented, if C18
And R4Between be double bond, then R4It is O, and C18And C3Between and C4And C19Between be singly-bound, C3And C4Between be double bond;If
C18And R4Between be singly-bound, then R4It is OR3, and C18And C3Between and C4And C19It is double bond, C3And C4Between be singly-bound.
According to triptolide derivative of the present invention, it is:With below general formula(II)The compound of shown structure, or light
Learn isomers or pharmaceutically acceptable salt hydrate:
(II)
Wherein, R1Definition and formula(I)In it is identical;
Or be with below general formula(III)The compound of shown structure, or optical isomer and its pharmaceutically acceptable salt
And hydrate:
(III)
Wherein, R1、R3、R4Definition respectively with formula(I)In corresponding R1、R3、R4Definition it is identical.
According to the present invention, wherein:R and R ' form piperidines, piperazine, pyrroles, the nafoxidine of substituted base, and the position of substitution is
Piperidines, piperazine, pyrroles, 3 or 4 of nafoxidine, substitution base be piperidines, piperazine, pyrroles, nafoxidine.
The salt that triptolide derivative is formed with acid, described acid is hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, hydrobromic acid,
Tartaric acid, butanedioic acid, lactic acid, hydrochloric acid, p-methyl benzenesulfonic acid, trifluoro formic acid, trifluoroacetic acid, acetic acid, citric acid maleic acid.
Combined selected from following compound according to triptolide class lactone derivatives of the present invention:
TTBT-1
TTBT-1A
TTBT-1B
TTBT-1C
TTBT-2
TTBT-2A
TTBT-2B
TTBT-2C。
The synthetic method of triptolide derivative of the invention is as follows:
Formula(II)、(III)Shown compound synthesis method:
Containing 14 triptolide derivatives of hydroxyl(MI)It is dissolved in pyridine, is subsequently adding the acylated examination of 1-20 times of molal quantity
Agent, under nitrogen protection at 4-100 DEG C after stirring 10-40 hour, addition 1-50 times of amino agents of molal quantity, reaction temperature is
10-110 DEG C, react 3-24 hours.Reaction solution is concentrated, and adds methyl alcohol, filtering, preparative separation to obtain formula and be(MII)It is shown
The compound of structure.Formula(II)The compound of shown structure under cryogenic, in NaH/THF, reacts 1-5 hours, plus
Enter acid anhydrides, obtaining formula is(MIII)The compound of shown structure, R1, R2, R3, R4Respectively with corresponding R in logical formula (I)1,
R2, R3, R4Definition is identical,
Reaction equation(1)
The building-up process of compound TTBT-1 and TTBT-2:
Such as reaction equation(2)It is shown, with triptolide as starting material, the chlorobenzoyl chloride of 1-20 times of molal quantity is subsequently adding,
Under nitrogen protection, after 4-100 DEG C of stirring 10-40 hour, addition 1-50 times of 4- piperidinyl piperidine of molal quantity, reaction temperature is
10-110 DEG C, react 3-24 hours, reaction solution concentration, add methyl alcohol, filtering, preparative separation to obtain product(TTBT-1),
TTBT-1 under cryogenic, in NaH/THF, reacts 1-5 hours, 1-10 times of benzoyl oxide is added, in-C18O 、C19Position connects
Upper benzoyl, preparative separation purifying obtains compound(TTBT-2),
Reaction equation(2).
The present invention is in C14Position introduces nitrogenous substitution base, can substantially increase water solubility with sour forming salt.And
Western blot show that this kind of compound can suppress NF-kB, with anti-inflammatory and suppression tumor cell proliferation effect.Liver particle
Body experiment shows that such compound metabolism stability preferably, is advantageously applied to prepare the medicine of long-acting slow-release.
Brief description of the drawings
Fig. 1 changes with time for TTBT-1 in people's hepatomicrosome.
Fig. 2 is inhibitory action of the TTBT-1 and TTBT-2 to NF-kB albumen in MDA-MB-231 cells.
Specific embodiment
Will be helpful to understand the present invention by implementation in detail below, but be not limited to present disclosure.
Embodiment 1
Compound 4- piperidinyl piperidine formic acid triptolide esters(TTBT-1)Structure
TTBT-1
Compound TTBT-1(4- piperidinyl piperidine formic acid triptolide esters)Synthesis
Triptolide (50 mg) is dissolved in pyridine (5 mL) at room temperature, adds chlorobenzoyl chloride(40 mg), nitrogen protection
Under be stirred at room temperature 24 hours.At room temperature to 4- piperidinyl piperidines (400mg) is added in reaction solution, 80 DEG C are warmed up to, reaction 3 is small
When.Reaction solution is concentrated, methyl alcohol dissolving, is prepared liquid phase separation and is obtained product faint yellow solid (19.8 mg, yield 26%).
Purifying(Using high performance liquid preparative chromatography)
Chromatographic condition:Chromatographic column is Waters Sunfire 20*250mm, 10 μm;With water(0.1%TFA)- ACN is mobile phase,
Gradient condition controls 0-10min, acetonitrile 30%-40%;Detection wavelength is 214nm/254nm;Mass is 555 [M+1].
Preparation method:Negate and answer concentrate, dissolved with methyl alcohol and be made into every 1ml the solution containing about 10mg, as trying
Product solution.Precision measures 5ml injection preparative liquid chromatographs, realizes that product is separated with impurity on C18 reversed-phase preparative chromatographies,
By setting Trigger Mass 555 [M+1], compound TTBT-1 is obtained.
Compound TTBT-1(Molecular formula:C31H42N2O7), ESI-MS m/z: 555 [M+H]+. 1H-NMR (400
MHz, CDCl3) δ 1.539-1.471 (2H, m, H-1), 1.362 (2H, m, H-6), 1.231 (3H, m, H-
20), 1.185 (3H, m, H-16), 1.125 (3H, m, H-17), 1.790 (2H, m), 1.889 (2H,m),
1.889 (2H, m), 2.042 (2H, m), 2.042 (2H, m), 2.042-2.128 (2H, m, H-2), 2.128
(1H, M, H-15), 2.230-2.277 (1H, d, J=18.8 Hz, H-5), 2.649 (1H, s), 2.716 (2H,
m), 2.894 (2H, m), 3.408 (2H, m), 3.450 (2H, m), 3.762 (1H, s, H-7), 4.276
(1H, d, J= 9.2Hz, H-12), 4.440 (1H, d, J= 12 Hz, H-11), 4.606 (2H, m, H-19),
4.810 (1H, s, H-14)。
Stability of the TTBT-1 in people's hepatomicrosome
In following examples, test-compound is provided by chemical synthesis embodiment of the present invention.
Purpose
Investigate metabolic stabilities of the TTBT-1 in people's hepatomicrosome.
Experiment material
People's hepatomicrosome is purchased from XENOTECH companies, and lot number 1410013 is preserved in -80oC.
Reducibility coenzyme II is purchased from Shanghai UNJA Biotechnology Ltd., article No. Roche 10621706001, the term of validity
In July, 2017, in 4 °C of preservations.
Experimental technique
TTBT-1 concentration is 2 μM in reaction system, is sampled within 0,5,15,30,45 and 60 minutes after the reaction respectively;Reached with miaow
Azoles logical sequence is positive control, and concentration is 2 μM, is sampled within 0,5,10,15 and 30 minutes after the reaction respectively;Replace reproducibility auxiliary with water
Enzyme II is used as negative control, and sample time is identical with tested material.Parallel 2 parts of the preparation of each time point.Determined with LC-MS/MS methods
TTBT-1 or midazolam in sample, calculate the ratio of each time point compound TTBT-1 average peak areas and internal standard average peak area
Value, and percentage of the ratio relative to 0 time point is calculated, and TTBT-1 metabolic stabilities are represented with the change of this percentage.
As a result
See Fig. 1, compound TTBT-1 half-life period in the liver particle of people is more than 1 hour, liver particles of the compound TTBT-1 in people
In it is very stable.
Embodiment 2
The structure of compound TTBT-2
TTBT-2
The synthesis of compound TTBT-2
Compound TTBT-1(0.1 mmol)In low temperature THF, NaH is added dropwise to(0.12 mmol)Low temperature(-78℃)THF is molten
In liquid.After 1 hour, acetic anhydride is instilled(0.25 mmol), reacted 1 hour within 20 degree, add second alcohol and water, MgSO4 to dry,
Concentration, preparative separation obtains TTBT-2(3 mg).
Purifying(Using high performance liquid preparative chromatography)
Chromatographic condition:Chromatographic column is Waters Sunfire20*250mm, 10 μm;With water(0.1%TFA)- ACN is mobile phase,
Gradient condition controls 0-10min, acetonitrile 20%-50%;Detection wavelength is 214nm/254nm;Trigger Mass are 763 [M+
1]。
Purification process:Negate and answer concentrate, dissolved with acetonitrile and be made into every 1ml the solution containing about 4mg products.Injection system
Standby liquid chromatograph, realizes that product is separated with impurity, by setting Trigger Mass 763 on C18 reversed-phase preparative chromatographies
[M+1], obtains compound TTBT-2.
Compound TTBT-2(Molecular formula:C45H50N2O9), ESI-MS m/z: 763 [M+H]+. 1H-NMR (400 MHz,
CDCl3)δ1.559-1.592 (2H, m, H-1), 1.415 (2H, m, H-6), 1.283 (3H, m, H-20),
1.215 (3H, m, H-16), 1.151 (3H, m, H-17), 1.838 (2H, m), 1.930 (2H, m), 1.925
(2H, m), 2.113 (2H, m), 2.062 (2H, m), 2.051-2.156 (2H, m, H-2), 2.123 (1H,
m, H-15), 2.241-2.285 (1H, m, H-5), 2.683 (1H, s), 2.752 (2H, m), 2.934 (2H,
m), 3.441 (2H, m), 3.472 (2H, m), 3.792 (1H, s, H-7), 4.285-4.295 (1H, m, H-
12), 4.491-4.463 (1H, m, H-11), 4.831 (1H, s, H-14), 7.581-7.7.672 (6H, m),
7.984 (4H, m)。
Embodiment 3
Compound TTBT-1 and TTBT-2 suppress the NF-kB protein expressions of tumour cell
NF-kB albumen plays an important role in cell propagation anti-apoptotic, suppresses the NF-kB in tumour cell and is conducive to suppressing swollen
Tumor cell growth.Triptolide and the like can suppress NF-kB, promote apoptosis of tumor cells.Human breast cancer cell
In 37 DEG C, 5% carbon dioxide, the DMEM culture mediums containing 10% hyclone adjust cell concentration extremely for MDA-MB-231 cell culture
2x105Individual/10cm.After 24 hours, treat cell attachment well-grown, with 0, the TTBT-1 of 100,200,600 nM concentration and
The DMSO solution of TTBT-2 is processed 72 hours.Collect the cell of different compound various concentrations treatment respectively, RIPA lysates in
Cell lysis 30 minutes on ice.The total concentration of protein of each sample is detected, the sample loading that gross protein is 50 μ g is taken
Mini-PROTEAN gel electrophoresises, 150 V, 30 minutes.Under constant current 200mA, transferring film 80 minutes to pvdf membrane.With 5% degreasing
The TBST of milk powder(50 mM Tris-HCl, 150 mM NaCl, 0.5% Tween-20) confining liquid room temperature closing pvdf membrane 1 it is small
When.Primary antibody beta actin and NF-kB dilutes 1000 times, 4 DEG C of night incubation pvdf membranes with confining liquid.Pvdf membrane is rinsed with TBST
3 times 30 minutes.At room temperature, it is incubated pvdf membrane 1.5 hours with secondary antibody, then TBST rinsings pvdf membrane 3 time 30 minutes, use
PIERCE ECL solution processes pvdf membrane, is exposed on tanon 4200, as a result such as Fig. 2.
Result display compound TTBT-1 and TTBT-2 substantially suppress the expression of NF-kB albumen in tumour cell.This kind ofization
The preparation that compound can be used in anti-inflammatory, immunosupress, antineoplastic.
According to the studies above result, compound water soluble of the invention is high, its hepatomicrosome metabolism display compound metabolism
Time is long, and metabolic stability is better than triptolide.And compound TTBT-1 and TTBT-2 substantially suppress NF-kB in tumour cell
The expression of albumen.The preparation that this kind of compound can be used in anti-inflammatory, immunosupress, antineoplastic.
Claims (10)
1. formula(I)Shown triptolide derivative, or optical isomer or its pharmaceutically acceptable salt or hydrate:
(I)
Wherein:
R1For-CONRR ';
R, R ' form the 5-8 circle heterocycles containing 1-2 N, O, S together, the heterocycle has 0-3 substituent R ' ', R ' ' be fluorine, chlorine, bromine,
Iodine, hydroxyl, methoxyl group or be XY;
In XY, X is the 0-2 aliphatic chain of carbon composition, and Y is to contain the 1-3 5-8 circle heterocycles of hetero atom N, O, S;
R2It is hydrogen, hydroxyl;
R3For hydrogen, formoxyl, acetyl group, propiono, benzoyl, to chlorobenzene formacyl, a chlorobenzene formacyl;
C18With R4Between, C3And C18Between, C3And C4Between, C4And C19Between "" singly-bound or double bond are represented, if C18
And R4Between be double bond, then R4It is O, and C18And C3Between and C4And C19Between be singly-bound, C3And C4Between be double bond;If
C18And R4Between be singly-bound, then R4It is OR3, and C18And C3Between and C4And C19It is double bond, C3And C4Between be singly-bound.
2. formula as claimed in claim 1(I)Shown triptolide derivative, it is:With below general formula(II)Institute
Show the compound of structure, or optical isomer or pharmaceutically acceptable salt hydrate:
(II)
Wherein, R1Definition and formula(I)In it is identical;
Or be with below general formula(III)The compound of shown structure, or optical isomer and its pharmaceutically acceptable salt
And hydrate:
(III)
Wherein, R1、R3、R4Definition respectively with formula(I)In corresponding R1、R3、R4Definition it is identical.
3. compound such as any one of claim 1-2, optical isomer, its pharmaceutically acceptable salt or hydrate, its
In:R and R ' form piperidines, piperazine, pyrroles, the nafoxidine of substituted base, and the position of substitution is piperidines, piperazine, pyrroles, tetrahydrochysene pyrrole
3 or 4 for coughing up, substitution base is piperidines, piperazine, pyrroles, nafoxidine.
4. compound such as any one of claim 1-3, optical isomer, its pharmaceutically acceptable salt or hydrate, its
In:The salt that triptolide derivative is formed with acid, described acid is hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, hydrobromic acid, winestone
Acid, butanedioic acid, lactic acid, hydrochloric acid, p-methyl benzenesulfonic acid, trifluoro formic acid, acetic acid, citric acid maleic acid.
5. such as the compound in claim 4, optical isomer, its pharmaceutically acceptable salt or hydrate, wherein:Thunder godvine
A prime derivative can be with hydrochloric acid forming salt.
6. compound as claimed in one of claims 1-5, optical isomer, its pharmaceutically acceptable salt or hydration
Thing, wherein:Triptolide derivative or its optical isomer or pharmaceutically acceptable salt or hydrate are:
TTBT-1;
TTBT-1A;
TTBT-1B;
TTBT-1C;
TTBT-2;
TTBT-2A;
TTBT-2B;
TTBT-2C。
7. the preparation method of the triptolide derivative as any one of claim 1-6, it is characterised in that comprising such as
It is prepared by the one or more steps in lower preparation method:
Such as reaction equation(1)It is shown, containing 14 triptolide derivatives of hydroxyl(MI)It is dissolved in pyridine, is subsequently adding molal quantity
1-20 times of acylating reagent, adds 1-50 times of amino of molal quantity to try at 4-100 DEG C after stirring 10-40 hour under nitrogen protection
Agent, reaction temperature is 10-110 DEG C, is reacted 3-24 hours, reaction solution concentration, adds methyl alcohol, filtering, preparative separation to obtain formula
For(MII)The compound of shown structure;Formula(II)The compound of shown structure under cryogenic, in NaH/THF, reacts
1-5 hours, acid anhydrides is added, obtaining formula is(MIII)The compound of shown structure, R1、R2、R3、R4Respectively and formula(I)Middle phase
The R for answering1、 R2、R3、 R4Definition is identical,
Reaction equation(1).
8. the preparation method of triptolide derivative as described in claim 7, compound TTBT-1 and compound TTBT-
2 preparation method is prepared with the one or more steps in following preparation method:
Such as reaction equation(2)It is shown, with triptolide(Triptolide)It is starting material, is subsequently adding the benzene of 1-20 times of molal quantity
Formyl chloride, under nitrogen protection, after 4-100 DEG C is stirred 10-40 hours, adds 1-50 times of 4- piperidinyl piperidine of molal quantity, reaction
Temperature is 10-110 DEG C, is reacted 3-24 hours, reaction solution concentration, adds methyl alcohol, filtering, preparative separation to obtain product(TTBT-
1), under cryogenic, in NaH/THF, reaction 1-5 hours adds 1-10 times of benzoyl oxide, in-C to TTBT-118O 、-C19
Benzoyl is connected, preparative separation purifying obtains compound(TTBT-2),
Reaction equation(2).
9. as claim 1-8 any one of triptolide derivative, optical isomer, its is pharmaceutically acceptable
Salt or hydrate, it is characterised in that the application in anti-inflammatory, immunosupress, antineoplastic is prepared.
10. a kind of pharmaceutical composition, the triptolide of its one or more such as claim 1-8 for including therapeutically effective amount spreads out
Biology, or its optical isomer or pharmaceutically acceptable salt or hydrate, it is characterised in that and pharmaceutically acceptable routine
Auxiliary material.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108888624A (en) * | 2018-06-05 | 2018-11-27 | 大连医科大学 | The application of triptolide and its derivative as people's Pregnane X Receptor native agonist |
CN109021061A (en) * | 2018-09-29 | 2018-12-18 | 郭可点 | Triptolide targeted prodrug and its preparation method and application |
CN110551171A (en) * | 2018-05-31 | 2019-12-10 | 欣凯医药化工中间体(上海)有限公司 | preparation method of triptolide derivative |
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CN103204861A (en) * | 2012-01-12 | 2013-07-17 | 上海汇伦生命科技有限公司 | Fluoro-substituted triptolide derivative, its preparation method and application |
CN102786576A (en) * | 2012-07-18 | 2012-11-21 | 中国医学科学院药物研究所 | Triptolide derivatives, and preparation methods, medicinal composition and uses thereof |
WO2015085447A1 (en) * | 2013-12-11 | 2015-06-18 | 香港浸会大学 | New triptolide derivatives and preparation method and use thereof |
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CN104327152A (en) * | 2014-10-14 | 2015-02-04 | 厦门大学 | Triptolide derivatives and application thereof |
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CN110551171B (en) * | 2018-05-31 | 2021-07-27 | 欣凯医药化工中间体(上海)有限公司 | Preparation method of triptolide derivative |
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