CN103204861A - Fluoro-substituted triptolide derivative, its preparation method and application - Google Patents
Fluoro-substituted triptolide derivative, its preparation method and application Download PDFInfo
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- CN103204861A CN103204861A CN201210008943XA CN201210008943A CN103204861A CN 103204861 A CN103204861 A CN 103204861A CN 201210008943X A CN201210008943X A CN 201210008943XA CN 201210008943 A CN201210008943 A CN 201210008943A CN 103204861 A CN103204861 A CN 103204861A
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- triptolide
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- fluoro
- fluorine
- cancer
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- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical class O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 230000003287 optical effect Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 32
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 20
- -1 tin anhydride Chemical class 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 10
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- SWOVVKGLGOOUKI-ZHGGVEMFSA-N triptonide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)C(=O)[C@]21[C@H]3O1 SWOVVKGLGOOUKI-ZHGGVEMFSA-N 0.000 claims description 3
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- 206010060862 Prostate cancer Diseases 0.000 claims description 2
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a fluoro-substituted triptolide derivative shown as formula (I) or its pharmaceutically acceptable salt or hydrate or their optical isomer, wherein the -- connecting OH and F can represent the following meaning. The invention also discloses a preparation method of the fluoro-substituted triptolide derivative and application of the derivative in medicaments treating cancers and cancer related diseases.
Description
Technical field
The present invention relates to structure of modification and the activity research of natural drug activeconstituents, be specifically related to the research that fluorine replaces triptolide derivatives and preparation method and treatment hyperplasia tumor disease.
Background technology
Trypterygine, the popular name Graceful Jessamine Herb is Celastraceae (Celastraceae) Thunder God Calamus bejuco, is the relatively abundanter kind of plant of resource that China has.Thunder God Calamus (Tripterygium) plant has four kinds, be trypterygine (Tripterygium wilfordii Hook f.), Tripterygium hypoglaucum (Tripterygium hypoglaucum Levl.Hutch), northeast trypterygine (black climing) (Tripterygium regelii Sprague et Takeda) and Cangshan trypterygine (Tripterygium forretiiDicls), in China distribution arranged all.Trypterygine is recorded the earliest in Shennong's Herbal, and its main chemical compositions has diterpene, triterpene, sesquiterpene, alkaloid etc., has isolated nearly 200 kinds of compound so far from tripterygium plant.Recent two decades comes studies show that it has antitumor, anti-inflammatory, immunosuppression, antifertility, various active such as antibiotic.
The trypterygine plant is in the existing history for many years of tumour that is used for the treatment of among the people, and wherein one of activeconstituents is triptolide.Triptolide also once entered clinical trial except obtaining antitumor action research widely, be used for the treatment of leukemia, but the bigger toxic side effect of triptolide, too narrow treatment window has limited it and has used in clinical.Structure of modification to triptolide was confined in the introduction of water soluble group mostly in the past, there is no essence on the agent structure and changed.After this class prodrug enters in the body, bring into play drug action in vivo by still changing triptolide after hydrolysis or the metabolism into, this has just determined them can not fundamentally improve the toxic side effect of triptolide.Simultaneously to triptolide C
14Find when transform-position that the group configuration of this position is very remarkable for the influence of compound activity, the problem of optical isomer is given synthetic and mask work has increased very big difficulty.
The research that focuses on the triptolide structure activity relationship of the present invention has carried out being different from transformation and the modification of prior art to its structure, has obtained the triptolide derivatives of a collection of novel texture, thereby has finished the present invention.
Summary of the invention
One of technical problem to be solved by this invention is at the existing problem of existing triptolide and at triptolide C
5Hydroxyl, C are introduced in-position
14Fluorine atom is introduced in-position, forms a collection of fluorine and replaces triptolide derivatives.
It is the preparation method of the fluorine replacement triptolide derivatives of basic structure with the fluorine-based triptolide of 5-hydroxyl-14-that two of technical problem to be solved by this invention is to provide a kind of.
Three of technical problem to be solved by this invention is the pharmacological toxicology experimental study by with the fluorine-based triptolide of 5-hydroxyl-14-being the fluorine replacement triptolide derivatives of basic structure, find that it is for tumor disease, especially the tumour of reproductive system has the good curing effect, have efficient, low toxicity, do not have the characteristics of cross-resistance with conventional cell poison antitumor drug, have the DEVELOPMENT PROSPECT that well is used for the treatment of proliferative diseases such as tumour.
It is compound shown in the general formula (I) or its pharmacy acceptable salt or hydrate or their optical isomer that fluorine provided by the invention replaces triptolide derivatives:
In following formula, connect OH, F's---can represent
Perhaps
In a preferred embodiment of the invention, OH is α (R) configuration in the general formula (I), and F is α (S) configuration, i.e. compound shown in the following general formula (Ia):
In a preferred embodiment of the invention, OH is α (R) configuration in the general formula (I), and F is β (R) configuration, i.e. compound shown in the following general formula (Ib):
Preparation method of the present invention is as follows:
1, the preparation method of compound shown in the general formula (Ia), be made up of following steps:
Step 1: under the nitrogen protection, to the dry methylene chloride solution that is dissolved with general formula (1) triptolide add (diethylamino) sulfur trifluoride with the 14-position hydroxyl of general formula (1) triptolide be converted into fluorine obtain general formula (2) (14S)-14-fluoro-Triptolide;
Step 2: with the general formula (2) of step 1 preparation (14S)-14-fluoro-Triptolide is dissolved in the dry dioxane solution, add tin anhydride general formula (2) (14S)-the 5-position of 14-fluoro-Triptolide introduces hydroxyl and obtains compound shown in the general formula (Ia); Concrete reaction formula is as follows:
2, the preparation method of compound shown in the general formula (Ib), be made up of following steps:
Step 1: the Triptonide of general formula (4) is dissolved in the organic solution, adds the table triptolide that chemical reducing agent is converted into general formula (5);
Step 2: under the nitrogen protection, add (diethylamino) sulfur trifluoride to the dry methylene chloride solution of the table triptolide that is dissolved with general formula (5) the 14-position hydroxyl of the table triptolide of general formula (5) is converted into (14R)-14-fluoro-Triptolide that fluorine obtains general formula (6);
Step 3: with step: (14R)-14-fluoro-Triptolide of the general formulas (6) of 2 preparations is dissolved in the dry dioxane solution, adds tin anhydride and introduces hydroxyl and obtain compound shown in the general formula (Ib) in the 5-position of (the 14R)-14-of general formula (6) fluoro-Triptolide; Concrete reaction formula is as follows:
Fluorine of the present invention replace triptolide derivatives for the preparation of the treatment cancer and with the medicine of cancer relative disease in application.
Described cancer is kidney, mammary cancer, lung cancer, malignant melanoma, colorectal carcinoma, prostate cancer or ovarian cancer.
Used term has following meaning in this specification sheets:
" pharmacy acceptable salt " can be enumerated and propionic acid particularly, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, organic acid and aspartic acids such as citric acid, acidic amino acids such as L-glutamic acid form behind the ester salt that forms with mineral alkali again, as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt that forms with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc., or and Methionin, arginine, basic aminoacidss such as ornithine form the hydrochloric acid behind the ester, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, the salt of mineral acids such as phosphoric acid, or and formic acid, acetic acid, picric acid, methylsulfonic acid, organic acid salt such as ethyl sulfonic acid.
The implication of " hydrate " comprises monohydrate, dihydrate, trihydrate.
The implication of " optical isomer " comprises mixture and the pure optical isomer of enantiomer, diastereomer, optical isomer.
Fluorine of the present invention replaces triptolide derivatives, its pharmacy acceptable salt or optical isomer and can be made into the various preparations that contain activeconstituents 0.001-99.9% (weight) and an amount of pharmaceutically acceptable carrier, as is suitable for the dosage form that oral, injection or enterally administering use.
Can use the pharmaceutical preparation that contains the The compounds of this invention for the treatment of significant quantity to the susceptibility of medicine etc. to the curee according to age of curee (monthly age or age in week), general health situation, disease severity and the course of disease, route of administration, human body.
Description of drawings
Fig. 1 is the amount-effect curve synoptic diagram that (5R)-5-hydroxyl-(the 14S)-14-fluoro-Triptolide of the embodiment of the invention 1 preparation and (5R)-5-hydroxyl of embodiment 2 preparations-(14R)-14-fluoro-Triptolide and Zorubicin (ADR) suppress vitro culture human ovarian cancer SK-OV-3 cell.
Fig. 2 is the amount-effect curve synoptic diagram that (5R)-5-hydroxyl-(the 14S)-14-fluoro-Triptolide of the embodiment of the invention 1 preparation and (5R)-5-hydroxyl of embodiment 2 preparations-(14R)-14-fluoro-Triptolide suppresses vitro culture human prostata cancer PC-3 cell.
Embodiment
Below in conjunction with example the present invention is further set forth, but these embodiment never are any limitation of the invention that scope of the present invention is determined by claim.
One, preparation embodiment
Embodiment 1
General formula (Ia) (5R)-preparation of 5-hydroxyl-(14S)-14-fluoro-Triptolide
Step 1
General formula (2) (14S)-preparation of 14-fluoro-Triptolide
Under the nitrogen protection, to be dissolved with general formula (1) triptolide (360mg, dry methylene chloride 1mmol) (5mL) solution add (diethylamino) sulfur trifluoride (DAST, 2mL).Reaction mixture adds saturated sodium bicarbonate solution (3mL) after stirring 2 hours under the room temperature, with three these reaction mixtures of methylene dichloride (5mL) extraction, merge organic phase, anhydrous sodium sulfate drying, concentrate back crude product column chromatography (ethyl acetate: sherwood oil=1: 1) obtain general formula (2) (14S)-the white solid compound (272mg, yield 75%) of 14-fluoro-Triptolide.MS(ESI)：m/z 363[M+1]
+。
General formula (Ia) (5R)-preparation of 5-hydroxyl-(14S)-14-fluoro-Triptolide
With general formula (2) (14S)-(181mg 0.5mmol) is dissolved in dry dioxane (5mL) solution, and (222mg, 2mmol), reaction system stirred 24 hours under reflux state to add tin anhydride for the compound of 14-fluoro-Triptolide.Above-mentioned reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing filter residue, removal of solvent under reduced pressure, resistates is handled with ethyl acetate and saturated sodium carbonate, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrate back crude product column chromatography (ethyl acetate: sherwood oil=1: 1) obtain general formula (Ia) (5R)-5-hydroxyl-(14S)-14-fluoro-Triptolide white solid compound (114mg, yield 60%).MS(ESI)：m/z 379[M+1]
+.
1H NMR(CDCl
3，300MHz)：δ5.20(d，1H)，4.74(q
AB，2H)，3.83(d，1H)，3.70(d，1H)，3.57(dd，1H)，2.68(s，1H)，2.41-2.14(m，5H)，1.79-1.68(m，1H)，1.31-1.22(m，1H)，1.16(s，3H)，1.10(d，3H)，0.91(d，3H)。
(5R)-5-hydroxyl of general formula (Ib)-(14R)-preparation of 14-fluoro-Triptolide
Step 1
The table triptolide preparation of general formula (5)
(358mg 1mmol) is dissolved in anhydrous methanol (5mL) solution, and (38mg, 1mmol), reaction system at room temperature stirred 6 hours to add sodium borohydride with the Triptonide of general formula (4).Above-mentioned reaction system is concentrated back crude product column chromatography (ethyl acetate: sherwood oil=1: 1) obtain the table triptolide white solid compound (198mg, yield 55%) of general formula (5).MS(ESI)：m/z 361[M+1]
+。
The preparation of (14R)-14-fluoro-Triptolide of general formula (6)
Under the nitrogen protection, to the table triptolide white solid compound that is dissolved with general formula (5) (180mg, dry methylene chloride 0.5mmol) (5mL) solution add (diethylamino) sulfur trifluoride (DAST, 1mL).Reaction mixture adds saturated sodium bicarbonate solution (3mL) after stirring 2 hours under the room temperature, with three these reaction mixtures of methylene dichloride (5mL) extraction, merge organic phase, anhydrous sodium sulfate drying, concentrate back crude product column chromatography (ethyl acetate: sherwood oil=1: 1) obtain (14R)-14-fluoro-Triptolide white solid compound (20mg, yield 11%) of general formula (6).MS(ESI)：m/z363[M+1]
+.
(5R)-5-hydroxyl of general formula (Ib)-(14R)-preparation of 14-fluoro-Triptolide
(36mg 0.1mmol) is dissolved in dry dioxane (5mL) solution, and (44mg, 4mmol), reaction system stirred 24 hours under reflux state to add tin anhydride with (14R)-14-fluoro-Triptolide white solid compound of general formula (6).Above-mentioned reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing filter residue, removal of solvent under reduced pressure, resistates is handled with ethyl acetate and saturated sodium carbonate, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrate back crude product column chromatography (ethyl acetate: sherwood oil=1: 1) obtain (5R)-5-hydroxyl of general formula (Ib)-(14R)-14-fluoro-Triptolide white solid compound (16mg, yield 42%).MS(ESI)：m/z 379[M+1]
+.
1H NMR(CDCl
3，300MHz)：δ4.69(q
AB，2H)，4.29(d，1H)，3.86(d，1H)，3.64(d，1H)，3.37(d，1H)，2.60(s，1H)，2.40-2.06(m，5H)，1.78-1.64(m，1H)，1.31-1.27(m，1H)，1.16(s，3H)，1.04(d，3H)，0.95(d，3H)。
Two, pharmacodynamics evaluation test example
Test example 1
(5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiments of the invention 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-2 compounds of 14-fluoro-Triptolide and control group Zorubicin (ADR) are to the growth-inhibiting effect research of the human ovarian cancer SK-OV-3 cell of vitro culture.
Human ovarian cancer SK-OV-3 cell is cultivated with the DMEM substratum (Gibco, the U.S.) that contains 10% foetal calf serum, and culture condition is 37 ℃, 5%CO
2, tumour cell 0.7x10
4/ hole is inoculated in the 96-orifice plate, and after 24 hours, adding storing solution is dimethyl sulfoxide (DMSO) configuration (10
-2M), each compound of physiological saline dilution, make that final concentration is 10 in the substratum
-5, 10
-6M acts on 72 hours.Discard nutrient solution, with 10% cold trichoroacetic acid(TCA) fixed cell, with sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed, flush away is not in conjunction with behind the SRB, Tris dissolving and protein bound SRB, microplate reader is measured the OD value under the 560nM wavelength, calculate inhibitory rate of cell growth by following formula: inhibiting rate=(OD value
Control wells-OD value
Administration The hole)/OD value
Control wellsX100%.Obtain the amount-effect curve (referring to Fig. 1) that (5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiment 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-14-fluoro-Triptolide and Zorubicin (ADR) suppress vitro culture human ovarian cancer SK-OV-3 cell.
(5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiment 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-14-fluoro-Triptolide and Zorubicin (ADR) see Table 1 to the growth-inhibiting exercising result of human ovarian cancer SK-OV-3 cell.
Table 1. compound is to the growth-inhibiting effect of human ovarian cancer SK-OV-3 cell
| Sequence number | IC50(nM) | Estimate |
| Ia | 150 | Effectively |
| Ib | 77 | Effectively |
| ADR | 120 | Effectively |
The activity data of listing in the table 1 shows that it is quite active that compound of the present invention and positive control Zorubicin (ADR) suppress, and has the effect of effective inhibition human ovarian cancer SK-OV-3 cell growth.
Test example 2
(5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiments of the invention 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-2 compounds of 14-fluoro-Triptolide are to the growth-inhibiting effect research of the human prostata cancer PC-3 cell of vitro culture.
Human prostata cancer PC-3 cell is cultivated with the F-12 substratum (Gibco, the U.S.) that contains 10% foetal calf serum, and culture condition is 37 ℃, 5%CO
2, tumour cell 0.7x10
4/ hole is inoculated in the 96-orifice plate, and after 24 hours, adding storing solution is dimethyl sulfoxide (DMSO) configuration (10
-2M), each compound of physiological saline dilution, make that final concentration is 10 in the substratum
-5, 10
-6M acts on 72 hours.Discard nutrient solution, with 10% cold trichoroacetic acid(TCA) fixed cell, with sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed, flush away is not in conjunction with behind the SRB, Tris dissolving and protein bound SRB, microplate reader is measured the OD value under the 560nM wavelength, calculate inhibitory rate of cell growth by following formula: inhibiting rate=(OD value
Control wells-OD value
Administration The hole)/OD value
Control wellsX100%.Obtain the amount-effect curve (referring to Fig. 2) that (5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiment 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-14-fluoro-Triptolide suppresses vitro culture human prostata cancer PC-3 cell.
(5R)-5-hydroxyl of (5R)-5-hydroxyl of embodiment 1 preparation-(14S)-14-fluoro-Triptolide and embodiment 2 preparations-(14R)-14-fluoro-Triptolide sees Table 2 to the growth-inhibiting exercising result of human prostata cancer PC-3 cell.
Table 2. compound is to the growth-inhibiting effect of human prostata cancer PC-3 cell
| Sequence number | IC50(nM) | Estimate |
| Ia | 160 | Effectively |
| Ib | 66 | Effectively |
The activity data of listing in the table 2 shows that compound of the present invention has the effect of effective inhibition human prostata cancer PC-3 cell growth.
Above compound embodiment and pharmacodynamics evaluation experimental example only are structure and preparation method thereof and the The pharmacological results that illustrates compound provided by the invention, but can make various modifications and variation to this to one skilled in the art, and not deviating from the spirit and scope of the present invention, appending claims covers all such modifications in the present invention.
Claims (7)
1. fluorine shown in the general formula (I) replaces triptolide derivatives or its pharmacy acceptable salt or hydrate or their optical isomer:
In following formula, connect OH, F's---can represent
Perhaps
2. fluorine as claimed in claim 1 replaces triptolide derivatives, and wherein OH is α (R) configuration, and F is α (S) configuration, namely following general formula (I a) shown in compound:
3. fluorine as claimed in claim 1 replaces triptolide derivatives, and wherein OH is α (R) configuration, and F is β (R) configuration, i.e. compound shown in the following general formula (I b):
4. one kind prepares the method that the described fluorine of claim 2 replaces triptolide derivatives, it is characterized in that compound is prepared from by following steps shown in the general formula (Ia):
Step 1: under the nitrogen protection, to the dry methylene chloride solution that is dissolved with general formula (1) triptolide add (diethylamino) sulfur trifluoride with the 14-position hydroxyl of general formula (1) triptolide be converted into fluorine obtain general formula (2) (14S)-14-fluoro-Triptolide;
Step 2: with the general formula (2) of step 1 preparation (14S)-14-fluoro-Triptolide is dissolved in the dry dioxane solution, add tin anhydride general formula (2) (14S)-the 5-position of 14-fluoro-Triptolide introduces hydroxyl and obtains compound shown in the general formula (Ia); Concrete reaction formula is as follows:
5. one kind prepares the method that the described fluorine of claim 3 replaces triptolide derivatives, it is characterized in that compound is prepared from by following steps shown in the general formula (Ib): be made up of following steps:
Step 1: the Triptonide of general formula (4) is dissolved in the organic solution, adds the table triptolide that chemical reducing agent is converted into general formula (5);
Step 2: under the nitrogen protection, add (diethylamino) sulfur trifluoride to the dry methylene chloride solution of the table triptolide that is dissolved with general formula (5) the 14-position hydroxyl of the table triptolide of general formula (5) is converted into (14R)-14-fluoro-Triptolide that fluorine obtains general formula (6);
Step 3: with step: (14R)-14-fluoro-Triptolide of the general formulas (6) of 2 preparations is dissolved in the dry dioxane solution, adds tin anhydride and introduces hydroxyl and obtain compound shown in the general formula (Ib) in the 5-position of (the 14R)-14-of general formula (6) fluoro-Triptolide; Concrete reaction formula is as follows:
Claim 1 or 2 described fluorine replace triptolide derivatives for the preparation of the treatment cancer and with the medicine of cancer relative disease in application.
7. application as claimed in claim 6, wherein said cancer are kidney, mammary cancer, lung cancer, malignant melanoma, colorectal carcinoma, prostate cancer or ovarian cancer.
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| CN104513290A (en) * | 2013-10-08 | 2015-04-15 | 中国医学科学院药物研究所 | Triptolidenol derivative and application thereof |
| CN106749496A (en) * | 2016-12-05 | 2017-05-31 | 张奇军 | New triptolide derivative and its preparation and use |
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| CN1511838A (en) * | 2002-12-27 | 2004-07-14 | �й���ѧԺ�Ϻ�ҩ���о��� | Triptolide alcohol derivative and its use |
| WO2005062913A2 (en) * | 2003-12-24 | 2005-07-14 | Pharmagenesis, Inc. | Triplide 5,6-derivatives as immunomodulators and anticancer agents |
| CN1753666A (en) * | 2003-02-25 | 2006-03-29 | 美国泛华医药公司 | Halogenated triptolide derivatives as immunomodulators and anticancer agents |
| WO2007112648A1 (en) * | 2006-04-04 | 2007-10-11 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | The medicinal compositions comprising triptolide derivatives and its dosage form and application |
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| CN1511838A (en) * | 2002-12-27 | 2004-07-14 | �й���ѧԺ�Ϻ�ҩ���о��� | Triptolide alcohol derivative and its use |
| CN1753666A (en) * | 2003-02-25 | 2006-03-29 | 美国泛华医药公司 | Halogenated triptolide derivatives as immunomodulators and anticancer agents |
| WO2005062913A2 (en) * | 2003-12-24 | 2005-07-14 | Pharmagenesis, Inc. | Triplide 5,6-derivatives as immunomodulators and anticancer agents |
| WO2007112648A1 (en) * | 2006-04-04 | 2007-10-11 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | The medicinal compositions comprising triptolide derivatives and its dosage form and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104513290A (en) * | 2013-10-08 | 2015-04-15 | 中国医学科学院药物研究所 | Triptolidenol derivative and application thereof |
| CN104513290B (en) * | 2013-10-08 | 2019-01-01 | 中国医学科学院药物研究所 | Triptolidenol derivative and its application |
| CN106749496A (en) * | 2016-12-05 | 2017-05-31 | 张奇军 | New triptolide derivative and its preparation and use |
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