CN103709227A - Double bond substituted triptolide derivative, and preparation method and applications thereof - Google Patents

Double bond substituted triptolide derivative, and preparation method and applications thereof Download PDF

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CN103709227A
CN103709227A CN201210380144.5A CN201210380144A CN103709227A CN 103709227 A CN103709227 A CN 103709227A CN 201210380144 A CN201210380144 A CN 201210380144A CN 103709227 A CN103709227 A CN 103709227A
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triptolide
dehydroxylation
methylene radical
cancer
preparation
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CN103709227B (en
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樊兴
秦继红
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Shanghai Huilun Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • 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
    • C07J73/003—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 by oxygen as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses a double bond substituted triptolide derivative represented by formula (I); or a pharmaceutically acceptable salt thereof; or a hydrate; or optical isomers of the double bond substituted triptolide derivative, the pharmaceutically acceptable salt, and the hydrate; wherein R1=OH and R2=H, or R1=H and R2=OH. The invention also discloses a preparation method, and applications of the double bond substituted triptolide derivative in preparation of medicines used for treating cancer and diseased related to cancer.

Description

Two keys replace triptolide derivatives and its preparation method and application
Technical field
The present invention relates to structure of modification and the activity research of biological active constituents from natural medicines, be specifically related to the research that two keys replace triptolide derivatives and preparation method and treatment hyperplasia tumor disease.
Background technology
Trypterygine, popular name Graceful Jessamine Herb, is Celastraceae (Celastraceae) Thunder God Calamus bejuco, is that the resource that has of China is than a more rich kind of plant.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 forretii Dicls), in China, all have distribution.Trypterygine is recorded the > in < < Shennong Bencaojing > the earliest, its main chemical compositions has diterpene, triterpene, sesquiterpene, alkaloid etc., from tripterygium plant, has isolated so far nearly 200 kinds of compound.The research that recent two decades comes shows that it has antitumor, anti-inflammatory, immunosuppression, antifertility, the various active such as antibacterial.
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 antitumor action research widely, also once entered clinical trial except obtaining, and was used for the treatment of leukemia, but the larger toxic side effect of triptolide, too narrow treatment window, has limited it in clinical middle application.The structure of modification of triptolide was confined in the introduction of water soluble group mostly in the past, and in agent structure, there is no essence and change.After this class prodrug enters in body, by still changing triptolide into and bring into play in vivo drug action after hydrolysis or metabolism, this has just determined that they can not fundamentally improve the toxic side effect of triptolide.Simultaneously to triptolide C 14when transform-position, find, the group configuration of this position is very remarkable for the impact of compound activity, and the problem of optical isomer has increased very large difficulty to synthetic and mask work.
The research focusing on triptolide structure activity relationship of the present invention, has carried out being different from transformation and the modification of prior art to its structure, obtained the triptolide derivatives of a collection of novel texture, thereby completed the present invention.
Summary of the invention
One of technical problem to be solved by this invention is for the existing problem of existing triptolide and at triptolide C 5-position or C 15hydroxyl, C are introduced in-position 14exocyclic double bond is introduced in-position, forms a collection of pair of key and replaces triptolide derivatives.
Two of technical problem to be solved by this invention is to provide a kind of 14-of take hydroxyl that two key Triptolides are basic structure to replace the preparation method of triptolide derivatives.
Three of technical problem to be solved by this invention is to replace the pharmacological toxicology experimental study of triptolide derivatives by take hydroxyl that the two key Triptolides of 14-are basic structure, find that it is for tumor disease, especially the tumour of reproductive system has good therapeutic action, there is efficient, low toxicity, with the feature of conventional cell poison antitumor drug without cross-resistance, there is the DEVELOPMENT PROSPECT that is well used for the treatment of the proliferative diseases such as tumour.
Provided by the invention pair of key replaces triptolide derivatives for compound or its pharmacy acceptable salt or hydrate or their optical isomer shown in logical formula I:
Figure BDA00002232919000021
Wherein, R 1=OH, R 2=H, or R 1=H, R 2=OH.
In a preferred embodiment of the invention, R in logical formula I 1=OH, R 2=H, following structural formula (I a) shown in compound:
Figure BDA00002232919000022
In a preferred embodiment of the invention, R in logical formula I 1=H, R 2=OH, i.e. compound shown in following structural formula (I b):
Figure BDA00002232919000031
Preparation method of the present invention is as follows:
1, structural formula (I a) shown in the preparation method of compound, by following steps, formed:
Figure BDA00002232919000032
Step 1: the Triptonide (1) of take is initiator, in non-protonic solvent, utilizes the C14 position carbonyl of methyl iodide grignard reagent attack Triptonide to obtain (14S)-14 Beta-methyl Epitriptolides (2);
Step 2:(14S)-14 Beta-methyl Epitriptolides (2) obtain C14 position exocyclic double bond product 14-dehydroxylation-14-methylene radical triptolide (3) with trifluoroacetic anhydride dehydration in non-protonic solvent;
Step 3:14-dehydroxylation-14-methylene radical triptolide (3) is cultivated and is prepared 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide (I a) in the potato substratum that contains Neurospora crassa
2, the preparation method of compound shown in structural formula (I b), is comprised of following steps:
Figure BDA00002232919000033
Step 1:14-dehydroxylation-14-methylene radical triptolide (3) is used rat liver microsomes albumen to hatch and prepares 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide (I b) in phosphate buffer solution
Fluorine of the present invention replace triptolide derivatives for the preparation for the treatment of 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.
In this specification sheets, term used has following meaning:
" 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, the organic acids such as citric acid and aspartic acid, the acidic amino acid such as L-glutamic acid forms after ester the salt forming with mineral alkali again, as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt forming with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc., or and Methionin, arginine, the basic aminoacidss such as ornithine form the hydrochloric acid after ester, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, the salt of the mineral acids such as phosphoric acid, or and formic acid, acetic acid, picric acid, methylsulfonic acid, the 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.
The of the present invention pair of key replaces triptolide derivatives, its pharmacy acceptable salt or optical isomer and can be made into the weight containing activeconstituents 0.001-99.9%() and the various preparations of appropriate pharmaceutically acceptable carrier, as be suitable for the dosage form that oral, injection or enterally administering are used.
Can to the susceptibility of medicine etc., to curee, use the pharmaceutical preparation containing the compounds of this invention for the treatment of significant quantity according to curee's age (monthly age or week age), general health situation, disease severity and the course of disease, route of administration, human body.
Accompanying drawing explanation
Fig. 1 is the amount-effect curve schematic diagram that 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide of the embodiment of the present invention 1 preparation suppresses vitro culture human ovarian cancer SK-OV-3 cell.
Fig. 2 is the amount-effect curve schematic diagram that 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide of the embodiment of the present invention 2 preparations suppresses vitro culture human ovarian cancer SK-OV-3 cell.
Embodiment
Below in conjunction with example, the present invention is further elaborated, but these embodiment are never any limitation of the invention, scope of the present invention is determined by claim.
One, Preparation Example
Embodiment 1
(I is the preparation of 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide a) for structural formula
Step 1
The preparation of structural formula (2) (14S)-14 Beta-methyl Epitriptolides
Figure BDA00002232919000051
Under argon shield, 10mL anhydrous diethyl ether is added in the reaction flask that contains magnesium chips (264mg, 11mmol), will be dissolved in MeI(1.42g, the 10mmol of 5mL anhydrous diethyl ether) through constant pressure funnel, be added drop-wise in above-mentioned reaction system.Finishing this lead reaction system at room temperature stirs half an hour.The MeMgI grignard reagent solution of getting the fresh preparation of 1.37mL, dropwise adds the Triptonide 1(90mg, the 0.25mmmol that have been dissolved in 8mL dry tetrahydrofuran) in.Under room temperature, react stopped reaction after 2 hours, reaction system saturated ammonium chloride solution cancellation, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, crude product after concentrated is through column chromatography purification (ethyl acetate: sherwood oil=1:5) obtain white solid (14S)-14 Beta-methyl Epitriptolide 2(70mg, yield 73%).MS(ESI):m/z 375[M+1] +。 1H NMR(CDCl 3,300MHz):δ4.66(s,2H),3.75(d,1H,J=3.2Hz),3.74(d,1H,J=3.2Hz),2.75-2.63(m,1H),2.47(sept,1H,J=6.9Hz),2.34-2.22(m,1H),2.21-2.03(m,2H),1.85(t,1H,J=14.1Hz),1.58-1.48(m,4H),1.24-1.10(m,1H),1.03(s,3H),0.94(d,3H,J=6.9Hz),0.79(d,3H,J=6.9Hz)。
Step 2
The preparation of structural formula (3) 14-dehydroxylation-14-methylene radical triptolide
Figure BDA00002232919000061
By MsCl(0.18mL, 2.2mmol), dry TEA(2.17mL, 15.6mmol) and dry pyridine (2.4mL, 29.6mmol) add successively in the DCM solution that 7mL is dry.Under room temperature, by (14S)-14 Beta-methyl Epitriptolide 2(130mg, 0.35mmol) be dissolved in the DCM that 5mL is dry, add in above-mentioned reaction system, stir downhill reaction system and drip trifluoro-acetic anhydride (0.24mL, 1.7mmol), add water termination reaction after reacting 2h under room temperature.Removal of solvent under reduced pressure, residue is extracted with ethyl acetate, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying.Crude product after concentrated is through column chromatography purification (ethyl acetate: sherwood oil=1:5) obtain white solid 14-dehydroxylation-14-methylene radical triptolide 3(102mg, yield 82%).MS(ESI):m/z 355[M+1] +。 1H NMR(CDCl 3,300MHz):δ5.53(s,1H),5.39(s,1H),4.83-4.80(m,2H),3.97(d,1H,J=3.0Hz),3.64(d,1H,J=3.0Hz),3.54-3.52(m,1H),3.07-3.05(m,1H),2.87-2.83(m,1H),2.53-2.42(m,1H),2.29-2.14(m,2H),1.99-1.89(m,1H),1.53-1.46(m,1H),1.42-1.33(m,1H),1.09(s,3H),0.97(d,3H,J=6.9Hz),0.87(d,3H,J=6.9Hz)。
Step 3
(I is the preparation of 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide a) for structural formula
Figure BDA00002232919000071
From test tube slant by Neurospora crassa, choose 250mL triangular flask (60mL potato substratum is housed), at 200rpm, 25 ℃, shaking culture adds the ethanolic soln (containing 10%DMSO) of 14-dehydroxylation-14-methylene radical triptolide 3 of 200 μ L 10mg/mL after 1 day, continues to cultivate 4 days under similarity condition.By filtering fermentation liquor, filtrate extracts 3 times by isopyknic ethyl acetate, and Neurospora crassa is used appropriate ethyl acetate supersound extraction 30 minutes.Merge two-part ethyl acetate, rotary evaporation, except desolventizing, obtains conversion product residue.This residue is separated through half preparative high-performance liquid chromatographic, collects stream part, and 40 ° of C concentrating under reduced pressure, except desolventizing, obtain 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide I a(0.4mg, yield 20%).MS(ESI):m/z 373[M+1] +。 1H NMR(CD 3OD,300MHz):δ5.55(s,1H),5.42(s,1H),4.84-4.80(m,2H),3.90(d,1H,J=2.7Hz),3.65(d,1H,J=2.7Hz),3.07-3.06(m,1H),2.52-2.43(m,1H),2.28-2.06(m,3H),1.91-1.81(m,1H),1.32-1.21(m,2H),1.13(s,3H),0.99(d,3H,J=6.3Hz),0.87(d,3H,J=6.3Hz)。
Embodiment 2
The preparation of structural formula (I b) 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide
Step 1
The preparation of structural formula (I b) 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide
Figure BDA00002232919000081
The storing solution (50mM) of 14-dehydroxylation-14-methylene radical triptolide 3 adopts methyl alcohol preparation, and in final incubation system, methanol content is 0.1%.Single incubation system volume is 10mL, medium is 100mM phosphoric acid buffer (PBS, pH7.4), comprise that final concentration is the rat liver microsomes albumen of 0.5mg/mL, 14-dehydroxylation-14-methylene radical triptolide 3 of 50 μ M and the NADPH of 1mM, 2h is hatched in 37 ° of C water-baths.With ethyl acetate extraction 14-dehydroxylation-14-methylene radical triptolide 3 rat liver microsomes artemia hatching solutions, 40 ° of C concentrating under reduced pressure are except desolventizing, with 5ml methyl alcohol: water 65:35 dissolves, this solution is separated through half preparative high-performance liquid chromatographic, collect stream part, 40 ° of C concentrating under reduced pressure, except desolventizing, obtain 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide I b(10mg, yield 10%).MS(ESI):m/z 373[M+1] +。 1H NMR(CDCl 3,400MHz):δ5.82(s,1H),5.65(s,1H),4.84-4.80(m,2H),3.97(d,1H,J=3.3Hz),3.87(d,1H,J=3.3Hz),3.07-3.06(m,1H),2.87-2.83(m,1H),2.28-2.08(m,3H),1.97-1.92(m,1H),1.52-1.38(m,2H),1.35(s,3H),1.34(s,3H),1.09(s,3H). 13C NMR(CDCl 3,100MHz):δ176.68,164.65,140.77,125.90,119.11,72.52,72.08,67.01,66.68,64.93,62.58,57.48,42.13,37.30,31.90,27.28,27.05,25.22,18.51,14.63。
Two, pharmacodynamic evaluation test example
The growth-inhibiting effect research of 2 compounds of 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide of 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide of embodiments of the invention 1 preparation and embodiment 2 preparations to 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.) containing 10% foetal calf serum, and culture condition is 37 ℃, 5%CO 2, tumour cell 0.7x10 4/ hole is inoculated in 96-orifice plate, and after 24 hours, adding storing solution is dimethyl sulfoxide (DMSO) configuration (10 -2m), each compound of normal saline dilution, making final concentration in substratum is 10 -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, wash away not in conjunction with after SRB, Tris dissolves and protein bound SRB, and microplate reader is measured OD value under 560nM wavelength, calculates inhibitory rate of cell growth: inhibiting rate=(OD value by following formula control wells-OD value dosing holes)/OD value control wellsx100%.Obtain the amount-effect curve (referring to Fig. 2) that 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide (referring to Fig. 1) of embodiment 1 preparation and 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide of embodiment 2 preparations suppress vitro culture human ovarian cancer SK-OV-3 cell.
14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide of 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide of embodiment 1 preparation and embodiment 2 preparations to the growth-inhibiting exercising result of human ovarian cancer SK-OV-3 cell in Table 1.
The growth-inhibiting effect of table 1. compound to human ovarian cancer SK-OV-3 cell
Sequence number IC 50(nM) Evaluate
Ia 3000 Effectively
Ib 390 Effectively
The activity data demonstration of listing in table 1, compound of the present invention has the effect of effective inhibition human ovarian cancer SK-OV-3 Growth of Cells.
Above compound Preparation Example and pharmacodynamic evaluation experimental example are only structure and preparation method thereof and the pharmacological results that illustrates compound provided by the invention, but can make to this various modifications and variation 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. shown in logical formula I, two keys replace triptolide derivatives or its pharmacy acceptable salt or hydrate or their optical isomer:
Wherein, R 1=OH, R 2=H, or R 1=H, R 2=OH.
2. as claimed in claim 1 pair of key replaces triptolide derivatives, wherein R 1=OH, R 2=H, be following structural formula (I a) shown in compound:
Figure FDA00002232918900012
3. as claimed in claim 1 pair of key replaces triptolide derivatives, wherein R 1=H, R 2=OH, is compound shown in following structural formula (I b):
Figure FDA00002232918900013
4. prepare the method that the claimed in claim 2 pair of key replaces triptolide derivatives, it is characterized in that, structural formula (I a) shown in compound by following steps, be prepared from:
Step 1: the Triptonide (1) of take is initiator, in non-protonic solvent, utilizes the C14 position carbonyl of methyl iodide grignard reagent attack Triptonide to obtain (14S)-14 Beta-methyl Epitriptolides (2);
Step 2:(14S)-14 Beta-methyl Epitriptolides (2) obtain C14 position exocyclic double bond product 14-dehydroxylation-14-methylene radical triptolide (3) with trifluoroacetic anhydride dehydration in non-protonic solvent;
Step 3:14-dehydroxylation-14-methylene radical triptolide (3) is cultivated and is prepared 14-dehydroxylation-14-methylene radical-5-hydroxyl triptolide (I a) in the potato substratum that contains Neurospora crassa.
5. prepare the method that claimed in claim 3 pair of key replaces triptolide derivatives, it is characterized in that, shown in structural formula (I b), compound is prepared from by following steps:
Step 1:14-dehydroxylation-14-methylene radical triptolide (3) is used rat liver microsomes albumen to hatch and prepares 14-dehydroxylation-14-methylene radical-15-hydroxyl triptolide (I b) in phosphate buffer solution.
The claimed in claim 1 pair of key replace triptolide derivatives for the preparation for the treatment of cancer and with the medicine of cancer relative disease in application.
7. application as claimed in claim 6, wherein said cancer is kidney, mammary cancer, lung cancer, malignant melanoma, colorectal carcinoma, prostate cancer or ovarian cancer.
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CN1726025A (en) * 2002-12-17 2006-01-25 泛华医药公司 Triptolide derivatives as immunomodulator and anticancer agents
CN101255186A (en) * 2008-04-10 2008-09-03 中国科学院上海药物研究所 Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof

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