CN101255186A - Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof - Google Patents
Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof Download PDFInfo
- Publication number
- CN101255186A CN101255186A CNA2008100358919A CN200810035891A CN101255186A CN 101255186 A CN101255186 A CN 101255186A CN A2008100358919 A CNA2008100358919 A CN A2008100358919A CN 200810035891 A CN200810035891 A CN 200810035891A CN 101255186 A CN101255186 A CN 101255186A
- Authority
- CN
- China
- Prior art keywords
- configuration
- triptolide
- hydrogen
- lldt
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
Abstract
The invention relates to tripterygium wilfordii diterpenes lactone derivates represented by the formula (1), optical isomers thereof and pharmaceutically acceptable salts and hydrate thereof, wherein C5 and C6 are combined by C-C or C=C bind; P and Q represent hydrogen, oxygen, hydroxyl, halogen, sulfhydryl, C1-C6 alkoxyl, C1-C6 alkylamino radical, or C1-C6 alksulfhydryl combined on positions C5 or C6 respectively when C5 and C6 are combined by C-C bind; and C14XY is combined at the position C14 with the structure shown in the view, and W and Z represent oxygen, hydroxyl, halogen, sulfhydryl, C1-C6 alkoxyl, C1-C6 alkylamino radical, or C1-C6 alksulfhydryl combined on positions C12 or C13 respectively, '-'combined with X, Y, Z, W, P and Q represent '' '' or '' ''. The invention further relates to a synthetic method thereof and the applications on preparing the medicine for treating hypertrophic tumor.
Description
Technical field
The present invention relates to tripterygium wilfordii diterpenes diterpenoids lactones derivative and be used for the treatment of application in the medicine of hyperplasia tumor disease in preparation.
Background technology
Trypterygine (Tripterygium wilfordii Hook F) claim herba fibraureae recisae again, belong to the Celastraceae tripterygium plant, in state-owned four kinds, wherein there are three kinds to be used as medicine, be respectively main product in the middle and lower reach of Yangtze River geographic trypterygine, main product in the Yangtze valley and southwest Tripterygium hypoglaucum and main product in northeast and Japan the northeast trypterygine.Trypterygine is recorded the earliest in " Dragon Lord book on Chinese herbal medicine through ", and its main chemical compositions has diterpene, triterpene, sesquiterpene, alkaloid etc., and recent two decades comes studies show that it has antitumor, anti-inflammatory, immunosuppression, antifertility, antibiotic isoreactivity.
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 a triptolide.Triptolide also once entered clinical trial except obtaining antitumor action research widely, be used for the treatment of leukemia, but the toxic side effect of triptolide has limited it and 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.Because in the past to the most no specificity of the antitumor drug effect research of triptolide alcohol derivative, therefore antitumor knurl spectrum is clear and definite inadequately.
The further investigation that focuses on the triptolide structure activity relationship of the present invention is different from the transformation and the modification of prior art to its structure, has obtained the tripterygium wilfordii diterpenes diterpenoids lactones derivative of a collection of novel texture.This series derivates that is obtained is compared with lead compound-triptolide and other tripterygium wilfordii diterpenes diterpenoids lactones derivative, and tangible essential distinction is arranged on its chemical structure.The result that studies for a long period of time both at home and abroad shows, the toxic side effect of active tripterygium wilfordii diterpenes diterpenoids lactones compound is mainly reflected in the reproductive system aspect, and the antitumor drug effect research of this compounds is never carried out the pharmacodynamics evaluation of system at genital system tumor in the past.The result of the external pharmacodynamics evaluation of the tripterygium wilfordii diterpenes diterpenoids lactones derivative with novel texture of the present invention shows, above-mentioned novel tripterygium wilfordii diterpenes diterpenoids lactones derivative has good tumors inhibition activity to the tumour of reproductive system, the present invention as the main indication of new drug development from now on, helps embodying the specificity of tripterygium wilfordii diterpenes diterpenoids lactones compound on antitumor action with the treatment of genital system tumor.
Summary of the invention
The invention provides the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in the general formula (1), its optical isomer and pharmacy acceptable salt and hydrate:
C wherein
5And C
6Link to each other with carbon-carbon single bond or carbon-carbon double bond;
Work as C
5And C
6When linking to each other with carbon-carbon single bond, P and Q represent to be connected C respectively
5Position and C
6Hydrogen on the position, oxygen, hydroxyl, sulfydryl, halogen, C1～C6 alkoxyl group, C1～C6 alkylamino radical or C1～C6 alkane sulfydryl;
Work as C
5And C
6When linking to each other with carbon-carbon double bond, this moment C
5Remove and C
4, C
6And C
10Connect outer other substituted radicals that do not have, P does not represent any substituted radical, C
6Substituting group Q then only represents hydrogen atom on the position;
C
14XY represents C
14The structure at place, position is
C
14=CH
2, C
14(OH) CH=CH
2, C
14(OH) CH
2OH, C
14(OH) CH
3,
C
14(OH) CH (OH) CH
2OH,
Or C
14(O) CH=CH
2
W and Z represent to be connected C respectively
12Position and C
13Oxygen on the position, halogen, sulfydryl, C1～C6 alkoxyl group, C1～C6 alkylamino radical or C1～C6 alkane sulfydryl;
In the general formula (1), "---" that connect X, Y, Z, W, P and Q can be represented
Perhaps
The present invention also provides the application in tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in the general formula (1) is used for the treatment of proliferative diseases such as tumour in preparation the medicine.
Beneficial effect
Existing structure activity study shows that the C-14-β hydroxyl of triptolide is active essential group, and the tripterygium wilfordii diterpenes diterpenoids lactones derivative overwhelming majority who does not contain free C-14-β hydroxyl that the present invention obtained has still kept good tumors inhibition activity, therefore the present invention has made significant contribution aspect its toxic research keeping bioactive the reduction simultaneously of triptolide, provides useful selection for seeking novel antitumor drug.
Because the toxic side effect of active tripterygium wilfordii diterpenes diterpenoids lactones compound is mainly reflected in the reproductive system aspect, the present invention as the main indication of new drug development, helps embodying the specificity of tripterygium wilfordii diterpenes diterpenoids lactones compound on antitumor action with the treatment of genital system tumor.Tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention can obviously suppress the tumour cell of multiple vitro culture, the particularly growth of genital system tumor cell, restraining effect has tangible dose-dependently, shows that above-claimed cpd has good research and using value to broad variety tumour especially genital system tumor.
Embodiment
A preferred embodiment of the present invention is C in the general formula (1)
14XY is (14S)-14, the 21-epoxy construction, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is the tripterygium wilfordii diterpenes diterpenoids lactones derivative of hydrogen, the compound shown in the promptly following general formula (2):
Another preferred embodiment of the present invention is C in the general formula (1)
14XY is (14S)-14, and 21-epoxy construction, W are the halogen of β (R) configuration, and Z is the hydroxyl of α (R) configuration, and P is the hydrogen or the hydroxyl of α (R) configuration, and Q is the tripterygium wilfordii diterpenes diterpenoids lactones derivative of hydrogen, the compound shown in the promptly following general formula (3):
Another preferred embodiment of the present invention is C in the general formula (1)
14XY is (14S)-14, the 21-epoxy construction, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, C
5And C
6With the tripterygium wilfordii diterpenes diterpenoids lactones derivative that carbon-carbon double bond links to each other, the compound shown in the promptly following general formula (4):
Another preferred embodiment of the present invention is C in the general formula (1)
14XY is C
14=CH
2, W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is the tripterygium wilfordii diterpenes diterpenoids lactones derivative of hydrogen, the compound shown in the promptly following general formula (5):
Another preferred embodiment of the present invention is C in the general formula (1)
14XY is
Be connected C
14The hydroxyl of-position can also can be (S) configuration, C for (R) configuration
21-position can be for (R) configuration also can be (S) configuration, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is the tripterygium wilfordii diterpenes diterpenoids lactones derivative of hydrogen, the compound shown in the promptly following general formula (6):
Another preferred embodiment of the present invention is C in the general formula (1)
14XY is C
14(OH) CH=CH
2, be connected C
14The hydroxyl of-position can also can be (S) configuration for (R) configuration, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is the tripterygium wilfordii diterpenes diterpenoids lactones derivative of hydrogen, the compound shown in the promptly following general formula (7):
The present invention also have a preferred embodiment be in the general formula (1) W and Z for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen of α (S) configuration, Q is a hydrogen, C
14XY is C
14(OH) CH
2OH,
Or
C
14The configuration of-position can also can be the tripterygium wilfordii diterpenes diterpenoids lactones derivative of (S) configuration for (R) configuration, the compound shown in the promptly following general formula (8):
The synthetic method of tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention is summarized as follows:
Compound shown in the general formula (1) mainly is to be initiator with Triptonide (LLDT-1).
For example, shown in reaction stream formula (1), (LLDT-1) is initiator with Triptonide, in aprotic polar solvent, under room temperature condition, utilizes Corey methylenation reagent at C
14The place forms a pair of epoxy compounds (the 14S)-14-dehydroxylation-14 of S and R configuration, 21-epoxy triptolide (LLDT-67) with (14R)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-69); With (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) is dissolved in the aprotic polar solvent, under heating condition, obtain (5R by the tin anhydride oxidation, 14S)-5 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-68) obtains a small amount of Δ simultaneously
5,6-dehydrogenation compound (14S)-Δ
5,6-dehydrogenation-14-dehydroxylation-14,21-epoxy triptolide (LLDT-70); With (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) is dissolved in the aprotic polar solvent, obtain (12R with hydrogenchloride or pyridine hydrochloride open loop oxygen, 13R, 14S)-and 12 β-chloro-13 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-76).
Reaction stream formula (1)
For example, shown in reaction stream formula (2), (LLDT-1) is initiator with Triptonide, in aprotic polar solvent, utilizes the C of vinyl bromination magnesium Grignard reagent attack triptolide
14-position carbonyl obtains (14S)-14 β-ethene base table triptolide (LLDT-65) and (12S, 13S, 14S)-12 Alpha-hydroxy-13 α, 14 α-epoxy-14 β-ethene base table triptolide (LLDT-73); Be raw material further, in polar solvent, C take place with peroxide reagent with (14S)-14 β-ethene base table triptolide (LLDT-65)
21, C
22The position epoxidation reaction obtain (14S, 21R)-14 β-oxa-cyclopropyl table triptolide (LLDT-74) and (14S, 21S)-14 β-oxa-cyclopropyl table triptolide (LLDT-75).
Reaction stream formula (2)
For example, shown in reaction stream formula (3), be initiator, with the C of Tamao Grignard reagent attack triptolide with Triptonide (LLDT-1)
14-position carbonyl obtains siliceous intermediate (14S)-14 β-isopropoxy dimethyl-silicon methyl table triptolide (LLDT-81), this intermediate carries out after simple extraction concentrates, directly be dissolved in without separation and purification in the mixed solvent of proton polar solvent and aprotic polar solvent, the oxydrolysis desiliconization obtains (14S)-14 β-methylol table triptolide (LLDT-62); Be raw material further with (14S)-14 β-methylol table triptolide (LLDT-62), in polar solvent, under the alkaline condition, utilize thionyl chloride adjacent diol structure to be converted into the (14S of five-ring sulfite structure, sulphur S)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-77) and (14S, sulphur R)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-78); Both further are converted into same saturated epithio ester compound (14S)-14 α, 21-ethylene glycol epithio acid esters triptolide (LLDT-79) under oxidizing condition.
Reaction stream formula (3)
For example, shown in reaction stream formula (4), (LLDT-1) is initiator with Triptonide, in aprotic polar solvent, utilizes the C of methyl iodide Grignard reagent attack triptolide
14-position carbonyl obtains (14S)-14 Beta-methyl table triptolides (LLDT-71); And then in aprotic polar solvent, obtain C again with the trifluoroacetic anhydride dehydration
14Position exocyclic double bond product 14-dehydroxylation-14-methylene radical triptolide (LLDT-72).
Reaction stream formula (4)
In addition; (14S)-and 14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) also can obtain in the following way, shown in reaction stream formula (5); with (14S)-14 β-methylol table triptolide (LLDT-62) is raw material, with sulfonylation agent with C
21Obtain (14S)-14 β-sulfonyloxy methyl table triptolide (wherein R is an alkylsulfonyl) behind the terminal hydroxyl sulfonylation of position, cyclization obtains (14S)-14-dehydroxylation-14 under the effect of alkali, 21-epoxy triptolide (LLDT-67).
Reaction stream formula (5)
Used term has following meaning in this specification sheets:
" alkoxyl group " can be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen, 2-methyl butoxy, 1,2-dimethyl propoxy-, 1-ethyl propoxy-, hexyloxy etc., preferred methoxyl group and oxyethyl group;
" alkylamino radical " can be low-grade alkane aminos such as methylamino, ethylamino-, Propylamino, isopropylamine base, butylamine base, isobutyl amine, sec-butylamine base, TERTIARY BUTYL AMINE base, amylamine base, isoamyl amido, uncle's amylamine base, uncle's amylamine base, neopentyl amine base, or two low-grade alkane aminos such as dimethylin, diethylin, dipropyl amido, dibutyl amino, diisobutylamine base, be preferably methylamino, ethylamino-, dimethylin and diethylin;
" alkane sulfydryl " can be first sulfydryl, second sulfydryl, third sulfydryl, different third sulfydryl, fourth sulfydryl, isobutyl sulfydryl, Zhong Ding sulfydryl, uncle's fourth sulfydryl, penta sulfydryl, isoamyl sulfydryl, uncle's penta sulfydryl, new penta sulfydryl, 2-methyl fourth sulfydryl, 1,2-dimethyl propylene sulfydryl, 1-ethyl third sulfydryl, own sulfydryl etc., preferred first sulfydryl and second sulfydryl;
" polar solvent " is for example ethyl acetate, dioxane, acetone, the trimethyl carbinol etc.;
" aprotic polar solvent " refers to for example methyl-sulphoxide, N, dinethylformamide, methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, ethylene glycol bis methyl ether etc.;
" proton polar solvent " refers to for example methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol etc.;
" heating condition " refers to that room temperature is above to the solvent refluxing temperature;
" peroxide reagent " is for example metachloroperbenzoic acid, peroxy tert-butyl alcohol, hydrogen peroxide etc.;
" sulfonylation agent " refers to for example methylsulfonyl chloride, ethyl sulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride, trifluoromethanesulfchloride chloride, trifluoromethanesulfanhydride anhydride etc.;
" 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, aluminium salt and amine 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, nitric acid, the salt of mineral acids such as phosphoric acid, or and formic acid, acetate, picric acid, methylsulfonic acid, organic acid salt such as ethyl sulfonic acid;
The implication of " optical isomer " comprises the mixture and the pure optical isomer of enantiomer, diastereomer, optical isomer.
The implication of " proliferative disease " comprises tumour, atypical hyperplasia, but be not limited to tumour and atypical hyperplasia.
The implication of " tumour " comprises innocent tumour and malignant tumour.
Description of drawings
Fig. 1. 15 compounds among the present invention, compare with triptolide, trypterygine table first element, to the growth-inhibiting effect of human ovarian cancer SK-OV-3 cell.
Fig. 2. 15 compounds among the present invention, compare with triptolide, trypterygine table first element, to the growth-inhibiting effect of human breast carcinoma MDA-MB-468 cell.
Fig. 3. 15 compounds among the present invention, compare with triptolide, trypterygine table first element, to the growth-inhibiting effect of human prostata cancer PC-3 cell.
Embodiment
Below in conjunction with embodiment the present invention is done further explaination, but these embodiment never are right Any restriction of the present invention.
Instrument and main experiment material are as follows:
Fisher-Johns micro-meldometer (temperature is not calibrated), the JASCODIP-181 polarimeter, Perkin-Elmer599B type and Nicole Magan750 type infrared spectrometer, BrukerAM-400 Type and Varian Mercury plus-400 type NMR, MAT-711 and MAT-95 type matter Spectrometer, H and 200-300 order column chromatography silica gel (Haiyang Chemical Plant, Qingdao), HSGF254TLC Plate (Yantai City chemical research institute).
Embodiment 1 (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67)
LLDT-1 LLDT-67
With (CH3)
3SOI (59.6mg, 0.27mmol) and NaH (60%, 9.5mg, 0.24mmol) Mix with solid form, add 2mL anhydrous dimethyl sulfoxide, stirring at room 20 under the argon shield Min is to wherein dripping the nothing that is dissolved with triptonide (LLDT-1) (53.7mg, 0.15mmol) Water dimethyl sulfoxide solution (2mL), stirring reaction. It is complete that TLC detects feedstock conversion, adds 3mL The shrend reaction of going out, ethyl acetate extraction, organic layer water, saturated common salt water washing, anhydrous sulphur Acid sodium drying removes solvent under reduced pressure, and the gained crude product is through column chromatography purification (eluant, eluent: acetic acid second Ester: cyclohexane=1: 5), obtain white solid (14S)-14-dehydroxylation-14, the 21-ring stereocpecificity Oxygen triptolide (LLDT-67) (47.5mg, 0.13mmol, productive rate: 85%).
1H-NMR(CDCl
3，300MHz)δ4.67(s，2H)，3.88(d，J＝3.1Hz，1H)，
3.52(d，J＝3.1Hz，1H)，3.40(d，J＝5.5Hz，1H)，2.84(d，J＝5.1Hz，1
H)；2.80-2.69(m，2H)，2.39-2.24(m，1H)，2.21-2.05(m，2H)，1.91-1.78
(m，2H)，1.57(dd，J＝8.7，4.9Hz，1H)，1.29-1.17(m，1H)，1.05(s，3H)，
0.86(d，J＝6.9Hz，3H)，0.80(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100
MHz)δ173.2(Cq)，160.2(Cq)，125.2(Cq)，69.9(CH
2)，65.2(Cq)，65.0
(Cq)，58.4(Cq)，56.8(CH)，55.9(CH)，55.6(Cq)，54.1(CH)，47.9(CH
2)，
40.4(CH)，35.6(Cq)，30.2(CH
2)，23.4(CH
2)，23.2(CH)，19.8(CH
3)，17.6
(CH
3)，17.0(CH
2)，13.5(CH
3)；IR(KBr)3427，3016，2981，2929，1745，
1674，1442，1022cm
-1；MS(EI，70eV)m/z(％)373([M+1]
+，2)，372(M
+，
1)，357(5)，343(21)，91(100)；HRMS(EI)calcd for C
21H
24O
6 372.1573，
found 372.1578；Anal.(C
21H
24O
6)calcd C 67.73，H 6.50，found C 67.54，
H6.62；[α]
D 20-138(c 0.109，CHCl
3)；mp 245-246℃.
Embodiment 2 (14S)-14 β-methylol Epitriptolide (LLDT-62)
Weighing magnesium chips (108mg, 4.5mL) in reaction bulb, argon replaces protective reaction system; Isopropoxy dimethyl chloride methyl-monosilane (0.72ml, 4.0mmol) is dissolved in the anhydrous tetrahydrochysene of 7mL In the furans, get this solution of 1mL under the argon shield and be added dropwise in the magnesium chips reaction system, and add two Drip 1,2-Bromofume, cause grignard reaction under 40 ℃ of stirrings, subsequently with remaining silane reagent Tetrahydrofuran solution dropwise splashes in the reaction system, and 5min dropwises, and this moment, reaction system was Lead. This reaction system that refluxes 45min is cooled to 0 ℃ subsequently. To be dissolved in anhydrous tetrahydrochysene furan The triptonide of muttering (LLDT-1) (358mg, 1.0mL) is added dropwise to the lattice of above-mentioned fresh preparation In family name's reagent. Stirring reaction is 2 hours under the room temperature, saturated ammonium chloride solution cancellation reaction, acetic acid The ethyl ester extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, decompression steams molten Agent gets a single addition compound product. The not purified 5mL first that directly under 40 ℃, is dissolved in of this addition compound product In the mixed solvent of pure and mild 8mL oxolane, stir the lower KHCO that adds successively3(416mg, 4.2mmol), KF (464mg, 4.9mmol) and H2O
2(30%, 1.1mL, 9.71mmol). 40 ℃ Lower reaction, and TLC (cyclohexane: after ethyl acetate=1: 1) the inspection raw material disappears, sodium thiosulfate water Solution (50%) stopped reaction. The reactant mixture ethyl acetate extraction, the organic layer saturated common salt Water washing, anhydrous sodium sulfate drying. Crude product after concentrating is through column chromatography purification (eluant, eluent: second Acetoacetic ester: cyclohexane=1: 3) get white solid (14S)-14 β-methylol Epitriptolide (LLDT-62) (273mg, 0.70mmol, productive rate: 70%).
1H-NMR(CDCl
3，300MHz)δ4.67(s，2H)，4.26(d，J＝11.6Hz，1H)，
3.88-3.79(m，2H)，3.64(d，J＝11.6Hz，1H)，3.46(d，J＝3.3Hz，1H)，
2.76-2.64(m，1H)，2.45(sept.，J＝6.9Hz，1H)，2.37-2.24(m，1H)，
2.23-2.04(m，2H)，1.89(t，J＝14.3Hz，1H)，1.55(dd，J＝12.5，4.9Hz，1
H)，1.24-1.11(m，1H)，1.07(s，3H)，0.92(d，J＝6.9Hz，3H)，0.89(d，J＝
6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.2(Cq)，160.2(Cq)，125.4
(Cq)，74.4(Cq)，70.0(CH
2)，67.5(Cq)，65.3(Cq)，65.2(CH
2)，65.0(Cq)，
56.5(CH)，56.1(CH)，54.4(CH)，40.3(CH)，36.0(Cq)，30.1(CH
2)，25.5
(CH)，23.4(CH
2)，20.9(CH
3)，18.6(CH
3)，17.1(CH
2)，13.7(CH
3)；IR(KBr)
3415，3361，2966，2927，2875，1755，1724，1672，1439，1074，1018cm
-1；
MS(EI，70eV)m/z(％)391([M+1]
+，2)，372(1)，71(100)；HRMS(EI)
calcd for C
21H
27O
7 391.1757，found 391.1752；[α]
D 20-116(c 0.085，CHCl
3)；
mp 237-239℃.
Embodiment 3 (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) and (14R)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-69)
Under the argon shield with (CH3)
3SOI (374mg, 1.7mmol) and t-BuOK (174mg, 1.5 Mmol) be dissolved in the methyl-sulfoxide of 6mL drying, this mixed system stirs 20min under room temperature. Be dissolved in triptonide (LLDT-1) in the dry dimethylsulfoxide solvent of 6mL (360mg, 1.0mmol) add in the said mixture, stirring reaction is complete to substrate conversion under the room temperature, adds The 10mL shrend reaction of going out, ethyl acetate extraction, organic layer water, saturated common salt water washing, Anhydrous sodium sulfate drying. Decompression steams behind the solvent crude product through column chromatography purification (eluant, eluent: second Acetoacetic ester: cyclohexane=1: 5). The gained white solid with half preparative HPLC separate obtain a pair of difference to Isomers (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) (0.196g, 0.53mmol, productive rate: 53%) and (14R)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-69) (0.126g, 0.34mmol, productive rate: 34%).
(14R)-and 14-dehydroxylation-14,21-epoxy triptolide (LLDT-69):
1H-NMR(CDCl
3，300MHz)δ4.79(dt，J＝16.8，2.6Hz，1H)，4.60
(dd，J＝16.8，3.0Hz，1H)，3.81(d，J＝3.0Hz，1H)，3.53(d，J＝3.0Hz，1
H)，3.39(d，J＝4.2Hz，1H)，2.89(d，J＝5.1Hz，1H)，2.85(d，J＝5.1Hz，
1H)，2.81-2.72(m，1H)，2.39-2.27(m，1H)，2.17(dt，J＝10.2，4.2Hz，1
H)，2.11-1.94(m，1H)，1.94-1.81(m，2H)，1.47-1.29(m，2H)，0.96(s，3
H)，0.89(d，J＝6.9Hz，3H)，0.77(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，
100MHz)δ173.2(Cq)，161.6(Cq)，125.4(Cq)，70.8(CH
2)，65.9(Cq)，
64.6(Cq)，58.3(Cq)，57.2(CH)，56.2(CH)，55.9(Cq)，54.7(CH)，48.2
(CH
2)，36.9(CH)，36.1(Cq)，28.4(CH
2)，26.9(CH
2)，23.0(CH)，21.7
(CH
3)，20.2(CH
3)，17.3(CH
3)，16.6(CH
2)；IR(KBr)3433，2947，2929，
1768，1755，1689，1442，1029cm
-1；MS(EI，70eV)m/z(％)372(M
+，1)，
357(9)，343(18)，325(34)，259(100)；HRMS(EI)calcd for C
21H
24O
6
372.1573，found 372.1586；[α]
D 20-156(c 0.135，CHCl
3)；mp 177-179℃.
Embodiment 4 (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67)
With (14S)-14 β-methylol Epitriptolide (LLDT-62) (0.50g, 1.3mmol) Be dissolved in the dry pyridine (4.0mL). Be added dropwise to MsCl (0.61 after this solution is cooled to 0 ℃ ML, 7.7mmol). Stirring reaction 10min under the room temperature, decompression steams solvent. Residue adds water Dilution, ethyl acetate extraction, organic layer water, saturated common salt water washing, anhydrous sodium sulfate is done Dry. Concentrate the thick product of gained through column chromatography purification (eluant, eluent: ethyl acetate: cyclohexane=1: 2) obtain One colorless oil (14S)-14-C-methylsulfonyl oxygen methyl Epitriptolide (LLDT-80) (0.390g, 0.85mmol, productive rate: 65%).
(14S)-14-C-methylsulfonyl oxygen methyl Epitriptolide (LLDT-80) (0.504g, 1.1mmol) is dissolved in the 20mL methanol solvate, adds K2CO
3(1.33g, 9.6mmol). Reduce pressure behind the stirring reaction 20min under the room temperature and steam solvent, residue thin up, ethyl acetate Extraction, saturated common salt water washing, anhydrous sodium sulfate drying. Thick product is through column chromatography purification (wash-out Agent: ethyl acetate: cyclohexane=1: 5) obtain white solid (14S)-14-dehydroxylation-14,21-epoxy thunder Public rattan lactone alcohol (LLDT-67) (307mg, 0.82mmol, productive rate: 75%).
(14S)-14-C-methylsulfonyl oxygen methyl Epitriptolide (LLDT-80):
1H-NMR(CDCl
3，300MHz)δ4.71-4.57(m，4H)，3.80(d，J＝3.2Hz，
1H)，3.77(d，J＝5.6Hz，1H)，3.47(d，J＝3.0Hz，1H)，3.10(s，3H)，
2.78-2.67(m，1H)，2.54(sept，J＝6.9Hz，1H)，2.37-2.26(m，1H)，
2.25-2.06(m，1H)，1.91(dd，J＝14.8，13.4Hz，1H)，1.59-1.51(m，1H)，
1.28-1.13(m，2H)，1.07(s，3H)，0.92(d，J＝8.2Hz，3H)，0.89(d，J＝8.2
Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.2(Cq)，160.1(Cq)，125.4
(Cq)，74.5(Cq)，72.0(CH
2)，69.9(CH
2)，67.8(Cq)，65.1(Cq)，63.3(Cq)，
55.9(CH)，55.4(CH)，54.0(CH)，40.5(CH)，37.5(CH)，36.0(Cq)，29.7
(CH
2)，25.6(CH
3)，23.5(CH
2)，20.5(CH
3)，18.5(CH
3)，17.1(CH
2)，13.5
(CH
3)；IR(KBr)3483，3024，2972，2937，1749，1674，1446，1354，1174
cm
-1；MS(EI，70eV)m/z(％)468(M
+)，450(3)，432(1)，407(1)，354(17)，
111(100)；HRMS(EI)calcd for C
22H
28SO
9 468.1454，found 468.1457；
[α]
D 23-114(c 0.530，Acetone).
Embodiment 5 (5R, 14S)-5 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-68) and (14S)-Δ5，6-dehydrogenation-14-dehydroxylation-14,21-epoxy triptolide (LLDT-70)
With (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) is dissolved in 8mL Isosorbide-5-Nitrae-dioxane, adds SeO2(111mg, 1.0mmol). Reaction system is at the backflow shape React 24h under the attitude, stop subsequently reaction, reaction system is cooled to room temperature, diatomite filtration, Ethyl acetate washing filter residue, removal of solvent under reduced pressure. Residue ethyl acetate and saturated sodium carbonate Solution-treated, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying. After concentrating Thick product through column chromatography purification (eluant, eluent: CH2Cl
2) obtain white solid (5R, 14S)-5-hydroxyl-14-dehydroxylation-14, and 21-epoxy triptolide (LLDT-68) (38.8mg, 0.1mmol, productive rate: 50%) and (14S)-Δ5，6-dehydrogenation-14-dehydroxylation-14,21-epoxy triptolide (LLDT-70) (7.4mg, 0.02mmol, productive rate: 10%).
(5R, 14S)-5 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-68):
1H-NMR(CDCl
3，300MHz)δ4.92(dt，J＝17.1，3.1Hz，1H)，4.71
(dd，J＝17.1，1.5Hz，1H)，3.92(d，J＝3.3Hz，1H)，3.63(d，J＝3.3Hz，1
H)，3.40(d，J＝4.7Hz，1H)，2.86(d，J＝5.1Hz，1H)，2.79(d，J＝5.1Hz，
1H)，2.41-2.06(m，4H)，1.95-1.74(m，2H)，1.29(dd，J＝12.7，4.9Hz，1
H)，1.12(s，3H)，0.87(d，J＝6.9Hz，3H)，0.84(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.2(Cq)，159.0(Cq)，128.0(Cq)，72.3
(Cq)，68.7(CH
2)，65.8(Cq)，63.2(Cq)，58.4(Cq)，56.4(CH)，55.5(Cq)，
55.0(CH)，54.5(CH)，48.0(Cq)，40.6(Cq)，31.0(CH
2)，24.6(CH
2)，23.4
(CH)，19.7(CH
3)，17.8(CH
3)，17.4(CH
2)，16.2(CH
3)；IR(KBr)3479，
2956，1736，1668，1442，1037cm
-1；MS(EI，70eV)m/z(％)389([M+1]
+，
2)，373(2)，359(100)，341(18)；HRMS(EI)calcd for C
21H
25O
7 389.1601，
found 389.1606；[α]
D 20-120(c 0.223，CHCl
3)；mp 233-235℃.
(14S)-Δ
5，6Dehydrogenation-14-dehydroxylation-14,21-epoxy triptolide (LLDT-70):
1H-NMR(CDCl
3，300MHz)δ6.03(d，J＝4.1Hz，1H)，4.95(d，J＝
16.0Hz，1H)，4.83(dd，J＝16.0，2.5Hz，1H)，3.86(d，J＝3Hz，1H)，
3.56-3.48(m，2H)，2.92(d，J＝4.9Hz，1H)，2.87(d，J＝4.9Hz，1H)，
2.51-2.39(m，1H)，2.37-2.20(m，1H)，1.90(sept.，J＝6.9Hz，1H)，
1.52-1.34(m，2H)，1.29(s，3H)，0.92(d，J＝6.9Hz，3H)，0.78(d，J＝6.9
Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.0(Cq)，153.1(Cq)，140.4
(Cq)，126.9(Cq)，121.8(CH)，68.9(CH
2)，65.1(Cq)，64.4(Cq)，61.3(Cq)，
56.6(CH)，55.8(Cq)，54.2(CH)，53.7(CH)，48.4(CH
2)，37.2(Cq)，30.3
(CH
2)，23.1(CH)，22.8(CH
3)，20.3(CH
3)，17.2(CH
3)，17.1(CH
2)；IR(KBr)
3433，2979，2927，1747，1657，1358，1024cm
-1；MS(EI，70eV)m/z(％)
370(M
+，13)，355(22)，341(91)，327(95)，115(100)；HRMS(EI)calcd for
C
21H
22O
6 370.1416，found 370.1404；[α]
D 20-443(c 0.174，Acetone)；mp
205-207℃.
Embodiment 6 (14S)-14 Beta-methyl Epitriptolide (LLDT-71)
Under argon shield, the 10mL absolute ether is added in magnesium chips (264mg, the 11.0mmol) reaction bulb, will be dissolved in the CH of 5mL dry ether3I is added drop-wise to the reaction body through constant pressure funnel In the system. Finish this lead reaction system and at room temperature stir 30min. Getting 1.37mL should be new The CH of bright preparation3MgI grignard reagent solution, dropwise adding has been dissolved in the dry tetrahydrochysene furan of 8mL In the triptonide of muttering (LLDT-1) (90mg, 0.25mmol). After reacting 1.5h under the room temperature Stop reaction, reaction system saturated ammonium chloride solution cancellation, ethyl acetate extraction, organic layer Use the saturated common salt water washing, anhydrous sodium sulfate drying, the thick product after concentrating (is washed through column chromatography purification Take off agent: ethyl acetate: cyclohexane=1: 4) obtain white solid (14S)-14 Beta-methyl table Triptolide Alcohol (LLDT-71) (70mg, 0.19mmol, productive rate: 73%).
1H-NMR(CDCl
3，300MHz)δ4.66(s，2H)，3.75(d，J＝3.2Hz，1H)，
3.74(s，1H)，3.42(d，J＝3.2Hz，1H)，2.75-2.63(m，1H)，2.47(sept.，J＝
6.9Hz，1H)，2.34-2.22(m，1H)，2.21-2.03(m，2H)，1.85(t，J＝14.1Hz，1
H)，1.58-1.48(m，4H)，1.24-1.10(m，1H)，1.03(s，3H)，0.94(d，J＝6.9
Hz，3H)，0.79(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.4
(Cq)，160.7(Cq)，125.2(Cq)，74.3(Cq)，70.0(CH
2)，68.8(Cq)，64.9(Cq)，
64.2(Cq)，57.1(CH)，55.1(CH)，54.2(CH)，40.4(CH)，36.0(Cq)，29.7
(CH
2)，25.5(CH)，24.3(CH)，23.8(CH
2)，21.4(CH
3)，18.3(CH
3)，17.1
(CH
2)，13.5(CH
3)；IR(KBr)3506，2964，2875，1765，1678，1441，1375，
1026cm
-1；MS(EI，70eV)m/z(％)375([M+1]
+’5)，357(7)，345(8)，331
(47)，71(100)；HRMS(EI)calcd for C
21H
27O
6 375.1808，found 375.1824；
[α]
D 20-79(c 0.080，CHCl
3)；mp 227-228℃.
Embodiment 714-dehydroxylation-14-methylene triptolide (LLDT-72)
Et with MsCl (0.18mL, 2.2mmol), drying3N (2.17mL, 15.6mmol) and dry pyridine (2.4mL, 29.6mmol) add the CH of 7mL drying successively2Cl
2In the solvent. Under the room temperature, with (14S)-14 Beta-methyl Epitriptolides (LLDT-71) (130mg, 0.35 Mmol) be dissolved in the CH of 5mL drying2Cl
2In, add in the above-mentioned reaction system, stir Drip trifluoroacetic anhydride (TFAA) (0.24mL, 1.7mmol) to this reaction system down, under the room temperature behind the reaction 2h Add the water stopped reaction. Removal of solvent under reduced pressure, the residue ethyl acetate extraction, the organic layer water, The saturated common salt water washing, anhydrous sodium sulfate drying. Thick product after concentrating (is washed through column chromatography purification Take off agent: ethyl acetate: cyclohexane=1: 5) obtain faint yellow solid 14-dehydroxylation-14-methylene Thunder God Rattan lactone alcohol (LLDT-72) (102mg, 0.29mmol, productive rate: 82%).
1H-NMR(CDCl
3，300MHz)δ5.56(s，1H)，5.36(s，1H)，4.67(s，2
H)，3.85(d，J＝3.2Hz，1H)，3.54(d，J＝3.2Hz，1H)，3.07(d，J＝5.3Hz，
1H)，2.82-2.70(m，1H)，2.44(sept.，J＝6.6Hz，1H)，2.35-2.23(m，1H)，
2.22-2.03(m，2H)，1.92(t，J＝13.8Hz，1H)，1.55(dd，J＝12.5，4.5Hz，1
H)，1.31-1.14(m，1H)，1.09(s，3H)，0.95(d，J＝6.6Hz，3H)，0.86(d，J＝
6.6Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.3(Cq)，160.4(Cq)，140.5
(Cq)，125.3(Cq)，116.2(CH
2)，70.0(CH
2)，64.7(Cq)，64.4(Cq)，63.1(CH)，
60.0(Cq)，56.2(CH)，55.3(CH)，40.4(CH)，35.6(Cq)，30.3(CH
2)，27.0
(CH)，23.9(CH
2)，18.7(CH
3)，17.1(CH
2)，16.9(CH
3)，13.7(CH
3)；IR(KBr)
3473，3033，2979，2945，2873，1751，1678，1633，1439，1390，1350，1072，
1016cm
-1；MS(EI，70eV)m/z(％)355([M-1]
+，7)，341(6)，328(21)，327
(100)；HRMS(EI)calcd for C
21H
23O
5 355.1546，found 355.1545；[α]
D 20
-106.1(c 0.555，CHCl
3)；mp 227-229℃.
Embodiment 8 (14S)-14 β-vinyl Epitriptolide (LLDT-65)
Triptonide (LLDT-1) (650mg, 1.8mmol) is dissolved in 16mL anhydrous four In the hydrogen furans, add 3.3mL vinyl bromination magnesium RMgBr (1M in 0 ℃ under the argon shield THF solution, 1.8mmol), under this temperature, react 3h, the saturated ammonium chloride solution cancellation is anti-Should, ethyl acetate extraction, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying, Thick product after concentrating is through column chromatography purification (eluant, eluent: ethyl acetate: cyclohexane=1: 2) obtain white Solid (14S)-14 β-vinyl Epitriptolide (LLDT-65) (286mg, 0.74mmol, Productive rate: 41%).
1H-NMR(CDCl
3，300MHz)δ6.47(dd，J＝17.6，11.1Hz，1H)，5.32
(dd，J＝16.8，11.1Hz，2H)，4.67(s，2H)，3.81(d，J＝3.2Hz，1H)，3.75(d，
J＝5.8Hz，1H)，3.48(d，J＝3.2Hz，1H)，2.78-2.66(m，1H)，2.46-2.24
(m，2H)，2.23-2.04(m，2H)，1.89(t，J＝14.7Hz，1H)，1.57(dd，J＝12.5，
4.2Hz，1H)，1.29-1.13(m，1H)，1.06(s，3H)，0.87(d，J＝6.9Hz，3H)，
0.82(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.3(Cq)，160.4
(Cq)，139.0(CH)，125.4(Cq)，115.1(CH
2)，77.0(Cq)，70.0(CH
2)，67.8
(Cq)，65.0(Cq)，63.5(Cq)，56.8(CH)，55.2(CH)，54.4(CH)，40.4(CH)，
36.1(Cq)，29.7(CH
2)，25.1(CH)，23.8(CH
2)，21.2(CH
3)，18.2(CH
3)，17.1
(CH
2)，13.4(CH
3)；IR(KBr)3467，2968，2933，2873，1751，1674，1442，
13851171，1020cm
-1；MS(EI，70eV)m/z(％)387([M+1]
+，1)，343(13)，
325(17)，297(100)；HRMS(EI)calcd for C
22H
26O
6 386.1730，found
386.1724；[α]
D 22-104.8(c 0.356，CHCl
3)；mp 191-193℃.
Embodiment 9 (14S)-14 β-vinyl Epitriptolide (LLDT-65) and (12S, 13S, 14S)-12 Alpha-hydroxy-13 α, 14 α-epoxy-14 β-vinyl Epitriptolide (LLDT-73)
Triptonide (LLDT-1) (650mg, 1.8mmol) is dissolved in 16mL anhydrous four In the hydrogen furans, argon shield adds 3.3mL vinyl bromination magnesium RMgBr (1M under room temperature THF solution, stirring reaction 2h 1.8mmol) and under room temperature, it is molten to add saturated ammonium chloride The liquid stopped reaction, ethyl acetate extraction, organic layer water, saturated common salt water washing, anhydrous sulphur Acid sodium drying, the thick product after concentrating is through column chromatography purification (eluant, eluent: ethyl acetate: cyclohexane=1: 2) obtain white solid (14S)-14 β-vinyl Epitriptolide (LLDT-65) (201 Mg, 0.52mmol, productive rate: 29%) and (12S, 13S, 14S)-12 Alpha-hydroxy-13 α, 14 α-epoxy-14 β-Vinyl Epitriptolide (LLDT-73) (139mg, 0.36mg, productive rate: 20%).
(12S, 13S, 14S)-12 Alpha-hydroxy-13 α, 14 α-epoxy-14 β-ethene base table triptolide (LLDT-73):
1H-NMR(CDCl
3，300MHz)δ5.88(dd，J＝17.1，10.8Hz，1H)，5.32(dd，J＝10.8，1.8Hz，1H)，5.25(dd，J＝17.1，2.1Hz，1H)，4.69(s，2H)，4.39(dd，J＝10.8，1.8Hz，1H)，3.49(d，J＝2.7Hz，1H)，3.42(d，J＝5.7Hz，1H)，2.65-2.54(m，1H)，2.41-2.27(m，1H)，2.21-1.90(m，3H)，1.69-1.55(m，1H)，1.74(sept.，J＝7.2Hz，1H)，1.36-1.23(m，1H)，1.09(d，J＝7.2Hz，3H)，1.07(s，3H)，0.87(d，J＝7.2Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.3(Cq)，160.0(Cq)，129.3(CH)，125.5(Cq)，119.4(CH
2)，70.3(Cq)，70.0(CH
2)，68.4(Cq)，61.3(CH)，60.8(Cq)，58.0(CH)，57.7(Cq)，55.3(CH)，40.2(CH)，35.0(Cq)，30.9(CH
2)，29.3(CH)，22.4(CH
2)，17.6(CH
3)，17.4(CH
3)，17.1(CH
2)，13.9(CH
3)；IR(KBr)3458，2966，2931，2873，1743，1676，1444，1390，1066，1022cm
-1；MS(EI，70eV)m/z(％)386(M
+，3)，371(4)，357(5)，339(8)，55(100)；HRMS(EI)calcd?forC
22H
26O
6?386.1729，found?386.1738；[α]
D 25-69(c?0.265，Acetone)；mp199-200℃.
Embodiment 10 (14S, 21R)-14 β-oxa-cyclopropyl table triptolide (LLDT-74) and (14S, 21S)-14 β-oxa-cyclopropyl table triptolide (LLDT-75)
(97mg 0.25mmol) is dissolved in 10mL CH with (14S)-14 β-ethene base table triptolide (LLDT-65)
2Cl
2In, add Na successively
2HPO
412H
2O (450mg, 1.3mmol) and m-CPBA (70-75%, 339mg, 2.0mmol).Reaction system is at room temperature reacted and is added the cancellation of saturated sodium thiosulfate solution behind the 36h, uses CH after adding water treatment
2Cl
2Extraction, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying, thick product after concentrating through column chromatography purification (eluent: chloroform) obtain white solid (14S, 21R)-14 β-oxa-cyclopropyl table triptolide (LLDT-74) (32.2mg, 0.08mmol, 32%) and (14S productive rate:, 21S)-14 β-oxa-cyclopropyl table triptolide (LLDT-75) (26.1mg, 0.065mmol, productive rate: 26%).
(14S, 21R)-14 β-oxa-cyclopropyl table triptolide (LLDT-74):
1H-NMR(CDCl
3，300MHz)δ4.67(s，2H)，3.84(d，J＝3.0Hz，1H)，3.70(d，J＝5.7Hz，1H)，3.61(dd，J＝4.2，3.0Hz，1H)，3.52(d，J＝3.0Hz，1H)，2.96(dd，J＝4.5，2.7Hz，1H)，2.85(t，J＝4.2Hz，1H)，2.78-2.66(m，1H)，2.47-2.23(m，2H)，2.21-2.04(m，2H)，1.84(t，J＝13.5Hz，1H)，1.55(dd，J＝12.3，5.4Hz，1H)，1.29-1.14(m，1H)，1.06(s，3H)，1.00(d，J＝6.9Hz，3H)，0.87(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.3(Cq)，160.4(Cq)，125.3(Cq)，71.8(Cq)，70.0(CH
2)，69.3(Cq)，65.6(Cq)，62.9(Cq)，55.6(CH)，55.3(CH)，54.2(CH)，53.6(CH)，43.9(CH
2)，40.5(CH)，36.0(Cq)，30.1(CH
2)，25.5(CH)，23.5(CH
2)，20.6(CH
3)，18.2(CH
3)，17.1(CH
2)，13.6(CH
3)；IR(KBr)3411，2964，2929，2875，1751，1680，1448，1248，1026cm
-1；MS(EI，70eV)m/z(％)402(M
+，3)，385(1)，360(6)，71(100)；HRMS(EI)calcd?for?C
22H
26O
7?402.1679，found?402.1685；[α]
D 23-98.2(c?0.450，Acetone)；mp?256-258℃.
(14S, 21S)-14 β-oxa-cyclopropyl table triptolide (LLDT-75):
1H-NMR(CDCl
3，300MHz)δ4.67(s，2H)，3.91(dd，J＝3.9，3.0Hz，1H)，3.84(d，J＝3.3Hz，1H)，3.63(d，J＝5.7Hz，1H)，3.47(d，J＝3.3Hz，1H)，2.79(dd，J＝3.0，2.7Hz，1H)，2.76-2.72(m，1H)，2.70(t，J＝3.9Hz，1H)，2.42-2.24(m，2H)，2.22-2.04(m，2H)，1.90(t，J＝14.1Hz)，1.58(dd，J＝12.6，5.7Hz，1H)，1.26-1.13(m，1H)，1.12(s，3H)，0.93(d，J＝6.9Hz，3H)，0.78(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.3(Cq)，160.3(Cq)，125.4(Cq)，72.8(Cq)，69.9(CH
2)，66.3(Cq)，65.5(Cq)，63.5(Cq)，55.1(CH)，55.0(CH)，53.5(CH)，52.8(CH)，42.0(CH
2)，40.5(CH)，36.2(Cq)，29.7(CH
2)，25.1(CH)，23.6(CH
2)，20.7(CH
3)，17.8(CH
3)，17.1(CH
2)，13.5(CH
3)；IR(KBr)3464，2929，2252，1751，1674，1446，1390，1090，1026cm
-1；MS(EI，70eV)m/z(％)403([M+1]
+，5)，402(M
+，1)，387(3)，359(32)，71(100)；HRMS(EI)calcd?for?C
22H
26O
7402.1679，found?402.1696；[α]
D 25-116.7(c?0.85，Acetone)；mp?165-167℃.
Embodiment 11 (12R, 13R, 14S)-and 12 β-chloro-13 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-76)
With (14S)-14-dehydroxylation-14,21-epoxy triptolide (LLDT-67) is dissolved in the 6mL acetone, and adding 6mL hydrochloric acid soln (1.67%, 2.7mmol).Mixture reacts 7h under reflux state.Decompression steams gained residue water treatment behind the solvent, ethyl acetate extraction, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying, the thick product after concentrating is through column chromatography purification (eluent: ethyl acetate: hexanaphthene=1: 3) obtain white solid (12R, 13R, 14S)-12 β-chloro-13 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide (LLDT-76) (17.5mg, 0.043mmol, productive rate: 39%).
1H-NMR(CDCl
3，300MHz)δ4.69(s，2H)，4.16(d，J＝5.4Hz，1H)，3.75(d，J＝5.7Hz，1H)，3.46(d，J＝6.0Hz，1H)，2.90(d，J＝4.9Hz，1H)，2.94-2.83(m，1H)，2.78(d，J＝4.9Hz，1H)，2.36-2.25(m，1H)，2.21-2.04(m，2H)，1.94-1.74(m，2H)，1.59(dd，J＝12.5，5.1Hz，1H)，1.35-1.21(m，1H)，1.03(s，3H)，0.99(d，J＝2.3Hz，3H)，0.96(d，J＝2.3Hz，3H)；
13C-NMR(Acetone-d
6，100MHz)δ173.7(Cq)，162.2(Cq)，124.6(Cq)，76.6(Cq)，70.7(CH
2)，69.9(Cq)，60.3(CH)，59.8(Cq)，58.3(CH)，58.2(Cq)，58.2(CH)，48.0(CH
2)，40.2(CH)，35.8(Cq)，31.3(CH
2)，28.8(CH)，23.1(CH
2)，18.0(CH
3)，17.4(CH
2)，16.3(CH
3)，13.9(CH
3)；IR(KBr)3462，2933，2252，1743，1674，1439，1003cm
-1；MS(EI，70eV)m/z(％)408(M
+，9)，390(3)，373(8)，365(100)；HRMS(EI)calcd?forC
21H
25ClO
6?408.1339，found?408.1339；[α]
D 25-97.9(c?1.15，Acetone)；mp174-175℃.
Embodiment 12 (14S, sulphur S)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-77) and (14S, sulphur R)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-78)
(14S)-14 β-methylol table triptolide (LLDT-62) is dissolved in the anhydrous CH of 6mL
2Cl
2In, drip exsiccant Et
3N (0.21mL, 1.6mmol).Reaction system is cooled to 0 ℃, under argon shield with SOCl
2(0.3mL 1.2mmol) carefully adds in the reaction system, behind the stirring reaction 2h, adds the entry stopped reaction, CH
2Cl
2Extraction, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying, the thick product after concentrating is through column chromatographic isolation and purification (eluent: ethyl acetate: hexanaphthene=1: 5) obtain white solid (14S, sulphur S)-14 α, 43%) and (14S 21-ethylene glycol cyclic sulfite triptolide (LLDT-77) (39.2mg, 0.09mmol, productive rate:, sulphur R)-14,21-ethylene glycol cyclic sulfite triptolide (LLDT-78) (30.5mg, 0.07mmol, productive rate: 36%).
(14S, sulphur S)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-77):
1H-NMR(CDCl
3，300MHz)δ4.93(d，J＝9.6Hz，1H)，4.68(s，2H)，4.58(d，J＝9.6Hz，1H)，3.84(d，J＝3.0Hz，1H)，3.71(d，J＝5.4Hz，1H)，3.61(d，J＝3.0Hz，1H)，2.78-2.67(m，1H)，2.61(sept.，J＝6.9Hz，1H)，2.38-2.26(m，1H)，2.25-2.04(m，2H)，1.91(t，J＝14.4Hz，1H)，1.54(dd，J＝12.3，4.5Hz，1H)，1.28-1.13(m，1H)，1.07(s，3H)，0.95(d，J＝6.9Hz，3H)，0.93(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.1(Cq)，159.8(Cq)，125.5(Cq)，91.9(Cq)，74.1(CH
2)，69.9(CH
2)，65.1(Cq)，64.9(Cq)，61.7(Cq)，56.5(CH)，55.6(CH)，55.5(CH)，40.4(CH)，35.8(Cq)，30.0(CH
2)，25.7(CH)，23.3(CH
2)，20.6(CH
3)，18.7(CH
3)，17.1(CH
2)，13.5(CH
3)；IR(KBr)3475，2972，2933，2875，1745，1680，1441，1219，1018cm
-1；MS(EI，70eV)m/z(％)436(M
+，2)，407(1)，393(6)，241(100)；HRMS(EI)calcd?for?C
21H
24SO
8?436.1192，found?436.1199；[α]
D 25-97.0(c?0.400，Acetone)；mp?269-271℃.
(14S, sulphur R)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-78):
1H-NMR(CDCl
3，300MHz)δ4.80(d，J＝9.6Hz，1H)，4.68(s，2H)，4.58(d，J＝9.6Hz，1H)，3.84(d，J＝3.2Hz，1H)，3.79(d，J＝5.4Hz，1H)，3.53(d，J＝3.2Hz，1H)，2.80-2.68(m，1H)，2.38-2.26(m，1H)，2.25-2.01(m，3H)，1.96(t，J＝14.4Hz，1H)，1.54(dd，J＝12.6，5.1Hz，1H)，1.28-1.15(m，1H)，1.09(s，3H)，0.92(d，J＝6.9Hz，3H)，0.90(d，J＝6.9Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ173.1(Cq)，159.9(Cq)，125.3(Cq)，92.5(Cq)，74.1(CH
2)，69.9(CH
2)，66.5(Cq)，65.0(Cq)，61.0(Cq)，58.3(CH)，55.4(CH)，54.7(CH)，40.4(CH)，35.7(Cq)，30.2(CH
2)，25.7(CH)，23.3(CH
2)，20.5(CH
3)，18.2(CH
3)，17.0(CH
2)，13.4(CH
3)；IR(KBr)3435，2970，2933，2877，2254，1755，1674，1444，1346，1223，1020cm
-1；MS(EI，70eV)m/z(％)436(M
+，7)，421(9)，71(100)；HRMS(EI)calcd?for?C
21H
24SO
8?436.1192，found?436.1182；[α]
D 25-96.9(c?0.425，Acetone)；mp?160-162℃.
Embodiment 13 (14S)-14 α, 21-ethylene glycol epithio acid esters triptolide (LLDT-79)
With (14S, sulphur S)-14 α, 21-ethylene glycol cyclic sulfite triptolide (LLDT-77) or (14S, sulphur R)-14 α, (40mg 0.092mmol) is dissolved in the 4mL acetonitrile 21-ethylene glycol cyclic sulfite triptolide (LLDT-78), adds sodium periodate (31mg successively, 0.14mmol), RuCl
33H
2O (6mg, 0.028mmol) and 1mL water, stirring reaction 15min under the room temperature, decompression steams solvent, uses ethyl acetate extraction behind the enriched material dilute with water, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, the thick product after concentrating is through column chromatography purification (eluent: ethyl acetate: hexanaphthene=1: 4) obtain white solid (14S)-14 α, 21-ethylene glycol epithio acid esters triptolide (LLDT-79) (36mg, 0.079mmol, productive rate: 86%).
1H-NMR(CDCl
3，300MHz)δ4.92(d，J＝10.2Hz，1H)，4.74-2.63(m，3H)，3.87(d，J＝2.8Hz，1H)，3.83(d，J＝5.4Hz，1H)，3.65(d，J＝2.8Hz，1H)，2.79-2.68(m，1H)，2.51(sept.，J＝6.6Hz，1H)，2.39-2.06(m，3H)，1.98(t，J＝13.8Hz，1H)，1.53(dd，J＝12.2，5.1Hz，1H)，1.29-1.13(m，1H)，1.09(s，3H)，0.99(d，J＝6.6Hz，3H)，0.97(d，J＝6.6Hz，3H)；
13C-NMR(CDCl
3，100MHz)δ172.9(Cq)，159.4(Cq)，125.6(Cq)，91.3(Cq)，73.4(CH
2)，69.9(CH
2)，66.3(Cq)，65.2(Cq)，61.9(Cq)，58.3(CH)，55.7(CH)，55.5(CH)，40.3(CH)，35.7(Cq)，30.2(CH
2)，25.5(CH)，23.2(CH
2)，20.4(CH
3)，18.3(CH
3)，17.0(CH
2)，13.4(CH
3)；IR(KBr)3442，2970，2941，1749，1676，1441，1394，1217，1001cm
-1；MS(EI，70eV)m/z(％)452(M
+，8)，437(10)，423(10)，111(100)；HRMS(EI)calcd?forC
21H
24SO
9?452.1141，found?452.1169；[α]
D 23-107(c?0.275，CHCl
3)；mp205-207℃.
Pharmacodynamics evaluation test example
Below the test example in, given the test agent is provided by chemosynthesis embodiment of the present invention, with lead compound triptolide (LLDT-2) as positive control.
Test example 1 15 compounds of the present invention are to the growth-inhibiting effect of the human ovarian cancer SK-OV-3 cell of vitro culture.
Method:
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
2Tumour cell 0.7 * 10
4/ hole is inoculated in the 96-orifice plate, and after 24 hours, adding stock solution is dimethyl sulfoxide (DMSO) preparation (10
-2M), each compound of physiological saline dilution, make that final concentration is 10 in the substratum
-4, 10
-5, 10
-6, 10
-7, 10
-8M acts on 72 hours.Discard nutrient solution, with 10% cold Tricholroacetic Acid fixed cell.With sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed.Flush away is not in conjunction with behind the SRB, and Tris dissolves and protein bound SRB, and 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
Dosing holes)/OD value
Control wells* 100%.Criterion as a result: invalid: 10
-5M＜50%; Effectively: 10
-5M 〉=50%.
The result
In 15 compounds of the present invention, 11 compound L LDT-65, LLDT-67, LLDT-68, LLDT-69, LLDT-70, LLDT-71, LLDT-72, LLDT-74, LLDT-75, LLDT-76, LLDT-78 dose-dependently ground suppress the human ovarian cancer SK-OV-3 cell growth of vitro culture, show that it has effective extracorporeal anti-tumor function.Concrete outcome sees Table 1 and accompanying drawing 1.
Table 1. compound is to the growth-inhibiting effect of human ovarian cancer SK-OV-3 cell.
Test example 2 15 compounds of the present invention are to the growth-inhibiting effect of the human breast carcinoma MDA-MB-468 cell of vitro culture.
Method:
Human breast carcinoma MDA-MB-468 cell is cultivated with 1640 substratum (Gibco, the U.S.) that contain 10% foetal calf serum, and culture condition is 37 ℃, 5%CO2.Tumour cell 0.7 * 104/ hole is inoculated in the 96-orifice plate, after 24 hours, the compound that adding is diluted with dimethyl sulfoxide (DMSO) preparation (10-2M), physiological saline, the final concentration that makes each compound in the substratum is 10-4,10-5,10-6,10-7,10-8M, acts on 72 hours.Discard nutrient solution, with 10% cold Tricholroacetic Acid fixed cell.With sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed.Flush away is not in conjunction with SRB, and Tris dissolving and protein bound SRB are measured the OD value with microplate reader under the 560nm wavelength.Calculate inhibitory rate of cell growth by following formula: inhibiting rate=(OD value control wells-OD value dosing holes)/OD value control wells * 100%.Criterion as a result: invalid: 10
-5M＜50%; Effectively: 10
-5M 〉=50%.
The result
In 15 compounds of the present invention, 9 compound L LDT-65, LLDT-67, LLDT-68, LLDT-69, LLDT-70, LLDT-72, LLDT-74, LLDT-75, LLDT-76 dose-dependently ground suppress the growth of the human breast carcinoma MDA-MB-468 tumour cell of vitro culture, show that it has the effective antitumour effect.Concrete outcome sees Table 2 and accompanying drawing 2.
Table 2. compound is to the effect of human breast carcinoma MDA-MB-468 cells in vitro growth-inhibiting.
Test example 3 15 compounds of the present invention are to the growth-inhibiting effect of the human prostata cancer PC-3 cell of vitro culture.
Method:
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%CO2.Tumour cell 0.7 * 104/ hole is inoculated in the 96-orifice plate, after 24 hours, the compound that adding is diluted with dimethyl sulfoxide (DMSO) preparation (10-2M), physiological saline, the final concentration that makes each compound in the substratum is 10-4,10-5,10-6,10-7,10-8M, acts on 72 hours.Discard nutrient solution, with 10% cold Tricholroacetic Acid fixed cell.With sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed.Flush away is not in conjunction with SRB, and Tris dissolving and protein bound SRB are measured the OD value with microplate reader under the 560nm wavelength.Calculate inhibitory rate of cell growth in order to following formula at last: inhibiting rate=(OD value control wells-OD value dosing holes)/OD value control wells * 100%.Criterion as a result: invalid: 10
-5M＜50%; Effectively: 10
-5M 〉=50%.
The result
In 15 compounds of the present invention, 11 compound L LDT-65, LLDT-67, LLDT-68, LLDT-69, LLDT-70, LLDT-71, LLDT-72, LLDT-74, LLDT-75, LLDT-76, LLDT-78 dose-dependently ground suppress the growth of the human prostata cancer PC-3 tumour cell of vitro culture, point out them may have antitumor action.Concrete outcome sees Table 3 and accompanying drawing 3.
Table 3. compound is to the growth-inhibiting effect of human prostata cancer PC-3 cell.
The present invention carries out the chemical structure modification and transforms the tripterygium wilfordii diterpenes diterpenoids lactones derivative that has obtained to have brand-new chemical structure the C-14 functional group of Triptonide emphatically.Existing structure activity study shows that the C-14-β hydroxyl of triptolide is active essential group, and the tripterygium wilfordii diterpenes diterpenoids lactones derivative overwhelming majority who does not contain free C-14-β hydroxyl that the present invention obtained has still kept good tumors inhibition activity, can obviously suppress the growth of the tumour cell of multiple vitro culture, comprise growth-inhibiting to human ovarian cancer SK-OV-3 cell, to the growth-inhibiting of human breast carcinoma MDA-MB-468 cell and to the growth-inhibiting of human prostata cancer PC-3 cell etc., and restraining effect has tangible dose-dependently, shows that above-claimed cpd has good research and using value to broad variety tumour especially genital system tumor.
Synthetic embodiment of above compound and pharmacodynamics evaluation test example only are structure and synthetic method 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 scope of the invention.
The possibility of utilizing on the industry
The present invention provides novel tripterygium wilfordii diterpenes diterpenoids lactones take triptonide as starting material Derivative and relevant synthetic method.
Tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention is except the small part compound swells at In Vitro Anti Outside invalid in the knurl experiment, other compound all can obviously suppress the tumour cell of multiple in vitro culture Growth, inhibitory action has obvious dose dependent, shows that above-claimed cpd is to multiple types The type tumour is all effective.
Tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention can be used for preparation and prevents and/or treats tumour Deng the medicine of proliferative disease, have good being used for the treatment of comprise prostate cancer, HOC, The breast cancer of breast cancer, liver cancer, granulocytic leukemia, colon cancer, adriamycin sensitivity, Ah The application prospect of the tumour of the proliferative diseases such as breast cancer of the anti-medicine of mycin.
Claims (10)
1, tripterygium wilfordii diterpenes diterpenoids lactones derivative, its optical isomer and pharmacy acceptable salt and hydrate shown in the formula (1):
C wherein
5And C
6Link to each other with carbon-carbon single bond or carbon-carbon double bond;
Work as C
5And C
6When linking to each other with carbon-carbon single bond, P and Q represent to be connected C respectively
5Position and C
6Hydrogen on the position, oxygen, hydroxyl, halogen, sulfydryl, C1～C6 alkoxyl group, C1～C6 alkylamino radical or C1～C6 alkane sulfydryl;
Work as C
5And C
6When linking to each other with carbon-carbon double bond, this moment C
5Remove and C
4, C
6And C
10Connect outer other substituted radicals that do not have, P does not represent any substituted radical, C
6Substituting group Q then only represents hydrogen atom on the position;
C
14XY represents C
14The structure at place, position is
C
14=CH
2, C
14(OH) CH=CH
2, C
14(OH) CH
2OH, C
14(OH) CH
3,
C
14(OH) CH (OH) CH
2OH,
Or C
14(O) CH=CH
2
W and Z represent to be connected C respectively
12Position and C
13Oxygen on the position, hydroxyl, halogen, sulfydryl, C1～C6 alkoxyl group, C1～C6 alkylamino radical or C1～C6 alkane sulfydryl;
In following formula, connect "---" representative of X, Y, Z, W, P and Q
Perhaps
2, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is (14S)-14, the 21-epoxy construction, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is a hydrogen, the compound shown in the promptly following general formula (2)
3, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is (14S)-14, and 21-epoxy construction, W are the halogen of β (R) configuration, and Z is the hydroxyl of α (R) configuration, and P is the hydrogen or the hydroxyl of α (R) configuration, and Q is a hydrogen, the compound shown in the promptly following general formula (3)
4, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is (14S)-14, the 21-epoxy construction, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, C
5And C
6Link to each other the compound shown in the promptly following general formula (4) with carbon-carbon double bond
5, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is C
14=CH
2, W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is a hydrogen, the compound shown in the promptly following general formula (5)
6, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is
Be connected C
14The hydroxyl of-position is (R) configuration or (S) configuration, C
21-position is (R) configuration or (S) configuration, and W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is a hydrogen, the compound shown in the promptly following general formula (6)
7, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, C
14XY is C
14(OH) CH=CH
2, be connected C
14The hydroxyl of-position is (R) configuration or is (S) configuration that W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen or the hydroxyl of α (R) configuration, Q is a hydrogen, the compound shown in the promptly following general formula (7)
8, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, wherein, W and Z are for being connected to C
12And C
13The oxygen of α (S) configuration of position, P is the hydrogen of α (S) configuration, Q is a hydrogen, C
14XY is C
14(OH) CH
2OH,
Or
C
14-position be configured as (R) configuration or for (S) configuration, the compound shown in the promptly following general formula (8)
9, tripterygium wilfordii diterpenes diterpenoids lactones derivative as claimed in claim 1, described derivative is:
(14S)-and 14-dehydroxylation-14,21-epoxy triptolide;
(14R)-and 14-dehydroxylation-14,21-epoxy triptolide;
(5R, 14S)-5 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide;
(12R, 13R, 14S)-and 12 β-chloro-13 Alpha-hydroxies-14-dehydroxylation-14,21-epoxy triptolide;
(14S)-Δ
5,6-dehydrogenation-14-dehydroxylation-14,21-epoxy triptolide;
14-dehydroxylation-14-methylene radical triptolide;
(14S, 21R)-14 β-oxa-cyclopropyl table triptolide;
(14S, 21S)-14 β-oxa-cyclopropyl table triptolide;
(14S)-14 β-ethene base table triptolide;
(14S)-14 β-methylol table triptolide;
(14S)-14 Beta-methyl table triptolide;
(12S, 13S, 14S)-12 Alpha-hydroxy-13 α, 14 α-epoxy-14 β-ethene base table triptolide;
(14S, sulphur S)-14 α, 21-ethylene glycol cyclic sulfite triptolide;
(14S, sulphur R)-14 α, 21-ethylene glycol cyclic sulfite triptolide;
(14S)-14 α, 21-ethylene glycol epithio acid esters triptolide.
10, the described tripterygium wilfordii diterpenes diterpenoids lactones derivative of claim 1 is used for the treatment of the application that comprises in prostate cancer, human ovarian cancer, three kinds of hyperplasia tumor diseases of the mammary cancer medicine in preparation.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100358919A CN101255186A (en) | 2008-04-10 | 2008-04-10 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
| CN2008101673060A CN101481401B (en) | 2008-04-10 | 2008-10-10 | Tripterygium wilfordii diterpenoid lactone derivative, pharmaceutical composition thereof and use in genital system tumor resistance |
| PCT/CN2009/000360 WO2009124460A1 (en) | 2008-04-10 | 2009-04-02 | Tripterygium wilfordii diterpene lactone derivatives, their pharmaceutical compositions and their application in inhibiting tumour of reproductive system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100358919A CN101255186A (en) | 2008-04-10 | 2008-04-10 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101255186A true CN101255186A (en) | 2008-09-03 |
Family
ID=39890340
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100358919A Withdrawn CN101255186A (en) | 2008-04-10 | 2008-04-10 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
| CN2008101673060A Expired - Fee Related CN101481401B (en) | 2008-04-10 | 2008-10-10 | Tripterygium wilfordii diterpenoid lactone derivative, pharmaceutical composition thereof and use in genital system tumor resistance |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101673060A Expired - Fee Related CN101481401B (en) | 2008-04-10 | 2008-10-10 | Tripterygium wilfordii diterpenoid lactone derivative, pharmaceutical composition thereof and use in genital system tumor resistance |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN101255186A (en) |
| WO (1) | WO2009124460A1 (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009124460A1 (en) * | 2008-04-10 | 2009-10-15 | 中国科学院上海药物研究所 | Tripterygium wilfordii diterpene lactone derivatives, their pharmaceutical compositions and their application in inhibiting tumour of reproductive system |
| CN102258525A (en) * | 2010-05-28 | 2011-11-30 | 上海汇伦生命科技有限公司 | Application of HQ-091212 to medicaments |
| CN102286065A (en) * | 2010-06-18 | 2011-12-21 | 中国科学院上海药物研究所 | Novel abietane-type diterpene derivative as well as preparation method and application thereof |
| CN102443040A (en) * | 2010-10-14 | 2012-05-09 | 中国科学院上海药物研究所 | N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof |
| CN102443045A (en) * | 2010-10-14 | 2012-05-09 | 中国科学院上海药物研究所 | N-substituted phenyl-14 beta -(aminomethyl) triptodiolide derivative and preparation method and application thereof |
| 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 |
| CN103709227A (en) * | 2012-10-09 | 2014-04-09 | 上海汇伦生命科技有限公司 | Double bond substituted triptolide derivative, and preparation method and applications thereof |
| CN106749496A (en) * | 2016-12-05 | 2017-05-31 | 张奇军 | New triptolide derivative and its preparation and use |
| CN108358993A (en) * | 2018-03-26 | 2018-08-03 | 海南师范大学 | A kind of new diterpene-kind compound and its preparation method and application |
| CN108530510A (en) * | 2017-03-02 | 2018-09-14 | 欣凯医药化工中间体（上海）有限公司 | A kind of C19- is acylated the preparation method of triptolide |
| CN111821308A (en) * | 2019-04-15 | 2020-10-27 | 中国科学院上海药物研究所 | Application of tripterygium wilfordii in preparation of medicine for treating non-alcoholic fatty liver disease |
| WO2023143330A1 (en) * | 2022-01-25 | 2023-08-03 | 杭州卫本医药科技有限公司 | Tripterygium wilfordii diterpene epoxide having function of killing myc positive cell, preparation method therefor, and application thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113429450A (en) * | 2020-03-23 | 2021-09-24 | 三峡大学 | Diterpenoid anti-inflammatory compound containing indole skeleton and preparation method thereof |
| CN114796238B (en) * | 2022-03-30 | 2023-04-28 | 华侨大学 | Tripterygium wilfordii composition for inhibiting drug-resistant cancers and preparation method and application thereof |
| CN114642670B (en) * | 2022-03-30 | 2023-05-12 | 华侨大学 | Application of triptolide derivative in preparing medicament for treating tumor drug resistance and pharmaceutical composition for treating tumor drug resistance |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100422191C (en) * | 2006-01-11 | 2008-10-01 | 浙江大学 | Method for separating and preparing triptolide diol from tripterygium wilfordii |
| 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 |
-
2008
- 2008-04-10 CN CNA2008100358919A patent/CN101255186A/en not_active Withdrawn
- 2008-10-10 CN CN2008101673060A patent/CN101481401B/en not_active Expired - Fee Related
-
2009
- 2009-04-02 WO PCT/CN2009/000360 patent/WO2009124460A1/en active Application Filing
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009124460A1 (en) * | 2008-04-10 | 2009-10-15 | 中国科学院上海药物研究所 | Tripterygium wilfordii diterpene lactone derivatives, their pharmaceutical compositions and their application in inhibiting tumour of reproductive system |
| CN102258525A (en) * | 2010-05-28 | 2011-11-30 | 上海汇伦生命科技有限公司 | Application of HQ-091212 to medicaments |
| CN102286065A (en) * | 2010-06-18 | 2011-12-21 | 中国科学院上海药物研究所 | Novel abietane-type diterpene derivative as well as preparation method and application thereof |
| CN102286065B (en) * | 2010-06-18 | 2012-11-14 | 中国科学院上海药物研究所 | Novel abietane-type diterpene derivative as well as preparation method and application thereof |
| CN102443040A (en) * | 2010-10-14 | 2012-05-09 | 中国科学院上海药物研究所 | N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof |
| CN102443045A (en) * | 2010-10-14 | 2012-05-09 | 中国科学院上海药物研究所 | N-substituted phenyl-14 beta -(aminomethyl) triptodiolide derivative and preparation method and application thereof |
| 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 |
| WO2014056401A1 (en) * | 2012-10-09 | 2014-04-17 | 上海汇伦生命科技有限公司 | Double-bond substituted tripterygium wilfordii lactone derivative and preparation method and use thereof |
| CN103709227A (en) * | 2012-10-09 | 2014-04-09 | 上海汇伦生命科技有限公司 | Double bond substituted triptolide derivative, and preparation method and applications thereof |
| CN103709227B (en) * | 2012-10-09 | 2017-07-04 | 上海汇伦生命科技有限公司 | Double bond substitution triptolide derivatives and its preparation method and application |
| CN106749496A (en) * | 2016-12-05 | 2017-05-31 | 张奇军 | New triptolide derivative and its preparation and use |
| CN108530510A (en) * | 2017-03-02 | 2018-09-14 | 欣凯医药化工中间体（上海）有限公司 | A kind of C19- is acylated the preparation method of triptolide |
| CN108358993A (en) * | 2018-03-26 | 2018-08-03 | 海南师范大学 | A kind of new diterpene-kind compound and its preparation method and application |
| CN111821308A (en) * | 2019-04-15 | 2020-10-27 | 中国科学院上海药物研究所 | Application of tripterygium wilfordii in preparation of medicine for treating non-alcoholic fatty liver disease |
| CN111821308B (en) * | 2019-04-15 | 2021-10-08 | 中国科学院上海药物研究所 | Application of tripterygium wilfordii in preparation of medicine for treating non-alcoholic fatty liver disease |
| WO2023143330A1 (en) * | 2022-01-25 | 2023-08-03 | 杭州卫本医药科技有限公司 | Tripterygium wilfordii diterpene epoxide having function of killing myc positive cell, preparation method therefor, and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101481401B (en) | 2012-05-23 |
| WO2009124460A1 (en) | 2009-10-15 |
| CN101481401A (en) | 2009-07-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101255186A (en) | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof | |
| EP3604306B1 (en) | Macrocyclic derivative of pyrazol[3,4-d]pyrimidin-3-one, pharmaceutical composition and use thereof | |
| Nanduri et al. | Synthesis and structure–activity relationships of andrographolide analogues as novel cytotoxic agents | |
| Yap et al. | Hispidacine, an unusual 8, 4′-oxyneolignan-alkaloid with vasorelaxant activity, and hispiloscine, an antiproliferative phenanthroindolizidine alkaloid, from Ficus hispida Linn. | |
| PT1767535E (en) | Synthesis of epothilones, intermediates thereto, analogues and uses thereof | |
| CN105473566B (en) | Rubescensin analog, composition and relative method | |
| Appendino et al. | The chemistry of coumarin derivatives. part vi. diels-alder trapping of 3-methylene-2, 4-chromandione. a new entry to substituted pyrano [3, 2-c] coumarins | |
| Ouyang et al. | Six new monoterpenoid indole alkaloids from the aerial part of Gelsemium elegans | |
| Cao et al. | Monoterpene indole alkaloids from the stem bark of Mitragyna diversifolia and their acetylcholine esterase inhibitory effects | |
| Gao et al. | Polyisoprenylated benzoylphloroglucinol derivatives from Hypericum scabrum | |
| Chen et al. | The chemistry of taxanes: skeletal rearrangements of baccatin derivatives via radical intermediates | |
| Bai et al. | Targeted isolation of cytotoxic germacranolide sesquiterpenes from Elephantopus scaber L. using small molecule accurate recognition technology | |
| Dong et al. | Artemzhongdianolides A1-A21, antihepatic fibrosis guaiane-type sesquiterpenoid dimers from Artemisia zhongdianensis | |
| JP4481300B2 (en) | Substituted benzopyrans are selective estrogen receptor beta agonists | |
| Vitellozzi et al. | Organometallic routes to novel steroids containing heterocyclic C-17 side-chains | |
| CN102190658A (en) | Structural analogue of antineoplastic marine natural product ecteinascidins | |
| CA2308327A1 (en) | Sarcodictyin and eleutherobin useful for stabilising microtubules | |
| CN107056680A (en) | Spiral shell [indoline of cyclopropane 1,3 '] 2 ' ketone compounds and medicinal usage containing difluoromethyl | |
| Gordaliza et al. | Synthesis and antineoplastic activity of cyclolignan aldehydes | |
| Lee et al. | Cytotoxic ent-abietane diterpenes from Gelonium aequoreum | |
| Hitotsuyanagi et al. | Structures of four new alkaloids from Stemona sessilifolia | |
| CN106188211B (en) | Betulic acid derivative and its application | |
| VanVliet et al. | A high yield preparation of 2-fluoropodophyllotoxin | |
| Araki et al. | Enantioselective Total Synthesis of (+)‐Ottelione A,(−)‐Ottelione B,(+)‐3‐epi‐Ottelione A and Preliminary Evaluation of Their Antitumor Activity | |
| Wang et al. | Monoterpene indole alkaloids from the roots of Bousigonia mekongensis and their anti-diabetic nephropathy activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |