CN103864880A - Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof - Google Patents
Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN103864880A CN103864880A CN201410094110.9A CN201410094110A CN103864880A CN 103864880 A CN103864880 A CN 103864880A CN 201410094110 A CN201410094110 A CN 201410094110A CN 103864880 A CN103864880 A CN 103864880A
- Authority
- CN
- China
- Prior art keywords
- alkene
- acid
- volatile oil
- beta
- uridylic
- 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.)
- Granted
Links
- 0 CC(C)(CC1)C*2C3=CCC([C@@](C)(CC4)C(CC5)C(C)(C)C4O)[C@]5(C)[C@]3(C)CC[C@@]12C(OC1CN(*)C1)=O Chemical compound CC(C)(CC1)C*2C3=CCC([C@@](C)(CC4)C(CC5)C(C)(C)C4O)[C@]5(C)[C@]3(C)CC[C@@]12C(OC1CN(*)C1)=O 0.000 description 2
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an oleanolic acid-pyrimidine conjugate, a preparation method thereof, and application of the oleanolic acid-pyrimidine conjugate in the field of pharmacy. The applicant discovers that the oleanolic acid-pyrimidine conjugate has much higher anti-tumor activity than oleanolic acid, a matrix of the oleanolic acid-pyrimidine conjugate, and a lead compound is provided for developing new anti-tumor drugs. The conjugate has a structure of the general formula (III) shown in the specification.
Description
The application is the divisional application of " Oleanolic Acid-miazines conjugate and its preparation method and application ", the applying date of original application is: on March 31st, 2012, application number is: 201210092658.0, and denomination of invention is: Oleanolic Acid-miazines conjugate and its preparation method and application.
Technical field
The present invention relates to medical technical field, be specifically related to a kind of Oleanolic Acid-miazines conjugate and its preparation method and application.
Background technology
Tumour especially malignant tumour remains the great disease of human life's Health hazard.International cancer research institution (IARC) points out according to global pathogenesis of cancer information database, and pathogenesis of cancer spreads to developing country from developed country, and the death that all kinds of tumor diseases cause is the second largest cause of the death that is only second to cardiovascular disorder.In recent years, chemotherapy of tumors has been obtained sizable progress, the survival time of tumour patient obviously extends, particularly to leukemia, the treatment of malignant lymphoma etc. has had breakthrough, but to harm humans life and health the most serious, the treatment that accounts for more than 90% solid tumor of malignant tumour also fails to reach satisfied effect, the expert in China's medicine and pharmacology field is constantly studying new drug and is finding new way for this reason.
Oleanolic Acid is a kind of Triterpenoids sapogenins compounds, be distributed widely in nature, and there is the liver of protecting, separate liver poison, the multiple biological activity (Sun Hongbin such as antitumor, anti-HIV, hypoglycemic, reducing blood-fat, the progress of pentacyclic triterpene natural product, pharmaceutical chemistry progress, 2006,4:253-279).Oleanolic Acid can significantly reduce the activity of gpt and glutamic-oxal(o)acetic transaminase; protect the emptying of liver gsh; alleviate hepatocellular sex change and reduce inflammatory reaction (Jeong; H.G.Inhibition of cytochrome P4502E1expression by oleanolic acid:hepatoprotective effects against carbon tetrachloride-induced hepatic injury.Toxicol Lett; 1999,105 (3): 215-222).Oleanolic Acid has good broad-spectrum anti-tumor activity in having liver protecting activity, can act on tumorigenic different steps, comprise and suppress formation, obstruction tumor promotion and the inducing tumor cell differentiation of tumour and effectively suppress tumor angiogenesis, stop infringement and the transfer (Ovesna of tumour cell, Z., Vachalkova, A.et al.Pentacyclic triterpenoic acids:New chemoprotective compounds.Neoplasma, 2004,51 (5): 327-333); Although Oleanolic Acid can act on tumorigenic different steps, its anti-tumor activity relatively weak (Huang Minshan, Huang Wei, Wu Qinian etc. Oleanolic Acid induction cell apoptosis in human breast cancer and with cell in Ca
2+the research of level, contemporary Chinese medical journal, 2004,14 (16): 58-60).
Pyrimidines is the very important material of a class in vital movement, extensively be present in occurring in nature, in nucleic acid as required in life, in modal 5 kinds of nitrogenous basic components, just there are 3 kinds containing pyrimidine structure (uridylic, cytosine(Cyt) and thymus pyrimidine), in VITMAIN B1, also contain pyrimidine ring.Therefore, pyrimidine ring causes people's concern (Bai Suzhen already as new drug molecular designing and synthetic basic building block, Lou Xinhua, Yin Guiling. the applied research progress of pyrimidine compound, Shanxi chemical industry, 2009,29 (1): 17-19), point of application based on pyridine derivatives antimetabolic is different, cross resistance is relatively less, and this compounds is mainly used in research (the molecular modification progress of Wang Weidong .5-fluorouracil cancer therapy drug, the pharmacy progress of antitumor drug, 2008,32 (12): 536-542).At present, the problem that pharmaceutical activity was modified and transformed to strengthen to the structure of natural product has caused the extensive concern of pharmaceutical chemists, using miazines small molecules as new drug molecular designing and synthetic basic building block become the important channel of antitumor drug research.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new Oleanolic Acid-miazines conjugate and preparation method thereof, and the application of above-mentioned Oleanolic Acid-miazines conjugate in pharmacy field.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
Have following general formula (I), (II) or (III) shown in Oleanolic Acid-miazines conjugate or its pharmacy acceptable salt or the ester of structure:
Wherein:
General formula (I) and (II) in, n=1～30, R
1represent hydrogen or methyl;
In general formula (III), R
2represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, naphthyl that the non-substituted or X of 1～30 carbon replaces;
X represents F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, SO
3h, COOH, OR
3, COR
4or COOR
5;
R
3represent F, Cl, Br, I, CN, NO
2, NH
2, CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement;
R
4represent NH
2, CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement;
R
5represent CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement.
State general formula (I) and (II) in, preferably n=2～12; In general formula (III), R
2be preferably methyl, ethyl, propyl group, butyl, pentyl, hexyl, heptane base, undecyl or pentadecyl.
Wherein preferred general formula (I) compound is:
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-propyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-propyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-pentyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-pentyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-nonyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-nonyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-positive decyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-positive decyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-undecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-undecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-dodecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-dodecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tridecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tridecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tetradecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tetradecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-Pentadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Pentadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexadecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexadecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-Octadecane base] ester; Or
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Octadecane base] ester;
Preferred general formula (II) compound is:
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen propyl group)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen propyl group)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2,4 (1H, 3H)-pyrimidine dione; Or
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2,4 (1H, 3H)-pyrimidine dione;
Preferred general formula (III) compound is:
3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-penta acyloxy-volatile oils-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-hexylyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-heptan acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-Xin acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides; Or
3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides.
Said structure general formula (I) and (II) shown in the synthetic route of Oleanolic Acid-miazines conjugate as follows:
Wherein, Y represents halogen atom; N=1～30, R
1represent hydrogen or methyl.
Concrete preparation method comprises the following steps:
A) take Oleanolic Acid, dihalo hydrocarbon and alkali by the mol ratio of 1:1.2～1.3:2～5, be placed in organic solvent and react 0.5～24h, revolve and desolventize, resistates acetic acid ethyl dissolution, washing, anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, silica gel column chromatography on gained residue, take the mixed solvent wash-out being made up of as sherwood oil and the ethyl acetate of 4～8:1 volume ratio, elutriant solvent evaporated, obtains halogenated alkane olea acid esters;
B) take halogenated alkane olea acid esters, uridylic or thymus pyrimidine and alkali by the mol ratio of 1:2～3.5:2～5 and be placed in organic solvent reaction 0.5～72h, decompression is revolved and is desolventized, resistates acetic acid ethyl dissolution, washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, silica gel column chromatography on gained residue, take the mixed solvent wash-out being formed as sherwood oil and the ethyl acetate of 3～5:1 by volume ratio, elutriant solvent evaporated, obtains the Oleanolic Acid-miazines conjugate shown in general formula (II); Then the mixed solvent wash-out to be made up of as sherwood oil and the ethyl acetate of 3～1:1 volume ratio, elutriant solvent evaporated, obtains the Oleanolic Acid-miazines conjugate shown in general formula (I).
The step of aforesaid method a) in, described dihalo hydrocarbon is difluoro alkane, two enparas, two bromoalkanes or diiodo-alkane, is preferably two enparas or two bromoalkanes.The temperature of described reaction is 0～60 ℃, preferably at room temperature carries out; Preferably 8～the 12h of time of reaction.
The step of aforesaid method is a) and b), and described alkali is pyridine, triethylamine, ammoniacal liquor, DMAP (DMAP), salt of wormwood, sodium carbonate, calcium carbonate, sodium bicarbonate or saleratus; Described organic solvent is for being selected from a kind of or two or more combination arbitrarily in tetrahydrofuran (THF) (THF), pyridine, methylene dichloride, ethyl acetate, ethyl formate, chloroform, toluene, dioxane and DMF (DMF); The consumption of described organic solvent is conventional amount used, as long as reactant all can be dissolved.
The synthetic route of the Oleanolic Acid-miazines conjugate shown in said structure general formula (III) is as follows:
Wherein, R
2definition as previously mentioned.
Concrete preparation method comprises the following steps:
1) prepare oxygen acyl group oleanolic acid derivate;
2) take oxygen acyl group oleanolic acid derivate and acyl halide reagent by the mol ratio of 1:3～20, stirring reaction 0.5～72h, decompression is revolved and is desolventized, and obtains oxygen acyl group Oleanolic Acid chloride compounds;
3) gained oxygen acyl group Oleanolic Acid chloride compounds organic solvent dissolution, then add and be equivalent to the uridylic of 2～8 times of oxygen acyl group oleanolic acid derivate molar weights and the alkali of 5～35 times, or else add or add the catalyzer that is equivalent to 0.1～0.5 times of oxygen acyl group oleanolic acid derivate molar weight, under nitrogen protection, react 0.5～72h, decompression is revolved and is desolventized, resistates dissolves with methylene dichloride, washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, silica gel column chromatography on gained residue, take the mixed solvent wash-out being formed as sherwood oil and the ethyl acetate of 5～1:1 by volume ratio, elutriant solvent evaporated, obtain the Oleanolic Acid-uridylic conjugate shown in general formula (III).
In the preparation method of the conjugate shown in said structure general formula (III):
Step 1) in, the preparation method that the preparation method of described oxygen acyl group oleanolic acid derivate is existing routine, can be specifically: Oleanolic Acid, alkali and esterifying reagent are placed in to organic solvent, add or do not add catalyst reaction 0.5～24h, revolve and desolventize, resistates diluted hydrochloric acid dissolution, be extracted with ethyl acetate again 1～3 time, merge organic layer, washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, and the mixed solvent recrystallization that the ethanol that it is 5～6:4～5 that gained residue is used by volume ratio and sherwood oil form, to obtain final product; Or by silica gel column chromatography on residue, take the mixed solvent wash-out being made up of as sherwood oil and the ethyl acetate of 10～20:1 volume ratio, elutriant solvent evaporated, to obtain final product.Described esterifying reagent can be acyl chlorides or acid anhydrides etc., and when oxygen acyl group oleanolic acid derivate is reacted in machine solvent by Oleanolic Acid, acyl chlorides and alkali while obtaining, their mol ratio is 1:3～4:5～35; When oxygen acyl group oleanolic acid derivate is to be reacted and obtain in machine solvent by Oleanolic Acid, acid anhydrides and alkali, their mol ratio is 1:1.5～2.0:5～35.In this step, the temperature of reaction is 0～60 ℃, preferably at room temperature carries out; Preferably 8～the 12h of time of reaction; The temperature of recrystallization is preferably 70～90 ℃, and described alkali and the selection of organic solvent are as previously mentioned.Described catalyzer is DMAP, and its add-on is 0.1～0.5 times of Oleanolic Acid molar weight, and the object that adds catalyzer is to improve the yield of this step; In this step, in the time directly using using DMAP as alkali, do not need to add in addition again the DMAP of catalyst levels.
Step 2) in, described acyl halide reagent is thionyl chloride or oxalyl chloride; The mol ratio of described oxygen acyl group oleanolic acid derivate and thionyl chloride or oxalyl chloride is 1:10～20, is preferably 1:15.
Step 3) in, described alkali is pyridine, triethylamine, ammoniacal liquor, DMAP (DMAP), salt of wormwood, sodium carbonate, calcium carbonate, sodium bicarbonate or saleratus; Described organic solvent is for being selected from a kind of or two or more combination arbitrarily in tetrahydrofuran (THF) (THF), pyridine, methylene dichloride, ethyl acetate, ethyl formate, chloroform, toluene, dioxane and DMF (DMF); The consumption of described organic solvent is conventional amount used, as long as reactant all can be dissolved.Described catalyzer is DMAP, its add-on is 0.1～0.5 times of Oleanolic Acid molar weight, the object that adds catalyzer is to improve the yield of this step, conventionally in the time not adding catalyzer, the yield of this step is lower, in 5～30% left and right, and while adding catalyzer, the yield of this step is 50～90%; In this step, in the time directly using using DMAP as alkali, do not need to add in addition again the DMAP of catalyst levels.
The present invention also comprise above-mentioned have general formula (I), (II) or (III) shown in the application in preparation prevention or treatment antitumor drug of Oleanolic Acid-miazines conjugate of structure.
Compared with prior art, the invention provides a kind of new Oleanolic Acid-miazines conjugate and preparation method thereof the application in pharmacy field with them, applicant finds that the anti-tumor activity that above-mentioned Oleanolic Acid-miazines conjugate has is much higher than its parent Oleanolic Acid, provides lead compound for developing new antitumor drug.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiment.
Embodiment 1:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester (I
1) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione (II
1) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 24.95mmol (3.44g) salt of wormwood and 6.49mmol (0.56mL) 1, 2-ethylene dibromide, 60 ℃ of stirring reactions 0.5 hour, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=8:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 1.60g(white solid, yield 57%),
1h NMR (500MHz, CDCl
3) 0.74,0.78,0.93,0.99and1.14 (5s, each3H), 0.90 (s, 6H), 0.71-1.98 (m, 23H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.49 (t, 2H), 4.23-4.42 (m, 2H), 5.30 (s, 1H) .APCI-MS m/z:545.36[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 0.71mmol (0.40g) is dissolved in 3mL DMF, add 3.55mmol (0.49g) salt of wormwood and 2.49mmol (0.28g) uridylic, stirring reaction 0.5 hour at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=5:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.12g Compound I I
1(white solid, yield 31%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 3:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.27g Compound I
1(white solid, yield 64%).
Gained Compound I
1detect through mass spectrum and proton nmr spectra:
m.p.289-291℃.APCI-MS?m/z:621.53[M+C
2H
3]
+.
1H?NMR(500MHz,CDCl
3)δ0.66,0.77,0.89,0.99and1.13(5s,each3H),0.91(s,6H)0.71-2.03(m,23H),2.80(d,1H),3.21(d,1H),3.39-4.05(m,2H),4.25(d,2H),5.24(s,1H),5.69(d,1H),7.18(d,1H,),8.38(brs,1H)。
Therefore, can determine Compound I
1be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester, its structural formula is as follows:
Gained Compound I I
1detect through mass spectrum and proton nmr spectra:
m.p.185-187℃.APCI-MS?m/z:1077.76[M-CH
3]
+.
1H?NMR(500MHz,CDCl
3):δ0.63,0.64,0.895,0.899,0.90,1.08and1.10(7s,each3H),0.76and0.96(2s,each6H),0.87(s,9H),0.71-1.73(m,46H),2.73–2.85(m,2H),3.18(dd,2H),3.83–4.23(m,8H),5.21(dd,2H),5.70(d,1H),7.13(d,1H)。
Therefore, can deterministic compound II
1be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 2:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester (I
2) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione (II
2) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 24.95mmol (3.44g) salt of wormwood and 6.49mmol (0.56mL) 1, 2-ethylene dibromide, 60 ℃ of stirring reactions 0.5 hour, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=8:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 1.60g(white solid, yield 57%),
1h NMR (500MHz, CDCl
3) 0.74,0.78,0.93,0.99and1.14 (5s, each3H), 0.90 (s, 6H), 0.71-1.98 (m, 23H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.49 (t, 2H), 4.23-4.42 (m, 2H), 5.30 (s, 1H) .APCI-MS m/z:545.36[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 0.71mmol (0.40g) is dissolved in 3mL DMF, add 3.55mmol (0.49g) salt of wormwood and 2.49mmol (0.31g) thymus pyrimidine, stirring reaction 0.5 hour at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=5:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.18g Compound I I
2(white solid, yield 47%).Then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 3:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.13g Compound I
2(white solid, yield 31%).
Gained Compound I
2detect through mass spectrum and proton nmr spectra:
m.p.162-165℃.
1H?NMR(500MHz,CDCl
3)δ0.73,0.77,0.88,0.90,0.91,0.97and1.11(7s,each3H),1.19(s,3H),0.63-2.03(m,23H),2.79(d,1H),3.20(dd,1H),3.95(m,2H),4.17-4.28(m,2H),5.22(s,1H),7.00(s,1H),8.61(s,1H)。
Therefore, can determine Compound I
2be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester, its structural formula is as follows:
Gained Compound I I
2detect through mass spectrum and proton nmr spectra:
m.p.172-175℃.APCI-MS?m/z:1113.88[M+Na]
+.
1H?NMR(500MHz,CDCl
3):δ0.65,0.77,0.88,0.90,0.91,0.97and1.11(7s,each6H),1.91(s,3H),0.64-2.06(m,46H),2.79(d,2H),3.20(dd,2H),3.95(m,2H),4.16-4.33(m,6H),5.19(s,1H),5.22(s,1H),6.98(s,1H)。
Therefore, can deterministic compound II
2for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen ethyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 3:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester; (I
3) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione (II
3) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 14.97mmol (2.07g) salt of wormwood and 0.72mL (5.99mmol) 1, 4-dibromobutane, 0 ℃ of stirring reaction 72 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=4:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 1.78g (white solid, yield 61%),
1h NMR (500MHz, CDCl
3) 0.72,0.77,0.89,0.90,0.92,0.98and1.12 (7s, each3H), 0.71-1.98 (m, 27H), 2.85 (dd, 1H), 3.20 (dd, 1H), 3.42 (t, 2H), 4.04 (t, 2H), 5.27 (s, 1H) .APCI-MSm/z:575.40[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 0.10mmol (0.59g) is dissolved in 3mL DMF, add 4.00mmol (0.55g) salt of wormwood and 2.50mmol (0.61g) uridylic, stirring reaction 24 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=4:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.17g Compound I I
3(white solid, yield 30%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 2:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.400g Compound I
3(white solid, yield 64%).
Gained Compound I
3detect through mass spectrum and proton nmr spectra:
m.p.131-134℃.APCI-MS?m/z:623.54[M+H]
+.
1H?NMR(500MHz,CDCl
3)δ0.71,0.78,0.89,0.90,0.92,0.99and1.13(7s,each3H),0.71-2.03(m,27H),2.80(d,1H),3.21(d,1H),3.75(t,2H),4.06(t,2H),5.27(s,1H),5.69(d,1H),7.18(d,1H),9.56(s,1H)。
Therefore, can determine Compound I
3be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester, its structural formula is as follows:
Gained Compound I I
3detect through mass spectrum and proton nmr spectra:
m.p.149-151℃.APCI-MS?m/z:1133.80[M-C
2H
5]
+.
1H?NMR(500MHz,CDCl
3):δ0.72,0.80,0.88,0.98and1.13(5s,each6H),0.90(s,12H),0.72-2.06(m,50H),2.86(dd,2H),3.21(dd,2H),3.75(m,2H),3.96(m,2H),4.00(dd,4H),5.27(s,2H),5.71(d,1H),7.08(d,1H)。
Therefore, can deterministic compound II
3be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 4:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester (I
4) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione (II
4) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 14.97mmol (2.07g) salt of wormwood and 0.72mL (5.99mmol) 1, 4-dibromobutane, 0 ℃ of stirring reaction 72 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=4:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 1.78g (white solid, yield 61%),
1h NMR (500MHz, CDCl
3) 0.72,0.77,0.89,0.90,0.92,0.98and1.12 (7s, each3H), 0.71-1.98 (m, 27H), 2.85 (dd, 1H), 3.20 (dd, 1H), 3.42 (t, 2H), 4.04 (t, 2H), 5.27 (s, 1H) .APCI-MSm/z:575.40[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 0.676mmol (0.40g) is dissolved in 3mL DMF, add 2.70mmol (0.37g) salt of wormwood and 1.69mmol (0.41g) thymus pyrimidine, stirring reaction 24 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=4:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.25g Compound I I
4(white solid, yield 65%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 2:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.04g Compound I
4(white solid, yield 8%).
Gained Compound I
4detect through mass spectrum and proton nmr spectra:
m.p.133-136℃.APCI-MS?m/z:637.44[M+H]
+.
1H?NMR(500MHz,CDCl
3)δ0.72,0.77,0.88,0.89,0.91,0.98and1.12(7s,each3H),1.19(s,3H),0.73-2.10(m,27H),2.85(dd,1H),3.20(dd,1H),3.72(t,2H),4.05(t,2H),5.26(s,1H),7.98(s,1H),8.84(s,1H)。
Therefore, can determine Compound I
4be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester, its structural formula is as follows:
Gained Compound I I
4detect through mass spectrum and proton nmr spectra:
m.p.157-160℃.APCI-MS?m/z:1148.96[M-C
2H
5]
+.
1H?NMR(500MHz,CDCl3):δ0.73,0.86,0.90,0.96and1.13(5s,each6H),0.88(s,12H),1.90(s,3H),0.69-2.06(m,50H),2.83(d,2H),3.19(d,2H),3.71(t,2H),3.95(t,2H),4.02(m,4H),5.24(s,2H),6.94(s,1H)。
Therefore, can deterministic compound II
4for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 5:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester (I
5) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione (II
5) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 19.96mmol (2.76g) salt of wormwood and 6.24mmol (0.96mL) 1, 6-dibromo-hexane, 40 ℃ of stirring reactions 12 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=6:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 1.80g (white solid, yield 58%),
1h NMR (500MHz, CDCl
3) 0.73,0.77,0.92,0.98and1.13 (5s, each3H), 0.89 (s, 6H), 0.71-1.98 (m, 31H), 2.86 (d, 1H), 3.21 (d, 1H), 3.40 (t, 2H), 4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:601.45[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 0.83mmol (0.51g) is dissolved in 3mL DMF, add 1.66mmol (0.23g) salt of wormwood and 1.66mmol (0.41g) uridylic, stirring reaction 72 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively HCl, water, saturated sodium bicarbonate, water and the saturated common salt water washing of 1N
Anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, and gained residue is through purification by silica gel column chromatography, and with the mixed solvent wash-out of sherwood oil: ethyl acetate=3:1 (volume ratio), elutriant solvent evaporated, obtains 0.22g Compound I I
5(white solid, yield 44%); Then the mixed solvent wash-out to be made up of as sherwood oil and the ethyl acetate of 1:1 volume ratio, elutriant solvent evaporated, obtains 0.239g Compound I
5(white solid, yield 44%).
Gained Compound I
5detect through mass spectrum and proton nmr spectra:
m.p.126-128℃.APCI-MS?m/z:651.56[M+H]
+.
1H?NMR(500MHz,CDCl
3)0.71,0.76,0.90,0.97and1.12(5s,each3H),0.88(s,6H),0.71-2.03(m,31H),2.84(d,1H),3.20(d,1H),3.70(t,2H),3.99(t,2H),5.25(s,1H),5.68(d,1H),7.13(d,1H),9.34(brs,1H)。
Therefore, can determine Compound I
5be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester, its structural formula is as follows:
Gained Compound I I
5detect through mass spectrum and proton nmr spectra:
m.p.140-142℃.APCI-MS?m/z:1189.87[M+H]
+.
1H?NMR(500MHz,CDCl
3)0.73,0.78,0.89,0.90,0.93,0.98and1.13(7s,each6H),0.72-2.06(m,62H),2.86(dd,2H),3.21(dd,2H),3.70-3.73(m,2H),3.91-3.94(m,2H),4.01(dd,4H),5.21(s,2H),5.71(d,1H),7.08(d,1H)。
Therefore, can deterministic compound II
5be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 6:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester (I
6) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione (II
6) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 19.96mmol (2.76g) salt of wormwood and 6.24mmol (0.96mL) 1, 6-dibromo-hexane, 40 ℃ of stirring reactions 12 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=6:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 1.80g (white solid, yield 58%),
1h NMR (500MHz, CDCl
3) 0.73,0.77,0.92,0.98and1.13 (5s, each3H), 0.89 (s, 6H), 0.71-1.98 (m, 31H), 2.86 (d, 1H), 3.21 (d, 1H), 3.40 (t, 2H), 4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:601.45[M-OH]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 0.81mmol (0.50g) is dissolved in 3mL DMF, add 1.62mmol (0.22g) salt of wormwood and 1.62mmol (0.20g) thymus pyrimidine, stirring reaction 72 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=3:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.20g Compound I I
6(white solid, yield 42%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 1:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.122g Compound I
6(white solid, yield 23%).
Gained Compound I
6detect through mass spectrum and proton nmr spectra:
m.p.115-119℃.APCI-MS?m/z:663.40[M-H]
-.
1H?NMR(500MHz,CDCl
3)0.73,0.77,0.91,0.98and1.12(5s,each3H),0.89(s,6H),1.19(s,3H),0.73-2.10(m,31H),2.85(d,1H),3.20(dd,1H),3.68(t,2H),4.00(t,2H),5.26(s,1H),6.96(s,1H),8.90(s,1H)。
Therefore, can determine Compound I
6be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester, its structural formula is as follows:
Gained Compound I I
6detect through mass spectrum and proton nmr spectra:
m.p.135-139℃.APCI-MS?m/z:1226.04[M+Na]
+.
1H?NMR(500MHz,CDCl
3)0.71,0.76,0.90,0.95and1.11(5s,each6H),0.88(s,12H),1.91(s,3H),0.69-2.06(m,62H),2.85(dd,2H),3.19(dd,2H),3.67(t,2H),3.95(t,2H),3.98(dd,4H),5.25(s,2H),6.93(s,1H)。
Therefore, can deterministic compound II
6for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 7:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester (I
7) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione (II
7) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 9.98mmol (1.38g) salt of wormwood and 6.49mmol (1.08mL) 1, 8-bis-bromooctanes, stirring at room temperature reaction 18 hours, steaming desolventizes, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=5:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 2.03g (white solid, yield 63%),
1h NMR (500MHz, CDCl
3) 0.72,0.77,0.89,0.90,0.93,0.98and1.13 (7s, each3H), 0.71-2.03 (m, 35H), 2.86 (dd, 1H), 3.20 (dd, 1H), 3.39 (t, 2H), 3.97-4.02 (m, 2H), 5.27 (s, 1H) .APCI-MS m/z:631.50[M-CH
3]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 0.23mmol (0.15g) is dissolved in 3mL DMF, add 0.69mmol (0.09g) salt of wormwood and 0.69mmol (0.17g) uridylic, stirring reaction 48 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=3.5:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.103g Compound I I
7(white solid, yield 72%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 1.5:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.016g Compound I
7(white solid, yield 11%).
Gained Compound I
7detect through mass spectrum and proton nmr spectra:
m.p.101-105℃.APCI-MS?m/z:679.60[M+H]
+.
1H?NMR(500MHz,CDCl
3)0.73,0.78,0.92,0.98and1.13(5s,each3H),0.90(s,6H),0.71-2.03(m,35H),2.86(dd,1H),3.21(dd,1H),3.71(t,2H),4.00(t,2H),5.27(s,1H),5.68(d,1H),7.13(d,1H),8.61(brs,1H)。
Therefore, can determine Compound I
7be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester, its structural formula is as follows:
Gained Compound I I
7detect through mass spectrum and proton nmr spectra:
m.p.125-128℃.APCI-MS?m/z:1245.90[M+H]
+.
1H?NMR(500MHz,CDCl
3)0.72,0.77,0.92,0.98and1.12(5s,each6H),0.89(s,12H),0.71-2.06(m,70H),2.86(dd,2H),3.21(dd,2H),3.69-3.72(m,2H),3.89-3.92(m,2H),3.99(dd,4H),5.27(s,2H),5.70(d,1H),7.08(d,1H)。
Therefore, can deterministic compound II
7be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 8:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester (I
8) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione (II
8) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mL DMF, add 9.98mmol (1.38g) salt of wormwood and 6.49mmol (1.08mL) 1, 8-bis-bromooctanes, stirring at room temperature reaction 18 hours, steaming desolventizes, resistates 50mL acetic acid ethyl dissolution, use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=5:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 2.03g (white solid, yield 63%),
1h NMR (500MHz, CDCl
3) 0.72,0.77,0.89,0.90,0.93,0.98and1.13 (7s, each3H), 0.71-2.03 (m, 35H), 2.86 (dd, 1H), 3.20 (dd, 1H), 3.39 (t, 2H), 3.97-4.02 (m, 2H), 5.27 (s, 1H) .APCI-MS m/z:631.50[M-CH
3]
-.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 0.23mmol (0.15g) is dissolved in 3mL DMF, add 0.69mmol (0.09g) salt of wormwood and 0.69mmol (0.09g) thymus pyrimidine, stirring reaction 48 hours at 50 ℃, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then use successively the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with the mixed solvent wash-out of sherwood oil: ethyl acetate=3.5:1 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain 0.026g Compound I I
8(white solid, yield 18%), then the mixed solvent wash-out to be formed as sherwood oil and the ethyl acetate of 1.5:1 by volume ratio, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.100g Compound I
8(white solid, yield 62%).
Gained Compound I
8detect through mass spectrum and proton nmr spectra:
m.p.101-104℃.APCI-MS?m/z:693.48[M+H]
+.
1H?NMR(500MHz,CDCl
3)0.72,0.76,0.91,0.97and1.12(5s,each3H),0.89(s,6H),1.31(s,3H),0.73-2.10(m,35H),2.85(d,1H),3.20(dd,1H),3.68(t,2H),3.92（d，1H）,4.00(t,2H),5.26(s,1H),6.95(s,1H)。
Therefore, can determine Compound I
8be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester, its structural formula is as follows:
Gained Compound I I
8detect through mass spectrum and proton nmr spectra:
m.p.116-119℃.APCI-MS?m/z:1282.15[M+Na]
+.
1H?NMR(500MHz,CDCl
3)0.71,0.76,0.91,0.97and1.12(5s,each6H),0.88(s,12H),1.91(s,3H),0.69-2.06(m,70H),2.85(d,2H),3.20(d,2H),3.67(t,2H),3.95(t,2H),3.98(d,4H),5.26(s,2H),6.93(s,1H)。
Therefore, can deterministic compound II
8for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
The preparation of embodiment 9:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-propyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen propyl group)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,3-dibromopropane.
Embodiment 10:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-propyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen propyl group)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,3-dibromopropane.
The preparation of embodiment 11:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-pentyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with pentamethylene bromide.
Embodiment 12:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-pentyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with pentamethylene bromide.
The preparation of embodiment 13:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,7-dibromo-heptane.
Embodiment 14:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,7-dibromo-heptane.
The preparation of embodiment 15:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-nonyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,9-, bis-bromononanes.
Embodiment 16:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-nonyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,9-, bis-bromononanes.
The preparation of embodiment 17:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-positive decyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,10-dibromo-decane.
Embodiment 18:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-positive decyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,10-dibromo-decane.
Embodiment 19:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-undecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,11-, bis-bromo-n-11s.
Embodiment 20:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-undecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,11-, bis-bromo-n-11s.
Embodiment 21:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-dodecyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,12-dibromo-dodecane.
Embodiment 22:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-dodecyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,12-dibromo-dodecane.
Embodiment 23:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tridecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,13-dibromo tridecane.
Embodiment 24:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tridecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,13-dibromo tridecane.
Embodiment 25:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tetradecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,14-, bis-bromo-tetradecanes.
Embodiment 26:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tetradecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,14-, bis-bromo-tetradecanes.
Embodiment 27:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-Pentadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,15-, bis-bromopen tadecanes.
Embodiment 28:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Pentadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,15-, bis-bromopen tadecanes.
Embodiment 29:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexadecyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,16-dibromo n-Hexadecane.
Embodiment 30:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexadecyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,16-dibromo n-Hexadecane.
Embodiment 31:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,17-dibromo heptadecane.
Embodiment 32:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,17-dibromo heptadecane.
Embodiment 33:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-Octadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,18-, bis-bromo-octadecanes.
Embodiment 34:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Octadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,18-, bis-bromo-octadecanes.
Embodiment 35:3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III
1) preparation
1) get Oleanolic Acid 11mmol (5.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and diacetyl oxide 16.5mmol (58.2mL), stirring at room temperature reaction 12 hours, concentration of reaction solution, resistates dissolves with 2N HCl, be extracted with ethyl acetate 2 times, merge organic layer; By organic layer successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, ethanol and sherwood oil mixed solvent (V for gained residue
ethanol: V
sherwood oil=6:5) in 80 ℃ of recrystallizations, obtain 3 β-acetoxyl group-volatile oil-12-alkene-28-acid 4.90g (white solid, yield 89%);
1h NMR (500MHz, CDCl
3) 0.76,0.85,0.87,0.91,0.93,0.94and1.13 (7s, each3H), 2.04 (s, 3H), 0.63-2.10 (m, 22H), 2.82 (d, 1H), 3.52 (brs, 1H), 4.50 (t, 1H), 5.28 (s, 1H).
2) get 3 β-acetoxyl group-volatile oil-12-alkene-28-acid 2.00mmol (1.00g) and be dissolved in anhydrous methylene chloride 1mL, at 0 ℃, drip oxalyl chloride 30.0mmol (2.6mL), stirring at room temperature reaction 7 hours, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of 1mL for gained resistates; then add uridylic 4.00mmol (0.45g) and triethylamine 1.00mmol (0.14mL); stirring at room temperature reaction 48 hours under nitrogen protection; concentration of reaction solution; resistates dissolves with 50mL methylene dichloride; water, saturated common salt water washing successively again; anhydrous magnesium sulfate drying; filter; filtrate is concentrated; gained residue is through purification by silica gel column chromatography, with the mixed solvent (V of methylene dichloride and methyl alcohol composition
sherwood oil: V
ethyl acetate=3:1) wash-out, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.349g compound III
1(white solid, yield 29%).
Above-claimed cpd detects through proton nmr spectra:
m.p.208-211℃.
1H?NMR(500MHz,CDCl
3)0.69,0.85,0.86,0.99and1.13(5s,each3H),0.92(s,6H),1.17(s,3H),0.63-2.10(m,22H),2.99(d,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.51(d,1H),8.20(brs,1H)。
Therefore, can determine compound III
1be 3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 36:3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III
2) preparation
1) get Oleanolic Acid 2.2mmol (1.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and propionic anhydride 4.4mmol (0.57mL), stirring at room temperature reaction 12 hours, concentration of reaction solution, resistates dissolves with 2N HCl, be extracted with ethyl acetate 1 time, by organic layer successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filters, filtrate is concentrated, ethanol and sherwood oil mixed solvent (V for gained residue
ethanol: V
sherwood oil=5:5) in 70 ℃ of recrystallizations, obtain 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid 0.85g (white solid, yield 76%);
1h NMR (500MHz, CDCl
3) δ 0.74,0.90,0.92,0.93and1.12 (5s, each3H), 0.85 (s, 6H), 0.81-2.10 (m, 25H), (2.32 q, 2H), 2.81 (d, 1H), 4.40 – 4.57 (m, 1H), 5.27 (s, 1H).
2) get 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid 0.59mmol (0.30g) and be dissolved in anhydrous methylene chloride 1mL, at 0 ℃, drip oxalyl chloride 5.90mmol (0.51mL), 0 ℃ of stirring reaction 12 hours, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of 1mL for gained resistates; then add uridylic 1.77mmol (0.43g), DMAP0.118mmol (0.014g) and triethylamine 7.17mmol (1mL); stirring at room temperature reaction 24 hours under nitrogen protection; concentration of reaction solution; resistates dissolves with 50mL methylene dichloride; water, saturated common salt water washing successively again; anhydrous magnesium sulfate drying; filter; filtrate is concentrated; gained residue is through purification by silica gel column chromatography, with the mixed solvent (V of methylene dichloride and methyl alcohol composition
sherwood oil: V
ethyl acetate=5:1) wash-out, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.21g compound III
2(white solid, yield 60%).
Above-claimed cpd detects through proton nmr spectra:
m.p.119-122℃.
1H?NMR(500MHz,CDCl
3)0.69,0.846,0.85,0,98and1.13(5s,each3H),0.91(s,6H),0.63-2.10(m,25H),2.32(q,2H),2.99(d,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.98(brs,1H)。
Therefore, can determine compound III
2be 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 37:3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III
3) preparation
1) get Oleanolic Acid 2.2mmol (1.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and butyryl oxide 2.75mmol (0.45mL), stirring at room temperature reaction 10 hours, concentration of reaction solution, resistates dissolves with 2N HCl, be extracted with ethyl acetate 2 times, merge organic layer; By organic layer successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, ethanol and sherwood oil mixed solvent (V for gained residue
ethanol: V
sherwood oil=6:4) in 90 ℃ of recrystallizations, obtain 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.79g (white solid, yield 68%);
1h NMR (500MHz, CDCl
3) 0.74,0.90,0.92,0.93,1.12and1.25 (6s, each3H), 0.85 (s, 6H), 0.63-2.10 (m, 24H), 2.28 (t, 2H), 2.81 (d, 1H), (3.66 s, 1H), 4.50 (d, 1H), 5.27 (s, 1H).
2) get 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.38mmol (0.20g) and be dissolved in anhydrous methylene chloride 1mL, at 0 ℃, drip oxalyl chloride 6.93mmol (0.59mL), 60 ℃ of stirring reactions 0.5 hour, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of 1mL for gained resistates; then add uridylic 1.73mmol (0.19g), DMAP0.035mmol (0.004g) and triethylamine 12.1mmol (1.69mL); stirring at room temperature reaction 12 hours under nitrogen protection; concentration of reaction solution; resistates dissolves with 50mL methylene dichloride; water, saturated common salt water washing successively again; anhydrous magnesium sulfate drying; filter; filtrate is concentrated; gained residue is through purification by silica gel column chromatography, with the mixed solvent (V of sherwood oil and ethyl acetate composition
sherwood oil: V
acetic acid second ester=5:1) wash-out, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.13g compound III
3(white solid, yield 56%).
Above-claimed cpd detects through mass spectrum and proton nmr spectra:
m.p.285-287℃.APCI-MS?m/z:619.38[M-H]
-.
1H?NMR(500MHz,CDCl
3)0.69,0.85,0.86,0.92,0.96,0.99and1.18(7s,each3H)0.63-2.10(m,27H),2.28(t,2H),2.99(d,1H),4.49(dd,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.13(brs,1H)。
Therefore, can determine compound III
3be 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 38:3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III
4) preparation
1) getting Oleanolic Acid 2.2mmol (1.00g) is dissolved in 3mL tetrahydrofuran (THF), add lauroyl chloride 6.6mmol (1.57mL) and triethylamine 11mmol (1.53mL), stirring at room temperature reaction 20 hours, concentration of reaction solution, resistates dissolves with 50mL methylene dichloride, water, saturated common salt water washing successively, anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with mixed solvent wash-out (V
ethyl acetate: V
sherwood oil=1:20), elutriant solvent evaporated, obtains 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid 1.04g (white solid, yield 75%);
1h NMR (500MHz, CDCl
3) 0.76,0.85,0.89,0.90,0.92,0.93and1.13 (7s, each3H), 0.63-2.10 (m, 43H), 2.29 (t, 2H), 2.76 (dd, 1H), 4.48-4.61 (m, 1H), 5.27 (s, 1H).
2) get 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid 0.44mmol (0.28g) and be dissolved in anhydrous methylene chloride 1mL, at 0 ℃, drip thionyl chloride 4.39mmol (0.31mL), 60 ℃ of stirring reactions 0.5 hour, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of 1mL for gained resistates; then add uridylic 4.08mmol (0.34g) and triethylamine 7.48mmol (1.04mL); stirring at room temperature reaction 24 hours under nitrogen protection; concentration of reaction solution; resistates dissolves with 50mL methylene dichloride; water, saturated common salt water washing successively again; anhydrous magnesium sulfate drying; filter; filtrate is concentrated; gained residue is through purification by silica gel column chromatography, with the mixed solvent (V of sherwood oil and ethyl acetate composition
sherwood oil: V
ethyl acetate=4:1) wash-out, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.072g compound III
4(white solid, yield 22%).
Above-claimed cpd detects through proton nmr spectra:
1H?NMR(500MHz,CDCl
3)0.70,1.00and1.19(3s,each3H),0.87and0.93(2s,each6H),0.63-2.10(m,43H),2.30(s,2H),3.01(d,1H),4.50(s,1H),5.30(s,1H),5.74(d,1H),7.52(d,1H),8.72(brs,1H)。
Therefore, can determine compound III
4be 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 39:3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III
5) preparation
1) getting Oleanolic Acid 2.2mmol (1.00g) is dissolved in 3mL tetrahydrofuran (THF), add palmityl chloride 8.8mmol (2.69mL) and triethylamine 77mmol (10.2mL), stirring at room temperature reaction 12 hours, concentration of reaction solution, resistates dissolves with 50mL methylene dichloride, water, saturated common salt water washing successively, anhydrous magnesium sulfate drying, filters, and filtrate is concentrated, gained residue is through purification by silica gel column chromatography, with mixed solvent wash-out (V
ethyl acetate: V
sherwood oil=1:15), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid 1.35g (white solid, yield 89%);
1h NMR (500MHz, CDCl
3) 0.76,0.85,0.89,0.90,0.93,0.94and1.14 (7s, each3H), 2.29 (t, 2H), 0.63-2.10 (m, 51H), 2.82 (dd, 1H), 4.50 (dd, 1H), 5.27 (s, 1H).
2) get 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.50mmol (0.35g) and be dissolved in anhydrous methylene chloride 1mL, at 0 ℃, drip thionyl chloride 7.40mmol (0.52mL), stirring at room temperature reaction 12 hours, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of 1mL for gained resistates; then add uridylic 1.11mmol (0.124g) and triethylamine 6.17mmol (0.86mL); stirring at room temperature reaction 24 hours under nitrogen protection; concentration of reaction solution; resistates dissolves with 50mL methylene dichloride; water, saturated common salt water washing successively again; anhydrous magnesium sulfate drying; filter; filtrate is concentrated; gained residue is through purification by silica gel column chromatography, with the mixed solvent (V of sherwood oil and ethyl acetate composition
sherwood oil: V
ethyl acetate=4:1) wash-out, thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, and elutriant solvent evaporated, obtains 0.04g compound III
5(white solid, yield 11%).
Above-claimed cpd detects through mass spectrum and proton nmr spectra:
m.p.89-91℃.APCI-MS?m/z:787.71[M-H]
-.
1H?NMR(500MHz,CDCl
3)0.69,0.85,0.86,0.99and1.18(5s,each3H),0.92(s,6H),0.63-2.10(m,51H),2.29(t,2H),2.99(dd,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.17(brs,1H)。
Therefore, can determine compound III
5be 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
The preparation of embodiment 40:3 β-penta acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with n-amyl chloride.
The preparation of embodiment 41:3 β-hexylyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with caproyl chloride.
The preparation of embodiment 42:3 acyloxy-volatile oil in β-heptan-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with oenanthyl chloro.
The preparation of embodiment 43:3 β-Xin acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with capryl(yl)chloride.
In order to absolutely prove the application of conjugate of the present invention in pharmacy, the compound that applicant makes embodiment 1～8 and embodiment 35～39 carries out extracorporeal anti-tumor cell-proliferation activity experiment (adopting the blue colorimetry of conventional tetramethyl-nitrogen azoles) to multiple mankind's tumor line:
1, cell strain and cell cultures
HepG-2 (human hepatoma cell strain), A549 (human lung carcinoma cell line), BGC-823 (stomach cancer cell line), MCF-7 (breast carcinoma cell strain), PC-3 (Prostatic cancer cell lines) are selected in this experiment.
All cells strain is all cultivated in 1640 substratum that contain 10% foetal calf serum, at 37 ℃ of 5%CO
2cell culture incubator in be cultured to cell and reach logarithmic phase.
2, primary dcreening operation
The purity of compound used therefor all >=95%, is mixed with 100 μ mol/L by all compounds, and solubility promoter DMSO final concentration≤0.5%, tests the inhibition degree of compound to growth of tumour cell under this concentration.In the time that compound final concentration is 10 μ mol/L, it is effective that inhibiting rate >=50% is judged to be primary dcreening operation.
3, experiment (MTT)
By test-compound to be measured with DMSO hydrotropy after, be made into the working fluid concentration of 100 μ mol/L, 50 μ mol/L, 10 μ mol/L, 5 μ mol/L, 1 μ mol/L and 0.1 μ mol/L, deposit in 4 ℃ of Refrigerator stores, the IC for test test-compound to selected tumor cell line
50value is used.
Get in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 × 10
4individual/mL, makes cell suspension; Obtained cell suspension is inoculated on 96 orifice plates, and 180 μ L/ holes, put constant temperature CO
2in incubator, cultivate 24 hours; Change liquid, add test-compound, 20 μ L/ holes, cultivate 72 hours; MTT is added in 96 orifice plates, and 20 μ L/ holes, react in incubator 4 hours; Suck supernatant liquor, add DMSO, 150 μ L/ holes, jolting 5 minutes on dull and stereotyped shaking table; Be the light absorption value in the every hole of mensuration, 570nm place with enzyme-linked immunosorbent assay instrument at wavelength, and calculate cell inhibitory rate (cell inhibitory rate %=(negative control group OD value-tested material group OD value)/negative control group OD value × 100%).Record the data (IC of the extracorporeal anti-tumor cell-proliferation activity of each test-compound
50, μ mol/L or μ M) as shown in the following Table 1:
Table 1:
IC
50value is the mean value of three experiments; NI does not have activity while being illustrated in 100 μ mol/L concentration.
According to the literature, the IC of the parent compound Oleanolic Acid of conjugate of the present invention to HepG-2 cell line and lung cancer A549 cell
50value is respectively 70 μ M and 39 μ M(Zheng, M.S.; Lee, Y.K.; Li, Y.; Et al.Inhibition of DNA topoisomerases I and II and cytotoxicity of compounds from Ulmus davidiana var.japonica.Archivesof Pharmacal Research, 2010,33 (9), 1307-1315); To the IC of MCF-7 Breast Cancer Cell
50be worth 88.36 μ M (Huang Minshan, Huang Wei, Wu Qinian etc. Oleanolic Acid induction cell apoptosis in human breast cancer and with cell in Ca
2+the research of level, contemporary Chinese medical journal, 2004,14 (16): 58-60).And pharmacological experimental data shows in table 1, in tested compound, Compound I I
5there is the highest anti-HepG-2 cell line proliferation activity (IC
50=0.99 μ M), be parent compound Oleanolic Acid (IC
50=70 μ M) 70 times of corresponding activity; Compound I
6, II
4, II
6and II
8there is very good suppressing lung cancer A 549 cell proliferation activity (IC
50< 0.1 μ M), be parent compound Oleanolic Acid (IC
50=39 μ M) the more than 390 times of corresponding activity; Compound I
7, II
5and III
1there is very high anti-breast cancer MCF-7 cell-proliferation activity (IC
50< 0.1 μ M), be at least parent compound Oleanolic Acid (IC
50=88.36 μ M) 880 times of corresponding activity.Compound III in addition
1, III
2and III
5show extraordinary anti-BGC-823 Cells proliferation activity (IC
50< 0.1
μm).
Show according to pharmacological experimental data in table 1, general formula of the present invention (I), (II) or (III) compound have good anti-tumor activity, to the inhibition IC of tested tumour cell
50value major part is all in micromole's level; In institute's test compounds, the activity of outstanding compound or even parent compound Oleanolic Acid activity more than 800 times; Therefore, of the present invention have above-mentioned general formula (I), (II) or (III) shown in the compound of structure there is good anti-tumor activity, can be used for the medicine of preparation prevention or treatment tumor disease.Have above-mentioned general formula (I), (II) or (III) shown in pharmacy acceptable salt or the ester of structural compounds, they and general formula (I), (II) or (III) the same medicine that can be used for preparation prevention or treatment tumor disease of compound.
The pharmaceutical preparation of the Oleanolic Acid-miazines conjugate described in the present invention can adopt common capsule, tablet, particle or other oral preparations; also can carry out administered parenterally; can take any conventionally form, such as injection, ointment, percutaneous dosing, inhalation etc.
Claims (8)
1. there is Oleanolic Acid-miazines conjugate or its pharmacy acceptable salt or the ester of structure shown in following general formula (III):
Wherein:
In general formula (III), R
2represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, naphthyl that the non-substituted or X of 1～30 carbon replaces;
X represents F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, SO
3h, COOH, OR
3, COR
4or COOR
5;
R
3represent F, Cl, Br, I, CN, NO
2, NH
2, CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement;
R
4represent NH
2, CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement;
R
5represent CF
3, 1～30 carbon the phenyl of straight or branched alkane, alkene, alkynes, phenyl or replacement.
2. Oleanolic Acid-miazines conjugate according to claim 1, is characterized in that:
Described R
2for methyl, ethyl, propyl group, butyl, pentyl, hexyl, heptane base, undecyl or pentadecyl.
3. Oleanolic Acid-miazines conjugate according to claim 1, is characterized in that:
Described general formula (III) compound is:
3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-penta acyloxy-volatile oils-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-hexylyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-heptan acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-Xin acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides; Or
3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides.
4. the preparation method of Oleanolic Acid-miazines conjugate claimed in claim 1, is characterized in that: comprise the following steps:
1) prepare oxygen acyl group oleanolic acid derivate;
2) take oxygen acyl group oleanolic acid derivate and acyl halide reagent by the mol ratio of 1:3～20, stirring reaction 0.5～72h, decompression is revolved and is desolventized, and obtains oxygen acyl group Oleanolic Acid chloride compounds;
3) gained oxygen acyl group Oleanolic Acid chloride compounds organic solvent dissolution, then add and be equivalent to the uridylic of 2～8 times of oxygen acyl group oleanolic acid derivate molar weights and the alkali of 5～35 times, or else add or add the catalyzer that is equivalent to 0.1～0.5 times of oxygen acyl group oleanolic acid derivate molar weight, under nitrogen protection, react 0.5～72h, decompression is revolved and is desolventized, resistates dissolves with methylene dichloride, washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, silica gel column chromatography on gained residue, take the mixed solvent wash-out being formed as sherwood oil and the ethyl acetate of 5～1:1 by volume ratio, elutriant solvent evaporated, obtain the Oleanolic Acid-uridylic conjugate shown in general formula (III).
5. preparation method according to claim 4, is characterized in that: in step 2) in, described acyl halide reagent is thionyl chloride or oxalyl chloride, the mol ratio of described oxygen acyl group oleanolic acid derivate and thionyl chloride or oxalyl chloride is 1:10～20.
6. according to preparation method claimed in claim 4, it is characterized in that: in step 1) in, the preparation method of described oxygen acyl group oleanolic acid derivate is: Oleanolic Acid, alkali and esterifying reagent are placed in to organic solvent, add or do not add catalyst reaction 0.5～24h, decompression is revolved and is desolventized, resistates diluted hydrochloric acid dissolution, be extracted with ethyl acetate again 1～3 time, merge organic layer, washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, and the mixed solvent recrystallization that the ethanol that it is 5～6:4～5 that gained residue is used by volume ratio and sherwood oil form, to obtain final product; Or by silica gel column chromatography on residue, take the mixed solvent wash-out being made up of as sherwood oil and the ethyl acetate of 10～20:1 volume ratio, elutriant solvent evaporated, to obtain final product.
7. according to the preparation method described in claim 4 or 6, it is characterized in that: described catalyzer is DMAP.
8. the application of Oleanolic Acid-miazines conjugate claimed in claim 1 in preparation prevention or treatment antitumor drug.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210092658.0A CN102633856B (en) | 2012-03-31 | 2012-03-31 | Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210092658.0A Division CN102633856B (en) | 2012-03-31 | 2012-03-31 | Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103864880A true CN103864880A (en) | 2014-06-18 |
| CN103864880B CN103864880B (en) | 2016-01-20 |
Family
ID=46618448
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410094110.9A Expired - Fee Related CN103864880B (en) | 2012-03-31 | 2012-03-31 | Oleanolic Acid-miazines conjugate and its preparation method and application |
| CN201210092658.0A Expired - Fee Related CN102633856B (en) | 2012-03-31 | 2012-03-31 | Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof |
| CN201410094143.3A Expired - Fee Related CN103864882B (en) | 2012-03-31 | 2012-03-31 | Oleanolic Acid-miazines conjugate and its preparation method and application |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210092658.0A Expired - Fee Related CN102633856B (en) | 2012-03-31 | 2012-03-31 | Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof |
| CN201410094143.3A Expired - Fee Related CN103864882B (en) | 2012-03-31 | 2012-03-31 | Oleanolic Acid-miazines conjugate and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN103864880B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104672294B (en) * | 2015-02-12 | 2017-01-25 | 广东药学院 | Synthesis method of compound 3-O-(2-(5-fluorouracil-1-)acetyl)-ursolic acid methyl ester and application of compound as antitumor drug |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1594354A (en) * | 2004-07-14 | 2005-03-16 | 中国药科大学 | Oleanolic acid couple derivatives and their pharmaceutical use |
| CN1916015A (en) * | 2006-07-19 | 2007-02-21 | 沈阳化工学院 | Amine, heterocycle of chemical modification object of ursolic acid |
| CN101190936A (en) * | 2006-12-01 | 2008-06-04 | 黄振华 | Compound with antiviral activity |
| WO2009146216A2 (en) * | 2008-04-18 | 2009-12-03 | Reata Pharmaceuticals. Inc. | Antioxidant inflammation modulators: novel derivatives of oleanolic acid |
| CN101607979A (en) * | 2009-03-02 | 2009-12-23 | 中国药科大学 | Pentacyclic triterpene-vitamin C conjugates, its preparation method and medicinal use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9505800B2 (en) * | 2006-11-03 | 2016-11-29 | Myrexis, Inc. | Extended triterpene derivatives |
| CN101679472B (en) * | 2007-02-28 | 2014-07-02 | 艾伯塔大学校董 | Compounds for preventing or treating viral infections and methods of use thereof |
-
2012
- 2012-03-31 CN CN201410094110.9A patent/CN103864880B/en not_active Expired - Fee Related
- 2012-03-31 CN CN201210092658.0A patent/CN102633856B/en not_active Expired - Fee Related
- 2012-03-31 CN CN201410094143.3A patent/CN103864882B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1594354A (en) * | 2004-07-14 | 2005-03-16 | 中国药科大学 | Oleanolic acid couple derivatives and their pharmaceutical use |
| CN1916015A (en) * | 2006-07-19 | 2007-02-21 | 沈阳化工学院 | Amine, heterocycle of chemical modification object of ursolic acid |
| CN101190936A (en) * | 2006-12-01 | 2008-06-04 | 黄振华 | Compound with antiviral activity |
| WO2009146216A2 (en) * | 2008-04-18 | 2009-12-03 | Reata Pharmaceuticals. Inc. | Antioxidant inflammation modulators: novel derivatives of oleanolic acid |
| CN101607979A (en) * | 2009-03-02 | 2009-12-23 | 中国药科大学 | Pentacyclic triterpene-vitamin C conjugates, its preparation method and medicinal use thereof |
Non-Patent Citations (6)
| Title |
|---|
| MIYAHARA S ET AL.: "Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 刘丹等.: "齐墩果酸和熊果酸结构修饰物的药理活性和构效关系研究进展", 《化学通报》 * |
| 白素贞等.: "嘧啶化合物的应用研究进展", 《山西化工》 * |
| 纪三郝: "甾体-核苷缀合物的合成及其性质研究", 《中国优秀硕士学位论文全文数据库（工程科技I辑）》 * |
| 金培元等.: "新型甾体缀合物的设计合成及活性研究", 《化学进展》 * |
| 钱珊等.: "具有抗肿瘤活性的齐墩果酸衍生物的研究进展", 《西华大学学报（自然科学版）》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103864882A (en) | 2014-06-18 |
| CN102633856B (en) | 2014-07-23 |
| CN103864880B (en) | 2016-01-20 |
| CN103864882B (en) | 2015-10-28 |
| CN102633856A (en) | 2012-08-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN106632379B (en) | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity | |
| Tuncay et al. | Synthesis of oleanolic acid analogues and their cytotoxic effects on 3T3 cell line | |
| CN103113386B (en) | Nitrogen heterocyclic substituted-dihydro artemisinin derivative and application thereof | |
| CN104447782A (en) | Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof | |
| CN114524716B (en) | Beta-elemene ethenyl coupling derivative, preparation thereof and application thereof in preparing antitumor drugs | |
| Chen et al. | Synthesis and antitumor evaluation of (aryl) methyl-amine derivatives of dehydroabietic acid-based B ring-fused-thiazole as potential PI3K/AKT/mTOR signaling pathway inhibitors | |
| CN102066362A (en) | Dihydroindolinone derivatives | |
| CN102627685B (en) | Nitric oxide-donating glutathione compound, preparation method and medical purpose thereof | |
| CN104151391A (en) | Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof | |
| CN102633856B (en) | Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof | |
| CN108484632A (en) | Qinghaosu-anilinoquinazoline analog derivative and its preparation method and application | |
| CN109651452A (en) | With the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage | |
| CN109320557A (en) | 99mTc(CO)3The Pa Boxini derivative and preparation method and application containing isonitrile of core label | |
| WO2020259620A1 (en) | Heterocyclo alkyl compounds used as ccr2/ccr5 antagonist | |
| CN108976195B (en) | 2-thioureido (ureido) thiophene-3-formate derivatives and application thereof | |
| CN103421048A (en) | Mono-chloride-dimethylsulfoxide-6-hydroxide radical oxidation iso-aporphine platinum (II) and synthesizing method and application thereof | |
| CN103159674A (en) | 2-benzene alkyl amid compound and preparation method, medical composition and use thereof | |
| CN102633855B (en) | Oleanolic acid-uridine conjugate as well as preparation method and application thereof | |
| CN102276500A (en) | Salicylamide antineoplastic compounds, synthesizing method thereof, and purpose thereof | |
| CN102516066B (en) | Ostopanic acid analog and Preparation method and use | |
| CN114573504A (en) | Beta-elemene derivative containing N-OH bond and preparation method and application thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| Das et al. | Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors | |
| CN109503697A (en) | 3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160120 Termination date: 20190331 |