CN102344481A - Derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene, preparation method thereof and application thereof - Google Patents
Derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene, preparation method thereof and application thereof Download PDFInfo
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- 0 CC(OC1=C(*)C[C@](C=CC(Cl)=O)C=C1)=O Chemical compound CC(OC1=C(*)C[C@](C=CC(Cl)=O)C=C1)=O 0.000 description 2
- RMIVRCBSQPCSCQ-RCVHYVRCSA-N CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O RMIVRCBSQPCSCQ-RCVHYVRCSA-N 0.000 description 1
- MPDGHEJMBKOTSU-VOPRYAMFSA-N CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O MPDGHEJMBKOTSU-VOPRYAMFSA-N 0.000 description 1
- RMIVRCBSQPCSCQ-QTGHMMOASA-N CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O RMIVRCBSQPCSCQ-QTGHMMOASA-N 0.000 description 1
- OJFDXYZWMIOCHW-RDTMDKBLSA-N CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3OC(/C=C/c(cc1)cc(OC(C)=O)c1OC(C)=O)=O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(OC)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3OC(/C=C/c(cc1)cc(OC(C)=O)c1OC(C)=O)=O OJFDXYZWMIOCHW-RDTMDKBLSA-N 0.000 description 1
- ZDIYGBWFISUTHI-GQCTYLIASA-N CC(Oc(ccc(/C=C/C(O)=O)c1)c1OC(C)=O)=O Chemical compound CC(Oc(ccc(/C=C/C(O)=O)c1)c1OC(C)=O)=O ZDIYGBWFISUTHI-GQCTYLIASA-N 0.000 description 1
- QAIPRVGONGVQAS-DUXPYHPUSA-N OC(/C=C/c(cc1)cc(O)c1O)=O Chemical compound OC(/C=C/c(cc1)cc(O)c1O)=O QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 1
- DZAUWHJDUNRCTF-UHFFFAOYSA-N OC(CCc(cc1)cc(O)c1O)=O Chemical compound OC(CCc(cc1)cc(O)c1O)=O DZAUWHJDUNRCTF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene represented by general formula (I) in the specification (R1 and R2 in the general formula (I) are selected from -CH3, COOH, COOQ, CONQ2, or COSQ, wherein Q is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; X is -C=O or CH2; and Y-Z is -CH2-CH2-, cis-CH=CH-, or trans-CH=CH-), a preparation method thereof, and pharmaceutically acceptable esters or salts thereof. The invention also discloses a medicinal composition. The composition comprises an effective dose of the derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene or the pharmaceutically acceptable esters or salts thereof, and pharmaceutically acceptable carriers thereof. The invention also discloses an application of the derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene or the pharmaceutically acceptable esters or salts thereof in the preparation of anti-inflammatory medicines, antiallergic medicines, liver protection medicines, antivirus medicines and the like.
Description
Technical field
The present invention relates to a kind of pentacyclic triterpene ester derivative, particularly relate to a kind of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative, its preparation method and application.
Background technology
Glycyrrhetinic acid (Glycyrrhetinic Acid writes a Chinese character in simplified form GA, and its chemical structural formula is seen (A)) another name glycyrrhetinic acid is the oleanane type pentacyclic triterpenoid that is extracted by the Radix Glycyrrhizae rhizome, with 18 β-glycyrrhetinic acid (C
30H
46O
4, molecular weight 470.64) and be main.Glycyrrhetinic acid and derivative pharmacological action thereof: have many-sided effect such as anti-inflammatory, antiulcer agent, antiviral, antitumor, antianaphylaxis; Glycyrrhetinic acid is classical anti-inflammatory drug clinically; Can be made into anti-inflammatory antianaphylaxis preparation, be used for treatment of arthritis, dermatitis, diseases of eye, ear, nose and throat section inflammation and ulcer etc.; Be applied to the immunologic function of scalable skin in the makeup, diminish inflammation, Ammonium Glycyrrhizate, cleaning skin, can detoxify etc.But such medicine is taken for a long time and can be caused a type aldosteronism; Also there is the report glycyrrhetinic acid that the effect that reduces basal metabolic rate(BMR) is arranged.Solvability, the absorptivity of glycyrrhetinic acid are relatively poor, have limited the application of glycyrrhetinic acid.
Oleanolic Acid (oleanolic acid is called for short OA, and its chemical structural formula is seen (B)) is a kind of oleanane type pentacyclic triterpenoid, chemistry (3a)-3-Hydroxyolean-12-en-28-oic acid by name, molecular formula C
30H
48O
3, colourless, tasteless, water insoluble for white bunch shape needle, dissolve in ethanol, chloroform, ether, acetone etc.As far back as 1908, the Powcrs of Britain just extracted from the leaf of wood spy section vegetables oil olive (Oleaeuropeae L) and has obtained Oleanolic Acid.Oleanolic Acid extensively is present in occurring in nature, and according to incompletely statistics, Oleanolic Acid is to dissociate or to be present in 190 various plants of about 60 sections with sugared bonded form.Since nineteen seventies, pharmaceutical researchers finds that gpt obviously descends in the carbon tetrachloride poisoning rat blood serum after the Oleanolic Acid treatment, and the liver tissues inflammatory habituation stops cirrhotic formation.Find again that afterwards Oleanolic Acid has hypoglycemic, reducing blood-fat, platelet aggregation-against, anti-inflammatory, multiple biological activity such as antiviral, and toxic side effect is very little, existing at present certain clinical value.Because Oleanolic Acid is not soluble in water, dissolution rate is slow, absorbs badly, and bioavailability is low, has limited its bioactive exploitation.In recent years, the various countries researchist had carried out a series of chemically modified and transformation to Oleanolic Acid, thereby sought the compound of high pharmacologically active, and sought their new biological activitys.
Coffic acid is a kind of natural two hydroxy-cinnamic acids, and through adding the two hydroxy phenylpropionic acids of hydrogen evolution, the two all extensively is present in the plant, has anti-bacteria and anti-virus, multiple biological activity such as anti-oxidant.
The two hydroxy phenylpropionic acids of coffic acid (Caffeic acid)
Therefore, can carry out structure of modification, so that seek the compound that activity is better, physico-chemical property is more suitable for preparation to above-claimed cpd.
Summary of the invention
One of technical problem that the present invention will solve provides a kind of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative or its pharmaceutically acceptable ester or salt with excellent activity.
Two of the technical problem that the present invention will solve provides a kind of preparation method of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative.
Three of the technical problem that the present invention will solve provides a kind of containing with 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative or its pharmaceutically acceptable ester or the salt pharmaceutical composition as effective constituent and one or more pharmaceutically acceptable carriers.
Four of the technical problem that the present invention will solve provide a kind of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative and pharmaceutically acceptable ester thereof or salt, and above-mentioned medicinal compositions in preparation anti-inflammatory, antianaphylaxis, protect the liver, the application in the aspect medicine such as antiviral.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
In one aspect of the invention, the 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative by formula (I) expression is provided, or it is at pharmaceutically acceptable ester or salt:
Wherein: R
1, R
2Be selected from-CH
3, COOH, COOQ, CONQ
2Or COSQ, Q wherein is that hydrogen, alkyl (like C1-C6 straight or branched fatty alkyl), substituted alkyl (comprise hydroxyl, amino or amido; Sulfydryl, carbonyl, carboxyl; Cyanic acid, the C1-C6 straight or branched fatty alkyl of groups such as aromatic nucleus), aryl (phenyl, naphthyl; Imidazoles, pyrazoles, virtue property bases such as indoles) or substituted aryl (hydroxyl; Amino or amido, sulfydryl, carbonyl; Carboxyl, cyanic acid, phenyl ring or aromatic heterocyclics such as nitro); X is-C=O or CH
2Y-Z is-CH
2-CH
2-, along or anti--CH=CH-.
R
1, R
2Preferably-CH
3, COOH, COOCH
3, CONHCH
3, COSCH
3, that is, preferred compound is:
3-O-caffeoyl glycyrrhetinic acid methyl esters, structural formula is:
3-O-caffeoyl glycyrrhetinic acid, structural formula is:
3-O-caffeoyl Oleanolic Acid ethyl ester, structural formula is:
3-O-caffeoyl Oleanolic Acid, structural formula is:
3-O-dihydro caffeoyl glycyrrhetinic acid methyl esters, structural formula is:
3-O-dihydro caffeoyl glycyrrhetinic acid, structural formula is:
3-O-dihydro caffeoyl Oleanolic Acid ethyl ester, structural formula is:
3-O-dihydro caffeoyl Oleanolic Acid, structural formula is:
3-O-caffeoyl-N-methyl-Radix Glycyrrhizae time acid amides, structural formula is:
3-O-caffeoyl-N-methyl-olea acid amides, structural formula is:
3-O-caffeoyl-S-methyl-glycyrrhetinic acid monothioester, structural formula is:
Or 3-O-caffeoyl-S-methyl-Oleanolic Acid monothioester, structural formula is:
3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative with general formula (I) of the present invention can react with organic acid, organic bases or mineral alkali, forms pharmaceutically acceptable ester or salt.These esters and salt can make by the preparation method of routine.
Described organic acid is selected from: C1-C6 straight or branched aliphatic carboxylic acid, or aromatics carboxylic acid; Its activated back forms corresponding ester with the middle phenol hydroxyl of compound (I), and structural formula is:
Described mineral alkali is selected from: NaOH, KOH, Ca (OH)
2, NaCO
3, KCO
3Deng; Described organic bases is selected from: NH
3, NH
2R, NHR
2(R is alkyl, substituted alkyl, aryl or substituted aryl), organic basess such as pyridine.R in compound (I)
1Or R2 is when being carboxylic acid, and itself and above alkali can generate salt; Or phenol hydroxyl and highly basic form corresponding salt in the compound (I).
In another aspect of this invention; A kind of preparation method with 3-0-caffeoyl oleanane type pentacyclic triterpene ester derivative of general formula (I) is provided; Its step comprises: (1) is with coffic acid or the Dihydrocaffeic acid and the corresponding acyl chlorides of thionyl chloride backflow generation of the normal diacetyl protection of 1-4; Perhaps the coffic acid of the normal diacetyl protection of 1-4 or the activated intermediate of Dihydrocaffeic acid and DCC coupling reagents such as (N, N '-dicyclohexylcarbodiimide) backflow formation are dissolved in the methylene dichloride; (2) add the normal pyridine of 1-5; Triethylamine; Acid binding agent and Potenlini or Radix Glycyrrhizae acid esters or Potenlini monothioester or Radix Glycyrrhizae acid amides etc. such as carbonate, or Oleanolic Acid or olea acid esters or Oleanolic Acid monothioester or olea acid amides were at 0-50 ℃ of following stirring reaction 1-60 hour; (3) step (2) product is purified through washing, drying, desolventizing and separation and is obtained said compound.Wherein, coffic acid or Dihydrocaffeic acid, Radix Glycyrrhizae acid esters or the Potenlini monothioester or the Radix Glycyrrhizae acid amides etc. of diacetyl protection, or olea acid esters or Oleanolic Acid monothioester or olea acid amides etc. can make by the preparation method of routine.
" equivalent " is chemical key concept in this article: the quality that the acid of one mole of proton is provided is monovalent acid; The quality of accepting the alkali of one mole of proton is a monovalent alkali;
" acid binding agent " refers in this article: in organic reaction, can form salt with the acid-respons that reaction is produced and get alkali, be generally weak base such as pyridine, triethylamine, carbonate etc.
" coupling reagent " refers in this article: this reagent and carboxylic acid group's reaction, the intermediate of formation is comparatively active, is easy to form ester with hydroxyl reaction.DCC (N, N '-dicyclohexylcarbodiimide) is a kind of coupling reagent wherein commonly used, also has CDI (1, the 1-carbonyl dimidazoles), HOBT (I-hydroxybenzotriazole) etc.
In another aspect of this invention; A kind of pharmaceutical composition is provided; What it contained the treatment significant quantity has general formula (I) 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative or its pharmaceutically acceptable ester or salt as the effective active composition, and contains one or more pharmaceutically acceptable carriers.
Said pharmaceutically acceptable carrier is the conventional pharmaceutical carrier of pharmaceutical field, comprising: weighting agent, tackiness agent, disintegrating agent, lubricant, wetting agent, absorption enhancer, tensio-active agent, absorption carrier, glidant, effervescent, correctives, sanitas, coating material or other vehicle.
Described weighting agent comprises one or more composition of lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant; Lubricant such as talcum powder, calcium stearate and magnesium, polyoxyethylene glycol etc.; Wetting agent such as glycerine; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay etc.
Compound of the present invention can medicinal compositions administered, its method of application can be oral, systemic administration (for example, transdermal, snuffing is gone into or use suppository) or parenteral administration (for example, intramuscular, intravenously or subcutaneous).Preferred method of application is oral and injection, can regulate according to disease degree.
The formulation of medicinal compositions of the present invention can as the effective active composition is mixed with one or more carriers, be prepared into required preparation, like formulations such as solid orally ingestible, liquid oral medicine, injections then according to the conventional working method preparation of pharmaceutical field.Said solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, said injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
The amount of effective active composition can change in the used four corner of those skilled in the art in the medicinal compositions of the present invention.Usually, containing weight ratio in the composition is the effective active composition of 0.1%-99.5%, and preferably containing weight ratio is the effective active composition of 0.5%-95%.
The amount of application of compound of the present invention can be done suitably adjustment according to the type and the light and heavy degree of route of administration, patient's age, body weight, disease.3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative or its pharmaceutically acceptable ester or the significant quantity of salt in treatment with general formula of the present invention (I) can be about every day of 0.05-50mg/kg acceptor body weight; Preferred about 0.5-10mg/kg/day.Therefore, use for the people of 70kg body weight, dosage range is most preferably 35-700 milligram every day.Can use by one or many.Consumption can be adjusted if any difference.
In another aspect of this invention, provide 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative and pharmaceutically acceptable ester thereof or salt, and above-mentioned medicinal compositions in preparation anti-inflammatory, antianaphylaxis, protect the liver, the application in the aspect medicine such as antiviral.Preferred 3-O-dihydro caffeoyl glycyrrhetinic acid or its pharmaceutically acceptable ester or salt in preparation anti-inflammatory, antianaphylaxis, protect the liver, application in the antiviral.3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative and pharmaceutically acceptable ester thereof or salt, and above-mentioned medicinal compositions (especially 3-O-dihydro caffeoyl glycyrrhetinic acid or its ester or salt) can be used for treating the various acute and chronic hepatitis medication preparation of (comprising viral hepatitis and non-viral hepatitis), for example be used to treat the medication preparation of various acute and chronic hepatitis due to hepatitis virus such as HAV, HBV, HCV, HEV and the non-hepatitis virus; Also can be used for treating the medication preparation of non-virogenetic acute and chronic hepatitis such as various toxic, metabolic, autoimmunity; Also can be used for treating the medication preparation of various acute and chronic severe hepatic insufficiencys (like hepatitis gravis, liver failure).
Find through experimentation on animals; Compound of the present invention has the double effects that reduces gpt, glutamic-oxal(o)acetic transaminase and removing jaundice (bilirubin direct); Have therapeutic and preventative liver-protecting activity; Can resist acute fatty liver, anti-hepatitis gravis; Simultaneously renal function also there is provide protection; Therefore, can be applicable to prepare anti-inflammatory, antianaphylaxis, protect the liver, in the aspect medicine such as antiviral.
Description of drawings
Below in conjunction with accompanying drawing and embodiment the present invention is done further detailed explanation:
Fig. 1 is the general structure of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative;
Fig. 2 is the preparation flow figure of 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative, wherein: the condition of i: AcONa/Ac
2O, backflow (reflux); The condition of ii: H
2, 5%Pd/C, MeOH, room temperature; The condition of iii: SOCl
2, reflux or N, N '-dicyclohexylcarbodiimide (DCC) activation, or other coupling reagent; The condition of iv: when reacting for glycyrrhetinic acid, condition is H
2SO
4/ MeOH, CH then
3SH or CH
3NH
2Reflux; When being Oleanolic Acid, condition is EtBr, KI/K
2CO
3/ acetone (acetone), backflow, CH then
3SH or CH
3NH
2Reflux; The condition of v: pyridine (pyridine) or other alkali/CH
2Cl
2, room temperature; The condition of vi: MeONa/MeOH, room temperature, LiOH/DMF/H
2O, strongly acidic cation-exchange then.
Embodiment
Reagent and instrument:
Instrument: X-4 numeral shows micro melting point apparatus (production of Tyke, Beijing Instr Ltd.), and fusing point is correction up not; The proton magnetic spectrum is tested by Bruker AV DPX300 nuclear magnetic resonance analyser; Infrared spectra adopts ShimadzuFTIR28400S infrared spectrometer record; The high resolution mass spectrum data are measured by Agilent Agilent 6510Q-TOFLC/MS type mass spectrograph.
Reagent: glycyrrhetinic acid (GA), Oleanolic Acid (OA), coffic acid are 98% purity, available from Shandong dawn vegetable products company limited; Column chromatography silica gel (200-300 order) is available from Yantai marine chemical industry factory; Other reagent are commercially available analytical pure.Used anhydrous solvent is all handled through strict, steams before use.
The preparation of embodiment 1 diacetyl coffic acid (2)
With coffic acid 1 (18.0g 0.10mol) is dissolved in the 200mL acetic anhydride, add sodium acetate, anhydrous (1.6g, 0.02mol), reflux 1 hour, be cooled to room temperature after, with in the reaction solution impouring 2L frozen water, fully stirred 3 hours under the vigorous stirring.Mixed solution suction filtration, solid water are given a baby a bath on the third day after its birth inferior, get light yellow solid diacetyl coffic acid 2 (23.5g, productive rate 89%) after the oven dry.
The preparation of embodiment 2 dihydro diacetyl coffic acids (3)
(2.6g 10mmol) is dissolved in the 50mL methyl alcohol, adds 5% palladium charcoal (Pd-C) catalyzer (0.1g), and normal temperature and pressure stirred 2 hours in hydrogen atmosphere, and tlc (TLC) detects to there not being raw material with diacetyl coffic acid 2.Elimination Pd-C rear filtrate desolventizing gets white solid dihydro diacetyl coffic acid 3 (2.5g, productive rate 94%).
The preparation of embodiment 3 glycyrrhetinic acid methyl esters (6a)
(4.7g 10mmol) is dissolved in the 50mL methyl alcohol, adds the 2mL vitriol oil, reflux 3 hours with glycyrrhetinic acid.After being cooled to room temperature, in reaction solution impouring 150mL water, the abundant stirring with dichloromethane extraction (50mL * 3), merges organic phase, washing, and anhydrous sodium sulfate drying gets white solid glycyrrhetinic acid methyl esters 6a (4.2g, productive rate 87%) behind the decompression desolventizing.
The preparation of embodiment 4 Oleanolic Acid ethyl esters (7a)
In the round-bottomed flask of 250mL with Oleanolic Acid (4.6g 10mmol) is dissolved in the exsiccant acetone (120mL), add salt of wormwood (5.5g, 40mmol), potassiumiodide (0.50g, 2.0mmol), monobromethane (4.4g, 40mmol), heating reflux reaction 4 hours.After being cooled to room temperature, in reaction solution impouring 200mL water, stir, dichloromethane extraction (50ml * 3), the organic phase washing, anhydrous sodium sulfate drying obtains white solid Oleanolic Acid ethyl ester 7a (4.5g, productive rate 94%) behind the decompression desolventizing.
Press embodiment 3,4 same procedure, can prepare the glycyrrhetinic acid ethyl ester, ester glycyrrhetinic acid benzyl ester, Oleanolic Acid methyl esters, olea acid benzyl ester etc.
The preparation of embodiment 5 3-O-diacetyl caffeoyl glycyrrhetinic acid methyl esters (8a)
Method one:
(1.6g 6.0mmol) is dissolved in the 20mL thionyl chloride reflux 2h with compound 2 (being made by embodiment 1).The remaining thionyl chloride of pressure reducing and steaming obtains diacetyl coffee acyl chlorides 4 thick products.At N
2Protection is dissolved in compound 4 thick products in the 30mL exsiccant methylene dichloride down, add compound 6a (making) by embodiment 3 (0.96g, 2.0mmol), pyridine (0.50g, 6.0mmol), reacted 24 hours by stirring at room.Directly separate [V (sherwood oil): V (ethyl acetate)=3: 1] after reaction solution concentrates, obtain 3-O-diacetyl caffeoyl glycyrrhetinic acid methyl esters 8a (1.12g, productive rate 72%) with column chromatography.3-O-diacetyl caffeoyl glycyrrhetinic acid methyl esters 8a is a light yellow solid, mp:176-178 ℃.
Method two:
(1.6g 6.0mmol) is dissolved in the 20mL methylene dichloride, adds DCC (6.6mmol), and stirring at room generated intermediate 5 in 1 hour with compound 2 (being made by embodiment 1).Add compound 6a (making) by embodiment 3 (2.88g, 6.0mmol), triethylamine (0.50g, 6.0mmol), stirring at room reaction 18 hours.Solids removed by filtration DCU directly separates [V (sherwood oil): V (ethyl acetate)=3: 1] with column chromatography after filtrating concentrates, and obtains 3-O-diacetyl caffeoyl glycyrrhetinic acid methyl esters 8a (3.71g, productive rate 83%).3-O-diacetyl caffeoyl glycyrrhetinic acid methyl esters 8a is a light yellow solid, mp:176-178 ℃.
The collection of illustrative plates of compound 8a is following:
IR，v/cm
-1：2935，2864，1770，1723，1630；HRMS：C
44H
58O
9；m/z＝731.4152([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.83(s，3H)，0.88(s，3H)，0.99(s，3H)，1.17(s，3H)，1.18(s，3H)，1.25(s，3H)，1.32(s，3H)，1.29-1.42(m，9H)，1.57-1.66(m，6H)，1.81-2.06(m，4H)，2.30(s，3H，O＝C-CH
3)，2.31(s，3H，O＝C-CH
3)，2.39(s，1H，H-9)，2.84(m，1H，H-18)，3.69(s，3H，O＝C-O-CH
3)，4.65(dd，J＝4.8Hz，11.4Hz，1H，H-3)，5.68(s，1H，H-12)，6.39(d，J＝15.9Hz，1H，＝C-H)，7.22(m，1H，Ar-H)，7.40(m，2H，Ar-H)，7.60(d，J＝15.9Hz，1H，＝C-H)。
The preparation of embodiment 63-O-(diacetyl caffeoyl) Oleanolic Acid ethyl ester (8b)
Identical with the operation of embodiment 5, make 3-O-(diacetyl caffeoyl) Oleanolic Acid ethyl ester 8b, productive rate 75% by compound 2 (making) and compound 7a (making) by embodiment 4 by embodiment 1.3-O-(diacetyl caffeoyl) Oleanolic Acid ethyl ester 8b is a faint yellow solid, mp:153-156 ℃;
The collection of illustrative plates of compound 8b is following:
IR，v/cm
-1：2935，2852，1769，1728，1654；HRMS：C
45H
62O
8；m/z＝731.4520([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.73(s，3H)，0.79(s，3H)，0.83(s，3H)，0.90(s，3H)，0.91(s，3H)，0.92(s，3H)，1.03(m，2H)，1.13(s，3H)，1.23(t，J＝7.8Hz，3H，CH
2-C-H
3)，1.24(m，4H)，1.39(m，2H)，1.51-1.67(m，10H)，1.84(m，2H)，2.30(s，3H，O＝C-CH
3)，2.31(s，3H，O＝C-CH
3)，2.87(dd，J＝4.5Hz，14.4Hz，1H，H-18)，4.09(m，2H，O＝C-O-CH
2-)，4.63(t，J＝7.8Hz，1H，H-3)，5.29(s，1H，H-12)，6.38(d，J＝15.9Hz，1H，＝C-H)，7.22(m，1H，Ar-H)，7.39(m，2H，Ar-H)，7.59(d，J＝15.9Hz，1H，＝C-H)。
The preparation of embodiment 7 3-O-(dihydro diacetyl caffeoyl) glycyrrhetinic acid methyl esters (8c)
Identical with the operation of embodiment 5, make 3-O-(dihydro diacetyl caffeoyl) glycyrrhetinic acid methyl esters 8c, productive rate 68% by compound 3 (making) and compound 6a (making) by embodiment 3 by embodiment 2.3-O-(dihydro diacetyl caffeoyl) glycyrrhetinic acid methyl esters 8c is little yellow solid, mp:172-174 ℃;
The collection of illustrative plates of compound 8c is following:
IR，v/cm
-1：2929，2843，1778，1710，1632；HRMS：C
44H
60O
9；m/z＝733.4310([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.84(s，3H)，0.88(s，3H)，0.97(s，3H)，1.15(s，3H)，1.18(s，3H)，1.25(s，3H)，1.33(s，3H)，1.29-1.41(m，9H)，1.58-1.66(m，6H)，1.81-2.04(m，4H)，2.28(s，3H×2，O＝C-CH
3×2)，2.35(s，1H，H-9)，2.63(t，J＝7.8Hz，2H，C-H
2)，2.79(m，1H，H-18)，2.95(t，J＝7.8Hz，2H，C-H
2)，3.69(s，3H，O＝C-O-CH
3)，4.52(dd，J＝4.8Hz，11.4Hz，1H，H-3)，5.67(s，1H，H-12)，7.04(s，1H，Ar-H)，7.09(s，2H，Ar-H)。
The preparation of embodiment 8 3-O-(dihydro diacetyl caffeoyl) Oleanolic Acid ethyl ester (8d)
Identical with the operation of embodiment 5, make 3-O-(dihydro diacetyl caffeoyl) Oleanolic Acid ethyl ester 8d, productive rate 71% by compound 3 (making) and compound 7a (making) by embodiment 4 by embodiment 2.3-O-(dihydro diacetyl caffeoyl) Oleanolic Acid ethyl ester 8d is a light yellow solid, mp:158-161 ℃;
The collection of illustrative plates of compound 8d is following:
IR，v/cm
-1：2947，2866，1776，1727，1636；HRMS：C
45H
64O
8；m/z＝733.4677([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.72(s，3H)，0.78(s，3H)，0.83(s，3H)，0.89(s，3H)，0.91(s，3H)，0.93(s，3H)，1.03(m，2H)，1.15(s，3H)，1.22(t，J＝7.8Hz，3H，CH
2-C-H
3)，1.24(m，4H)，1.38(m，2H)，1.52-1.68(m，10H)，1.86(m，2H)，2.28(s，3H×2，O＝C-CH
3×2)，2.63(t，J＝7.8Hz，2H，C-H
2)，2.86(dd，J＝4.5Hz，14.4Hz，1H，H-18)，2.95(t，J＝7.8Hz，2H，C-H
2)，4.08(m，2H，O＝C-O-CH
2-)，4.50(t，J＝7.8Hz，1H，H-3)，5.28(s，1H，H-12)，7.04(s，1H，Ar-H)，7.09(s，2H，Ar-H)。
Embodiment 9 deacetylations reaction general method
(for example compound 8a, 8b, 8c, the 8d that is made by embodiment 5,6,7,8 respectively) is dissolved in the methyl alcohol with compound 8, adds the sodium Metal 99.5 of catalytic amount, stirring at room reaction 0.5h, and TLC detects no raw material.After adding strongly acidic cation-exchange stirring 2h, the elimination resin, the filtrating desolventizing promptly gets compound 9 (compound 9a, 9b, 9c, the 9d of face as follows).
3-O-caffeoyl glycyrrhetinic acid methyl esters (9a): productive rate 93%.Faint yellow solid, mp:＜250 ℃ of decomposition; Water insoluble, be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9a is following:
IR，v/cm
-1：3431，2928，2858，1704，1634；HRMS：C
40H
54O
7；m/z＝647.3945([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.83(s，3H)，0.89(s，3H)，0.98(s，3H)，1.17(s，3H)，1.19(s，3H)，1.27(s，3H)，1.35(s，3H)，1.29-1.43(m，9H)，1.59-1.66(m，6H)，1.81-2.03(m，4H)，2.49(s，1H，H-9)，2.83(m，1H，H-18)，3.73(s，3H，O＝C-O-CH
3)，4.71(dd，J＝4.5Hz，11.7Hz，1H，H-3)，5.75(s，1H，H-12)，6.25(d，J＝15.9Hz，1H，＝C-H)，6.89(m，2H，Ar-H)，7.47(s，1H，Ar-H)，7.59(d，J＝15.9Hz，1H，＝C-H)。
3-O-caffeoyl Oleanolic Acid ethyl ester (9b): productive rate 90%.White solid, mp:184-186 ℃; Water insoluble, be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9b is following:
IR，v/cm
-1：3432，2933，2848，1727，1665；HRMS：C
41H
58O
6；m/z＝647.4308([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.73(s，3H)，0.78(s，3H)，0.84(s，3H)，0.90(s，3H)，0.91(s，3H)，0.93(s，3H)，1.02(m，2H)，1.13(s，3H)，1.23(t，J＝7.8Hz，3H，CH
2-C-H
3)，1.24(m，4H)，1.37(m，2H)，1.54-1.69(m，10H)，1.86(m，2H)，2.86(dd，J＝4.5Hz，14.4Hz，1H，H-18)，4.10(m，2H，O＝C-O-CH
2-)，4.61(t，J＝8.1Hz，1H，H-3)，5.27(s，1H，H-12)，6.27(d，J＝15.9Hz，1H，＝C-H)，6.89(m，1H，Ar-H)，7.01(m，1H，Ar-H)，7.13(s，1H，Ar-H)，7.57(d，J＝15.9Hz，1H，＝C-H)。
3-O-(dihydro caffeoyl) glycyrrhetinic acid methyl esters (9c): productive rate 95%.White solid, mp:234-236 ℃; Water insoluble, be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9c is following:
IR，v/cm
-1：3428，2950，2872，1730，1659；HRMS：C
40H
56O
7；m/z＝649.4110([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.83(s，3H)，0.90(s，3H)，0.97(s，3H)，1.15(s，3H)，1.18(s，3H)，1.27(s，3H)，1.32(s，3H)，1.31-1.44(m，9H)，1.59-1.67(m，6H)，1.79-2.04(m，4H)，2.37(s，1H，H-9)，2.58(t，J＝7.8Hz，2H，C-H
2)，2.77(m，1H，H-18)，2.85(t，J＝7.8Hz，2H，C-H
2)，3.69(s，3H，O＝C-O-CH
3)，4.51(dd，J＝4.8Hz，11.2Hz，1H，H-3)，5.68(s，1H，H-12)，6.63(m，1H，Ar-H)，6.76(m，2H，Ar-H)。
3-O-(dihydro caffeoyl) Oleanolic Acid ethyl ester (9d): productive rate 91%.Faint yellow solid, mp:143-145 ℃; Water insoluble, be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9d is following:
IR，v/cm
-1：3424，2946，2856，1727，1611；HRMS：C
41H
60O
6；m/z＝649.4462([M+H]
+)；
1H?NMR(300MHz，CDCl
3)d：0.74(s，3H)，0.79(s，3H)，0.83(s，3H)，0.91(s，3H)，0.92(s，3H)，0.93(s，3H)，1.03(m，2H)，1.12(s，3H)，1.23(t，J＝7.8Hz，3H，CH
2-C-H
3)，1.24(m，4H)，1.38(m，2H)，1.50-1.65(m，10H)，1.84(m，2H)，2.58(t，J＝7.8Hz，2H，C-H2)，2.84(t，J＝7.8Hz，2H，C-H2)，2.88(dd，J＝4.5Hz，14.4Hz，1H，H-18)，4.09(m，2H，O＝C-O-CH
2-)，4.49(t，J＝7.8Hz，1H，H-3)，5.27(s，1H，H-12)，6.70(m，3H，Ar-H)。
The hydrolysis of embodiment 10 methyl ethyl esters
Compound 9 (for example compound 9a, 9b, 9c, the 9d that is made by embodiment 10 respectively) is dissolved in dimethyl formamide (DMF) and the less water, adds 1.3eq LiOH, stirring at room, TLC detects no raw material.Add the dilute hydrochloric acid acidifying, behind the stirring 2h, add water, filter and promptly get compound 9 ' (compound 9a ', 9b ', 9c ', the 9d ' of face as follows):
9a '-caffeoyl glycyrrhetinic acid; White solid; Mp:＜269 ℃ of decomposition; Water insoluble, be slightly soluble in alkaline aqueous solution; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9a ' is following:
HRMS：C
39H
52O
7；m/z＝633.3785([M+H]
+)；1H?NMR(300MHz，CDCl3)d：0.83(s，3H)，0.89(s，3H)，0.98(s，3H)，1.17(s，3H)，1.19(s，3H)，1.27(s，3H)，1.35(s，3H)，1.29-1.43(m，9H)，1.59-1.66(m，6H)，1.81-2.03(m，4H)，2.49(s，1H，H-9)，2.83(m，1H，H-18)，4.71(dd，J＝4.5Hz，11.7Hz，1H，H-3)，5.75(s，1H，H-12)，6.25(d，J＝15.9Hz，1H，＝C-H)，6.89(m，2H，Ar-H)，7.47(s，1H，Ar-H)，7.59(d，J＝15.9Hz，1H，＝C-H).
9b '-caffeoyl Oleanolic Acid; White solid; Mp:300 ℃＜decompose; Water insoluble, be slightly soluble in alkaline aqueous solution; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9b ' is following:
IR，v/cm
-1：3350，2920，1695，1595，1510，1440，1360，1270，1180，1110，1105970，810，755；p?HRMS：C
39H
54O
6；m/z＝619.3992([M+H]
+)；
1H-NMR(300MHz，acetone-d
6)d：0.83(s，3H)，0.91(s，3H)，0.93(s，3H)，0.95(s，3H)，0.96(s，3H)，100(s，3H)，1.21(s，3H)，1.92(dd，2H)，2.90(dd，1H)，4.58(dd，1H)，5.26(t，1H)，6.29(d，1H)，6.86(d，1H)，7.04(dd，1H)，7.16(d，1H)，7.54(d，1H)，6.89.....
9c ' 3-O-(dihydro caffeoyl) glycyrrhetinic acid; White solid; Mp:＜257 ℃ of decomposition; Water insoluble, be slightly soluble in alkaline aqueous solution; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9c ' is following:
HRMS：C
39H
54O
7；m/z＝635.3942([M+H]
+)；1H?NMR(300MHz，CDCl3)d：0.83(s，3H)，0.90(s，3H)，0.97(s，3H)，1.15(s，3H)，1.18(s，3H)，1.27(s，3H)，1.32(s，3H)，1.31-1.44(m，9H)，1.59-1.67(m，6H)，1.79-2.04(m，4H)，2.37(s，1H，H-9)，2.58(t，J＝7.8Hz，2H，C-H2)，2.77(m，1H，H-18)，2.85(t，J＝7.8Hz，2H，C-H2)，4.51(dd，J＝4.8Hz，11.2Hz，1H，H-3)，5.68(s，1H，H-12)，6.63(m，1H，Ar-H)，6.76(m，2H，Ar-H).
9d ' 3-O-(dihydro caffeoyl) Oleanolic Acid.White solid; Mp:＜300 ℃ of decomposition; Water insoluble, be slightly soluble in alkaline aqueous solution; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
The collection of illustrative plates of compound 9d ' is following:
HRMS：C
39H
56O
6；m/z＝621.4147([M+H]
+)；1H?NMR(300MHz，CDCl3)d：0.74(s，3H)，0.79(s，3H)，0.83(s，3H)，0.91(s，3H)，0.92(s，3H)，0.93(s，3H)，1.03(m，2H)，1.12(s，3H)，1.24(m，4H)，1.38(m，2H)，1.50-1.65(m，10H)，1.84(m，2H)，2.58(t，J＝7.8Hz，2H，C-H2)，2.84(t，J＝7.8Hz，2H，C-H2)，2.88(dd，J＝4.5Hz，14.4Hz，1H，H-18)，4.49(t，J＝7.8Hz，1H，H-3)，5.27(s，1H，H-12)，6.70(m，3H，Ar-H).
The preparation of embodiment 11N-methyl-Radix Glycyrrhizae time acid amides and N-methyl-olea acid amides
With compound 0.01mol 6a (making) (R by embodiment 3
1=COOCH
3, R
2=CH
3) be dissolved in the methylene dichloride, add the 1.3eq methylamine, stirring at room, TLC detects no raw material.Recrystallization behind the decompression desolventizing gets compound 6b (R
1=CONHCH
3, R
2=CH
3), i.e. N-methyl-Radix Glycyrrhizae time acid amides 6b (productive rate 89%).Faint yellow solid; Mp:＜251 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
Compound 6b's
1H NMR (300MHz, CDCl
3) d:0.83 (s, 3H), 0.88 (s, 3H), 0.99 (s, 3H), 1.17 (s, 3H), 1.18 (s, 3H), 1.25 (s, 3H), 1.32 (s, 3H), 1.29-1.42 (m, 9H), 1.57-1.66 (m, 6H), 1.81-2.06 (m, 4H), 2.39 (s, 1H, H-9), 2.74 (s, 3H, N-CH
3), 2.84 (m, 1H, H-18), 3.23 (m, 1H, H-3), 5.68 (s, 1H, H-12), 6.89 (s, 1H, N-H).
The same method is with compound 7a (being made by embodiment 4) (R
2=COOCH
2CH
3, R
1=CH
3) react with methylamine, obtain compound 7b (R
2=CONHCH
3, R
1=CH
3) N-methyl-olea acid amides, white solid (productive rate 92%); Mp:＜270 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
Compound 7b's
1H NMR (300MHz, CDCl
3) d:0.73 (s, 3H), 0.79 (s, 3H), 0.83 (s, 3H), 0.90 (s, 3H), 0.91 (s, 3H), 0.92 (s, 3H), 1.03 (m, 2H), 1.13 (s, 3H), 1.24 (m, 4H), 1.39 (m, 2H), 1.51-1.67 (m, 10H), 1.84 (m, 2H), 2.72 (s, 3H, N-CH
3), 2.87 (dd, J=4.5Hz, 14.4Hz, 1H, H-18), 3.21 (m, 1H, H-3), 5.29 (s, 1H, H-12), 6.77 (s, 1H, N-H).
The preparation of embodiment 12S-methyl-glycyrrhetinic acid monothioester and S-methyl-Oleanolic Acid monothioester
With compound 0.01mol 6a (making) (R by embodiment 3
1=COOCH
3, R
2=CH
3) be dissolved in the methylene dichloride, add the 1.2eq thiomethyl alcohol, heat back and heat up in a steamer stirring, TLC detects no raw material.Column chromatography (sherwood oil: ethyl acetate=10: 2), get white solid 6c (R behind the decompression desolventizing
1'=COSCH
3, R
2'=CH
3) S-methyl-glycyrrhetinic acid monothioester (productive rate 80%), mp:＜280 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
Compound 6c's
1H NMR (300MHz, CDCl
3) d:0.83 (s, 3H), 0.88 (s, 3H), 0.99 (s, 3H), 1.17 (s, 3H), 1.18 (s, 3H), 1.25 (s, 3H), 1.32 (s, 3H), 1.29-1.42 (m, 9H), 1.57-1.66 (m, 6H), 1.81-2.06 (m, 4H), 2.30 (s, 3H, S-CH
3), 2.39 (s, 1H, H-9), 2.84 (m, 1H, H-18), 3.23 (m, 1H, H-3), 5.68 (s, 1H, H-12).
The same method is with compound 7a (being made by embodiment 4) (R
2=COOCH
2CH
3, R
1=CH
3) react with thiomethyl alcohol, obtain compound 7c (R
2'=COSCH
3, R
1'=CH
3) S-methyl-Oleanolic Acid monothioester (productive rate 85%).Faint yellow solid, mp:＜270 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
Compound 7c's
1H NMR (300MHz, CDCl
3) d:0.73 (s, 3H), 0.79 (s, 3H), 0.83 (s, 3H), 0.90 (s, 3H), 0.91 (s, 3H), 0.92 (s, 3H), 1.03 (m, 2H), 1.13 (s, 3H), 1.24 (m, 4H), 1.39 (m, 2H), 1.51-1.67 (m, 10H), 1.84 (m, 2H), 2.31 (s, 3H, S-CH
3), 2.87 (dd, J=4.5Hz, 14.4Hz, 1H, H-18), 3.21 (m, 1H, H-3), 5.29 (s, 1H, H-12).
The preparation of embodiment 13 3-O-diacetyl caffeoyl-N-methyl-Radix Glycyrrhizaes time acid amides (21a) and 3-O-diacetyl caffeoyl-N-methyl-olea acid amides (21b)
(1.6g 6.0mmol) is dissolved in the 20mL thionyl chloride reflux 2h with compound 2 (being made by embodiment 1).The remaining thionyl chloride of pressure reducing and steaming obtains the thick product of diacetyl coffee acyl chlorides (4).At N
2Protection is dissolved in compound 4 thick products in the 30mL exsiccant methylene dichloride down, adds compound 6b (being made by embodiment 11) (R
1=CONHCH
3, R
2=CH
3) (0.96g, 2.0mmol), salt of wormwood (0.84g, 6.0mmol), stirring at room reaction.Directly separate [V (sherwood oil): V (ethyl acetate)=3: 1] after reaction solution concentrates, obtain light yellow solid 21a (1.12g, productive rate 72%), 3-O-diacetyl caffeoyl-N-methyl-Radix Glycyrrhizae time acid amides with column chromatography.
The same method is with compound 7b (being made by embodiment 11) (R
2=CONHCH
3, R
1=CH
3) react, obtain compound 21b (R
2=CONHCH
3, R
1=CH
3) 3-O-diacetyl caffeoyl-N-methyl-olea acid amides, light yellow solid (productive rate 81%).
The preparation of embodiment 143-O-diacetyl caffeoyl-S-methyl-glycyrrhetinic acid monothioester (22a) and 3-O-diacetyl caffeoyl-S-methyl-Oleanolic Acid monothioester (22b)
(1.6g 6.0mmol) is dissolved in the 20mL thionyl chloride reflux 2h with compound 2 (being made by embodiment 1).The remaining thionyl chloride of pressure reducing and steaming obtains the thick product of diacetyl coffee acyl chlorides (4).At N
2Protection is dissolved in compound 4 thick products in the 30mL exsiccant methylene dichloride down, add compound 6c (making) by embodiment 12 (0.98g, 2.0mmol), pyridine (0.50g, 6.0mmol), react by stirring at room.Directly separate [V (sherwood oil): V (ethyl acetate)=3: 1] after reaction solution concentrates, obtain light yellow solid 22a (3-O-diacetyl caffeoyl-S-methyl-glycyrrhetinic acid monothioester) (1.23g, productive rate 80%) with column chromatography.
The same method is with compound 7c (being made by embodiment 12) (R
2=COSCH
3, R
1=CH
3) react, obtain compound 22b (R
2=COSCH
3, R
1=CH
3) 3-O-diacetyl caffeoyl-S-methyl-Oleanolic Acid monothioester, light yellow solid (productive rate 75%).
Embodiment 15 deacetylation prepared in reaction 3-O-caffeoyl-N-methyl-Radix Glycyrrhizaes time acid amides (10a) and 3-O-caffeoyl-N-methyl-olea acid amides (10b)
Compound 21a or 21b (being made by embodiment 13) are dissolved in the methyl alcohol, add the sodium Metal 99.5 of catalytic amount, stirring at room reaction 0.5h, TLC detects no raw material.After adding strongly acidic cation-exchange stirring 2h, the elimination resin, the filtrating desolventizing promptly gets compound 10a (R
1=CONHCH
3, R
2=CH
3) 3-O-caffeoyl-N-methyl-Radix Glycyrrhizae time acid amides, light yellow solid (productive rate 77%).Mp:＜255 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO; Or obtain compound 10b (R
2=CONHCH
3, R
1=CH
3) 3-O-caffeoyl-N-methyl-olea acid amides, faint yellow solid (productive rate 79%).Mp:＜261 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO;
Compound 10a's
1H NMR (300MHz, CDCl
3) d:0.83 (s, 3H), 0.89 (s, 3H), 0.98 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.27 (s, 3H), 1.35 (s, 3H), 1.29-1.43 (m, 9H), 1.59-1.66 (m, 6H), 1.81-2.03 (m, 4H), 2.49 (s, 1H, H-9), 2.76 (s, 3H, N-CH
3), 2.83 (m, 1H, H-18), 4.71 (dd, J=4.5Hz, 11.7Hz, 1H, H-3), 5.75 (s; 1H, H-12), 6.25 (d, J=15.9Hz, 1H ,=C-H), 6.89 (m, 2H, Ar-H), 7.47 (s; 1H, Ar-H), 7.59 (d, J=15.9Hz, 1H ,=C-H), 8.54 (s, 1H, N-H).HRMS：C
40H
55NO
6；m/z＝646.4101([M+H]
+)；
Compound 10b's
1H NMR (300MHz, CDCl
3) d:0.73 (s, 3H), 0.78 (s, 3H), 0.84 (s, 3H), 0.90 (s, 3H), 0.91 (s, 3H), 0.93 (s, 3H), 1.02 (m, 2H), 1.13 (s, 3H), 1.24 (m, 4H), 1.37 (m, 2H), 1.54-1.69 (m, 10H), 1.86 (m, 2H), 2.72 (s, 3H, N-CH
3), 2.86 (dd, J=4.5Hz, 14.4Hz, 1H, H-18); 4.61 (t, J=8.1Hz, 1H, H-3), 5.27 (s, 1H; H-12), 6.27 (d, J=15.9Hz, 1H ,=C-H), 6.89 (m; 1H, Ar-H), 7.01 (m, 1H, Ar-H); 7.13 (s, 1H, Ar-H), 7.57 (d, J=15.9Hz; 1H ,=C-H), 8.54 (s, 1H, N-H).HRMS：C
40H
57NO
5；m/z＝632.43110([M+H]
+)；
The same method is with compound 22a (being made by embodiment 14) (R
1=COSCH
3, R
2=CH
3) or compound 22b (making by embodiment 14) (R
2=COSCH
3, R
1=CH
3) carry out the deacetylation reaction, obtain compound 11a (R
1=COSCH
3, R
2=CH
3) 3-O-caffeoyl-S-methyl-glycyrrhetinic acid monothioester, light yellow solid (productive rate 75%).Mp:＜268 ℃ of decomposition; Water insoluble; Be dissolved in alcohol, methylene dichloride, DMF is in the organic solvents such as DMSO; Or obtain compound 11b 3-O-diacetyl caffeoyl-S-methyl-Oleanolic Acid monothioester, light yellow solid (productive rate 80%).Mp:238-241 ℃; Water insoluble, be dissolved in the organic solvents such as alcohol, methylene dichloride, DMF, DMSO;
Compound 11a's
1H NMR (300MHz, CDCl
3) d:0.83 (s, 3H), 0.89 (s, 3H), 0.98 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.27 (s, 3H), 1.35 (s, 3H), 1.29-1.43 (m, 9H), 1.59-1.66 (m, 6H), 1.81-2.03 (m, 4H), 2.30 (s, 3H, S-CH
3), 2.49 (s, 1H, H-9), 2.83 (m, 1H, H-18), 4.71 (dd, J=4.5Hz, 11.7Hz; 1H, H-3), 5.75 (s, 1H, H-12), 6.25 (d, J=15.9Hz, 1H ,=C-H), 6.89 (m; 2H, Ar-H), 7.47 (s, 1H, Ar-H), 7.59 (d, J=15.9Hz, 1H ,=C-H).HRMS：C
40H
54O
6S；m/z＝663.3711([M+H]
+)；
Compound 11b's
1H NMR (300MHz, CDCl
3) d:0.73 (s, 3H), 0.78 (s, 3H), 0.84 (s, 3H), 0.90 (s, 3H), 0.91 (s, 3H), 0.93 (s, 3H), 1.02 (m, 2H), 1.13 (s, 3H), 1.24 (m, 4H), 1.37 (m, 2H), 1.54-1.69 (m, 10H), 1.86 (m, 2H), 2.34 (s, 3H, S-CH
3), 2.86 (dd, J=4.5Hz, 14.4Hz, 1H, H-18), 4.61 (t, J=8.1Hz, 1H, H-3); 5.27 (s, 1H, H-12), 6.27 (d, J=15.9Hz, 1H ,=C-H), 6.89 (m, 1H, Ar-H); 7.01 (m, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 7.57 (d, J=15.9Hz, 1H ,=C-H).HRMS：C
40H
56O
5S；m/z＝649.3929([M+H]
+)；
The preparation of embodiment 16 medicament composition capsule agent of the present invention
Each capsule (106mg) contains the capsule of 50mg effective active composition, prepares as follows:
Consumption/grain
Effective active composition (the compound 9a sample of embodiment 9) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Effective active composition, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes; The system softwood sieves, and the system wet granular is in 50-60 ℃ of drying; Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly get.
The preparation of embodiment 17 drug combination injections of the present invention
Every peace bottle (50mL) contains the injection of 50mg effective active composition, prepares as follows:
Consumption/50mL
Effective active composition (the compound 9c sample of embodiment 9) 50mg
Hydrocerol A 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and Hydrocerol A, stirring and dissolving and after; Add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0; Add 0.2 gram activated carbon; Stirred 20 minutes under the room temperature, filter, filtrating; Strength of solution is decided in middle detection; By 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Below beneficial effect of the present invention is done further to set forth through Test Example:
Liver injury experiment due to the therapeutic liver-protecting activity of Test Example 1 compound, anti-Yi Liuqingsuannaizhi
1. material
1.1 160 of animal health male mouse of kunming, body weight 20 scholar 2g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 11 groups by the table of random number method; Be 10 of normal group, pathological model group (15), coffic acid group (15), glycyrrhetinic acid group (15), Oleanolic Acid group (15), coffic acid+glycyrrhetinic acid group (15), coffic acid+Oleanolic Acid group (15), 3-caffeoyl glycyrrhetinic acid methyl esters (9a; 15), 3-caffeoyl Oleanolic Acid ethyl ester (9b; 15), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c; 15), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d, 15).The 12h fasting before test of all mouse, but freely drink water.
1.2 medicine coffic acid, glycyrrhetinic acid, Oleanolic Acid commercially available prod, 3-caffeoyl glycyrrhetinic acid methyl esters (9a), 3-caffeoyl Oleanolic Acid ethyl ester (9b), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d) self-control.
1.3 the reagent Yi Liuqingsuannaizhi (a-Naphthyl isothiocyanate, ANIT), CP (chemical pure), Tong County, Beijing Fine Chemical Works of cultivating people of ability, NO 911209; Gpt (ALT; IU/L), glutamic-oxal(o)acetic transaminase (AST; IU/L), bilirubin direct (DB; Umol/L), TOTAL BILE ACID (BA; Umol/L), blood urea nitrogen (BUN; Mmol/L), (CR umol/L) measures test kit, the DXC800 of Beckman Coulter Inc. automatic clinical chemistry analyzer dedicated kit to creatinine.
1.4 key instrument equipment DXC800 automatic clinical chemistry analyzer (U.S. Beckman Coulter Inc.).
2 methods
2.1 modeling and administration are except that normal group; Other mouse is adopted ANIT to be dissolved in and is mixed with 14mg/ml concentration in an amount of vegetables oil; Irritate stomach modeling with ANIT 70mg/Kg dosage with the 0.1ml/20g per os experiment the 1st day; Test the 2nd; Group adopted coffic acid respectively in 3 days; Glycyrrhetinic acid; Oleanolic Acid; Coffic acid+glycyrrhetinic acid; Coffic acid+Oleanolic Acid; 3-caffeoyl glycyrrhetinic acid methyl esters (9a); 3-caffeoyl Oleanolic Acid ethyl ester (9b); 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c); Each 50 μ mol/Kg of 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d) are with the 0.1ml/20g oral administration; The pathology control group adopts equal-volume distilled water oral administration, and 24 hours (contaminating 72 hours) backs of time administration execution collection sample does not supply to detect.
2.2 detect index and method
Machine detects on the serum liver renal function index detection reference reagent box specification sheets.
3. result
Serum liver renal function index experimental result is seen shown in the table 1.
The different group serum liver of table 1 renal function index changes
Liver injury experiment due to the therapeutic liver-protecting activity of Test Example 2 compounds, anti-tetracol phenixin
1. material
1.1 70 of the female kunming mices of animal health, body weight 20 scholar 2g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 4 groups by the table of random number method; Promptly be divided into normal group (10), model group (10) and sweet flat group (10), 3-caffeoyl glycyrrhetinic acid methyl esters (9a; 10), 3-caffeoyl Oleanolic Acid ethyl ester (9b; 10), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c; 10), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d, 10).The 12h fasting before test of all mouse, but freely drink water.The 12h fasting before test of all mouse, but freely drink water.
1.2 the sweet flat commercially available prod of medicine, 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) self-control.
1.3 the reagent tetracol phenixin (Carbon tetrachoride, CCL4), AR (analytical pure), Suzhou City's second chemical institute; (ALT IU/L) measures test kit, the DXC800 of Beckman Coulter Inc. automatic clinical chemistry analyzer dedicated kit to gpt.
1.4 key instrument equipment key instrument equipment DXC800 automatic clinical chemistry analyzer (U.S. Beckman Coulter Inc.).
2. method
2.1 modeling and administration are except that normal group; Other respectively organizes mouse in experiment the 1st; All adopted tetracol phenixin (CCL4) to be dissolved in peanut oil in 3 days; With CCI42ML/Kg is that the 0.1ml/20g per os is irritated the stomach modeling; Experiment the 2nd after the modeling; 3; 4 days sweet flat group; 3-caffeoyl glycyrrhetinic acid methyl esters (9a) group; 3-caffeoyl Oleanolic Acid ethyl ester (9b) group; 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c) group; 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d) group adopts sweet flat; 3-caffeoyl glycyrrhetinic acid methyl esters (9a); 3-caffeoyl Oleanolic Acid ethyl ester (9b); 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c); (0.05mmol/Kg dosage is with the 0.1ml/20G oral administration for each 50 μ mol/Kg of 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d); Normal and pathology control group adopts equal-volume water liquid oral administration, and execution was collected sample and supplied detection after (for the second time) modeling was for the last time contaminated 24 hours.
2.2 detect index and method
Machine detects on the serum liver renal function index detection reference reagent box specification sheets.
3. result
Each is organized serum glutamic pyruvic transminase (ALT) and changes referring to table 2.
Table 2 is respectively organized mice serum ALT and is changed
Liver injury experiment due to the preventative liver-protecting activity of Test Example 3 compounds, anti-Yi Liuqingsuannaizhi
1. material
1.1 70 of animal health male SD mouses, body weight 200 scholar 20g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 11 groups by the table of random number method; Be 10 of normal group, pathological model group (10), sweet flat group (10), 3-caffeoyl glycyrrhetinic acid methyl esters (9a; 10), 3-caffeoyl Oleanolic Acid ethyl ester (9b; 10), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c; 10), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d, 10).The 12h fasting before test of all rats, but freely drink water.
1.2 the sweet flat commercially available prod of medicine, 3-caffeoyl glycyrrhetinic acid methyl esters (9a), 3-caffeoyl Oleanolic Acid ethyl ester (9b), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d) self-control.
1.3 the reagent Yi Liuqingsuannaizhi (a-Naphthyl isothiocyanate, ANIT), CP (chemical pure), Tong County, Beijing Fine Chemical Works of cultivating people of ability, NO 911209; Gpt (ALT; IU/L), glutamic-oxal(o)acetic transaminase (AST; IU/L), Pseudocholinesterase (CHE; IU/L), glutamyltranspeptidase (GGT; IU/L), alkaline phosphatase (AKP; IU/L), serum lactic dehydrogenase (LDH; IU/L), cholesterol (CHOL; Mmol/L), creatinine (CR, umol/L), bilirubin direct (DB, umol/L), TOTAL BILE ACID (BA; Umol/L), uric acid (UA; Umol/L), (BUN mmol/L) measures test kit, the DXC800 of Beckman Coulter Inc. automatic clinical chemistry analyzer dedicated kit to blood urea nitrogen.
1.4 key instrument equipment DXC800 automatic clinical chemistry analyzer (U.S. Beckman Coulter Inc.).
2. method
2.1 modeling and administration are except that normal group and model group rat; Other is respectively organized rat and began to adopt sweet flat commercially available prod on the 1st day in experiment; 3-caffeoyl glycyrrhetinic acid methyl esters (9a), 3-caffeoyl Oleanolic Acid ethyl ester (9b), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9d) 50 μ mol/Kg are with the 0.1ml/20g oral administration; Once a day; Totally 7 days, the pathology control group adopted equal-volume distilled water oral administration.Other is respectively organized rat and adopts ANIT to be dissolved in to be mixed with 14mg/ml concentration in an amount of vegetables oil except that normal group to test the 5th day; Irritate the stomach modeling with ANIT 70mg/Kg dosage with the 0.1ml/20g per os, test the 8th day promptly inferior administration 24 hours (contaminating 72 hours) backs execution collection sample and supply detection.
2.2 detect index and method
Machine detects on the Serum ALT detection reference reagent box specification sheets.
3. result
Serum liver renal function index experimental result is seen shown in the table 3.
The different group serum liver of table 3 renal function index changes
Liver injury experiment due to the preventative liver-protecting activity of Test Example 4 compounds, anti-tetracol phenixin
1. material
1.1 40 of the female kunming mices of animal health, body weight 20 scholar 2g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 4 groups by the table of random number method; Promptly be divided into normal group (10), model group (10) and sweet flat group (10), 3-caffeoyl glycyrrhetinic acid methyl esters group (9a; 10), 3-caffeoyl Oleanolic Acid ethyl ester group (9b, 10), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c, 10).The 12h fasting before test of all mouse, but freely drink water.
1.2 the sweet flat commercially available prod of medicine, 3-caffeoyl glycyrrhetinic acid methyl esters (9a), 3-caffeoyl Oleanolic Acid ethyl ester (9b), 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) self-control.
1.3 the reagent tetracol phenixin (Carbon tetrachoride, CCL4), AR (analytical pure), Suzhou City's second chemical institute; (ALT IU/L) measures test kit, the DXC800 of Beckman Coulter Inc. automatic clinical chemistry analyzer dedicated kit to gpt.
1.4 key instrument equipment DXC800 automatic clinical chemistry analyzer (U.S. Beckman Coulter Inc.).
2. method
2.1 modeling and administration are except that normal group and model group mouse; Sweet flat group began to adopt sweet gentle 3-caffeoyl glycyrrhetinic acid methyl esters (9a), 3-caffeoyl Oleanolic Acid ethyl ester (9b), each 50 μ mol/Kg of 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) with the 0.1ml/20g oral administration with 3-caffeoyl glycyrrhetinic acid methyl esters (9a) group, 3-caffeoyl Oleanolic Acid ethyl ester (9b) group, 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) group mouse on the 1st day in experiment; Once a day; Totally 7 days, the pathology control group adopted equal-volume distilled water oral administration.Other is respectively organized mouse and adopts tetracol phenixin (CCL4) to be dissolved in peanut oil except that normal group to test the 7th day, is that the 0.1ml/20g per os is irritated the stomach modeling with CCL42ML/Kg, test the 8th day promptly 24 hours (contaminate 24 hours) backs of time administration put to death and collect sample and supply detection.
2.2 detect index and method
Serum glutamic pyruvic transminase (ALT) is measured, and reference reagent box specification sheets detects, and reads the OD value.
3. result
Each is organized serum glutamic pyruvic transminase (ALT) and changes referring to table 4.
Table 4 is respectively organized mice serum ALT and is changed
The anti-acute fatty liver experiment of Test Example 5 compounds
1. material
1.1 40 of the female kunming mices of animal health, body weight 20 scholar 2g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 4 groups by the table of random number method, promptly is divided into normal group (10), model group (10) and sweet flat group (10), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c), 10).The 12h fasting before test of all mouse, but freely drink water.
1.2 the sweet flat commercially available prod of medicine, 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) self-control.
1.3 basal feed 40% is adopted in the self-control of reagent high lipid food, commercially available caster sugar 6%, and edible lard 20%, egg 34% is processed; Dexamethasone adopts dexamethasone acetate (Dexamethasone Acetate) injection liquid, 5mg/lml, Shandong Hua Xin Pharmacy stock Co., Ltd; Dehydrated alcohol (Ethanol, Ethylalcohol), AR (analytical pure), development chemical plant, Shanghai, NO 200709328; Gpt (ALT) is measured test kit, and bio-engineering research institute product is built up in Nanjing, and NO 20100114.
1.4 key instrument equipment constant water bath box (the last Nereid of DK-S26 is grand), microplate reader (SpectraMaxM5, Molecular Devices).
2. method
2.1 modeling and administration experiment began except that normal group (10) in first day; All adopt high fat diet; High fat diet is divided into 3 groups at random after 3 days; Be model group (10) and sweet flat (10); 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c; 10); Sweet gentle 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c) group adopts sweet flat respectively; Each 50 μ mol/Kg (0.05mmol/Kg dosage of 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c); With the 0.1ml/20G oral administration; The 20%ALC liquid preparation of adopting 0.5%CMC to join); The 20%ALC liquid equal-volume oral administration normal and the pathology control group adopts 0.5%CMC to join; Once a day, continuous 12d; In experiment beginning in the 6th day, except that the normal control group, all the other each groups are all drunk and were contained 20mg dexamethasone/L water totally 4 days, the 9th day equal ig 50% ethanol 0.1ml/10g of other each treated animals of experiment except that normal group (10).After water 16h is can't help in the last fasting, get the hematometry serum ALT activities.
2.2 detect index and method
Serum ALT detects, and reference reagent box specification sheets detects, and reads the OD value.
3. result
Each is organized serum glutamic pyruvic transminase (ALT) and changes referring to table 5.
Each group survival mouse Serum ALT of table 5 changes (OD value)
The anti-hepatitis gravis experiment of Test Example 6 compounds
1. material
1.1 80 of animal health male mouse of kunming, body weight 20 scholar 2g are provided by Shuguang Hospital's experimental animal room.Mouse is divided into 4 groups by the table of random number method, promptly is divided into normal group (20), model group (20) and sweet flat group (20), 3-dihydro caffeoyl glycyrrhetinic acid methyl esters group (9c, 20).The 12h fasting before test of all mouse, but freely drink water.
1.2 the sweet flat commercially available prod of medicine, 3-dihydro caffeoyl Oleanolic Acid ethyl ester (9c) self-control.
1.3 the reagent concanavalin A, the SIGMA product; Gpt (ALT) is measured test kit, and bio-engineering research institute product is built up in Nanjing, and NO 20100114.
1.4 key instrument equipment constant water bath box (the last Nereid of DK-S26 is grand), microplate reader (SpectraMaxM5, Molecular Devices).
2. method
2.1 modeling and administration are except that normal group and model group mouse; Sweet gentle 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c) group mouse began to adopt each 50 μ mol/Kg of sweet gentle 3-dihydro caffeoyl glycyrrhetinic acid methyl esters (9c) with the 0.1ml/20g oral administration on the 1st day in experiment; Once a day; Totally 5 days, the pathology control group adopted equal-volume distilled water oral administration.Other is respectively organized mouse and adopts concanavalin A 15mg/Kg (with 0.1ml physiological saline/20G dosage) to carry out the tail vein to attack contamination except that normal group everyday to test the 5th, test the 6th day promptly 24 hours (attacking poison 24 hours) backs of time administration put to death and collect sample and supply to detect.
2.2 detect index and method
(1) mouse generalized case: comprise activity, hair color, take the photograph water and food and mortality ratio.
(2) serum glutamic pyruvic transminase (ALT) is measured: reference reagent box specification sheets detects, and reads the OD value.
3. result
(1) generalized case changes: after concanavalin A tail vein is attacked the half an hour of contaminating, and the mouse listlessness, the mouse that has after 3-4 hour begins death, and it is as shown in table 6 that death toll is respectively organized in experiment.
Table 6 is respectively organized death toll and is changed
(2) serum glutamic pyruvic transminase (ALT) changes: each group survival mouse Serum ALT changes referring to table 7.
Each group survival mouse Serum ALT of table 7 changes (OD value)
Claims (11)
- By the 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative of formula (I) expression or its at pharmaceutically acceptable ester or salt:
Wherein: R 1, R 2Be selected from-CH 3, COOH, COOQ, CONQ 2Or COSQ, Q wherein is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; X is-C=O or CH 2Y-Z is-CH 2-CH 2-, along or anti--CH=CH-. - 2. 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative as claimed in claim 1 or its is characterized in that: described R at pharmaceutically acceptable ester or salt 1, R 2Be selected from-CH 3, COOH, COOCH 3, CONHCH 3Or COSCH 3
- 3. 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative as claimed in claim 1 or it is at pharmaceutically acceptable ester or salt; It is characterized in that: described pharmaceutically acceptable ester is compound and the organic acid reaction with general formula (I); Form pharmaceutically acceptable ester; Described organic acid is selected from: C1-C6 straight or branched aliphatic carboxylic acid, or aromatics carboxylic acid.
- 4. 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative as claimed in claim 1 or it is at pharmaceutically acceptable ester or salt; It is characterized in that: described pharmacy acceptable salt is compound and mineral alkali or the organic bases reaction with general formula (I); Form pharmacy acceptable salt; Described mineral alkali is selected from: NaOH; KOH, Ca (OH) 2, NaCO 3Or KCO 3Said organic bases is selected from NH 3, NH 2R, NHR 2Or pyridine, wherein R is alkyl, substituted alkyl, aryl or substituted aryl.
- 5. the preparation method of a 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative as claimed in claim 1; Its step comprises: coffic acid or Dihydrocaffeic acid and the corresponding acyl chlorides of thionyl chloride backflow generation that the normal diacetyl of 1-4 is protected in (1) perhaps are dissolved in the coffic acid of the normal diacetyl protection of 1-4 or the activated intermediate of coupling reagents backflow formation such as Dihydrocaffeic acid and DCC in the methylene dichloride; (2) add the normal pyridine of 1-5; Triethylamine; Acid binding agent and Potenlini or Radix Glycyrrhizae acid esters or Potenlini monothioester or Radix Glycyrrhizae acid amides etc. such as carbonate, or Oleanolic Acid or olea acid esters or Oleanolic Acid monothioester or olea acid amides were at 0-50 ℃ of following stirring reaction 1-60 hour; (3) step (2) product is purified through washing, drying, desolventizing and separation and is obtained said compound.
- 6. pharmaceutical composition is characterized in that: contain 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative as claimed in claim 1 or its pharmaceutically acceptable ester or the salt of treating significant quantity, and pharmaceutically acceptable carrier.
- 7. pharmaceutical composition as claimed in claim 6 is characterized in that: the formulation of said pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
- As claim 6 or 7 described pharmaceutical compositions in preparation anti-inflammatory, antianaphylaxis, protect the liver, application in the antiviral.
- As each described 3-O-caffeoyl oleanane type pentacyclic triterpene ester derivative of claim 1-4 or its pharmaceutically acceptable ester or salt in preparation anti-inflammatory, antianaphylaxis, protect the liver, application in the antiviral.
- 10. according to Claim 8 or 9 described application, it is characterized in that said anti-inflammatory comprises viral hepatitis and non-viral hepatitis for the various acute and chronic hepatitis of treatment; Said viral hepatitis is various acute and chronic hepatitis due to hepatitis viruss such as HAV, HBV, HCV, HEV and the non-hepatitis virus; Described non-viral hepatitis is non-virogenetic acute and chronic hepatitis such as various toxic, metabolic, autoimmunity.
- 11. according to Claim 8 or 9 described application; It is characterized in that; 3-O-dihydro caffeoyl glycyrrhetinic acid or its are treated various acute and chronic severe hepatic insufficiencys at pharmaceutically acceptable ester or salt in preparation, comprise hepatitis gravis, the application in the medicine of liver failure.
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| CN102532246A (en) * | 2012-02-27 | 2012-07-04 | 浙江大学 | Oleanolic acid derivative as well as preparation method and application thereof |
| CN103342729A (en) * | 2013-03-26 | 2013-10-09 | 中国科学院上海药物研究所 | Caffeoyl substituted pentacyclic triterpenoid derivatives and purpose thereof |
| WO2014154131A1 (en) * | 2013-03-26 | 2014-10-02 | 中国科学院上海药物研究所 | Caffeoyl substituted pentacyclic triterpene derivative and use thereof |
| CN103342729B (en) * | 2013-03-26 | 2016-09-14 | 中国科学院上海药物研究所 | Substituted ramification of pentacycle triterpene of coffee acyl and application thereof |
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| CN104224796B (en) * | 2013-06-16 | 2017-04-12 | 浙江大学 | Application of oleanane triterpene ester derivative in preparation for anti-neurodegeneration medicine |
| CN109789073A (en) * | 2016-03-31 | 2019-05-21 | 株式会社爱茉莉太平洋 | For skin moisture-keeping or skin-whitening, the caffeic acid ester containing pentacyclic triterpene composition |
| CN111018938A (en) * | 2019-12-10 | 2020-04-17 | 中国人民解放军第二军医大学 | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof |
| CN111018938B (en) * | 2019-12-10 | 2021-05-25 | 中国人民解放军第二军医大学 | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof |
| CN111789854A (en) * | 2020-07-27 | 2020-10-20 | 大理大学 | Medical application of 2-alkene-1-alcohol glycyrrhetinic acid methyl ester in preparation of antiviral hepatitis B |
| CN114133424A (en) * | 2020-09-03 | 2022-03-04 | 沈阳药科大学 | Triterpenoid compound and preparation method and application thereof |
| CN112898373A (en) * | 2021-01-23 | 2021-06-04 | 沈阳药科大学 | Pentacyclic triterpenoid compound and preparation method and application thereof |
| CN114014905A (en) * | 2021-12-03 | 2022-02-08 | 浙江科技学院 | PPAR gamma targeted glycyrrhetinic acid derivative and preparation method and application thereof |
| WO2023151292A1 (en) * | 2022-02-11 | 2023-08-17 | 北京青颜博识健康管理有限公司 | 3α-OLEANOLIC ACID DERIVATIVES AS HYALURONIDASE INHIBITORS AND USES THEREOF IN COSMETIC PRODUCTS |
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