CN101235071B - Diene oleanolic acid pentacyclic triterpenes derivatives and use thereof - Google Patents

Diene oleanolic acid pentacyclic triterpenes derivatives and use thereof Download PDF

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CN101235071B
CN101235071B CN 200710194190 CN200710194190A CN101235071B CN 101235071 B CN101235071 B CN 101235071B CN 200710194190 CN200710194190 CN 200710194190 CN 200710194190 A CN200710194190 A CN 200710194190A CN 101235071 B CN101235071 B CN 101235071B
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diene
compound
acid
oleanane
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CN101235071A (en
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赵昱
冯菊红
周长新
白骅
巫秀美
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Zhejiang University ZJU
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Abstract

The invention provides a diene oleanolic acid pentacyclic triterpenoid derivative, relative medicine salt or solvate, represented as formula (1). The inventive compound can inhibit the growth activity of tumor cell to be applied in anti-tumor drug and can inhibit mice ear swelling caused by dimethylbenzene to be applied in anti-inflammatory agent. The formula (1) is represented as above.

Description

Diene oleanolic acid pentacyclic triterpenes derivatives and purposes
The application is to be on December 29th, 2004 applying date, and application number is dividing an application of 200410102895.6 Chinese patent application.
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, particularly, the present invention relates to ramification of pentacycle triterpene of polyoxy replacement and its production and use.The present invention with this series compound to six kinds of tumor cell lines such as Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), human cervical carcinoma cell (Hela) have carried out growth of tumour cell and have suppressed screening active ingredients.This compounds is found to have certain growth inhibitory activity to tumor cell, can expect as antineoplastic use.In addition, this compounds also p-Xylol causes mice ear significant restraining effect is arranged, and pointing out this compounds to expect becomes anti-inflammatory drug.
Background technology
At present, because the problems such as environmental pollution of bringing in the industrial development, human living environment quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the specifics for the treatment of tumor disease can not be satisfactory, and at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, limited the general applicability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide study hotspot.We also are devoted to the research of antitumor drug.For a long time, triterpene acids and triterpene compound are because of its special cytotoxicity (Chi-I Chang etc. that excite wide spread interest, Journal of Natural Products, (natural product magazine), 67 volumes in 2004, the 91-93 page or leaf), be hopeful therefrom to find to become the lead compound of new antitumor drug.Therefore the object of the invention is to this compounds is synthesized and structure of modification, growth produces the ramification of pentacycle triterpene of stronger inhibiting polyoxy replacement to tumor cell line to seeking.According to the whole world especially susceptibility of often swell knurl spectrum of disease and the tumour cell of China, we have selected Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), human cervical carcinoma cell (Hela) six strain tumour cells are as the index of in vitro cytotoxic effect Pharmacological Evaluation.
Inflammatory reaction is a kind of defensive reaction that human body chemical factors, paathogenic factor etc. stimulate.Find in the recent period: tumour and senile dementia, and old and feeble etc. all with inflammation direct or indirect relation is arranged.
Desirable anti-inflammatory drug not only requires anti-inflammatory action strong, satisfactory effect, and also long-term taking should have no adverse reaction.The steroidal anti-inflammatory medicine (SAID) such as glucocorticosteroid although anti-inflammatory action stronger than NSAID (non-steroidal anti-inflammatory drug) (NSAID) effect, curative effect to many inflammation is very fast, but because long-term taking may cause serious whole body property untoward reaction, generally do not make choice drug.When adopting the NSAID (non-steroidal anti-inflammatory drug) unsatisfactory curative effect, just consider to select.But the NSAID (non-steroidal anti-inflammatory drug) adverse reaction rate is also very high, generally shows to bring out or increase the weight of digestive tract ulcer, has limited its widespread use.Recent research also finds, the long-term and large dose oral administration such as the medicine such as acetylsalicylic acid, Phenylbutazone, Visubutina, INDOMETHACIN can cause liver injury, severe patient even cause liver failure and death.
From Chinese herbal medicine resource, seek potent antiphlogistic effects can be arranged, can avoid again bringing out the medicine of digestive tract ulcer or compound with and composition be that world wide is all in one of focus of paying close attention to.Many reports all relate to triterpenic acid and triterpene compound has definite effect (such as Ana-Isabel Huguet etc., European Journal of Pharmacology (European pharmacology magazine), 2000 years 410 volume 69-81 pages or leaves) to the anti-inflammatory class; In China, be used for the treatment of hepatitis disease (Sun Ding people etc., national clinical new drug collection, Chinese Medicine science and technology press, 335 pages) such as Oleanolic Acid or marketed drug.In addition, the people such as Dai Yue have reported that also the inflammatory models such as rat footpad swelling that Oleanolic Acid causes different proinflammatory agents and mice caused by dimethylbenzene xylene ear swelling have obvious restraining effect (Dai Yue etc., the anti-inflammatory action of Oleanolic Acid, Chinese J Pharmacol Toxicol, volume Two in 1989,97 pages).Therefore the object of the invention is to this compounds is synthesized and structure of modification, to seeking the ramification of pentacycle triterpene that inflammation is had stronger inhibiting polyoxy replacement.Select p-Xylol to cause mice ear restraining effect model as anti-inflammatory action preliminary assessment standard among the present invention.
Goal of the invention
The purpose of this invention is to provide a kind of have ramification of pentacycle triterpene and pharmacologically acceptable salt or solvate cytotoxic activity, that have the polyoxy replacement shown in the formula (1):
Wherein:
R 1～R 6Can be identical or different, be selected from respectively hydrogen, contain the alkoxyl group of 1～8 carbon atom, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl; Between the prosposition, between 9,11, between 11,12, between 12,13, and/or can be carbon-carbon single bond or two key independently of one another between 13,18; It can also be epoxy group(ing) between the prosposition;
R 7And R 8Can be identical or different, be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl; Wherein " replace or not replace " refer to that group can not be substituted or be substituted, be selected from halogen, amino, nitro as the substituting group that replaces, sulfydryl, cyano group, hydroxyl contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the acyl group of 1～8 carbon, phenyl, aryl;
Another purpose of the present invention has provided the purposes for the preparation of control tumor disease medicine of formula (1) compound;
Another purpose of the present invention has provided the purposes for the preparation of anti-inflammatory drug of formula (1) compound;
Another object of the present invention has provided a kind of pharmaceutical composition that is used for anti-tumor disease that contains formula (1) compound.
A further object of the present invention has provided a kind of composition that is used for anti-inflammatory drug that contains formula (1) compound.
Summary of the invention
The invention provides a kind of ramification of pentacycle triterpene and pharmacologically acceptable salt or solvate with the polyoxy replacement shown in the formula (1):
Figure S2007101941905D00022
Wherein: R 1～R 6Can be identical or different, be selected from respectively hydrogen, contain the alkoxyl group of 1～8 carbon atom, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl; Between the prosposition, between 9,11, between 11,12, between 12,13, and/or can be carbon-carbon single bond or two key independently of one another between 13,18; It can also be epoxy group(ing) between the prosposition; R 7And R 8Can be identical or different, be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl; Wherein " replace or not replace " refer to that group can not be substituted or be substituted, be selected from halogen, amino, nitro as the substituting group that replaces, sulfydryl, cyano group, hydroxyl contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the acyl group of 1～8 carbon, phenyl, aryl; Except as otherwise noted, the alkyl among the present invention refers to the alkyl of 1-8 carbon atom.
In formula of the present invention (1) compound, being two keys between prosposition, between 11,12, between 12,13, and/or is carbon-carbon single bond or two key between 13,18, R 1And R 2Hydrogen atom, R 8During for methyl, be the preferred formula of a class (I) compound:
Figure S2007101941905D00031
Wherein: R 3, R 4And R 7Identical with the definition in formula (1) compound; Its condition is, is two keys between prosposition, is two keys between 12,13, when being singly-bound between 9,11, and R 3And R 4Between can not be hydrogen simultaneously.Preferred R 3, R 4Be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl; R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl;
The preparation process of this compounds is specific as follows:
Compound I, Ic are respectively by compound 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-11,13 (18)-diene, 3-sulfonyloxy methyl oxygen base-oleanane-28-carboxylic methyl-11,13 (18)-diene demethylating sulfonic acid under the Quilonum Retard effect obtain.Ie is obtained by lithium aluminium hydride reduction by compound I c.Obtain after the reaction of compound 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-12-alkene (3-sulfonyloxy methyl oxygen base-oleanane-28-carboxylic methyl-12-alkene) and N-bromosuccinimide compound I Ia (IIe) again demethylating sulfonic acid obtain Ih (Im), hydrolysis obtains Ig (II) again.Compound I i, In are by compound oleanane-28-acid-2, and 12-diene, oleanane-28-carboxylic methyl-2 obtain through reduction after 12-diene and the chromium trioxide reaction again.Ik, Ip are respectively by compound oleanane-28-acid-2, and 12-diene, oleanane-28-carboxylic methyl-2,12-diene and tin anhydride react and obtain, and alkaline hydrolysis obtains compound I j, Io again.Compound I I～Ip obtains corresponding product Iq～Iu with lithium aluminium hydride reduction.Ib is by compound oleanane-28-acid-2, and the 12-diene obtains through lithium aluminium hydride reduction after by the chromium trioxide oxidation again, can obtain compound I d with diazomethane reaction.
Synthetic route is as follows:
Synthetic route 1
Figure S2007101941905D00032
Synthetic route 2
Figure S2007101941905D00041
Synthetic route 3
Figure S2007101941905D00042
Synthetic route 4
Synthetic route 5
Figure S2007101941905D00044
The preparation of preparation example 1: compound I i
Compound 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-12-alkene (1.0mmol) is added 5 milliliters of DMAC (N, N '-N,N-DIMETHYLACETAMIDE) dissolving, add again Quilonum Retard (2.0mmol).Reaction mixture reflux half an hour.After the cooling, the Quilonum Retard that elimination is excessive, filtrate adds in 10 ml waters, and with extracted with diethyl ether, organic phase is washed to neutrality.Anhydrous sodium sulfate drying.Silicon magnetic column chromatography (elutriant: petrol ether/ethyl acetate: 8/1), obtain white solid oleanane-28-acid-2,12-diene, productive rate 82%.
In 20 milliliters of acetic acid (containing 5% acetic anhydride), add compound oleanane-28-acid-2,12-diene (0.82mmol) and chromium trioxide (4.92mmol) stir under the room temperature and spend the night.Compound of reaction is poured in 20 ml waters, used chloroform extraction.Organic phase is washed with saturated sodium carbonate, is washed to neutrality again.Anhydrous sodium sulfate drying.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 4/1), obtain white solid IVb, productive rate 47%.
Compound IV b (0.38mmol) is dissolved in 10 ml methanol, and 0 ℃ of lower sodium borohydride (1.52mmol) that adds stirred under the room temperature 6～7 hours.After reaction finishes, add the 1M hcl acidifying, slough most of methyl alcohol, add 10 milliliters in 10 milliliters of ethyl acetate and water, after the layering, water layer is again with ethyl acetate extraction.Merge organic phase, be washed to neutrality, anhydrous sodium sulfate drying.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 3/1), obtain white solid Ii, productive rate 78%.
Method according to preparation example 1 prepares preparation example 2～preparation example 22 compounds shown below:
Preparation example 2: oleanane-28-acid-2,11, the preparation of 13 (18)-triolefins (Ia), C 30H 44O 2, MS:ESIm/e436 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.63, 1HNMR (400MHz, CDCl 3) δ: 2.51 (brd, 1H, J=14.2Hz, H-19), 5.31-5.43 (m, 3H, H-2, H-3, H-12), 6.35 (d, 1H, J=10.4Hz, H-11).
Preparation example 3: oleanane-28-acid-2,9 (11), the preparation of 12-triolefin (Ib), C 30H 44O 2, MS:ESI m/e 436 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.63, 1HNMR (400MHz, CDCl 3) δ: 5.31-5.40 (m, 3H, H-2, H-3, H-12), 5.46 (d, 1H, J=10.0Hz, H-11).
Preparation example 4: oleanane-28-carboxylic methyl-2,11, the preparation of 13 (18)-triolefins (Ic), C 31H 46O 2, MS:ESI m/e450 (M +); Rf (sherwood oil/chloroform: 1/1): 0.65, 1HNMR (400 MHz, CDCl 3) δ: 3.66 (s, 3H, OCH 3), 5.40-5.48 (m, 2H, H-2, H-3), 5.63 (d, 1H, J=10.4Hz, H-12), 6.44 (d, 1H, J=10.4Hz, H-11).
Preparation example 5: oleanane-28-carboxylic methyl-2,9 (11), the preparation of 12-triolefin (Id), C 31H 46O 2, MS:ESI m/e450 (M +); Rf (sherwood oil/chloroform: 1/1): 0.65, 1H NMR (400MHz, CDCl 3) δ: 3.65 (s, 3H, OCH 3), 5.33-5.43 (m, 3H, H-2, H-3, H-12), 5.50 (d, 1H, J=9.6Hz, H-11).
Preparation example 6:28-hydroxyl-volatile oil-2,11, the preparation of 13 (18)-triolefins (Ie), C 30H 46O, MS:ESIm/e422 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.57; 1H NMR (400MHz, CDCl 3) δ: 3.62 (m, 2H, H-28, H-28 ') 5.42 (m, 2H, H-2, H-3), 5.63 (m, 1H, H-12), 6.45 (brd, 1H, J=72Hz, H-11).
Preparation example 7:28-hydroxyl-volatile oil-2,9 (11), the preparation of 12-triolefin (If), C 30H 46O, MS:ESI m/e 422 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.57; 1H NMR (400MHz, CDCl 3) δ: 3.62 (m, 2H, H-28, H-28 '), 5.33 (d, 1H, J=10.0Hz, H-12), 5.42 (m, 2H, H-2, H-3), 5.55 (brd, 1H, J=10.0Hz, H-11).
Preparation example 8:11-hydroxyl-oleanane-28-acid-2, the preparation of 12-diene (Ig), C 30H 46O 3, MS:ESI m/e454 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.55, 1HNMR (400MHz, CDCl 3) δ: 4.01 (brs, 1H, H-11), 536-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 9:11-bromo-oleanane-28-acid-2, the preparation of 12-diene (Ih), C 30H 45BrO 2, MS:ESIm/e 516 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.60, 1H NMR (400MHz, CDCl 3) δ: 3.56 (brs, 1H, H-11), 5.36-5.44 (m, 3H, H-2, H-3, H-12).
Preparation example 10:1,11-dihydroxyl-oleanane-28-acid-2, the preparation of 12-diene (Ii), C 30H 46O 4, MS:ESIm/e 470 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.50, 1H NMR (400 MHz, CDCl 3) δ: 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 11:1-hydroxyl-oleanane-28-acid-2, the preparation of 12-diene (Ij), C 30H 46O 3, MS:ESI m/e 454 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.55, 1H NMR (400MHz, CDCl 3) δ: 2.88 (brd, 1H, J=10.2Hz, H-18), 3.55 (d, 1H, J=5.6Hz, H-1), 5.32 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 12:1-acetoxyl group-oleanane-28-acid-2, the preparation of 12-diene (Ik), C 32H 48O 4, MS:ESIm/e496 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.65, 1HNMR (400MHz, CDCl 3) δ: 2.86 (dd, 1H, J=4.0,13.6Hz, H-18), 4.74 (d, 1H, J=5.6Hz, H-1), 527 (brs, 1H, H-12), 5.60 (d, 1H, J=9.6Hz, H-3), 5.66 (m, 1H, H-2).
Preparation example 13:11-hydroxyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (II), G 31H 48O 3, MS:ESIm/e468 (M +); (stone does not have ether/ethyl acetate to Rf: 8/1): 0.35; 1HNMR (400MHz, CDCl 3) δ: 3.69 (s, 3H, OCH 3), 4.01 (brs, 1H, H-11), 5.36-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 14:11-bromo-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (Im), C 31H 47BrO 2, MS:ESI m/e 530 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.40; 1HNMR (400MHz, CDCl 3) δ: 3.67 (s, 3H, OCH 3), 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 15:1,11-dihydroxyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (In), C 31H 48O 4, MS:ESIm/e484 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.31; 1H NMR (400MHz, CDCl 3) δ: 3.67 (s, 3H, OCH 3), 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 16:1-hydroxyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (Io), C 31H 48O 3, MS:ESI m/e468 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.35; 1HNMR (400MHz, CDCl 3) δ: 2.88 (brd, 1H, J=102Hz, H-18), 3.55 (d, 1H, J=5.6Hz, H-1), 3.66 (s, 3H, OCH 3), 5.32 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 17:1-acetoxyl group-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (Ip), C 33H 50O 4, MS:ESIm/e510 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.55; 1H NMR (400MHz, CDCl 3) δ: 2.86 (dd, 1H, J=4.0,13.6Hz, H-18), 3.63 (s, 3H, OCH 3), 4.74 (d, 1H, J=5.6Hz, H-1), 527 (brs, 1H, H-12), 5.60 (d, 1H, J=9.6Hz, H-3), 5.66 (m, 1H, H-2).
Preparation example 18:11,28-dihydroxyl-volatile oil-2, the preparation of 12-diene (Iq), C 30H 48O 2, MS:ESI m/e 440 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.35; 1H NMR (400MHz, CDCl 3) δ: 323 (d, 1H, J=10.8Hz, H-28), 3.57 (d, 1H, J=10.8Hz, H-28 '), 4.01 (brs, 1H, H-11), 5.36-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 19:11-bromo-28-hydroxyl-volatile oil-2, the preparation of 12-diene (Ir), C 30H 47BrO, MS:ESI m/e 502 (M +): Rf (petrol ether/ethyl acetate: 5/1): 0.42; 1H NMR (400MHz, CDCl 3) δ: 325 (d, 1H, J=10.4Hz, H-28), 3.57 (d, 1H, J=10.4Hz, H-28 '), 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), (5.53 d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 20:1,11,28-trihydroxy--volatile oil-2, the preparation of 12-diene (Is), Rf (petrol ether/ethyl acetate: 5/1): 0.31; 1HNMR (400MHz, CDCl 3) δ: 3.66 (brs, 2H, H-28, H-28 '), 4.21 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 21:1,28-dihydroxyl-volatile oil-2, the preparation of 12-diene (It), C 30H 48O 2, MS:ESI m/e 440 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.35; 1H NMR (400MHz, CDCl 3) δ: 2.88 (brd, 1H, J=10.2Hz, H-18), 3.55 (m, 2H, H-1, H-28), (3.60 d, 1H, J=10.4Hz, H-28 '), 5.32 (brs, 1H, H-12), (5.53 d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 22:1-acetoxyl group-28-hydroxyl-volatile oil-2, the preparation of 12-diene (Iu), C 32H 50O 3, MS:ESIm/e482 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.55; 1HNMR (400MHz, CDCl 3) δ: 2.86 (dd, 1H, J=4.0,13.6Hz, H-18), (3.30 d, 1H, J=10.4Hz, H-28), 3.56 (d, 1H, J=10.4Hz, H-28 '), 4.74 (d, 1H, J=5.6Hz, H-1), 5.27 (brs, 1H, H-12), 5.60 (d, 1H, J=9.6Hz, H-3), 5.66 (m, 1H, H-2).
In formula of the present invention (1) compound, be two keys between 12,13, R 4Be bromine atoms, R 3, R 5And R 6Hydrogen atom, R 8During for methyl, be the preferred formula of a class (II) compound:
Figure S2007101941905D00071
Wherein: R 1, R 2And R 7Identical with the definition of formula (1) compound.
Preferred R 1, R 2Can be identical or different, be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl, perhaps R 1And R 2Between can form epoxy group(ing); R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
The preferred formula of the present invention (II) compound and pharmacologically acceptable salt thereof or solvate are:
3 Beta-methyls sulfonyloxy-11-bromo-oleanane-28-acid-12-alkene (IIa);
2 β, 3 beta-dihydroxyies-11-bromo-oleanane-28-acid-12-alkene (IIb);
2,3-epoxy-11-bromo-oleanane-28-acid-12-alkene (IIc);
3 β-acetoxyl group-11-bromo-oleanane-28-acid-12-alkene (IId);
3 Beta-methyls sulfonyloxy-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIe);
2 β, 3 beta-dihydroxyies-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIf);
2,3-epoxy-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIg);
3 β-acetoxyl group-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIh).
Figure S2007101941905D00072
The preparation process of this compounds is specific as follows:
Compound I Ia (IIe) is done at Isosorbide-5-Nitrae-dioxane and water by compound 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-12-alkene (3-sulfonyloxy methyl oxygen base-oleanane-28-carboxylic methyl-12-alkene) and NBS (N-bromosuccinimide) that reaction obtains in the solvent.Obtain compound I h (Im) behind the demethylating sulfonic acid, obtain compound I Ic (IIg) by metachloroperbenzoic acid (mCPBA) epoxidation, obtained compound I Ib (IIf) by the concentrated hydrochloric acid open loop again.Compound I Id, IIh are obtained by compound 3-acetoxyl group-oleanane-28-acid-12-alkene, 3-acetoxyl group-oleanane-28-carboxylic methyl-12-alkene and N-bromosuccinimide reaction respectively.
Synthetic route is as follows:
Synthetic route 5
Figure S2007101941905D00081
Synthetic route 6
Figure S2007101941905D00082
The preparation of preparation example 23: compound I Ia
Compound 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-12-alkene (1.0mmol) adds 10 milliliters of Isosorbide-5-Nitrae-dioxane, stirs lower adding salt of wormwood (2.00mmol), adds N-bromosuccinimide (2.50mmol) under the illumination.Reacted two hours, and filtered, filtrate adds water and 10 milliliters of ethyl acetate of 10 milliliters, after the layering, and the water layer ethyl acetate extraction, organic phase washes with water to neutrality, anhydrous sodium sulfate drying.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 12/1), obtain white solid IIa, productive rate 30%.
Method according to preparation example 23 prepares preparation example 24～preparation example 31 compounds shown below:
The preparation of preparation example 24:3 Beta-methyl sulfonyloxy-11-bromo-oleanane-28-acid-12-alkene (IIa), C 31H 49BrO 5S, MS:ESIm/e612 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.52, 1HNMR (400MHz, CDCl 3) δ: 3.04 (s, 3H, SCH 3), 3.57 (brs, 1H, H-11), 3.04 (s, 3H, SCH3), 4.13 (dd, 1H, J=7.2,14.0Hz, H-3), 5.30 (brs, 1H, H-12).
Preparation example 25:2 β, the preparation of 3 beta-dihydroxyies-11-bromo-oleanane-28-acid-12-alkene (IIb), C 30H 47BrO 4, MS:ESIm/e550 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.41, 1HNMR (400MHz, CDCl 3) δ: 3.56 (brs, 1H, H-11), 3.77 (d, 1H, J=11.2Hz, H-3), 4.09 (dd, 1H, J=11.2,20.4Hz, H-2), 5.23 (s, 1H, H-12).
Preparation example 26:2, the preparation of 3-epoxy-11-bromo-oleanane-28-acid-12-alkene (IIc), C 30H 45BrO 3, MS:ESIm/e532 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.60, 1HNMR (400MHz, CDCl 3) δ: 3.60 (brs, 1H, H-11), 3.03 (m, 2H, H-2, H-3), 3.56 (brs, 1H, H-11), 5.23 (s, 1H, H-12).
The preparation of preparation example 27:3 β-acetoxyl group-11-bromo-oleanane-28-acid-12-alkene (IId), C 32H 49BrO 4, MS:ESIm/e576 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 055, 1HNMR (400MHz, CDCl 3) δ: 4.52 (m, 1H, H-3), 3.57 (brs, 1H, H-11), 5.26 (s, 1H, H-12).
The preparation of preparation example 28:3 Beta-methyl sulfonyloxy-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIe), C 32H 51BrO 5S, MS:ESIm/e626 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.55, 1HNMR (400MHz, CDCl 3) δ: 3.04 (s, 3H, SCH 3), 3.57 (brs, 1H, H-11), 3.04 (s, 3H, SCH 3), 3.69 (s, 3H, OCH 3), 4.13 (dd, 1H, J=7.2,14.0Hz, H-3), 5.30 (brs, 1H, H-12).
Preparation example 29:2 β, the preparation of 3 beta-dihydroxyies-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIf), C 31H 49BrO 4, MS:ESIm/e564 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.35, 1HNMR (400MHz, CDCl 3) δ: 3.56 (brs, 1H, H-11), 3.69 (s, 3H, OCH 3), 3.77 (d, 1H, J=11.2Hz, H-3), 4.09 (dd, 1H, J=11.2,20.4Hz, H-2), 5.23 (s, 1H, H-12).
Preparation example 30:2, the preparation of 3-epoxy-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIg), C 31H 47BrO 3, MS:ESIm/e546 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.65, 1HNMR (400MHz, CDCl 3) δ: 3.60 (brs, 1H, H-11), 3.03 (m, 2H, H-2, H-3), 3.56 (brs, 1H, H-11), 3.67 (s, 3H, OCH 3), 529 (s, 1H, H-12).
The preparation of preparation example 31:3 β-acetoxyl group-11-bromo-oleanane-28-carboxylic methyl-12-alkene (IIh), C 33H 51BrO 4, MS:ESI m/e 590 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.55, 1HNMR (400MHz, CDCl 3) δ: 3.67 (s, 3H, OCH 3), 4.52 (m, 1H, H-3), 3.57 (brs, 1H, H-11), 5.26 (s, 1H, H-12).
In formula of the present invention (1) compound, work as R 3And R 4Hydrogen atom, R 8Being methyl, during without any pair of key, is the preferred formula of a class (III) compound in the structure:
Figure S2007101941905D00091
Wherein: R 1, R 2, R 5, R 6, R 7The definition of formula (1) compound is identical.
Preferred R 1, R 2, R 5, R 6Can be identical or different, be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl, perhaps R 1And R 2Between can form epoxy group(ing); R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
The preferred formula of the present invention (III) its pharmacologically acceptable salt of compound or solvate are:
3 β, 12,13-trihydroxy--oleanane-28-acid (IIIa);
2 β, 3 β, 12,13-tetrahydroxy-oleanane-28-acid (IIIb);
2 α, 3 β, 12,13-tetrahydroxy-oleanane-28-acid (IIIc);
3 β, 12,13-trihydroxy--oleanane-28-carboxylic methyl (IIId);
2 β, 3 β, 12,13-tetrahydroxy-oleanane-28-carboxylic methyl (IIIe);
2 α, 3 β, 12,13-tetrahydroxy-oleanane-28-carboxylic methyl (IIIf).
Figure S2007101941905D00092
Figure S2007101941905D00101
This compounds preparation process is specific as follows:
Compound III a～IIIc is respectively by raw materials of compound Oleanolic Acid and compound oleanane-28-acid-2,12-diene epoxidation again under different condition open loop obtain.Compound III d～IIIf is obtained by compound III a～IIIc and diazomethane reaction respectively.
Synthetic route is as follows:
Synthetic route 7
Figure S2007101941905D00102
Synthetic route 8
Figure S2007101941905D00103
Synthetic route 9
The preparation of preparation example 10: compound III b:
With compound oleanane-28-acid-2,12-diene (0.42mmol) is dissolved in 5 milliliters the methylene dichloride, adds mCPBA (metachloroperbenzoic acid) (0.84mmol), stirs under the room temperature and spends the night.Directly in reaction solution, drip 2 concentrated hydrochloric acids.Room temperature reaction 3 hours.Question response adds 5 ml waters after finishing, after the layering, and water layer 5 milliliters of extractions of methylene dichloride, organic phase is washed to neutrality.Anhydrous sodium sulfate drying.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate: 3/1), obtain white solid IIIb, productive rate 28%.
Method according to preparation example 32 prepares preparation example 33～preparation example 38 compounds shown below:
Preparation example 33:3 β, the preparation of 12,13-trihydroxy--oleanane-28-acid (IIIa), C 30H 50O 5, MS:ESI m/e 490 (M +);
Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.37, 1H NMRR (400MHz, CDCl 3) δ: 3.23 (dd, 1H, H, J=4,10.4Hz, H-3), 3.89 (brs, 1H, H-12).
Preparation example 34:2 β, 3 β, the preparation of 12,13-tetrahydroxy-oleanane-28-acid (IIIb), C 30H 50O 6, MS:ESIm/e 506 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.20, 1HNMR (400MHz, CDCl 3) δ: 3.80 (d, 1H, J=11.6Hz, H-3), 3.89 (brs, 1H, H-12), 4.16 (dd, 1H, J=9.6,11.6Hz, H-2).
Preparation example 35:2 α, 3 β, the preparation of 12,13-tetrahydroxy-oleanane-28-acid (IIIc), C 30H 50O 6, MS:ESIm/e506 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.23, 1HNMR (400MHz, CDCl 3) δ: 3.68 (m, 2H, H-2, H-3), 3.91 (brs, 1H, H-12).
Preparation example 36:3 β, the preparation of 12,13-trihydroxy--oleanane-28-carboxylic methyl (IIId), C 31H 52O 5, MS:ESIm/e 504 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.56, 1HNMR (400MHz, CDCl 3) δ: 3.23 (dd, 1H, J=4,10.4Hz, H-3), 3.69 (s, 3H, OCH 3), 3.89 (brs, 1H, H-12).
Preparation example 37:2 β, 3 β, the preparation of 12,13-tetrahydroxy-oleanane-28-carboxylic methyl (IIIe), C 31H 52O 6, MS:ESIm/e520 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.42, 1HNMR (400MHz, CDCl 3) δ: 3.69 (s, 3H, OCH 3), 3.80 (d, 1H, J=11.6Hz, H-3), 3.89 (brs, 1H, H-12), 4.16 (dd, 1H, J=9.6,11.6Hz, H-2).
Preparation example 38:2 α, 3 β, the preparation of 12,13-tetrahydroxy-oleanane-28-carboxylic methyl (IIIf), C 31H 52O 6, MS:ESIm/e520 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.45, 1HNMR (400MHz, CDCl 3) δ: 3.68 (m, 5H, H-2, H-3, OCH 3), 3.91 (brs, 1H, H-12).
In formula of the present invention (1) compound, be two keys simultaneously between prosposition, between 12,13, R 4Be ketone carbonyl, R 1, R 2And R 5Hydrogen atom, R 8During for methyl, be the preferred formula of a class (IV) compound:
Wherein: R 3And R 7Identical with the definition of formula (1) compound.
Preferred R 3Be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, the sulfonyloxy that contains 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl or carbonyl; R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9Or-CON (R 9) 2R wherein 9Alkyl, replacement or unsubstituted phenyl or replacement or the unsubstituted benzene alkyl that contains 1～8 carbon atom.
The preferred formula of the present invention (IV) compound and pharmacologically acceptable salt thereof or solvate are:
11-hydroxyl-oleanane-28-acid-2,12-diene (IVa);
1,11-dicarbapentaborane-oleanane-28-acid-2,12-diene (IVb);
1-bromo-11-carbonyl-oleanane-28-acid-2,12-diene (IVc);
1-acetoxyl group-11-carbonyl-oleanane-28-acid-2,12-diene (IVd);
1-hydroxyl-11-carbonyl-oleanane-28-acid-2,12-diene (IVe);
11-hydroxyl-oleanane-28-carboxylic methyl-2,12-diene (IVf);
1,11-dicarbapentaborane-oleanane-28-carboxylic methyl-2,12-diene (IVg);
1-bromo-11-carbonyl-oleanane-28-carboxylic methyl-2,12-diene (IVh);
1-acetoxyl group-11-carbonyl-oleanane-28-carboxylic methyl-2,12-diene (IVi);
1-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl-2,12-diene (IVj).
Figure S2007101941905D00121
The preparation process of this compounds is specific as follows:
Compound IV a, IVf are obtained by compound 3 Beta-methyls sulfonyloxy-11-carbonyl-oleanane-28-acid-12-alkene, 3 Beta-methyls sulfonyloxy-11-carbonyl-oleanane-28-carboxylic methyl-12-alkene demethylating sulfonic acid respectively, oxidation through chromium trioxide obtains compound IV b, IVg again, compound IV c, IVh do solvent reaction by compound IV a, IVf and N-bromosuccinimide at Isosorbide-5-Nitrae-dioxane and water respectively and obtain.Compound IV d, IVi are obtained by the tin anhydride oxidation by compound IV a, IVf respectively, and alkaline hydrolysis obtains respectively compound IV e, IVj again.
Synthetic route is as follows:
Figure S2007101941905D00122
Synthetic route 11
Figure S2007101941905D00131
Synthetic route 12
Figure S2007101941905D00132
The preparation of preparation example 39: compound IV j:
Compound IV f (1.00mmol) is added 10 milliliters of acetate dissolutions, adds again tin anhydride (1.00mmol), reflux after react completely, cooling.Suction filtration, filtrate are poured in 10 ml waters, with chloroform extraction.Organic phase is washed to water layer alkalescence with saturated sodium carbonate solution, is washed to neutrality again.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate: 10/1), obtain white solid IVi, productive rate 20%.
0.80mmol potassium hydroxide is dissolved in 0.5 ml water, adds 10 milliliters of ethanol again.Compound IV i is joined in the mentioned solution reflux.After the cooling, slough most of methyl alcohol, add 10 ml waters and 10 milliliters of ethyl acetate, after the layering, water layer is with ethyl acetate extraction.Merge organic phase, the washing of 1M hydrochloric acid soln is washed to neutrality to acid.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 10/1), obtain white solid IVj, productive rate 35%.
According to the standby preparation example 40 shown below of preparation example 39 legal systems to preparation example 49 compounds:
Preparation example 40:11-carbonyl-oleanane-28-acid-2, the preparation of 12-diene (IVa), C 30H 44O 3, MS:ESIm/e 452 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.43, 1HNMR (400MHz, CDCl 3) δ: 5.31-5.43 (m, 2H, H-2, H-3), 5.76 (s, 1H, H-12).
Preparation example 41:1,11-dicarbapentaborane-oleanane-28-acid-2, the preparation of 12-diene (IVb), C 30H 42O 4, MS:ESIm/e466 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.38, 1HNMR (400MHz, CDCl 3) δ: 5.74 (s, 1H, H-12), 5.82 (d, 1H, J=10.4Hz, H-3), 624 (dd, 1H, J=10.4Hz, H-2).
Preparation example 42:1-bromo-11-carbonyl-oleanane-28-acid-2, the preparation of 12-diene (IVc), C 30H 43BrO 3, MS:ESIm/e530 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.46, 1HNMR (400MHz, CDCl 3) δ: 3.88 (brs, 1H, H-1), 5.60 (m, 2H, H-2, H-3), 5.76 (s, 1H, H-12).
Preparation example 43:1-acetoxyl group-11-hydroxyl-oleanane-28-acid-2, the preparation of 12-diene (IVd), C 32H 46O 5, MS:ESIm/e510 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.50, 1HNMR (400MHz, CDCl 3) δ: 4.74 (d, 1H, J=5.6Hz, H-1), 5.60 (d, 1H, J=9.6Hz, H-3), 5.66 (m, 1H, H-2), 5.78 (s, 1H, H-12).
Preparation example 44:1-hydroxyl-11-carbonyl-oleanane-28-acid-2, the preparation of 12-diene (IVe), C 30H 44O 4, MS:ESIm/e468 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.42, 1HNMR (400MHz, CDCl 3) δ: 3.55 (d, 1H, J=5.6Hz, H-1), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2), 5.79 (s, 1H, H-12).
Preparation example 45:11-carbonyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVf), C 31H 46O 3, MS:ESIm/e466 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.61, 1HNMR (400MHz, CDCl 3) δ: 3.66 (s, 3H, OCH 3), 5.31-5.43 (m, 2H, H-2, H-3), 5.76 (s, 1H, H-12).
Preparation example 46:1,11-dicarbapentaborane-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVg), C 31H 44O 4, MS:ESIm/e 480 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.60, 1HNMR (400MHz, CDCl 3) δ: 3.69 (s, 3H, OCH 3), 5.71 (s, 1H, H-12), 5.85 (d, 1H, J=10.0Hz, H-3), 623 (dd, 1H, H=10.0Hz, H-2).
Preparation example 47:1-bromo-11-carbonyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVh), C 31H 45BrO 3, MS:ESIm/e544 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.67, 1HNMR (400MHz, CDCl 3) δ: 3.66 (s, 3H, OCH 3), 3.89 (brs, 1H, H-1), 5.65 (m, 2H, H-1, H-2), 5.86 (s, 1H, H-12).
Preparation example 48:1-acetoxyl group-11-hydroxyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVi), C 33H 48O 5, MS:ESIm/e 524 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.60, 1HNMR (400MHz, CDCl 3) δ: 3.68 (s, 3H, OCH 3), 4.74 (d, 1H, J=5.6Hz, H-1), 5.60 (d, 1H, J=9.6Hz, H-3), 5.69 (m, 1H, H-2), 5.76 (s, 1H, H-12).
Preparation example 49:1-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVj), C 31H 46O 4, MS:ESIm/e482 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.43, 1HNMR (400MHz, CDCl 3) δ: 3.55 (d, 1H, J=5.6Hz, H-1), 3.66 (s, 3H, OCH 3), 5.32 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
In formula of the present invention (1) compound, work as R 5Being the ketone carbonyl, is two keys between 13,18, R 2, R 3And R 4Hydrogen atom, R 8During for methyl, be the preferred formula of a class (V) compound:
Figure S2007101941905D00141
Wherein: R 1And R 7Identical with the definition of formula (1) compound.
Preferred R 1Be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl; R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or the unsubstituting phenenyl alkyl.
The preferred formula of the present invention (V) compound and pharmacologically acceptable salt thereof or solvate are:
3 beta-hydroxies-12-carbonyl-oleanane-28-acid-13 (18)-alkene (Va);
3 β-acetoxyl group-12-carbonyl-oleanane-28-acid-13 (18)-alkene (Vb);
3 Beta-methyls sulfonyloxy-12-carbonyl-oleanane-28-acid-13 (18)-alkene (Vc);
3 beta-hydroxies-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Vd);
3 β-acetoxyl group-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Ve);
3 Beta-methyls sulfonyloxy-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Vf).
Figure S2007101941905D00151
The preparation process of this compounds is specific as follows:
Compound Vd, Ve, Vf are respectively by compound 3-hydroxyl-oleanane-28-carboxylic methyl-11,13 (18)-diene, 3-acetoxyl group-oleanane-28-carboxylic methyl-11,13 (18)-diene, 3-sulfonyloxy methyl oxygen base-oleanane-28-carboxylic methyl-11,13 (18)-diene and metachloroperbenzoic acid oxidized obtaining under acid bar.Compound Va～Vb is obtained by compound Vd～Vf hydrolysis respectively.
Synthetic route is as follows:
Synthetic route 13
Figure S2007101941905D00152
Preparation example 50: the preparation of compound Va
With compound 3-hydroxyl-oleanane-28-carboxylic methyl-11,13 (18)-diene (2.00mmol) dissolve with 10 milliliters of methylene dichloride, add metachloroperbenzoic acid (2.00mmol), stir three hours, drip 10 of concentrated hydrochloric acids, room temperature reaction two hours.Add 10 ml waters, after the layering, water layer 10 milliliters of extractions of chloroform.Merge organic phase, saturated NaHCO 3Solution washing is to alkalescence, and water Xian is to neutral.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 10/1), obtain white solid Vd, productive rate 11%.
In 5 milliliters of dimethyl formamides, add compound Vd (0.22mmol) and lithium iodide (1.10mmol), reaction mixture reflux to reaction finishes.Suction filtration, filtrate are poured in 10 ml waters, 10 milliliters of extractions of ethyl acetate.Organic phase water Xian is to neutral.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 5/1), obtain white solid Va, productive rate 55%.
According to the standby preparation example 51 shown below of preparation example 50 legal systems to preparation example 56 compounds:
The preparation of preparation example 51:3 beta-hydroxy-12-carbonyl-oleanane-28-acid-13 (18)-alkene (Va), C 30H 46O 4, MS:ESIm/e470 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.33, 1HNMR (400MHz, CDCl 3) δ: 2.91 (brd, 1H, H-11), 3.25 (m, 1H, H-3).
The preparation of preparation example 52:3 β-acetoxyl group-12-hydroxyl-oleanane-28-acid-13 (18)-alkene (Vb), C 32H 48O 5, MS:ESIm/e512 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.45, 1HNMR (400MHz, CDCl 3) δ: 2.90 (brd, 1H, H-11), 4.52 (m, 1H, H-3).
The preparation of preparation example 53:3 Beta-methyl sulfonyloxy-12-carbonyl-oleanane-28-acid-13 (18)-alkene (Vc), C 31H 48O 6S, MS:ESIm/e548 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.36, 1HNMR (400MHz, CDCl 3) δ: 2.93 (brd, 1H, H-11), 3.03 (s, 3H, CH 3S), 4.38 (dd, 1H, J=4.0,11.6Hz, H-3).
The preparation of preparation example 54:3 beta-hydroxy-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Vd), C 31H 48O 4, MS:ESIm/e484 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.80, 1HNMR (400MHz, CDCl 3) δ: 2.91 (brd, 1H, H-11), 3.25 (m, 1H, H-3), 3.65 (s, 3H, OCH 3).
The preparation of preparation example 55:3 β-acetoxyl group-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Ve), C 33H 50O 5, MS:ESIm/e 526 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.67, 1HNMR (400MHz, CDCl 3) δ: 2.90 (brd, 1H, H-11), 3.66 (s, 3H, OCH 3), 4.52 (m, 1H, H-3).
The preparation of preparation example 56:3 Beta-methyl sulfonyloxy-12-carbonyl-oleanane-28-carboxylic methyl-13 (18)-alkene (Vf), C 32H 50O 6S, MS:ESIm/e562 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.52, 1HNMR (400MHz, CDCl 3) δ: 2.93 (brd, 1H, H-11), 3.03 (s, 3H, CH 3S), 3.70 (s, 3H, OCH 3), 4.38 (m, 1H, H-3).
In formula of the present invention (1) compound, work as R 4Be ketone carbonyl, R 3Hydrogen atom, R 8During for methyl, be the preferred formula of a class (VI) compound:
Wherein: R 1, R 2, R 5, R 6And R 7Identical with the definition of formula (1) compound.
Preferred R 1, R 2, R 5, R 6Can be identical or different, be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl, perhaps R 1And R 2Between can form epoxy group(ing); R 7Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
The preferred formula of the present invention (VI) compound and pharmacologically acceptable salt thereof or solvate are:
3 β, 13-dihydroxyl-11-carbonyl-oleanane-28-acid (VIa);
3 β-acetoxyl group-11-carbonyl-13-hydroxyl-oleanane-28-acid (VIb);
3 Beta-methyls sulfonyloxy-11-carbonyl-13-hydroxyl-oleanane-28-acid (VIc);
3 β, 13-dihydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VId);
3 β-acetoxyl group-11-carbonyl-13-hydroxyl-oleanane-28-carboxylic methyl (VIe);
3 Beta-methyls sulfonyloxy-11-carbonyl-13-hydroxyl-oleanane-28-carboxylic methyl (VIf);
3 β, 12-dihydroxyl-11-carbonyl-oleanane-28-acid (VIg);
3 β-acetoxyl group-11-carbonyl-12-hydroxyl-oleanane-28-acid (VIh);
3 Beta-methyls sulfonyloxy-11-carbonyl-12-hydroxyl-oleanane-28-acid (VIi);
3 β, 12-dihydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIj);
3 β-acetoxyl group-12-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIk);
3 Beta-methyls sulfonyloxy-12-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIl);
11-carbonyl-12-hydroxyl-oleanane-28-acid-2-alkene (VIm);
2,3-epoxy-11-carbonyl-12-hydroxyl-oleanane-28-acid (VIn);
2 β, 3 β, 12-trihydroxy--11-carbonyl-oleanane-28-acid (VIo);
11-carbonyl-12-hydroxyl-oleanane-28-carboxylic methyl-2-alkene (VIp);
2,3-epoxy-11-carbonyl-12-hydroxyl-oleanane-28-carboxylic methyl (VIq);
2 β, 3 β, 12-trihydroxy--11-carbonyl-oleanane-28-carboxylic methyl (VIr).
The preparation process of this compounds is specific as follows:
Compound VI a～VIc, VIg～VIi are corresponding to be obtained when acetonitrile, methylene dichloride and the water as solvent by raw material agent pier tartaric acid, compound 3-acetoxyl group-oleanane-28-acid-12-alkene, 3-sulfonyloxy methyl oxygen base-oleanane-28-acid-12-alkene and N-bromosuccinimide.They are methylated obtain corresponding carboxylate methyl ester derivative VId～VIf, VIj～VIl.Compound VI m (VIp) is obtained by compound VI i (VIl) demethylating sulfonic acid.Obtain compound VI n (VIq) with the oxidation of metachloroperbenzoic acid initial ring, acidic hydrolysis obtains compound VI o (VIr).
Synthetic route is as follows:
Synthetic route 14
Figure S2007101941905D00181
R 1=OH Oleanolic Acid R 1=OH, R 5=H, R 6=OH VIa R 1=OH, R 5=H, R 6=OH VId
R 1＝OH，R 5＝OH，R 6＝H VIg R 1＝OH，R 5＝OH，R 6＝H VIj
R 1＝OAc R 1＝OAc，R 5＝H，R 6＝OH VIb R 1＝OH，R 5＝H，R 6＝OH VIe
R 1＝OH，R 5＝OH，R 6＝H VIh R 1＝OH，R 5＝OH，R 6＝H VIk
R 1＝OMs R 1＝OH，R 5＝H，R 6＝OH VIc R 1＝OH，R 5＝H，R 6＝OH VIf
R 1＝OH，R 5＝OH，R 6＝H VIi R 1＝OH，R 5＝OH，R 6＝H VIl
Synthetic route 15
Figure S2007101941905D00182
Preparation example 57: compound VI a, the preparation of VIg
Raw material Oleanolic Acid (1.00mmol) is added the mixed solvent of 20 milliliters of acetonitriles, methylene dichloride and water (15/1/0.1), add N-bromosuccinimide (2.00mmol) under the illumination.Add 0.20 milliliter of triethylamine, illumination was stirred about four hours, added 10 milliliter of 5% Sulfothiorine Na 2S 2O 3Solution, 10 milliliters of extractions of ethyl acetate.Merge organic phase, successively with 1M hydrochloric acid, water, saturated nacl aqueous solution washing.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate: 8/1), obtain compound VI a (white solid, Rf=0.3 petrol ether/ethyl acetate: 8/1), VIg (white solid, the Rf=0.2 petrol ether/ethyl acetate: 8/1), productive rate is respectively 19%, 34%.
According to the standby preparation example 58 shown below of preparation example 57 legal systems to preparation example 75 compounds:
Preparation example 58:3 β, the preparation of 13-dihydroxyl-11-carbonyl-oleanane-28-acid (VIa), C 30H 48O 5, MS:ESIm/e488 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.30, 1HNMR (400MHz, CDCl 3) δ: 3.22 (dd, 1H, J=6.4,10.8Hz, H-3).
The preparation of preparation example 59:3 β-acetoxyl group-11-hydroxyl-13-hydroxyl-oleanane-28-acid (VIb), C 3H 50O 6, MS:ESIm/e530 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.44, 1HNMR (400MHz, CDCl 3) δ: 4.52 (m, 1H, H-3).
The preparation of preparation example 60:3 Beta-methyl sulfonyloxy-11-carbonyl-13-hydroxyl-oleanane-28-acid (VIc), C 31H 50O 7S, MS:ESIm/e566 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.35, 1HNMR (400MHz, CDCl 3) δ: 3.03 (s, 3H, CH 3S), 4.40 (dd, 1H, J=11.8,5.6Hz, H-3).
Preparation example 61:3 β, the preparation of 13-dihydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VId), C 31H 50O 5, MS:ESIm/e502 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.51, 1HNMR (400MHz, CDCl 3) δ: 3.32 (dd, 1H, J=6.0,10.8Hz, H-3), 3.65 (s, 3H, OCH 3).
The preparation of preparation example 62:3 β-acetoxyl group-11-carbonyl-13-hydroxyl-oleanane-28-carboxylic methyl (VIe), C 33H 52O 6, MS:ESIm/e544 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.62, 1HNMR (400MHz, CDCl 3) δ: 3.68 (s, 3H, OCH 3), 4.52 (m, 1H, H-3).
The preparation of preparation example 63:3 Beta-methyl sulfonyloxy-11-carbonyl-13-hydroxyl-oleanane-28-carboxylic methyl (VIf), C 32H 52O 7S, MS:ESIm/e580 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.55, 1HNMR (400MHz, CDCl 3) δ: 3.03 (s, 3H, CH 3S), 3.68 (s, 3H, OCH 3), 4.33 (dd, 1H, J=11.4,5.6Hz, H-3).
Preparation example 64:3 β, the preparation of 12-dihydroxyl-11-carbonyl-oleanane-28-acid (VIg), C 31H 48O 5, MS:ESIm/e488 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.20, 1HNMRR (400MHz, CDCl 3) δ: 3.23 (dd, 1H, J=5.6,10.8Hz, H-3), 3.68 (s, 1H, H-12).
The preparation of preparation example 65:3 β-acetoxyl group-11-carbonyl-12-hydroxyl-oleanane-28-acid (VIh), C 32H 50O 6, MS:ESIm/e530 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.35, 1HNMR (400MHz, CDCl 3) δ: 3.66 (s, 1H, H-12), 4.52 (m, 1H, H-3).
The preparation of preparation example 66:3 Beta-methyl sulfonyloxy-11-carbonyl-12-hydroxyl-oleanane-28-acid (VIi), C 31H 50O 7S, MS:ESIm/e566 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.25, 1HNMR (400MHz, CDCl 3) δ: 3.03 (s, 3H, CH 3S), 3.68 (s, 1H, H-12), 4.33 (dd, 1H, J=11.4,5.6Hz, H-3).
Preparation example 67:3 β, the preparation of 12-dihydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIj), C 31H 50O 5, MS:ESIm/e502 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.20, 1HNMR (400MHz, CDCl 3) δ: 3.23 (dd, 1H, J=5.6,10.8Hz, H-3), 3.68 (m, 4H, H-12, OCH 3).
The preparation of preparation example 68:3 β-acetoxyl group-12-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIk), C 33H 52O 6, MS:ESIm/e544 (M+); Rf (petrol ether/ethyl acetate: 8/1): 0.67, 1HNMR (400MHz, CDCl 3) δ: 3.68 (brs, 4H, OCH 3, H-12), 4.52 (m, 1H, H-3).
The preparation of preparation example 69:3 Beta-methyl sulfonyloxy-12-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VIl), C 32H 52O 7S, MS:ESIm/e580 (M +); Rf (petrol ether/ethyl acetate: 8/1): 0.25, 1HNMR (400MHz, CDCl 3) δ: 3.03 (s, 3H, CH 3S), 3.68 (brs, 4H, H-12, OCH 3), 4.33 (dd, 1H, J=11.0,5.2Hz, H-3).
The preparation of preparation example 70:11-carbonyl-12-hydroxyl-oleanane-28-acid-2-alkene (VIm), C 30H 46O 4, MS:ESIm/e470 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.65, 1HNMR (400MHz, CDCl 3) δ: 3.69 (s, 1H, H-12), 5.41 (m, 2H, H-2, H-3).
Preparation example 71:2, the preparation of 3-epoxy-11-hydroxyl-12-hydroxyl-oleanane-28-acid (VIn), C 30H 46O 5, MS:ESIm/e486 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.60, 1HNMR (400MHz, CDCl 3) δ: 321 (m, 2H, H-2, H-3), 3.68 (s, 1H, H-12).
Preparation example 72:2 β, 3 β, the preparation of 12-trihydroxy--11-carbonyl-oleanane-28-acid (VIo), C 30H 48O 6, MS:ESIm/e504 (M +); Rf (petrol ether/ethyl acetate: 3/1): 0.40, 1HNMR (400MHz, CDCl 3) δ: 3.68 (s, 1H, H-12), 3.73 (dd, 1H, J=11.2Hz, H-3), 4.10 (dd, 1H, J=9.6,18.0Hz, H-2).
The preparation of preparation example 73:11-carbonyl-12-hydroxyl-oleanane-28-carboxylic methyl-2-alkene (VIp), C 31H 48O 4, MS:ESIm/e484 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.65, 1HNMR (400MHz, CDCl 3) δ: 3.65 (s, 3H, OCH 3), 3.69 (s, 1H, H-12), 5.41 (m, 2H, H-2, H-3).
Preparation example 74:2, the preparation of 3-epoxy-11-carbonyl-12-hydroxyl-oleanane-28-carboxylic methyl (VIq), C 31H 48O 5, MS:ESIm/e500 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.62, 1HNMR (400MHz, CDCl 3) δ: 3.21 (m, 2H, H-2, H-3), 3.68 (brs, 4H, H-12, OCH 3).
Preparation example 75:2 β, 3 β, the preparation of 12-trihydroxy--11-carbonyl-oleanane-28-carboxylic methyl (VIr), C 31H 50O 6, MS:ESIm/e518 (M +); Rf (petrol ether/ethyl acetate: 5/1): 0.47, 1HNMR (400MHz, CDCl 3) δ: 3.68 (brs, 4H, H-12, OCH 3), 3.73 (dd, 1H, J=11.2Hz, H-3), 4.10 (dd, 1H, J=9.6,18.0Hz, H-2).
In formula of the present invention (1) compound, work as R 7Be methyl, R 4And R 5Being hydrogen atom, is two keys between the prosposition, between 9,11 and 12,13 when be pair key, is the preferred formula of a class (VII) compound:
Figure S2007101941905D00201
Wherein: R 1, R 2, R 3And R 8Identical with the definition of formula (1) compound.
Preferred R 1, R 2, R 3Be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl, perhaps R 1And R 2Between can form epoxy group(ing); R 8Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
The preferred formula of the present invention (VII) compound and pharmacologically acceptable salt thereof or solvate are:
1-hydroxyl-volatile oil-30-acid-2,9 (11), 12-triolefin (VIIa);
Volatile oil-30-acid-2,9 (11), 12-triolefin (VIIb);
1,30-dihydroxyl-volatile oil-2,9 (11), 12-triolefin (VIIc);
30-hydroxyl-volatile oil-2,9 (11), 12-triolefin (VIId).
The preparation process of this compounds is specific as follows:
Compound VI Ia and VIIb be respectively by raw material 1,11-dicarbapentaborane-volatile oil-30-acid-2, and 12-diene, 11-hydroxyl-volatile oil-30-acid-2, the 12-diene obtains by lithium aluminium hydride reduction.Compound VI Ic and VIId be respectively by compound 1-hydroxyl-11-carbonyl-volatile oil-30-carboxylate methyl ester-2,12-diene and 11-carbonyl-volatile oil-30-carboxylate methyl ester-2, and the 12-diene obtains by lithium aluminium hydride reduction.
Synthetic route 16
Figure S2007101941905D00211
Synthetic route 17
Preparation example 76:1-hydroxyl-volatile oil-30-acid-2; 9 (11); the preparation of 12-triolefin (VIIa); under nitrogen protection; in anhydrous tetrahydrofuran solution (5 milliliters) suspension of lithium aluminium hydride (0.9mmol), carefully drip 1; 11-dicarbapentaborane-volatile oil-30-acid-1, the anhydrous tetrahydrofuran solution of 12-diene (0.3mmol), and continue to stir.After dropwising, reaction was at room temperature carried out one hour.The careful 1M hydrochloric acid that adds is until emit without gas.Product extracts four times with 10 milliliters of ethyl acetate.Merge organic phase, water Xian Di is to neutral.Anhydrous sodium sulfate drying, behind the precipitation, silica gel column chromatography (eluent: petrol ether/ethyl acetate: 1/1), obtain white solid VIIa, productive rate 39%.C 30H 44O 3, MS:ESIm/e452 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.52, 1HNMR (400MHz, CDCl 3) δ: 3.59 (d, 1H, J=5.6Hz, H-1), 5.50 (d, 1H, J=14.0Hz, H-3), 5.59 (d, 1H, J=6.0Hz, H-12), 5.65 (d, 1H, J=6.0Hz, H-11), 5.68 (dd, 1H, J=6.0,14.4Hz, H-2).
According to the standby preparation example 77 shown below of preparation example 76 legal systems to preparation example 79 compounds:
Preparation example 77: volatile oil-30-acid-2,9 (11), the preparation of 12-triolefin (VIIb), C 30H 44O 2, MS:ESIm/e 436 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.66, 1HNMR (400MHz, CDCl 3) δ: 5.31-5.43 (m, 2H, H-2, H-3), 5.60 (d, 1H, J=5.6Hz, H-12), 5.63 (d, 1H, J=5.6Hz, H-11).
Preparation example 78:1,30-dihydroxyl-volatile oil-2,9 (11), the preparation of 12-triolefin (VIIc), C 30H 46O 2, MS:ESIm/e438 (M +); Rf (petrol ether/ethyl acetate: 1/1): 0.52, 1HNMR (400MHz, CDCl 3) δ: 3.37 (s, 1H, OH), 3.49 (d, 1H, J=10.8Hz, H-30), 3.62 (d, 1H, J=10.8Hz, H-30 '), 426 (brs, 1H, H-1), 528 (d, 1H, J=10.0Hz, H-12), 5.46 (d, 1H, J=10.0Hz, H-11), 5.55 (d, 1H, J=5.6Hz, H-2), 6.65 (d, 1H, J=5.6Hz, H-3).
Preparation example 79:30-hydroxyl-volatile oil-2,9 (11), the preparation of 12-triolefin (VIId), C 30H 46O, MS:ESIm/e 422 (M +); Rf (petrol ether/ethyl acetate: 1/1): 0.68, 1HNMR (400MHz, CDCl 3) δ: 3.49 (d, 1H, J=10.8Hz, H-30), 3.62 (d, 1H, J=10.8Hz, H-30 '), 5.35-5.47 (m, 2H, H-2, H-3), 5.60 (d, 1H, J=5.6Hz, H-12), 5.63 (d, 1H, J=5.6Hz, H-11).
In formula of the present invention (1) compound, work as R 7Be methyl, R 1, R 2And R 5Being hydrogen atom, when being two key between the prosposition and between 12,13, is the preferred formula of a class (VIII) compound:
Figure S2007101941905D00221
Wherein: R 3, R 4And R 8Identical with the definition of formula (1) compound.
Preferred R 3, R 4Be selected from respectively hydrogen, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl, carbonyl; R 8Be selected from-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9,-CON (R 9) 2, R wherein 9Be the alkyl that contains 1～8 carbon atom, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
The preferred formula of the present invention (VIII) compound and pharmacologically acceptable salt thereof or solvate are:
Volatile oil-30-acid-2,12-diene (VIIIa);
11-hydroxyl-volatile oil-30-acid-2,12-diene (VIIIb);
1-acetoxyl group-volatile oil-30-acid-2,12-diene (VIIIc);
1-hydroxyl-volatile oil-30-acid-2,12-diene (VIIId);
1,11-dihydroxyl-volatile oil-30-acid-2,12-diene (VIIIe);
Volatile oil-30-carboxylate methyl ester-2,12-diene (VIIIf);
11-hydroxyl-volatile oil-30-carboxylate methyl ester-2,12-diene (VIIIg);
1-acetoxyl group-volatile oil-30-carboxylate methyl ester-2,12-diene (VIIIh);
1-hydroxyl-volatile oil-30-carboxylate methyl ester-2,12-diene (VIIIi);
1,11-dihydroxyl-volatile oil-30-carboxylate methyl ester-2,12-diene (VIIIj).
Figure S2007101941905D00231
The preparation process of this compounds is specific as follows:
Compound 3 beta-hydroxies-11-carbonyl-volatile oil-30-carboxylate methyl ester-12-alkene is pressed literature method and is generated 11-deoxidation methyl glycyrrhetate, obtains compound VIII f by aforesaid dehydroxylation method again, obtains compound VIII a in hydrolysis.Compound VIII b, VIIIg, VIIIe, VIIIJ are respectively by compound 11-carbonyl-volatile oil-30-acid-2,12-diene, 11-carbonyl-volatile oil-30-carboxylate methyl ester-2,12-diene, 1,11-dicarbapentaborane-volatile oil-30-acid-2,12-diene, 1,11-dicarbapentaborane-volatile oil-30-carboxylate methyl ester-2, the 12-diene obtains by sodium borohydride reduction.Compound VIII c, VIIIh are obtained by compound VIII a, VIIAnd if tin anhydride reaction respectively, and alkaline hydrolysis obtains compound VIII d, VIIIi again.
Synthetic route is as follows:
Synthetic route 18
Figure S2007101941905D00232
Synthetic route 19
Synthetic route 20
Figure S2007101941905D00234
The preparation of preparation example 80: compound VIII b
With compound 11-carbonyl-volatile oil-30-acid-2,12-diene (1.0mmol) is dissolved in 10 ml methanol, and 0 ℃ of lower adding sodium borohydride (4.0mmol) stirred under the room temperature 6～7 hours.After reaction finishes, add the 1M hcl acidifying, slough most of methyl alcohol, add 10 milliliters in 10 milliliters of ethyl acetate and water, after the layering, water layer is again with 10 milliliters of extracting twice of ethyl acetate.Merge organic phase, be washed to neutrality, anhydrous sodium sulfate drying.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate/: 3/1), obtain white solid VIIIb, productive rate 69%.
According to the standby preparation example 81 shown below of preparation example 80 legal systems to preparation example 90 compounds:
Preparation example 81: volatile oil-30-acid-2, the preparation of 12-diene (VIIIa), C 30H 46O 2, MS:ESI m/e 438 (M +); Rf (petrol ether/ethyl acetate: 1/1): 0.60, 1HNMR (400MHz, CDCl 3) δ: 531-5.43 (m, 3H, H-2, H-3, H-12).
Preparation example 82:11-hydroxyl-volatile oil-30-acid-2, the preparation of 12-diene (VIIIb), C 30H 46O 3, MS:ESIm/e 454 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.45, 1HNMR (400MHz, CDCl 3) δ: 4.01 (brs, 1H, H-11), 536-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 83:1-acetoxyl group-volatile oil-30-acid-2, the preparation of 12-diene (VIIIc), C 32H 48O 4, MS:ESIm/e 496 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.55, 1HNMR (400MHz, CDCl 3) δ: 4.74 (d, 1H, J=5.6Hz, H-1), 5.27 (brs, 1H, H-12), 5.60 (d, 1H, J=9.6Hz, H-3), 5.66 (m, 1H, H-2).
Preparation example 84:1-hydroxyl-volatile oil-30-acid-2, the preparation of 12-diene (VIIId), C 30H 46O 3, MS:ESIm/e 454 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.37, 1HNMR (400 MHz, CDCl 3) δ: 3.55 (d, 1H, J=5.6Hz, H-1), 5.32 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 85:1,11-dihydroxyl-volatile oil-30-acid-2, the preparation of 12-diene (VIIIe), C 30H 46O 4, MS:ESI m/e470 (M +); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.33, 1HNMR (400MHz, CDCl 3) δ: 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 86: volatile oil-30-carboxylate methyl ester-2, the preparation of 12-diene (VIIIf), C 31H 48O 2, MS:ESI m/e 452 (M +); Rf (petrol ether/ethyl acetate: 16/1): 0.72, 1H NMR (400MHz, CDCl 3) δ: 3.68 (s, 3H, OCH 3), 5.31-5.43 (m, 3H, H-2, H-3, H-12).
Preparation example 87:11-hydroxyl-volatile oil-30-carboxylate methyl ester-2, the preparation of 12-diene (VIIIg), C 31H 48O 3, MS:ESI m/e468 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.48, 1HNMR (400MHz, CDCl 3) δ: 3.66 (s, 3H, OCH 3), 4.01 (brs, 1H, H-11), 536-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 88:1-acetoxyl group-volatile oil-30-carboxylate methyl ester-2, the preparation of 12-diene (VIIIh), C 33H 50O 4, MS:ESIm/e 510 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.63, 1HNMR (400 MHz, CDCl 3) δ: 3.67 (s, 3H, OCH 3), 4.01 (brs, 1H, H-11), 5.36-5.44 (m, 2H, H-2, H-3), 5.66 (brs, 1H, H-12).
Preparation example 89:1-hydroxyl-volatile oil-30-carboxylate methyl ester-2, the preparation of 12-diene (VIIIi), C 31H 48O 3, MS:ESI m/e468 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.45, 1HNMR (400MHz, CDCl 3) δ: 3.55 (d, 1H, J=6.0Hz, H-1), 3.68 (s, 3H, OCH 3), 5.32 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Preparation example 90:1,11-dihydroxyl-volatile oil-30-carboxylate methyl ester-2, the preparation of 12-diene (VIIIj), C 31H 48O 4, MS:ESIm/e484 (M +); Rf (petrol ether/ethyl acetate: 6/1): 0.39, 1HNMR (400MHz, CDCl 3) δ: 3.67 (s, 3H, OCH 3), 3.98 (brs, 1H, H-11), 5.66 (brs, 1H, H-12), 5.53 (d, 1H, J=10.0Hz, H-3), 5.73 (m, 1H, H-2).
Formula (1) compound has important biological activity, external six strain tumour cells are comprised Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), (oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the test of the cytotoxic activity of human cervical carcinoma cell (Hela) shows that the ramification of pentacycle triterpene of this type of polyoxy replacement and intermediate series compound (specifically seeing embodiment) thereof are inhibited to growth of tumour cell, might develop into new control tumour medicine.In addition, the ramification of pentacycle triterpene of this type of polyoxy replacement (specifically seeing embodiment) demonstrates the activity of obvious inhibition mice caused by dimethylbenzene xylene ear swelling, might develop into new nonsteroidal anti-inflammatory drug.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can be combined with spoke material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned various kinds of drug composition can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can be combined with spoke material or carrier pharmaceutically commonly used, suppress the active pharmaceutical composition that can be used for the treatment of inflammation of mice caused by dimethylbenzene xylene ear swelling thereby prepare to have.Above-mentioned various kinds of drug composition can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can with the antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, gemzar), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare the cytotoxic composition with tumor growth inhibition activity, can be used for treating tumor disease.Such pharmaceutical composition can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can be united use with the nonsteroidal anti-inflammatory drug that has now gone on the market or steroidal anti-inflammatory medicine such as indomethacin (Indometacin), Ibuprofen BP/EP (Ibuprofen), Phenylbutazone (Phenylbutazone), crovaril, Sulpyrine (MetamizoleSodium), Naproxen Base (Naproxen), clofenamic acid (Clofenamic acid) etc., prepare the composition with anti-inflammatory activity.Can be used for treating inflammatory disease.Such pharmaceutical composition can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
In order to understand better essence of the present invention, the result that the below tests inhibiting the pharmacological results and the inhibition mice caused by dimethylbenzene xylene ear swelling of six kinds of tumor cell line growths with compound respectively illustrates its new purposes in pharmacy field.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, preparation example of the present invention and embodiment are for explanation the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Pharmacology embodiment 1: compound IV a is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell RPMI1640 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the compound VI a that will newly join respectively joins in each hole with concentration gradient, makes that the compound ultimate density is respectively 100 μ g/mL in the hole, 33.3 μ g/mL, 11.1 μ g/mL and 3.7 μ g/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ L MTT (5mg/mL), continue again 37 ℃ of cultivations after 4 hours, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with the MTT crystal formazan (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Wherein compound IV a is to KB cell 503nhibiting concentration (IC 50) obtained by dose effect curve.
The IC of compound IV a 50For: 3.2 * 10 -5M
Experiment conclusion: the KB cell is that test compounds is to Cytotoxic effective tool and the evaluation index of tumour cell.This experiment shows ramification of pentacycle triterpene and the intermediate series compound thereof that this type of has the polyoxy replacement, and the KB cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 1, we have tested prepared compound to the pharmacologically active of KB cell, and concrete data see Table one.
Table one
The compound code name VIIc IVb
IC 50 1.7×10 -6M 9.6×10 -5M
Pharmacology embodiment 2:Compound Vf is to the cytotoxic activity of PC-3 cell
PC-3 (prostate cancer) cell F-12 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound Vf 50For: 7.6 * 10 -6M
Experiment conclusion: this experiment shows that ramification of pentacycle triterpene and intermediate series compound thereof that this type of has the polyoxy replacement have stronger cytotoxicity to the PC-3 cell, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 2, we have tested prepared compound to the pharmacologically active of PC-3 cell, and concrete data sees Table two:
Table two
The compound code name IVb IVa
IC 50 9.74×10 -5M 6.28×10 -6M
Pharmacology embodiment 3:Compound IV a is to the cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell RPMI1640 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.With every hole 5 * 10 3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound IV a 50For: 1.99 * 10 -5M
Experiment conclusion: this experiment shows that ramification of pentacycle triterpene and intermediate series compound thereof that this type of has the polyoxy replacement have stronger cytotoxicity to the CNE cell, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 3, we have tested prepared compound to the pharmacologically active of CNE cell, and concrete data see Table three.
Table three
The compound code name IVb VIIIf
IC 50 9.8×10 -6M 2.7×10 -6M
Pharmacology embodiment 4:Compound I k is to the cytotoxic activity of A549 cell
A549 (people's lung cancer) cell RPMI1640 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound I k 50For: 3.1 * 10 -6M
Experiment conclusion: this experiment shows that ramification of pentacycle triterpene and intermediate series compound thereof that this type of has the polyoxy replacement have stronger cytotoxicity to the A549 cell, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 4, we have tested prepared compound to the pharmacologically active of A549 cell, and concrete data (see Table four) as an example of several embodiment example.
Table four
The compound code name IVa Ic
IC 50 6.4×10 -5M 3.7×10 -5M
Pharmacology embodiment 5:Compound IV a is to the cytotoxic activity of BEL-7404 cell
BEL-7404 (people's liver cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound IV a 50For: 3.7 * 10 -5M
Experiment conclusion: this experiment shows that ramification of pentacycle triterpene and intermediate series compound thereof that this type of has the polyoxy replacement have stronger cytotoxicity to the BEL-7404 cell, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 5, we have tested prepared compound to the pharmacologically active of BEL-7404 cell, and concrete data see Table five.
Table five
The compound code name VIIc VIIIb
IC 50 3.6×10 -5M 2.4×10 -5M
Pharmacology embodiment 6: compound IV f is to the cytotoxic activity of Hea cell
Hela (human cervical carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound IV f 50For: 1.7 * 10 -5M
Experiment conclusion: this experiment shows that ramification of pentacycle triterpene and intermediate series compound thereof that this type of has the polyoxy replacement have stronger cytotoxicity to the Hela cell, might develop into the new medicine with antitumor action.
According to the method for pharmacology embodiment 6, we have tested prepared compound to the pharmacologically active of Hela cell, and concrete data see Table six.
Table six
The compound code name IVb IVd
IC 50 1.8×10 -5M 2.5×10 -5M
Pharmacology embodiment 7: compound IV f p-Xylol causes the restraining effect of scorching mice ear
Materials and methods:
One, purpose:
The anti-inflammatory activity of parallel comparative compound IVf is strong and weak under same dose.
Two, model: mice caused by dimethylbenzene xylene auricle edema model
1, animal: the ICR mouse, 21 ± 2g, complete male.
2, proinflammatory agent: dimethylbenzene
3, positive drug: dexamethasone acetate (DEX) tablet normal saline solution.Celestial jade pendant medicine is produced lot number: 2002032206.
Three, grouping: (64 mouse, 8/group.)
1, physiological saline group: NS
2, DMSO group: DMSO,
3, positive drug group: DEX, 5mg/kg, (ig)
4, the heavy dose of group of compound IV f: Il-H, 80mg/kg, (ig)
5, dosage group: Il-M among the compound IV f, 40mg/kg, (ig)
6, compound IV f small dose group: Il-L, 20mg/kg, (ig)
Four, method and step:
Animal grouping, numbering and weighing.
Each organizes mouse by corresponding dosage gastric infusion 3 days, 1 times/day.After the last administration 45 minutes, copy local inflammation with 30 μ l dimethylbenzene at the mouse right ear exterior feature, left ear compares.Cause scorching rear 30 minutes, the dislocation of mouse cervical vertebra is put to death, and cuts left and right sides auricle, sweeps away left and right sides auricle with the punch tool of diameter 9mm, weighs.Weight difference with same mouse left and right sides auricle represents " swelling ", and whether the difference of the positive group of statistical and reagent group and physiological saline group Mice Auricle expansibility is remarkable.
Table seven
NS DMSO DEX IVf-H IVf-M IVf-L
Mean 16.63 16.66 6.34 7.32 9.65 10.98
Standard deviation 3.77 4.23 4.42 4.75 6.33 5.89
The t-check *** *** *** *
Inhibiting rate 62％ 56％ 42％ 34％
*Expression significant difference (p＜0.05); *Expression difference highly significant (p＜0.01); * *Expression difference is (p＜0.001) extremely significantly.Test-results shows: ICR mouse stomach compound IV f high dosage, middle dosage and low dosage p-Xylol cause the auricle edema inhibiting rate and are respectively 56%, 42% and 34%, with the blank group significant difference are arranged relatively.Illustrate that compound IV f has significant restraining effect to acute inflammation model.
In order to understand better essence of the present invention, the below uses respectively the various pharmaceutical dosage form examples of this compounds such as the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, and its new application in pharmacy field is described.
Example of formulations 1:Tablet
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, according to adding spoke material 8000mg behind the general pressed disc method mixing of pharmaceutics, be pressed into 100, every heavy 100mg.
Example of formulations 2:Capsule
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, according to the requirement of pharmaceutics capsule with 8000mg spoke material mixing after, the Capsules of packing into, the heavy 100mg of each capsule.
Example of formulations 3:Injection
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, according to the conventional dose method, carry out charcoal absorption, behind 0.65 μ filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation.Every canned 2ml of injection, canned 1000 bottles altogether.
Example of formulations 4:Aerosol
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, after an amount of propylene glycol dissolving, add distilled water and other spoke material after, make the settled solution of 200ml and get final product.
Example of formulations 5:Suppository
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, it porphyrize adding glycerine is an amount of, grind well the glycogelatin that rear adding has been melted, grind evenly, impouring has been coated with in the model of lubricant, makes 20 on compound I f bolt.
Example of formulations 6:Film
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, polyvinyl alcohol, medicinal glycerin, water etc. are stirred the dissolving of expansion post-heating, 80 eye mesh screens filter, and again compound I f are joined stirring and dissolving in the filtrate, 200 of film applicator maskings.
Example of formulations 7:Pill
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, behind the matrix 700mg heat fused mixings such as gelatin, splash in the cryogenic liquid paraffin, make altogether dripping pill 100 balls.
Example of formulations 8:Externally-applied liniment
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2g, according to the conventional dose method, with spoke material 0.5g mixed grindings such as emulsifying agents, adding distil water is made to 50ml again.
Example of formulations 9:Ointment
With containing compound in claim 1 and the claim 2 (take compound I f as example) 2000mg, grind well and get final product with oleaginous base 198g such as Vaseline behind the porphyrize.

Claims (5)

1. diene oleanolic acid pentacyclic triterpenes derivatives has the general structure shown in the formula (VIII), and it is characterized in that: described compound contains its pharmacologically acceptable salt,
Figure FDA00002252391200011
Formula (VIII)
Wherein: R 3, R 4Select respectively hydrogen, contain the acyloxy of 1～8 carbon atom, the sulfonyloxy that contains 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl or carbonyl;
R 8Select-CH 3,-COOH ,-CH 2OH ,-COOR 9,-CONH 2,-CONHR 9Or-CON (R 9) 2In a kind of;
R 9Select a kind of in the alkyl that contains 1～8 carbon atom, the unsubstituted phenyl;
Abandon compound volatile oil-30-acid-2,12-diene, volatile oil-30-carboxylate methyl ester-2,12-diene, 11-carbonyl-volatile oil-30-acid-2,12-diene.
2. diene oleanolic acid pentacyclic triterpenes derivatives according to claim 1 is characterized in that described compound is:
VIIIb.11-hydroxyl-volatile oil-30-acid-2, the 12-diene;
VIIIc.1-acetoxyl group-volatile oil-30-acid-2, the 12-diene;
VIIId.1-hydroxyl-volatile oil-30-acid-2, the 12-diene;
VIIIe.1,11-dihydroxyl-volatile oil-30-acid-2,12-diene;
VIIIg.11-hydroxyl-volatile oil-30-carboxylate methyl ester-2, the 12-diene;
VIIIh.1-acetoxyl group-volatile oil-30-carboxylate methyl ester-2, the 12-diene;
VIIIi.1-hydroxyl-volatile oil-30-carboxylate methyl ester-2, the 12-diene;
VIIIj.1,11-dihydroxyl-volatile oil-30-carboxylate methyl ester-2,12-diene.
3. diene oleanolic acid pentacyclic triterpenes derivatives according to claim 1 and 2 or its pharmacologically acceptable salt application in preparation control tumor disease medicine.
4. diene oleanolic acid pentacyclic triterpenes derivatives according to claim 1 and 2 or its pharmacologically acceptable salt application in the preparation anti-inflammatory drug.
5. according to claim 3 or 4 described application, it is characterized in that: the dosage form of described medicine is tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment or ointment.
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