CN101235070B - Oleanane triterpene with A ring containing double bond and C ring containing conjugated ketenes, and use thereof - Google Patents
Oleanane triterpene with A ring containing double bond and C ring containing conjugated ketenes, and use thereof Download PDFInfo
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- CN101235070B CN101235070B CN2007101941892A CN200710194189A CN101235070B CN 101235070 B CN101235070 B CN 101235070B CN 2007101941892 A CN2007101941892 A CN 2007101941892A CN 200710194189 A CN200710194189 A CN 200710194189A CN 101235070 B CN101235070 B CN 101235070B
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- 0 CC(C)(C1CC2)C=CC3=N[C@@]13C1[C@]2(C)[C@](C)(CCC2(C)C3C[C@@](C)(C*)CC2)C3=CC1 Chemical compound CC(C)(C1CC2)C=CC3=N[C@@]13C1[C@]2(C)[C@](C)(CCC2(C)C3C[C@@](C)(C*)CC2)C3=CC1 0.000 description 2
- KHQGGBLAWNAZPB-OWCHYKADSA-N CC(C)(C(CC1)[C@@]23C4[C@]1(C)[C@](C)(CCC(C)(CC1)C5C[C@@]1(C)C(OC)=O)C5=CC4)C=CC2[O]3C(C)=O Chemical compound CC(C)(C(CC1)[C@@]23C4[C@]1(C)[C@](C)(CCC(C)(CC1)C5C[C@@]1(C)C(OC)=O)C5=CC4)C=CC2[O]3C(C)=O KHQGGBLAWNAZPB-OWCHYKADSA-N 0.000 description 1
- BSRBYCQHNQFDJM-PBKOJRAFSA-N CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CCC(C)(CC2)C3C[C@@]2(C)C(O)=O)C3=CC1 Chemical compound CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CCC(C)(CC2)C3C[C@@]2(C)C(O)=O)C3=CC1 BSRBYCQHNQFDJM-PBKOJRAFSA-N 0.000 description 1
- BSLOJWPFBHAVFO-ANVLXFTQSA-N CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(O)=O)C3=CC1O Chemical compound CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(O)=O)C3=CC1O BSLOJWPFBHAVFO-ANVLXFTQSA-N 0.000 description 1
- IJSGIYUFQVVEMN-ABEKIGJISA-N CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OC)=O)C3=CC1 Chemical compound CC(C)(CCC1)C(CC2)[C@@]1(C)C1[C@]2(C)[C@](C)(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OC)=O)C3=CC1 IJSGIYUFQVVEMN-ABEKIGJISA-N 0.000 description 1
- GPDFCXJPEYFGNU-GFCVRNTBSA-N CC1C=C(C(C[C@](C)(CC2)C(OC)=O)C2(C)CC2)[C@]2(C)C(CC2)C1[C@]1(C)C2C(C)(C)C=CC1 Chemical compound CC1C=C(C(C[C@](C)(CC2)C(OC)=O)C2(C)CC2)[C@]2(C)C(CC2)C1[C@]1(C)C2C(C)(C)C=CC1 GPDFCXJPEYFGNU-GFCVRNTBSA-N 0.000 description 1
- WIOCLIRTOPLJCT-PYGZWIKISA-N C[C@H](CC[C@]1(C)CC[C@@]2(C)[C@]3(C)CCC4C(C)(C)C=C5)CC1C2=CCC3[C@@]4(C)C5OC(C)=O Chemical compound C[C@H](CC[C@]1(C)CC[C@@]2(C)[C@]3(C)CCC4C(C)(C)C=C5)CC1C2=CCC3[C@@]4(C)C5OC(C)=O WIOCLIRTOPLJCT-PYGZWIKISA-N 0.000 description 1
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Abstract
The invention provides an oleanane triterpene compound, whose A ring contains double bonds and C ring contains conjugated ketene, represented as formula (1). The inventive compound can inhibit the growth activity of tumor cell, thereby being applied in the preparation of anti-tumor drug and can inhibit mice ear swelling caused by dimethylbenzene, thereby being applied in the preparation of anti-inflammatory agent. The formula (1) is represented as above.
Description
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 and the basic preparation method and the purposes of polyoxy replacement.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 has certain inhibition tumor cell growth activity, can expect as the antitumor drug purposes.In addition, this compounds also p-Xylol causes mice ear significant inhibitory effect is arranged, and pointing out this compounds to expect becomes anti-inflammatory drug.
Background technology
At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the special efficacy of treatment 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 research focus.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-IChang etc. that excite wide spread interest, Journal of Natural Products, (natural product magazine), 2004 67 volumes, the 91-93 page or leaf), be hopeful therefrom to find to become the lead compound of new antitumor drug.Therefore the objective 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 in the hope of seeking.According to the whole world especially susceptibility of often swell the 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), the index that human cervical carcinoma cell (Hela) six strain tumour cells are estimated as cell in vitro cytotoxic activity pharmacology.
Inflammatory reaction is a kind of defensive reaction that human body stimulates chemical factors, paathogenic factor etc.Find in the recent period: tumour and senile dementia, and aging etc. all has direct or indirect relation with inflammation.
The ideal anti-inflammatory drug not only requires anti-inflammatory action strong, satisfactory effect, and take for a long time and should have no adverse reaction.Steroidal anti-inflammatory medicine (SAID) such as glucocorticosteroid though anti-inflammatory action stronger than NSAID (non-steroidal anti-inflammatory drug) (NSAID) effect, very fast to the curative effect of many inflammation, may cause serious whole body property untoward reaction because of taking for a long time, generally do not make choice drug.When adopting the NSAID (non-steroidal anti-inflammatory drug) unsatisfactory curative effect, just consider to select for use.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, long-term and large dose oral administration can cause liver injury such as medicines such as acetylsalicylic acid woods, Phenylbutazone, Visubutina, INDOMETHACIN, 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 (as Ana-Isabel Huguet etc., European Journal of Pharmacology (European pharmacology magazine), 2000 years 410 volume 69-81 pages or leaves) to anti-inflammatory; In China, still be that marketed drug is 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.In addition, people such as Dai Yue have reported that also inflammatory models such as rat footpad swelling that Oleanolic Acid causes different proinflammatory agents and mice caused by dimethylbenzene xylene ear swelling all have obvious suppression effect (Dai Yue etc., the anti-inflammatory action of Oleanolic Acid, Chinese J Pharmacol Toxicol, 1989 second volumes, 97 pages).Therefore the objective of the invention is to this compounds is synthesized and structure of modification, in the hope of seeking the ramification of pentacycle triterpene that inflammation is had stronger inhibiting polyoxy replacement.Select for use p-Xylol to cause mice ear restraining effect model among the present invention as anti-inflammatory action preliminary assessment standard.
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 hydrogen respectively, contain the alkoxyl group of 1～8 carbon atom, contain the acyloxy of 1～8 carbon atom, contain the sulfonyloxy of 1～8 disconnected 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; Can also 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 " be meant 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 that is used to prepare control tumor disease medicine of formula (1) compound;
Another purpose of the present invention has provided the purposes that is used to prepare 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 present invention has provided a kind of ramification of pentacycle triterpene and pharmacologically acceptable salt or solvate with the polyoxy replacement shown in the formula (1):
Wherein: R
1～R
6Can be identical or different, be selected from hydrogen respectively, 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; Can also 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,-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 " be meant 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 is meant 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
1, R
2And R
5Be hydrogen atom, R
8During for methyl, be the preferred formula of a class (I) compound:
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 hydrogen respectively, 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 a, Ic are obtained by compound 3-sulfonyloxy methyl oxygen base-volatile oil-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 respectively.Ie is obtained by lithium aluminium hydride reduction by Compound I c.Obtain after the reaction of compound 3-sulfonyloxy methyl oxygen base-volatile oil-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 volatile oil-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 volatile oil-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 l～Ip obtains corresponding product Iq～Iu with lithium aluminium hydride reduction.Ib is by compound volatile oil-28-acid-2, and the 12-diene obtains through lithium aluminium hydride reduction after by the chromium trioxide oxidation again, should obtain Compound I d with diazomethane.
Synthetic route is as follows:
Synthetic route 1
Synthetic route 2
Synthetic route 3
Synthetic route 4
Synthetic route 5
The preparation of preparation example 1: Compound I i
Compound 3-sulfonyloxy methyl oxygen base-volatile oil-28-acid-12-alkene (1.0mmol) is added 5 milliliters of DMAC (N, N '-N,N-DIMETHYLACETAMIDE) dissolving, add Quilonum Retard (2.0mmol) again.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.Silica gel column chromatography (elutriant: petrol ether/ethyl acetate: 8/1), obtain white solid volatile oil-28-acid-2,12-diene, productive rate 82%.
In 20 milliliters of acetic acid (containing 5% acetic anhydride), add compound volatile oil-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 ℃ adds sodium borohydride (1.52mmol) down, 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 chemical combination shown below:
Preparation example 2: volatile oil-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: volatile oil-28-acid-2,9 (11), the preparation of 12-triolefin (Id), C
30H
44O
2, MS:ESIm/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:ESIm/e450 (M
+); Rf (sherwood oil/chloroform: 1/1): 0.65,
1HNMR (400MHz, 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:ESIm/e450 (M
+); Rf (sherwood oil/chloroform: 1/1): 0.65,
1HNMR (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 (sherwood oil/acetoacetic ester: 3/1): 0.57;
1HNMR (400MHz, CDCl
3) δ: 3.62 (m, 2H, 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): 057;
1HNMR (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-volatile oil-28-acid-2, the preparation of 12-diene (Ig), C
30H
46O
3, MS:ESIm/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-volatile oil-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,
1HNMR (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-volatile oil-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,
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 11:1-hydroxyl-volatile oil-28-acid-2, the preparation of 12-diene (Ij), C
30H
46O
3, MS:ESIm/e454 (M
+); Rf (sherwood oil/chloroform/methanol 4/4/0.6): 0.55,
1HNMR (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-volatile oil-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), 5.27 (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 (Il), C
31H
48O
3, MS:ESIm/e468 (M
+); Rf (petrol ether/ethyl acetate: 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:ESIm/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;
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 16:1-hydroxyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (Io), C
31H
48O
3, MS:ESIm/e468 (M
+); Rf (petrol ether/ethyl acetate: 8/1): 0.35;
1HNMR (400MHz, CDCl
3) δ: 2.88 (brd, 1H, J=10.2Hz, 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;
1HNMR (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), 5.27 (brs, 1H, 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:ESIm/e440 (M
+); Rf (petrol ether/ethyl acetate: 5/1): 0.35;
1HNMR (400MHz, CDCl
3) δ: 3.23 (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:ESIm/e 502 (M
+); Rf (petrol ether/ethyl acetate: 5/1): 0.42;
1HNMR (400MHz, CDCl
3) δ: 3.25 (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;
1HNMR (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, between 12,13 two keys, R
4Be bromine atoms, R
3, R
5And R
6Hydrogen atom, R
8During for methyl, be the preferred formula of a class (II) compound:
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 hydrogen respectively, 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-volatile oil-28-acid-12-alkene (IIa);
2 β, 3 beta-dihydroxyies-11-bromo-volatile oil-28-acid-12-alkene (IIb);
2,3-epoxy-11-bromo-volatile oil-28-acid-12-alkene (IIc);
3 β-acetoxyl group-11-bromo-volatile oil-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).
The preparation process of this compounds is specific as follows:
1,4-dioxane and water do that reaction obtains in the solvent to Compound I Ia (IIe) by compound 3-sulfonyloxy methyl oxygen base-volatile oil-28-acid-12-alkene (3-sulfonyloxy methyl oxygen base-oleanane-28-carboxylic methyl-12-alkene) and NBS (N-bromosuccinimide).Obtain Compound I h (Im) behind the demethylating sulfonic acid, obtain Compound I Ic (IIg), obtained Compound I Ib (IIf) by the concentrated hydrochloric acid open loop again by metachloroperbenzoic acid (mCPBA) epoxidation.Compound I Id, IIh are obtained by compound 3-acetoxyl group-volatile oil-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
Synthetic route 6
The preparation of preparation example 23: Compound I Ia
Compound 3-sulfonyloxy methyl oxygen base-volatile oil-28-acid-12-alkene (1.0mmol) adds 10 milliliter 1, and the 4-dioxane stirs adding salt of wormwood (2.00mmol) down, and illumination adds N-bromosuccinimide (2.50mmol) down.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-volatile oil-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-volatile oil-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, J=11.2,20.4HzH-2), 5.23 (s, 1H, H-12).
Preparation example 26:2, the preparation of 3-epoxy-11-bromo-volatile oil-28-acid-12-alkene (IIc), C
30H
45BrO
3, MS:ESIm/e532 (M
+); Rf (sherwood oil/chloroform/methanol: 4/4/0.6):
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-volatile oil-28-acid-12-alkene (IId), C
32H
49BrO
4, MS:ESIm/e576 (M
+); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.55,
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), 530 (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/e 564 (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/e 546 (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), 5.29 (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:ESIm/e590 (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
4Be hydrogen atom, Rx is a methyl, during no any pair of key, is the preferred formula of a class (III) compound in the structure:
Wherein: R
1, R
2, R
5, R
6, 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 hydrogen respectively, 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) compound and pharmacologically acceptable salt thereof or solvate are:
3 β, 12,13-trihydroxy--volatile oil-28-acid (IIIa);
2 β, 3 β, 12,13-tetrahydroxy-volatile oil-28-acid (IIIb);
2 α, 3 β, 12,13-tetrahydroxy-volatile oil-28-acid (IIIe);
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).
The preparation process of this compounds is specific as follows:
Compound III a～IIIc is respectively by raw materials of compound Oleanolic Acid and compound volatile oil-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
Synthetic route 8
Synthetic route 9
The preparation of preparation example 10: compound III b:
With compound volatile oil-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, 12, the preparation of 13-trihydroxy--volatile oil-28-acid (IIIa), C
30H
50O
5, MS:ESI m/e490 (M
+); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.37,
1HNMR (400MHz, CDCl
3) δ: 3.23 (dd, 1H, J=4,10.4Hz, H-3), 3.89 (bts, 1H, H-12).
Preparation example 34:2 β, 3 β, 12, the preparation of 13-tetrahydroxy-volatile oil-28-acid (IIIb), C
30H
50O
6, MS:ESI m/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, 12, the preparation of 13-tetrahydroxy-volatile oil-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, 12, the preparation of 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, 12, the preparation of 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, 12, the preparation of 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
5Be hydrogen 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 hydrogen respectively, 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
9Be alkyl, 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-carbonyl-volatile oil-28-acid-2,12-diene (IVa);
1,11-dicarbapentaborane-volatile oil-28-acid-2,12-diene (IVb);
1-bromo-11-carbonyl-volatile oil-28-acid-2,12-diene (IVc);
1-acetoxyl group-11-carbonyl-volatile oil-28-acid-2,12-diene (IVd);
1-hydroxyl-11-carbonyl-volatile oil-28-acid-2,12-diene (IVe);
11-carbonyl-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).
The preparation process of this compounds is specific as follows:
Compound IV a, IVf are obtained by compound 3 Beta-methyls sulfonyloxy-11-carbonyl-volatile oil-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 respectively by compound IV a, IVf and N-bromosuccinimide 1,4-dioxane and water are done molten reaction and are obtained.Compound IV d, IVi are obtained by the tin anhydride oxidation by compound IV a, IVf respectively, and alkaline hydrolysis obtains compound IVe, IVj respectively again.
Synthetic route 11
Synthetic route 12
The preparation of preparation example 39: compound IV j:
Compound IV f (1.00mmol) is added 10 milliliters of acetate dissolutions, adds tin anhydride (1.00mmol) again, 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 above-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%.
Prepare preparation example 40 shown below to preparation example 49 compounds according to preparation example 39 methods:
Preparation example 40:11-carbonyl-volatile oil-28-acid-2, the preparation of 12-diene (IVa), C
30H
44O
3, MS:ESIm/e452 (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-volatile oil-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), 6.24 (dd, 1H, J=10.4Hz, H-2).
Preparation example 42:1-bromo-11-carbonyl-volatile oil-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-carbonyl-volatile oil-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-volatile oil-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/e480 (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), 6.23 (dd, 1H, J=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-carbonyl-oleanane-28-carboxylic methyl-2, the preparation of 12-diene (IVi), C
33H
48O
5, MS:ESIm/e524 (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
4Be hydrogen atom, R
8During for methyl, be the preferred formula V compound of a class:
Wherein: R
1And R
7Identical with the definition of formula (1) compound.
Section is selected R
1Be selected from hydrogen respectively, 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 to contain 1～8 alkyl that carbon is former, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl.
Preferred formula V compound of the present invention and basic pharmacologically acceptable salt or solvate are:
3 beta-hydroxies-12-carbonyl-volatile oil-28-acid-13 (18)-alkene (Va);
3 β-acetoxyl group-12-carbonyl-volatile oil-28-acid-13 (18)-alkene (Vb);
3 Beta-methyls sulfonyloxy-12-carbonyl-volatile oil-28-acid-13 (18)-alkene (Vc);
3 β hydroxyl-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).
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 acidic conditions.Compound Va～Vb is obtained by compound Vd～Vf hydrolysis respectively.
Synthetic route is as follows:
Synthetic route 13
Preparation example 50: the preparation of compound Va
Compound 3-hydroxyl-oleanane-28-carboxylic methyl-11,13 (18)-diene (2.00mmol) is dissolved with 10 milliliters of methylene dichloride, add m-chloro and cross chloro-benzoic acid (2.00mmol), stirred 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 washed to neutrality to alkalescence.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 washes with water to neutrality.Anhydrous sodium sulfate drying, silica gel column chromatography (elutriant: petrol ether/ethyl acetate: 5/1), obtain white solid Va, productive rate 55%.
Prepare preparation example 51 shown below to preparation example 56 compounds according to preparation example 50 methods:
The preparation of preparation example 51:3 beta-hydroxy-12-carbonyl-volatile oil-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-carbonyl-volatile oil-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-volatile oil-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-volatile oil alkane-28-carboxylate methyl ester-13 (18)-alkene (Ve), C
33H
50O
5, MS:ESIm/e526 (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
3Be hydrogen atom, R
8During for methyl, be class preferred formula (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 hydrogen respectively, 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-volatile oil-28-acid (VIa);
3 β-acetoxyl group-11-carbonyl-13-hydroxyl-volatile oil-28-acid (VIb);
3 Beta-methyls sulfonyloxy-11-carbonyl-13-hydroxyl-volatile oil-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-volatile oil-28-acid (VIg);
3 β-acetoxyl group-11-carbonyl-12-hydroxyl-volatile oil-28-acid (VIh);
3 Beta-methyls sulfonyloxy-11-carbonyl-12-hydroxyl-volatile oil-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-volatile oil-28-acid-2-alkene (VIm);
2,3-epoxy-11-carbonyl-12-hydroxyl-volatile oil-28-acid (VIn);
2 β, 3 β, 12-trihydroxy--11-carbonyl-volatile oil-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 Oleanolic Acid, compound 3-acetoxyl group-volatile oil-28-acid-12-alkene, 3-sulfonyloxy methyl oxygen base-volatile oil-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
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
Preparation example 57: compound VI a, the preparation of VIg
With the mixed solvent of raw material Oleanolic Acid (1.00mmol) adding 20 milliliters of acetonitriles, methylene dichloride and water (15/1/0.1), illumination adds N-bromosuccinimide (2.00mmol) down.Add 020 milliliter of triethylamine, illumination was stirred about four hours, added 10 milliliter of 5% Sulfothiorine NaS
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), (white solid Rf=02 petrol ether/ethyl acetate: 8/1), productive rate is respectively 19%, 34% to VIg.
Prepare preparation example 58 shown below to preparation example 75 compounds according to preparation example 57 methods:
Preparation example 58:3 β, the preparation of 13-dihydroxyl-11-carbonyl-volatile oil-28-acid (VIa), C
30H
48O
5, MS:ESIm/e488 (M
+); Rf (petrol ether/ethyl acetate: 8/1): 0.30,
1HNMR (400MHz, CDl
3) δ: 3.22 (dd, 1H, J=6.4,10.8Hz, H-3).
The preparation C of preparation example 59:3 β-acetoxyl group-11-carbonyl-13-hydroxyl-volatile oil-28-acid (VIb)
32H
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-volatile oil 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 C of 13-dihydroxyl-11-carbonyl-oleanane-28-carboxylic methyl (VId)
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:ESI m/e 580 (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), 433 (dd, 1H, J=11.4,5.6Hz, H-3).
Preparation example 64:3 β, the preparation of 12-dihydroxyl-11-carbonyl-volatile oil-28-acid (VIg), C
31H
48O
5, MS:ESIm/e488 (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 (s, 1H, H-12).
The preparation of preparation example 65:3 β-acetoxyl group-11-carbonyl-12-hydroxyl-volatile oil-28-acid (VIh), C
32H
50O
6, MS:ESIm/e 530 (M
+); Rf (petrol ether/ethyl acetate: 8/2): 035,
1HNMR (400MHz, CDCl
3) δ: 3.66 (s, 1H, H-12), 45.2 (m, 1H H-3).
The preparation of preparation example 66:3 Beta-methyl sulfonyloxy-11-carbonyl-12-hydroxyl-volatile oil-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:ESI m/e 544 (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): 025,
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-volatile oil-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-carbonyl-12-hydroxyl-volatile oil-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: 3.21 (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-volatile oil-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, CDC1
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:
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 hydrogen respectively, 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-carbonyl-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
Synthetic route 17
Preparation example 76:1-hydroxyl-volatile oil-30-acid-2; 9 (11); the preparation of 12-triolefin (VIIa); under nitrogen protection; careful dropping 1 in anhydrous tetrahydrofuran solution (5 milliliters) suspension of lithium aluminium hydride (0.9mmol); 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 emitted until no gas.Product extracts four times for 10 milliliters with ethyl acetate.Merge organic phase, be washed with water to neutrality.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).
Prepare preparation example 77 shown below to preparation example 79 compounds according to preparation example 76 methods:
Preparation example 77: volatile oil-30-acid-2,9 (11), the preparation of 12-triolefin (VIIb), C
30H
44O
2, MS:ESIm/e436 (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), 3.49 (d, 1H, J=10.8Hz, H-30), 3.62 (d, 1H, J=10.8Hz, H-30 '), 4.26 (brs, 1H, H-1), 5.28 (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/e422 (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, between the prosposition and when be pair key between 12,13, is the preferred formula of a class (VIII) compound:
Wherein: R
3, R
4And R
8Identical with the definition of formula (1) compound.
Preferred R
3, R
4Be selected from hydrogen respectively, 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 basic pharmacologically acceptable salt 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).
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 glycyrrhetinic acid methyl esters, 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
Synthetic route 19
Synthetic route 20
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 ℃ adds sodium borohydride (4.0mmol) down, 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%.
Prepare preparation example 81 shown below to preparation example 90 compounds according to preparation example 80 methods:
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: 5.31-5.43 (m, 3H, H-2, H-3, H-2).
Preparation example 82:11-hydroxyl-volatile oil-30-acid-2, the preparation of 12-diene (VIIIb), C
30H
46O
3, MS:ESIm/e454 (M
+); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.45,
1HNMR (400MHz, CDCl
3) δ: 4.01 (brs, 1H, H-11), 5.36-5.44 (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:ESI m/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/e454 (M
+); Rf (sherwood oil/chloroform/methanol: 4/4/0.6): 0.37,
1HNMR (400MHz, 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:ESIm/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:ESIm/e 452 (M
+); Rf (petrol ether/ethyl acetate: 6/1): 0.72,
1HNMR (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), 5.36-5.44 (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 (400MHz, 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/e 484 (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, 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 combine 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 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 combine 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 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 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, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have that tumour is long to suppress active cytotoxicity composition, can be used for treating tumor disease.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound or basic pharmacologically acceptable salt 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 antiphlogistic activity.Can be used for treating inflammatory disease.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
In order to understand essence of the present invention better, the result who with compound the inhibiting The pharmacological results and the inhibition mice caused by dimethylbenzene xylene ear swelling of six kinds of tumor cell line growths is tested respectively illustrates its new purposes in pharmacy field below.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, preparation example of the present invention and embodiment are used to illustrate 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.
Medicine thing 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 joins in each hole with concentration gradient respectively, 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, add the phosphate buffered saline buffer of 10 μ L MTT (5mg/mL), continue again after 4 hours, to remove unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole 37 ℃ of cultivations.With the MTT crystal Jia Za (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) obtain by dose effect curve.
The IC of compound IV a
50For: 3.2 * 10
-5M
Experiment conclusion: the KB cell is Cytotoxic effective tool and the evaluation index of test compounds to 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 the pharmacologically active of prepared compound to the 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 the pharmacologically active of prepared compound to the PC-3 cell, and concrete data see 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 Va
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 the pharmacologically active of prepared compound to the 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 dirty function of tumor.
According to the method for pharmacology embodiment 4, we have tested the pharmacologically active of prepared compound to the A549 cell, and concrete data are example (seeing Table four) with several embodiment.
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 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 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 the pharmacologically active of prepared compound to the 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 Hela cell
Hela (human cervical carcinoma) 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 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 the pharmacologically active of prepared compound to the 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 power of parallel comparative compound IVf 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 company 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 time/day.After the last administration 45 minutes, duplicate local inflammation with 30 μ l dimethylbenzene at the mouse right ear exterior feature, left ear compares.Cause scorching back 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 is represented " swelling degree ", and whether the difference of the positive group of statistical and reagent group and physiological saline group mice auricle swelling degree 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％ |
* represent significant difference (p＜0.05); * represents difference highly significant (p＜0.01); * * represents difference extremely significantly (p＜0.001).
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 inhibitory effect to the acute inflammation model.
In order to understand essence of the present invention better, use 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 below respectively, its new application in pharmacy field is described.
Example of formulations 1:Tablet
With containing compound in claim 1 and the claim 2 (is example with Compound I f) 2000mg, according to adding spoke material 8000mg behind the general platen press mixing of pharmaceutics, be pressed into 100, every heavy 100mg.
Preparation is executed example 2:Capsule
With containing compound in claim 1 and the claim 2 (is example with Compound I f) 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 (is example with Compound I f) 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 (is example with Compound I f) 2000mg, after an amount of the third two dissolvings, add distilled water and other spoke material after, the settled solution of making 200ml is promptly.
Example of formulations 5:Suppository
With containing compound in claim 1 and the claim 2 (is example with Compound I f) 2000mg, it porphyrize adding glycerine is an amount of, grind well the back and add the glycogelatin that has melted, to 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 (is example with Compound I f) 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 the machine-processed films of filming.
Example of formulations 7:Pill
With containing compound in claim 1 and the claim 2 (is example with Compound I f) 2000mg, behind matrix 700mg heat fused mixings such as gelatin, splash in the cryogenic liquid paraffin, make dripping pill 100 balls altogether.
Example of formulations 8:Externally-applied liniment
With containing compound in claim 1 and the claim 2 (is example with Compound I f) 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 (is example with Compound I f) 2000mg, grind well promptly with oleaginous base 198g such as Vaseline behind the porphyrize.
Claims (5)
1. a class A ring containing double bond and the oleanane triterpene compound of the ring containing conjugated ketenes of C has the general structure shown in the formula (IV), it is characterized in that: described compound contains its pharmacologically acceptable salt,
Wherein: be two keys simultaneously between the prosposition and between 12,13; R
1, R
2, R
5And R
6It is hydrogen atom; R
8It is methyl;
R
3Be selected from hydrogen, contain in the acyloxy of 1～8 carbon atom, the sulfonyloxy that contains 1～8 carbon atom, halogen, amino, nitro, cyano group, hydroxyl or the carbonyl a kind of;
R
7Be selected from-CH
3,-COOH ,-CH
2OH ,-COOR
9,-CONH
2,-CONHR
9, or-CON (R
9)
2
R
9Be selected from a kind of in the alkyl, replacement or the unsubstituted phenyl that contain 1～8 carbon atom or replacement or the unsubstituted benzene alkyl.
2. a class A the ring containing double bond according to claim 1 and oleanane triterpene compound of the ring containing conjugated ketenes of C is characterized in that described compound is:
IVa.11-carbonyl-volatile oil-28-acid-2, the 12-diene;
IVb.1,11-dicarbapentaborane-volatile oil-28-acid-2,12-diene;
IVc.1-bromo-11-carbonyl-volatile oil-28-acid-2, the 12-diene;
IVd.1-acetoxyl group-11-carbonyl-volatile oil-28-acid-2, the 12-diene;
IVe.1-hydroxyl-11-carbonyl-volatile oil-28-acid-2, the 12-diene);
IVg.1,11-dicarbapentaborane-oleanane-28-carboxylic methyl-2,12-diene;
IVh.1-bromo-11-carbonyl-oleanane-28-carboxylic methyl-2, the 12-diene;
IVi.1-acetoxyl group-11-carbonyl-oleanane-28-carboxylic methyl-2, the 12-diene;
IVj.1-hydroxyl-11-carbonyl-oleanane-28-carboxylic methyl-2, the 12-diene.
3. the application in preparation control tumor disease medicine of the oleanane triterpene compound of a class A ring containing double bond according to claim 1 and 2 and the ring containing conjugated ketenes of C and pharmacologically acceptable salt thereof.
4. the application in the preparation anti-inflammatory drug of the oleanane triterpene compound of a class A ring containing double bond according to claim 1 and 2 and the ring containing conjugated ketenes of C and pharmacologically acceptable salt thereof.
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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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1034334C (en) * | 1993-08-14 | 1997-03-26 | 贵州省中医研究所 | Process for prepn. of sodium olean-phthalate |
| CN1100062C (en) * | 1996-06-03 | 2003-01-29 | 中国科学院成都生物研究所 | New medicine for curing presenile dementia and cerebral apoplexy sequelae |
-
2004
- 2004-12-29 CN CN2007101941892A patent/CN101235070B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1034334C (en) * | 1993-08-14 | 1997-03-26 | 贵州省中医研究所 | Process for prepn. of sodium olean-phthalate |
| CN1100062C (en) * | 1996-06-03 | 2003-01-29 | 中国科学院成都生物研究所 | New medicine for curing presenile dementia and cerebral apoplexy sequelae |
Non-Patent Citations (4)
| Title |
|---|
| D. DALOZE.Triterpenes. IX. Abnormal reduction with lithium aluminumhydride..《 Tetrahedron Letters》.1967,第14卷全文. * |
| J. Derkoseh.Infrared spectra of isocyanates and substituted ureas.《Monatshefte fuer Chemie》.1957,第88卷全文. * |
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| 王德仁.齐墩果酸研究新进展.《天津药学》.2003,第15卷(第3期),56-58. * |
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