CN102079772A - Pentacyclic triterpene-13,28-lactone compounds as well as preparation method and application thereof - Google Patents
Pentacyclic triterpene-13,28-lactone compounds as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses pentacyclic triterpene-13,28-lactones with antineoplastic activity, shown as a general formula I, or pharmaceutically acceptable salts thereof as well as a preparation method and medical application thereof, belonging to the field of biological medicines. The preparation method of the compounds, provided by the invention, has the advantages of mild reaction conditions, simplicity in operation, higher yield as well as strong practicability and structural universality. Shown by a pharmacologic test result, the compounds provided by the invention have favorable antineoplastic activity and can be applied as an antineoplastic drug in clinic.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a class pentacyclic triterpene-13,28-lactone compound and preparation method thereof, the present invention also further relates to their application in the preparation antitumor drug.
Background technology
Oleanane type (oleanane) and ursane type pentacyclic triterpenoids such as (ursane) distribute very extensive in vegitabilia, be the main effective constituent of many herbal medicine commonly used, have wide biological activity (Neoplasma, 2004,51,327-333).Based on the optimization of these natural compound structures with to derive be one of focus of Natural Medicine Chemistry research.
Recently discover, the important member-volatile oil of natural pentacyclic triterpenoid-13, the 28-lactone has notable antitumor activity.For example, isolating lactone (1,2) from platycodon grandiflorum root such as Zhang shows potent cytotoxicity (IC to people's esophageal cancer cell ECA-109
50Be respectively 0.93,0.59 μ M) (Molecules, 2007,12,832-841).The lactone (3,4) that Yamaguchi etc. extract from betula ermanii bark can be used as chemopreventive agent, has the generation of inhibition mouse skin carcinoma and effect (the Chemistry ﹠amp of development; Biodiversity, 2009,6,1093-1100).Above-mentioned discovery causes people's showing great attention to and paying attention to the pentacyclic triterpene lactone.
R
1?glucosyl- R
1?glucosyl-glucosyl
R
2?CH
2OH R
2?CH
3
But, study the pentacyclic triterpene lactone at present and still have problems.At first, because this compounds content in natural phant is low, the compound that is difficult to an amount of and structure diversity are provided more is difficult to be provided for a large amount of samples of clinical study for medicine efficacy screening; Secondly, the lactone difficulty that obtains this class formation complexity by chemical synthesis process is big, and rarely has bibliographical information.Be equipped with the volatile oil lactone though there are several examples to use the superoxide legal system, condition is very harsh.For example, need react down at-70 ℃ during the volatile oil lactone of synthetic 12 hydroxyls replacement of employing such as Ali ozone method (Phytochemistry, 2002,60,295-299.).Moreover, adopt the superoxide legal system to be equipped with the volatile oil lactone and destroy some sensitive groups on the substrate structure easily, as two keys, hydroxyl, amino etc.Therefore, it is narrower that the superoxide legal system is equipped with the range of application of pentacyclic triterpene lactone.
Summary of the invention
The present invention discloses a class novel pentacyclic triterpene-13,28-lactone compound and preparation method thereof and medicinal use first.Compare with the superoxide method of bibliographical information, the preparation method of The compounds of this invention is the reaction conditions gentleness not only, can not destroy on the structure the group of peroxidation agent sensitivity and have the group of reactive hydrogen, and simple to operate, yield is higher, side reaction seldom, be easy to aftertreatment, also have practicality and universality simultaneously.The pharmacological results shows that The compounds of this invention has good anti-tumor activity, and therefore, this compounds can be used as antitumor drug clinically and uses.
One of purpose of the present invention is to provide the pentacyclic triterpene shown in the general formula I-13,28-lactone compound or its pharmacy acceptable salt:
Wherein:
Between C1 and the C2 carbon-carbon single bond or carbon-carbon double bond;
Between C9 and the C11 carbon-carbon single bond or carbon-carbon double bond;
R
1Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom, 3-carboxyl-1-propionyloxy, the amide group that contains 1～8 carbon atom, oximido or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, itrile group, hydroxyl oximido, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom or and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
Specifically, compound of Formula I or its pharmacy acceptable salt is characterized in that described compound of Formula I is:
Wherein:
R
1Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom, 3-carboxyl-1-propionyloxy, the amide group that contains 1～8 carbon atom, oximido or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, itrile group, hydroxyl oximido, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
Further, compound or its pharmacy acceptable salt shown in the general formula I (comprising Ia, Ib, Ic) is characterized in that:
R
1Be selected from hydroxyl, ketonic oxygen, 3-carboxyl-1-propionyloxy, acetoxyl group or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, itrile group or and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
Specifically, the pentacyclic triterpene-13 shown in the general formula I (comprising Ia, Ib, Ic), the 28-lactone is preferably from following compounds:
(1) 3 β-acetoxyl group-12-oxo volatile oil-13,28-lactone (compound number: Ia-1, down together)
(2) 3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-1)
(3) 3,12-dioxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-2)
(4) 3 β-(3-carboxyl-1-propionyloxy)-12-oxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-3)
(5) 3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-13,28-lactone (Ib-4)
(6) 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-13,28-lactone (Ib-5)
(7) A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-13,28-lactone (Ib-6)
(8) 2-itrile group-3-loses carbon-3,4-open loop-12-oxygen-volatile oil-9 (11)-alkene-13,28-lactone (Ib-7)
(9) 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-13,28-lactone (Ic-1)
The compound of described general formula I (comprising Ia, Ib, Ic), further preferably from 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-13,28-lactone (Ic-1).
Another object of the present invention is to provide the preparation method of the described compound of general formula I of the present invention (comprising Ia, Ib, Ic), it is characterized by and be, pentacyclic triterpenoid shown in the formula II is under the effect of dehydrogenating agent, remove the hydrogen of C13 position and the hydrogen on the carboxyl of C28 position, generate the pentacyclic triterpene-13 shown in the general formula I (comprising Ia, Ib, Ic), the 28-lactone compound:
Wherein, R
1, R
2, R
3And R
4Described as defined above.
The dehydrogenating agent that adopts is selected from 2,3-two chloro-5,6-dicyanobenzoquinone, tetrachlorobenzoquinone, tin anhydride, 1,1-phenylbenzene-2-trinitrophenyl-hydrazine, 2,2,6, one or more in 6-tetramethyl piperidine nitrogen oxygen free radical or the tin anhydride; The reaction solvent that adopts is benzene,toluene,xylene, dioxane, acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform, ethylene dichloride, methyl alcohol, acetone, ethyl acetate or N, one or more in the dinethylformamide; Temperature of reaction is 50-120 ℃.
Pentacyclic triterpenoid (II shown in the formula II
1～II
9) synthetic method as follows:
(1) 3 β-acetoxyl group-12-oxo oleanane-28-carboxylic (II
1)
With Oleanolic Acid (OA) is raw material, makes formula (II through the benzyl esterification of C28 position carboxyl, the acetylize of C3 position hydroxyl, the oxidation and the C28 position debenzylation of C12 position respectively
1) compound:
Reagents?and?conditions：(a)PhCH
2Cl；(b)Ac
2O；(c)H
2O
2；(d)H
2，Pd-C.
(2) 3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-28-carboxylic acid (II
2)
With above-mentioned intermediate 7 is raw material, makes formula (II through the two keys of C9 (11) position structure, C3 position deacetylation, C28 position debenzylation respectively
2) compound:
Reagents?and?conditions：(a)Br
2，HBr；(b)KOH；(c)H
2，Pd-C.
(3) 3,12-dioxo volatile oils-9 (11)-alkene-28-carboxylic acid (II
3)
With above-mentioned intermediate 9 is raw material, makes formula (II through the oxidation of C3 position, C28 position debenzylation respectively
3) compound:
Reagents?and?conditions：(a)Jones?reagent；(b)H
2，Pd-C.
(4) 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-carboxylic acid (II
4)
With above-mentioned intermediate 10 is raw material, makes formula (II through the nucleophilic addition(Adn) of C2 position, Cheng Huan, C28 position debenzylation respectively
4) compound:
Reagents?and?conditions：(a)HCOOC
2H
5；(b)NH
2OH·HCl；(c)H
2，Pd-C.
(5) 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxyl (II
5)
With above-mentioned intermediate II
4Be raw material, make formula (II through Kemp reaction, DDQ dehydrogenation respectively
5) compound:
Reagents?and?conditions：(a)NaOMe；(b)DDQ.
(6) 3 β-(3-carboxyl-1-propionyloxy)-12-oxo volatile oil-9 (11)-alkene-28-carboxyl (II
6) compound:
With above-mentioned intermediate II
2Be raw material, make formula (II with the Succinic anhydried reaction
6) compound:
Reagents?and?conditions：(a)(CH
3CH
2CO)
2O.
(7) A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-28-carboxyl (II
7)
With above-mentioned intermediate 10 is raw material, carries out C3 position hydroxyl oximate respectively, and A encircles ring expansion, and C28 position debenzylation makes formula (II
7) compound:
Reagents?and?conditions：(a)NH
2OH·HCl；(b)TsCl；(c)H
2，Pd-C.
(8) 2-itrile group-3-loses carbon-3,4-open loop-12-oxygen-volatile oil-9 (11)-alkene-28-carboxyl (II
8)
With above-mentioned intermediate 14 is raw material, carries out the open loop of A ring respectively, and C28 position debenzylation makes formula (II
8) compound:
Reagents?and?conditions：(a)SOCl
2；(b)H
2，Pd-C.
(9) 3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-28-carboxyl (II
9)
With urson (UA) is raw material, makes formula (II through the benzyl esterification of C28 position carboxyl, the acetylize of C3 position hydroxyl, oxidation, C11 (9) position alkylene, C3 position deacetylation and the C28 position debenzylation of C12 position respectively
9) compound:
Reagents?and?conditions：(a)PhCH
2Cl；(b)Ac
2O；(c)H
2O
2；(d)Br
2，HBr；(e)KOH；(f)H
2，Pd-C.
Further purpose of the present invention is to provide a kind of general formula I of the present invention (comprising Ia, Ib, the Ic) compound of effective dosage and pharmaceutical composition of pharmaceutically acceptable carrier or auxiliary material of containing.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc. can be used the oral dosage form administration, but as tablet, capsule dispersed powders, granule etc.The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in the pharmaceutical field.Can contain for example activeconstituents of 0.05%～90% weight with carrier combinations in these medicinal preparationss, the activeconstituents of weight between more common about 15%～60%.The compounds of this invention dosage can be 0.005～5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or formulation.
A further object of the present invention provides the application of representation compound of the present invention in preparation treatment chronic inflammatory diseases and tumour medicine.
The compounds of this invention can with other antitumor drugs for example alkylating agent (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (as camptothecine), mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), DNA intercalating agent (as Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumor drugs or radiotherapy can give simultaneously or at different time with The compounds of this invention.Thereby these combination therapys can produce synergy helps to improve result of treatment.
Be the part pharmacological testing and the result of representation compound of the present invention below:
The blue colorimetry antitumor activity in vitro of tetramethyl-nitrogen azoles
Adopt the blue colorimetry of tetramethyl-nitrogen azoles (MTT) to estimate the antiproliferative activity of The compounds of this invention routinely to 7 kinds of human cancer cell strains.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Select to be at present the CDDO-Me (RTA-402, bardoxolone methyl) of II clinical trial phase treatment carcinoma of the pancreas and chronic nephropathy as positive control drug.It is worthy of note, CDDO-Me be present clinical study the most deeply, a pentacyclic triterpene compound that biological activity is the strongest, authoritative magazine once specially to its carried out summary (Nature Reviews Cancer, 2007,7,357-69).
Human cancer cell strain: liver cancer cell HepG2, SMMC-7721, BEL-7402, cervical cancer cell Hela, breast cancer cell MCF-7, lung carcinoma cell H460 and melanoma cell A-375.
Human normal cell line: liver cell LO2.
Experimental technique is as follows: get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, make every milliliter and contain 5 * 10
4～7 * 10
4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 100 μ L put constant temperature CO
2Cultivated 24 hours in the incubator.Change liquid, (compound dilutes with nutrient solution with DMSO dissolving back, and test-compound concentration is respectively 5 * 10 to add test-compound
-5, 1.25 * 10
-5, 3.125 * 10
-6, 7.812 * 10
-7, 1.953 * 10
-7Mol/L), every hole 200 μ L cultivated 48 hours.MTT (concentration is 5mg/mL) is added in 96 orifice plates, every hole 20 μ L, reaction is 4 hours in the incubator.Supernatant liquor is removed in suction, adds DMSO, every hole 150 μ L, and jolting is 5 minutes on the dull and stereotyped shaking table.Is the optical density that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, calculates cell inhibitory rate.Experimental result is as shown in table 1.
Cell inhibitory rate=(negative control group OD value-tried thing group OD value)/negative control group OD value * 100%.
Table 1 representation compound of the present invention is to part tumor cell proliferation inhibition activity (IC
50, μ mol/L)
A series of tumour cell test results show that Compound I c-1 has the antitumor action of wide spectrum, its IC
50Value all is in micromole's rank.Wherein, Ic-1 is especially outstanding to HepG2, Bel-7402, the isocellular effect of MCF-7, A-375, and is quite active with positive control drug CDDO-Me.Meanwhile, Ic-1 then is lower than CDDO-Me to the toxicity of normal cell LO2.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1
The preparation of 3 beta-hydroxies volatile oil-12-alkene-28-benzyl carboxylate (5)
With Oleanolic Acid (100g, 220mmol) and salt of wormwood (61g, 440mmol) place DMF (800mL), drip Benzyl Chloride (33mL in 50～55 ℃ in following 20 minutes, 290mmol), keep this temperature after dropwising and continue reaction 3～4 hours, reaction solution is chilled to room temperature, filter, filter cake washs with DMF (50mL * 3), in (3000mL), have a large amount of white solids to separate out in the mother liquor impouring frozen water that obtains, leave standstill treat solid particulate become big after, suction filtration, the water thorough washing, the dry white solid 5 (114g, 95.5%) that gets.Compound 5 is known compounds, and its CAS number is 303114-51-4.
Embodiment 2
The preparation of 3 β-acetoxyl group volatile oil-12-alkene-28-benzyl carboxylate (6)
(5.46g 10mmol) is dissolved in the pyridine (20mL), and 0 ℃ slowly drips diacetyl oxide (10.2g with compound 5,100mmol), and adding DMAP after dropwising (0.12g, 1mmol), there is solid to separate out, continues reaction 1～2 hour under the room temperature, add an amount of methylene dichloride (50mL) dissolving, solution 5% dilute hydrochloric acid solution, saturated sodium bicarbonate solution, the saturated common salt aqueous solution respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets white solid 6 (5.4g, 91.3%) after removing solvent.Compound 6 is known compounds, and CAS number is 357953-27-6.
Embodiment 3
The preparation of 3 β-acetoxyl group-12-oxo oleanane-28-carboxylic benzyl ester (7)
(5.88g 10mmol) is dissolved in an amount of methylene dichloride (50mL), adds formic acid (10mL), H with compound 6
2O
2(1.36g, 40mmol), room temperature reaction 24 hours, TLC monitoring reaction process, after treating that raw material point disappears, with saturated sodium bicarbonate solution reaction solution is washed till nearly neutrality, saturated common salt solution washing 3 times, anhydrous sodium sulfate drying, decompression get light yellow solid, AcOH-H after removing solvent
2The O recrystallization gets white solid 7 (4.7g, 78%).Compound 7 is known compounds, and CAS number is 357953-28-7.
Embodiment 4
3 β-acetoxyl group-12-oxo oleanane-28-carboxylic (II
1) preparation
(0.6g 1mmol) is dissolved in an amount of tetrahydrofuran (THF) (15mL) to compound 7, adds the palladium carbon (0.06g) of catalytic amount, and normal temperature and pressure descends and hydrogen reaction makes white solid II
1(0.50g, 98%).Compound I I
1Be known compound, CAS number is 357953-29-8.
Embodiment 5
The preparation of 3 β-acetoxyl group-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (8)
With compound 7 (6.04g, 10mmol) be dissolved in the acetate (300mL), drip Hydrogen bromide (40%, the acetate) solution of catalytic amount, be heated to 40～45 ℃, slow dropping liquid bromine (1.6g, acetic acid solution 10mmol) is after dropwising, stir a moment, (reaction is 24 hours under the room temperature for 3.2g, acetic acid solution 20mmol) for the liquid feeding bromine in addition.After reacting end, in solution impouring frozen water, collect and separate out solid, use saturated sodium bisulfite solution respectively, water washing, oven dry gets faint yellow crude product, and recrystallizing methanol gets white solid 8 (4.39g, 79.8%).
m.p.216-218℃；
ESI-MS：603[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，4.46(m，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.05(s，3H)，2.01，1.57，1.16，1.00，0.95，0.92，0.89(s，each?3H)ppm.
Embodiment 6
The preparation of 3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (9)
With compound 8 (6.02g, 10mmol), potassium hydroxide (33.6g, 600mmol) be dissolved in methyl alcohol (300mL), add and refluxed 30～45 minutes, solvent is removed in decompression, and remaining solid is washed till nearly neutrality with the dilute hydrochloric acid solution of 6mol/L, water layer extracts with methylene dichloride (100mL * 3), organic layer saturated sodium bicarbonate solution, the saturated common salt aqueous solution respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets white solid 9 (5.32g, 95%) after removing solvent.
m.p.197-198℃；
ESI-MS?m/z：561[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.22-3.17(m，1H)，3.03(m，1H)，2.25(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 7
3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-28-carboxylic acid (II
2) preparation
With reference to II
1The preparation method, make white solid II by compound 9 and palladium carbon, hydrogen reaction
2, yield 98%.
m.p.294-296℃；
ESI-MS?m/z：469[M-H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ5.8(s，1H)，3.24(m，1H)，3.19(m，1H)，2.93(d，J＝4.5Hz，1H)，1.25，1.17，1.03，1.00，1.00，0.89，0.83(s，each?3H)ppm.
Embodiment 8
3, the preparation of 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (10)
With compound 9 (5.6g, 10mmo1) be dissolved in the acetone (200mL), 0 ℃ slowly drips Jones reagent (3.8mL) down, dropwised the back room temperature reaction 10～20 minutes, TLC monitoring reaction process, after treating that raw material point disappears, solvent is removed in decompression, adds water in the residue, extracts with methylene dichloride (100mL * 3), the organic layer saturated sodium bicarbonate solution, the saturated common salt aqueous solution respectively washs 3 times, anhydrous sodium sulfate drying, and decompression gets the light brown solid after removing solvent, silica gel column chromatography makes white solid 10 (4.9g, 88%) fast.
m.p.146-147℃；
ESI-MS?m/z：559[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.38-7.28(m，5H)，5.8(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H，)，3.06(m，1H)，2.78(d，J＝4.5Hz，1H)，2.66，2.49，2.17(m，each?1H)，1.26，1.11，1.07，1.00，0.97，0.95，0.89(s，each?3H)ppm.
Embodiment 9
3,12-dioxo volatile oil-9 (11)-alkene-28-carboxylic acid (II
3) preparation
With reference to II
1The preparation method, make white solid II by compound 10 and palladium carbon, hydrogen reaction
3, yield 98%.
m.p.264-268℃；
ESI-MS?m/z：469[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ5.8(s，1H)，3.02(m，1H)，2.93(d，J＝4.8Hz，1H)，2.66，2.49，2.22(m，each?1H)，1.30，1.29，1.25，1.23，1.19，1.13，1.09(s，each?3H)ppm.
Embodiment 10
2-hydroxyl methyne-3, the preparation of 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (11)
With compound 10 (5.58g, 10mmol) be dissolved in the exsiccant methylene dichloride, 0 ℃ adds new system sodium methylate (3.24g, 60mmol), form suspension, stir moments later, slowly drip ethyl formate (3.33g, 45mmol), room temperature reaction 12 hours is after reaction finishes, regulate reacting liquid pH value down to neutral for 0 ℃, the methylene dichloride dilution, organic layer saturated sodium bicarbonate solution, the saturated common salt aqueous solution respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets faint yellow solid after removing solvent, makes white solid 11 (5.3g, 90.2%) through quick silica gel column chromatography.
m.p.110-114℃；
ESI-MS：587[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ14.85(d，J＝2.4Hz，1H)，8.75(s，1H)，7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.03(m，1H)，2.83(d，J＝4.5Hz，1H)，2.61(d，J＝14.4Hz，1H)，2.25(d，J＝14.4Hz，1H)，1.24，1.15，1.14，1.01，0.98，0.94，0.85(s，each?3H)ppm.
Embodiment 11
The preparation of 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-benzyl carboxylate (12)
With compound 11 (5.8g, 10mmol), oxammonium hydrochloride (6.95g, 100mmol) be dissolved in ethanol (100mL, 95%), reflux 1 hour, reaction finishes, concentrate residue ethyl acetate (50mL) dissolving, organic layer saturated sodium bicarbonate solution, the saturated common salt aqueous solution respectively washs 3 times, anhydrous sodium sulfate drying, decompression get white solid 12 (4.8g, 82.7%) after removing solvent.
m.p.120-122℃；
ESI-MS：584[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(s，1H)，7.34-7.26(m，5H)，5.8(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.10(m，1H)，2.80(d，J＝4.5Hz，1H)，2.75(d，J＝15Hz，1H)，3.38(d，J＝15Hz，1H)，1.37，1.26，1.12，1.01，0.99，0.95，0.90(s，each?3H)ppm.
Embodiment 12
12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-carboxylic acid (H
4) preparation
With reference to II
1The preparation method, make white solid II by compound 12 and palladium carbon, hydrogen reaction
4, yield 98%.
m.p.224-226℃；
ESI-MS：492[M-H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(s，1H)，5.8(s，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.78(d，J＝15.3Hz，1H)，2.40(d，J＝15.3Hz，1H)，1.35，1.31，1.26，1.16，1.01，0.97，0.85(s，each?3H)ppm.
Embodiment 13
The preparation of 2-cyano-3-hydroxy-12-oxo volatile oil-2,9 (11)-diene-28-carboxylic acid (13)
With Compound I I
4(0.49g 1mmol), is dissolved in the mixing solutions of methyl alcohol (6mL), ether (12mL), 0 ℃ adds sodium methylate (1.62g down, 30mmol), waited a moment room temperature reaction 45 minutes, the methylene dichloride dilution, with 5% dilute hydrochloric acid acidifying, organic layer is washed 3 times with saturated sodium bicarbonate, saturated common salt washing 3 times, anhydrous sodium sulfate drying, decompression gets faint yellow solid 13 (0.44g, 89%) after removing solvent.Product need not to be further purified, and purity satisfies the requirement of next step reaction.
m.p.198-200℃；
ESI-MS：492[M-H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.01(s，1H)，5.9(s，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.41(d，J＝9.0Hz，1H)，2.26(d，J＝9.0Hz，1H)，1.26，1.21，1.24，1.20，1.16，1.00，0.91(s，each?3H)ppm.
Embodiment 14
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (II
5) preparation
(0.25g, 0.51mmol) (0.25g 0.51mmol) is dissolved in the dry-out benzene (20mL), and reflux 20 minutes after reaction finishes, is filtered, and filtrate concentrates, and rapid column chromatography gets white solid II with dicyan dichloro quinone (DDQ) with compound 13
5(0.23g, 91.1%).Compound I I
5Be known compound, CAS number is 218600-44-3.
m.p.180-182℃；
ESI-MS?m/z：490[M-H]
-，492[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(1H，s)，5.99(1H，s)，3.03-2.98(2H，m)，1.55，1.38，1.34，1.22，1.00，0.91，0.85(each?3H，s，CH
3)ppm.
Embodiment 15
3 β-(3-carboxyl-1-propionyloxy)-12-oxo volatile oil-9 (11)-alkene-28-carboxyl (II
6) preparation
Compound I I
2(2.0g, 4.26mmol), Succinic anhydried (1.7g, 17.0mmol), DMAP (0.51g, 4.26mmol) be dissolved in methylene dichloride (50mL), reflux 12 hours, reaction solution water, saturated aqueous common salt respectively wash three times, anhydrous sodium sulfate drying filters, concentrates, and rapid column chromatography gets Compound I I
6(1.99g, 82.1%).
m.p.186-190℃；
ESI-MS：571[M+H]
+；
1HNMR(300M?Hz，DMSO-d
6，25℃，TMS)：δ5.8(s，1H)，4.51(m，1H)，2.98(m，1H)，2.93(d，J＝4.5Hz，1H)，2.69-2.64(m，4H)，1.57，1.26，1.61，1.09，1.06，1.00，0.94(s，each?3H)ppm.
Embodiment 16
The preparation of 3-hydroxyl imide base-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (14)
With compound 10 (5.6g, 10mmol), oxammonium hydrochloride (1.0g, 15mmol) and sodium bicarbonate (1.26g 15mmol) is dissolved in the ethanol (100mL), 60 ℃ of down reactions 12 hours, concentrate, the methylene dichloride dilution, organic layer water, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, concentrate, silica gel column chromatography makes white solid 14 (5.0g, 88%) fast.
m.p.94-96℃；
ESI-MS?m/z：574[M+H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.37-7.26(m，5H)，5.72(s，1H)，5.14(d，J＝12Hz，1H)，5.13(d，J＝12Hz，1H)，3.20(m，1H)，3.08(m，1H)，2.76(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 17
The preparation of A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-28-benzyl carboxylate (15)
With compound 14 (2.0g, 3.5mmol), to toluene benzene sulfonyl chloride (0.66g, 3.5mmol) be dissolved in the pyridine (50mL), normal-temperature reaction 12 hours concentrates, acetic acid ethyl dissolution, organic layer 5% dilute hydrochloric acid, saturated sodium bicarbonate, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, concentrate, silica gel column chromatography makes white solid 15 (1.7g, 83%) fast.
m.p.156-158℃；
ESI-MS?m/z：574[M+H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.37-7.26(m，5H)，5.83(s，1H)，5.77(s，1H)，5.14(d，J＝12Hz，1H)，5.13(d，J＝12Hz，1H)，3.06(m，1H)，2.79(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 18
A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-28-carboxylic acid (II
7) preparation
With reference to II
1The preparation method, make white solid II by compound 15 and palladium carbon, hydrogen reaction
7, yield 98%.
m.p.135-137℃；
ESI-MS：483[M+H]
+；
1HNMR(300M?Hz，DMSO-d
6，25℃，TMS)：δ7.12(s，1H)，5.83(s，1H)，3.06(m，1H)，2.79(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 19
2-itrile group-3-loses carbon-3, the preparation of 4-open loop-12-oxygen-volatile oil-9 (11)-alkene-28-benzyl carboxylate (16)
With compound 14 (2.0g, 3.5mmol), thionyl chloride (4.2g, 35mmol) be dissolved in the dioxane (50mL), normal-temperature reaction 15 minutes concentrates, the ethyl acetate dilution, the organic layer saturated sodium bicarbonate, saturated aqueous common salt respectively washs 3 times, and anhydrous sodium sulfate drying concentrates, silica gel column chromatography makes white solid 16 (1.5g, 75%) fast.
m.p.145-148℃；
ESI-MS?m/z：556[M+H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.37-7.26(m，5H)，5.71(s，1H)，5.14(d，J＝12Hz，1H)，5.13(d，J＝12Hz，1H)，4.99(s，1H)，4.74(s，1H)，3.06(m，1H)，2.79(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 20
2-itrile group-3-loses carbon-3,4-open loop-12-oxygen-volatile oil-9 (11)-alkene-28-carboxylic acid (II
8) preparation
With reference to II
1The preparation method, make white solid II by compound 16 and palladium carbon, hydrogen reaction
8, yield 98%.
m.p.136-138℃；
ESI-MS?m/z：466[M+H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ5.78(s，1H)，4.76(s，1H)，4.33(s，1H)，3.06(m，1H)，2.79(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 21
The preparation of 3 beta-hydroxies ursane-12-alkene-28-benzyl carboxylate (17)
The preparation method of reference compound 5 makes white solid 17, yield 97% by urson and Benzyl Chloride reaction.Compound 17 is known compounds, and CAS number is 192211-41-9.
Embodiment 22
The preparation of 3 β-acetoxyl group ursane-12-alkene-28-benzyl carboxylate (18)
The preparation method of reference compound 6 makes white solid 18, yield 92% by compound 17 and acetic anhydride reaction.
m.p.172-174℃；
ESI-MS：627[M+K]
+；
1HNMR(300M?Hz，CDCl3，25℃，TMS)：δ7.32-7.25(m，5H)，5.23(m，1H)，5.12(d，J＝12.5Hz，1H)，4.99(d，J＝12.5Hz，1H)，4.49(t，J＝8Hz，1H)，1.35，1.31，1.26，1.16，1.01，0.97，0.85(s，each?3H)ppm；
Embodiment 23
The preparation of 3 β-acetoxyl group-12-oxo ursane-28-benzyl carboxylate (19)
The preparation method of reference compound 7 makes white solid 19, yield 81% by compound 18 and hydrogen peroxide reaction.
m.p.179-180℃；
ESI-MS：605[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.61-7.35(m，5H)，5.21(d，J＝12.5Hz，1H)，5.10(d，J＝12.5Hz，1H)，4.49(m，1H)，2.84(m，1H)，2.62(m，1H)，2.39(m，1H)，1.35，1.31，1.26，1.16，1.01，0.97，0.85(s，each?3H)ppm；
Embodiment 24
The preparation of 3 β-acetoxyl group-12-oxo ursane-9 (11)-alkene-28-benzyl carboxylate (20)
The preparation method of reference compound 8 makes white solid 20, yield 80% by compound 19 and liquid bromine reaction.
m.p.208-210℃；
ESI-MS：603[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，4.46(m，1H)，3.01(m，1H)，2.71-2.67(d，J＝11.0Hz，1H)，2.51(m，1H)，2.01，1.57，1.16，1.00，0.95，0.92，0.89(s，each?3H)ppm.
Embodiment 25
The preparation of 3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-28-benzyl carboxylate (21)
The preparation method of reference compound 9 makes white solid 21, yield 95% by compound 20 and potassium hydroxide reaction.
m.p.190-192℃；
ESI-MS：561[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.28-7.25(m，5H)，6.09(s，1H)，5.21(d，J＝12.5Hz，1H)，5.10(d，J＝12.5Hz，1H)，3.23(m，1H)，3.01(d，J＝7.8HZ，1H)，1.35，1.31，1.26，1.16，1.01，0.97，0.85(s，each?3H)ppm；
Embodiment 26
3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-28-carboxylic acid (II
9) preparation
Reference compound II
1The preparation method, get white solid II by compound 21 and palladium carbon, hydrogen reaction
9, yield 98%.
m.p.242-244℃；
ESI-MS：470[M+H]
+，493[M+Na]
+；
1HNMR(300M?Hz，DMSO-d
6，25℃，TMS)：δ5.74(s，1H)，4.41(brs，1H)，3.01(m，1H)，2.71-2.67(d，J＝11.0Hz，1H)，2.51(m，1H)，1.13，1.09，1.05，0.95，0.86，0.73(s，each?3H)ppm.
Embodiment 27
3 β-acetoxyl group-12-oxo volatile oil-13, the preparation of 28-lactone (Ia-1)
With Compound I I
1(0.5g, 0.97mmol) and DDQ (0.23g 1.0mmol) is dissolved in the dry-out benzene (20mL), and reflux 48 hours after reaction finishes, is filtered, and filtrate concentrates, and rapid column chromatography gets white solid Ia-1 (0.21g, 68%).Compound I a-1 is a known compound, and CAS number is 35959-11-6.
Embodiment 28
3 beta-hydroxies-12-oxo volatile oil--9 (11)-alkene-13, the preparation of 28-lactone (Ib-1)
With reference to the preparation method of Ia-1, by II
2Make white solid Ib-1, yield 82% with the DDQ reaction.
m.p.230-232℃；
ESI-MS：469[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ6.0(s，1H，)，3.23(m，1H)，2.93(m，1H)，1.52，1.26，1.12，1.00，0.96，0.96，0.85(s，each?3H)ppm.
Embodiment 29
3,12-dioxo volatile oil-9 (11)-alkene-13, the preparation of 28-lactone (Ib-2)
With reference to the preparation method of Ia-1, by II
3Make white solid Ib-2, yield 84% with the DDQ reaction.
m.p.243-245℃；
ESI-MS?m/z：467[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ5.8(s，1H)，2.98(m，1H)，2.66，2.49，2.22(m，each?1H)，1.57，1.44，1.38，1.14，1.11，1.00，0.92(s，each?3H)ppm.
Embodiment 30
3 β-(3-carboxyl-1-propionyloxy)-12-oxo volatile oil-9 (11)-alkene-13, the preparation of 28-lactone (Ib-3)
With reference to the preparation method of Ia-1, by II
6Make white solid Ib-3, yield 78% with the DDQ reaction.
m.p.255-257℃；
ESI-MS：569[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ5.9(s，1H)，4.51(m，1H)，2.97(m，1H)，2.69-2.64(m，4H)，1.46，1.28，1.20，0.99，0.97，0.93，0.93(s，each?3H)ppm.
Embodiment 31
3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-13, the preparation of 28-lactone (Ib-4)
With reference to the preparation method of Ia-1, by II
9Make white solid Ib-4, yield 85% with the DDQ reaction.
m.p.256-258℃；
ESI-MS：469[M+H]
+，491[M+Na]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ6.06(s，1H)，3.25-3.20(m，1H)，2.55-2.51(d，J＝11.6Hz，1H)，1.49，1.26，1.16，1.05，0.95，0.93，0.85(s，each?3H)ppm.
Embodiment 32
12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-13, the preparation of 28-lactone (Ib-5)
With reference to the preparation method of Ia-1, by II
4Make white solid Ib-5, yield 89% with the DDQ reaction.
m.p.278-280℃；
ESI-MS?m/z：492[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.08(s，1H)，6.12(s，1H)，3.03(m，1H)，2.81(d，J＝15.0Hz，1H)，2.40(d，J＝15.0Hz，1H)，1.57，1.26，1.61，1.09，1.06，1.00，0.94(s，each?3H)ppm.
Embodiment 33
A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-13, the preparation of 28-lactone (Ib-6)
With reference to the preparation method of Ia-1, by II
7Make white solid Ib-6, yield 71% with the DDQ reaction.
m.p.167-169℃；
ESI-MS：482[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ6.04(s，1H)，5.53(s，1H)，2.98(d，J＝12Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 34
2-itrile group-3-loses carbon-3, the preparation of 4-open loop-12-oxygen-volatile oil-9 (11)-alkene-28-carboxylic acid (Ib-7)
With reference to the preparation method of Ia-1, by II
8Make white solid Ib-7, yield 78% with the DDQ reaction.
m.p.162-164℃；
ESI-MS：486[M+Na]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ6.01(s，1H)，4.78(s，1H)，4.10(s，1H)，3.01(d，J＝15Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 35
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-13, the preparation of 28-lactone (Ic-1)
With reference to the preparation method of Ia-1, by II
5Make white solid Ic-1, yield 82% with the DDQ reaction.
m.p.260-262℃；
ESI-MS?m/z：490[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.01(s，1H)，5.9(s，1H)，3.03(m，1H)，1.57，1.26，1.61，1.09，1.06，1.00，0.94(s，each?3H)ppm.
Claims (10)
1. the pentacyclic triterpene shown in the general formula I-13,28-lactone compound or its pharmacy acceptable salt:
Wherein:
Between C1 and the C2 carbon-carbon single bond or carbon-carbon double bond;
Between C9 and the C11 carbon-carbon single bond or carbon-carbon double bond;
R
1Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom, 3-carboxyl-1-propionyloxy, the amide group that contains 1～8 carbon atom, oximido or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, itrile group, hydroxyl oximido, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom or and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
2. compound of Formula I as claimed in claim 1 or its pharmacy acceptable salt is characterized in that described compound of Formula I is:
Wherein:
R
1Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom, 3-carboxyl-1-propionyloxy, the amide group that contains 1～8 carbon atom, oximido or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, ketonic oxygen, hydroxyl, amino, itrile group, hydroxyl oximido, the alkoxyl group that contains 1～8 carbon atom, the acyloxy that contains 1～8 carbon atom and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
3. claim 1 and 2 described pentacyclic triterpenes-13,28-lactone compound or its pharmacy acceptable salt is characterized in that described compound, wherein:
R
1Be selected from hydroxyl, ketonic oxygen, 3-carboxyl-1-propionyloxy, acetoxyl group or and R
2Form isoxazole [4,5-b] ring;
R
2Be selected from hydrogen, itrile group or and R
1Form isoxazole [4,5-b] ring;
The A ring is six-membered carbon ring, and ring expansion formed the lactams seven-membered ring after perhaps the C2 of A ring and C3 position disconnected, and perhaps the C2 of A ring and the open loop of C3 position form 3, the 4-open-loop products;
The B ring is six-membered carbon ring;
R
3Be selected from hydrogen or methyl;
R
4Be selected from hydrogen or methyl.
4. claim 1 to 3 described pentacyclic triterpene-13, the 28-lactone is selected from following compounds:
(1) 3 β-acetoxyl group-12-oxo volatile oil-13,28-lactone (compound number: Ia-1, down together)
(2) 3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-1)
(3) 3,12-dioxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-2)
(4) 3 β-(3-carboxyl-1-propionyloxy)-12-oxo volatile oil-9 (11)-alkene-13,28-lactone (Ib-3)
(5) 3 beta-hydroxies-12-oxo ursane-9 (11)-alkene-13,28-lactone (Ib-4)
(6) 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-13,28-lactone (Ib-5)
(7) A-ring expansion-3a-azepine-12-oxygen-volatile oil-9 (11)-alkene-13,28-lactone (Ib-6)
(8) 2-itrile group-3-loses carbon-3,4-open loop-12-oxygen-volatile oil-9 (11)-alkene-13,28-lactone (Ib-7)
(9) 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-13,28-lactone (Ic-1)
5. claim 1 to 4 described pentacyclic triterpene-13, the 28-lactone compound is preferably: 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-13,28-lactone (Ic-1).
6. claim 1 to 5 described pentacyclic triterpene-13, the preparation method of 28-lactone compound, it is characterized in that, compound shown in the formula II is under the effect of dehydrogenating agent, remove the hydrogen of C13 position and the hydrogen on the carboxyl of C28 position, pentacyclic triterpene-13 shown in the difference production I (comprising Ia, Ib, Ic), the 28-lactone compound:
Wherein, R
1, R
2, R
3And R
4Described as defined above.
7. the preparation method of claim 6 is characterized in that, the dehydrogenating agent of employing is selected from 2,3-two chloro-5,6-dicyanobenzoquinone, tetrachlorobenzoquinone, tin anhydride, 1,1-phenylbenzene-2-trinitrophenyl-hydrazine, 2,2,6, one or more in 6-tetramethyl piperidine nitrogen oxygen free radical or the tin anhydride.
8. the preparation method of claim 6, it is characterized in that, the reaction solvent that adopts is benzene,toluene,xylene, dioxane, acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform, ethylene dichloride, methyl alcohol, acetone, ethyl acetate or N, one or more in the dinethylformamide; The temperature of reaction that adopts is 50-120 ℃.
9. pharmaceutical composition is gone up the claim 1 of effective dose and 2 described formula I (comprising Ia, Ib, Ic) compound and pharmaceutically acceptable carrier or auxiliary material by treatment and is formed.
10. the described formula I of claim 1 to 5 (comprising Ia, Ib, Ic) compound is in the purposes of preparation in the antitumor drug.
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