CN100526317C - Gambogicacid derivative and its preparation method and uses in pharmacy - Google Patents
Gambogicacid derivative and its preparation method and uses in pharmacy Download PDFInfo
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- CN100526317C CN100526317C CNB200610088252XA CN200610088252A CN100526317C CN 100526317 C CN100526317 C CN 100526317C CN B200610088252X A CNB200610088252X A CN B200610088252XA CN 200610088252 A CN200610088252 A CN 200610088252A CN 100526317 C CN100526317 C CN 100526317C
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Abstract
The invention discloses the preparing method and application of cambogic acid derivation. The cambogic acid derivation is made by nitric oxide donator and cambogic acid. The cambogic acid derivation has the antineoplastic action.
Description
Technical field
The invention belongs to pharmacy field, relate to a kind of Gamboges acid derivative with antitumor action, be specially and adopt dissimilar nitrogen protoxide (being called for short NO) donor to carry out the link coupled compound, the invention still further relates to the preparation method of this derivative and the application in pharmacy by ester bond or amido linkage and morellic acid.
Background technology
The natural compounds morellic acid separates from the Gamboge of Garcinia platymiscium first finds that morellic acid (Gambogic acid) is the antineoplastic important effective constituent of gamboge.Morellic acid can be optionally effective kill tumor cell, and to normal hemopoietic system and not influence of immunologic function, studies have shown that morellic acid and derivative thereof are the agonist and the apoptotic inductors of caspase, can be used as a kind of cell death inducer that effectively is at kinds of tumors.
Because morellic acid and and derivative compound have significant cytotoxicity, in order to search out the more excellent compound of biological activity, scholars have showed keen interest to the chemically modified synthetic and the dependency structure position of Gamboges acid derivative, San Diego, USA Marxim institute of materia medica CAISUI XIONG research group (US2003078292, WO0044216), studying aspect the structure of modification modification of natural product morellic acid, related morellic acid structure of modification modification work mainly concentrates on C-30, C-8, C-6, C-12, C-9,10.
The NO of high density is by producing cytotoxicity in the body, and inducing apoptosis of tumour cell stops the diffusion and the transfer of tumour cell.The NO donor is meant that a class discharges the compound of a certain amount of NO in vivo through enzyme and non-enzyme effect.But do not adopt the report of the synthetic nitric oxide donator type Gamboges acid derivative of NO donor and morellic acid at present.
Summary of the invention
The objective of the invention is provides a kind of Gamboges acid derivative at the problems referred to above, is specially to adopt dissimilar nitrogen protoxide (being called for short NO) donor and morellic acid to carry out the Gamboges acid derivative that coupling forms by ester bond or amido linkage.
Another object of the present invention provides the preparation method of above-mentioned Gamboges acid derivative.
A further object of the invention provides the application of above-mentioned Gamboges acid derivative in pharmacy.
Technical scheme of the present invention is based on the effect of NO high density inducing apoptosis of tumour cell, the synthetic nitric oxide donator type Gamboges acid derivative of ultimate principle design of drug application design, provide novel Gamboges acid derivative with this with good resistance tumor promotion, provide simultaneously its corresponding preparation method with and application in pharmacy.
The objective of the invention is to realize by following technical measures:
A kind of Gamboges acid derivative, this derivative are to carry out the compound that coupling obtains by nitric oxide donors and morellic acid by ester bond or amido linkage.
Described Gamboges acid derivative, wherein nitric oxide donors is-ONO
2,
Described Gamboges acid derivative, this derivative are the compounds shown in the general formula (I):
Wherein:
R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented;
R
5Independent representative-(CH
2)
n-, n=1～6 ,-CH
2CH=CHCH
2-,-CH
2-pyridine (2,6)-CH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4;
(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Representative-(CH
2)
n-, n=1～4; (32,33) position, independent separately ethylene linkage, the epoxy group(ing) represented of the empty line part in (37,38) position.
Described Gamboges acid derivative, this derivative are the compounds shown in the general formula (II):
Wherein:
R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented;
R
5Independent H, OH, the CH of representing
3O; R
6Representative-CO ,-CH=CHCO-;
R
7Representative-(CH
2)
n-, n=1～6 ,-CH
2CH=CHCH
2-,-CH
2-pyridine (2,6)-CH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Independent H, OH, the CH of representing
3O; R
6Representative-CO ,-CH=CHCO-; R
7Representative-(CH
2)
n-, n=2～4 ,-CH
2CH=CHCH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4; (32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position.
Described Gamboges acid derivative, this derivative are the compounds shown in the general formula (III):
Wherein:
R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented;
R
5Independent representative-(CH
2)
nO-, n=1～4 ,-CH (CH
3) CH
2CH
2O-,-(CH
2)
n-phenyl-OCH
2-(, or to), n=0～4 ,-(CH
2)
n-phenyl-O-(, or to), n=0～4; R
6Represent phenyl, benzenesulfonyl; X representative-O-,-NH-.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Independent representative-(CH
2)
nO-, n=1～4 ,-CH (CH
3) CH
2CH
2O-; R
6Represent phenyl, benzenesulfonyl; X representative-O-; (32,33) position, independent separately ethylene linkage, the epoxy group(ing) represented of the empty line part in (37,38) position.
Described Gamboges acid derivative, this derivative are the compounds shown in the general formula (IV):
Wherein: R
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether;
R
5, R
6Identical or different, independent separately H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, allyl group, the propenyl represented;
(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether; R
5, R
6Identical or different, independent separately H, methyl, ethyl, the sec.-propyl represented; (32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position.
Described Gamboges acid derivative, this derivative are the compounds shown in the general formula (VII):
Wherein:
R
1Independent representative-(CH
2)
n-, n=2～6 ,-CH
2CH=CHCH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, propyl group, sec.-propyl, butyl, allyl group, the propenyl represented; R
4Independent represent H, methyl, ethyl, propyl group, sec.-propyl, butyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented.
Described Gamboges acid derivative, wherein R
1Independent representative-(CH
2)
n-, n=2～6; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, sec.-propyl, the allyl group represented; R
4Independent represent H, methyl, ethyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented.
The preparation method of described Gamboges acid derivative, this method are with Gamboges acid derivative (1) and R
5Halogenated alkane generate compd A, then compd A again with the Silver Nitrate reaction, its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented; R
5Independent representative-(CH
2)
n-, n=1～6 ,-CH
2CH=CHCH
2-,-CH
2-pyridine (2,6)-CH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4; (32,33) position, independent separately ethylene linkage, epoxy bond, the o-dihydroxy represented of the empty line part in (37,38) position; X is a halogen.R
5Halogenated alkane be preferably two bromoalkanes.
The preparation method of described Gamboges acid derivative, this method act on Gamboges acid derivative (2) and intermediate B generating compound (II) under DMAP, DCC existence condition, its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented; R
5Independent H, OH, the CH of representing
3O; R
6Representative-CO ,-CH=CHCO-; R
7Representative-(CH
2)
n-, n=1～6 ,-CH
2CH=CHCH
2-,-CH
2-pyridine (2,6)-CH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented.
The preparation method of described Gamboges acid derivative, this method generate compound (III) with the Compound D effect with Gamboges acid derivative (3) under DMAP, DCC existence condition, its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, cyano group, methoxyl group, nitro, the acetoxyl group represented; R
5Independent representative-(CH
2)
nO-, n=1～4 ,-CH (CH
3) CH
2CH
2O-,-(CH
2)
n-phenyl-OCH
2-(, or to), n=0～4 ,-(CH
2)
n-phenyl-O-(, or to), n=0～4; R
6Represent phenyl, benzenesulfonyl; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented; X representative-O-,-NH-.
The preparation method of described Gamboges acid derivative, this method are with Gamboges acid derivative (7) and Ph
3P-I
2-imidazoles is at anhydrous Et
2Reaction generates R in the O-acetonitrile solution
1, R
2, R
3Or R
4Have a Gamboges acid derivative that is replaced by I at least, will be somebody's turn to do the Gamboges acid derivative and the Silver Nitrate reactivity that are replaced by I again and generate compound (IV);
R wherein
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether; R
5, R
6Identical or different, independent separately H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, allyl group, the propenyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
Work as R
4When being substituted, its building-up process is as follows:
The preparation method of described Gamboges acid derivative, this method are with Gamboges acid derivative (6) and R
1Halogenated alkane reaction generate intermediate F, compound F 17-hydroxy-corticosterone and Silver Nitrate reactivity generation compound (VII), its building-up process is as follows:
R wherein
1Independent representative-(CH
2)
n-, n=2～6 ,-CH
2CH=CHCH
2-,-phenyl-(CH
2)
n-(neighbour,, or to), n=1～4; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, propyl group, sec.-propyl, butyl, allyl group, the propenyl represented; R
4Independent represent H, methyl, ethyl, propyl group, sec.-propyl, butyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; X is a halogen.R
1Halogenated alkane be preferably two bromoalkanes.
The application of described Gamboges acid derivative in the preparation anti-tumor drug.
Beneficial effect of the present invention:
At present, the screening active ingredients of antineoplastic compound is that the cytotoxic activity with compound embodies routinely, experimental data shows that The compounds of this invention has significant cytotoxicity (seeing the experimental data among the embodiment for details) to vitro human lung carcinoma cell (A549), colon cancer cell (HT-29), gastric carcinoma cells (BGC823), human liver cancer cell (Bel7402) and Proliferation of Human Ovarian Cell (SKOV3).
Embodiment
The invention will be further elaborated by the following examples, but do not limit the present invention in any way.
Agents useful for same is commercially available among the following embodiment.The silica gel column chromatography that the 100-200 order silica gel that related column chromatography adopts Haiyang Chemical Plant, Qingdao to produce is loaded.
Embodiment 1: morellic acid-2 '-nitroxide ethyl ester (I-1)
Morellic acid 250mg (0.4mmol) is dissolved among the acetone 15ml, add ethylene dibromide 0.18ml (2.08mmol) and triethylamine 0.4ml under the room temperature respectively, reaction solution is a yellow transparent, behind reinforced the finishing, and back flow reaction 6 hours, direct concentration of reaction solution, the dry method upper prop, column chromatography, petrol ether/ethyl acetate (4:1) wash-out, be prepared into yellow oil (A-1) 80mg, productive rate about 27%.And then compound (A-1) 80mg (0.11mmol) is dissolved among anhydrous tetrahydro furan and the acetonitrile mixed solvent 10ml (1:1), add Silver Nitrate 28mg (0.17mmol) under the room temperature, the lucifuge back flow reaction got final product in 5 hours, with reacting liquid filtering, and disgorging, filtrate concentrates, the dry method upper prop, column chromatography, petrol ether/ethyl acetate (4:1) wash-out, be prepared into yellow thickness compound (I-1) 20mg, yield 26%.
IR(KBr)：v＝3456，2967，2925，2858，1737，1710，1632，1594，1438，1383，1330，1278，1228，1177，1140，1048cm
-1。
1HNMR(300M，CDCl
3)：δ?12.86(1H，s，6-OH)，7.56(1H，brs，H-10)，6.67(1H，m，H-4)，6.14(1H，m，H-27)，5.45(1H，m，H-3)，5.06(2H，m，H-32，H-37)，4.39((2H，m，H-1’)，3.88(3H，m，H-2’，H-11)，3.30(1H，m，H-31a)，3.23(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.52(1H，m，H-22)，2.36(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.03(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.66(3H，brs，H-39)，1.70(3H，brs，H-35)，1.63(3H，brs，H-34)，1.57(3H，s，H-40)，1.46(3H，s，H-24)，1.37(1H，m，H-21b)，1.28(3H，s，H-19)，
ESI-MS?718[M+H]
+，740[M+Na]
+，756[M+K]
+。
HRMS(M+Na)m/z?754.3219(calcd?for?C
41H
49O
11Na?754.3203)。
Embodiment 2: morellic acid-3 '-nitroxide propyl ester (I-2)
The preparation method of reference compound (A-1) makes yellow oil (A-2) 750mg, yield 95% by morellic acid 628mg (1.0mmol) and dibromopropane 0.55ml (5.3mmol) with triethylamine 0.92ml (1.0mmol) reaction.The preparation method of reference compound I-1, by compound (A-2) 710mg (0.95mmol) and Silver Nitrate 242mg (1.43mmol) back flow reaction, aftertreatment is the same, makes yellow dope (I-2) 140mg, yield 20%.
IR(KBr)：v＝3456，2967，2924，2858，1736，1710，1632，1593，1438，1383，1331，1279，1228，1177，1140，1048cm
-1.
1HNMR(300M，CDCl
3)：δ?12.86(1H，s，6-OH)，7.56(1H，brs，H-10)，6.67(1H，m，H-4)，6.14(1H，m，H-27)，5.45(1H，m，H-3)，5.06(2H，m，H-32，H-37)，4.39((2H，m，H-1’)，3.90(2H，m，H-3’)，3.48(3H，m，H-2’，H-11)，3.30(1H，m，H-31a)，3.23(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.52(1H，m，H-22)，2.36(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.03(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.66(3H，brs，H-39)，1.70(3H，brs，H-35)，1.63(3H，brs，H-34)，1.57(3H，s，H-40)，1.28(3H，s，H-19)，1.46(3H，s，H-24)，1.37(1H，m，H-21b).
ESI-MS?732[M+H]
+，754[M+Na]
+，770[M+K]
+。
Ultimate analysis: C
41H
49NO
11Found C 67.09%, H 6.72%, N 1 .85%, O 23.98%; Calcd C67.29%, H 6.75%, and N 1.91%, and O 24.05%.
Embodiment 3: morellic acid-4 '-nitroxide butyl ester (I-3)
The preparation method of reference compound (A-1) makes yellow oil (A-3) 630mg, yield 83% by morellic acid 628mg (1.0mmol) with dibromobutane 0.63ml (5.3mmol), triethylamine 0.92ml (1.0mmol) reaction.The preparation method of reference compound (I-1), by compound (A-3) 630mg (1.22mmol) and Silver Nitrate 311mg (1.83mmol), back flow reaction, aftertreatment is the same, makes yellow dope (I-3) 160mg, yield 39%.
IR(KBr)：v＝3455，2967，2924，2858，1736，1710，1632，1593，1438，1382，1331，1278，1228，1176，1140，1048cm
-1。
1HNMR(300M，CDCl
3)：δ?12.86(1H，s，6-OH)，7.56(1H，brs，H-10)，6.67(1H，m，H-4)，6.11(1H，m，H-27)，5.45(1H，m，H-3)，5.07(2H，m，H-32，H-37)，4.54((2H，m，H-1’)，3.53(4H，m，H-2’，H-3’)，4.10(2H，m，H-4’)，3.48(1H，m，H-11)，3.30(1H，m，H-31a)，3.21(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.51(1H，m，H-22)，2.36(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.02(2H，m，H-36)，1.75(3H，s，H-25)，1.71(2H，m，H-20)，1.66(3H，brs，H-39)，1.70(3H，brs，H-35)，1.63(3H，brs，H-34)，1.57(3H，s，H-40)，1.28(3H，s，H-19)，1.46(3H，s，H-24)，1.37(1H，m，H-21b).
ESI-MS?746[M+H]
+，768[M+Na]
+，784[M+K]
+.
Ultimate analysis: C
42H
51NO
11Found C 67.49%, H6.87%, N1.88%, O23.68%; Calcd C67.63%, H 6.89%, and N 1.88%, and O 23.60%.
Embodiment 4:(32,33), (37,38)-bis-epoxy-morellic acid-3 '-nitroxide propyl ester (I-4)
The preparation method of reference compound (A-1), by compound (32,33), (37,38)-bis-epoxy-morellic acid (1) 180mg (0.27mmol) and dibromopropane 0.14ml (1.4mmol), triethylamine 0.25ml (0.27mmol) reaction makes yellow dope (A-4) 40mg, yield 19%; The preparation method of reference compound (I-1), by compound (A-4) 30mg (0.038mmol) and Silver Nitrate 9.8mg (0.058mmol) back flow reaction, aftertreatment is the same, makes yellow dope (I-4) 18mg, yield 62%.
IR(KBr)：v＝3475，3417，2960，2924，2853，1725，1635，1595，1452，1384，1331，1280，1228，1179，1140，1048cm
-1。
1HNMR(300M，CDCl
3)：δ?12.88(1H，s，6-OH)，7.55(1H，brs，H-10)，6.67(1H，m，H-4)，6.04(1H，m，H-27)，5.42(1H，m，H-3)，4.39((2H，m，H-1’)，3.90(2H，m，H-3’)，3.48(2H，m，H-2’)，3.30(1H，m，H-11)，2.86(2H，m，H-32，H-37)，3.30(1H，m，H-31a)，3.21(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.51(1H，m，H-22)，2.36(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.02(2H，m，H-36)，1.76(3H，s，H-25)，1.72(2H，m，H-20)，1.66(3H，brs，H-39)，1.67(3H，brs，H-35)，1.65(3H，brs，H-34)，1.54(3H，s，H-40)，1.40(3H，s，H-24)，1.32(1H，m，H-21b)，1.29(3H，s，H-19).
ESI-MS：764[M+H]
+，786[M+Na]
+，802[M+K]
+。
Ultimate analysis: C
41H
49NO
13Found C 64.27%, H 6.41%, and N 1.82%, and O 27.13%; Calcd C 64.47%, H 6.47%, and N 1.83%, and O 27.23%.
Embodiment 5:3-(4-phenyl-1,2, the methoxyphenol (D-1) of 5-oxadiazoles-2-oxide compound-3-)
With 3-methylol-4-phenyl-1,2,5-oxadiazoles-2-oxide compound 3.46g (18.02mmol) is dissolved in the 15ml methylene dichloride, add pyridine 3.34ml (41.4mmol), thionyl chloride 3.4ml (46.8mmol) under 0 ℃ successively, reaction solution is faint yellow transparent, stirring at room, room temperature reaction finished in 16 hours.Reaction solution dilutes with methylene dichloride, washes, saturated common salt washing anhydrous MgSO then with water
4Drying steams solvent, gets orange-yellow oily 3-chloromethyl-4-phenyl-1,2,5-oxadiazoles-2-oxide compound 3.44g, productive rate about 90%.
With 3-chloromethyl-4-phenyl-1,2,5-oxadiazoles-2-oxide compound 820mg (3.9mmol) is dissolved among the acetonitrile 15ml, add Resorcinol 451mg (4.1mmol), Anhydrous potassium carbonate 809mg (5.8mmol), potassiumiodide 130mg (0.78mmol) under the room temperature successively, reaction solution is faint yellow muddiness, stirring at room, room temperature reaction stopped in 12 hours, and reaction solution is coffee-like muddy.Acetonitrile in the reaction solution steamed remove, dilute residue, wash with water, the saturated common salt washing, anhydrous MgSO with ethyl acetate
4Drying steams solvent, and column chromatography petrol ether/ethyl acetate (2:1) wash-out gets pale yellow powder (D-1) 580mg, productive rate about 53%.Mp：110-112℃。
30-{3 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-1)
Morellic acid 314mg (0.5mmol) is dissolved among the methylene dichloride 10ml, add compound (D-1) 142mg (0.5mmol), 4-N under the room temperature successively, N-Dimethylamino pyridine 61mg (0.5mmol), dicyclohexyl carbon imide 124mg (0.6mmol), stir, room temperature reaction 3 hours, reaction solution dilutes with methylene dichloride, washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (4:1) wash-out gets yellow thick liquid (III-1) 380mg, productive rate 85%.
IR(KBr)：v＝3467，3414，2958，2924，2853，1735，1637，1507，1453，1434，1382，1238，1178，1136，1012cm
-1。
1HNMR(300M，CDCl
3)：δ?7.83(2H，m，Ar-H)，7.54(4H，m，Ar-H)，7.51(1H，m，H-10)，7.14(1H，m，Ar-H)，6.66(1H，d，J＝6.1Hz，H-4)，6.58(2H，m，Ar-H)，6.23(1H，t，H-27)，5.43(1H，d，J＝6.1Hz，H-3)，5.05(2H，m，H-32，37)，5.09(2H，s，-O-CH
2)，3.44(1H，m，H-11)，3.31(1H，m，H-31a)，3.15(1H，dd，H-31b)，1.68(3H，s，H-34)，1.71(3H，s，H-29)，1.72(2H，m，H-20)，2.31(1H，m，H-21a)，1.40(1H，brs，H-21b)，2.52(1H，d，J＝2.7Hz，H-22)，1.65(9H，brs，H-35，36，39)，1.54(3H，s，H-24)，1.75(3H，s，H-25)，1.29(3H，s，H-19)，2.03(1H，m，H-36)，1.59(3H，s，H-40)，12.85(1H，s，6-OH).
ESI-MS?895[M+H]
+，917[M+Na]
+。
HRMS(M+Na)m/z?917.3647(calcd?for?C
53H
54N
2O
11Na?917.3625)。
Embodiment 6:30-{4 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-2), 4-(4-phenyl-1,2, the methoxyphenol (D-2) of 5-oxadiazoles-2-oxide compound-3-)
The preparation method of reference compound (D-1), by compound 4-chloro methyl-4-phenyl-1,2,5-oxadiazoles-2-oxide compound 1.4g (6.7mmol), with Resorcinol 771mg (7.0mmol), Anhydrous potassium carbonate 1.38g (10.1mmol), potassiumiodide 221mg (1.33mmol) reaction, column chromatography petrol ether/ethyl acetate (2:1) wash-out, get yellow powder (D-2) 810mg, yield 43%.Mp：123-125℃.。
Synthesizing of reference compound (III-1), with morellic acid 200mg (0.32mmol) and compound (D-2) 90mg (0.32mmol), 4-N, N-Dimethylamino pyridine 39mg (0.32mmol), dicyclohexyl carbon imide 66mg (0.32mmol) reaction, column chromatography, petrol ether/ethyl acetate (4:1) wash-out, get yellow solid (III-2) 180mg, productive rate 64%.Mp：150-152℃.
IR(KBr)：v＝3468，3414，2958，2924，2853，1733，1635，1507，1453，1434，1382，1233，1174，1136，1012cm
-1。
1HNMR(300M，CDCl
3)：δ?7.85(2H，m，Ar-H)，7.54(4H，m，Ar-H)，7.52(1H，m，H-10)，6.90(1H，d，Ar-H)，6.86(2H，m，Ar-H)，6.66(1H，m，H-3)，6.35(1H，t，H-27)，5.43(1H，m，H-4)，5.05(1H，m，H-32，37)，5.04(2H，s，-OCH
2O-)，3.48(1H，m，H-11)，3.34(1H，m，H-31a)，3.15(1H，dd，H-31b)，2.95(2H，m，H-26)，2.54(1H，m，H-22)，2.04(2H，m，H-36)，1.73(3H，s，H-25).1.69(3H，s，H-29)，2.31(1H，m，H-21a)，1.68(3H，s，H-34)，1.63(3H，s，H-35)，1.65(3H，s，H-39)，1.55(3H，s，H-40)，1.72(2H，m，H-20)，1.47(3H，s，H-24)，1.36(1H，m，H-21b)，1.29(3H，s，H-19)。
ESI-MS?895[M+H]
+，917[M+Na]
+。
HRMS(M+Na)m/z?917.3637(calcd?for?C
53H
54N
2O
11Na?917.3625)。
Embodiment 7:30-{2 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-3), 2-(4-phenyl-1,2, the methoxyphenol (D-3) of 5-oxadiazoles-2-oxide compound-3-)
The preparation method of reference compound (D-1), by compound 2-chloromethyl-4-phenyl-1,2,5-oxadiazoles-2-oxide compound 580mg (2.76mmol), with pyrocatechol 320mg (2.9mmol), Anhydrous potassium carbonate 572mg (4.14mmol), potassiumiodide 92mg (0.55mmol) reaction, column chromatography, petrol ether/ethyl acetate (2:1) wash-out gets yellow powder (D-3) 420mg, yield 54%.Mp：113-115℃.
Reference compound III-1's is synthetic, morellic acid 314mg (0.5mmol), compound (D-3) 142mg (0.5mmol), 4-N, N-Dimethylamino pyridine 61mg (0.5mmol), dicyclohexyl carbon imide 124mg (0.6mmol), reaction, column chromatography, petrol ether/ethyl acetate (4:1) wash-out gets yellow thick liquid (III-3) 410mg, productive rate about 91%.
IR(KBr)：v＝3460，3411，2958，2924，2853，1735，1633，1507，1458，1434，1382，1238，1176，1136，1012cm
-1。
1HNMR(300M，CDCl
3)：δ?7.84(2H，m，Ar-H)，7.55(4H，m)，7.52(1H，m，H-10)，6.59(2H，m，Ar-H)，6.90(1H，m，Ar-H)，6.66(1H，m，H-3)，6.35(1H，t，H-27)，5.43(1H，m，H-4)，5.05(1H，m，H-32，37)，5.04(2H，s，-OCH
2O-)，3.48(1H，m，H-11)，3.34(1H，m，H-31a)，3.15(1H，dd，H-31b)，2.95(2H，m，H-26)，2.54(1H，m，H-22)，2.31(1H，m，H-21a)，2.04(2H，m，H-36)，，1.73(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-29)，1.68(3H，s，H-34)，1.63(3H，s，H-35)，1.65(3H，s，H-39)，1.55(3H，s，H-40)，1.47(3H，s，H-24)，1.36(1H，m，H-21b)，1.28(3H，s，H-19).
ESI-MS：893[M-H]
+，895[M+H]
+，917[M+Na]
+。
HRMS(M+Na)m/z?917.3640(calcd?for?C
53H
54N
2O
11?Na?917.3625)。
Embodiment 8:
34-hydroxyl-30-{2 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-4)
Reference compound III-1's is synthetic, 34-hydroxyl-30-{2 '-(4 "-phenyl-1 "; 2 "; 5 "-oxadiazoles-2 "-methoxyl group) morellic acid 90mg (0.14mmol), compound (D-3) 40mg (0.14mmol), 4-N; N-Dimethylamino pyridine 17mg (0.14mmol), dicyclohexyl carbon imide 35mg (0.17mmol), reaction, column chromatography; petrol ether/ethyl acetate (2: 1) wash-out gets yellow solid (III-4) 40mg, productive rate about 31%.Mp：94-96℃.
IR(KBr)：v＝3467，3419，2927，2852，1737，1698，1632，1593，1529，1452，1436，1382，1330，1224，1176，1138，1086cm
-1。
1HNMR(300M，CDCl
3)：δ?7.84(2H，m，Ar-H)，7.55(4H，m)，7.52(1H，m，H-10)，6.90(1H，m，Ar-H)，6.59(2H，m，Ar-H)，6.56(1H，m，H-3)，6.50(1H，m，H-27)，5.42(2H，m，H-37，H-4)，5.07(1H，m，H-32)，5.04(2H，s，-OCH
2-)，3.96(2H，m，H-34)，3.45(1H，m，H-11)，3.31(1H，dd，J＝14.7Hz，7.6Hz，H-31a)，3.13(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，m，H-22)，2.26(1H，m，H-21a)，2.05(2H，m，H-36)，1.72(2H，m，H-20)，1.69(3H，s，H-29)，1.66(3H，s，H-39)，1.62(3H，s，H-35)，1.57(3H，s，H-40)，1.48(1H，m，H-24)，1.38(1H，m，H-21b)，1.25(3H，s，H-19).
ESI-MS：893[M-H]
+.
HRMS(M+Na)m/z?933.3582(calcd?for?C
39H
56N
7O
18Na?933.3580)。
Embodiment 9:
34-hydroxyl-30-{4 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-5)
Synthesizing of reference compound (III-1), 34-hydroxyl-30-{4 '-(4 "-phenyl-1 "; 2 "; 5 "-oxadiazoles-2 "-methoxyl group) morellic acid 90mg (0.14mmol), compound (D-3) 40mg (0.14mmol), DMAP (4-N, N-dimethyl aminopyridine) 17mg (0.14mmol),, DCC (dicyclohexyl carbon imide) 35mg (0.17mmol); reaction; column chromatography, petrol ether/ethyl acetate (2:1) wash-out gets yellow solid (III-5) 60mg, productive rate about 47%.Mp：130-131℃
IR(KBr)：v＝3458，2927，2853，1735，1693，1631，1595，1531，1453，1437，1382，1331，1224，1176，1137，1086，1045，760cm
-1。
1HNMR(300M，CDCl
3)：δ?7.84(2H，d，J＝7.86Hz，Ar-H)，7.55(4H，m，Ar-H)，7.52(1H，m，10-H)，6.84(1H，dd，J＝2.5Hz，Ar-H)，7.23(1H，dd，J＝1.9Hz，1.4Hz，Ar-H)，6.58(1H，m，Ar-H)，6.59(1H，m，H-3)，6.57(1H，m，H-27)，5.42(2H，m，H-37，H-4)，5.07(1H，m，H-32)，5.04(2H，s，-OCH2-)，3.96(2H，m，H-34)，3.45(1H，m，H-11)，3.31(1H，dd，J＝14.7Hz，7.6Hz，H-31a)，3.13(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，m，H-22)，2.26(1H，m，H-21a)，1.72(2H，m，H-20)，2.05(2H，m，H-36)，1.38(1H，m，H-21b)，1.48(1H，m，H-24)，1.62(3H，s，H-35)，1.69(3H，s，H-29)，1.66(3H，s，H-39)，1.57(3H，s，H-40)，1.29(3H，s，H-19).
ESI-MS909[M-H]
+。
HRMS(M+Na)m/z?933.358(calcd?for?C
39H
56N
7O
18Na?933.358)。
Embodiment 10:(32,33), (37,38)-diepoxy-30-{3 '-(4 "-phenyl-1 "; 2 "; 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-6) and (37; 38)-epoxy-30-{4 '-(4 "-phenyl-1 ", 2 " and, 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-7)
Synthesizing of reference compound (III-1), (32,33), (37,38)-diepoxy-30-morellic acid and (37,38)-epoxy-30-morellic acid respectively with compound (D-1) 100mg (0.35mmol), 4-N, N-Dimethylamino pyridine 43mg (0.35mmol), dicyclohexyl carbon imide 87mg (0.35mmol) reaction, column chromatography, petrol ether/ethyl acetate (2:1) wash-out, it is as follows to prepare compound respectively:
Faint yellow solid (III-6) 60mg, Mp:92-94 ℃.
IR(KBr)：v＝3464，3075，2971，2925，2851，1718，1695，1633，1597，1429，1304，1258，1176，1138，750cm
-1.
1HNMR(300M，CDCl
3)：δ?12.84(1H，m，6-OH)，7.84(2H，d，J＝7.86Hz，Ar-H)，7.55(4H，m，Ar-H)，7.26(1H，m，10-H)，6.84(1H，dd，J＝2.5Hz，Ar-H)，6.58(2H，m，Ar-H)，6.53(1H，m，H-4)，6.35(1H，m，H-27)，5.41(1H，m，H-3)，5.05(2H，brs，-OCH2-)，3.47(1H，m，H-11)，3.31(1H，dd，J＝14.7Hz，7.6Hz，H-31a)，3.15(1H，m，H-32)，3.29(1H，m，H-37)，3.05(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，m，H-22)，2.28(1H，m，H-21a)，2.05(2H，m，H-36)，1.86(3H，s，H-29)，1.73(3H，s，H-25)，1.70(2H，m，H-20)，1.68((3H，s，H-34).1.66(3H，s，H-39)，1.62(3H，s，H-35)，1.56(3H，s，H-40)，1.38(1H，m，H-21b)，1.48(1H，m，H-24)，1.29(3H，s，H-19).
ESI-MS?927[M+H]
+，949[M+Na]
+.
HRMS(M+Na)?m/z?949.3526(calcd?for?C
53H
54N
2O
13Na?949.3524).
Faint yellow solid (III-7) 20mg, M.p.72-74 ℃.
IR(KBr)：v＝3452，2967，2925，2853，1734，1633，1598，1452，1380，1329，1247，1179，1139，1089，1043，766cm
-1.
1HNMR(300M，CDCl
3)：δ?12.84(1H，m，6-OH)，7.84(2H，d，J＝7.86Hz，Ar-H)，7.55(4H，m，Ar-H)，7.26(1H，m，10-H)，6.84(1H，dd，J＝2.5Hz，Ar-H)，6.58(2H，m，Ar-H)，6.53(1H，m，H-4)，6.35(1H，m，H-27)，5.41(1H，m，H-3)，5.06(3H，m，H-32，-OCH
2)，5.04(2H，s，-OCH
2-)，3.47(1H，m，H-11)，3.29(1H，m，H-37)，3.31(1H，dd，J＝14.7Hz，7.6Hz，H-31a)，3.05(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，m，H-22)，2.28(1H，m，H-21a)，1.86(3H，s，H-29)，1.66(3H，s，H-39)，1.62(3H，s，H-35)，1.73(3H，s，H-25).1.68((3H，s，H-34).1.56(3H，s，H-40)，1.70(2H，m，H-20)，2.05(2H，m，H-36)，1.38(1H，m，H-21b)，1.48(1H，m，H-24)，1.29(3H，s，H-19).
ESI-MS：909[M-H]
+.
Ultimate analysis: C
53H
56N
2O
12Found C 69.77%, H 6.17%, and N 3.02%, and O 21.03%; Calcd C69.72%, H 6.18%, and N 3.07%, and O 21.03%.
Embodiment 11:(37,38)-epoxy-30-{2 '-(4 "-phenyl-1 "; 2 "; 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenyl ester (III-8) and (32; 33), (37,38)-epoxy-30-{2 '-(4 "-phenyl-1 "; 2 ", 5 "-oxadiazoles-2 "-methoxyl group) morellic acid phenol ester (III-9)
Synthesizing of reference compound (III-1), (37,38)-epoxy-30-morellic acid and (32,33), (37,38)-epoxy-30-morellic acid respectively with compound (D-3) 100mg (0.35mmol), 4-N, N-Dimethylamino pyridine 43mg (0.35mmol), dicyclohexyl carbon imide 87mg (0.35mmol) reaction, column chromatography, petrol ether/ethyl acetate (2:1) wash-out., it is as follows to prepare compound respectively:
Faint yellow solid (III-8) 20mg, Mp:75-77 ℃.
IR(KBr)：v＝3460，3420，2974，2930，1727，1696，1634，1598，1434，1381，1298，1254，1185，1141，749cm
-1.
1HNMR(300M，CDCl
3)：δ?5.43(1H，m，H-4)，6.62(1H，brd，J＝10.1，H-3)，6.35(1H，m，H-27)，5.01(1H，m，H-32)，5.09(2H，brd，H-7’a，7’b)，3.47(1H，m，H-11)，3.29(1H，m，H-37)，3.05(2H，m，H-31)，2.92(2H，m，H-26)，2.54(1H，m，H-22)，2.32(1H，brdd，J＝4.0Hz，3.9Hz，H-21a)，1.59(3H，s，H-24)，1.87(3H，s，H-25)，1.56(3H，s，H-40)，1.66(3H，s，H-39)，1.70(3H，s，H-34)，1.68(3H，H-35)，2.04(2H，m，H-36)，1.41(1H，m，H-21b)，1.72(2H，m，H-20)，1.28(3H，s，H-19)，6.59(2H，m，Ar-H)，6.90(1H，m，H-12’)，7.52(1H，m，H-10)，7.84(2H，m，H-3’，6’)，7.55(4H，m).
ESI-MS：909[M-H]
+。
Ultimate analysis: C
53H
56N
2O
12Found C69.75% H6.15% N3.05% O21.02%; Calcd C69.72% H6.18% N3.07% O21.03%
Faint yellow solid (III-9) 36mg, Mp:90-92 ℃.
1HNMR(300M，CDCl
3)：δ?5?.43(1H，m，H-4)，6.62(1H，brd，J＝10.1，H-3)，6.35(1H，m，H-27)，5.09(2H，brd，H-7’a，7’b)，3.47(1H，m，H-11)，3.31(2H，m，H-37，H-32)，3.05(2H，m，H-31)，2.92(2H，m，H-26)，2.54(1H，m，H-22)，2.32(1H，brdd，J＝4.0Hz，3.9Hz，H-21a)，1.59(3H，s，H-24)，1.87(3H，s，H-25)，1.56(3H，s，H-40)，1.66(3H，s，H-39)，1.70(3H，s，H-34)，1.68(3H，H-35)，2.04(2H，m，H-36)，1.41(1H，m，H-21b)，1.72(2H，m，H-20)，1.28(3H，s，H-19)，6.59(2H，m，H-13’，11’)，6.90(1H，m，H-12’)，7.52(1H，m，H-10)，7.84(2H，m，H-3’，6’)，7.55(4H，m).
ESI-MS：927[M+H]
+，949[M+Na]
+.
HRMS(M+Na)m/z?949.3526(calcd?for?C
53H
54N
2O
13Na?949.3524)。
Embodiment 12:40-nitric ether-6-methoxyl group-morellic acid methyl esters (IV)
Under the room temperature, with triphenyl phosphorus 175mg (0.6mmol), iodine 140mg (0.55mmol) and imidazoles 82mg (0.6mmol) are dissolved in anhydrous Et
2Among O-acetonitrile solution 20ml, add 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 322mg (0.5mmol) then, be heated to 45 degree reactions 10 hours, the reaction solution concentrating under reduced pressure dilutes dope with ethyl acetate, washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent and gets yellow thick liquid (G) 180mg, productive rate 50%.And then compound (G) 82mg (0.11mmol) is dissolved among anhydrous tetrahydro furan and the acetonitrile mixed solvent 10ml (1:1), add Silver Nitrate 30mg (0.17mmol) under the room temperature, the lucifuge back flow reaction got final product in 6 hours, with reacting liquid filtering, disgorging, filtrate concentrates system sand, column chromatography, petrol ether/ethyl acetate (2:1) wash-out is prepared into yellow thickness compound (IV) 26mg, yield 27%.
IR(KBr)：v＝2957，2914，2858，1736，1710，1630，1583，1438，1382，1331，1278，1228，1177，1120，1048cm
-1。
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.32(1H，m，H-37)，5.09(1H，m，H-32)，4.11(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，4.65(2H，s，H-40)，1.38(1H，m，H-21b)，1.44(3H，s，H-24).1.28(3H，s，H-19)。
HRMS(M+H)m/z?718.6379(calcd?for?C
40H
48O
11N?717.6376)。
Embodiment 13
Morellic acid-30-{2 '-(3 '-benzenesulfonyl-1 ', 2 ', 5 '-oxadiazoles-2 '-oxide compound) } 2-ethoxyethyl acetate (III-10), 2 '-(3 '-benzenesulfonyl-1 ', 2 ', 5 '-oxadiazoles-2 '-oxide compound) oxyethanol (D-4)
Thiophenol 5.0g (51mmol), sodium hydroxide 2.04g (51mmol) are dissolved among the ethanol 30ml, stir, reaction solution is yellow-green colour, add the mixed solution that is made into by Mono Chloro Acetic Acid 4.3g (45.9mmol), yellow soda ash 2.97g (0.55mmol) under the room temperature, stir, reaction solution becomes white casse by yellow-green colour, room temperature reaction 3 hours, refluxed 1 hour, and be cooled to room temperature, remove ethanol under reduced pressure, transfer pH=2 with 6N hydrochloric acid, white precipitate is separated out, and suction filtration gets thiophenyl acetate white solid 6.87g, Mp:60-62 ℃. yield 89%.
Continuation mixes thiophenyl acetate 3.0g (17.8mmol) with Glacial acetic acid 50ml; stir; under the room temperature; dropping contains 30% aqueous hydrogen peroxide solution of 4.03g (35.7mmol); stirring at room is three hours then, and solution is water white transparency, slowly drips nitrosonitric acid 6.9ml (160.2mmol) then under the ice bath; keep reacting liquid temperature to be lower than 60 ℃; dropwise half an hour approximately, be accompanied by a large amount of reddish-brown gases and emerge, temperature rises to 100 degree; stir five hours stopped reaction; be cooled to room temperature, reaction solution is light yellow transparent solution, steams except that placing the refrigerator cooling after the part acid solution; white solid 3; 4-two benzenesulfonyls-1,2,5-oxadiazoles-2-oxide compound is separated out 2.1g; Mp:123-125 ℃, yield 70%.
With 3; 4-two benzenesulfonyls-1; 2,5-oxadiazoles-2-oxide compound 570mg (1.56mmol) is dissolved among the tetrahydrofuran (THF) 30ml, stirs; adding ethylene glycol 968.3mg (0.87ml), reaction solution are water white transparency under the room temperature; drip 25% aqueous sodium hydroxide solution 68.6mg (1.72mmol) under the room temperature, stir, reaction solution becomes white casse; room temperature reaction 8 hours stops to leave standstill.The upper strata is faint yellow clear liquor, and lower floor is white floss.Then reaction solution is poured in the 20ml water, used ethyl acetate extraction three times, organic phase washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (2:1) wash-out gets white solid (D-4) 110mg, and M.p.160-162 ℃, productive rate about 51%.
Morellic acid 73mg (0.12mmol) is dissolved among the methylene dichloride 10ml, add compound (D-4) 40mg (0.14mmol), 4-N under the room temperature successively, N-Dimethylamino pyridine 15mg (0.14mmol), dicyclohexyl carbon imide 29mg (0.14mmol), stir, room temperature reaction 3 hours, reaction solution dilutes with methylene dichloride, washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (2: 1) wash-out gets yellow thick liquid (III-10) 70mg, and Mp:80-83 ℃, productive rate 65%.
IR(KBr)：v＝3466，3417，2967，2925，2859，1734，1714，1627，1593，1550，1446，1399，1331，1259，1226，1172，1138，1090，1044，804，594cm
-1.
1HNMR(300M，CDCl
3)：δ?8.02(2H，d，J＝1.2Hz，Ar-H)，7.99(1H，m，Ar-H)，7.57(2H，m，Ar-H)，7.51(1H，m，H-10)，6.65(1H，d，J＝10.1Hz，H-4)，6.1(1H，m，27-H)，5.43(1H，d，J＝10.1Hz，H-3)，5.05(2H，m，H-32，37)，4.49(2H，m，-COO
CH 2 -)，4.25(2H，m，-O
CH 2 CH
2-)，3.49(1H，m，H-11)，3.30(1H，d，J＝7.56，H-31a)，3.19(1H，dd，J＝7.5Hz，2.2Hz，H-31b)，2.97(2H，m，H-26)，2.51(1H，d，J＝9.2Hz，H-22)，2.32(1H，dd，J＝4.6Hz，4.6Hz，H-21a)，2.02(2H，dd，J＝3.5Hz，3.7Hz，H-36)，1.74(5H，brs，H-25，20)，1.72(3H，s，H-34)，1.69(3H，s，H-39)，1.65(3H，s，H-35)，1.42(3H，s，H-24)，1.40(3H，s，H-19)，1.36(1H，dd，J＝3.4Hz，2.4Hz，H-21b)，12.85(1H，s，6-OH).ESI-MS：919[M+Na]
+，935[M+K]
+.
Ultimate analysis: C
48H
54N
2O
13S, Found:C64.01%, H6.05%, N3.02%; Calcd:C64.13%, H6.05%, N3.12%.
Embodiment 14:
34-hydroxyl-morellic acid-30-{2 '-(3 '-benzenesulfonyl-1 ', 2 ', 5 '-oxadiazoles-2 '-oxide compound) } 2-ethoxyethyl acetate (III-11)
Compound 34-hydroxyl-morellic acid 114mg (0.18mmol) is dissolved among the methylene dichloride 10ml, add compound (D-4) 61mg (0.21mmol), 4-N under the room temperature successively, N-Dimethylamino pyridine 21.6mg (0.18mmol), dicyclohexyl carbon imide 43.7mg (0.21mmol), stir, room temperature reaction 3 hours, reaction solution dilutes with methylene dichloride, washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (2: 1) wash-out gets yellow thick liquid (III-11) 60mg, and Mp:116-118 ℃, productive rate 37%.
IR(KBr)：v＝3464，3417，2967，2923，2859，1734，1714，1627，1593，1550，1446，1399，1331，1259，1226，1172，1138，1090，1048，1020，806，594cm
-1.
1HNMR(300M，CDCl
3)：δ?8.02(2H，d，J＝1.2Hz，Ar-H)，7.99(1H，m，Ar-H)，7.57(2H，m，Ar-H)，7.54(1H，m，10-H)，6.59(1H，d，J＝10.1Hz，H-4)，5.8(1H，m，H-27)，5.43(1H，d，J＝10.1Hz，H-3)，5.38(1H，m，H-37)，5.05(1H，m，H-32)，4.49(2H，m，-COO
CH 2 -，4.25(2H，m，-O
CH 2 CH
2-)，3.90(2H，d，J＝5.5Hz，H-34)，3.49(1H，m，H-11)，3.3131a)，3.13(1H，dd，J＝8.6Hz，8.6Hz，H-31b)，2.96(2H，dd，J＝4.4Hz，4.3Hz，H-26)，2.51(1H，d，J＝9.2Hz，H-22)，2.32(1H，dd，J＝4.6Hz，4.6Hz，H-21a)，2.02(2H，dd，J＝3.5Hz，3.7Hz，H-36)，1.74(5H，brs，H-25，H-20)，1.72(3H，s，H-34)，1.69(3H，s，H-39)，1.65(3H，s，H-35)，1.42(3H，s，H-24)，1.40(3H，s，H-19)，1.36(1H，dd，J＝3.4Hz，2.4Hz，H-21b)，1.25(3H，s，H-19)，12.85(1H，s，6-OH).
ESI-MS：935[M+Na]
+，951[M+K]
+。
Ultimate analysis: C
48H
54N
2O
14S Found:C 63.01%, H 6.00%, and N 3.05%, and O 24.43%, and S 3.52%; Calcd:C 63.01%, and H 5.95%, and N 3.06%, and O 24.48%, and S 3.50%.
Embodiment 15: morellic acid-30-(3,4-resorcylic acid-2-nitroxide ethyl ester) (II)
The preparation method of reference compound I-1, by 3, the 4-resorcylic acid is a starting raw material, through making bromide with ethylene dibromide, triethylamine reaction, again gained white bromide is dissolved in anhydrous tetrahydro furan and the acetonitrile mixed solvent, add Silver Nitrate under the room temperature, it is required 3 that the lucifuge back flow reaction obtains, 4-resorcylic acid-2-nitroxide ethyl ester.Then morellic acid 314mg (0.5mmol) is dissolved among the methylene dichloride 10ml, add 3 successively under the room temperature, 4-resorcylic acid-2 nitroxide ethyl ester 122mg (0.5mmol), 4-N, N-Dimethylamino pyridine 61mg (0.5mmol), dicyclohexyl carbon imide 124mg (0.6mmol), stir, room temperature reaction 6 hours, reaction solution dilutes with methylene dichloride, washing, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, and column chromatography petrol ether/ethyl acetate (1:1) wash-out gets yellow solid (II) 280mg, productive rate 65%.
IR(KBr)：v＝3456，3010，2967，2925，2856，1737，1710，1632，1594，1586，1438，1383，1330，1278，1228，1120，1048cm
-1。
1HNMR(300M，CDCl
3)：δ?12.86(1H，s，6-OH)，7.56(1H，brs，H-10)，7.28(2H，m，Ar-H)，6.60(2H，m，H-4，Ar-H)，6.12(1H，m，H-27)，5.45(1H，m，H-3)，5.06(2H，m，H-32，H-37)，4.32(2H，m，H-1’)，3.76(3H，m，H-2’，H-11)，3.30(1H，m，H-31a)，3.25(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.52(1H，m，H-22)，2.36(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.04(2H，m，H-36)，1.76(3H，s，H-25)，1.71(2H，m，H-20)，1.66(3H，brs，H-39)，1.70(3H，brs，H-35)，1.63(3H，brs，H-34)，1.57(3H，s，H-40)，1.46(3H，s，H-24)，1.38(1H，m，H-21b)，1.28(3H，s，H-19)，ESI-MS?854[M+H]
+，876[M+Na]
+。
HRMS(M+Na)m/z?876.7219(calcd?for?C
47H
53O
15NNa?876.7213)。
Embodiment 16:40-carboxyl-(2-nitroxide ethyl ester)-6-methoxyl group-morellic acid methyl esters (VII)
Raw material 40-carboxyl-6-methoxyl group-morellic acid methyl esters 263mg (0.4mmol) is dissolved among the acetone 15ml, add ethylene dibromide 0.18ml (2.08mmol) and triethylamine 0.4ml under the room temperature respectively, reaction solution is a yellow transparent, behind reinforced the finishing, back flow reaction 6 hours, directly concentration of reaction solution system sand, column chromatography, petrol ether/ethyl acetate (4:1) wash-out is prepared into yellow oil (F) 90mg, productive rate about 30%.And then compound (F) (0.09mmol) is dissolved among anhydrous tetrahydro furan and the acetonitrile mixed solvent 10ml (1:1), add Silver Nitrate 36mg (0.2mmol) under the room temperature, the lucifuge back flow reaction got final product in 4 hours, with reacting liquid filtering, disgorging, filtrate concentrate system sand, column chromatography, petrol ether/ethyl acetate (2:1) wash-out is prepared into yellow thickness compound (VII) 28mg.Productive rate 25%
IR(KBr)：v＝3456，2960，2921，2857，1738，1713，1632，1594，1438，1385，1330，1279，1224，1187，1120，1048cm
-1。
1HNMR(300M，CDCl
3)：δ7.56(1H，brs，H-10)，6.67(1H，m，H-4)，6.1(2H，m，H-27，H-37)，5.48(1H，m，H-3)，5.16(1H，m，H-32)，4.39((2H，m，H-1’)，3.88(3H，m，H-2’，H-11)，3.82(3H，s，6-OCH
3)3.41(3H，s，COOCH
3)，3.30(1H，m，H-31a)，3.23(1H，m，H-31b)，2.98(2H，dd，J＝9.7Hz，7.9Hz，H-26)，2.53(1H，m，H-22)，2.34(1H，dd，J＝13.0Hz，4.6Hz，H-21a)，2.01(2H，m，H-36)，1.76(3H，s，H-25)，1.72(2H，m，H-20)，1.66(3H，brs，H-39)，1.71(3H，brs，H-35)，1.63(3H，brs，H-34)，1.46(3H，s，H-24)，1.37(1H，m，H-21b)，1.28(3H，s，H-19)。
ESI-MS776[M+H]
+，798[M+Na]
+。
Embodiment 17: the cytotoxic activity data of target compound among the embodiment 1～16.
This mensuration adopts bromination tetrazole indigo plant (MTT) method routinely, promptly use the trysinization tumour cell, to contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, take the logarithm the vegetative period cell cultures in 96 well culture plates, every hole 100 μ l (containing 1000～1200 tumour cells).Next day, the administration group adds and contains the different concns compound, and every medicine is established 4～5 dosage groups, establishes 3 parallel holes at least for every group.Control group adds and the isopyknic solvent of compound.Put 5%CO
2In 37 ℃ of cultivations, discard nutrient solution after 4 days in the incubator, every hole adds 200 μ l0.2%MTT solution (RPMI1640 preparation).37 ℃ are incubated 4 hours, supernatant discarded, and every hole adds DMSO 150 μ l dissolving first hairpin particle, behind the gentle agitation, uses microplate reader, measures optical density value (OD) under reference wavelength 450nm, detection wavelength 570nm condition.The tumour cell of handling with solvent control is a control group, calculates the inhibiting rate of medicine to tumour cell with following formula, and calculates IC
50
Reagent source:
MTT: bromination tetrazole indigo plant (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company;
RPMI1640 substratum: GIBCO company product;
Pancreatin (Trypsin): GIBCO company product
DMSO: dimethyl sulfoxide (DMSO), the Beijing Chemical Plant produces;
Calf serum: military region animal doctor's centre of prevention and cure
Table one experimental data shows that The compounds of this invention has strong cytotoxicity to human lung carcinoma cell (A549), colon cancer cell (HT-29), gastric carcinoma cells (BGC823), human liver cancer cell (Bel7402) and Proliferation of Human Ovarian Cell (SKOV3).Wherein the cytotoxic activity of part of compounds obviously is better than positive control drug morellic acid or suitable with its cytotoxic activity.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely,, can mix the preparation antitumor drug so The compounds of this invention has anti-tumor activity with pharmaceutical carrier.
Table one, nitric oxide donator type Gamboges acid derivative MTT The selection result of the present invention
Claims (5)
1, a kind of Gamboges acid derivative, it is characterized in that this derivative be general formula (I), (II), (III), (IV) or (VII) shown in compound:
In the formula (I): R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Representative-(CH
2)
n-, n=1～6; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
In the formula (II): R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; R
5Independent H, the OH of representing; R
6Representative-CO; R
7Representative-(CH
2)
n-, n=1～6;
In the formula (III): R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; R
5Independent representative-(CH
2)
nO-, n=1～4 ,-CH (CH
3) CH
2CH
2O-,-(CH
2)
n-phenyl--OCH
2-, n=0～4 ,-(CH
2)
n-phenyl-right-OCH
2-, n=0～4; R
6Represent phenyl, benzenesulfonyl; X representative-O-;
In the formula (IV): R
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether; R
5, R
6Identical or different, independent separately H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, allyl group, the propenyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
In the formula (VII): R
1Independent representative-(CH
2)
n-, n=2～6; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, propyl group, sec.-propyl, butyl, allyl group, the propenyl represented; R
4Independent represent H, methyl, ethyl, propyl group, sec.-propyl, butyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented.
2, Gamboges acid derivative according to claim 1 is characterized in that R in the formula (IV)
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether; R
5, R
6Identical or different, independent separately H, methyl, ethyl, the sec.-propyl represented; (32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position.
3, Gamboges acid derivative according to claim 1 is characterized in that R in the formula (VII)
1Independent representative-(CH
2)
n-, n=2～6; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, sec.-propyl, the allyl group represented; R
4Independent represent H, methyl, ethyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented.
4, the preparation method of the described Gamboges acid derivative of claim 1 is characterized in that:
Gamboges acid derivative prepares by following manner shown in the formula (I): Gamboges acid derivative (1) and R
5Halogenated alkane generate compd A, then compd A again with the Silver Nitrate reaction, its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Independent representative-(CH
2)
n-, n=1～6; (32,33) position, independent separately ethylene linkage, the epoxy bond represented of the empty line part in (37,38) position; X is a halogen;
Gamboges acid derivative prepares by following manner shown in the formula (II): Gamboges acid derivative (2) acts under DMAP, DCC existence condition with intermediate B and generates compound (II), and its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Independent H, the OH of representing; R
6Representative-CO; R
7Representative-(CH
2)
n-, n=1～6; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
Gamboges acid derivative prepares by following manner shown in the formula (III): Gamboges acid derivative (3) generates compound (III) with the Compound D effect under DMAP, DCC existence condition, its building-up process is as follows:
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented; R
5Independent representative-(CH
2)
nO-, n=1～4 ,-CH (CH
3) CH
2CH
2O-,-(CH
2)
n-phenyl--OCH
2-, n=0～4 ,-(CH
2)
n-phenyl-right-OCH
2-, n=0～4; R
6Represent phenyl, benzenesulfonyl; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; X representative-O-;
Gamboges acid derivative prepares by following manner shown in the formula (IV): Gamboges acid derivative (7) and Ph
3P-I
2-imidazoles is at anhydrous Et
2Reaction generates R in the O-acetonitrile solution
1, R
2, R
3Or R
4Have a Gamboges acid derivative that is replaced by I at least, will be somebody's turn to do the Gamboges acid derivative and the Silver Nitrate reactivity that are replaced by I again and generate compound (IV);
R wherein
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, nitric ether separately, but wherein have at least one to be nitric ether; R
5, R
6Identical or different, independent separately H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, allyl group, the propenyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
Work as R
4When being substituted, its building-up process is as follows:
Gamboges acid derivative prepares by following manner shown in the formula (VII): Gamboges acid derivative (6) and R
1Halogenated alkane reaction generate intermediate F, compound F 17-hydroxy-corticosterone and Silver Nitrate reactivity generation compound (VII), its building-up process is as follows:
R wherein
1Independent representative-(CH
2)
n-, n=2～6; R
2Independent H, hydroxyl, aldehyde radical, the carboxyl represented; R
3Independent H, methyl, ethyl, propyl group, sec.-propyl, butyl, allyl group, the propenyl represented; R
4Independent represent H, methyl, ethyl, propyl group, sec.-propyl, butyl ,-(CH
2)
nONO
2-, n=1～6 ,-CH
2CH=CHCH
2ONO
2(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; X is a halogen.
5, the application of the described arbitrary Gamboges acid derivative of claim 1～3 in the preparation anti-tumor drug.
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| WO2021221208A1 (en) * | 2020-04-29 | 2021-11-04 | 재단법인 대구경북첨단의료산업진흥재단 | Dihydropyrano[3,2-g]cromen-2-one derivative and pharmaceutical composition for preventing or treating cancer, comprising same as active ingredient |
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