CN108530508A - Oleanane type nitrogen glycoside compounds and its application in preparing treatment antidiabetic medicine - Google Patents

Oleanane type nitrogen glycoside compounds and its application in preparing treatment antidiabetic medicine Download PDF

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CN108530508A
CN108530508A CN201810596681.0A CN201810596681A CN108530508A CN 108530508 A CN108530508 A CN 108530508A CN 201810596681 A CN201810596681 A CN 201810596681A CN 108530508 A CN108530508 A CN 108530508A
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刘庆超
郭甜甜
白乃生
刘浪浪
李国林
刘甜
韩稳荣
卢英辉
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Northwest University
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Abstract

The invention discloses a kind of oleanane type nitrogen glycoside compounds and its application in treating antidiabetic medicine is being prepared, the structural formula of the compound isR represents glycosyl in formula, is with oleanolic acid C28Amino-n-hexanoic acid methyl esters is starting material, converts after amino its 3 hydroxyls to and introduces different sugar units and be prepared.Such compound has application value in terms of anti-diabetic, pharmacological activity test display has good inhibitory activity to protein tyrosine phosphatase 1B, illustrates that such oleanane type nitrogen glycoside compounds can be subject to research and utilization as a kind of novel antidiabetic medicine.

Description

Oleanane type nitrogen glycoside compounds and its prepare treat antidiabetic medicine in Using
Technical field
The invention belongs to chemicals technical fields, and in particular to oleanane type nitrogen glycoside compounds and its be controlled in preparation Treat the application in antidiabetic medicine.
Background technology
Type-2 diabetes mellitus as a kind of endocrine disturbance be metabolized class disease, have become after tumour, cardiovascular pathological changes it The third-largest chronic disease for seriously threatening human health afterwards.The World Health Organization (WHO) report, 2015, in worldwide Interior, the number for directly dying of type-2 diabetes mellitus has reached 1,600,000, if not taking effectively measure, it is contemplated that the year two thousand thirty, extremely It can be double in the total number of persons of type-2 diabetes mellitus.Protein-tyrosine-phosphatase 1B (protein tyrosinephosphatase 1B, PTP1B) there is important cell biological function, it has also become the important new role target of generally acknowledged anti-type-2 diabetes mellitus drug Mark.Currently, using PTP1B as target spot for treat type-2 diabetes mellitus PTP1B inhibitor (such as Trodusquemine and Ertiprotafib clinical investigation phase) is come into.But with deepening continuously to the exploitation of PTP1B inhibitor, find big Most efficient, highly selective small molecule PTP1B inhibitor, since compound itself is easy ionization, cell permeability and biology Availability is less desirable, leads to the anti-type-2 diabetes mellitus drug for being difficult to be developed into therapeutic value.Therefore, find efficiently, The highly selective and good novel PTP1B inhibitor of pharmaceutical properties has important research significance and application prospect.
The diversity and novelty of Structures of Natural Products are the important sources of new drug lead compound, to natural activity chemical combination It is the key link and important topic for realizing innovation drug research that object, which carries out chemical synthesis and study on the modification again,.Research shows that neat pier Fruit alkyl compound has significant anti-type-2 diabetes mellitus activity as a kind of novel PTP1B inhibitor, has become at present anti- One of the hot spot in type-2 diabetes mellitus drug research field.It is to be directed to neat pier at present to inhibit the activity of protein-tyrosine-phosphatase 1B The main policies of the structural modification of tartaric acid anti-diabetic, structural modification is mainly to C-3, A ring, C rings and C-28 modifications.
The report that the prior art carries out oleanolic acid in modification screening PTP1B inhibitor is more, and about oleanolic acid nitrogen There is not been reported for the research for the PTP1B inhibitory activity that glycosyl compound carries out.
Invention content
The object of the present invention is to provide a new class of oleanane type nitrogen glycoside compounds, and provide one kind for the compound New application.
For above-mentioned purpose, the structural formula of oleanane type nitrogen glycoside compounds of the present invention is as follows：
Wherein, R is selected from D-Glucose base, D-Glucose aldehydic acid base, D- galactosyls, D-MANNOSE base, D-MANNOSE aldehyde It is arbitrary in acidic group, D- xylosyls, L- rhamnopyranosyls, L-arabinose base, D- fucosidos, D- lactose base, D- sialic acid glycosyls One kind, preferably β-D- glucopyranosyls, α-D- glucopyranosyls, beta d glucopyranosiduronic acid base, α-D- glucopyras Alditol acidic group, β-D- galactopyranosyls glycosyl, α-D- galactopyranosyls glycosyl, β-D- mannopyranoses base, α-D- mannopyranoses base, β-D- mannopyranose aldehydic acid base, α-D- mannopyranose aldehydic acid base, β-D- xylopyranosyls, alpha-D-xylose base, β-L- pyrans Rhamnopyranosyl, α-L- rhamnopyranosyls, β-L- arabopyranoses base, α-L- arabopyranoses base, β-D- pyrans rock algaes Glycosyl, α-D- fucopyranosyls, β-D- pyrans lactose base, α-D- pyrans lactose base, β-D- sialic acids glycosyl, α-D- sialic acids Any one in glycosyl.
The synthetic route and specific synthetic method of oleanane type nitrogen glycoside compounds of the present invention are as follows：
1, compound 24 is synthesized
It is 1 in molar ratio by compound 23 and pyridinium dichromate (PDC) using dry methylene chloride as solvent:2, room temperature It is stirred to react 4h.After completion of the reaction, it filters, removes solvent under reduced pressure, concentrate obtains compound 24 through silica gel column chromatography.
2, compound 25 is synthesized
With methanol and pyridine volume ratio 12~13:1 mixed liquor is solvent, and compound 24 and methoxy amido hydrochloride are pressed Molar ratio is 1:1.5~2, reaction 30min is stirred at room temperature.After completion of the reaction, solvent is removed under reduced pressure, concentrate is dissolved in dichloromethane In alkane, 1mol/L hydrochloric acid, saturated common salt water washing, anhydrous sodium sulfate drying is used to filter successively, concentration obtains compound 25.
3, compound 26 is synthesized
With ethyl alcohol and dioxane volume ratio 1:2.5~3 mixed liquor is solvent, by compound 25 and sodium cyanoborohydride It is 1 in molar ratio:3~3.5, it is stirred to react 3h at 0 DEG C.After completion of the reaction, solvent is removed under reduced pressure, concentrate is dissolved in dichloro In methane, anhydrous sodium sulfate drying is filtered, and concentration, silica gel column chromatography obtains compound 26.
4, oleanane type nitrogen glycoside compounds are synthesized
With dimethylformamide and acetic acid volume ratio 3:1 mixed liquor is solvent, (i.e. with saccharide compound by compound 26 RH it is) 1 in molar ratio:1.1~1.3,60 DEG C are stirred to react 48h.After reaction, it is concentrated under reduced pressure, silica gel column chromatography obtains here Pier fruit alkane type nitrogen glycoside compounds.
Oleanane type nitrogen glycoside compounds of the present invention are preparing the purposes in treating antidiabetic medicine, routinely medicine With preparation, be made according to the conventional fabrication process of various preparations with pharmaceutically acceptable carrier, can be tablet, granule, Capsule.
The present invention is introduced using oleanolic acid C28- Amino-n-hexanoic acids methyl esters as parent after converting its 3 hydroxyls to amino Different sugar units prepares oleanane type nitrogen glycoside compounds.It is detected through pharmacological activity, such compound for protein matter junket ammonia Acid phosphoric acid esterase 1B shows good inhibitory activity, can be used for preparing the drug for the treatment of diabetes.
Specific implementation mode
With reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these realities Apply example.
Embodiment 1
Prepare oleanane type nitrogen glycoside compounds 1~22
1, compound 24 is synthesized
5g (8.57mmol) compound 23 is dissolved in 50mL dry methylene chlorides, lower addition 6.44g is stirred at room temperature (17.14mmol) pyridinium dichromate (PDC) keeps room temperature to continue to be stirred to react 4h.After completion of the reaction, it filters, removes under reduced pressure Solvent, concentrate is through silica gel column chromatography (ethyl acetate/petroleum ether=1:4, V/V) white solid 4.6g, i.e. chemical combination are refining to obtain Object 24, yield 92.3%, structural characterization data are：1H NMR(600MHz,DMSO-d6)δ:7.23 (t, J=5.5Hz, 1H, N-H), 5.20 (t, J=3.2Hz, 1H, H-12), 3.57 (s, 3H, H-37), 3.03 (m, 1H, H-31-1), 2.93 (m, 1H, H-31- 2), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.27 (t, J=7.7,7.4Hz, 2H, H-35-1, H-35-2), 1.87- 1.91(m,1H,H-16-1),1.08,0.97,0.88,0.86,0.85,0.75,0.66(s,3H,CH3×7)；13C NMR (150MHz,CD3OD)δ:215.0(C-3),180.3(C-28),175.8(C-36),145.4(C-13),123.9(C-12), 56.9,52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9, 33.6,31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7；HR-MS (ESI):M/z theoretical values C37H60NO4[M+H]+582.4517 measured value 582.4563.
2, compound 25 is synthesized
4g (6.88mmol) compound 24 is dissolved in the in the mixed solvent of 15mL methanol and 1.2mL pyridines.It is stirred at room temperature Lower addition 917mg (10.98mmol) methoxy amido hydrochloride keeps room temperature to continue to be stirred to react 30min.After completion of the reaction, subtract Solvent is evaporated off in pressure, and concentrate is dissolved in dichloromethane, uses 1mol/L hydrochloric acid, saturated common salt water washing, anhydrous sodium sulfate successively It is dry, it filters, concentration obtains 3.82g compounds 25, yield 91%, structural characterization data are：1H NMR(600MHz,DMSO- d6)δ:7.24 (t, J=5.5Hz, 1H, N-H), 5.21 (t, J=3.2Hz, 1H, H-12), 3.93 (s, 3H, OCH 3),3.57(s, 3H, H-37), 3.03 (m, 1H, H-31-1), 2.93 (m, 1H, H-31-2), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.27 (t, J=7.7,7.4Hz, 2H, H-35-1, H-35-2), 1.87-1.91 (m, 1H, H-16-1), 1.08,0.97,0.88, 0.86,0.85,0.75,0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.3(C-28),175.8(C- 36),162.4(C-3),145.4(C-13),123.9(C-12),61.9,56.9,52.0,47.7,47.5,42.9,42.6, 40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.6,31.6,30.1,28.5,27.7,27.0, 26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7；HR-MS(ESI):M/z theoretical values C38H63N2O4[M+H]+ 611.4782 measured value 611.4751.
3, compound 26 is synthesized
3.50g (5.73mmol) compound 25 is dissolved in the in the mixed solvent of 8mL ethyl alcohol and 21mL dioxane, 0 DEG C Lower addition 1.19g (18.94mmol) sodium cyanoborohydride is kept for 0 DEG C and continues to be stirred to react 3h.After completion of the reaction, it removes under reduced pressure Solvent, concentrate are dissolved in dichloromethane, and anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography (ethyl acetate/oil Ether=1:1, V/V) it is refining to obtain 2.28g compounds 26, yield 65%, structural characterization data are：1H NMR(600MHz,DMSO- d6)δ:7.24 (t, J=5.5Hz, 1H, N-H), 5.21 (t, J=3.2Hz, 1H, H-12), 3.67 (s, 3H, OCH 3),3.57(s, 3H, H-37), 3.03 (m, 1H, H-31-1), 2.93 (m, 1H, H-31-2), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7,7.4Hz, 2H, H-35-1, H-35-2), 1.87-1.91 (m, 1H, H- 16-1),1.08,0.97,0.88,0.86,0.85,0.75,0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ: 180.3(C-28),175.8(C-36),145.4(C-13),123.9(C-12),66.5(C-3),65.2,56.9,52.0, 47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.6,31.6, 30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7；HR-MS(ESI):M/z is managed By value C38H65N2O4[M+H]+613.4939 measured value 613.4971.
4, compound 1 is synthesized
By 100mg (0.16mmol) compound 26 and 34mg (0.192mmol) β-D-Glucose be dissolved in 2.5mL DMF and HOAc volume ratios are 3:1 in the mixed solvent, 60 DEG C are stirred to react 48h.After reaction, it is concentrated under reduced pressure, silica gel column chromatography obtains To white foam solid compound 1.
In above-mentioned steps 4, with equimolar alpha-D-glucose, β-D-Glucose aldehydic acid, alpha-D-glucose aldehydic acid, β-D- galas Sugar, α-D- galactolipins, β-D-MANNOSE, α-D-MANNOSE, beta-D-mannuronic acid, α-D-MANNOSE aldehydic acid, β-D- xyloses, α- D- xyloses, β-L- rhamnoses, α-L- rhamnoses, β-L-arabinose, α-L-arabinose, β-D- fucoses, α-D- fucoses, β-D- lactose, α-D- lactose, β-D- sialic acids, α-D- sialic acids replace β-D-Glucose respectively, other steps and 1 phase of embodiment Together, compound 2~22 is obtained successively.
The substituent group and yield of 1 compound 1~22 of table
Compound R Yield
1 β-D- glucopyranosyls 35%
2 α-D- glucopyranosyls 31%
3 Beta d glucopyranosiduronic acid base 38%
4 α-D- glucopyranosiduronic acid bases 35%
5 β-D- galactopyranosyl glycosyls 45%
6 α-D- galactopyranosyl glycosyls 33%
7 β-D- mannopyranose bases 39%
8 α-D- mannopyranose bases 30%
9 β-D- mannopyranose aldehydic acid bases 29%
10 α-D- mannopyranose aldehydic acid bases 27%
11 β-D- xylopyranosyls 43%
12 α-D- xylopyranosyls 35%
13 β-L- rhamnopyranosyls 37%
14 α-L- rhamnopyranosyls 29%
15 β-L- arabopyranose bases 29%
16 α-L- arabopyranose bases 27%
17 β-D- fucopyranosyls 33%
18 α-D- fucopyranosyls 29%
19 β-D- pyrans lactose bases 36%
20 α-D- pyrans lactose bases 29%
21 β-D- sialic acid glycosyls 28%
22 α-D- sialic acid glycosyls 24%
The structural characterization data of compound 1 are：1H NMR(600MHz,CD3OD)δ:7.24 (t, J=5.5Hz, 1H, N-H), 5.21 (t, J=3.2Hz, 1H, H-12), 4.09 (d, J=8.8Hz, 1H), 3.67 (s, 3H, OCH 3),3.61(s,3H,OCH 3), 3.59 (t, J=9.0Hz, 1H), 3.44 (br s, 1H), 3.37 (m, 2H), 3.15 (m, 1H), 3.03 (m, 1H, H-31-1), 2.93 (m, 1H, H-31-2), 2.84 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7,7.4Hz, 2H, H-35-1, H-35-2), 1.87-1.91 (m, 1H, H-16-1), 1.08,0.97, 0.88,0.86,0.85,0.75,0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.1(C-28),175.8 (C-36),145.4(C-13),123.9(C-12),94.7,81.3,77.6,71.2,68.9,66.5(C-3),65.2,61.9, 56.9,56.3,52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3, 33.9,33.6,31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7； HR-MS(ESI):M/z theoretical values C44H75N2O9[M+H]+775.5467 measured value 775.5483.
The structural characterization data of compound 2 are：1H NMR(600MHz,CD3OD)δ:7.24 (t, J=5.5Hz, 1H, N-H), 5.19 (br s, 1H, H-12), 4.07 (d, J=8.7Hz, 1H), 3.67 (s, 3H, OCH 3), 3.59 (t, J=9.1Hz, 1H), 3.57(s,3H,OCH 3),3.44(br s,1H),3.37(m,2H),3.15(m,1H),3.03(m,1H,H-31-1),2.93(m, 1H, H-31-2), 2.84 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7,7.4Hz, 2H, H-35-1, H-35-2), 1.87-1.91 (m, 1H, H-16-1), 1.08,0.97,0.88,0.86, 0.85,0.75,0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.3(C-28),175.8(C-36), 145.4(C-13),123.9(C-12),94.9,81.3,77.6,71.3,68.9,66.5(C-3),65.2,61.7,56.7, 56.5,52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9, 33.6,31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7；HR-MS (ESI):M/z theoretical values C44H75N2O9[M+H]+775.5467 measured value 775.5441.
The structural characterization data of compound 3 are：1H NMR(600MHz,CD3OD)δ:7.26 (t, J=5.6Hz, 1H, N-H), 5.21 (br s, 1H, H-12), 4.63 (d, J=8.0Hz, 1H), 3.63 (s, 3H, OCH 3), 3.59 (t, J=8.8Hz, 1H), 3.58(s,3H,OCH 3),3.44(br s,1H),3.33(m,1H),3.01(m,1H,H-31-1),2.93(m,1H,H-31-2), 2.84 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7, 7.4Hz,2H,H-35-1,H-35-2),1.87-1.91(m,1H,H-16-1),1.08,0.97,0.88,0.86,0.85,0.75, 0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.5(C-28),176.1(C-6),175.8(C-36), 145.4(C-13),123.9(C-12),94.9,81.3,77.6,71.3,68.9,66.5(C-3),65.2,56.9,56.3, 52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.6, 31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.0,15.7；HR-MS(ESI): M/z theoretical values C44H73N2O10[M+H]+789.5260 measured value 789.5273.
The structural characterization data of compound 4 are：1H NMR(600MHz,CD3OD)δ:7.26 (t, J=5.6Hz, 1H, N-H), 5.20 (br s, 1H, H-12), 4.65 (d, J=7.8Hz, 1H), 3.67 (s, 3H, OCH 3),3.60(s,3H,OCH 3),3.59(t, J=8.8Hz, 1H), 3.44 (br s, 1H), 3.33 (m, 1H), 3.02 (m, 1H, H-31-1), 2.95 (m, 1H, H-31-2), 2.85 (m, 1H), 2.78 (dd, J=13.7,3.7Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7, 7.4Hz,2H,H-35-1,H-35-2),1.87-1.91(m,1H,H-16-1),1.08,0.97,0.88,0.86,0.85,0.75, 0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.5(C-28),176.3(C-6),175.8(C-36), 145.3(C-13),123.7(C-12),94.7,81.3,77.6,71.3,68.9,66.9(C-3),65.2,56.9,56.5, 52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.6, 31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.3,15.7；HR-MS(ESI): M/z theoretical values C44H73N2O10[M+H]+789.5260 measured value 789.5244.
The structural characterization data of compound 5 are：1H NMR(600MHz,CD3OD)δ:7.21 (t, J=5.5Hz, 1H, N-H), 5.21 (t, J=3.6Hz, 1H, H-12), 4.19 (d, J=8.5Hz, 1H), 3.65 (s, 3H, OCH 3), 3.59 (t, J=9.3Hz, 1H),3.59(s,3H,OCH 3),3.44(br s,1H),3.24-3.29(m,2H),3.18(m,1H),3.03(m,1H,H-31- 1), 2.93 (m, 1H, H-31-2), 2.88 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.55 (t, J= 3.6Hz, 1H), 2.27 (t, J=7.7,7.3Hz, 2H, H-35-1, H-35-2), 1.89 (m, 1H, H-16-1), 1.07,0.97, 0.88,0.86,0.83,0.75,0.66(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:179.9(C-28),175.9 (C-36),144.9(C-13),123.5(C-12),95.1,81.7,77.6,71.2,68.3,66.3(C-3),65.2,61.9, 56.7,56.3,52.0,47.7,47.5,42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3, 33.9,33.6,31.6,30.1,28.5,27.7,27.0,26.5,25.7,24.5,24.1,19.3,17.6,17.0,15.9； HR-MS(ESI):M/z theoretical values C44H75N2O9[M+H]+775.5467 measured value 775.5497.
The structural characterization data of compound 6 are：1H NMR(600MHz,CD3OD)δ:7.21 (t, J=5.5Hz, 1H, N-H), 5.21 (t, J=3.6Hz, 1H, H-12), 4.19 (d, J=8.7Hz, 1H), 3.65 (s, 3H, OCH 3), 3.57 (t, J=9.6Hz, 1H),3.57(s,3H,OCH 3),3.43(br s,1H),3.31(m,2H),3.18(m,1H),3.03(m,1H,H-31-1), 2.93 (m, 1H, H-31-2), 2.88 (m, 1H), 2.78 (dd, J=13.7,3.7Hz, 1H, H-18), 2.57 (t, J=3.6Hz, 1H), 2.27 (t, J=7.5,7.1Hz, 2H, H-35-1, H-35-2), 1.92 (m, 1H, H-16-1), 1.07,0.97,0.89, 0.86,0.83,0.75,0.67(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:179.6(C-28),175.9(C- 36),144.6(C-13),123.7(C-12),95.3,81.7,77.6,71.2,68.3,66.5(C-3),65.2,61.9, 56.7,56.3,52.0,47.7,47.3,42.9,42.5,40.7,40.3,40.2,39.5,37.7,35.1,34.7,34.3, 33.9,33.5,31.6,30.1,28.3,27.7,27.0,26.5,25.7,24.5,24.3,19.3,17.6,17.0,15.1； HR-MS(ESI):M/z theoretical values C44H75N2O9[M+H]+775.5467 measured value 775.5453.
The structural characterization data of compound 7 are：1H NMR(600MHz,CD3OD)δ:7.25 (t, J=5.7Hz, 1H, N-H), 5.27 (t, J=3.4Hz, 1H, H-12), 4.13 (d, J=7.8Hz, 1H), 3.67 (s, 3H, OCH 3),3.62(s,3H,OCH 3), 3.59 (t, J=9.0Hz, 1H), 3.43 (m, 1H), 3.36 (m, 2H), 3.15 (m, 1H), 3.03 (m, 1H, H-31-1), 2.93 (m, 1H, H-31-2), 2.84 (m, 1H), 2.78 (dd, J=13.7,4.3Hz, 1H, H-18), 2.55 (t, J=3.6Hz, 1H), 2.25(m,2H,H-35-1,H-35-2),1.88(m,1H,H-16-1),1.08,0.97,0.88,0.86,0.85,0.75,0.66 (s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.1(C-28),175.8(C-36),145.3(C-13),123.9 (C-12),94.7,81.0,77.6,71.2,68.9,66.5(C-3),65.2,61.7,56.9,56.3,52.0,47.7,47.5, 42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.7,31.6,30.1,28.5, 27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.9,17.3,16.7；HR-MS(ESI):M/z theoretical values C44H75N2O9[M+H]+775.5467 measured value 775.5440.
The structural characterization data of compound 8 are：1H NMR(600MHz,CD3OD)δ:7.24 (t, J=5.5Hz, 1H, N-H), 5.19 (br s, 1H, H-12), 4.07 (d, J=8.7Hz, 1H), 3.67 (s, 3H, OCH 3),3.61(s,3H,OCH 3),3.53(t, J=9.3Hz, 1H), 3.44 (br s, 1H), 3.32 (m, 1H), 3.15-3.19 (m, 2H), 3.05 (m, 1H, H-31-1), 2.95 (m, 1H, H-31-2), 2.84 (m, 1H), 2.77 (dd, J=13.7,3.7Hz, 1H, H-18), 2.53 (t, J=3.6Hz, 1H), 2.29(m,2H,H-35-1,H-35-2),1.87-1.90(m,1H,H-16-1),1.05,0.95,0.89,0.86,0.83, 0.75,0.67(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.1(C-28),175.9(C-36),145.1(C- 13),124.1(C-12),95.3,81.5,77.9,71.3,68.9,67.5(C-3),65.2,61.7,56.7,56.5,52.0, 47.9,47.5,42.9,42.6,40.7,40.6,40.1,39.3,37.7,35.1,34.7,34.3,33.9,33.6,31.6, 30.1,28.5,27.7,27.0,26.5,25.7,24.6,24.0,19.3,17.3,17.0,16.3；HR-MS(ESI):M/z is managed By value C44H75N2O9[M+H]+775.5467 measured value 775.5479.
The structural characterization data of compound 9 are：1H NMR(600MHz,CD3OD)δ:7.23 (t, J=5.6Hz, 1H, N-H), 5.23 (s, 1H, H-12), 4.73 (d, J=7.9Hz, 1H), 3.65 (s, 3H, OCH 3),3.59(s,3H,OCH 3), 3.56 (t, J= 9.3Hz,1H),3.44(br s,1H),3.35(m,1H),3.01(m,1H,H-31-1),2.91(m,1H,H-31-2),2.85 (m, 1H), 2.78 (dd, J=13.7,3.7Hz, 1H, H-18), 2.56 (t, J=3.7Hz, 1H), 2.27 (t, J=7.6Hz, 2H, H-35),1.88(m,1H,H-16-1),1.06,0.97,0.89,0.87,0.85,0.75,0.67(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:180.1(C-28),176.3(C-6),175.6(C-36),145.3(C-13),123.7(C- 12),95.3,81.3,77.6,71.3,68.9,66.7(C-3),65.2,56.7,56.3,52.0,47.7,47.5,42.9, 42.6,40.7,40.6,40.2,39.9,37.7,35.1,34.7,34.5,33.9,33.6,31.6,30.1,28.5,27.9, 27.1,26.5,25.7,24.6,24.0,19.3,17.9,17.3,15.9；HR-MS(ESI):M/z theoretical values C44H73N2O10[M+ H]+789.5260 measured value 789.5287.
The structural characterization data of compound 10 are：1H NMR(600MHz,CD3OD)δ:7.23 (t, J=5.3Hz, 1H, N-H), 5.21 (s, 1H, H-12), 4.61 (d, J=7.8Hz, 1H), 3.67 (s, 3H, OCH 3),3.63(s,3H,OCH 3),3.59(t, J=9.6Hz, 1H), 3.44 (m, 1H), 3.31 (m, 1H), 3.02 (m, 1H, H-31-1), 2.97 (m, 1H, H-31-2), 2.86 (m, 1H), 2.78 (dd, J=13.7,3.7Hz, 1H, H-18), 2.57 (t, J=3.7Hz, 1H), 2.27 (t, J=7.5Hz, 2H, H-35-1,H-35-2),1.87(m,1H,H-16-1),1.07,0.96,0.88,0.86,0.83,0.75,0.66(s,3H,CH3 ×7)；13C NMR(150MHz,CD3OD)δ:179.7(C-28),176.1(C-6),175.6(C-36),145.3(C-13), 123.6(C-12),95.3,81.5,78.1,71.3,68.7,66.7(C-3),65.3,56.9,56.5,52.0,47.7,47.5, 42.9,42.6,40.7,40.6,40.2,39.8,37.7,35.1,34.7,34.3,33.9,33.6,31.6,30.1,28.5, 27.7,27.0,26.5,25.7,24.3,24.0,19.3,18.3,17.6,15.9；HR-MS(ESI):M/z theoretical values C44H73N2O10[M+H]+789.5260 measured value 789.5251.
The structural characterization data of compound 11 are：1H NMR(600MHz,CD3OD)δ:7.23 (t, J=5.1Hz, 1H, N-H), 5.23 (t, J=3.6Hz, 1H, H-12), 4.73 (d, J=8.0Hz, 1H), 3.67 (s, 3H, OCH 3), 3.61 (t, J= 9.6Hz,1H),3.56(s,3H,OCH 3),3.49(m,1H),3.15(m,1H),3.01(m,1H,H-31-1),2.95(m,1H, ), H-31-2 2.87 (m, 1H), 2.77 (dd, J=13.7,3.7Hz, 1H, H-18), 2.56 (t, J=3.6Hz, 1H), 2.27 (t, J=7.5Hz, 2H, H-35), 1.89 (m, 1H, H-16), 1.07,0.97,0.87,0.86,0.83,0.75,0.63 (s, 3H, CH3 ×7)；13C NMR(150MHz,CD3OD)δ:179.3(C-28),175.5(C-36),144.6(C-13),123.5(C-12), 96.7,77.0,71.2,68.6,68.1(C-3),65.2,56.9,56.3,52.1,47.6,47.3,42.9,42.5,40.7, 40.6,40.2,39.3,37.7,35.1,34.5,34.3,33.9,33.6,31.7,30.3,28.5,27.9,27.3,26.5, 25.3,24.6,24.1,19.3,17.5,17.1,16.3；HR-MS(ESI):M/z theoretical values C43H73N2O8[M+H]+ 745.5361 measured value 745.5393.
The structural characterization data of compound 12 are：1H NMR(600MHz,CD3OD)δ:7.24 (t, J=5.3Hz, 1H, N-H), 5.23 (t, J=3.6Hz, 1H, H-12), 4.69 (d, J=7.9Hz, 1H), 3.67 (s, 3H, OCH 3), 3.60 (t, J= 9.3Hz,1H),3.57(s,3H,OCH 3),3.47(m,1H),3.15(m,1H),3.03(m,1H,H-31-1),2.95(m,1H, ), H-31-2 2.89 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.57 (t, J=3.6Hz, 1H), 2.27 (t, J=7.3Hz, 2H, H-35), 1.87 (m, 1H, H-16), 1.06,0.97,0.87,0.85,0.83,0.75,0.61 (s, 3H, CH3 ×7)；13C NMR(150MHz,CD3OD)δ:179.3(C-28),175.3(C-36),144.6(C-13),123.4(C-12), 96.3,77.3,71.2,68.9,68.3(C-3),65.1,56.7,56.3,52.3,47.3,47.1,42.8,42.5,40.7, 40.6,40.2,39.3,37.7,35.1,34.5,34.3,33.9,33.6,31.7,30.5,28.6,27.9,27.4,26.5, 25.3,24.6,24.3,19.3,17.5,17.1,16.5；HR-MS(ESI):M/z theoretical values C43H73N2O8[M+H]+ 745.5361 measured value 745.5343.
The structural characterization data of compound 13 are：1H NMR(600MHz,CD3OD)δ:7.20 (t, J=5.1Hz, 1H, N-H), 5.24 (t, J=3.6Hz, 1H, H-12), 5.05 (d, J=1.9Hz, 1H), 3.96 (dd, J=3.8,1.4Hz, 1H), 3.75-3.78(m,2H),3.67(s,3H,OCH 3),3.59(s,3H,OCH 3), 3.39 (t, J=9.6Hz, 1H), 3.15 (m, 1H), 3.01 (m, 1H, H-31-1), 2.95 (m, 1H, H-31-2), 2.87 (m, 1H), 2.77 (dd, J=13.7,3.7Hz, 1H, ), H-18 2.56 (t, J=3.6Hz, 1H), 2.27 (t, J=7.5Hz, 2H, H-35), 1.89 (m, 1H, H-16), 1.24 (d, J= 6.4Hz,3H),1.05,0.96,0.87,0.85,0.83,0.74,0.63(s,3H,CH3×7)；13C NMR(150MHz, CD3OD)δ:178.9(C-28),174.5(C-36),144.7(C-13),124.3(C-12),100.7,76.7,71.3,66.6, 68.3(C-3),65.1,56.6,56.1,52.1,47.6,47.3,42.7,42.5,40.9,40.6,40.2,39.3,37.9, 35.3,34.5,34.3,33.9,33.6,31.7,30.6,28.5,27.9,27.3,26.5,25.5,24.7,24.3,19.3, 17.7,17.1,16.0；HR-MS(ESI):M/z theoretical values C44H75N2O8[M+H]+759.5518 measured value 759.5563.
The structural characterization data of compound 14 are：1H NMR(600MHz,CD3OD)δ:7.21 (t, J=5.3Hz, 1H, N-H), 5.24 (t, J=3.7Hz, 1H, H-12), 5.06 (d, J=2.0Hz, 1H), 3.96 (dd, J=3.8,1.6Hz, 1H), 3.76 (m,2H),3.67(s,3H,OCH 3),3.61(s,3H,OCH 3), 3.35 (t, J=9.6Hz, 1H), 3.16 (m, 1H), 3.03 (m, 1H, H-31-1), 2.96 (m, 1H, H-31-2), 2.87 (m, 1H), 2.78 (dd, J=13.7,4.1Hz, 1H, H-18), 2.59 (t, J=3.6Hz, 1H), 2.28 (t, J=7.5Hz, 2H, H-35), 1.90 (m, 1H, H-16), 1.23 (d, J=6.5Hz, 3H), 1.05,0.97,0.87,0.85,0.81,0.74,0.65(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:179.3 (C-28),174.3(C-36),144.5(C-13),124.5(C-12),100.4,76.8,71.3,66.7,68.1(C-3), 65.3,56.7,56.1,52.1,47.9,47.3,42.7,42.5,40.9,40.7,40.2,39.4,37.9,35.5,34.5, 34.1,33.9,33.3,31.7,30.6,28.7,27.9,27.3,26.7,25.3,24.7,24.5,19.6,17.7,17.3, 16.1；HR-MS(ESI):M/z theoretical values C44H75N2O8[M+H]+759.5518 measured value 759.5541.
The structural characterization data of compound 15 are：1H NMR(600MHz,CD3OD)δ:7.21 (t, J=5.3Hz, 1H, N-H), 5.27 (t, J=3.6Hz, 1H, H-12), 4.55 (d, J=5.0Hz, 1H), 3.85 (dd, J=11.6,6.0Hz, 1H), 3.78 (m, 2H), 3.71 (dd, J=7.2,3.8Hz, 1H), 3.66 (s, 3H, OCH 3),3.63(s,3H,OCH 3),3.48(dd,J =11.6,2.8Hz, 1H), 3.15 (m, 1H), 3.03 (m, 1H, H-31-1), 2.97 (m, 1H, H-31-2), 2.85 (m, 1H), 2.79 (dd, J=13.7,3.7Hz, 1H, H-18), 2.61 (t, J=3.6Hz, 1H), 2.27 (t, J=7.7Hz, 2H, H-35), 1.93(m,1H,H-16),1.06,0.99,0.87,0.86,0.81,0.75,0.63(s,3H,CH3×7)；13C NMR (150MHz,CD3OD)δ:179.8(C-28),174.1(C-36),144.3(C-13),123.7(C-12),102.0,77.8, 73.3,68.7,68.1(C-3),64.5,56.7,56.3,52.1,47.6,47.3,42.6,42.3,40.9,40.5,40.2, 39.4,37.7,35.5,34.5,34.1,33.9,33.1,31.7,30.5,28.7,27.9,27.3,26.8,25.3,24.9, 24.5,19.3,17.5,17.3,16.0；HR-MS(ESI):M/z theoretical values C43H73N2O8[M+H]+745.5361, measured value 745.5383.
The structural characterization data of compound 16 are：1H NMR(600MHz,CD3OD)δ:7.20 (t, J=5.6Hz, 1H, N-H), 5.27 (t, J=3.7Hz, 1H, H-12), 4.53 (d, J=4.9Hz, 1H), 3.89 (dd, J=11.6,6.2Hz, 1H), 3.79 (m, 2H), 3.75 (dd, J=7.2,3.4Hz, 1H), 3.64 (s, 3H, OCH 3),3.59(s,3H,OCH 3),3.47(dd,J =11.6,2.7Hz, 1H), 3.16 (m, 1H), 3.01 (m, 1H, H-31-1), 2.97 (m, 1H, H-31-2), 2.85 (m, 1H), 2.79 (dd, J=13.7,3.7Hz, 1H, H-18), 2.63 (t, J=3.7Hz, 1H), 2.27 (t, J=7.7Hz, 2H, H-35), 1.94(m,1H,H-16),1.06,0.97,0.87,0.85,0.81,0.76,0.63(s,3H,CH3×7)；13C NMR (150MHz,CD3OD)δ:179.3(C-28),174.5(C-36),144.6(C-13),123.5(C-12),101.9,77.8, 72.3,68.7,68.1(C-3),64.9,56.7,56.7,52.1,47.6,47.3,42.7,42.4,40.9,40.5,40.2, 39.5,37.9,35.7,34.5,34.1,33.7,33.1,31.7,30.5,28.7,27.9,27.5,26.9,25.3,24.7, 24.3,19.6,17.9,17.3,16.3；HR-MS(ESI):M/z theoretical values C43H73N2O8[M+H]+745.5361, measured value 745.5346.
The structural characterization data of compound 17 are：1H NMR(600MHz,CD3OD)δ:7.21 (t, J=5.3Hz, 1H, N-H), 5.27 (t, J=3.6Hz, 1H, H-12), 4.07 (d, J=7.8Hz, 1H, H-1'), 3.66 (s, 3H, OCH 3),3.59(s, 3H,OCH 3), 3.45 (dd, J=12.8,5.9Hz, 1H), 3.38 (t, J=4.1,4.6Hz, 1H), 3.24-3.27 (m, 1H), 3.15-3.19 (m, 1H, H), 3.08 (dd, J=11.9,4.1Hz), 2.99 (m, 1H, H-31-1), 2.94 (m, 1H, H-31-2), 2.79 (dd, J=12.4,3.3Hz, 1H, H-18), 2.27 (t, J=7.3Hz, 2H, H-35), 1.93 (m, 1H, H-16), 1.01, 0.97,0.87,0.86,0.83,0.75,0.61(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:178.9(C-28), 175.3(C-36),145.1(C-13),123.7(C-12),102.7(C-1'),75.3,73.1,72.4,71.6,66.1(C- 3),57.4,51.9,47.7,47.5,42.9,42.6,40.7,40.6,39.6,39.1,38.3,35.1,34.7,34.3, 33.9,33.6,31.6,30.1,28.9,28.5,27.7,26.7,26.5,26.1,25.7,24.6,24.3,24.0,19.5, 18.5,17.3,16.9,16.1；HR-MS(ESI):M/z theoretical values C44H75N2O8[M+H]+759.5518, measured value 759.5543.
The structural characterization data of compound 18 are：1H NMR(600MHz,CD3OD)δ:7.23 (t, J=5.4Hz, 1H, N-H), 5.27 (t, J=3.7Hz, 1H, H-12), 4.07 (d, J=7.9Hz, 1H, H-1'), 3.66 (s, 3H, OCH 3),3.57(s, 3H,OCH 3), 3.45 (dd, J=12.8,5.6Hz, 1H), 3.38 (t, J=4.5Hz, 1H), 3.26 (m, 1H), 3.19 (m, 1H, ), H 3.08 (dd, J=11.9,4.4Hz), 2.99 (m, 1H, H-31-1), 2.94 (m, 1H, H-31-2), 2.78 (dd, J= 12.4,3.7Hz, 1H, H-18), 2.27 (t, J=7.3Hz, 2H, H-35), 1.95 (m, 1H, H-16), 1.01,0.95,0.87, 0.85,0.79,0.75,0.63(s,3H,CH3×7)；13C NMR(150MHz,CD3OD)δ:178.6(C-28),175.5(C- 36),145.3(C-13),123.4(C-12),102.1(C-1'),75.3,73.1,72.4,71.6,66.3(C-3),57.5, 51.9,47.7,47.5,42.9,42.7,40.5,40.3,39.6,39.1,38.3,35.1,34.7,34.3,33.8,33.5, 31.6,30.1,28.7,28.5,27.5,26.7,26.5,26.1,25.7,24.6,24.1,24.0,19.7,18.5,17.6, 16.9,16.0；HR-MS(ESI):M/z theoretical values C44H75N2O8[M+H]+759.5518 measured value 759.5539.
The structural characterization data of compound 19 are：1H NMR(600MHz,DMSO-d6):δ 7.23 (t, J=5.7Hz, 1H, N-H), 5.23 (br s, 1H, H-12), 5.12 (d, J=4.1Hz, 1H), 5.06 (d, J=5.5Hz, 1H), 4.81 (d, J= 5.0Hz, 1H), 4.65-4.68 (m, 2H), 4.53 (d, J=4.6Hz, 1H), 4.47 (t-like, J=6.3,5.9Hz, 1H), 4.19-4.22 (m, 2H), 3.72 (dd, J=11.0,5.5Hz, 1H), 3.66 (s, 3H, OCH 3),3.60(s,3H,OCH 3), 3.45-3.51 (m, 5H), 3.24-3.31 (m, 4H), 2.92-3.06 (m, 4H), 2.78 (dd, J=13.7,5.0Hz, 1H, H- 18), 2.29 (t, J=7.5Hz, 2H, H-35), 1.05,0.97,0.88,0.86,0.83,0.75,0.63 (s, 3H, CH3×7) ；13C NMR(150MHz,CD3OD):δ178.5(C-28),174.7(C-36),144.7(C-13),123.4(C-12),104.7 (C-1'),103.5(C-1”),79.3,75.6,75.1,74.6,73.9,73.6,71.3,69.2,68.3(C-3),61.2, 60.7,56.8,55.7,50.7,46.4,46.2,41.6,41.3,39.5,39.3,39.1,38.7,36.6,33.8,33.5, 33.0,32.7,32.3,30.3,28.9,27.2,26.4,25.9,25.1,24.4,23.3,22.7,22.7,17.9,16.7, 15.9,15.7,14.3；HR-MS(ESI):M/z theoretical values C50H85N2O14[M+H]+937.5995 measured value 937.5941.
The structural characterization data of compound 20 are：1H NMR(600MHz,DMSO-d6):δ 7.23 (t, J=5.5Hz, 1H, N-H), 5.21 (br s, 1H, H-12), 5.14 (d, J=4.5Hz, 1H), 5.03 (d, J=5.3Hz, 1H), 4.83 (d, J= 5.1Hz, 1H), 4.66 (m, 2H), 4.55 (d, J=4.8Hz, 1H), 4.49 (t, J=6.1Hz, 1H), 4.20 (m, 2H), 3.72 (dd, J=11.0,5.6Hz, 1H), 3.66 (s, 3H, OCH 3),3.60(s,3H,OCH 3),3.45-3.51(m,5H),3.24- 3.31 (m, 4H), 3.02 (m, 4H), 2.78 (dd, J=13.7,4.6Hz, 1H, H-18), 2.29 (t, J=7.5Hz, 2H, H- 35),1.03,0.97,0.88,0.86,0.81,0.75,0.61(s,3H,CH3×7)；13C NMR(150MHz,CD3OD):δ 178.9(C-28),174.3(C-36),144.3(C-13),122.5(C-12),105.1(C-1'),103.9(C-1”),79.4, 75.9,75.3,74.9,73.9,73.7,71.2,69.1,68.6(C-3),61.2,60.7,56.8,55.7,50.7,46.4, 46.2,41.6,41.3,39.4,39.3,39.1,38.5,36.6,33.8,33.4,33.0,32.6,32.3,30.3,28.8, 27.2,26.4,25.7,25.1,24.4,23.3,22.7,22.6,17.9,16.7,15.7,15.0,14.6；HR-MS(ESI): M/z theoretical values C50H85N2O14[M+H]+937.5995 measured value 937.5963.
The structural characterization data of compound 21 are：1H NMR(600MHz,CD3OD):δ 5.34 (t, J=3.6Hz, 1H, H- 12), 3.89 (m, 1H), 3.86 (t, J=3.4Hz, 1H), 3.83 (t, J=2.3Hz, 1H), 3.80 (s, 3H, COOCH3),3.73 (t, J=10.0Hz, 1H), 3.65 (s, 3H, COOCH3),3.60(s,3H,OCH 3), 3.63 (m, 3H), 3.47 (dd, J=9.3, 1.9Hz, 1H), 3.38 (dd, J=10.5,1.8Hz, 1H), 3.21 (m, 1H, H-31-1), 3.08 (m, 1H, H-31-2), 3.04 (m, 1H, H-3), 2.78 (dd, J=13.7,3.7Hz, 1H, H-18), 2.78 (dd, J=12.8,4.6Hz, 1H, H-3 ' eq), 2.32 (t, J=7.3Hz, 2H, H-35), 2.00 (s, 3H, NAc), 1.16,1.05,0.95,0.94,0.90,0.78,0.73 (s, 3H,CH3×7)；13C NMR(150MHz,CDCl3):δ179.3,174.5,174.1,170.7,144.3(C-13),122.7(C- 12),97.6(C-2'),73.7,71.5,68.9,67.6(C-3),67.4,63.7,55.9,52.5,46.4,46.2,41.6, 41.3,40.8,39.3,39.2,38.3,36.5,33.9,33.4,33.2,32.5,32.2,30.3,29.5,28.8,28.1, 27.2,26.5,25.1,24.5,24.3,23.2,22.6,21.3,18.6,16.7,15.7,14.5；HR-MS(ESI):M/z is managed By value C49H82N3O12[M+H]+904.5893 measured value 904.5865.
The structural characterization data of compound 22 are：1H NMR(600MHz,CD3OD):δ 5.33 (t, J=3.3Hz, 1H, H- 12), 3.92 (m, 1H), 3.86 (t, J=3.6Hz, 1H), 3.83 (t, J=2.1Hz, 1H), 3.77 (s, 3H, COOCH3),3.73 (t, J=10.0Hz, 1H), 3.66 (s, 3H, COOCH3),3.63(s,3H,OCH 3), 3.63 (m, 3H), 3.47 (dd, J=9.3, 2.1Hz, 1H), 3.38 (dd, J=10.5,2.3Hz, 1H), 3.21 (m, 1H, H-31-1), 3.12 (m, 1H, H-31-2), 3.06 (m, 1H, H-3), 2.77 (dd, J=13.7,3.7Hz, 1H, H-18), 2.76 (dd, J=12.8,4.6Hz, 1H), 2.31 (t, J =7.3Hz, 2H, H-35), 2.01 (s, 3H, NAc), 1.16,1.07,0.97,0.94,0.91,0.77,0.73 (s, 3H, CH3× 7)；13C NMR(150MHz,CDCl3):δ179.7,174.3,174.1,170.5,144.5(C-13),122.9(C-12),97.7 (C-2'),73.9,71.5,68.7,67.5,67.3(C-3),63.7,55.9,52.7,46.3,46.2,41.7,41.3,40.6, 39.3,39.2,38.5,36.5,33.9,33.4,33.3,32.5,32.1,30.3,29.5,28.9,28.1,27.3,26.5, 25.3,24.5,24.3,23.2,22.6,21.5,18.6,16.5,15.7,14.7；HR-MS(ESI):M/z theoretical values C49H82N3O12[M+H]+904.5893 measured value 904.5878.
Embodiment 2
Oleanane type nitrogen glycoside compounds of the present invention are preparing the application in treating antidiabetic medicine
Compound 1~22 of the inventor respectively by above-described embodiment synthesis is used as test-compound, tests it to protein The inhibitory activity of tyrosine-phosphatase 1B (PTP1B), specific test situation are as follows：
Containing PTP1B (recombinant expression), buffer solution (25mM HEPES, 50mM sodium chloride, 2.5mM in 200 μ L reaction systems EDTA, 0.1%BSA, pH 7.2) and above-mentioned oleanane type nitrogen glycoside compounds, while set up blank control (without enzyme and Above-mentioned oleanane type nitrogen glycoside compounds) and negative control (being free of above-mentioned oleanane type nitrogen glycoside compounds), 37 DEG C reaction 10min, is added protein tyrosine phosphatase substrate PNPP, 37 DEG C are reacted 30min again, and 2M Na are added2CO3It terminates anti- It answers, 405nm measures OD values.Inhibiting rate, inhibiting rate=[1- (OD sample-OD blank)/(OD feminine genders-OD skies are calculated according to OD values In vain)] × 100%.Each sample list concentration sets duplicate hole when primary dcreening operation, and sample of the inhibiting rate more than 70% measures IC50Value, each sample Six concentration of product gradient dilution, each concentration set duplicate hole.According to inhibiting rate, using the 4Parameter in Xlfit softwares Logistic Model calculate IC50.Test result is shown in Table 2.
The inhibitory activity of 2 compound of table, 1~22 external PTP1B
By the Activity Results of table 2 as it can be seen that the oleanane type nitrogen glycoside compounds of the present invention are to protein tyrosine phosphatase Esterase 1B shows good inhibitory activity, with obvious effects to be better than positive control sodium vanadate, can be used for preparing treatment glycosuria The drug of disease.

Claims (3)

1. oleanane type nitrogen glycoside compounds, it is characterised in that the structural formula of the compound is as follows：
Wherein, R be selected from D-Glucose base, D-Glucose aldehydic acid base, D- galactosyls, D-MANNOSE base, D-MANNOSE aldehydic acid base, Any one in D- xylosyls, L- rhamnopyranosyls, L-arabinose base, D- fucosidos, D- lactose base, D- sialic acid glycosyls.
2. oleanane type nitrogen glycoside compounds according to claim 1, it is characterised in that：The R is selected from β-D- pyrroles Glucopyranoside base, α-D- glucopyranosyls, beta d glucopyranosiduronic acid base, α-D- glucopyranosiduronic acids base, β-D- pyrroles It mutters galactosyl, α-D- galactopyranosyls glycosyl, β-D- mannopyranoses base, α-D- mannopyranoses base, β-D- mannopyranoses Aldehydic acid base, α-D- mannopyranose aldehydic acid base, β-D- xylopyranosyls, alpha-D-xylose base, β-L- rhamnopyranosyls, α-L- pyrroles It mutters rhamnopyranosyl, β-L- arabopyranoses base, α-L- arabopyranoses base, β-D- fucopyranosyls, α-D- pyrans rocks Any one in algae glycosyl, β-D- pyrans lactose base, α-D- pyrans lactose base, β-D- sialic acids glycosyl, α-D- sialic acid glycosyls.
3. the oleanane type nitrogen glycoside compounds of claim 1 are preparing the application in treating antidiabetic medicine.
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