Oleanane triazole glycoside compound and application thereof in preparation of PTP1B (protein tyrosine phosphatase 1B) inhibitor and antidiabetic drug

Abstract

The invention discloses an oleanane type triazole glycoside compound and application thereof in preparation of PTP1B (protein tyrosine phosphatase 1B) inhibitors and antidiabetic drugs, the structural formula of the compound is # imgabs0, in the formula, R represents glycosyl, oleanolic acid C28-amino methyl n-hexanoate is used as an initial raw material, and the compound is prepared through a one-step reaction. 3-hydroxyl is converted into 4-pentyne ester, then the 4-pentyne ester and an azido sugar compound are subjected to a click reaction, and different sugar units are introduced. Pharmacological activity tests show that the oleanane type triazole glycoside has good inhibitory activity on protein tyrosine phosphatase 1B, and can be researched and utilized as a novel PTP1B inhibitor and an anti-diabetic drug.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drugs, and specifically relates to an oleanane-type triazole glycoside compound and an application thereof in preparing a PTP1B inhibitor and an anti-diabetic drug. Background Art

[0002] Diabetes mellitus (DM) is a chronic disease prevalent worldwide. With the development of the economy, the improvement of living standards and changes in eating habits, the prevalence rate has gradually increased, and it has become a major problem that plagues human health. According to data from the International Diabetes Federation (IDF), diabetes has caused 6.7 million deaths in 2021. As of 2021, one in ten people is a diabetic, and the total number of adult diabetic patients (20-79 years old) has reached 537 million. It is estimated that by 2030, this number will rise to 639 million, and by 2045, 783 million people will be troubled by diabetes. Protein tyrosine phosphatase 1B (PTP1B) has important cell biological functions and has become a recognized important new target for anti-type II diabetes drugs. Since the amino acid sequences of all PTPs at the catalytic site are highly conserved, qualified PTP1B inhibitors need to have good selectivity and act only on PTP1B to reduce adverse reactions; at the same time, the catalytic site of PTP1B carries a high positive charge, which easily attracts negatively charged inhibitors, but most competitive PTP1B inhibitors have negatively charged polar groups and are difficult to penetrate the cell membrane. Therefore, finding new PTP1B inhibitors with high efficiency, high selectivity and good pharmaceutical properties has important research significance and application prospects.

[0003] Oleanolic acid is a natural pentacyclic triterpene compound with rich pharmacological activity. Studies have shown that oleanane compounds, as a new type of PTP1B inhibitors, have significant anti-type II diabetes activity and have become one of the hot spots in the field of anti-type II diabetes drug research. There are many reports on modifying oleanolic acid to screen PTP1B inhibitors in the prior art. For example, CN 108530508 A discloses an oleanane-type azaglycoside compound and its use in the preparation of anti-diabetic drugs. The compound is prepared by converting the 3-hydroxyl group of oleanolic acid C28-amino hexanoic acid methyl ester into an amino group and then introducing different sugar units. Pharmacological activity tests show that it has good inhibitory activity against protein tyrosine phosphatase 1B; CN117720610 A discloses an oleanolic acid mannoside compound and its use in the preparation of anti-diabetic drugs. The compound is prepared by introducing a D-mannose group into the 3-hydroxyl group of oleanolic acid C28-amino hexanoic acid methyl ester, and then converting the C6-OH of the D-mannose group into a fatty ester group or a heteroatom substituent, and exposing the hydroxyl groups at other positions or converting them into acetyl groups. Pharmacological activity tests showed that this class of compounds had good inhibitory activity against protein tyrosine phosphatase 1B. Except for compounds 5, 12, 13, 20 and 21, the effects of other compounds were significantly better than the positive control sodium orthovanadate and the most active compound 18 reported in CN 108530508 A. However, no research on the PTP1B inhibitory activity of oleanolic acid triazole glycoside compounds has been reported. Summary of the invention

[0004] The purpose of the present invention is to provide a new type of oleanane-type triazole glycoside compound and a new use of the compound.

[0005] For the above purpose, the structural formula of the oleanane-type triazole glycoside compound provided by the present invention is as follows:

[0006]

[0007] wherein R is selected from any one of D-peracetylmannanosyl, D-peracetylglucosyl, D-peracetylglucosyl, L-peracetylglucosyl, L-peracetylarbinosyl, D-peracetylarbinosyl, L-peracetyxyl, D-peracetyxyl, D-peracetylcellobiosyl, D-peracetygalactose (1→4)-D-peracetylglucosyl, D-peracetylglucosyl (1→4)-D-peracetylglucosyl, D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactose (1→4)-D-glucosyl, and D-glucose (1→4)-D-glucosyl.

[0008] Furthermore, the above R is preferably β-D-peracetylated mannopyranosyl, β-D-peracetylated glucopyranosyl, β-D-peracetylated galactopyranosyl, α-L-peracetylated rhamnosyl, α-L-peracetylated arabinopyranosyl, β-D-peracetylated arabinopyranosyl, α-L-peracetylated xylopyranosyl, β-D-peracetylated xylopyranosyl, β-D-peracetylated cellobiosyl, β-D-peracetylated galactopyranosyl (1→4)-α-D-peracetylated glucopyranosyl, β-D-peracetylated glucopyranosyl, Any one of glucose (1→4)-β-D-peracetylated glucopyranosyl, β-D-mannopyranosyl, β-D-glucopyranosyl, β-D-galactopyranosyl, α-L-rhamnopyranosyl, α-L-arabinopyranosyl, β-D-arabinopyranosyl, α-L-xylopyranosyl, β-D-xylopyranosyl, β-D-cellobiosyl, β-D-galactopyranosyl (1→4)-α-D-glucopyranosyl, and β-D-glucopyranosyl (1→4)β-D-glucopyranosyl.

[0009] The synthesis method of the oleanane-type triazole glycoside compound of the present invention is as follows:

[0010] 1. Synthesis of compound 24

[0011] Using dry dichloromethane as solvent, compound 23, 4-pentynoic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 4-dimethylaminopyridine (DMAP) were stirred at room temperature for 5 to 6 hours in a molar ratio of 1:2 to 3:3 to 4:0.1 to 0.5; after the reaction, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and the concentrate was subjected to silica gel column chromatography to obtain compound 24. The reaction equation is as follows:

[0012]

[0013] 2. Synthesis of oleanane-type triazole glycoside compounds

[0014] Using tert-butyl alcohol as solvent, compound 24 and azido sugar R-N3 are mixed at a molar ratio of 1:1.0-1.2; using deionized water as solvent, CuSO4 and sodium ascorbate (Na ascorbate) are mixed at a molar ratio of 1:1.5-2.5; then the two solutions are mixed, stirred at 35-45°C for 2-4h; after the reaction, dilute with distilled water, extract three times with ethyl acetate, combine the ethyl acetate phases, wash with distilled water and saturated brine in turn, dry with anhydrous sodium sulfate, filter, concentrate, and perform silica gel column chromatography to obtain compound A. The reaction equation is as follows:

[0015]

[0016] In the formula, R′ represents any one of D-peracetylated mannosyl, D-peracetylated glucosyl, D-peracetylated galactosyl, L-peracetylated rhamnosyl, L-peracetylated arabinosyl, D-peracetylated arabinosyl, L-peracetylated xylosyl, D-peracetylated xylosyl, D-peracetylated cellobiosyl, D-peracetylated galactosyl (1→4)-D-peracetylated glucosyl, and D-peracetylated glucose (1→4)-D-peracetylated glucosyl.

[0017] The above compound A was dissolved in a mixed solvent of methanol and dichloromethane, sodium methoxide was added to adjust the pH to 8.5-9.5, the reaction was stirred at room temperature for 30-40 minutes, the pH was adjusted to 7 with a cation exchange resin, the cation exchange resin was filtered out, the solvent was removed by concentration under reduced pressure, and compound B was obtained after purification by silica gel column chromatography. The reaction equation is as follows:

[0018]

[0019] In the formula, R″ represents any one selected from D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactosyl (1→4)-D-glucosyl, and D-glucose (1→4)-D-glucosyl.

[0020] The present invention provides the use of the oleanane-type triazole glycoside compound in the preparation of PTP1B inhibitors and antidiabetic drugs. The oleanane-type triazole glycoside compound is prepared according to conventional pharmaceutical preparations and a pharmaceutically acceptable carrier according to conventional preparation processes of various preparations, and can be tablets, granules, or capsules.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention uses oleanolic acid C 28 -amino hexanoic acid methyl ester is used as the starting material, and its 3-hydroxyl group is converted into 4-pentynyl ester and then introduced into different sugar units through click reaction with azido sugar compounds to prepare oleanane-type triazole glycoside compounds. According to pharmacological activity detection, this type of compound shows good inhibitory activity against protein tyrosine phosphatase 1B and can be used to prepare PTP1B inhibitors and drugs for the treatment of diabetes. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0024] Example 1

[0025] Preparation of oleanane-type triazole glycoside compounds 1 to 22

[0026] 1. Synthesis of compound 24

[0027] Compound 23 (1 g, 1.70 mmol, 1.00 eq.) was dissolved in 35 mL of dichloromethane, 4-pentynoic acid (330 mg, 3.40 mmol, 2.00 eq.) was added, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g, 5.61 mmol, 3.30 eq.) and 4-dimethylaminopyridine (61 mg, 0.48 mmol, 0.28 eq.) were added in sequence. The mixture was stirred at room temperature for 6 h. After the reaction was completed as monitored by TLC (petroleum ether: ethyl acetate = 2:1), the mixture was filtered, and the solvent was removed by concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 24 (1.08 g, yield 95.0%), the structural characterization data of which are as follows: 1 H-NMR (400MHz, CHLOROFORM-D): δ5.94(s,1H),5.36(s,1H),4.52(s,1H),3.66(s,3H),3.35(s,1H),2.98(dq,J=12.7,6.4Hz,1H),2.60-2.44(m,6H),2 .30(s,2H),1.93(dq,J=24.0,4.9,3.0Hz,4H),1.81-1.41(m,15H),1.39-1. 23(m,6H),1.15(s,4H),1.02(d,J=14.6Hz,2H),0.89(s,15H),0.75(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.43,174.14,171.66,145.26,122.73,82.73,81.39, 69.17,55.31,51.64,47.57,46.88,46.39,42.45,42.22,39.50,39.36,38.25,37.85,36.9 7,34.26,34.02,33.97,33.10,32.60,32.40,30.84,29.82,29.17,28.16,27.39,26.70,25.83,24.65,23.88,23.71,18.27,17.03,16.83,15.52,14.67,14.33; HR-MS (ESI): m / z theoretical value C 42 H 65 NO5[M+H + ]:664.4936, measured value: 664.4921.

[0028] 2. Synthesis of compounds 1 to 11

[0029] Compound 24 (120 mg, 0.18 mmol, 1.00 eq.) and β-D-peracetylpyranose azido (0.18 mmol, 1.00 eq.) were dissolved in 1 mL of tert-butanol; CuSO4 (5.78 mg, 0.036 mmol, 0.20 eq.) and sodium ascorbate (15.3 mg, 0.072 mmol, 0.40 eq.) were dissolved in 1 mL of deionized water; the two solutions were then mixed, heated to 40°C, and stirred for 3 h. After the reaction was completed as monitored by TLC (petroleum ether: ethyl acetate = 1:1), 5 mL of distilled water was added for dilution, and the mixture was extracted three times with ethyl acetate (3 mL × 3). The ethyl acetate phases were combined, washed with distilled water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol = 80:1) to obtain compound 1.

[0030] The above-mentioned azido β-D-peracetylpyranose mannoside is replaced in sequence with azido β-D-peracetylpyranose glucopyranosyl, azido β-D-peracetylpyranose galactosyl, azido α-L-peracetylpyranose rhamnosyl, azido α-L-peracetylpyranose arabinosyl, azido β-D-peracetylpyranose arabinosyl, azido α-D-peracetylpyranose xylopyranosyl, azido β-D-peracetylpyranose xylopyranosyl, azido β-D-peracetylcellobiosyl, azido β-D-peracetylpyranose galactosyl (1→4)-α-D-peracetylpyranose glucopyranosyl, and azido β-D-peracetylpyranose glucopyranosyl (1→4)-β-D-peracetylpyranose glucopyranosyl to obtain triazole glycoside compounds 2 to 11 in sequence.

[0031] The structural characterization data of compound 1 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.59(s,1H),6.10(s,1H),5.92(t,J=5.8Hz,1H),5.68(s,1H),5.42-5.19(m,3H),4.47(dd,J=11.0,5.2Hz,1H ),4.35-4.13(m,2H),3.93(dd,J=9.8,6.1Hz,1H),3.66(s,3H),3.35(dq,J=13.9,7.1Hz,1H),3.00(dt,J=22.7,6.8Hz,3H),2.72(t,J=7.3Hz,2H ),2.54-2.45(m,1H),2.30(t,J=7.4Hz,2H),2.21-2.04(m,9H),1.99(s,3H),1.95-1.83(m,3H),1.72(d,J=27.6Hz,5H),1.60(dd,J=17.1,7.5H z,4H),1.47(td,J=16.1,15.3,8.3Hz,5H),1.39-1.23(m,6H),1.16(d,J =12.0Hz,5H),1.02(d,J=13.8Hz,2H),0.95-0.77(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.14,172.49,170.66,169.90,169.74,169.22,146.74,145.28,122.70, 120.41,84.81,81.25,75.80,70.99,68.99,65.11,62.38,55.33,51.65,47.59,46.91,46.38,42.44,42.21,39.49,3 9.33,38.25,37.84,36.98,34.26,34.03,33.93,33.12,32.64,32.40,30.86,29.21,28.14,27.39,26.72,25.83,24.66,23.90,23.72,23.66,23.61,21.18,20.88,20.81,20.73,20.63,18.27,17.03,16.81,15.51; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value 1037.5978.

[0032] The structural characterization data of compound 2 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.56 (s, 1H), 5.92 (s, 1H), 5.83 (d, J = 8.5Hz, 1H), 5.49-5.30 (m, 3H), 5.22 (t, J = 9. 2Hz,1H),4.50(t,J=8.0Hz,1H),4.28(dd,J=12.9,5.0Hz,1H),4.13(d,J=12.6Hz,1H),3.97(d,J=10.3Hz,1H),3.66( s,3H),3.35(dq,J=13.6,6.9Hz,1H),3.01(dt,J=27.0,6.8Hz,3H),2.72(q,J=7.0Hz,2H),2.49(d,J=13.7Hz,1H),2 .30(t,J=6.5Hz,2H),2.12-2.00(m,10H),1.86(s,6H),1.77-1.56(m,12H),1.28-0.98(m,12H),0.95-0.71(m,21H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.13,172.37,170.60,170.05,169.50,169.01,147.39,145.29,122.70, 119.51,85.81,81.23,75.21,72.84,70.34,67.85,61.71,55.32,51.64,47.59,46.90,46.39,42.45,42.22,39.50,3 9.33,38.27,37.85,36.98,34.27,34.04,33.95,33.11,32.66,32.41,30.86,29.21,28.13,27.40,26.72,25.82,24.67,23.91,23.72,23.67,23.61,21.27,20.82,20.67,20.65,20.29,18.28,17.04,16.83,15.52; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value: 1037.6035.

[0033] The structural characterization data of compound 3 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.62(s,1H),5.92(t,J=5.6Hz,1H),5.79(d,J=9.3Hz,1H),5.61-5.45(m,2H),5.36(d,J=4.3Hz,1H), 5.22(d,J=10.4Hz,1H),4.50(t,J=7.9Hz,1H),4.26-4.03(m,3H),3.65(d,J=1.8Hz,3H),3.35(dq,J=13.8,7.0Hz,1H),3.02(dt,J=25. 3,7.3Hz,3H),2.73(q,J=6.9Hz,2H),2.49(dd,J=13.1,4.3Hz,1H),2.30(t,J=7.5Hz,2H),2.21(d,J=1.7Hz,3H),2.02(dd,J=13.8,1.7 Hz,6H),1.94–1.70(m,9H),1.60(tq,J=16.0,8.4,5.1Hz,9H),1.52-1.44(m,4H),1.39-1.11(m,11H),0.94-0.79(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.13,172.40,170.45,170.10,169.95,169.17,147.32,145.28,122.68, 119.61,86.33,81.21,74.08,70.97,67.90,66.99,61.30,55.30,51.64,47.58,46.89,46.37,42.43,42.20,39.48,3 9.32,38.26,37.84,36.97,34.25,34.03,33.99,33.11,32.64,32.39,30.85,29.20,28.12,27.38,26.71,25.82,24.66,23.89,23.71,23.65,23.60,21.28,20.80,20.77,20.63,20.39,18.27,17.03,16.83,15.53; HR-MS (ESI): m / z theoretical value C 56 H 84 N4O 14 [M+H + ]:1037.6057, measured value: 1037.6035.

[0034] The structural characterization data of compound 4 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.58(s,1H),6.05(s,1H),5.91(d,J=5.8Hz,1H),5.68(s,1H),5.36(d,J=4.0Hz,1H),5.24-5.03(m, 2H), 4.46 (t, J = 8.1Hz, 1H), 3.79 (p, J = 6.6Hz, 1H), 3.66 (d, J = 1.9Hz, 3H), 3.36 (dq, J = 14.2, 7.1Hz, 1H), 3.00 (dq, J = 26.0, 6.9, 6.2Hz, 3 H),2.73(d,J=7.3Hz,2H),2.49(d,J=12.6Hz,1H),2.31(t,J=7.5Hz,2H),2.10(d,J=9.1Hz,5H),2.01-1.87(m,5H),1.81-1.63(m,6H), 1.59(t,J=8.3Hz,5H),1.48(dt,J=14.5,6.8Hz,4H),1.39-1.26(m,7H),1.20(d,J=38.4Hz,5H),1.06-0.89(m,9H),0.86-0.62(m,9H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.24,174.11,172.48,169.98,169.92,169.29,145.25,122.64,120.25,84.76, 81.23,77.48,76.84,74.03,70.94,69.72,69.24,55.25,51.62,47.53,46.85,46.33,42.38,42.17,39.44,39.29,38 .21,37.78,36.92,34.23,34.00,33.94,33.09,32.60,32.34,30.83,29.79,29.17,28.08,27.35,26.68,25.80,24.63,23.86,23.69,23.62,23.58,21.22,20.87,20.75,20.65,18.22,17.64,17.00,16.79,15.48; HR-MS (ESI): m / z theoretical value C 54 H 82 N4O 12 [M+H + ]:979.6002, measured value: 979.5917.

[0035] The structural characterization data of compound 5 are: 1H-NMR(400MHz, CHLOROFORM-D): δ 7.64(s, 1H), 5.92(t, J = 5.7Hz, 1H), 5.70(d, J = 9.1Hz, 1H), 5.57(t, J = 9.6Hz, 1H), 5.46 - 5.29(m, 2H), 5.22(dt, J = 10.2, 2.4Hz, 1H), 4.49(t, J = 7.9Hz, 1H), 4.16(d, J = 13.5Hz, 1H), 3.92(d, J = 13.5Hz, 1H), 3.65(d, J = 1.9Hz, 3H), 3.35(dq, J = 13.8, 7.0Hz, 1H), 3.02(dt, J = 25.0, 7.4Hz, 3H), 2.73(s, 2H), 2.56 - 2.39(m, 1H), 2.30(t, J = 7.4Hz, 2H), 2.21(d, J = 1.9Hz, 3H), 2.02(d, J = 1.9Hz, 3H), 1.89(d, J = 10.5Hz, 5H), 1.72(d, J = 27.2Hz, 5H), 1.59(tt, J = 14.9, 6.2Hz, 7H), 1.47(td, J = 15.2, 14.6, 7.4Hz, 5H), 1.37 - 1.22(m, 5H), 1.09(d, J = 42.6Hz, 7H), 0.96 – 0.77(m, 15H), 0.74(s, 3H); 13 C-NMR(101MHz, CHLOROFORM-D): δ 178.13, 174.01, 172.27, 170.14, 169.89, 169.08, 145.17, 122.55, 119.46, 86.67, 81.07, 77.38, 77.06, 76.74, 70.59, 68.07, 67.75, 67.25, 55.18, 51.53, 47.45, 46.76, 46.25, 42.30, 42.08, 39.36, 39.19, 38.14, 37.70, 36.84, 34.13, 33.91, 32.99, 32.52, 32.28, 30.74, 29.09, 27.99, 27.27, 26.59, 25.70, 24.54, 23.77, 23.60, 23.53, 23.45, 21.19, 20.97, 20.60, 20.30, 18.15, 16.91, 16.71, 15.39; HR-MS(ESI): m / z calculated for C 53 H 80 N4O 12 [M + H + : 965.5846, found 965.5770.

[0036] The structural characterization data of compound 6 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.62 (s, 1H), 5.91 (dd, J = 6.5, 4.6Hz, 1H), 5.70 ( d,J=9.2Hz,1H),5.56(t,J=9.6Hz,1H),5.42(dt,J=3.5,1.6Hz,1H),5.39-5.34(m, 1H),5.22(dd,J=10.1,3.4Hz,1H),4.59-4.37(m,1H),4.15(dd,J=13.5,2.1Hz,1H ),3.92(dd,J=13.5,1.3Hz,1H),3.65(s,3H),3.35(dq,J=13.7,7.0Hz,1H),3.10-3 .01(m,2H),2.97(ddt,J=13.7,7.1,3.4Hz,1H),2.72(dd,J=8.3,6.9Hz,2H),2.52 -2.42(m,1H),2.30(t,J=7.4Hz,2H),2.21(s,3H),2.02(s,3H),1.96-1.83(m,6H), 1.79-1.69(m,2H),1.68-1.53(m,9H),1.48(dd,J=15.0,6.9Hz,4H),1.39-1.26(m ,5H),1.14(s,4H),1.01(dt,J=13.9,3.6Hz,2H),0.97-0.77(m,17H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.23,174.11,172.40,170.24,169.99,169.18,147.20,145.27,122.66,11 9.53,86.76,81.19,70.69,68.17,67.86,67.35,55.29,51.63,47.56,46.87,46.35,42.41,42.18,39.46,39.30 ,38.24,37.83,36.94,34.24,34.02,33.99,33.10,32.62,32.38,30.85,29.20,28.16,27.38,26.70,25.80,24.65,23.88,23.70,23.64,23.58,21.29,21.07,20.70,20.40,18.26,17.02,16.82,15.50; HR-MS (ESI): m / z theoretical value C 53 H 80N4O 12 [M+H + ]:965.5846, measured value: 965.5823.

[0037] The structural characterization data of compound 7 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.54(s,1H),5.92(t,J=5.6Hz,1H),5.73(d,J=8.5Hz,1H),5.37(dd,J=11.7,8.2Hz,3H),5.17-5.06(m,1H),4. 49(t,J=8.0Hz,1H),4.27(dd,J=11.9,5.7Hz,1H),3.66(d,J=1.9Hz,3H),3.57(t,J=11.1Hz,1H),3.35(dq,J=14.0,7.1Hz,1H),3.01(dt,J=19.5, 7.2Hz,3H),2.83-2.59(m,2H),2.55-2.40(m,1H),2.30(t,J=7.5Hz,2H),2.06(d,J=9.2Hz,6H),1.93(dd,J=19.6,6.2Hz,3H),1.87(s,3H),1.72 (d,J=30.2Hz,4H),1.61(dt,J=15.5,6.5Hz,6H),1.53-1.40(m,5H),1.3 8-1.20(m,7H),1.09(d,J=43.2Hz,6H),0.94-0.78(m,15H),0.75(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.30,174.14,172.37,170.03,169.91,169.10,147.32,145.29,122.70,119. 47,86.41,81.21,72.24,70.48,68.57,65.66,55.29,51.65,47.57,46.89,46.38,42.44,42.21,39.49,39.32,38 .26,37.83,36.97,34.27,34.04,33.98,33.11,32.64,32.40,30.86,29.83,29.21,28.12,27.39,26.72,25.83,24.67,23.90,23.72,23.66,23.58,21.28,20.78,20.74,20.33,18.27,17.04,16.83,15.51; HR-MS (ESI): m / z theoretical value C 53 H80 N4O 12 [M+H + ]:965.5846, measured value: 965.5776.

[0038] The structural characterization data of compound 8 are: 1 H-NMR (600MHz, CHLOROFORM-D): δ7.54(s,1H),5.94-5.91(m,1H),5.73(d,J=9.0Hz,1H),5.43-5.27(m,4H),5.19-5.06(m,1H),4.49(dd,J=9.9,6.1H z,1H),4.26(dd,J=11.6,5.7Hz,1H),3.65(s,3H),3.56(dd,J=11.6,10.4H z,1H),3.35(dq,J=13.8,7.1Hz,1H),3.03(td,J=7.4,2.4Hz,2H),2.99-2. 95(m,1H),2.70(t,J=7.6Hz,3H),2.48(dd,J=13.0,4.3Hz,1H),2.30(t,J= 7.5Hz,3H),2.05(d,J=14.0Hz,7H),1.91-1.85(m,6H),1.79-1.66(m,4H), 1.64-1.60(m,4H),1.48-1.44(m,3H),1.32(ddd,J=8.8,4.6,2.8Hz,3H),1 .14(s,4H),1.01(dt,J=13.6,3.5Hz,3H),0.91(s,3H),0.89-0.71(m,18H); 13C-NMR (151MHz, CHLOROFORM-D): δ178.28,174.15,172.38,170.04,169.92,169.10,147.29,145.25,122.68,11 9.45,86.36,81.19,72.16,70.42,68.53,65.61,55.25,51.65,47.52,46.84,46.33,42.38,42.16,39.44,39.29 ,38.20,37.80,36.92,34.22,34.01,33.91,33.10,32.58,32.34,30.84,29.18,28.12,27.34,26.69,25.80,24.63,23.86,23.69,23.62,23.56,21.24,20.78,20.74,20.33,18.23,16.99,16.81,15.49; HR-MS (ESI): m / z theoretical value C 53 H 80 N4O 12 [M+H + ]:965.5846, measured value: 965.5829.

[0039] The structural characterization data of compound 9 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.50 (s, 1H), 5.92 (t, J = 5.8Hz, 1H), 5.76 (d, J = 7.6Hz, 1H), 5.37 (dd, J = 6.4, 3.3Hz, 3H), 5.11 (dtd, J = 31.8, 9.4, 2. 1Hz,2H),4.99-4.84(m,1H),4.63-4.43(m,3H),4.38(dt,J=12.7,3.5Hz, 1H),4.19-4.00(m,2H),3.91(q,J=7.6,5.8Hz,2H),3.65(d,J=2.1Hz,4H), 3.35(dq,J=13.5,6.8Hz,1H),3.11-2.87(m,3H),2.70(p,J=8.6,7.7Hz,2 H),2.49(d,J=12.4Hz,1H),2.30(td,J=7.5,2.1Hz,2H),2.20-1.96(m,17H ),1.88(dd,J=20.2,5.9Hz,5H),1.77-1.56(m,12H),1.55-1.39(m,6H),1 .31(dt,J=20.9,13.3Hz,5H),1.09(d,J=43.7Hz,7H),0.96-0.60(m,18H);13 C-NMR (101MHz, CHLOROFORM-D): δ178.28,174.14,172.42,170.61,170.35,170.26,169.67,169.44,169.22,169.19,147.23,145.29, 122.67,119.61,100.95,85.62,81.24,76.00,72.95,72.49,72.25,71.68,70.46,67.83,61.79,61.67,55.30,51.65,47.59,46.89,46 .38,42.43,42.21,39.49,39.32,38.26,37.84,36.96,34.26,34.03,33.92,33.11,32.64,32.39,30.86,29.20,28.11,27.39,26.71,25.82,24.66,23.90,23.71,23.66,23.60,21.23,20.94,20.82,20.67,20.58,20.34,18.27,17.03,16.81,15.52; HR-MS (ESI): m / z theoretical value C 68 H 100 N4O 22 [M+H + ]:1325.6902, measured value: 1325.6802.

[0040] The structural characterization data of compound 10 are: 11H-NMR (400 MHz, CHLOROFORM-D): δ 7.51 (s, 1H), 5.92 (t, J = 5.7 Hz, 1H), 5.77 (d, J = 7.7 Hz, 1H), 5.37 (d, J = 8.3 Hz, 4H), 5.12 (dd, J = 10.3, 8.1 Hz, 1H), 4.96 (dt, J = 10.6, 2.6 Hz, 1H), 4.62 - 4.39 (m, 3H), 4.25 - 4.05 (m, 3H), 3.90 (q, J = 8.6, 7.5 Hz, 3H), 3.65 (d, J = 1.9 Hz, 3H), 3.35 (dq, J = 14.0, 7.1 Hz, 1H), 3.01 (dt, J = 16.6, 7.3 Hz, 3H), 2.71 (q, J = 6.9 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.30 (t, J = 7.4 Hz, 2H), 2.16 (d, J = 1.9 Hz, 3H), 2.13 - 2.01 (m, 12H), 1.99 - 1.87 (m, 6H), 1.85 (d, J = 1.9 Hz, 3H), 1.72 (d, J = 22.0 Hz, 6H), 1.60 (q, J = 7.6 Hz, 6H), 1.52 - 1.41 (m, 5H), 1.38 - 1.22 (m, 6H), 1.15 (s, 3H), 1.02 (d, J = 13.6 Hz, 2H), 0.94 - 0.73 (m, 18H); 13 13C-NMR (101 MHz, CHLOROFORM-D): δ 178.29, 174.15, 172.41, 170.52, 170.33, 170.25, 170.21, 169.64, 169.27, 169.21, 145.29, 122.67, 101.24, 85.59, 81.23, 75.97, 75.75, 72.75, 71.03, 70.95, 70.54, 69.13, 66.67, 61.90, 60.92, 55.29, 51.65, 47.57, 46.88, 46.37, 42.42, 42.20, 39.48, 39.32, 38.25, 37.83, 36.96, 34.25, 34.03, 33.90, 33.11, 32.63, 32.38, 30.85, 29.20, 28.10, 27.38, 26.71, 25.82, 24.65, 23.89, 23.71, 23.65, 21.23, 20.94, 20.85, 20.81, 20.78, 20.76, 20.64, 20.36, 18.26, 17.03, 16.81, 15.51; HR-MS (ESI): m / z calculated for C 68 H 100N4O 22 [M+H + ]:1325.6902, measured value 1325.6718.

[0041] The structural characterization data of compound 11 are: 1 H-NMR (400MHz, CHLOROFORM-D): δ7.50 (s, 1H), 5.92 (t, J = 5.7Hz, 1H), 5.84 (d, J = 9. 3Hz,1H),5.51-5.41(m,2H),5.34(dtd,J=21.3,10.0,9.3,1.9Hz,3H),5.07(t,J=9 .9Hz,1H),4.87(dt,J=10.8,2.7Hz,1H),4.58-4.39(m,2H),4.24(dt,J=13.3,4.6H z,2H),4.18-4.02(m,2H),3.96(d,J=10.3Hz,2H),3.65(d,J=1.9Hz,3H),3.35(dq,J =14.1,7.1Hz,1H),3.00(dt,J=23.7,6.9Hz,3H),2.71(q,J=6.9Hz,2H),2.49(d,J= 12.3Hz,1H),2.30(td,J=7.5,1.9Hz,2H),2.11(dd,J=8.4,1.9Hz,6H),2.08-2.00( m,11H),1.98-1.87(m,3H),1.83(d,J=1.9Hz,3H),1.80-1.56(m,13H),1.52-1.44( m,4H),1.36-1.23(m,5H),1.15(s,5H),1.02(d,J=13.4Hz,2H),0.95-0.68(m,18H); 13C-NMR (101MHz, CHLOROFORM-D): δ178.29,174.15,172.41,170.73,170.66,170.45,170.08,170.06,169.57,169.34,147.28,145.29,12 2.67,119.60,96.01,85.31,81.24,75.41,75.33,72.51,70.95,70.12,69.32,68.87,68.01,62.66,61.54,55.30,51.65,47.58,46.89, HR-MS(ESI):m / ztheoretical valueC 68 H 100 N4O 22 [M+H + ]:1325.6902, measured value 1325.6721.

[0042] 3. Synthesis of compounds 12-22

[0043] Compound 1 (60 mg, 1.00 eq) was dissolved in 6 mL of a mixed solvent of methanol and dichloromethane (1:1, V:V), sodium methoxide was added to adjust the pH to 9, and the reaction was stirred at room temperature for 30 min. After the reaction was completed as monitored by TLC (dichloromethane: methanol = 10:1), the pH was adjusted to 7 with a cation exchange resin, the cation exchange resin was removed by filtration, the solvent was removed by concentration under reduced pressure, and compound 12 was obtained after purification by silica gel column chromatography (dichloromethane: methanol = 30:1).

[0044] The above compound 1 was replaced with equimolar compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 in sequence to obtain compounds 13 to 22 from which the acetyl group was removed.

[0045] The structural characterization data of compound 12 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.85(s,1H),5.94(d,J=5.9Hz,1H),5.79(s,1H),5.30(d,J=47.1Hz,4H),4.65-4.14(m,3H), 3.97(s,1H),3.94-3.72(m,3H),3.66(d,J=2.0Hz,3H),3.48(d,J=8.7Hz,1H),3.36(dq,J=13.7,6.9Hz,1H),2.97(dt,J=20.8,7 .0Hz,3H),2.69-2.44(m,6H),2.31(t,J=7.4Hz,2H),2.03-1.84(m,3H),1.68-1.54(m,8H),1.49(q,J=7.5,6.9Hz,4H),1.33(q, J=8.0,7.6Hz,4H),1.16(d,J=15.2Hz,5H),1.01(d,J=12.5Hz,3H),0.91(d,J=6.9Hz,9H),0.81(d,J=11.0Hz,7H),0.74(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.26,174.18,172.85,146.03,145.20,122.62,121.93,86.55, 81.46,79.25,73.60,70.84,65.84,60.92,55.21,51.70,51.66,47.53,46.87,46.32,42.29,42.13, 39.43,39.31,38.18,37.83,36.93,34.21,34.01,33.15,32.66,32.35,30.86,29.82,29.21,28.15,27.38,26.67,25.88,24.63,23.72,21.09,18.26,17.00,16.88,15.51,14.27; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5572.

[0046] The structural characterization data of compound 13 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.66(s,1H),5.95(d,J=5.8Hz,1H),5.57(s,2H),5.49(d,J=8.2Hz,1H),5.36( s,1H),4.47(t,J=7.6Hz,2H),4.06(s,1H),3.77(d,J=19.3Hz,3H),3.66(d,J=2.0Hz,3H),3.56(s,1H),3.36(dq, J=13.8,7.0Hz,1H),3.08-2.78(m,4H),2.64-2.48(m,4H),2.31(t,J=7.4Hz,2H),2.19-1.82(m,4H),1.79-1.40( m,15H),1.34(p,J=8.0,6.9Hz,4H),1.26(d,J=12.1Hz,3H),1.15(s,3H),1.06-0.97(m,2H),0.96-0.72(m,18H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.22,174.17,172.66,146.28,145.21,122.60,122.06,87.77, 81.38,78.92,72.47,68.77,68.25,60.96,55.22,51.70,51.65,47.55,46.86,46.32,42.28,42.13, 39.43,38.18,37.84,36.93,34.20,34.01,33.71,33.15,32.67,32.36,30.86,30.42,29.23,28.19,27.38,26.67,25.89,24.63,23.72,20.98,18.26,17.00,16.90,15.52,14.20; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5590.

[0047] The structural characterization data of compound 14 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.72(s,1H),5.94(d,J=6.7Hz,1H),5.39(d,J=30.0Hz,3H),5.00(s,1H),4.60-4.01(m,4H) ,3.77(t,J=21.2Hz,3H),3.65(d,J=2.1Hz,4H),3.36(dq,J=13.5,6.7Hz,1H),3.05-2.84(m,3H),2.61(s,3H),2.51(d,J=12. 7Hz,2H),2.31(t,J=7.3Hz,3H),1.84-1.69(m,2H),1.61(dq,J=26.1,9.0,8.1Hz,8H),1.48(p,J=7.6,7.1Hz,5H),1.33(q,J= 7.9,7.5Hz,4H),1.25(s,4H),1.15(s,3H),1.01(d,J=12.0Hz,3H),0.91(d,J=5.5Hz,9H),0.81(d,J=7.9Hz,6H),0.74(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.22,174.15,172.70,146.31,145.22,122.63,122.40,88.36,81 .46,73.91,70.11,68.84,61.03,55.26,51.66,47.57,46.89,46.35,42.32,42.16,39.47,39.33,38. 22,37.86,36.96,34.25,34.02,33.74,33.16,32.71,32.41,30.87,29.82,29.24,28.22,27.42,26.68,25.90,24.64,23.85,23.74,23.65,21.00,18.29,17.03,16.92,15.53,14.26; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O 10 [M+H + ]:869.5634, measured value 869.5568.

[0048] The structural characterization data of compound 15 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.77(s,1H),5.97(t,J=5.7Hz,1H),5.72(s,1H),5.36(s,1H),4.48(t,J=7.9Hz,1H),4.38(s,1H),3.73(d,J= 7.6Hz,1H),3.66(d,J=1.9Hz,3H),3.56(d,J=7.7Hz,2H),3.34(dt,J=14.1,7.0Hz,1H),3.00(t,J=8.0Hz,4H),2.71(d,J=7.6Hz,2H),2.49(dd,J =12.6,4.1Hz,1H),2.31(td,J=7.4,1.9Hz,3H),1.94(dd,J=29.2,11.8Hz,4H),1.85-1.69(m,2H),1.68-1.55(m,8H),1.51-1.44(m,4H),1.35( dd,J=22.9,6.9Hz,7H),1.26(d,J=11.0Hz,2H),1.15(s,4H),1.02(d,J=13.5Hz,3H),0.91(d,J=9.1Hz,9H),0.81(d,J=7.0Hz,7H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.54,174.19,172.68,146.04,145.20,122.76,121.81,86.45 ,81.39,75.40,73.99,72.48,70.40,55.29,51.69,47.56,46.87,46.39,42.40,42.20,39.48,39. 39,38.23,37.85,36.96,34.24,34.01,33.11,32.63,32.38,30.85,29.15,28.16,27.38,26.68,25.84,24.62,23.88,23.71,21.22,18.27,17.80,17.03,16.86,16.11,15.53; HR-MS (ESI): m / z theoretical value C 48 H 76 N4O9[M+H + ]:853.5685, measured value 853.5622.

[0049] The structural characterization data of compound 16 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.66(s,1H),5.94(d,J=5.8Hz,1H),5.35(d,J=16.2Hz,2H),4.82-4.21(m,4H),4.18-3.92(m,3H),3 .88-3.72(m,2H),3.67(d,J=2.0Hz,3H),3.36(dq,J=13.9,7.0Hz,1H),2.99(q,J=6.8,6.4Hz,3H),2.69(d,J=7.6Hz,2H),2.50(d,J=1 1.3Hz,1H),2.32(t,J=7.4Hz,2H),1.91(d,J=9.8Hz,4H),1.80–1.71(m,2H),1.70-1.54(m,9H),1.50(q,J=8.1,7.1Hz,4H),1.34(d,J =8.9Hz,3H),1.27(d,J=10.5Hz,3H),1.15(s,3H),1.03(d,J=13.4Hz,3H),0.92(d,J=7.8Hz,9H),0.82(d,J=8.3Hz,6H),0.75(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.35,174.19,172.66,146.39,145.23,122.68,121.80,88.60 ,81.38,73.61,70.26,68.62,55.25,51.69,47.54,46.86,46.34,42.36,42.16,39.44,39.33,38. 20,37.82,36.93,34.22,34.02,33.87,33.13,32.61,32.35,30.86,29.83,29.19,28.16,27.36,26.68,25.85,24.64,23.85,23.71,23.63,21.09,18.25,17.00,16.86,15.51; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5459.

[0050] The structural characterization data of compound 17 are: 1H-NMR (600MHz, CHLOROFORM-D): δ7.63 (s, 1H), 5.93 (dd, J = 6.4, 4.6Hz, 1H), 5.3 7(t,J=3.6Hz,1H),5.32-5.29(m,1H),4.48(dd,J=9.2,7.0Hz,1H),4.39(t,J=9 .0Hz,1H),4.27(s,1H),4.16(d,J=12.7Hz,1H),4.07(s,1H),3.93(s,1H),3.84 (dd,J=9.2,3.3Hz,1H),3.78(d,J=12.7Hz,1H),3.66(s,4H),3.49(s,1H),3.36( dq,J=13.7,7.0Hz,1H),3.00(dt,J=13.8,6.9Hz,4H),2.70(td,J=7.4,2.5Hz,2 H),2.53-2.47(m,1H),2.31(t,J=7.4Hz,2H),2.01-1.86(m,4H),1.80-1.70(m,2 H),1.66-1.60(m,6H),1.53-1.46(m,5H),1.38-1.30(m,5H),1.15(s,4H),1.03 (d,J=14.1Hz,3H),0.91(d,J=12.7Hz,9H),0.82(d,J=10.6Hz,6H),0.75(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.36,174.18,172.65,146.63,145.28,122.71,121. 47,88.44,81.38,73.51,70.52,69.08,68.36,55.29,51.68,47.59,46.90,46.38,42.42, 42.21,39.49,38.29,37.85,36.97,34.04,33.13,32.64,32.35,30.88,29.20,28.17,27.43,26.72,25.86,24.66,23.73,21.16,18.30,17.04,16.86,15.53; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5510.

[0051] The structural characterization data of compound 18 are: 1H-NMR (400MHz, CHLOROFORM-D): δ7.64(s,1H),5.95(d,J=5.8Hz,1H),5.74-5.14(m,3H),4.47(t,J=7.7Hz,3H),4.16-3.66(m ,5H),3.66(d,J=2.1Hz,3H),3.39(dp,J=27.4,7.0,5.7Hz,3H),2.99(t,J=7.0Hz,3H),2.68(t,J=7.5Hz,2H),2.50(d,J=12.5H z,2H),2.31(td,J=7.4,2.0Hz,2H),1.97(d,J=13.5Hz,1H),1.61(dq,J=27.3,11.1,9.6Hz,8H),1.48(p,J=6.6Hz,5H),1.33(q ,J=10.4,7.1Hz,4H),1.26(d,J=9.3Hz,2H),1.16(d,J=16.5Hz,5H),1.02(d,J=13.1Hz,2H),0.96-0.76(m,16H),0.74(s,3H); 13 C-NMR (101MHz, CHLOROFORM-D): δ178.37,174.18,172.71,146.68,145.22,122.69,121.66,88.33 ,81.47,72.58,69.33,68.40,64.79,55.27,51.68,47.57,46.89,46.37,42.37,42.18,39.48,39. 36,38.23,37.85,36.97,34.26,34.03,33.91,33.14,32.67,32.40,30.87,29.20,28.19,27.40,26.69,25.88,24.64,24.15,23.73,23.38,21.15,18.27,17.03,16.89,15.52; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5469.

[0052] The structural characterization data of compound 19 are: 1H-NMR (600MHz, CHLOROFORM-D): δ7.64(s,1H),5.96(t,J=5.6Hz,1H),5.41(d,J=8.6Hz,1H),5.33(d,J=38.1Hz,3H),5.12(s,1H),4.75(s, 1H),4.47(t,J=7.9Hz,1H),4.02(s,2H),3.81-3.74(m,1H),3.65(s,5H),3.43(s,1H),3.35(dq,J=13.7,7.0Hz,1H),3.01-2.96(m,3H),2.6 8(q,J=7.1Hz,2H),2.54-2.43(m,2H),2.31(t,J=7.4Hz,2H),2.05-1.83(m,4H),1.80-1.67(m,3H),1.64-1.61(m,3H),1.58(s,2H),1.48(h ept,J=6.8,6.2Hz,6H),1.34-1.31(m,3H),1.14(s,4H),1.01(d,J=12.7Hz,3H),0.90(d,J=7.9Hz,9H),0.80(d,J=9.8Hz,6H),0.73(s,3H); 13 C-NMR (151MHz, CHLOROFORM-D): δ178.40,174.19,172.65,146.61,145.19,122.68,121.72,88.28, 81.41,72.47,69.29,68.39,55.22,51.69,47.52,46.85,46.34,42.33,42.14,39.43,39.34,38.18, 37.82,36.92,34.21,34.01,33.87,33.13,32.61,32.34,30.85,29.83,29.18,28.16,27.36,26.67,25.85,24.62,23.85,23.71,23.62,22.82,21.12,18.25,17.00,16.86,15.50; HR-MS (ESI): m / z theoretical value C 47 H 74 N4O9[M+H + ]:839.5529, measured value 839.5510.

[0053] The structural characterization data of compound 20 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(d,J=2.1Hz,1H),7.24(t,J=5.8Hz,1H),5.59(dd,J=9.3,2.1Hz,1H),5.35(s,1H),4.69-4.24( m,3H),4.01-3.84(m,4H),3.84-3.52(m,8H),3.38(d,J=9.0Hz,2H),3.32-3.11(m,5H),3.05(dt,J=23.2,7.0Hz,3H),2.76(dt,J=22. 5,9.0Hz,3H),2.32(td,J=7.3,2.1Hz,2H),2.03(d,J=13.8Hz,1H),1.96-1.88(m,2H),1.78(t,J=13.4Hz,2H),1.61(dq,J=16.9,7.7 Hz,9H),1.48(d,J=7.4Hz,3H),1.42-1.37(m,1H),1.31(dd,J=15.2,8.3Hz,5H),1.18(s,6H),1.07-1.01(m,2H),1.00-0.66(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.24,175.78,173.93,147.55,145.40,123.82,122.67,104.56,89.22,82. 64,79.61,79.48,78.14,77.82,76.82,74.87,73.68,71.35,62.45,61.44,56.68,52.02,47.65,47.49,42.93, 42.57,40.67,40.58,39.28,38.77,38.08,35.11,34.69,34.35,33.75,33.58,31.63,30.77,30.08,28.65,28.51,27.67,26.48,25.69,24.55,24.50,24.05,23.97,21.96,19.29,17.96,17.25,15.93; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6016.

[0054] The structural characterization data of compound 21 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(d,J=1.9Hz,1H),7.24(t,J=5.5Hz,1H),5.59(d,J=9.2Hz,1H),5.35(s,1H),4.61( s,1H),4.52-4.30(m,2H),4.06-3.43(m,15H),3.30(d,J=2.5Hz,3H),3.19(dt,J=13.4,6.7Hz,1H),3.05(dt,J=23.0,7.0 Hz,3H),2.75(dt,J=15.2,8.9Hz,3H),2.32(td,J=7.4,1.9Hz,2H),2.05(t,J=12.9Hz,1H),1.99-1.86(m,2H),1.78(t,J =13.4Hz,2H),1.68-1.45(m,14H),1.41(d,J=8.7Hz,2H),1.31(dd,J=15.1,8.3Hz,4H),1.18(s,6H),1.08-0.55(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.25,175.78,173.94,147.55,145.40,123.82,122.70,105.07,89.24,82 .64,79.64,79.47,77.14,76.84,74.79,73.61,72.52,70.29,62.52,61.51,56.68,52.02,47.65,47.49,42. 93,42.57,40.67,40.58,39.29,38.77,38.08,35.11,34.69,34.35,33.75,33.58,31.63,30.08,28.64,28.51,27.67,26.47,25.69,24.55,24.50,24.04,23.96,21.96,19.29,17.96,17.24,15.92; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6016.

[0055] The structural characterization data of compound 22 are: 1H-NMR (400MHz, METHANOL-D4): δ7.97(s,1H),7.24(t,J=5.8Hz,1H),5.58(d,J=8.9Hz,1H),5.35(s,1H),5.24( s,1H),4.71-4.36(m,2H),3.99-3.42(m,15H),3.35-3.13(m,5H),3.05(dt,J=23.6,7.1Hz,3H),2.76(dt,J=22. 9,5.9Hz,3H),2.32(t,J=7.4Hz,2H),2.05(t,J=12.6Hz,1H),1.98-1.86(m,2H),1.78(t,J=13.5Hz,2H),1.62(d d,J=14.7,8.1Hz,9H),1.55-1.42(m,6H),1.31(dd,J=15.3,8.3Hz,4H),1.21-1.05(m,6H),1.04-0.69(m,21H); 13 C-NMR (101MHz, METHANOL-D4): δ180.26,175.79,173.95,147.56,145.41,123.82,122.70,102.93,89.33,82. 65,80.28,79.56,78.22,75.06,74.87,74.16,73.58,71.47,62.73,61.83,56.69,52.02,47.65,47.50,42.93, 42.58,40.67,40.58,39.28,38.77,38.08,35.11,34.69,34.35,33.75,33.57,31.63,30.78,30.09,28.64,28.51,27.67,26.46,25.69,24.55,24.50,24.04,23.96,21.96,19.29,17.96,17.24,15.92; HR-MS (ESI): m / z theoretical value C 54 H 86 N4O 15 [M+H + ]:1031.6162, measured value 1031.6021.

[0056] Table 1 Substituents and yields of compounds 1 to 22

[0057]

[0058]

[0059]

[0060] Example 2

[0061] Application of the oleanane-type azaglycoside compound of the present invention in the preparation of PTP1B inhibitors and anti-diabetic drugs

[0062] The compounds 1 to 22 synthesized in the above examples were respectively used as test compounds to test their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B). The specific test results are as follows:

[0063] 200 μL reaction system contains PTP1B (recombinant expression), buffer (25mM HEPES, 50mM sodium chloride, 2.5mM EDTA, 0.1% BSA, pH 7.2) and test compound, and blank control (without PTP1B and test compound) and negative control (without test compound) are set up at the same time, react at 37°C for 10min, add protein tyrosine phosphatase substrate PNPP, react at 37°C for another 30min, add 2M Na2CO3 aqueous solution to terminate the reaction, and measure OD value at 405nm. Inhibition rate is calculated according to OD value, inhibition rate = [1-(OD sample-OD blank) / (OD negative-OD blank)] × 100%. The test results are shown in Table 2.

[0064] Table 2 In vitro PTP1B inhibitory activity of compounds 1 to 22

[0065]

[0066]

[0067] It can be seen from the activity results in Table 2 that the oleanane-type triazole glycoside compound of the present invention exhibits a good inhibitory activity against protein tyrosine phosphatase 1B, and the effect is significantly better than the positive control sodium orthovanadate, and is also better than the best 6-iodoperacetyl D-mannosyl substituted oleanane-type glycoside compound (Compound 2) disclosed in CN117720610 A, and can be used to prepare protein tyrosine phosphatase 1B inhibitors and drugs for treating diabetes.

Claims

1. An oleanane-type triazole glycoside compound, characterized in that: The structural formula of the compound is shown below: wherein R is selected from any one of D-peracetylmannanosyl, D-peracetylglucosyl, D-peracetylglucosyl, L-peracetylglucosyl, L-peracetylarbinosyl, D-peracetylarbinosyl, L-peracetyxyl, D-peracetyxyl, D-peracetylcellobiosyl, D-peracetygalactose (1→4)-D-peracetylglucosyl, D-peracetylglucosyl (1→4)-D-peracetylglucosyl, D-mannosyl, D-glucosyl, D-galactosyl, L-rhamnosyl, L-arabinosyl, D-arabinosyl, L-xylosyl, D-xylosyl, D-cellobiosyl, D-galactose (1→4)-D-glucosyl, and D-glucose (1→4)-D-glucosyl.

2. The oleanane-type triazole glycoside compound according to claim 1, characterized in that: R is selected from β-D-peracetylated mannopyranosyl, β-D-peracetylated glucopyranosyl, β-D-peracetylated galactopyranosyl, α-L-peracetylated rhamnosyl, α-L-peracetylated arabinopyranosyl, β-D-peracetylated arabinopyranosyl, α-L-peracetylated xylopyranosyl, β-D-peracetylated xylopyranosyl, β-D-peracetylated cellobiosyl, β-D-peracetylated galactopyranosyl (1→4)-α-D-peracetylated glucopyranosyl, β-D-peracetylated glucopyranosyl, Any one of (1→4)-β-D-peracetylated glucopyranosyl, β-D-mannopyranosyl, β-D-glucopyranosyl, β-D-galactopyranosyl, α-L-rhamnopyranosyl, α-L-arabinopyranosyl, β-D-arabinopyranosyl, α-L-xylopyranosyl, β-D-xylopyranosyl, β-D-cellobiosyl, β-D-galactopyranosyl (1→4)-α-D-glucopyranosyl, and β-D-glucopyranosyl (1→4)-β-D-glucopyranosyl.

3. Use of the oleanane-type triazole glycoside compound of claim 1 in the preparation of a PTP1B inhibitor.

4. Use of the oleanane-type triazole glycoside compound of claim 1 in the preparation of antidiabetic drugs.

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