A class of eugenol ester derivatives and preparation method and application thereof

Abstract

The present application proposes a class of zhonguning ester derivatives and their preparation method and application, which relates to the field of medicine. The class of zhonguning ester derivatives can be used as zhonguning prodrugs to improve the bioavailability of zhonguning in the prevention and / or treatment of diseases.

Description

Technical Field

[0001] The present application relates to the field of medicine, and in particular, to a class of uni-uning ester derivatives and preparation methods and applications thereof. Background Art

[0002] Cardiovascular and cerebrovascular diseases are one of the most serious diseases threatening human beings in the world today. Its morbidity and mortality have surpassed tumors and ranked first in the world. Heart failure is a serious manifestation or late stage of various heart diseases, with high mortality and re-hospitalization rates. The prevalence of heart failure in developed countries is 1.5% to 2.0%, and the prevalence of people aged ≥70 years is ≥10%.

[0003] Zhongwuning is a C19-diterpene alkaloid isolated and identified from Aconitum carmichaelii, which has a significant effect on improving cardiac function, and can effectively prevent and treat acute heart failure caused by myocardial ischemia-reperfusion injury (Wang Fengpeng et al., CN102146057B), prevent and / or treat myocardial fibrosis and chronic heart failure or cardiac remodeling caused by myocardial fibrosis (Hu Zhuowei et al., CN 107913273B), and prevent and treat nephritis, renal fibrosis and prevent and / or treat renal failure.

[0004] However, zhonguning has low oral bioavailability due to its low lipophilicity and poor membrane permeability. Summary of the invention

[0005] The purpose of the present application is to provide a class of zhonguning ester derivatives and their preparation method and application. The class of zhonguning ester derivatives can be used as zhonguning prodrugs to improve the bioavailability of zhonguning in the prevention and / or treatment of diseases.

[0006] The present application solves the technical problem by adopting the following technical solution.

[0007] In the first aspect, the present application provides a class of uni-union ester derivatives having a general structural formula (I):

[0008]

[0009] Where R 1 , R 2 , R 3 Each independently selected from H, Among them, R 6 is a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group or a substituted phenyl group; R 7 A straight chain alkyl group, Where R 4 , R 5 Each is independently selected from H.

[0010] In some embodiments of the present application, the above R 6The straight chain alkyl group includes one of methyl, ethyl, propyl, butyl, pentyl, hexyl, nonyl, undecyl and cis-, cis-8,11-heptadecadiene.

[0011] In some embodiments of the present application, the above R 6 The branched alkyl groups include One of them.

[0012] In some embodiments of the present application, the above R 6 The cycloalkyl groups include One of them.

[0013] In some embodiments of the present application, the above R 6 Substituted phenyl groups include One of them.

[0014] In some embodiments of the present application, the above R 7 The straight-chain alkyl group includes one of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.

[0015] In some embodiments of the present application, the above derivatives are:

[0016] Compound 1: Compound 2: Compound 3:

[0017] Compound 4: Compound 5: Compound 6:

[0018] Compound 7: Compound 8: Compound 9: Compound 10: Compound 11:

[0019] Compound 12: Compound 13: Compound 14: Compound 15: Compound 16:

[0020] Compound 17: Compound 18: Compound 19: Compound 20: Compound 21: Compound 22: Compound 23: Compound 24: Compound 25: Compound 26: Compound 27: Compound 28: Compound 29: Compound 30: Compound 31: Compound 32: Compound 33: or compound 34:

[0021] In a second aspect, the present application provides a method for preparing the above-mentioned Zhongwu Ning ester derivatives, comprising:

[0022] Zhongwuning undergoes esterification reaction with acyl chloride under the conditions of dichloromethane and N,N-diisopropylethylamine. The reaction formula is as follows:

[0023]

[0024] Zhongwuning undergoes esterification reaction with acyl chloride under the conditions of N,N-diisopropylethylamine, 4-dimethylaminopyridine and dichloromethane. The reaction formula is as follows:

[0025]

[0026] Zhongwuning undergoes esterification reaction with various acid anhydrides under the conditions of 4-dimethylaminopyridine and dichloromethane. The reaction formula is as follows:

[0027]

[0028] Zhonguning undergoes esterification reaction with acid under the conditions of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and DMF. The reaction formula is as follows:

[0029]

[0030] Zhongwuning reacts with Fmoc-Cl in dichloromethane to protect the 3-position, then reacts with acyl chloride, and finally removes the protecting group. The reaction formula is as follows:

[0031]

[0032] Zhongwuning and Boc anhydride are reacted in dichloromethane in the presence of DMAP to carry out 3-position Boc protection reaction, and then react with acyl chloride, and finally remove the protecting group. The reaction formula is as follows:

[0033]

[0034] Zhongwuning reacts with excess Boc anhydride in dichloromethane under DMAP catalysis. The reaction formula is as follows:

[0035]

[0036] Zhongwuning and chloroformate are subjected to esterification reaction in the presence of dichloromethane or base to obtain 3-substituted oxycarbonyl compounds, and the reaction formula is as follows:

[0037]

[0038] In a third aspect, the present application provides the use of the above-mentioned Zhongwuning ester derivatives in the preparation of Zhongwuning prodrugs.

[0039] Compared with the prior art, the embodiments of the present application have at least the following advantages or beneficial effects: the above-mentioned ester derivatives of Zhonguning can be used as Zhonguning prodrugs to improve the bioavailability of Zhonguning in the prevention and / or treatment of diseases. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0041] The Chinese and English abbreviations in the present invention are shown in Table 1 below.

[0042] Table 1 Chinese and English abbreviations

[0043]

[0044] Example 1

[0045] Preparation of compound 1:

[0046]

[0047] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.24 g of acetic anhydride and 0.12 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 1.

[0048] Structural data of compound 1:

[0049] ESI-MS m / z[M+H] + : 612.30;

[0050] 1H NMR(600MHz, CDCl3)δ:1.78(s,1H),1.99(m,2H),2.05(s,3H)2.07(s,3H),2.21(s,3H),2.20(s,1H),2.28(m,1H),2.32(s,3H),2. 35(m,1H),2.42(m,1H,),2.57(d,1H,J=6.0Hz),2.64(d,1H,J=10.8Hz),2.82(s,1H),2.92(dd,1H,J=4.2,14.4Hz),2.97(d,1H,J=8 .4Hz),3.10(dd,1H,J=7.2,10.2Hz),3.20(s,3H),3.25(s,3H),3.27(s,3H),3.55(s,3H),3.35(d,1H,J=6.0Hz),3.59(s,1H),3.95 (d,1H,J=8.4Hz,),4.00(s,1H),4.13(d,1H,J=6.6Hz),4.65(d,1H,J=4.8Hz),4.88(dd,1H,J=4.8,12.6Hz),5.24(d,1H,J=6.0Hz).

[0051] 13 C NMR(150MHz, CDCl3)δ:21.0,21.0,21.2,31.9,36.0,40.7,42.3,42.5,44.4,44.8,48.5,49.6,50.0,56 .5,57.8,58.7,61.3,62.0,71.3,71.6,74.3,76.3,78.6,81.8,82.6,87.3,88.4,170.1,170.9,173.4.

[0052] Example 2

[0053] Preparation of compound 2:

[0054]

[0055] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.14 g of propionyl chloride and 0.22 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 2.

[0056] Structural data of compound 2:

[0057] ESI-MS m / z[M+H] + :654.30;

[0058] 1 H NMR (600MHz, MeOD) δ: 5.38 (d, J = 6.7 Hz, 1H), 4.91 ( dd, J = 11.9, 5.6 Hz, 1H), 4.70 ( d, J = 5.2 Hz, 1H), 4.14 ( d, J = 6.9 Hz, 1H) ,3.98(d,J=8.8Hz,1H),3.52(s,3H),3.31(m,1H),3.29(s,3H),3.28(s,3H),3.22(m,1H),3.20(s,3H),3.03(d,J=8.8H z,1H),2.90(s,1H),2.81(m,1H),2.67(d,J=11.4Hz,1H),2.53(m,2H),2.49(m,1H),2.45(m,1H),2.36(m,7H),2.30(m, 1H),2.25(d,J=6.9Hz,1H),2.14(m,1H),2.03(m,1H),1.90(m,1H),1.32(m,1H),1.29(m,2H),1.21(m,3H),1.13(m,6H).

[0059] Example 3

[0060] Preparation of compound 3 and compound 4:

[0061]

[0062] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.09 g of butyric anhydride and 0.05 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 3 and compound 4.

[0063] Structural data of compound 3:

[0064] ESI-MS m / z[M+H] + :556.10;

[0065] 1H NMR (400MHz, MeOD) δ5.81(d,J=7.0Hz,1H),4.21(m,1H),4.07(m,1H),3.81(d,J=4.1Hz,1H),3.45(m,2H),3.42(s,3H),3.35(m,2H),3.29(s,6H ),3.26(d,J=5.1Hz,1H),3.23(s,3H),3.19(s,1H),2.91(s,3H),2.33(m ,3H),2.20(m,4H),2.07(m,1H),1.61(m,3H),1.49(m,1H),0.88(m,4H).

[0066] Structural data of compound 4:

[0067] ESI-MS m / z[M+H] + :556.10;

[0068] 1 H NMR (400MHz, MeOD) δ: 5.27 (m, 1H), 4.41 (d, J = 6.1Hz, 1H), 4.21 (m, 1H), 3.78 ( d,J=4.7Hz,1H),3.53(s,3H),3.46(m,3H),3.33(m,5H),3.24(s,1H),3.22(s, 3H),3.21(m,1H),3.20(s,3H),2.98(m,1H),2.89(s,3H),2.48(d,J=1.6Hz,1H ),2.34(m,3H),2.17(m,3H),1.99(m,1H),1.61(m,3H),0.89(t,J=7.4Hz,3H).

[0069] Example 4

[0070] Preparation of compound 5:

[0071]

[0072] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.52 g of butyric anhydride and 0.20 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 5.

[0073] Structural data of compound 5:

[0074] ESI-MS m / z[M+H] + : 696.20;

[0075] 1H NMR(400MHz,MeOD)δ:5.30(d,J=6.8Hz,1H),4.86(t,J=8.3Hz,1H),4.60(d,J=5.1Hz,1H),4.05 (d,J=7.0Hz,1H),3.85(d,J=8.7Hz,1H),3.43(s,3H),3.24(d,J=5.7Hz,1H),3.19(s,3H),3.18 (s,3H),3.16(m,1H),3.12(s,3H),2.99(d,J=8.7Hz,1H),2.85(s,1H),2.65(m,2H),2.31(s,3H ),2.40(m,4H),2.22(m,7H),2.05(m,1H),1.95(m,1H),1.83(s,1H),1.59(m,6H),0.89(m,9H).

[0076] Example 5

[0077] Preparation of compound 6:

[0078]

[0079] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.11 g of valeric anhydride and 0.05 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 6.

[0080] Structural data of compound 6:

[0081] ESI-MS m / z[M+H] + :570.30;

[0082] 1 H NMR(400MHz,MeOD)δ:5.28(m,1H),4.40(d,J=6.1Hz,1H),4.22(m,1H),3.78(d,J=4 .8Hz,1H),3.53(s,3H),3.46(m,3H),3.35(d,J=3.4Hz,2H),3.32(s,3H),2.98(m,1 H),2.91(s,3H),2.56(s,8H),2.47(d,J=1.6Hz,1H),2.36(m,3H),2.16(m,3H),2.0 5(t,J=13.0Hz,1H),1.61(m,1H),1.51(m,3H),1.31(m,2H),0.86(t,J=7.3Hz,3H).

[0083] Example 6

[0084] Preparation of compound 7:

[0085]

[0086] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.22 g of valeric anhydride and 0.11 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 7.

[0087] Structural data of compound 7:

[0088] ESI-MS m / z[M+H] + :654.30

[0089] Example 7

[0090] Preparation of compound 8:

[0091]

[0092] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.35 g of valeric anhydride and 0.20 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 8.

[0093] Structural data of compound 8:

[0094] ESI-MS m / z[M+H] + :738.50;

[0095] 1 H NMR(400MHz,MeOD)δ:5.28(d,J=6.8Hz,1H),4.82(m,1H),4.60(d,J=5.1Hz,1H),4.01(m ,1H),3.87(d,J=8.7Hz,1H),3.43(s,3H),3.19(s,3H),3.18(s,3H),3.15(m,1H),3.11( s,3H),2.96(d,J=8.7Hz,1H),2.82(s,1H),2.64(m,2H),2.43(m,4H),2.25(m,9H),2.15 (m,2H),2.05(m,1H),1.93(m,1H),1.80(s,1H),1.61(m,6H),1.29(m,6H),0.85(m,9H).

[0096] Example 8

[0097] Preparation of compound 9:

[0098]

[0099] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.08 g of hexanoyl chloride and 0.09 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 9.

[0100] Structural data of compound 9:

[0101] ESI-MS m / z[M+H] + :584.40;

[0102] 1 H NMR(400MHz,MeOD)δ:5.40(m,1H),4.52(d,J=6.1Hz,1H),4.33(m,1H),3.89(d,J=4.7H z,1H),3.65(s,3H),3.59(m,3H),3.46(d,J=2.4Hz,2H),3.44(s,3H),3.36(s,1H),3.3 3(s,3H),3.32(s,3H),3.09(m,1H),3.01(s,3H),2.59(d,J=1.6Hz,1H),2.47(m,3H),2 .31(t,J=3.7Hz,1H),2.26(m,2H),2.18(m,1H),1.71(m,4H),1.37(m,4H),0.95(m,3H).

[0103] Example 9

[0104] Preparation of compound 10:

[0105]

[0106] Weigh 0.40 g of Zhongwuning into a reaction bottle, add 1.5 mL of dichloromethane, and then add 0.23 g of Fmoc-Cl. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain 3-Fmoc-Zhongwuning.

[0107] Weigh 0.09 g of 3-Fmoc-zhonguning into a reaction bottle, add 3 mL of dichloromethane, then add 0.02 g of hexanoyl chloride, stir at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain 3-Fmoc-zhonguning-14-hexyl ester.

[0108] Weigh 0.02 g of 3-Fmoc-zhonguning-14-hexyl ester into a reaction bottle, add 2 mL of dichloromethane, and then add 0.04 g of piperidine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 10.

[0109] Structural data of compound 10:

[0110] ESI-MS m / z[M+H] + :584.50;

[0111] 1 H NMR (600MHz, DMSO-d6) δ: 4.76 (s, 1H), 4.43 (d, J = 5.0Hz, 1H), 4.21 (d, J = 38.0Hz, 2H), 4.12 (d, J = 6.5Hz, 1H), 3.90 (d,J=6.9Hz,1H),3.67(d,J=7.9Hz,1H),3.40(m,1H),3.31(d,J=7.7Hz,1H),3.19(s,3H),3.15(s,3H),3.10(s,3 H),2.95(m,1H),2.83(d,J=6.4Hz,1H),2.67(s,1H),2.57(m,1H),2.47(m,3H),2.18(t,J=7.5Hz,2H),2.11(m,7H ),2.05(m,1H),1.94(d,J=7.0Hz,1H),1.87(m,1H),1.76(m,1H),1.48(m,2H),1.23(m,5H),0.83(t,J=6.9Hz,3H).

[0112] Example 10

[0113] Preparation of compound 11:

[0114]

[0115] Weigh 0.40 g of Zhongwuning into a reaction bottle, add 5 mL of dichloromethane, then add 0.20 g of Boc anhydride and 0.10 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain 3-Boc-Zhongwuning.

[0116] Weigh 0.18 g of 3-Boc-zhonguning into a reaction bottle, add 3 mL of dichloromethane, then add 0.10 g of hexanoyl chloride and 0.71 g of N,N-diisopropylethylamine, and stir at room temperature for 12 hours. Then, add 0.85 g of HCl ethyl acetate solution, and stir at room temperature for 12 hours. Then, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 11.

[0117] Structural data of compound 11:

[0118] ESI-MS m / z[M+H] + : 682.40;

[0119] 1 H NMR (400MHz, MeOD) δ: 5.56 (d, J = 6.6 Hz, 1H), 4.81 (m, 1H), 4.13 (d, J = 7.0 Hz, 1H), 3.91 (d,J=8.7Hz,1H),3.76(d,J=5.2Hz,1H),3.51(m,1H),3.40(d,J=5.2Hz,3H),3.21(s, 3H),3.17(s,3H),3.11(s,3H),2.95(d,J=8.6Hz,1H),2.84(s,1H),2.60(t,J=12.7Hz ,2H),2.38(m,3H),2.21(m,10H),1.93(m,3H),1.56(m,5H),1.25(m,9H),0.83(m,7H).

[0120] Embodiment 11

[0121] Preparation of compound 12:

[0122]

[0123] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.09 g of heptanoyl chloride and 0.09 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 12.

[0124] Structural data of compound 12:

[0125] ESI-MS m / z[M+H] + :598.30;

[0126] 1H NMR(800MHz,MeOD)δ:5.26(t,J=5.1Hz,1H),4.51(d,J=6.1Hz,1H),4.31(dd,J=6.9,1.7Hz,1H),3.89(d,J=5.1Hz,1H) ,3.73(d,J=8.6Hz,1H),3.64(s,3H),3.47(t,J=4.7Hz,1H),3.43(d,J=8.5Hz,1H),3.42(s,3H),3.32(s,3H),3.30(s, 3H),3.25(m,2H),3.21(m,1H),3.09(d,J=6.1Hz,1H),2.85(s,3H),2.55(s,1H),2.42(m,2H),2.40(m,1H),2.30(m,1H ),2.26(m,1H),2.22(m,1H),2.11(m,1H),1.91(m,2H),1.65(m,2H),1.36(m,6H),1.24(s,2H),0.93(t,J=7.0Hz,3H).

[0127] Example 12

[0128] Preparation of compound 13:

[0129]

[0130] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.20 g of decanoyl chloride and 0.21 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 13.

[0131] Structural data of compound 13:

[0132] ESI-MS m / z[M+H] + : 640.40;

[0133] 1H NMR (400MHz, MeOD) δ: 5.14 (s, 1H), 4.45 (d, J = 6.1Hz, 1H), 4.27 (d, J = 6.6Hz, 1H), 3.84 (d, J = 5.0Hz, 2H), 3.60 (s, 3H), 3.38 (s, 3H), 3.27 (s, 3H), 3. 25(s,3H),3.16(s,2H),3.04(d,J=6.1Hz,2H),2.68(s,3H),2.30(m,7H), 2.08(m,3H),1.62(m,2H),1.31(d,J=9.6Hz,12H),0.89(t,J=6.8Hz,3H).

[0134] Embodiment 13

[0135] Preparation of compound 14:

[0136]

[0137] Weigh 0.50 g of Zhonguning and add it into a reaction bottle, then add 4 mL of N,N-dimethylformamide, 0.28 g of lauric acid, 0.60 g of HATU and 0.21 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 14.

[0138] Structural data of compound 14:

[0139] ESI-MS m / z[M+H] + : 668.60;

[0140] 1 H NMR(600MHz, CDCl3)δ:5.52(d,J=6.2Hz,1H),4.18(d,J=6.6Hz,1H),3.95(d,J=4.5Hz,1H),3.90(m ,1H),3.64(m,2H),3.56(s,3H),3.39(m,2H),3.31(s,3H),3.30(s,7H),3.21(m,2H),3.13(d,J=11. 2Hz,1H),2.98(s,1H),2.73(d,J=11.5Hz,1H),2.55(s,3H),2.42(m,3H),2.29(m,2H),2.09(t,J=1 3.6Hz,2H),2.01(m,1H),1.91(d,J=16.1Hz,2H),1.67(m,2H),1.25(m,17H),0.87(t,J=6.8Hz,3H).

[0141] Embodiment 14

[0142] Preparation of compound 15:

[0143]

[0144] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.06 g of isobutyryl chloride and 0.11 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 15.

[0145] Structural data of compound 15:

[0146] ESI-MS m / z[M+H] + :556.50;

[0147] 1 H NMR(600MHz,MeOD)δ:5.34(d,J=4.1Hz,1H),4.50(d,J=6.1Hz,1H),4.32(d,J=6.9Hz,1H),3.88(d,J =5.0Hz,1H),3.63(s,3H),3.57(m,3H),3.46(t,J=11.8Hz,2H),3.42(s,3H),3.35(s,1H),3.33(s,3 H),3.30(s,3H),3.08(d,J=6.1Hz,1H),3.00(s,3H),2.67(m,1H),2.57(s,1H),2.46(d,J=6.8Hz,1H ),2.26(m,3H),2.15(m,1H),1.74(m,1H),1.63(m,1H),1.21(d,J=1.5Hz,3H),1.19(d,J=1.5Hz,3H).

[0148] Embodiment 15

[0149] Preparation of compound 16:

[0150]

[0151] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.06 g of pivaloyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 16.

[0152] Structural data of compound 16:

[0153] ESI-MS m / z[M+H] + :570.40;

[0154] 1 H NMR(400MHz,MeOD)δ:4.82(m,1H),4.41(d,J=6.1Hz,1H),4.22(d,J=7.0Hz,1H) ,4.08(d,J=8.7Hz,1H),3.82(d,J=5.1Hz,1H),3.58(s,3H),3.34(s,3H),3.24( s,3H),3.20(s,3H),3.14(m,1H),3.02(t,J=6.3Hz,2H),2.97(s,1H),2.67(m,2 H),2.47(d,J=11.4Hz,1H),2.33(m,5H),2.22(m,3H),1.93(m,2H),1.19(s,9H).

[0155] Example 16

[0156] Preparation of compound 17:

[0157]

[0158] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.15 g of pivaloyl chloride, 0.16 g of N,N-diisopropylethylamine and 0.03 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 17.

[0159] Structural data of compound 17:

[0160] ESI-MS m / z[M+H] + :654.30;

[0161] 1 H NMR(600MHz,MeOD)δ:4.65(d,J=5.1Hz,1H),4.39(d,J=6.2Hz,1H),4.14(d,J=6.8Hz,1 H),3.94(s,1H),3.61(s,3H),3.33(s,3H),3.29(m,5H),3.27(s,3H),3.21(s,3H),3.13 (s,1H),3.08(d,J=6.3Hz,1H),3.02(s,1H),2.78(s,1H),2.62(s,1H),2.44(s,2H),2. 38(m,1H),2.34(s,1H),2.27(m,3H),2.12(s,1H),2.01(m,1H),1.20(d,J=1.7Hz,18H).

[0162] Embodiment 17

[0163] Preparation of compound 18:

[0164]

[0165] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.12 g of isobutyryl chloride and 0.22 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 18.

[0166] Structural data of compound 18:

[0167] ESI-MS m / z[M+H] + :626.20;

[0168] 1 H NMR(600MHz,MeOD)δ:5.12(s,1H),4.70(d,J=5.0Hz,1H),4.39(d,J=6.3Hz,1H),4.1 7(d,J=6.8Hz,1H),3.78(s,1H),3.62(s,3H),3.38(m,1H),3.36(s,3H),3.30(m,3H), 3.29(s,3H),3.25(s,3H),3.17(s,1H),3.11(d,J=6.3Hz,1H),2.68(s,2H),2.58(m, 3H),2.45(s,1H),2.39(m,1H),2.35(m,1H),2.27(m,3H),2.07(m,2H),1.17(m,12H).

[0169] Embodiment 18

[0170] Preparation of compound 19:

[0171]

[0172] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.18 g of isobutyryl chloride, 0.21 g of N,N-diisopropylethylamine and 0.03 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 19.

[0173] Structural data of compound 19:

[0174] ESI-MS m / z[M+H] + : 696.40;

[0175] 1 H NMR (400MHz, CDCl3) δ: 5.28 (d, J = 6.4Hz, 1H), 4.86 (dd, J = 12.7, 5.2Hz, 1H), 4.67 (d, J = 5.1Hz, 1H), 4.1 5(d,J=6.5Hz,1H),3.94(m,2H),3.56(m,4H),3.36(d,J=6.1Hz,1H),3.27(m,6H),3.19(s,3H),3.11(m ,1H),3.00(d,J=8.5Hz,1H),2.91(d,J=11.8Hz,1H),2.83(s,1H),2.68(m,2H),2.56(m,3H),2.41(m,2 H),2.25(m,5H),2.07(m,2H),1.76(s,1H),1.29(d,J=7.2Hz,3H),1.25(d,J=6.9Hz,3H),1.18(m,12H).

[0176] Embodiment 19

[0177] Preparation of compound 20:

[0178]

[0179] Compound 20

[0180] Weigh 0.10 g of Zhonguning and add it into a reaction bottle, then add 2 mL of dichloromethane, 0.06 g of 2-ethylhexanoyl chloride and 0.11 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 20.

[0181] Structural data of compound 20:

[0182] ESI-MS m / z[M+H] + : 612.30;

[0183] 1H NMR (400MHz, MeOD) δ: 5.35 (m, 1H), 4.50 (d, J = 6.1Hz, 1H), 4.30 (m, 1H), 3.87 (d, J = 4. 5Hz,1H),3.65(m,1H),3.62(s,3H),3.53(m,2H),3.41(m,5H),3.34(s,1H),3.32(d,J =1.3Hz,3H),3.27(d,J=0.8Hz,3H),3.07(m,1H),2.97(s,3H),2.57(d,J=1.6Hz,1H), 2.41(m,2H),2.21(m,4H),1.83(m,1H),1.73–1.43(m,3H),1.31(m,4H),0.93(m,6H).

[0184] Embodiment 20

[0185] Preparation of compound 21:

[0186]

[0187] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.04 g of cyclopropanecarbonyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 21.

[0188] Structural data of compound 21:

[0189] ESI-MS m / z[M+H] + :554.20

[0190] 1 H NMR (400MHz, CDCl3) δ: 5.30 (t, J = 4.0Hz, 2H), 4.68 (d, J = 5.2Hz, 1H), 4.31 (d, J = 6.9Hz, 1H), 3.93 (d, J = 4.9Hz, 1H), 3.66 (m, 4H), 3.43 (m ,7H),3.31(s,3H),3.27(m,4H),3.09(d,J=5.1Hz,1H),3.02(s,3H),2.83(s,1H),2.31(m,3H),2.15(m,2H),1.66(m,3H),1.00(m,4H).

[0191] Embodiment 21

[0192] Preparation of compound 22:

[0193]

[0194] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.05 g of cyclobutanecarbonyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 22.

[0195] Structural data of compound 22:

[0196] ESI-MS m / z[M+H] + :568.20;

[0197] 1 H NMR (400MHz, MeOD) δ: 5.35 (m, 1H), 4.49 (d, J = 6.0Hz, 1H), 4.30 (m, 1H), 3.86 (d ,J=4.7Hz,1H),3.62(s,3H),3.56(m,3H),3.45(m,1H),3.41(s,3H),3.35(m,3H ),3.30(s,3H),3.28(m,1H),3.17(m,1H),3.06(m,1H),2.98(s,3H),2.56(m,1 H),2.45(d,J=6.8Hz,1H),2.26(m,7H),2.10(m,4H),1.71(m,1H),1.61(m,1H).

[0198] Embodiment 22

[0199] Preparation of compound 23:

[0200]

[0201] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.06 g of cyclopentanecarbonyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 23.

[0202] Structural data of compound 23:

[0203] ESI-MS m / z[M+H] + :582.30;

[0204] 1H NMR(400MHz,MeOD)δ:5.19(t,J=4.5Hz,1H),4.40(d,J=6.0Hz,1H),4.21(m,1H),3.7 7(d,J=4.1Hz,1H),3.55(m,1H),3.53(s,3H),3.39(m,2H),3.31(s,3H),3.24(m,1H) ,3.22(s,3H),3.21(m,2H),3.19(s,3H),2.97(m,1H),2.82(s,2H),2.76(m,2H),2.4 5(s,1H),2.32(d,J=6.8Hz,1H),2.16(m,3H),2.02(m,1H),1.85(m,2H),1.63(m,9H).

[0205] Embodiment 23

[0206] Preparation of compound 24:

[0207]

[0208] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.06 g of cyclohexanoyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 24.

[0209] Structural data of compound 24:

[0210] ESI-MS m / z[M+H] + :596.30;

[0211] 1 H NMR(400MHz,MeOD)δ:5.34(d,J=4.1Hz,1H), 4.50(d,J=6.1Hz,1H), 4.31(d,J=6.8Hz,1H), 3.87(d,J=4.8Hz,1H),3.62(s,3H),3.56(s,3H),3.44(d,J=4.3Hz,2H),3.41(s,3H),3.35 (s, 1H), 3.32 (s, 3H), 3.29 (s, 3H), 3.07 (d, J = 6.1 Hz, 1H), 3.00 (s, 3H), 2.57 (s, 1H), 2.45 (m, 2H), 2.26 (m, 3H), 2.14 (t, J = 13.0 Hz, 1H), 1.93 (m, 2H), 1.69 (m, 5H), 1.37 (m, 5H). Example 24

[0212] Preparation of compound 25:

[0213]

[0214] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.12 g of cyclohexanoyl chloride and 0.17 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 25.

[0215] Structural data of compound 25:

[0216] ESI-MS m / z[M+H] + :706.40;

[0217] 1 H NMR(400MHz,MeOD)δ:5.27(t,J=4.2Hz,1H),4.70(d,J=4.9Hz,1H),4.41(d,J=6.3 Hz,1H),4.20(d,J=6.7Hz,1H),3.64(s,3H),3.62(s,1H),3.51(s,1H),3.46(d,J=8 .5Hz,1H),3.38(s,3H),3.31(s,3H),3.27(s,3H),3.14(d,J=6.3Hz,1H),2.90(s,3 H),2.54(s,1H),2.34(m,6H),2.17(t,J=13.2Hz,1H),1.83(m,13H),1.37(m,11H).

[0218] Embodiment 25

[0219] Preparation of compound 26:

[0220]

[0221] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.22 g of cyclohexanoyl chloride and 0.35 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 26.

[0222] Structural data of compound 26:

[0223] ESI-MS m / z[M+H] + :816.70;

[0224] 1H NMR(400MHz,MeOD)δ:5.43(d,J=7.0Hz,1H),4.95(m,1H),4.66(d,J=5.1Hz,1H) ,4.15(d,J=7.0Hz,1H),3.91(d,J=8.7Hz,1H),3.52(s,3H),3.29(s,3H),3.28(s ,3H),3.21(s,3H),3.10(d,J=8.6Hz,1H),2.97(s,1H),2.78(d,J=11.5Hz,1H),2 .63(m,2H),2.46(s,3H),2.31(m,6H),1.97(m,9H),1.75(m,11H),1.34(m,17H).

[0225] Embodiment 26

[0226] Preparation of compound 27:

[0227]

[0228] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.06 g of cyclopentylacetyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 27.

[0229] Structural data of compound 27:

[0230] ESI-MS m / z[M+H] + :596.40;

[0231] 1 H NMR (400MHz, MeOD) δ: 5.34 (d, J = 1.9 Hz, 1H), 4.49 (d, J = 6.1 Hz, 1H), 4.30 (d, J = 6.7 Hz, 1H), 3. 87(d,J=4.5Hz,1H),3.62(s,3H),3.59(m,1H),3.54(m,2H),3.41(s,3H),3.40(s,2H),3.32( m,2H),3.30(m,5H),3.07(d,J=6.1Hz,1H),2.96(s,3H),2.56(s,1H),2.43(m,3H),2.26(m,4 H),2.13(t,J=13.3Hz,1H),1.86(m,2H),1.75(m,1H),1.65(m,3H),1.59(m,2H),1.21(m,2H).

[0232] Embodiment 27

[0233] Preparation of compound 28:

[0234]

[0235] Compound 28

[0236] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.07 g of p-fluorobenzoyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 28.

[0237] Structural data of compound 28:

[0238] ESI-MS m / z[M+H] + : 608.30;

[0239] Embodiment 28

[0240] Preparation of compound 29:

[0241]

[0242] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.09 g of pentafluorobenzoyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 29.

[0243] Structural data of compound 29:

[0244] ESI-MS m / z[M+H] + : 680.30;

[0245] Embodiment 29

[0246] Preparation of compound 30:

[0247]

[0248] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.09 g of 2-trifluoromethyl-4-fluoro-benzoyl chloride and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 30.

[0249] Structural data of compound 30:

[0250] ESI-MS m / z[M+H] + : 676.30;

[0251] Embodiment 30

[0252] Preparation of compound 31:

[0253]

[0254] Weigh 0.25 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.11 g of di-tert-butyl dicarbonate and 0.04 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 31.

[0255] Structural data of compound 31:

[0256] ESI-MS m / z[M+H] + :586.40;

[0257] 1 H NMR(400MHz,MeOD)δ:5.06(s,1H),4.46(d,J=6.1Hz,1H),4.27(d,J=6.8Hz,1H),3 .84(d,J=4.1Hz,1H),3.62(d,J=2.1Hz,1H),3.60(s,3H),3.51(t,J=4.4Hz,2H),3 .39(d,J=2.4Hz,3H),3.35(m,1H),3.28(m,9H),3.05(d,J=6.2Hz,1H),2.86(s,2H ),2.52(s,1H),2.34(m,2H),2.22(m,2H),2.10(m,1H),1.74(m,2H),1.48(s,9H).

[0258] Embodiment 31

[0259] Preparation of compound 32:

[0260]

[0261] Weigh 0.25 g of Zhonguning and add it into a reaction bottle, then add 4 mL of dichloromethane, 0.28 g of di-tert-butyl dicarbonate and 0.13 g of 4-dimethylaminopyridine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 32.

[0262] Structural data of compound 32:

[0263] ESI-MS m / z[M+H] + :786.30;

[0264] 1H NMR(400MHz,MeOD)δ:5.11(d,J=6.4Hz,1H),4.66(m,1H),4.46(d,J=5.1Hz,1H),4.16(d,J=7 .0Hz,1H),4.06(d,J=8.8Hz,1H),3.52(s,3H),3.28(s,3H),3.27(s,3H),3.24(s,1H),3.21( s,3H),3.17(m,1H),3.00(d,J=8.8Hz,1H),2.83(m,2H),2.56(m,2H),2.36(m,7H),2.22(d,J =6.9Hz,1H),2.07(m,1H),2.01(m,1H),1.90(s,1H),1.52(s,9H),1.47(s,9H),1.45(s,9H).

[0265] Embodiment 32

[0266] Preparation of compound 33:

[0267]

[0268] Weigh 0.20 g of Zhonguning and add it into a reaction bottle, then add 5 mL of dichloromethane, 0.14 g of benzyl chloroformate and 0.08 g of N,N-diisopropylethylamine. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 33.

[0269] Structural data of compound 33:

[0270] ESI-MS m / z[M+H] + :620.30;

[0271] 1 H NMR(600MHz,MeOD)δ:7.35(m,5H),5.19(m,2H),5.12(s,1H),4.58(s,1H),4.46( d,J=6.1Hz,1H),4.26(d,J=6.8Hz,1H),3.84(d,J=4.2Hz,1H),3.65(s,1H),3.60 (s,3H),3.45(s,2H),3.38(s,3H),3.23(m,8H),3.04(d,J=6.0Hz,1H),2.80(s,3 H), 2.49 (s, 1H), 2.35 (m, 2H), 2.20 (m, 2H), 2.07 (t, J = 13.4Hz, 1H), 1.85 (s, 1H).

[0272] Embodiment 33

[0273] Preparation of compound 34:

[0274]

[0275] Weigh 0.20 g of Zhongwu Ning and add it into a reaction bottle, then add 5 mL of dichloromethane and 0.16 g of 9-fluorenylmethyl chloroformate. After stirring at room temperature for 12 hours, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by preparative chromatography to obtain compound 34.

[0276] Structural data of compound 34:

[0277] ESI-MS m / z[M+H] + :708.50;

[0278] 1 H NMR(400MHz,MeOD)δ:7.81(m,2H),7.63(d,J=7.5Hz,2H),7.40(t,J=7.4Hz,2H) ,7.32(m,2H),4.58(s,2H),4.42(d,J=6.0Hz,1H),4.26(t,J=6.1Hz,1H),4.20(m ,1H),3.89(s,1H),3.81(d,J=5.1Hz,1H),3.59(s,3H),3.35(s,3H),3.17(m,8H) ,3.02(m,2H),2.73(s,2H),2.48(s,3H),2.38(s,1H),2.22(m,4H),1.96(m,3H).

[0279] Test Example 1

[0280] Experimental animals: SD rats (200-250 g), half male and half female, were housed in the laboratory and fed a standard diet before the experiment.

[0281] Experimental procedure: One day before the experiment, rats were anesthetized with 10% chloral hydrate (about 0.8-1 ml), cannulated the jugular vein, separated into cages, fasted overnight after waking up, and only fed with water. On the day of the experiment, the rats were randomly divided into two groups (n=3), weighed, and blank blood was collected from the jugular vein. Compound 1 was prepared into 2 mg / mL and 5 mg / mL solutions with water. One group was administered via the tail vein (dose of 5 mg / kg), and the other group was administered by gavage (dose of 50 mg / kg). 0.5 mL of blood was collected from the jugular vein at 0 min, 5 min, 15 min, 30 min, 1, 2, 4, 8, 12, and 24 h. After each blood collection, the fluid was replenished with heparinized saline. The 0.5 mL of blood collected was added to a heparinized test tube, shaken, centrifuged at 3500 rpm for 10 min, and the supernatant was taken to obtain plasma, which was stored at -20°C for later use.

[0282] Blood drug concentration determination:

[0283] (1) Plasma treatment: Take 100 μL of plasma, add 10 μL of internal standard solution (20 μg / mL), add 400 μL of methanol, vortex mix for 3 min, centrifuge at 13000 rpm for 15 min, and take 5 μL of supernatant for injection.

[0284] (2) Chromatographic conditions: Waters Acquity UPLC connected to Quattro Premier XE mass spectrometer, electrospray interface, MassLynx V4.1 workstation. Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm), mobile phase A: 0.1% formic acid, B: methanol, gradient elution as shown in the table below (Table 2 shows the gradient conditions for Zhongwu Ning, which can be adjusted). Column temperature: 30°C. Flow rate: 0.25 mL / min.

[0285] Table 2

[0286] t / min A B 0 90％ 10％ 2.0 90％ 10％ 4.0 30％ 70％ 6.0 30％ 70％ 6.01 90％ 10％ 8.0 90％ 10％

[0287] (3) Mass spectrometry conditions: positive ion mode, MRM monitoring, the monitoring ion pair of triacetyl-zhonguning was 612.3→520.2, the monitoring ion pair of zhonguning was 486.2→436.2, and the monitoring ion pair of internal standard was 422.2→390.1.

[0288] The parameters are set as follows:

[0289] declustering potential:90V;entrance potential:10V;collision energy:48eV;collision cell exit potential:10V;Ion source:Turbo spray;Curtain gas:20.0psi;collision gas:Medium;Ionspray voltage:5500V;Temperature:500℃;Ionsource gas 1:60.0psi;Ion source gas 2:60.0psi.

[0290] At the same time, make an accompanying standard curve and calculate according to the standard curve method.

[0291] Standard curve concentration points:

[0292]

[0293] Preliminary bioavailability test of compound 1: The results are shown in Table 3.

[0294] Table 3 Bioavailability of Compound 1

[0295]

[0296] According to the data in Table 3, we can know that:

[0297] Bioavailability of Compound 1 after oral administration:

[0298] After oral administration of compound 1,

[0299] After injection of compound 1,

[0300] Experimental conclusion:

[0301] (1) After oral administration of compound 1, the bioavailability of compound 1 was 48%, which was higher than the bioavailability of direct administration of Zhongwuning (bioavailability was 2-3%);

[0302] (2) After oral or intravenous administration of compound 1, if there is only one metabolite, Zhongwuning, the conversion rate of Zhongwuning is about 20% (the results of oral and intravenous administration are consistent);

[0303] (3) According to the bioavailability and conversion rate of compound 1, the bioavailability of Zhongwuning is about: 48%×18.5%=8.9%, indicating that compound 1 has the potential to be a prodrug.

[0304] In summary, the ester derivatives of zhonguning provided in the present application can be used as zhonguning prodrugs to improve the bioavailability of zhonguning in the prevention and / or treatment of diseases.

[0305] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

Claims

1. Application of a class of ester derivatives of zhongwuning in the preparation of zhongwuning prodrugs, characterized in that: The derivative is: Compound 1:

2. The use of the ester derivatives of Zhongwuning according to claim 1 in the preparation of Zhongwuning prodrugs, characterized in that: The preparation method of the compound 1 comprises: weighing 0.20 g of Zhongwu Ning and adding it into a reaction bottle, then adding 4 mL of dichloromethane, 0.24 g of acetic anhydride and 0.12 g of 4-dimethylaminopyridine, stirring at room temperature for 12 hours, removing the solvent by rotary evaporation under reduced pressure, and purifying the residue by preparative chromatography to obtain the compound 1.

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