A ginsenoside-progeny hydrogen sulfide donor derivative, and a preparation method and use thereof

Abstract

The application discloses a ginsenoside-protopanaxadiol hydrogen sulfide donor derivative, a preparation method and application thereof, and belongs to the technical field of natural medicines and medicinal chemistry. Ginsenoside-protopanaxadiol is used as a lead compound, a series of ginsenoside-protopanaxadiol hydrogen sulfide donor derivatives are designed and synthesized, and myocardial protection activities of the synthesized derivatives are tested. The results show that the ginsenoside-protopanaxadiol hydrogen sulfide donor derivative prepared by the application has better cardiac protection activities for treating myocardial ischemia, arrhythmia and myocardial infarction, and has the potential as a cardiac protection drug.

Description

Technical Field

[0001] This invention relates to the fields of natural medicines and medicinal chemistry, and more specifically, to a ginsenoside hydrogen sulfide donor derivative, its preparation method, and its uses. Background Technology

[0002] Cardiovascular disease ranks first among causes of death for urban and rural residents in my country, accounting for 48.0% and 45.9% of deaths in rural and urban areas respectively in 2020. Ischemic heart disease is one of the leading causes of cardiovascular disease death in my country. Therefore, finding innovative treatment options is not only of great practical significance, but also an urgent need for people in my country and around the world.

[0003] Ginsenosides are a class of active ingredients extracted from ginseng plants, possessing various pharmacological effects, including antioxidant, anti-inflammatory, and anti-aging properties. Studies have found that ginsenosides can scavenge free radicals and reduce oxidative stress damage to the heart, which may be beneficial in preventing cardiovascular diseases. Furthermore, ginsenosides can protect cardiac muscle cells from damage by regulating signal transduction pathways within cardiomyocytes, thereby enhancing their antioxidant and anti-inflammatory capabilities. Although preclinical trials have demonstrated the cardiovascular protective effects of ginsenosides, their limited water solubility, strong neurotoxicity, and unstable clinical efficacy limit their clinical application. Moreover, when used as a cardioprotective agent, ginsenosides require high therapeutic doses, often accompanied by various side effects (such as arrhythmias, hepatotoxicity, and nephrotoxicity).

[0004] Hydrogen sulfide (H2S), as a gaseous signaling neurotransmitter, has been recognized in recent years for its protective effects on the heart. It can protect the heart by scavenging free radicals and reducing oxidative stress. Hydrogen sulfide may also protect the heart from damage by regulating myocardial energy metabolism pathways, such as mitochondrial function and ATP production. Summary of the Invention

[0005] The purpose of this invention is to overcome the above-mentioned defects in the prior art and to provide a ginsenoside hydrogen sulfide donor derivative, its preparation method, and its uses.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] A ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt, wherein the general structural formula of the ginsenoside hydrogen sulfide donor derivative is shown below:

[0008]

[0009] Wherein, R1 is a substituted hydrocarbon group or substituted aryl group containing 1-15 carbon atoms and 1-8 N, O, S or halogen atoms; R2 is hydrogen, hydroxyl or substituted hydroxyl, wherein the substituent in the substituted hydroxyl group is a hydrocarbon group or aryl group containing 1-15 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-15 carbon atoms and 1-8 N, O, S or halogen atoms; R3 is a hydrocarbon group or aryl group containing 1-15 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-15 carbon atoms and 1-8 N, O, S or halogen atoms.

[0010] Optionally, R1 is a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-8 N, O, S or halogen atoms; R2 is hydrogen, hydroxyl or substituted hydroxyl, wherein the substituent in the substituted hydroxyl group is a hydrocarbon group or aryl group containing 1-15 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-8 N, O, S or halogen atoms; R3 is a hydrocarbon group or aryl group containing 1-12 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-8 N, O, S or halogen atoms.

[0011] Optionally, R1 is a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-6 N, O, S or halogen atoms; R2 is hydrogen, hydroxyl or substituted hydroxyl, wherein the substituent in the substituted hydroxyl group is a hydrocarbon group or aryl group containing 1-12 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-6 N, O, S or halogen atoms; R3 is a hydrocarbon group or aryl group containing 1-12 carbon atoms, or a substituted hydrocarbon group or substituted aryl group containing 1-12 carbon atoms and 1-6 N, O, S or halogen atoms.

[0012] Optionally, the structural formula of the ginsenoside hydrogen sulfide donor derivative is shown below:

[0013] .

[0014] This invention also discloses a method for synthesizing the above-mentioned ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt, the synthetic route of which is shown below:

[0015] .

[0016] Optionally, the synthesis method includes the following steps:

[0017] Compounds 1-2 were prepared by alkaline hydrolysis of total saponins from American ginseng stems and leaves using a high-temperature organic solvent method; wherein the mass ratio of total saponins from American ginseng stems and leaves to solid sodium hydroxide was 1:2 to 1:5; and the mass ratio of total saponins from American ginseng stems and leaves to glycerol was 1:10 to 1:15.

[0018] Compounds 1-2 were oxidized with m-chloroperoxybenzoic acid to obtain compounds 3-6. Hydrogen sulfide donor acids 7-11 were esterified under EDCI and DMAP conditions to obtain compounds 12-37. The molar ratio of compounds 1-2 to m-chloroperoxybenzoic acid ranged from 1:1 to 1:3; the molar ratio of compounds 1-6 to DMAP was 10:1 to 10:3; the molar ratio of compounds 1-6 to EDCI was 1:1 to 1:3; and the molar ratio of compounds 1-6 to hydrogen sulfide donor acids was 1:1 to 1:3.

[0019] The present invention also discloses a pharmaceutical composition comprising the above-mentioned ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt.

[0020] Optionally, the pharmaceutical composition contains a therapeutically effective amount of the ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

[0021] The present invention also discloses the use of the above-described ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt, or the above-described pharmaceutical composition, in the preparation of a medicament for treating heart disease.

[0022] Optionally, the heart disease includes one or more of myocardial ischemia, myocardial infarction, and arrhythmia.

[0023] Implementing the embodiments of the present invention will have the following beneficial effects:

[0024] This invention uses ginsenosides as a lead compound to design and synthesize derivatives of ginsenosides combined with hydrogen sulfide donors. The protective activity of the synthesized derivatives in cardiomyopathy was tested. Pharmacological tests showed that the ginsenoside hydrogen sulfide donor derivatives prepared in this invention have good cardioprotective activity against various cardiomyopathy (myocardial ischemia, myocardial infarction, arrhythmia) and have the potential to be used as cardioprotective drugs. Attached Figure Description

[0025] Figure 1 This is a graph showing the protective activity of some compounds against arrhythmia and myocardial infarction in embodiments of the present invention. Detailed Implementation

[0026] The present invention will be further described below with reference to specific embodiments, but this does not limit the present invention in any way.

[0027] Example 1

[0028] Preparation of ginsenosides

[0029] 20 g of total saponins from American ginseng stems and leaves were placed in a 2 L three-necked flask. 100 g of solid sodium hydroxide and 500 mL of glycerol were added, and the mixture was stirred. The mixture was heated to 230 °C under normal pressure and maintained at this temperature for 12 h. The reaction was detected by TLC upon completion. The reaction solution was poured into 1.5 L of cold water and stirred, resulting in the precipitation of a precipitate. The precipitate was allowed to stand, filtered under reduced pressure, washed with water until neutral, and dried to obtain 9.6 g of the crude alkaline hydrolysis product. Separation was performed by silica gel column chromatography with a gradient elution of n-hexane-ethyl acetate (3:1 – 2:1) to obtain intermediates 1 (1.7 g) and 2 (1.4 g).

[0030] 276 mg of compound 1 (0.60 mmol) was dissolved in 30 mL of anhydrous dichloromethane. 134 mg of m-chloroperoxybenzoic acid (0.66 mol) was slowly added under ice-salt bath conditions, and the mixture was stirred for 30 min. The mixture was then moved to room temperature and stirred for 2 h. TLC was used to confirm the complete reaction. 5 mL of isopropanol (64.88 mmol) was added, and stirring continued for 1 h. The organic phase was extracted sequentially with saturated sodium bicarbonate solution, saturated sodium thiosulfate solution, and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a white solid. Separation was achieved by silica gel column chromatography with a hexane-ethyl acetate gradient elution (3:1 – 3:2). Recrystallization from ethyl acetate yielded 155 mg of compound 3 (white crystals, 54% yield) and 81 mg of compound 4 (white crystals, 28% yield).

[0031] 649 mg of compound 2 (1.36 mmol) was dissolved in 60 mL of anhydrous dichloromethane. 305 mg of m-chloroperoxybenzoic acid (1.50 mmol) was slowly added under an ice-salt bath, and the mixture was stirred for 30 min. The mixture was then moved to room temperature and stirred for 2 h. TLC analysis confirmed the reaction was complete. 5 mL of isopropanol (64.88 mmol) was added, and stirring continued for 1 h. The organic phase was extracted sequentially with saturated sodium bicarbonate solution, saturated sodium thiosulfate solution, and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a white solid. Separation was achieved by silica gel column chromatography with a hexane-ethyl acetate gradient elution (2:1 – 1:1). Recrystallization from ethyl acetate yielded 202 mg of compound 5 (white crystals, 30% yield) and 187 mg of compound 6 (white crystals, 28% yield), respectively. The synthetic route is shown below:

[0032] .

[0033] Example 2

[0034] Preparation of Ginsenoside Hydrogen Sulfide Donor Derivatives

[0035] Compound 3 (50.0 mg, 0.5 mmol) was dissolved in anhydrous DCM, and DMAP (6.1 mg, 0.05 mmol), EDCI (96 mg, 0.5 mmol), and hydrogen sulfide donor 7 (1.5 eq) were added. The mixture was reacted overnight at room temperature, the solvent was removed by vacuum distillation, the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 12 as a white solid in 83.5% yield. 1 H NMR (600 MHz, CDCl3) d 4.48 (dd, J = 11.0, 5.5 Hz, 1H), 3.85 (dd, J = 8.9, 6.4 Hz, 1H), 3.60 (m,1H), 3.52 (td, J = 10.5, 4.6 Hz, 1H), 3.23 (m, 3H), 2.50 – 2.43 (m, 1H), 2.33(dt, J = 21.7, 7.4 Hz, 3H), 2.19 (td, J = 10.9, 3.8 Hz, 1H), 2.10 – 1.95 (m, 2H), 1.94 – 1.83 (m, 4H), 1.80 – 1.40 (m, 19H), 1.36 – 1.15 (m, 8H), 1.15 – 0.91(m, 9H), 0.91 – 0.81 (m, 12H). 13 C NMR (151 MHz, CDCl3) d 173.28, 86.52, 85.34, 80.64, 77.35, 77.14, 76.93, 70.95, 70.24, 56.33, 56.31, 56.03, 52.01, 50.40, 49.30, 47.92, 40.20, 39.75, 38.61, 38.49, 38.47, 37.88, 37.06, 34.74, 34.60, 34.54, 33.76, 32.60, 31.25, 31.17, 28.77, 28.70, 28.58, 28.01, 27.86, 27.58,26.10, 25.00, 24.85, 24.49, 23.72, 18.16, 16.51, 16.38, 15.37. HRMS (ESI-MSm / z ) calculated for C 39 H 67 O5S2[M+H] + 679.4430, found 679.4429.

[0036] The structure of compound 12 is shown below:

[0037] .

[0038] Example 3

[0039] Compound 16 was prepared as a white solid with a yield of 92.3% by following the synthesis method in Example 2. 1 H NMR (600MHz, CDCl3) d 5.78 (m, 1H), 5.16 (m, 2H), 4.50 (dd, J = 11.4, 5.1 Hz, 1H), 3.85(dd, J = 8.9, 6.4 Hz, 1H), 3.51 (td, J = 10.4, 4.5 Hz, 1H), 3.16 (m, 2H), 2.75(m, 2H), 2.67 (m, 2H), 2.19 (td, J = 10.8, 9.2, 3.8 Hz, 1H), 2.08 – 1.94 (m,2H), 1.93 – 1.82 (m, 3H), 1.74 – 1.41 (m, 10H), 1.39 – 1.15 (m, 9H), 1.14 –1.03 (m, 6H), 1.01 – 0.81 (m, 16H). 13 C NMR (151 MHz, CDCl3) d197.28, 171.60, 134.15, 117.22, 86.51, 85.43, 81.13, 77.29, 77.08, 76.86, 70.93, 70.08, 56.07, 52.01, 50.41, 49.40, 47.96, 39.77, 38.61, 37.90, 37.06, 34.97, 34.76, 34.71, 32.61, 31.34, 31.20, 28.59, 28.01, 27.91, 27.61, 26.15, 25.74, 25.00, 23.71, 18.16, 16.54, 16.48, 16.37, 15.39. HRMS (ESI-MS m / z ) calculated forC 36 H 61 O5S2[M+H] + 637.3960, found 637.3959.

[0040] The structure of compound 16 is shown below:

[0041] .

[0042] Example 4

[0043] Compound 20 was prepared as a white solid with a yield of 73.3% by following the synthesis method in Example 2. 1 H NMR (600MHz, CDCl3) d 8.05 (m, 2H), 7.29 (m, 2H), 4.71 (dd, J = 11.2, 4.9 Hz, 1H), 3.85(dd, J = 8.9, 6.5 Hz, 1H), 3.53 (td, J = 10.5, 4.6 Hz, 1H), 2.24 (m, 1H), 2.09 –1.95 (m, 2H), 1.95 – 1.83 (m, 3H), 1.83 – 1.62 (m, 5H), 1.61 – 1.41 (m, 5H),1.35 – 1.24 (m, 8H), 1.17 – 1.08 (m, 6H), 1.05 – 0.85 (m, 15H). 13 C NMR (151MHz, CDCl3) d165.06, 135.41, 130.98, 129.53, 125.63, 86.52, 85.44, 81.96, 77.29, 77.08, 76.86, 70.93, 70.09, 56.11, 52.02, 50.44, 49.42, 47.97, 39.79, 38.64, 38.25, 37.12, 34.76, 32.63, 31.38, 31.21, 28.60, 28.14, 27.92, 27.62, 26.16, 25.01, 23.75, 18.21, 18.19, 16.71, 16.40, 15.41. HRMS (ESI-MS m / z ) calculated for C 38 H 56 NO5S [M+H] + 638.3879, found 638.3861.

[0044] The structure of compound 20 is shown below:

[0045] .

[0046] Example 5

[0047] Compound 24 was prepared as a yellow solid with a yield of 63.1% by the synthesis method described in Example 2. 1 H NMR (600MHz, CDCl3) d 8.18 (m, 2H), 7.32 (m, 2H), 4.53 (dd, J = 10.7, 5.7 Hz, 1H), 3.85(dd, J = 8.8, 6.5 Hz, 1H), 3.52 (td, J = 10.5, 4.6 Hz, 1H), 2.98 (m, 4H), 2.26(m, 1H), 2.08 – 1.95 (m, 2H), 1.92 – 1.82 (m, 3H), 1.74 – 1.60 (m, 5H), 1.59– 1.39 (m, 5H), 1.34 – 1.25 (m, 8H), 1.15 – 1.02 (m, 6H), 0.98 (s, 3H), 0.94– 0.73 (m, 13H). 13 C NMR (151 MHz, CDCl3) d186.82, 185.83, 171.68, 170.27, 155.68, 129.80, 128.90, 122.73, 86.56, 85.40, 81.62, 77.27, 77.06, 76.85, 71.00, 70.29, 56.07, 52.02, 50.43, 49.40, 47.96, 39.77, 38.62, 37.95, 37.07, 34.74, 32.63, 31.34, 31.22, 29.47, 29.31, 28.60, 27.99, 27.92, 27.63, 26.10,25.04, 23.70, 18.17, 16.48, 16.38, 15.38. HRMS (ESI-MS m / z ) calculated forC 42 H 60 NO8S2[M+H] + 770.3760, found 770.3761.

[0048] The structure of compound 24 is shown below:

[0049] .

[0050] Other compounds 13-15, 17-19, 21-23, and 25-37 were prepared according to the synthetic method in Example 2, and their spectral data are shown below:

[0051] Compound 13, white solid, yield 81.2%. 1 H NMR (600 MHz, CDCl3) d 4.49 (dd, J = 11.1, 5.4 Hz, 1H), 3.88 (dd, J = 11.0, 5.4 Hz, 1H), 3.55 (dd, J = 10.4, 4.8 Hz, 2H),3.23 – 3.06 (m, 2H), 2.49 (m, 1H), 2.32 (t, J = 7.4 Hz, 2H), 2.25 (dd, J= 11.3,5.8 Hz, 1H), 2.09 – 1.82 (m, 7H), 1.79 – 1.60 (m, 10H), 1.59 – 1.37 (m, 8H), 1.36 – 1.21 (m, 9H), 1.20 – 1.15 (m, 1H), 1.14 – 1.05 (m, 5H), 1.01 (s, 3H), 0.93 – 0.80 (m, 13H). 13 C NMR (151 MHz, CDCl3) d 173.24, 87.40, 87.15, 80.64, 77.29, 77.08, 76.86, 70.50, 70.07, 56.35, 56.02, 52.16, 50.14, 48.90, 48.78, 40.21, 39.76, 38.58, 38.48, 37.90, 37.09, 34.69, 34.62, 34.55, 32.21, 31.63, 28.87, 28.79, 28.53, 28.03, 27.96, 25.08, 24.87, 24.22, 23.76, 18.19, 17.77,16.53, 16.35, 15.47. HRMS (ESI-MS m / z ) calculated for C 39 H 67 O5S2[M+H] + 679.4430, found 679.4424.

[0052] Compound 14, white solid, yield 89.4%. 1 H NMR (600 MHz, CDCl3) d 4.45 (dd, J = 11.6, 5.1 Hz, 1H), 4.11 (td, J = 10.6, 3.8 Hz, 1H), 3.85 (dd, J = 8.8, 6.7 Hz, 1H), 3.62 (m, 2H), 3.18 (dd, J = 7.2, 5.4 Hz, 1H), 3.12 (dt, J = 11.0, 6.9 Hz, 1H),2.50 (m, 1H), 2.33 (dt, J= 7.5, 3.7 Hz, 2H), 2.19 (td, J = 9.6, 5.0 Hz, 1H),2.09 – 1.79 (m, 7H), 1.75 – 1.53 (m, 16H), 1.52 – 1.42 (m, 5H), 1.28 – 1.25(m, 9H), 1.16 (s, 2H), 1.14 – 1.12 (m, 1H), 1.09 (s, 3H), 1.07 – 1.05 (m, 5H), 1.01 – 0.96 (m, 2H), 0.94 – 0.92 (m, 5H). 13 C NMR (151 MHz, CDCl3) d 173.33, 86.50, 85.45, 80.45, 77.25, 77.04, 76.83, 70.81, 70.13, 68.44, 61.37, 56.35, 51.82, 49.90, 49.03, 47.89, 47.06, 40.88, 40.22, 38.97, 38.49, 38.39, 38.27, 34.64, 34.56, 32.61, 31.26, 31.20, 30.69, 29.71, 28.81, 28.59, 27.90, 27.55, 26.15, 24.96, 24.85, 23.42, 18.12, 17.49, 16.93, 16.63. HRMS (ESI-MS m / z ) calculated for C 39 H 66 O6S2Na [M+Na] + 717.4199, found 717.4207.

[0053] Compound 15, white solid, yield 83.2%. 1 H NMR (600 MHz, CDCl3) d 4.46 (dd, J =11.6, 5.0 Hz, 1H), 4.12 (td, J = 10.6, 3.8 Hz, 1H), 3.87 (dd, J= 11.1, 5.4 Hz,1H), 3.61 (m, 2H), 3.24 (m, 2H), 2.52 – 2.41 (m, 1H), 2.35 (m, 2H), 2.29 (m,1H), 2.07 – 1.83 (m, 7H), 1.79 – 1.76 (m, 1H), 1.73 – 1.60 (m, 10H), 1.55 –1.46 (m, 5H), 1.29 – 1.24 (m, 8H), 1.22 (s, 3H), 1.18 – 1.16 (m, 3H), 1.11 –1.09 (m, 6H), 1.06 (s, 3H), 1.02 – 0.87 (m, 9H). 13 C NMR (151 MHz, CDCl3) d 173.35, 87.43, 87.12, 80.47, 77.25, 77.03, 76.82, 70.40, 70.07, 68.48, 61.34, 56.35, 51.96, 49.61, 48.87, 48.42, 46.99, 40.89, 40.21, 39.01, 38.48, 38.33, 38.27, 34.62, 34.56, 32.18, 31.64, 31.52, 30.69, 29.70, 28.86, 28.80, 28.53, 28.01, 25.04, 24.85, 24.23, 23.43, 17.70, 17.43, 17.01, 16.64. HRMS (ESI-MS m / z ) calculated for C 39 H 66 O6S2Na [M+Na] + 717.4199, found 717.4215.

[0054] Compound 17, colorless oil, yield 93.7%. 1 H NMR (600 MHz, CDCl3) d 5.83 (m, 1H),5.25 (m, 2H), 4.51 (dd, J = 11.4, 5.1 Hz, 1H), 3.87 (dd, J = 11.0, 5.4 Hz, 1H), 3.53 (td, J= 10.4, 4.8 Hz, 1H), 3.15 (d, J = 7.1 Hz, 2H), 2.78 (m, 2H), 2.68 (m,2H), 2.32 (m, 1H), 2.10 – 1.80 (m, 6H), 1.80 – 1.59 (m, 6H), 1.56 – 1.44 (m,5H), 1.32 – 1.22 (m, 8H), 1.20 – 1.08 (m, 6H), 1.01 (s, 3H), 0.93 – 0.83 (m,13H). 13 C NMR (151 MHz, CDCl3) d 171.60, 134.16, 117.23, 87.38, 87.14, 81.14, 77.27, 77.06, 76.85, 70.47, 70.02, 56.03, 52.16, 50.14, 48.93, 48.83, 39.77, 38.57, 37.91, 37.08, 34.98, 34.72, 34.70, 32.20, 31.70, 31.62, 28.89, 28.55, 28.03, 25.75, 25.04, 24.29, 23.74, 18.19, 17.77, 16.51, 16.33, 15.47. HRMS(ESI-MS m / z ) calculated for C 36 H 61 O5S2[M+H] + 637.3960, found 637.3969.

[0055] Compound 18, colorless oil, yield 90.9%. 1 H NMR (600 MHz, CDCl3) d 5.86 (m, 1H),5.16 (m, 2H), 4.47 (dd, J = 11.7, 4.7 Hz, 1H), 4.11 (td, J = 10.6, 3.8 Hz, 1H), 3.85 (dd, J = 8.7, 6.7 Hz, 1H), 3.51 (td, J= 10.5, 4.6 Hz, 1H), 3.21 (m, 2H), 2.85 (m, 4H), 2.26 (m, 1H), 2.06 – 1.82 (m, 5H), 1.72 – 1.39 (m, 10H), 1.34 –1.25 (m, 10H), 1.20 – 1.11 (m, 5H), 1.10 – 1.05 (m, 9H), 0.98 – 0.93 (m, 6H). 13 C NMR (151 MHz, CDCl3) d 171.70, 134.16, 117.26, 86.50, 85.45, 80.96, 77.25, 77.04, 76.82, 70.80, 70.13, 68.43, 61.37, 51.82, 49.89, 49.03, 47.89, 47.06, 40.88, 38.96, 38.37, 38.26, 34.97, 34.74, 32.61, 31.25, 31.20, 30.70, 28.59, 27.90, 27.55, 26.15, 25.73, 24.96, 23.39, 18.12, 17.47, 16.93, 16.60. HRMS(ESI-MS m / z ) calculated for C 36 H 61 O6S2[M+H] + 653.3910, found 653.3936.

[0056] Compound 19, colorless oil, yield 90.6%. 1 H NMR (600 MHz, CDCl3) d 5.89 (m,2H), 5.14 (m, 2H), 4.48 (dd, J = 11.7, 4.8 Hz, 1H), 4.19 (m, 1H), 3.87 (dd, J =11.1, 5.4 Hz, 1H), 3.53 (td, J= 10.4, 4.8 Hz, 1H), 3.18 (m, 2H), 2.75 (m, 4H), 2.30 (m, 1H), 2.10 – 1.82 (m, 7H), 1.79 – 1.62 (m, 10H), 1.55 – 1.51 (m, 3H), 1.26 (s, 14H), 1.11 – 1.09 (m, 6H), 0.89 – 0.87 (m, 5H). 13 C NMR (151 MHz, CDCl3) d 171.69, 134.16, 117.26, 87.42, 87.10, 80.97, 77.24, 77.03, 76.82, 70.35, 70.04, 68.49, 61.35, 51.96, 49.61, 48.90, 48.45, 47.02, 40.90, 39.01, 38.32, 38.26, 34.98, 34.75, 32.17, 31.94, 31.64, 30.71, 28.87, 28.53, 28.03, 25.74, 25.04, 24.26, 23.41, 17.71, 17.42, 17.02, 16.62. HRMS (ESI-MS m / z ) calculated for C 36 H 60 O6S2Na [M+Na] + 675.3729, found 675.3727.

[0057] Compound 21, white solid, yield 76.3%. 1 H NMR (600 MHz, CDCl3) d 8.10 (m, 2H),7.26 (m, 2H), 4.71 (dd, J = 9.1, 4.9 Hz, 1H), 3.89 (dd, J = 11.0, 5.5Hz, 1H), 3.55 (td, J= 10.3, 4.7 Hz, 1H), 2.33 (m, 1H), 2.09 – 1.91 (m, 4H), 1.90 – 1.82(m, 2H), 1.82 – 1.65 (m, 9H), 1.62 – 1.42 (m, 7H), 1.29 – 1.21 (m, 9H), 1.13– 1.07 (m, 5H), 1.05 – 0.98 (m, 7H), 0.93 (m, 4H). 13 C NMR (151 MHz, CDCl3) d 165.08, 135.42, 130.99, 129.55, 125.64, 87.40, 87.16, 81.98, 77.25, 77.04, 76.83, 70.48, 70.04, 56.08, 52.18, 50.17, 48.94, 48.85, 39.80, 38.60, 38.27, 37.23, 34.70, 32.22, 31.74, 31.63, 28.90, 28.56, 28.15, 28.05, 25.05, 24.28, 23.78, 18.23, 17.79, 16.73, 16.37, 15.50. HRMS (ESI-MS m / z ) calculated forC 38 H 56 NO5S [M+H] + 638.3879, found 638.3884.

[0058] Compound 22, white solid, yield 79.2%. 1 H NMR (600 MHz, CDCl3) d 8.09 (m, 2H),7.31 (m, 2H), 4.69 (dd, J = 11.7, 5.1 Hz, 1H), 4.15 (td, J = 10.6, 3.8 Hz, 1H), 3.85 (dd, J = 8.7, 6.7 Hz, 1H), 3.53 (td, J= 10.5, 4.6 Hz, 1H), 2.25 (m, 1H), 2.08 – 1.92 (m, 3H), 1.92 – 1.70 (m, 6H), 1.70 – 1.39 (m, 8H), 1.35 – 1.30(m, 1H), 1.29 – 1.19 (m, 14H), 1.18 – 1.13 (m, 2H), 1.11 – 1.08 (m, 6H), 0.99– 0.94 (m, 6H). 13 C NMR (151 MHz, CDCl3) d 165.16, 135.47, 131.01, 129.45, 125.67, 86.50, 85.46, 81.80, 77.25, 77.04, 76.83, 70.80, 70.14, 68.40, 61.38, 51.83, 49.91, 49.03, 47.89, 47.10, 40.91, 39.00, 38.63, 38.39, 32.62, 31.28, 31.20, 30.82, 28.60, 27.91, 27.55, 26.15, 24.96, 23.43, 18.13, 17.51, 16.96,16.82. HRMS (ESI-MS m / z ) calculated for C 38 H 56 NO6S [M+H] + 654.3828, found654.3849.

[0059] Compound 23, white solid, yield 74.5%. 1 H NMR (600 MHz, CDCl3) d 8.07 (m, 2H),7.28 (m, 2H), 4.69 (dd, J = 11.5, 4.9 Hz, 1H), 4.25 (m, 1H), 3.87 (dd, J = 11.1, 5.5 Hz, 1H), 3.56 (td, J= 10.3, 4.8 Hz, 1H), 2.29 (m, 1H), 2.10 – 1.89 (m,5H), 1.88 – 1.75 (m, 6H), 1.71 – 1.63 (m, 4H), 1.59 – 1.52 (m, 3H), 1.29 –1.20 (m, 17H), 1.13 – 1.09 (m, 7H), 1.02 – 0.96 (m, 4H). 13 C NMR (151 MHz, CDCl3) d 165.16, 135.49, 131.01, 129.61, 129.45, 125.67, 87.44, 87.12, 81.80, 77.24, 77.03, 76.82, 70.37, 70.07, 68.46, 61.35, 51.97, 49.62, 48.89, 48.45, 47.05, 40.92, 39.05, 38.63, 38.34, 32.19, 31.65, 31.56, 30.83, 28.87, 28.53, 28.01, 25.05, 24.24, 23.44, 17.72, 17.45, 17.04, 16.83. HRMS (ESI-MS m / z ) calculated for C 38 H 56 NO6S [M+H] + 654.3828, found 654.3815.

[0060] Compound 25, yellow solid, yield 64.8%. 1 H NMR (600 MHz, CDCl3) d 8.16 (m, 2H),7.33 (m, 2H), 4.60 (m, 1H), 3.92 (m, 1H), 3.54 (td, J = 10.4, 4.9 Hz, 1H), 2.95(m, 4H), 2.29 (m, 1H), 2.09 – 1.83 (m, 7H), 1.79 – 1.61 (m, 6H), 1.57 – 1.42(m, 6H), 1.37 – 1.21 (m, 10H), 1.20 – 1.06 (m, 7H), 0.92 – 0.85 (m, 12H). 13CNMR (151 MHz, CDCl3) d 186.80, 185.78, 171.64, 170.27, 155.68, 129.79, 128.89, 122.73, 87.41, 87.17, 81.61, 77.29, 77.08, 76.87, 70.50, 70.06, 56.03, 52.16, 50.15, 48.91, 48.80, 39.76, 38.57, 37.95, 37.08, 34.68, 32.22, 31.68, 31.63, 29.47, 29.30, 28.88, 28.54, 28.00, 25.06, 24.28, 23.71, 18.18, 17.77, 16.50,16.35, 15.47. HRMS (ESI-MS m / z ) calculated for C 42 H 60 NO8S2[M+H] + 770.3760, found770.3755.

[0061] Compound 26, yellow solid, yield 69.4%. 1 H NMR (600 MHz, CDCl3) d 8.13 (m, 2H),7.30 (m, 2H), 4.50 (dd, J = 9.4, 4.7 Hz, 1H), 4.10 (m, 1H), 3.85 (dd, J = 8.7, 6.7 Hz, 1H), 3.51 (td, J = 10.5, 4.5 Hz, 1H), 3.02 (m, 4H), 2.26 (m, 1H), 2.07– 1.79 (m, 5H), 1.78 – 1.39 (m, 10H), 1.35 – 1.20 (m, 10H), 1.17 (s, 3H),1.12 – 1.04 (m, 10H), 1.04 – 0.95 (m, 3H), 0.95 – 0.90 (m, 5H). 13 C NMR (151MHz, CDCl3) d184.66, 183.67, 169.58, 168.09, 153.52, 127.66, 126.76, 120.59, 84.35, 83.29, 79.31, 75.12, 74.91, 74.70, 68.65, 68.03, 66.20, 59.17, 49.67, 47.75, 46.86, 45.73, 44.89, 38.72, 36.80, 36.21, 36.15, 30.46, 29.10, 29.05, 28.53, 27.32, 27.17, 26.44, 25.75, 25.40, 23.99, 22.81, 21.22, 15.96, 15.34,14.79, 14.44. HRMS (ESI-MS m / z ) calculated for C 42 H 60 NO9S2[M+H] + 786.3709, found786.3736.

[0062] Compound 27, yellow solid, yield 60.8%. 1 H NMR (600 MHz, CDCl3) d 8.23 (m, 1H),7.76 (m, 1H), 7.33 (m, 2H), 4.51 (dd, J = 11.1, 5.5 Hz, 1H), 4.17 (m, 1H), 3.87(dd, J = 11.1, 5.5 Hz, 1H), 3.54 (td, J = 10.3, 4.8 Hz, 1H), 2.95 (m, 4H), 2.29(m, 1H), 2.10 – 1.82 (m, 7H), 1.82 – 1.58 (m, 11H), 1.57 – 1.50 (m, 4H), 1.28– 1.22 (m, 10H), 1.18 – 1.16 (m, 3H), 1.15 – 1.11 (m, 3H), 1.02 – 0.98 (m,2H), 0.97 – 0.93 (m, 6H). 13 C NMR (151 MHz, CDCl3) d186.81, 185.84, 171.72, 170.25, 155.66, 129.81, 128.81, 122.73, 121.39, 87.45, 87.12, 81.46, 77.24, 77.03, 76.82, 70.38, 70.09, 68.44, 61.31, 51.95, 50.87, 49.61, 48.87, 48.41, 47.00, 40.89, 39.00, 38.30, 32.18, 31.65, 31.51, 30.68, 29.70, 29.46, 28.86,28.52, 27.98, 25.06, 24.21, 23.38, 17.71, 17.43, 17.01, 16.61. HRMS (ESI-MS m / z ) calculated for C 42 H 60 NO9S2[M+H] + 786.3709, found 786.3730.

[0063] Compound 28, yellow solid, yield 64.8%. 1 H NMR (600 MHz, CDCl3) d 7.73 (m, 2H),7.42 (m, 1H), 7.29 (m, 2H), 4.57(dd, J = 11.0, 5.5 Hz, 1H), 3.85 (dd, J = 8.8, 6.4 Hz, 1H), 3.51 (td, J = 10.5, 4.5 Hz, 1H), 2.97 (m, 4H), 2.23 (m, 1H), 2.09– 1.94 (m, 2H), 1.92 – 1.82 (m, 3H), 1.75 – 1.60 (m, 5H), 1.60 – 1.39 (m,5H), 1.34 – 1.24 (m, 8H), 1.15 – 1.02 (m, 6H), 0.98 (s, 3H), 0.93 – 0.79 (m,13H). 13 C NMR (151 MHz, CDCl3) d215.51, 171.72, 171.67, 170.49, 153.58, 136.03, 129.23, 128.23, 122.88, 86.53, 85.43, 81.58, 77.29, 77.08, 76.86, 70.94, 70.11, 56.08, 52.01, 50.43, 49.41, 47.96, 39.77, 38.62, 37.95, 37.08, 34.75, 32.63, 31.36, 31.21, 29.44, 29.34, 28.59, 28.01, 27.92, 27.62, 26.16, 25.01,23.71, 18.17, 16.48, 16.39, 15.40. HRMS (ESI-MS m / z ) calculated for C 43 H 60 O7S3Na[M+Na] + 807.3399, found 807.3398.

[0064] Compound 29, yellow solid, yield 74.2%. 1 H NMR (600 MHz, CDCl3) d 7.74 (m, 2H),7.44 (m, 1H), 7.30 (m, 2H), 4.54(dd, J = 11.5, 5.0 Hz, 1H), 3.87 (dd, J = 11.0, 5.5 Hz, 1H), 3.53 (td, J = 10.5, 4.8 Hz, 1H), 2.98 (m, 5H), 2.29 (m, 1H), 2.10– 1.81 (m, 7H), 1.80 – 1.58 (m, 7H), 1.57 – 1.43 (m, 6H), 1.38 – 1.21 (m,10H), 1.12 – 1.08 (m, 4H), 1.02 – 0.99 (m, 3H), 0.91 – 0.85 (m, 9H). 13 C NMR (151 MHz, CDCl3) d215.49, 171.71, 171.65, 170.50, 153.58, 136.02, 129.22, 128.22, 122.88, 87.39, 87.14, 81.58, 77.30, 77.09, 76.88, 70.46, 70.02, 56.03, 52.15, 50.15, 48.92, 46.94, 39.76, 38.57, 37.94, 37.09, 34.69, 32.21, 31.71, 31.62, 29.44, 29.33, 28.89, 28.54, 28.01, 25.05, 24.30, 23.72, 18.19,17.77, 16.51, 16.35, 15.47. HRMS (ESI-MS m / z ) calculated for C 43 H 61 O7S3[M+H] + 785.3579, found 785.3606.

[0065] Compound 30, yellow solid, yield 70.3%. 1 H NMR (600 MHz, CDCl3) d 7.72 (m, 2H),7.27 (m, 2H), 4.51 (dd, J = 11.4, 5.0 Hz, 1H), 4.10 (td, J = 10.6, 3.8 Hz, 1H), 3.85 (dd, J = 8.7, 6.7 Hz, 1H), 3.51 (td, J = 10.5, 4.6 Hz, 1H), 2.96 (m, 5H), 2.22 (m, 1H), 2.08 – 1.80 (m, 6H), 1.73 – 1.46 (m, 10H), 1.34 – 1.24 (m,11H), 1.17 (s, 3H), 1.14 – 1.12 (m, 1H), 1.09 (s, 3H), 1.07 – 1.06 (m, 3H), 0.95 – 0.89 (m, 6H). 13 C NMR (151 MHz, CDCl3) d215.55, 171.73, 171.73, 170.47, 153.57, 136.05, 129.25, 128.24, 122.89, 86.49, 85.45, 81.41, 77.25, 77.04, 76.83, 70.79, 70.14, 68.38, 61.34, 51.81, 49.90, 49.02, 47.88, 47.06, 40.88, 38.95, 38.36, 38.30, 32.61, 31.26, 31.20, 30.69, 29.44, 29.35, 28.59, 27.91,27.55, 26.14, 24.96, 23.38, 18.12, 17.49, 16.94, 16.60. HRMS (ESI-MS m / z ) calculated for C 43 H 61 O8S3[M+H] + 801.3529, found 801.3528.

[0066] Compound 31, yellow solid, yield 63.9%. 1 H NMR (600 MHz, CDCl3) d 7.71 (m, 2H),7.26 (m, 2H), 4.52 (dd, J = 11.6, 5.0 Hz, 1H), 4.12 (td, J = 10.6, 3.8 Hz, 1H), 3.87 (dd, J = 11.1, 5.4 Hz, 1H), 3.53 (td, J = 10.3, 4.8 Hz, 1H), 3.02 (m, 5H), 2.28 (m, 1H), 2.09 – 1.81 (m, 7H), 1.80 – 1.60 (m, 8H), 1.56 – 1.50 (m, 3H), 1.28 – 1.22 (m, 9H), 1.20 – 1.16 (m, 4H), 1.11 – 1.07 (m, 9H), 0.98 – 0.92(m, 6H). 13 C NMR (151 MHz, CDCl3) d215.55, 171.74, 171.71, 170.49, 153.57, 136.06, 129.25, 128.24, 122.89, 87.44, 87.11, 81.42, 77.25, 77.03, 76.82, 70.37, 70.06, 68.44, 61.32, 51.95, 49.61, 48.87, 48.42, 47.02, 40.90, 39.00, 38.32, 38.29, 32.18, 31.64, 31.53, 30.69, 29.43, 29.34, 28.86, 28.52, 28.00,25.05, 24.23, 23.38, 17.70, 17.43, 17.01, 16.61. HRMS (ESI-MS m / z ) calculated for C 43 H 61 O8S3[M+H] + 801.3529, found 801.3530.

[0067] Compound 32, white solid, yield 55.7%. 1 H NMR (600 MHz, CDCl3) d 5.16 (td, J = 7.2, 1.6 Hz, 1H), 4.49 (dd, J = 10.9, 5.5 Hz, 1H), 3.65 (m, 2H), 3.24 (m, 3H), 2.49(m, 1H), 2.35 (m, 2H), 2.21 (m, 1H), 2.08 – 2.01 (m, 2H), 1.94 – 1.79 (m,3H), 1.76 – 1.57 (m, 16H), 1.57 – 1.37 (m, 9H), 1.30 – 1.26 (m, 5H), 1.19 (s,3H), 1.10 – 1.02 (m, 2H), 0.99 (s, 3H), 0.91 – 0.88 (m, 6H), 0.86 – 0.84 (m, 6H). 13 C NMR (151 MHz, CDCl3) d171.85, 130.44, 123.48, 79.20, 75.79, 75.58, 75.37, 73.06, 69.41, 54.91, 54.46, 51.98, 50.13, 48.50, 46.32, 38.76, 38.30, 37.16, 37.02, 36.45, 35.57, 33.23, 33.16, 33.11, 32.95, 29.73, 29.50, 28.24, 27.34, 26.59, 25.56, 25.02, 24.32, 23.41, 22.26, 20.90, 16.70, 16.31, 15.37,15.12, 14.73, 14.25. HRMS (ESI-MS m / z ) calculated for C 39 H 67 O4S2[M+H] + 663.4481, found 663.4473.

[0068] Compound 33, white solid, yield 50.3%. 1 H NMR (600 MHz, CDCl3) d 5.16 (td, J = 7.1Hz, 1H), 4.46 (dd, J = 11.5, 5.2 Hz, 1H), 4.11 (td, J = 10.4, 4.1 Hz, 1H), 3.58(m, 2H), 3.21 (m, 2H), 2.50 (m, 1H), 2.36 (m, 3H), 2.24 (m, 2H), 2.09 – 1.99(m, 3H), 1.95 – 1.83 (m, 4H), 1.74 – 1.62 (m, 16H), 1.55 – 1.43 (m, 7H), 1.25 (s, 5H), 1.21 – 1.19 (m, 3H), 1.17 (s, 3H), 1.09 – 1.05 (m, 6H), 0.97 – 0.96(m, 3H), 0.91(s, 3H). 13 C NMR (151 MHz, CDCl3) d173.35, 132.14, 124.74, 80.48, 77.24, 77.03, 76.82, 74.93, 70.69, 68.43, 61.18, 56.39, 56.36, 53.29, 51.38, 49.41, 47.44, 47.01, 40.95, 40.22, 39.02, 38.49, 38.39, 38.25, 34.63, 34.56, 34.20, 30.93, 30.91, 30.73, 29.70, 28.80, 27.04, 26.41, 25.78, 24.84, 23.38,22.33, 17.78, 17.25, 16.83, 16.69. HRMS (ESI-MS m / z ) calculated for C 39 H 67 O5S2[M+H] + 679.4430, found 679.4415.

[0069] Compound 34, colorless oil, yield 60.7%. 1 H NMR (600 MHz, CDCl3) d 5.91 (m, 1H),5.19 (m, 2H), 4.51 (dd, J = 11.3, 5.3 Hz, 1H), 3.60 (td, J = 10.4, 5.2 Hz, 1H), 3.15 (d, J = 7.1 Hz, 2H), 2.77 (m, 4H), 2.21 (m, 1H), 2.09 – 1.99 (m, 2H), 1.89– 1.81 (m, 2H), 1.76 – 1.66 (m, 7H), 1.64 (s, 3H), 1.57 – 1.37 (m, 7H), 1.33– 1.26 (m, 4H), 1.25 (s, 3H), 1.20 (s, 3H), 1.09 – 1.02 (m, 2H), 0.99 (s,3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87 – 0.85 (m, 6H). 13 C NMR (151 MHz, CDCl3) d171.66, 134.16, 131.96, 124.92, 117.25, 81.15, 77.25, 77.04, 76.83, 74.60, 70.87, 55.93, 53.43, 51.60, 49.95, 47.81, 39.77, 38.61, 37.92, 37.03, 34.99, 34.74, 34.70, 34.37, 31.19, 30.97, 28.05, 27.06, 26.49, 25.78, 25.76, 23.70, 22.37, 18.16, 17.77, 16.84, 16.57, 16.18, 15.71. HRMS (ESI-MS m / z ) calculated for C 36 H 60 O4S2Na [M+Na] + 643.3831, found 643.3839.

[0070] Compound 35, colorless oil, yield 55.1%. 1 H NMR (600 MHz, CDCl3) d 5.94 (m, 1H), 5.17 (m, 2H), 4.48 (dd, J = 11.6, 5.0 Hz, 1H), 4.11 (td, J = 10.4, 4.0 Hz, 1H), 3.60 (td, J = 10.4, 5.2 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H), 2.78 (m, 2H), 2.66 (m,2H), 2.24 (m, 4H), 1.94 – 1.79 (m, 3H), 1.74 – 1.62 (m, 10H), 1.61 – 1.50 (m,4H), 1.27 – 1.24 (m, 6H), 1.21 – 1.17 (m, 6H), 1.08 – 1.05 (m, 6H), 0.96 (s, 3H), 0.91 (s, 3H), 0.90 – 0.82 (m, 3H). 13 C NMR (151 MHz, CDCl3) d171.72, 134.15, 132.15, 124.71, 117.26, 80.99, 77.24, 77.03, 76.82, 75.00, 70.70, 68.42, 61.18, 53.27, 51.38, 49.40, 47.41, 47.00, 40.95, 39.01, 38.38, 38.25, 34.98, 34.75, 34.19, 30.94, 30.89, 30.74, 29.70, 27.00, 26.40, 25.77, 25.73, 23.35, 22.33, 17.77, 17.24, 16.82, 16.67. HRMS (ESI-MS m / z ) calculated forC 36 H 60 O5S2Na [M+Na] + , 659.3780, found 659.3777.

[0071] Compound 36, white solid, yield 53.4%. 1 H NMR (600 MHz, CDCl3) d 8.09 (m, 2H),7.32 (m, 2H), 5.23 (m, 1H), 4.72 (dd, J = 11.5, 4.7 Hz, 1H), 3.62 (td, J = 10.4,5.2 Hz, 1H), 2.26 (m, 1H), 2.10 – 1.95 (m, 2H), 1.90 – 1.72 (m, 5H), 1.72 –1.61 (m, 6H), 1.61 – 1.35 (m, 6H), 1.34 – 1.24 (m, 6H), 1.20 (s, 3H), 1.17 –1.08 (m, 1H), 1.07 – 0.98 (m, 6H), 0.95 (s, 3H), 0.92 – 0.86 (m, 6H). 13 C NMR (151 MHz, CDCl3) d165.12, 137.69, 135.46, 131.91, 130.99, 129.50, 125.65, 124.96, 81.98, 77.26, 77.05, 76.84, 74.50, 70.82, 55.97, 53.47, 51.61, 49.98, 47.82, 39.79, 38.63, 38.27, 34.42, 31.23, 30.98, 28.18, 27.04, 26.49, 25.79, 23.73, 22.37, 18.18, 17.79, 16.86, 16.79, 16.21, 15.73. HRMS (ESI-MS m / z ) calculated for C 38 H 56 NO4S [M+H] + 622.3930, found 622.3926.

[0072] Compound 37, white solid, yield 44.5%. 1 H NMR (600 MHz, CDCl3) d 8.03 (m, 2H),7.28 (m, 2H), 4.69 (dd, J = 11.4, 4.5 Hz, 1H), 4.15 (td, J = 10.4, 4.2 Hz, 1H), 3.62 (dt, J = 10.3, 5.1 Hz, 1H), 2.26 (m, 1H), 2.11 – 1.97 (m, 2H), 1.94 – 1.84(m, 2H), 1.83 – 1.72 (m, 5H), 1.70 (s, 3H), 1.64 (s, 3H), 1.60 – 1.35 (m,6H), 1.35 – 1.24 (m, 6H), 1.25 – 1.19 (m, 9H), 1.19 – 1.13 (m, 2H), 1.09 (s,3H), 1.07 – 1.04 (m, 2H), 1.01 (s, 3H), 0.93 (s, 3H). 13 C NMR (151 MHz, CDCl3) d165.19, 137.71, 135.51, 132.13, 131.02, 129.42, 125.68, 124.76, 81.82, 77.25, 77.04, 76.83, 74.83, 70.64, 68.41, 61.19, 53.33, 51.39, 49.43, 47.47, 47.05, 40.97, 39.06, 38.61, 38.40, 34.23, 31.03, 30.95, 30.86, 27.07, 26.42, 25.78, 23.39, 22.34, 17.78, 17.27, 16.88, 16.85. HRMS (ESI-MS m / z ) calculated forC 38 H 56 NO5S [M+H] + 638.3879, found 638.3885.

[0073] Example 38

[0074] This embodiment examines the pharmacological activity of the prepared ginsenoside hydrogen sulfide donor derivative.

[0075] Experimental equipment and reagents

[0076] 2. Experimental Methods

[0077] Cell protective activity assay methods

[0078] Cells were cultured routinely in an incubator at 37°C and 5% CO2 saturated humidity. Cells in the logarithmic growth phase were digested with trypsin cell digestion solution (0.25% trypsin + 0.01% EDTA), centrifuged, resuspended, and counted to prepare a concentration of 8 × 10⁻⁶ cells / mL. 5Cell suspensions of 100 μL / ml were seeded into 96-well plates and incubated overnight in a CO2 incubator. After cell adhesion, the drug compound was diluted to the required concentration using culture medium, and 100 μL of the corresponding drug-containing culture medium at different concentrations was added to each well. Three auxiliary wells were set up for each drug group, along with blank control, negative control, and positive control. The 96-well plates with the added drugs were incubated for 24 h. Except for the blank and negative control groups, 10 μL of diluted cobalt chloride solution was added to each well of the 96-well plate to induce hypoxia for 12 h in an incubator. 10 μL of CCK-8 was added to each well of the 96-well plate, and the plates were incubated for another 1 h. Subsequently, the OD value of each well was measured at 450 nm using a microplate reader, and cell viability was calculated.

[0079] Survival rate calculation formula:

[0080]

[0081] The relative OD value of the experimental group = the absolute OD value of the experimental group - the absolute OD value of the blank control well.

[0082] 3. Experimental Results

[0083] The protective activity of the ginsenoside hydrogen sulfide donor derivative prepared in this invention against cobalt chloride-induced hypoxic rat embryonic cardiomyocytes H9c2 is shown in Table 1.

[0084] Table 1. Effect of the derivatives prepared in this invention on the survival rate of rat cardiomyocytes (μM)

[0085]

[0086] As shown in Table 1, the compounds prepared in this invention exhibit excellent protective activity against cobalt chloride-induced hypoxic cardiomyocytes, with compounds 17, 19, 24, 25, and 27 showing the best effects. Therefore, these compounds were selected for further investigation into their protective activity against isoproterenol-induced arrhythmias and myocardial infarction in rats. Figure 1 As shown, the compound prepared in this invention has good cardioprotective activity against isoproterenol-induced arrhythmia and myocardial infarction in rats.

[0087] The above pharmacological tests show that the target derivative of the present invention has good cardioprotective activity and good safety, and has the potential to be used as a cardioprotective drug.

[0088] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A ginsenoside hydrogen sulfide donor derivative and its pharmaceutically acceptable salt, characterized in that, The structural formula of the ginsenoside hydrogen sulfide donor derivative is shown below: 。 2. A method for synthesizing the ginsenoside hydrogen sulfide donor derivative as described in claim 1 and its pharmaceutically acceptable salt, characterized in that, The synthetic route of the synthetic method is shown below: 。 3. The synthesis method according to claim 2, characterized in that, The synthesis method includes the following steps: preparing compounds 1-2 by high-temperature organic solvent alkaline hydrolysis of total saponins from American ginseng stems and leaves; wherein the mass ratio of total saponins from American ginseng stems and leaves to solid sodium hydroxide is 1:2 to 1:5; and the mass ratio of total saponins from American ginseng stems and leaves to glycerol is 1:10 to 1:

15. Compounds 1-2 were oxidized with m-chloroperoxybenzoic acid to obtain compounds 3-6. Hydrogen sulfide donor acids 7-11 were esterified under EDCI and DMAP conditions to obtain compounds 12-37. The molar ratio of compounds 1-2 to m-chloroperoxybenzoic acid ranged from 1:1 to 1:3; the molar ratio of compounds 1-6 to DMAP was 10:1 to 10:3; the molar ratio of compounds 1-6 to EDCI was 1:1 to 1:3; and the molar ratio of compounds 1-6 to hydrogen sulfide donor acids was 1:1 to 1:

3.

4. A pharmaceutical composition, characterized in that, It includes the ginsenoside hydrogen sulfide donor derivative as described in claim 1 and its pharmaceutically acceptable salt.

5. The pharmaceutical composition according to claim 4, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of the ginsenoside hydrogen sulfide donor derivative thereof, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

6. The use of a ginsenoside hydrogen sulfide donor derivative as described in claim 1 and its pharmaceutically acceptable salt, or the pharmaceutical composition as described in claim 4, in the preparation of a medicament for treating heart disease.

7. The application according to claim 6, characterized in that, The heart disease includes one or more of myocardial ischemia, myocardial infarction, and arrhythmia.

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