Cyclovirobuxin d derivatives and preparation method and application thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and particularly relates to a cyclovirobuxin D derivative structural formula (I) or formula (Ia) compound, a preparation method and application. Experimental results show that the structural formula (I) or formula (Ia) compound has different degrees of hypoxia tolerance and ischemia capacity, and therefore the above-mentioned compound can be used as a drug for preventing or treating cardiovascular and cerebrovascular diseases, and has potential for treating cardiovascular and cerebrovascular diseases. The cardiovascular and cerebrovascular diseases include but are not limited to angina pectoris, arrhythmia, hypertension, hyperlipidemia and ischemic stroke.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of cycloviniferin D derivatives, their preparation methods, and applications. Background Technology

[0002] Cyclovirobuxine D (CVB-D) is an effective monomeric alkaloid extracted from the Buxus microphylla plant (Buxus microphylla). It is a drug for treating cardiovascular and cerebrovascular diseases and can be widely used in the medical field as a prodrug for new drug development. Pharmacological activity studies have demonstrated that Cyclovirobuxine D is effective in treating angina pectoris, arrhythmia, and ischemic stroke. The structural formula of Cyclovirobuxine D is as follows:

[0003]

[0004] Pharmacological experiments have shown that Cyclovinoxin D can exert its therapeutic effect on ischemic stroke through multiple pathways, such as inhibiting the production of inflammatory factors and protecting nerve cells from oxidative damage. It is a multi-target, multi-mechanism therapeutic drug.

[0005] In recent years, various improvements have been made to the structure of cycloviniferin D to enhance its hypoxia tolerance, water solubility, or bioavailability. For example, the literature "Xiang Tao et al. Synthesis of 3-C monosubstituted cycloviniferin D derivatives and their hypoxia tolerance activity study [J]. Organic Chemistry, 2016, 36(2):5.DOI:10.6023 / cjoc201508030" reports a series of 3-amino monosubstituted compounds and conducts hypoxia tolerance experiments, showing good activity. Although existing studies have further improved the physiological activity of cycloviniferin D derivatives, its structure still has the potential for further modification, especially the modification of the steroid nucleus structure. Summary of the Invention

[0006] This invention discloses a novel structure of cycloviniferin D derivatives with hypoxia-resistant physiological activity. This is primarily achieved through nucleus modification, followed by the introduction of new metabolic sites based on the modified tetracyclic nucleus, while maintaining good activity. Clinically, ischemic stroke is often treated with combination therapy to exert a multi-mechanism therapeutic effect. Based on this approach, after obtaining a series of new nuclei, a molecular hybridization strategy was employed to introduce structures similar to those of marketed drugs edaravone, aspirin, and ferulic acid into cycloviniferin D, further enhancing its activity.

[0007] This invention provides a class of cyclovinifera D derivatives, which, by modifying their core structure or their 20-position amino structure, yield a class of new compounds with good activity for the prevention or treatment of cardiovascular and cerebrovascular diseases.

[0008] The structural formula of the cycloviscose D derivative is as follows:

[0009]

[0010] In formula (I), the carbon atom at position 8 and carbon atom at position 9 forms a single or double bond, and the carbon atom at position 9 and carbon atom at position 11 forms a single or double bond; in formula (I), R1 is either H or F; R2 is either H or carbonyl; R3 is either H, carbonyl, or -OH; R5 is H or any of the following structures. Indicates the connection site:

[0011]

[0012] In equation (Ⅰa), R6 can be any of the following structures: Indicates the connection site:

[0013]

[0014] Furthermore, formula (Ⅰ) is preferably configured in the following ways:

[0015]

[0016] Compounds of structural formula (I) or (Ia) of this invention can form pharmaceutically acceptable salts with a variety of organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, nitric acid, phosphoric acid, boric acid, tartaric acid, citric acid, succinic acid, benzoic acid, ascorbic acid, or salicylic acid. Compounds of structural formula (I) or (Ia) of this invention can also form salts with alkali metals such as sodium, potassium, or lithium, with alkaline earth metals such as calcium or magnesium, and with organic bases such as dicyclohexylamine, tributylamine, pyridine, and amino acids such as arginine and lysine. It should be understood that solvates of compounds of formula (I) or (Ia), such as hydrates, are also within the scope of this invention. Solvation methods are generally known in the art. Compounds of this invention can exist in a variety of optical isomers, geometric isomers, and stereoisomers. All such isomers and mixtures of their racemic forms are included within the scope of this invention.

[0017] This invention also provides a method for preparing compound b in formula (Ⅰ), which involves ring-opening via heating cycloviscose D in hydrochloric acid solution to obtain the compound. The synthetic route for compound b is as follows:

[0018]

[0019] This invention also provides a method for preparing compound Ib of formula (Ⅰ), wherein compound Ib is reacted with a series of derivative acyl chlorides using DCM as a solvent to obtain the compound. The synthetic route of compound Ib is as follows:

[0020]

[0021] This invention also provides a method for preparing compounds Ic and Id of formula (I). Compound b is obtained by trifluoroacetylation, oxidation, removal of trifluoroacetylation, and reduction, followed by reactions with the corresponding acyl chlorides to yield the compounds. The synthetic routes for compounds Ic and Id are as follows:

[0022]

[0023] This invention also provides a method for preparing compound IF in formula (Ⅰ), which involves reacting compound b with trifluoroacetylation, peroxidation, fluorination, and deacetylation, followed by combination with the corresponding acyl chloride to obtain the compound. The synthetic route for compound IF is as follows:

[0024]

[0025] This invention also provides a method for preparing compound Ih in formula (Ⅰ), which involves ring-opening of cycloviscose D in hydrochloric acid solution by heating to obtain compound g, followed by acetylation, oxidation, deacetylation, and combination with the corresponding acyl chloride to obtain the compound. The synthetic route of compound Ih is as follows:

[0026]

[0027] This invention also provides a method for preparing compound i of formula (Ⅰ), which involves deacetylation of compound g-1 followed by reduction to obtain the compound. The synthetic route for compound i is as follows:

[0028]

[0029] The compounds of structural formula (I) or (Ia) of this invention are mixed with pharmaceutically acceptable carriers to prepare various formulations. When the compounds of structural formula (I) or (Ia) are mixed with commonly used auxiliary additives acceptable in oral formulations, such as disintegrants, excipients, lubricants, binders, and fillers, they can be formulated into solid dosage forms such as tablets, pills, capsules, or various corresponding sustained-release and controlled-release formulations for the prevention and treatment of cardiovascular and cerebrovascular diseases using conventional methods. When mixed with commonly used solubilizers, emulsifiers, wetting agents, foaming or defoaming agents, surfactants, diluents, preservatives, stabilizers, flavoring agents, and thickeners, they can be formulated into liquid dosage forms such as aqueous solutions and syrups for the prevention and treatment of cardiovascular and cerebrovascular diseases using appropriate solvents and excipients commonly used in injections, corresponding intramuscular or intravenous injection formulations of cardiovascular and cerebrovascular diseases can also be prepared.

[0030] Beneficial effects: Animal experiments have shown that the new compounds, namely those of structural formula (I) or formula (Ia), exhibit varying degrees of tolerance to hypoxia and ischemia. Therefore, these compounds have the potential to be used as drugs for the prevention or treatment of cardiovascular and cerebrovascular diseases. Cardiovascular and cerebrovascular diseases include, but are not limited to, angina pectoris, arrhythmia, hypertension, hyperlipidemia, and ischemic stroke. Detailed Implementation

[0031] Example 1: Preparation of Compound Ia1

[0032] Compound Ia1 is 3-methyl-1-phenyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecano-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0033]

[0034] Preparation steps: CVB-D (0.5 g, 1.24 mmol) was added to 20 mL of dry dichloromethane. Under ice bath and nitrogen protection, triethylamine (0.127 g, 1.24 mmol) was added and stirred thoroughly until dissolved. Edaravone acyl chloride (0.22 g, 1.24 mmol) dissolved in dry dichloromethane was slowly added dropwise and stirred until the reaction was complete. The reaction was detected by TLC to indicate that the reaction had reached the endpoint. The reaction solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 35:1) to obtain 0.24 g of a pale yellow solid, with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.59(d,J=7.9Hz,2H),7.44(d,J=7.7Hz,2H),7.33(t,J=7.5Hz,1H),6.07(s,1H),4.46(dd,J=11.5,6.5Hz,1H),4.07( t,J=7.4Hz,1H),2.91(d,J=2.1Hz,3H),2.48(s,3H),2.34(s,3H),2.07(d ,J=5.5Hz,1H),2.04(d,J=6.5Hz,1H),2.02–1.99(m,2H),1.99–1.94(m,2H ),1.85(dd,J=13.8,8.8Hz,1H),1.69(d,J=12.1Hz,2H),1.64(d,J=9.0Hz ,2H),1.52(s,2H),1.45(dd,J=12.2,4.7Hz,2H),1.40(s,1H),1.34(d,J=4 .5Hz,1H),1.32(d,J=3.7Hz,2H),1.29(s,3H),1.27(d,J=4.4Hz,2H),1.17 (s,3H),1.16(s,3H),1.15(s,3H),1.05(s,3H).MS(ESI):m / z603.43[M+H] + .

[0035] Example 2 Preparation of compound Ia2

[0036] Compound Ia2 is 4-1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0037]

[0038] The preparation process is the same as that for compound Ia1, except that edaravone acyl chloride is replaced with 4-chloro-edaravone acyl chloride, yielding 0.3 g of a light brown solid with a yield of 36%. 1H NMR(500MHz,Chloroform-d)δ7.51(d,J=8.4Hz,2H),7.37(d,J=8.3Hz,2H),6.04(s,1H),4.45(d,J=4.6Hz ,1H),4.11(t,J=7.5Hz,1H),2.89(d,J=3.1Hz,3H),2.48(s,3H),2.29(s,3H),1.94(d,J=13.0Hz,2H),1.86 (dd,J=14.0,8.9Hz,2H),1.72–1.67(m,2H),1.62(d,J=11.4Hz,2H),1.50(s,3H),1.44–1.40(m,2H),1.35 –1.33(m,2H),1.30(s,2H),1.27(s,2H),1.25(s,2H),1.16(s,3H),1.03(s,3H),0.99(s,3H).MS(ESI):m / z 637.39[M+H] + .

[0039] Example 3 Preparation of compound Ia3

[0040] Compound Ia3 is 5-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0041]

[0042] The preparation process is the same as that for compound Ia1, except that edaravone acyl chloride is replaced with 4-fluoro-edaravone acyl chloride, yielding 0.25 g of a light white solid with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.51(dd,J=8.8,4.8Hz,2H),7.10(d,J=8.4Hz,2H),6.03(s,1H),4.44(dd,J=11.5,6.7Hz,1H),4.10(t,J=7. 2Hz,1H),2.86(s,3H),2.74(s,3H),2.50(d,J=7.5Hz,1H),2.30(d,J=2.2Hz,3H),2.03(d,J=16.8Hz,2H),1.98(d,J=3.8Hz,2H),1.94(d,J= 12.7Hz,1H),1.84(dd,J=13.9,8.9Hz,1H),1.66(s,2H),1.54–1.51(m,1H),1.48(dd,J=13.1,4.3Hz,2H),1.45–1.40(m,2H),1.38–1.35(m, 2H),1.34–1.32(m,2H),1.30(d,J=5.1Hz,2H),1.24(s,3H),1.14(s,2H),1.13(s,3H),1.11(s,3H),1.04(s,3H),1.02(s,3H).MS(ESI):m / z 621.42[M+H] + .

[0043] Example 4 Preparation of compound Ia4

[0044] Compound Ia4 is 4-3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecano-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0045]

[0046] The preparation process is the same as that for compound Ia1, except that edaravone acyl chloride is replaced with 4-trifluoromethyl-edaravone acyl chloride, yielding 0.30 g of a light white solid with a yield of 36%. 1HNMR(500MHz,Chloroform-d)δ7.74(d,J=8.5Hz,2H),7.66(d,J=8.4Hz,2H),6.07(s,1H),4.45(dd,J=11.3,6.9Hz,1H),4.12 (d,J=7.1Hz,1H),2.93(s,3H),2.89(s,1H),2.76(s,3H),2.54(d,J=8.1Hz,1H),2.31(s,3H),2.02(d,J=5.3Hz,2H),2.00–1. 99(m,1H),1.86(d,J=5.1Hz,1H),1.67(s,2H),1.54–1.50(m,2H),1.38(d,J=3.9Hz,1H),1.36(d,J=4.0Hz,2H),1.34(d,J=5. 5Hz,2H),1.27(s,3H),1.25(d,J=1.7Hz,2H),1.17(s,2H),1.16(s,2H),1.13(s,3H),1.07(s,3H),1.02(s,3H).MS(ESI):m / z 671.42[M+H] + .

[0047] Example 5 Preparation of compound Ia5

[0048] Compound Ia5 is 3-methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0049]

[0050] The preparation process is the same as that for compound Ia1, except that edaravone acyl chloride is replaced with 4-nitro-edaravone acyl chloride, yielding 0.20 g of a brownish-yellow solid with a yield of 25%. 1HNMR(500MHz,Chloroform-d)δ8.28–8.26(m,2H),7.85–7.82(m,2H),6.10(s,1H),4.47(dd,J=11.4,6.5Hz,1H),4.16(t,J=7.5Hz,1H),2.97(s,3H),2.92 (d,J=4.0Hz,1H),2.62(s,3H),2.31(s,3H),2.07(t,J=5.8Hz,2H),1.99–1.9 5(m,2H),1.91–1.87(m,1H),1.72(d,J=12.1Hz,2H),1.64(d,J=13.1Hz,2H),

[0051] 1.53–1.49(m,2H),1.43(t,J=6.3Hz,2H),1.34–1.32(m,2H),1.25(s,3H),1.20(s,2H),1.18 (s,2H),1.15(s,3H),1.13(s,3H),1.11–1.08(m,2H),1.03(s,3H),0.93(s,3H).MS(ESI):m / z

[0052] 648.41 [M+H] + .

[0053] Example 6 Compound Ia 10 preparation

[0054] Compound Ia 10 It is a 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0055]

[0056] The preparation process is the same as that for compound Ia1, except that edaravone chloride is replaced with trifluoromethyledaravone chloride, yielding 0.22 g of white solid with a yield of 27%. 1H NMR(500MHz,Chloroform-d)δ7.58(dd,J=7.6,1.8Hz,2H),7.46(d,J=7.8Hz,2H),6.53(s,1H),4.41(dd,J=11.4,6.5Hz,1H),4.0 4(t,J=7.4Hz,1H),2.93(s,1H),2.85(s,3H),2.75(s,3H),2.53(s,1H),2.05(s,1H),1.99(s,2H),1.82(d,J=4.8Hz,1H),1.66(s, 2H),1.53(s,2H),1.50(s,2H),1.43(dd,J=12.5,4.3Hz,2H),1.38(t,J=4.8Hz,2H),1.36(d,J=3.4Hz,2H),1.33(s,2H),1.27(s, 3H),1.26(s,3H),1.24–1.19(m,2H),1.13(s,2H),1.12(s,2H),1.10(s,3H),1.06(s,3H),1.01(s,3H).MS(ESI):m / z657.39[M+H] + .

[0057] Example 7 Compound Ia 11 preparation

[0058] Compound Ia 11 It is 2-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamoyl)phenyl acetate, with the following structural formula:

[0059]

[0060] The preparation process is the same as that for compound Ia1, except that edaravone chloride is replaced with aspirin chloride, yielding 0.15 g of white solid with a yield of 21%. 1H NMR(500MHz,Chloroform-d)δ7.52–7.48(m,1H),7.42(s,1H),7.22(d,J=8.2Hz,1H),6.92–6.90(m,1H),4.68(d,J=12.9Hz,1H) ,3.09(d,J=9.0Hz,2H),3.01(d,J=10.3Hz,2H),2.96–2.92(m,1H),2.86(d,J=10.9Hz,2H),2.82(s,3H),2.33–2.30(m,3H),2.29 (d,J=8.6Hz,3H),2.18(d,J=7.6Hz,2H),2.14(d,J=6.1Hz,2H),2.06–2.02(m,2H),1.80(d,J=12.7Hz,2H),1.53(s,2H),1.37(d, J=3.7Hz,2H),1.29(s,2H),1.22(s,3H),1.18(s,3H),1.16(s,3H),1.06(d,J=2.6Hz,3H),0.96(s,3H).MS(ESI):m / z563.39[MH] + .

[0061] Example 8 Compound Ia 12 preparation

[0062] Compound Ia 12 The structural formula of N-(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecano-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide is as follows:

[0063]

[0064] The preparation process is the same as that for compound Ia1, except that edaravone chloride is replaced with 3,4-dimethoxybenzoyl chloride, yielding 0.13 g of white solid with a yield of 43%. 1H NMR(500MHz,Chloroform-d)δ7.02(s,1H),6.96(s,1H),6.85(t,J=7.0Hz,1H),3.89(s,3H),3.88(s,3H),2.49(d, J=5.4Hz,3H),2.47(s,3H),2.20(s,2H),2.17–2.14(m,2H),2.04(d,J=10.2Hz,2H),1.93(d,J=12.7Hz,1H),1.85– 1.79(m,1H),1.69(d,J=11.8Hz,2H),1.62(d,J=12.9Hz,2H),1.49–1.43(m,2H),1.34(s,2H),1.33–1.30(m,2H),1 .25(s,2H),1.15(s,3H),1.14(s,3H),1.12(s,3H),1.08(d,J=8.5Hz,2H),0.98(s,3H),0.78(s,3H).MS(ESI):m / z 567.41[M+H] + .

[0065] Example 9 Compound Ia 13 Preparation

[0066] Compound Ia 13 It is (E)-4-(3-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecano-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenylacetic acid ester

[0067]

[0068] The preparation process is the same as that for compound Ia1, except that edaravone chloride is replaced with ferulic acid chloride, yielding 0.14 g of a yellow solid with a yield of 18%. 1H NMR(500MHz,Chloroform-d)δ7.63(dd,J=15.4,9.4Hz,1H),7.16–7.08(m,2H),7.06–7.01(m,2H),6.91–6.78(m,1H),4.19(d,J=7.6Hz,1H),3 .87(d,J=4.2Hz,3H),3.86(s,3H),3.06(d,J=13.4Hz,2H),2.96(d,J=5.6Hz,1H),2.75(s,3H),2.70(d,J=2.0Hz,1H),2.52(dd,J=12.3,4.2Hz, 1H),2.31(s,3H),2.20–2.15(m,1H),2.09–2.04(m,2H),1.93–1.87(m,2H),1.73(d,J=11.6Hz,2H),1.61(d,J=8.8Hz,2H),1.49(d,J=15.0Hz, 2H),1.36(d,J=6.7Hz,2H),1.32(s,2H),1.29(d,J=4.7Hz,2H),1.24(s,3H),1.15(s,3H),1.14(s,3H),1.11(s,3H),1.05(s,3H).MS(ESI):m / z 621.41[M+H] + .

[0069] Example 10 Compound Ia 14 Preparation

[0070] Compound Ia 14 It is (E)-4-(3-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetratetrahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate, with the following structural formula:

[0071]

[0072] The preparation process is the same as that for compound Ia1, except that edaravone chloride is replaced with (E)-3-(4-acetoxyphenyl)acryloyl chloride, yielding 0.20 g of a yellow solid with a yield of 27%. 1H NMR(500MHz,Chloroform-d)δ7.66(d,J=15.6Hz,1H),7.52(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.83(d,J=15.3Hz,1H),5.15(dd,J=11.2,6. 8Hz,1H),4.19(t,J=7.3Hz,1H),3.05(s,2H),2.48(s,3H),2.31(d,J=3. 3Hz,3H),2.20(s,1H),2.13(d,J=22.6Hz,2H),2.07(s,2H),2.05(d,J=4 .2Hz,2H),1.97–1.90(m,2H),1.88(d,J=5.4Hz,1H),1.72(d,J=5.7Hz,1 H),1.60(t,J=14.2Hz,2H),1.50–1.44(m,2H),1.38–1.33(m,2H),1.31( s,2H),1.29(d,J=3.0Hz,2H),1.26(t,J=3.8Hz,2H),1.15(s,3H),1.14( s,3H),1.12(s,3H),0.98(s,3H),0.79(s,3H).MS(ESI):m / z591.41[M+H] + .

[0073] Example 11 Preparation of compound b

[0074] Compound b is 4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)

[0075] (2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-16-ol, with the following structural formula:

[0076]

[0077] 15 g (37.3 mmol) of CVB-D was placed in a 1 L three-necked flask, and 540 mL of 3 mol / L hydrochloric acid was added. The temperature was controlled at 90 °C, and the reaction was carried out for 7-8 h. Heating was stopped, and the mixture was allowed to cool naturally to room temperature. The crude hydrochloride product was obtained by filtration. The filtered product was dissolved in water, and the pH was adjusted to >8. The mixture was extracted thoroughly in 1000 mL of dichloromethane in three portions. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 13 g of crude compound b. Compound b was then recrystallized twice with a mixed solvent of ethyl acetate / methanol to obtain 4 g of compound b. The yield was 27% (HPLC purity was 91%).

[0078] 1 H NMR(500MHz,Chloroform-d)δ5.25(d,J=6.0Hz,1H),4.16(ddd,J=9.7,6.9,2.5Hz,1H),2.51(dd,J=10.7,6.0Hz,1H),2.47(s,3H),2.47(s, 3H),2.19–2.14(m,2H),2.00–1.93(m,2H),1.94–1.89(m,2H),1.85–1.77(m,2H),1.74(dq,J=12.1,2.9,2.4Hz,1H),1.69(ddt,J=11.8,5.7 ,2.7Hz,1H),1.63(dd,J=10.4,6.9Hz,1H),1.55–1.48(m,1H),1.45(dd,J=13.6,2.7Hz,2H),1.40(dt,J=12.9,3.2Hz,2H),1.32(q,J=10.6H z,1H),1.13(d,J=6.1Hz,2H),1.06(s,3H),1.00(s,3H),0.98(s,3H),0.93(dd,J=11.9,2.2Hz,1H),0.79(s,3H),0.66(s,3H).MS(ESI):m / z 402.36[M+H] + .

[0079] Example 12 Preparation of compound b-1

[0080] Compound b-1 is 4,4,10,13,14-pentamethyl-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0081]

[0082] Compound b (3 g, 7.48 mmol) was placed in a round-bottom flask and 60 mL of dichloromethane was added. DMAP (91.38 mg, 0.748 mmol) and triethylamine (3.0 g, 29.9 mmol) were added sequentially. The mixture was placed in an ice bath and stirred until fully dissolved. Trifluoroacetic anhydride (7.9 g, 37.4 mmol) was slowly added dropwise. After the addition was complete, the reaction was observed to be complete by TLC. 60 mL of dichloromethane was added, and the mixture was washed successively with 1 M HCl, saturated NaHCO3, and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 14.89 g of pale yellow solid b, with a yield of 95%.

[0083] Example 13 Preparation of compound b-2

[0084] Compound b-2 is 4,4,10,13,14-pentamethyl-12-oxo-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0085]

[0086] CrO3 (2.9 g, 29 mmol) was placed in 100 mL of acetic acid and stirred. The temperature was raised to 80 °C. Compound b1 (5 g, 7.24 mmol) was added to the reaction flask and reacted for 2 h. The reaction was observed to be complete by TLC. The reaction mixture was poured into ice water to precipitate. After filtration, the obtained solid was dissolved in dichloromethane and washed successively with saturated NaHCO3 and saturated NaCl. Water was removed by anhydrous sodium sulfate, and dichloromethane was removed by rotary evaporation to obtain 4.5 g of white solid, with a yield of 88.2%.

[0087] Example 14 Preparation of compound c

[0088] Compound c is 16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,2,3,4,5,6,7,8,10,13,14,15,16,17-tetradecano-12H-cyclopentadieno[a]phenanthrene-12-one, with the following structural formula:

[0089]

[0090] Compound b-2 (1 g, 1.4 mmol) was placed in a round-bottom flask, 20 mL of MeOH was added, and the mixture was stirred. Then, 15 mL of saturated KOH solution was added, and the mixture was heated under reflux overnight. The reaction was detected by TLC and the MeOH was removed by rotary evaporation. 30 mL of dichloromethane was added to the reaction flask, and the mixture was extracted thoroughly. The mixture was washed with saturated NaCl solution, dehydrated with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 0.57 g of white solid compound c, with a yield of 96%. 1H NMR(500MHz,Chloroform-d)δ4.17(dt,J=48.5,8.2Hz,1H),2.50(d,J=6.7Hz,3H),2.46(d,J=10.1Hz,3H),2.16(s,1H),2. 09(s,1H),2.01(s,1H),1.92(s,2H),1.83(s,1H),1.81(d,J=12.2Hz,2H),1.70(s,2H),1.62(s,3H),1.50(s,2H),1.38(s,3 H),1.33(s,2H),1.28(d,J=7.0Hz,3H),1.19(d,J=16.6Hz,3H),1.13(s,2H),1.11(d,J=6.1Hz,2H),1.07(d,J=12.2Hz,1H) ,1.04(s,2H),1.02(s,1H),1.01(d,J=1.8Hz,3H),0.91s,1H),0.83(d,J=9.3Hz,3H),0.78(s,1H).MS(ESI):m / z417.3[M+H] + .

[0091] Example 15 Preparation of compound d

[0092] Compound d is 4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)

[0093] [a]phenanthrene-12,16-diol, with the following structural formula:

[0094]

[0095] Compound c (1 g, 2.4 mmol) was placed in a round-bottom flask, 20 mL of MeOH was added, followed by CeCl3·7H2O (1.34 g, 3.6 mmol), and then NaBH4 (0.136 g, 3.6 mmol) was added in portions. The mixture was heated under reflux overnight, and the reaction was checked by TLC to confirm completion. The remaining MeOH was evaporated to dryness, and 30 mL of dichloromethane was added to the reaction flask to dissolve the solid. The mixture was washed with saturated NaCl solution, dehydrated with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 0.92 g of white solid compound c, with a yield of 92%. 1HNMR(500MHz,Chloroform-d)δ5.98(d,J=6.7Hz,1H),5.59(s,1H),4.17(d,J=29.0Hz,2H),3.48(s,2H),2 .93(d,J=14.9Hz,1H),2.48(s,3H),2.46(s,3H),2.36(s,2H),2.23(d,J=33.3Hz,2H),1.97–1.95(m,2H),1 .90(d,J=12.2Hz,2H),1.78(s,2H),1.65(s,2H),1.56(d,J=14.2Hz,2H),1.42(d,J=10.4Hz,2H),1.25(s, 3H),1.20(d,J=5.3Hz,2H),1.14(s,3H),1.02(s,3H),0.97(s,3H),0.80(s,3H).MS(ESI):m / z419.36[M+H] + .

[0096] Example 16 Preparation of compound Ib1

[0097] 3-Methyl-1-phenyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0098]

[0099] Compound b (0.5 g, 1.24 mmol) was placed in a round-bottom flask, 30 mL of dry dichloromethane was added, followed by triethylamine (0.13 g, 1.24 mmol). The mixture was stirred until fully dissolved, and under ice bath conditions, edaravone chloride (0.22 g, 1.24 mmol) was slowly added dropwise under nitrogen protection. The reaction was confirmed by TLC. The solution was washed successively with saturated NaHCO3 and saturated brine, dehydrated with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The solution was purified by column chromatography (DCM:MeOH = 35:1), and the purified solution was evaporated to dryness to give 10.24 g of a pale white solid, compound Ib, in a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.57–7.51(m,2H),7.43–7.38(m,3H),7.25(s,3H),6.05–6.00(m,1H),4.41(s,1H), 4.06(d,J=7.8Hz,1H),3.47(dd,J=4.4,2.3Hz,1H),2.89–2.84(m,5H),2.62(d,J=4.6Hz,5H),2.30(s,5H),2.17(s, 3H),2.13(s,2H),1.93(s,2H),1.87(s,3H),1.73(s,3H),1.46(d,J=12.5Hz,2H),1.37(s,4H),1.28(d,J=3.6Hz,3 H),1.22(d,J=4.9Hz,3H),1.03(s,7H),0.96(s,7H),0.94(s,9H),0.93(s,8H),0.65(d,J=6.2Hz,5H).MS(ESI):m / z 603.43[M+H] + .

[0100] Example 17 Preparation of compound Ib2

[0101] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0102]

[0103] The preparation process is the same as that for compound Ib1, except that edaravone acyl chloride is replaced with 4-chloro-edaravone acyl chloride, yielding 0.15 g of a pale yellow solid with a yield of 19%.

[0104] 1 H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.51(s,1H),7.38(s,1H),7.37(d,J=2.0Hz, 1H),6.04(s,1H),4.44(dd,J=11.1,6.4Hz,1H),4.13(d,J=7.6Hz,1H),3.64(p,J=6.1Hz,

[0105] 1H),2.89(s,3H),2.82(s,1H),2.54(s,3H),2.30(s,3H),2.05(d,J=6.2Hz,2H),1.93(s,2H),

[0106] 1.84(d,J=12.8Hz,2H),1.71(d,J=12.3Hz,2H),1.64(s,2H),1.38(s,2H),1.25(s,2H),1.16(s, 2H),1.13(s,3H),1.12(s,3H),1.06(s,3H),1.03(s,3H),0.96(s,3H),0.86(s,3H).MS(ESI):m / z 637.39[M+H] + .

[0107] Example 18 Preparation of compound Ib3

[0108] 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0109]

[0110] The preparation process is the same as that for compound Ib1, except that edaravone acyl chloride is replaced with 4-fluoro-edaravone acyl chloride, yielding 0.17 g of a pale yellow solid with a yield of 22%. 1 H NMR(500MHz,Chloroform-d)δ7.57–7.53(m,2H),7.12(d,J=8.7Hz,2H),6.06(s,1H),4.53–4.45(m, 1H),4.16(s,1H),3.76–3.69(m,1H),3.17(s,1H),3.15(s,3H),3.14(s,3H),3.12(s,1H),2.90(s,2 H),2.80(s,3H),2.48(d,J=12.3Hz,2H),2.33(s,3H),2.17(s,2H),2.05(s,2H),1.96(s,1H),1.45( s,2H),1.44(s,3H),1.42(s,2H),1.31(s,3H),1.13(s,3H),1.10(s,3H),1.09(s,3H).MS(ESI):m / z 621.42[M+H] + .

[0111] Example 19 Preparation of compound Ib4

[0112] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0113]

[0114] The preparation process is the same as that for compound Ib1, except that edaravone chloride is replaced with 4-trifluoromethyl-edaravone chloride, yielding 0.13 g of white solid with a yield of 16%. 1 H NMR(500MHz,Chloroform-d)δ7.78(s,1H),7.77(s,1H),7.71(s,1H),7.69(s,1H),6.11(s,1H),4.47(d ,J=10.8Hz,1H),4.34(t,J=6.7Hz,1H),4.18(s,1H),2.97(s,3H),2.81(s,3H),2.35(s,3H),2.18(s,2H) ,2.09(s,2H),2.03(s,2H),1.98(d,J=9.0Hz,2H),1.77–1.75(m,2H),1.53(s,2H),1.47(d,J=4.3Hz,2H ),1.32(d,J=3.3Hz,3H),1.31(s,3H),1.29(s,3H),1.14(s,3H),1.09(s,3H),1.00(s,3H).MS(ESI):m / z 641.42[M+H] + .

[0115] Example 20 Preparation of compound Ib5

[0116] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0117]

[0118] The preparation process is the same as that of compound Ib1, except that edaravone chloride is replaced with 4-nitro-edaravone chloride, yielding 0.13 g of brown solid with a yield of 16%. 1 H NMR(500MHz,Chloroform-d)δ8.28(s,2H),8.26(d,J=1.9Hz,3H),7.84(s,2H),7.83(d,J=1.9Hz,2H),6.10(s,1H),4.46 (dd,J=11.3,6.4Hz,1H),4.17(d,J=7.6Hz,1H),2.97(s,3H),2.93(s,2H),2.76(s,6H),2.31(s,5H),2.20(s,1H),2.15( d,J=12.4Hz,3H),2.07(d,J=5.6Hz,3H),1.99(d,J=10.0Hz,4H),1.74(d,J=12.4Hz,4H),1.39(s,3H),1.28(d,J=2.9Hz, 9H),1.27(s,9H),1.25(s,7H),1.22(d,J=6.1Hz,5H),1.20(s,4H),1.10(s,7H),1.06(s,7H),0.97(s,6H).MS(ESI):m / z 648.41[M+H] + .

[0119] Example 21 Compound Ib 10 Preparation

[0120] 1-Phenylacetyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0121]

[0122] The preparation process is the same as that for compound Ib1, except that edaravone chloride is replaced with trifluoromethyledaravone chloride, yielding 0.15 g of white solid with a yield of 18%. 1H NMR(500MHz,Chloroform-d)δ7.59(s,1H),7.58(s,1H),7.47(s,1H),7.45(s,1H ),6.53(s,1H),4.44–4.38(m,1H),4.16(d,J=7.5Hz,1H),4.05(d,J=7.4Hz,1H),2 .86(s,3H),2.66(s,3H),2.65(s,3H),2.26(s,2H),2.13(s,2H),2.02(d,J=6.0Hz ,2H),1.91(s,2H),1.79(s,2H),1.75(d,J=9.2Hz,2H),1.65(s,2H),1.37(s,2H),

[0123] 1.26(d,J=4.8Hz,2H),1.17(s,3H),1.03(s,2H),1.02(s,3H),1.00(s,3H),0.96(s,3H),0.94(s,3H).MS(ESI):m / z 657.40[M+H] + .

[0124] Example 22 Compound Ib 11 Preparation

[0125] 2-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)carbamoyl)phenylacetate, with the following structural formula:

[0126]

[0127] The preparation process is the same as that for compound Ib1, except that edaravone chloride is replaced with aspirin chloride, yielding 0.17 g of white solid with a yield of 24%. 1H NMR (500MHz, DMSO-d6) δ6.68–6.65(m,2H),6.35(d,J=7.8Hz,2H),4.40(dd,J=10.5,6.6Hz,1H),3.75(t,J=7 .6Hz,1H),3.49(d,J=7.3Hz,1H),2.36(s,3H),2.31(s,3H),1.99(s,1H),1.96(s,3H),1.66(s,2H),1.61(s,2 H),1.44(s,2H),1.32(s,2H),0.87(s,3H),0.74(d,J=4.6Hz,2H),0.69(s,2H),0.65(d,J=6.1Hz,2H),0.55( d,J=6.7Hz,2H),0.51(s,3H),0.48(s,3H),0.45(s,3H),0.43(s,3H),0.26(s,3H).MS(ESI):m / z565.40[M+H] + .

[0128] Example 23 Compound Ib 12 Preparation

[0129] N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, with the following structural formula:

[0130]

[0131] The preparation process is the same as that for compound Ib1, except that edaravone chloride is replaced with 3,4-dimethoxybenzoyl chloride, yielding 0.15 g of white solid with a yield of 21%. 1H NMR(500MHz,Chloroform-d)δ7.40(d,J=15.6Hz,1H),7.34(d,J=8.3Hz,1H),6.91(s,1H),4.90(dd,J=11.4,6.5Hz,1H),3.92(t,J=7 .2Hz,1H),2.86(d,J=7.2Hz,3H),2.27(s,3H),2.10(s,3H),1.98(t,J=16.3Hz,2H),1.86(dd,J=11.2,5.8Hz,1H),1.73(s,2H),1.62( dd,J=15.3,8.0Hz,2H),1.52–1.42(m,2H),1.26(d,J=12.4Hz,1H),1.20(s,2H),1.13(d,J=11.7Hz,2H),1.06(d,J=7.8Hz,2H),0.94( d,J=6.8Hz,2H),0.83(s,3H),0.79(s,3H),0.77(s,3H),0.70(d,J=11.6Hz,1H),0.64(s,2H),0.58(s,3H),0.56(s,3H).MS(ESI):m / z 567.42[M+H] + .

[0132] Example 24 Compound Ib 13 Preparation

[0133] (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxopropyl-1-en-1-yl)-2-methoxyphenylacetate, with the following structural formula:

[0134]

[0135] The preparation process is the same as that for compound Ib1, except that edaravone chloride is replaced with ferulic acid chloride, yielding 0.2 g of a pale yellow solid with a yield of 26%. 1H NMR(500MHz,Chloroform-d)δ7.13(d,J=3.5Hz,1H),7.08(d,J=1.9Hz,1H),5.15(dd,J=11.5,6.5Hz,1H ),4.56(d,J=12.7Hz,1H),4.23(s,1H),3.09(s,3H),3.06(s,3H),2.98(s,2H),2.23(d,J=16.4Hz,1H),2 .16(d,J=12.5Hz,2H),2.11–2.07(m,1H),1.96(d,J=13.2Hz,2H),1.86–1.81(m,1H),1.69(s,2H),1.50 (t,J=12.3Hz,2H),1.42(s,2H),1.34(d,J=6.5Hz,1H),1.25(s,2H),1.16(d,J=6.8Hz,2H),1.10(s,3H),

[0136] 1.00(s,3H),0.94(d,J=4.9Hz,2H),0.92(s,3H),0.91(s,3H),0.79(s,3H).MS(ESI):m / z

[0137] 621.43 [M+H] + .

[0138] Example 25 Compound Ib 14 Preparation of (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxopropyl-1-en-1-yl)phenylacetate, with the following structural formula:

[0139]

[0140] The preparation process was the same as that of compound Ib1, except that edaravone chloride was replaced with (E)-3-(4-acetoxyphenyl)acryloyl chloride, yielding 0.18 g of a pale yellow solid with a yield of 24.6%. 1H NMR(500MHz,Chloroform-d)δ7.02(s,2H),6.84(d,J=8.1Hz,2H),5.24(s,1H),4.34(s,1H),3.8 9(s,3H),3.88(s,3H),3.01(s,1H),2.92(s,2H),2.49(s,3H),2.17(d,J=5.9Hz,2H),2.15(d,J=5 .9Hz,2H),1.95(s,2H),1.92(s,2H),1.71(d,J=12.1Hz,2H),1.40(s,2H),1.37(s,2H),1.34(s, 2H),1.25(s,3H),1.23(s,3H),1.01(s,3H),0.99(s,3H),0.80(s,3H).MS(ESI):m / z591.42[M+H] + .

[0141] Example 26 Compound Ic 12 Preparation

[0142] N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-12-oxo-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, with the following structural formula:

[0143]

[0144] The preparation process is the same as that of compound Ib. 12 The preparation steps differed only in that compound b was replaced with compound c, yielding 0.18 g of a pale yellow solid with a yield of 25.8%. 1 H NMR(500MHz,Chloroform-d)δ6.99(d,J=37.4Hz,2H),6.85(d,J=7.7Hz,1H),3.92(d,J=2.5Hz,1H),3.89(s,3H),3. 89–3.87(m,3H),3.03–2.97(m,2H),2.91(d,J=15.9Hz,2H),2.48(d,J=2.2Hz,3H),2.47–2.44(m,3H),1.96(s,2H),

[0145] 1.80(s,2H),1.56(d,J=5.5Hz,2H),1.46(d,J=11.5Hz,2H),1.35(d,J=6.6Hz,2H),1.30(d,J=7.8Hz,2H),1.2 5(s,3H),1.15(s,3H),1.02(s,3H),1.01(s,3H),0.83(d,J=4.9Hz,3H),0.77(d,J=17.1Hz,3H).MS(ESI):m / z 581.40[M+H] + .

[0146] Example 27 Compound Ic 14 Preparation

[0147] (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-12-oxo

[0148] -2,3,4,5,6,7,8,10,12,13,14,15,16,17-Tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenylacetate, with the following structural formula:

[0149]

[0150] The preparation process is the same as that of compound Ib. 14 The preparation steps differed only in that: compound b was replaced with compound c, yielding 0.18 g of a pale yellow solid and 0.13 g of a pale yellow solid, with a yield of 17.9%. 1 HNMR(500MHz,Chloroform-d)δ7.39–7.36(m,2H),6.93(d,J=8.1Hz,2H),4.11(t,J=6.7Hz,1H),3.96(d,J= 25.1Hz,1H),2.94(s,1H),2.86(t,J=8.8Hz,2H),2.77(d,J=5.1Hz,2H),2.41(t,J=1.9Hz,3H),2.13(s,3H),

[0151] 1.97–1.89(m,2H),1.63(d,J=15.1Hz,2H),1.56–1.52(m,1H),1.42–1.37(m,2H),1.27(t,J=4.0Hz,2H),1.12(d,J=7.1Hz,2 H),1.03(d,J=2.8Hz,3H),0.99(d,J=5.0Hz,3H),0.92(s,3H),0.81(d,J=3.7Hz,3H),0.73(s,3H),0.71(s,3H).MS(ESI):m / z 605.40[M+H] + .

[0152] Example 28 Preparation of compound Id3

[0153] 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0154]

[0155] The preparation process is the same as that of compound Ib3, except that compound b is replaced with compound d, yielding 0.13 g of a light white solid with a yield of 17.1%. 1 H NMR(500MHz,Chloroform-d)δ7.55(dd,J=6.3,3.2Hz,2H),7.14–7.12(m,2H),6.05(d,J=4.3Hz,1H),5.62 (d,J=8.2Hz,1H),4.34(dd,J=11.7,7.0Hz,1H),4.19(s,1H),3.74(s,1H),3.51(s,2H),2.96(d,J=4.1Hz,3 H),2.87(s,3H),2.80(s,3H),2.62–2.55(m,2H),2.46(dd,J=23.1,12.9Hz,2H),2.07(s,2H),1.87(s,2H) ,1.33(s,3H),1.30(s,3H),1.23(s,3H),1.17(s,3H),1.10(s,3H),1.04(s,3H),0.86(s,3H).MS(ESI):m / z

[0156] 637.41[M+H] + .

[0157] Example 29 Preparation of compound Id4

[0158] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0159]

[0160] The preparation process is the same as that of compound Ib4, except that compound b is replaced with compound d, yielding 0.18 g of white solid with a yield of 21.9%.

[0161] 1 H NMR(500MHz,Chloroform-d)δ7.66–7.62(m,2H),7.55(d,J=4.3Hz,2H),5.97(d,J=8.2Hz,1H),5.48–5.40(m,1H),4.0 5(s,1H),3.55(d,J=3.5Hz,1H),2.99–2.95(m,1H),2.84(d,J=15.0Hz,2H),2.76(d,J=16.5Hz,2H),2.61(s,3H),2.57 (s,3H),2.17(s,3H),1.91(s,2H),1.69(d,J=13.3Hz,2H),1.45(s,2H),1.27(t,J=7.5Hz,2H),1.17(d,J=5.1Hz,2H), 1.14(s,3H),1.12(s,2H),1.09(s,3H),1.07(s,2H),1.04(s,3H),1.03(s,2H),0.97(s,3H),0.90(s,3H).MS(ESI):m / z 687.41[M+H] + .

[0162] Example 30 Preparation of compound Id5

[0163] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0164]

[0165] The preparation process is the same as that of compound Ib5, except that compound b is replaced with compound d, yielding 0.16 g of white solid with a yield of 20.2%.

[0166] 1 H NMR(500MHz,Chloroform-d)δ8.28(dd,J=6.8,2.5Hz,2H),7.82(d,J=8.7Hz,2H),6.09(d,J=5.5Hz,1H),5.59(s,1H),4.30 (t,J=6.7Hz,1H),3.70(s,1H),3.64(p,J=6.1Hz,1H),3.10(q,J=7.4Hz,2H),3.03(s,1H),2.95(s,1H),2.75(s,3H),2.72(s ,3H),2.44–2.40(m,1H),2.32(s,3H),2.04(s,2H),1.94(d,J=13.0Hz,2H),1.84(s,2H),1.71(t,J=7.3Hz,2H),1.39(d,J= 7.3Hz,2H),1.28(d,J=2.5Hz,3H),1.26(s,3H),1.19(s,3H),1.17(d,J=4.6Hz,3H),1.13(s,3H),1.12(s,3H).MS(ESI):m / z 664.41[M+H] + .

[0167] Example 31 Compound Id 10 Preparation

[0168] 1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0169]

[0170] The preparation process is the same as that of compound Ib. 10 The preparation steps are the same as before, except that compound b is replaced with compound d, yielding 0.14 g of white solid with a yield of 17.4%. 1H NMR(500MHz,Chloroform-d)δ7.63–7.60(m,2H),7.52–7.49(m,2H),7.47(dd,J=11.0,3.9Hz,1H),6.56(d,J=5.7Hz,1H),5.6 3(s,1H),4.32(s,1H),4.14(s,1H),2.97(dd,J=9.8,4.7Hz,3H),2.88(d,J=6.7Hz,2H),2.77(d,J=6.9Hz,3H),2.45(d,J=17. 3Hz,2H),2.16(d,J=13.2Hz,2H),1.98(t,J=14.2Hz,2H),1.86(d,J=12.8Hz,2H),1.79–1.72(m,2H),1.49(d,J=10.4Hz,2H), 1.34(s,3H),1.29(s,3H),1.27(s,2H),1.23(s,2H),1.20(d,J=3.8Hz,3H),1.18(d,J=3.0Hz,3H),1.15(s,3H).MS(ESI):m / z 673.39[M+H] + .

[0171] Example 32 Preparation of compound b-3

[0172] 1,1,4a,6a,9a-pentamethyl-2-(2,2,2-trifluoro-N-methylacetamido)-7-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)hexadecylcyclopentenico[1,2]phenanthro[4,4a-b]epoxyethylene-8-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0173]

[0174] Compound b-1 (3 g, 4.34 mmol) was placed in a round-bottom flask, and 50 mL of dichloromethane was added and stirred until fully dissolved. Under ice bath conditions, m-CPBA (1.5 g, 8.69 mmol) was slowly added, and the reaction was stirred until complete. A saturated Na₂S₂O₃ solution was added to the reaction flask to remove excess m-CPBA. The organic phase was separated and washed successively with NaHCO₃ and saturated brine, then dehydrated with anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain 2.55 g of a white solid, compound b₃. ， The yield was 83.1%.

[0175] Example 33 Preparation of compound b-4

[0176] 9-Fluoro-4,4,10,13,14-pentamethyl-11-oxo-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)hexadecylhydro-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0177]

[0178] Compound b-3 (3 g, 4.14 mmol) was placed in a round-bottom flask, and 50 mL of dichloromethane was added to maintain the temperature below 0 °C in an ice bath. BF3·ET2O (5.88 g, 41.4 mmol) was slowly added until the reaction was complete. The reaction was detected by TLC. 50 mL of dichloromethane was added to the reaction flask, and the mixture was washed successively with water, saturated NaHCO3, and saturated NaCl solution. Anhydrous sodium sulfate was used to remove water, and excess solvent was removed by rotary evaporation. The mixture was purified by column chromatography (DCM:MeOH = 100:1) and dried to obtain 2.28 g of white solid, with a yield of 76.1%.

[0179] Example 34 Preparation of compound e

[0180] 9-Fluoro-16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)hexadecylhydro-11H-cyclopentadieno[a]phenanthrene-11-one, with the following structural formula:

[0181]

[0182] The preparation process is the same as that for compound c, except that compound b-2 is replaced with compound b-4, yielding 1.16 g of white solid with a yield of 96%.

[0183] 1 H NMR(500MHz,Chloroform-d)δ3.63(t,J=7.6Hz,1H),2.29(d,J=13.5Hz,1H),2.12–

[0184] 2.10(m,4H),1.93(s,3H),1.93(s,3H),1.68(d,J=13.6Hz,1H),1.46–1.40(m,2H),1.36(dd,J=11.9,4 .0Hz,1H),1.29(d,J=11.2Hz,2H),1.22–1.14(m,2H),0.95–0.92(m,1H),0.86(d,J=12.2Hz,1H),0.81 (s,3H),0.78(s,2H),0.74(d,J=13.7Hz,1H),0.57(d,J=6.2Hz,2H),0.55(s,3H),0.48(s,3H),0.45–0 .40(m,1H),0.37(s,2H),0.29(d,J=11.0Hz,1H),0.24(s,3H),0.20(s,3H).MS(ESI):m / z419.37[M+H] + .

[0185] Example 35 Preparation of compound If1

[0186] 3-Methyl-1-phenyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylcyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0187]

[0188] The preparation process is the same as that of compound Ib1, except that compound b is replaced with compound f, yielding 0.14 g of white solid with a yield of 16.8%. 1H NMR(500MHz,Chloroform-d)δ7.54(d,J=7.7Hz,2H),7.41(d,J=8.0Hz,2H),7.31(t,J=7.4Hz,1H),6.02(d,J=5.4Hz,1H),4.3 7(s,1H),4.09(t,J=7.2Hz,1H),2.92(d,J=4.4Hz,1H),2.87(d,J=6.1Hz,3H),2.60(d,J=3.1Hz,3H),2.31(s,3H),2.15(s,2H ),2.11(d,J=16.0Hz,2H),1.87(d,J=10.0Hz,2H),1.82(d,J=10.8Hz,2H),1.68(s,2H),1.34(s,2H),1.31(d,J=7.7Hz,2H),1 .27(s,3H),1.13(s,3H),1.12(s,3H),1.09(s,2H),1.05(d,J=3.0Hz,3H),0.92(s,3H),0.72(s,3H).(ESI):m / z619.42[M+H] + .

[0189] Example 36 Preparation of compound If2

[0190] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylcyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0191]

[0192] The preparation process is the same as that of compound Ib2, except that compound b is replaced with compound f, yielding 0.15 g of white solid with a yield of 18.9%. 1H NMR(500MHz,Chloroform-d)δ7.52–7.49(m,2H),7.38(d,J=8.7Hz,2H),6.03(d,J=4.0Hz,1H),4.40(s,1H),4.1 8(s,1H),2.96–2.93(m,1H),2.88(d,J=6.1Hz,3H),2.68(s,3H),2.29(s,3H),2.16(d,J=13.9Hz,2H),1.89(s,2H ),1.84(s,2H),1.72(s,2H),1.33(s,2H),1.29(s,3H),1.25(s,3H),1.20(s,3H),1.13(d,J=5.5Hz,2H),1.07(s ,3H),1.01(s,3H),0.96(t,J=7.4Hz,2H),0.87(d,J=5.6Hz,2H),0.83(d,J=11.7Hz,2H),0.73(s,3H).(ESI):m / z 653.39[M+H] + .

[0193] Example 37 Preparation of compound If3

[0194] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylcyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0195]

[0196] The preparation process is the same as that of compound Ib3, except that compound b is replaced with compound f, yielding 0.2 g of white solid with a yield of 26.3%. 1H NMR(500MHz,Chloroform-d)δ7.57–7.52(m,2H),7.14(d,J=8.2Hz,2H),6.05(s,1H),4.49–4.46( m,1H),4.33(d,J=7.0Hz,1H),4.20(s,1H),3.73(d,J=8.2Hz,1H),2.75(s,3H),2.68(s,3H),2.33( s,3H),2.21(s,2H),1.93(s,2H),1.89(s,2H),1.75(s,2H),1.57(d,J=13.6Hz,2H),1.32(s,3H),1 .26(s,3H),1.11(s,3H),1.10(s,3H),1.07(s,3H),0.99(t,J=7.4Hz,2H),0.73(s,3H).(ESI):m / z 637.42[M+H] + .

[0197] Example 38 Preparation of compound If4

[0198] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylhydrocyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0199]

[0200] The preparation process is the same as that of compound Ib4, except that compound b is replaced with compound f, yielding 0.18 g of white solid with a yield of 21.9%. 1H NMR(500MHz,Chloroform-d)δ7.67(d,J=8.4Hz,2H),7.58(d,J=7.6Hz,2H),6.01(s,1H),4.31(s,1H),4.20(t, J=6.7Hz,1H),4.10(d,J=8.5Hz,1H),3.55(dd,J=12.1,5.9Hz,1H),2.82(d,J=3.5Hz,3H),2.63(s,3H),2.20(s ,3H),2.06(d,J=13.1Hz,2H),1.80(s,2H),1.73(d,J=11.4Hz,2H),1.37–1.33(m,1H),1.31(d,J=4.5Hz,2H),1 .21(d,J=7.1Hz,4H),1.14(s,3H),1.03(s,3H),1.02(s,3H),0.97(s,3H),0.94(s,3H),0.64(s,3H).(ESI):m / z 687.41[M+H] + .

[0201] Example 39 Preparation of compound If5

[0202] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylhydrocyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0203]

[0204] The preparation process is the same as that of compound Ib5, except that compound b is replaced with compound f, yielding 0.1 g of brown solid with a yield of 12.6%. 1H NMR(500MHz,Chloroform-d)δ8.02–8.00(m,2H),7.61–7.57(m,2H),5.82(d,J=20.1Hz,1H),4.12(s,1H) ,3.91(d,J=18.5Hz,1H),2.87–2.80(m,1H),2.41(s,3H),2.29(dt,J=4.0,1.9Hz,3H),2.01(s,3H),1.89– 1.84(m,2H),1.41(s,2H),1.35(s,2H),1.11(t,J=7.4Hz,2H),1.04(s,2H),1.01(s,2H),0.92(s,3H),0.9 2(s,3H),0.78(s,3H),0.72(s,3H),0.67–0.60(m,2H),0.51(s,2H),0.45(s,3H).(ESI):m / z664.41[M+H] + .

[0205] Example 40 Compound If 10 Preparation

[0206] 1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylcyclopenteno[1,2]phenanthro[4,4a-b]epoxyethylene-7-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0207]

[0208] The preparation process is the same as that of compound Ib. 10 The preparation steps differed only in that compound b was replaced with compound f, yielding 0.18 g of a brown solid with a yield of 22.4%. 1H NMR(500MHz,Chloroform-d)δ7.57(d,J=7.7Hz,2H),7.47(d,J=7.0Hz,2H),7.42(t,J=7.2Hz,1H),6.52(s,1H),4.36(s,1H),4.13–4 .09(m,1H),3.13–3.09(m,1H),2.98(d,J=13.5Hz,1H),2.84(d,J=6.4Hz,3H),2.74(s,3H),2.59(d,J=13.6Hz,1H),2.45(d,J=11.5H z,1H),2.15(d,J=13.7Hz,1H),2.10(d,J=12.4Hz,1H),2.03–1.96(m,2H),1.89(s,2H),1.85(s,2H),1.70(s,2H),1.41(d,J=7.3Hz, 2H),1.33(s,2H),1.27(s,3H),1.25(s,3H),1.08(s,3H),1.07(s,3H),0.89(d,J=12.5Hz,2H),0.72(s,3H).(ESI):m / z673.40[M+H] + .

[0209] Example 41 Compound If 12 Preparation

[0210] N-(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexadecylcyclopenteno[1,2]phenanthro[4,4a-b]epoxyvinyl-7-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, with the following structural formula:

[0211]

[0212] The preparation process is the same as that of compound Ib. 12 The preparation steps differed only in that compound b was replaced with compound f, yielding 0.11 g of a brown solid with a yield of 15.8%. 1H NMR(500MHz,Chloroform-d)δ7.01(s,1H),6.94(d,J=6.8Hz,1H),6.84(d,J=7.8Hz,1H),4.19(s,1H),3.89 (s,3H),3.88(d,J=2.7Hz,3H),2.91(d,J=9.8Hz,3H),2.47(d,J=6.2Hz,3H),2.15(s,2H),1.91(d,J=11.2Hz ,2H),1.81(d,J=12.5Hz,2H),1.66(d,J=11.8Hz,2H),1.57–1.50(m,2H),1.44(d,J=15.3Hz,2H),1.31(s,2H ),1.25(s,3H),1.11(d,J=4.6Hz,3H),1.05(d,J=5.9Hz,3H),0.81(s,3H),0.68(d,J=3.4Hz,3H).(ESI):m / z 583.41[M+H] + .

[0213] Example 42 Preparation of compound g

[0214] 4,4,10,13,14-Pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)

[0215] (2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-16-ol, with the following structural formula:

[0216]

[0217] Take a 1L three-necked flask, add 550mL of 2mol / L hydrochloric acid, heat to reflux, add CVB-D (10g, 24.9mmol), react for 12h, stop heating, and allow to cool naturally to room temperature. Filter to obtain crude hydrochloride. Dissolve the filtered product in water, adjust the pH to >8, and extract thoroughly with 1000mL of dichloromethane in three portions. Separate the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 8.4g of crude compound b. The purity was 49% as determined by HPLC, and the yield was 41%.

[0218] Example 43 Preparation of compound g-1

[0219] 4,4,10,13,14-Pentamethyl-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-Tetradecano-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0220]

[0221] The preparation process is the same as that of compound b-1, except that compound b is replaced with compound g, yielding 4.8 g of a light white solid with a yield of 93.2%.

[0222] Example 44 Preparation of compound g-2

[0223] 4,4,10,13,14-pentamethyl-7,11-dioxo-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0224]

[0225] The preparation process was the same as that for compound b-2, except that compound b-1 was replaced with compound g-1, yielding 4.3 g of yellow solid with a yield of 83%.

[0226] Example 45 Preparation of compound g-3

[0227] 7-Hydroxy-4,4,10,13,14-pentamethyl-11-oxo-3-(2,2,2-trifluoro-N-methylacetamido)-17-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, with the following structural formula:

[0228]

[0229] The preparation process is the same as for compound d, except that compound c is replaced with compound g-2, yielding 0.9 g of a yellow solid with a yield of 90%.

[0230] Example 46 Preparation of Compound i

[0231] 7,16-Dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,2,3,4,5,6,7,10,12,13,14,15,16,17-tetradecano-11H-cyclopentadien[a]phenanthrene-11-one, with the following structural formula:

[0232]

[0233] The preparation process is the same as that of compound c, except that compound b-2 is replaced with compound g-3, yielding 0.57 g of a pale yellow solid with a yield of 95%. 1 H NMR(500MHz,Chloroform-d)δ4.58(dd,J=9.7,5.2Hz,1H),4.27(dd,J=9.8,4.4Hz,1H),3.70(td,J=10.1,5.0H z,1H),3.00–2.93(m,1H),2.87–2.82(m,2H),2.55–2.52(m,2H),2.50(d,J=3.0Hz,2H),2.48(s,3H),2.40(s,3H ),2.10(t,J=9.5Hz,1H),2.06–2.02(m,1H),1.61–1.57(m,1H),1.44(s,2H),1.41(d,J=3.0Hz,2H),1.31(d,J= 2.4Hz,3H),1.29(s,3H),1.15(s,2H),1.14(s,2H),1.04(s,3H),0.85(s,3H),0.81(d,J=8.5Hz,3H).(ESI):m / z 433.34[M+H] + .

[0234] Example 47 Preparation of compound h

[0235] 16-Hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,3,4,5,6,10,12,13,14,15,16,17-dodecano-7H-cyclopentadien[a]phenanthrene-7,11(2H)-dione, with the following structural formula:

[0236]

[0237] The preparation process is the same as that of compound c, except that compound b-2 is replaced with compound g-2, yielding 0.56 g of a pale yellow solid with a yield of 95%. 1H NMR(500MHz,Chloroform-d)δ3.99(t,J=8.0Hz,1H),2.72(t,J=15.2Hz,2H),2.48(s,2H),2.38(d,J=5.8Hz, 2H),2.36–2.35(m,2H),2.34(s,2H),2.31(s,3H),2.30(s,3H),2.20(dd,J=14.6,9.4Hz,2H),2.04–2.00(m,1 H),1.83–1.77(m,2H),1.58(dd,J=10.5,6.5Hz,1H),1.41(dd,J=10.0,7.2Hz,1H),1.26(s,3H),1.14(s,3H), 1.00(t,J=5.0Hz,1H),0.97(d,J=6.2Hz,2H),0.87(s,3H),0.68(s,3H),0.65(s,3H).(ESI):m / z430.32[M+H] + .

[0238] Example 48 Preparation of Compound Ih1

[0239] 1-Phenylacetyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0240]

[0241] The preparation process is the same as that for compound Ib1, except that compound b is replaced with compound h, yielding 0.13 g of white solid with a yield of 13%. 1H NMR(500MHz,Chloroform-d)δ7.54(d,J=8.1Hz,2H),7.42(d,J=7.8Hz,2H),7.34(d,J=7.6Hz,1H),6.02(s,1H ),4.40(s,1H),4.03(t,J=7.1Hz,1H),2.89(s,2H),2.47(d,J=3.7Hz,1H),2.44(s,3H),2.31(s,3H),1.55(s, 2H),1.54(d,J=4.7Hz,2H),1.39(s,3H),1.35–1.31(m,2H),1.27(s,3H),1.25(s,3H),1.15(s,2H),1.14(d,J =3.2Hz,2H),1.00(s,3H),0.96(t,J=7.3Hz,1H),0.83(s,3H),0.81(d,J=3.1Hz,3H).(ESI):m / z631.39[M+H] + .

[0242] Example 49 Preparation of Compound Ih2

[0243] 1-(4-chlorophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0244]

[0245] The preparation process is the same as that of compound Ib2, except that compound b is replaced with compound h, yielding 0.13 g of white solid with a yield of 17.2%. 1H NMR(500MHz,Chloroform-d)δ7.23(dd,J=8.8,1.5Hz,2H),7.10–7.07(m,2H),5.73(d,J=15.8Hz,1H),4.06( s,1H),3.91(s,1H),3.80(s,1H),3.34(s,1H),2.81–2.78(m,2H),2.39(s,3H),2.25(q,J=1.8Hz,3H),2.16(s ,2H),2.11(d,J=16.5Hz,2H),1.94(d,J=1.5Hz,3H),1.85–1.79(m,2H),1.26(d,J=12.8Hz,2H),1.08(d,J=1. 5Hz,3H),1.07(d,J=1.4Hz,3H),0.98(s,3H),0.94(s,3H),0.85(s,2H),0.78(s,3H),0.52(s,3H).(ESI):m / z 665.35[M+H] + .

[0246] Example 50 Preparation of compound Ih3

[0247] 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0248]

[0249] The preparation process is the same as that of compound Ib3, except that compound b is replaced with compound h, yielding 0.11 g of a light white solid with a yield of 14.6%. 1H NMR(500MHz,Chloroform-d)δ7.26–7.20(m,2H),6.83–6.80(m,2H),5.73(d,J=18.6Hz,1H),4.08(s,1H),3.80(t,J= 7.1Hz,1H),3.35(s,1H),2.71(d,J=13.8Hz,2H),2.56(s,3H),2.51(d,J=25.2Hz,2H),2.39(s,3H),2.26(p,J=1.9Hz, 3H),2.17(d,J=3.0Hz,2H),1.91(d,J=9.7Hz,1H),1.85–1.79(m,2H),1.67(s,2H),1.10(s,2H),1.09–1.08(m,2H),0 .99(s,3H),0.94(s,3H),0.93(s,2H),0.85(d,J=2.4Hz,2H),0.85–0.83(m,2H),0.79(s,3H),0.53(s,3H).(ESI):m / z 649.38[M+H] + .

[0250] Example 51 Preparation of compound Ih4

[0251] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0252]

[0253] The preparation process is the same as that for compound Ib4, except that compound b is replaced with compound h, yielding 0.13 g of white solid with a yield of 16%. 1H NMR(500MHz,Chloroform-d)δ7.58(d,J=8.4Hz,2H),7.50(d,J=8.3Hz,2H),5.90(d,J=6.6Hz,1H),3.94(s,1H),3.4 8(s,1H),2.84(d,J=13.6Hz,1H),2.75(s,2H),2.71(s,1H),2.53(s,3H),2.38(p,J=1.9Hz,3H),2.30(d,J=4.8Hz,2H ),2.25(d,J=15.9Hz,1H),2.09(s,3H),1.97(d,J=14.3Hz,2H),1.83–1.77(m,2H),1.38(d,J=6.7Hz,1H),1.24(s,3 (ESI): m / z 699.37[M+H] + .

[0254] Example 52 Preparation of compound Ih5

[0255] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0256]

[0257] The preparation process is the same as that of compound Ib5, except that compound b is replaced with compound h, yielding 0.12 g of brown solid with a yield of 12.7%. 1H NMR(500MHz,Chloroform-d)δ8.22(d,J=9.1Hz,2H),7.77(d,J=9.1Hz,2H),6.03(s,1H),4.10(s,1H),3 .46(s,1H),3.04(d,J=7.3Hz,3H),3.01(d,J=7.3Hz,3H),2.89(s,2H),2.49–2.45(m,2H),2.41(s,2H),2 .22(s,3H),2.09(d,J=14.4Hz,2H),1.98(q,J=12.5,11.6Hz,2H),1.35(s,2H),1.34(s,2H),1.32(s,3H) ,1.31(s,2H),1.23(s,2H),1.21(s,3H),1.20(s,2H),1.16(s,3H),1.06(s,3H),0.77(s,3H).(ESI):m / z 676.37[M+H] + .

[0258] Example 53 Compound Ih 10 Preparation

[0259] 1-Phenylacetyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, with the following structural formula:

[0260]

[0261] The preparation process is the same as that of compound Ib. 10 The preparation steps differed only in that compound b was replaced with compound h, yielding 0.16 g of a yellow solid with a yield of 12.7%. 1H NMR(500MHz,Chloroform-d)δ7.43(d,J=8.3Hz,2H),7.31–7.29(m,2H),7.25–7.21(m,1H),6.44(s,1H),3.94 (s,1H),3.64(s,1H),2.86(d,J=13.1Hz,1H),2.70(d,J=9.7Hz,3H),2.67(s,3H),2.40(q,J=2.0Hz,2H),2.32 (d,J=7.1Hz,2H),2.22(dd,J=30.7,16.0Hz,2H),1.95(d,J=17.5Hz,2H),1.80(d,J=19.2Hz,2H),1.44–1.34( m,2H),1.23(s,3H),1.13(s,3H),1.13(s,3H),1.09(s,3H),0.99(s,2H),0.94(s,3H),0.67(s,3H).(ESI):m / z 685.36[M+H] + .

[0262] Example 54 Compound Ih 11 Preparation

[0263] 2-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)carbamoyl)phenylacetate, with the following structural formula:

[0264]

[0265] The preparation process is the same as that of compound Ib. 11 The preparation steps differed only in that compound b was replaced with compound h, yielding 0.10 g of a yellow solid with a yield of 14.5%. 1H NMR(500MHz,Chloroform-d)δ7.01(s,2H),6.69(d,J=8.1Hz,2H),2.69(s,2H),2 .39(p,J=2.0Hz,3H),2.15(t,J=8.7Hz,2H),2.06(d,J=11.4Hz,2H),1.88(s,2H), 1.17(s,2H),1.11(s,2H),1.09(s,2H),1.06(s,3H),1.01(s,2H),0.93(s,3H),0 .92(s,3H),0.89(d,J=6.1Hz,2H),0.85(d,J=3.3Hz,3H),0.66(s,3H).(ESI):m / z 593.36 [M+H] + .

[0266] Example 55 Compound Ih 12 Preparation

[0267] Compound Ih 12 The structure of N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadieno[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide is as follows:

[0268]

[0269] The preparation process is the same as that of compound Ib. 12 The preparation steps differed only in that compound b was replaced with compound h, yielding 0.12 g of a yellow solid with a yield of 17.4%. 1 H NMR(500MHz,Chloroform-d)δ7.03(s,2H),6.84(d,J=8.1Hz,1H),3.89(s,3H),3.87 (s,3H),3.01–2.93(m,3H),2.87(s,3H),2.51–2.47(m,2H),2.25–2.12(m,2H),1.94( t,J=10.4Hz,2H),1.45(s,3H),1.38(d,J=12.4Hz,2H),1.29(s,2H),1.25(s,3H),1. 17(d,J=12.8Hz,2H),1.01(s,3H),0.95(s,2H),0.82(s,3H).(ESI):m / z595.38[M+H] + .

[0270] Example 56 Compound Ih 14 Preparation

[0271] Compound Ih 14 The structure of (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenylacetate is as follows:

[0272]

[0273] The preparation process is the same as that of compound Ib. 14 The preparation steps differed only in that compound b was replaced with compound h, yielding 0.16 g of a yellow solid with a yield of 22.3%. 1 H NMR(500MHz,Chloroform-d)δ7.54(s,1H),7.53(s,1H),7.11(s,1H),7.10(s,1H),5.15(s,1H),4.63(d,J=12. 5Hz,1H),4.25(s,1H),3.09(s,3H),3.06(s,3H),2.98(s,2H),2.52–2.46(m,3H),2.10(dd,J=28.6,14.5Hz,2H ),1.87–1.81(m,1H),1.75–1.66(m,1H),1.46(s,2H),1.42(t,J=7.3Hz,2H),1.36(s,3H),1.27(d,J=14.2Hz,2 (ESI): m / z 618.37[M+H] + .

[0274] Test example: Mouse hypoxia tolerance test

[0275] The following are animal experiments on the above compounds, namely, mouse hypoxia tolerance experiments. The specific procedures and results are as follows:

[0276] Animals used: male ICR mice, 25g±2g; grouping: blank control group, CVB-D positive control group, and test compound group were set up, and the mice were randomly divided into groups of 6 mice each; the dosage of CVB-D positive control group and test compound group was 7.5mg / kg, and the blank control group was given the same equivalent of physiological saline.

[0277] Experimental methods: The drug was dissolved in physiological saline and administered by gavage. Two hours after administration, mice in each group were placed in 250mL ground-glass stoppered bottles containing 15g of soda lime, sealed with Vaseline to prevent air leakage, and timed. The time of death due to hypoxia was observed and recorded as the indicator of respiratory arrest. The results were compared with the blank group and the CVB-D group, and a t-test was performed to calculate the p-value.

[0278] Results: As shown in Table 1 below, there was a significant difference between the CVB-D group and the blank control group in the above hypoxia tolerance experiment (p≤0.05), indicating that CVB-D can significantly enhance hypoxia tolerance.

[0279] Table 1 Comparison of Animal Experiment Results:

[0280]

[0281] Where p1 represents the difference from the blank control group, and p2 represents the difference from the CVB-D positive control group;

[0282] * indicates that the tested compound was significantly different from the blank control group, i.e., p≤0.05;

[0283] ** indicates that the tested compound showed a significant difference from both the blank control group and the CVB-D group, i.e., p≤0.05;

[0284] In Table 1 above, compounds b, e, i, Ia3, Ia4, Ia5, and Ia... 11 Ⅰa 12 Ⅰa 13 Ⅰa 14 Ⅰb2, Ⅰb3, Ⅰb4, Ⅰb 11 、Ⅰb 12 、Ⅰb 13 、Ⅰb 14 、Ⅰc 12 Ⅰd3, Ⅰh5, Ⅰh 10 、Ⅰh 14 All of them showed significant differences compared with the blank control group (p≤0.05), including Ia 12 Ⅰb2, Ⅰb3, Ⅰb 12 、Ⅰb 13 Compared with the blank control group and the CVB-D positive control group, both showed significant differences, demonstrating excellent hypoxia tolerance.

Claims

1. A class of cyclovinyl cinnamon D derivatives, characterized in that, The structural formula of the cycloviscose D derivative is shown below: 、 、 、 、 、 ； R5 is any one of the following structures: H or below. "Indicates the connection site: 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutically acceptable salt of the cycloviniferin D derivative as described in claim 1.

3. A pharmaceutical composition comprising the cycloviniferin D derivative of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. The use of the cyclovinyl cinnamic acid D derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of cardiovascular and cerebrovascular diseases.

5. The application of claim 4, wherein the cardiovascular and cerebrovascular diseases are angina pectoris, arrhythmia, hypertension, hyperlipidemia and ischemic stroke.

Images