A fuziside analogue and a preparation method and use thereof

Abstract

The application provides a fuzi glycoside analogue shown in formula I with a cardiotonic effect, and provides a new choice for clinical drugs with cardiotonic and anti-heart failure effects; meanwhile, the application also provides a synthesis method of the fuzi glycoside analogue, and enriches the total synthesis route of the fuzi glycoside analogue.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of compound synthesis, and particularly relates to a fuzinoside analogue and a preparation method and use thereof. BACKGROUND

[0002] Aconite is the rootlet processing product of Aconitum carmichaelii Debx. of Ranunculaceae, mainly produced in Jiangyou, Sichuan, Hanzhong, Shaanxi and Lijiang, Yunnan. As a famous traditional Chinese medicine, aconite is widely used for restoring yang, relieving cold and relieving pain in China, Japan and Southeast Asia (Chinese Pharmacopoeia, 2010 edition, Part I, page 177).

[0003] Cardiotonic effect is one of the main effects of traditional Chinese medicine aconite. The cardiotonic components found in aconite reported so far include racemic norlaudanosine (Chem. Pharm. Bull. 1976, 24, 178), methyldopamine hydrochloride (Planta Medica, 1979, 35, 150), salsoline (Acta Pharm. Sinica, 1982, 17, 792), uracil (Nat. Prod. Res. Dev. 1997, 9, 30), fuzinoside (Zhongcaoyao, 2004, 35, 964; Chinese patent CN100386338 C), zhongwuning (Chinese patent CN102146057 B) and the like.

[0004] Fuzinoside is a glycoside compound with significant cardiotonic activity isolated from Jiangyou aconite, and its presumed structure is shown in formula I. Experiments have proved that fuzinoside has the effect of increasing the content of calcineurin in rats. Since fuzinoside has a very low content in plants and its source is limited, a chemical synthesis method is expected to efficiently prepare the compound and new structural derivatives thereof, which has important significance for solving the source problem and discovering new cardiotonic active drugs.

[0005] SUMMARY

[0006] The present application aims to provide a fuzinoside analogue and a preparation method and use thereof.

[0007] The present application provides a fuzinoside analogue, which has the structure shown in formula I:

[0008]

[0009] wherein R is NH2 or OR', and R' is nitro, phosphate, sulfate, sulfite or borate;

[0010] R1 and R2 are independently selected from H or and R1 and R2 are not H at the same time.

[0011] Further, R' is nitro.

[0012] Further, R1 is H, and R2 is or R1 is R2 is H.

[0013] Further, the aconitine analogue has the structure shown in formula II:

[0014]

[0015] Further, it has any of the following structures:

[0016]

[0017] The present application also provides a preparation method of the aforesaid aconitine analogue, comprising the following steps:

[0018] (1) reacting compound A with a silyl ether protecting agent in an organic solvent under the action of a base to obtain an intermediate, then removing water from the intermediate and further reacting the intermediate with compound B in the presence of a promoter and a catalyst to obtain a silyl ether-protected compound C;

[0019] (2) reacting compound C in an organic solvent under the action of a deprotecting agent a to obtain compound D;

[0020] (3) reacting compound D in an organic solvent under the action of a deprotecting agent b to obtain the aconitine analogue shown in formula I; the reaction scheme is as follows:

[0021]

[0022] wherein, R a , R b are each independently selected from a silyl ether protecting group or and R a , R b are not simultaneously a silyl ether protecting group;

[0023] R a ', R b ' are each independently selected from H or and R a ', R b ' are not simultaneously H;

[0024] Bz is benzoyl, and STol is p-tolylthio.

[0025] Further, the molar ratio of compound A to the silyl ether protecting agent and the base in step (1) is 1:(1-1.5):(1.5-2.5), preferably 1:1.2:2;

[0026] The molar ratio of the intermediate to compound B, the promoter and the catalyst is 1: (1-2): (2-4): (0.1-0.5), preferably 1:1.5:3:0.2;

[0027] The silyl ether protecting agent is TIPSOTf, TBSOTf, TESOTf or TBDPSOTf, preferably TIPSOTf; the silyl ether protecting group is TIPS, TBS, TES or TBDPS, preferably TIPS;

[0028] The base is triethylamine, pyridine, p-dimethylaminopyridine, dimethylpyridine, imidazole, DBU or tetramethylpiperidine, preferably triethylamine;

[0029] The organic solvent is dichloromethane, 1,2-dichloroethane, trichloromethane, tetrahydrofuran, toluene or diethyl ether, preferably dichloromethane;

[0030] The promoter is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodonium bromide, preferably N-iodosuccinimide;

[0031] The catalyst is silver trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic acid, preferably silver trifluoromethanesulfonate;

[0032] The water is removed by adding 4A molecular sieve.

[0033] Further, the molar ratio of the compound C to the deprotecting agent a in step (2) is 1: (0.05-0.1), preferably 1: (0.7-0.8);

[0034] The organic solvent is a mixed solvent of tetrahydrofuran and water, tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water; preferably, the organic solvent is a mixed solvent of tetrahydrofuran and water with a volume ratio of 1:1;

[0035] The deprotecting agent a is trifluoroacetic acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, preferably trifluoroacetic acid.

[0036] Further, the molar ratio of the compound D to the deprotecting agent b in step (3) is 1: (4-8), preferably 1: (4-5);

[0037] The organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;

[0038] The deprotecting agent a is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide.

[0039] Further, the reaction condition of the compound A with the silyl ether protecting agent in step (1) is as follows: after adding base at 0-5°C for 5-15 min, dropwise adding the silyl ether protecting agent and reacting for 20-40 min, then increasing the temperature to 20-30°C and reacting for 8-14 h;

[0040] The reaction condition of the intermediate with the compound B is as follows: reacting the intermediate with the compound B in an organic solvent at -30 to -50°C for 10 min, then adding a promoter and reacting for 20-40 min, further adding a catalyst, increasing the temperature to 0-5°C and reacting for 8-14 h.

[0041] Further, the reaction condition in step (2) is as follows: adding trifluoroacetic acid at 0-5°C and reacting at 30-50°C for 8-14 h.

[0042] Further, the reaction condition in step (3) is as follows: reacting at 20-30°C for 3-5 h.

[0043] Further, the intermediate in step (1) is purified by the following method before reacting with the compound B: dichloromethane extraction, water washing, saturated brine washing, drying and concentration, and then silica gel column chromatography purification.

[0044] The compound C in step (2) is purified by the following method before reacting with the deprotecting agent a: saturated Na2S2O3 solution washing, dichloromethane extraction, water washing, saturated brine washing, drying and concentration, and then silica gel column chromatography purification.

[0045] The compound D in step (3) is purified by the following method before reacting with the deprotecting agent b: adjusting the pH value to 6.5-7.5, ethyl acetate extraction, water washing, saturated brine washing, drying and concentration, and then silica gel column chromatography purification.

[0046] Further, in the above preparation method, when R is OR', the compound A is prepared according to the following method steps:

[0047] (1') reacting the compound B with the compound 2 in an organic solvent, in the presence of a promoter, a catalyst and a water-removing agent to obtain the compound 3;

[0048] (2') reacting the compound 3 in an organic solvent, in the presence of an acid to obtain the compound 4;

[0049] (3') reacting the compound 4 with the compound R'-OH in an acid anhydride to obtain the compound 5;

[0050] (4') reacting the compound 5 in an organic solvent with a deprotecting agent to obtain the compound 6;

[0051] (5') reacting the compound 6 with the compound 1 in an organic solvent, in the presence of a catalyst to obtain the compound A.

[0052] The reaction formula is as follows:

[0053]

[0054] wherein STol is a p-tolylthio group, Bz is a benzoyl group, Ph is a phenyl group, and R' is a nitro group, a phosphate group, a sulfate group, a sulfite group, or a borate group.

[0055] Further, the molar ratio of the compound B to the compound 2, the promoter, the catalyst, and the water-removing agent in step (1') is 1:(1-2):(1-2):(0.05-0.15), preferably 1:1.5:1.5:0.1; and the mass ratio of the compound B to the water-removing agent is 1:(0.5-3), preferably 1:1.

[0056] The organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, toluene, or diethyl ether, preferably dichloromethane.

[0057] The promoter is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, or bromine iodine, preferably N-iodosuccinimide.

[0058] The catalyst is silver trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, or trifluoromethanesulfonic acid, preferably silver trifluoromethanesulfonate.

[0059] The water-removing agent is a 4A molecular sieve.

[0060] Further, the molar ratio of the compound 3 to the acid in step (2') is 1:(0.01-0.05), preferably 1:(0.03-0.04).

[0061] The acid is hydrochloric acid, trifluoroacetic acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, or camphorsulfonic acid, preferably hydrochloric acid.

[0062] The organic solvent is tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water, preferably tetrahydrofuran.

[0063] Further, the mass-to-volume ratio of the compound 4 to the compound R'-OH in step (3') is (1-5) g:1 mL.

[0064] The anhydride is acetic anhydride, and the R'-OH is nitric acid, phosphoric acid, sulfuric acid, sulfurous acid, or boric acid, preferably nitric acid.

[0065] Further, the molar ratio of the compound 5 to the deprotecting agent in step (4') is 1:(4-5), preferably 1:4.5;

[0066] The organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;

[0067] The deprotecting agent is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide.

[0068] Further, the molar ratio of the compound 6, the compound 1 and the catalyst in step (5') is 1:(2-3):(0.05-0.15), preferably 1:2.5:0.1;

[0069] The catalyst is d-camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, preferably d-camphorsulfonic acid;

[0070] The organic solvent is acetone, dichloromethane, trichloromethane or tetrahydrofuran, preferably acetone.

[0071] Further, the reaction condition in step (1') is that the compound B and the compound 2 are reacted in the organic solvent at 0-5℃ for 10 min, then the accelerator is added and reacted for 20-40 min, the catalyst is added and the temperature is raised to 20-30℃ for 2-4 h.

[0072] Further, the reaction condition in step (2') is that the compound 3 is added with acid at 0-5℃, then the temperature is raised to 20-30℃ for 2-4 h.

[0073] Further, the reaction condition in step (3') is that the compound 4 and R'-OH are reacted at 0-5℃ for 15-35 min, then the temperature is raised to 20-30℃ for 2-4 h.

[0074] Further, the reaction condition in step (4') is that the temperature is 20-30℃ for 1-3 h.

[0075] Further, the reaction condition in step (5') is that the temperature is 20-30℃ for 3-5 h.

[0076] Further, the product after each reaction in steps (1')-(5') is purified by silica gel column chromatography.

[0077] The application also provides the use of the above-mentioned compound in the preparation of a drug for strengthening heart contraction and / or resisting heart failure.

[0078] Further, the above-mentioned drug is a drug for strengthening heart contraction.

[0079] The application also provides a cardiotonic agent which is a preparation prepared from the above compound as an active ingredient and pharmaceutically acceptable adjuvants.

[0080] The application provides a new aconitine analogue with cardiotonic effect, and provides a new choice for clinical cardiotonic and anti-heart failure drugs.

[0081] In the application, TIPSOTf refers to triisopropylsilyl trifluoromethanesulfonate (CAS: 1328887-45-1); TIPS refers to a-SiPr3 protecting group, and Pr refers to isopropyl.

[0082] TBSOTf refers to tert-butyldimethylsilyl trifluoromethanesulfonate (CAS: 69739-34-0); TBS refers to a tert-butyldimethylsilyl protecting group;

[0083] TESOTf refers to triethylsilyl trifluoromethanesulfonate (CAS: 79271-56-0); TES refers to a-SiEt3 protecting group, and Et is ethyl.

[0084] TBDPSOTf refers to tert-butyldiphenylsilyl trifluoromethanesulfonate; TBDPS refers to a t-BuPh2Si- group, t-Bu is a tert-butyl group, and Ph is a phenyl group.

[0085] DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0086] In the application, “nitric acid, phosphoric acid, sulfuric acid, sulfurous acid or boric acid” refers to pure acid in a liquid state or a high-concentration aqueous solution thereof. For example, a high-concentration nitric acid solution (concentrated nitric acid) refers to a nitric acid aqueous solution with a concentration of 8 mol / L or higher, preferably a nitric acid aqueous solution with a concentration of 8 mol / L or higher.

[0087] Obviously, according to the above content of the application, according to the ordinary technical knowledge and common means in the art, other various forms of modifications, replacements or changes can be made without departing from the above basic technical idea of the application.

[0088] The above content of the application will be further described in detail through the following embodiment form. However, it should not be understood that the scope of the above subject matter of the application is limited to the following examples. Any technology realized based on the above content of the application belongs to the scope of the application. DETAILED DESCRIPTION

[0089] The raw materials and equipment used in the application are known products, which are obtained by purchasing commercially available products.

[0090] The K-H solution used in the application is prepared and has the following concentrations.

[0091]

[0092] Rats for rat isolated heart function experiment: healthy SD rats, body weight 250 g, male and female. Provided by Sichuan University Animal Experiment Center, animal qualification certificate number: SCXK (Chuan) 2018-026.

[0093] Example 1, synthesis of the fuzi glycoside analog of the application

[0094] Synthetic route:

[0095]

[0096] Preparation of compound 3: 1 (30 g, 42.7 mmol) and 2 (11.5 g, 64.1 mmol) were dissolved in dry dichloromethane (450 mL), followed by the addition of 4A molecular sieves (30 g). After the reaction solution was stirred at 0°C for 10 min, NIS (14.4 g, 64.1 mmol) was added. After the addition, the reaction was continued to stir at this temperature for 30 min, and then AgOTf (1.1 g, 4.3 mmol) was added. After the addition, the reaction solution was slowly raised from 0°C to room temperature. After 3 h of reaction, the reaction was quenched with Et3N, and the molecular sieves were filtered off. The filtrate was washed with saturated Na2S2O3 solution, extracted with dichloromethane (200 mL x 2), washed with water and saturated brine, and dried over anhydrous MgSO4. After vacuum concentration, the crude product was purified by silica gel column chromatography (PE:EA = 10:1 to 5:1 gradient elution) to obtain white foamy solid 3 (23.7 g, 73%).

[0097] 1 H NMR (400 MHz, Chloroform-d) δ 8.11 - 8.03 (m, 4H), 7.94 (dd, J = 12.8, 7.2 Hz, 4H), 7.56 - 7.45 (m, 6H), 7.37 - 7.25 (m, 11H), 6.10 - 6.02 (m, 1H), 5.67 (d, J = 5.4 Hz, 1H), 5.65 (s, 1H), 5.57 (d, J = 11.6 Hz, 2H), 4.85 - 4.79 (m, 1H), 4.74 (d, J = 5.3 Hz, 2H), 4.42 (d, J = 11.8 Hz, 2H), 4.09 (t, J = 11.9 Hz, 2H), 3.71 (s, 1H).

[0098] 13C NMR (100 MHz, CDC13) δ 166.09, 165.77, 165.69, 165.39, 138.18, 133.39, 133.36, 133.22, 133.07, 130.05, 129.95, 129.84, 129.70, 129.46, 129.03, 128.92, 128.41, 128.37, 128.32, 128.22, 126.21, 105.07, 101.43, 82.28, 81.80, 70.46, 70.32, 69.40, 68.82, 63.31

[0099] HRMS (ESI): m / z calcd for C 44 H 38 O 12 [M+Na] + 781.2255, found 781.2259.

[0100] Preparation of compound 4: 3 (23.7 g, 31.2 mmol) was dissolved in tetrahydrofuran (450 mL), followed by the addition of 4 M HC1 (300 mL) at 0 °C. After the addition, the reaction solution was slowly raised from 0 °C to room temperature. After 3 h of reaction, the pH was adjusted to about 7 by slowly adding saturated NaHC03solution at 0 °C. Ethyl acetate (300 mL x 2) was extracted, washed with water and saturated brine, and dried over anhydrous MgS04. After concentration under vacuum, the crude product was purified by silica gel column chromatography (PE:EA = 2:1 to 1:2 gradient elution) to obtain white foamy solid 4 (15.5 g, 74%).

[0101] 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J = 7.6 Hz, 2H), 8.00 (dd, J = 11.5, 7.8 Hz, 4H), 7.92 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 4H), 7.46 - 7.29 (m, 8H), 6.00 - 5.96 (m, 1H), 5.73 (dd, J = 5.7, 1.8 Hz, 1H), 5.52 (s, 1H), 5.49 (d, J = 1.8 Hz, 1H), 4.82 (dd, J = 5.5, 4.1 Hz, 1H), 4.77 (d, J = 4.7 Hz, 1H), 4.72 (dd, J = 11.9, 6.7 Hz, 1H), 3.93 - 3.89 (m, 1H), 3.81 - 3.66 (m, 4H).

[0102] 13C NMR (100 MHz, CDC13) δ 166.18, 166.13, 165.65, 165.56, 133.66, 133.38, 133.21, 129.95, 129.88, 129.75, 129.44, 129.30, 128.74, 128.52, 128.47, 128.41, 106.50, 83.28, 81.01, 80.97, 70.21, 63.08, 63.05, 62.39.

[0103] HRMS (ESI): m / z calcd for C 37 H 34 O 12 [M+Na] + 693.1942, found 693.1938.

[0104] Preparation of compound 5: 4 (15.5 g, 23.1 mmol) was dissolved in acetic anhydride (200 mL), followed by slow dropwise addition of concentrated HNO3 solution (10 mL dissolved in 200 mL acetic anhydride) at ice bath. After addition, the reaction was slowly raised to room temperature after stirring at 0 °C for 20 minutes. After 2.5 h of reaction, the pH was adjusted to about 7 by slowly adding saturated NaHCO3 solution at 0 °C. Ethyl acetate (200 x 2) was extracted, washed with water and saturated brine, and dried over anhydrous MgSO4. After concentration under vacuum, the crude product was purified by silica gel column chromatography (PE:EA = 8:1 to 6:1 gradient elution) to give 5 as a white foamy solid (15.3 g, 87%).

[0105] 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J = 7.5 Hz, 2H), 8.03 (d, J = 7.5 Hz, 2H), 7.98 (d, J = 7.7 Hz, 2H), 7.88 (d, J = 7.5 Hz, 2H), 7.60 - 7.52 (dd, 4H), 7.46 - 7.22 (m, 8H), 6.07 - 6.03 (m, 1H), 5.66 (d, J = 6.3 Hz, 1H), 5.48 (s, 1H), 5.45 (s, 1H), 4.80 - 4.72 (m, 3H), 4.70 - 4.58 (m, 4H), 4.39 - 4.30 (m, 1H). 13C NMR (100 MHz, CDC13) δ 166.06, 165.67, 165.58, 165.46, 133.62, 133.53, 133.33, 133.15, 129.96, 129.87, 129.85, 129.67, 129.42, 129.32, 128.73, 128.51, 128.47, 128.43, 128.35, 105.37, 82.55, 81.97, 77.21, 70.89, 70.29, 70.16, 69.81, 63.23.

[0106] HRMS (ESI): m / z calcd for C 37 H 32 N2O 16 [M+Na] + 783.1644, found 783.1641.

[0107] Preparation of compound 6: 5 (15.3 g, 20.1 mmol) was dissolved in methanol (400 mL) followed by the addition of NaOMe (4.9 g, 90.6 mmol). After addition, it was stirred at room temperature. After 2 h of reaction, the pH of the reaction was adjusted to around 7 using activated cation exchange resin. It was suction filtered and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1 to 7:1 gradient elution) to give 6 as a white foamy solid (5.9 g, 86%).

[0108] 1 H NMR (400 MHz, DMSO-d6) δ 5.37 (d, J = 6.0 Hz, 1H), 5.11 (d, J = 5.4 Hz, 1H), 4.91 (d, J = 1.6 Hz, 1H), 4.73 (dd, J = 11.6, 4.0 Hz, 1H), 4.66 (d, J = 4.8 Hz, 2H), 4.61 (dd, J = 12.2, 6.0 Hz, 2H), 4.52 (t, J = 5.9 Hz, 1H), 4.26 - 4.21 (m, 1H), 3.88 - 3.81 (m, 1H), 3.80 - 3.72 (m, 2H), 3.54 - 3.48 (m, 1H), 3.40 - 3.32 (m, 2H).

[0109] 13 C NMR (100 MHz, DMSO) δ 108.20, 83.01, 82.61, 77.07, 72.71, 72.46, 70.39, 70.07, 63.36.

[0110] HRMS (ESI): m / z calcd for C9H16 N2O 12 [M+Na] + 367.0601, found 367.0598.

[0111] Preparation of compound 7: 6 (5.9 g, 17.1 mmol) was dissolved in dry acetone (150 mL) followed by the addition of 2,2-dimethoxypropane (5.3 mL, 42.9 mmol) and D-CSA (0.4 g, 1.7 mmol). After addition, it was stirred at room temperature. After 4 h of reaction, the reaction was quenched by the addition of Et3N and directly concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 2:1 to 1:1.5 gradient elution) to give 7 as a light yellow oil (6.4 g, 97%).

[0112] 1 H NMR (400 MHz, Chloroform-d) δ 5.18 (s, 1H), 4.77 (s, 2H), 4.70 (dd, J = 12.0, 4.1 Hz, 1H), 4.63 (dd, J = 12.2, 4.8 Hz, 1H), 4.53 (dd, J = 12.2, 5.4 Hz, 1H), 4.45 (dd, J = 11.8, 7.2 Hz, 1H), 4.37 - 4.31 (m, 2H), 4.19 (t, J = 1.3 Hz, 1H), 4.15 - 4.06 (m, 2H), 4.01 - 3.91 (m, 2H), 1.40 (d, J = 8.7 Hz, 6H).

[0113] 13 C NMR (100 MHz, CDC13) δ 110.30, 108.54, 86.38, 78.53, 78.28, 75.43, 71.07, 70.03, 69.82, 65.57, 25.50, 25.44.

[0114] HRMS (ESI): m / z calcd for C 12 H 20 N2O 12 [M+Na] + 407.0908, found 407.0912.

[0115] Preparation of compounds 8 and 9: 7 (4.9 g, 12.7 mmol) was dissolved in dry dichloromethane (100 mL) followed by the addition of triethylamine (Et3N) (3.5 mL, 25.5 mmol) at 0 °C. After the addition, the reaction was stirred at this temperature for 10 min before the slow addition of triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) (4.1 mL, 15.3 mmol). After the addition, the reaction was stirred for 30 min before it was allowed to warm up to room temperature slowly. The reaction was left to stir overnight before it was quenched by the addition of saturated NH4Cl solution. Dichloromethane (60 mL x 2) was used to extract the product, which was then washed with water and saturated brine before being dried over anhydrous MgSO4. After being concentrated in vacuo, the crude product was purified by silica gel column chromatography (PE:EA = 7:1 to 2:1 gradient elution) to give a mixture of yellowish oil 4.1 g.

[0116] The above mixture (4.1 g, 7.6 mmol) and 1 (8.0 g, 11.4 mmol) were dissolved in dry dichloromethane (150 mL) followed by the addition of 4A molecular sieves (5 g). After the reaction was stirred at -40 °C for 10 min, NIS (5.1 g, 22.8 mmol) was added. After the addition, the reaction was stirred at this temperature for another 30 min before silver trifluoromethanesulfonate (AgOTf) (0.4 g, 1.5 mmol) was added. After the addition, the reaction was allowed to warm up from -40 °C to 0 °C slowly. The reaction was left to stir overnight before it was quenched by the addition of Et3N and the molecular sieves were filtered off. The filtrate was washed with saturated Na2S2O3 solution and extracted with dichloromethane (100 mL x 2) before being washed with water and saturated brine and dried over anhydrous MgSO4. After being concentrated in vacuo, the crude product was purified by silica gel column chromatography (PE:EA = 9:1 to 5:1 gradient elution) to give yellowish foamy solid 8 (2.4 g, 19%, 2 steps) and yellowish foamy solid 9 (4.8 g, 37%, 2 steps).

[0117] Compound 8:

[0118] 1H NMR (400 MHz, Chloroform-d) δ 8.09 - 8.00 (m, 4H), 7.98 - 7.90 (m, 4H), 7.56 - 7.49 (m, 3H), 7.45 - 7.30 (m, 9H), 6.05 - 6.01 (m, 1H), 5.71 - 5.62 (m, 1H), 5.53 (s, 1H), 5.42 (s, 1H), 5.40 - 5.30 (m, 1H), 4.81 (dd, J = 11.6, 4.6 Hz, 1H), 4.75 - 4.67 (m, 2H), 4.65 - 4.60 (m, 1H), 4.57 - 4.49 (m, 2H), 4.46 - 4.37 (m, 1H), 4.31 (dd, J = 6.2, 3.4 Hz, 1H), 4.27 - 4.22 (m, 1H), 4.09 - 4.02 (m, 2H), 3.95 - 3.85 (m, 2H), 3.50 (s, 1H), 1.39 (s, 3H), 1.34 (s, 3H), 1.11 - 1.06 (m, 3H), 1.05 (d, J = 4.8 Hz, 18H).

[0119] 13 C NMR (100 MHz, CDC13) δ 166.05, 165.55, 165.52, 165.11, 133.56, 133.47, 133.37, 133.19, 129.92, 129.86, 129.71, 129.33, 128.45, 128.40, 109.54, 107.29, 106.03, 90.95, 83.22, 81.91, 81.87, 77.59, 74.68, 71.06, 70.42, 70.33, 70.21, 65.55, 63.06, 26.27, 25.48, 17.91, 17.88.

[0120] HRMS (ESI): m / z calcd for C 55 H 66 N2O 21 Si[M+Na] + 1141.3819, found 1141.3817.

[0121] Compound 9:

[0122] 1H NMR (400 MHz, Chloroform-d) δ 8.07 - 8.02 (m, 4H), 7.99 - 7.89 (m, 4H), 7.60 - 7.48 (m, 4H), 7.42 (t, J = 7.8 Hz, 2H), 7.38 - 7.30 (m, 6H), 6.05 - 6.01 (m, 1H), 5.67 (dd, J = 4.9, 1.1 Hz, 1H), 5.50 (d, J = 1.2 Hz, 1H), 5.44 (s, 1H), 5.13 (s, 1H), 4.78 (dd, J = 12.0, 4.2 Hz, 1H), 4.74 - 4.67 (m, 2H), 4.58 (dd, J = 11.8, 4.0 Hz, 1H), 4.53 (dd, J = 12.1, 4.9 Hz, 1H), 4.48 - 4.39 (m, 3H), 4.36 - 4.25 (m, 2H), 4.21 (dd, J = 6.3, 4.1 Hz, 1H), 4.04 (dd, J = 4.0, 0.9 Hz, 1H), 3.95 (dd, J = 8.4, 7.0 Hz, 1H), 3.89 (dd, J = 8.3, 6.3 Hz, 1H), 1.42 (s, 3H), 1.31 (s, 3H), 1.12 - 1.06 (m, 3H), 1.03 (d, J = 5.5 Hz, 18H).

[0123] 13 C NMR (100 MHz, CDC13) δ 165.98, 165.60, 165.54, 165.22, 133.56, 133.43, 133.26, 133.08, 129.92, 129.89, 129.81, 129.67, 129.45, 129.41, 128.90, 128.75, 128.44, 128.39, 128.34, 109.91, 108.20, 105.74, 85.31, 84.64, 82.04, 82.00, 80.83, 75.58, 70.97, 70.78, 70.49, 69.16, 65.49, 63.35, 26.39, 25.14, 17.72, 11.89.

[0124] HRMS (ESI): m / z calcd for C 55 H 66 N2O 21 Si[M + Na] + 1141.3819, found 1141.3817.

[0125] Preparation of compound 10: 9 (4.8 g, 4.2 mmol) was dissolved in a mixture of tetrahydrofuran-water (48 mL, 1 : 1), followed by slow dropwise addition of CF3COOH (24 mL) at 0 °C. After addition, the reaction was stirred at 40 °C. The reaction was left overnight, and the pH was adjusted to about 7 by adding saturated NaHC03solution. Ethyl acetate (40 mL x 2) was extracted, washed with water and saturated brine, and dried over anhydrous MgS04. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE:EA = 1.5:1 to PE:EA = 1:2.5 gradient elution) to give 10 as a white foamy solid (3.1 g, 80%).

[0126] 1 H NMR (400 MHz, Chloroform-d) δ 8.12 - 8.02 (m, 4H), 8.00 - 7.94 (m, 2H), 7.91 - 7.83 (m, 2H), 7.65 - 7.55 (m, 1H), 7.55 - 7.48 (m, 3H), 7.44 (t, J = 7.6 Hz, 2H), 7.39 - 7.27 (m, 6H), 6.14 - 6.10 (m, 1H), 5.61 (dd, J = 5.4, 0.9 Hz, 1H), 5.52 (d, J = 1.6 Hz, 1H), 5.50 (s, 1H), 5.15 (s, 1H), 4.79 (dd, J = 11.8, 4.1 Hz, 1H), 4.76 - 4.65 (m, 2H), 4.54 (dd, J = 11.7, 4.5 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.36 - 4.25 (m, 4H), 4.23 - 4.18 (m, 1H), 3.98 (s, 1H), 3.78 - 3.368 (m, 2H).

[0127] 13 C NMR (100 MHz, CDC13) δ 166.62, 165.73, 165.66, 165.54, 133.60, 133.46, 133.30, 129.92, 129.84, 129.77, 129.70, 129.28, 129.22, 128.85, 128.62, 128.46, 128.42, 128.40, 107.89, 106.05, 84.96, 84.11, 82.13, 81.92, 78.53, 77.55, 71.19, 70.75, 70.42, 70.05, 69.34, 63.94, 63.76.

[0128] HRMS (ESI): m / z calcd for C 43 H 42 N2O 21 [M+Na]+ 945.2172, found 945.2174.

[0129] Preparation of compound 11: 10 (2.9 g, 3.1 mmol) was dissolved in methanol (100 mL), followed by the addition of NaOMe (0.76 g, 14.1 mmol). After addition, it was stirred at room temperature. After 4 h, the pH of the reaction was adjusted to about 7 with activated cation exchange resin. It was suction filtered, and the filtrate was concentrated under vacuum. The crude product was purified by normal silica gel column chromatography (eluted with DCM:MeOH:H2O = 15:5:1) and reverse phase silica gel column chromatography (eluted with H2O:MeOH = 5:1). After lyophilization, 11 was obtained as a white solid (1.48 g, 93%).

[0130] 1 H NMR (400 MHz, D2O) δ 5.21 (s, 1H), 5.13 (d, J = 1.6 Hz, 1H), 4.86 (dd, J = 12.4, 4.0 Hz, 1H), 4.77 - 4.65 (m, 3H), 4.47 - 4.42 (m, 1H), 4.23 (dd, J = 1.9, 1.1 Hz, 1H), 4.18 - 4.10 (m, 3H), 4.08 (dd, J = 6.7, 3.9 Hz, 1H), 3.96 - 3.92 (m, 2H), 3.86 - 3.82 (m, 1H), 3.69 (qd, J = 11.6, 6.0 Hz, 4H).

[0131] 13 C NMR (100 MHz, D2O) δ 107.30, 106.99, 83.04, 83.01, 82.71, 81.25, 79.35, 76.53, 71.65, 70.96, 70.44, 70.36, 62.84, 62.81.

[0132] HRMS (ESI): m / z calcd for C 15 H 26 N2O 17 [M+Na] + 529.1123, found 529.1126.

[0133] Preparation of compound 12: 8 (2.4 g, 2.1 mmol) was dissolved in a mixture of tetrahydrofuran-water (24 mL, 1 : 1), followed by slow dropwise addition of CF3COOH (12 mL) at 0 °C. After addition, the reaction was stirred at 40 °C. The reaction was left overnight, and the pH was adjusted to about 7 by adding saturated NaHC03solution. Ethyl acetate (20 mL x 2) was extracted, washed with water and saturated brine, and dried over anhydrous MgS04. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE:EA = 1.5:1 to 1 :2.5 gradient elution) to give 12 as a white foamy solid (1.6 g, 82%).

[0134] 1 H NMR (400 MHz, Chloroform-d) δ 8.10 - 7.95 (m, 6H), 7.90 - 7.84 (m, 2H), 7.60 - 7.49 (m, 4H), 7.45 - 7.24 (m, 8H), 6.06 - 6.02 (m, 1H), 5.67 (dd, J = 5.2, 1.1 Hz, 1H), 5.51 (s, 1H), 5.45 (d, J = 1.3 Hz, 1H), 5.28 (d, J = 0.9 Hz, 1H), 4.84 (dd, J = 11.8, 4.5 Hz, 1H), 4.75 - 4.65 (m, 2H), 4.59 - 4.54 (m, 2H), 4.52 - 4.43 (m, 2H), 4.33 - 4.26 (m, 1H), 4.21 (dd, J = 3.6, 1.3 Hz, 1H), 4.19 - 4.14 (m, 1H), 4.06 - 4.03 (m, 1H), 3.88 - 3.83 (m, 1H), 3.77 - 3.71 (m, 2H), 3.30 (s, 1H), 2.66 (s, 1H), 2.44 (s, 1H).

[0135] 13 C NMR (100 MHz, CDC13) δ 165.17, 164.96, 164.66, 164.62, 132.67, 132.39, 132.27, 128.95, 128.90, 128.88, 128.72, 128.37, 128.28, 127.73, 127.49, 127.46, 127.43, 105.08, 105.01, 86.95, 83.34, 81.61, 80.70, 76.10, 75.08, 70.14, 70.02, 69.63, 69.22, 69.14, 62.88, 62.18.

[0136] HRMS (ESI): m / z calcd for C 43 H 42 N2O21 [M+Na] + 945.2172, found 945.2171.

[0137] Preparation of compound 13: 12 (1.4 g, 1.5 mmol) was dissolved in methanol (50 mL), followed by the addition of NaOMe (0.37 g, 6.8 mmol). After addition, it was stirred at room temperature. After 4 h of reaction, the pH of the reaction solution was adjusted to about 7 with activated cation exchange resin. After suction filtration, the filtrate was concentrated under vacuum, and the crude product was purified by normal silica gel column chromatography (eluted with DCM:MeOH:H2O = 15:5:1) and reverse phase silica gel column chromatography (eluted with H2O:MeOH = 5:1), and then lyophilized to obtain white solid 13 (0.69 g, 90%).

[0138] 1 H NMR (400 MHz, D2O) δ 5.29 (s, 1H), 5.17 (d, J = 1.2 Hz, 1H), 4.85 (dd, J = 12.4, 4.0 Hz, 1H), 4.77 (d, J = 3.9 Hz, 1H), 4.72 (dd, J = 12.8, 5.9 Hz, 2H), 4.46 - 4.41 (m, 1H), 4.23 (dd, J = 6.6, 2.9 Hz, 1H), 4.13 - 4.06 (m, 3H), 4.03 - 3.97 (m, 2H), 3.88 - 3.83 (m, 2H), 3.77 - 3.60 (m, 4H).

[0139] 13 C NMR (100 MHz, D2O) δ 107.14, 105.81, 87.26, 83.31, 82.65, 81.22, 76.65, 75.33, 71.71, 71.07, 70.67, 70.56, 70.22, 62.79, 62.74.

[0140] HRMS (ESI): m / z calcd for C 15 H 26 N2O 17 [M+Na] + 529.1123, found 529.1122.

[0141] The beneficial effects of the present application are demonstrated by the following experimental examples.

[0142] Experimental Example 1, Results of the in vitro frog heart experiment of the aconitum glycoside analog of the present application

[0143] 1. Experimental method

[0144] The cardiotonic effects of the compounds 6, 11, 14, 16, 17 prepared by the embodiment 1 of the present application and the positive drug cediranate are verified and compared through the isolated frog heart experiment.

[0145] 2. Experimental results

[0146] As shown in Table 1

[0147] Table 1: Results of the isolated frog heart experiment

[0148]

[0149] It can be seen that the compounds 11 and 13 both have excellent cardiotonic activity.

[0150] Experimental Example 2: Effects of the aconitum glycoside analogues of the present application on the isolated heart function of rats

[0151] 1. Test method

[0152] 1.1 Animal grouping

[0153] The healthy SD rats are randomly divided into 19 groups, and three positive drug control groups are respectively set, including: the deacetylcynarin injection group (0.015 mg), the dopamine injection group (0.075 mg), and the nitroglycerin injection group (0.15 mg); another compound 13 drug group, respectively: 0.075 mg, 0.15 mg, 0.3 mg, 0.6 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg dose groups, and the compound 11 drug group, respectively: 0.075 mg, 0.15 mg, 0.3 mg, 0.6 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg dose groups.

[0154] 1.2 Drug preparation

[0155] 1.2.1 Preparation of the compound 13 drug

[0156] 1 ml of the compound 13 drug stock solution (5 mg / ml) is added into K-H solution in a continuous doubling dilution manner to obtain 2.5 mg / ml, 2.5 mg / ml, 1.25 mg / ml, 0.625 mg / ml, 0.3 mg / ml, 0.15 mg / ml, and 0.075 mg / ml drug solutions, respectively. Each concentration of the drug solution is administered at a dose of 0.3 ml / time.

[0157] 1.2.2 Preparation of the compound 11 drug

[0158] Take compound 11 stock solution (5 mg / ml) 1 ml, according to the continuous doubling dilution method to add K-H liquid respectively obtained 2.5 mg / ml, 2.5 mg / m, 1.25 mg / ml, 0.625 mg / ml, 0.3 mg / ml, 0.15 mg / ml, 0.075 mg / ml drug solution. Each concentration of drug solution according to 0.3 ml / time drug dosage.

[0159] 1.2.3 The configuration of desacetyllanatoside injection group

[0160] Take desacetyllanatoside injection stock solution (0.2 mg / ml) 1 ml, add K-H liquid 3 ml, mix well, and then desacetyllanatoside injection 4 times dilution solution (0.05 mg / ml) is obtained. Each time 0.3 ml of drug is administered. 0.05 mg / ml

[0161] 1.2.4 The configuration of dopamine injection

[0162] Take hydrochloric acid dopamine injection stock solution (10 mg / ml) 1 μl, add K-H liquid 9999 μl, mix well, and then 1 μg / ml is obtained. Take hydrochloric acid dopamine injection (1 μg / ml) 1 ml. Add K-H liquid 3 ml, mix well, and then 0.3 ml of drug is administered each time. 0.25 μg / ml

[0163] 1.2.5 The configuration of nitroglycerin injection

[0164] Take nitroglycerin injection stock solution (5 mg / ml) 1 ml, add K-H liquid 9 ml, mix well, and then nitroglycerin 10 times dilution solution (0.5 mg / ml) is obtained. Each time 0.3 ml of drug is administered. 0.5 mg / ml 0.5 mg / ml 0.5 mg / ml 0.5 mg / ml 0.5

[0165] 1.3 Observation index:

[0166] Collect heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), left ventricular pressure difference (ΔLVP), left ventricular end diastolic pressure (LVEDP), left ventricular pressure change rate (±dp / dtmax), epicardial electrocardiogram and other indicators before and after administration.

[0167] 1.4 Langendorff isolated heart perfusion method

[0168] ​​​SD rats weighing 250-400 g were selected, and general anesthesia was performed by intraperitoneal injection of 2.5% chloral hydrate 1-1.5 ml + 1% heparin 1 ml (or other anesthetics), fixed, opened the chest, quickly exposed the heart and lifted it, and the aorta was transected at a distance of 0.5-1.5 cm from the aortic root. The heart was immediately placed in 4°C K-H solution to stop beating, and the blood in the coronary artery was squeezed out by pressing the heart several times. The right atrium was cut to facilitate the outflow of the perfusion solution. The aortic stump was clamped with an ophthalmic clamp and hung on the Langendorff isolated heart perfusion device. After fixation, the water stop clamp was opened, and K-H solution was perfused into the coronary artery at a constant pressure (8.33 kPa) and constant temperature (37°C) through the aorta, and the heart was reactivated. After stabilization, the indicators of cardiac function were recorded (three times in one minute, and the average value was taken). Then the isolated hearts in each group were administered according to the grouping, and the above-mentioned indicators were observed and recorded.

[0169] 1.4 Statistical method

[0170] The effective and safe dose was determined according to the response of animals to each dose, and the data of 6 effective animals from each dose group were taken for statistical processing, and the average value ± standard deviation was represented. The SPSS 13.0 statistical software was used for t test between groups, and the test level α = 0.05.

[0171] 2. Test results

[0172] 2.1 Effect of compound 13 drug on isolated rat heart function

[0173] The results of the effect of compound 13 drug on isolated rat heart function are shown in Tables 1-1 and 1-2.

[0174] Table 1-1

[0175]

[0176]

[0177] Table 1-2

[0178]

[0179] The results show that compared with the heart rate before administration of each isolated heart, after administration of compound 13 in each dose group, the positive control group of deacetyl lanatoside group, dopamine group and nitroglycerin group, there was no significant effect on the perfusion heart rate of isolated rat heart (P > 0.05) ; compared with each positive drug control group, there was also no significant difference in the effect of compound 13 in each dose group on heart rate (P > 0.05).

[0180] Compound 13 in 8 dose groups all significantly increased LVSP (P<0.01); the positive drug control group of dopamine hydrochloride and lanatoside A also significantly increased LVSP (P<0.05) after administration, while nitroglycerin significantly decreased LVSP (P>0.05) after administration; compared with the positive control drug groups of dopamine and lanatoside A, compound 13 more significantly increased LVSP (P<0.05).

[0181] The above results show that compound 13 has a very definite effect of enhancing myocardial contractility, and the effect is more obvious than that of dopamine and lanatoside A. Even at a low concentration (0.075 mg), compound 13 can increase left ventricular systolic pressure by 71.5%.

[0182] The results also show that, compared with the LVEDP before administration of each isolated perfused heart in the compound 13 different concentration administration groups, the positive drug control groups of lanatoside A, dopamine and nitroglycerin, the LVEDP after administration has no significant effect (P>0.05); compared with the LVEDP in each positive drug control group, the LVEDP in the compound 13 different concentration administration groups also has no significant effect (P>0.05). The left ventricular end-diastolic pressure mainly reflects the diastolic function of the left ventricle. The above results show that, while enhancing LVSP, compound 13, like dopamine, lanatoside A and other drugs that enhance LVSP, has no adverse effect on ventricular diastolic function.

[0183] Further, compared with before administration, the compound 13 administration groups, the positive drug control groups of lanatoside A and dopamine all significantly increased the maximum rate of left ventricular pressure rise (+dp / dtmax) of the isolated rat heart after administration (P<0.05-0.01); especially, even at a low concentration (0.075 mg), compound 13 increased the +dp / dtmax rate by 125% (P<0.01); while the other positive control drug nitroglycerin had no significant change in +dp / dtmax after administration (P>0.05); compared with lanatoside A and dopamine, the effects of compound 13 at different concentrations were similar to those of dopamine, and more obvious than those of lanatoside A (P<0.05).

[0184] Further, compared with the heart rate before administration, the left ventricular end-diastolic pressure of the rats in each of the compound 13 dose groups, the positive control group of lanatoside C, the positive control group of dopamine and the positive control group of nitroglycerin was increased after administration, i.e. the absolute value was obviously or very obviously increased (P<0.05-0.01). There was no significant difference in the increase of the left ventricular end-diastolic pressure among the compound 13 dose groups. The increase of the left ventricular end-diastolic pressure in the compound 13 dose groups was similar to that in the positive control groups of dopamine and lanatoside C. However, the absolute value of the left ventricular end-diastolic pressure in the positive control group of nitroglycerin was obviously decreased (P<0.05).

[0185] The above results show that each of the compound 13 dose groups has an obvious effect of improving heart function.

[0186] 2.2 Effect of compound 11 on the function of isolated rat heart

[0187] The results of the effect of compound 11 on the function of isolated rat heart are shown in Tables 2-1 and 2-2.

[0188] Table 2-1

[0189]

[0190] Table 2-2

[0191]

[0192]

[0193] The results show that, compared with the heart rate before administration, the heart rate of the rats in each of the compound 11 dose groups, the positive control group of lanatoside C, the positive control group of dopamine and the positive control group of nitroglycerin was not obviously affected after administration (P>0.05). There was no significant difference in the effect of each of the compound 11 dose groups on the heart rate (P>0.05). There was also no significant difference in the effect of each of the compound 11 dose groups on the heart rate compared with the positive control groups (P>0.05).

[0194] Compound 11 at 8 doses, positive drug control group dopamine, and Lanatoside C all significantly or very significantly increased LVSP (P<0.05~0.01), especially Compound 11 even at a low concentration (0.075 mg) increased LVSP by more than 1-fold; between different dose groups of Compound 11, there was no significant difference in the effect of each dose group on LVSP, i.e. with the increase of the concentration of Compound 11, LVSP did not have a tendency to increase with the increase of the drug concentration; compared with the positive drug control group dopamine and Lanatoside C, Compound 11 had a more obvious effect on increasing LVSP; while nitroglycerin significantly decreased LVSP (P>0.05) after administration.

[0195] Further, compared with before administration, Compound 11 at different doses, positive drug control group Lanatoside C, dopamine, and nitroglycerin had no significant effect on LVEDP after administration (P>0.05); between different dose groups of Compound 11, there was no significant difference in the effect of each dose group on LVEDP (P>0.05); compared with the positive drug control group dopamine, Lanatoside C, and nitroglycerin, there was also no significant difference in the effect of different concentrations of Compound 11 on LVEDP (P>0.05).

[0196] Further, compared with before administration, Compound 11 at different doses, positive drug control group Lanatoside C and dopamine significantly increased the maximum left ventricular pressure rise rate (+dp / dtmax) of the isolated rat heart after administration (P<0.05~0.01); especially Compound 11 even at a low concentration (0.075 mg) increased the +dp / dtmax rate by 157% (P<0.01); between different dose groups of Compound 11, there was no significant difference in the effect of each dose group on +dp / dtmax (P>0.05); compared with Lanatoside C and dopamine, Compound 11 at different concentrations had a similar effect as dopamine and a more obvious effect than Lanatoside C (P<0.05); while another positive control drug nitroglycerin had no significant change in +dp / dtmax after administration (P>0.05);

[0197] Further, compared with before administration, Compound 11 at different doses, positive drug control group Lanatoside C and dopamine significantly increased the maximum left ventricular pressure rise rate (+dp / dtmax) of the isolated rat heart after administration (P<0.05~0.01); especially Compound 11 even at a low concentration (0.075 mg) increased the +dp / dtmax rate by 157% (P<0.01); between different dose groups of Compound 11, there was no significant difference in the effect of each dose group on +dp / dtmax (P>0.05); compared with Lanatoside C and dopamine, Compound 11 at different concentrations had a similar effect as dopamine and a more obvious effect than Lanatoside C (P<0.05); while another positive control drug nitroglycerin had no significant change in +dp / dtmax after administration (P>0.05);

[0198] In summary, the aforementioned results show that both compound 13 and compound 11 significantly enhance LVSP and +dp / dtmax. Compound 11 has a more pronounced enhancing effect on LVSP and a more significant enhancing effect on +dp / dtmax than compound 13. Neither compound 13 nor compound 11 has a significant effect on left ventricular end-diastolic pressure (LVEDP) in isolated rat hearts, but both significantly accelerate the rate of decrease in -dp / dtmax. Overall, both compound 13 and compound 11 significantly improve the function of isolated rat hearts without significantly affecting heart rate, with compound 11 showing a more pronounced effect.

[0199] Therefore, compared with the positive control drugs deslanoside and dopamine, which also enhance cardiac function, compounds 13 and 11 have similar or even more pronounced effects.

[0200] Experimental Example 3: Effective concentration of the aconitine analogue of the present invention on the function of isolated rat heart

[0201] Based on the results of Experiment 2, it can be found that compounds 13 and 11 still have a strong cardiotonic effect at only 0.075 mg / ml (1 / 8 times). Therefore, further efficacy tests were conducted to significantly reduce their drug concentrations.

[0202] Preliminary test results for compound 11 after significant dilution showed that the concentration of compound 11 reached 0.024 μg / ml. Even at concentrations of 0.0048 μg / ml, it still has a weak effect, but there is no significant difference compared to KH buffer; at concentrations of 0.0048 μg / ml... When the concentration was approximately 10 times higher than that of the KH buffer solution, the differences in various cardiac function indicators were less significant compared to those of the KH buffer solution. The results are shown in Tables 3-1 and 3-2.

[0203] Preliminary test results for compound 13 after significant dilution showed that the concentration of compound 13 reached 0.015 μg / ml. Even at a concentration of 0.0075 μg / ml, it still had a weak effect, but there was no significant difference compared to the results with KH buffer; the dilution concentration reached 0.0075 μg / ml. When the concentration was approximately 10 times higher than that of the KH buffer solution, the effect essentially disappeared, and the cardiac function indicators showed little difference compared to those obtained with the KH buffer solution. The results are shown in Tables 3-1 and 3-2.

[0204] Table 3-1

[0205]

[0206] Table 3-2

[0207]

[0208] The above results show that the ineffective concentration of the compound 11 compound on isolated rat heart may be in the range of 0.0048 μg / ml (fold) to 0.024 μg / ml (fold), and the minimum effective concentration is near 0.024 μg / ml (fold). The ineffective concentration of the compound 13 compound on isolated rat heart may be in the range of 0.0075 μg / ml (fold) to 0.015 μg / ml (fold); and the minimum effective concentration is also near 0.015 μg / ml (fold). That is, the compound of the present application can also exhibit inotropic effect at a lower concentration.

[0209] In summary, the present application provides a new fuziline analogue with inotropic effect, which provides a new choice for inotropic and anti-heart failure clinical drugs. Meanwhile, the present application also provides a synthesis method of the fuziline analogue, which enriches the total synthesis route of the fuziline analogue.​​​​​​

Claims

1. A fuzinoside analogue, characterized in that, It has the structure shown in Formula I: Wherein, R is OR', R' is nitro; R1, R2are each independently selected from H or and R1, R2are not simultaneously H.

2. The fuzisin analogue of claim 1, wherein, It has any one of the following structures:

3. The method of preparing an aconitum glycoside analogue according to claim 1 or 2, characterized in that, Comprising the following steps: (1) Compound A is reacted with a silyl ether protecting agent in an organic solvent under the action of a base to obtain an intermediate, the intermediate is dehydrated, and then the intermediate is further reacted with compound B in the presence of a promoter and a catalyst to obtain a silyl ether protecting group-protected compound C; (2) Compound C is reacted with a deprotecting agent a in an organic solvent to obtain compound D; (3) Compound D is reacted with a deprotecting agent b in an organic solvent to obtain a tuberoside analogue shown in Formula I; the reaction formula is as follows: wherein R a , R b are each independently selected from a silyl ether protecting group or and R a , R b are not the same silyl ether protecting group; R a ’ and R b ’ are each independently selected from H or and R a ’ and R b ’ are not simultaneously H; Bz is benzoyl, and STol is p-tolylthio.

4. The production method according to claim 3, wherein The molar ratio of compound A to the silyl ether protecting agent and the base in step (1) is 1:(1-1.5):(1.5-2.5); The molar ratio of the intermediate to compound B, the promoter and the catalyst is 1:(1-2):(2-4):(0.1-0.5); The silyl ether protecting agent is TIPSOTf, TBSOTf, TESOTf or TBDPSOTf; the silyl ether protecting group is TIPS, TBS, TES or TBDPS; And / or the base is triethylamine, pyridine, p-dimethylaminopyridine, dimethylpyridine, imidazole, DBU or tetramethylpiperidine; And / or the organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether; And / or the promoter is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodonium bromide; And / or the catalyst is silver trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic acid; And / or the dehydration is dehydration by adding 4A molecular sieves; The reaction conditions of compound A and the silyl ether protecting agent are as follows: after the base is added at 0-5°C for 5-15 min, the silyl ether protecting agent is added dropwise, and the reaction is carried out at 20-30°C for 8-14 h after the reaction is carried out at 20-30°C for 20-40 min; The reaction conditions of the intermediate and compound B are as follows: the intermediate and compound B are reacted in an organic solvent at -30 to -50°C for 10 min, then the promoter is added and the reaction is carried out at 20-30°C for 20-40 min, and then the catalyst is added and the reaction is carried out at 0-5°C for 8-14 h.

5. The production method according to claim 4, wherein The molar ratio of compound A to the silyl ether protecting agent and the base in step (1) is 1:1.2:2; And / or, the molar ratio of the intermediate to compound B, the promoter and the catalyst in step (1) is 1:1.5:3:0.2; And / or, the silyl ether protecting agent in step (1) is TIPSOTf; And / or, the silyl ether protecting group in step (1) is TIPS; And / or, the base in step (1) is triethylamine; And / or, the organic solvent in step (1) is dichloromethane; And / or, the promoter in step (1) is N-iodosuccinimide; And / or, the catalyst in step (1) is silver trifluoromethanesulfonate.

6. The production method according to claim 3, wherein The molar ratio of compound C to the deprotecting agent a in step (2) is 1:(0.05-0.1). The organic solvent is a mixed solvent of tetrahydrofuran and water, tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water; And / or the reaction condition is: after adding trifluoroacetic acid at 0-5℃, reacting at 30-50℃ for 8-14h.

7. The production method according to claim 6, wherein The organic solvent in step (2) is a mixed solvent of tetrahydrofuran and water with a volume ratio of 1:

1.

8. The production method according to claim 3, wherein The molar ratio of compound D and deprotecting agent b in step (3) is 1:(4-8); The organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran; And / or the deprotecting agent b is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate; The reaction condition is: reacting at 20-30℃ for 3-5h.

9. The production method according to claim 8, wherein The molar ratio of compound D and deprotecting agent b in step (3) is 1:(4-5); And / or, the organic solvent in step (3) is methanol; And / or, the deprotecting agent b in step (3) is sodium methoxide.

10. The production method according to any one of claims 4 to 9, characterized by, R is OR', and the compound A is prepared according to the following steps: (1') Compound B reacts with compound 2 in an organic solvent, in the presence of a promoter, a catalyst and a water removal agent to obtain compound 3; (2') Compound 3 reacts with an acid in an organic solvent to obtain compound 4; (3') Compound 4 reacts with compound R'-OH in an acid anhydride to obtain compound 5; (4') Compound 5 reacts with a deprotecting agent in an organic solvent to obtain compound 6; (5') Compound 6 reacts with compound 1 in an organic solvent in the presence of a catalyst to obtain compound A; The reaction formula is as follows: Wherein, STol is p-tolylthio, Bz is benzoyl, Ph is phenyl, and R' is nitro.

11. The production method according to claim 10, wherein The molar ratio of compound B, compound 2, the promoter and the catalyst in step (1') is 1:(1-2):(1-2):(0.05-0.15); the mass ratio of compound B and the water removal agent is 1:(0.5-3); The organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether; And / or the promoter is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or brominated iodine; And / or the catalyst is silver trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic acid; And / or the water removal agent is 4A molecular sieve; The reaction condition is: compound B and compound 2 are reacted in an organic solvent at 0-5℃ for 10min, then the promoter is added and reacted for 20-40min, then the catalyst is added, the temperature is raised to 20-30℃, and reacted for 2-4h; The molar ratio of compound 3 and the acid in step (2') is 1:(0.01-0.05); The acid is hydrochloric acid, trifluoroacetic acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid; The organic solvent is tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water; The reaction condition is that compound 3 is added with acid at 0-5℃, then the temperature is raised to 20-30℃ and reacted for 2-4h; The mass-volume ratio of compound 4 and compound R'-OH in step (3') is (1-5)g:1mL; The acid anhydride is acetic anhydride, and R'-OH is nitric acid; The reaction condition is that compound 4 and R'-OH are reacted at 0-5℃ for 15-35min, then the temperature is raised to 20-30℃ and reacted for 2-4h; The molar ratio of compound 5 and deprotection agent in step (4') is 1: (4-5); The organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran; The deprotection agent is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate; The reaction condition is that the temperature is 20-30℃ and the reaction time is 1-3h; The molar ratio of compound 6, compound 1 and catalyst in step (5') is 1: (2-3): (0.05-0.15); The catalyst is d-camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; The organic solvent is acetone, dichloromethane, trichloromethane or tetrahydrofuran; The reaction condition is that the temperature is 20-30℃ and the reaction time is 3-5h.

12. The production method according to claim 11, wherein The molar ratio of compound B, compound 2, promoter, catalyst in step (1') is 1: 1.5: 1.5: 0.1; And / or, the mass ratio of compound B and water-removing agent is 1:1; And / or, the organic solvent in step (1') is dichloromethane; And / or, the promoter in step (1') is N-iodosuccinimide; And / or, the catalyst in step (1') is silver trifluoromethanesulfonate; And / or, the molar ratio of compound 3 and acid in step (2') is 1: (0.03-0.04); And / or, the acid in step (2') is hydrochloric acid; And / or, the organic solvent in step (2') is tetrahydrofuran; And / or, the acid anhydride in step (3') is nitric acid; And / or, the molar ratio of compound 5 and deprotection agent in step (4') is 1:4.5; And / or, the organic solvent in step (4') is methanol; And / or, the deprotection agent in step (4') is sodium methoxide; And / or, the molar ratio of compound 6, compound 1 and catalyst in step (5') is 1:2.5:0.1; And / or, the catalyst in step (5') is d-camphorsulfonic acid; And / or, the organic solvent in step (5') is acetone.

13. The use of the compound of claim 1 or 2 in the preparation of a drug for strengthening heart contraction and / or resisting heart failure.

14. Use according to claim 13, wherein the compound is ###0002### The drug is a drug for strengthening myocardial contraction.

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