Icaritin derivatives, and preparation method and use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry and relates to icariin derivatives, such as formula (II), and their pharmacologically tolerable salts and processes for their preparation, and their use for the preparation of medicaments for the treatment of asthma and myelosuppression.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to icaritin derivatives and pharmaceutically acceptable salts thereof, and a preparation method and application thereof. BACKGROUND

[0002] Icaritin (ICT) is a monomer component of flavonoids in Epimedium, and its structural formula is as follows:

[0003]

[0004] Icaritin can be separated from Epimedium or in-vivo metabolites of icariin (Sun Pengyue, Xu Ying, Wen Ye, et al., Chemical constituents of Epimedium koreanum Nakai, Chinese Journal of Pharmaceutical Analysis, 1998, 8(2): 122-125; Liu Tiehan, Wang Yi, Wu Lijun, et al., Intestinal bacterial metabolism of icariin I. Metabolic transformation of icariin by intestinal bacteria, 2000, 31(11): 834-837), or separated from icariin by enzymatic hydrolysis (Ye Haiyong, Liu Jian, Lou Yijia, Preparation of icariin derivatives and study on their estrogen-like effects, Journal of Zhejiang University, 2005, 34(2): 131-136).

[0005] It is reported in the literature that icaritin has an effect of resisting apoptosis of primary cultured nerve cells of rats caused by Aβ peptide (Zhang Xiangnan, Wang Huanhuan, Wang Zhiqiang, et al., Effect of icaritin on resisting apoptosis of primary cultured nerve cells of rats caused by Aβ peptide, Journal of Zhejiang University, 2007, 36(3): 224-226). Chinese patent CN101836976A discloses that icaritin has an effect of resisting tumor angiogenesis. Chinese patent CN101428015A discloses that icaritin has an effect of resisting endotoxemia. Chinese patent CN101284000A discloses that icaritin has an effect of preventing and treating obesity or fatty liver. Chinese patent CN1869204A discloses an effect of icaritin in inducing directional differentiation of stem cells in vitro.

[0006] Icaritin has extensive pharmacological activities, but it has poor solubility, slightly soluble in dichloromethane and ethyl acetate, almost insoluble in methanol, anhydrous ethanol and water, and almost insoluble or insoluble in different pH buffer solutions. Icaritin has low oral bioavailability. SUMMARY

[0007] The present application aims to provide icaritin derivatives and pharmaceutically acceptable salts thereof with novel structures.

[0008] In a first aspect of the present application, icaritin derivatives and pharmaceutically acceptable salts thereof are provided, and the structure of the icaritin derivatives is shown in formula (II),

[0009]

[0010] In formula (II), R1 and R3 are independently selected from hydrogen, C 1-4 alkyl, L, -(CH2) m OX, C 1-4 alkyl-substituted aminoacyl;

[0011] L is selected from hydrogen, glycine, alanine, valine, isoleucine, leucine, threonine, serine, glutamic acid, lysine, -CO(CH2) m COOH;

[0012] The halogen X is selected from F, Cl, Br or I; each m is independently selected from any integer from 1 to 6;

[0013] R1 and R3 are not simultaneously H or C 1-4 alkyl-substituted by amino, hydroxyl, carboxyl.

[0014] Further, the C 1-4 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

[0015] Specifically, the structural formula (II) of the Icariin aglycone derivative is selected from the following structural formulae:

[0016]

[0017] The preparation method of the Icariin aglycone derivative of the present application can be, but is not limited to, prepared by the following method:

[0018] Method I: when R1 and R3 take the same group, the steps are as follows:

[0019]

[0020] Icariin aglycone (A) is directly condensed with L or halogenated R1 under the condition of a condensing agent to generate a compound of formula (II); or Icariin aglycone (A) is first substituted with a halogenated alcohol under the action of a base to generate an intermediate, and the intermediate is then condensed with L under the condition of a condensing agent to generate a compound of formula (II).

[0021] Method I: when R1 and R3 take the same group, the steps are as follows:

[0022] 1) the starting material B is directly condensed with L or halogenated R3 under the condition of a condensing agent under basic conditions to generate a compound C;

[0023]

[0024] 2) C is removed under acidic conditions to remove the Boc protection; and then reacted with L or halogenated R1 under basic conditions to form (II);

[0025]

[0026] wherein the condensing agent is selected from one of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride / 4-dimethylaminopyridine EDCI / DMAP, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole / N,N- diisopropylethylamine EDCI / HOBT / DIPEA, 2-(7-oxazolylbenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate / N,N-diisopropylethylamine HATU / DIPEA, dicyclohexylcarbodiimide / 4-dimethylaminopyridine DCC / DMAP;

[0027] The condensing agent is used in an amount of 0.1-25 equivalents.

[0028] It is another object of the present application to provide a pharmaceutical composition containing the icariagenin derivative or a pharmacologically acceptable salt thereof.

[0029] It is another object of the present application to provide the use of the icariagenin derivative or a pharmacologically acceptable salt thereof in the preparation of a medicament for treating asthma or myelosuppression.

[0030] The icariagenin derivative of the present application has a significantly better therapeutic effect on asthma than icariin. The icariagenin derivative of the present application has a significantly better therapeutic effect on myelosuppression caused by radiotherapy or chemotherapy than icariin. The bioavailability of the icariagenin derivative of the present application is significantly better than that of icariin, which indicates that the compound of the present application has a significant technical advantage in drug development.

[0031] The icariagenin derivative of the present application has a significantly better therapeutic effect on asthma than the compound of formula I. The icariagenin derivative of the present application has a significantly better therapeutic effect on myelosuppression caused by radiotherapy or chemotherapy than the compound of formula I. The bioavailability of the icariagenin derivative of the present application is significantly better than that of the compound of formula I, which indicates that the compound of the present application has a significant technical advantage in drug development. More importantly, long-term toxicity experiments have found that the compound of formula I has certain liver and kidney toxicity and causes mammary gland hyperplasia in female rats, etc. The compound of the present application has no obvious toxicity, and has a higher clinical use safety than the compound of formula I.

[0032] The compound of formula I is compound 5 in the literature (Dell'Agli M, Galli G V, Dal C E, et al. Potent inhibition of human phosphodiesterase-5 by icariin derivatives. [J]. Journal of Natural Products, 2008, 71 (9): 1513-1517.). The structural formula of the compound of formula I is as follows:

[0033] DETAILED DESCRIPTION

[0034] The content of the present application is further described in detail below through examples of specific embodiments. However, the examples should not be understood as limiting the present application. Various substitutions or changes made according to ordinary technical knowledge and conventional means without departing from the above-mentioned idea of the present application are all included in the present application.

[0035] Synthesis of intermediate 1 in Example 1

[0036]

[0037] The raw material icariinogen (ICT) 500 mg (1.4 mmol) was dissolved in 20 ml of acetone, 188 mg (1.4 mmol) of potassium carbonate and 0.1 ml (1.4 mmol) of 2-bromoethanol were added, and refluxed until the reaction was complete. The solvent was distilled off under reduced pressure and rotary evaporation, dissolved in ethyl acetate, and purified by column chromatography (dichloromethane: acetone = 40:1 and petroleum ether: ethyl acetate = 1:1 gradient elution) to obtain a yellow solid product intermediate 1 378 mg with a yield of 61%.

[0038] 1 HNMR (300 MHz, CDCl3): 12.44 (s, 1H), 8.13 (d, J = 9.00 Hz, 2H), 7.08 (d, J = 9.06 Hz, 2H), 6.43 (s, 1H), 5.20 (q, J = 15.53 Hz, 1H), 4.20 (t, J = 8.91 Hz, 2H), 4.02 (m, 4H), 3.93 (s, 3H), 3.83 (m, 2H), 3.56 (d, J = 6.72 Hz, 2H), 1.82 (s, 3H), 1.72 (s, 3H).

[0039] ESI-MS (m / z): 479 [M+Na] + .

[0040] Synthesis of compound W-1 in Example 2

[0041]

[0042] The starting material icariogenin (ICT) 500 mg (1.4 mmol) was dissolved in 15 ml of dichloromethane, and BOC-valine 270 mg (1.4 mmol), carbodiimide (EDCI) 240 mg (1.5 mmol), 4-dimethylaminopyridine (DMAP) 25 mg (0.2 mmol) were added, stirred at room temperature for 1 h, after the reaction was complete, the solvent was distilled and dried under reduced pressure, dissolved in ethyl acetate, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a yellow solid product 654 mg, yield 85%.

[0043] The yellow solid product obtained above was dissolved in 10 ml of dichloromethane, and 139 mg (1.39 mmol) of concentrated hydrochloric acid was added under stirring conditions, and after the dropwise addition was complete, it was stirred at room temperature for 20 min, and a yellow solid product W-1 was obtained by suction filtration, total yield 81%.

[0044] 1 HNMR (300 MHz, CDCl3): 12.03 (s, 1H), 9.01 (s, 1H), 7.94 (d, J = 8.7 Hz, 6H), 7.20 (d, J = 9 Hz, 2H), 6.95 (s, 1H), 5.07 (s, 1H), 4.40 (s, 1H), 4.23 (s, 1H), 3.88 (s, 3H), 3.94 (s, 2H), 1.67 (d, J = 13.8 Hz, 6H), 1.12 (s, 12H).

[0045] ESI-MS (m / z): 567 [M+H] + .

[0046] Synthesis of compound W-2 of Example 3

[0047]

[0048] The starting material icariogenin (ICT) 500 mg (1.4 mmol) was dissolved in 15 ml of dichloromethane, and BOC-valine 270 mg (1.4 mmol), carbodiimide (EDCI) 240 mg (1.5 mmol), 4-dimethylaminopyridine (DMAP) 25 mg (0.2 mmol) were added, stirred at room temperature for 1 h, after the reaction was complete, the solvent was distilled and dried under reduced pressure, dissolved in ethyl acetate, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a yellow solid product 654 mg, yield 85%.

[0049] The yellow solid product obtained above was dissolved in 10 ml dichloromethane, 139 mg (1.39 mmol) of concentrated hydrochloric acid was added under stirring condition, after the addition was completed, it was stirred at room temperature for 20 min, and then filtered to obtain yellow solid product W-2 670 mg, with a total yield of 80%.

[0050] 1 H NMR (300 MHz, CDC13): 12.03 (s, 1H), 8.90 (s, 6H), 7.97 (d, J = 8.7 Hz, 2H), 7.2 (d, J = 9.0 Hz, 2H), 6.94 (s, 1H), 3.97 (s, 3H), 3.68 (s, 2H), 3.47 (s, 1H), 2.83 (s, 1H), 1.63 (s, 12H).

[0051] ESI-MS (m / z): 511 [M+H] + .

[0052] Synthesis of compound W-3 in Example 4

[0053]

[0054] The intermediate W-1 456 mg (1 mmol) was dissolved in 20 ml dichloromethane, BOC-alanine 189 mg (1 mmol), carbodiimide (EDCI) 192 mg (1 mmol), 4-dimethylaminopyridine (DMAP) 122 mg (1 mmol) were added, and it was stirred at room temperature for 2 h under nitrogen protection. After the reaction was completed, column chromatography purification (petroleum ether: ethyl acetate = 4: 1) was performed to obtain yellow solid product 570 mg with a yield of 91%.

[0055] The yellow solid product 570 mg obtained above was dissolved in 10 ml dichloromethane, 139 mg (1.39 mmol) of concentrated hydrochloric acid was added under stirring condition, after the addition was completed, it was stirred at room temperature for 20 min, and then filtered to obtain yellow solid product W-3 700 mg, with a total yield of 81%.

[0056] 1 H NMR (300 MHz, CDC13): 12.54 (s, 1H), 8.43 (s, 6H), 7.95 (d, J = 9.09 Hz, 2H), 7.01 (d, J = 8.94 Hz, 2H), 6.49 (s, 1H), 5.00 (s, 1H), 3.96-3.85 (m, 2H), 3.73 (s, 3H), 2.67 (s, 2H), 1.48 (s, 6H), 1.29-1.20 (m, 6H).

[0057] ESI-MS (m / z): 599 [M+H] + .

[0058] Example 5 Effect of the compounds of the present application on myelosuppression caused by chemotherapy in tumor mice

[0059] 1. Model preparation and administration grouping: 84 Balb / C mice were selected, weighed, and randomly divided into 7 groups, i.e. normal group, blank control group, icariin group, formula I compound group, and each administration group of the compounds of the present application, 12 mice in each group. The mice were intraperitoneally injected with 50 mg / kg of cyclophosphamide every day for one week, which could significantly reduce the number of platelets. One week before the model was made, each treatment group was given the following treatment drugs:

[0060] Normal group: given the same volume of sodium carboxymethyl cellulose;

[0061] Blank control group: given the same volume of sodium carboxymethyl cellulose;

[0062] Icariin group: given 5 mg / kg of icariin by gavage;

[0063] Formula I group: given 5 mg / kg of formula I compound by gavage;

[0064] W-1 group: given 0.5 mg / kg of compound W-1 by gavage;

[0065] W-2 group: given 0.5 mg / kg of compound W-2 by gavage;

[0066] W-3 group: given 0.5 mg / kg of compound W-3 by gavage;

[0067] Each treatment group was given the drug once a day, and was normally fed. After 3 weeks of continuous administration, the mice were anesthetized, blood was taken, and the number of white blood cells and platelets was detected to investigate the effect of the compounds of the present application on white blood cells and platelets.

[0068] 2. Experimental results

[0069] Through this example, the effect of each compound of the present application on white blood cells and platelets of mice caused by cyclophosphamide was found (Table 1), and it was found that each compound of the present application had an unexpected effect of relieving myelosuppression caused by chemotherapy.

[0070] Compared with the model control group, the total number of white blood cells and the total number of platelets of each compound group of the present application were increased, and there was a significant difference.

[0071] Compared with the icariin group, the total number of white blood cells and the total number of platelets of each compound group of the present application were increased, and there was a significant difference.

[0072] Compared with the formula I group, the total number of white blood cells and the total number of platelets of each compound group of the present application were increased, and there was a significant difference.

[0073] Table 1 Effect of each compound on leukopenia and thrombocytopenia induced by cyclophosphamide

[0074]

[0075]

[0076] Compared with the blank control group, $ p<0.05, $$ p<0.01;

[0077] Compared with the icariin group, # p<0.05, ## p<0.01;

[0078] Compared with the formula I group, & p<0.05, && p<0.01.

[0079] Example 6 Effect of the compound of the present application on the number of blood cells of Co-irradiated mice 60 Example 6 Effect of the compound of the present application on the number of blood cells of Co-irradiated mice

[0080] 1. Model preparation and grouping: 100 Kunming mice were selected. Except for the normal group (10 mice), the mice in other groups were irradiated with 4Gy of Co 60 The mice were irradiated with 4Gy of Co in one time, and the absorbed dose was 4Gy and the absorbed dose rate was 0.88Gy / min. The whole blood cell count was detected by taking blood from the orbital vein on the 3rd, 7th and 10th day after irradiation. The mice with the white blood cell count lower than 3.0x10 9 / L or the platelet count lower than 500x10 9 / L in two consecutive whole blood cell tests were removed, and the remaining mice were used as experimental mice.

[0081] The mice meeting the experimental requirements after irradiation were randomly divided into the following model group, icariin group, formula I compound group, W-1 group, W-2 group and W-3 group, 10 mice in each group, half male and half female. Each group was treated or administered as follows.

[0082] Normal group: given the same volume of sodium carboxymethyl cellulose;

[0083] Model group: given the same volume of sodium carboxymethyl cellulose;

[0084] Icariin group: intraperitoneally injected with 1mg / kg icariin;

[0085] Formula I group: intraperitoneally injected with 1mg / kg formula I compound;

[0086] W-1 group: intraperitoneally injected with 0.1mg / kg compound W-1;

[0087] Group W-2: Intraperitoneal injection of 0.1 mg / kg of compound W-2;

[0088] Group W-3: Intraperitoneal injection of 0.1 mg / kg of compound W-3;

[0089] Each treatment group was administered the drug once daily and fed normally. After 10 consecutive days of administration, mice were anesthetized, blood was collected, and the numbers of white blood cells and platelets were measured to investigate the effect of the compound of this invention on white blood cells and platelets.

[0090] 2. Experimental Results

[0091] Through the various compounds of the present invention, the acceptor 60 The effects of Co radiation on white blood cells and platelets in mice (Table 2) revealed that the compounds of this invention have an unexpected effect in alleviating radiotherapy-induced bone marrow suppression.

[0092] Compared with the model control group, the total number of white blood cells and the total number of platelets in each compound group of the present invention were significantly increased.

[0093] Compared with the icariin group, the total number of white blood cells and platelets in each compound group of the present invention increased significantly.

[0094] Compared with Formula I, the total number of white blood cells and the total number of platelets in each compound group of the present invention are significantly increased.

[0095] Table 2. Pairs of each compound 60 Effect of Co-irradiated mice on blood cell count

[0096]

[0097] Compared with the blank control group, $ p<0.05, $$ p<0.01;

[0098] Compared with the icariin group, # p<0.05, ## p<0.01;

[0099] Compared with Equation I, & p<0.05, && p<0.01.

[0100] Example 7: Inhibitory effect of the compounds of the present invention on airway smooth muscle

[0101] Airway remodeling is an important pathological feature of bronchial asthma, and airway smooth muscle cells (ASMCs) are the main effector cells causing airway remodeling. Compared with normal individuals, patients with severe asthma have significantly increased ASMC levels, a phenomenon mainly caused by smooth muscle cell proliferation.

[0102] 1.1 Materials

[0103] 150~200g SD rats; DMEM medium (Gibico Company); fetal bovine serum (Hangzhou Sijiqing Bioengineering Limited Company); trypsin (Sigma Company).

[0104] 1.2 Experimental method

[0105] 1.2.1 Culture of rat ASMC

[0106] According to the method in the relevant literature: under sterile conditions, the trachea was cut longitudinally, the outer membrane was carefully peeled off and the inner membrane was gently scraped, the trachea segment was carefully cut into 1mm x 1mm x 1mm small tissue blocks with ophthalmic scissors, and was attached to the bottom surface of a 5cm x 5cm culture bottle, equidistantly arranged, 2mL of DMEM (high sugar) medium containing 25% fetal bovine serum was added, and the culture solution did not contact the tissue blocks. The culture bottle was placed upside down in a 37℃ and 5% carbon dioxide incubator for about 3h, so that the tissue blocks were almost dried, the culture bottle was gently turned over, and the culture solution just covered the surface of the tissue blocks. After 3d of semi-open absolute static culture, the culture solution was added to 5mL, and the medium was changed every 6d. After about 7d of growth, the cells were subcultured, and the 4th to 5th generation cells were selected for the experiment. The cultured rat ASMC were identified by morphological method.

[0107] 1.2.2 Detection of proliferation of rat ASMC by CCK-8 method

[0108] The 4th generation of cultured rat ASMC were taken, and a single cell suspension was prepared, which was inoculated into a 96-well culture plate at 1x10 4 cells / well, and was cultured at 37℃ and 5% carbon dioxide for 24h. When the cells grew to a confluence state, 0.1% fetal bovine serum-containing culture solution was added (so that the cells were arrested in G0 phase) for continuous culture for 24h.

[0109] The culture solution containing 1% fetal bovine serum was used, and was randomly divided into:

[0110] The control group was added with DMEM per well;

[0111] The icariin group was added with icariin at a concentration of 1x10 -6 mol / L per well;

[0112] The formula I group was added with formula I compound at a concentration of 1x10 -6 mol / L per well;

[0113] The W-1 group was added with compound W-1 at a concentration of 1x10 -6 mol / L per well;

[0114] The W-2 group was added with compound W-2 at a concentration of 1x10 -6mol / L;

[0115] W-3 group: the concentration of compound W-3 is 1x10 -6 mol / L;

[0116] 5 wells are set in each group, and a blank group (without cells, but the DMEM concentration is consistent with the corresponding group) is set in each group. After being cultured at 37℃ and 5% carbon dioxide for 48h, 10μL of CCK-8 reagent is added to each well, and the culture is continued for 4h. At wavelength 450nm, the OD value of each well is detected. According to the formula, the growth inhibition rate of each group of cells is calculated: cell growth inhibition rate = 1-[(OD value of each administration group-OD value of the corresponding blank group) / (OD value of the control group-OD value of the corresponding blank group)]x100%.

[0117] 2 Results

[0118] 2.1 Identification of ASMC

[0119] It is found by inverted phase contrast microscope observation that the ASMC before confluence is spindle-shaped, and the cells in some areas after confluence are arranged in bundles, showing a typical "peak-valley" shape.

[0120] 2.2 Effect on the proliferation of ASMC

[0121] After the action of each compound of the application on ASMC for 48h, compared with the icariin group, the OD value of the cells in each compound group of the application is obviously reduced, and the difference is significant.

[0122] Compared with the icariin group, the inhibition rate of the cells in each compound group of the application is obviously increased, and the difference is significant.

[0123] Compared with the icariin group, the inhibition rate of the cells in each compound group of the application is obviously increased, and the difference is significant.

[0124] (see Tables 3 and 4)

[0125] Table 3 OD value of each compound acting on ASMC for 48h

[0126]

[0127] Compared with the normal control group, $ p<0.05, $$ p<0.01;

[0128] Compared with the icariin group, # p<0.05, ## p<0.01;

[0129] Compared with the icariin group, & p<0.05, &&p<0.01.

[0130] Inhibition rate of each compound on ASMC after 48h

[0131]

[0132] Compared with icariogenin group, $ p<0.05, $$ p<0.01;

[0133] Compared with formula I group, & p<0.05, && p<0.01.

[0134] Determination of bioavailability of compounds of the present application

[0135] 1. Animal grouping and administration

[0136] 60 Wistar rats (270±30) g, half male and half female, were provided by the Experimental Animal Center of Shandong Xindai Pharmaceutical Co., Ltd., production license number: SCXK (Lu) 20060019. They were raised under the conditions of temperature 20-22℃, relative humidity 45%-65%, light / dark 12h / 12h, and free access to food and water.

[0137] Compound of the present application gavage group: 30 healthy Wistar rats, half male and half female, which had been free of water for 12 hours, were divided into 5 groups, icariogenin group (gavaged with icariogenin), formula I group (gavaged with formula I compound), W-1 group (gavaged with compound W-1), W-2 group (gavaged with compound W-2), and W-3 group (gavaged with compound W-3). Each group was given a single gavage, and the dose was 3mg / kg. They were fasted for 12 hours before administration and had free access to water. Blood was taken from the retro-orbital plexus at 0h (before administration), 0.083h, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h after administration, about 300μL, anticoagulated with heparin, centrifuged at 12000rpm for 5min at 4℃, and the plasma was separated and stored in a -20℃ refrigerator. They had free access to water during the experiment and ate 2 hours after gavage.

[0138] The compound of the present application intravenous administration group: 30 healthy Wistar rats, half male and half female, which have been free of water for 12 hours, are divided into 5 groups, icariogenin group (icariogenin is injected to give), formula I group (formula I compound is injected to give), W-1 group (compound W-1 is injected to give), W-2 group (compound W-2 is injected to give), and W-3 group (compound W-3 is injected to give). Each group is injected into the tail vein to give, and the dose is 3 mg / kg. Blood is taken from the retro-orbital plexus at 0 h (before administration), 0.033 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration, about 300 μL of blood is taken, heparin is used for anticoagulation, 5 min centrifugation is carried out at 12000 rpm under the condition of 4 ℃, plasma is separated, and is stored in a low-temperature refrigerator at -20 ℃. Food and water are free during the experiment.

[0139] 2. Plasma sample determination

[0140] All treated plasma samples are subjected to UPLC-MS / MS quantitative analysis to determine the plasma drug concentration.

[0141] 3. Calculation of bioavailability

[0142] The determined blood concentration-time data are used to calculate the pharmacokinetic parameters by using DAS software (Drug and Statistics, China Mathematical Pharmacology Society, Sun Ruigen et al.).

[0143]

[0144] 4. Absolute bioavailability of each compound

[0145] Table 5 Bioavailability of each compound

[0146]

[0147] As can be seen from the above table, the bioavailability of each compound in the present application is obviously higher than that of icariogenin and formula I compound, which shows that the compound of the present application has obvious technical advantages in the aspect of medicine.

[0148] Example 9 Toxicity test of repeated injection of the compound W-1, W-2, W-3 and formula I compound of the present application in rats

[0149] SD rats are divided into five groups: normal control group, formula I compound group (formula I compound is injected intravenously at 100 mg / kg / d), W-1 group (W-1 is injected intravenously at 100 mg / kg / d), W-2 group (W-2 is injected intravenously at 100 mg / kg / d), and W-3 group (W-3 is injected intravenously at 100 mg / kg / d).

[0150] Each group of animals was continuously dosed for 28 days, once a day, and stopped for 4 weeks. At the end of the dosing period, blood samples were collected from the abdominal vena cava, and hematological, coagulation time, blood biochemistry and electrolyte tests were performed. Then, systematic dissection was performed, and the morphologies of the organs were observed. The brain, spleen, thymus, heart, kidneys (both sides), liver, adrenal glands (both sides), mammary glands (female rats), and prostate (male rats) were weighed and the organ coefficients were calculated.

[0151] It was found that the levels of creatinine, alkaline phosphatase and glutamic-pyruvic transaminase in the rats in the compound of formula I group were increased. Histopathological examination showed varying degrees of renal tubular damage and obvious nephrotoxicity damage. The mammary glands of female rats were hyperplastic. The compound of formula I showed certain toxic side effects.

[0152] Under the conditions of this test, no abnormal changes related to the toxicity of W-1 were found, and W-1 injection had no obvious toxicity, and was relatively safe for clinical use.

[0153] Under the conditions of this test, no abnormal changes related to the toxicity of W-2 were found, and W-2 injection had no obvious toxicity, and was relatively safe for clinical use.

[0154] Under the conditions of this test, no abnormal changes related to the toxicity of W-3 were found, and W-3 injection had no obvious toxicity, and was relatively safe for clinical use.

Claims

1. A icariagenin derivative, having a structure as shown in formula (II): ###0001### (II) wherein, R1 is H or OH; R2 is H or OH; R3 is H or OH; R4 is H or OH; R5 is H or OH; R6 is H or OH; R7 is H or OH; R8 is H or OH; R9 is H or OH; R10 is H or OH; R11 is H or OH; R12 is H or OH; R13 is H or OH; R14 is H or OH; R15 is H or OH; R16 is H or OH; R17 is H or OH; R18 is H or OH; R19 is H or OH; R20 is H or OH; R21 is H or OH; R22 is H or OH; R23 is H or OH; R24 is H or OH; R25 is H or OH; R26 is H or OH; R27 is H or OH; R28 is H or OH; R29 is H or OH; R30 is H or OH; R31 is H or OH; R32 is H or OH; R33 is H or OH; R34 is H or OH; R35 is H or OH; R36 is H or OH; R37 is H or OH; R38 is H or OH; R39 is H or OH; R40 is H or OH; R41 is H or OH; R42 is H or OH; R43 is H or OH; R44 is H or OH; R45 is H or OH; R46 is H or OH; R47 is H or OH; R48 is H or OH; R49 is H or OH; R50 is H or OH; R51 is H or OH; R52 is H or OH; R53 is H or OH; R54 is H or OH; R55 is H or OH; R56 is H or OH; R57 is H or OH; R58 is H or OH; R59 is H or OH; R60 is H or OH; R61 is H or OH; R62 is H or OH; R63 is H or OH; R64 is H or OH; R65 is H or OH; R66 is H or OH; R67 is H or OH; R68 is H or OH; R69 is H or OH; R70 is H or OH; R71 is H or OH; R72 is H or OH; R73 is H or OH; R74 is H or OH; R75 is H or OH; R76 is H or OH; R77 is H or OH; R78 is H or OH; R79 is H or OH; R80 is H or OH; R81 is H or OH; R82 is H or OH; R83 is H or OH; R84 is H or OH; R85 is H or OH; R86 is H or OH; R87 is H or OH; R88 is H or OH; R89 is H or OH; R90 is H or OH; R91 is H or OH; R92 is H or OH; R93 is H or OH; R94 is H or OH; R95 is H or OH; R96 is H or OH; R97 is H or OH; R98 is H or OH; R99 is H or OH; R100 is H or OH; R101 is H or OH; R102 is H or OH; R103 is H or OH; R104 is H or OH; R105 is H or OH; R106 is H or OH; R107 is H or OH; R108 is H or OH; R109 is H or OH; R110 is H or OH; R111 is H , in particular selected from , or wherein R1and R3are as described above for formula W-1, W-2, W-3.

2. The method of claim 1, wherein the icariagenin derivative is represented by the following formula 1: ###0001### Formula 1 ​ ； ​ 3. The method for synthesizing the icariin derivative as described in claim 2, characterized in that, ​ ​ ​ ​ 6. Use according to claim 5, characterized in that, ​

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