WO2016095248A1 - 20(r)-ginsenoside rg3 derivative, preparation method, and application of same - Google Patents

Abstract

The present invention provides a 20(R)-ginsenoside Rg3 derivative, as represented by the formula (I), and a preparation method and antitumor application of same. R1=H, R2=C_nH_2n+1CO or R1=C_nH_2n+1CO, R2=H or R1=R2=C_nH_2n+1CO, and n=3 to 30.

Description

20(R)-ginsenoside Rg3 derivative, preparation method and application thereof Technical field

The present invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to a 20(R)-ginsenoside Rg3 derivative and a process for the preparation thereof, and to a pharmaceutical use thereof.

Background technique

20(R)-ginsenoside Rg3, whose structure is as shown in the following formula, was originally isolated and identified by Japanese scholar Kitagawa in 1980. Due to the low extraction rate, the extraction rate from red ginseng (cultivated ginseng dried or dried and then steamed) is only 0.003%, so it is expensive.

After the sputum, 20(R)-ginsenoside Rg3 proved to be one of the effective active ingredients in ginseng. It has an effect of improving and preventing many diseases. For common diseases of middle and old age, cardiovascular and cerebrovascular diseases, coronary heart disease, limb weakness, legs and feet Inconvenience and memory loss have curative effects.

In recent years, studies on derivatives of ginsenoside Rg3 have focused on the isomer 20(S)-ginsenoside Rg3. For example, the international application WO9731933A discloses a method for extracting a 20(S)-ginsenoside Rg3 derivative from red ginseng, but since the result is crude, it has not been confirmed whether it has an inhibitory effect on a tumor. In 2013, Wang Hui et al. (Food Science, 34(5): 45) synthesized 20(S)-ginsenoside Rg3 derivatives, but the inhibitory effect of this derivative on tumor cells in vitro and the corresponding amount of ginsenoside Rg3 Quite even slightly worse. Since ginsenoside Rg3 is an expensive raw material, if the raw material is lost in consideration of the synthesis of the derivative, There is no incentive to study ginsenoside Rg3 derivatives for the preparation of drugs for the treatment of tumors. Because this is uneconomical in terms of cost/effectiveness, it is better to use ginsenoside Rg3 directly.

In addition, although ginsenoside Rg3 and its derivatives have certain ability to inhibit the growth of tumor cells in vitro, the effect of inhibiting tumors in vivo is not very satisfactory, and it is rarely used in the 20(S)-ginsenoside Rg3 which is mainly used. 20(R)-ginsenoside Rg3, even in large doses (high cost), the tumor inhibition rate (therapeutic effect) is still only 70% or less (see Chinese patents CN1243128A and CN1883492A).

Therefore, there is insufficient interest in the continued research of ginsenoside Rg3 and its derivatives against tumors. These years of research trends also confirm that people are abandoning the use of ginsenoside Rg3 derivatives to treat tumors. For example, Chinese patents CN101133075A, CN101031580A and CN101322714A are all committed to antiviral or treatment of Alzheimer's disease. Studies on tumor diseases, in which ginsenoside Rg3 derivatives are also mostly used as intermediates for preparation.

In addition, a patent for 20(S)-ginsenoside Rg3 in the treatment of non-small cell lung cancer found that this ingredient was not synergistically synergistic with the chemotherapeutic drug cyclophosphamide (Chinese patent CN101732332A).

After long-term research, the inventors have overcome the adverse effects of the prior art, and synthesized some long-chain derivatives of 20(R)-ginsenoside Rg3, which are of little interest in the technology, and unexpectedly discovered these derivatives for human lung cancer. Gastrointestinal tumors such as breast cancer, gastric cancer, colon cancer, and pancreatic cancer have obvious tumor cell apoptosis and inhibit proliferation (rather than cytotoxicity), and their effects are significantly better than Rg3; especially in vivo, 20(R) - Ginsenoside Rg3 derivative has a significant therapeutic effect on tumor suppression and prolonged survival in various cancers such as lung cancer, breast cancer, gastric cancer and liver cancer when it is 6 times less than the original dose of 20(R)-ginsenoside Rg3. The low-dose treatment effect is significantly higher than the high-dose 20(R)-ginsenoside Rg3 itself, so that the effective dose for administration is low (the therapeutic effect is small, and the potential side effects are reduced), and the cost of medication is saved. In addition, the inventors have also optimized a preparation method of 20(R)-ginsenoside Rg3 derivative suitable for industrial scale-up production, in which the lost 20(R)-ginsenoside Rg3 raw material is small, thereby further saving cost.

Summary of the invention

The technical problem to be solved by the present invention is to provide a novel 20(R)-ginsenoside Rg3 derivative. Compared with 20(R)-ginsenoside Rg3, the 20(R)-ginsenoside Rg3 derivative provided by the invention has a significantly improved effect on treating cancer even if the dosage of administration is significantly reduced, even if the loss of preparation is deducted, Can also make this Some of the 20(R)-ginsenoside Rg3 derivatives are economically used, so that the corresponding drugs can be promoted in practice. The present invention also provides methods for using these 20(R)-ginsenoside Rg3 derivatives, including pharmaceutical application methods and treatment methods, and the like. In addition, the present invention also provides a process for preparing these 20(R)-ginsenoside Rg3 derivatives, which can reduce the loss of the 20(R)-ginsenoside Rg3 raw material, and is suitable for industrial scale-up production.

In order to achieve the object of the present invention, an aspect of the present invention provides a 20(R)-ginsenoside Rg3 derivative represented by the structural formula (I).

Wherein R1=H, R2=C _n H _2n+1 CO or R1=C _n H _2n+1 CO, R2=H or R1=R2=C _n H _2n+1 CO, n=3-30.

Among them, n is preferably 8 to 25, more preferably 12 to 20, still more preferably 15 to 17, and still more preferably 15.

Another aspect of the present invention provides a pharmaceutically acceptable salt of a 20(R)-ginsenoside Rg3 derivative represented by the above formula (I).

Pharmaceutically acceptable salts are well known in the art. Representative acid addition salts include, but are not limited to, acetate, dihexanoate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate Acid salt, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, 3-phenylpropionate, propionate, succinate, tartrate , phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Preferred acids which can be used to form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid. The cations in the pharmaceutically acceptable base addition salts include, but are not limited to, alkali metal or alkaline earth metal ions such as lithium, sodium, potassium, calcium, magnesium, and aluminum, and non-toxic Quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, diethylamine, ethanolamine, Diethanolamine, piperidine, piperazine, and the like. Preferred base addition salts include phosphates, tris and acetates. These salts are generally capable of increasing the solubility of the polypeptide, and the salt formed does not substantially alter the pharmaceutical activity of the 20(R)-ginsenoside Rg3 derivative of the present invention.

The present invention provides a pharmaceutical composition comprising the 20(R)-ginsenoside Rg3 derivative of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

Pharmaceutically acceptable excipients refer to non-toxic solid, semi-solid or liquid fillers, diluents, carriers, pH adjusters, ionic strength modifiers, sustained or controlled release agents, encapsulating materials or other formulation excipients. The carrier used may be adapted to the corresponding administration form, and may be formulated into an injection, a lyophilized powder for injection, a spray, an oral solution, an oral suspension, a tablet, a capsule, or the like, which is known to those skilled in the art. Formulations such as enteric-coated tablets, pills, powders, granules, sustained release or delayed release. Preferably, the 20(R)-ginsenoside Rg3 derivative of the first aspect of the invention is administered by injection or by digestive tract, and therefore, the pharmaceutical composition of the present invention is preferably an injection or a preparation for administration via the digestive tract, that is, suitable for Excipients formulated for administration by injection and transgestive route are particularly preferred. Wherein, "administered by the digestive tract" as used herein refers to a mode of administration of a pharmaceutical preparation through the digestive tract of a patient, including oral, intragastric, and enema administration, preferably oral, as may be known to those skilled in the art. The auxiliary materials are formulated into an oral solution, an oral suspension, a tablet, a capsule, an enteric-coated tablet, a pill, a powder, a granule, a sustained release or a delayed release release; wherein the preparation for injection administration is mainly an injection and a powder injection.

According to still another aspect of the present invention, there is provided a method for producing a 20(R)-ginsenoside Rg3 derivative, comprising the steps of:

1) 20(R)-ginsenoside Rg3 is dissolved in an organic solvent to prepare a 20(R)-ginsenoside Rg3 solution;

2) adding an acylating reagent to carry out an esterification reaction;

3) After removing the solvent from the mixture after the esterification reaction, the mixture is subjected to silica gel column chromatography to obtain.

Wherein, the organic solvent described in the step 1) is selected from pyridine, 2,4,6-trimethylpyridine or 2,6-lutidine.

In particular, the organic solvent is selected from anhydrous pyridine, anhydrous 2,4,6-trimethylpyridine, or anhydrous 2,6-lutidine.

Wherein the ratio of the weight of the 20(R)-ginsenoside Rg3 to the volume of the organic solvent in the step 1) is 1:10 to 100 (g/ml), preferably 1:30 to 60, further preferably 1 :45.

Wherein the acylating reagent in step 2) selects an acid chloride.

In particular, the acid chloride has the structural formula C _n H _2n+1 COCl, wherein n = 3 to 30.

In particular, the number of carbon atoms of the acid chloride is preferably n = 8 to 25, more preferably 12 to 20, still more preferably n = 15 to 17, and still more preferably n = 15.

In particular, the concentration of the 20(R)-ginsenoside Rg3 solution is from 0.0212 to 0.0424 M, preferably 0.028 M.

Wherein the reaction temperature of the esterification reaction in the step 2) is from -10 ° C to 20 ° C, preferably from 0 to 10 ° C.

In particular, the esterification reaction is carried out for a period of from 0.5 to 12 h, preferably from 1 to 10 h.

Wherein the molar ratio of the acylating agent in the step 2) to the 20(R)-ginsenoside Rg3 in the step 1) is from 1.5 to 3:1, preferably from 1.7 to 2.5:1, further preferably from 1.9 to 2.3. More preferably, it is 2.0 to 2.2:1, and most preferably 2:1.

Specifically, the acylating agent is added to the 20(R)-ginsenoside Rg3 solution by dropwise addition in the step 2).

In particular, the rate of dropwise addition of the acylating reagent is such that one drop of the acylating reagent is added every 1-5 seconds to a solution of 20(R)-ginsenoside Rg3 at a concentration of 0.028 M, that is, every 1-5 seconds. 50 ul of the acylating agent is added, preferably 50 ul of the acylating agent is added every 1.5 to 4 seconds, and further preferably 50 ul of the acylating agent is added every 2 seconds.

Specifically, during the dropwise addition of the acylating agent, the acylating agent is added under the condition that an inert gas is introduced to prevent moisture in the air from denaturation of the acid chloride.

In particular, the inert gas is selected from nitrogen or argon, preferably nitrogen.

In particular, the acylating agent is added dropwise under the conditions of maintaining the temperature at -10 to 0 ° C, preferably 0 °C.

In particular, the esterification reaction is carried out after the dropwise addition of the acylating agent, and the esterification reaction is carried out at a temperature of from -10 ° C to 20 ° C, preferably from 0 to 10 ° C.

In particular, the esterification reaction is carried out under the protection of an inert gas.

In particular, the inert gas is selected from nitrogen or argon, preferably nitrogen.

Specifically, it also includes quenching the esterification reaction, and adding one or more of water, anhydrous methanol or absolute ethanol to the esterification reaction system to terminate the esterification reaction.

Among them, in step 3), the solvent in the mixture after the esterification reaction is removed by vacuum distillation.

In particular, the relative pressure is controlled to be <0 MPa, preferably -0.095 to 0.05 MPa during the vacuum distillation.

Specifically, in the silica gel column chromatography in the step 3), a mixture of chloroform and methanol is selected as an eluent to be separated by silica gel column elution.

Wherein the ratio of the volume of chloroform to methanol in the eluent is 9:1.

In particular, the silica gel in the silica gel column was selected from GF254 silica gel.

According to still another aspect of the present invention, a 20(R)-ginsenoside Rg3 derivative as described above is prepared for use in therapy or pretreatment Anti-tumor, cancer drug applications.

The 20(R)-ginsenoside Rg3 derivative of the present invention is useful for preventing or treating lung cancer, breast cancer, gastric cancer, liver cancer, colon cancer or pancreatic cancer.

The present inventors have found that the inhibition rate of the 20(R)-ginsenoside Rg3 derivative of the present invention and the life extension rate of cancer or tumor patients are significantly improved, and the cancer can be directly treated. Therefore, the pharmaceutical composition of the present invention does not have to be mainly used for preventing cancer or tumor metastasis like 20(R)-ginsenoside Rg3 of the prior art, and therefore it is preferred that the pharmaceutical composition of the present invention is not used for preventing cancer or tumor metastasis, and It is preferably used for the treatment of cancer or tumors, such as increasing the tumor inhibition rate and/or increasing the life extension rate of cancer or tumor patients.

The 20(R)-ginsenoside Rg3 derivative of the present invention or a pharmaceutically acceptable salt thereof inhibits tumor cell apoptosis or inhibits proliferation and growth of tumor cells, and the direct apoptosis and proliferation inhibition effect on tumor cells is not through cytotoxicity. The role to achieve, has the utility and commercial value of becoming a drug.

According to still another aspect of the present invention, the above 20(R)-ginsenoside Rg3 derivative is prepared for preparing anti-multiple animal solid tumors, anti-human lung cancer, anti-breast cancer, anti-gastric cancer, anti-intestinal cancer, anti-liver cancer, anti-pancreatic cancer, etc. Application in medicine.

The 20(R)-ginsenoside Rg3 derivative of the invention is used for treating a nude mouse transplantation model of human lung cancer cells, breast cancer cells, gastric cancer cells and liver cancer cells, and is less than 20 (R)-ginsenoside Rg3 original drug 6 times dose At a low dose level, a therapeutic effect superior to that of 20(R)-ginsenoside Rg3 [higher than 20(R)-ginsenoside Rg3 derivative 6 times dose] was obtained, which significantly inhibited tumor growth and prolonged survival. The therapeutic effect is obvious, and the anti-cancer and anti-tumor effect is obvious, which significantly increases the tumor inhibition rate and improves the life extension rate of cancer or tumor patients.

The 20(R)-ginsenoside Rg3 derivative of the invention has the pharmacological characteristics of a trace high activity, that is, the 20(R)-ginsenoside Rg3 derivative is administered at a dose lower than that of the 20(R)-ginsenoside Rg3 original drug. When it is doubled, its effect of inhibiting lung cancer and breast cancer in humans reaches 80-91%, while the 20(R)-ginsenoside Rg3 drug inhibits tumors when it is higher than 20 (R)-ginsenoside Rg3 derivative at 6 times dose. The effect is only 61-68%; 20(R)-ginsenoside Rg3 derivative can significantly prolong the tumor-bearing survival of human tumor xenograft model animals at low dose, and its life on human gastric cancer and liver cancer nude mice The elongation rate is 181-1192%, while the 20(R)-ginsenoside Rg3 drug is only 156-159% at high doses.

The differences between prevention and treatment are well known to those skilled in the art. Prevention is the use of drugs (including administration to healthy individuals) when the condition has not occurred or discovered, such as preventing tumor metastasis from being used to prevent secondary cancer; and treatment is the use of drugs after the occurrence or discovery of the condition, usually only for the disease The individual is administered.

The 20(R)-ginsenoside Rg3 derivative of the present invention is effective in low-dose use alone, and provides a basis for use alone. The 20(R)-ginsenoside Rg3 derivative or a pharmaceutically acceptable salt thereof may be used alone, but is not limited to use in combination with other anticancer compounds or anticancer therapies.

The effective amount of the 20(R)-ginsenoside Rg3 derivative of the present invention is 0.001 to 20 mg/kg human, preferably 0.005 to 10 mg/kg human, more preferably 0.01 to 1 mg/kg human, more preferably 0.02. ～0.5 mg/kg human individual, more preferably 0.03 to 0.1 mg/kg human individual, more preferably 0.05-0.08 mg/kg human individual, such as 0.064 mg/kg human individual. When administered, the amount can be calculated based on the weight of the individual.

Accordingly, since most cancer patients are adults, pharmaceutical companies can also convert the unit preparation of the drug (such as a tablet or a capsule oral pharmaceutical preparation, or a needle injection or powder injection) into the medium by the average weight of the adult. The content of the 20(R)-ginsenoside Rg3 derivative of the invention. Preferably, the content of the 20(R)-ginsenoside Rg3 derivative of the first aspect of the invention in the unit preparation of the medicament is 0.06 to 1200 mg, preferably 0.3 to 600 mg, more preferably 0.6 to 60 mg, more preferably 1.2 to 30 mg, more preferably 1.8 to 6 mg, still more preferably 3 to 4.8 mg, such as 3.84 mg.

The preparation method of the 20(R)-ginsenoside Rg3 derivative of the invention has mild conditions, is easy to control, has high comprehensive yield of products, and is suitable for industrial large-scale production.

The 20(R)-ginsenoside Rg3 derivative of the invention has good antitumor activity when used at low dose, so it breaks through the dogma of organic synthesis, which is expected to have few synthesis by-products, and the adjusted preparation process parameters are for a single type of 20 (R). The yield of the ginsenoside Rg3 derivative is not optimal, only about 40-60%, but other by-products of the 20(R)-ginsenoside Rg3 derivative belonging to the present invention also have a certain yield, so that 20 ( R) - ginsenoside Rg3, an expensive raw material, can be more fully utilized.

DRAWINGS

1 is a micrograph of a 20(R)-ginsenoside Rg3 derivative of the present invention for inhibiting human colon cancer cells in vitro;

2 is a micrograph of a 20(R)-ginsenoside Rg3 derivative of the present invention for inhibiting human gastric cancer cells in vitro;

Fig. 3 is a photomicrograph showing inhibition of human pancreatic cancer cells by the 20(R)-ginsenoside Rg3 derivative of the present invention in vitro.

Detailed ways

For ease of understanding, the present invention will be described in detail below through specific embodiments. It is to be understood that the specific examples are merely illustrative and are not intended to limit the scope of the invention. It is apparent that those skilled in the art can make various modifications and changes to the present invention within the scope of the present invention, and such modifications and changes are also included in the scope of the present invention. In addition, the present invention is hereby incorporated by reference in its entirety in its entirety in its entirety herein in its entirety in its entirety in its entirety in its entirety in the the the the the the

Example 1

1. 20(R)-ginsenoside Rg3 (4g, 5.09mmol) is added to 180ml of dried anhydrous pyridine and stirred to dissolve to obtain 20(R)-ginsenoside Rg3 solution;

In the embodiment of the present invention, an organic solvent for dissolving 20(R)-ginsenoside Rg3 may be selected from anhydrous pyridine, anhydrous 2,4,6-trimethylpyridine or anhydrous 2,6-dimethyl. Pyridine.

2. Under ice bath (0 ° C), nitrogen gas is introduced into the reaction vessel to remove air, and the moisture in the air is prevented from coming into contact with the acid chloride reagent, resulting in the denaturation of the acid chloride to 20(R)-ginsenoside Rg3. Palmitoyl chloride (3.07 ml, about 10 mmol) was added dropwise to the solution, and stirred while dropping, and the dropping rate was 1 drop (about 50 ul / drop) / 2 s (that is, at a rate of one drop every 2 seconds to 20 (R) - ginseng The saponin Rg3 solution is added dropwise palmitoyl chloride) until the palmitoyl chloride is added dropwise to prepare a ginsenoside-acid chloride mixture; wherein the molar ratio of 20(R)-ginsenoside Rg3 to palmitoyl chloride is 1:2;

In the embodiment of the present invention, the inert gas which is passed through is taken as an example, and other inert gases are also suitable for the present invention, such as argon gas, helium gas and the like.

3. After the completion of the dropwise addition, nitrogen gas was introduced into the reaction vessel, and heated under stirring to raise the ginsenoside-acid chloride mixture to 10 ° C, and the esterification reaction was carried out for 1 hour while maintaining the temperature at 10 ° C. ;

4, adding anhydrous methanol (5ml), quenching the esterification reaction to obtain an esterification reaction mixture;

The quenching reagent for quenching the esterification reaction in the examples of the present invention is exemplified by anhydrous methanol, and one or more of others such as water, anhydrous methanol or absolute ethanol are suitable for use in the present invention.

5. The esterification reaction mixture is subjected to vacuum distillation treatment, and the solvent is removed, followed by silica gel column chromatography, and eluted with a mixture of chloroform and methanol as an eluent to obtain three compounds, wherein the vacuum distillation process is performed. The relative pressure in the medium is -0.095 MPa, and the silica gel in the silica gel column is selected from GF254 silica gel, and the ratio of the volume of chloroform to methanol in the eluent is 9:1.

Compound 1 (3 g) was a white solid dissolved in chloroform and methanol. After spraying on a TLC plate (chromic solution was chloroform/methanol 10:1, Rf was 0.4), a 10% H ₂ SO ₄ -ethanol reagent was sprayed to give a purple-red color. In the ESI-MS spectrum, m/z [M+Na] ⁺ was 1284.0 and the molecular weight was 1261.3.

The ¹ H-NMR and ¹³ C-NMR of Compound 1 are as follows:

^{1 H-NMR (400MHz, DMSO} -d6) δ (ppm): 5.05 (1H, m, H-24), 4.46 (2H, d, J = 7.6Hz, H-1 "), 4.28 (3H, dd, J=8.5 Hz, 17 Hz, H-6'&H-1'), 4.01 (2H, s, H-6'), 3.41 (2H, J = 8.4 Hz, H-12α &H-3"), 3.37 (2H, s, H-20 &H-4"), 3.31 (2H, s, H-2'&H-2"), 3.19 (1H, t, J = 8.8 Hz, H-3'), 3.09 (1H, d, J = 8.8 Hz, H-4'), 3.04 (2H, t, J = 9.4 Hz, H-5'&H-5"), 2.95 (1H, d, J = 10.8 Hz, H-3α), 2.2 (4H , t, J = 6 Hz, H-2 ^a & H-2 ^b ), 1.70-2.0 (4H, s, H-16 & H-2), 1.59 (4H, m, H-26, H-13), 1.53 (8H ,m,H-27&Me-30&Me-6),1.43-1.32,(52H,m,fatty carbon),1.10-1.15(4H,s,H-11&H-15),0.97(5H,H-21&H-23) , 0.93 (3H, dd, J = 12.8 Hz, H-28), 0.85 (6H, s, H-16 ^a & H-16 ^b ), 0.71 (9H, s, Me-18 & Me-19 & Me-29), 0.67 ( 1H, t, J = 12.8Hz, H-5);

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ (ppm): 172.96 (C-1a), 172.75 (C-1b), 129.23 (C-25), 124.59 (C-24), 104.60 (C-1) "), 103.72 (C-1'), 89.00 (C-3), 82.71 (C-2'), 77.11 (C-3"), 76.68 (C-3'), 75.47 (C-2"), 74.43 (C-5"), 73.91 (C-5'), 72.46 (C-20), 70.86 (C-4"), 70.36 (C-4'), 70.18 (C-12), 63.92 (C- 6′′&6′), 56.34 (C-5), 51.39 (C-14), 50.16 (C-17), 49.99 (C-9), 48.73 (C-13), 42.59 (C-22), 40.25 ( C-4), 40.04 (C-8), 39.25 (C-1), 36.85 (C-10), 35.01 (C-7), 34.22 (C-2a & C-2b), 31.59 (C-11), 31.16 (C-15), 29.47 (C-3a&C-4a&C-5a&C-6a&C-3b&C-4b&C-5b&C-6b), 29.40 (C-7a&C-8a&C-9a&C-7b&C-8b&C-9b), 29.18 (C-10a&C- 11a&C-12a&C-10b&C-11b&C-12b), 29.05 (C-13a&C-13b), 27.22 (C-28), 25.64 (C-16), 24.96 (C-2), 24.83 (C-26), 22.39 ( C-21), 22.31 (C-15a & C-15b), 21.93 (C-23), 18.29 (C-6), 17.65 (C-30), 17.26 (C-27), 16.17 (C-29), 16.13 (C-19), 15.80 (C-18), 14.03 (C-16a & C-16b) ppm

According to the test data of ESI-MS, ¹ H-NMR and ¹³ C-NMR, the structural formula of the compound 1 was determined to be

Compound 1 was determined to be 20(R)-ginsenoside Rg3-6',6"-dipalmitate.

Compound 2 (680 mg) was obtained as a white solid. The 10% H ₂ SO ₄ -ethanol reagent was sprayed on a TLC plate (the chromatographic solution was chloroform/methanol 7:1, Rf was 0.4). In the ESI-MS spectrum, m/z [M+Na] ⁺ was 1045.7 and its molecular weight was 1022.7.

The ¹ H-NMR and ¹³ C-NMR of the compound 2 are as follows:

^{1 H-NMR (400MHz, DMSO} -d6) δ (ppm): 5.07 (1H, m, H-24), 4.42 (1H, d, J = 7.6Hz, H-1 "), 4.29 (2H, dd, J=8.5 Hz, 17 Hz, H-6'&H-1'), 4.03 (3H, s, H-6'), 3.62 (2H, d, J = 9.44 Hz, H-12α &H-3"), 3.59 ( 2H, s, H-20 &H-4"), 3.50 (2H, s, H-2'&H-2"), 3.35 (1H, t, J = 8.8 Hz, H-3'), 3.13 (1H, d , J = 8.8 Hz, H-4'), 3.04 (2H, t, J = 9.4 Hz, H-5'&H-5"), 2.95 (1H, d, J = 10.8 Hz, H-3α), 2.27 (2H, t, J = 1.8 Hz, H-2 ^a ), 1.69-2.03 (4H, s, H-16 & H-2), 1.62 (4H, m, H-26, H-13), 1.55 (8H, m, H-27 & Me-30 & Me-6), 1.23 (26H, m, H-fattycarbon), 1.05-1.14 (4H, s, H-11 & H-15), 0.97 (5H, d, J = 5.2 Hz, H- 21&H-23), 0.91 (3H, m, H-28), 0.85 (6H, s, H-16 ^a ), 0.73 (9H, s, Me-18 & Me-19 & Me-29), 0.67 (1H, t, J = 12.8 Hz, H-5).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ (ppm): 172.98 (C-1a), 130.41 (C-25), 125.62 (C-24), 104.51 (C-1"), 103.99 (C- 1'), 88.86 (C-3), 81.70 ((C-2')), 77.29 (C-3"), 76.56 (C-3'), 76.45 (C-5"), 75.72 (C-2 "), 73.63 (C-5'), 72.38 (C-20), 70.22 (C-4"&C-4'), 70.15 (C-12), 63.85 (C-6'), 61.23 (C-6 "), 56.13 (C-5), 51.39 (C-14), 49.68 (C-9), 48.48 (C-13), 42.57 (C-22), 40.31 (C-4), 40.03 (C-8 ), 39.26 (C-1), 36.68 (C-10), 34.85 (C-7), 34.24 (C-1'), 31.82 (C-14a), 31.78 (C-11), 31.68 (C-14a&C -14b), 31.08 (C-15), 29.68 (C-3a & 4a & 5a), 29.64 (C-6a & 7a), 29.57 (C-8a & 9a), 29.42 (C-10a & 11a), 29.24 (C-12a), 29.18 (C- 13a), 27.82 (C-28), 26.21 (C-1'), 26.10 (C-1'), 25.95 (C-16), 25.11 (C-2), 22.60 (C-15a), 21.92 (C -23), 18.18 (C-6), 17.83 (C-30), 17.13 (C-27), 16.36 (C-29), 15.75 (C-18), 14.43 (C-16a).

According to the test data of ESI-MS, ¹ H-NMR and ¹³ C-NMR, the structural formula of the compound 2 was determined to be

Compound 2 was determined to be 20(R)-ginsenoside Rg3-6'-palmitate.

Compound 3 (690 mg) was obtained as a white solid. The 10% H ₂ SO ₄ -ethanol reagent was sprayed on a TLC plate (the chromatographic solution was chloroform/methanol 7:1, Rf was 0.4). In the ESI-MS spectrum, m/z [M+Na] ⁺ was 1045.7 and its molecular weight was 1022.7.

The ¹ H-NMR and ¹³ C-NMR of the compound 3 are as follows:

^{1 H-NMR (400MHz, DMSO} -d6) δ (ppm): 5.05 (1H, m, H-24), 4.45 (1H, d, J = 7.6Hz, H-1 "), 4.31 (2H, dd, J = 8.5 Hz, 17 Hz, H-6'&H-1'), 3.99 (3H, s, H-6'), 3.74 (2H, d, J = 9.44 Hz, H-12α &H-3"), 3.64 ( 2H, s, H-20 &H-4"), 3.57 (2H, s, H-2'&H-2"), 3.23 (1H, t, J = 8.8 Hz, H-3'), 3.17 (1H, d , J = 8.8 Hz, H-4'), 3.09 (2H, t, J = 9.4 Hz, H-5'&H-5"), 2.99 (1H, d, J = 10.8 Hz, H-3α), 2.25 (2H, t, J = 1.8 Hz, H-2 ^a ), 1.69-2.03 (4H, s, H-16 & H-2), 1.62 (4H, m, H-26, H-13), 1.55 (8H, m, H-27 & Me-30 & Me-6), 1.22 (26H, m, fatty carbon), 1.05-1.14 (4H, s, H-11 & H-15), 0.97 (5H, d, J = 5.2 Hz, H-21 & H -23), 0.91 (3H, m, H-28), 0.85 (6H, s, H-16 ^a ), 0.72 (9H, s, Me-18 & Me-19 & Me-29), 0.69 (1H, t, J = 12.8 Hz, H-5).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ (ppm) of Compound 3: 173.29 (C-1a), 130.45 (C-25), 125.54 (C-24), 104.85 (C-1′′), 103.88 (C-1'), 88.75 (C-3), 83.31 (C-2'), 77.10 (C-3"), 76.89 (C-3'), 76.33 (C-5'), 75.46 (C- 2"), 74.11 (C-5"), 72.34 (C-20), 70.08 (C-4"), 69.83 (C-12), 63.95 (C-6"), 61.42 (C-6'), 55.94(C-5), 51.35(C-14), 49.98(C-17), 49.76(C-9), 48.42(C-13), 42.49(C-22), 40.29(C-4), 39.03 (C-8&C-1), 36.65 (C-10), 34.81 (C-7), 33.88 (C-2b), 31.82 (C-14a), 31.79 (C-11), 31.03 (C-1") , 30.43 (C-14b), 29.62 (C-3b & C-4b & C-5b), 29.57 (C-6b & 7b), 29.42 (C-8b & 9b), 29.39 (C-10b & 11b), 29.32 (C-12b), 29.20 (C -13b), 27.63 (C-28), 26.19 (C-16), 25.91 (C-2), 24.87 (C-26), 22.56 (C-15b), 22.48 (C-21), 21.89 (C- 23), 18.19 (C-6), 17.84 (C-30), 17.14 (C-27), 16.36 (C-29), 16.13 (C-19), 15.74 (C-18), 14.37 (C-16b) ).

According to the test data of ESI-MS, ¹ H-NMR and ¹³ C-NMR, the structural formula of the compound 3 was determined to be

Compound 3 was determined to be 20(R)-ginsenoside Rg3-6"-palmitate.

Example 2

1. Add 20(R)-ginsenoside Rg3 (4g, 5.09mmol) to 180ml of dry anhydrous pyridine and stir. Solving, preparing 20(R)-ginsenoside Rg3 solution;

2. Under the condition of ice bath (-10 °C), nitrogen gas is introduced into the reaction vessel to remove air, and the moisture in the air is prevented from coming into contact with the acid chloride reagent, resulting in denaturing of the acid chloride to 20(R)-ginsenoside Rg3. Palmitoyl chloride (3.07 ml, about 10 mmol) was added dropwise to the solution, and the mixture was stirred while dropping, and the dropping rate was 1 drop/2 s until the palmitoyl chloride was added dropwise to prepare a ginsenoside-acid chloride mixture; wherein 20(R)- The molar ratio of ginsenoside Rg3 to palmitoyl chloride was 1:1.9.

In the embodiment of the present invention, the dropping acceleration in the process of dropping the acylating reagent acid chloride is described by taking 1 drop/2s as an example, and other dropping accelerations such as 1 drop/1-5 s are suitable for the present invention.

3. After continuously adding an inert gas (nitrogen) to the reaction vessel, the acid chloride reagent is added dropwise, and then heated under stirring to raise the ginsenoside-acid chloride mixture to 0 ° C and keep the temperature at 0 ° C. Esterification reaction for 10h;

4, adding anhydrous methanol (5ml), quenching the esterification reaction to obtain an esterification reaction mixture;

5. The esterification reaction mixture is subjected to vacuum distillation treatment, and the solvent is removed, followed by silica gel column chromatography, and eluted with a mixture of chloroform and methanol as an eluent to obtain three compounds, wherein the vacuum distillation process is performed. The relative pressure in the medium is -0.095 MPa, and the silica gel in the silica gel column is selected from GF254 silica gel, and the ratio of the volume of chloroform to methanol in the eluent is 9:1.

The three compounds obtained were determined by ESI-MS, ¹ H-NMR and ¹³ C-NMR, and were identical to the three compounds prepared in Example 1, respectively, Compound 1 (3.1 g); Compound 2 (820 mg); 3 (810 mg).

Example 3

1. 20(R)-ginsenoside Rg3 (4g, 5.09mmol) is added to 180ml of dried anhydrous pyridine and stirred to dissolve to obtain 20(R)-ginsenoside Rg3 solution;

2. Under ice bath (0 ° C), nitrogen gas is introduced into the reaction vessel to remove air, and the moisture in the air is prevented from coming into contact with the acid chloride reagent, resulting in the denaturation of the acid chloride to 20(R)-ginsenoside Rg3. Palmitoyl chloride (3.07 ml, about 10 mmol) was added dropwise to the solution, and the mixture was stirred while dropping, and the dropping rate was 1 drop/2 s until the palmitoyl chloride was added dropwise to prepare a ginsenoside-acid chloride mixture; wherein 20(R)- The molar ratio of ginsenoside Rg3 to stearoyl chloride is 1:2.3;

3. After the inert acid gas (nitrogen) is always introduced into the reaction vessel, the acid chloride reagent is added dropwise, and then heated under stirring to raise the ginsenoside-acid chloride mixture to 5 ° C and maintain the temperature at 5 ° C. Under the conditions, the esterification reaction is carried out for 1 h;

4, adding anhydrous methanol (5ml), quenching the esterification reaction to obtain an esterification reaction mixture;

5. The esterification reaction mixture is subjected to vacuum distillation treatment, and the solvent is removed, followed by silica gel column chromatography to obtain a volume ratio. After 9:1 of a mixture of chloroform and methanol was eluted as an eluent, three compounds (compounds 4, 5, and 6) were obtained, wherein the relative pressure during the vacuum distillation treatment was -0.095 MPa.

The three compounds obtained were determined by ESI-MS, ¹ H-NMR and ¹³ C-NMR, and were identical to the three compounds prepared in Example 1, respectively, Compound 1 (2.9 g); Compound 2 (710 mg); 3 (700 mg).

Example 4

1. 20(R)-ginsenoside Rg3 (4g, 5.09mmol) is added to 180ml of dried anhydrous pyridine and stirred to dissolve to obtain 20(R)-ginsenoside Rg3 solution;

2. Under ice bath (0 ° C), nitrogen gas is introduced into the reaction vessel to remove air, and the moisture in the air is prevented from coming into contact with the acid chloride reagent, resulting in the denaturation of the acid chloride to 20(R)-ginsenoside Rg3. Palmitoyl chloride (3.07 ml, about 10 mmol) was added dropwise to the solution, and the mixture was stirred while stirring, and the dropping rate was 1 drop/2 s until the stearyl chloride was added dropwise to prepare a ginsenoside-acid chloride mixture; wherein 20(R) - The molar ratio of ginsenoside Rg3 to stearoyl chloride is 1:2.

3. After the inert acid gas (nitrogen) is always introduced into the reaction vessel, the acid chloride reagent is added dropwise, and then heated under stirring to raise the ginsenoside-acid chloride mixture to 5 ° C and maintain the temperature at 5 ° C. Under the conditions of the esterification reaction for 10h;

4, adding anhydrous methanol (5ml), quenching the esterification reaction to obtain an esterification reaction mixture;

5. The esterification reaction mixture is subjected to vacuum distillation treatment, and the solvent is removed, followed by silica gel column chromatography, and eluted with a mixture of chloroform and methanol as an eluent to obtain three compounds, wherein the vacuum distillation process is performed. The relative pressure in the medium is -0.095 MPa, and the silica gel in the silica gel column is selected from GF254 silica gel, and the ratio of the volume of chloroform to methanol in the eluent is 9:1.

The three compounds obtained were determined by ESI-MS, ¹ H-NMR and ¹³ C-NMR, and were identical to the three compounds prepared in Example 1, respectively, Compound 1 (3.3 g); Compound 2 (800 mg); 3 (800 mg).

Example 5 Comparison of 20(R)-ginsenoside Rg3 and its derivatives in vitro against digestive tract tumors

1. Experimental materials

1) Test drug

20(R)-ginsenoside Rg3 derivatives (ie, compounds 1, 2, 3) and 20(R)-ginsenoside Rg3 prepared by the first embodiment of the present invention (China Bioproducts Inspection Institute, by high performance liquid chromatography) Ultraviolet detector and evaporative light scattering detector area normalization method, the purity is 99.6%)

10 μg of each of the above compounds 1, 2, and 3 was accurately weighed and added to 100 μl of DMEM medium for dissolution at 3000 rpm. Centrifuge, aspirate the supernatant, and store at -20 °C. The 0.22 μm filter was sterilized by filtration and used.

3 parts of 20(R)-ginsenoside Rg3 were accurately weighed, 50 μg each, dissolved in 100 μl of DMEM medium, centrifuged at 3000 rpm, and the supernatant was aspirated and stored frozen at -20 °C. The 0.22 μm filter was sterilized by filtration and used.

2) Preparation solution

DMEM culture solution: purchased from Hyclone, the basal medium, the medium used for culturing the cells is 90%, and the fetal bovine serum is 10%.

Cryopreservation solution: fetal bovine serum (inactivated, filter sterilized) 90c / o mixed with dimethyl sulfoxide (DMSO) 10c / o, stored in a refrigerator at -20 ° C.

BS buffer: Accurately weigh NaCl 8g, KCl 0.2g, Na ₂ HPO41.44g, KH ₂ PO ₄ 0.24g, make up 1L, adjust pH 7.4, make 0.01mol/L (1*PBS), filter and sterilize , sub-package, 4 ° C save spare.

3) Cell line selection

Tumor cell line: gastric cancer SGC-7901 cells, pancreatic cancer PANC1 cell line, colon cancer LOVO cell line.

2. Test methods and main steps

1) Experimental grouping:

1 normal culture group (Normal); 2Rg3 original drug group: 20 (R)-ginsenoside Rg3 solution at a concentration of 50 μg/ml; 3 derivative group 1 is compound 1, 2; derivative group 2 is compound 3, 4 The derivative group 3 was the compounds 5 and 6, and their concentrations were all 10 μg/ml.

2) Observation of cell growth:

A tumor cell line with good growth condition, routinely digested into a single cell suspension, counted, adjusted to a cell concentration of 5×10 ⁴ /ml, and uniformly seeded the cells in a 24-well plate, and each experiment group has 6 replicate wells, a total of 4 test group. The above cell line test well plates were placed in a 37 ° C, 5% CO 2 incubator. After passage, the cells were grown to 60-70% confluence, the normal culture group was changed, and the other groups were added with the corresponding concentrations of drugs, and the dosing time was recorded. point. After the administration for 24 h, 48 h, and 72 h, the inverted plates were photographed at each time point using an inverted fluorescence microscope (Olympus BX51, Olympus DP70; manufactured by Olympus, Japan). Each well was selected according to the overall condition of the re-pore. Representative pictures are determined primarily by observing the number of cells and the state.

3) Experimental results

20(R)-Ginsenoside Rg3 and its derivatives in vitro anti-human colon cancer test results shown in Figure 1, 20 (R) ginsenoside Rg3 original drug and its derivatives in vitro on the proliferation of human colon cancer LOVO cell line Results (fluorescence micrograph). Rg3 derivatives A and B (ie, compounds 1 and 2) have apoptotic and proliferation-inhibiting effects on human colon cancer LOVO cells at a dose lower than that of Rg3, which is superior to Rg3.

20(R)-ginsenoside Rg3 and its derivatives in vitro anti-gastric cancer test results shown in Figure 2, 20 (R) ginsenoside Rg3 original drug and its derivatives in vitro on the gastric cancer SGC-7901 cell line preliminary observation results fluorescent Micro photo. Rg3 derivatives B and C (compounds 2 and 3) have apoptosis and inhibit proliferation and growth effects on human gastric cancer SGC-7901 cells at a dose lower than that of Rg3, which is superior to Rg3.

20(R)-Ginsenoside Rg3 and its derivatives in vitro anti-human pancreatic cancer test results are shown in Figure 3, 20 (R) ginsenoside Rg3 original drug and its derivatives in vitro on the proliferation of human pancreatic cancer PANC1 cell line preliminary observation results (fluorescence micrograph). Rg3 derivatives A and C (compounds 1 and 3) have apoptotic and proliferation-inhibiting effects on human gastric cancer SGC-7901 cells at a dose lower than that of Rg3, which is superior to Rg3.

It can be seen from the above experimental results that in vitro experiments show that 20(R)-ginsenoside Rg3 derivatives have obvious effects on tumor cell apoptosis and proliferation inhibition in human gastric cancer, colon cancer, pancreatic cancer and other digestive tract tumor cells, rather than cytotoxicity. Its effect is also significantly better than 20(R)-ginsenoside Rg3; unlike other chemically synthesized drugs, 20(R)-ginsenoside Rg3 derivatives have no cytotoxic effect and can inhibit and inhibit tumor cells. Its proliferation and growth, which will show low toxicity and high efficiency in clinical treatment, which is also a therapeutic advantage of 20(R)-ginsenoside Rg3 derivatives.

Example 6 Inhibition of Tumor by 20(R)-Ginsenoside Rg3 and Derivatives

1. Test materials and methods

1.1 test animals

Nude mice and C57BL/6 mice were sold by the Experimental Animal Center of Bethune Medical College of Jilin University, and the certificate number was SCXK 20020001. Nude mice are 6 weeks old, and C57BL/6 mice are 18-22 grams, both male and female.

1.2 drugs and instruments

Test drug: Compound 1-3 prepared in Example 1 was more than 98.2% pure; 20(R)-ginsenoside Rg3 (abbreviated as 20(R)-Rg3), purity 98.5%, purchased from Dalian Fusheng Natural Medicine Development Co., Ltd. Company, batch number: 20110515.

Dilution excipient: 0.5% CMC-Na solution.

Preparation method Accurately weigh a certain amount of 20 (R)-ginsenoside Rg3 and its derivatives into 5% CMC-Na to make a suspension to the desired concentration.

Positive drug: cyclophosphamide for injection (abbreviated as CTX), produced by Shanghai Hualian Pharmaceutical Group, batch number: 20110120.

Tumor source: human lung cancer A549 model, human breast cancer Bcap-37 model, human gastric cancer MGC model and human liver cancer QGY were used as tumor sources for the second generation or more, all purchased from Shanghai Pharmaceutical Industry Research Institute.

1.3 Experimental methods

1.3.1 Dosing regimen

Each of the 20(R)-ginsenoside Rg3 derivative groups (ie, the compound 1-6 group) of the test group was administered once every other day at 3.0 mg/kg, 1.5 mg/kg, and 0.75 mg/kg, and a total of 10 doses were administered. The 20(R)-ginsenoside Rg3 group (20(R)-Rg3 group) was administered at a dose of 3.0 mg/kg. Chemotherapy was administered to the cyclophosphamide group (CTX, positive control group) or intraperitoneal administration once a day for 7 consecutive days. The negative control group was the 0.5% CMC-Na suspension of the corresponding excipients.

1.3.2 Human lung cancer A549, human breast cancer Bcap-37 subcutaneous inoculation model

Obtain a vigorous growth source under sterile conditions, prepare a cell suspension of about 1~2×10 ⁷ /ml by homogenization; inoculate 0.2ml/mouse under the skin of the corresponding host (or nude mouse) under the skin of the toes or the skin. The next day, according to the experimental design, the animals were sacrificed in three weeks. The tumors were weighed and the tumor inhibition rate was calculated according to the following formula:

Tumor inhibition rate%=[(control group average tumor weight-average tumor weight of administration group)/control group average tumor weight]×100%

1.3.3 gastric in situ vaccination model

Under the sterile conditions, the 2 generations of MGC gastric cancer with vigorous growth were prepared, and about 2×10 ⁷ /ml cell suspension was prepared by homogenization method, and the cell suspension was injected into the large curved muscle layer of the nude mice. 0.05 ml, the next day according to the experimental design, the life extension rate of the tumor-bearing host was calculated according to the following formula:

Life extension rate%=average survival days of the administration group/average survival days of the control group×100%

1.3.4 Liver in situ vaccination model

Under the sterile conditions, the second-generation QGY tumor source was obtained by vigorous growth, and a cell suspension of about 1-2×10 ⁷ /ml was prepared by homogenization method 1:6, and the homogenate was filtered through a 100-mesh stainless steel mesh. . Nude mice were routinely sterilized, anesthetized in the mid-abdominal sacral process to open the skin and abdominal cavity, expose the liver, and inject 0.05 ml of cell suspension into the liver parenchyma with an imported 28 ga 1/2 ml syringe, close the abdominal cavity, suture the abdominal cavity and skin layer by layer. . The nude mice were placed in a laminar flow rack, and the feed, litter, cages, and instruments in contact were used after autoclaving. The next day, according to the experimental design, the survival time of each group of animals was observed within 45 days, compared with the negative control group, and the life extension rate was calculated. The calculation method was the same as 1.3.3.

2, test results

The results of the anti-tumor test of human lung cancer A549 in each compound group are shown in Table 1; the results of anti-tumor test on human breast cancer Bcap-37 (subcutaneous inoculation) are shown in Table 2; the nude mice were inoculated with human gastric cancer MGC (in situ vaccination) and The prolonged life test results of human liver cancer QGY (in situ vaccination) are shown in Tables 3 and 4, respectively.

Table 1 efficacy test on human lung cancer A549 (subcutaneous inoculation) (n=3)

^*** : p value <0.01 compared with the negative control group;

^### : The p value is <0.01 for the Rg3 derivative compared with the Rg3 original drug.

Table 2 Efficacy test of Rg3 original drug and derivative on human breast cancer Bcap-37 (subcutaneous inoculation) nude mouse model (n=3)

^*** : p value <0.01 compared with the negative control group;

^### : The p value is <0.01 for the Rg3 derivative compared with the Rg3 original drug.

Table 3 efficacy test of human gastric cancer MGC nude mouse model (in situ vaccination) (n=3)

^*** : p value <0.01 compared with the negative control group;

^### : The p value is <0.01 for the Rg3 derivative compared with the Rg3 original drug.

Table 4 Efficacy test of human liver cancer QGY nude mouse model (in situ vaccination) (n=3)

^*** : p value <0.01 compared with the negative control group;

^### : The p value is <0.01 for the Rg3 derivative compared with the Rg3 original drug.

From the experimental results in Table 1-4 above, it can be known that Compound 1-3 can significantly inhibit human breast cancer Bcap-37 (subcutaneous inoculation), and has obvious effects on human gastric cancer MGC nude mouse model and human liver cancer QGY nude mouse model. Life extension.

Test Example 7 Acute Toxicity Test

Twenty healthy NIH mice were selected and weighed 18 to 20 grams, half male and half female. The rats were fasted for 12 hours before the experiment. In the experiment, the 20(R)-ginsenoside Rg3 derivative-compound 1-3 of the present invention was formulated into 30% in the maximum concentration and the maximum volume which the mice could tolerate. The concentration was intragastrically administered once at 15 g/kg body weight for 7 days. The experimental results did not detect the LD ₅₀ value of the traditional Chinese medicine composition of the present invention to the mouse, which is equivalent to 2343750 times of the clinical dose, and the maximum tolerance of the Rg3 series derivative of the present invention to the intragastric administration of the mouse is more than 15 g/kg. It shows that the 20(R)-ginsenoside Rg3 derivative of the present invention has no acute toxicity reaction and is safe.

Claims (10)

a 20(R)-ginsenoside Rg3 derivative represented by the structural formula (I) or a pharmaceutically acceptable salt thereof,

Wherein R1=H, R2=C _n H _2n+1 CO or R1=C _n H _2n+1 CO, R2=H or R1=R2=C _n H _2n+1 CO, n=3-30. A method for preparing a 20(R)-ginsenoside Rg3 derivative according to claim 1, comprising the steps of: 1) 20(R)-ginsenoside Rg3 is dissolved in an organic solvent to prepare a 20(R)-ginsenoside Rg3 solution; 2) adding an acylating reagent to carry out an esterification reaction; 3) After removing the solvent from the mixture after the esterification reaction, the mixture is subjected to silica gel column chromatography to obtain. The process according to claim 2, wherein the organic solvent is selected from the step 1) of pyridine, 2,4,6-trimethylpyridine or 2,6-lutidine. The process according to claim 2 or 3, wherein the acylating agent in step 2) is an acid chloride. The process according to claim 4, wherein the acid chloride has a structural formula of C _n H _2n+1 COCl, wherein n = 3 to 30. The preparation method according to claim 2 or 3, wherein the step 2) the acylating reagent and the step 1) The molar ratio of 20(R)-ginsenoside Rg3 is 1.5 to 3:1. The process according to claim 2 or 3, wherein the reaction temperature of the esterification reaction in the step 2) is from -10 ° C to 20 ° C; and the reaction time is from 0.5 to 12 h. The process according to claim 2 or 3, wherein the esterification reaction is carried out under the protection of an inert gas. The use of the 20(R)-ginsenoside Rg3 derivative according to claim 1 for the preparation of a medicament for preventing or/and treating cancer and tumors. The use of the 20(R)-ginsenoside Rg3 derivative according to claim 1 for preparing a medicament against various animal solid tumors, anti-lung cancer, anti-breast cancer, anti-gastric cancer, anti-intestinal cancer, anti-hepatocarcinoma and anti-pancreatic cancer .

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