Cycloicaritin carbamate prodrugs and salts thereof

Abstract

The invention discloses a cyclo-icaritin carbamate prodrug and salt thereof, belongs to the technical field of medicines, and particularly relates to a carbamate prodrug formed between cyclo-icaritin and amino acid, pharmaceutically acceptable salt of the carbamate prodrug and preparation and application of the carbamate prodrug. Specifically, in combination with the structural characteristics of cycloicaritin and the inherent advantages of the prodrug, amino acid is taken as a modification group and is covalently bound with 3-site hydroxyl in the cycloicaritin structure to form a series of cycloicaritin carbamate prodrugs. According to the compound, the water solubility, permeability and metabolic stability of cycloicaritin can be remarkably improved, the bioavailability of drugs is improved, and the anti-tumor effect is better achieved. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to cycloicariin carbamate and pharmaceutically acceptable salts thereof and a preparation method thereof. Background Art

[0002] Cycloicariin is an isomer of icariin, with the chemical name 3,5-dihydroxy-2-(4-methoxy-phenyl)-8,8-dimethyl-9,10-dihydro-8H-pyrano[2,3-f]chromene-4-one, and is a flavonoid compound. Cycloicariin can be isolated from the traditional Chinese medicine Epimedium, or prepared by hydrolysis of icariin. Studies have found that cycloicariin has good anti-tumor activity and can effectively inhibit a variety of tumor cells without obvious toxic side effects. In addition, cycloicariin also has multiple effects such as anti-osteoporosis, hypoglycemic, anti-inflammatory, antioxidant, cardiovascular and cerebrovascular improvement, immune enhancement and improvement of estrogen levels, and has good application prospects.

[0003] Cycloicariin has poor solubility, poor permeability, and the hydroxyl groups in the structure are easily metabolized in the intestinal tract and liver in vivo, with a strong first-pass effect and poor oral absorption, resulting in low bioavailability, which restricts the efficacy of the drug. Therefore, it is very necessary to improve the oral bioavailability of cycloicariin. However, existing drug delivery systems include liposomes, self-microemulsions, phospholipid complexes, and polymer micelles, but there are problems such as low drug loading, poor formulation stability, and poor oral absorption, and it is very challenging to improve its bioavailability by formulation means.

[0004] Prodrugs are chemically modified from the drug's own structure to achieve the purpose of improving bioavailability. They are an important means and strategy for designing and developing innovative drugs. Amino acids are diverse, cheap, easy to obtain, and highly safe. They can form carbamate prodrugs with hydroxyl groups, which can increase the solubility of the parent drug in water. In order to improve the poor solubility, poor permeability, and easy metabolism of cycloicariin, we used a prodrug strategy to couple the main metabolic site of cycloicariin with a series of amino acids through a carbamate bond to obtain a series of carbamate prodrugs, thereby improving its water solubility, membrane permeability, and metabolic stability, thereby improving its oral bioavailability and better exerting its efficacy. Summary of the invention

[0005] The object of the present invention is to provide cycloicariin carbamate prodrugs and pharmaceutically acceptable salts thereof, and use of the prodrugs in improving the water solubility and bioavailability of cycloicariin.

[0006] The cycloicariin carbamate prodrug is prepared by modifying the 3-hydroxyl group of cycloicariin with an amino acid, wherein the amino acid is one of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine.

[0007] Specifically, the general structural formula of the cycloicariin carbamate prodrug of the present invention is as follows:

[0008]

[0009] Wherein R is the residue of a selected amino acid, preferably glycine, L-isoleucine, L-phenylalanine, L-valine, L-leucine, L-alanine, L-glutamic acid, and more preferably L-leucine, and its structure is as follows:

[0010]

[0011] The synthesis of the cycloicariin carbamate prodrug is carried out according to the following method:

[0012] The first step: dissolving compound I and a carbonylation reagent in a reaction solvent, and adding a basic catalyst dropwise to obtain compound II.

[0013] wherein the carbonylation reagent is selected from dimethyl carbonate, 4-nitrophenyl carbonate, phosgene and solid phosgene;

[0014] The reaction solvent is selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylhexanamide; the alkaline catalyst is selected from triethylamine, potassium carbonate, sodium carbonate, strong potassium oxide, sodium hydroxide, pyridine. The dropping temperature is -20°C to 0°C.

[0015] Step 2: Add compound II dropwise into cycloicariin dissolved in an aprotic solvent and react at room temperature for 1-3 hours to obtain compound III;

[0016] The aprotic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone. The reaction temperature is 10°C-40°C

[0017] Step 3: Dissolve compound III in acid, first place in an ice bath for 30 minutes, then react at room temperature for 1-3 hours, remove the solvent by rotary evaporation, and separate the preparative liquid phase to obtain compound IV;

[0018] The acid is selected from hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, and p-toluenesulfonic acid. The reaction temperature is 0°C-40°C.

[0019] Step 4: Dissolve compound IV in different bases to obtain its salt form.

[0020] The base used includes: potassium hydroxide, potassium bicarbonate, potassium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonia water, diethylamine, triethylamine.

[0021]

[0022] R represents an amino acid residue;

[0023] a: carbonylation reagent (dimethyl carbonate, 4-nitrophenyl carbonate, phosgene or solid phosgene), basic catalyst (triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, pyridine) and solvent (dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylhexanamide);

[0024] b: solvent (dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone);

[0025] c: Acid (hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid).

[0026] Advantages and beneficial effects of the present invention:

[0027] The present invention synthesizes amino acid modified cycloicariin carbamate prodrugs and pharmaceutically acceptable salts thereof for the first time, and these compounds can significantly improve the water solubility, permeability and metabolic stability of cycloicariin. When cycloicariin, the compound of Example 2 and the compound of Example 5 are orally administered, the in vivo exposure of cycloicariin is significantly increased; the absolute bioavailability is 0.11%, 5.7% and 2.8%, respectively. Compared with oral cycloicariin, the oral bioavailability of the compound of Example 2 and the compound of Example 5 is increased by 52 times and 25 times, respectively, and the oral bioavailability is significantly improved, achieving the intended purpose. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The remaining percentage-time curve of cycloicariin and its prodrug after phase II reaction in rat liver microsomes (n=3);

[0029] Figure 2 The blood concentration-time curves of icariin, the compound of Example 2 and the compound of Example 5 (n=5);

[0030] a. Oral administration of cycloicariin (200 mg / kg);

[0031] b. Oral administration of the compound of Example 2 (200 mg / kg in terms of cycloicariin);

[0032] c. Oral administration of the compound of Example 5 (200 mg / kg in terms of cycloicariin);

[0033] d. intravenous injection of cycloicariin (2 mg / kg);

[0034] Figure 3 (A) Changes in tumor volume of 4T1 tumor-bearing mice after oral gavage of cycloicariin or the compound of Example 2; (B) Tumor images of 4T1 tumor-bearing mice 15 days after administration; (C) Tumor bearing rate of 4T1 tumor-bearing mice 15 days after administration; (D) Changes in body weight of 4T1 tumor-bearing mice after oral gavage of cycloicariin or the compound of Example 2 (n=6). DETAILED DESCRIPTION

[0035] The following specific examples are used to further illustrate the present invention, but are by no means intended to limit the scope thereof.

[0036] According to the synthetic route of cycloicariin carbamate prodrug, the following compounds were prepared respectively.

[0037] Example 1

[0038] Step 1: Dissolve glycine tert-butyl ester hydrochloride (1 g) and solid phosgene (1.2 g) in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0039] Step 2: Dissolve cycloicariin (1.47 g) in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0040] Step 3: Dissolve the mixture of compound III in trifluoroacetic acid (TFA, 20 mL), protect with nitrogen, ice bath for 30 min, and then react at room temperature for 1 h. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-glycylcycloicariin.

[0041] Referring to the preparation method of Example 1, Examples 2-7 were implemented.

[0042] Example 2

[0043] The first step: dissolve L-leucine tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0044] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0045] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-L-leucyl cycloicariin.

[0046] Example 3

[0047] The first step: dissolve L-phenylalanine tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0048] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0049] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-L-phenylalanyl cycloicariin.

[0050] Example 4

[0051] The first step: dissolve L-isoleucine tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0052] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0053] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-L-isoleucyl cycloicariin.

[0054] Example 5

[0055] The first step: dissolve L-valine tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0056] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0057] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-L-valylcycloicariin.

[0058] Example 6

[0059] The first step: dissolve L-alanine tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0060] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0061] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain the compound 3-alanyl cycloicariin.

[0062] Example 7

[0063] The first step: dissolve L-glutamic acid tert-butyl ester hydrochloride and solid phosgene in dichloromethane, fill with nitrogen, control the dropping temperature to -20°C-0°C, and add triethylamine dropwise to obtain compound II.

[0064] Step 2: dissolve cycloicariin in N,N-dimethylformamide, add dropwise the reaction solution containing compound II, fill with nitrogen, react at room temperature for 2 hours, dilute the reaction solution with water, extract three times with dichloromethane, wash with aqueous solution and saturated brine in turn, filter, and spin dry to remove the solvent to obtain a mixture containing compound III.

[0065] Step 3: Dissolve the compound III mixture in trifluoroacetic acid (TFA), protect with nitrogen, ice bath for 30 minutes, and then react at room temperature for 1 hour. Evaporate the solvent under reduced pressure, wash with anhydrous dichloromethane 3 times, spin dry, and separate by preparative liquid phase to obtain 3-L-glutamylcycloicariin.

[0066] The identification information of cycloicariin and its amino acid modified cycloicariin carbamate prodrug compounds is shown in Table 1:

[0067] Table 1 Related information of cycloicariin and its prodrugs

[0068]

[0069]

[0070] Example 8

[0071] Equilibrium Solubility Test of Cycloicariin Carbamate Prodrug in Water

[0072] The poor water solubility of cycloicariin is an important reason that limits its bioavailability. Therefore, investigating the equilibrium solubility of a series of prodrugs in the aqueous phase is conducive to predicting the dissolution and absorption of cycloicariin carbamate prodrugs in vivo. Take an excess of cycloicariin and amino acid-modified cycloicariin carbamate prodrugs and add an appropriate amount of water, shake in an air constant temperature oscillator at 37°C to equilibrium, and obtain the equilibrium solubility of cycloicariin and amino acid-modified cycloicariin carbamate prodrugs in water. The results are shown in Table 2.

[0073] Table 2 Equilibrium solubility of cycloicariin and its prodrugs in water

[0074]

[0075] The results showed that each prodrug significantly improved the water solubility of cycloicariin, among which the compounds of Example 2 and Example 5 had better water solubility, increasing the water solubility by about 16.3 and 14 times, respectively.

[0076] Example 9

[0077] Study on Phase Ⅱ Metabolism of Cycloicariin and Its Carbamate Prodrug

[0078] Severe phase II metabolism is a major factor limiting the oral bioavailability of cycloicariin. In order to determine whether the designed prodrug can improve its metabolic stability, we selected the compounds of Example 2 and Example 5 with greatly improved water solubility, and used an in vitro liver microsome incubation method to simulate the metabolism of the prodrug in vivo. The specific incubation process is as follows: rat liver microsomes, magnesium chloride, D-glucaric acid 1,4-lactone, Triton and the drug to be tested were prepared into appropriate concentrations with buffer, added to a stoppered glass test tube, and pre-incubated in a constant temperature water bath shaker at 37°C. 5′-diphosphoglucuronic acid trisodium solution was added to initiate the glucuronidation reaction, and incubated in a constant temperature water bath shaker at 37°C. Three replicates were performed, and samples were taken at different time points for measurement. The percentage of remaining prodrug and parent drug was used as an indicator to evaluate the metabolism of cycloicariin and prodrug in rat liver microsomes. The results are shown in Figure 1 shown.

[0079] The results showed that the glucuronidation reaction of cycloicariin and its carbamate prodrug was time-dependent. As the incubation time increased, cycloicariin was rapidly metabolized, while the compounds of Example 2 and Example 5 were slowly metabolized, and both of them could significantly improve the phase II metabolic stability of cycloicariin.

[0080] Example 10

[0081] In vivo intestinal perfusion study of cycloicariin and its carbamate prodrug

[0082] In order to study whether the prodrug can improve the permeability of the parent drug, we conducted an in vivo intestinal perfusion test on cycloicariin, the compound of Example 2 and the compound of Example 5. A rat jejunum of about 10 cm in length was taken, and cannulated at both ends. Cycloicariin, the compound of Example 2 and the compound of Example 5 were dissolved in Kreb-Ringers nutrient solution (pH 6.0) at a concentration of 5 μM. The drug-containing perfusion solution was passed through the rat jejunum at a flow rate of 0.2 mL / min to obtain the membrane permeability of cycloicariin, the compound of Example 2 and the compound of Example 5 in the jejunum.

[0083] Table 3 Membrane permeability of cycloicariin and its prodrugs

[0084]

[0085] The results showed that compared with cycloicariin, the effective permeability coefficients of the compounds of Example 2 and Example 5 were increased by 2.2 times and 1.8 times, respectively, and the permeability was significantly improved.

[0086] Embodiment 11

[0087] Pharmacokinetic study in rats

[0088] After cycloicariin was modified with amino acids to form carbamate, the water solubility of the compounds of Examples 2-7 was improved to varying degrees compared with cycloicariin, among which the water solubility of the compounds of Example 2 and Example 5 was increased by 16.3 and 14 times, respectively, with the greatest increase in water solubility; after the hydroxyl group was protected, the phase II metabolism of the compounds of Example 2 and Example 5 was significantly reduced. In vivo intestinal perfusion experiments found that the effective permeability coefficients of the compounds of Example 2 and Example 5 were increased by 2.2 times and 1.8 times, respectively, and the permeability was significantly improved. Preliminary in vitro evidence showed that the expected purpose was achieved. In order to further study the design to improve its bioavailability, we selected the compounds of Example 2 and Example 5, which have high water solubility, good permeability and are not prone to phase II metabolism, for in vivo pharmacokinetics studies.

[0089] The experimental group and the control group Sprague-Dawley rats were gavaged with cycloicariin, the compound of Example 2 and the compound of Example 5 (200 mg / kg in terms of cycloicariin) and injected intravenously with cycloicariin solution (2 mg / kg) to measure the concentration of cycloicariin in plasma. The results are shown in Tables 4 and Figure 2 .

[0090] Table 4 Pharmacokinetic parameters of cycloicariin in rats after oral administration of cycloicariin, the compound of Example 2 and the compound of Example 5 (calculated as cycloicariin 200 mg / kg)

[0091]

[0092] From Table 4 and Figure 2 It can be seen that after oral administration of Epimedium cyclohexene, the compound of Example 2 and the compound of Example 5, the area under the drug-time curve (AUC 0-t ) is significantly higher than cycloicariin, and the in vivo exposure of cycloicariin is significantly increased; calculated from the data of intravenous injection of cycloicariin, the absolute bioavailability of cycloicariin and its prodrug is 0.11%, 5.7% and 2.8%, respectively. Compared with oral cycloicariin, the oral bioavailability of Example 2 compound and Example 5 compound is increased by 52 times and 25 times, respectively, and the oral bioavailability is significantly improved.

[0093] Example 12

[0094] Pharmacodynamic evaluation

[0095] The compound of Example 2 with high oral absolute bioavailability was selected for pharmacodynamic study to investigate its anti-tumor activity. Eighteen BALB / c mice (female, weight 18-22 g) were injected into the subcutaneous tissue of the right rear back of the mice at a density of 1×10 7cells / mL of mouse breast cancer cells (4T1). When the tumor volume in the tumor-bearing mice grows to 100mm 3 The mice were randomly divided into groups of 6 animals each. Olive oil, cycloicariin with olive oil as solvent and the compound of Example 2 were administered orally at an equivalent dose of 70 mg / kg for 15 consecutive days. The tumor volume and body weight of the tumor-bearing mice were measured and recorded every other day. After the efficacy experiment, all tumor-bearing mice were killed, tumor tissues were isolated and obtained, and the tumor-bearing rate was calculated. The results are shown in Figure 3 shown.

[0096] The results showed that compared with cycloicariin, the compound of Example 2 showed good anti-tumor effect, which could effectively inhibit tumor growth, with almost no change in body weight and good safety. The compound designed by the present invention significantly improves the bioavailability of cycloicariin, is safe and effective, and has good development prospects.

Claims

1. A cycloicariin carbamate prodrug or a pharmaceutically acceptable salt thereof, characterized in that: The prodrug is prepared by coupling the 3-hydroxyl group of cycloicariin with an amino acid amino group through a carbamate bond, wherein the amino acid is one of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine.

2. The cycloicariin carbamate prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The amino acids are selected from the group consisting of glycine, L-alanine, L-valine, L-isoleucine, L-leucine, L-phenylalanine, and L-glutamic acid.

3. The cycloicariin carbamate prodrug or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The prodrug structural formula is: Wherein R is an amino acid residue selected from the following structures:

4. The method for preparing the cycloicariin carbamate prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Follow these steps: The first step: dissolving compound I and a carbonylation reagent in a reaction solvent, and adding a basic catalyst dropwise to obtain compound II; Step 2: Add compound II dropwise into cycloicariin dissolved in an aprotic solvent and react at room temperature for 1-3 hours to obtain compound III; Step 3: Dissolve compound III in acid, first place in an ice bath for 30 minutes, then react at room temperature for 1-3 hours, remove the solvent by rotary evaporation, and separate the preparative liquid phase to obtain compound IV; Step 4: dissolving compound IV in different bases to obtain its salt form; R represents an amino acid residue.

5. The preparation method according to claim 4, characterized in that: In the first step, the carbonylation reagent is selected from dimethyl carbonate, 4-nitrophenyl carbonate, phosgene, and solid phosgene; the alkaline catalyst is selected from triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, and pyridine; and the solvent is selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, and N,N-dimethylhexanamide.

6. The preparation method according to claim 4, characterized in that: In the second step, the aprotic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone.

7. The preparation method according to claim 4, characterized in that: In the third step, the acid is selected from hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, and p-toluenesulfonic acid.

8. The preparation method according to claim 4, characterized in that: In the fourth step, the base is selected from potassium hydroxide, potassium bicarbonate, potassium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonia water, diethylamine, and triethylamine.

9. A pharmaceutical composition, characterized in that The invention comprises the cycloicariin carbamate prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

10. Use of the cycloicariin carbamate prodrug according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 9 in the preparation of a drug for improving the solubility, permeability, metabolic stability and bioavailability of cycloicariin.

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