Lanosterol derivative, and preparation method and use thereof

Abstract

The present application relates to the technical field of medicine and provides a lanosterol derivative, a preparation method therefor and a use thereof. The structural formula of the lanosterol derivative provided by the present application is as shown in formula I or II. The lanosterol derivative provided by the present application has both lipid solubility and water solubility, and can effectively penetrate into the pathological site in the body, thereby improving the drug utilization rate. The results of embodiments show that the lanosterol derivative provided by the present application has a significantly higher solubility in water than lanosterol or 25-hydroxylanosterol and shows a significant therapeutic effect on a cataract in animal in vivo experiments. Therefore, the derivative has wide prospects in the preparation of drugs for treating eye diseases or conditions.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the technical field of medicines, in particular to a lanosterol derivative, and a preparation method and use thereof. BACKGROUND ART

[0002] Among eye diseases that could cause blindness, cataract ranks No. 1, and thus it is of great significance to develop effective methods for treating cataract. The incidence of cataract is affected by many factors, such as aging, heredity, local nutritional disorders, immune and metabolic abnormalities, long-term exposure to strong light, smoking and drinking, malnutrition, long-term use of glucocorticoids, which would lead to turbidity in the crystalline lens of the eyeball and visual impairment. The common types of cataracts include senile cataract, complicated cataract, traumatic cataract, metabolic cataract and so on, among which senile cataract is the most common. The initial symptoms of cataract are not obvious, but with the deepening of lens opacity, blurred vision, diplopia, myopia, glare and other symptoms occur, which will continue to develop and lead to complete blindness.

[0003] At present, surgery is the main method for treating cataract, including removal of the turbid crystalline lens and implantation of intraocular lens. Although surgical treatment has provided great help for patients, the cure rate of surgical treatment is far lower than the incidence rate, and there may be complications. Compared with surgical treatment, drug treatment of cataract is an indispensable and effective method, which has the advantages of good patient compliance, low treatment cost and small side effects. Protein aggregation plays an important role in the pathogenesis of cataract. In recent years, studies have shown that gene mutation, protein amino acid residue isomerization, deamidation, ubiquitination, ion interaction, and protein-protein interaction are the causes of protein aggregation. It is reported in related technologies that: the content of protein aggregates could be reduced after treatment with lanosterol, and treatment with lanosterol could improve the transparency of isolated cataract crystalline lenses of rabbit and dog, which provides a new idea for the development of cataract treatment drugs.

[0004] However, lanosterol is a liposoluble substance with poor solubility in water. The use of lanosterol in the treatment of cataract would easily encounter the problem of poor drug absorption after topical administration in the eye. SUMMARY

[0005] In view of this, the present disclosure provides a lanosterol derivative, and a preparation method and use thereof. The lanosterol derivative according to the present disclosure combines favorable water solubility and liposolubility, enabling effective penetration into lesion sites within the body while exhibiting high bioavailability.

[0006] To achieve the object, the present disclosure provides the following technical solutions:

[0007] Provided is a lanosterol derivative or a pharmaceutically acceptable salt thereof, where the lanosterol derivative has a structural formula shown in formula I or formula II, formula II, where in formula I and formula II, Y1, Y2, and Y3 each are independently hydrogen, deuterium, C1-C4 alkyl or unsaturated hydrocarbyl; X is independently oxygen, sulfur, or an NR1 group, R1 in the NR1 group being hydrogen or alkyl; R is independently hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylformyl, substituted arylformyl, heteroarylformyl, or substituted heteroarylformyl; and

[0008] in formula I and formula II, under a condition that X is oxygen, not all of R, Y1, Y2, and Y3 are hydrogen.

[0009] In some embodiments, a substituent in the substituted aryl, the substituted heteroaryl, the substituted arylformyl, and the substituted heteroarylformyl is independently at least one selected from the group consisting of halogen, deuterium, hydroxyl, mercapto, and methylthio.

[0010] In some embodiments, R in formula I and formula II is hydrogen or hydroxypyridylformyl.

[0011] In some embodiments, the lanosterol derivative is any one selected from the group consisting of OH o j-yv / x HO^N formula I-1 OH 0 x | X'' HOx^Yx^XXY Yj ° X N'"' formula I-3 OH o XlX^7 ^xx N^X formula I-5 OH 'N^OH formula I-2 OH 0 y^t ° x Nx^ formula I-4 OH Ld T T ' ho’^Xy^ formula I-6 formula I-7 formula I-8 formula I-9 formula II-1 and formula II-2.

[0012] The present disclosure also provides a method for preparing the lanosterol derivative as described in above technical solutions, where under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method I including the steps of:

[0013] mixing a compound having a structure shown in formula A-3, a compound having a structure shown in formula C, a condensation agent, a catalyst, and a solvent, and subjecting a resulting mixture to condensation to obtain the lanosterol derivative; formula A-3, R-OH formula C,

[0014] under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method II including the steps of:

[0015] mixing the compound having the structure shown in formula A-3, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula A-4; and

[0016] mixing the compound having a structure shown in formula A-4, deuterated chloroform, and a catalyst, and conducting deuteration to obtain a compound having a structure shown in formula A-5; and formula A-4,                             formula A-5,

[0017] mixing the compound having the structure shown in formula A-5, methanol, and deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula I-6, formula I-6;

[0018] under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method III including the steps of:

[0019] mixing the compound having the structure shown in formula A-4, methanol, deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula I-7, formula I-7;

[0020] under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1 and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method IV including the steps of:

[0021] mixing the compound having the structure shown in formula I-6 or formula I-7, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative;

[0022] under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method V including the steps of:

[0023] mixing lanosterol, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative;

[0024] under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method VI including:

[0025] steps of method II, except that the compound having the structure shown in formula A-3 is replaced with the lanosterol, to obtain the lanosterol derivative having a structure shown in formula B-2, formula B-2;

[0026] under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method VII including:

[0027] mixing the lanosterol, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula D; and

[0028] mixing the compound having the structure shown in formula D, methanol, deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula B-3; formula D,                              formula B-3;

[0029] under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1 and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method VIII including the steps of:

[0030] mixing the compound having the structure shown in formula B-2 or formula B-3, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative.

[0031] In some embodiments, the compound having the structure shown in formula A-3 is prepared by a process including:

[0032] mixing a mixture solution of lanosterol and dihydrolanosterol, acetic anhydride, and a catalyst, and conducting esterification to obtain a crude product, the crude product being a mixture of a compound having a structure shown in formula A-1 and a compound having a structure shown in formula B-1; formula A-1,                               formula B-1,

[0033] mixing the crude product, N-bromosuccinimide, and a solvent, and conducting bromination, and sequentially subjecting a resulting reaction mixture to rotary evaporation, subjecting a resulting residue to extraction, drying a resulting organic phase, subjecting a dried organic phase to further rotary evaporation, and silica gel column chromatography to obtain a compound having a structure shown in formula A-2; and formula A-2

[0034] mixing the compound having the structure shown in formula A-2, a reducing agent, and a solvent, and conducting debromination-ester reduction to obtain the compound having the structure shown in formula A-3.

[0035] The present disclosure further provides a pharmaceutical composition, including an active ingredient and a pharmaceutically acceptable auxiliary material; where the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in above technical solutions.

[0036] In some embodiments, the pharmaceutically acceptable auxiliary material is an excipient.

[0037] The present disclosure further provides use of the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in above technical solutions, or the pharmaceutical composition as described in above technical solutions, in the preparation of a drug for treating an eye disease or condition.

[0038] The present disclosure further provides an eye drop, including: in parts by mass, 2-4 parts of an active ingredient, 5-7 parts of hydroxypropylmethylcellulose, 30-50 parts of polysorbate, 10-20 parts of boric acid, 1-2 parts of borax, 0.03-0.06 parts of benzalkonium chloride, and 1000 parts of water, where the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in above technical solutions.

[0039] The present disclosure provides a lanosterol derivative or a pharmaceutically acceptable salt thereof, where the lanosterol derivative has a structural formula shown in formula I or formula II. In the present disclosure, the structure of lanosterol or 25-hydroxylanosterol is modified, thereby providing the lanosterol derivative having a structure shown in formula I or formula II. The lanosterol derivative according to the present disclosure combines favorable water solubility and liposolubility, enabling effective penetration into lesion sites within the body while improving bioavailability. Further, some of compound molecules provided in the present disclosure contain a basic group, which could form salts with a pharmaceutically acceptable acid to further improve the solubility in aqueous solutions. Some of compounds provided in the present disclosure could release the drug active ingredient 25-hydroxylanosterol or lanosterol under the action of various hydrolases in the body; and the hydroxynicotinic acid or hydroxyisonicotinic acid produced under the action of hydrolases also has certain antioxidation and anti-inflammatory effects. In addition, some compounds provided in the present disclosure contain a deuterium atom, and a primary or secondary alcohol hydroxyl group would be oxidized in human or animal body under the catalysis of various dehydrogenases. The deuterium-containing lanosterol derivative provided in the present disclosure, due to higher bond energy of carbon-deuterium bond than that of carbon-hydrogen bond, could disadvantage this reaction and improve the metabolic stability of the compounds.

[0040] Results in examples show that the lanosterol derivative according to the present disclosure has a significantly higher solubility in water than that of lanosterol or 25-hydroxylanosterol, and exhibits obvious therapeutic effects on cataract in animal in vivo experiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 shows the hydrogen nuclear magnetic resonance (1H-NMR) spectrum of the lanosterol derivative having the structure shown in formula I-1 prepared in Example 1;

[0042] FIG. 2 shows the mass spectrum of the lanosterol derivative having the structure shown in formula I-1 prepared in Example 1;

[0043] FIG. 3 shows the 1H-NMR spectrum of the lanosterol derivative having the structure shown in formula I-8 prepared in Example 8;

[0044] FIG. 4 shows the mass spectrum of the lanosterol derivative having the structure shown in formula I-8 prepared in Example 8;

[0045] FIG. 5 shows the relationship curve between the content of lanosterol and the HPLC peak area and the corresponding regression equation in Example 12;

[0046] FIG. 6 shows the relationship curve between the content of 25-hydroxylanosterol and the HPLC peak area and the corresponding regression equation in Example 12;

[0047] FIG. 7 shows the relationship curve between the content of compound I-1 and the HPLC peak area and the corresponding regression equation in Example 12;

[0048] FIG. 8 shows a chart illustrating crystalline lens transparency scores of animals in each group in Example 14;

[0049] FIG. 9 shows a screenshot of a photograph by Pentacam imaging analysis before administration in the model control group in Example 15;

[0050] FIG. 10 shows a screenshot of a photograph by Pentacam imaging analysis before administration in 0.2% lanosterol derivative I-1 group in Example 15;

[0051] FIG. 11 shows a screenshot of a photograph by Pentacam imaging analysis before administration in 0.4% lanosterol derivative I-1 group in Example 15;

[0052] FIG. 12 shows a screenshot of a photograph by Pentacam imaging analysis 20 days after administration in the model control group in Example 15;

[0053] FIG. 13 shows a screenshot of a photograph by Pentacam imaging analysis after 20 days of administration in 0.2% lanosterol derivative I-1 group in Example 15;

[0054] FIG. 14 shows a screenshot of a photograph by Pentacam imaging analysis after 20 days of administration in 0.4% lanosterol derivative I-1 group in Example 15;

[0055] FIG. 15 shows a screenshot of a photograph by Pentacam imaging analysis after 40 days of administration in the model control group in Example 15;

[0056] FIG. 16 shows a screenshot of a photograph by Pentacam imaging analysis after 40 days of administration in 0.2% lanosterol derivative I-1 group in Example 15;

[0057] FIG. 17 shows a screenshot of a photograph by Pentacam imaging analysis after 40 days of administration in 0.4% lanosterol derivative I-1 group in Example 15;

[0058] FIG. 18 shows a screenshot of a photograph by Pentacam imaging analysis after 60 days of administration in the model control group in Example 15;

[0059] FIG. 19 shows a screenshot of a photograph by Pentacam imaging analysis after 60 days of administration in 0.2% lanosterol derivative I-1 group in Example 15;

[0060] FIG. 20 shows a screenshot of a photograph by Pentacam imaging analysis after 60 days of administration in 0.4% lanosterol derivative I-1 group in Example 15; and

[0061] FIG. 21 shows slit-lamp photographs of animals in each group in Example 15. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0062] The present disclosure provides a lanosterol derivative or a pharmaceutically acceptable salt thereof, where the lanosterol derivative has a structural formula shown in formula I or formula II, formula II, where in formula I and formula II, Y1, Y2, and Y3 each are independently hydrogen, deuterium, C1-C4 alkyl or unsaturated hydrocarbyl; X is independently oxygen, sulfur, or an NR1 group, R1 in the NR1 group being hydrogen or alkyl; R is independently hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylformyl, substituted arylformyl, heteroarylformyl, or substituted heteroarylformyl; and

[0063] in formula I and formula II, under a condition that X is oxygen, not all of R, Y1, Y2, and Y3 are hydrogen.

[0064] In some embodiments of the present disclosure, under a condition that R1 in the NR1 group is alkyl, the alkyl has 1-10, preferably 1-5 carbon atoms.

[0065] In some embodiments of the present disclosure, a substituent in the substituted aryl, the substituted heteroaryl, the substituted arylformyl, and the substituted heteroarylformyl is independently at least one selected from the group consisting of halogen, deuterium, hydroxyl, mercapto, and methylthio; in some embodiments, the heteroaryl or heteroaryl in the substituted heteroarylformyl is pyridyl.

[0066] In some embodiments of the present disclosure, R in formula I and formula II is hydrogen or hydroxypyridylformyl, specifically the hydroxypyridylformyl is any one of / ^co'      c°- HO^^ / CO- HO / CO- f J if T JT i f ■”       '                 ,          ■                  ,                                      ,            J                       , and

[0067] In some embodiments of the present disclosure, in formula I and formula II, Y1, Y2 and Y3 each are independently hydrogen or deuterium.

[0068] In some embodiments of the present disclosure, the lanosterol derivative is one or more shown in formula I-1 to formula I-9 and formula II-1 to formula II-2 (see the above for the specific structures).

[0069] In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the lanosterol derivative is an organic acid salt or an inorganic acid salt; in some embodiments, the organic acid salt includes one or more of an acetate, a methanesulfonate, and a tartrate; in some embodiments, the inorganic acid salt includes one or more of a hydrochloride, a sulfate, and a phosphate.

[0070] The present disclosure also provides a method for preparing the lanosterol derivative as described in the above technical solutions. According to the structure of the lanosterol derivative, the method is divided into method I to method VIII, which are described separately below.

[0071] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method I including the steps of:

[0072] mixing a compound having a structure shown in formula A-3, a compound having a structure shown in formula C, a condensation agent, a catalyst, and a solvent, and subjecting a resulting mixture to condensation to obtain the lanosterol derivative; formula A-3, R-OH formula C.

[0073] In some embodiments of the present disclosure, the compound having the structure shown in formula A-3 is prepared by a process comprising:

[0074] mixing a mixture solution of lanosterol and dihydrolanosterol, acetic anhydride, and 4-dimethylaminopyridine, conducting esterification, and subjecting a resulting reaction liquid to washing, drying, and rotary evaporation to obtain a crude product, the crude product being a mixture of a compound having a structure shown in formula A-1 and a compound having a structure shown in formula B-1; formula A-1, formula B-1,

[0075] mixing the crude product, N-bromosuccinimide, and a solvent, and conducting bromination, and sequentially subjecting a resulting reaction mixture to rotary evaporation, subjecting a resulting residue from the rotary evaporation to extraction, drying a resulting organic phase, and subjecting a dried organic phase to further rotary evaporation, and silica gel column chromatography to obtain the compound having a structure shown in formula A-2; formula A-2,

[0076] mixing the compound having the structure shown in formula A-2, a reducing agent, and a solvent, and conducting debromination-ester reduction to obtain the compound having the structure shown in formula A-3.

[0077] In the present disclosure, a mixed solution of lanosterol and dihydrolanosterol, acetic anhydride, and a catalyst are mixed, and a resulting mixture is subjected to esterification, obtaining a crude product. In the present disclosure, a solvent in the mixed solution of lanosterol and dihydrolanosterol is petroleum ether. In specific examples of the present disclosure, commercially available lanosterol is used, in which a mass fraction of lanosterol is 50-60% and a fraction of dihydrolanosterol is 40-50%. In some embodiments, a ratio of a total amount in moles of lanosterol and dihydrolanosterol to a volume of acetic anhydride is in a range of 23-24 mmol : 3-4 mL, preferably 23.47 mmol : 3.85 mL; in some embodiments, the catalyst used for the esterification is 4-(N,N-dimethyl)aminopyridine (DMAP); in some embodiments, a ratio of a total amount in moles of lanosterol and dihydrolanosterol to an amount in moles of DMAP is in a range of 9.5-10.5 : 1; in some embodiments, the esterification is conducted under a reflux condition, and the esterification is conducted for 3-5 hours, preferably 4 hours; in specific examples of the present disclosure, TLC monitoring is conducted until the starting materials disappear. In some embodiments of the present disclosure, after completion of the esterification, the resulting reaction liquid is washed, dried, and then subjected to rotary evaporation to remove the solvent; in specific embodiments of the present disclosure, the resulting reaction liquid is cooled to room temperature and then washed; in some embodiments, the washing is performed by sequentially washing with a hydrochloric acid solution, a sodium bicarbonate solution, and water; in some embodiments, a desiccant used for drying is anhydrous sodium sulfate. In the present disclosure, the crude product is a mixture of the compound having a structure represented by formula A-1 and the compound having a structure represented by formula B-1; the two compounds have similar structures and are difficult to separate by conventional purification methods; therefore, the crude product is directly used in the next reaction step.

[0078] In the present disclosure, after obtaining the crude product, the crude product, N-bromosuccinimide (NBS), and a solvent are mixed, and a resulting mixture is subjected to bromination; a resulting reaction mixture is sequentially subjected to rotary evaporation, extraction, drying, further rotary evaporation, and silica gel column chromatography to obtain the specific compound having a structure represented by formula A-2. In some embodiments of the present disclosure, the solvent is a mixed solvent of tetrahydrofuran (THF) and water; in some embodiments, a volume ratio of THF to water in the mixed solvent is in a range of 3-5 : 1, preferably 4 : 1; in some embodiments, a ratio of a total amount in moles of the compound having a structure represented by formula A-1 and the compound having a structure represented by formula B-1 in the crude product to an amount in moles of NBS is in a range of 10 : 5-6, preferably 10 : 5.5. In the present disclosure, the compound represented by formula B-1 has no unsaturated bond on its side chain, by controlling the amount of NBS, the compound having a structure represented by formula B-1 does not react with NBS; after the bromination is completed, the compound having the structure represented by formula B-1 could be separated by conventional methods. In some embodiments, the bromination is conducted at room temperature; in some embodiments, the bromination is conducted for 1-3 hours, and preferably 2 hours. In some embodiments of the present disclosure, after completion of the bromination, most of the THF is removed by rotary evaporation, and the resulting residue is diluted with water, followed by extraction with dichloromethane to obtain an organic phase; the organic phase is then dried over anhydrous sodium sulfate, followed by another rotary evaporation to remove the solvent; a resulting residue is subjected to silica gel column chromatography. In some embodiments, an eluent used for silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and preferably a volume ratio of petroleum ether to ethyl acetate is 5 : 1.

[0079] In the present disclosure, after obtaining the compound having a structure represented by formula A-2, the compound having a structure represented by formula A-2, a reducing agent, and a solvent are mixed, and a resulting mixture is subjected to debromination-ester reduction, to obtain the compound having the structure shown in formula A-3. In some embodiments of the present disclosure, the reducing agent is LiAlH4; in some embodiments, the solvent is THF; in some embodiments, a molar ratio of the compound having the structure represented by formula A-2 to the reducing agent is in a range of 1 : 1.5-2.5, and preferably 1 : 2; in some embodiments, the debromination-ester reduction is conducted at a temperature of 60-65°C, preferably 63°C; in some embodiments, the debromination-ester reduction is conducted for 3-5 hours, and preferably 4 hours. In some embodiments, after completion of the debromination-ester reduction, the reaction is quenched with water, the resulting mixture is extracted with dichloromethane; the obtained organic phase is dried over anhydrous sodium sulfate, and subjected to rotary evaporation to remove the solvent; the residue is purified by silica gel column chromatography to obtain the compound having the structure represented by formula A-3.

[0080] In the present disclosure, after obtaining the compound having the structure represented by formula A-3, the compound having the structure represented by formula A-3, the compound having the structure represented by formula C, a condensing agent, a catalyst, and a solvent are mixed, and a resulting mixture is subjected to condensation, to obtain the lanosterol derivative. In some embodiments of the present disclosure, the condensing agent is dicyclohexylcarbodiimide (DCC); in some embodiments, a molar ratio of the compound having the structure represented by formula A-3 to the condensing agent is in a range of 1 : 2-3, and preferably 3 : 8; in some embodiments, the catalyst for the condensation is DMAP; in some embodiments, a molar ratio of the compound having the structure represented by formula A-3 to the catalyst is 2 : 1; in some embodiments, the solvent is dichloromethane.

[0081] In some embodiments of the present disclosure, under a condition that R in formula I is hydroxypyridylformyl, the compound represented by formula C is hydroxy nicotinic acid, specifically including 6-hydroxynicotinic acid, 2-hydroxynicotinic acid, 2-hydroxyisonicotinic acid, 5-hydroxynicotinic acid, or 3-hydroxynicotinic acid; in some embodiments, a molar ratio of the compound having the structure represented by formula A-3 to the compound having the structure represented by formula C is in a range of 1 : 2-2.5, and preferably 1 : 2; in some embodiments, the condensation is conducted at room temperature; in some embodiments, the condensation is conducted for 20-24 hours, and preferably 20 hours; in some embodiments, after completion of the condensation, the solvent in the resulting mixture is removed, and the residue is purified by silica gel column chromatography to obtain the lanosterol derivative.

[0082] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method II comprising the steps of:

[0083] mixing the compound having the structure shown in formula A-3, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula A-4;

[0084] mixing the compound having a structure shown in formula A-4, deuterated chloroform, and a catalyst, and conducting deuteration to obtain a compound having a structure shown in formula A-5; and

[0085] mixing the compound having the structure shown in formula A-5, methanol, and deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula I-6, formula A-5,

[0086] In the present disclosure, the compound having the structure shown in formula A-3, pyridinium chlorochromate (PCC), sodium acetate, and a solvent are mixed, and a resulting mixture is subjected to oxidation to obtain the compound having the structure shown in formula A-4. In some embodiments of the present disclosure, the solvent is dichloromethane; in some embodiments, a molar ratio of the compound having the structure shown in formula A-3 to PCC is 1 : 1; in some embodiments, a molar ratio of the compound having the structure shown in formula A-3 to the sodium acetate is in a range of 1 : 0.5-0.6; in some embodiments, the oxidation is conducted at room temperature, which is monitored by TLC until the raw materials disappear; in some embodiments of the present disclosure, after the oxidation, the obtained reaction liquid is mixed with water and a resulting mixture is then layered to obtain an organic phase and an aqueous phase; the aqueous phase is extracted with dichloromethane; the organic phase obtained after the extraction and the organic phase after layering are combined, then dried over anhydrous sodium sulfate, and then subjected to rotary evaporation to remove the solvent; and the obtained crude product is purified by silica gel column chromatography to obtain the compound having the structure shown in formula A-4.

[0087] In the present disclosure, after obtaining the compound having the structure shown in formula A-4, the compound having the structure shown in formula A-4, deuterated chloroform, and a catalyst are mixed, and a resulting mixture is subjected to deuterization to obtain the compound having the structure shown in formula A-5. In some embodiments of the present disclosure, the catalyst for the deuterization is 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD); in some embodiments, a molar ratio of the compound having the structure shown in formula A-4 to the catalyst is 1 : 0.1; in some embodiments, the deuterization is conducted at room temperature; in some embodiments, the deuterization is conducted for 12 h; in some embodiments of the present disclosure, after the deuterization is completed, the obtained reaction liquid is subjected to rotary evaporation to remove the solvent, and the obtained crude product is purified by column chromatography to obtain the compound having the structure shown in formula A-5.

[0088] In the present disclosure, after obtaining the compound having the structure shown in formula A-5, the compound having the structure shown in formula A-5, methanol, and deuterated sodium borohydride are mixed, and a resulting mixture is subjected to reduction to obtain the lanosterol derivative having the structure shown in formula I-6. In some embodiments of the present disclosure, a molar ratio of the compound having the structure shown in formula A-5 to deuterated sodium borohydride is in a range of 1 : 0.5-1; in some embodiments, the reduction is conducted at a temperature ranging from 0 °C to room temperature; in some embodiments, the reduction is conducted for 1-3 hours; in some embodiments, after completion of the reduction, methanol in the resulting reaction liquid is removed, the resulting residue, water, and ethyl acetate are mixed, followed by layering, the resulting organic phase is subjected to rotary evaporation to remove the solvent, and the obtained crude product is purified by silica gel column chromatography to obtain the lanosterol derivative having the structure shown in formula I-6.

[0089] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method III including the steps of:

[0090] mixing the compound having the structure shown in formula A-4, methanol, deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula I-7, formula I-7.

[0091] In some embodiments of the present disclosure, a molar ratio of the compound having the structure shown in formula A-4 to deuterated sodium borohydride is in a range of 1.0 : 0.5-1; in some embodiments, the reduction is conducted at a temperature ranging from 0 °C to room temperature; in some embodiments, the reduction is conducted for 1-3 hours. The post-treatment method after the reduction is the same as the post-treatment method of the reduction in method II, and will not be repeated here.

[0092] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method IV including the steps of:

[0093] mixing a compound having the structure shown in formula I-6 or a compound having the structure shown in formula I-7, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative;

[0094] In the present disclosure, in the method IV, the type and amount of the condensing agent, the catalyst and the solvent, as well as the specific conditions of the condensation are the same as those in the method I, except that the compound having the structure shown in formula I-6 or the compound having the structure shown in formula I-7 substitutes for the compound having the structure shown in formula A-3, which will not be repeated here.

[0095] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method V including the steps of:

[0096] mixing lanosterol, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative.

[0097] In the present disclosure, in the method V, the type and amount of the condensing agent, the catalyst and the solvent, as well as the specific conditions of the condensation are the same as those in the method I, except that lanosterol substitutes for the compound having the structure shown in formula A-3, which will not be repeated here.

[0098] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method VI including:

[0099] conducting steps of method II, except that the compound having the structure shown in formula A-3 is replaced with the lanosterol, to obtain the lanosterol derivative having a structure shown in formula B-2, formula B-2.

[0100] In the present disclosure, specific operation conditions of the method VI are the same as those of method II, except that lanosterol substitutes for the compound having the structure shown in formula A-3 to undergo oxidation, the product obtained from oxidation substitutes for the compound having the structure shown in formula A-4 to undergo deuterization, and the product obtained from deuterization substitutes for the compound having the structure shown in formula A-5 to undergo reduction. The specific conditions of the oxidation, deuterization, and reduction will not be repeated herein.

[0101] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method VII including:

[0102] mixing the lanosterol, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula D; and

[0103] mixing the compound having the structure shown in formula D, methanol, deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula B-3; formula D,                              formula B-3.

[0104] In the present disclosure, oxidation conditions of the method VII are the same as those of method II, except that lanosterol substitutes for the compound having the structure shown in formula A-3; reduction conditions of the method VII are the same as those of method III, except that the compound having the structure shown in formula D substitutes for the compound having the structure shown in formula A-4.

[0105] In the present disclosure, under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1 and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method VIII including the steps of:

[0106] mixing a compound having the structure shown in formula B-2 or a compound having the structure shown in formula B-3, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative.

[0107] In the present disclosure, in the method VIII, conditions of the condensation are the same as those in the method I, except that the compound having the structure shown in formula B-2 or formula B-3 substitutes for the compound having the structure shown in formula A-3, which will not be repeated here.

[0108] The present disclosure also provides a pharmaceutical composition, including an active ingredient and a pharmaceutically acceptable auxiliary material; where the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in the above technical solutions.

[0109] In some embodiments of the present disclosure, the pharmaceutically acceptable auxiliary material is an excipient. In the present disclosure, there is no special requirement for the type of the excipient, and those well known to those skilled in the art may be used.

[0110] The present disclosure also provides use of the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in the above technical solutions, or the pharmaceutical composition as described in the above technical solutions, in the preparation of a drug for treating an eye disease or an eye condition; in some embodiments, the eye disease includes cataract or retinal degeneration.

[0111] The present disclosure also provides an eye drop, including the following components: in parts by mass, 2-4 parts of an active ingredient, 5-7 parts of hydroxypropylmethylcellulose, 30-50 parts of polysorbate, 10-20 parts of boric acid, 1-2 parts of borax, 0.03-0.06 parts of benzalkonium chloride, and 1000 parts of water; in some embodiments, the eye drop includes 2 or 4 parts by mass of the active ingredient; in some embodiments, the eye drop includes 6 parts by mass of hydroxypropylmethylcellulose; in some embodiments, the eye drop includes 40 parts by mass of polysorbate; in some embodiments, the eye drop includes 16 parts by mass of boric acid; in some embodiments, the eye drop includes 1.6 parts by mass of borax; in some embodiments, the eye drop includes 0.05 parts by mass of benzalkonium chloride; the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as described in the above technical solutions; in some embodiments, the polysorbate is polysorbate 80; in some embodiments, the water is sterile water for injection.

[0112] In some embodiments of the present disclosure, the eye drop is prepared by a process including: dissolving hydroxypropylmethylcellulose with part of water to obtain a solution I; dissolving boric acid, borax, and benzalkonium chloride with part of water, mixing a resulting solution with the solution I, adding polysorbate thereto, and then adding water in an amount of 85-90% of a total prescription amount of water to obtain a solution II; adding the active ingredient into the solution II, and performing high-shear emulsification to obtain a solution III; subjecting the solution III to high-pressure homogenization to obtain a solution IV; finally, adding the remaining water to the solution IV until reaching a predetermined volume; in some embodiments, the high-shear emulsification is performed at a rotational speed of 10,000 r / min; in some embodiments, the high-shear emulsification is performed for 5-10 minutes; in some embodiments, the high-pressure homogenization is performed at a pressure of 240 bar to 2,600 bar; in some embodiments, the high-pressure homogenization is performed once; in some embodiments, after the high-pressure homogenization, a pipeline of a high-pressure homogenizer is flushed with an appropriate amount of water, the flushing liquid is collected and mixed with a drug liquid.

[0113] The technical solutions in the present disclosure will be clearly and completely described below in conjunction with examples in the present disclosure. Obviously, the described examples are only part of, not all of examples of the present disclosure. Based on the examples in the present disclosure, all other examples obtained by those skilled in the art without creative labor fall within the scope of the present disclosure.

[0114] Example 1

[0115] In this example, a lanosterol derivative having a structure shown in formula I-1 was synthesized, with the following reaction route:

[0116] The specific steps were as follows:

[0117] Step 1: preparation of an intermediate A-1: DMAP (2.35 mmol) and 3.85 mL of acetic anhydride were added to 100 mL of a solution of lanosterol (10 g of a mixture of lanosterol and dihydrolanosterol, 23.47 mmol, containing 50% of the lanosterol) in petroleum ether. A resulting mixture was refluxed for 4 hours, until that raw material disappeared when detected by TLC. A resulting reaction mixture was cooled to room temperature, and then washed with 2 x 10 mL of 5 wt% aqueous hydrochloric acid solution, 2 x 10 mL of 10 wt% aqueous sodium bicarbonate solution, and 2 x 20 mL of water sequentially, followed by drying over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, the obtained crude product was directly used for the next step.

[0118] Step 2: preparation of an intermediate A-2: the crude product-a mixture of A1 and B1 (50%, 10 mmol) was dissolved in THF / H2O (240 mL / 60 mL), and NBS (5.5 mmol) was added to a reaction solution, and a resulting mixture was stirred at room temperature for 2 h. Most of THF of the system was removed by rotary evaporation, water was added to the resulting residue for dilution, and extraction was conducted with dichloromethane. An organic phase obtained from the extraction was dried over anhydrous sodium sulfate, and rotary evaporation was then conducted to remove the solvent therein, and a resulting crude product was subjected to silica gel column chromatography (a volume ratio of petroleum ether: ethyl acetate=5 : 1) to obtain the intermediate A-2.

[0119] Step 3: preparation of an intermediate A-3: the intermediate A-2 (10 mmol) was added into a round bottomed flask, and a solution of LiAlH4 in THF (20 mmol) was added thereto at 0 °C; nitrogen was charged for protection, and a resulting mixture was heated to 63 °C and reacted for 4 h. A resulting reaction mixture was cooled to room temperature, 1.6 mL of water was added for quenching reaction, 150 mL of dichloromethane was then added, 50 mL of water was further added thereto; an organic phase was separated, and a resulting aqueous phase was extracted twice with 50 mL of dichloromethane. Organic phases were combined, and dried over anhydrous sodium sulfate; the solvent therein was removed by rotary evaporation, and a resulting crude product was subjected to silica gel column chromatography (a volume ratio of ethyl acetate : petroleum ether=5 : 1) to obtain the intermediate A-3.

[0120] Step 4: preparation of the target compound of formula I-1: the intermediate A-3 (3 mmol), DMAP (1.5 mmol), 6-hydroxynicotinic acid (6 mmol), DCC (8 mmol) were added into a round bottom flask, nitrogen was charged for protection, and 40 mL of anhydrous dichloromethane was added thereto at 0 °C, and a resulting mixture was reacted at room temperature for 20 h. The solvent therein was removed. The residue was directly loaded in a silica gel column for separation (a volume ratio of petroleum ether : ethyl acetate=4 : 1) to obtain the lanosterol derivative having the structure shown in formula I-1. Characterization data of the structure of the compound were as follows: 1H-NMR (400 MHz, CDCI3) 5 8.15 (d, J = 2.5 Hz, 1H), 8.00 (dd, J = 9.6, 2.5 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 4.70 (dd, J = 11.5, 4.3 Hz, 1H), 2.04 (d, J = 14.7 Hz, 3H), 1.94 (d, J = 12.4 Hz, 2H), 1.81-1.76 (m, 2H), 1.73-1.66 (m, 4H), 1.53-1.33 (m, 9H), 1.28 (d, J = 19.4 Hz, 2H), 1.22 (s, 7H), 1.11 (d, J = 10.2 Hz, 2H), 1.04 (s, 3H), 0.98 (s, 3H), 0.92 (d, J = 1.9 Hz, 5H), 0.89 (s, 3H), 0.70 (s, 3H). Ms: 566.28(M++1). FIG. 1 shows the 1H-NMR spectrum of the lanosterol derivative having the structure shown in formula I-1, and FIG. 2 shows the mass spectrum of the lanosterol derivative having the structure shown in formula I-1.

[0121] Example 2

[0122] In Example 2, the target compound had a structure shown in formula I-2. The synthesis method was the same as Example 1, except that the intermediate A-3 was reacted with only 2-hydroxynicotinic acid. Characterization data of the structure of the obtained product were as follows: 1H NMR (400 MHz, Chloroform-d) 5= 8.19(d, J=9.62Hz, 1H), 6.85(m, 1H), 7.57(d, J=8.65Hz,1H), 4.52-4.32(m,1H), 4.13(s, 1H), 3.43(s,  1H), 2.01-1.56(m,  13H),  1.60-1.51(m,  19H),  1.02(s, 3H),  1.07(s, 3H), 0.87-0.83(m, 8H), 0.79(s, 3H). Ms: 566.26 (M++1).

[0123] Example 3 formula I-3

[0124] In Example 3, the target compound had a structure shown in formula I-3. The synthesis method was the same as Example 1, except that the intermediate A-3 was reacted with 5-hydroxynicotinic acid. Characterization data of the structure of the obtained product were as follows: 1H NMR (400 MHz, Chloroform-d)5= 7.96(s 1H), 8.03(s, 1H), 8.17(s,1H), 4.52-4.32(m,1H), 4.25(s, 1H), 1.91-1.59(m, 13H), 1.58-1.48(m, 19H), 1.05(s, 3H), 1.03(s, 3H), 0.88-0.82(m, 8H), 0.81(s, 3H). Ms: 566.26(M++1).

[0125] Example 4 formula I-4

[0126] In Example 4, the target compound had a structure shown in formula I-4. The synthesis method was the same as Example 1, except that the intermediate A-3 was reacted with 2-hydroxyisonicotinic acid. Characterization data of the structure of the obtained product were as follows: 1H NMR (400 MHz, Chloroform-d) 5= 10.69(s 1H), 7.93(d, J=8.39Hz, 1H), 7. 19(d, J=7.35Hz, 1H), 4.41-4.30(m, 1H), 4.39(s, 1H), 1.98-1.63(m, 13H), 1.61-1.52(m, 19H), 1.05(s, 3H), 1.05(s, 3H), 0.90-0.84(m, 8H), 0.83(s, 3H). Ms: 566.26(M++1).

[0127] Example 5 formula I-5

[0128] In Example 5, the target compound had a structure shown in formula I-5. The synthesis method was the same as Example 1, except that the intermediate A-3 was reacted with 3-hydroxynicotinic acid. Characterization data of the structure of the obtained product were as follows: 1H NMR (400 MHz, Chloroform-d) 8= 12.53(s 1H), 8.35(s, ), 7. 89(d, J=8.69Hz, 1H), 7.97(d, J=9.01Hz, 1H)4.42-4.33(m, 1H), 4.38(s, 1H), 1.99-1.65(m, 13H), 1.61-1.55(m, 19H), 1.08(s, 3H), 1.07(s, 3H), 0.91-0.85(m, 8H), 0.85(s, 3H). Ms: 566.26 (M++1).

[0129] Example 6

[0130] In Example 6, the target compound had a structure shown in formula I-6, with the following synthesis route.

[0131] The specific steps were as follows:

[0132] Step 1: compound having a structure represented by formula A-3 (1 mmol) was dissolved in 20 mL of dichloromethane, and 215 mg of PCC and 45 mg of NaOAc were added thereto. A resulting mixture was stirred at room temperature until raw materials disappeared as monitored by thin-layer chromatography (TLC). After reaction, 10 mL of water was added to the reaction product mixture, an organic phase was separated, and a resulting aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, then subjected to rotary evaporation to remove the solvent. A resulting crude product was purified by silica gel column chromatography to obtain an intermediate A-4.

[0133] Step 2: the intermediate A-4 (1 mmol) was dissolved in 15 mL of deuterated chloroform, and catalyst TBD (1 mmol) was added thereto, and a resulting mixture was stirred at room temperature for 12 hours. After rotary evaporation to remove the solvent therein, a crude product was purified by column chromatography to obtain an intermediate A-5.

[0134] Step 3: the intermediate A-5 (1 mmol) was dissolved in methanol, and deuterated sodium borohydride (1 mmol) was added in an ice bath. A resulting mixture was subjected to reaction for 1 hour. After the reaction, methanol was removed, and water and ethyl acetate were added to the resulting residue, followed by stirring; an organic layer was separated, and then subjected to rotary evaporation to remove the solvent therein, followed by silica gel column chromatography, to obtain deuterated 25-hydroxylanosterol I-6. Characterization data of the structure of the compound was as follows: Ms: 413.7 [M+-34(2OH)).

[0135] Example 7

[0136] In Example 7, the target compound had a structure shown in formula I-7, with the following synthesis method.

[0137] The synthesis steps were the same as Example 6, except that after the intermediate A-4 was obtained, the intermediate A-4 (1 mmol) was dissolved in 15 mL of methanol, and deuterated sodium borohydride (1 mmol) was added in an ice bath; a resulting mixture was subjected to reaction for 1 hour. Characterization data of the structure of the compound was as follows: Ms: 411.7 [M+-34(2OH)).

[0138] Example 8

[0139] In Example 8, the target compound had a structure shown in formula I-8. The synthesis method was the same as Example 1, except that: the compound I-6 substituted for the intermediate A-3, and was reacted with 6-hydroxynicotinic acid in the presence of the dehydrating agent DCC and the catalyst DMAP to obtain the product. Characterization data of the structure of the compound were as follows: 1H-NMR (400 MHz, CDCI3) 8 8.17 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 9.6, 2.5 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H), 2.10-2.00 (m, 4H), 1.75 (dd, J = 17.9, 11.1 Hz, 3H), 1.58-1.34 (m, 10H), 1.26 (s, 6H), 1.22 (s, 6H), 1.04 (s, 3H), 0.98 (s, 3H), 0.93-0.88 (m, 9H), 0.70 (s, 3H). Ms: 569.3 (M++1). FIG. 3 shows the 1H-NMR spectrum of the lanosterol derivative having the structure of formula I-8. FIG. 4 shows the mass spectrum of the lanosterol derivative having the structure of formula I-8.

[0140] Example 9

[0141] In Example 9, the target compound had a structure shown in formula I-9. The synthesis method was the same as Example 1, except that: the compound I-7 substituted for the intermediate A-3, and was reacted with 6-hydroxynicotinic acid in the presence of the dehydrating agent DCC and the catalyst DMAP to obtain the product. Characterization data of the structure of the compound were as follows: 1H NMR (400 MHz, CDCl3) 8 8.17 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 9.6, 2.5 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 2.04 (d, J = 7.7 Hz, 4H), 1.97-1.90 (m, 3H), 1.81-1.75 (m, 2H), 1.54-1.30 (m, 12H), 1.26 (dd, J = 5.7, 3.1 Hz, 3H), 1.22 (s, 7H), 1.04 (s, 3H), 0.98 (s, 3H), 0.94-0.86 (m, 9H), 0.70 (s, 3H). Ms: 567.3(M++1).

[0142] Example 10

[0143] In Example 10, the target compound had a structure shown in formula II-1. The synthesis method was the same as Example 1, except that: lanosterol as raw material substituted for the intermediate A-3, and was reacted with 6-hydroxynicotinic acid in the presence of the dehydrating agent DCC to obtain the product. Characterization data of the structure of the compound were as follows: 1H-NMR (400 MHz, CDCI3) 6 8.15 (s, 1H), 7.99 (dd, J = 9.6, 2.5 Hz, 1H), 6.57 (d, J = 9.6 Hz, 1H), 4.69 (dd, J = 11.5, 4.4 Hz, 1H), 3.47 (d, J = 10.5 Hz, 1H), 2.04 (s, 3H), 1.93 (d, J = 13.0 Hz, 2H), 1.83-1.66 (m, 6H), 1.59-1.43 (m, 4H), 1.43-1.35 (m, 4H), 1.33 (s, 2H), 1.21 (s, 7H), 1.16-1.06 (m, 2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.91 (d, J = 7.6 Hz, 5H), 0.89 (s, 3H), 0.70 (s, 3H). Ms: 548.3 (M++1).

[0144] Example 11

[0145] In Example 11, the target compound had a structure shown in formula II-2. The synthesis method was according to part of steps in Example 6. Lanosterol as raw material was oxidized with PCC, followed by reduction with deuterated sodium borohydride, and then reaction with 6-hydroxynicotinic acid in the presence of the dehydrating agent DCC to obtain the product. Characterization data of the structure of the product is as follows: Ms: 549.3 (M++1).

[0146] Example 12

[0147] The solubility of lanosterol, 25-hydroxylanosterol, and some compounds provided in the present disclosure in water was tested using an HPLC method. The specific procedures were as follows:

[0148] Step 1: Plotting relationship curve between the content of compound to be tested and HPLC peak area (taking lanosterol as an example)

[0149] Analytical Conditions: column: Agilent 959990-902 (4.6 x 250 mm, 5 gm); column temperature: 35 °C; mobile phase: methanol; flow rate: 1.0 mL / min; detection wavelength: 210 nm; sample injection volume: 20 gL; elution mode: isocratic elution.

[0150] Approximately 10.00 mg of lanosterol was weighed and placed into a 100 mL volumetric flask. An appropriate amount of methanol was added thereto, followed by sonication for dissolution. The resulting solution was then diluted by adding methanol to reach the mark, followed by shaking to be uniform, and the resulting mixture was served as a stock solution for plotting relationship curve between the compound content and HPLC peak area. Appropriate volumes of the stock solution were pipetted into a 25 mL volumetric flask, and diluted by adding methanol to reach the mark, followed by shaking to be uniform, to obtain lanosterol solutions of different concentrations. These solutions were separately injected into the chromatograph and tested according to chromatographic conditions described in "Analytical Conditions", and peak areas were recorded. A regression equation was established with peak area (y) as the ordinate and concentration (x) as the abscissa, i.e., y = 11639032.6320x-8583.6303, with a correlation coefficient R2 = 0.9997. The test results indicate a good linear relationship within the concentration range of 0.1000 mg / mL to 0.0025 mg / mL.

[0151] Using the same method, relationship curves between contents of 25-hydroxylanosterol and part of compounds provided in the present disclosure and HPLC peak areas and regression equations were obtained respectively. The relationship curve between the content of lanosterol and HPLC peak area and corresponding regression equation are shown in FIG. 5. In FIG. 5, the ordinate represents the measured HPLC peak area, and the abscissa represents the corresponding content of lanosterol in the methanol solution. The relationship curve between 25-hydroxylanosterol content and HPLC peak area and corresponding regression equation are shown in FIG. 6. The relationship curve between the content of compound I-1 and HPLC peak area and corresponding regression equation are shown in FIG. 7.

[0152] Step 2: Compound solubility testing. Lanosterol, 25-hydroxylanosterol, and part of compounds provided in present disclosure, in an excess amount, were separately placed into 5 mL of purified water. The resulting solutions were placed in a constant-temperature water bath at 37 ± 0.5 °C with magnetic stirring (500 rpm), and solids were maintained excess throughout the test. After 6 hours, the solutions were taken out and centrifuged at a rotation speed of 10,000 rpm for 5 minutes. The supernatant in each solution system was collected, and filtered through a 0.22 pm polyethersulfone filter membrane. Each sample was subjected to HPLC analysis according to the analytical conditions above. The experimental results are shown in Table 1.

[0153] Table 1 Solubility of lanosterol and derivatives thereof in purified water Samples Lanosterol 25-hydroxylanosterol Compound I-1 Compound I-5 Compound I-8 Compound I-9 Solubility in purified water mg / mL Not detected Not detected 3.95x10-4 3.81x10-4 3.78x10-4 4.05x10-4

[0154] As can be seen from the results in Table 1, the lanosterol derivatives according to the present disclosure have improved solubility in water, significantly higher than that of lanosterol or 25-hydroxylanosterol, due to the introduction of polar groups in the molecule.

[0155] Example 13

[0156] 25-Hydroxylanosterol and compounds I-6 and I-7 were subjected to hepatic microsomal metabolic stability test. Due to the higher stability of the carbon-deuterium bond than that of the carbon-hydrogen bond, substituting hydrogen atoms with deuterium atoms at metabolically labile sites in drug molecules may alter their metabolic rate, resulting in that the drug molecules have a longer half-life, lower clearance, and improved bioavailability. Given that the hydrogen atom on the carbon bearing the secondary hydroxyl group in 25-hydroxylanosterol is a potential metabolic site, and considering that drug metabolism primarily occurs in the liver, compound I-6, compound I-7, and 25-hydroxylanosterol were selected in the present disclosure for hepatic microsomal metabolic stability test. The specific procedures were as follows:

[0157] Step 1: determination of the standard curve. Appropriate amounts of samples to be tested, i.e., 25-hydroxylanosterol and deuterated 25-hydroxylanosterol, were accurately weighed and dissolved in a calculated volume of pure acetonitrile to achieve a concentration of 1 mg / mL. Concentrations for the standard curve were set at 0, 2, 4, 6, 8, and 10 uML. The standard curve was plotted based on the peak areas obtained from HPLC analysis.

[0158] Step 2: preparation of test system (system using 0.5 mg / mL liver microsomal protein) and HPLC analysis. Liver microsomes stored at -80 °C were thawed in an ice bath for later use. The substrate to be tested (1 mg / mL), NADPH solution A (10 uL), and NADPH solution B (2 uL) were mixed and incubated at 37 °C for 10 minutes, then placed on ice. Liver microsomes (5 uL) were mixed with 0.1 M PBS buffer (181 uL) and two substrates to be tested (2 uL each) to be uniform and a resulting mixture was placed on ice; the resulting mixture was added to the pre-incubated NADPH mixture and incubated at 37 °C. Sampling was conducted at time points 0, 5, 10, 15, 20, 30, 60, 90, 120, and 240 minutes (duplicate sampling per time point). At each designated time point, an equal volume of pre-chilled acetonitrile was added to the incubation system to terminate the reaction. The samples were mixed to be uniform, and centrifuged at 12,500 rpm at 4 °C for 10 minutes. Each resulting supernatant was filtered through a microporous filter membrane and then subjected to HPLC analysis. According to the peak area and the standard curve, the half-life and clearance rate of each compound were calculated. In the test, negative control groups were set as not adding NADPH solution A and NADPH solution B. Blank control groups were set as containing only the compound to be tested and 0.1 M PBS buffer. The HPLC conditions were as follows: column temperature: 25 °C; mobile phase: 100% methanol for isocratic elution; flow rate: 0.80 mL / min; detection wavelength: 210 nm; injection volume: 20 uL. The test results of 25-hydroxylanosterol and deuterated compounds I-6 and I-7 are shown in Table 2.

[0159] Table 2 Hepatic microsomal metabolic stability of 25-hydroxylanosterol and deuterated compounds I-6 and I-7 Samples K (rate constant) T1 / 2 (half-life), minute) CLint (min / mL / pg, clearance rate) 25-Hydroxylanosterol 0.06581 10.53 0.01316 Compound I-7 0.04936 14.11 0.00988 Compound I-6 0.03510 19.85 0.00695

[0160] The results of hepatic microsomal metabolic stability test shown in Table 2 show that: after the hydrogen atom on the carbon atom bearing the secondary hydroxyl in 25-hydroxylanosterol is deuterated, the metabolic stability thereof is significantly improved. Compound I-6, where hydrogen atoms on the carbon atom bearing the secondary hydroxyl and the adjacent carbon atom are deuterated, has the longest half-life (19.85 minutes), and the lowest in vitro clearance rate; while the non-deuterated 25-hydroxylanosterol has the shortest half-life (10.53 minutes), and the highest in vitro clearance rate. The above results indicate that deuterization at appropriate sites in a compound could change its metabolic stability and further improve its bioavailability.

[0161] Example 14 Effects of lanosterol derivatives on New Zealand rabbits with sodium selenite-induced cataract model

[0162] 1. Experimental animals

[0163] 32 New Zealand rabbits, 2.0-3.0 months old, weighing 1.5-2.5 kg, conventional animals, both males and females.

[0164] 2. Prescription and preparation process of lanosterol derivatives

[0165] 2.1 Prescription

[0166] Table 3 Prescription of eye drop Ingredients Amount / g Lanosterol / I- 1 / II-1 2 / 4 HPMC 6 Polysorbate 80 40 Boric acid 16 Borax 1.6 Benzalkonium chloride 0.05 Water 1000 mL

[0167] 2.2 Preparation process:

[0168] (1) Hydroxypropylmethylcellulose was dissolved in approximately 10% of the prescription amount of boiled water for injection. An appropriate amount of cold water for injection was then added, and the resulting mixture was stirred until complete dissolution to obtain a solution I.

[0169] (2) prescription amounts of boric acid, borax, and benzalkonium chloride were dissolved in an appropriate amount of water for injection with stirring. The resulting solution was added to the solution I. The prescription amount of polysorbate 80 was slowly added thereto while stirring. Water for injection was added to reach approximately 90% of the final prescription volume, followed by stirring to obtain a solution II.

[0170] (3) Prescription amounts of lanosterol, compound I-1, or compound II-1 were weighed and added to the solution II. The resulting mixture was dispersed using a high-shear emulsifier at a rate of 10,000 r / min for 5-10 minutes until uniform to obtain a solution III.

[0171] (4) The solution III was placed in a high-pressure homogenizer and subjected to one cycle of homogenization at a pressure of 250 bar ± 10 bar. The resulting drug liquid was collected. The pipelines in the high-pressure homogenizer were flushed with an appropriate amount of sterile water for injection, and the flushing solution was collected and combined with the drug liquid to obtain a solution IV.

[0172] (5) The solution IV was diluted with sterile water for injection to reach a final volume of 1 L.

[0173] (6) Samples were taken to test pH, osmotic pressure, and content. After passing quality control, the solution was aseptically filled into low-density polyethylene medicinal eye drop bottles, with 5 mL of drug liquid per bottle.

[0174] 3. Modeling, grouping, and administration

[0175] 3.1 Modeling: 32 New Zealand rabbits with transparent and normal crystalline lenses were selected for modeling. After anesthetizing the animals for modeling, 0.1 mL of a 10 mM sodium selenite solution was slowly injected into the anterior chamber. The day when the modeling and injection were conducted was designated as D0.

[0176] 3.2 Grouping: On D3, the successfully modeled animals were randomly and evenly grouped according to crystalline lens opacity grading score and gender. The groups were: model control group, lanosterol eye drop group (0.4 wt%), lanosterol derivative I-1 eye drop group (0.4 wt%), and lanosterol derivative II-1 eye drop group (0.4 wt%). Each group had 8 rabbits, with both males and females.

[0177] 3.3 Administration: Starting on D4, eye drops were administrated to the modeled right eyes according to the protocol, three times daily at an approximately 3-hour interval, for 21 consecutive days. The left eyes, which were neither modeled nor administrated, served as the normal self-control.

[0178] 4. Indicator test

[0179] Slit-lamp photography was performed for grading score before administration, 13 days post administration, and 20 days post administration (D3, D16, and D23). Approximately 2 hours after the second administration on D24, the animals' eyeballs were enucleated. The crystalline lens, including the capsular membrane, was completely separated. A crystalline lens was placed on grid paper and photographed to show the clarity of grid lines viewed through the crystalline lens, and the clarity of the crystalline lens was scored.

[0180] 5. Experimental results

[0181] (1) Effect on crystalline lens opacity grading score of animals with cataract model

[0182] Table 4 Crystalline lens opacity grading score results of New Zealand rabbits with sodium selenite-induced cataract model ( x±S, n=8) Groups Crystalline lens opacity grading score D3 D16 D23 Model control group 3.2±0.8 3.5±0.8 3.5±0.8 Lanosterol eye drop group 3.0±0.9 2.0±1.0*^ 1.9±1.1*^ Lanosterol derivative I-1 eye drop group 3.0±0.9 1.3±0.5**^ 1.3±0.5**^ Lanosterol derivative II-1 eye drop group 3.0±0.9 1.4±0.5**^ 1.4±0.5**A^

[0183] Notes: Compared with A: * represents p < 0.05, ** represents p < 0.01; Compared with D3, ▲ means p<0.05, ▲▲ means p<0.01.

[0184] The results of crystalline lens opacity grading score in Table 4 show that: compared with the model control group and before administration (D3), the D16 and D23 crystalline lens opacity grading conversion scores of animals in the lanosterol eye drop group, lanosterol derivative I-1 eye drop group, and lanosterol derivative II-1 eye drop group are significantly decreased (P < 0.05 or P < 0.01); compared with the lanosterol eye drop group, the D16 and D23 crystalline lens opacity grading conversion scores in the lanosterol derivative I-1 eye drop group and lanosterol derivative II-1 eye drop group are significantly decreased.

[0185] (2) Effect on crystalline lens transparency score of animals with cataract model

[0186] Table 5 Crystalline lens transparency score results of New Zealand rabbits with sodium selenite-induced cataract model ( x±S, n=8) Groups Crystalline lens transparency scores Model control group 3.6±1.3 Lanosterol eye drop group 1.8±1.2* Lanosterol derivative I-1 eye drop group 1.3±0.5** Lanosterol derivative II-1 eye drop group 2.0±0.9*

[0187] Note: compared with A: * represents p < 0.05, ** represents p < 0.01.

[0188] FIG. 8 shows crystalline lens transparency scores of animals in each group.

[0189] The crystalline lens transparency score results in Table 5 show that: compared with the model control group, the crystalline lens transparency scores of animals in the lanosterol eye drop group, lanosterol derivative I-1 eye drop group, and lanosterol derivative II-1 eye drop group are significantly decreased (P < 0.05 or P < 0.01); compared with the lanosterol eye drop group, the crystalline lens transparency scores of animals in the lanosterol derivative I-1 eye drop group are significantly decreased.

[0190] 6. Conclusion

[0191] In summary, the lanosterol eye drop, lanosterol derivative I-1 eye drop, and lanosterol derivative II-1 eye drop have a significant improvement effect on New Zealand rabbits with sodium selenite-induced cataract model, which is manifested by the reduced crystalline lens opacity grading score and reduced crystalline lens transparency score of modeled animals. The lanosterol derivative I-1 eye drop and lanosterol derivative II-1 eye drop at the same concentration have a better effect on New Zealand rabbits with cataract model, compared with the lanosterol eye drop.

[0192] Example 15 Experimental study on effects of lanosterol derivatives on cynomolgus monkeys with spontaneous cataracts

[0193] 1. Experimental animals

[0194] 12 cynomolgus monkeys, weighing 4.0-8.0 kg, conventional animals, and both females and males.

[0195] 2. Screening, grouping, and administration

[0196] Screening: Crystalline lens opacity in both eyes of cynomolgus monkeys were detected using slit-lamp photography. 12 monkeys with spontaneous cataracts were screened out and randomly divided into 3 groups, i.e., the model control group, the low-concentration lanosterol derivative I-1 eye drop group (0.2 wt%), and the high-concentration lanosterol derivative I-1 eye drop group (0.4 wt%). Each group had 4 animals (8 eyes in total). The day of animal enrollment was designated as D0. The formulation and preparation method of the eye drops were the same as described in Example 14.

[0197] Administration: After grouping, eye drops were administrated to both eyes according to predetermined requirements, 4 times daily at approximately a 3-hour interval, for 60 consecutive days.

[0198] 3. Indicator test

[0199] The average density (Avg) and maximum density (Max) of the crystalline lenses in each group of cynomolgus monkeys were measured using the Pentacam HR anterior segment analyzer before administration (D0), and on D20, D40, and D60.

[0200] Slit-lamp photography was performed before administration (D0), and on D20, D40, and D60 to capture photographs of crystalline lens of animals in each group. Finally, photographs of the crystalline lens of the cynomolgus monkeys taken by slit-lamp photography were graded according to the Lens Opacities Classification System III (LOCS III).

[0201] 4. Experimental results

[0202] (1) Effects on density of crystalline lenses of cynomolgus monkeys with spontaneous cataracts

[0203] Table 6 Measured results of average density (Avg) of crystalline lenses in cynomolgus monkeys with spontaneous cataracts ( x±S, n=8) Groups Avg (%) Before administration (D0) D20 D40 D60 Model control group 9.0±0.9 8.9±0.9 9.1±1.0 9.2±0.8 0.2 wt% lanosterol I-1 eye drop group 7.7±0.3 7.5±0.4a 7.2±0.6 ▲ 7.2±0.5 ▲ 0.4 wt% lanosterol I-1 eye drop group 11.2±0.4 10.7±0.6 ▲ 9.9±0.5 ▲ 9.4±0.6 ▲

[0204] Note: Compared with those before administration, ▲ means P < 0.05, ▲▲ means P < 0.01.

[0205] Table 7 Measured results of maximum density (Max) of crystalline lenses in cynomolgus monkeys with spontaneous cataracts ( x±S, n=8) Groups Max (%) Before D20 D40 D60 administration (D0) Model control group 25.0±3.0 25.2±1.8 27.3±2.5 27.7±1.9 0.2 wt% lanosterol I-1 eye drop group 24.7±2.1 21.3±1.1 ▲ 19.3±2.6 ▲ 18.0±1.8 ▲ 0.4 wt% lanosterol I-1 eye drop group 26.2±2.1 25.5±1.8 20.1±2.5 ▲ 19.3±2.1 ▲

[0206] Note: Compared with before administration, ▲ means P < 0.05, ▲▲ means P < 0.01.

[0207] FIGs 9-11 show screenshots of photographs by Pentacam imaging analysis of animals in each group before administration; FIGs 12-14 show screenshots of photographs by Pentacam imaging analysis of animals in each group 20 days post administration; FIGs 15-17 show screenshots of photographs by Pentacam imaging analysis of animals in each group 40 days post administration; FIGs 18-20 shows screenshots of photographs by Pentacam imaging analysis of animals in each group 60 days post administration.

[0208] The results of densities of crystalline lenses in Table 6 and Table 7 show that: compared with before administration (D0), the average densities (Avg) and maximum densities (Max) of crystalline lenses of animals in the model control group on D20, D40 and D60 are not significantly different (P > 0.05), and the average densities (Avg) and maximum densities (Max) of crystalline lenses of animals in the low (0.2%) and high (0.4%)-concentration lanosterol derivative I-1 eye drop groups on D20, D40 and D60 are significantly decreased (P < 0.05 or P < 0.01).

[0209] (2) Effects on crystalline lens opacity score of cynomolgus monkeys with spontaneous cataracts

[0210] Table 8 Crystalline lens opacity score results of cynomolgus monkeys with spontaneous cataracts ( x±S, n=8) Groups Avg (%) Before administration D20 D40 D60 Model control group 2.4±0.3 2.4±0.3 2.5±0.5 2.5±0.5 0.2% lanosterol I-1 eye drop group 3.0±0.3 2.5±0.4 ▲ ▲ 2.2±0.6a ▲ 2.2±0.5a ▲ 0.4% lanosterol I-1 eye drop group 3.0±0.4 2.8±0.4 ▲ 2.5±0.4a ▲ 2.5±0.4a ▲

[0211] Note: compared with those before administration, ▲ means P < 0.05, ▲▲ means P < 0.01

[0212] FIG. 21 shows slit-lamp photographs of animals in each group.

[0213] The crystalline lens opacity score results in Table 8 show that: compared with those before administration (D0), the crystalline lens opacity scores of animals in the model control group on D20, D40 and D60 are not significantly different (P > 0.05), and the crystalline lens opacity scores of animals in low (0.2 wt%) and high (0.4 wt%)-concentration lanosterol derivative I-1 eye drop groups are significantly decreased (P < 0.05 or P < 0.01).

[0214] 5. conclusion

[0215] In conclusion, low (0.2 wt%)- and high (0.4 wt%)-concentration lanosterol derivative I-1 eye drops have obvious therapeutic effects on cynomolgus monkeys with spontaneous cataracts, which is manifested by reduced density and opacity of crystalline lenses in modeled animals.

[0216] The above is only preferred embodiments of the present disclosure. It should be pointed out that for those skilled in the art, improvements and refinements could be made without departing from the principles of the present disclosure. These improvements and refinements should also be deemed as falling within the scope of the present disclosure.

Claims

1. A lanosterol derivative or a pharmaceutically acceptable salt thereof, wherein thelanosterol derivative has a structural formula shown in formula I or formula II,formula I,                                   formula II,wherein in formula I and formula II,Y1, Y2, and Y3 each are independently hydrogen, deuterium, C1-C4 alkyl or unsaturated hydrocarbyl;X is independently oxygen, sulfur, or an NR1 group, R1 in the NR1 group being hydrogen or alkyl;R is hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylformyl, substituted arylformyl, heteroarylformyl, or substituted heteroarylformyl; andin formula I and formula II, under a condition that X is oxygen, not all of R, Y1, Y2, and Y3 are hydrogen.

2. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein a substituent in the substituted aryl, the substituted heteroaryl, the substituted arylformyl, and the substituted heteroarylformyl is independently at least one selected from the group consisting of halogen, deuterium, hydroxyl, mercapto, and methylthio.

3. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R in formula I and formula II is hydrogen or hydroxypyridylformyl.

4. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 3, wherein the hydroxypyridylformyl is any one selected from thegroup consisting5. The lanosterol derivative or the pharmaceutically acceptable salt thereof asclaimed in claim 1, wherein the lanosterol derivative is any one selected from the groupconsisting of:formula I-1formula I-2formula I-3formula I-4formula I-6formula I-7formula I-8formula I-9formula II-1andformula II-2.

6. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the pharmaceutically acceptable salt of the lanosterol derivative is an organic acid salt or an inorganic acid salt, the organic acid salt comprises at least one selected from the group consisting of an acetate, a methanesulfonate, and a tartrate, and the inorganic acid salt comprises at least one selected from the group consisting of a hydrochloride, a sulfate, and a phosphate.

7. A method for preparing the lanosterol derivative as claimed in any one of claims 1 to 6, whereinunder a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method I comprising the steps of:mixing a compound having a structure shown in formula A-3, a compound having a structure shown in formula C, a condensation agent, a catalyst, and a solvent, and subjecting a resulting mixture to condensation to obtain the lanosterol derivative;formula A-3,R-OH formula C,under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method II comprising the steps of:mixing the compound having the structure shown in formula A-3, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula A-4; andmixing the compound having the structure shown in formula A-4, deuteratedchloroform, and a catalyst, and conducting deuteration to obtain a compoundhaving a structure shown in formula A-5; andformula A-4,formula A-5,mixing the compound having the structure shown in formula A-5, methanol,and deuterated sodium borohydride, and conducting reduction to obtain thelanosterol derivative having a structure shown in formula I-6,formula I-6;under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method III comprising the steps of:mixing the compound having the structure shown in formula A-4, methanol, deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula I-7,formula I-7;under a condition that the lanosterol derivative has the structural formula shown informula I where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formula shown in formula I where X is oxygen, Y1 and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformy, the method is method IV comprising the steps of:mixing a compound having the structure shown in formula I-6 or a compound having the structure shown in formula I-7, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative;under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all hydrogen, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method V comprising the steps of:mixing lanosterol, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative;under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is hydrogen, the method is method VI comprising:conducting steps of the method II except that the compound having the structure shown in formula A-3 is replaced with lanosterol, to obtain the lanosterol derivative having a structure shown in formula B-2,formula B-2;under a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, R, Y1, and Y2 are all hydrogen, and Y3 is deuterium, the method is method VII comprising:mixing lanosterol, pyridinium chlorochromate, sodium acetate, and a solvent, and conducting oxidation to obtain a compound having a structure shown in formula D; andmixing the compound having the structure shown in formula D, methanol, and deuterated sodium borohydride, and conducting reduction to obtain the lanosterol derivative having a structure shown in formula B-3;formula D,                              formula B-3;andunder a condition that the lanosterol derivative has the structural formula shown in formula II where X is oxygen, Y1, Y2, and Y3 are all deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, alternatively under a condition that the lanosterol derivative has the structural formulashown in formula II where X is oxygen, Y1 and Y2 are both hydrogen, Y3 is deuterium, and R is the arylformyl, the substituted arylformyl, the heteroarylformyl, or the substituted heteroarylformyl, the method is method VIII comprising the steps of:mixing a compound having the structure shown in formula B-2 or a compound having the structure shown in formula B-3, the compound having the structure shown in formula C, a condensation agent, a catalyst, and a solvent, and conducting condensation to obtain the lanosterol derivative.

8. The method as claimed in claim 7, wherein the compound having the structure shown in formula A-3 is prepared by a process comprising:mixing a mixture solution of lanosterol and dihydrolanosterol, acetic anhydride, and a catalyst, and conducting esterification to obtain a crude product, the crude product being a mixture of a compound having a structure shown in formula A-1 and a compound having a structure shown in formula B-1;formula A-1,                               formula B-1;mixing the crude product, N-bromosuccinimide, and a solvent, and conducting bromination, and sequentially subjecting a resulting reaction mixture to rotary evaporation, subjecting a resulting residue from the rotary evaporation to extraction, drying a resulting organic phase, and subjecting a dried organic phase to further rotary evaporation, and silica gel column chromatography to obtain a compound having a structure shown in formula A-2; andformula A-2,mixing the compound having the structure shown in formula A-2, a reducing agent, and a solvent, and conducting debromination-ester reduction to obtain the compound having the structure shown in formula A-3.

9. A pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable auxiliary material, wherein the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7.

10. The pharmaceutical composition as claimed in claim 9, wherein the pharmaceutically acceptable auxiliary material is an excipient.

11. Use of the lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6, or the pharmaceutical composition as claimed in claim 7 or 8 in the preparation of a drug for treating an eye disease or an eye condition.

12. The use as claimed in claim 11, wherein the eye disease comprises cataract or retinal degeneration.

13. An eye drop, comprising: in parts by mass, 2-4 parts of an active ingredient, 5-7 parts of hydroxypropylmethylcellulose, 30-50 parts of polysorbate, 10-20 parts of boric acid, 1-2 parts of borax, 0.03-0.06 parts of benzalkonium chloride, and 1,000 parts of water, whereinthe active ingredient is the lanosterol derivative or the pharmaceutically acceptablesalt thereof as claimed in any one of claims 1-6.

14. The eye drop as claimed in claim 13, wherein the polysorbate is polysorbate 80.

15. A method for treating an eye disease, comprisingadministrating a drug to an eye for treatment,wherein the drug is the lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, the pharmaceutical composition as claimed in claim 9 or 10, or the eye drop as claimed in claim 13 or 14.ABSTRACT OF THE DISCLOSUREThe present disclosure relates to the technical field of medicines, in particular to a lanosterol derivative, and a preparation method and use thereof. The lanosterol derivative has a structural formula shown in formula I or formula II. The lanosterol derivative combines favorable water solubility and liposolubility, enabling effective penetration into lesion sites within the body while exhibiting high bioavailability. Results in examples show that the lanosterol derivative has a significantly higher solubility in water than that of lanosterol or 25-hydroxylanosterol, and exhibits obvious therapeutic effects on cataract in animal in vivo experiments. The lanosterol derivative has a broad prospect in preparation of drugs for treating eye diseases or eye conditions.Item name:686-4 Item deseri pt ion:2e6Channel name:2:Average l ime 1,5035 min:Quad MSI (50-2000) ESI-:Combined566.28000                                                         2.21e6§1.5e6-o O567.645002 / 11284.70000634.335001 13,78250 I d.....U ,     1,1712.23750■I —.»1 ..... ■1154.20500        1622.47250I 1410.92250      \1946.587504   - - ..- ..I., -Ir ——■— ------[------—,-1.—"—ii—,100 200 300 400 500 600 700 800 900 10001100 12001300 14001500 16001700 18001900 2000Observed mass |m / z|FIG. 23d565.

10. fid3 / 11Item name:568Item descriptionI ,25e6]1 e6j7.5e5-Channel name:2: Average Time 1.5035 min: Quad MSI (50-2000) ESI-: Combined569.302501.3e6Intensity [Counts]59.28000 / 62.10750568.32750rl 45.86000-256.42500 itnsn T284.70000571.35000 '655.200001160.64000J                  ................................................. ....... ........... । —100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000Observed mass [mz]FIG. 44 / 111400000 1200000 1000000 C3 g 800000 3 600000 400000 200000 0 y=i 0,877.6 00.5907 x-8.583 .6303 R2 -0.9997 x' *0      0.02     0.04     0.06     0.08      0.1      0.12ConcentrationFIG. 52000000 1800000 1600000 1400000 £ 1200000 1000000 u 800000 600000 400000 200000 0 y=12 .527.: '04.3C llx-1 6,148 .8360 R2= 0.999 iT / 0    0.02 0.04 0.06 0.08   0.1   0.12 0.14 0.16ConcentrationPeak areaFIG. 7FIG. 9FIG. 12FIG. 13FIG. 16FIG. 18FIG. 19FIG. 21

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