Lanosterol derivative, and preparation method and use thereof

Abstract

The 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. formula II formula I

Claims

<pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A lanosterol derivative or a pharmaceutically acceptable salt thereof, wherein the lanosterol derivative has a structural formula shown in formula I or formula II, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 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; and in formula I and formula II, under a condition that X is oxygen, not all of R, Y1, Y2, and Y3 are hydrogen. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 3, wherein the hydroxypyridylformyl is any one selected from the [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the lanosterol derivative is any one selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] formula I-1 formula I-2 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] formula I-3 formula I-4 [Image disponible dans le document PDF, Image available in the PDF document] formula II-2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. A method for preparing the lanosterol derivative as claimed in any one of claims 1 to 6, wherein 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 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; [Image disponible dans le document PDF, Image available in the PDF document] 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; and mixing the compound having the 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 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] formula 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 the lanosterol derivative having a structure shown in formula I-6, [Image disponible dans le document PDF, Image available in the PDF document] 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, [Image disponible dans le document PDF, Image available in the PDF document] formula I-7; 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 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, [Image disponible dans le document PDF, Image available in the PDF document] 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; and mixing 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; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] formula D, formula B-3; and 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 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>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; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 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; and [Image disponible dans le document PDF, Image available in the PDF document] formula 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. The pharmaceutical composition as claimed in claim 9, wherein the pharmaceutically acceptable auxiliary material is an excipient. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The use as claimed in claim 11, wherein the eye disease comprises cataract or retinal degeneration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>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, wherein the active ingredient is the lanosterol derivative or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The eye drop as claimed in claim 13, wherein the polysorbate is polysorbate < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00080"> <pat:ClaimNumber>80< / pat:ClaimNumber> <pat:ClaimText>80.

15. Use of the lanosterol derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1-7, the pharmaceutical composition according to claim 9 or 10, or the eye drop according to claim 13 or 14 to treat an eye disease or an eye condition. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. The use of the lanosterol derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1-7, the pharmaceutical composition according to claim 9 or 10, or the eye drop according to claim 13 or 14 to treat the eye disease or the eye condition as claimed in claim 15, wherein the eye disease comprises cataract or retinal degeneration. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>