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WO2018137683A1 - 羊毛甾醇前药化合物及其制备方法和应用 - Google Patents

羊毛甾醇前药化合物及其制备方法和应用 Download PDF

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Publication number
WO2018137683A1
WO2018137683A1 PCT/CN2018/074120 CN2018074120W WO2018137683A1 WO 2018137683 A1 WO2018137683 A1 WO 2018137683A1 CN 2018074120 W CN2018074120 W CN 2018074120W WO 2018137683 A1 WO2018137683 A1 WO 2018137683A1
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Prior art keywords
group
compound
pharmaceutically acceptable
acceptable salt
isomer
Prior art date
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PCT/CN2018/074120
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English (en)
French (fr)
Inventor
刘奕志
王延东
李小林
罗志
沈良
候丽娟
文欣欣
贺海鹰
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Zhongshan Ophthalmic Center
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Medshine Discovery Inc
Zhongshan Ophthalmic Center
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Priority to US16/346,111 priority Critical patent/US10738076B2/en
Priority to BR112019013598-7A priority patent/BR112019013598B1/pt
Priority to CN201880002549.0A priority patent/CN109415406B/zh
Priority to KR1020197012855A priority patent/KR102267924B1/ko
Priority to DK18744021.9T priority patent/DK3536698T3/da
Priority to EP18744021.9A priority patent/EP3536698B1/en
Priority to ES18744021T priority patent/ES2890667T3/es
Priority to AU2018212270A priority patent/AU2018212270B2/en
Application filed by Medshine Discovery Inc, Zhongshan Ophthalmic Center filed Critical Medshine Discovery Inc
Priority to RU2019115533A priority patent/RU2720677C1/ru
Priority to JP2019552560A priority patent/JP6704535B2/ja
Publication of WO2018137683A1 publication Critical patent/WO2018137683A1/zh
Priority to ZA2019/04124A priority patent/ZA201904124B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to compounds of formula (I), (II) and (III), pharmaceutically acceptable salts and isomers thereof, and to the use in the manufacture of a medicament for the treatment of ophthalmic diseases.
  • Cataracts are diseases of the eye that occur on the lens in the eyeball.
  • the opacity of the lens is collectively referred to as cataract.
  • Aging, genetic, metabolic abnormalities, trauma, radiation, poisoning and local malnutrition can cause damage to the lens capsule, increase its permeability, loss of barrier function, or lead to metabolic disorders of the lens, which can denature the lens protein and form turbidity.
  • the lens of the eyeball changes from transparent to opaque, affecting the eyes receiving sunlight, it will affect the eyesight of the eye. When the eyeball is light and opaque, the effect on vision is lighter. As the degree of turbidity gradually deepens, the visual acuity will also increase, and severe cases will lead to blindness.
  • Cataract is one of the most common blinding eye diseases and it is a major cause of blindness. Since the mechanism of cataract formation is still unclear, no breakthrough has been made in drug therapy. Therefore, the only effective treatment currently available is surgical treatment.
  • cataracts include: 1 aldose reductase inhibitors, such as catalin (carbacetin, Carlin, white end), facoline, benzalysine, etc.; Oxidative damage drugs, such as glutathione, taurine, aspirin, etc.; 3 nutrient metabolism drugs, such as vitamins, carotenoids, etc.; 4 Chinese medicine compound including Shiqi Luguang Pill, Qiju Dihuang Pill, Shijuan San and so on. These drugs for the treatment of cataracts have been confirmed by long-term clinical trials, which can only delay the deterioration of cataracts, and can not reverse the condition, thus treating cataracts.
  • 1 aldose reductase inhibitors such as catalin (carbacetin, Carlin, white end), facoline, benzalysine, etc.
  • Oxidative damage drugs such as glutathione, taurine, aspirin, etc.
  • 3 nutrient metabolism drugs such as vitamins, carotenoids, etc.
  • Chinese medicine compound
  • Wool sterol is an amphiphilic molecule enriched in the lens. It is synthesized by a key cyclization reaction of lanosterol synthase (LSS) in the cholesterol synthesis pathway, which can reduce the abnormal aggregation of lens proteins and make them renewed. Regularly arranged to restore crystal transparency. Studies have shown that lanosterol synthase can be detected in the lens. Furthermore, in the Shumiya cataract rat study, a specific combination of homozygous mutations of creatinine synthase and farnesyl diphosphate farnesyltransferase 1 (FDFT1) can alleviate cholesterol levels in the lens and cause cataracts.
  • LDS lanosterol synthase
  • Kalinyou Eye Drops is a medicine produced by Japan's Shentian Pharmaceutical Bead Club for the treatment of early senile cataract.
  • the structural formula of its active ingredients is as follows:
  • the present invention provides compounds of formula (I), (II) and (III), pharmaceutically acceptable salts and isomers thereof:
  • m is: 0 or 1, when m is 0, the structural unit does not exist;
  • n 0 or 1;
  • R 2 is selected from the group consisting of 1, 2 or 3 R substituted: phenyl-O- and 5- to 10-membered heteroaryl;
  • R 3 is selected from the group consisting of 1, 2 or 3 R substituted: 6 to 10 membered aryl, 6 to 10 membered aryl-C 1-3 alkyl group, 5 to 10 membered heteroaryl group and 5 to 10 a heteroaryl-C 1-3 alkyl- group, but R 3 does not contain a phenyl group and
  • R 4 is selected from H, F, Cl, Br, I, OH, NH 2 or R 4 is selected from C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from H, or a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 6 is selected from H, or a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 7 and R 6 are linked to each other to form a 3 to 10 membered ring optionally substituted by 1, 2 or 3 R;
  • R 7 and R 4 are bonded to each other to form a 3 to 10 membered ring optionally substituted by 1, 2 or 3 R;
  • R 7 is simultaneously bonded to R 4 and R 6 to form a 3 to 10 membered ring optionally substituted by 1, 2 or 3 R;
  • R 8 is selected from the group consisting of H and C 1-3 alkyl
  • R 9 is selected from the group consisting of H and C 1-3 alkyl
  • R' is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , OH, CN, COOH;
  • hetero of the 5- to 10-membered heteroaryl group and the C 1-6 heteroalkyl group are each independently selected from: -NH-, N, -O-, and -S-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 and 3.
  • R 1 is selected from the group consisting of optionally substituted by 1, 2 or 3 R Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of Other variables are as defined by the present invention.
  • R 2 is selected from Other variables are as defined by the present invention.
  • R 3 above is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, thienyl, pyridyl, quinolinyl, pyrimidinyl, isoxazolyl and 1,2, 4-oxadiazolyl, but R 3 does not contain phenyl and Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: However, R 3 does not contain a phenyl group, and other variables are as defined in the present invention.
  • R 3 is selected from Other variables are as defined by the present invention.
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 and -CH 2 -CH 3 , and other variables are as defined herein.
  • R 5 above is selected from the group consisting of H and CH 3 , and other variables are as defined herein.
  • R 6 above is selected from the group consisting of H and CH 3 , and other variables are as defined herein.
  • the above R 7 and R 4 are bonded to each other to form a 3 to 10 membered ring, and the 3 to 10 membered ring is Other variables are as defined by the present invention.
  • the above R 7 and R 6 are bonded to each other to form a 3 to 10 membered ring, and the 3 to 10 membered ring is selected from the group consisting of Other variables are as defined by the present invention.
  • the above R 7 is simultaneously bonded to R 4 and R 6 to form a 3 to 10 membered ring, and the 3 to 10 membered ring is selected from the group consisting of:
  • Other variables are as defined by the present invention.
  • R 8 above is selected from the group consisting of H and CH 3 , and other variables are as defined herein.
  • R 9 above is selected from the group consisting of H and CH 3 , and other variables are as defined herein.
  • the invention also provides compounds of formula (I), (II) and (II), pharmaceutically acceptable salts and isomers thereof:
  • n is selected from: 0, 1, 2, 3, 4, 5 or 6, when m is 0, the structural unit does not exist;
  • n is selected from: 0, 1, 2 or 3;
  • R 2 is selected from phenyl-O-, 5- to 10-membered heteroaryl optionally substituted by 1, 2 or 3;
  • R 3 is selected from the group consisting of 1, 2 or 3 R substituted: 6 to 10 membered aryl, 6 to 10 membered aryl-C 1-3 alkyl group, 5 to 10 membered heteroaryl group, 5 to 10 Nonheteroaryl-C 1-3 alkyl-;
  • R 4 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , or a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from the group consisting of: H, or a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 6 is selected from the group consisting of: H, or a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 7 and R 6 are connected to each other to form a ring of 3 to 10 members;
  • R 7 and R 4 are connected to each other to form a ring of 3 to 10 members;
  • R 7 is simultaneously bonded to R 4 and R 6 to form a ring of 3 to 10 members;
  • R 8 is selected from the group consisting of: H, C 1-3 alkyl
  • R 9 is selected from the group consisting of: H, C 1-3 alkyl
  • R is selected from the group consisting of: F, Cl, Br, I, NH 2 , NO 2 , OH, COOH, or selected from C 1-3 alkyl;
  • hetero of the 5- to 10-membered heteroaryl group and the C 1-6 heteroalkyl group are each independently selected from: -NH-, N, -O-, -S-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , OH, COOH, CH 3 or CH 3 CH 2 -.
  • R 1 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 1 is selected from the group consisting of
  • the above R 2 is selected from
  • R 3 above is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, thienyl, pyridyl, quinolinyl.
  • R 3 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 3 is selected from the group consisting of
  • the above R 7 and R 4 are bonded to each other to form a 3 to 10 membered ring, and the 3 to 10 membered ring is selected from the group consisting of:
  • the above R 7 and R 6 are bonded to each other to form a 3 to 10 membered ring, and the 3 to 10 membered ring is selected from the group consisting of:
  • the above R 7 is bonded to R 4 and R 6 to form a 3 to 10 membered ring, and the 3 to 10 membered ring is selected from the group consisting of:
  • the invention also provides a compound of the formula: a pharmaceutically acceptable salt and isomers thereof:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating ophthalmic diseases.
  • the above ophthalmic disease drug is a drug for treating cataract.
  • the medicament for treating cataract is cataract eye drops.
  • the compound of the present invention has good permeability and is effectively converted into lanosterol in vivo, which greatly improves the drug utilization rate of lanosterol.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • cycloalkenylalkyl or “cycloalkenylalkyl” refers to a cycloalkenyl substituted alkyl.
  • cycloalkynyl or “cycloalkynylalkyl” refers to a cycloalkynyl substituted alkyl.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 1 Slit lamp observation of lanosterol and its prodrug 026 eye drops on sodium selenite-induced neonatal rabbit cataract model.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • Figure 2 Comparison of in vitro lens transparency assays in each group after 42 days of dosing with sodium selenite-induced neonatal rabbit cataract.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • the grid is 2.12 x 2.12 mm
  • Figure 3 Sodium selenite-induced neonatal rabbit cataract model.
  • the glutathione peroxidase (GSH-PX) activity of each group was compared after 42 days of administration.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • V.S PC:++ indicates p ⁇ 0.01, and + indicates p ⁇ 0.05.
  • Figure 4 Slit lamp observation of lanosterol and its prodrug 026 eye drops on UV-induced New Zealand rabbit cataract model.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • Figure 5 Comparison of in vitro lens transparency assays in the UV-induced New Zealand rabbit cataract model after 42 days of dosing.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • the grid is 2.12 x 2.12 mm.
  • Figure 6 UV-induced New Zealand rabbit cataract model. Comparison of lens glutathione peroxidase (GSH-PX) activity in each group after 42 days of administration.
  • NC Normal control group
  • MC Model control group
  • PC Positive control group
  • LT Lanosterol eye drops treatment group
  • 026 Lanosterol prodrug 026 eye drops treatment group.
  • V.S PC:++ indicates p ⁇ 0.01, and + indicates p ⁇ 0.05.
  • Step 1 Synthesis of Compound BB-1.
  • the mixture BB-1-1 was subjected to supercritical fluid chromatography (separation conditions: Column: Chiralpak AD-3 150 ⁇ 4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: ethanol (0.05% diethanolamine); gradient: 5 minutes Time B was obtained from 5% to 40%, B 40% for 2.5 minutes, then B5% for 2.5 minutes; flow rate: 2.5 mL/min; column temperature: 35 ° C; wavelength: 220 nm) to obtain compound BB-1.
  • Step 1 Synthesis of Compound 6-1.
  • Step 1 Synthesis of compound 11-1.
  • O-hydroxybenzoic acid (632.35 mg, 3.51 mmol) was dissolved in dichloromethane (10.00 mL), and oxalyl chloride (594.03 mg, 4.68 mmol) was added dropwise to the reaction flask and stirred at 25 ° C for 2.0 hours. The liquid was spun dry to give a crude product. The crude product was redissolved in dichloromethane (20.00 mL). Compound BB-1 (500.00 mg, 1.17 mmol) and triethylamine (710.35 mg, 7.02 mmol) were added to the reaction mixture and stirred at 25 ° C for 10.0 hours. The reaction was quenched with water (100 mL).
  • New Zealand white rabbits (body weight greater than 2 kg, age greater than 12 weeks) were used as experimental animals. Two New Zealand white rabbits were used for each compound study. Each rabbit was instilled with 50 ⁇ L of eye drops in both eyes, 3 The eye is used to collect aqueous samples and the other eye is used as a backup.
  • the eye drop formula is 1.2% hydroxypropyl methylcellulose (E5 size), 20.5% Poloxamer (P407 size), 1.6% Poloxamer (P188 size), compound concentration 5mM, eye drops It is a homogeneous suspension.
  • the anterior aqueous humor was collected at 0.5, 2, 4, and 6 hours after administration, and the volume of each sample was not more than 50 ⁇ L. Each animal was given mild anesthesia before collecting samples. The time point is 3 samples. The collected aqueous samples were stored in dry ice immediately after collection or stored in a refrigerator at -80 ⁇ 10 °C. After the sample collection, the animals were euthanized. Samples were analyzed for compound concentration using a triple quadrupole mass spectrometer (API 4000). Tables 1 and 2 show the in vivo DMPK assay detection methods; Tables 3 to 9 show the drug concentrations in the aqueous humor after the compound lanosterol (parent) and the prodrug compound eye drops (250 nM per eye).
  • API 4000 triple quadrupole mass spectrometer
  • Table 7 Average concentration of sample (nM) in aqueous humor after New Zealand white rabbits were dropped into 250 nmol of compound 9 per eye.
  • Table 9 Average concentration of sample (nM) in aqueous humor after New Zealand white rabbits were dropped into 250 nmol of compound 12 per eye.
  • Newborn New Zealand rabbits are P7 days old, normal grade, and 5 young rabbits per litter are breast-fed with a mother rabbit.
  • the experimental young rabbits were randomly divided into 5 groups, 5 rabbits in each group.
  • NC Normal control group
  • Model control group P10 days young rabbits were injected subcutaneously with sodium selenite solution (in physiological saline) at 20 ⁇ mol/kg body weight, and for 15 days after P15, with drug-free blank drops. Eye drops right eye, 3 times a day.
  • PC Positive control group
  • Lanosterol eye drops treatment group P10 days, young rabbits were injected subcutaneously with sodium selenite solution (in physiological saline) at 20 ⁇ mol/kg body weight, and used for 42 days after P15 days. Wool sterol drops in the right eye, 3 times a day.
  • Lanosterol prodrug 026 eye drops treatment group (026): P10 days young rabbits were injected subcutaneously with sodium selenite solution (in physiological saline) 20 ⁇ mol/kg body weight, after P15 days For 42 consecutive days, the lanosterol prodrug 026 drops the right eye of the eye, 3 times a day.
  • Glutathione peroxidase (GSH-PX) activity assay The isolated rabbit lens is detected by the method provided in the specification of GSH-PX activity detection kit (Nanjing Institute of Bioengineering). GSH-PX activity. The experimental data were analyzed by One-Way ANOVA with SPSS statistical software. The LSD method was used to compare the groups. The difference level of the school was p ⁇ 0.05.
  • Figure 1 shows that sodium selenite can induce cataract in newborn New Zealand rabbit lens. Slit lamp observation of lanosterol prodrug 026 eye drops for 42 days (Fig. 1-I). Significant reduction in cataract symptoms compared with pre-dose (Fig. 1-J). The cataract symptoms did not change before and after the administration of Kalinyou eye drops (Fig. 1-E, 1-F) and lanosterol eye drops (Fig. 1-G, 1-H).
  • Figure 2 compares the lens transparency of each group after 42 days of dosing in a fresh New Zealand rabbit cataract model induced by sodium selenite. On the left side of each photograph is the left eye lens (left eye is not administered as a self-control), and on the right is the right eye lens (the right eye is administered in different groups). After 42 days of administration of lanosterol prodrug 026 eye drops, the transparency of the right eye lens was significantly higher than that of the left eye, and also significantly higher than that of the MC group, but it was still lower than that of the NC group. There was no significant change in lens transparency after administration of the right eye in the LT group.
  • GSH-PX activity test After 42 days of administration, the GSH-PX activity of the lens in each group showed (see Figure 3). After subcutaneous injection of sodium selenite, the activity of GSH-PX in the lens of rabbit eyes was significantly reduced, and the NC group There was a statistical difference (p ⁇ 0.01). The lanosterol prodrug 026 eye drops and the positive control drug Kalinyou eye drops can increase the GSH-PX activity of the lens, which is statistically different from the MC group (p ⁇ 0.01), and the improvement effect of 026 is better than that of Carlin. More pronounced (p ⁇ 0.01). The effect of lanosterol eye drops on the activity of lens GSH-PX was significantly lower than that of 026 and Carlin, and there was no statistical difference compared with MC group (p>0.05).
  • the experimental animals were randomly divided into 5 groups of 5 each.
  • NC Normal control group
  • Model control group (MC) 313 nm ultraviolet irradiation was used for 24 hours to mold, and then for 42 consecutive days, the right eye of the drug-free blank eye drops was used 3 times a day.
  • PC Positive control group
  • Lanosterol prodrug 026 eye drops treatment group (026): 313nm ultraviolet irradiation for 24 hours modeling, followed by 42 days with lanosterol prodrug 026 eye drops right eye, 3 per day Times.
  • Glutathione peroxidase (GSH-PX) activity assay The isolated rabbit lens is detected by the method provided in the specification of GSH-PX activity detection kit (Nanjing Institute of Bioengineering). GSH-PX activity. The experimental data were analyzed by One-Way ANOVA with SPSS statistical software. The LSD method was used to compare the groups. The difference level of the school was p ⁇ 0.05.
  • Figure 4 shows that UV can induce cataract in New Zealand rabbit lens. Slit lamp observation of lanosterol prodrug 026 eye drops was administered for 42 days (Fig. 4-I) and cataract symptoms were significantly reduced compared to pre-dose (Fig. 4-J). The cataract symptoms did not change significantly before and after the administration of Kalinyou eye drops (Fig. 4-E, 4-F) and before and after the administration of lanosterol eye drops (Fig. 4-G, 4-H).
  • Figure 5 compares the lens transparency of the UV-induced New Zealand rabbit cataract model for each group after 42 days of dosing. On the left side of each photograph is the left eye lens (left eye is not administered as a self-control), and on the right is the right eye lens (the right eye is administered in different groups). After 42 days of administration of lanosterol prodrug 026 eye drops, the transparency of the right eye lens was significantly higher than that of the left eye, and also significantly higher than that of the MC group, but it was still lower than that of the NC group. There was no significant change in lens transparency after administration of the right eye in the LT group.
  • GSH-PX activity assay After 42 days of administration, the GSH-PX activity of the lens in each group showed (see Figure 6). After UV irradiation, the activity of GSH-PX in the rabbit lens was significantly reduced, compared with the NC group. Academic differences (p ⁇ 0.01 or p ⁇ 0.05). The lanosterol prodrug 026 eye drops and the positive control drug Kalinyou eye drops can increase the GSH-PX activity of the lens, which is statistically different from the MC group (p ⁇ 0.01), and the improvement effect of 026 is better than that of Carlin. More pronounced (p ⁇ 0.05). The effect of lanosterol eye drops on the activity of lens GSH-PX was significantly lower than that of 026 and Carlin, and there was no statistical difference compared with MC group (p>0.05).
  • lanosterol prodrug 026 eye drops can alleviate UV-induced New Zealand rabbit cataract symptoms, improve lens transparency and lens GSH-PX activity.

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Abstract

一种羊毛甾醇前药化合物、药学上可接受的盐及其异构体，以及包含羊毛甾醇前药化合物的药物组合物，及其在制备治疗白内障药物上的应用。羊毛甾醇前药化合物与羊毛甾醇相比具有更好的渗透性。

Description

羊毛甾醇前药化合物及其制备方法和应用
相关申请的交叉引用
本申请主张2017年1月25日提交的中国专利申请CN201710061039.8和2017年09月22日提交的中国专利申请CN201710868274.6的优先权，其内容在此并入本申请。
技术领域
本发明涉及式(Ⅰ)、(Ⅱ)和(Ⅲ)所示化合物、药学上可接受的盐及其异构体，并涉及在在制备治疗眼科疾病的药物上的应用。
背景技术
白内障属于眼睛的疾病，发生在眼球内的晶状体上，晶状体的浑浊统称为白内障。老化、遗传、代谢异常、外伤、辐射、中毒和局部营养不良等都可引起晶状体囊膜损伤，使其渗透性增加，丧失屏障作用，或导致晶状体代谢紊乱，使晶状体蛋白发生变性，形成混浊。如果眼球的晶状体从透明变成不透明、影响到眼睛接收阳光，那么就会影响眼睛的视力情况。在眼球浑浊较轻时对视力的影响较轻，随着浑浊的程度逐渐加深，视力也会随之加大，严重者会导致失明。白内障是最常见的致盲眼病之一，它是导致失明的主要因素。由于白内障形成的机制尚不明确，药物治疗至今未取得突破性进展。因此，目前唯一确定有效的治疗方法就是手术治疗。
尽管白内障手术方式的不断进步为白内障的治疗提供了巨大的帮助，但手术治疗的治愈率仍然远远低于发生率，存在发生严重并发症的可能；另一方面，白内障的手术治疗成本十分高昂，即使是发达国家，白内障也给医疗保险体系带来了巨大的负担。因此药物的防治起到举足轻重的作用。目前，临床上针对白内障的治疗药物包括：①醛糖还原酶抑制剂，如卡他林(卡他灵、卡林优、白内停)、法可林、苄达赖氨酸等；②抗氧化损伤药物，如谷胱甘肽、牛磺酸、阿司匹林等；③营养代谢类药物，如维生素类、类胡萝卜素等；④中药复方包括石斛夜光丸、杞菊地黄丸、石决明散等。而这些治疗白内障的药物经长期临床试验证实，只能延缓白内障的病情恶化，不能使病情逆转，从而治疗白内障。同时，随着我国开始步入老龄化社会，白内障患者日益增多，对于白内障药物的需求将更为迫切。因此，临床上非常需要安全、疗效好、眼内穿透力强、性质稳定的新品种眼科外用抗白内障药物。
羊毛甾醇是富集于晶状体内的两亲性分子，它是由羊毛甾醇合酶(LSS)在胆固醇合成途径中的一个关键的环化反应来合成，能够降低晶状体蛋白的异常聚集，使其重新规则排列从而恢复晶体透明。已有研究表明，在晶状体中可以检测到羊毛甾醇合酶。此外，在Shumiya白内障大鼠研究中，毛甾醇合酶和法尼基二磷酸法尼基转移酶1(FDFT1)的纯合突变特定组合可以减轻晶状体中胆固醇的水平，并导致白内障。同时我们最近的研究发现，羊毛甾醇在体外和细胞水平可以显著降低预形成的晶状体蛋白质聚集体。在在体水平也证实，羊毛甾醇可以使白内障的病情逆转，晶状体变的澄清透明，此结果已近期发表在Nature杂志，引起全世界广泛注意，是预防和治疗白内障的新分子。
[根据细则26改正12.03.2018]　
Figure WO-DOC-FIGURE-yangmao
卡林优滴眼液，是由日本参天制药珠式会社生产的，用于治疗初期老年性白内障的药物，其有效成分的结构式如下：
[根据细则26改正12.03.2018]　
Figure WO-DOC-FIGURE-kalinyou
发明内容
本发明提供了式(Ⅰ)、(Ⅱ)和(Ⅲ)所示化合物、药学上可接受的盐及其异构体：
[根据细则26改正12.03.2018]　
Figure WO-DOC-FIGURE-123
其中，
[根据细则26改正12.03.2018]　
m是：0或1，当m为0时，结构单元
Figure WO-DOC-FIGURE-789
不存在；
n是：0或1；
R 1选自任选被1、2或3个R取代的：C 1-3烷基-O-C(＝O)-C 1-3烷基-NH-；
R 2选自任选被1、2或3个R取代的：苯基-O-和5～10元杂芳基；
R 3选自任选被1、2或3个R取代的：6～10元芳基、6～10元芳基-C 1-3烷基-、5～10元杂芳基和5～10元杂芳基-C 1-3烷基-，但是R 3不包含苯基和
Figure PCTCN2018074120-appb-000005
R 4选自H、F、Cl、Br、I、OH、NH 2，或R 4选自任选被1、2或3个R取代的C 1-6烷基；
R 5选自H，或任选被1、2或3个R取代的C 1-6烷基；
R 6选自H，或任选被1、2或3个R取代的C 1-6烷基；
R 7选自H、F、Cl、Br、I、OH、COOH、CONH 2、NH 2、SH或NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷基、C 1-6杂烷基、苯基和5～10元杂芳基；
或R 7与R 6相互连接形成一个任选被1、2或3个R取代的3～10元环；
或R 7与R 4相互连接形成一个任选被1、2或3个R取代的3～10元环；
或R 7同时与R 4和R 6相互连接形成一个任选被1、2或3个R取代的3～10元环；
R 8选自H和C 1-3烷基；
R 9选自H和C 1-3烷基；
R分别独立地选自F、Cl、Br、I、NH 2、NO 2、OH、CN、COOH、NH 2C(＝NH)NH-，或选自任选被
1、2或3个R'取代的C 1-3烷基和-C(＝O)O-C 1-3烷基；
R'选自F、Cl、Br、I、NH 2、NO 2、OH、CN、COOH；
所述5～10元杂芳基、C 1-6杂烷基之“杂”分别独立地选自：-NH-、N、-O-和-S-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2和3。
本发明的一些方案中，上述R分别独立地选自：F、Cl、Br、I、NH 2、NO 2、OH、CN、COOH、CH 3、NH 2C(＝NH)NH-、CH 3CH 2-、CF 3和-O-C(＝O)-CH 3，其他变量如本发明定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的
Figure PCTCN2018074120-appb-000006
其他变量如本发明定义。
本发明的一些方案中，上述R 1选自
Figure PCTCN2018074120-appb-000007
其他变量如本发明定义。
本发明的一些方案中，上述R 2选自
Figure PCTCN2018074120-appb-000008
其他变量如本发明定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：苯基、噻吩基、吡啶基、喹啉 基、嘧啶基、异噁唑基和1,2,4-噁二唑基，但是R 3不包含苯基和
Figure PCTCN2018074120-appb-000009
其他变量如本发明定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：
Figure PCTCN2018074120-appb-000010
Figure PCTCN2018074120-appb-000011
但是R 3不包含苯基，其他变量如本发明定义。
本发明的一些方案中，上述R 3选自
Figure PCTCN2018074120-appb-000012
Figure PCTCN2018074120-appb-000013
其他变量如本发明定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、I、OH、NH 2、CH 3和-CH 2-CH 3，其他变量如本发明定义。
本发明的一些方案中，上述R 5选自H和CH 3，其他变量如本发明定义。
本发明的一些方案中，上述R 6选自H和CH 3，其他变量如本发明定义。
本发明的一些方案中，上述R 7选自H、OH、COOH、CONH 2、NH 2、SH、NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷基、C 1-3烷基-S-C 1-3烷基-、C 1-6烷氧基、C 1-6烷硫基、苯基、
Figure PCTCN2018074120-appb-000014
其他变量如本发明定义。
本发明的一些方案中，上述R 7选自H、OH、COOH、CONH 2、NH 2、NH 2C(＝NH)NH-、SH、CH 3S-、
Figure PCTCN2018074120-appb-000015
Figure PCTCN2018074120-appb-000016
其他变量如本发明定义。
本发明的一些方案中，上述R 7与R 4相互连接形成一个3～10元环，所述3～10元环是
Figure PCTCN2018074120-appb-000017
其他变量如本发明定义。
本发明的一些方案中，上述R 7与R 6相互连接形成一个3～10元环，所述3～10元环选自
Figure PCTCN2018074120-appb-000018
其他变量如本发明定义。
本发明的一些方案中，上述R 7同时与R 4和R 6相互连接形成一个3～10元环，所述3～10元环选自：
Figure PCTCN2018074120-appb-000019
其他变量如本发明定义。
本发明的一些方案中，上述R 8选自H和CH 3，其他变量如本发明定义。
本发明的一些方案中，上述R 9选自H和CH 3，其他变量如本发明定义。
本发明还提供了式(Ⅰ)、(Ⅱ)和(Ⅱ)所示化合物、药学上可接受的盐及其异构体：
Figure PCTCN2018074120-appb-000020
其中，
m选自：0、1、2、3、4、5或6，当m为0时，结构单元
Figure PCTCN2018074120-appb-000021
不存在；
n选自：0、1、2或3；
R 1选自任选被1、2或3个R取代的：C 1-3烷基-O-C(＝O)-C 1-3烷基-NH-；
R 2选自任选被1、2或3个R取代的：苯基-O-、5～10元杂芳基；
R 3选自任选被1、2或3个R取代的：6～10元芳基、6～10元芳基-C 1-3烷基-、5～10元杂芳基、5～10元杂芳基-C 1-3烷基-；
R 4选自：H、F、Cl、Br、I、OH、NH 2、或任选被1、2或3个R取代的C 1-6烷基；
R 5选自：H、或任选被1、2或3个R取代的C 1-6烷基；
R 6选自：H、或任选被1、2或3个R取代的C 1-6烷基；
R 7选自：H、F、Cl、Br、I、OH、COOH、CONH 2、NH 2、SH、NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷氧基、C 1-6烷硫基、芳基和5～10元杂芳基；
或R 7与R 6相互连接形成一个3～10元的环；
或R 7与R 4相互连接形成一个3～10元的环；
或R 7同时与R 4和R 6相互连接形成一个3～10元的环；
R 8选自：H、C 1-3烷基；
R 9选自：H、C 1-3烷基；
R选自：F、Cl、Br、I、NH 2、NO 2、OH、COOH，或选自C 1-3烷基；
所述5～10元杂芳基、C 1-6杂烷基之“杂”分别独立地选自：-NH-、N、-O-、-S-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自：F、Cl、Br、I、NH 2、NO 2、OH、COOH、CH 3或CH 3CH 2-。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：
Figure PCTCN2018074120-appb-000022
本发明的一些方案中，上述R 1选自
Figure PCTCN2018074120-appb-000023
本发明的一些方案中，上述R 2选自
Figure PCTCN2018074120-appb-000024
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：苯基、噻吩基、吡啶基、喹啉基。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：
Figure PCTCN2018074120-appb-000025
Figure PCTCN2018074120-appb-000026
本发明的一些方案中，上述R 3选自：
Figure PCTCN2018074120-appb-000027
本发明的一些方案中，上述R 7选自：H、OH、COOH、CONH 2、NH 2、SH、NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷氧基、C 1-6烷硫基、苯基、
Figure PCTCN2018074120-appb-000028
Figure PCTCN2018074120-appb-000029
本发明的一些方案中，上述R 7选自：H、OH、COOH、CONH 2、NH 2、NH 2C(＝NH)NH-、SH、CH 3S-、
Figure PCTCN2018074120-appb-000030
本发明的一些方案中，上述R 7与R 4相互连接形成一个3～10元的环，所述3～10元环选自：
Figure PCTCN2018074120-appb-000031
本发明的一些方案中，上述R 7与R 6相互连接形成一个3～10元的环，所述3～10元的环选自：
Figure PCTCN2018074120-appb-000032
本发明的一些方案中，上述R 7同时与R 4和R 6相互连接形成一个3～10元的环，所述3～10元的环选自：
Figure PCTCN2018074120-appb-000033
本发明还有一些方案是由上述变量任意组合而来。
本发明还提供了下式化合物、药学上可接受的盐及其异构体：
Figure PCTCN2018074120-appb-000034
Figure PCTCN2018074120-appb-000035
Figure PCTCN2018074120-appb-000036
Figure PCTCN2018074120-appb-000037
本发明还提供了一种药物组合物，包括治疗有效量的上述化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或者上述组合物在制备治疗眼科疾病药物上的应用。
本发明的一些方案中，上述眼科疾病药物是用于治疗白内障的药物。
本发明的一些方案中，上述治疗白内障的药物是白内障药滴眼液。
技术领域
作为羊毛甾醇的新型前药，本发明的化合物具有良好的渗透性，并在体内有效的转化为羊毛甾醇，大大提高了羊毛甾醇的药物利用率。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有 机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018074120-appb-000038
和楔形虚线键
Figure PCTCN2018074120-appb-000039
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018074120-appb-000040
和直形虚线键
Figure PCTCN2018074120-appb-000041
表示立体中心的相对构型，用波浪线
Figure PCTCN2018074120-appb-000042
表示楔形实线键
Figure PCTCN2018074120-appb-000043
或楔形虚线键
Figure PCTCN2018074120-appb-000044
或用波浪线
Figure PCTCN2018074120-appb-000045
表示直形实线键
Figure PCTCN2018074120-appb-000046
和直形虚线键
Figure PCTCN2018074120-appb-000047
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。 价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018074120-appb-000048
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018074120-appb-000049
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018074120-appb-000050
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018074120-appb-000051
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另 一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基 (Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，“环烯烷基”或“环烯基烷基”指环烯基取代的烷基。
除非另有规定，“环炔烷基”或“环炔基烷基”指环炔基取代的烷基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯 基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸； DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；羊毛甾醇前药026代表本发明的化合物8即实施例8。
化合物经手工或者
Figure PCTCN2018074120-appb-000052
软件命名，市售化合物采用供应商目录名称。
附图说明
图1：裂隙灯观察羊毛甾醇及其前药026滴眼液对亚硒酸钠诱导的新生新西兰兔白内障模型的作用。NC：正常对照组(Normal control group)；MC：模型对照组(Model control group)；PC：阳性对照组(Positive control group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。
图2：亚硒酸钠诱导的新生新西兰兔白内障模型在给药42天后各组体外晶状体透明度检测结果比较。NC：正常对照组(Normal control group)；MC：模型对照组(Model control group)；PC：阳性对照组(Positive control group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。网格为2.12×2.12mm
图3：亚硒酸钠诱导的新生新西兰兔白内障模型在给药42天后各组的晶状体谷胱甘肽过氧化物酶(Glutathione peroxidase,GSH-PX)活性检测结果比较。NC：正常对照组(Normal control group)；MC：模型对照组(Model control group)；PC：阳性对照组(Positive control group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。V.S NC：﹡﹡表示p﹤0.01,﹡表示p﹤0.05；V.S MC：##表示p﹤0.01,#表示p﹤0.05；V.S PC：++表示p﹤0.01,+表示p﹤0.05。
图4：裂隙灯观察羊毛甾醇及其前药026滴眼液对紫外线诱导的新西兰兔白内障模型的作用。NC：正常对照组(Normal control group)；MC：模型对照组(Model control group)；PC：阳性对照组(Positive control group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。
图5：紫外线诱导的新西兰兔白内障模型在给药42天后各组体外晶状体透明度检测结果比较。NC：正常对照组(Normal control group)；MC：模型对照组(Model control group)；PC：阳性对照组(Positivecontrol group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。网格为2.12×2.12mm。
图6：紫外线诱导的新西兰兔白内障模型在给药42天后各组的晶状体谷胱甘肽过氧化物酶(Glutathione peroxidase,GSH-PX)活性检测结果比较。NC：正常对照组(Normal control group)；MC：模型对 照组(Model control group)；PC：阳性对照组(Positive control group)；LT：羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group)；026：羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group)。V.S NC：﹡﹡表示p﹤0.01,﹡表示p﹤0.05；V.S MC：##表示p﹤0.01,#表示p﹤0.05；V.S PC：++表示p﹤0.01,+表示p﹤0.05。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段BB-1
Figure PCTCN2018074120-appb-000053
合成路线：
Figure PCTCN2018074120-appb-000054
步骤1：化合物BB-1的合成。
将混合物BB-1-1经过超临界流体色谱(分离条件Column:Chiralpak AD-3 150×4.6mm I.D.,3μm；流动相:A:CO 2B:乙醇(0.05％二乙醇胺)；梯度:5分钟时间B从5％到40％，B 40％走2.5分钟，,然后B5％走2.5分钟；流速:2.5mL/min；柱温:35℃；波长:220nm)分离得到化合物BB-1。 1H NMR  1H NMR(CHLOROFORM-d,400MHz):δ＝5.06-5.15(m,1H),5.10(br t,J＝7.2Hz,1H),3.20-3.22(m,1H),3.24(dd,J＝11.5,4.5Hz,1H),1.64-2.09(m,15H),0.77-1.57(m,29H),0.65-0.72ppm(m,3H)。
实施例1
Figure PCTCN2018074120-appb-000055
合成路线：
Figure PCTCN2018074120-appb-000056
步骤1：化合物1-1的合成
将化合物BB-1(1.00g，2.34mmol)溶解在二氯甲烷(10mL)中，冷却至0℃，随后加入二氯磷酸苯酯(1.48g，7.02mmol)和4-二甲氨基吡啶(1.72g，14.04mmol)在氮气保护下升温至室温搅拌过夜。反应完成后，冰水淬灭反应，分出有机相减压旋干，所得残留物经层析柱分离(洗脱剂：乙酸乙酯/石油醚＝0～5％)得到目标化合物1-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.46-7.31(m,2H),7.29-7.27(m,1H),7.27-7.19(m,2H),5.10(br t,J＝7.0Hz,1H),4.52-4.20(m,1H),2.15-1.96(m,6H),1.92-1.66(m,9H),1.56-1.46(m,2H),1.43(s,2H),1.38-1.11(m,7H),1.08-0.99(m,7H),0.93-0.85(m,11H),0.68(s,3H)。
步骤2：化合物1的合成
将化合物1-1(500mg，0.8316mmol)溶于二氯甲烷(10mL)中，冷却至0摄氏度，随后加入L-丙氨酸甲酯盐酸盐(348.23mg，2.49mmol)和4-二甲氨基吡啶(609.59mg，4.99mmol)并升温至室温搅拌过夜。反应完成后，减压除去溶剂，所得残留物经层析柱分离(洗脱剂：乙酸乙酯/石油醚＝0～5％)得到目标化合物1。 1H NMR(400MHz,DMSO-d 6)δ:2.89-2.88(m,2H),2.64-2.63(m,2H),2.06-2.03(m,1H),1.73-1.62(m,4H),1.07-1.02(m,2H),0.66-0.63(m,2H)。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.33-7.27(m,2H),7.24-7.18(m,2H),7.17-7.08(m,1H),5.09(br s,1H),4.19-3.93(m,2H),3.77-3.64(m,3H),3.52-3.36(m,1H),2.02(br d,J＝9.5Hz,6H),1.92-1.75(m,3H),1.68(s,4H),1.60(s,3H),1.38(br d,J＝7.0Hz,4H),1.42-1.35(m,1H),1.33-1.08(m,7H),0.99(t,J＝5.8Hz,4H),1.03(br s,1H),0.93-0.79(m,14H),0.67(s,3H)。
实施例2
Figure PCTCN2018074120-appb-000057
合成路线：
Figure PCTCN2018074120-appb-000058
步骤1：化合物2的合成
将化合物BB-1(500mg，1.17mmol)溶解在二氯甲烷(10.00mL)中，室温搅拌下加入吡啶-3-羧酸(288.08mg，2.34mmol)、二环己基碳二亚胺(555.23mg，2.69mmol)和4-二甲氨基吡啶(328.76mg，2.3mmol)，室温搅拌过夜。反应完毕后，减压除去溶剂，所得残留物经层析柱分离(洗脱剂：乙酸乙酯/石油醚＝0～5％)得到目标化合物2。 1H NMR(400MHz,CHLOROFORM-d)δ＝9.24(d,J＝1.3Hz,1H),8.77(dd,J＝1.8,4.8Hz,1H),8.30(td,J＝1.9,8.0Hz,1H),7.48-7.32(m,1H),5.10(br t,J＝7.0Hz,1H),4.85-4.73(m,1H),2.10-1.67(m,17H),1.56-1.16(m,10H),1.05(d,J＝5.0Hz,7H),0.98-0.86(m,10H),0.70(s,3H)。
实施例3
Figure PCTCN2018074120-appb-000059
合成路线：
Figure PCTCN2018074120-appb-000060
步骤1：化合物3-1的合成
参考实施例2中步骤一，得到化合物3-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝5.10(br t,J＝7.0Hz,1H),5.00(br s,1H),4.67-4.49(m,1H),3.90(br d,J＝5.3Hz,2H),2.04-1.61(m,15H),1.58-1.29(m,18H),1.20-0.80(m,20H),0.74-0.63(m,3H)。
步骤2：化合物3的合成
将化合物3-1(200.00mg,0.3425mmol)溶于二氯甲烷(5.00mL)中，冷却至0℃，然后缓慢加入氯化氢的乙酸乙酯溶液(0.5M,10.00mL)，反应缓慢升至室温搅拌过夜。反应结束后，减压旋干溶剂盐酸制备分离得到目标化合物3。 1H NMR(METHANOL-d 4,400MHz):δ＝5.07-5.15(m,1H),4.64-4.72(m,1H),3.81-3.93(m,2H),1.17-2.17(m,30H),0.88-1.13(m,14H),0.71-0.81ppm(m,3H).
实施例4
Figure PCTCN2018074120-appb-000061
合成路线：
Figure PCTCN2018074120-appb-000062
步骤1：化合物4的合成.
将化合物BB-1(200.00mg,0.4687mmol)溶于二氯甲烷(10.00mL)中，室温下加入4-二甲氨基吡啶(68.71mg，0.5624mmol)，对硝基苯甲酸(93.99mg，0.5624mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(107.82mg,0.5624mmol)，混合液室温搅拌过夜。反应结束后减压除去溶剂，所得残留物经层析柱分离(洗脱剂：乙酸乙酯/石油醚＝0～5％)得到目标化合物4。 1H NMR(CHLOROFORM-d,400MHz):δ＝8.20-8.25(m,2H),8.11-8.16(m,2H),5.04(br t,J＝7.0Hz,1H),4.69-4.76(m,1H),1.08-2.05(m,29H),0.99(d,J＝4.0Hz,6H),0.89(s,3H),0.85(d,J＝6.5Hz,3H),0.83(s,3H),0.64ppm(s,3H)。
实施例5
Figure PCTCN2018074120-appb-000063
合成路线：
Figure PCTCN2018074120-appb-000064
步骤1：化合物5的合成.
参考实施例2中步骤一，得到化合物5。 1H NMR(CHLOROFORM-d,400MHz):δ＝9.41(d,J＝1.5Hz,1H),8.76(d,J＝2.0Hz,1H),8.10(d,J＝8.5Hz,1H),7.88(d,J＝8.0Hz,1H),7.77(td,J＝7.7,1.3Hz,1H),7.52-7.60(m,1H),5.04(br t,J＝7.0Hz,1H),4.79(dd,J＝11.3,4.8Hz,1H),1.94-2.07(m,5H),1.71-1.91(m,6H),1.60-1.68(m,6H),1.49-1.57(m,5H),1.12-1.39(m,7H),1.02(d,J＝8.5Hz,6H),0.93(s,3H),0.80-0.87(m,6H),0.64ppm(s,3H)。
实施例6
Figure PCTCN2018074120-appb-000065
合成路线：
Figure PCTCN2018074120-appb-000066
步骤1：化合物6-1的合成.
参考实施例2中步骤一，得到化合物6-1。 1H NMR(CHLOROFORM-d,400MHz):δ＝7.19-7.25(m,2H),7.14-7.18(m,1H),7.08-7.13(m,2H),5.03(br t,J＝7.0Hz,1H),4.83(br d,J＝8.5Hz,1H),4.39-4.63(m,2H),2.90-3.13(m,2H),1.73-2.01(m,8H),1.39-1.69(m,16H),1.32(s,9H),1.21-1.27(m,2H),0.95-1.14(m,3H),0.92(s,3H),0.84(d,J＝6.0Hz,3H),0.80(s,3H),0.75(d,J＝7.0Hz,6H),0.61ppm(s,3H).
步骤2：化合物6的合成.
参考实施例3中步骤二，得到化合物6。 1H NMR(METHANOL-d 4,400MHz):δ＝7.25-7.32(m,2H),7.19-7.25(m,3H),5.00(br t,J＝6.8Hz,1H),4.50(br dd,J＝10.8,5.3Hz,1H),4.25(br t,J＝7.3Hz,1H),3.19(br s,1H),3.03(dd,J＝14.3,7.8Hz,1H),1.98(br s,5H),1.40-1.74(m,15H),1.12-1.29(m,7H),0.91-0.96(m,3H),0.56-0.86ppm(m,17H).
实施例7
Figure PCTCN2018074120-appb-000067
合成路线：
Figure PCTCN2018074120-appb-000068
步骤1：化合物7的合成.
参考实施例2中步骤一，得到化合物7。 1H NMR(CHLOROFORM-d,400MHz):δ＝9.30(s,1H),9.22(s,2H),5.03(br t,J＝7.0Hz,1H),4.75(dd,J＝11.0,4.5Hz,1H),1.65-2.04(m,13H),1.62(s,3H),1.54(s,3H),1.05-1.50(m,10H),0.98(d,J＝7.5Hz,6H),0.89(s,3H),0.85(br d,J＝6.5Hz,3H),0.80-0.83(m,3H),0.63ppm(s,3H).
实施例8
Figure PCTCN2018074120-appb-000069
合成路线：
Figure PCTCN2018074120-appb-000070
步骤1：化合物8的合成.
参考实施例2中步骤一，得到化合物8。 1H NMR(CHLOROFORM-d,400MHz):δ＝10.97(s,1H),7.85(dd,J＝8.0,1.5Hz,1H),7.41-7.53(m,1H),6.99(d,J＝8.5Hz,1H),6.89(t,J＝7.5Hz,1H),5.12(br t,J＝7.0Hz,1H),4.77-4.85(m,1H),1.68-2.13(m,16H),1.13-1.64(m,13H),1.07(d,J＝3.0Hz,6H),0.98(s,3H),0.94(d,J＝6.5Hz,3H),0.91(s,3H),0.72ppm(s,3H).
实施例9
Figure PCTCN2018074120-appb-000071
合成路线：
Figure PCTCN2018074120-appb-000072
步骤1：化合物9的合成.
参考实施例2中步骤一，得到化合物9。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.36(d,J＝1.8Hz,1H), 6.93(d,J＝1.8Hz,1H),5.10(br t,J＝7.2Hz,1H),4.78(dd,J＝4.8,11.0Hz,1H),2.10-1.66(m,17H),1.58-1.16(m,12H),1.03(d,J＝14.6Hz,6H),0.97-0.83(m,9H),0.70(s,3H).
实施例10
Figure PCTCN2018074120-appb-000073
合成路线：
Figure PCTCN2018074120-appb-000074
步骤1：化合物10的合成.
参考实施例2中步骤一，得到化合物10。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.05(s,1H),5.03(br t,J＝7.0Hz,1H),4.66-4.49(m,1H),2.06-1.89(m,5H),1.74-1.62(m,3H),1.55-1.16(m,17H),0.95(s,3H),0.87-0.75(m,16H),0.62(s,3H).
实施例11
Figure PCTCN2018074120-appb-000075
合成路线：
Figure PCTCN2018074120-appb-000076
步骤1：化合物11-1的合成.
参考实施例2中步骤一，得到化合物11-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝5.13-4.92(m,2H),4.48(dd,J＝5.0,11.0Hz,1H),4.24(br t,J＝7.0Hz,1H),2.13-1.74(m,8H),1.69-1.47(m,13H),1.38(s,12H),1.34(br d,J＝7.0Hz,5H),1.20-0.72(m,18H),0.62(s,3H).
步骤2：化合物11的合成.
参考实施例3中步骤二，得到化合物11。 1H NMR(400MHz,METHANOL-d 4)δ＝5.12(br t,J＝7.3Hz,1H),4.78-4.54(m,1H),4.12(q,J＝7.0Hz,1H),2.15-1.73(m,13H),1.77-1.58(m,11H),1.49-1.20(m,7H),1.17-0.85(m,16H),0.80-0.64(m,3H)。
实施例12
Figure PCTCN2018074120-appb-000077
合成路线：
Figure PCTCN2018074120-appb-000078
步骤1：化合物12的合成.
反应瓶中加入邻羟基苯甲酸(632.35mg,3.51mmol)溶解在二氯甲烷(10.00mL)中，草酰氯(594.03mg,4.68mmol)滴加入反应瓶中，在25℃下搅拌2.0小时，反应液旋干得到粗品。该粗品重新溶解在二氯甲烷(20.00mL)中，化合物BB-1(500.00mg,1.17mmol)和三乙胺(710.35mg,7.02mmol)加入反应 液中，在25℃下搅拌10.0小时。反应加入水(100mL),二氯甲烷萃取(100mL*2)，合并有机相旋干的到粗品，经柱层析纯化得到化合物12。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.96(d,J＝8.0Hz,1H),7.63-7.46(m,1H),7.13(t,J＝7.5Hz,1H),6.98(t,J＝8.8Hz,1H),5.21-4.99(m,1H),3.84-3.57(m,1H),2.04-1.61(m,17H),1.60(s,3H),1.49-1.05(m,11H),1.01-0.82(m,13H),0.74(s,3H),0.70-0.64(m,3H)
实施例14
Figure PCTCN2018074120-appb-000079
合成路线：
Figure PCTCN2018074120-appb-000080
步骤1：化合物14的合成.
参考实施例2中步骤一，得到化合物14。 1H NMR(CHLOROFORM-d,400MHz):δ＝8.06(d,J＝8.0Hz,2H),7.68(d,J＝8.5Hz,2H),5.04(br t,J＝7.0Hz,1H),4.68-4.74(m,1H),1.63-2.04(m,13H),1.62(s,3H),1.54(s,3H),1.25-1.50(m,7H),1.01-1.19(m,3H),0.99(s,3H),0.97(s,3H),0.88(s,3H),0.85(d,J＝6.0Hz,3H),0.82(s,3H),0.63ppm(s,3H).
实施例15
Figure PCTCN2018074120-appb-000081
合成路线：
Figure PCTCN2018074120-appb-000082
步骤1：化合物15的合成.
参考实施例2中步骤一，得到化合物15。 1H NMR(CHLOROFORM-d,400MHz):δ＝8.08(d,J＝8.0Hz,2H),7.64(d,J＝8.5Hz,2H),5.04(br t,J＝7.0Hz,1H),4.68-4.74(m,1H),1.75-2.04(m,8H),1.60-1.73(m,7H),1.37-1.55(m,7H),1.02-1.37(m,7H),0.98(d,J＝5.0Hz,6H),0.81-0.90(m,9H),0.64ppm(s,3H).
19F NMR(CHLOROFORM-d,377MHz):δ＝-63.06ppm(br s,3F).
实施例16
Figure PCTCN2018074120-appb-000083
合成路线：
Figure PCTCN2018074120-appb-000084
步骤1：化合物16的合成.
参考实施例2中步骤一，得到化合物16。 1H NMR(CHLOROFORM-d,400MHz):δ＝7.72-7.81(m,2H),7.11-7.19(m,1H),5.03(br t,J＝7.0Hz,1H),4.63-4.74(m,1H),1.60-2.04(m,16H),1.40-1.56(m,7H),1.04-1.35(m,6H),0.97(d,J＝9.0Hz,6H),0.81-0.89(m,9H),0.63ppm(s,3H).
19F NMR(CHLOROFORM-d,377MHz):δ＝-150.84--103.14ppm(m,1F).
生物活性测试
实验例一：体内眼部药物渗透以及药物转化为羊毛甾醇的研究
本研究采用新西兰大白兔(体重大于2公斤，周龄大于12周)为实验动物，每一个化合物研究使用2只新西兰大白兔，每只兔子左右两眼均滴入50μL的滴眼液，3只眼睛用于采集房水样品，另外1只眼睛作为备用。滴眼液配方为1.2％羟丙基甲基纤维素(E5规格)，20.5％波洛沙姆(P407规格)，1.6％波洛沙姆(P188规格)，化合物配制浓度为5mM，滴眼液为均一混悬液。滴眼液滴入兔子眼睛后，分别于给药后0.5、2、4和6小时采集前房水，每次采样品体积不超过50μL，每次动物采集样品前将给予轻度麻醉，每个时间点为3个样品。采集的房水样品在采集后即刻放入干冰保存或者于-80±10℃冰箱进行保存。样品采集结束后，动物进行安乐死。样品使用三重四极杆质谱仪(API4000)分析化合物浓度。表1及表2表示了体内DMPK分析检测方法；表3至表9展示了化合物羊毛甾醇(母药)以及前药化合物滴眼(250nM每只眼睛)后房水中的药物浓度。
结果表明羊毛甾醇本身及其本发明前药化合物均能够从角膜或者通过其他途径渗透入房水；并且前药化合物能够在渗透过程中转化为母药羊毛甾醇，并在房水中表现出更高的羊毛甾醇浓度和暴露量。
表1体内DMPK分析检测方法
Figure PCTCN2018074120-appb-000085
Figure PCTCN2018074120-appb-000086
表2体内DMPK羊毛甾醇以及化合物8液相方法梯度
Figure PCTCN2018074120-appb-000087
表3新西兰大白兔滴每只眼睛眼液滴入250nmol羊毛甾醇后，房水中的样品平均浓度(nM)
滴眼液化合物名称 羊毛甾醇(母药)
测试化合物名称 羊毛甾醇(母药)
时间(小时) 平均浓度(nM)
0.5 106*
2 496
4 300
6 225
AUC(nM.h) 1779
*BQL:低于检测限,AUC：暴露量。
表4新西兰大白兔滴每只眼睛眼液滴入250nmol化合物1后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000088
*BQL:低于检测限.
表5新西兰大白兔滴每只眼睛眼液滴入250nmol化合物4后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000089
*BQL:低于检测限.
表6新西兰大白兔滴每只眼睛眼液滴入250nmol化合物8后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000090
*BQL:低于检测限，AUC：暴露量。
表7新西兰大白兔滴每只眼睛眼液滴入250nmol化合物9后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000091
*BQL:低于检测限.
表8新西兰大白兔滴每只眼睛眼液滴入250nmol化合物10后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000092
Figure PCTCN2018074120-appb-000093
*BQL:低于检测限.
表9新西兰大白兔滴每只眼睛眼液滴入250nmol化合物12后，房水中的样品平均浓度(nM)
Figure PCTCN2018074120-appb-000094
*BQL:低于检测限.AUC：暴露量。
实验例二：羊毛甾醇滴眼液及其前药对亚硒酸钠诱导的新生新西兰兔白内障模型的药效学研究
1、实验动物
新生新西兰兔P7天龄，普通级，每窝5只幼兔配一只妈妈兔哺乳。
2、分组及处理
实验幼兔随机分为5组，每组5只幼兔。
1)正常对照组(Normal control group,NC)：P10天时幼兔颈部皮下注射生理盐水0.25ml，P15天后不给药。
2)模型对照组(Model control group,MC)：P10天时幼兔颈部皮下注射亚硒酸钠溶液(于生理盐水中)20μmol/kg体重，P15天之后连续42天用不含药物的空白滴眼液滴右眼，每天3次。
3)阳性对照组(Positive control group,PC)：P10天时幼兔颈部皮下注射亚硒酸钠溶液(于生理盐水中)20μmol/kg体重，P15天之后连续42天用卡林优滴眼液(日本参天制药)滴右眼，每天3次。
4)羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group,LT)：P10天时幼兔颈部皮下注射亚硒酸钠溶液(于生理盐水中)20μmol/kg体重，P15天之后连续42天用羊毛甾醇滴眼液滴右眼，每天3次。
5)羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group,026)：P10天时幼兔颈部皮下注射亚硒酸钠溶液(于生理盐水中)20μmol/kg体重，P15天之后连续42天用羊毛甾醇前药 026滴眼液滴右眼，每天3次。
3、实验检测
1)裂隙灯照像：亚硒酸钠诱导的新生新西兰兔每组分别于给药前、给药后7天、14天、21天和42天进行裂隙灯观察；
2)体外晶状体透明度检测：最后一天，解剖出动物眼球，完整分离出包含囊膜的晶状体，将晶状体至于方格纸上(2.12×2.12mm)，拍照显示透过晶状体所拍摄的方格的清晰度。
3)谷胱甘肽过氧化物酶(Glutathione peroxidase,GSH-PX)活性检测：参照GSH-PX活性检测试剂盒(南京建成生物工程研究所)说明书提供的方法检测分离出的各组兔晶状体的GSH-PX活性。实验数据用SPSS统计软件进行One-Way ANOVA分析，用LSD法做各组间比较，统学计差异水平为p﹤0.05。
4、实验结果
1)裂隙灯观察：图1显示亚硒酸钠可诱导新生新西兰兔晶状体发生白内障。裂隙灯观察羊毛甾醇前药026滴眼液给药42天(图1-I)与给药前(图1-J)相比较白内障症状明显减轻。而卡林优滴眼液给药前后(图1-E、1-F)和羊毛甾醇滴眼液给药前后(图1-G、1-H)白内障症状变化不明显。
2)体外晶状体透明度检测：图2比较了亚硒酸钠诱导的新生新西兰兔白内障模型在给药42天后各组的晶状体透明度。每张照片左侧的是左眼晶状体(左眼未给药，作为自身对照)，右侧的是右眼晶状体(右眼按不同分组相应给药)。羊毛甾醇前药026滴眼液给药42天后右眼晶状体透明度明显高于自身左眼的透明度，也明显高于MC组晶状体的透明度，但尚低于NC组的透明度。LT组右眼给药后晶状体透明度未见明显改变。
3)GSH-PX活性检测：给药42天后各组的晶状体GSH-PX活性检测结果显示(见图3)，亚硒酸钠皮下注射后，兔眼晶状体GSH-PX活性显著降低，与NC组相比具有统计学差异(p﹤0.01)。羊毛甾醇前药026滴眼液和阳性对照药卡林优滴眼液可提高晶状体GSH-PX活性，与MC组相比具有统计学差异(p﹤0.01)，且026的提高效果比卡林优更明显(p﹤0.01)。羊毛甾醇滴眼液对晶状体GSH-PX活性的影响明显不如026和卡林优，与MC组相比没有统计学差异(p＞0.05)。
5、结论
上述结果提示，羊毛甾醇前药026滴眼液可减轻亚硒酸钠诱导的新生新西兰兔白内障症状、提高晶状体透明度以及晶状体GSH-PX活性。
实验三、羊毛甾醇滴眼液及其前药对紫外线诱导的新西兰兔白内障模型的药效学研究
1、实验动物
成年新西兰兔2.0-2.5kg，普通级，雌雄不拘，共25只。
2、分组及处理
实验动物随机分为5组，每组5只。
1)正常对照组(Normal control group,NC)：正常饲养，不给药。
2)模型对照组(Model control group,MC)：313nm紫外线照射24小时造模，之后连续42天用不含药物的空白滴眼液滴右眼，每天3次。
3)阳性对照组(Positive control group,PC)：313nm紫外线照射24小时造模，之后连续42天用卡林优滴眼液(日本参天制药)滴右眼，每天3次。
4)羊毛甾醇滴眼液处理组(Lanosterol eye drops treatment group,LT)：313nm紫外线照射24小时造模，之后连续42天用羊毛甾醇滴眼液滴右眼，每天3次。
5)羊毛甾醇前药026滴眼液处理组(Lanosterolprodrug 026 eye drops treatment group,026)：313nm紫外线照射24小时造模，之后连续42天用羊毛甾醇前药026滴眼液滴右眼，每天3次。
3、实验检测
1)裂隙灯照像：每组分别于造模后给药前、给药后7天、14天、21天和42天进行裂隙灯观察；
2)体外晶状体透明度检测：最后一天，解剖出动物眼球，完整分离出包含囊膜的晶状体，将晶状体至于方格纸上(2.12×2.12mm)，拍照显示透过晶状体所拍摄的方格的清晰度。
3)谷胱甘肽过氧化物酶(Glutathione peroxidase,GSH-PX)活性检测：参照GSH-PX活性检测试剂盒(南京建成生物工程研究所)说明书提供的方法检测分离出的各组兔晶状体的GSH-PX活性。实验数据用SPSS统计软件进行One-Way ANOVA分析，用LSD法做各组间比较，统学计差异水平为p﹤0.05。
4、实验结果
1)裂隙灯观察：图4显示紫外线可诱导新西兰兔晶状体发生白内障。裂隙灯观察羊毛甾醇前药026滴眼液给药42天(图4-I)与给药前(图4-J)相比较白内障症状明显减轻。而卡林优滴眼液给药前后(图4-E、4-F)和羊毛甾醇滴眼液给药前后(图4-G、4-H)白内障症状变化不明显。
2)体外晶状体透明度检测：图5比较了紫外线诱导的新西兰兔白内障模型在给药42天后各组的晶状体透明度。每张照片左侧的是左眼晶状体(左眼未给药，作为自身对照)，右侧的是右眼晶状体(右眼按不同分组相应给药)。羊毛甾醇前药026滴眼液给药42天后右眼晶状体透明度明显高于自身左眼的透明度，也明显高于MC组晶状体的透明度，但尚低于NC组的透明度。LT组右眼给药后晶状体透明度未见明显改变。
3)GSH-PX活性检测：给药42天后各组的晶状体GSH-PX活性检测结果显示(见图6)，紫外线照射后，兔眼晶状体GSH-PX活性显著降低，与NC组相比具有统计学差异(p﹤0.01或p﹤0.05)。羊毛甾醇前药026滴眼液和阳性对照药卡林优滴眼液可提高晶状体GSH-PX活性，与MC组相比具有统计学差异(p﹤0.01)，且026的提高效果比卡林优更明显(p﹤0.05)。羊毛甾醇滴眼液对晶状体GSH-PX活 性的影响明显不如026和卡林优，与MC组相比没有统计学差异(p＞0.05)。
5、结论
上述结果提示，羊毛甾醇前药026滴眼液可减轻紫外线诱导的新西兰兔白内障症状、提高晶状体透明度以及晶状体GSH-PX活性。

Claims (23)

  1. 式(Ⅰ)、(Ⅱ)和(Ⅲ)所示化合物、药学上可接受的盐及其异构体：
    Figure PCTCN2018074120-appb-100001
    其中，
    m是：0或1，当m为0时，结构单元
    Figure PCTCN2018074120-appb-100002
    不存在；
    n是：0或1；
    R 1选自任选被1、2或3个R取代的：C 1-3烷基-O-C(＝O)-C 1-3烷基-NH-；
    R 2选自任选被1、2或3个R取代的：苯基-O-和5～10元杂芳基；
    R 3选自任选被1、2或3个R取代的：6～10元芳基、6～10元芳基-C 1-3烷基-、5～10元杂芳基和5～10元杂芳基-C 1-3烷基-，但是R 3不包含苯基和
    Figure PCTCN2018074120-appb-100003
    R 4选自H、F、Cl、Br、I、OH、NH 2，或R 4选自任选被1、2或3个R取代的C 1-6烷基；
    R 5选自H，或任选被1、2或3个R取代的C 1-6烷基；
    R 6选自H，或任选被1、2或3个R取代的C 1-6烷基；
    R 7选自H、F、Cl、Br、I、OH、COOH、CONH 2、NH 2、SH或NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷基、C 1-6杂烷基、苯基和5～10元杂芳基；
    或R 7与R 6相互连接形成一个任选被1、2或3个R取代的3～10元环；
    或R 7与R 4相互连接形成一个任选被1、2或3个R取代的3～10元环；
    或R 7同时与R 4和R 6相互连接形成一个任选被1、2或3个R取代的3～10元环；
    R 8选自H和C 1-3烷基；
    R 9选自H和C 1-3烷基；
    R分别独立地选自F、Cl、Br、I、NH 2、NO 2、OH、CN、COOH、NH 2C(＝NH)NH-，或选自任选被1、2或3个R'取代的C 1-3烷基和-C(＝O)O-C 1-3烷基；
    R'选自F、Cl、Br、I、NH 2、NO 2、OH、CN和COOH；
    所述5～10元杂芳基、C 1-6杂烷基之“杂”分别独立地选自：-NH-、N、-O-和-S-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2和3。
  2. 根据权利要求1所述的化合物、药学上可接受的盐及其异构体，其中，R分别独立地选自：F、Cl、Br、I、NH 2、NO 2、OH、CN、COOH、CH 3、NH 2C(＝NH)NH-、CH 3CH 2-、CF 3和CH 3--C(＝O)-O-。
  3. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 1选自任选被1、2或3个R取代的
    Figure PCTCN2018074120-appb-100004
  4. 根据权利要求3所述的化合物、药学上可接受的盐及其异构体，其中，R 1选自
    Figure PCTCN2018074120-appb-100005
  5. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 2选自
    Figure PCTCN2018074120-appb-100006
  6. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 3选自任选被1、2或3个R取代的：苯基、噻吩基、吡啶基、喹啉基、嘧啶基、异噁唑基和1,2,4-噁二唑基，但是R 3不包含苯基和
    Figure PCTCN2018074120-appb-100007
  7. 根据权利要求6所述的化合物、药学上可接受的盐及其异构体，其中，R 3选自任选被1、2或3个R取代的：
    Figure PCTCN2018074120-appb-100008
    但是R 3不包含苯基。
  8. 根据权利要求7所述的化合物、药学上可接受的盐及其异构体，其中，R 3选自
    Figure PCTCN2018074120-appb-100009
    Figure PCTCN2018074120-appb-100010
    Figure PCTCN2018074120-appb-100011
  9. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 4选自H、F、Cl、Br、I、OH、NH 2、CH 3和-CH 2CH 3。
  10. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 5选自H和CH 3。
  11. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 6选自H和CH 3。
  12. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 7选自H、OH、COOH、CONH 2、NH 2、SH、NH 2C(＝NH)NH-，或者R 7选自任选被1、2或3个R取代的C 1-6烷基、C 1-3烷基-S-C 1-3烷基-、C 1-6烷氧基、C 1-6烷硫基、苯基、
    Figure PCTCN2018074120-appb-100012
  13. 根据权利要求12所述的化合物、药学上可接受的盐及其异构体，其中，R 7选自H、OH、COOH、CONH 2、NH 2、NH 2C(＝NH)NH-、SH、CH 3S-、
    Figure PCTCN2018074120-appb-100013
    Figure PCTCN2018074120-appb-100014
  14. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 7与R 4相互连接形成一个3～10元环，所述3～10元环是
    Figure PCTCN2018074120-appb-100015
  15. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 7与R 6相互连接形成一个3～10元环，所述3～10元环选自
    Figure PCTCN2018074120-appb-100016
    Figure PCTCN2018074120-appb-100017
  16. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 7同时与R 4和R 6相互连接形成一个3～10元环，所述3～10元环选自：
    Figure PCTCN2018074120-appb-100018
  17. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 8选自H和CH 3。
  18. 根据权利要求1或2所述的化合物、药学上可接受的盐及其异构体，其中，R 9选自H和CH 3。
  19. 下式化合物、药学上可接受的盐及其异构体：
    Figure PCTCN2018074120-appb-100019
    Figure PCTCN2018074120-appb-100020
    Figure PCTCN2018074120-appb-100021
  20. 一种药物组合物，包括治疗有效量的根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  21. 根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐或者权利要求20的组合物在制备治疗眼科疾病药物上的应用。
  22. 根据权利要求21所述的应用，其特征在于，所述眼科疾病药物是用于治疗白内障的药物。
  23. 根据权利要求22所述的应用，其特征在于，所述治疗白内障的药物是白内障药滴眼液。
PCT/CN2018/074120 2017-01-25 2018-01-25 羊毛甾醇前药化合物及其制备方法和应用 Ceased WO2018137683A1 (zh)

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WO2025061048A1 (zh) * 2023-09-20 2025-03-27 润尔眼科药物（广州）有限公司 甾体化合物及其应用
CN119708108A (zh) * 2024-12-24 2025-03-28 广东莱恩医药研究院有限公司 一种羊毛甾醇衍生物及其制备方法和应用

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