WO2023143452A1 - Application d'un composé stéroïdien dans la prévention et/ou le traitement de la cataracte - Google Patents

Application d'un composé stéroïdien dans la prévention et/ou le traitement de la cataracte Download PDF

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WO2023143452A1
WO2023143452A1 PCT/CN2023/073362 CN2023073362W WO2023143452A1 WO 2023143452 A1 WO2023143452 A1 WO 2023143452A1 CN 2023073362 W CN2023073362 W CN 2023073362W WO 2023143452 A1 WO2023143452 A1 WO 2023143452A1
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substituted
cataract
alkyl
unsubstituted
aryl
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PCT/CN2023/073362
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English (en)
Chinese (zh)
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王延东
于垂亮
苏映雪
曹琛
梁光江
梁翅勇
吴美容
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广州润尔眼科生物科技有限公司
润尔眼科药物（广州）有限公司
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Priority to CN202380014248.0A priority Critical patent/CN118176004A/zh
Publication of WO2023143452A1 publication Critical patent/WO2023143452A1/fr

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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

Definitions

  • the invention belongs to the field of chemical medicine, and in particular relates to the application of steroid compounds in medicines for preventing and/or treating cataract.
  • Cataracts are diseases of the eye. Diseases that occur in the lens of the eye, causing clouding of the lens, are collectively known as cataracts. Aging, genetics, abnormal metabolism, trauma, radiation, poisoning and local malnutrition can all cause damage to the lens capsule, increase its permeability, lose its barrier function, or lead to metabolic disorders of the lens, denature the lens protein, and form turbidity. If the lens of the eyeball changes from transparent to opaque, which affects the ability of the eyes to receive sunlight, it will affect the vision of the eyes. When the turbidity of the eyeball is light, the impact on vision is relatively mild. As the degree of turbidity gradually deepens, the impact on vision will also increase. Severe cases can lead to blindness.
  • cataracts There are many types and causes of cataracts. For example, trauma can cause traumatic cataracts, genetic or developmental abnormalities can cause congenital cataracts, high myopia can cause concurrent cataracts, and aging can cause age-related cataracts. According to the shape of lens opacity, it is divided into punctate, coronal, and perinuclear cataracts, etc., and according to the location of lens opacities, it is divided into cortical, nuclear, and posterior subcapsular cataracts. Cortical cataract is mainly characterized by gray-white opacity of the lens cortex, and its development process can be divided into four stages, namely, initial stage, immature stage, mature stage, and overmature stage. At present, there is no drug with good efficacy for cortical cataract or mixed cataract with cortical cataract.
  • the steroid compound of the present invention can have excellent therapeutic, slowing down and preventive effects on cortical cataracts or mixed cataracts containing cortical cataracts, and can greatly alleviate and/or cure cortical cataracts or mixed cataracts containing cortical cataracts. type cataract, and improve the patient's distance vision.
  • the present invention provides an application of a steroid compound in the preparation of a medicament for preventing and/or treating cataract
  • the steroid compound has a structure as shown in formula I, or is a compound with a structure as shown in formula I
  • n Qs are each independently selected from -H, -D, halogen, hydroxyl, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or hetero Aryl;
  • n 0, 1, 2 or 3.
  • R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
  • R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
  • the C6-10 can be C6, C7, C8, C9, C10.
  • the C2-9 can be C3, C4, C5, C6, C7, C8.
  • the C3-8 can be C4, C5, C6, C7.
  • the C2-10 can be C3, C4, C5, C6, C7, C8, C9.
  • Said C1-6 can be C2, C3, C4, C5.
  • the X is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, mercaptomethyl mercaptoethyl, aminomethyl, aminoethyl, aminopropyl, phenylmethyl, phenylethyl, imidazolylmethyl, carboxymethyl, carboxyethyl, methylthiomethyl, methylthio Ethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane Dihydropyranyl, dithiocyclopentyl, tetrahydropyranyl, di
  • n Qs are each independently selected from -H, -D, halogen, hydroxyl, amino, cyano, nitro, carboxyl, C 1-6 alkylcarbonyl, C 1-6 Alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 2-9 heteroaryl.
  • Said C1-6 can be C2, C3, C4, C5.
  • the C3-8 can be C4, C5, C6, C7.
  • the C2-9 can be C3, C4, C5, C6, C7, C8.
  • the C6-10 can be C6, C7, C8, C9, C10.
  • n Qs are each independently selected from -H, -D, -F, -Cl, -Br, hydroxyl, amino, cyano, carboxyl, formyl, acetyl, methyl , ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothio
  • the compound of the structure shown in the formula I is selected from the following compounds:
  • the steroidal compounds provided by the present invention can be provided as raw chemicals or as active ingredients of pharmaceutical compositions.
  • the cataract is a cortical cataract.
  • the cataract is mixed cataract with cortical cataract.
  • the mixed cataract containing cortical cataract may include both nuclear cataract and cortical cataract.
  • the present invention provides an application of the composition in the preparation of a medicament for preventing and/or treating cataract, the composition comprising the steroid compound described in the first aspect, and a pharmaceutically acceptable excipient.
  • compositions may include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid ; potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salt; electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon; magnesium trisilicate; Polyvinylpyrrolidone; Polyacrylates; Waxes; Polyethylene-polyoxypropylene-blocking polymers; Lanolin; Sugars, such as lactose, glucose and sucrose; Starches, such as corn starch and potato starch; Cellulose and its derivatives , such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients, such as cocoa butter and
  • the cataract is a cortical cataract.
  • the cataract is mixed cataract with cortical cataract.
  • the mixed cataract may include both cortical and nuclear cataracts.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a steroid compound of the invention.
  • the steroid compound of the present invention can be effectively used for preventing, treating, treating or alleviating cataracts in patients, preferably cortical cataracts or mixed cataracts containing cortical cataracts, while improving the distance vision of patients.
  • Figure 1 shows a standard photograph of the lens opacity classification system III.
  • stereoisomer refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • the compounds of the present disclosure may be present as mixtures of one or more of the possible isomers, such as racemates and diastereomeric mixtures (depending on the asymmetric carbon number of atoms).
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers on the basis of differences in the physicochemical properties of the components (for example, by chromatography and/or fractional crystallization), enantiomers isomers, diastereomers.
  • Structural formulas depicted in this disclosure include all isomeric forms, such as enantiomers, diastereomers and geometric isomers (or conformers), unless expressly stated otherwise.
  • the formulas described in this disclosure may contain R, S configurations of asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the disclosed compounds or mixtures thereof as enantiomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the present disclosure.
  • prodrug refers to a compound that can be converted into a compound of Formula I in vivo. Such conversion is effected by hydrolysis of the prodrug in blood, or enzymatic conversion to the parent structure in blood or tissues.
  • the prodrug compounds of the present disclosure may be esters, such as phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound containing a hydroxyl group can be acylated to give the compound in prodrug form.
  • Other prodrug forms may include phosphate esters, eg, phosphorylated hydroxyl groups on the parent.
  • prodrugs are found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chem istry, 2008 , 51, 2328-2345.
  • racemates of any resulting final products or intermediates may be resolved into the optical antipodes by methods familiar to those skilled in the art, for example by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, for example high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers may be prepared by asymmetric synthesis, see, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E .Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E.L.
  • tautomer or “tautomeric form” refers to different energies that pass through a low energy barrier (low energy barrier) Structural isomers that transform into each other. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerization examples include, for example, the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • Specific examples of phenol-keto tautomerization include, for example, the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salts refers to compounds of the present invention prepared with relatively non-toxic acids or bases.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts may include: inorganic acid salts such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, sulfite, nitrate, perchlorate salts, etc.; and, organic acid salts, such as carboxylates, sulfonates, sulfinates, thiocarboxylates, and the like.
  • Pharmaceutically acceptable salts may include, but are not limited to, mesylate, esylate, formate, acetate, succinate, benzoate, succinate, pamoate , salicylate, galactarate, glucoheptanoate, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, carbonate, trifluoroacetate, Glycolic acid salt, isethionate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malic acid salt, fumarate, lactate, lactobionate or oxalic acid, or salts obtained by known methods such as ion exchange.
  • salts may include, but are not limited to, adipate, alginate, ascorbate, aspartate, besylate, bisulfate, borate, butyrate, camphor salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Laurate, Lauryl Sulfate, Nicotinate, Nitrate, Oleate, Palmitate , pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, Valerate etc.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • the pharmaceutically acceptable base addition salts may be alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Pharmaceutically acceptable base addition salts may also include quaternary ammonium salts of N-containing compounds. Water-soluble or oil-soluble or dispersed products can be Obtained by quaternization.
  • Alkali or alkaline earth metal salts may include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts may also include suitable, nontoxic ammonium, quaternary ammonium salts, and amine cations formed as counterions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates Acids and aromatic sulfonates.
  • suitable, nontoxic ammonium, quaternary ammonium salts, and amine cations formed as counterions such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates Acids and aromatic sulfonates.
  • solvate refers to an association of one or more solvent molecules with a compound. Solvents that form solvates may include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • compositions means one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, in combination with other chemical components (collectively referred to herein as "excipients") excipient”), such as a mixture of carriers, stabilizers, diluents, dispersants, suspending agents and/or thickening agents.
  • excipients such as a mixture of carriers, stabilizers, diluents, dispersants, suspending agents and/or thickening agents.
  • Pharmaceutical compositions facilitate the administration of a compound to an organism.
  • Various techniques of administering compounds exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the pharmaceutical compositions of the present disclosure may be used for ophthalmic administration.
  • excipient or “pharmaceutically acceptable excipient” as used herein generally refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulation material.
  • each component is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications.
  • pharmaceutically acceptable in the sense that it is commensurate with a reasonable benefit/risk ratio.
  • the term "therapeutically effective amount” refers to, but is not limited to, an amount that can treat or prevent cataracts (eg, cortical cataracts or mixed cataracts containing cortical cataracts) by administering the steroidal compounds described herein.
  • the amount is an amount sufficient to exhibit a detectable therapeutic, prophylactic or ameliorating effect.
  • Such effects may include, for example and without limitation, treatment of conditions listed herein, such as cortical cataracts or mixed cataracts with cortical cataracts.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.
  • treating may refer to ameliorating the symptoms of a disease or disorder, for example may refer to slowing, arresting or alleviating the development of a disease or at least one clinical symptom thereof.
  • treating can refer to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • treating can refer to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both.
  • “treating” can refer to preventing or delaying the onset, occurrence or worsening of a disease or condition.
  • alkyl as used herein means 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 A saturated straight-chain or branched monovalent hydrocarbon group of 2 carbon atoms, wherein the alkyl group can be independent and Optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C(CH 3
  • alkyl and its prefix “alk” as used herein includes straight and branched saturated carbon chains.
  • alkylene as used herein means a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , Hypoisopropyl and so on.
  • cycloalkyl refers to a monovalent or multivalent aliphatic saturated or partially unsaturated ring, and does not contain heteroatoms, and may include a monocyclic ring with 3 to 12 carbon atoms or a bicyclic ring with 7 to 12 carbon atoms .
  • a bicyclic ring with 7 to 12 carbon atoms can be a bicyclic [4,5], [5,5], [5,6] or [6,6] system, and a bicyclic ring with 9 or 10 carbon atoms It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • cycloalkyl examples include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl -3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclo Octyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • heterocycle refers to monocyclic, bicyclic or tricyclic ring systems in which one or more carbon atoms in the ring are independently and optionally substituted by heteroatoms having In the above sense, a “ring” may be fully saturated, or contain one or more degrees of unsaturation, but is not aromatic, and has only one point of attachment to other molecules.
  • ring hydrogen atoms are independently and optionally substituted with one or more substituents described herein.
  • a “heterocycle”, “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group may be a 3-7 membered monocyclic ring containing 1-6 carbons atom and 1 to 3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms, such as SO, SO 2 , PO, PO 2 ; or, 7 ⁇ 10-membered bicyclic ring, which contains 4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms, for example Groups of SO, SO 2 , PO, PO 2 .
  • heterocyclyl may be carbonyl or heteroatomyl.
  • Heterocyclic group may include groups formed by combining a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Thiazolidinyl, Oxazolidinyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl , piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepyl, thiepanyl, 4-
  • heterocyclic group also include, 1,1-dioxothiomorpholinyl, and a pyrimidinedione group in which two carbon atoms on the ring are replaced by oxygen atoms.
  • aryl can be used alone or as a part of "aralkyl", “aralkoxy” or “aryloxyalkyl” to represent monocyclic, bicyclic and tricyclic rings containing 6 to 14 rings in total.
  • Carbocyclic ring systems wherein at least one ring system is aromatic, wherein each A ring system contains 3-7 membered rings with only one point of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring”.
  • aromatic rings may include phenyl, naphthyl and anthracenyl.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5 to 14 membered rings, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have Meaning as described herein, wherein each ring system comprises 3 to 7 membered rings and only one point of attachment is attached to the rest of the molecule.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • heteroaryl includes, but is not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5 -imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole -5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl , pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-
  • heteroatom may include O, S, N, P, and Si atoms, and includes forms of any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or, The form in which the hydrogen on the nitrogen atom is substituted, for example, N (for example 3, N) in 4-dihydro-2H-pyrrolyl), NH (eg NH in pyrrolidinyl) or NR (eg NR in N-substituted pyrrolidinyl).
  • heteroalkyl means that one or more heteroatoms may be inserted in the middle of the alkyl chain, wherein the alkyl group and the heteroatom have the meanings as described in the present invention.
  • the heteroalkyl group contains 1 to 10 carbon atoms.
  • the heteroalkyl group contains 1 to 8 carbon atoms.
  • the heteroalkyl group contains 1 to 6 carbon atoms.
  • the heteroalkyl group contains 1 to 4 carbon atoms.
  • the heteroalkyl group contains 1 to 3 carbon atoms.
  • heteroalkyl group examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, CH 3 SCH 2 CH 2 - , (CH 3 ) 2 NCH 2 - , (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, etc.
  • halogen refers to F, Cl, Br or I.
  • halo means that the following group is replaced by halogen, and the number of substitutions can be one or more.
  • Haldroxy substituted as used herein means that the subsequent group is substituted with hydroxy, and the number of substitutions can be one or more.
  • patient refers to animals, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice.
  • primates e.g., humans
  • monkeys cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice.
  • subject and patient are used interchangeably herein, for example, with respect to a mammalian subject such as a human.
  • Cataract refers to a disease in which lens metabolism is disturbed due to various reasons such as aging, genetics, local nutritional disorders, immune and metabolic abnormalities, trauma, poisoning, radiation, etc., resulting in lens protein denaturation and turbidity. People with cataracts have blurred vision because light is blocked by the cloudy lens from reaching the retina. Cataracts can be divided into cortical cataracts, nuclear cataracts, and posterior subcapsular cataracts according to the location of the opacity.
  • Embodiment 1 Eye drops component and preparation method
  • eye drops were prepared according to the ingredients and weights listed in Table 1.
  • Embodiment 2 Lens turbidity and visual acuity test method
  • Example 1 Patients with cortical cataract were recruited, and after signing the informed consent form, the eye drops prepared in Example 1 were administered daily, four times a day, one drop per eye each time, for 12 consecutive weeks.
  • the visual acuity test uses the ETDRS distance visual acuity chart to test the patient's best corrected distance visual acuity and uncorrected distance visual acuity.
  • Cortical turbidity C1-C5 According to the grading standards of cortical turbidity C1-C5 shown in Figure 1, compare the slit lamp photos with the standard photos C1-C5 and grade them. If the degree of turbidity is between the two standard levels, it is expressed with a decimal point. Cortical opacities range from minimal cortical changes to complete cortical opacities. Scoring criteria: 0.1 to 5.9. However, slight water voids, voids, lamellar separation and isolated point-like turbidity can be ignored.

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Abstract

La présente invention concerne une application d'un composé stéroïdien dans la préparation d'un médicament pour la prévention et/ou le traitement de la cataracte. Le composé stéroïdien selon la présente invention peut avoir de bons effets de traitement, d'atténuation et de prévention sur la cataracte, en particulier la cataracte corticale ou la cataracte mixte qui comprend la cataracte corticale, peut atténuer et/ou guérir la cataracte corticale dans une large mesure, et améliorer la vision de loin d'un patient.
PCT/CN2023/073362 2022-01-28 2023-01-20 Application d'un composé stéroïdien dans la prévention et/ou le traitement de la cataracte WO2023143452A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN106344587A (zh) * 2016-08-24 2017-01-25 上海毕傲图生物科技有限公司 羊毛甾醇类化合物眼用制剂
WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
CN109021051A (zh) * 2017-06-12 2018-12-18 盛世泰科生物医药技术(苏州)有限公司 四环三萜类化合物的晶型及其用途
WO2020020306A1 (fr) * 2018-07-25 2020-01-30 中山大学中山眼科中心 Forme cristalline d'un composé de promédicament de lanostérol et son application
CN114129575A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种药物组合物的制备方法和应用
CN114129574A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种甾体化合物的应用、含其的组合物及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106344587A (zh) * 2016-08-24 2017-01-25 上海毕傲图生物科技有限公司 羊毛甾醇类化合物眼用制剂
WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
CN109021051A (zh) * 2017-06-12 2018-12-18 盛世泰科生物医药技术(苏州)有限公司 四环三萜类化合物的晶型及其用途
WO2020020306A1 (fr) * 2018-07-25 2020-01-30 中山大学中山眼科中心 Forme cristalline d'un composé de promédicament de lanostérol et son application
CN114129575A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种药物组合物的制备方法和应用
CN114129574A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种甾体化合物的应用、含其的组合物及其制备方法

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