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WO2023020535A1 - 甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用 - Google Patents

甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用 Download PDF

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Publication number
WO2023020535A1
WO2023020535A1 PCT/CN2022/113024 CN2022113024W WO2023020535A1 WO 2023020535 A1 WO2023020535 A1 WO 2023020535A1 CN 2022113024 W CN2022113024 W CN 2022113024W WO 2023020535 A1 WO2023020535 A1 WO 2023020535A1
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Prior art keywords
alkyl
aryl
pyridazinyl
pyrimidinyl
thiodiazolyl
Prior art date
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PCT/CN2022/113024
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English (en)
French (fr)
Inventor
王延东
苏映雪
曹琛
吴美容
薛亚萍
于垂亮
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Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
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Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
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Priority to AU2022328942A priority Critical patent/AU2022328942B2/en
Priority to EP22857846.4A priority patent/EP4389130A4/en
Priority to JP2024509379A priority patent/JP7784526B2/ja
Priority to CN202280048822.XA priority patent/CN117693346A/zh
Priority to KR1020247007854A priority patent/KR20240046546A/ko
Priority to CA3228646A priority patent/CA3228646A1/en
Priority to US18/682,111 priority patent/US20240374615A1/en
Publication of WO2023020535A1 publication Critical patent/WO2023020535A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2024/01755A priority patent/ZA202401755B/en
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the invention belongs to the technical field of chemistry and medicine, and relates to the application of a steroid compound in the preparation of medicines for preventing and/or treating floaters.
  • Floaters generally caused by vitreous degeneration, which is a natural aging phenomenon. With aging, the vitreous body "liquefies” and produces some turbidity. Therefore, the official name of floaters is "vitreous chaos" or “vitreous floaters”. Seeing black dots flying in front of my eyes, it looks like flying mosquitoes, hence the name. Floaters are projections of opaque objects in the vitreous on the retina, which are more pronounced against brightly lit or white backgrounds; sensitive individuals can even picture their various shapes. Many floaters exist for a long time, remain unchanged throughout the year, do not affect vision, and there are no eye organ lesions after examination, often do not need treatment, and there is no effective treatment method.
  • Floaters are a very special and common eye disease. A few of these floaters will seriously threaten the eyeballs, while most of them are benign, or "physiological floaters", and generally do not require treatment, but even so, they will seriously affect the physical and mental health of patients. Although there are some drugs on the market that can relieve symptoms, they have relatively large side effects. At present, there is no drug that has a definite curative effect on this disease. Therefore, drugs that have good clinical effects and few side effects for the treatment of floaters are currently an urgent problem to be solved.
  • the object of the present invention is to provide a steroid compound in the preparation of medicines for preventing and/or treating floaters.
  • the steroid compound provided by the invention can have a good effect on floaters.
  • the therapeutic, mitigation and preventive effects can greatly reduce and/or cure floaters and improve visual clarity.
  • the present invention provides the application of a steroid compound in the preparation of a medicament for preventing and/or treating floaters, the steroid compound has a structure as shown in formula I, or is as shown in formula I Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of structural compounds;
  • 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 any one of the following compounds:
  • the steroidal compounds provided by the present invention can be used as raw chemicals for treatment, and can also be provided as active ingredients of pharmaceutical compositions.
  • the present invention provides the application of the composition in the preparation of medicines for preventing and/or treating floaters.
  • the composition includes the steroid compound described in the first aspect, and pharmaceutically acceptable carriers, excipients One or more of excipients, diluents, adjuvants or vehicles.
  • Substances which may serve as pharmaceutically acceptable carriers 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 phosphate; 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; polyethylene Pyrrolidone; 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 carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and
  • the present invention has the following beneficial effects:
  • the present invention finds that the steroid compound provided by the present invention can be used for preventing, treating, treating or alleviating floaters in patients, and the side effects are extremely small and basically free.
  • stereoisomer in the present invention refers to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • the compounds of the present invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) form exists.
  • 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, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, (Z), (E) isomer of the double bond, and (Z), (E) conformational isomer.
  • R containing an asymmetric center , S configuration for example, R containing an asymmetric center , S configuration, (Z), (E) isomer of the double bond, and (Z), (E) conformational isomer.
  • the single stereochemical isomer of the compound of the present invention or its enantiomer Mixtures of isomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.
  • prodrug used in the present invention means that a compound is transformed into a compound represented by formula I in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure.
  • the prodrug compound of the present invention can be an ester.
  • the ester can be used as a prodrug with phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters.
  • a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound.
  • prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups.
  • phosphate esters eg, phosphorylated parent hydroxyl groups.
  • a complete discussion of prodrugs can be 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 Chemistry, 2008, 51, 2328-2345.
  • racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, 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.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine Isomerization.
  • Valence tautomers involve interconversion by recombination of some of the bonding electrons.
  • keto-enol tautomerization is pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerism are interconversions of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, such as literature: Berge et al., describe pharmaceutically acceptable salts in detail in J .Pharmacol Sci, 1997, 66, 1-19 described.
  • Non-limiting examples of pharmaceutically acceptable salts include salts of inorganic acids formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates , perchlorate, and organic acid salts, such as carboxylate, sulfonate, sulfinate, thiocarboxylate, etc., specifically, but not limited to, methanesulfonate, ethanesulfonate, methanesulfonate Acetate, Acetate, Succinate, Benzoate, Succinate, Pamoate, Salicylate, Galactarate, Glucoheptanoate, Mandelate, 1,2 -Ethyl disulfonate, 2-naphthalenesulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, Citrate, succinate, malonate, benz
  • salts include adipate, alginate, ascorbate, aspartate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonic acid salt, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproic acid Salt, hydriodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, fruit Gellate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc.
  • pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • bases such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates compounds and aromatic sulfonates.
  • salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/carbonates , bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline salt, citrate, edisulphonate, fumarate, glucoheptonate, gluconate, Glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, propanediol Mandelate, Methanesulfonate, Methylsulfate, Naphthoate, Naphthalenesulfonate, Nicotinate, Nitrate, Octadenate, Oleate, Oxalate, Palmitate , pamoate, phosphate/hydrogen phosphate/dihydr
  • Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • “Pharmaceutical composition” means a mixture of one or more compounds described herein, salts, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as physiologically/pharmaceutically acceptable acceptable carrier or excipient.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, “treating” refers to preventing or delaying the onset, development or worsening of a disease or condition.
  • alkyl used in the present invention means 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or A saturated linear or branched monovalent hydrocarbon group of 1-3 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention.
  • 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” are used herein to include straight and branched saturated carbon chains.
  • alkylene is used herein to denote a saturated divalent hydrocarbon radical obtained by elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , Hypoisopropyl and so on.
  • cycloalkyl means a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including monocyclic rings of 3-12 carbon atoms or 7-12 carbon atoms of the second ring.
  • Bicyclic carbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • cycloaliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-2-enyl, Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Cyclooctyl, Cyclononyl, Cyclodecyl, Cycloundecyl, Cyclododecyl, etc.
  • heterocycle refers to monocyclic, bicyclic, or tricyclic ring systems in which one or more each of the carbon atoms is independently and optionally substituted by a heteroatom having the meaning described herein, the ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatic, Only one junction connects to other molecules.
  • One or more ring hydrogen atoms are independently and optionally substituted with one or more substituents described herein.
  • a “heterocycle”, “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , when said When the ring is a three-membered ring, there is only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a group such as SO, SO2 , PO, PO2 ).
  • a heterocyclic group may be a carbon group or a heteroatom group.
  • Heterocyclyl also includes the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocycle. 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-methoxy-piperidin
  • 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 may be used alone or as a part of “aralkyl”, “aralkoxy” or “aryloxyalkyl”, and denotes monocyclic, bicyclic, and Tricyclic carbocyclic ring systems wherein at least one ring system is aromatic, wherein each ring system contains 3-7 membered rings, and has only one point of attachment to the rest of the molecule.
  • aromatic ring eg aromatic rings may include phenyl, naphthyl and anthracenyl.
  • heteroaryl means monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein hetero Atoms have the meanings described herein, wherein each ring system contains 3-7 membered rings and only one point of attachment is 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-methylisoxazolyl- 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-triazolyl),
  • heteroatom means one or more O, S, N, P and Si atoms, including the form of any oxidation state of N, S and P; the form of primary, secondary, tertiary amine and quaternary ammonium salt; or the form of The form in which the hydrogen on the nitrogen atom is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as N-substituted pyrrole NR in the alkyl).
  • N such as N in 3,4-dihydro-2H-pyrrolyl
  • NH such as NH in pyrrolidinyl
  • NR such as N-substituted pyrrole NR in the alkyl
  • 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.
  • heteroalkyl groups contain 1-10 carbon atoms, in other embodiments, heteroalkyl groups contain 1-8 carbon atoms, in other embodiments, heteroalkyl groups contain 1 - 6 carbon atoms, still other embodiments, heteroalkyl groups contain 1-4 carbon atoms, still other embodiments, heteroalkyl groups contain 1-3 carbon atoms.
  • Such examples include, but are not limited to , CH3OCH2- , CH3CH2OCH2- , CH3SCH2- , CH3SCH2CH2- , ( CH3 ) 2NCH2- , ( CH3 ) 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 in the present invention means that the following group is replaced by halogen, and the number of substitutions can be one or more.
  • Haldroxy substituted in the present invention means that the subsequent group is substituted with hydroxy, and the number of substitutions can be one or more.
  • substituted in the present invention is used between two groups, it is preceded by a substituent, such as "aryl substituted alkyl” means that there is an aryl substituent on the alkyl, "alkoxycarbonyl "Substituted alkyl” means that the alkyl has an alkoxycarbonyl substituent.
  • substitution relationship is in order, such as "arylalkyl”, which means an aryl-substituted alkyl group, and "alkoxyalkoxy”, which means an alkoxy group Substituted alkoxy.
  • the invention provides a kind of eye drop, is made of following components:
  • the preparation method is as follows:
  • This embodiment provides a method for using the eye drops provided in Embodiment 1.
  • Example 1 Use the eye drops provided by Example 1 every day, four times a day, and use 1-2 drops each time.

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Abstract

一种甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用。所述甾体化合物能够对飞蚊症有很好的治疗、减缓和预防效果，能够极大程度的减轻和/或治愈飞蚊症，提高视力清晰度。

Description

甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用 技术领域
本发明属于化学医药技术领域，涉及一种甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用。
背景技术
飞蚊症(floaters)：一般是由玻璃体变性引起的，是一种自然老化现象，随着年纪老化，玻璃体会“液化”，产生一些浑浊物。因此，飞蚊症正式的名称是“玻璃体混沌”或称“玻璃体浮物”。眼前见黑点飞舞，犹如飞蚊故名。飞蚊症是玻璃体内的不透明物体投影在视网膜上产生的，在光线明亮或白色背景衬托下，更为明显；敏感的人甚至可以描绘出他们的各种不同形状。很多飞蚊症长时间存在，终年不变，不影响视力，经过检查也没有眼部器官病变，往往不需要治疗，也没有有效的治疗方法。
有些老年人眼前突然出现一两个黑影且不伴有其他症状，往往是由于玻璃体后界膜脱离，一般没有多大危害。但如突然出现大量黑点，应想到视网膜血管破裂出血或视网膜裂孔形成，可能是视网膜剥离的先兆，应进一步详细检查眼底。脉络膜炎时许多炎性细胞或渗出物可以进入玻璃体内，也是病理性飞蚊症的常见原因，但往往因为同时存在视力障碍而不易觉察。近视眼患者所感到的飞蚊症，常与玻璃体液化变性有关。
飞蚊症是眼睛毛病中很特别也相当普遍的一种。其中少数飞蚊症会对眼球发生严重威胁，而大部分飞蚊症是良性的，或称“生理性飞蚊症”，一般无需治疗，但是，即便这样，也会严重影响患者的身心健康。市面上虽有些药物可以缓解症状，但副作用较大，目前并没有针对此病的确切疗效的药物，因此临床效果好，副作用小的治疗飞蚊症的药物是目前亟需解决的问题。
发明内容
针对现有技术存在的不足，本发明的目的在于提供一种甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用，本发明提供的甾体化合物能够对飞蚊症有很好的治疗、减缓和预防效果，能够极大程度的减轻和/或治愈飞蚊症，提高视力清晰度。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供了一种甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用，所述甾体化合物具有如式I所示的结构，或为如式I所示结构化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药；
Figure PCTCN2022113024-appb-000001
其中，X选自芳基、杂芳基、环烷基、杂环烷基、杂烷基、取代或未取代的烷基，所述取代的基团选自羟基、巯基、氨基、芳基、杂芳基、羧基、R 1R 2NC(＝O)-或R 1R 2NC(＝NH)-NR 3-；
本发明所述的R 1R 2NC(＝O)-或R 1R 2NC(＝NH)-NR 3-中包括的R 1、R 2均是与N相连的两个基团。
n个Q各自独立地选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基或杂芳基；
本发明所述的烷基羰基指的是R-C(＝O)-，其中，R为烷基，与X相连的为羰基碳。
n为0、1、2或3。
R 1、R 2和R 3各自独立地选自-H、-D或烷基。
作为本发明的一种优选技术方案，所述X选自C 6-10芳基、C 2-9杂芳基、C 3-8环烷基、C 2-10杂环烷基、C 1-6杂烷基、取代或未取代的C 1-6烷基，所述C 1-6烷基若带有取代基，所述取代基选自羟基、巯基、氨基、C 6-10芳基、C 2-9杂芳基、羧基、R 1R 2NC(＝O)-或R 1R 2NC(＝NH)-NR 3-；
R 1、R 2和R 3各自独立地选自-H、-D或C 1-6烷基。
所述C 6-10可以是C6、C7、C8、C9、C10。所述C 2-9可以是C3、C4、C5、C6、C7、C8。所述C 3-8可以是C4、C5、C6、C7。所述C 2-10可以是C3、C4、C5、C6、C7、C8、C9。所述C 1-6可以是C2、C3、C4、C5。
作为本发明的一种优选技术方案，所述X选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌 嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、
Figure PCTCN2022113024-appb-000002
Figure PCTCN2022113024-appb-000003
带有H 2NC(＝O)-取代基的C 1-3烷基或带有H 2NC(＝NH)-NH-取代基的C 1-3烷基。
作为本发明的一种优选技术方案，n个Q各自独立地选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、C 1-6烷基羰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基或C 2-9杂芳基。
所述C 1-6可以是C2、C3、C4、C5。所述C 3-8可以是C4、C5、C6、C7。所述C 2-9可以是C3、C4、C5、C6、C7、C8。所述C 6-10可以是C6、C7、C8、C9、C10。
作为本发明的一种优选技术方案，n个Q各自独立地选自-H、-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
作为本发明的一种具体实施方式，所述式I所示结构的化合物选自如下化合物中的任意一种：
Figure PCTCN2022113024-appb-000004
Figure PCTCN2022113024-appb-000005
Figure PCTCN2022113024-appb-000006
Figure PCTCN2022113024-appb-000007
Figure PCTCN2022113024-appb-000008
本发明提供的甾体化合物可以作为未加工的化学药品用于治疗，也可以作为药物组合物的活性成分提供。
第二方面，本发明提供了组合物在制备预防和/或治疗飞蚊症的药物中的应用，所述组合物包括第一方面所述的甾体化合物，及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐；电解质，如硫酸鱼精蛋白；磷酸氢二钠；磷酸氢钾；氯化钠；锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。
与现有技术相比，本发明具有以下有益效果：
本发明发现，本发明提供的甾体化合物可以用于预防、处理、治疗或减轻患者的飞蚊症，并且副作用极小，基本没有。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述具体实施方式仅仅是帮助理解本发明，不应视为对本发明的具体限制。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。
本发明所述的“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对 映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式I所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium 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 S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考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.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH & Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(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(protontautomer)(也称为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。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明所提到的盐为药学上可接受的盐，其中“药学上可接受的盐”在所属领域是为我们所熟知的，如文献：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括与氨基基团反应形成的无机酸盐，如有盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐，和有机酸盐，如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等，具体的如，但不限于，甲磺酸盐、乙磺酸盐、甲酸盐、乙酸盐、丁二酸盐、苯甲酸盐、琥珀酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、碳酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐或草酸，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、月桂酸盐、月桂基硫酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、十一酸盐、戊酸盐，等等。此外，药学上可接受的盐还包括通过适当的碱得到的盐，如碱金属、碱土金属、铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
可药用的盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
“药物组合物”表示一种或多种本文所述化合物、盐或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体或赋形剂。药物组合物的目的是促进化合物对生物体的给药。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明使用的术语“烷基”表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代。烷基的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，异丁基(i-Bu，-CH 2CH(CH 3) 2)，仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基，次乙基，次异丙基等等。
术语“环烷基”是指一价或多价，非芳香族，饱和或部分不饱和的环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括，但并 不限于，环烷基，环烯基和环炔基。环状脂肪族基的实例包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，环烷基、杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基等等。
术语“杂环”，“杂环基”，“杂脂环族”或“杂环的”在此处可交换使用，都是指单环，双环，或三环体系，其中环上一个或多个碳原子独立且任选地被杂原子所取代，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是，“杂环”，“杂环基”，“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团)。
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，噻唑烷基，噁唑烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，4-甲氧基-哌啶-1-基，1,2,3,6-四氢吡啶-1-基，氧氮杂
Figure PCTCN2022113024-appb-000009
基，二氮杂
Figure PCTCN2022113024-appb-000010
基，硫氮杂
Figure PCTCN2022113024-appb-000011
基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，1,2,6-噻二嗪烷1,1-二氧代-2-基，4-羟基-1,4-氮杂磷烷4-氧化物-1-基，2-羟基-1-(哌嗪-1-基)乙酮-4-基，2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基，5,6-二氢-4H-1,2,4-噁二嗪-4-基，2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，2-甲基-5,6,7,8-四氢-[1,2,4]三唑[1,5-c]嘧啶-6-基，4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基，3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基，2-氧-5-氮杂双环[2.2.2]辛烷-5-基，喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧代硫代吗啉基，和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂 环基可以是取代或未取代的，其中取代基可以是，但并不限于，氧代(＝O)，羟基，氨基，卤素，氰基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基等等。
术语“芳基”可以单独使用或作为“芳烷基”，“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基，等等。
术语“杂芳基”表示共含有5-14元环的单环，双环，和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，环烷基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)-，烷基-C(＝O)-，烷基-S(＝O)-，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)-，羟基取代的烷基-S(＝O) 2-，羧基烷氧基等等。
另外一些实施方案是，杂芳基包括以下的单环，但并不限于这些单环：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，4-甲基异噁唑-5-基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，嘧啶-5-基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5-四唑基)，三唑基(如2-三唑基和5-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如2-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,2,3-三唑基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，1,3,4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，和异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，苯并[d]噻唑-2-基，咪唑并[1,5-a]吡啶-6-基。
术语“杂原子”表示一个或多个O，S，N，P和Si原子，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被 取代的形式，例如，N(例如3，4-二氢-2H-吡咯基中的N)，NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。
术语“杂烷基”表示烷基链中间可以插入一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明，杂烷基基团含有1-10个碳原子，另外一些实施方案是，杂烷基基团含有1-8个碳原子，另外一些实施方案是，杂烷基基团含有1-6个碳原子，另外一些实施方案是，杂烷基基团含有1-4个碳原子，另外一些实施方案是，杂烷基基团含有1-3个碳原子。这样的实例包括，但并不限于，CH 3OCH 2-，CH 3CH 2OCH 2-，CH 3SCH 2-，CH 3SCH 2CH 2-，(CH 3) 2NCH 2-，(CH 3) 2CH 2OCH 2-，CH 3OCH 2CH 2-，CH 3CH 2OCH 2CH 2-等。
术语“卤素”是指F，Cl，Br或I。
本发明所述的“卤代”表示用卤素取代其后接的基团，取代的个数可以是一个或多个。
本发明所述的“羟基取代的”表示用羟基取代其后接的基团，取代的个数可以是一个或多个。
本发明所述的“取代的”用于两个基团之间时，则其前面为取代基，如“芳基取代的烷基”表示烷基上具有芳基取代基，“烷氧基羰基取代的烷基”表示烷基上具有烷氧基羰基取代基。
当本发明多个基团联合使用时，从左到右，依次为取代关系，如“芳基烷基”，表示芳基取代的烷基，“烷氧基烷氧基”，表示烷氧基取代的烷氧基。
实施例1
本发明提供了一种滴眼液，由如下组分构成：
Figure PCTCN2022113024-appb-000012
制备方法如下：
在无菌操作下，将上述成分混合，于2-8℃搅拌过夜，得到均一混合液后， 在眼药瓶中保存。
实施例2
本实施例提供了一种实施例1提供的眼药水的使用方法。
每日使用实施例1提供的眼药水，一日四次，每次1～2滴使用。
效果测试
选取10名患有飞蚊症的患者进行临床效果评价，自确诊日起，患者每日使用实施例1提供的眼药水四次，每次1～2滴使用，于第15日、第30日复诊，其治疗效果见下表1：
表1：
Figure PCTCN2022113024-appb-000013
Figure PCTCN2022113024-appb-000014
从表1可以看出，在临床使用效果中，用药15天左右既能明显使眼前黑点或者条带变浅且提高了对比敏感度，减少了在观察天花板、墙壁等白色背景时的视觉困扰；用药30天左右可以使飞蚊症基本治愈，飘动的黑点或者条带几乎消失，观察天花板、墙壁等白色背景没有视觉困扰，对比敏感度等视觉质量改善明显，且无其它副作用。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (7)

  1. 甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用，其特征在于，所述甾体化合物具有如式I所示的结构，或为式I所示结构化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药；
    Figure PCTCN2022113024-appb-100001
    其中，X选自芳基、杂芳基、环烷基、杂环烷基、杂烷基、取代或未取代的烷基，所述取代的基团选自羟基、巯基、氨基、芳基、杂芳基、羧基、R 1R 2NC(＝O)-或R 1R 2NC(＝NH)-NR 3-；
    n个Q各自独立地选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基或杂芳基；
    n为0、1、2或3；
    R 1、R 2和R 3各自独立地选自-H、-D或烷基。
  2. 根据权利要求1所述的应用，其特征在于，所述X选自C 6-10芳基、C 2-9杂芳基、C 3-8环烷基、C 2-10杂环烷基、C 1-6杂烷基、取代或未取代的C 1-6烷基，所述C 1-6烷基若带有取代基，所述取代基选自羟基、巯基、氨基、C 6-10芳基、C 2-9杂芳基、羧基、R 1R 2NC(＝O)-或R 1R 2NC(＝NH)-NR 3-；
    R 1、R 2和R 3各自独立地选自-H、-D或C 1-6烷基。
  3. 根据权利要求2所述的应用，其特征在于，所述X选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3- 噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、
    Figure PCTCN2022113024-appb-100002
    带有H 2NC(＝O)-取代基的C 1-3烷基或带有H 2NC(＝NH)-NH-取代基的C 1-3烷基。
  4. 根据权利要求1所述的应用，其特征在于，n个Q各自独立地选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、C 1-6烷基羰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基或C 2-9杂芳基。
  5. 根据权利要求4所述的应用，其特征在于，n个Q各自独立地选自-H、-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
  6. 根据权利要求1-5中的任一项所述的应用，其特征在于，所述式I所示结构的化合物选自如下化合物中的任意一种：
    Figure PCTCN2022113024-appb-100003
    Figure PCTCN2022113024-appb-100004
    Figure PCTCN2022113024-appb-100005
    Figure PCTCN2022113024-appb-100006
    Figure PCTCN2022113024-appb-100007
    Figure PCTCN2022113024-appb-100008
  7. 组合物在制备预防和/或治疗飞蚊症的药物中的应用，其特征在于，所述组合物包括权利要求1-6中的任一项所述的甾体化合物，及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
PCT/CN2022/113024 2021-08-18 2022-08-17 甾体化合物在制备预防和/或治疗飞蚊症的药物中的应用 Ceased WO2023020535A1 (zh)

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Publication number Priority date Publication date Assignee Title
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
WO2025242181A1 (zh) * 2024-05-22 2025-11-27 润尔眼科药物（广州）有限公司 一种甾体化合物及其医药用途

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