WO2023143452A1 - Application of steroidal compound in prevention and/or treatment of cataracts - Google Patents

Application of steroidal compound in prevention and/or treatment of cataracts Download PDF

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Publication number
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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French (fr)
Chinese (zh)
Inventor
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/en
Publication of WO2023143452A1 publication Critical patent/WO2023143452A1/en

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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

The present invention provides an application of a steroidal compound in the preparation of a drug for preventing and/or treating cataracts. The steroidal compound provided by the present invention can have good treatment, alleviation and prevention effects on cataracts, especially cortical cataract or mixed cataract that comprises the cortical cataract, can alleviate and/or cure the cortical cataract to a great extent, and improves the distant vision of a patient.

Description

甾体化合物在预防和/或治疗白内障中的应用Use of steroids in the prevention and/or treatment of cataracts 技术领域technical field
本发明属于化学医药领域，具体涉及甾体化合物在预防和/或治疗白内障药物中的应用。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.
背景技术Background technique
白内障属于眼睛的疾病。发生在眼球内的晶状体，导致晶状体浑浊的疾病统称为白内障。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，对视力的影响也会随之加大，严重者会导致失明。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.
白内障的类型和病因有多种。如外伤可以引起外伤性白内障，遗传或者发育异常可以引起先天性白内障，高度近视可以引起并发性白内障，老化还会引起年龄相关性白内障。按照晶状体浑浊形态分为点状、冠状、绕核性白内障等，按照晶状体浑浊部位分为皮质性、核性、后囊下白内障等。皮质性白内障是以晶状体皮质灰白色混浊为主要特征，其发展过程可分为四期，即初发期、未成熟期、成熟期、过熟期。目前还没有针对皮质性白内障或含皮质性白内障的混合型白内障具有良好疗效的药物。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.
因此临床上亟需效果好且副作用小的治疗或含皮质性白内障的混合型白内障的药物。Therefore, clinically, there is an urgent need for a treatment with good effect and little side effects or a drug for mixed cataract containing cortical cataract.
发明内容Contents of the invention
为了至少解决上述技术问题之一，提供甾体化合物在预防和/或治疗白内障，特别是皮质性白内障或者含皮质性白内障的混合型白内障的药物中的应用。本发明的甾体化合物能够对皮质性白内障或者含皮质性白内障的混合型白内障具有优异的治疗、减缓和预防效果，能够极大程度的减轻和/或治愈皮质性白内障或者含皮质性白内障的混合型白内障，并提高患者的远视力。 In order to solve at least one of the above technical problems, the use of steroidal compounds in the prevention and/or treatment of cataracts, especially cortical cataracts or mixed cataracts containing cortical cataracts is provided. 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.
根据一个方面，本发明提供了一种甾体化合物在制备预防和/或治疗白内障的药物中的应用，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；
According to one aspect, 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 Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of
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、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；Wherein, X is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroalkyl, substituted or unsubstituted alkyl, and the substituted group is selected from hydroxyl, mercapto, amino, aryl, Heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;
本发明所述的R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-中包括的R1、R2均是与N相连的两个基团。R 1 and R 2 included in R 1 R 2 NC( = O)- or R 1 R 2 NC(=NH)-NR 3 - in the present invention are two groups connected to N.
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；The n Qs are each independently selected from -H, -D, halogen, hydroxyl, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or hetero Aryl;
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。The alkylcarbonyl group mentioned in the present invention refers to R-C(=O)-, wherein, R is an alkyl group, and the carbonyl carbon connected to X is.
n为0、1、2或3。n is 0, 1, 2 or 3.
R1、R2和R3各自独立地选自-H、-D或烷基。R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
作为本发明的一种优选技术方案，所述X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环烷基、C1-6杂烷基、取代或未取代的C1-6烷基，所述C1-6烷基若带有取代基，所述取代基选自羟基、巯基、氨基、C6-10芳基、C2-9杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；As a preferred technical solution of the present invention, the X is selected from C 6-10 aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 heterocycloalkyl, C 1- 6 Heteroalkyl, substituted or unsubstituted C 1-6 alkyl, if the C 1-6 alkyl has a substituent, the substituent is selected from hydroxyl, mercapto, amino, C 6-10 aryl, C 2-9 heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;
R1、R2和R3各自独立地选自-H、-D或C1-6烷基。R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
所述C6-10可以是C6、C7、C8、C9、C10。所述C2-9可以是C3、C4、C5、C6、C7、C8。所述C3-8可以是C4、C5、C6、C7。所述C2-10可以是C3、C4、C5、C6、C7、C8、C9。所述C1-6可以是C2、C3、C4、C5。 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.
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、***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-***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]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基、带有H2NC(＝O)-取代基的C1-3烷基或带有H2NC(＝NH)-NH-取代基的C1-3烷基。As a preferred technical solution of the present invention, 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, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine Base, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, Diazapinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, Pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl , benzoimidazolyl, benzofuryl, benzothienyl, indolyl, purinyl, quinolinyl, isoquinolyl, imidazo[1,2-a]pyridyl, pyrazolo[1, 5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b] Pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, C 1-3 alkyl with H 2 NC(=O)-substituent or C 1-3 alkyl with H 2 NC(=NH)-NH-substituent.
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、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。As a preferred technical solution of the present invention, 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.
所述C1-6可以是C2、C3、C4、C5。所述C3-8可以是C4、C5、C6、C7。所述C2-9可以是C3、C4、C5、C6、C7、C8。所述C6-10可以是C6、C7、C8、C9、C10。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.
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、***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-***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]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基或[1,2,4]***并[1,5-a]吡啶基。As a preferred technical solution of the present invention, 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, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl , homopiperazinyl, homopiperidinyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3 ,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, Pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl , benzoimidazolyl, benzofuryl, benzothienyl, indolyl, purinyl, quinolinyl, isoquinolyl, imidazo[1,2-a]pyridyl, pyrazolo[1, 5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b] Pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.
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以下化合物：





As a specific embodiment of the present invention, the compound of the structure shown in the formula I is selected from the following compounds:





本发明提供的甾体化合物可以作为未加工的化学药品提供，也可以作为药物组合物的活性成分提供。The steroidal compounds provided by the present invention can be provided as raw chemicals or as active ingredients of pharmaceutical compositions.
根据一些实施方式，所述白内障为皮质性白内障。根据一些实施方式，所述白内障为含皮质性白内障的混合型白内障。根据具体的实施方式，所述含皮质性白内障的混合型白内障可以包括核性白内障和皮质性白内障二者。According to some embodiments, the cataract is a cortical cataract. According to some embodiments, the cataract is mixed cataract with cortical cataract. According to a specific embodiment, the mixed cataract containing cortical cataract may include both nuclear cataract and cortical cataract.
根据第二方面，本发明提供了组合物在制备预防和/或治疗白内障的药物中的应用，所述组合物包括第一方面所述的甾体化合物，及药学上可接受的赋形剂。According to the second aspect, 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.
可作为药学上可接受的赋形剂可以包括，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。Pharmaceutically acceptable excipients 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 suppository waxes; oils, such as peanut oil, cottonseed oil, Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as hydrogen Magnesium oxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethanol, phosphate buffer, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, release agents, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.
根据一些实施方式，所述白内障为皮质性白内障。根据一些实施方式，所述白内障为含皮质性白内障的混合型白内障。根据具体的实施方式，所述混合型白内障可以包括皮质性白内障和核性白内障二者。According to some embodiments, the cataract is a cortical cataract. According to some embodiments, the cataract is mixed cataract with cortical cataract. According to a specific embodiment, the mixed cataract may include both cortical and nuclear cataracts.
根据第三方面，提供了一种治疗或预防白内障的方法。根据一些实施方式，所述方法包括向有需要的受试者施用治疗有效量的本发明的甾体化合物。According to a third aspect, there is provided a method of treating or preventing cataracts. According to some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a steroid compound of the invention.
本发明的甾体化合物可有效用于预防、处理、治疗或减轻患者的白内障，优选皮质性白内障或者含皮质性白内障的混合型白内障，同时提高患者的远视力。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.
附图说明Description of drawings
图1示出了晶状体浑浊分类***III的标准照片。Figure 1 shows a standard photograph of the lens opacity classification system III.
具体实施方式Detailed ways
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。The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the specific implementation is only to help understand the present invention, and should not be regarded as a specific limitation on the present invention.
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。Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.
本文所用的术语“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的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。As used herein, the term "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. .
依据起始物料和方法的选择，本公开的化合物可以以可能的异构体中的一种或多种的混合物，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。Depending on the choice of starting materials and methods, 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.
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(例如，通过色谱法和/或分步结晶法)，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。 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.
除非明确表明，否则本公开所描述的结构式包括所有的同分异构形式，例如对映异构、非对映异构和几何异构(或构象异构)。例如，本公开所描述的结构式可以含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本公开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)的混合物都属于本公开的范围。Structural formulas depicted in this disclosure include all isomeric forms, such as enantiomers, diastereomers and geometric isomers (or conformers), unless expressly stated otherwise. For example, 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.
本文所使用的术语“前体药物”或“前药”代表一化合物，其在体内可转化为式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。本公开的前体药物类化合物可以是酯，例如苯酯类，脂肪族(C1-24)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，一化合物包含羟基，其可以经酰化得到前体药物形式的化合物。其他的前体药物形式可以包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基经磷酸化得到的。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.14 of 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。As used herein, the term "prodrug" or "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. For example, 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. 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 Chem istry, 2008 , 51, 2328-2345.
可以用通过本领域技术人员熟悉的方法，将任何所得终产物或中间体的外消旋体拆分成光学对映体，例如通过对获得的非对映异构的盐进行分离。外消旋产物也可以通过手性色谱来分离，例如使用手性吸附剂的高效液相色谱(HPLC)来分离。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)。The 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. In particular, 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. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L.Eli el,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).
本文所使用的术语“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(也称为质子转移互变异构体)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例如包括戊烷-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-酮互变异构的具体实例例如包括吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，否则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。As used herein, the term "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. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. Specific examples of keto-enol tautomerization 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.
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。The term "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.
本文所使用的术语“药学上可接受的盐”是指本发明的化合物与相对无毒的酸或碱制备得到。当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非限定性实例可以包括：无机酸盐，例如盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐等；和，有机酸盐，例如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等。药学上可接受的盐可以包括，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，或通过已知方法(例如离子交换法)得到的盐。其他药学上可接受的盐可以包括，但不限于，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。当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可以碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。药学上可接受的碱加成盐也可以包括含N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可以包括钠、锂、钾、钙、镁等。药学上可接受的盐还可以包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，例如卤化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。As used herein, the term "pharmaceutically acceptable salts" refers to compounds of the present invention prepared with relatively non-toxic acids or bases. When compounds contain relatively basic functional groups, 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. Non-limiting examples of 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. Other pharmaceutically acceptable 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. When compounds contain relatively acidic functional groups, 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.
本文所使用的术语“溶剂化物”是指一个或多个溶剂分子与化合物所形成的缔合物。形成溶剂化物的溶剂可以包括，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。As used herein, the term "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. The term "hydrate" refers to an association of solvent molecules with water.
本文所使用的术语“药物组合物”表示一种或多种本文所述的化合物或者其生理学上/药学上可以接受的盐或前体药物，与其他化学组分(在本文中统称为“赋形剂”)，例如载体、稳定剂、稀释剂、分散剂、悬浮剂和/或增稠剂的混合物。药物组合物有助于将化合物施用于生物体。本领域中存在施用化合物的多种技术，包括但不限于，直肠、口服、静脉内、气雾剂、肠胃外、眼部、肺部和外用施用。在本公开的实施方式中，本公开的药物组合物可用于眼部施用。The term "pharmaceutical composition" as used herein 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. 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. In an embodiment of the present disclosure, the pharmaceutical compositions of the present disclosure may be used for ophthalmic administration.
本文所使用的术语“赋形剂”或“药学上可接受的赋形剂”通常指药学上可接受的材料、组合物或媒介物，如液体或固体填充剂、稀释剂、载体、溶剂或包封材料。在一些实施方式中，每种组分在于药物配制品的其他成分相容，且适用于与人和动物的组织或器官接触而无过度毒性、刺激、过敏应答、免疫原性或其他问题或并发症，与合理益处/风险比相称的意义上是“药学上可接受的”。The term "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. In some embodiments, 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.
本文所使用的术语“治疗有效量”指，但不限于，通过施用本文所述的甾体化合物可治疗或预防白内障(例如皮质性白内障或者含皮质性白内障的混合型白内障)的量。所述量是足以展现出可检测的治疗、预防或改善效果的量。所述效果可以包括例如但不限于治疗本文列出的病症，例如皮质性白内障或者含皮质性白内障的混合型白内障。对于受试者的精确有效量将取决于受试者的体型和健康状况、所治疗的病症的性质和程度、治疗医师的建议以及选择用于施用的治疗剂或治疗剂的组合。As used herein, 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.
本文所使用的术语“治疗”可以指改善疾病或病症的症状，例如可以指减缓、阻止或减轻疾病或其至少一种临床症状的发展。在一些实施方式中，“治疗”可以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。在一些实施方式中，“治疗”可以指在身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面上调节疾病或病症。在一些实施方式中，“治疗”可以指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" as used herein 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. In some embodiments, "treating" can refer to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In some embodiments, "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. In some embodiments, "treating" can refer to preventing or delaying the onset, occurrence or worsening of a disease or condition.
本文所使用的术语“烷基”表示含1～20个碳原子，1～10个碳原子，1～8个碳原子，1-6个碳原子，1～4个碳原子，或1～3个碳原子的饱和的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，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，异丁基(i-Bu，-CH2CH(CH3)2)，仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基等。术语“烷基”和其前缀“烷”在此处使用，包含直链和支链的饱和碳链。本文所使用的术语“烷撑”，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。The term "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. Examples of 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 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2- Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ) , 2-methyl-3-pentyl (-CH(CH 2 CH 3 ) CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alk" as used herein includes straight and branched saturated carbon chains. The term "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.
术语“环烃基”是指一价或多价的脂肪族饱和或部分不饱和的环，且不包含杂原子，可以包括3～12个碳原子的单环或7～12个碳原子的二环。具有7～12个碳原子的二环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个碳原子的二环可以是二环[5,6]或[6,6]体系。合适的环烃基包括，但并不限于，环烷基，环烯基和环炔基。环烃基的实例包括，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。本文使用的术语“环状脂肪族基”、“碳环”、“碳环基”或“环烃基”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。The term "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. Examples of cycloalkyl 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. As used herein, the term "cycloaliphatic", "carbocycle", "carbocyclyl" or "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxyl, amino, Halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy radical, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy, and the like.
术语“杂环”，“杂环基”，“杂脂环族”或“杂环的”在此处可交换使用，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，但不属于芳香族类，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。在一些实施方式中，“杂环”、“杂环基”、“杂脂环族”或“杂环的”基团可以为：3～7元环的单环，其含有1～6个碳原子和选自N、O、P、S中的1～3个杂原子，其中S或P任选地被一个或多个氧原子取代，例如SO、SO2、PO、PO2；或，7～10元双环，其含有4～9个碳原子和选自N、O、P、S中的1～3个杂原子，其中S或P任选地被一个或多个氧原子所取代，例如SO、SO2、PO、PO2的基团。The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer 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. One or more ring hydrogen atoms are independently and optionally substituted with one or more substituents described herein. In some embodiments, 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 .
术语“杂环基”可以是碳基或杂原子基。“杂环基”可以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，氧氮杂基，二氮杂基，硫氮杂基，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]***[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。The term "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-methoxy-piperidin-1-yl, 1,2, 3,6-tetrahydropyridin-1-yl, oxazepine base, diazepine base, thiazepine Base, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanexyl, 1,3-di Oxypentyl, pyrazolinyl, dithianyl, dithianolyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinoline base, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphine 4-oxide-1-yl, 2-hydroxy-1 -(Piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4 -yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanone -4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7 ,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridine- 5-yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl , quinozinyl and N-pyridyl urea. Examples of the heterocyclic group also include, 1,1-dioxothiomorpholinyl, and a pyrimidinedione group in which two carbon atoms on the ring are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkane Amino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O ), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy Base etc.
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。例如，芳香环可以包括苯基，萘基和蒽基。所述芳基可以是取代或未取代的，其中取代基可以包括，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。The term "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. The term "aryl" is used interchangeably with the term "aromatic ring". For example, aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl group may be substituted or unsubstituted, where the substituents may include, but are not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl radical, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S (=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy, and the like.
术语“杂芳基”指含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。所述杂芳基可以是取代或未取代的，其中取代基可以包括，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。The term "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. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". The heteroaryl group may be substituted or unsubstituted, wherein the substituents may include, but are not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O )-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2- , carboxyalkoxy, etc.
在另外一些实施方式中，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)，***基(如2-***基和5-***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-***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)，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。In other embodiments, 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-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5 -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl , 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes The following bicyclic rings, but by no means limited to these bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinoline base, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), benzo[d]thiazole- 2-yl, imidazo[1,5-a]pyridin-6-yl.
术语“杂原子”可以包括O、S、N、P和Si原子，且包括N、S和P的任何氧化态的形式；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)。The term "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).
术语“杂烷基”表示烷基链中间可以***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。在一些实施方式中，所述杂烷基含有1～10个碳原子。在另外一些实施方式中，所述杂烷基含有1～8个碳原子。在又一些实施方式中，所述杂烷基含有1～6个碳原子。在又一些实施方式中，所述杂烷基含有1～4个碳原子。在又一些实施方式中，所述杂烷基含有1～3个碳原子。所述杂烷基的实例包括，但并不限于，CH3OCH2-，CH3CH2OCH2-，CH3SCH2-，CH3SCH2CH2-，(CH3)2NCH2-，(CH3)2CH2OCH2-，CH3OCH2CH2-，CH3CH2OCH2CH2-等。The term "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. In some embodiments, the heteroalkyl group contains 1 to 10 carbon atoms. In other embodiments, the heteroalkyl group contains 1 to 8 carbon atoms. In yet other embodiments, the heteroalkyl group contains 1 to 6 carbon atoms. In yet other embodiments, the heteroalkyl group contains 1 to 4 carbon atoms. In yet other embodiments, the heteroalkyl group contains 1 to 3 carbon atoms. Examples of the heteroalkyl group 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.
术语“卤素”指F、Cl、Br或I。The term "halogen" refers to F, Cl, Br or I.
本文所述的“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。The "halo" mentioned herein means that the following group is replaced by halogen, and the number of substitutions can be one or more.
本文所述的“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。"Hydroxy substituted" as used herein means that the subsequent group is substituted with hydroxy, and the number of substitutions can be one or more.
本文所述的“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。When the "substituted" mentioned in this article is used between two groups, it is preceded by a substituent, such as "aryl substituted alkyl" means that the alkyl has an aryl substituent, "alkoxycarbonyl substituted The alkyl" means that the alkyl has an alkoxycarbonyl substituent. When multiple groups are used in combination, from left to right, the substitution relationship is in order, such as "arylalkyl" means aryl substituted alkyl, "alkoxyalkoxy" means alkoxy substituted alkoxy base.
本文所用的术语“患者”或者“受试者”指动物，包括但不限于灵长类动物(例如，人)、猴、牛、猪、绵羊、山羊、马、狗、猫、兔、大鼠或小鼠。术语“受试者”和“患者”在本文中例如关于哺乳动物受试者(如人)可互换使用。The term "patient" or "subject" as used herein refers to animals, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to a mammalian subject such as a human.
本文所用的术语“白内障”指，由于老化、遗传、局部营养障碍、免疫与代谢异常、外伤、中毒、辐射等各种原因引起晶状体代谢紊乱，导致晶状体蛋白质变性而发生混浊的疾病。白内障患者因光线被混浊的晶状体阻挠而无法投射在视网膜上，导致视物模糊。白内障根据混浊部位，可分为皮质性白内障、核性白内障、后囊下型白内障。The term "cataract" as used herein 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.
为使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步的详细说明。此处所描述的具体实施例仅用于解释本发明，并不用于构成对本发明的任何限制。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本公开的概念。这样的结构和技术在许多出版物中也进行了描述。 In order to make the object, technical solution and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with the examples. The specific embodiments described here are only used to explain the present invention, and are not intended to constitute any limitation to the present invention. Also, in the following description, descriptions of well-known structures and techniques are omitted to avoid unnecessarily obscuring the concept of the present disclosure. Such structures and techniques are also described in numerous publications.
实施例Example
实施例1.眼药水组分及制备方法Embodiment 1. Eye drops component and preparation method
本实施例中，按照表1中列出的成分和重量制备眼药水。In this example, eye drops were prepared according to the ingredients and weights listed in Table 1.
表1.
Table 1.
在无菌条件下，将上述成分混合，于2～8℃搅拌过夜，得到均一的滴眼液，罐装保存。Under aseptic conditions, the above ingredients are mixed, stirred overnight at 2-8° C. to obtain uniform eye drops, which are stored in jars.
实施例2.晶状体浑浊度和视力测试方法Embodiment 2. Lens turbidity and visual acuity test method
招募皮质性白内障患者，在签署了知情同意书之后，每日施用实施例1制备的滴眼液，一日四次，每次每只眼睛滴入1滴，连续给药12周。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.
在给药前，给药后的2周、4周、8周和12个月，进行视力检查及裂隙灯检查，监测患者的白内障症状改善情况。Before administration, 2 weeks, 4 weeks, 8 weeks and 12 months after administration, visual acuity examination and slit lamp examination were performed to monitor the improvement of cataract symptoms in patients.
视力检查采用ETDRS远视力表，测试患者的最佳矫正远视力和裸眼远视力。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.
另外，采用数码裂隙灯(瑞士HAAG-STREIT公司BX900型)采集晶状体数码照片后，由独立的2～3个阅片专家参照LOCSⅢ标准裂隙灯图片(图1)，对患者的晶状体核浑浊程度进行评分，取平均值，得到最终评分结果。 In addition, after collecting digital photos of the lens with a digital slit lamp (BX900 from HAAG-STREIT, Switzerland), 2 to 3 independent reviewers will evaluate the opacity degree of the patient's lens nucleus by referring to the LOCSⅢ standard slit lamp pictures (Fig. 1). Score and take the average to get the final scoring result.
根据图1所示的皮质性浑浊度C1～C5分级标准，将裂隙灯照片同标准照片C1～C5进行比较而分级。如果混浊程度介于两标准级之间，则用小数点表示。皮质混浊的范围从极微小皮质改变到完全的皮质混浊。评分标准：0.1～5.9。但轻度的水隙、空泡、板层分离及孤立的点状混浊均可忽略不计。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.
测试结果示于下表2中。The test results are shown in Table 2 below.
表2.皮质性白内障病人晶状体浑浊度及最佳矫正远视力测试结果
Table 2. Lens opacity and best corrected distance visual acuity test results in patients with cortical cataract
注：表中括号里的“-”指的是降低。Note: "-" in brackets in the table refers to reduction.
从表2的结果可以看出，不同程度的皮质性白内障患者在连续使用滴眼液四周后，晶状体皮质性混浊度有了一定的改善，混浊度评分较用药前平均降低了0.9左右。而且，最佳矫正远视力也较用药前有了明显提升，用药四周后较用药前平均提升了7个左右字母数。这些结果表明本发明的滴眼液对皮质性白内障的有良好的治疗效果，且安全。It can be seen from the results in Table 2 that after four weeks of continuous use of eye drops in patients with different degrees of cortical cataract, the cortical turbidity of the lens has improved to a certain extent, and the turbidity score has decreased by about 0.9 on average compared with before the medication. Moreover, the best corrected distance visual acuity has also improved significantly compared with before the medication, and the average number of letters has increased by about 7 letters after four weeks of medication. These results show that the eye drops of the present invention have a good therapeutic effect on cortical cataract and are safe.
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。 Although, the present invention has been described in detail with general description, specific implementation and test above, but on the basis of the present invention, some modifications or improvements can be made to it, which will be obvious to those skilled in the art . Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (9)

  1. 甾体化合物在制备预防和/或治疗白内障的药物中的应用，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；
    The application of a steroid compound in the preparation of a medicament for preventing and/or treating cataract, characterized in that the steroid compound has a structure as shown in formula I, or is a stereoisomer, mutual isomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs;
    其中，in,
    X选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的杂烷基或者取代或未取代的烷基，其中取代基选自羟基、巯基、氨基、芳基、杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；X is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroalkyl or substituted or Unsubstituted alkyl, wherein the substituent is selected from hydroxyl, mercapto, amino, aryl, heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=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；The 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为0、1、2或3；n is 0, 1, 2 or 3;
    R1、R2和R3各自独立地选自-H、-D或烷基。R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
  2. 根据权利要求1所述的应用，其特征在于，所述X选自取代或未取代的C6-10芳基、取代或未取代的C2-9杂芳基、取代或未取代的C3-8环烷基、取代或未取代的C2-10杂环烷基、取代或未取代的C1-6杂烷基或者取代或未取代的C1-6烷基，其中取代基选自羟基、巯基、氨基、C6-10芳基、C2-9杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；The application according to claim 1, wherein said X is selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 2-9 heteroaryl, substituted or unsubstituted C 3 -8 cycloalkyl, substituted or unsubstituted C 2-10 heterocycloalkyl, substituted or unsubstituted C 1-6 heteroalkyl or substituted or unsubstituted C 1-6 alkyl, wherein the substituent is selected from Hydroxyl, mercapto, amino, C 6-10 aryl, C 2-9 heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;
    R1、R2和R3各自独立地选自-H、-D或C1-6烷基。R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
  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、***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-***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]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基、带有H2NC(＝O)-取代基的C1-3烷基，或带有H2NC(＝NH)-NH-取代基的C1-3烷基。The application according to claim 2, wherein said 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, methylthioethyl, phenyl, naphthyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithiane base, thiaxyl, homopiperazinyl, homopiperidinyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl , 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazole Base, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1 ,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophene base, indolyl, purinyl, quinolinyl, isoquinolyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5 -a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo [1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, C 1-3 alkyl with H 2 NC(=O)-substituent, or C 1-3 alkyl with H 2 NC(=NH)-NH-substituent.
  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、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。The application according to claim 1, wherein n Qs are each independently selected from the group consisting of -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.
  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、***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-***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]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基或[1,2,4]***并[1,5-a]吡啶基。The application according to claim 4, wherein 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, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyridine Pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiopyranyl Oxanyl, homopiperazinyl, homopiperidinyl, oxepinyl, thiepanyl, oxazepinyl, diazapinyl, thiazepinyl, indolinyl, 1, 2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrole Base, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazole Base, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuryl, benzothienyl, ind Indolyl, Purinyl, Quinolinyl, Isoquinolyl, Imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl , [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]tri Azolo[1,5-a]pyridyl.
  6. 根据权利要求1-5中任一项所述的应用，其特征在于，所述式I所示结构的化合物选自以下化合物：




    The application according to any one of claims 1-5, wherein the compound of the structure shown in the formula I is selected from the following compounds:




  7. 根据权利要求1-6中任一项所述的应用，其特征在于，所述白内障为皮质性白内障或 者含皮质性白内障的混合型白内障。The application according to any one of claims 1-6, wherein the cataract is a cortical cataract or Mixed cataract with cortical cataract.
  8. 组合物在制备预防和/或治疗白内障药物中的应用，其特征在于，所述组合物包括权利要求1-7中任一项所述的甾体化合物，及药学上可接受的赋形剂。The application of the composition in the preparation of a medicament for preventing and/or treating cataract, characterized in that the composition comprises the steroid compound according to any one of claims 1-7, and a pharmaceutically acceptable excipient.
  9. 根据权利要求8所述的应用，其特征在于，所述白内障为皮质性白内障或者含皮质性白内障的混合型白内障。 The application according to claim 8, wherein the cataract is cortical cataract or mixed cataract containing cortical cataract.
PCT/CN2023/073362 2022-01-28 2023-01-20 Application of steroidal compound in prevention and/or treatment of cataracts WO2023143452A1 (en)

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