Application of steroid compound in preparation of medicine for preventing and / or treating ophthalmic diseases

Abstract

The invention provides an application of a steroid compound in preparation of a medicine for preventing and / or treating myopia. The steroid compound provided by the invention is shown as a formula (I), has treatment, slowing down and prevention effects on myopia, and can greatly delay, improve and / or cure myopia and improve vision definition. # imgabs0 #

Description

Application of steroid compounds in the preparation of drugs for preventing and / or treating ophthalmic diseases Technical Field

[0001] The present invention belongs to the technical field of chemical medicine and relates to the application of a steroid compound in the preparation of a medicine for preventing and / or treating myopia. Background Art

[0002] Myopia is a type of refractive error. When the eye is relaxed, light entering the eye parallel to the optical axis is focused in front of the retina, resulting in a lack of clear image formation on the retina. This is usually caused by an excessively long anteroposterior diameter of the eyeball (axial length), but may also be caused by excessive corneal curvature and / or increased refractive power of the lens. Generally, when the eye's spherical equivalent power is less than -0.5D in the relaxed state, it is considered myopia, and less than -6.0D, it is considered high myopia.

[0003] Studies have shown that in 2000, the number of people with myopia worldwide was 1.406 billion (prevalence rate 22.9%), and it is predicted that this number will reach 4.758 billion (prevalence rate 49.8%) by 2050, of which 938 million will be severely myopic (prevalence rate 9.8%). In China, data from the 2018 National Survey on Myopia among Children and Adolescents showed an overall prevalence of 53.6%, including 14.5% among six-year-olds, 36.0% among elementary school students, 71.6% among junior high school students, and 81.0% among high school students. Among the myopic senior high school students, 21.9% suffered from moderate to severe myopia. The rising prevalence of myopia and the younger age of patients have become a major public health issue affecting the eye health of Chinese citizens, especially adolescents.

[0004] The rising incidence of myopia is closely linked to environmental risk factors, socioeconomic development, and lifestyle changes, resulting from a complex interaction between genetic susceptibility and environmental exposure. Myopia prevention and control measures include creating a positive eye environment, enhancing awareness of healthy eye use, and implementing early detection and intervention.

[0005] Currently, the treatment of myopia is mainly achieved by changing the axial length of the eyeball or the refractive power of the cornea and lens. Specific methods include optical and surgical correction of vision, and drugs to delay the progression of myopia.

[0006] Optical correction involves wearing traditional single-vision lenses, contact lenses, progressive addition glasses, bifocal glasses, etc. However, optical correction does not fundamentally resolve the problem of refractive error. In other words, this treatment has no significant effect on changing the axial length of the eye or the refractive power of the lens, nor can it prevent eye diseases caused by high myopia.

[0007] Surgical correction methods primarily include corneal refractive surgery, scleral refractive surgery, and intraocular refractive surgery. Surgical changes to the lens' refractive state are considered intraocular refractive surgery. These procedures treat myopia by preventing axial growth or reducing the lens's refractive power. Traditional photorefractive keratectomy (PRK) ablates the corneal epithelium to alter refractive power. However, due to the slow healing of the corneal epithelium, it can cause eye pain, require a long postoperative recovery period, and is prone to the sequelae of corneal stromal opacities, making it largely obsolete. Currently, the most commonly used surgical method for correcting myopia is laser in situ keratomileusis (LASIK). Compared to PRK, LASIK does not require corneal epithelial ablation, resulting in less postoperative discomfort and faster visual recovery. It also reduces the wound healing process and the incidence of stromal opacities. However, LASIK is not suitable for patients with thin corneas, as it may result in mild myopia undercorrection and carries postoperative risks such as flap displacement and diffuse lamellar keratitis. Another new minimally invasive corneal refractive surgery, femtosecond laser small incision lenticule extraction (SMILE), has become one of the leading refractive surgeries due to its flapless, minimally invasive, small-incision, and all-femtosecond technology. SMILE significantly reduces complications associated with flap creation and excimer laser surgery, improving surgical safety. It also improves short- and long-term corneal biomechanical stability and reduces the risk of postoperative visual acuity loss and edema. However, compared with LASIK, SMILE results in slower visual recovery. While these surgical methods for vision correction are generally effective, they all have their limitations and require a high level of surgeon experience. Their long-term risks remain to be evaluated.

[0008] Research on drugs to delay the progression of myopia mainly focuses on muscarinic receptor (M receptor) antagonists, the most representative of which is atropine. In September 2021, the Australian Therapeutic Goods Administration (TGA) approved Aspen's Eikance, 0.01% atropine sulfate eye drops, for slowing the development of myopia in children and adolescents. Eikance can be used as a treatment option to slow the progression of myopia for children aged 4 to 14 years whose myopia progresses ≥-1.0D diopters per year. However, the adverse reactions of atropine eye drops include mydriasis, photophobia, iris adhesion, ciliary muscle paralysis, myopia rebound after discontinuation of the drug, etc. In addition, atropine has both peripheral and central M receptor antagonism, is non-selective for M1 and M2 receptors in the body, and is not highly selective for tissues and organs. Therefore, it is also necessary to avoid systemic absorption of atropine during clinical use.

[0009] Myopia in children requires long-term treatment. Therefore, there is an urgent need for safe and effective drugs that can prevent, alleviate, improve and / or treat myopia.

[0010] Summary of the Invention

[0011] In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a steroid compound for use in the preparation of a drug for preventing and / or treating myopia. The steroid compound provided by the present invention can have a good therapeutic, alleviating and preventive effect on myopia, can greatly reduce and / or cure myopia, and improve visual clarity.

[0012] To achieve this object, the present invention adopts the following technical solutions:

[0013] In a first aspect, the present invention provides a use of a steroidal compound in the preparation of a medicament for preventing and / or treating myopia, wherein the steroidal compound is a compound having a structure as shown in Formula I, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound having a structure as shown in Formula I;

[0014] wherein R is H, D (representing deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl, or -C(O)-X;

[0015] X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;

[0016] The aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl, alkylsilyl and alkyl groups in R and X are optionally substituted with 1, 2, 3 or 4 substituents which are the same or different;

[0017] The substituent is selected from D, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;

[0018] R 1 、R 2 and R 3 Each is independently selected from -H, -D or alkyl.

[0019] In some embodiments, the steroidal compound is a compound having a structure as shown in Formula II, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure as shown in Formula II;

[0020] wherein R is defined as in formula (I).

[0021] In some embodiments, R is H, D, C 1-6 Alkyl, sulfate, phosphate, C 1-6 Alkylsilyl, benzyl or -C(O)-X.

[0022] In some embodiments, X is selected from C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl or C 1-6 alkyl.

[0023] In some embodiments, the C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl, C 1-6 Alkylsilyl or C 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different.

[0024] In some embodiments, the substituent is selected from D, halogen, hydroxy, thiol, amino, cyano, nitro, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl, carboxyl (e.g. -COOH), R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -.

[0025] In some embodiments, R 1 、R 2 and R 3 Each independently selected from -H, -D or C 1-6 alkyl.

[0026] In some embodiments, X is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, mercaptoethyl, aminomethyl, aminoethyl, aminopropyl, phenylmethyl, phenylethyl, imidazolylmethyl, carboxymethyl, carboxyethyl, methylthiomethyl, methylthioethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -tetrahydroisoquinolyl, furanyl, 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, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, 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, [1,2,4]triazolo[1,5-a]pyridinyl, C with H2NC(=O)-substituent 1-3 Alkyl or C with H2NC(=NH)-NH-substituent 1-3 alkyl.

[0027] In some embodiments, the substituents in R and X are selected from -H, -D, halogen, hydroxy, amino, cyano, nitro, carboxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 Heteroaryl.

[0028] In other embodiments, the substituents in R and X are 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, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, disulfide pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazole yl, 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, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolinyl, isoquinolinyl, 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]triazolo[1,5-a]pyridinyl.

[0029] As a specific embodiment of the present invention, X is selected from any of the following groups:

[0030] As a specific embodiment of the present invention, the compound represented by the structure of Formula I or II is selected from any one of the following compounds:

[0031] The steroid compound provided by the present invention can be used as a raw chemical drug for treatment, or can be provided as an active ingredient of a pharmaceutical composition.

[0032] In a second aspect, the present invention provides the use of a composition in the preparation of a drug for preventing and / or treating myopia, wherein the composition comprises the steroid compound described in the first aspect, and one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants or vehicles.

[0033] Examples of 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 phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts; electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocked polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; and cellulose and its derivatives, such as carboxymethyl cellulose. sodium cellulose, ethylcellulose 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; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0034] In some embodiments, the composition comprises: a steroidal compound described herein, hypromellose, poloxamer 407, poloxamer 188, and water. In some embodiments, the mass percentage of the steroidal compound described herein in the composition is 0.05%-0.5%, for example, 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, etc.

[0035] In some embodiments, the composition includes: 10 to 40 parts by mass (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 or 40 parts by mass) of the steroid compound of the present invention, 110 to 120 parts by mass (e.g., 110, 112, 114, 116, 118 or 120 parts by mass) of hypromellose, 2050 to 2060 parts by mass (e.g., 2050, 2052, 2054, 2056, 2058 or 2060 parts by mass) of poloxamer 407, 160 to 170 parts by mass (e.g., 160, 162, 164, 166, 168 or 170 parts by mass) of poloxamer 188 and 10,000 parts by mass of water.

[0036] In some embodiments, the composition may be eye drops. The eye drops may be suspension eye drops. In some embodiments of the present invention, the eye drops may have a size of 5 mL or 10 mL.

[0037] In a third aspect, the present invention provides a method for preventing and / or treating myopia, comprising administering to a subject a steroid compound defined in the application described in the first or second aspect or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or compositions.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The steroid compound provided by the present invention can prevent, alleviate, improve and / or treat the patient's myopia by improving the patient's refractive power, improving the axial length, equatorial diameter and anteroposterior diameter of the eyeball, and has extremely small side effects. DETAILED DESCRIPTION

[0040] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the specific embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0042] As used herein, "stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0043] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon 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 substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0044] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0045] Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0046] The term "prodrug" as used herein refers to a compound that is converted in vivo into a compound represented by Formula I. Such conversion is affected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see 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 SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0047] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see 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, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL 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).

[0048] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), 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 isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0049] The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarates, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or such salts may be obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible 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 appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0050] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0051] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0052] 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, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0053] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0054] A "pharmaceutical composition" refers to a mixture of one or more compounds, salts, or physiologically / pharmaceutically acceptable salts or prodrugs thereof described herein with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0055] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., 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 regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0056] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl radicals include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), ... -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0057] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocycles having 7-12 atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocycles having 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way 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, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the "cyclic aliphatic group" or "carbocycle", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, thiol, 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.

[0058] The terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring(s) are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings herein, the ring(s) may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to another molecule. One or more hydrogen atoms in the ring(s) are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0059] Heterocyclic groups can be carbon groups or heteroatom groups. "Heterocyclic group" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 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-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethan-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]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. The heterocyclic group may be substituted or unsubstituted, and the substituents may be, but are not limited to, oxo (=O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, 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.

[0060] The term "aryl" can be used alone or as part of "aralkyl," "aralkoxy," or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," and aromatic rings can include, for example, phenyl, naphthyl, and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, 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.

[0061] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 ring members, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meanings herein, and wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic" or "heteroaromatic compound." And the heteroaryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, thiol, 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.

[0062] In other embodiments, heteroaryl includes the following monocyclic rings, but is not limited to these monocyclic rings: 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-methylisoxazol-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 is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0063] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).

[0064] The term "heteroalkyl" means that one or more heteroatoms may be inserted into the middle of the alkyl chain, wherein the alkyl group and heteroatom have the meanings as described herein. Unless otherwise specified, the heteroalkyl group contains 1-10 carbon atoms, in other embodiments, the heteroalkyl group contains 1-8 carbon atoms, in other embodiments, the heteroalkyl group contains 1-6 carbon atoms, in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms. Such examples include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, CH3SCH2CH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, etc.

[0065] The term "halogen" refers to F, Cl, Br or I.

[0066] The term "halogenated" used in the present invention means that the group following it is substituted with halogen, and the number of substitutions can be one or more.

[0067] The term "hydroxy-substituted" used in the present invention means that the group following it is substituted with a hydroxyl group, and the number of substitutions may be one or more.

[0068] When "substituted" in the present invention is used between two groups, it is preceded by a substituent, such as "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means that the alkyl group has an alkoxycarbonyl substituent.

[0069] When multiple groups of the present invention are used in combination, they are in a substitution relationship from left to right, such as "arylalkyl" represents an alkyl substituted by an aryl group, and "alkoxyalkoxy" represents an alkoxy substituted by an alkoxy group.

[0070] Example 1

[0071] In this example, two eye drops were prepared, and the compositions are shown in Table 1.

[0072] Table 1

[0073] The preparation method is as follows:

[0074] Under aseptic operation, the above ingredients were mixed, stirred at 2-8°C overnight to obtain a homogeneous mixed solution, and then stored in an eye dropper bottle.

[0075] Example 2 Guinea Pig Myopia Effect Test

[0076] 1. Model establishment

[0077] Thirty-two male tricolor guinea pigs that passed quarantine were randomly divided into four groups according to body weight, namely: model control group (Group A), positive control group (Group B, 0.01% atropine eye drops), prescription group 1 (Group C), and prescription group 2 (Group D), with 8 animals in each group. The correspondence between the groups and the experimental numbers is shown in Table 2.

[0078] Table 2. Group and animal number table

[0079] Note: Animal number is represented by group number + sex number (1 for male) + the last two digits of quarantine number.

[0080] After inducing anesthesia in the animals using 3-4% isoflurane, shave the hair around the eye sockets, maintain anesthesia with 1.5-2.5% isoflurane, disinfect the skin around the eye sockets with iodine, and fix a simple spherical resin lens with a refractive power of -10.0D in front of the right eye of the modeling animal. The day of surgery is recorded as day 0, the next day is recorded as day 1, and so on, until the administration is completed. During the modeling and administration process, check the lens for looseness, falling off, and lens cleanliness once in the morning and afternoon every day to ensure good light transmittance of the lens. If the lens position falls off, adjust it in time to ensure that the lens is fixed in front of the right eye. If the animal's eyes have excessive secretions, wipe them clean with a cotton swab soaked in saline.

[0081] 2. Indicator detection and frequency

[0082] 1) Body weight: Weigh once a week after model establishment.

[0083] 2) Refractive Index Test: Refractive index was measured before grouping and on days 7, 14, 21, and 27. Procedure: Guinea pigs were placed in the conjunctival sac of both eyes, with one drop of compound tropicamide eye drops instilled into the pupils. Ten minutes later, the drops were repeated twice, and the eyes were placed in a dark room for approximately one hour. After the pupils were fully dilated, the refractive index of both eyes was measured. The working distance was 0.5 m, and the refractive index was measured to the nearest 0.25 D. Three parallel measurements were performed, and the average value was calculated.

[0084] 3) Axial length: The axial length of the eye was measured before grouping, and on days 6, 13, 20, and 27. Specific procedures: The guinea pigs were captured and anesthetized using 3-4% isoflurane for induction, followed by 1.5-2.5% isoflurane for maintenance. 0.4% oxybuprocaine hydrochloride eye drops were used for infiltration anesthesia of the eyeball surface, with one drop administered every 5 minutes for a total of three times. The axial length of both eyes (the distance from the corneal surface to the vitreoretinal interface at the posterior pole of the eyeball) was measured to the nearest 0.01 mm. The test was repeated five times in parallel, and the average value was taken. After the test, ofloxacin eye drops were administered to prevent infection.

[0085] 4) Equatorial and anteroposterior diameters of the eyeball: On day 28, the rats were anesthetized with an intramuscular injection of 0.02 mL / 100 g of compound ketamine and sacrificed by exsanguination via the abdominal aorta. The muscles and connective tissue surrounding the eyeballs were separated, and the eyeballs of both eyes were removed for measurement of the equatorial and anteroposterior diameters of the eyeballs.

[0086] 5) Method of animal sacrifice or treatment of surviving animals at the end of the experiment: After anesthesia with intramuscular injection of 0.02 mL / 100 g of compound ketamine, animals were sacrificed by exsanguination from the abdominal aorta.

[0087] 3. Results and Conclusions

[0088] 1) Body weight: The body weight of animals in each group increased normally, and there was no significant difference between the groups, indicating that the test substances had no significant effect on the body weight of the animals.

[0089] 2) Refractive index test: The results are shown in Tables 3, 4, and 5 below:

[0090] Table 3. Effects on the refractive power of the left eye ( n=8, unit: D)

[0091] Note: vs. model control group A: *, p < 0.05, **, p < 0.01; a, group D, n = 7.

[0092] As shown in Table 3, the overall trend of left eye refraction in each group of animals was an initial increase followed by a decrease. This may be related to the changes in refraction during the growth of the experimental animals from 3 to 4 weeks of age, as well as the experimental detection method. During the first week of modeling and drug administration (1 week), the left eye refraction of Groups B, C, and D was significantly higher than that of the model control, Group A (p < 0.01). Combined with the refraction results at other time points and the axial length results at week 1, this is likely due to a certain stress response to modeling in these animals, resulting from individual differences and is not clinically significant.

[0093] Table 4. Effects on the refractive power of the right eye ( n=8, unit: D)

[0094] Note: vs. model control group A: *, p < 0.05, **, p < 0.01; vs. left eye refraction of each group: ##, p < 0.01; a, group C, n = 7,

[0095] Group D, n = 6; b, Groups B and C, n = 7.

[0096] As shown in Table 4, starting from the first week of model establishment and drug administration, the right eye refractive index of all groups was significantly lower than that of the left eye (p < 0.01), indicating successful model establishment. Starting from the second week, the right eye refractive index of all drug groups was significantly higher than that of the model control group A at the same time, with statistical significance (p < 0.01 or 0.05). Comparison of the mean right eye refractive index of each drug group showed that group D > group C > group B.

[0097] Table 5. Effects on the diopter difference between left and right eyes (left eye - right eye) n=8, unit: D)

[0098] Note: vs. model control group A: *, p < 0.05, **, p < 0.01; a, group C, n = 7, group D, n = 6; b, groups B and C, n = 7.

[0099] As can be seen from Table 5, at the 2nd and 4th weeks after model establishment and drug administration, the differences in diopter between the left and right eyes in each drug group were significantly lower than those in Model Control Group A (p<0.01); at the 4th week, when comparing the mean values of the differences in diopter between the left and right eyes in each group, the change trend was completely consistent with the change in the diopter of the right eye.

[0100] 3) Axial length of the eye: Tables 6, 7, and 8 statistically analyzed the axial lengths of the left and right eyes of the animals in each group and the comparison situation.

[0101] Table 6. Influence on the axial length of the left eye ( n = 8, unit: mm)

[0102] Table 7. Influence on the axial length of the right eye ( n = 8, unit: mm)

[0103] Note: vs Model Control Group A: *, p<0.05, **, p<0.01.

[0104] Table 8. Influence on the difference in axial length between the left and right eyes (right eye - left eye) ( n = 8, unit: mm)

[0105] Note: vs Model Control Group A: *, p<0.05, **, p<0.01.

[0106] As can be seen from Tables 6, 7, and 8, the overall axial lengths of the left and right eyes of the animals in each group gradually increased, which was consistent with the development trend of the animal eyeballs. There was no significant difference in the axial length of the left eye among the groups; for the axial length of the right eye, at the 1st week after model establishment and drug administration, each drug group was significantly lower than Model Control Group A (p<0.01 or 0.05), indicating that Groups B, C, and D could delay the increase in the axial length of the eyes in early - stage myopic animals; since the 1st week, for the difference in axial length between the left and right eyes, each drug group was lower than Model Control Group A. At the 2nd and 4th weeks, when comparing the mean values of the axial length of the right eye and the difference in axial length between the left and right eyes in each drug group, Groups C and D < Group B.

[0107] 4) Equatorial diameter and anteroposterior diameter of the eyeball: Tables 9 and 10 statistically analyzed the equatorial diameter and anteroposterior diameter values of the left and right eyes of the animals in each group.

[0108] Table 9. Influence on the equatorial diameter of the eyeball at 4 weeks ( n = 8, unit: mm)

[0109] Note: vs Model Control Group: *, p<0.05, **, p<0.01.

[0110] Table 10. Influence on the anteroposterior diameter of the eyeball at 4 weeks ( n = 8, unit: mm)

[0111] Note: vs the model control group: *, p < 0.05, **, p < 0.01; vs the left eyes of each group: #, p < 0.05.

[0112] As can be seen from Table 9 and Table 10, at the 4th week after modeling and administration, the equatorial diameter and anteroposterior diameter of the right eyeballs of the animals in Model Control Group A were higher than those of the left eyes, indicating successful modeling; the equatorial diameter of the left eyeballs in Group D was significantly higher than that in Model Control Group A, which should be due to individual differences in animals and has no clinical significance; there were no significant differences in the equatorial diameter of the right eyeballs and the difference in the equatorial diameter between the left and right eyeballs of each group of animals; there were no significant differences in the anteroposterior diameter of the left eyeballs of each group of animals, and the anteroposterior diameter of the right eyeballs and the difference in the anteroposterior diameter between the left and right eyeballs in Groups B, C, and D were significantly lower than those in Model Control Group A (p < 0.01). When comparing the mean values of the equatorial diameter of the right eyeballs and the difference in the equatorial diameter between the left and right eyeballs of each drug group, Groups C and D < Group B; when comparing the mean values of the anteroposterior diameter of the right eyeballs and the difference in the anteroposterior diameter between the left and right eyeballs, Group D < Group C < Group B.

[0113] 5) Conclusion

[0114] Under the conditions of this experiment, an optically defocused guinea pig myopia model was prepared, with the right eye as the modeled eye and the left eye as the control eye. After modeling, the diopter of the right eye of the animals in the model control group was significantly lower than that of the left eye, the equatorial diameter and anteroposterior diameter of the right eyeballs were significantly higher than those of the left eye, and the axial length of the right eye was also higher than that of the left eye, indicating successful modeling; modeling and administration had no significant effect on the body weight of the animals. Instilling 20 μL of Prescription 1 (0.2%) or Prescription 2 (0.4%) once a day for 28 consecutive days could significantly delay the decrease in the diopter of the right eye, the increase in the equatorial diameter and anteroposterior diameter of the eyeballs in the model animals, and also had a certain improvement effect on the axial length of the eyes, indicating that Prescription 1 and Prescription 2 had the effects of delaying, improving, and reversing myopia. After comprehensive comparison, at the same administration volume, the effect of Prescription 2 was better than that of Prescription 1, and both Prescription 1 and Prescription 2 were better than the positive control drug.

[0115] Although the present invention has been described in detail above with general descriptions, specific embodiments and experiments, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

Claims

1. Use of a steroid compound in the preparation of a medicament for preventing and / or treating myopia, characterized in that: The steroidal compound is a compound having a structure as represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound having a structure as represented by formula (I); wherein R is H, deuterium, alkyl, sulfate, phosphate, alkylsilyl, benzyl, or -C(O)-X; X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl; The aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl, alkylsilyl and alkyl groups in R and X are optionally substituted with 1, 2, 3 or 4 substituents which are the same or different; The substituent is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -; R 1 、R 2 and R 3 Each is independently selected from H, deuterium or alkyl.

2. The use according to claim 1, wherein The steroid compound is a compound having a structure as represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound having a structure as represented by formula (II), wherein R is defined as in formula (I).

3. The use according to claim 1 or 2, wherein: R is H, deuterium, or C 1-6 Alkyl, sulfate, phosphate, C 1-6 Alkylsilyl, benzyl or -C(O)-X; X is selected from C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl or C 1-6 alkyl; R and X are described in C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl, C 1-6 Alkylsilyl or C 1-6 The alkyl group is optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different; The substituent is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -; R 1 、R 2 and R 3 are each independently selected from H, deuterium or C 1-6 alkyl.

4. The use according to any one of claims 1 to 3, characterized in that X is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, mercaptoethyl, aminomethyl, aminoethyl, aminopropyl, phenylmethyl, phenylethyl, imidazolylmethyl, carboxymethyl, carboxyethyl, methylthiomethyl, methylthioethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, cyclohex ... pentyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-[4-(2-methyl-2-oxo-4-yl)-1-oxo-4-oxo-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-triazine yl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolinyl, isoquinolinyl, 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, [1,2,4]triazolo[1,5-a]pyridinyl, C with H2NC(=O)-substituent 1-3 Alkyl or C with H2NC(=NH)-NH-substituent 1-3 alkyl.

5. The use according to any one of claims 1 to 4, characterized in that The substituent is selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 Heteroaryl.

6. The use according to any one of claims 1 to 5, characterized in that The substituents are selected from deuterium, -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, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl , 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazole yl, 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, benzothiophenyl, indolyl, purinyl, quinolinyl, isoquinolinyl, 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]triazolo[1,5-a]pyridinyl.

7. The use according to any one of claims 1 to 6, characterized in that X is selected from any of the following groups:

8. The use according to any one of claims 1 to 7, characterized in that: The compound represented by the formula I is selected from any one of the following compounds:

9. Use of the composition in preparing a medicament for preventing and / or treating myopia, characterized in that: The composition comprises the steroid compound according to any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants or vehicles.

10. The use according to claim 9, characterized in that The composition comprises: a steroid compound, hypromellose, poloxamer 407, poloxamer 188 and water; Preferably, the composition comprises: 10-40 parts by mass of a steroid compound, 110-120 parts by mass of hypromellose, 2050-2060 parts by mass of poloxamer 407, 160-170 parts by mass of poloxamer 188 and 10,000 parts by mass of water.

11. A method for preventing and / or treating myopia, comprising administering to a subject a steroid compound as defined in any one of claims 1 to 10 or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition thereof.

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