WO2024017315A1 - 甾体化合物在制备预防和/或治疗眼科疾病药物中的应用 - Google Patents
甾体化合物在制备预防和/或治疗眼科疾病药物中的应用 Download PDFInfo
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- WO2024017315A1 WO2024017315A1 PCT/CN2023/108280 CN2023108280W WO2024017315A1 WO 2024017315 A1 WO2024017315 A1 WO 2024017315A1 CN 2023108280 W CN2023108280 W CN 2023108280W WO 2024017315 A1 WO2024017315 A1 WO 2024017315A1
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- Prior art keywords
- alkyl
- compound
- group
- aryl
- heteroaryl
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- -1 steroid compound Chemical class 0.000 title claims abstract description 154
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- the invention belongs to the technical field of chemical medicine and relates to the application of a steroid compound in the preparation of medicines for preventing and/or treating myopia.
- Myopia is a type of refractive error.
- the light entering the eye parallel to the optical axis is focused in front of the retina, resulting in the inability to form a clear image on the retina.
- This is usually due to an excessively long anteroposterior diameter (axial length) of the eyeball, which may also be caused by excessive curvature of the cornea and/or increased refractive power of the lens.
- the spherical equivalent power of the eyes in the relaxed state is less than -0.5D, it is myopia, and when it is less than -6.0, it is high myopia.
- myopia The increasing incidence of myopia is closely related to environmental risk factors, socioeconomic development and lifestyle changes, and is the result of a complex interaction between genetic susceptibility and environmental exposure. Prevention and control measures for myopia include creating a good eye environment, enhancing awareness of healthy eye use, early detection and early intervention, etc.
- 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.
- Optical correction refers to wearing traditional single vision lenses, contact lenses, progressive multifocal glasses, bifocal glasses, etc.
- optical correction does not fundamentally solve the problem of refractive error.
- this treatment method has no obvious effect on changing the axial length of the eye and the refractive power of the lens, nor can it prevent eye lesions caused by high myopia.
- Surgical correction methods mainly include corneal refractive surgery, scleral refractive surgery and intraocular refractive surgery.
- the refractive state of the lens that is surgically changed is intraocular refractive surgery.
- These methods treat myopia by preventing axial growth of the eye or reducing the power of the lens.
- Traditional excimer laser photorefractive keratectomy photorefractive keratectomy, PRK
- PRK photorefractive keratectomy
- LASIK excimer laser in situ keratomileusis
- SMILE minimally invasive corneal refractive surgery - femtosecond laser small incision corneal stromal lens extraction
- SMILE can greatly reduce the complications related to corneal flap production and excimer laser, improve the safety of the operation, and at the same time, this surgical method can improve short-term and long-term improvement. It can provide long-term corneal biomechanical stability and reduce the risk of visual regression and edema after laser surgery.
- visual recovery after SMILE is slower. It can be seen that most of these methods of surgical vision correction have good effects, but they all have their own limitations and require high surgical experience of surgeons, and their long-term risks still need to be evaluated.
- Atropine muscarinic receptor
- TGA Therapeutic Goods Administration
- Aspen's Eikance 0.01% atropine sulfate eye drops
- Eikance is indicated as a treatment option to slow the progression of myopia in children aged 4 to 14 years whose myopia progresses by ⁇ -1.0 D of diopter per year.
- the adverse reactions of atropine eye drops include mydriasis, photophobia, iris synechiae, cycloplegia, myopia rebound after drug withdrawal, etc.
- atropine has both peripheral and central M receptor antagonism, no selectivity for M1 and M2 receptors in the body, and low selectivity for tissues and organs. Therefore, it is necessary to avoid systemic absorption of atropine during clinical use.
- the purpose of the present invention is to provide an application of a steroid compound in the preparation of medicines for preventing and/or treating myopia.
- the steroid compound provided by the invention can effectively treat and slow down myopia. And preventive effect, it can greatly reduce and/or cure myopia and improve the clarity of vision.
- the present invention adopts the following technical solutions:
- the present invention provides the use of a steroid compound in the preparation of medicines for preventing and/or treating myopia.
- the steroid compound is a compound with a structure shown in Formula I, or a compound with a structure shown in Formula I.
- R is H, D (representing deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl or -C(O)-X;
- X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;
- aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl, alkylsilyl and alkyl groups mentioned in R and X are optionally substituted by 1, 2, 3 or 4 identical or different substituents replaced;
- R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
- the steroid compound is a compound with a structure as shown in Formula II, or a stereoisomer, tautomer, nitrogen oxide, solvate, or a compound with a structure as shown in Formula II.
- R is the same as formula (I).
- R is H, D, 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 heterocyclyl, C 1-6 heteroalkyl or C 1 -6 alkyl.
- R and , C 1-6 alkylsilyl or C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 identical or different substituents.
- R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
- 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, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydr
- the substituents described in R and C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 2-9 heteroaryl.
- X is selected from any of the following groups:
- the compound of the structure shown in formula I or II is selected from any one of the following compounds:
- the steroidal compounds provided by the present invention can be used for treatment as raw chemicals or can be provided as active ingredients of pharmaceutical compositions.
- the present invention provides the use of a composition in the preparation of a medicine for preventing and/or treating myopia.
- the composition includes the steroid compound described in the first aspect, and a pharmaceutically acceptable carrier and excipient. , diluents, auxiliaries or vehicles.
- Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; sorbate Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salt; electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocked polymer; lanolin; sugar, such as lactose, glucose and sucrose; starch, such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and s
- the composition includes: a steroid compound of the invention, hypromellose, poloxamer 407, poloxamer 188, and water.
- the mass percentage of the steroid compound of the present invention in the composition is 0.05%-0.5%, such as 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.3% , 0.35%, 0.4%, 0.45%, etc.
- the composition includes: 10 to 40 parts by mass (for example, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 or 40 parts by mass) steroid compound according to the present invention, 110 to 120 parts by mass (such as 110, 112, 114, 116, 118 or 120 parts by mass) hypromellose, 2050 to 2060 parts by mass (such as 2050, 2052, 2054, 2056, 2058 or 2060 parts by mass) poloxamer 407, 160 to 170 parts by mass (such as 160, 162, 164, 166, 168 or 170 parts by mass) poloxamer 188 and 10000 parts by mass water.
- 10 to 40 parts by mass for example, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 or 40 parts by mass
- 110 to 120 parts by mass such as 110, 112, 114, 116, 118 or 120 parts by mass
- hypromellose such as 2050, 2052, 2054, 2056, 2058 or 2060 parts by mass
- the composition can be eye drops.
- the eye drops may be suspension eye drops.
- the specifications of the eye drops may be 5 mL or 10 mL.
- the present invention provides a method for preventing and/or treating myopia, comprising administering to a subject a steroid compound or a stereoisomer thereof defined in the application described in the first or second aspect, Tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or combinations.
- the present invention has the following beneficial effects:
- the steroid compound provided by the invention can prevent, reduce, improve and/or treat the patient's myopia by increasing the patient's refractive power, improving the axial length, equatorial diameter and anteroposterior diameter of the eyeball, and has minimal side effects.
- Stereoisomers refer to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
- the compounds of the invention can be expressed as one of the possible isomers or as a mixture thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) exists in the form.
- 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.
- Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
- the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Therefore, the individual stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.
- prodrug used in the present invention represents a compound that is converted into a compound of Formula I in the body. Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue.
- the prodrug compound of the present invention can be an ester.
- esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonate esters. , carbamates and amino acid esters.
- a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound.
- prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent.
- phosphate esters which are obtained by phosphorylation of the hydroxyl group of the parent.
- racemate of the final product or intermediate may be resolved into its optical antipodes by known methods familiar to those skilled in the art, e.g., by subjecting the diastereomeric salts thereof obtained separation.
- Racemic products can also be Separation can be achieved by chiral chromatography, such as high performance liquid chromatography (HPLC) using chiral adsorbents.
- HPLC high performance liquid chromatography
- 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.
- tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
- protontautomers also called prototropic tautomers
- Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.
- keto-enol tautomerism is pentane-2,4-dione and tautomerism of 4-hydroxypent-3-en-2-one.
- tautomerism is phenol-ketone tautomerism.
- a specific example of phenol-ketone tautomerism is an interconversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- salts mentioned in the present invention are pharmaceutically acceptable salts, and "pharmaceutically acceptable salts" are well known in the art.
- pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, and nitrates.
- organic acid salts such as carboxylates, sulfonates, sulfinates, sulfur carboxylates, etc., specifically such as, but not limited to, methanesulfonate, ethanesulfonate, methanesulfonate, etc.
- Acid acetate, succinate, benzoate, succinate, pamoate, salicylate, galactoate, glucoheptanoate, mandelate, 1,2 -Ethanyl disulfonate, 2-naphthalene sulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, Citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate or oxalic acid, or as described in books and literature Other methods such as ion exchange are used to obtain these salts.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonic acid Salt, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enanthate, caproic acid Salt, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamate, fruit Collate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc.
- pharmaceutically acceptable salts also include salts derived from appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- bases such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- the present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and others.
- 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.
- salts can be formed with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/carbonates , bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline salt, citrate, ethylene disulfonate, fumarate, glucoheptonate, gluconate, Glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactosuronate, lauryl sulfate, malate, maleate, propylene glycol acid salt, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate , Pamate, phosphate
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts may 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, etc.
- Solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association of solvent molecules with water.
- “Pharmaceutical composition” means a mixture of one or more compounds, salts or physiologically/pharmaceutically acceptable salts or prodrugs thereof as described herein with other chemical components, e.g. physiologically/pharmaceutically acceptable Acceptable carrier or excipient.
- the purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism.
- any disease or condition as used herein means ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof).
- “treating” or “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient.
- “treating” or “treating” refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both.
- “treating” or “treating” refers to preventing or delaying the onset, development, or progression of a disease or condition.
- alkyl as used herein means 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 A saturated linear or branched chain monovalent hydrocarbon group of 1 to 3 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention.
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 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-
- alkyl and its prefix “alkyl” as used herein include both straight and branched saturated carbon chains.
- alkylene refers to a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a linear or branched saturated hydrocarbon. Examples of such include, but are not limited to, methylene, ethylene , sub-isopropyl and so on.
- cycloalkyl refers to a monovalent or polyvalent, nonaromatic, saturated or partially unsaturated ring and containing no heteroatoms, including a monocyclic ring of 3 to 12 carbon atoms or a monocyclic ring of 7 to 12 carbon atoms.
- the second ring Bicyclic carbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system.
- Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
- cyclic aliphatic groups 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 base, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
- heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms are independently and optionally substituted by heteroatoms having the meaning as described herein, the ring may be fully saturated or contain one or more degrees of unsaturation, but is never aromatic, There is only one connection point to other molecules. Hydrogen atoms on one or more rings are independently and optionally substituted with one or more substituents described herein.
- the "heterocycle", “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , when said When the ring is a three-membered ring with only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P optionally substituted by one or more oxygen atoms to give groups such as SO, SO 2 , PO, PO 2 ).
- Heterocyclyl groups may be carbon or heteroatom groups.
- Heterocyclyl also includes groups formed by combining a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles 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, oxepanyl, thiepanyl, 4-meth
- heterocyclic groups also include, 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms on the ring are replaced by oxygen atoms.
- aryl may be used alone or as a large part of "aralkyl", “aralkoxy” or “aryloxyalkyl” to mean monocyclic, bicyclic, and bicyclic rings containing a total of 6 to 14 members.
- a tricyclic carbocyclic ring system in which at least one ring system is aromatic and in which each ring system contains a 3- to 7-membered ring and has only one point of attachment to the rest of the molecule.
- aryl may be 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 a total of 5 to 14 membered rings, in which at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroaryl Atoms have the meaning given herein, wherein each ring system contains a 3-7 membered ring and has only one point of attachment to the rest of the molecule.
- heteroaryl may be used interchangeably with the term “aromatic heterocycle” or "heteroaromatic compound.”
- the heteroaryl group includes, but is not limited to, the following 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-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-triazoly
- 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 heterocycles
- N e.g. N in 3,4-dihydro-2H-pyrrolyl
- NH e.g. NH in pyrrolidinyl
- NR e.g. N-substituted pyrrole NR in alkyl groups.
- heteroalkyl means that one or more heteroatoms may be inserted into the middle of the alkyl chain, wherein the alkyl group and the heteroatoms have the meanings described herein. Unless otherwise specified, heteroalkyl groups contain 1 to 10 carbon atoms. In other embodiments, heteroalkyl groups contain 1 to 8 carbon atoms. In other embodiments, heteroalkyl groups contain 1. -6 carbon atoms, in other embodiments the heteroalkyl group contains 1-4 carbon atoms, in other embodiments the heteroalkyl group contains 1-3 carbon atoms.
- Such 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 as used in the present invention means substituting a subsequent group with a halogen, and the number of substitutions may be one or more.
- Hydro-substituted in the present invention means that the following groups are replaced with hydroxyl groups, and the number of substitutions can be one or more.
- substituted in the present invention is used between two groups, it is preceded by a substituent.
- aryl-substituted alkyl means that the alkyl group has an aryl substituent
- alkoxycarbonyl "Substituted alkyl” means an alkyl group having an alkoxycarbonyl substituent.
- substitution relationship is from left to right, such as "arylalkyl”, which represents an aryl-substituted alkyl group, and "alkoxyalkoxy”, which represents an alkoxy group. Substituted alkoxy.
- the preparation method is as follows:
- the animal number is represented by the group number + gender number (1 is male) + the last two digits of the quarantine number.
- Diopter test Diopter test before grouping and on days 7, 14, 21, and 27. Specific operation: Grab the guinea pig, drop 1 drop of compound tropicamide eye drops into the conjunctival sac of both eyes to dilate the pupils, and then drop it again 10 minutes later, for a total of 2 times, and place it in a dark room for about 1 hour until the pupils are completely dilated. Then, check the diopter of both eyes. The working distance is 0.5m, accurate to 0.25D, parallel detection is performed 3 times, and the average value is taken.
- Axial length of the eye Detect the axial length of the eye before grouping and on days 6, 13, 20, and 27. Specific operations: Grab the guinea pig, use 3-4% isoflurane to induce anesthesia, maintain anesthesia with 1.5-2.5% isoflurane, and use 0.4% oxybuvacaine hydrochloride eye drops to inject the eyeball. Surface infiltration anesthesia, 1 drop each time, once every 5 minutes, 3 times in total, measure the axial length of both eyes (take the distance from the corneal surface to the vitreoretinal interface at the posterior pole of the eyeball), accurate to 0.01mm, and measure 5 times in parallel. take the average. After the test, ofloxacin eye drops are dripped to prevent infection.
- Equatorial diameter and anteroposterior diameter of the eyeballs On the 28th day, 0.02mL/100g compound ketamine was injected intramuscularly for anesthesia, and the subjects were sacrificed by bleeding from the abdominal aorta. The muscles and connective tissues around the eyeballs were separated, and both eyes were removed to detect the equatorial diameter and the anteroposterior diameter of the eyeballs.
- Tables 6, 7, and 8 provide statistics on the axial length and comparison of the left and right eyes of animals in each group.
- vs model control group A *, p ⁇ 0.05, **, p ⁇ 0.01.
- vs model control group A *, p ⁇ 0.05, **, p ⁇ 0.01.
- Equatorial diameter and anteroposterior diameter of the eyeball show the equatorial diameter and anteroposterior diameter of the left and right eyes of each group of animals.
- vs model control group *, p ⁇ 0.05, **, p ⁇ 0.01.
- vs model control group *, p ⁇ 0.05, **, p ⁇ 0.01; vs left eye of each group: #, p ⁇ 0.05.
- Groups B, C and D The anteroposterior diameter of the right eyeball and the difference between the anteroposterior diameter of the left and right eyeballs in the group were significantly lower than those in the model control group A (p ⁇ 0.01). Comparing the mean difference between the equatorial diameter of the right eyeball and the equatorial diameter of the left and right eyeballs in each drug group, Group C and D were ⁇ Group B; comparing the mean difference between the anteroposterior diameter of the right eyeball and the anteroposterior diameter of the left and right eyeballs, Group D ⁇ Group C ⁇ Group B.
- an optical defocus guinea pig myopia model was prepared.
- the right eye was the modeling eye and the left eye was the control eye.
- the diopter of the right eye in the model control group was significantly lower than the left eye after modeling.
- the equatorial diameter and anteroposterior diameter of the right eyeball were It was significantly longer than that of the left eye, and the axial length of the right eye was also longer than that of the left eye.
- the modeling was successful; both modeling and administration had no significant effect on the animal's weight.
- Eye drops administered 20 ⁇ L of Prescription 1 (0.2%) or Prescription 2 (0.4%) once a day for 28 consecutive days can significantly delay the decrease in the refractive power of the right eye of the model animal and the increase in the equatorial diameter and anterior-posterior diameter of the eyeball. It also has an effect on the axial length of the eye. There is a certain improvement effect, indicating that Prescription 1 and Prescription 2 have the effect of delaying, improving, and reversing myopia. Comprehensive comparison, under the same dosage volume, Prescription 2 is better than Prescription 1, and Prescription 1 and Prescription 2 are both better than the positive control drug.
Abstract
本发明提供了一种甾体化合物在制备预防和/或治疗近视的药物中的应用。本发明提供的甾体化合物如式(I)所示,对近视具有治疗、减缓和预防效果,能够极大程度地延缓、改善和/或治愈近视,提高视力清晰度。
Description
本发明属于化学医药技术领域,涉及一种甾体化合物在制备预防和/或治疗近视的药物中的应用。
近视/近视眼(Myopia),是屈光不正的一种,当眼睛调节放松时,平行于光轴进入眼睛的光线被聚焦在视网膜前,导致视网膜上不能形成清晰像。这通常是由于眼球前后径(眼轴长度)过长,也可能是由角膜过度弯曲和(或)晶状体屈光力增加造成的。通常,调节放松状态下眼睛的等效球镜度小于-0.5D时为近视,小于-6.0时为高度近视。
研究表明,2000年全球近视患病人数14.06亿(患病率22.9%),预测2050年将达到47.58亿(患病率49.8%),其中9.38亿为高度近视(患病率9.8%)。在中国,2018年全国儿童青少年近视调查数据显示,患病率总体为53.6%,其中6岁儿童为14.5%、小学为36.0%、初中为71.6%、高中为81.0%,高三近视人群中中高度近视占21.9%。近视患病率升高,患者低龄化,已成为影响中国国民尤其是青少年眼健康的重大公共卫生问题。
近视发生率的升高与环境危险因素、社会经济发展和生活方式改变密切相关,是遗传易感性和环境暴露之间复杂的相互作用的结果。近视的防控措施有营造良好用眼环境、增强健康用眼意识、早发现早干预等。
目前治疗近视主要通过改变眼球轴向长度或者角膜、晶状体的屈光度来实现,具体手段包括光学和手术矫正视力,以及药物延缓近视进展三大类。
光学矫正是指佩戴传统的单光镜片、角膜接触镜,以及渐进多焦点眼镜、双焦点眼镜等。然而,光学矫正并未从根本上解决屈光不正的问题,也就是说,这种治疗手段对改变眼睛的轴长及晶状体的屈光度无明显作用,也不能阻止高度近视导致的眼部病变。
手术矫正手段主要包括角膜屈光手术、巩膜屈光手术和眼内屈光手术,其中对晶状体施行手术改变的屈光状态属眼内屈光手术。这些手段通过阻止眼睛轴向生长或降低晶状体屈光度来治疗近视。传统的准分子激光屈光性角膜切削术(photorefractive keratectomy,PRK)通过切削角膜上皮改变屈光度。由于角膜上皮愈合较慢,会引起眼睛疼痛,需要较长的术后恢复时间,此外还易出现角膜基质混浊后遗症,已基本被淘汰。目前较常用的手术矫正近视方法是准分子激光原位角膜磨镶术(laser in situ keratomileusis,LASIK)。与PRK相比,LASIK无需切除角膜上皮,术后患者眼睛的不适感降低,视觉康复也较迅速,同时减少了伤口愈合反应,降低了基质混浊发生率。但LASIK不适合角膜偏薄的患者,可能出现轻微的近视矫正不足,且存在角膜瓣移位、弥漫性层间角膜炎等术后风险。另一种新型微创角膜屈光手术-飞秒激光小切口角膜基质透镜取出术(small incision lenticule extraction,SMILE)以其无瓣、微创、小切口和全飞秒等特点,成为最主要的屈光手术之一。SMILE能较大程度地降低与角膜瓣制作和准分子激光相关的并发症,提高手术的安全性,同时该手术方法可改善短期和长
期的角膜生物力学稳定性,减少激光术后视力回退和水肿的风险。然而与LASIK相比,SMILE术后的视力恢复较慢。可以看出,这些手术矫正视力的方式大部分效果较好,但均有各自的局限性,且对外科医生的手术经验要求较高,其长期风险仍有待评估。
药物延缓近视进展研究主要有毒蕈碱型受体(M受体)拮抗药,其中最具代表性的是阿托品。2021年9月份,澳大利亚治疗用品管理局(TGA)批准Aspen公司的Eikance,即0.01%硫酸阿托品滴眼液,用于减缓儿童和青少年近视的发展。Eikance可作为一种减缓近视进展的治疗方案用于近视每年进展≥-1.0D屈光度的4至14岁儿童。但阿托品滴眼液的不良反应有瞳孔散大、畏光、虹膜粘连、睫状肌麻痹、停药后的近视反弹等等。此外,阿托品同时具备外周和中枢M受体拮抗作用,对体内M1和M2型受体无选择性,对组织器官的选择性不高,因此临床使用时还需避免阿托品被全身吸收。
儿童近视需要长期的治疗,因此,临床上亟需安全有效的可以预防、缓解、改善和/或治疗近视的药物。
发明内容
针对现有技术存在的不足,本发明的目的在于提供一种甾体化合物在制备预防和/或治疗近视的药物中的应用,本发明提供的甾体化合物能够对近视有很好的治疗、减缓和预防效果,能够极大程度的减轻和/或治愈近视,提高视力清晰度。
为达此目的,本发明采用以下技术方案:
第一方面,本发明提供了一种甾体化合物在制备预防和/或治疗近视的药物中的应用,所述甾体化合物为如式I所示结构的化合物,或为如式I所示结构的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;
其中,R为H、D(表示氘)、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X;
X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基;
R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代;
所述取代基选自D、卤素、羟基、巯基、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、芳基烷基、杂芳基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;
R1、R2和R3各自独立地选自-H、-D或烷基。
在一些实施方案中,所述甾体化合物为如式II所示结构的化合物,或为如式II所示结构的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;
其中R的定义同式(I)。
在一些实施方案中,R为H、D、C1-6烷基、硫酸基、磷酸基、C1-6烷基硅基、苄基或-C(O)-X。
在一些实施方案中,X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基。
在一些实施方案中,R和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代。
在一些实施方案中,所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、羧基(例如-COOH)、R1R2NC(=O)-或R1R2NC(=NH)-NR3-。
在一些实施方案中,R1、R2和R3各自独立地选自-H、-D或C1-6烷基。
在一些实施方案中,X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]
嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、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。
在一些实施方案中,R和X中所述取代基选自-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。
在另外一些实施方案中,R和X中所述取代基选自-H、-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
作为本发明的一种具体实施方式,X选自如下任一基团:
作为本发明的一种具体实施方式,所述式I或II所示结构的化合物选自如下化合物中的任意一种:
本发明提供的甾体化合物可以作为未加工的化学药品用于治疗,也可以作为药物组合物的活性成分提供。
第二方面,本发明提供了组合物在制备预防和/或治疗近视的药物中的应用,所述组合物包括第一方面所述的甾体化合物,及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
可作为药学上可接受载体的物质包括,但并不限于,离子交换剂;铝;硬脂酸铝;卵磷脂;血清蛋白,如人血清蛋白;缓冲物质如磷酸盐;甘氨酸;山梨酸;山梨酸钾;饱和植物脂肪酸的部分甘油酯混合物;水;盐;电解质,如硫酸鱼精蛋白;磷酸氢二钠;磷酸氢钾;氯化钠;锌盐;胶体硅;三硅酸镁;聚乙烯吡咯烷酮;聚丙烯酸脂;蜡;聚乙烯-聚氧丙烯-阻断聚合体;羊毛脂;糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
在一些实施方案中,所述组合物包括:本发明所述的甾体化合物、羟丙甲纤维素、泊洛沙姆407、泊洛沙姆188和水。在一些实施方案中,本发明所述的甾体化合物在所述组合物中的质量百分含量为0.05%-0.5%,例如0.05%、0.1%、0.15%、0.20%、0.25%、0.3%、0.35%、0.4%、0.45%等。
在一些实施方案中,所述组合物包括:10~40质量份(例如10、12、14、16、18、20、22、24、26、28、30、32、34、36、38或40质量份)本发明所述的甾体化合物、110~120质量份(例如110、112、114、116、118或120质量份)羟丙甲纤维素、2050~2060质量份(例如2050、2052、2054、2056、2058或2060质量份)泊洛沙姆407、160~170质量份(例如160、162、164、166、168或170质量份)泊洛沙姆188和10000质量份水。
在一些实施方案中,所述组合物可以是滴眼液。所述滴眼液可为混悬型滴眼液。本发明的一些方案中,所述滴眼液的规格可为5mL、10mL。
在第三方面,本发明提供了一种预防和/或治疗近视的方法,包括向受试者施用第一方面或第二方面所述的应用中限定的甾体化合物或其立体异构体、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,或组合物。
与现有技术相比,本发明具有以下有益效果:
本发明提供的甾体化合物可以通过提高患者的屈光度,改善眼轴长度、眼球赤道径和前后径,来预防、减轻、改善和/或治疗患者的近视,并且副作用极小。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述具体实施方式仅仅是帮助理解本发明,不应视为对本发明的具体限制。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。
本发明所述的“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)、阻转异构体,等等。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有一个双键,取代基可能为E或Z构型;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式I所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(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。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.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。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构的盐进行分离。外消旋的产物也可
以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。特别地,对映异构体可以通过不对称合成制备,例如,可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer)包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明所提到的盐为药学上可接受的盐,其中“药学上可接受的盐”在所属领域是为我们所熟知的,如文献:Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括与氨基基团反应形成的无机酸盐,如有盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐,和有机酸盐,如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等,具体的如,但不限于,甲磺酸盐、乙磺酸盐、甲酸盐、乙酸盐、丁二酸盐、苯甲酸盐、琥珀酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、碳酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐或草酸,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、月桂酸盐、月桂基硫酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、十一酸盐、戊酸盐,等等。此外,药学上可接受的盐还包括通过适当的碱得到的盐,如碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐
和抗平衡离子形成的胺阳离子,如卤化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
可药用的盐可与无机酸和有机酸形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
“药物组合物”表示一种或多种本文所述化合物、盐或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物,其他组分例如生理学上/药学上可以接受的载体或赋形剂。药物组合物的目的是促进化合物对生物体的给药。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明使用的术语“烷基”表示1-20个碳原子,或1-10个碳原子,或1-8个碳原子,或1-6个碳原子,或1-4个碳原子,或1-3个碳原子的饱和直链或支链的单价烃基,其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代。烷基的实例包括,但并不限于,甲基(Me,-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,等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。术语“烷撑”在此处使用,表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基,这样的实例包括,但并不限于,亚甲基,次乙基,次异丙基等等。
术语“环烷基”是指一价或多价,非芳香族,饱和或部分不饱和的环,且不包含杂原子,其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5],[5,5],[5,6]或[6,6]体系,同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括,但并不限于,环烷基,环烯基和环炔基。环状脂肪族基的实例包括,但绝不限于,环丙基,环丁基,环戊基,1-环戊基-1-烯基,1-环戊基-2-烯基,1-环戊基-3-烯基,环己基,1-环己基-1-烯基,1-环己基-2-烯基,1-环己基-3-烯基,环己二烯基,环庚基,环辛基,环壬基,环癸基,环十一烷基,环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,环烷基、杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基等等。
术语“杂环”,“杂环基”,“杂脂环族”或“杂环的”在此处可交换使用,都是指单环,双环,或三环体系,其中环上一个或多个碳原子独立且任选地被杂原子所取代,所述杂原子具有如本发明所述的含义,环可以是完全饱和的或包含一个或多个不饱和度,但绝不是芳香族类,只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是,“杂环”,“杂环基”,“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO2,PO,PO2的基团,当所述的环为三元环时,其中只有一个杂原子),或7-10元的双环(4-9个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO2,PO,PO2的基团)。
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括,但并不限于,吡咯烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,四氢吡喃基,二氢吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,噻噁烷基,噻唑烷基,噁唑烷基,哌嗪基,高哌嗪基,氮杂环丁基,氧杂环丁基,硫杂环丁基,哌啶基,高哌啶基,环氧丙基,氮杂环庚基,氧杂环庚基,硫杂环庚基,4-甲氧基-哌啶-1-基,1,2,3,6-四氢吡啶-1-基,氧氮杂基,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]三唑[1,5-c]嘧啶-6-基,4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基,3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基,2-氧-5-氮杂双环[2.2.2]辛烷-5-基,喹嗪基和N-吡啶基尿素。杂环基团的实例还包括,1,1-二氧代硫代吗啉基,和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或未取代的,其中取代基可以是,但并不限于,氧代(=O),羟基,氨基,卤素,氰基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基等等。
术语“芳基”可以单独使用或作为“芳烷基”,“芳烷氧基”或“芳氧基烷基”的一大部分,表示共含有6-14元环的单环,双环,和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含3-7元环,且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用,如芳香环可以包括苯基,萘基和蒽基。并且所述芳基可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基,等等。
术语“杂芳基”表示共含有5-14元环的单环,双环,和三环体系,其中至少一个环体系是芳香族的,且至少一个环体系包含一个或多个杂原子,其中杂原子具有本发明所述的含义,其中每一个环体系包含3-7元环,且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,环烷基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O)-,烷基-C(=O)-,烷基-S(=O)-,烷基-S(=O)2-,羟基取代的烷基-S(=O)-,羟基取代的烷基-S(=O)2-,羧基烷氧基等等。
另外一些实施方案是,杂芳基包括以下的单环,但并不限于这些单环:2-呋喃基,3-呋喃基,N-咪唑基,2-咪唑基,4-咪唑基,5-咪唑基,3-异噁唑基,4-异噁唑基,5-异噁唑基,2-噁唑基,4-噁唑基,5-噁唑基,4-甲基异噁唑-5-基,N-吡咯基,2-吡咯基,3-吡咯基,2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,嘧啶-5-基,哒嗪基(如3-哒嗪基),2-噻唑基,4-噻唑基,5-噻唑基,四唑基(如5-四唑基),三唑基(如2-三唑基和5-三唑基),2-噻吩基,3-噻吩基,吡唑基(如2-吡唑基),异噻唑基,1,2,3-噁二唑基,1,2,5-噁二唑基,1,2,4-噁二唑基,
1,2,3-三唑基,1,2,3-硫代二唑基,1,3,4-硫代二唑基,1,2,5-硫代二唑基,1,3,4-噻二唑-2-基,吡嗪基,吡嗪-2-基,1,3,5-三嗪基;也包括以下的双环,但绝不限于这些双环:苯并咪唑基,苯并呋喃基,苯并噻吩基,吲哚基(如2-吲哚基),嘌呤基,喹啉基(如2-喹啉基,3-喹啉基,4-喹啉基),和异喹啉基(如1-异喹啉基,3-异喹啉基或4-异喹啉基),苯并[d]噻唑-2-基,咪唑并[1,5-a]吡啶-6-基。
术语“杂原子”表示一个或多个O,S,N,P和Si原子,包括N,S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(例如3,4-二氢-2H-吡咯基中的N),NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。
术语“杂烷基”表示烷基链中间可以插入一个或多个杂原子,其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明,杂烷基基团含有1-10个碳原子,另外一些实施方案是,杂烷基基团含有1-8个碳原子,另外一些实施方案是,杂烷基基团含有1-6个碳原子,另外一些实施方案是,杂烷基基团含有1-4个碳原子,另外一些实施方案是,杂烷基基团含有1-3个碳原子。这样的实例包括,但并不限于,CH3OCH2-,CH3CH2OCH2-,CH3SCH2-,CH3SCH2CH2-,(CH3)2NCH2-,(CH3)2CH2OCH2-,CH3OCH2CH2-,CH3CH2OCH2CH2-等。
术语“卤素”是指F,Cl,Br或I。
本发明所述的“卤代”表示用卤素取代其后接的基团,取代的个数可以是一个或多个。
本发明所述的“羟基取代的”表示用羟基取代其后接的基团,取代的个数可以是一个或多个。
本发明所述的“取代的”用于两个基团之间时,则其前面为取代基,如“芳基取代的烷基”表示烷基上具有芳基取代基,“烷氧基羰基取代的烷基”表示烷基上具有烷氧基羰基取代基。
当本发明多个基团联合使用时,从左到右,依次为取代关系,如“芳基烷基”,表示芳基取代的烷基,“烷氧基烷氧基”,表示烷氧基取代的烷氧基。
实施例1
本实施例制备了两种滴眼液,组成如表1所示。
表1
制备方法如下:
在无菌操作下,将上述成分混合,于2-8℃搅拌过夜,得到均一混合液后,在眼药瓶中保存。
实施例2豚鼠近视效果测试试验
1,模型建立
取检疫合格的三色豚鼠32只,雄性,按体重随机分为4组,即:模型对照组(A组)、阳性对照组(B组,0.01%阿托品滴眼液)、处方1组(C组)、处方2组(D组),每组8只,组别与试验编号对应见表2。
表2、组别与动物编号表
注:动物编号用组别编号+性别编号(1为雄性)+检疫号末两位表示。
使用3-4%异氟烷诱导动物麻醉后,剃去眼眶周围被毛,1.5-2.5%异氟烷维持麻醉,碘伏消毒眼眶周围皮肤,将屈光度为-10.0D的单纯球镜树脂镜片固定于造模动物右眼前,手术当天记为第0天,第二天记为第1天,以此类推,直至给药完毕。造模及给药过程中,每天上、下午各检查一次镜片有无松动、脱落及镜片清洁度,确保镜片的透光良好。镜片位置若有脱落及时给予调整,确保镜片固定于右眼前。若动物眼睛分泌物过多,用生理盐水浸湿的棉签擦拭干净。
2,指标检测与频率
1)体重称量:造模后每周称量一次。
2)屈光度测试:分组前、第7、14、21、27天检测屈光度。具体操作:抓取豚鼠,双眼结膜囊内滴1滴复方托吡卡胺滴眼液散瞳,10分钟后再滴1次,共2次,置于暗室中约1小时,待瞳孔完全散大后,检测双眼屈光度。工作距离为0.5m,精确到0.25D,平行检测3次,取平均值。
3)眼轴长度:分组前、第6、13、20、27天检测眼轴长度。具体操作:抓取豚鼠,使用3-4%异氟烷诱导麻醉后,1.5-2.5%异氟烷维持麻醉,使用0.4%盐酸奥布卡因滴眼液进行眼球
表面浸润麻醉,每次1滴,每隔5min 1次,共3次,测定双眼眼轴长度(取角膜表面到眼球后极部玻璃体视网膜界面的距离),精确到0.01mm,平行检测5次,取平均值。检测结束后滴加氧氟沙星滴眼液防止感染。
4)眼球赤道径和前后径:第28天,0.02mL/100g复方氯胺酮肌肉注射麻醉,腹主动脉放血处死,分离眼球周围肌肉及结缔组织,摘取双眼眼球,检测眼球赤道径和前后径。
5)动物处死方式或试验结束存活动物处理方式:0.02mL/100g复方氯胺酮肌肉注射麻醉后,腹主动脉放血处死。
3,结果和结论
1)体重称量:各组动物体重均正常增长,各组间无明显差异,提示各受试物对动物体重无明显影响。
2)屈光度测试:结果如下表3、4、5所示:
表3、对左眼屈光度的影响(n=8,单位:D)
注:vs模型对照A组:*,p<0.05,**,p<0.01;a,D组,n=7。
由表3可见,各组动物左眼屈光度整体趋势为先升高,后降低,可能与本试验动物从3-4周龄,生长过程中自身屈光度变化,以及本试验检测方法有关。造模及给药第1周(1w),B组、C组和D组左眼屈光度明显高于模型对照A组(p<0.01),结合其他时间点屈光度和第1周眼轴长度结果,应为本组动物对造模有一定应激反应,个体差异导致,应无临床意义。
表4、对右眼屈光度的影响(n=8,单位:D)
注:vs模型对照A组:*,p<0.05,**,p<0.01;vs各组左眼屈光度:##,p<0.01;a,C组,n=7,
D组,n=6;b,B组和C组,n=7。
由表4可见,造模及给药自第1周起,各组动物右眼屈光度与左眼比较,均明显降低(p<0.01),提示造模成功。自第2周起,各药物组右眼屈光度均高于同时间模型对照A组,均有明显统计学意义(p<0.01或0.05)。各药物组右眼屈光度均值比较,D组>C组>B组。
表5、对左右眼屈光度差值(左眼-右眼)的影响(n=8,单位:D)
注:vs模型对照A组:*,p<0.05,**,p<0.01;a,C组,n=7,D组,n=6;b,B组和C组,n=7。
由表5可见,造模及给药第2周、第4周,各药物组左右眼屈光度差值均明显低于模型对照A组(p<0.01);第4周,各组左右眼屈光度差值均值比较,变化趋势与右眼屈光度变化完全一致。
3)眼轴长度:表6、7、8统计了各组动物左右眼眼轴长度及对比情况
表6、对左眼眼轴长度的影响(n=8,单位:mm)
表7、对右眼眼轴长度的影响(n=8,单位:mm)
注:vs模型对照A组:*,p<0.05,**,p<0.01。
表8、对左右眼眼轴长度差值(右眼-左眼)的影响(n=8,单位:mm)
注:vs模型对照A组:*,p<0.05,**,p<0.01。
由表6、表7和表8可见,各组动物左、右眼眼轴长度整体均逐渐增加,与动物眼球发育趋势一致。左眼眼轴长度,各组间无明显差异;右眼眼轴长度,造模及给药第1周,各药物组明显比模型对照A组低(p<0.01或0.05),提示B组、C组、D组可延缓近视早期动物
眼轴长度增加;自第1周起,左右眼轴长度差值,各药物组均低于模型对照A组,第2周和第4周,各药物组右眼轴长度和左右眼轴长度差值均值比较,C组和D组<B组。
4)眼球赤道径和前后径:表9和10统计了各组动物左右眼的眼球赤道径和前后径值
表9、对4周眼球赤道径的影响(n=8,单位:mm)
注:vs模型对照组:*,p<0.05,**,p<0.01。
表10、对4周眼球前后径的影响(n=8,单位:mm)
注:vs模型对照组:*,p<0.05,**,p<0.01;vs各组左眼:#,p<0.05。
由表9、表10可见,造模及给药第4周,模型对照A组动物右眼球赤道径和前后径均高于左眼,造模成功;D组左眼球赤道径明显高于模型对照A组,应为动物个体差异,无临床意义;各组动物右眼球赤道径和左右眼球赤道径差值均无明显差异;各组动物左眼球前后径无明显差异,B组、C组和D组右眼球前后径和左右眼球前后径差值均明显低于模型对照A组(p<0.01)。各药物组右眼球赤道径和左右眼球赤道径差值均值比较,C组和D组<B组;右眼球前后径和左右眼球前后径差值均值比较,D组<C组<B组。
5)结论
本试验条件下,制备光学离焦性豚鼠近视模型,右眼为造模眼,左眼为对照眼,模型对照组动物造模后右眼屈光度明显低于左眼,右眼球赤道径和前后径明显高于左眼,右眼轴长度也高于左眼,造模成功;造模及给药对动物体重均无明显影响。滴眼给予处方1(0.2%)或处方2(0.4%)20μL,每天1次,连续28天,可明显延缓模型动物右眼屈光度降低、眼球赤道径和前后径升高,对眼轴长度也有一定改善作用,表明处方1和处方2对近视具有延缓、改善、逆转作用,综合比较,相同给药体积下,处方2作用优于处方1,处方1和处方2均优于阳性对照药。
虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (11)
- 甾体化合物在制备预防和/或治疗近视的药物中的应用,其特征在于,所述甾体化合物为如式(I)所示结构的化合物,或为式(I)所示结构的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;
其中,R为H、氘、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X;X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基;R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代;所述取代基选自氘、卤素、羟基、巯基、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、芳基烷基、杂芳基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;R1、R2和R3各自独立地选自H、氘或烷基。 - 根据权利要求1所述的应用,其中,所述甾体化合物为如式(II)所示结构的化合物或为式(II)所示结构的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,
其中R的定义同式(I)。 - 根据权利要求1或2所述的应用,其中,R为H、氘、C1-6烷基、硫酸基、磷酸基、C1-6烷基硅基、苄基或-C(O)-X;X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基;R和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代;所述取代基选自氘、卤素、羟基、巯基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;R1、R2和R3各自独立地选自H、氘或C1-6烷基。
- 根据权利要求1-3任一项所述的应用,其特征在于,X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、 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。
- 根据权利要求1-4任一项所述的应用,其特征在于,所述取代基选自氘、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。
- 根据权利要求1-5任一项所述的应用,其特征在于,所述取代基选自氘、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四 氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
- 根据权利要求1-6任一项所述的应用,其特征在于,X选自如下任一基团:
- 根据权利要求1-7任意一项所述的应用,其特征在于,所述式I所示结构的化合物选自如下化合物中的任意一种:
- 组合物在制备预防和/或治疗近视的药物中的应用,其特征在于,所述组合物包括权利要求1-8中的任一项所述的甾体化合物,及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
- 根据权利要求9所述的应用,其特征在于,所述组合物包括:甾体化合物、羟丙甲纤维素、泊洛沙姆407、泊洛沙姆188和水;优选地,所述组合物包括:10~40质量份甾体化合物、110~120质量份羟丙甲纤维素、2050~2060质量份泊洛沙姆407、160~170质量份泊洛沙姆188和10000质量份水。
- 一种预防和/或治疗近视的方法,包括向受试者施用权利要求1-10任一项所述的应用中限定的甾体化合物或其立体异构体、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,或者组合物。
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US20170239273A1 (en) * | 2014-08-22 | 2017-08-24 | Kang Zhang | Compositions and methods to treat and/or prevent vision disorders of the lens of the eye |
US20190256548A1 (en) * | 2017-01-25 | 2019-08-22 | Zhongshan Ophthalmic Center, Sun Yat-Sen University | Lanosterol prodrug compound and preparation method therefor and use thereof |
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