WO2021180080A1 - 用于治疗近视眼的化合物及其制备方法 - Google Patents

用于治疗近视眼的化合物及其制备方法 Download PDF

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WO2021180080A1
WO2021180080A1 PCT/CN2021/079780 CN2021079780W WO2021180080A1 WO 2021180080 A1 WO2021180080 A1 WO 2021180080A1 CN 2021079780 W CN2021079780 W CN 2021079780W WO 2021180080 A1 WO2021180080 A1 WO 2021180080A1
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pharmaceutical composition
compound
myopia
formula
preparation
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PCT/CN2021/079780
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English (en)
French (fr)
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徐奎
赵宏
刘逸凡
詹书胜
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安徽恒星制药有限公司
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Publication of WO2021180080A1 publication Critical patent/WO2021180080A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/08—Mydriatics or cycloplegics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/02—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C305/04—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton being acyclic and saturated
    • C07C305/06—Hydrogenosulfates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton

Definitions

  • the present invention relates to the field of medical technology, and more specifically to a compound for treating myopia and a preparation method thereof.
  • Myopia is one of the eye diseases with the highest incidence in the world.
  • the number of myopia patients in my country is nearly 300 million, and it is an out-and-out big country with myopia.
  • the occurrence and development of myopia is closely related to the lengthening of the eye axis.
  • the current treatment whether it is optometry or various refractive surgery, although it can correct the visual abnormalities caused by myopia, it is for fundamental eyeball changes.
  • ophthalmologists have been struggling to find a way to fundamentally treat myopia by blocking the length of the eye axis.
  • Atropine a non-selective cholinergic receptor antagonist
  • myopia due to its non-selectivity, it brings side effects such as dilated pupils, photophobia, lacrimation, and paralysis, which affect its use and patient compliance.
  • the present invention aims to solve one of the existing technical problems at least to a certain extent.
  • an embodiment of the present invention provides a compound that is a sulfonate of 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine.
  • the compound has a structure represented by formula (I) or formula (II):
  • the compound represented by formula (I) is 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine methyl sulfate; the compound represented by formula (II) is 3- [(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine taurate.
  • the embodiments of the present application provide a pharmaceutical composition containing a therapeutically effective dose of the compound of the first aspect and pharmaceutically acceptable excipients.
  • the pharmaceutical composition is formulated as eye drops, ophthalmic gel, injection or inhalant, preferably eye drops.
  • the eye drops containing the compound of the present invention are formulated to have a pH in the range of pH 5.0 to 9.0, preferably a pH value of 5.2 to 6.2, and most preferably a pH value of 5.6. Within this pH range, the stability of the compound and corneal permeability are achieved without causing irritation and damage to the eyes.
  • the pharmaceutical composition contains 0.01 mg to 0.1 mg of the compound represented by formula (I) or formula (II), 6.0 mg to 7.0 mg of sodium chloride, 0.1 mg ⁇ 0.5mg calcium chloride dihydrate, 0.01mg ⁇ 0.05mg sodium bicarbonate, 2.0mg ⁇ 4.0mg potassium aspartate, appropriate amount of benzalkonium chloride, polyvinyl alcohol and pH regulator.
  • the pharmaceutical composition has a pH of 5.2-6.2 and an osmotic pressure of 0.9-1.1.
  • the embodiments of the present application provide a preparation method for preparing the compound represented by formula (I), including the steps:
  • reaction solvent in step b is selected from one or more of acetone, methyl isobutyl ketone, N-methylpyrrolidone, and absolute ethanol, preferably acetone.
  • the embodiments of the present application provide a preparation method for preparing the compound represented by formula (II), including the steps:
  • reaction solvent in step a is selected from acetone or methyl isobutyl ketone
  • reaction solvent in step b is selected from acetonitrile
  • the embodiments of the present application provide the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for the prevention or treatment of myopia-related diseases.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the embodiments of the present application also provide the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for mydriasis.
  • the compound of the first aspect or the pharmaceutical composition of the second aspect can also be used to prepare a medicament for the treatment of chronic obstructive pulmonary disease (COPD), bronchitis or asthma. Therefore, in a specific embodiment, the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), bronchitis or asthma is provided.
  • COPD chronic obstructive pulmonary disease
  • the embodiments of the present application provide the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the prevention or treatment of myopia-related diseases.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the embodiments of the present application provide a method for treating myopia-related diseases, including administering the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject in need thereof.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the compound of the first aspect or the pharmaceutical composition of the second aspect is administered to the ocular tissue of the subject, preferably the eyeball.
  • the compound provided by the present invention has significant advantages: it has suitable properties that are particularly suitable for use as medicines, including non-hygroscopicity, suitable solubility, stability, and powder flowability, especially when made into drops.
  • Eye drops and injections have excellent stability in physiological pH value, and there is almost no local irritation, so they are suitable for development into eye drops and injections.
  • the compound when the compound is prepared into eye drops, it exhibits excellent stability and corneal permeability, at the same time, it does not cause irritation and damage to eye tissues, has good tolerance, and has no toxic effect on eye tissues.
  • Glycopyrrolate a quaternary ammonium anticholinergic drug similar to atropine, has a strong inhibitory effect on gastric juice secretion and a slight gastrointestinal spasmodic effect.
  • This medicine can regulate gastrointestinal motility, reduce gastric juice secretion and free acid concentration, and inhibit excessive secretion of trachea and bronchi.
  • this drug also has a stronger anti-saliva secretion effect than atropine, and the effect lasts longer.
  • the quaternary ammonium group of the drug restricts its passage through lipid cell membranes such as the blood-cerebrospinal fluid barrier, there are very few adverse reactions related to the central nervous system.
  • This drug is 5 to 6 times more potent than the equivalent amount of atropine; its anti-salivation effect is better than atropine, and its sedative effect is lighter than scopolamine; its adverse reactions such as accelerated heart rate, blurred vision, and fever are lighter than atropine; delayed pupil dilation
  • the systemic administration of atropine is more significant, but this drug only causes minor changes; the combination of this drug and neostigmine corrects the overdose of competitive muscle relaxants. Compared with atropine and neostigmine, there is less tachycardia , The effect of anti-salivation is better.
  • Its chemical name is 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine bromate, and its structural formula is as follows:
  • glycopyrrolate is used in ophthalmic preparations. At present, there is no other research report except that the inventors have done a lot of research and have achieved certain results. But simple glycopyrronium bromide is used directly as an API in liquid preparations, especially the pH is extremely unstable in the range of 6-8, and the local irritation in this pH range is minimal. More specifically, glycopyrrolate is stable in an acidic solution with pH 3.0 and mostly exists as a dissociated type, but it is not conducive to improving the corneal permeability of the drug. It mostly exists as a non-dissociated type in a neutral solution with pH 7.0. , Can ensure higher corneal permeability and intraocular concentration of the drug, close to tears, less irritating, but unstable. As a result, the development of ophthalmic drugs is severely restricted.
  • the inventor surprisingly found that when the bromate of glycopyrrolate is replaced with sulfonate, especially when methanesulfuric acid and taurine are replaced, the complex formed is easy to prepare, has good water solubility, and stability. Good and good fluidity, especially with a pH suitable for eye drops, it is an excellent medicinal form of glycopyrrolate substitute.
  • an embodiment of the present invention provides a compound that is a sulfonate of 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine.
  • the compound has a structure represented by formula (I) or formula (II):
  • the compound represented by formula (I) is 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine methyl sulfate; the compound represented by formula (II) is 3- [(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidine taurate.
  • the embodiments of the present application provide a pharmaceutical composition containing a therapeutically effective dose of the compound of the first aspect and pharmaceutically acceptable excipients.
  • the pharmaceutical composition is formulated as eye drops, ophthalmic gel, injection or inhalant, preferably eye drops.
  • the eye drops containing the compound of the present invention are formulated to have a pH in the range of pH 5.0 to 9.0, preferably a pH value of 5.2 to 6.2, and most preferably a pH value of 5.6. Within this pH range, the stability of the compound and corneal permeability are achieved without causing irritation and damage to the eyes.
  • the pharmaceutical composition contains 0.01 mg to 0.1 mg of the compound represented by formula (I) or formula (II), 6.0 mg to 7.0 mg of sodium chloride, 0.1 mg ⁇ 0.5mg calcium chloride dihydrate, 0.01mg ⁇ 0.05mg sodium bicarbonate, 2.0mg ⁇ 4.0mg potassium aspartate, appropriate amount of benzalkonium chloride, polyvinyl alcohol and pH regulator.
  • the pharmaceutical composition has a pH of 5.2-6.2 and an osmotic pressure of 0.9-1.1.
  • the embodiments of the present application provide a preparation method for preparing the compound represented by formula (I), including the steps:
  • reaction solvent in step b is selected from one or more of acetone, methyl isobutyl ketone, N-methylpyrrolidone, and absolute ethanol, preferably acetone.
  • the embodiments of the present application provide a preparation method for preparing the compound represented by formula (II), including the steps:
  • reaction solvent in step a is selected from acetone or methyl isobutyl ketone
  • reaction solvent in step b is selected from acetonitrile
  • the embodiments of the present application provide the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for the prevention or treatment of myopia-related diseases.
  • myopia-related diseases refers to diseases that are positively related to refractive errors. Specifically, when the eye is in a relaxed state of adjustment, parallel rays of light enter the eye and focus on the front of the retina, resulting in the inability to form a clear image on the retina.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the embodiments of the present application also provide the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for mydriasis.
  • the compound of the first aspect or the pharmaceutical composition of the second aspect can also be used to prepare a medicament for the treatment of chronic obstructive pulmonary disease (COPD), bronchitis or asthma. Therefore, in a specific embodiment, the use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), bronchitis or asthma is provided.
  • COPD chronic obstructive pulmonary disease
  • the embodiments of the present application provide the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the prevention or treatment of myopia-related diseases.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the embodiments of the present application provide a method for treating myopia-related diseases, including administering the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject in need thereof.
  • the myopia-related disease includes cycloplegia or juvenile myopia.
  • the compound of the first aspect or the pharmaceutical composition of the second aspect is administered to the ocular tissue of the subject, preferably the eyeball.
  • composition is intended to encompass products containing specified amounts of specified ingredients, as well as any product produced directly or indirectly from a combination of specified amounts of specified ingredients.
  • the term in connection with pharmaceutical compositions is intended to cover products containing active ingredients and inert ingredients that constitute carriers, as well as products that are directly or indirectly composed of any combination, complexation or polymerization of two or more ingredients, or by other types of reactions or Any product resulting from an interaction (for example, causing one or more ingredients to break down). Therefore, the pharmaceutical composition of the present invention encompasses any composition made by mixing the compound of the present invention and pharmaceutically acceptable excipients.
  • the term "subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the mammalian category: humans; non-human primates, such as chimpanzees, and other ape and monkey species; agricultural animals, such as cows, horses, sheep, goats, pigs; domestic animals , Such as rabbits, dogs, and cats; and experimental animals including rodents, such as rats, mice, and guinea pigs.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, compositions, or vehicles that participate in imparting the form or consistency of the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed. When administered to patients, such interactions will not greatly reduce the efficacy of the compounds of the invention and produce pharmaceutically unacceptable compositions.
  • each excipient must of course have a sufficiently high purity to make it pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable excipients will vary according to the particular dosage form selected.
  • suitable pharmaceutically acceptable excipients can be selected to achieve their specific functions in the composition.
  • certain pharmaceutically acceptable excipients can be selected because of their ability to promote uniform dosage forms.
  • Certain pharmaceutically acceptable excipients can be selected because of their ability to produce stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be selected because once they are administered to the patient, they help to carry or transport the compound of the invention from one organ or part of the patient's body to another organ or part of the body.
  • Certain pharmaceutically acceptable excipients can be selected because of their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, auxiliary materials Solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, Surfactants and buffers.
  • certain pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions.
  • the ophthalmic solution should have the same value as the tear fluid. According to the structural characteristics of glycopyrrolate, in accordance with the development requirements of eye drops, After hundreds of inspections, the following are the best examples.
  • Example 4 (1ml) prescription
  • Example 5 (1ml) prescription
  • Example 6 (1ml) prescription
  • Compound of formula (I) (0.01mg ⁇ 0.1mg)
  • Compound of formula (II) (0.01mg ⁇ 0.1mg)
  • Glycopyrrolate (0.01mg ⁇ 0.1mg)
  • Sodium chloride (6.0mg ⁇ 7.0mg)
  • Sodium chloride (6.0mg ⁇ 7.0mg)
  • Calcium chloride dihydrate 0.1mg ⁇ 0.5mg) Calcium chloride dihydrate (0.1mg ⁇ 0.5mg) Calcium chloride dihydrate (0.1mg ⁇ 0.5mg)
  • Sodium bicarbonate (0.01mg ⁇ 0.05mg)
  • Sodium bicarbonate (0.01mg ⁇ 0.05mg)
  • Sodium bicarbonate (0.01mg ⁇ 0.05mg)
  • Potassium aspartate (2.0mg ⁇ 4.0mg)
  • Potassium aspartate (2.0mg ⁇ 4.0mg)
  • Potassium aspartate (2.0mg ⁇
  • Benzalkonium chloride (appropriate amount) Benzalkonium chloride (appropriate amount) Benzalkonium chloride (appropriate amount) Polyvinyl alcohol (appropriate amount) Polyvinyl alcohol (appropriate amount) Polyvinyl alcohol (appropriate amount) pH adjuster (appropriate amount) pH adjuster (appropriate amount) pH adjuster (appropriate amount) pH adjuster (appropriate amount) pH: 5.2 ⁇ 6.2 pH: 5.2 ⁇ 6.2 pH: 5.2 ⁇ 6.2 Osmotic pressure: 0.9 ⁇ 1.1 Osmotic pressure: 0.9 ⁇ 1.1 Osmotic pressure: 0.9 ⁇ 1.1
  • Preparation method add benzalkonium chloride to an appropriate amount of deionized water, heat to about 60°C and stir to fully dissolve it, and set aside. Add polyvinyl alcohol to an appropriate amount of deionized water, stir and moisten it, and let it stand overnight. Under stirring, add the solution of the main drug and benzalkonium chloride in the above prescription one by one, add water to the full amount, and use 0.1N hydrogen.
  • Example 4 The samples of Examples 4 to 6 were removed from the outer packaging, and placed under high temperature conditions (40°C), high humidity conditions (25°C, 75% ⁇ 5%RH), and strong light conditions (4500 ⁇ 500Lx) for 10 days. Sampling and testing on the 5th and 10th day respectively, the results are as follows:
  • the eye drops made of the compounds of formula (I) and formula (II) of the present invention are far more stable than glycopyrrolate eye drops regardless of high temperature, high humidity and light.
  • the liquid is stable, and the most stable pH of glycopyrrolate solution is 2 ⁇ 3. At this time, it is not suitable for making eye drops.
  • One-time administration method :
  • Example 4 Group and Example 5 There was no abnormality in the left and right eyes of the group, indicating that the present invention had no special irritation response to the rabbit eyes, while in the Example 6 group, irritation reactions such as eye congestion, tearing, photophobia, edema, and increased secretion were observed in the rabbit eyes.
  • the eyeball fixation solution 50% formaldehyde 20ml+glacial acetic acid 10ml+95% ethanol 100ml+distilled water 70ml
  • the eyeball fixation solution 50% formaldehyde 20ml+glacial acetic acid 10ml+95% ethanol 100ml+distilled water 70ml
  • the slices are sliced and opened in warm water at 40°C. Move to a 40°C incubator and bake for 12-24 hours, stain with HE, mount the slide, and observe under a light microscope.
  • the first group of eye drops, the second group of eye drops, sodium chloride solution eye drops and the open and untreated eyeballs were compared under a light microscope.
  • the third group of eye drops showed slight swelling of the cornea, iris, ciliary body, retina and posterior sclera.
  • Each guinea pig is anesthetized by injection of ketamine hydrochloride into the thigh, at a dose of 75-100 mg/kg body weight.
  • the right eyelid is sutured with a 5-0 non-absorbable woven medical polyester suture mattress, and the left eye is open without any treatment to facilitate the animals to eat and move.
  • Observe every day if the suture is found to be caught off, make it up in time until the end of the experiment after 4 weeks. If animals are found dead during the experiment, they will be eliminated, but it must be ensured that there are no less than 8 animals in each group at the end of the experiment.
  • 66 guinea pigs after modeling were sequentially weighed, labeled and numbered, and divided into 6 groups according to the random number method. Among them, 3 groups were given eye drops of Example 4, Example 5 and Example 6 respectively, and the other 2 groups were given eye drops of sodium chloride solution and 1% atropine solution respectively, serving as the negative control group and the positive control group respectively, and finally One group was treated as a blank control group without any treatment.
  • the form-deprived eyes were administered at 9 a.m. and 4 p.m. every day. A 100 ⁇ L micro-injector was used to administer the drug, and the dose for each administration was 75 ⁇ L. The dose was divided into 5 drops, with an interval of 2min, and the drip was completed within 10min.

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Abstract

本发明公开了化合物及其制备方法，所述化合物具有式(I)及式(II)所示的结构。所述化合物用于在预防或治疗近视相关疾病中使用。

Description

用于治疗近视眼的化合物及其制备方法
优先权信息
本申请请求2020年03月13日向中国国家知识产权局提交的、专利申请号为202010177040.9的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及医药技术领域，更具体地说涉及用于治疗近视眼的化合物及其制备方法。
背景技术
近视眼是全球发病率最高的眼病之一，我国的近视患者数量将近3亿，是不折不扣的近视眼大国。近视的发生发展与眼轴的延长密切相关，但是就目前的治疗手段而言，无论是验光配镜还是各种屈光手术，虽然能够矫正近视带来的视觉异常，但是对于根本性的眼球变大、眼轴延长却无能为力，所以目前尚无有效的对因治疗方法。长期以来，眼科学者一直在苦苦探寻一种通过阻滞眼轴延长从而达到从根本上治疗近视的方法。非选择性胆碱能受体拮抗剂阿托品虽然能够阻滞近视发展，但是因其非选择性，带来诸如瞳孔散大、畏光流泪、调节麻痹等副作用，影响其使用和患者的依从性。
因此，选择一种疗效显著、使用方便、副作用又小的近视药物迫在眉睫。
发明内容
本发明旨在至少在一定程度上解决现有的技术问题之一。
在第一方面，本发明的实施方案提供了化合物，所述化合物是3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷的磺酸盐。
在具体的实施方案中，所述化合物具有式(I)或式(II)所示的结构：
Figure PCTCN2021079780-appb-000001
其中，式(I)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷甲基硫酸盐；式(II)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷牛磺酸盐。
在第二方面，本申请的实施方案提供了含有治疗有效剂量的第一方面的化合物及药学上可接受的辅料的药物组合物。
在一个实施方案中，所述药物组合物被配制成滴眼液、眼用凝胶、注射液或吸入剂，优选为滴眼液。
在具体实施方案中，将包含本发明化合物的滴眼液配制成具有在pH 5.0～9.0范围内的pH值，优选为5.2～6.2的pH值，最优选为5.6的pH值。在此pH值范围内，实现了化合物的稳定性和角膜通透率，同时对眼部不造成刺激和损伤。
在具体实施方案中，基于1ml的药物组合物，所述药物组合物包含0.01mg～0.1mg的式(I)或式(II)所示的化合物、6.0mg～7.0mg的氯化钠、0.1mg～0.5mg的二水合氯化钙、0.01mg～0.05mg的碳酸氢钠、2.0mg～4.0mg的门冬氨酸钾，适量的苯扎氯胺、聚乙烯醇和pH调节剂。其中，所述药物组合物具有5.2～6.2的pH值和0.9～1.1的渗透压。
在第三方面，本申请的实施方案提供了制备方法，用于制备式(I)所示的化合物，包括步骤：
Figure PCTCN2021079780-appb-000002
其中，步骤b中的反应溶剂选自丙酮、甲基异丁酮、N-甲基吡咯烷酮、无水乙醇中的一种或几种，优选丙酮。
在第四方面，本申请的实施方案提供了制备方法，用于制备式(II)所示的化合物，包括步骤：
Figure PCTCN2021079780-appb-000003
其中，步骤a中的反应溶剂选自丙酮或甲基异丁酮，步骤b中的反应溶剂选自乙腈。
在第五方面，本申请的实施方案提供了第一方面的化合物或第二方面的药物组合物在制备用于预防或治疗近视相关疾病的药物中的用途。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在这方面，本申请的实施方案还提供了第一方面的化合物或第二方面的药物组合物在制备用于散瞳的药物中的用途。
在该方面，第一方面的化合物或第二方面的药物组合物还可以用于制备治疗慢性阻塞性肺病(COPD)、支气管炎或哮喘的药物。因此，在具体的实施方案中，提供了第一方面的化合物或第二方面的药物组合物在制备用于治疗慢性阻塞性肺病(COPD)、支气管炎或哮喘的药物中的用途。
在第六方面，本申请的实施方案提供了第一方面的化合物或第二方面的药物组合物在预防或治疗近视相关疾病中使用。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在第七方面，本申请的实施方案提供了治疗近视相关疾病的方法，包括向有此需要的受试者施用第一方面的化合物或第二方面的药物组合物。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在具体的实施方案中，将第一方面的化合物或第二方面的药物组合物施用至所述受试者的眼部组织，优选眼球。
本发明与现有技术相比，本发明提供的化合物具有显著的优点：具有特别适于作为药物的适宜性质，包括不易吸湿、适宜的溶解性、稳定性、和粉末流动性，尤其制成滴眼液及注射液在生理pH值方面具有优良的稳定性，且局部几乎无刺激性，适合开发成滴眼液及注射液。特别是，当该化合物制备成滴眼液时，表现成优异的稳定性和角膜通透率，同时对眼部组织不造成刺激和损伤、耐受性好、对眼部组织没有毒性作用。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下面详细描述本发明的实施例，所述实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
本申请是发明人对以下问题和事实的发现而做出的：
格隆溴铵，是一种类似阿托品的季铵类抗胆碱能药物，具有较强的抑制胃液分泌作用及轻微的胃肠道解痉作用。本药可以调节胃肠蠕动，降低胃液分泌量和游离酸浓度以及抑制气管和支气管的过度分泌。另外，本药还具有比阿托品更强的抗唾液分泌作用，且作用维持时 间更长。此外，由于本药的季铵基团限制了它通过诸如血-脑脊液屏障这样的脂细胞膜，所以与中枢神经系统相关的不良反应发生极少。本药比等量的阿托品效力强5～6倍；其抗流涎作用较阿托品为佳，镇静作用较东莨菪碱轻；其加速心率、视力模糊，发热等不良反应较阿托品轻；延迟性瞳孔散大在阿托品全身用药时较为显著，但本药仅会引起很小的变化；本药与新斯的明合用纠正竞争性肌肉松弛药过量，与阿托品合用新斯的明相比，心动过速出现较少，止涎作用较佳。其化学名为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷溴酸盐，其结构式如下：
Figure PCTCN2021079780-appb-000004
然而，格隆溴铵在眼科制剂用药，目前除本发明人做出大量研究并取得了一定成效外，无其它研究报道。但单纯格隆溴铵作为API直接用在液体制剂中尤其pH在6～8范围内极不稳定，而这pH的范围局部刺激性最小。更具体地，格隆溴铵在pH3.0的酸性溶液中稳定，多以解离型存在，但是不利于提高药物的角膜通透，在pH7.0中性溶液中多以非解离型存在，可以保证较高的药物角膜通透率和眼内浓度，与泪液的接近，刺激性小，但不稳定。因而严重限制了眼科用药的发展。
经大量研究，发明人令人惊奇地发现，格隆溴铵的溴酸盐用磺酸盐替代、特别是甲硫酸及牛磺酸替代时，形成的复合物制备简便、水溶性好、稳定性好及流动性好，尤其具有适合滴眼液的pH，是格隆溴铵替代物的一种优良的药用形式。
在第一方面，本发明的实施方案提供了化合物，所述化合物是3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷的磺酸盐。
在具体的实施方案中，所述化合物具有式(I)或式(II)所示的结构：
Figure PCTCN2021079780-appb-000005
其中，式(I)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷甲基硫酸盐；式(II)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷牛磺酸盐。
在第二方面，本申请的实施方案提供了含有治疗有效剂量的第一方面的化合物及药学上可接受的辅料的药物组合物。
在一个实施方案中，所述药物组合物被配制成滴眼液、眼用凝胶、注射液或吸入剂，优选为滴眼液。
在具体实施方案中，将包含本发明化合物的滴眼液配制成具有在pH 5.0～9.0范围内的pH值，优选为5.2～6.2的pH值，最优选为5.6的pH值。在此pH值范围内，实现了化合物的稳定性和角膜通透率，同时对眼部不造成刺激和损伤。
在具体实施方案中，基于1ml的药物组合物，所述药物组合物包含0.01mg～0.1mg的式(I)或式(II)所示的化合物、6.0mg～7.0mg的氯化钠、0.1mg～0.5mg的二水合氯化钙、0.01mg～0.05mg的碳酸氢钠、2.0mg～4.0mg的门冬氨酸钾，适量的苯扎氯胺、聚乙烯醇和pH调节剂。其中，所述药物组合物具有5.2～6.2的pH值和0.9～1.1的渗透压。
在第三方面，本申请的实施方案提供了制备方法，用于制备式(I)所示的化合物，包括步骤：
Figure PCTCN2021079780-appb-000006
其中，步骤b中的反应溶剂选自丙酮、甲基异丁酮、N-甲基吡咯烷酮、无水乙醇中的一种或几种，优选丙酮。
在第四方面，本申请的实施方案提供了制备方法，用于制备式(II)所示的化合物，包括步骤：
Figure PCTCN2021079780-appb-000007
其中，步骤a中的反应溶剂选自丙酮或甲基异丁酮，步骤b中的反应溶剂选自乙腈。
在第五方面，本申请的实施方案提供了第一方面的化合物或第二方面的药物组合物在制备用于预防或治疗近视相关疾病的药物中的用途。
如本文所用，术语“近视相关疾病”是指与屈光不正相关的疾病。具体地，当眼在调节放松状态下，平行光线进入眼内，其聚焦在视网膜之前，导致视网膜上不能形成清晰像。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在这方面，本申请的实施方案还提供了第一方面的化合物或第二方面的药物组合物在制备用于散瞳的药物中的用途。
在该方面，第一方面的化合物或第二方面的药物组合物还可以用于制备治疗慢性阻塞性肺病(COPD)、支气管炎或哮喘的药物。因此，在具体的实施方案中，提供了第一方面的化合物或第二方面的药物组合物在制备用于治疗慢性阻塞性肺病(COPD)、支气管炎或哮喘的药物中的用途。
在第六方面，本申请的实施方案提供了第一方面的化合物或第二方面的药物组合物在预防或治疗近视相关疾病中使用。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在第七方面，本申请的实施方案提供了治疗近视相关疾病的方法，包括向有此需要的受 试者施用第一方面的化合物或第二方面的药物组合物。
在具体的实施方案中，所述近视相关疾病包括睫状肌麻痹或青少年近视。
在具体的实施方案中，将第一方面的化合物或第二方面的药物组合物施用至所述受试者的眼部组织，优选眼球。
如本文所用，术语“组合物”旨在涵盖包含指定量的指定成分的产品，以及直接或间接地由指定量的指定成分的组合产生的任何产品。与药物组合物有关的该术语旨在涵盖包含构成载体的活性成分和惰性成分的产品，以及直接或间接由任何两种或多种成分的组合、络合或聚合，或者由其他类型的反应或相互作用(例如导致一种或多种成分分解)产生的任何产品。因此，本发明的药物组合物涵盖通过混合本发明的化合物和药学上可接受的辅料制成的任何组合物。
如本文所用，术语“受试者”涵盖哺乳动物和非哺乳动物。哺乳动物的示例包括但不限于哺乳动物类别的任何成员：人类；非人类灵长类动物，例如黑猩猩，以及其他猿类和猴子物种；农畜，例如牛、马、绵羊、山羊、猪；家畜，例如兔、狗和猫；以及包括啮齿动物的实验动物，例如大鼠、小鼠和豚鼠等。非哺乳动物的示例包括但不限于鸟类、鱼类等。在本发明的一个实施方案中，哺乳动物是人。
如本文所用，“药学上可接受的辅料”是指参与赋予药物组合物形式或稠度的药学上可接受的材料、组合物或媒介物。每种辅料在混合时必须与药物组合物的其他成分兼容。当向患者施用时，这样相互作用将不会大幅度降低本发明化合物的药效，并产生药物学上不可接受的组合物。另外，每种辅料当然必须具有足够高的纯度以使其在药学上可接受。
合适的药学上可接受的辅料将根据所选的特定剂型而变化。另外，可以选择合适的药学上可接受的辅料以实现它们在组合物中的特定功能。例如，可以选择某些药学上可接受的辅料，因为它们具有促进产生均匀剂型的能力。可以选择某些药学上可接受的辅料，因为它们具有产生稳定剂型的能力。可以选择某些药学上可接受的辅料，因为一旦向患者施用它们，便有助于携带或运输本发明的化合物从患者的一个器官或身体的一部分到另一器官或身体的一部分。可以选择某些药学上可接受的辅料，因为它们具有增强患者依从性的能力。
合适的药学上可接受的辅料包括以下类型的辅料：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、助溶剂、悬浮剂、乳化剂、甜味剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将理解，取决于制剂中存在多少辅料和制剂中存在什么其他成分，某些药学上可接受的辅料可以发挥一种以上的功能并且可以发挥替代的功能。
技术人员具有本领域的知识和技能，以使他们能够选择适当量的合适的药学上可接受的辅料用于本发明。另外，本领域技术人员可获得描述药学上可接受的辅料的资源，并且这些资源可用于选择合适的药学上可接受的辅料。示例包括《雷明顿药物科学》(Remington's Pharmaceutical Sciences)(Mack Publishing Company)、《药物添加剂手册》(The Handbook of Pharmaceutical Additives)(Gower Publishing Limited)，以及《药物辅料手册》(The Handbook of Pharmaceutical Excipients)(the American Pharmaceutical Association and the Pharmaceutical Press).
在“《雷明顿：药学的科学与实践》(Remington:The Science and Practice of Pharmacy),第21版,2005,D.B.Troy编,Lippincott Williams&Wilkins,费城”和“《医药技术百科全书》(Encyclopedia of Pharmaceutical Technology),J.Swarbrick和J.C.Boylan编,1988-1999,Marcel Dekker,纽约”中公开了用于配制药学上可接受的组合物的各种载体及其制备的已知技术，其每个的内容通过引用并入本文。除非任何常规载体介质与本发明化合物不兼容，例如通过产生任何不良的生物学作用或以有害的方式与药学上可接受的组合物的任何其他组分相互作用，否则其用途是预期在本发明的范围内的。
除非另外定义，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。如果发生冲突，以本说明书(包括定义)为准。在整个说明书和权利要求书中，词语“包括”或诸如“包含”或“含有”的变体将被理解为暗示包含所述整体或整体的组但不排除任何其它整体或整体的组。除非上下文另有要求，否则未用数量词限定的名词包括单数和复数指示对象。术语“例如”或“如”之后的任何实例并不意味着穷举或限制。
实施例1：式(I)3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷甲基硫酸盐的制备
a、在干燥的5L反应釜中，加环戊基扁桃酸400g(1.82mol)、N,N-二甲基甲酰胺2000ml，冷却至20±5℃，加N'N-羰基二咪唑360g(2.22mol)，搅拌20min，加入3-羟基-1-甲基四氢吡咯228g(2.25mol)，在50～60min内加热至60±5℃，反应22h，TLC鉴别反应完毕后，冷却至20℃，抽入10L分液器，加2.8L纯化水搅拌，加入3.2L甲苯，搅拌10分钟，分液，有机层用纯化水1440ml×5洗涤，50℃减压浓缩至干，得到油状物质约580克，直接用于下一步。
b、上述产物580g(1.91mol)，加入3000ml丙酮，冷却至0～5℃，加241g(1.91mol)硫酸二甲酯，搅拌1h，过滤，固体用适量丙酮洗涤，65～70℃真空干燥5h，得式(I)白色结晶性粉末化合物，914g，收率86％。HPLC含量99.7％。
Figure PCTCN2021079780-appb-000008
1H—NMR(400MHz，CDCl 3/TMS，ppm)：
δ：1.17(m，1H，H9)，1.46(m，H12)，1.47(m，1H，H10)，1.48(m，1H，H10)，1.49(m，1H，H11)，1.52(m，1H，H9)，1.57(m，1H，H11)，1.63(m，1H，H12)，2.06(m，1H，H4)，2.62(m，1H，H4)，2.95(s，3H，20-CH 3)，3.07(m，1H，H8)，3.12(s，3H，20-CH 3)，3.50(m，2H，H5，H5)，3.68(d，J＝14Hz，1H，H2)，3.77(dd，J＝6Hz，14Hz，1H，H2)，3.85(s，3H，OCH 3)，5.43(m，1H，H3)，7.32(t，J＝7.5Hz，1H，H16)，7.39(t，J＝7.5Hz，2H，H15、H17)，7.56(d，J＝7.5Hz，2H，H14、H18)。
MS:m/z(M +)319(M-CH 3O 4S+H)。
实施例2：式(II)3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷牛磺酸盐的制备
准备：在干燥的1000ml反应釜中，加环戊基扁桃酸40g(0.182mol)、N,N-二甲基甲酰胺200ml，冷却至20±5℃，加N'N-羰基二咪唑36g(0.222mol)，搅拌20min，加入3-羟基-1-甲基四氢吡咯22.8g(0.225mol)，在50～60min内加热至60±5℃，反应24h，TLC鉴别反应完毕后，冷却至20℃，抽入5L分液器，加280ml纯化水搅拌，加入320ml甲苯，搅拌10分钟，分液，有机层用纯化水144ml×5洗涤，50℃减压浓缩至干，得到油状物质约59.2克，直接用于下一步。
a、上述产物59g(0.194mol)，33g(0.194mol)苯磺酸甲酯，450ml丙酮加入到1000ml反应釜中，冷却至0℃，搅拌5小时，TLC监控，确认反应完全.，减压蒸馏，去除丙酮，蒸干，得到淡黄色油状物90克，直接用于下一步。
b、上述产物，加入400ml乙腈，冷却至10～15℃搅拌，加25g(0.194mol)牛磺酸锂，搅拌10h，过滤，固体用适量乙腈洗涤，滤液减压浓缩，加350ml正丁醇，加热，搅拌，溶解，加入3g针用药用炭，回流30min。抽滤脱碳，滤液冷却至0～5℃搅拌析晶，抽滤，65～70℃真空干燥8h，得式(II)白色结晶性粉末化合物，68g，总收率79％。HPLC含量99.6％。
Figure PCTCN2021079780-appb-000009
1H—NMR(400MHz，CDCl 3/TMS，ppm)：
δ：1.17(m，1H，H9)，1.46(m，H12)，1.47(m，1H，H10)，1.48(m，1H，H10)，1.49(m，1H，H11)，1.52(m，1H，H9)，1.57(m，1H，H11)，1.63(m，1H，H12)，2.06(m，1H，H4)， 2.62(m，1H，H4)，2.95(s，3H，20-CH 3)，3.07(m，1H，H8)，3.12(s，3H，20-CH 3)，3.50(m，2H，H5，H5)，3.68(d，J＝14Hz，1H，H2)，3.77(dd，J＝6Hz，14Hz，1H，H2)，3.21(t，J＝7.5Hz，2H，H 2N-CH 2-)，3.69(t，J＝7.5Hz，2H，SO 3-CH 2-)，5.43(m，1H，H3)，7.32(t，J＝7.5Hz，1H，H16)，7.39(t，J＝7.5Hz，2H，H15、H17)，7.56(d，J＝7.5Hz，2H，H14、H18)。
MS:m/z(M +)319(M-C 2H 6NO 3S+H)。
实施例3：理化性质比较
按照中国药典2015版四部凡例试验。
Figure PCTCN2021079780-appb-000010
结论：本发明的式(I)及式(II)化合物，具有适宜的溶解度及流动性，且不吸湿。
实施例4～6：滴眼液的制备
滴眼剂pH值过高或过低对眼都会有刺激性，为了尽可能减轻不适感，眼用溶液应具有和泪液相同的值，根据格隆溴铵结构特点，按照滴眼液研发要求，经过数百次考察，以下是最佳实施例。
处方：
实施例4(1ml)处方 实施例5(1ml)处方 实施例6(1ml)处方
式(I)化合物(0.01mg～0.1mg) 式(II)化合物(0.01mg～0.1mg) 格隆溴铵(0.01mg～0.1mg)
氯化钠(6.0mg～7.0mg) 氯化钠(6.0mg～7.0mg) 氯化钠(6.0mg～7.0mg)
二水合氯化钙(0.1mg～0.5mg) 二水合氯化钙(0.1mg～0.5mg) 二水合氯化钙(0.1mg～0.5mg)
碳酸氢钠(0.01mg～0.05mg) 碳酸氢钠(0.01mg～0.05mg) 碳酸氢钠(0.01mg～0.05mg)
门冬氨酸钾(2.0mg～4.0mg) 门冬氨酸钾(2.0mg～4.0mg) 门冬氨酸钾(2.0mg～4.0mg)
苯扎氯胺(适量) 苯扎氯胺(适量) 苯扎氯胺(适量)
聚乙烯醇(适量) 聚乙烯醇(适量) 聚乙烯醇(适量)
pH调节剂(适量) pH调节剂(适量) pH调节剂(适量)
pH：5.2～6.2 pH：5.2～6.2 pH：5.2～6.2
渗透压：0.9～1.1 渗透压：0.9～1.1 渗透压：0.9～1.1
制备方法：将苯扎氯胺加入适量的去离子水水，加热至60℃左右搅拌使之充分溶解，备用。将聚乙烯醇加入适量的去离子水中，搅拌润湿，静置过夜，此溶液，在搅拌下，依次加入上述处方里面的主药及苯扎氯胺的溶液，加水至全量，用0.1N氢氧化钠溶液或0.1N盐酸溶液调节pH至5.6，充分搅拌均匀，用0.22μm微孔滤膜过滤，滤液灌装，加涤纶薄膜，胶塞、机压铝盖，115℃热压灭菌灭菌30min，在无菌环境下，由分装机分装於洗净的5ml无菌高密度聚乙烯瓶中，每支灌封5ml，用聚丙烯塑料盖严封即得。
实施例7：稳定性研究
1、影响因素试验
将实施例4～6样品，去除外包装，分别于高温条件(40℃)、高湿条件(25℃，75％±5％RH)、强光条件(4500±500Lx)下放置10d，于第5日和第10日分别取样检测，结果如下：
实施例4样品 影响因素试验试验结果
Figure PCTCN2021079780-appb-000011
实施例5样品 影响因素试验试验结果
Figure PCTCN2021079780-appb-000012
Figure PCTCN2021079780-appb-000013
实施例6样品 影响因素试验试验结果
Figure PCTCN2021079780-appb-000014
结论：在影响因素稳定性考察下，本发明的式(I)及式(II)化合物制成的滴眼液，无论高温、高湿及光照，其稳定性远远比格隆溴铵滴眼液稳定，其中格隆溴铵溶液的最稳定pH是2～3，此时，不适合制成滴眼液。
实施例8：药理学安全性研究
1、眼刺激性试验
参照《化学药物刺激性、过敏性和溶血性研究技术指导原则》中的有关规定，本实验采用一次给药法及多次给药法进行兔眼刺激性试验。
一次给药法：
取健康、双眼正常成年家兔18只，体重(2.8±0.4kg)。将本品0.1ml滴入左眼睑内，右眼同时滴入生理盐水作对照。分别经过1h、24h、72h观察角膜、结膜、虹膜及分泌物情况，结果实施例4组及实施例5组未见兔眼充血、流泪、畏光、水肿、分泌物增加等刺激反应。采用手持裂隙灯检查角膜、虹膜变化，未见异常，观察到实施例6组兔眼有充血、流泪、分泌物增加等刺激反应。
多次给药法：
取健康、双眼正常成年家兔18只，体重(2.8±0.4kg)。将本品0.1ml滴入左眼睑内，右眼同时滴入生理盐水作对照。每日四次(qid)，连续滴14天，每天给药前及最后一次给药后1h、24h、72h对眼部进行检查，记录每天的局部反应情况，结果实施例4组及实施例5组左右眼均未见异常，表明本发明对兔眼无特殊刺激反应，而实施例6组，观察到兔眼充血、流泪、畏光、水肿、分泌物增加等刺激反应。
2、眼部毒性试验
取健康荷兰种花色豚鼠30只，分为三组，每组10只。第一组动物的右眼均给予实施例4滴眼液，左眼给予0.9％氯化钠溶液，第二组动物的右眼均给予实施例5滴眼液，左眼不给任何药物，第三组动物右眼均给予实施例6滴眼液，左眼给予0.9％氯化钠溶液，给药方法和给药频率均与多次给药法试验相同。四周后实验结束后，颈椎脱臼处死动物，摘除双侧眼球进行组织学检查。
将眼球放入眼球固定液(40％甲醛20ml+冰醋酸10ml+95％乙醇100ml+蒸馏水70ml)内固定48小时，取出，蒸馏水冲洗干净。经过80％酒精(30min)，95％酒精(Ⅰ、Ⅱ、Ⅲ各30min)和100％酒精(Ⅰ、Ⅱ、Ⅲ各30min)后，浸入二甲苯(Ⅰ、Ⅱ各15min)透明；再放入石蜡中渗透2～6小时；将温箱中浸蜡完毕的组织取出包埋于纸盒内，待石蜡冷却凝固后进行切片切成的薄片在40℃温水中展开，铺片于预先涂过赖氨酸的载玻片上；移至40℃温箱中烤12～24h，常规HE染色，封片，光镜下观察。
结果，第一组滴眼液、第二组滴眼液、氯化钠溶液滴眼和开放未经任何处理的眼球在光镜下比较，角膜、虹膜、睫状体、视网膜和后部巩膜等组织，均未发生细胞肿胀、变形、融解破坏,细胞核萎缩、崩解或核周空泡，以及胶原纤维水肿、断裂等异常的形态学改变。第三组滴眼液，角膜、虹膜、睫状体、视网膜和后部巩膜等组织有轻微的肿胀。
说明本发明滴眼液对眼球各组织没有明显的毒性反应，而格隆溴铵组有轻微毒性反应。
实施例9：疗效研究
1、形觉剥夺性近视眼模型的建立
每只豚鼠股部注射盐酸氯氨酮麻醉，剂量为75～100mg/kg体重。以5-0不可吸收型编织式医用涤纶缝线褥式缝合右眼眼睑，左眼开放不做处理便于动物吃食和活动。每天观察，如发现缝线被抓脱及时补缝，直至4周后实验结束。在实验过程中如发现有动物死亡则予以剔除，但必须确保实验结束时每组动物只数不少于8只。
2、给药方案
对66只建模后的豚鼠依次称重、标记编号，按随机数字法分6组。其中3组分别给予实施例4、实施例5及实施例6滴眼剂滴眼，另2组分别给予氯化钠溶液和1％阿托品溶液滴眼，分别作为阴性对照组和阳性对照组，最后一组不予任何处理，作为空白对照组。分别于每天上午9点和下午4点对形觉剥夺眼给药。使用100μL微量进样器给药，每次给药剂量为75μL，将药量均分为5次滴，间隔2min，10min内滴完。
3、眼轴生物测量
实验前后，各个组别中，实验眼的前房深度和晶状体厚度的变化均没有统计学意义。实验眼经遮盖4周后，未处理组，0.9％氯化钠溶液滴眼组和实施例6格隆溴铵滴眼组的玻璃体腔深度及眼轴长度较实验前明显延长，分别为0.046±0.043mm，0.052±0.047mm和0.031±0.033，差异有统计学意义(P<0.05)，而实验前后，实施例4组滴眼液、实施例5滴眼液和阿托品溶液滴眼组，其玻璃体腔深度及眼轴长度的变化没有统计学差异(P>0.05)。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (21)

  1. 化合物，所述化合物是3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷的磺酸盐。
  2. 根据权利要求1所述的化合物，其中所述化合物具有式(I)或式(II)所示的结构：
    Figure PCTCN2021079780-appb-100001
  3. 根据权利要求2所述的化合物，其中式(I)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷甲基硫酸盐，和
    式(II)所示的化合物为3-[(环戊基羟基苯乙酰)氧]-1,1-二甲基吡咯烷牛磺酸盐。
  4. 一种药物组合物，含有治疗有效剂量的根据权利要求1至3中任一项所述的化合物及药学上可接受的辅料。
  5. 根据权利要求4所述的药物组合物，其中所述药物组合物被配制成滴眼液、眼用凝胶、注射液或吸入剂，优选为滴眼液。
  6. 根据权利要求4或5所述的药物组合物，其中将所述滴眼液配制成具有在pH 5.0～9.0范围内的pH值，优选为5.2～6.2的pH值，最优选为5.6的pH值。
  7. 根据权利要求4至6中任一项所述的药物组合物，其中基于1ml的所述药物组合物，包含0.01mg～0.1mg的式(I)或式(II)所示的化合物、6.0mg～7.0mg的氯化钠、0.1mg～0.5mg的二水合氯化钙、0.01mg～0.05mg的碳酸氢钠、2.0mg～4.0mg的门冬氨酸钾，适量的苯扎氯胺、聚乙烯醇和pH调节剂。
  8. 根据权利要求7所述的药物组合物，其中所述药物组合物具有5.2～6.2的pH值和0.9～1.1的渗透压。
  9. 一种制备方法，用于制备式(I)所示的化合物，包括步骤：
    Figure PCTCN2021079780-appb-100002
  10. 根据权利要求9所述的制备方法，其中步骤b中的反应溶剂选自丙酮、甲基异丁酮、N-甲基吡咯烷酮、无水乙醇中的一种或几种。
  11. 一种制备方法，用于制备式(II)所示的化合物，其包括步骤：
    Figure PCTCN2021079780-appb-100003
  12. 根据权利要求10所述的制备方法，其中步骤a中的反应溶剂选自丙酮或甲基异丁酮，和步骤b中的反应溶剂为乙腈。
  13. 如权利要求1至3中任一项所述的化合物或如权利要求4至8中任一项所述的药物组合物在制备用于预防或治疗近视相关疾病的药物中的用途。
  14. 根据权利要求13所述的用途，其中所述近视相关疾病包括睫状肌麻痹或青少年近视。
  15. 如权利要求1至3中任一项所述的化合物或如权利要求4至8中任一项所述的药物组合物在制备用于散瞳的药物中的用途。
  16. 如权利要求1至3中任一项所述的化合物或如权利要求4至8中任一项所述的药物组合物在制备用于治疗慢性阻塞性肺病(COPD)、支气管炎或哮喘的药物中的用途。
  17. 如权利要求1至3中任一项所述的化合物或如权利要求4至8中任一项所述的药物组合物在预防或治疗近视相关疾病中使用。
  18. 根据权利要求17使用的所述化合物或所述药物组合物，其中所述近视相关疾病包括睫状肌麻痹或青少年近视。
  19. 一种治疗近视相关疾病的方法，包括向有此需要的受试者施用如权利要求1至3中任一项所述的化合物或如权利要求4至8中任一项所述的药物组合物。
  20. 根据权利要求19所述的方法，其中所述近视相关疾病包括睫状肌麻痹或青少年近视。
  21. 根据权利要求19所述的方法，其中将所述化合物或所述药物组合物施用至所述受试者的眼部组织，优选眼球。
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