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WO2022073446A1 - 戊乙奎醚在治疗或预防视力损伤性眼部疾病中的用途 - Google Patents

戊乙奎醚在治疗或预防视力损伤性眼部疾病中的用途 Download PDF

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Publication number
WO2022073446A1
WO2022073446A1 PCT/CN2021/121385 CN2021121385W WO2022073446A1 WO 2022073446 A1 WO2022073446 A1 WO 2022073446A1 CN 2021121385 W CN2021121385 W CN 2021121385W WO 2022073446 A1 WO2022073446 A1 WO 2022073446A1
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Prior art keywords
myopia
amblyopia
vision
eye
myopic
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PCT/CN2021/121385
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English (en)
French (fr)
Inventor
黄岭
张晓花
朱墨
向文殿
刘超
康静
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远大生命科学(武汉)有限公司
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Application filed by 远大生命科学(武汉)有限公司 filed Critical 远大生命科学(武汉)有限公司
Priority to AU2021356807A priority Critical patent/AU2021356807B2/en
Priority to KR1020237015162A priority patent/KR20230083315A/ko
Priority to CA3198402A priority patent/CA3198402A1/en
Priority to JP2023546375A priority patent/JP2023544652A/ja
Priority to EP21876964.4A priority patent/EP4226924A4/en
Publication of WO2022073446A1 publication Critical patent/WO2022073446A1/zh
Priority to US18/131,963 priority patent/US20230241042A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to the use of penehyclidine in the treatment or prevention of vision-impairing eye diseases.
  • Atropine eye drops are recommended for the prevention and treatment of myopia and amblyopia in foreign countries, such as 1% atropine sulfate eye drops marketed in the United States and Japan.
  • Low-concentration atropine sulfate eye drops (0.01%) have been approved for marketing in Taiwan and Macau for relieving myopia or treating myopia, and there are clinical trial reports on relieving myopia progression in Hong Kong, Singapore, the United States, the United Kingdom, India, etc., indicating that Low-concentration atropine can effectively delay the progression of myopia in children and adolescents.
  • myopia progression is related to ciliary muscle accommodation. Sato's adjustment tension theory believes that long-term use of adjustment can cause ciliary muscle adjustment tension, so it is speculated that the use of atropine to relax and release adjustment tension can achieve the effect of juvenile myopia control.
  • Atropine can block mammalian ciliary muscle M receptors, thereby relieving the regulation tension of ciliary muscle, while chick ciliary muscle is striated muscle, which is regulated by nicotine (N)-like receptors, so atropine cannot make ciliary muscle regulated tension.
  • Chick cycloplegia Chick cycloplegia.
  • Atropine is a non-selective inhibitor, it has been found that atropine treatment of myopia is related to various pathways; tropamide is also another non-selective M receptor blocker. , through the comparison test with atropine, it is found that it cannot effectively prevent or delay the development of myopia.
  • Atropine sulfate eye drops currently under research abroad have certain risks.
  • Atropine is prone to systemic side effects, such as dry face, dry mouth, increased heart rate, urinary retention, etc., and even cause poisoning and anaphylactic shock.
  • Intravenous maximum dose of 2 mg each time, exceeding the above dose, will cause poisoning, overdose manifested as clumsy and unstable movements, confusion, convulsions, dyspnea, abnormal rapid heartbeat, etc. Therefore, the safety issue of atropine sulfate eye drops in myopia and weak use has been a factor limiting its large-scale promotion. At present, it is imminent to find safer and more effective drugs for the treatment of eye diseases on the market.
  • the present invention aims to solve one of the technical problems in the related art at least to a certain extent.
  • the present invention proposes the use of the compound of formula (I) or its nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of medicines the use of the medicament for the treatment and/or prevention of vision-impairing eye diseases,
  • the inventors have found through a large number of studies that the compound of formula (I) or its derivatives (nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts) has good treatment or prevention of visually impaired eyes The effect of disease, and the systemic toxicity and side effects are significantly lower than atropine, has a good application prospect.
  • the above-mentioned use may further include at least one of the following additional technical features:
  • the salt of the compound represented by the formula (I) includes an organic salt or an inorganic salt.
  • penehyclidine The compound shown in formula (I) is called penehyclidine, and the inventors have found through a lot of research that penehyclidine and its derivatives, such as its organic salts or inorganic salts, can effectively treat or prevent myopia. or amblyopia and other vision-impairing eye diseases, the prevention and control effect is better than that of atropine sulfate eye drops of the same concentration, and it has the advantages of less mydriasis, less local irritation to the eye, and better safety, and can be used for a long time. .
  • the salt of the compound represented by the formula (I) is a hydrochloride, and the structure of the hydrochloride is represented by the formula (II).
  • the medicament is used for treating and/or preventing myopia and/or amblyopia.
  • the causes of the myopia and/or amblyopia include myopic shift in diopter, myopic vitreous cavity depth extension, myopic axial length extension, form deprivation, anisometropia and astigmatism one or more of.
  • the myopia and/or amblyopia includes mild myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, visual fatigue, exotropia, strabismus
  • One or more of amblyopia, fundus damage, occlusion, visual distortion, double vision, abnormal color vision, abnormal light perception, decreased contrast sensitivity, and refractive error amblyopia do not include vision problems caused by trauma.
  • the present invention provides a pharmaceutical composition for treating and/or preventing vision-impairing eye diseases.
  • the compound of the structure represented by formula (I) or its nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof is contained as an active ingredient.
  • the above-mentioned pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition is used for treating and/or preventing myopia and/or amblyopia.
  • the causes of the myopia and/or amblyopia include myopic shift in diopter, myopic vitreous cavity depth extension, myopic axial length extension, form deprivation, anisometropia and astigmatism one or more of.
  • the myopia and/or amblyopia includes mild myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, visual fatigue, exotropia, strabismus
  • One or more of amblyopia, fundus damage, occlusion, visual distortion, double vision, abnormal color vision, abnormal light perception, decreased contrast sensitivity, and refractive error amblyopia do not include vision problems caused by trauma.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the carrier includes, but is not limited to, an aqueous carrier, a water-miscible carrier, a non-aqueous carrier, an antimicrobial agent or an anti-microbial growth preservative, a stabilizer, a dissolution enhancer , osmotic pressure regulators, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, antifreeze agents, cryoprotectants, thickening agents
  • the pH adjusting agent and the inert gas can be selected by those skilled in the art according to the actual requirements of the formulation.
  • the dosage form of the pharmaceutical composition is an ophthalmic preparation, including eye drops, eye ointment, eye cream, eye emulsion, eye gel, eye pill, eye film, intraocular one or more of the implants.
  • the mass fraction of the active ingredient in the pharmaceutical composition is 0.005%-2%.
  • the mass volume fraction of the active ingredient in the pharmaceutical composition is 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.105%, 0.11%, 0.115%, 0.12%, 0.125% , 0.13%, 0.135%, 0.14%, 0.145%, 0.15%, 0.155%, 0.16%, 0.165%, 0.17%, 0.175%, 0.18%, 0.185%, 0.19%, 0.195%, 0.2%, 0.205%, 0.21 %, 0.215%, 0.22%, 0.225%, 0.23%, 0.235%, 0.24%, 0.245%, 0.25%, 0.25
  • the administered dose of the pharmaceutical composition depends on the type and weight of the subject, the nature and severity of the disease, the type of formulation and the administration mode of the drug, and the administration period or time interval.
  • the present invention provides an ophthalmic preparation for treating and/or preventing vision-impairing eye diseases.
  • the mass fraction of the active ingredient in the ophthalmic preparation is 0.005%-2%, and the active ingredient is the compound of the structure represented by formula (I) or its nitrogen oxides, solvates, metabolites , a pharmaceutically acceptable salt or prodrug.
  • the inventor found through a large number of experiments that the ophthalmic preparation has a definite dose-related relaxation effect on the ciliary muscle, and has the effect of significantly delaying the growth of the eye axis, which can delay the progression of myopia, achieve the effect of treating myopia, and can make animals amblyopia.
  • the amblyopia trend of the model gradually recovered, and the incubation period gradually shortened. After a certain period of administration, the amblyopia basically returned to the normal level.
  • the above-mentioned ophthalmic preparation may further include at least one of the following additional technical features:
  • the salt of the compound represented by the formula (I) as the active ingredient is a hydrochloride salt.
  • the ophthalmic preparation is used for the treatment and/or prevention of myopia and/or amblyopia.
  • the causes of the myopia and/or amblyopia include myopic shift in diopter, myopic vitreous cavity depth extension, myopic axial length extension, form deprivation, anisometropia and astigmatism one or more of.
  • the myopia and/or amblyopia includes mild myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, visual fatigue, exotropia, strabismus
  • One or more of amblyopia, fundus damage, occlusion, visual distortion, double vision, abnormal color vision, abnormal light perception, decreased contrast sensitivity, and refractive error amblyopia do not include vision problems caused by trauma.
  • the present invention provides a method for treating or preventing myopia and/or amblyopia.
  • the method comprises: administering the above-described composition or the above-described ophthalmic formulation to the ocular surface of the subject.
  • the inventor found through a large number of experiments that the above-mentioned composition or ophthalmic preparation can delay the progression of myopia in the subject, achieve the effect of treating myopia, and can also restore the subject's amblyopia to the normal level.
  • the method is for treating or preventing myopia and/or amblyopia.
  • the cause of said myopia and/or amblyopia is selected from the group consisting of myopic shift in diopter, myopic vitreous cavity depth extension, myopic axial length extension, form deprivation, anisometropia and one or more of astigmatism.
  • the myopia and/or amblyopia includes mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, visual fatigue, Exotropia, strabismus amblyopia, axial lengthening, fundus damage, occlusion, visual distortion, double vision, abnormal color vision, abnormal light vision, decreased contrast sensitivity, anisometropic amblyopia, refractive error
  • amblyopia unilateral form deprivation amblyopia, bilateral form deprivation amblyopia.
  • Embodiments of the present invention are described in detail below.
  • the embodiments described below are exemplary, only for explaining the present invention, and should not be construed as limiting the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used.
  • the reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
  • first and second are only used for descriptive purposes, and should not be construed as indicating or implying relative importance or implying the number of indicated technical features. Thus, a feature delimited with “first”, “second” may expressly or implicitly include at least one of that feature.
  • plurality means at least two, such as two, three, etc., unless otherwise expressly and specifically defined.
  • the use of the compound of formula (I) disclosed in the present invention or its nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of medicines is: preparation for treatment, prevention, improvement .
  • the medicine for controlling or alleviating the visual impairment of mammals, especially human beings, can also be used to prepare other medicines for antagonizing M receptors, and the toxic and side effects are small.
  • a “solvate” of the present invention means having a solvent on the surface, in the lattice, or both on the surface and in the lattice.
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, in the lattice, or both on the surface and in the lattice.
  • the "metabolite” of the present invention refers to a product obtained by metabolism of the compound of formula (I) or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. As used herein, “pharmaceutically acceptable salts” refer to organic and inorganic salts of the compounds of the present invention.
  • prodrug refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • composition refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the meaning of this term in relation to a pharmaceutical composition includes a product comprising the active ingredient (single or multiple) and inert ingredient (single or multiple) that make up the carrier, as well as a mixture, complex or aggregate of any two or more ingredients , or any product that results directly or indirectly from the decomposition of one or more components, or from other types of reactions or interactions of one or more components.
  • the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition provided by the present invention includes at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition dosage form is an ophthalmic formulation.
  • compositions provided by the present invention may further include: suitable antimicrobial agents or preservatives, suitable isotonic agents, suitable antioxidants, suitable local anesthetics, suitable suspending and dispersing agents, suitable emulsifying agents , a suitable sequestrant or chelating agent, a suitable pH adjuster and other carriers.
  • the pharmaceutical composition of the present invention can also be used in veterinary treatment of mammals in pets, introduced breed animals and farm animals. Examples of other animals include horses, dogs and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • Embodiment the preparation of penehyclidine hydrochloride solution test sample
  • Quarantined healthy cynomolgus monkeys aged 2.5-3.5 years, weighing 2.0-4.0 kg, male or female, were selected and randomly divided into 6 groups with 3 animals in each group, totaling 18 animals.
  • Groups 1, 2, and 3 were given 1%, 0.1%, and 0.01% atropine sulfate eye drops (commercially available 1% atropine sulfate eye drops, diluted with PBS to different concentrations), respectively.
  • the test groups were given 1%, 0.1%, and 0.01% penehyclidine hydrochloride solution, single dose to both eyes, 30 ⁇ L/eye.
  • the results of lens thickness are shown in Figure 1.
  • the lens thickness of each administration group decreased to the lowest 6h after the drug, and the higher the concentration, the stronger the effect of reducing lens thickness. 6h after the drug, the effect of reducing lens thickness was in the order of 1% test article > 0.1% test article ⁇ 1% atropine > 0.01% test article > 0.1% atropine > 0.01% atropine.
  • Each dose group gradually recovered from D1. The lower the concentration, the faster the recovery.
  • the 0.01%-0.1% test article and atropine group recovered completely 3-5 days after the drug, and the 1% test article and 1% atropine group were on the drug. Still not fully recovered after 14 days. It shows that penehyclidine hydrochloride has a clear dose-related relaxation effect on the ciliary muscle in the body, which can delay the progression of myopia and achieve the effect of treating myopia, and the effect is stronger than that of atropine.
  • the pupil diameter results are shown in Figure 2.
  • the 0.01% test group did not produce mydriasis, while the pupil diameters of other groups showed a dose-dependent dilation, which reached the maximum at 6h after the drug, and the mydriatic effect was ranked as 1. % atropine > 0.1% atropine > 1% test article > 0.01% atropine > 0.1% test article.
  • Mydriasis slowly recovered after 6 hours, the 0.1%-1% test product group and 0.01% atropine group returned to normal within 2-4 days (D3-D5) after the drug, and the 0.1%-1% atropine group returned to normal within 14 days after the drug (D15) still not fully recovered.
  • the side effects of 0.1%-1% of the test articles were significantly reduced, and the recovery time was shorter, which could significantly reduce the side effects such as photophobia and blurred vision caused by mydriasis.
  • the diffuser can be freely disassembled and installed, there is no light leakage except the diffuser, the disinfection and surgical procedures are controlled within 3 to 5 minutes, and the animal wakes up after 5 to 10 minutes.
  • 0.01%, 0.1%, 0.5%, and 1% penehyclidine hydrochloride solution, 1% atropine sulfate eye drops, and phosphate buffered saline (PBS) were used, respectively. , 1 time/day, 20 ⁇ L/eye/time, continuous administration for 6 weeks. During the test period, the observation of the animal state and the adhesion state of the diffuser was carried out once a day.
  • Retinoscopy and A-ultrasound were used to measure the diopter and axial length of the animals in each group before the test (D-1), two weeks of the test (D14), four weeks of the test (D28), and six weeks of the test (D42). See Table 1 and Table 2.
  • the diopter results are shown in Table 1.
  • Table 1 The diopter results are shown in Table 1.
  • Table 1 The diopter results are shown in Table 1.
  • the diopter values of each group of modeled eyes After 2 weeks of administration, relative myopia of -2.69 ⁇ 3.21D was induced in the modeled eyes of the animals in the PBS eye drop group, and the diopter of each administration group shifted to myopia, but no relative myopia was induced.
  • the relative myopia degree of the modeled eyes in the PBS group increased, and the relative myopia degree of the other groups increased slightly.
  • the axial lengths of the guinea pigs at D-1 in this example were all between 8.2 and 8.3 mm, and there was no significant difference in the length of the left and right eye axes in each group (P>0.05%), and there was no significant difference between the groups (P>0.05%). P>0.05%).
  • the results of the growth of the eye axis are shown in Table 2. 2 weeks after the administration of the model, the growth of the eye axis of the model eye was significantly higher than that of the OD eye (P ⁇ 0.05%), indicating that in addition to the normal growth of the eye axis, the model caused a Significant increase in axial length.
  • the 0.01%-1% penehyclidine hydrochloride solution provided in the embodiment of the present invention can effectively treat the development of myopia, and the effect is better than that of 1% atropine sulfate eye drops.
  • PBS penehyclidine hydrochloride solution test group
  • atropine control group 6 in each group.
  • Right lateral rectus muscle amputation was performed at the time of surgery.
  • P-VEP pattern visual evoked potential
  • Phosphate buffered saline (PBS) 1%, 2% test group
  • 1% atropine sulfate eye drops intraconjunctival sac eye drop administration, 1/day, 20 ⁇ L/eye/time, continuous administration for 12 weeks, record P-VEP every 4 weeks, the results are shown in Table 3.
  • a total of 30 healthy Dutch rabbits that have passed the quarantine were selected, male or female, and randomly divided into 5 groups with 6 rabbits in each group, including vehicle control group, 1% atropine control group, 0.01%, 1%, and 2% pentamethylene hydrochloride
  • the patients were administered eye drops in the conjunctival sac of both eyes once a day, 30 ⁇ L/eye/time, and the administration was repeated for 12 weeks.
  • death, morbidity, respiration, secretions, feces, diet and drinking conditions were observed.
  • the pupillary light reflex of each animal was visually observed before each administration, and the eye irritation was observed within 1 minute after each administration, including but not limited to squinting, blinking and head shaking. If the animal found the above abnormality, the frequency of occurrence (numbers per minute) and/or duration (recorded as less than or more than 60 seconds) were recorded. All animals underwent local ocular observation on D1, 4 weeks, 8 weeks, and 12 weeks before administration. Local ocular observations included but not limited to redness, swelling, conjunctival hyperemia, and secretions. A hand-held slit lamp and direct ophthalmoscope were used to examine the eyes of the eyes. The joints and fundus were examined, and the results are shown in Table 4-6.
  • Frequency means times per minute
  • S means the duration is less than 60s
  • L means the duration is greater than 60s
  • ⁇ means no abnormality
  • the eye irritation results are shown in Table 4.
  • the 1% atropine group showed moderate irritation and the pupillary light reflex disappeared.
  • 1 % and 0.01% test product groups were not irritating, similar to the vehicle control group, and the pupillary light reflex was normal, indicating that penehyclidine hydrochloride has good ocular drug safety, and has little effect on the pupil.

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Abstract

本发明提供了一种式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药在制备药物中的用途。

Description

戊乙奎醚在治疗或预防视力损伤性眼部疾病中的用途 技术领域
本发明涉及医药领域，具体的，本发明涉及戊乙奎醚在治疗或预防视力损伤性眼部疾病中的用途。
背景技术
根据流行病学报道，我国弱视的发病率为1.6-3.6％，部分地区高达11.8％，中国5岁以上人口的近视患病率将增长到51％左右，患病人口将达7亿。
目前国外针对近视防控和弱视治疗的药物推荐阿托品滴眼液，如美国、日本上市的1％硫酸阿托品滴眼液，适应症为诊断或治疗为目的散瞳和调节麻痹及弱视治疗；近年来低浓度硫酸阿托品滴眼液(0.01％)在中国台湾和澳门获批上市用于缓解近视或治疗近视，并在香港、新加坡、美国、英国、印度等均有缓解近视进展的临床试验报道，表明低浓度阿托品可有效延缓儿童青少年近视进展。
在近视发病机制的假设中，曾提出近视发展与睫状肌调节相关。Sato的调节紧张学说认为长期使用调节可造成睫状肌调节紧张，故推测采用阿托品放松和解除调节张力可达到青少年近视控制的作用。阿托品可阻断哺乳动物睫状肌M受体，从而缓解睫状肌的调节张力，而小鸡的睫状肌是横纹肌，受烟碱(nicotine，N)样受体调节支配，故阿托品不能使小鸡睫状肌麻痹。但McBrien等向小鸡形觉剥夺性近视(formdeprivation myopia，FDM)模型眼玻璃体腔注射质量分数0.01％阿托品后8d可诱导形成-2.8D近视，眼轴延长0.21mm，而假注射组和生理盐水注射组小鸡分别诱导形成-18.5D近视和-20.9D近视，眼轴分别延长1.04mm和1.00mm，即阿托品仍然可以显著抑制小鸡近视的形成和进展，提示阿托品通过非调节性机制抑制近视，或睫状肌调节麻痹不是阿托品近视控制的唯一靶点。阿托品被证实可以阻止部分动物模型和人类的近视发展，但阿托品抗近视作用的机制尚不完全明确。
目前，各种药物与近视的治疗关系尚未确立，由于阿托品为非选择性抑制剂，已经发现阿托品治疗近视与多种通路有关；托品酰胺也是另外一种非选择性的M受体阻断剂，通过和阿托品的比对试验发现，其不能有效阻止或延缓近视发展。
Stone等于1991年报道用M1受体阻断剂哌仑西平每天睑结膜下注射的方法可以抑制FDM的发生，而M2受体阻断剂methoctramine和M3受体阻断剂4-DAMP无效，提示可能与M1受体相关，但对于哌仑西平的研究发现，不同研究组治疗近视的实验结果并不一致；而Flitcroft应用另一种M1受体阻断剂Trihexyphenidyl局部滴眼或口服，虽然能够达到较高的视网膜浓度，但结果显示其不能有效阻止实验性近视的发展。
Luft等研究了阿托品(非选择)、哌仑西平(M1)、Oxyphenonium(M2)等十余种 具有M胆碱受体阻断作用的药物，发现仅有Oxypheneonium、阿托品、哌仑西平和Himbacine有一定的阻止FDM且无视网膜损害的作用，其他药物或者不能阻止FDM或者有不同程度的视网膜损害。M受体介导多种功能，甚至同一组织中M受体的不同亚型具有不同的药理学性质。在呼吸道，M2受体的功能与M1和M3受体的功能截然相反。因此，对不同亚型的M受体的选择性是决定抗胆碱药物应用前景的关键。因此，从研究文献的报道看，M受体与近视的对应关系尚未建立。
综上所述，新的治疗或者预防近视、弱视等视力损伤的药物亟待开发。
迄今为止，尚未见到有关戊乙奎醚及其衍生物在防治近视和弱视效果的报道。
发明内容
近视和弱视的治疗中，目前国外在研的硫酸阿托品滴眼液具有一定危险性，阿托品易产生全身系统副作用，如面潮口干、心率上升、尿潴留等，甚至引起中毒和过敏性休克，静脉每次极量2mg，超过上述用量，会引起中毒，用药过量表现为动作笨拙不稳、神志不清、抽搐、呼吸困难心跳异常加快等。因此，硫酸阿托品滴眼液在近视和弱势使用中的安全性问题一直是限制其大规模推广的因素。目前市场上寻找更为安全有效的眼疾治疗药物迫在眉睫。
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。
为此，在本发明的第一方面，本发明提出了式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药在制备药物中的用途，所述药物用于治疗和/或预防视力损伤性眼部疾病，
Figure PCTCN2021121385-appb-000001
发明人通过大量的研究发现，式(I)所示结构的化合物或其衍生物(氮氧化物、溶剂化物、代谢产物、药学上可接受的盐)具有良好的治疗或者预防视力损伤性眼部疾病的效果，并且全身毒副作用显著低于阿托品，具有良好的应用前景。
根据本发明的实施例，上述用途还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述式(I)所示化合物的盐包括有机盐或无机盐。
式(I)所示化合物被称为戊乙奎醚，发明人经过大量的研究意外而惊喜地发现，戊乙奎醚及其衍生物，如其有机盐或者无机盐等形式可以有效治疗或者预防近视或弱视等视力 损伤性眼部疾病，防控效果优于同浓度的硫酸阿托品滴眼液，并且具有散瞳作用更小、对眼局部刺激性更小及安全性更好等优点，可长期使用。
根据本发明的实施例，所述式(I)所示化合物的盐为盐酸盐，所述盐酸盐的结构如式(II)所示。
Figure PCTCN2021121385-appb-000002
发明人经过反复试验，发现上述盐酸戊乙奎醚的形式在治疗和/或预防近视、弱视等疾病中具有良好的效果。
根据本发明的实施例，所述药物用于治疗和/或预防近视和/或弱视。
根据本发明的实施例，造成所述近视和/或弱视的原因包括屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
根据本发明的实施例，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光不正性弱视中的一种或多种。需要注意的是，本申请所述的视力损伤性眼部疾病不包括外伤引起的视力问题。
在本发明的第二方面，本发明提出了一种药物组合物，所述药物组合物用于治疗和/或预防视力损伤性眼部疾病。根据本发明的实施例，含有式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药作为活性成分。
根据本发明的实施例，上述药物组合物还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物组合物用于治疗和/或预防近视和/或弱视。
根据本发明的实施例，造成所述近视和/或弱视的原因包括屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
根据本发明的实施例，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光不正性弱视中的一种或多种。需要注意的是，本申请所述的视力损伤性眼部疾病不包括外伤引起的 视力问题。
根据本发明的实施例，所述药物组合物进一步包括药学上可接受的至少一种载体。根据本发明实施例的药物组合物，所述载体包括，但不限于，含水运载体、水混溶性运载体、非水运载体、抗微生物剂或抗微生物生长的防腐剂、稳定剂、溶解增强剂、渗透压调节剂、缓冲剂、抗氧剂、局部麻醉剂、助悬剂和分散剂、湿润剂或乳化剂、络合剂、多价螯合剂或螯合剂、防冻剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体，本领域技术人员可依据制剂的实际需求加以选择。
根据本发明的实施例，所述药物组合物剂型为眼用制剂，包括滴眼剂、眼膏剂、眼用乳膏剂、眼用乳剂、眼用凝胶剂、眼丸剂、眼膜剂、眼内植入剂中一种或多种。
根据本发明的实施例，所述活性成分在所述药物组合物中的质量分数为0.005％-2％。根据本发明实施例的药物组合物，所述活性成分在所述药物组合物中的质量体积分数为0.005％、0.01％、0.015％、0.02％、0.025％、0.03％、0.035％、0.04％、0.045％、0.05％、0.055％、0.06％、0.065％、0.07％、0.075％、0.08％、0.085％、0.09％、0.095％、0.1％、0.105％、0.11％、0.115％、0.12％、0.125％、0.13％、0.135％、0.14％、0.145％、0.15％、0.155％、0.16％、0.165％、0.17％、0.175％、0.18％、0.185％、0.19％、0.195％、0.2％、0.205％、0.21％、0.215％、0.22％、0.225％、0.23％、0.235％、0.24％、0.245％、0.25％、0.255％、0.26％、0.265％、0.27％、0.275％、0.28％、0.285％、0.29％、0.295％、0.3％、0.305％、0.31％、0.315％、0.32％、0.325％、0.33％、0.335％、0.34％、0.345％、0.35％、0.355％、0.36％、0.365％、0.37％、0.375％、0.38％、0.385％、0.39％、0.395％、0.4％、0.405％、0.41％、0.415％、0.42％、0.425％、0.43％、0.435％、0.44％、0.445％、0.45％、0.455％、0.46％、0.465％、0.47％、0.475％、0.48％、0.485％、0.49％、0.495％、0.5％、0.505％、0.510％、0.515％、0.520％、0.525％、0.530％、0.535％、0.540％、0.545％、0.550％、0.555％、0.560％、0.565％、0.570％、0.575％、0.580％、0.585％、0.590％、0.595％、0.600％、0.605％、0.610％、0.615％、0.620％、0.625％、0.630％、0.635％、0.640％、0.645％、0.650％、0.655％、0.660％、0.665％、0.670％、0.675％、0.680％、0.685％、0.690％、0.695％、0.700％、0.705％、0.710％、0.715％、0.720％、0.725％、0.730％、0.735％、0.740％、0.745％、0.750％、0.755％、0.760％、0.765％、0.770％、0.775％、0.780％、0.785％、0.790％、0.795％、0.800％、0.805％、0.810％、0.815％、0.820％、0.825％、0.830％、0.835％、0.840％、0.845％、0.850％、0.855％、0.860％、0.865％、0.870％、0.875％、0.880％、0.885％、0.890％、0.895％、0.900％、0.905％、0.910％、0.915％、0.920％、0.925％、0.930％、0.935％、0.940％、0.945％、0.950％、0.955％、0.960％、0.965％、0.970％、0.975％、0.980％、0.985％、0.990％、0.995％、1.000％、1.005％、1.010％、1.015％、1.020％、1.025％、1.030％、1.035％、1.040％、1.045％、1.050％、1.055％、1.060％、1.065％、1.070％、1.075％、1.080％、1.085％、1.090％、1.095％、 1.100％、1.105％、1.110％、1.115％、1.120％、1.125％、1.130％、1.135％、1.140％、1.145％、1.150％、1.155％、1.160％、1.165％、1.170％、1.175％、1.180％、1.185％、1.190％、1.195％、1.200％、1.205％、1.210％、1.215％、1.220％、1.225％、1.230％、1.235％、1.240％、1.245％、1.250％、1.255％、1.260％、1.265％、1.270％、1.275％、1.280％、1.285％、1.290％、1.295％、1.300％、1.305％、1.310％、1.315％、1.320％、1.325％、1.330％、1.335％、1.340％、1.345％、1.350％、1.355％、1.360％、1.365％、1.370％、1.375％、1.380％、1.385％、1.390％、1.395％、1.400％、1.405％、1.410％、1.415％、1.420％、1.425％、1.430％、1.435％、1.440％、1.445％、1.450％、1.455％、1.460％、1.465％、1.470％、1.475％、1.480％、1.485％、1.490％、1.495％、1.500％、1.505％、1.510％、1.515％、1.520％、1.525％、1.530％、1.535％、1.540％、1.545％、1.550％、1.555％、1.560％、1.565％、1.570％、1.575％、1.580％、1.585％、1.590％、1.595％、1.600％、1.605％、1.610％、1.615％、1.620％、1.625％、1.630％、1.635％、1.640％、1.645％、1.650％、1.655％、1.660％、1.665％、1.670％、1.675％、1.680％、1.685％、1.690％、1.695％、1.700％、1.705％、1.710％、1.715％、1.720％、1.725％、1.730％、1.735％、1.740％、1.745％、1.750％、1.755％、1.760％、1.765％、1.770％、1.775％、1.780％、1.785％、1.790％、1.795％、1.800％、1.805％、1.810％、1.815％、1.820％、1.825％、1.830％、1.835％、1.840％、1.845％、1.850％、1.855％、1.860％、1.865％、1.870％、1.875％、1.880％、1.885％、1.890％、1.895％、1.900％、1.905％、1.910％、1.915％、1.920％、1.925％、1.930％、1.935％、1.940％、1.945％、1.950％、1.955％、1.960％、1.965％、1.970％、1.975％、1.980％、1.985％、1.990％、1.995％、2.000％。
根据本发明的具体实施例，药物组合物的给药剂量取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。
在本发明的第三方面，本发明提出了一种眼用制剂，用于治疗和/或预防视力损伤性眼部疾病。根据本发明的实施例，所述眼用制剂中活性成分的质量分数为0.005％-2％，所述活性成分为式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药。发明人通过大量试验发现，该眼用制剂对睫状肌有明确的剂量相关的松弛作用，以及具有显著延缓眼轴增长的效果，可发挥延缓近视进展，达到治疗近视作用，并能使动物弱视模型的弱视趋势逐渐恢复，潜伏期逐渐缩短，当给药一定时间后，弱视基本恢复至正常水平。
根据本发明的实施例，上述眼用制剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述活性成分为式(I)所示化合物的盐为盐酸盐。
根据本发明的实施例，所述眼用制剂用于治疗和/或预防近视和/或弱视。
根据本发明的实施例，造成所述近视和/或弱视的原因包括屈光度的近视性偏移、近视 性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
根据本发明的实施例，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光不正性弱视中的一种或多种。需要注意的是，本申请所述的视力损伤性眼部疾病不包括外伤引起的视力问题。
在本发明的第四方面，本发明提出了一种治疗或者预防近视和/或弱视的方法。根据本发明的实施例，所述方法包含：向受试者的眼表施用上述的组合物或者上述的眼用制剂。发明人通过大量试验发现，采用上述的组合物或眼用制剂，可发挥延缓受试者的近视进展，达到治疗近视作用，并且，还可以使受试者的弱视基本恢复至正常水平。
根据本发明的实施例，所述方法用于治疗或者预防近视和/或弱视。
根据本发明的实施例，造成所述近视和/或弱视的原因选自屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
根据本发明的实施例，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、屈光性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼轴变长、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光参差性弱视、屈光不正性弱视、单侧形觉剥夺性弱视、双侧形觉剥夺性弱视中的一种或多种。
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。
附图说明
图1为给药前后各组相对晶状体厚度变化(Mean±SD，n＝6眼/组)；
图2为给药前后各组相对瞳孔直径变化(Mean±SD，n＝6眼/组)。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为 可以通过市购获得的常规产品。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
制药用途
本发明所公开式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药在制备药物中的用途为：制备用于治疗、预防、改善、控制或减轻哺乳动物，特别是人类的视力损伤性疾病的药品，也可以用于制备用于拮抗M受体的其他药品，且毒副作用小。
本发明的“溶剂化物”是指在表面、在晶格中或者在表面上和在晶格中具有溶剂。溶剂化物的一个具体例子是水合物，其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
本发明的“代谢产物”是指式(I)所示结构的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。
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。
药物组合物
本发明所使用的术语“组合物”是指包含规定量的规定成分的产物，以及规定量的规定成分的组合所直接或间接地产生的任何产物。与药物组合物相关的这种术语的含义包括包含活性成分(单个或者多个)和组成载体的惰性成分(单个或者多个)的产物，以及由任何两种或多种成分混合、复合或聚集，或者由一种或多种成分分解，或者由一种或多种成分的其他类型的反应或相互作用而直接或间接产生的任何产物。因此，本发明药物组合物包括通过将本发明化合物与可药用载体混合而制备的任何组合物。
本发明提供的药物组合物包括药学上可接受的至少一种载体。示例性地，药物组合物剂型为眼用制剂。例如，滴眼剂、眼膏剂、眼用乳膏剂、眼用乳剂、眼用凝胶剂、眼丸剂、眼膜剂、眼内植入剂。
本发明提供的药物组合物还可以进一步包括：合适的抗微生物剂或防腐剂、合适的等渗剂、合适的抗氧化剂、合适的局部麻醉剂、合适的助悬剂和分散剂、合适的乳化剂、合 适的多价螯合剂或螯合剂、合适的pH调节剂等载体。
本发明的药物组合物除了对人类视力损伤性眼部疾病有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。
需要解释说明的是，下述实施例中数据结果均是以Mean±SD进行统计的。
实施例：盐酸戊乙奎醚溶液供试品的制备
将盐酸戊乙奎醚和生理盐水混合，搅拌至完全溶解，分别制得0.01％、0.1％、0.5％、1％和2％的盐酸戊乙奎醚溶液供试品。
效果实施例
效果实施例1：盐酸戊乙奎醚对猴晶状体和瞳孔的作用
选取经检疫合格的健康食蟹猴，年龄2.5～3.5岁，体重2.0～4.0kg，雌雄不限，随机分为6组，每组3只，共18只。第1、2、3组分别给予1％、0.1％、0.01％的硫酸阿托品滴眼液(选用市售1％硫酸阿托品滴眼液，采用PBS稀释成不同浓度)，第4、5、6供试品组分别给予1％、0.1％、0.01％盐酸戊乙奎醚溶液，单次双眼给药，30μL/眼。于给药前、药后1h、2h、4h、6h、24h、D3、D5、D7、D13、D15采用A超检查双眼晶状体厚度和瞳孔直径，以给药前为基准，计算相对晶状体厚度和瞳孔直径(Mean±SD，n＝6眼/组)，结果如图1和图2所示。
晶状体厚度的结果如图1所示，各给药组在药后6h晶状体厚度降低至最低，浓度越高降低晶状体厚度的效果越强。药后6h降低晶状体厚度效果强弱依次为1％供试品＞0.1％供试品≈1％阿托品＞0.01％供试品＞0.1％阿托品＞0.01％阿托品。各剂量组从D1开始逐渐恢复，浓度越低，恢复越快，0.01％～0.1％供试品和阿托品组在药后3-5天完全恢复，1％供试品与1％阿托品组在药后14天仍未完全恢复。表明盐酸戊乙奎醚对在体的睫状肌有明确的剂量相关的松弛作用，可发挥延缓近视进展，达到治疗近视作用，作用强度强于阿托品。
瞳孔直径结果如图2所示，0.01％供试品组不会产生散瞳作用，其他各组瞳孔直径呈现剂量相关性的扩大，于药后6h达到最大，散瞳作用效果强弱依次为1％阿托品＞0.1％阿托品＞1％供试品＞0.01％阿托品＞0.1％供试品。6h后散瞳作用慢慢恢复，0.1％～1％供试品组和0.01％阿托品组于药后2-4天(D3-D5)恢复至正常，0.1％～1％阿托品组药后14天(D15)仍未完全恢复。与阿托品组相比，0.1％～1％供试品散瞳副作用明显减弱，且恢复时间更短，其可显著降低因瞳孔扩大而导致的畏光和视物模糊等副作用。
效果实施例2：盐酸戊乙奎醚治疗形觉剥夺型豚鼠近视研究
选取2周龄的断乳、健康短毛三色花豚鼠，雌雄不限，检疫合格后，筛选单眼屈光度≥+1.00D，双眼屈光参差≤1.50D的花豚鼠共48只，随机分成6组：供试品组(高、中、低剂量)、阴性对照组、阳性对照组(阿托品组)，每组8只。所有动物左眼造模，右眼不作处理，造模方法为异氟烷吸入麻醉，使用氰基丙烯酸酯胶，将自制的苯乙烯塑料漫射体的尼龙搭扣底面和眼周皮肤粘合，确认粘合牢固，漫射体可自由拆卸安装，除漫射体外无漏光，消毒及手术过程控制在3～5分钟内，动物在5～10分钟后苏醒。造模当天分别采用0.01％、0.1％、0.5％、1％的盐酸戊乙奎醚溶液、1％硫酸阿托品滴眼液、磷酸盐缓冲液(PBS)，造模眼结膜囊内滴眼给药，1次/天，20μL/眼/次，连续给药6周。试验期间每天进行1次动物状态和漫射体粘附状态观察。各组动物分别于试验前(D-1)、试验两周(D14)、试验四周(D28)、试验六周(D42)时分别采用检影镜和A超进行屈光度和眼轴长度测量，结果见表1和表2。
表1：屈光度结果
Figure PCTCN2021121385-appb-000003
注：a表示与D-1相比，p≤0.05％；b表示与同期PBS组相比，p≤0.05％。
屈光度结果如表1所示，不同时间段，与D-1相比，造模眼各组屈光度值均有统计学差异。给药2周后，PBS滴眼组动物的造模眼诱导出-2.69±3.21D的相对近视，各给药组屈光度向近视偏移，但未诱导出相对近视。随着时间的延长，PBS组造模眼相对近视程度增加，其他各组相对近视程度略有增加。给药6周后，PBS滴眼组动物的造模眼诱导出-5.06±1.04D的相对近视，1％阿托品滴眼组、1％、0.5％、0.1％、0.01％盐酸戊乙奎醚溶液供试品组的造模眼分别诱导出-1.18±2.52D、-0.28±1.79D、-0.35±1.56D、-0.48±1.49D、-1.06±2.48D的相对近视，各给药组屈光度值显著低于PBS组(P＜0.05％)。表明各给药组均具有明显的治疗近视作用，不同浓度供试品组治疗后的相对近视度数更低，治疗近视效果均强于1％的阿托品组。
表2：眼轴增长量结果
Figure PCTCN2021121385-appb-000004
注：a表示与同期OD相比，p＜0.05％；b表示与PBS相比，p＜0.05％。
本实施例中的D-1时花豚鼠的眼眼轴长度均在8.2～8.3mm之间，各组左右眼眼轴增长量无明显差异(P＞0.05％)，组间也无显著差异(P＞0.05％)。眼轴增长量结果如表2所示，造模给药后2周，造模眼眼轴增长量显著高于OD眼(P＜0.05％)，表明眼轴除正常增长外，造模引起了眼轴长度的显著增长。
造模给药后4周，PBS组和1％阿托品组OS眼轴增长量仍显著高于同期OD眼(P＜0.05％)，0.01％～1％供试品组眼轴增长量与同期OD眼无显著差异(P＞0.05％)；1.0％、0.5％和0.1％供试品组OS眼轴增长量显著低于PBS组OS眼(P＜0.05％)，表明各浓度供试品组比阿托品组更早产生了显著延缓眼轴增长的效果。
造模给药后6周，PBS组OS眼轴增长量仍显著高于同期OD眼(P＜0.05％)，各给药组OS眼轴增长量均与同期OD眼无显著差异(P＞0.05％)。1.0％、0.5％和0.1％供试品组OS眼轴增长量显著低于PBS组OS眼(P＜0.05％)，0.01％供试品与1％阿托品组OS眼轴增长量与PBS组OS眼无显著差异(P＞0.05％)，表明各给药组均产生了延缓眼轴长度增长的效果，且0.1％～1％供试品组眼轴长度增长幅度更小，表明治疗近视效果比1％阿托品强。
综上所述，本发明实施例所提供的0.01％～1％盐酸戊乙奎醚溶液可以有效治疗近视发展，且相比于1％硫酸阿托品滴眼液效果更好。
效果实施例3：盐酸戊乙奎醚治疗猫斜视性弱视研究
选取普通4周龄家猫24只，随机分为PBS组、1％、2％盐酸戊乙奎醚溶液供试品组和1％阿托品对照组，每组各6只，各组于4周龄时行右眼外直肌切断术，术后4周经图形视觉诱发电位(P-VEP)检测确定形成弱视后，分别采用磷酸盐缓冲液(PBS)、1％、2％供 试品组、1％硫酸阿托品滴眼液，结膜囊内滴眼给药，1次/天，20μL/眼/次，连续给药12周，每4周纪录一次P-VEP，结果如表3所示。
表3：P-VEP结果
Figure PCTCN2021121385-appb-000005
如表3所示，造模前，各组P波的潜伏期和波幅(nv)基本一致，造模4周后，各组P-VEP出现潜伏期显著延长及波幅显著降低，较造模前差异均有统计学意义，表明经行右眼外直肌切断术，4周后各组均成功造出了动物弱视模型。连续给药4-12周期间，PBS组P-VEP潜伏期继续延长，波幅继续降低；各给药治疗组P-VEP趋势逐渐恢复，潜伏期逐渐缩短，波幅逐渐增大，至给药12周时，1％和2％供试品组接近恢复至造模前，且1％和2％供试品弱视恢复效果比1％阿托品高。表明1％～2％盐酸戊乙奎醚溶液有治疗弱视效果，且作用比阿托品强。
效果实施例4：盐酸戊乙奎醚兔重复滴眼毒性研究
选取经检疫合格的健康荷兰兔共30只，雌雄不限，随机分为5组，每组6只，包含溶媒对照组、1％阿托品对照组、0.01％、1％、2％的盐酸戊乙奎醚溶液供试品组，每天双眼结膜囊滴眼给药1次，30μL/眼/次，重复给药12周。所有动物试验期间每天至少1次，观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等。每只动物在每次给药之前肉眼观察瞳孔对光反射情况，每次给药后1分钟内观察眼刺激性，刺激性观察内容包括但不限于眯眼、眨眼和甩头。若动物发现上述异常，记录发生频率(每分钟次数)和/或持续时间(记录为少于或多于60秒)。所有动物在D1、4周、8周、12周给药前进行眼局部观察，眼局部观察包括但不限于发红、肿胀、结膜充血和分泌物，使用手持式裂隙灯、直接检眼镜对眼前节、眼底进行检查，结果如表4-6所示。
表4：眼部刺激性结果
Figure PCTCN2021121385-appb-000006
注：频率表示每分钟次数，S表示持续时间小于60s，L表示持续时间大于60s，√表示无异常。
眼部刺激性结果如表4所示，1％阿托品组显示中度刺激性，瞳孔对光反射消失，供试品组除2％高剂量组有轻微刺激性、瞳孔对光反射减弱外，1％、0.01％供试品组均无刺激性，与溶媒对照组类似，瞳孔对光反射正常，表明盐酸戊乙奎醚具有很好的眼部用药安全性，且对瞳孔的影响较小。
表5：眼科检查结果
Figure PCTCN2021121385-appb-000007
表6：眼局部观察结果
Figure PCTCN2021121385-appb-000008
Figure PCTCN2021121385-appb-000009
眼局部观察结果如表6所示，不同浓度的供试品重复滴眼给药12周，角膜均未产生混浊，结膜也未产生水肿，眼压与溶媒对照组类似，而阿托品组在重复给药后4周开始，出现轻度角膜混浊，结膜也出现了轻微水肿，表明盐酸戊乙奎醚重复给药安全性明显优于同浓度阿托品。
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 (22)

  1. 式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药在制备药物中的用途，所述药物用于治疗和/或预防视力损伤性眼部疾病，
    Figure PCTCN2021121385-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，所述式(I)所示化合物的盐选自有机盐或无机盐。
  3. 根据权利要求1所述的用途，其特征在于，所述式(I)所示化合物的盐为盐酸盐，优选地，所述盐酸盐的结构如式(II)所示，
    Figure PCTCN2021121385-appb-100002
  4. 根据权利要求1所述的用途，其特征在于，所述药物用于治疗和/或预防近视和/或弱视。
  5. 根据权利要求4所述的用途，其特征在于，造成所述近视和/或弱视的原因选自屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
  6. 根据权利要求1所述的用途，其特征在于，所述药物用于治疗和/或预防近视和/或弱视，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、屈光性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼轴变长、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光参差性弱视、屈光不正性弱视、单侧形觉剥夺性弱视、双侧形觉剥夺性弱视中的一种或多种。
  7. 一种药物组合物，所述药物组合物用于治疗和/或预防视力损伤性眼部疾病，其特征在于，其含有权利要求1所述式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药作为活性成分。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物进一步包括药学 上可接受的至少一种载体。
  9. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物的剂型为眼用制剂，包括滴眼剂、眼膏剂、眼用乳膏剂、眼用乳剂、眼用凝胶剂、眼丸剂、眼膜剂、眼内植入剂中一种或多种。
  10. 根据权利要求7所述的药物组合物，其特征在于，组合物以重量计，所述活性成分在所述药物组合物中的质量分数为0.005％-2％。
  11. 根据权利要求7-10任一项所述的药物组合物，其特征在于，所述药物组合物用于治疗或者预防近视和/或弱视。
  12. 根据权利要求11所述的药物组合物，其特征在于，造成所述近视和/或弱视的原因选自屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
  13. 根据权利要求11所述的药物组合物，其特征在于，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、屈光性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼轴变长、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光参差性弱视、屈光不正性弱视、单侧形觉剥夺性弱视、双侧形觉剥夺性弱视中的一种或多种。
  14. 一种眼用制剂，所述眼用制剂用于治疗和/或预防视力损伤性眼部疾病，其特征在于，所述眼用制剂中活性成分的质量分数为0.005％-2％，所述活性成分为权利要求1所述式(I)所示结构的化合物或其氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药。
  15. 根据权利要求14所述的眼用制剂，其特征在于，所述活性成分为式(I)所示化合物的盐为盐酸盐。
  16. 根据权利要求14-15任一项所述的眼用制剂，其特征在于，所述眼用制剂用于治疗或者预防近视和/或弱视。
  17. 根据权利要求16所述的眼用制剂，其特征在于，造成所述近视和/或弱视的原因选自屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
  18. 根据权利要求16所述的眼用制剂，其特征在于，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、屈光性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼轴变长、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光参差性弱视、屈光不正性弱视、单侧形觉剥夺性弱视、双侧形觉剥夺性弱视中的一种或多种。
  19. 一种治疗和/或预防视力损伤性眼部疾病的方法，其特征在于，包含：
    向受试者的眼表施用权利要求7-13任一项所述的组合物或者权利要求14-18任一项所述的眼用制剂。
  20. 根据权利要求19所述的方法，其特征在于，所述方法用于治疗或者预防近视和/或弱视。
  21. 根据权利要求20所述的方法，其特征在于，造成所述近视和/或弱视的原因选自屈光度的近视性偏移、近视性玻璃体腔深度的延长、近视性眼轴长度的延长、形觉剥夺、屈光参差和散光中的一种或多种。
  22. 根据权利要求20所述的方法，其特征在于，所述近视和/或弱视包括轻度近视、中度近视、高度近视、轴性近视、屈光性近视、单纯性近视、病理性近视、远视力减退、视疲劳、外斜视、斜视性弱视、眼轴变长、眼底损伤、视物遮挡、视物变形、视物重影、色觉异常、光觉异常、对比敏感度下降、屈光参差性弱视、屈光不正性弱视、单侧形觉剥夺性弱视、双侧形觉剥夺性弱视中的一种或多种。
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