Methods of treating visual loss in human subjects using photoreactive compounds

Abstract

The present disclosure provides a method of treating a human subject having a retinal disease, the method comprising administering to the eye of the subject by intravitreal injection a composition comprising a compound of formula (I) as described herein.

Description

Technical Field

[0001] This disclosure provides a method for treating a human subject with a retinal disease, the method comprising administering a composition comprising a compound of formula (I) as described herein into the subject's eye via intravitreal injection. Background Technology

[0002] Some photochromic azobenzene compounds exhibit photoswitching behavior, thereby undergoing photoisomerization to alter their length and geometry. These compounds can interact with proteins, and therefore, photoisomerization can change protein function. In vitro experiments have shown that these compounds confer photosensitivity to degenerating retina through interaction with membrane proteins in retinal ganglion cells and upstream neurons. Summary of the Invention

[0003] In some embodiments, this disclosure provides a method for treating a human subject with a retinal disease, the method comprising administering a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof into the subject's eye via intravitreal injection: The azo (N=N) bonds in this structure can be cis or trans.

[0004] In some embodiments, the retinal disease is caused by a hereditary eye condition. In some embodiments, the hereditary eye condition is retinitis pigmentosa. In some embodiments, the retinal disease is age-related macular degeneration. In some embodiments, the retinal disease is choroidal agenesis.

[0005] In some embodiments, the compound of formula (I) is administered to both eyes of the subject. In some embodiments, the compound of formula (I) is administered to only one eye of the subject. In some embodiments, administration to one eye of the subject provides a therapeutic effect in both eyes.

[0006] In some embodiments, administration to one eye is a first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately one week to two months after the first administration. In some embodiments, administration to one eye is a first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately one week to two months after the first administration. In some embodiments, administration to one eye is a first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately three to five weeks after the first administration. In some embodiments, administration to one eye is a first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately three to five weeks after the first administration. In some embodiments, administration to one eye is a first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately one month after the first administration. In some embodiments, administration to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately one to two months after the first administration.

[0007] In some embodiments, treating a human subject includes enhancing the subject's ability to detect light and contrast, an ability measured by a light response test. In some embodiments, treating a human subject includes stimulating the subject's striatal (VI) and non-striatal (V2 and / or V3) cortical activity, as measured by functional magnetic resonance imaging (FMRI).

[0008] In some embodiments, treating human subjects includes increasing the subject's tolerance to glare and photosensitivity. In some embodiments, treating human subjects includes improving measurements of functional vision. In some embodiments, treating human subjects reduces nonspecific, non-stimulatory random electrical activity of the retina.

[0009] In some embodiments, the composition further comprises cyclodextrin. In some embodiments, the molar ratio of cyclodextrin to compound (I) in the composition is from about 20:1 to about 1:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) in the composition is from about 15:1 to about 3:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) in the composition is from about 5:1.

[0010] In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.1 mM to about 10 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.2 mM to about 5 mM. In some embodiments, about 1 μg to about 100 μg of the compound of formula (I) is administered to one eye of the human subject. In some embodiments, about 7.5 μg to about 50 μg of the compound of formula (I) is administered to one eye of the human subject.

[0011] In some embodiments, this disclosure provides a method for treating a human subject with a retinal disease, the method comprising: (a) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the contralateral eye of the subject for the second time via intravitreal injection; or (b) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the same eye of the subject for the second time via intravitreal injection, wherein the compound (I) has the following structure: Or a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

[0012] In some embodiments, the second dose to the contralateral eye is administered simultaneously or substantially simultaneously with the first dose, or immediately after the first dose. In some embodiments, the second dose to the contralateral eye is administered approximately 3 to 5 weeks after the first dose. In some embodiments, the second dose to the same eye is administered approximately 3 to 5 weeks after the first dose.

[0013] In some embodiments, this disclosure provides a method for improving the tolerance of human subjects with retinal diseases to glare and photosensitivity, the method comprising: (a) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the contralateral eye of the subject for the second time via intravitreal injection; or (b) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the same eye of the subject for the second time via intravitreal injection, wherein the compound (I) has the following structure: Or a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans. Attached Figure Description

[0014] The following figures form part of this specification and are intended to further illustrate exemplary embodiments of certain aspects of this disclosure.

[0015] Figure 1 The clinical study design described in Example 1 is shown.

[0016] Figure 2A-2C The intensity and contrast assessment results of subjects (subject 1-01) who were given KIO-301 are shown. Figure 2A The results of intensity and contrast assessments of the subject's right eye (OD) are shown. Figure 2B The results of intensity and contrast assessments for the subject's left eye (OS) are shown. Figure 2C The photoresponse index of the subjects relative to light intensity is shown.

[0017] Figure 3A and Figure 3B The dynamic visual field assessment results of subject 1-01 are shown. Figure 3A The resulting field of view is shown, where the solid circle represents the baseline and the shaded circle represents the result one month after injection. Figure 3B The total horizontal and vertical visual field diopters of both eyes are shown at baseline and approximately one month after injection.

[0018] Figure 4 The results of the window position assessment for subject 1-01 over 30 days are shown. OD: right eye; OS: left eye; OU: both eyes.

[0019] Figure 5 The results of functional MRI of subject 1-01 at baseline and on days 2, 14, and 28 post-injection are shown.

[0020] Figure 6 The results of a functional MRI performed on subject 1-01, in which the subject was subjected to checkerboard stimulation, are shown.

[0021] Figure 7 The results of the Quality of Life Questionnaire (VFQ-25) for subject 1-01 at baseline and on day 29 post-injection are shown.

[0022] Figures 8A-8C The intensity and contrast assessment results of subjects (subjects 1-02) who were given KIO-301 are shown. Figure 2A The results of intensity and contrast assessments of the subject's right eye (OD) are shown. Figure 2B The results of intensity and contrast assessments for the subject's left eye (OS) are shown. Figure 2C The results of intensity and contrast assessments for the subjects' eyes (OU) are shown.

[0023] Figure 9A and Figure 9BThe dynamic visual field assessment results for subject 1-02 are shown. Figure 9A The resulting field of view is shown. Figure 9B The baseline and a summary of total horizontal and vertical visual field diopters for both eyes are shown approximately one week after injection.

[0024] Figure 10 The results of functional MRI performed on subject 1-02 at baseline and on days 2, 14, and 28 post-injection are shown. Detailed Implementation

[0025] Unless otherwise defined, scientific and technical terms used in this disclosure shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms.

[0026] The articles “a” and “an” used in this article refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” refers to one or more elements.

[0027] The use of the term "or" in the claims is intended to mean "and / or" unless it is explicitly stated that it refers only to an option or that the options are mutually exclusive, although this disclosure supports the definition of referring only to an option and referring to "and / or".

[0028] As used herein, the terms “comprising” (and any variations or forms of comprising, such as “comprise” and “comprises”), “having” (and any variations or forms of having, such as “have” and “has”), “including” (and any variations or forms of including, such as “includes” and “include)”), or “containing” (and any variations or forms of containing, such as “contains” and “contain)”) are inclusive or open-ended and do not exclude additional, unreferenced, elements, or method steps.

[0029] The use of the term "for example" and its corresponding abbreviation "eg" indicates that the specific term referenced is a representative example and implementation of this disclosure, and is not limited to the specific example referenced unless otherwise expressly stated.

[0030] As used herein, the term “about” can mean a value plus or minus 10%. If a range of values ​​is provided, the range includes boundary values. “About” can also mean within 10% of the specified value, or within 5% of the specified value, or in some cases within 2.5% of the specified value; or “about” can mean rounded to the nearest significant figure.

[0031] As used in this article, "between" is a range that includes the end of the range. For example, numbers between x and y explicitly include the numbers x and y, as well as any numbers that fall within x and y.

[0032] As used herein, the term "active agent" includes any pharmaceutical preparation, drug, compound, composition, or other substance that can be used or administered to a subject (e.g., a human or animal subject) for any purpose, including therapeutic agents, pharmaceutical preparations, pharmacological agents, diagnostic agents, cosmetic agents, preventative agents, and immunomodulators. The term "active agent" is used interchangeably with the terms "drug," "pharmaceutical preparation," "formulation," "pharmaceutical substance," and "therapeutic agent." In some embodiments, the active agents of this disclosure include compounds of formula (I).

[0033] In some embodiments, the compositions described herein are "pharmaceutical acceptable". The term "pharmaceutical acceptable" when referring to the compositions, excipients, carriers, diluents, or ingredients described herein means that the composition and / or its components are suitable for human and / or animal use without excessive adverse side effects (e.g., toxicity, irritation, and sensitization), i.e., with a reasonable benefit / risk ratio.

[0034] The terms “side effect” or “adverse event” refer to physiological disorders and / or adverse conditions caused by treatment in addition to the expected effects.

[0035] In some embodiments, the compositions described herein are effective for the treatments described herein. The term "efficacy" refers to the ability to produce the intended effect. The term "effective amount" refers to the amount of a therapeutic agent (e.g., the compound of formula (I) described herein) used to treat, alleviate, or prevent a target disease or condition (e.g., retinal disease described herein), or the amount that exhibits a detectable therapeutic or preventive effect. The exact effective amount for a subject depends on the subject's body size and health status, the nature and severity of the condition, and the chosen therapeutic agent and / or combination of therapeutic agents.

[0036] "Therapeutic effective dose" refers to the dosage of a compound (such as the compound of formula (I) described herein) that achieves a therapeutic effect by inhibiting a patient's condition or disorder (such as retinitis pigmentosa (RP)). A therapeutic effective dose may refer to a dosage that alleviates, to some extent, one or more symptoms of a patient's condition or disorder; partially or completely restores one or more physiological or biochemical parameters associated with or causing the condition or disorder to normal; and / or reduces the likelihood of the onset of the condition or disorder.

[0037] The terms “administration” or “application” refer to the route by which a compound or composition provided herein is introduced into an individual to perform its intended function. Examples of possible routes of administration include, but are not limited to, parenteral administration, such as intravitreal injection.

[0038] The term "subject" refers to any subject who requires treatment (e.g., treatment using a composition containing compound (I)), particularly a mammalian subject. In some embodiments, the term "subject" refers to a human subject. As used herein, "subject in need" refers to a subject who desires treatment (e.g., a subject suffering from the retinal disease described herein). In some embodiments, the term "subject in need" may refer to a subject at higher risk of developing a condition suitable for treatment using a composition containing compound (I) as described herein, regardless of whether the subject exhibits physical manifestations of such a condition.

[0039] Treatment of retinal diseases In some embodiments, this disclosure provides a method for treating a human subject with a retinal disease, the method comprising administering a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof into the subject's eye via intravitreal injection: (I), Among them, R 1 R 2 R 3 R 4 R 5 R 6 x and y are as described in this article.

[0040] In some embodiments, this disclosure provides a method for treating a human subject with a retinal disease, the method comprising: (a) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the contralateral eye of the subject for the second time via intravitreal injection; or (b) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the same eye of the subject for the second time via intravitreal injection, wherein the compound (I) has the following structure: (I), Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 R 5 R 6 x and y are as described in this article.

[0041] In some embodiments, this disclosure provides a method for improving the tolerance of human subjects with retinal diseases to glare and photosensitivity, the method comprising: (a) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the contralateral eye of the subject for the second time via intravitreal injection; or (b) administering a composition containing compound (I) to one eye of the subject via intravitreal injection for the first time; and administering the composition containing compound (I) to the same eye of the subject for the second time via intravitreal injection, wherein the compound (I) has the following structure: (I), Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 R 5 R 6 x and y are as described in this article.

[0042] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: The azo (N=N) bonds in the structure can be cis or trans.

[0043] Surprisingly, compositions comprising the compounds described herein (e.g., compounds of formula (I)) have been found to be effective in treating human retinal diseases. In some embodiments, the compositions described herein can confer photosensitivity to human retinal pigment epithelial cells and cells located in the neurosensory retina (e.g., photoreceptor cells and Müller cells). Throughout this disclosure, any reference to “subject” is intended to include human subjects.

[0044] In some embodiments, the retinal disease is diabetic retinopathy, age-related macular degeneration (AMD or ARMD) (wet), dry AMD, retinopathy of prematurity, retinitis pigmentosa, choroidal agenesis, and / or glaucoma, including open-angle glaucoma (e.g., primary open-angle glaucoma), angle-closure glaucoma, and secondary glaucoma (e.g., pigmentary glaucoma, pseudoexfoliative glaucoma, and glaucoma caused by trauma and inflammatory diseases). In some embodiments, the retinal disease is AMD (e.g., wet AMD or dry AMD). In some embodiments, the retinal disease is retinitis pigmentosa. In some embodiments, the retinal disease is choroidal agenesis. In some embodiments, the retinal disease has been diagnosed by a qualified medical professional.

[0045] In some embodiments, the retinal disease is retinal detachment, age-related or other macular degeneration, photoretinopathy, surgical retinopathy, toxic retinopathy, retinopathy of prematurity, retinopathy due to ocular trauma or penetrating injury, hereditary retinal degeneration, surgical retinopathy, toxic retinopathy, and / or retinopathy due to ocular trauma or penetrating injury.

[0046] In some embodiments, the retinal disease is caused by a hereditary eye disease. Exemplary hereditary eye diseases include, but are not limited to: Bader-Bead syndrome (autosomal recessive), congenital amaurosis (autosomal recessive), cone or cone-rod dystrophy (autosomal dominant and X-linked), congenital stationary night blindness (autosomal dominant, autosomal recessive, and X-linked), macular degeneration (autosomal dominant and autosomal recessive), optic atrophy (autosomal dominant and X-linked), retinitis pigmentosa (autosomal dominant, autosomal recessive, and X-linked), syndromic or systemic retinopathy (autosomal dominant, autosomal recessive, and X-linked), Usher syndrome (autosomal recessive), and choroidal agenesis (X-linked). In some embodiments, the hereditary eye disease is retinitis pigmentosa. In some embodiments, the hereditary eye disease is choroidal agenesis.

[0047] The compositions described herein can be administered to the eye via a variety of routes, such as those described herein. The compositions can be administered intraocularly, including topical application to the eye or intraocular injection (e.g., injection into the vitreous or subretinal (interretinal) space). Alternatively, the compositions can be administered topically by implantation or injection into periocular tissues. The compositions can be administered systemically, including oral routes or subcutaneous, intravenous, or intramuscular injection. Alternatively, the compositions can be administered via catheters or implants, wherein such implants are made of porous, non-porous, or gel-like materials, including membranes (e.g., silicone membranes or fibers), biodegradable polymers, or protein materials. The compositions can be administered before the onset of a condition (e.g., during ocular surgery), immediately after the onset of a pathological condition, or during an acute or chronic flare-up to prevent its occurrence. In some embodiments, compositions comprising compounds of formula (I) described herein are administered via intravitreal injection (IVT).

[0048] In some embodiments, the compound of formula (I) is administered to both eyes of a human subject. In some embodiments, it is administered simultaneously or substantially simultaneously to both eyes of a human subject. In some embodiments, it is administered to the other eye immediately after administration to one eye of a human subject. In some embodiments, it is administered to the other eye within 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours after administration to one eye of a human subject. In some embodiments, it is administered to the other eye within approximately 1 day to approximately 3 months, or approximately 1 week to approximately 2 months, or approximately 2 weeks to approximately 6 weeks, or approximately 3 weeks to approximately 5 weeks, or approximately 1 month after administration to one eye of a human subject. In some embodiments, the compound of formula (I) is administered to both eyes of a human subject during a single clinical or hospital visit. In some embodiments, the compound of formula (I) is administered to each eye of a human subject during different clinical or hospital visits.

[0049] In some embodiments, the compound of formula (I) is administered to only one eye of the subject. Surprisingly, administration to one eye of the subject has been found to provide therapeutic effects in both eyes. In some embodiments, the therapeutic effects include one or more of the following: improving the subject's ability to detect light and contrast, as measured by a light response test; increasing the subject's visual field; improving the subject's ability to determine the direction of light; stimulating the subject's striatal (VI) and / or non-striatal (V2 and / or V3) cortical activity, as measured by functional MRI; improving the subject's tolerance to glare and photosensitivity; improving the subject's functional visual measures, such as by a functional visual assessment (FVA); and reducing nonspecific, non-stimulatory random electrical activity of the retina (also known as brain-perceived ocular "tinnitus").

[0050] Functional magnetic resonance imaging (fMRI) measures brain activity by detecting changes in blood flow. In some implementations, when a region of the brain is used, fMRI can rely on the fact that blood flow to that region increases due to the coupling between cerebral blood flow and neuronal activation. In some implementations, fMRI uses oxygen level-dependent (BOLD) contrast techniques. See, for example, SA Huettel et al. (2009), pp. 4 and 26. Functional Magnetic Resonance Imaging (Second Edition), Massachusetts: Sinauer. In some implementations, functional MRI can utilize arterial spin labeling and diffusion MRI. See, for example, JA Detre, John A. et al. (May 2012). Journal of Magnetic Resonance Imaging. 35 (5): 1026-1037. Diffusion MRI is similar to BOLD fMRI, but it provides contrast based on the degree of diffusion of water molecules in the brain. Functional visual assessment (FVA) refers to any standardized test used to assess how a subject uses their remaining visual acuity in a variety of familiar and unfamiliar environments. In some implementations, FVA examines how a subject uses their visual acuity for (i) near tasks, less than 16 inches; (ii) intermediate tasks, 16 inches to 3 feet; and (iii) far tasks, more than 3 feet. In some implementations, FVA is performed by trained professionals. In some implementations, FVA may include one or more of the following: (i) the clarity and sharpness of the subject's visual acuity; (ii) visual field, or the areas seen laterally, above, and below the subject (called the peripheral area of ​​the visual field); (iii) contrast sensitivity, or the subject's ability to detect differences in grayscale and the differences between an object and its background; (iv) color vision, or the ability to detect different colors and hues within colors; and (v) light sensitivity, or the response to light (sunlight or artificial light).

[0051] In some embodiments, the method provided herein includes administering compound (I) to one eye of the human subject (i.e., a first administration), followed by a second administration of compound (I) to the same eye or the contralateral eye of the human subject. In some embodiments, the second administration is performed simultaneously or substantially simultaneously with the first administration, or immediately after the first administration. In some embodiments, the second administration includes administering compound (I) to the contralateral eye of the subject simultaneously or substantially simultaneously with the first administration, or immediately after the first administration. In some embodiments, the second administration includes administering compound (I) to the contralateral eye of the subject on the same day as the first administration, or approximately 1 day to approximately 3 months, or approximately 1 week to approximately 2 months, or approximately 2 weeks to approximately 6 weeks, or approximately 3 weeks to approximately 5 weeks, or approximately 1 month after the first administration. In some embodiments, the second administration includes administering compound (I) to the contralateral eye of the subject approximately 1 week to approximately 2 months after the first administration. In some embodiments, the second administration includes administering compound (I) to the contralateral eye of the subject approximately 3 to 5 weeks after the first administration. In some embodiments, the second administration includes administering the compound of formula (I) to the contralateral eye of the subject approximately one month after the first administration.

[0052] In some embodiments, intravitreal administration of the compound of formula (I) can be performed continuously more than once, more than twice, more than three times, more than four times, more than five times, more than six times, more than seven times, more than eight times, more than nine times, or more than ten times at a frequency of weekly to monthly. Thus, for example, the compound of formula (I) can be performed continuously for more than six months, more than twelve months, more than eighteen months, more than two years, more than five years, or for the remainder of the subject's life at a frequency of weekly to monthly. In some embodiments, intravitreal administration of the compound of formula (I) can be performed continuously more than once, more than twice, more than three times, more than four times, more than five times, more than six times, more than seven times, more than eight times, more than nine times, or more than ten times at a frequency of every three to five weeks. Thus, for example, the compound of formula (I) can be performed continuously for more than six months, more than twelve months, more than eighteen months, more than two years, more than five years, or for the remainder of the subject's life at a frequency of every three to five weeks. In some embodiments, the compound of formula (I) is administered permanently to the human subject throughout their lifetime. In some embodiments, the compound of formula (I) is administered permanently to the patient "when needed" or the human subject "when desired," for the duration of the subject's life.

[0053] In some embodiments, the second administration includes administering the compound of formula (I) to the same eye of the subject simultaneously or substantially simultaneously with the first administration, or immediately after the first administration. In some embodiments, the second administration includes administering the compound of formula (I) to the same eye of the subject on the same day as the first administration, or about 1 day to about 3 months, or about 1 week to about 2 months, or about 2 weeks to about 6 weeks, or about 3 weeks to about 5 weeks, or about 1 month after the first administration. In some embodiments, the second administration includes administering the compound of formula (I) to the same eye of the subject about 1 week to about 2 months after the first administration. In some embodiments, the second administration includes administering the compound of formula (I) to the same eye of the subject about 3 to 5 weeks after the first administration. In some embodiments, the second administration includes administering the compound of formula (I) to the same eye of the subject about 1 month after the first administration. In some embodiments, the second administration to the same eye as the first administration provides a therapeutic effect in both eyes of the subject.

[0054] In some implementations, treating a subject with retinal disease includes one or more of the following: improving the subject's ability to detect light and contrast, as measured by a light response test; increasing the subject's visual field; improving the subject's ability to determine the direction of light; stimulating the subject's striatal (VI) and / or non-striatal (V2 and / or V3) cortical activity, as measured by functional MRI; improving the subject's tolerance to glare and photosensitivity; improving the subject's functional visual measures, such as through functional visual assessment (FVA); and reducing nonspecific, non-stimulatory random electrical activity in the retina (also known as brain-perceived ocular "tinnitus").

[0055] In some embodiments, the treatment includes improving a subject's ability to detect light and contrast (i.e., the difference between light and dark perception) at different light intensities. Exemplary methods for assessing a subject's ability to detect light and contrast include presenting the subject with a series of visual stimuli (e.g., flashes of light) of varying intensities and asking the subject to confirm the stimuli upon perception. In some embodiments, the range of light intensities tested on the subject is approximately 10. 13 To about 10 17 photons / cm 2•s. In some embodiments, after 2 days of treatment, the percentage increase in accuracy of the subject in recognizing visual stimuli monocularly or binocularly is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiments, after 10 days of treatment, the percentage increase in accuracy of the subject in recognizing visual stimuli monocularly or binocularly is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiments, after 30 days of treatment, the percentage increase in accuracy of the subject in recognizing visual stimuli monocularly or binocularly is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiments, the treatment comprises administering a composition comprising a compound of formula (I) to one eye of the subject as described herein, wherein the improvement in the subject's ability to detect light and contrast occurs in both eyes of the subject. In some embodiments, the treatment comprises administering a composition comprising a compound of formula (I) to both eyes of the subject as described herein.

[0056] In some embodiments, the treatment includes increasing the subject's visual field, for example, by increasing total horizontal visual acuity and / or total vertical visual acuity. In some embodiments, after about 2 to about 30 days following treatment (e.g., about 2 days, about 7 days, about 10 days, about 15 days, or about 30 days after treatment), the subject's total horizontal visual acuity and / or total vertical visual acuity increases by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 10 times. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to one eye of the subject as described herein, wherein the increase in the subject's visual field occurs in both eyes of the subject. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to both eyes of the subject as described herein.

[0057] In some embodiments, the treatment includes improving a subject's ability to determine the direction of light. Exemplary methods for assessing a subject's ability to determine the direction of light include asking the subject to identify the location of a window, which tests the subject's ability to determine direction. In some embodiments, after 2 days of treatment, the percentage accuracy of the subject in identifying the window location using one or both eyes increases by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 10 times. In some embodiments, after 10 days of treatment, the percentage accuracy of the subject in identifying the window location using one or both eyes increases by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiments, after 30 days of treatment, the percentage accuracy of the subject in identifying the window location using one or both eyes increases by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to one eye of the subject as described herein, wherein the improvement in the subject's ability to determine the direction of light occurs in both eyes of the subject. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to both eyes of a subject as described herein.

[0058] In some embodiments, the treatment includes enhancing visual cortical activity in the subject. In some embodiments, a visual stimulus (e.g., a chessboard) is presented to the subject, and the subject's neural activity is measured using functional MRI. In some embodiments, the treatment includes stimulating striatal (VI) and non-striatal (V2 and / or V3) cortical activity in the subject, which is measured by functional MRI. VI is the primary visual cortex, the first stage of visual processing. V2 is the secondary visual cortex, receiving integrated information from VI and having feedforward connections with V3-V5. V3 refers to the third visual complex, which may play a role in processing motion and color sensitivity. See, for example, Huff et al., Neuroanatomy, Visual Cortex. [Updated July 25, 2022], in: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2023. In some embodiments, the V1, V2, and / or V3 cortical activity of the subject is stimulated approximately 2 to approximately 30 days after treatment (e.g., approximately 2 days, approximately 7 days, approximately 10 days, approximately 15 days, or approximately 30 days after treatment). In some embodiments, the treatment comprises administering a composition containing a compound of formula (I) to one or both eyes of the subject as described herein.

[0059] In some implementations, the treatment includes improving the subject's visual acuity while simultaneously increasing the subject's tolerance to glare and photosensitivity, such as by enhancing the subject's ability to detect light and contrast as described herein; increasing the subject's field of vision; and / or improving the subject's ability to determine the direction of light. Glare sensitivity refers to the loss of visual acuity in bright light (e.g., near a strong light source or in bright outdoor light). Subjects with glare sensitivity cannot see the individual outlines of bright objects, and their surroundings may blend into a bright white "wall." Surprisingly, the compound of formula (I) described herein is a photoreactive compound that allows human subjects with low vision to be exposed to bright light without the glare side effects expected in typical vision-restoring treatments. Exemplary methods for assessing glare tolerance have been described, for example, by Fotios et al. LEUKOS As described in (2020) doi: 10.1080 / 15502724.2020.1803082. In some embodiments, the treatment comprises administering a composition containing a compound of formula (I) to one or both eyes of a subject as described herein.

[0060] In some embodiments, the treatment includes reducing nonspecific, non-stimulatory random electrical activity in the retina, also known as brain-perceived eye "tinnitus." An unexpected advantage of the photoreactive compounds of formula (I) described herein is that they can improve vision in human subjects without causing eye "tinnitus." In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to one or both eyes of a subject as described herein.

[0061] In some embodiments, the treatment includes improving measures of a subject's functional vision. In some embodiments, a subject's functional vision may be measured using a functional visual assessment (FVA). In some embodiments, the FVA includes testing a subject's visual acuity, visual field, contrast discrimination, sensitivity, color vision, and / or light sensitivity. In some embodiments, the treatment includes assessments of improving a subject's visual quality of life. In some embodiments, a subject's visual quality of life may be assessed using a questionnaire such as the National Eye Institute Visual Function Questionnaire 25 (VFQ-25). In some embodiments, a subject's VFQ-25 score increases by approximately 1 to 5 points, or approximately 2 to 4 points, at approximately 2 days, 7 days, 10 days, 15 days, or 30 days after treatment. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to one eye of a subject as described herein, wherein the increase in the subject's VFQ-25 score is based on results from both eyes of the subject. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to both eyes of a subject as described herein.

[0062] compound In some embodiments, the methods provided herein include administering a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof into the eye of a subject via intravitreal injection: (I), Among them, R 1 R 2 R 3 R 4 R 5 R 6 x and y are as described in this article.

[0063] In some implementations, each R 1 Selected independently from C 1-10 Alkyl, substituted C 1-10 Alkyl, -NR 10 R 11 -NR 12 C(O)R 13 C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, heteroaryl, heterocyclic, heterocyclic hydroxyl, heterocyclic thiol, heteroaryl amino, heterocyclic amino, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl, substituted C 4-10 Cycloalkenyl, cyano, halogen, -OR 10 -C(O)OR 10 and -S(O)2R 10 .

[0064] In some implementations, R 3 R 4 and R 5 Independently selected from hydrogen, C 2-8 Alkyl, substituted C 2-10 Alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl and substituted C 4-10 Cycloalkenyl.

[0065] In some implementations, x is an integer from 0 to 5. In some implementations, y is an integer from 0 to 4.

[0066] In some implementations, R 2 Selected from hydrogen, C 1-10 Alkyl, substituted C 1-10 Alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl and substituted C 4-10 Cycloalkenyl.

[0067] In some implementations, each R 6 Independently selected from hydrogen, C 1-10 Alkyl, substituted C 1-10 Alkyl, -NR 10 R 11 -NR 12 C(O)R 13 C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, heteroaryl, heterocyclic, heterocyclic hydroxyl, heterocyclic thiol, heteroaryl amino, heterocyclic amino, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl, substituted C 4-10 Cycloalkenyl, cyano, halogen, -OR 10 -C(O)OR 10 -S(O)R 10 and -S(O)2R 10 .

[0068] In some implementations, R 10 and R 11 Independently selected from hydrogen, C 1-10 Alkyl, substituted C 1-10 Alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, C4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl and substituted C 4-10 Cycloalkenyl.

[0069] In some implementations, R 12 Selected from hydrogen, C 1-10 Alkyl, substituted C 1-10 Alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C 6-20 Aryl, substituted C 6-20 Aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl and substituted C 4-10 Cycloalkenyl.

[0070] In some implementations, R 13 Selected from hydrogen, C 1-10 Alkyl, substituted C 1-10 Alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl group, C6-C 10 Aryl, substituted C 6-20 Aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 Cycloalkenyl, substituted C 4-10 Cycloalkenyl, -CH2-N(CH2CH3)3 + and -CH2-SO3 - .

[0071] In some implementations, each R 1 Independently selected from halogens, C 1-10 Alkyl, -NR 10 R 11 and -NR 12 C(O)R 13 .

[0072] In some implementations, R 2 It can be hydrogen or ethyl.

[0073] In some implementations, x is 0 or 1. In some implementations, y is 0 or 1.

[0074] In some implementations, R 3 R4 and R 5 Both are ethyl.

[0075] In some implementations, R 6 Halogen or C 1-10 alkyl.

[0076] In some implementations, R 10 or R 11 Independently selected from hydrogen, C 1-10 Alkyl and substituted C 1-10 alkyl.

[0077] In some implementations, R 12 It is hydrogen.

[0078] In some implementations, R 13 Selected from C 1-10 Alkyl, substituted C 1-10 Alkyl, C 2-8 alkenyl and C 6-10 Aryl.

[0079] Although formula (I) describes the azo bond in the trans configuration, it should be understood that the formula includes both cis and trans configurations, unless otherwise stated herein.

[0080] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following structures: In the compound of formula (I), the azo (N=N) bond can be cis or trans, unless otherwise stated herein.

[0081] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: The azo bonds in the structure can be cis or trans.

[0082] The term "pharmaceutically acceptable salt" refers to a salt that retains the bioavailability and properties of a compound and does not cause biological or other adverse reactions when used as a pharmaceutical. In some embodiments, the compounds described herein are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acidic addition salts can form with inorganic and organic acids. For example, inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable basic addition salts can form with inorganic and organic bases. For example, inorganic bases from which salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum; particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Exemplary salts are described in WO 87 / 05297.

[0083] As used in this article, "C" a To C b "or "C a-b (where "a" and "b" are integers) refers to the number of carbon atoms in a specific group. That is, the group can contain carbon atoms from "a" to "b" (inclusive). Therefore, for example, "C1 to C4 alkyl" or "C 1-4 "Alkyl" refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0084] As used herein, the term "halogen" or "halo" refers to any radioactive stable atom in Group 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0085] As used herein, “alkyl” refers to a fully saturated (i.e., free of double or triple bonds) straight or branched hydrocarbon chain. Alkyl groups can have 1 to 20 carbon atoms (wherein “1 to 20” appears in this document, it refers to every integer within the given range; for example, “1 to 20 carbon atoms” means that an alkyl group can consist of 1, 2, 3, etc., up to 20 carbon atoms, but this definition also includes the use of the term “alkyl” where no numerical range is specified). Alkyl groups can also be of medium size, having 1 to 9 carbon atoms. Alkyl groups can also be of lower grades, having 1 to 4 carbon atoms. Alkyl groups in a compound can be represented as “C…”. 1-4 Alkyl or similar names. For example only, "C 1-4 "Alkyl" indicates that the alkyl chain has 1 to 4 carbon atoms, meaning the alkyl chain is selected from groups composed of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0086] As used herein, “haloalkyl” refers to a straight-chain or branched alkyl group having 1 to 12 carbon atoms in the chain, wherein one or more hydrogen atoms are substituted with a halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that can be determined to be equivalent to any of the foregoing examples based on ordinary skill in the art and the teachings provided herein.

[0087] As used herein, "alkoxy" refers to the formula -OR, where R is an alkyl group as defined above, such as "C". 1-9 "Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0088] As used herein, "heteroalkyl" refers to a straight-chain or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the main chain. Heteroalkyl can have 1 to 20 carbon atoms, but this definition also includes the use of the term "heteroalkyl" when no numerical range is specified. Heteroalkyl can also be a medium-sized heteroalkyl having 1 to 9 carbon atoms. Heteroalkyl can also be a lower heteroalkyl having 1 to 4 carbon atoms. In various embodiments, heteroalkyl can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. Heteroalkyl in a compound can be represented as "C". 1-4 "Heteroalkyl" or similar names. Heteroalkyl groups may contain one or more heteroatoms. For example only, "C..." 1-4"Heteroalkyl" means that the heteroalkyl chain has 1 to 4 carbon atoms and the main chain also contains one or more heteroatoms.

[0089] The term "aromatic" refers to a ring or ring system having a conjugated π-electron system, including carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent atomic pairs) groups, provided that the entire ring system is aromatic.

[0090] As used herein, "aryl" refers to an aromatic ring or ring system whose ring skeleton contains only carbon (i.e., two or more fused rings sharing two adjacent carbon atoms). When aryl is a ring system, each ring in the system is aromatic. Aryl groups can have 6 to 18 carbon atoms, but this definition also includes the use of the term "aryl" when no numerical range is specified. In some embodiments, the aryl group has 6 to 10 carbon atoms. Aryl can be represented as "C 6-10 "Aryl", "C6 or C" 10 "Aryl" or similar names. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulel, and anthracene.

[0091] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is an aryl group as defined above, for example, "C 6-10 "Aryloxy" or "C" 6-10 "Arylthio" and others, including but not limited to phenoxy groups.

[0092] "Aralkyl" or "arylalkyl" refers to an aryl group linked by an alkylene group as a substituent, such as "C 7-14 Aryl alkyl groups, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthyl alkyl groups. In some cases, the alkylene group is a lower alkylene group (i.e., C14). 1-4 Alkylene).

[0093] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) whose ring skeleton contains one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur). When a heteroaryl is a ring system, each ring in the system is aromatic. A heteroaryl may have 5-18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also includes the use of the term "heteroaryl" without specifying a numerical range. In some embodiments, a heteroaryl has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl may be referred to as "5-7-membered heteroaryl," "5-10-membered heteroaryl," or similar names. In various embodiments, a heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl group contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furanyl, thiophene, phthalazinyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indole, isoindole, and benzothiophene.

[0094] "Heteroaralkyl" or "heteroarylalkyl" refers to a heteroaryl group linked by an alkylene group as a substituent. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolithyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C14). 1-4 Alkylene).

[0095] As used herein, "carbocyclic group" refers to a non-aromatic cyclic ring or ring system whose ring skeleton contains only carbon atoms. When the carbocyclic group is a ring system, two or more rings may be joined together by fusion, bridging, or helicaling. The carbocyclic group may have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. Therefore, carbocyclic groups include cycloalkyl, cycloalkenyl, and cycloynyl groups. A carbocyclic group may have 3 to 20 carbon atoms, but this definition also includes the use of the term "carbocyclic group" where no numerical range is specified. A carbocyclic group may also be a medium-sized carbocyclic group having 3 to 10 carbon atoms. A carbocyclic group may also be a carbocyclic group having 3 to 6 carbon atoms. A carbocyclic group may be represented as "C". 3-6"Carbocyclic" or similar names. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bis[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl.

[0096] "(Carbocyclic)alkyl" refers to a carbocyclic group linked by an alkylene substituent, such as "C 4-10 "(Carbocyclo)alkyl", etc., including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene is a lower alkylene.

[0097] As used herein, "cycloalkyl" refers to a fully saturated carbocyclic ring or cyclic system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0098] As used herein, "cycloalkenyl" refers to a carbocyclic ring or ring system having at least one double bond, wherein none of the rings in the ring system is aromatic. An example is cyclohexenyl.

[0099] As used herein, a "heterocyclic group" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in its ring skeleton. Heterocyclic groups can be joined together by fusion, bridging, or helical bonding. Heterocyclic groups can have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. Heteroatoms can be present in non-aromatic or aromatic rings within the ring system. Heterocyclic groups can have 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also includes the use of the term "heterocyclic group" where no numerical range is specified. Heterocyclic groups can also be of medium size with 3 to 10 ring members. Heterocyclic groups can also be heterocyclic groups with 3 to 6 ring members. Heterocyclic groups can be referred to as "3-6 membered heterocyclic groups" or similar names.

[0100] In various embodiments, the heterocyclic group contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In a preferred six-membered monocyclic heterocyclic group, the heteroatoms are selected from 1 to 3 of O, N, or S; in a preferred five-membered monocyclic heterocyclic group, the heteroatoms are selected from 1 or 2 of O, N, or S. Examples of heterocyclic groups include, but are not limited to, azaheptenyl, acridineyl, carbazoleyl, cyclolinyl, dioxopentyl, imidazolinyl, imidazoalkyl, morpholinyl, ethylene oxide, oxacycloheptenyl, thioheptenyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolyl, pyrrolidoneyl, pyrrolidoneyl, 4-piperidinoneyl, pyrazolinyl, pyrazolylyl, 1,3-dioxinyl, 1,3-dioxinyl, 1,4-dioxinyl, 1,4-dioxylyl, 1,3-oxothiocyclohexyl, 1,4-oxothiocyclohexenyl, 1,4-oxothiocyclohexyl, 2H- 1,2-Oxazinyl, trioxane, hexahydro-1,3,5-triazinyl, 1,3-dioxacyclopentenyl, 1,3-dioxacyclopentenyl, 1,3-dithiocyclopentenyl, isoxazolinyl, isoxazolinyl, oxazolinyl, oxazolinyl, oxazolidinoneyl, thiazolinyl, thiazolinyl, 1,3-oxothiocyclopentenyl, indolinyl, isindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiaranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl, and tetrahydroquinolinyl.

[0101] "(Heterocyclic)alkyl" refers to a heterocyclic group linked by an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0102] As used herein, "acyl" refers to -C(=O)R, where R, as defined herein, is hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Carbocyclic, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic. Non-limiting examples include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0103] The “O-carboxyl” group refers to the “-OC(=O)R” group, where R, as defined in this article, is selected from hydrogen, C… 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Carbocyclic, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic.

[0104] The "C-carboxyl" group refers to the "-C(=O)OR" group, where R, as defined in this article, is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Carbocyclic, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic. Non-limiting examples include carboxyl groups (i.e., -C(=O)OH).

[0105] The "cyano" group refers to the "-CN" group.

[0106] The "cyanate" group refers to the "-OCN" group.

[0107] The "isocyanate" group refers to the "-NCO" group.

[0108] The "thiocyanate" group refers to the "-SCN" group.

[0109] The "isothiocyanate" group refers to the "-NCS" group.

[0110] The "sulfinyl" group refers to the "-S(=O)R" group, where R, as defined in this article, is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0111] The "sulfonyl" group refers to the "-SO2R" group, where R, as defined in this article, is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0112] The "S-sulfonamide group" refers to "-SO2NR". A R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0113] The "N-sulfonamide group" refers to "-N(R)". A SO2R B"group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0114] The "O-carbamoyl" group refers to "-OC(=O)NR". A R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0115] The "N-carbamoyl" group refers to "-N(R)". A )OC(=O)R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0116] The "O-thiocarbamoyl" group refers to "-OC(=S)NR". A R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0117] The "N-thiocarbamoyl" group refers to "-N(R)". A )OC(=S)R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0118] The "C-amide group" refers to "-C(=O)NR". A R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0119] The "N-amide group" refers to "-N(R)". A )C(=O)R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0120] The "amino" group refers to "-NR". A R B "group, wherein R A and R B As defined in this article, each is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0121] The "aminoalkyl" group refers to an amino group linked by an alkylene group.

[0122] The "alkoxyalkyl" group refers to an alkoxy group linked by an alkylene group, such as "C". 2-8 "Alkoxyalkyl", etc.

[0123] As used herein, substituents are derived from unsubstituted parent groups, wherein one or more hydrogen atoms of the parent group are exchanged for another atom or group. Unless otherwise stated, when a group is considered “substituted,” it means that the group is substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloalkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclo-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 5-10 membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclic -C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6... Alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted, 5-10 membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6)alkyl (i.e. ether group) Aryloxy, thiohydro (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, quaternary ammonium, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted," it means that the group can be substituted by the above substituents.

[0124] In some embodiments, the substituent group is replaced by one or more substituents selected individually and independently from C1-C4 alkyl, amino, hydroxyl, and halogen groups.

[0125] It should be understood that, depending on the context, certain radical nomenclature rules can include monoradicals or diradicals. For example, when a substituent requires two linking sites to connect with the rest of the molecule, the substituent should be understood as a diradical. For example, substituents identified as alkyl that require two linking sites include diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical nomenclature rules explicitly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

[0126] In some embodiments, the compound of formula (I) described herein is administered in the form of a composition. In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.1 mM to about 10 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.2 mM to about 5 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.3 mM to about 2 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is from about 0.5 mM to about 1 mM.

[0127] Cyclodextrin In some embodiments, the compositions comprising formula (I) described herein further comprise cyclodextrin. In some embodiments, the cyclodextrin in the composition is the cyclodextrin described in WO 2022 / 093652. In some embodiments, the cyclodextrin is an alkylated cyclodextrin. As used herein, "alkylated cyclodextrin" refers to a cyclodextrin in which one or more hydrogen atoms on the hydroxyl substituent are substituted with an alkyl group, which may optionally be substituted with other substituents. In one embodiment, the alkylated cyclodextrin or a pharmaceutically acceptable salt thereof for the purposes described herein has the structure of formula (II): (II) Wherein, p is 4, 5 or 6, and R1 is independently selected from -OH and optionally substituted -O-C1-C8 alkyl groups in each case, wherein at least one R1 is an optionally substituted alkyl group.

[0128] Optional substituents for replacing -O-C1-C8 alkyl groups include C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), and 5-10-membered heterocyclic groups (optionally substituted with halogen). 5-10 membered heterocyclic-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy) 5-10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heteroaryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6)alkyl (i.e. ether), aryloxy Thiohydrin (mercapto), halogenated (C1-C6) alkyl (e.g., -CF3), halogenated (C1-C6) alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl and oxo (=O).

[0129] In some embodiments, p is 5 (i.e., the cyclodextrin is β-cyclodextrin). In some embodiments, the alkylated cyclodextrin is a sulfonyl alkyl ether-β-cyclodextrin. For example, in some embodiments, at least one R1 is O-(C2-C6 alkylene)-SO3. - -T, where each occurrence of T is independently selected from pharmaceutically acceptable cations. Suitable examples of T include H + Alkali metals (e.g., Li) + Na + K+ ), alkaline earth metals (e.g., Ca) +2 Mg +2 Ammonium ions and amine cations (such as cations of (C1-C6)alkylamines, piperidine, pyrazine, (C1-C6)alkanolamines, ethylenediamine and (C4-C8)cycloalkanolamines, and combinations thereof)

[0130] In some embodiments, the alkylated cyclodextrin has the structure of formula (III): (III) Each R is independently -H or -(CH2)4-SO3-Na + Furthermore, all cyclodextrin molecules in this composition are bound by -(CH2)4-SO3-Na + The average degree of substitution is 6 to 7.1. For example, in some embodiments, the alkylated cyclodextrin may be CAPTISOL®.

[0131] In the compositions described herein, individual cyclodextrin molecules in the composition may have different degrees of substitution with respect to specific substituents. Therefore, such compositions are typically characterized by the average degree of substitution (ADS) for a specific substituent. Thus, for example, an ADS of 6 to 7.1 indicates that although each cyclodextrin molecule in the composition has an integer degree of substitution with respect to a specific substituent, this degree of substitution exists in the composition with an average value of 6 to 7.1.

[0132] Further exemplary sulfonyl ether (SAE)-CD derivatives include: Table 1 Where x represents the average degree of substitution. In some embodiments, the alkylated cyclodextrin is formed in the form of a salt.

[0133] Different embodiments of sulfonyl ether cyclodextrins include ecicosero-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, hepta-O-(sulfomethyl)-tetradecano-O-(3-sulfopropyl)-β-cyclodextrin, hepta-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecano-O-(3-sulfopropyl)-β-cyclodextrin, hepta-O-(sulfomethyl)-tetradecano-O-(3-sulfopropyl)-β-cyclodextrin, and hepta-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecano-O-(sulfomethyl)-β-cyclodextrin. Other known alkylated cyclodextrins containing a sulfonyl moiety include sulfonyl thio and sulfonyl thioalkyl ether derivatives, such as octa-(S-sulfonylpropyl)-octathio-γ-cyclodextrin, octa-O-[3-[(2-sulfonylethyl)thio]propyl]-β-cyclodextrin], and octa-S-(2-sulfonylethyl)-octathio-γ-cyclodextrin.

[0134] In some embodiments, the alkylated cyclodextrin composition of this disclosure is a sulfonyl ether-β-cyclodextrin composition having ADS of 2 to 9, 4 to 8, 4 to 7.5, 4 to 7, 4 to 6.5, 4.5 to 8, 4.5 to 7.5, 4.5 to 7, 5 to 8, 5 to 7.5, 5 to 7, 5.5 to 8, 5.5 to 7.5, 5.5 to 7, 5.5 to 6.5, 6 to 8, 6 to 7.5, 6 to 7.1, 6.5 to 7.1, 6.2 to 6.9 or 6.5 for each alkylated cyclodextrin molecule, with the remaining substituents being -H.

[0135] In some implementations, R in formula (II) 1 It is -OH or an unsubstituted -O-C1-C8 alkyl group. Such alkylated cyclodextrins are called alkyl ether (AE)-cyclodextrins. Exemplary AE-CD derivatives include: Table 2 Where ME represents methyl ether, EE represents ethyl ether, PE represents propyl ether, BE represents butyl ether, PtE represents pentyl ether, HE represents hexyl ether, and y represents the average degree of substitution.

[0136] In some embodiments, at least one R1 of formula (II) is a hydroxyl-substituted -O-C1-C6 alkyl group (e.g., hydroxypropyl-β-cyclodextrin). Other exemplary hydroxyalkyl ether (HAE)-CD derivatives include: Table 3 Where HME represents hydroxymethyl ether, HEE represents hydroxyethyl ether, HPE represents hydroxypropyl ether, HBE represents hydroxybutyl ether, HPtE represents hydroxypentyl ether, HHE represents hydroxyhexyl ether, and z represents the average degree of substitution.

[0137] In some embodiments, the provided alkylated cyclodextrin has mixed substituents (e.g., simultaneously containing sulfoalkyl ether and alkyl ether substituents (SAE-AE-CD)). Specific embodiments of such derivatives include: 1) the alkylene moiety of SAE has the same number of carbon atoms as the alkyl moiety of AE; 2) the alkylene moiety of SAE has a different number of carbon atoms than the alkyl moiety of AE; 3) the alkyl and alkylene moieties are independently selected from the group consisting of straight-chain or branched moieties; 4) the alkyl and alkylene moieties are independently selected from the group consisting of saturated or unsaturated moieties; 5) the ADS of the SAE group is greater than or close to the ADS of the AE group; or 6) the ADS of the SAE group is less than the ADS of the AE group. Some embodiments include SAE-HAE-CD.

[0138] The alkylated cyclodextrin may include SAE-CD, HAE-CD, SAE-HAE-CD, HANE-CD, HAE-AE-CD, HAE-SAE-CD, AE-CD, SAE-AE-CD, neutral cyclodextrin, anionic cyclodextrin, cationic cyclodextrin, halogen-derived cyclodextrin, amino-derived cyclodextrin, nitrile-derived cyclodextrin, aldehyde-derived cyclodextrin, carboxylate-derived cyclodextrin, sulfate-derived cyclodextrin, sulfonate-derived cyclodextrin, mercapto-derived cyclodextrin, alkylamino-derived cyclodextrin, or succinyl-derived cyclodextrin.

[0139] In some embodiments, for example, alkylated cyclodextrins (such as mixed ether alkylated cyclodextrins) include those listed in Table 4 below: Table 4 Other examples of alkylated cyclodextrins that may be included in the compositions described herein are described in U.S. Patent Nos. 5,438,133, 6,479,467 and 6,610,671, the disclosure of each of which is incorporated herein by reference in its entirety.

[0140] In a given alkylated cyclodextrin composition, the substituents of the alkylated cyclodextrin can be the same or different. For example, the SAE or HAE moiety appearing each time in the alkylated cyclodextrin composition can have the same or different types of alkylene (alkyl) groups. In such embodiments, the alkylene group in the SAE or HAE moiety appearing each time in the alkylated cyclodextrin composition can be ethyl, propyl, butyl, pentyl, or hexyl.

[0141] The alkylated cyclodextrins can vary in the following aspects: degree of functional group substitution, number of carbon atoms in the functional groups, molecular weight, number of pyranose units in the cyclodextrin matrix used to form the derivatized cyclodextrin, and / or substitution pattern. Furthermore, the derivatization process of cyclodextrins by functional groups is carried out in a controlled but not precise manner. Therefore, the degree of substitution is actually a number representing the average number of functional groups on each cyclodextrin (e.g., SBE7-β-CD has an average of 7 substituents per cyclodextrin). Therefore, its average degree of substitution (“ADS”) is 7. In some embodiments, the ADS can be determined by techniques including capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, or combinations thereof. Furthermore, the regiochemistry of hydroxyl substitution in cyclodextrins is variable with respect to the substitution of specific hydroxyl groups on the hexose ring. Therefore, different hydroxyl substitutions may occur during the preparation of derivatized cyclodextrins, and a particular derivatized cyclodextrin may have a preferred (but not unique or specific) substitution pattern. Given the above, the molecular weight of a particular derivatized cyclodextrin composition may vary from batch to batch.

[0142] In a single parent cyclodextrin molecule, there are 3v+6 hydroxyl moieties available for derivatization. When v=4 (α-cyclodextrin), the degree of substitution "y" of the hydroxyl moieties ranges from 1 to 18. When v=5 (β-cyclodextrin), the degree of substitution "y" of the hydroxyl moieties ranges from 1 to 21. When v=6 (γ-cyclodextrin), the degree of substitution "y" of the hydroxyl moieties ranges from 1 to 24. Typically, the value of "y" also ranges from 1 to 3v+g, where g ranges from 0 to 5. In some embodiments, the value of "y" ranges from 1 to 2v+g, or from 1 to 1v+g.

[0143] The degree of substitution (“DS”) of a specific group (e.g., SAE, HAE, or AE) is an indicator of the number of SAE (HAE or AE) substituents attached to a single cyclodextrin molecule; in other words, the number of moles of substituents per mole of cyclodextrin. Therefore, for a single alkylated cyclodextrin species, each substituent has its own DS. The average degree of substitution (“ADS”) measures the total number of substituents present in each cyclodextrin molecule to reflect the distribution of alkylated cyclodextrins in the alkylated cyclodextrin compositions of this disclosure. Therefore, the ADS (per CD molecule) of SAE4-CD is 4.

[0144] Some embodiments of this disclosure include those in which: 1) more than half of the hydroxyl portion of the alkyl cyclodextrin is derivatized; 2) half or less of the hydroxyl portion of the alkyl cyclodextrin is derivatized; 3) the substituents of the alkyl cyclodextrin are the same each time they appear; 4) the substituents of the alkyl cyclodextrin include at least two different substituents; or 5) the substituents of the alkyl cyclodextrin include one or more substituents selected from groups consisting of: unsubstituted alkyl, substituted alkyl, halide (halogen), haloalkyl, amine (amino), aminoalkyl, aldehyde, carbonylalkyl, nitrile, cyanoalkyl, sulfonylalkyl, hydroxyalkyl, carboxylalkyl, thioalkyl, unsubstituted alkylene, substituted alkylene, aryl, aralkyl, heteroaryl, and heteroarylalkyl.

[0145] Alkylated cyclodextrin compositions may comprise multiple alkylated cyclodextrin molecules with varying degrees of substitution. For example, alkylated cyclodextrin molecules may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more hydroxyl groups of the parent cyclodextrin, which are functionalized with substituents (e.g., sulfonyl ethers). In such compositions, as described herein, the average degree of substitution (ADS) can be calculated based on the relative amounts of alkylated cyclodextrin molecules with a specific degree of substitution. Therefore, the ADS of SAE in an SAE-CD derivative composition represents the weighted average of the degrees of substitution of the individual SAE-CD molecules in the composition. For example, SAE... 5.2 -CD composition contains multiple SAEs x The distribution of -CD molecules, where, for a single cyclodextrin molecule, the value of "x" (DS of the SAE group) can be an integer from 1 to 12; however, for the SAE-cyclodextrin molecule population, the average value of "x" (ADS of the SAE group) is 5.2.

[0146] Alkylated cyclodextrin compositions can have high, medium, and low levels of ADS. Alkylated cyclodextrin compositions can also have a wide or narrow “span,” which refers to the number of alkylated cyclodextrin molecules with different degrees of substitution in the composition. For example, a composition containing a single alkylated cyclodextrin species (with a single degree of substitution) is said to have a span of 1, in which case the degree of substitution of the alkylated cyclodextrin molecule is equal to the ADS of its alkylated cyclodextrin composition. For example, for an electrophoretic graph of an alkylated cyclodextrin with a span of 1, there should only be one alkylated cyclodextrin species in terms of degree of substitution. An alkylated cyclodextrin composition with a span of 2 includes two separate alkylated cyclodextrin species with different degrees of substitution; for example, its electrophoretic graph would show two alkylated cyclodextrin species with different degrees of substitution. Similarly, an alkylated cyclodextrin composition with a span of 3 includes three alkylated cyclodextrin species with different degrees of substitution. The span value of an alkylated cyclodextrin composition is typically 5 to 15, 7 to 12, or 8 to 11.

[0147] The parent cyclodextrin comprises secondary hydroxyl groups at the C-2 and C-3 positions of the pyranose residues constituting the cyclodextrin, and a primary hydroxyl group at the C-6 position of the pyranose residues. Each of these hydroxyl moieties can be derivatized by a substituent precursor. Depending on the synthetic method employed, the substituent moieties can be randomly distributed or distributed in an ordered manner at the available hydroxyl positions. The regioisomerism of the substituent derivatization can also be modified as needed. The regioisomerism of each composition is independently selected. For example, most of the substituents present can be located on the primary hydroxyl group of the parent cyclodextrin, or on one or two secondary hydroxyl groups. In some embodiments, the dominant distribution of substituents is C-3>C-2>C-6, while in other embodiments, the dominant distribution of substituents is C-2>C-3>C-6. Some embodiments of this disclosure include an alkylated cyclodextrin molecule in which a minority of the substituent moieties are located at the C-6 position, and a majority of the substituent moieties are located at the C-2 and / or C-3 positions. Other embodiments of this disclosure include an alkylated cyclodextrin molecule wherein the substituent moieties are substantially uniformly distributed between the C-2, C-3 and C-6 positions.

[0148] Alkylated cyclodextrin compositions comprise a distribution of multiple individual alkylated cyclodextrin species, each with an individual degree of substitution (“IDS”). The content of each cyclodextrin in a particular composition can be quantified using capillary electrophoresis. This analytical method (e.g., capillary electrophoresis for charged alkylated cyclodextrins) is sensitive enough to distinguish compositions containing only 5% of one alkylated cyclodextrin and 95% of another alkylated cyclodextrin from an initial alkylated cyclodextrin composition containing a single alkylated cyclodextrin.

[0149] The variations in the distribution of different species of alkyl cyclodextrins can lead to changes in the complexation equilibrium constant K. 1:1 The equilibrium constant also varies with temperature, thus requiring a margin in the proportions to ensure the surfactant remains soluble during temperature fluctuations that may occur during manufacturing, storage, transportation, and use. The equilibrium constant also varies with pH, ​​therefore requiring a margin in the proportions to ensure the surfactant remains soluble during pH fluctuations that may occur during manufacturing, storage, transportation, and use. The equilibrium constant can also vary due to the presence of other excipients (e.g., buffers, preservatives, antioxidants). Therefore, the ratio of derivatized cyclodextrin to surfactant can differ from the ratio described herein to compensate for these variables.

[0150] In some embodiments, the compositions described herein comprise a compound of formula (I) and a cyclodextrin (e.g., an alkylated cyclodextrin) in a predetermined molar ratio. In various embodiments, the molar ratio of the cyclodextrin to the compound of formula (I) has a lower limit of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 30:1, 50:1, or 100:1 and an upper limit of 10:1, 15:1, 20:1, 30:1, 40:1, 50:1, 70:1, 100:1, 120:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 600:1, 750:1, and 1000:1. For example, in various embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is 1:1 to 500:1, 1:1 to 300:1, 1:1 to 150:1, 1:1 to 100:1, 2:1 to 350:1, 2:1 to 200:1, 2:1 to 100:1, 3:1 to 200:1, 3:1 to 150:1, 3:1 to 100:1, 3:1 to 50:1, 4:1 to 150:1, and 4:1 to 100:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is about 20:1 to about 1:1, or about 18:1 to about 2:1, or about 15:1 to about 3:1, or about 10:1 to about 4:1, or about 8:1 to about 5:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is about 20:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 18:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 15:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 12:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 10:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 8:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 5:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 4:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 3:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 2:1. In some embodiments, the molar ratio of cyclodextrin to compound (I) is about 1:1.

[0151] Different amounts of compound (I) are administered to one eye in a single dose. In some embodiments, about 7.5 μg to about 50 μg of compound (I) is administered to one eye of a human subject in a single dose. In some embodiments, about 5.0 μg to about 10 μg or about 7.5 μg of compound (I) is administered to one eye of a human subject in a single dose. In some embodiments, about 20 μg to about 30 μg or about 25 μg of compound (I) is administered to one eye in a single dose. In some embodiments, about 40 μg to about 60 μg or about 50 μg of compound (I) is administered to one eye in a single dose. In some embodiments, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg, or about 100 μg of compound (I) are administered to one eye in a single dose. In some embodiments, less than 5 μg of compound (I) is administered to one eye in a single dose. In some embodiments, more than 100 μg of compound (I) is administered to one eye in a single dose.

[0152] Composition The compounds of formula (I) provided herein, and compositions comprising cyclodextrin in some embodiments, may be provided in solid or liquid dosage forms. For example, a solid dosage form may be provided that is suitable for reconstitution with a diluent prior to administration to a subject. For example, a suitable diluent for reconstitution may include, for example, sterile water or physiological saline. When provided in a liquid dosage form or after reconstitution in a solid dosage form, the composition may be an aqueous solution or a suspension.

[0153] The liquid dosage form of this disclosure can be converted into a solid dosage form for reconstitution. The reconstituteable solid composition of this disclosure includes an active agent (e.g., a compound of formula (I)), a derivatized cyclodextrin, and optionally at least one other pharmaceutical excipient. The reconstituteable composition can be reconstituted with an aqueous liquid to form a storable liquid dosage form. The composition may comprise a mixture of a solid derivatized cyclodextrin and a solid containing the active agent (with minimal or no inclusion complexes) and optionally at least one solid pharmaceutical excipient, such that most of the active agent is not complexed with the derivatized cyclodextrin prior to reconstitution. Alternatively, the composition may comprise a solid mixture of a derivatized cyclodextrin and an active agent, wherein most of the active agent is complexed with the derivatized cyclodextrin prior to reconstitution. The reconstituteable solid composition may also comprise a derivatized cyclodextrin and an active agent, wherein substantially all or at least most of the active agent is complexed with the derivatized cyclodextrin.

[0154] The resolvable solid composition can be prepared according to any of the following methods: first, a liquid dosage form of the present disclosure is prepared, and then the solid is prepared for resolvation by lyophilization (freeze-drying), spray drying, spray freeze-drying, antisolvent precipitation, sterile spray drying, various methods using supercritical or near-supercritical fluids, or other methods known to those skilled in the art.

[0155] The liquid carriers included in the dosage forms disclosed herein may include aqueous liquid carriers (e.g., water), aqueous alcohols, aqueous organic solvents, non-aqueous liquid carriers, and combinations thereof.

[0156] The compositions disclosed herein may include one or more pharmaceutical excipients, such as conventional preservatives, defoamers, antioxidants, buffers, acidifiers, alkalizers, complexing enhancers, cryoprotectants, electrolytes, glucose, emulsifiers, oils, plasticizers, solubilizers, stabilizers, isotonic modifiers, diluents, complexing agents, and other excipients and combinations thereof known to those skilled in the art for use in dosage forms.

[0157] As used herein, the term "alkalizing agent" is intended to refer to a compound used to provide an alkaline medium for product stability. Examples of such compounds include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine bases, basic amino acids, and other compounds known to those skilled in the art.

[0158] As used herein, the term "acidifier" is intended to refer to a compound used to provide an acidic medium for product stability. Examples of such compounds include, but are not limited to, acetic acid, acidic amino acids, citric acid, fumaric acid and other α-hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid, as well as other compounds known to those skilled in the art.

[0159] As used herein, conventional preservatives refer to compounds used to at least reduce the rate of bioburden increase, but to maintain or reduce bioburden stability after contamination. Examples of such compounds include, but are not limited to, benzalkonium chloride, benzyl chloride, benzoic acid, benzyl alcohol, hexadecylpyridine chloride, chlorobutanol, phenol, phenethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, m-cresol, myristyl-γ-pyridine chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, methylparaben, ethylparaben, propylparaben, or butylparaben, and other compounds known to those skilled in the art.

[0160] As used herein, the term "antioxidant" is intended to refer to a formulation that inhibits oxidation reactions, thereby preventing the dosage form from deteriorating due to oxidation. Examples of such compounds include, but are not limited to, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphite, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, mercaptoacetic acid, ethylenediaminetetraacetic acid (EDTA), triaminepentaacetate, and sodium metabisulfite, as well as other compounds known to those skilled in the art.

[0161] As used herein, the term "buffer" is intended to refer to a compound that resists changes in pH upon dilution or the addition of an acid or base. Examples of such compounds include, but are not limited to, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, tris(hydroxymethyl)aminomethane, sodium tartrate, anhydrous sodium citrate, and sodium citrate dihydrate, as well as other compounds known to those skilled in the art.

[0162] Complexing enhancers can be added to the compositions disclosed herein. When such formulations are present, the cyclodextrin / active agent ratio can be altered. The complexing enhancer is one or more compounds that enhance the complexation of the active agent (e.g., the compound of formula (I)) with cyclodextrin. Suitable complexing enhancers include one or more pharmacologically inert water-soluble polymers, hydroxy acids, and others commonly used in preservatives to enhance the complexation of a particular formulation with cyclodextrin.

[0163] Hydrophilic polymers can be used as complexing enhancers, solubilizers, and / or water activity reducers to improve the properties of cyclodextrin-containing compositions. Suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (e.g., water-soluble derivatives of cellulose), and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, alginate derivatives (e.g., sodium alginate), and agar, as well as polypeptides (e.g., casein and gelatin). Semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, their mixed ethers (e.g., hydroxypropyl methylcellulose), and other mixed ethers (e.g., hydroxyethyl-ethylcellulose and hydroxypropyl ethylcellulose), hydroxypropyl methylcellulose phthalates, and carboxymethylcellulose and their salts (especially sodium carboxymethylcellulose). Synthetic polymers include polyoxyethylene derivatives (polyethylene glycol), polyethylene derivatives (polyvinyl alcohol, polyvinylpyrrolidone, and polystyrene sulfonates), and various acrylic copolymers (e.g., carbomer). Other natural, semi-synthetic, and synthetic polymers not mentioned herein but meeting the criteria of water solubility, pharmaceutical acceptability, and pharmacological inertness are also considered to be within the scope of this disclosure. For example, more exemplary polymers are described in WO 2022 / 093652.

[0164] As used herein, the term "stabilizer" is intended to refer to a compound used to stabilize a therapeutic agent from physical, chemical, or biochemical processes that could reduce the therapeutic activity of the formulation. Suitable stabilizers, for example, include, but are not limited to, albumin, sialic acid, creatine, glycine and other amino acids, nicotinamide, sodium acetyltryptophan, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate, sodium saccharin, and other stabilizers known to those skilled in the art.

[0165] As used herein, the term "isotonic regulator" is intended to refer to a compound that can be used to adjust the osmotic pressure of a liquid dosage form of the compositions described herein. Suitable isotonic regulators include glycerol, lactose, mannitol, glucose, sodium chloride, sodium sulfate, sorbitol, trehalose, and other isotonic regulators known to those skilled in the art. In some embodiments, the osmotic pressure of the liquid dosage form is close to that of blood or plasma.

[0166] In some embodiments, the liquid dosage forms described herein include buffers and / or isotonic adjusters to achieve properties suitable for injection into the eye. For example, in various embodiments, the pH range of such liquid compositions may be 6.0 to 8.0, 6.0 to 7.5, 6.0 to 6.8, 6.5 to 7.5, or 6.8 to 7.2. In various embodiments, the osmotic pressure range of such liquid compositions may be 200 mOsm to 500 mOsm, 200 mOsm to 400 mOsm, or 250 mOsm to 350 mOsm.

[0167] As used herein, the term "defoamer" is intended to refer to a compound that prevents or reduces the amount of foam forming on the surface of a liquid formulation of the compositions described herein. Suitable defoamers include polydimethylsiloxane, simethicone, octyl styrene, and other defoamers known to those skilled in the art.

[0168] As used herein, the term "cryoprotectant" is intended to refer to a compound used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Examples of such compounds include, but are not limited to, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and other compounds known to those skilled in the art.

[0169] As used herein, the term "emulsifier" or "emulsifying agent" is intended to refer to a compound added to one or more phase components of an emulsion to stabilize droplets of the inner phase on the outer phase. Examples of such compounds include, but are not limited to, lecithin, polyoxyethylene-polyoxypropylene ether, polyoxyethylene-sorbitan monolaurate, polysorbate, sorbitan ester, stearyl alcohol, tyrosalicylate, astragalus gum, xanthan gum, gum arabic, agar, alginic acid, sodium alginate, bentonite, carbomer, sodium carboxymethyl cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, octyl phenyl ether, oleyl alcohol, polyvinyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, and other compounds known to those skilled in the art.

[0170] Solubilizers may be added to the compositions disclosed herein. A solubilizer is one or more compounds that improve the solubility of an active agent (e.g., the compound of formula (I)) in a liquid dosage form. When such a formulation is present, the cyclodextrin / active agent ratio can be altered. Suitable solubilizers include one or more organic solvents, detergents, soaps, surfactants, and other organic compounds commonly used in parenteral dosage forms to improve the solubility of a particular formulation.

[0171] For example, suitable organic solvents include ethanol, glycerol, polyethylene glycol, propylene glycol, poloxamer, and other solvents known to those skilled in the art.

[0172] The compositions disclosed herein may include oils (e.g., fixed oils, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, etc.), fatty acids (e.g., oleic acid, stearic acid, isostearic acid, etc.), fatty acid esters (e.g., ethyl oleate, isopropyl myristate, etc.), fatty acid glycerides, acetylated fatty acid glycerides, and combinations thereof. The compositions disclosed herein may also include alcohols (e.g., ethanol, isopropanol, cetyl alcohol, glycerol, propylene glycol, etc.), glyceryl ketals (e.g., 2,2-dimethyl-1,3-dioxolane-4-methanol, etc.), ethers (e.g., poly(ethylene glycol) 450, etc.), petroleum hydrocarbons (e.g., mineral oil, petrolatum, etc.), water, surfactants, suspending agents, emulsifiers, and combinations thereof.

[0173] In various embodiments of the compositions described herein, the compound of formula (I) may be entirely or substantially entirely cis or trans configuration. In various embodiments, more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% of the molecule of formula (I) in the composition is trans configuration. In other various embodiments, more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% of the molecule of formula (I) in the composition is cis configuration.

[0174] In some embodiments, the provided composition has more than 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5% of the compound of formula (I) complexed with cyclodextrin, with the remainder being in a free, uncomplexed form. In some embodiments, the provided composition has less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% of the compound of formula (I) complexed with cyclodextrin. In some embodiments, the provided composition has the compound of formula (I) complexed with cyclodextrin at a first percentage, and then exposed to light to produce a composition having a second, lower percentage of the compound of formula (I) complexed with cyclodextrin.

[0175] All references cited in this article, including patents, patent applications, papers, textbooks, and those that have not been cited to some extent, are hereby incorporated into this article through citation.

[0176] Example Example 1: Phase 1b Clinical Study An open-label, single-escalation dose trial was conducted in two non-randomized cohorts. A summary of the study design is as follows: Figure 1 As shown (only the evaluation days for queue 1 are displayed).

[0177] Study Design. Cohort 1 included patients with non-light perception (NLP) / bare-light perception (BLP). Cohort 2 included patients with finger counting (CF) / hand motion (HM) visual acuity. Each eye in each cohort received a single intravitreal (IVT) injection of KIO-301. Primary outcome measures included adverse events (AEs), pharmacokinetic (PK), and laboratory results. Secondary outcome measures included object recognition, intensity, and contrast assessments, with repeated assessments for each eye in each cohort for several days. Representative results are discussed below.

[0178] Results - Subject 1-01 Systemic and ocular safety assessments were conducted. No adverse events (AEs) were reported. Slit-lamp examination revealed abnormal baseline corneal lesions in the subject. Intraocular pressure (IOP) at baseline was normal. Dilated fundus photography performed within 6 hours post-injection and on day 29 showed abnormal baseline findings. Electrocardiogram at baseline was normal. No clinically significant differences were observed in safety parameters compared to baseline.

[0179] Intensity and contrast assessment. Subjects were presented with a series of six visual stimuli and were asked to confirm (verbally and physically) their perceived shapes or objects. Results were as follows: Figure 2A-2C As shown. Figure 2A and 2B The accuracy (%) of the subjects' perception of shapes or objects using their right or left eye is shown separately. Figure 2C The subjects' photoreactivity index relative to light intensity is shown. Results showed a significant increase in activity from baseline to 48 hours. Subjects showed a higher sensitivity to low levels of light (3 × 10⁻⁶). 14 photons / cm 2 •s) There is a response.

[0180] Dynamic visual field. Dynamic visual field was assessed using a Goldmann Haag-Streit tonometer. The assessment was performed by a vision therapist. Total horizontal and vertical visual field diopters were measured. Results are as follows: Figure 3A and 3B As shown.

[0181] Window location. Subjects' ability to orient themselves was tested on day 30 post-injection. Subjects were asked to identify a "window" randomly placed in a designated location eight times. Results are as follows: Figure 4 As shown, an increasing trend in accuracy (%) was observed, but this effect diminished over time. The results were consistent with the subjects' reported results.

[0182] Functional MRI – Qualitative Overlap of 3 Visual Paradigms. Functional MRI was performed on subjects at baseline and on days 2, 14, and 28. Results are as follows: Figure 5As shown. Increased striatal (VI) and non-striatal (V2 and V3) activity was observed on days 2 and 14. Activity on day 28 was comparable to baseline. Bilateral responses were consistent with other visual function measurements.

[0183] Functional MRI – Quantitative Increase: Checkerboard. Functional MRI was performed on subjects using checkerboard stimulation. Results are as follows: Figure 6 As shown in the figure. The blue area represents an increase, p < 0.05.

[0184] Quality of Life Survey – VFQ-25. Participants answered the National Eye Institute Visual Function Questionnaire (VFQ-25) at baseline and on day 29 post-injection. An increase of 2 to 4 points was generally considered clinically significant. Results are as follows: Figure 7 As shown. The overall increase is due to an increase in vision-specific problems (mental health and role difficulties) and the eye pain subscale.

[0185] Results - Subject 1-02 Subject 1-02 is in the fifth decade of his life, has had NLP for more than 10 years, and has an unknown gene mutation.

[0186] Systemic and ocular safety assessment. No adverse events (AEs) were reported. Slit-lamp examination showed no change from baseline. Intraocular pressure (IOP) at baseline was normal and unchanged from baseline. Baseline mydriatic fundus photography showed abnormalities but no change from baseline. Spectral-domain optical coherence tomography (SD-OCT) showed no macular edema or thinning.

[0187] Intensity and contrast assessment. As described above, a series of six visual stimuli were presented to the subjects at different light levels. The results are as follows: Figures 8A-8C As shown, this indicates an increase in light perception within two weeks after injection. High light levels (5 × 10⁻⁶) were perceived. 15 photons / cm 2 •s, below cloudy (s, below cloudy).

[0188] Dynamic field of view. The dynamic field of view was tested as described above. Results are as follows: Figure 9A and 9B As shown. When the right eye moves, a blue level 2 is observed in the far end of the peripheral vision.

[0189] Functional MRI – Qualitative overlap of three visual paradigms. Functional MRI was performed as described above. Results are as follows: Figure 10 As shown. Compared to baseline, a significant increase in striatal (VI) activity was observed on days 2 and 14. By day 28, activity levels returned to a similar level to baseline. The unilateral increase in VI activity was consistent with other visual function measurements.

[0190] Subject feedback: Subjects were confident that they perceived more light with both eyes and could periodically see small flashes of light. Although light / dark perception was not 100% clear, subjects reported greater confidence in their perception of light and dark directions and were able to see a lit mobile phone screen in the dark. In a functional MRI performed 48 hours after injection, subjects reported persistent flashes of light in their right eye when the stimulus was presented. The observations of subject 1-02 were consistent with the kinetics of subject 1-01, and confirmatory functional MRI data were consistent with a stronger unilateral response.

Claims

1. A method for treating a human subject with a retinal disease, the method comprising administering, via intravitreal injection, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof into the subject's eye: in, The azo bonds in the structure can be cis or trans.

2. The method according to claim 1, wherein, The retinal disease is caused by a hereditary eye condition.

3. The method according to claim 2, wherein, The hereditary eye disease mentioned is retinitis pigmentosa.

4. The method according to claim 1, wherein, The retinal disease mentioned is age-related macular degeneration.

5. The method according to claim 1, wherein, The retinal disease in question is choroidal detachment.

6. The method according to any one of claims 1 to 5, wherein, The compound of formula (I) was administered to both eyes of the subject.

7. The method according to any one of claims 1 to 5, wherein, The compound of formula (I) is administered to only one eye of the subject.

8. The method according to claim 7, wherein, The drug is administered to one eye of the subject, providing a therapeutic effect to both eyes of the subject.

9. The method according to claim 7 or 8, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately one week to approximately two months after the first administration.

10. The method according to claim 7 or 8, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately one week to approximately two months after the first administration.

11. The method according to any one of claims 7 to 9, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately 3 to 5 weeks after the first administration.

12. The method according to any one of claims 7, 8 or 10, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately 3 to 5 weeks after the first administration.

13. The method according to any one of claims 7, 8, 9 or 11, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the contralateral eye of the subject approximately one month after the first administration.

14. The method according to any one of claims 7, 8, 10 or 12, wherein, The administration of the drug to one eye is the first administration, and the method further includes a second administration, wherein the second administration comprises administering the compound of formula (I) to the same eye of the subject approximately one to two months after the first administration.

15. The method according to any one of claims 1 to 14, wherein, Treatment of human subjects includes improving the subject's ability to detect light and contrast, as measured by a light response test.

16. The method according to any one of claims 1 to 15, wherein, Treatment of human subjects involved stimulating the striatal (VI) and non-striatal (V2 and / or V3) cortical activity of the subjects, as measured by functional MRI.

17. The method according to any one of claims 1 to 16, wherein, Treatment of human subjects includes improving the subjects' tolerance to glare and photosensitivity.

18. The method according to any one of claims 1 to 17, wherein, Treatments for human subjects included improvements in measures of functional vision.

19. The method according to any one of claims 1 to 18, wherein, Treatment in human subjects reduced nonspecific, non-stimulatory random electrical activity in the retina.

20. The method according to any one of claims 1 to 19, wherein, The composition also contains cyclodextrin.

21. The method according to claim 20, wherein, The molar ratio of cyclodextrin to the compound of formula I in the composition is about 20:1 to about 1:

1.

22. The method according to claim 20 or 21, wherein, The molar ratio of cyclodextrin to the compound of formula I in the composition is from about 15:1 to about 3:

1.

23. The method according to any one of claims 20 to 22, wherein, The molar ratio of cyclodextrin to the compound of formula I in the composition is about 5:

1.

24. The method according to any one of claims 1 to 23, wherein, The concentration of the compound of formula (I) in the composition is from about 0.1 mM to about 10 mM.

25. The method according to any one of claims 1 to 24, wherein, The concentration of the compound of formula (I) in the composition is from about 0.2 mM to about 5 mM.

26. The method according to any one of claims 1 to 25, wherein, The compound of formula (I) was administered to one eye of the human subject by a dose of about 1 μg to about 100 μg.

27. The method according to any one of claims 1 to 26, wherein, The compound of formula (I) was administered to one eye of the human subject in an eye at a dose of about 7.5 μg to about 50 μg.

28. A method for treating a human subject suffering from a retinal disease, the method comprising: A composition comprising a compound of formula (I) is administered to one eye of a subject for the first time via intravitreal injection. A composition comprising a compound of formula (I) administered to the contralateral eye of the subject via intravitreal injection for a second administration; or A composition comprising a compound of formula (I) administered for the first time to one eye of the subject via intravitreal injection; and a composition comprising a compound of formula (I) administered for the second time to the same eye of the subject via intravitreal injection. The compound of formula (I) has the following structure: Or a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

29. The method according to claim 28, wherein, The second administration to the contralateral eye is performed simultaneously or substantially simultaneously with the first administration, or immediately after the first administration.

30. The method according to claim 28, wherein, The second administration to the contralateral eye is performed approximately 3 to 5 weeks after the first administration.

31. The method according to claim 28, wherein, The second dose to the same eye is administered approximately 3 to 5 weeks after the first dose.

32. A method for improving the tolerance of human subjects with retinal diseases to glare and photosensitivity, the method comprising: A composition comprising a compound of formula (I) is administered to one eye of a subject for the first time via intravitreal injection. A composition comprising a compound of formula (I) administered to the contralateral eye of the subject via intravitreal injection for a second administration; or A composition comprising a compound of formula (I) administered for the first time to one eye of the subject via intravitreal injection; and a composition comprising a compound of formula (I) administered for the second time to the same eye of the subject via intravitreal injection. The compound of formula (I) has the following structure: Or a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

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