A method for treating vision loss in human subjects using photoreactive compounds.

Abstract

This disclosure provides a method for treating a human subject suffering from retinal disorders, comprising the step of administering a composition comprising a compound of formula (I) as described herein to the eye of the subject via intravitreal injection.

Description

[Technical Field]

[0001] This disclosure provides a method for treating a human subject suffering from retinal disorders, comprising the step of administering a composition comprising a compound of formula (I) as described herein to the eye of the subject via intravitreal injection. [Background technology]

[0002] Certain photochromic azobenzene compounds exhibit photoswitch behavior, thereby undergoing photoisomerization and altering the compound's length and geometric shape. Such compounds interact with proteins, thereby altering protein function upon photoisomerization. These compounds have been shown in vitro to confer photosensitivity to degenerated retina through interaction with membrane proteins in retinal ganglion cells and upstream neurons. [Overview of the Initiative] [Means for solving the problem]

[0003] In some embodiments, the present disclosure relates to a method for treating a human subject suffering from retinal disorders, comprising a compound of formula (I): [ka]

[0004] The present invention provides a method comprising the step of administering a composition containing a pharmaceutically acceptable salt thereof (the azo (N=N) bond in the structure may be cis or trans) to the eye of a subject via intravitreal injection.

[0005] In some embodiments, the retinal disorder is caused by a hereditary eye disease. In some embodiments, the hereditary eye disease is retinitis pigmentosa. In some embodiments, the retinal disorder is age-related macular degeneration. In some embodiments, the retinal disorder is colloideremia.

[0006] 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 results in a therapeutic effect on both eyes of the subject.

[0007] In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the opposite eye of the subject approximately one week to approximately two months after the first dose. In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the same eye of the subject approximately one week to approximately two months after the first dose. In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the opposite eye of the subject approximately three weeks to approximately five weeks after the first dose. In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the same eye of the subject approximately three weeks to approximately five weeks after the first dose. In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the opposite eye of the subject about one month after the first dose. In some embodiments, administration to one eye constitutes a first dose, and the method further comprises a second dose, the second dose comprising administering the compound of formula (I) to the same eye of the subject about one to two months after the first dose.

[0008] In some embodiments, treatment of a human subject includes increasing the subject's ability to detect light and contrast, as measured by photoresponse testing. In some embodiments, treatment of a human subject includes stimulating the subject's striatal (V1) and non-striatal (V2 and / or V3) cortical activity, as measured by functional MRI.

[0009] In some embodiments, treatment of human subjects includes increasing tolerance to glare and photosensitivity in the subjects. In some embodiments, treatment of human subjects includes increasing a measure of functional vision. In some embodiments, treatment of human subjects reduces random electrical activity of nonspecific non-stimulus generation in the retina.

[0010] In some embodiments, the composition further comprises cyclodextrin. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) in the composition is about 20:1 to about 1:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) in the composition is about 15:1 to about 3:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) in the composition is about 5:1.

[0011] In some embodiments, the concentration of the compound of formula (I) in the composition is approximately 0.1 mM to approximately 10 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is approximately 0.2 mM to approximately 5 mM. In some embodiments, human subjects are administered approximately 1 μg to approximately 100 μg of the compound of formula (I) into one eye. In some embodiments, human subjects are administered approximately 7.5 μg to approximately 50 μg of the compound of formula (I) into one eye.

[0012] In some embodiments, the present disclosure relates to a method for treating a human subject suffering from a retinal disorder, comprising: (a) a first administration to one eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); and a second administration to the opposite eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); or (b) a first administration to one eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); and a second administration to the same eye of the subject via intravitreal injection of a composition comprising the compound of formula (I), wherein the compound of formula (I) has the structure: [ka]

[0013] The present invention provides a method having a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

[0014] In some embodiments, the second dose to the opposite eye is administered simultaneously with, substantially simultaneously with, or immediately after the first dose. In some embodiments, the second dose to the opposite 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.

[0015] In some embodiments, the present disclosure provides a method for increasing tolerance to glare and photosensitivity in a human subject suffering from retinal disorders, comprising: (a) a first administration to one eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); and a second administration to the opposite eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); or (b) a first administration to one eye of the subject via intravitreal injection of a composition comprising the compound of formula (I); and a second administration to the same eye of the subject via intravitreal injection of a composition comprising the compound of formula (I). The compound of formula (I) has the structure: [ka]

[0016] The present invention provides a method having a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

[0017] The following drawings form part of this specification and are included to further demonstrate exemplary embodiments of particular aspects of this disclosure. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows the clinical trial design described in Example 1. [Figure 2A]Figure 2A shows the results of intensity and contrast evaluation for a subject (Subject 1-01) administered KIO-301, specifically the right eye (OD) of the subject. [Figure 2B] Figure 2B shows the results of intensity and contrast evaluations for a subject (Subject 1-01) administered KIO-301, specifically the results for the subject's left eye (OS). [Figure 2C] Figure 2C shows the results of intensity and contrast evaluations for subjects (Subject 1-01) administered KIO-301, and is a diagram showing the photoresponse index of the subjects to light intensity. [Figure 3A] Figure 3A shows the results of the dynamic visual field evaluation for subject 1-01, and the resulting visual field chart, with black circles indicating baseline and hatched circles indicating the results one month after injection. [Figure 3B] Figure 3B shows the results of dynamic visual field evaluation for subject 1-01, illustrating the total horizontal and total vertical visual field of the right and left eyes at baseline and one month after injection. [Figure 4] Figure 4 shows the results of the window position evaluation for subject 1-01 conducted over 30 days. OD: right eye; OS: left eye; OU: both eyes. [Figure 5] Figure 5 shows the results of functional MRI performed on subject 1-01 at baseline and on days 2, 14, and 28 after injection. [Figure 6] Figure 6 shows the results of functional MRI performed on subject 1-01, who received checkerboard stimulation. [Figure 7] Figure 7 shows the results of the quality of life questionnaire (VFQ-25) responses from Subject 1-01 at baseline and 29 days after injection. [Figure 8A] Figure 8A shows the results of intensity and contrast evaluations for subjects (Subject 1-02) administered KIO-301, and specifically the results for the right eye (OD) of each subject. [Figure 8B]Figure 8B shows the results of intensity and contrast evaluations for subjects (Subject 1-02) administered KIO-301, and specifically the results for the left eye (OS) of each subject. [Figure 8C] Figure 8C shows the results of intensity and contrast evaluations for subjects (Subjects 1-02) administered KIO-301, and is a diagram showing the intensity and contrast evaluation results for both eyes (OU) of the subjects. [Figure 9A] Figure 9A shows the results of the dynamic visual field evaluation for subject 1-02, and is a diagram of the resulting visual field chart. [Figure 9B] Figure 9B shows the results of dynamic visual field evaluation for subject 1-02, illustrating an overview of the total horizontal and total vertical visual field of the right and left eyes at baseline and one week after injection. [Figure 10] Figure 10 shows the results of functional MRI performed on subject 1-02 at baseline and on days 2, 14, and 28 after injection. [Modes for carrying out the invention]

[0019] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have meanings generally understood by those skilled in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural forms, and plural terms shall include singular forms.

[0020] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0021] The use of the term “or” in the claims is used to mean “and / or” unless it is expressly indicated that it refers only to substitutes or that the substitutes are not mutually exclusive; however, this disclosure supports the definitions that refer only to substitutes and “and / or.”

[0022] 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 comprehensive or open-ended and do not exclude any additional unenumerated elements or method steps.

[0023] The use of the term "for example" and its corresponding abbreviation "eg" means that the specific terms listed are representative examples and embodiments of this disclosure, and are not intended to be limited to the specific examples mentioned or cited unless otherwise specified.

[0024] As used herein, “about” may mean plus or minus 10% of the given value. If a range is given, they include boundary values. “About” may additionally or alternatively mean within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value, or “about” may mean rounded to the nearest significant figure.

[0025] As used herein, “between” refers to a range that includes the ends of the range. For example, the numbers between x and y explicitly include the numbers x and y, as well as any numbers that fall within the range x and y.

[0026] As used herein, the term “active agent” includes any agent, 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, pharmaceuticals, pharmacological agents, diagnostic agents, cosmetics, and prophylactic agents, as well as immunomodulators. The term “active agent” may be used interchangeably with the terms “drug,” “pharmaceutical,” “medicament,” “drug substance,” and “therapeutic.” In some embodiments, the active agent of this disclosure includes a compound of formula (I).

[0027] In some embodiments, the compositions described herein are “pharmaceutically acceptable.” When referring to the compositions described herein, or the excipients, carriers, diluents, or components described herein, the term “pharmaceutically acceptable” means that the composition and / or components are suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, or allergy), i.e., with a reasonable benefit-risk ratio.

[0028] The terms "side effect" or "adverse event" refer to physiological disorders and / or adverse conditions resulting from a procedure other than the desired effect.

[0029] In some embodiments, the compositions herein are effective for the treatments described herein. The term “efficacy” means the ability to produce a desired effect. The term “effective amount” means the amount of a therapeutic agent (e.g., a compound of formula (I) described herein) used to treat, alleviate or prevent a target disease or condition (e.g., a retinal disorder described herein), or the amount that exhibits a detectable therapeutic or preventive effect. The exact effective amount for a subject may depend on the size and health status of the subject, the nature and severity of the condition, and the selected therapeutic agent and / or combination of therapeutic agents.

[0030] The "therapeutic effective amount" is the amount 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). The therapeutic effective amount may be an amount that alleviates one or more symptoms of the patient's condition or disorder to some extent; an amount that partially or completely restores one or more physiological or biochemical parameters associated with or causing the condition or disorder to normal; and / or an amount that reduces the likelihood of the onset of the disorder.

[0031] The terms “administration” or “administering” refer to a route through which a compound or composition provided herein is introduced into an organism to perform an intended function. Examples of possible routes of administration include, but are not limited to, parenteral administration, such as intravitreal injection.

[0032] The term “subject” means any subject, particularly a mammalian subject, that requires treatment with a composition containing, for example, the compound of formula (I). In some embodiments, the term “subject” refers to a human subject. As used herein, “subject in need thereof” refers to a subject that is desirable to be treated, for example, a subject having the retinal disorder described herein. In some embodiments, the term “subject in need thereof” may refer to a subject at high risk of developing a condition suitable for treatment with a composition containing the compound of formula (I) described herein, regardless of whether the subject has physical signs of such a condition.

[0033] Treatment of retinal disorders In some embodiments, the present disclosure relates to a method for treating a human subject suffering from retinal disorders, comprising a compound of formula (I): [ka]

[0034] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The present invention provides a method comprising the step of administering a composition comprising (x, and y as described herein) to a target eye via intravitreal injection.

[0035] In some embodiments, the present disclosure provides a method of treating a human subject suffering from a retinal disorder, comprising: (a) a first administration to one eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); and a second administration to the opposite eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); or (b) a first administration to one eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); and a second administration to the same eye of the subject via intravitreal injection of a composition comprising a compound of formula (I), wherein the compound of formula (I) has the structure:

Chemical formula

[0036] 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 herein).

[0037] In some embodiments, the present disclosure provides a method of increasing tolerance to glare and photosensitivity in a human subject suffering from a retinal disorder, comprising: (a) a first administration to one eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); and a second administration to the opposite eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); or (b) a first administration to one eye of the subject via intravitreal injection of a composition comprising a compound of formula (I); and a second administration to the same eye of the subject via intravitreal injection of a composition comprising a compound of formula (I), wherein the compound of formula (I) has the structure:

Chemical formula

[0038] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6The present invention provides a method having (where x, and y are as described herein).

[0039] In some embodiments, the compound of formula (I) has the structure: [ka]

[0040] Alternatively, it may have a pharmaceutically acceptable salt thereof, and the azo (N=N) bond in the structure may be cis or trans.

[0041] Surprisingly, compositions containing the compounds described herein, for example, the compound of formula (I), have been found to be effective in treating human retinal disorders. In some embodiments, the compositions described herein confer photosensitivity to human retinal pigment epithelial cells and cells located in the neurosensory retina, such as photoreceptor cells and Müller cells. Throughout this disclosure, any reference to “subject” means that it includes human subjects.

[0042] In some embodiments, the retinal disorder is glaucoma, including diabetic retinopathy, age-related macular degeneration (AMD or ARMD) (exudative type), atrophic AMD, retinopathy of prematurity, retinitis pigmentosa, colloideremia, and / or open-angle glaucoma (e.g., primary open-angle glaucoma), closed-angle glaucoma, and secondary glaucoma (e.g., pigment glaucoma, pseudoexfoliation glaucoma, and glaucoma resulting from trauma and inflammatory disease). In some embodiments, the retinal disorder is AMD, e.g., exudative AMD or atrophic AMD. In some embodiments, the retinal disorder is retinitis pigmentosa. In some embodiments, the retinal disorder is colloideremia. In some embodiments, the retinal disorder is diagnosed by a qualified medical professional.

[0043] In some embodiments, retinal disorders include retinal detachment, age-related or other macular degeneration, photoretinopathy, surgery-induced retinopathy, toxic retinopathy, retinopathy of prematurity, retinopathy due to trauma or invasive lesions of the eye, hereditary retinal degeneration, surgery-induced retinopathy, toxic retinopathy, and / or retinopathy due to trauma or invasive lesions of the eye.

[0044] In some embodiments, retinal disorders are caused by hereditary eye diseases. Exemplary hereditary eye diseases include, but are not limited to, Valday-Beedl syndrome (autosomal recessive), congenital amaurosis (autosomal recessive), cone or cone-rod dystrophy (autosomal dominant and X-linked), congenital arresting night blindness (autosomal dominant, autosomal recessive, and X-linked), macular degeneration (autosomal dominant and autosomal recessive), optic nerve atrophy (autosomal dominant and X-linked), retinitis pigmentosa (autosomal dominant, autosomal recessive, and X-linked), symptomatic or systemic retinopathy (autosomal dominant, autosomal recessive, and X-linked), Usher syndrome (autosomal recessive), and colloideremia (X-linked). In some embodiments, the hereditary eye disease is retinitis pigmentosa. In some embodiments, the hereditary eye disease is colloideremia.

[0045] The compositions described herein can be administered to the eye via various routes, for example, as described herein. The compositions may be delivered intraocularly by topical application to the eye or by intraocular injection, for example, into the vitreous humor or subretinal (interphotoreceptor) space. Alternatively, the compositions may be delivered topically by insertion or injection into the tissues surrounding the eye. The compositions may be delivered systemically by oral route or by subcutaneous, intravenous, or intramuscular injection. Alternatively, the compositions may be delivered by catheter or implant, such implants being made of porous, non-porous, or gelatinous materials, including membranes such as silastic membranes or fibers, biodegradable polymers, or proteinaceous materials. The compositions may be administered to prevent the onset of a condition, for example, before the onset of a condition, during eye surgery, immediately after the onset of a pathological condition, or during the onset of an acute or prolonged condition. In some embodiments, compositions containing the compound of formula (I) described herein are administered by intravitreal injection (IVT).

[0046] In some embodiments, the compound of formula (I) is administered to both eyes of a human subject. In some embodiments, it is administered to both eyes of a human subject simultaneously or substantially simultaneously. In some embodiments, it is administered to one human subject immediately after administration to the other eye. In some embodiments, it is administered to one eye of a human subject within 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours of administration to the other eye. In some embodiments, it is administered to one eye of a human subject within approximately 1 day to 3 months, or within approximately 1 week to 2 months, or within approximately 2 weeks to 6 weeks, or within approximately 3 weeks to 5 weeks, or within approximately 1 month of administration to the other eye. In some embodiments, the compound of formula (I) is administered to both eyes of a human subject during a single clinical visit or outpatient visit. In some embodiments, the compound of formula (I) is administered to one eye of a human subject during separate clinical visits or outpatient visits.

[0047] In some embodiments, the compound of formula (I) is administered to only one eye of a human subject. Surprisingly, it has been found that administration of the compound of formula (I) to one eye of a subject results in a treatment effect in both eyes of the subject. In some embodiments, the treatment effect includes one or more of the following: increasing the subject's ability to detect light and contrast as measured by photoresponse testing; increasing the subject's visual field; increasing the subject's ability to determine the direction of light; stimulating the subject's striated (V1) and / or non-striated (V2 and / or V3) cortical activity as measured by functional MRI; increasing the subject's tolerance to glare and photosensitivity; increasing the subject's measure of functional vision, e.g., via functional visual assessment (FVA); and reducing random electrical activity of nonspecific non-stimulus-generating retinal activity (also known as "ringing" of the eye as perceived by the brain).

[0048] Functional magnetic resonance imaging, or functional MRI, measures brain activity by detecting changes related to blood flow. In some embodiments, functional MRI can rely on the fact that cerebral blood flow and neuronal activation are linked, and that when a certain region of the brain is being used, blood flow to that region also increases. In some embodiments, functional MRI uses blood oxygen level-dependent (BOLD) contrast. See, for example, SAHuettel, et al (2009), page 4 and page 26, Functional Magnetic Resonance Imaging (2nd ed.), Massachusetts: Sinauer. In some embodiments, functional MRI can use arterial spin labeling and diffusion-weighted MRI. See, for example, JADetre, John A. et al. (May 2012), Journal of Magnetic Resonance Imaging. 35(5):1026-1037. Diffusion-weighted MRI is similar to BOLD fMRI but provides contrast based on the magnitude of water molecule diffusion in the brain. Functional visual assessment (FVA) refers to any standardized test that evaluates how a subject uses their remaining vision across a variety of familiar and unfamiliar environments. In some embodiments, an FVA investigates how a subject uses their vision for (i) near tasks, closer than 16 inches; (ii) intermediate tasks, 16 inches to 3 feet; and (iii) far tasks, greater than 3 feet. In some embodiments, an FVA is performed by a trained professional. In some embodiments, an FVA may include one or more of the following: (i) how clear and sharp the subject's vision is; (ii) field of vision, or the areas the subject looks to the sides, above, and below (known as peripheral vision); (iii) contrast sensitivity, or the subject's ability to detect differences in the degree of gray 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 response to light (sunlight or artificial light).

[0049] In some embodiments, the method provided herein includes administering the compound of formula (I) to one eye of a human subject, i.e., a first dose and a subsequent second dose of the compound of formula (I) to the same eye or the opposite eye of the human subject. In some embodiments, the second dose is simultaneous with or substantially simultaneous with the first dose, or immediately after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the opposite eye of the subject simultaneously with or substantially simultaneously with the first dose, or immediately after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the opposite eye of the subject on the same day as the first dose, 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 dose. In some embodiments, the second dose includes administering the compound of formula (I) to the eye opposite the subject about one week to about two months after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the eye opposite the subject about three weeks to about five weeks after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the eye opposite the subject about one month after the first dose.

[0050] In some embodiments, intravitreal administration of the compound of formula (I) can be continued weekly to every two months over more than one, two, three, four, five, six, seven, eight, nine, or ten doses. Therefore, for example, the compound of formula (I) can be administered weekly to monthly over more than six months, twelve, eighteen, two, five, or the life expectancy of the subject. In some embodiments, intravitreal administration of the compound of formula (I) can be continued every three to five weeks over more than one, two, three, four, five, six, seven, eight, nine, or ten doses. Therefore, for example, the compound of formula (I) can be administered every three to five weeks over more than six months, twelve, eighteen, two, two, five, or the life expectancy of the subject. In some embodiments, the compound of formula (I) is administered continuously to human subjects throughout their lifetime. In some embodiments, the compound of formula (I) is administered by the patient "as needed" or by human subjects "as desired" throughout their lifetime.

[0051] In some embodiments, the second dose includes administering the compound of formula (I) to the same eye of the subject at the same time as or substantially at the same time as the first dose, or immediately after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the same eye of the subject on the same day as the first dose, or about 1 day to about 3 months after the first dose, or about 1 week to about 2 months after, or about 2 weeks to about 6 weeks after, or about 3 weeks to about 5 weeks after, or about 1 month after, the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the same eye of the subject about 1 week to about 2 months after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the same eye of the subject about 3 weeks to about 5 weeks after the first dose. In some embodiments, the second dose includes administering the compound of formula (I) to the same eye of the subject about 1 month after the first dose. In some embodiments, a second administration to the same eye as the first administration results in a therapeutic effect on both eyes of the subject.

[0052] In some embodiments, treatment of subjects suffering from retinal damage includes one or more of the following: increasing the subject's ability to detect light and contrast as measured by photoresponse testing; increasing the subject's visual field; increasing the subject's ability to determine the direction of light; stimulating the subject's striatal (V1) and / or non-striatal (V2 and / or V3) cortical activity as measured by functional MRI; increasing the subject's tolerance to glare and photosensitivity; increasing the subject's measure of functional vision, for example, via functional visual assessment (FVA); and reducing random electrical activity of nonspecific, non-stimulus-generating retinal events (also known as "ringing" of the eye as perceived by the brain).

[0053] In some embodiments, the treatment involves increasing the subject's ability to detect light and contrast (i.e., differences in the perception of light and dark) at varying intensities of light. An exemplary method for evaluating a subject's ability to detect light and contrast involves presenting the subject with a series of visual stimuli (e.g., flashes) of varying intensities and asking the subject to indicate when a stimulus is perceived. In some embodiments, the light intensities tested in the subject are approximately 10 13 ~about 10 17 photon / cm 2 The range is s. In some embodiments, the percentage accuracy of the subject for identifying visual stimuli with 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 two days after treatment. In some embodiments, the percentage accuracy of the subject for identifying visual stimuli with 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 ten days after treatment. In some embodiments, the percentage accuracy of the subject for identifying visual stimuli with 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 thirty days after treatment. In some embodiments, the treatment comprises administering a composition comprising a compound of formula (I) to one eye of the subject, as described herein, and the increase in the subject's ability to detect light and contrast is 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.

[0054] In some embodiments, the treatment includes increasing the field of view of the subject, for example, increasing the total horizontal field of view and / or total vertical field of view. In some embodiments, the total horizontal field of view and / or total vertical field of view of the subject 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 about 2 to 30 days after the treatment, for example, about 2 days, about 7 days, about 10 days, about 15 days, or about 30 days after the treatment. In some embodiments, the treatment includes administering a composition containing the compound of formula (I) to one eye of the subject, as described herein, and the increase in the field of view of the subject is in both eyes of the subject. In some embodiments, the treatment includes administering a composition containing the compound of formula (I) to both eyes of the subject, as described herein.

[0055] In some embodiments, the treatment includes increasing the subject's ability to determine the direction of light. An exemplary method for evaluating the subject's ability to determine the direction of light includes asking the subject to identify a window location, thereby testing the subject's ability to determine direction. In some embodiments, the subject's percent accuracy for identifying a window location with 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 two days after the treatment. In some embodiments, the subject's percent accuracy for identifying a window location with 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 ten days after the treatment. In some embodiments, the subject's percent accuracy for identifying a window location with 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 thirty days after the treatment. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I) to one eye of the subject, as described herein, and the increase in the subject's ability to determine the direction of light is present in both eyes of the subject. In some embodiments, the treatment involves administering a composition containing the compound of formula (I) to both eyes of the subject, as described herein.

[0056] In some embodiments, the treatment involves increasing activity in the subject's visual cortex. In some embodiments, a visual stimulus, such as a checkerboard, is presented to the subject, and the subject's neural activity is measured using functional MRI. In some embodiments, the treatment involves stimulating the subject's striatal (V1) and non-striatal (V2 and / or V3) cortical activity, as measured by functional MRI. V1 is the primary visual cortex and represents the first stage of visual processing. V2 is the secondary visual cortex, receiving integrated information from V1 and having feedforward connections with V3-V5. V3 refers to a third visual cortical complex that may play a role in processing motion and color sensitivity. See, for example, Huff et al., Neuroanatomy, Visual Cortex. [Updated 2022 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. In some embodiments, the V1, V2, and / or V3 cortical activity of the subject is stimulated approximately 2 to 30 days after treatment, for example, approximately 2, 7, 10, 15, or 30 days after treatment. In some embodiments, the treatment involves administering a composition comprising the compound of formula (I) to one or both eyes of the subject, as described herein.

[0057] In some embodiments, the treatment includes increasing the object's tolerance to glare and photosensitivity while improving the object's visual acuity, for example, by increasing the object's ability to detect light and contrast; increasing the object's field of vision; and / or increasing the object's ability to determine the direction of light, as described herein. Glare sensitivity is the loss of vision in bright lighting, such as near a bright light source or outdoors in bright sunlight. An object suffering from glare sensitivity may not be able to see the distinct contours of a brightly lit object, which may merge into a bright white "wall" around it. Unexpectedly, the photoreactive compounds of formula (I) described herein allow human objects with poor visual acuity to be exposed to bright light without the adverse glare effects expected with typical vision restoration treatments. An exemplary assessment of glare tolerance is described, for example, in Fotios et al., LEUKOS (2020) doi:10.1080 / 15502724.2020.1803082. In some embodiments, the treatment involves administering a composition containing the compound of formula (I) to one or both eyes of the subject, as described herein.

[0058] In some embodiments, the treatment involves reducing random electrical activity of nonspecific, non-stimuli-generated events in the retina of a subject, also known as "ringing" of the eye as perceived by the brain. An unexpected advantage of the photoreactive compounds of formula (I) described herein is that they can improve the visual acuity of a human subject without causing "ringing" of the eye. In some embodiments, the treatment involves administering a composition containing the compound of formula (I) to one or both eyes of a subject, as described herein.

[0059] In some embodiments, the treatment includes increasing a measure of the subject's functional vision. In some embodiments, the subject's functional vision may be measured via a Functional Visual Assessment (FVA). In some embodiments, the FVA includes testing the subject's visual acuity, visual field, contrast discrimination, sensitivity, color vision, and / or light sensitivity. In some embodiments, the treatment includes increasing a measure of the subject's visual quality of life. In some embodiments, the subject's visual quality of life may be assessed via a survey, e.g., the National Ophthalmological Society's 25-item Visual Function Questionnaire 25 (VFQ-25). In some embodiments, the subject's VFQ-25 score increases by approximately 1–5 points, or approximately 2–4 points, approximately 2 days, approximately 7 days, approximately 10 days, approximately 15 days, or approximately 30 days after the treatment. In some embodiments, the treatment includes administering a composition comprising a compound of formula (I), as described herein, to one eye of the subject, and the increase in the subject's VFQ-25 score is based on results from both eyes of the subject. In some embodiments, the treatment involves administering a composition containing the compound of formula (I) to both eyes of the subject, as described herein.

[0060] compound In some embodiments, the methods provided herein involve compounds of formula (I): [ka]

[0061] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The step of administering a composition comprising (x, and y are as described herein) to the eye of a target via intravitreal injection.

[0062] Several embodiments, each R 1 C 1~10 Alkyl, substituted C 1~10 Alkyl, -NR 10 R 11 , -NR12 C(O)R 13 , C 2~10 Alkenyl, substituted C 2~10 Alkenil, C 2~10 Alkinyl, Substitute C 2~10 Alkinyl, C 6~20 Aryl substitution C 6~20 Aryl, heteroaryl, heterocyclyl, heterocyclooxy, heterocyclothio, heteroarylamino, heterocycloamino, C 4~10 Cycloalkyl, substituted C 4~10 Cycloalkyl, C 4~10 Cycloalkenyl, substituted C 4~10 Cycloalkenyl, cyano, halo, -OR 10 , -C(O)OR 10 , and -S(O)2R 10 It is selected independently of others.

[0063] In some embodiments, R 3 , R 4 , and R 5 is hydrogen, C 2~8 Alkyl, substituted C 2~10 Alkyl, C 2~10 Alkenyl, substituted C 2~10 Alkenil, C 2~10 Alkinyl, Substitute C 2~10 Alkinyl, C 6~20 Aryl substitution C 6~20 Ariel, C 4~10 Cycloalkyl, substituted C 4~10 Cycloalkyl, C 4~10 Cycloalkenyl and substituted C 4~10 It is selected independently of cycloalkenyls.

[0064] In some embodiments, x is an integer between 0 and 5. In some embodiments, y is an integer between 0 and 4.

[0065] In some embodiments, R 2 is hydrogen, C 1~10 Alkyl, substituted C 1~10 Alkyl, C 2~10 Alkenyl, substituted C 2~10 Alkenil, C2~10 alkynyl, substituted C 2~10 alkynyl, 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 is selected from cycloalkenyl.

[0066] In some embodiments, each R 6 is 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, C 6~20 aryl, substituted C 6~20 aryl, heteroaryl, heterocyclic, heterocyclooxy, heterocyclothio, heteroarylamino, heterocycloamino, C 4~10 cycloalkyl, substituted C 4~10 cycloalkyl, C 4~10 cycloalkenyl, substituted C 4~10 cycloalkenyl, cyano, halo, -OR 10 、-C(O)OR 10 、-S(O)R 10 、and -S(O)2R 10 is independently selected from.

[0067] In some embodiments, R 10 and R 11 are 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, C 6~20 aryl, substituted C 6~20 aryl, C 4~10Cycloalkyl, substituted C 4~10 Cycloalkyl, C 4~10 Cycloalkenyl and substituted C 4~10 It is selected independently of cycloalkenyls.

[0068] In some embodiments, R 12 is hydrogen, C 1~10 Alkyl, substituted C 1~10 Alkyl, C 2~10 Alkenyl, substituted C 2~10 Alkenil, C 2~10 Alkinyl, Substitute C 2~10 Alkinyl, C 6~20 Aryl substitution C 6~20 Ariel, C 4~10 Cycloalkyl, substituted C 4~10 Cycloalkyl, C 4~10 Cycloalkenyl and substituted C 4~10 Selected from cycloalkenyls.

[0069] In some embodiments, R 13 is hydrogen, C 1~10 Alkyl, substituted C 1~10 Alkyl, C 2~10 Alkenyl, substituted C 2~10 Alkenil, C 2~10 Alkinyl, Substitute C 2~10 Alkinyl, C6~C 10 Aryl substitution C 6~20 Ariel, 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 - Selected from.

[0070] Several embodiments, each R 1 Hello, C 1~10 Alkyl, -NR 10 R 11 , and -NR 12 C(O)R 13 It is selected independently of others.

[0071] In some embodiments, R 2 It is hydrogen or ethyl.

[0072] In some embodiments, x is 0 or 1. In some embodiments, y is 0 or 1.

[0073] In some embodiments, R 3 , R 4 , and R 5 Each of them is ethyl.

[0074] In some embodiments, R 6 is Halo or C 1~10 It is alkyl.

[0075] In some embodiments, R 10 or R 11 is hydrogen, C 1~10 Alkyl and substituted C 1~10 It is selected independently of alkyl.

[0076] In some embodiments, R 12 It is hydrogen.

[0077] In some embodiments, R 13 C 1~10 Alkyl, substituted C 1~10 Alkyl, C 2~8 Alkenyl and C 6~10 Selected from the arrows.

[0078] Equation (I) shows an azo bond in a trans configuration, but it should be understood that unless otherwise specified herein, the equation encompasses both cis and trans configurations.

[0079] In some embodiments, the compound of formula (I) has the following structure: [ka]

[0080] TIFF2026515818000011.tif251158

[0081] TIFF2026515818000012.tif252153

[0082] TIFF2026515818000013.tif215136

[0083] Alternatively, a selection may be made from a pharmaceutically acceptable salt thereof, and the azo (N=N) bond in the compound of formula (I) may be cis or trans unless otherwise specified herein.

[0084] In some embodiments, the compound of formula (I) has the structure: [ka]

[0085] Alternatively, it may have a pharmaceutically acceptable salt thereof, and the azo bond in the structure may be cis or trans.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of a compound that retains the biological efficacy and properties of the compound, without being biologically or otherwise undesirable for use in medicine. In some embodiments, the compounds herein can form acid salts and / or base salts by the presence of an amino group and / or a carboxyl group or similar groups. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids that can induce salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can induce salts 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, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases that can derive salts include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts being particularly preferred. Examples of organic bases that can derive salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Exemplary salts are described in International Publication No. 87 / 05297.

[0087] When used herein, "C a ~C b " or "C a~b"(wherein "a" and "b" are integers)" refers to the number of carbon atoms in the specified group. That is, a group can contain "a" to "b" (including both ends) carbon atoms. Thus, for example, "C1-C4 alkyl (C1 to C4 alkyl)" or "C 1~4 Alkyl (C 1-4 The "alkyl)" group refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0088] The terms "halogen" or "halo," as used herein, mean any one of the radiostable atoms of Group 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0089] As used herein, “alkyl(alkyl)” refers to a fully saturated (i.e., without any double or triple bonds) straight or branched hydrocarbon chain. Alkyl groups may have 1 to 20 carbon atoms (wherever they appear herein, numerical ranges such as “1 to 20” refer to each integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 20 or fewer carbon atoms, such as 1 carbon, 2 carbon, 3 carbon, etc., but this definition also covers the existence of the term “alkyl(alkyl)” without a specified numerical range). Alkyl groups may also be medium-sized alkyl groups having 1 to 9 carbon atoms. Alkyl groups may also be lower alkyl groups having 1 to 4 carbon atoms. The alkyl group of a compound is “C 1~4 Alkyl (C 1-4 It may be designated as "(alkyl)" or a similar designation. Just as an example, "C 1~4 Alkyl (C 1-4"Alkyl)" indicates that the alkyl chain has 1 to 4 carbon atoms, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0090] As used herein, “haloalkyl” refers to a linear or branched alkyl group having 1 to 12 carbon atoms in the chain, in which one or more hydrogen atoms are substituted with halogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that are considered equivalent to any one of the above examples in light of the usual skill in the art and the teachings provided herein.

[0091] As used herein, "alkoxy" includes, but is not limited to, compounds of the formula -OR (wherein R is an alkyl as defined above), such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. 1~9 Alkoxy(C) 1-9 This refers to "alkoxy".

[0092] As used herein, “heteroalkyl” refers to a linear or branched hydrocarbon chain whose chain skeleton contains one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. A heteroalkyl group may have 1 to 20 carbon atoms, but this definition also covers the existence of the term “heteroalkyl” without a specified numerical range. A heteroalkyl group may also be a medium-sized heteroalkyl group having 1 to 9 carbon atoms. A heteroalkyl group may also be a lower heteroalkyl group having 1 to 4 carbon atoms. In various embodiments, a heteroalkyl group may have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of a compound is “C 1~4 Heteroalkyl(C 1-4 A heteroalkyl group may be designated as "(C1-4 heteroalkyl)" or a similar designation. A heteroalkyl group may contain one or more heteroatoms. For example, "C1-4 heteroalkyl" indicates that the heteroalkyl chain contains one to four carbon atoms, and that the chain's backbone contains one or more heteroatoms.

[0093] The term "aromatic" refers to a ring or ring system having a conjugated π-electron system, and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused polycyclic groups (i.e., rings sharing adjacent pairs of atoms) provided that the entire ring system is aromatic.

[0094] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) whose ring skeleton contains only carbon atoms. If the aryl is a ring system, all rings in the system are aromatic. While an aryl group may have 6 to 18 carbon atoms, this definition also covers the existence of the term “aryl” without a specified numerical range. In some embodiments, an aryl group has 6 to 10 carbon atoms. 6~10 Ariel (C 6-10 aryl)", "C6 or C 10 Aryl (C6 or C 10 It may be designated as "aryl)" or a similar designation. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azlenyl, and anthracenyl.

[0095] As used herein, “aryloxy” and “arylthio” include, but are not limited to, RO- and RS- (wherein R is an aryl as defined above), such as phenyloxy, and “C 6~10 Aryloxy (C 6-10 aryloxy) or "C 6~10 Arylthio(C 6-10 It refers to "arylthio".

[0096] "Aralkyl" or "arylalkyl" refers to an aryl group bonded as a substituent via an alkylene group, including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl groups. 7~14 Aralkill (C) 7-14 Examples include "ar alkyl)". In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0097] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in its ring skeleton. If the heteroaryl is a ring system, all rings in the system are aromatic. A heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also covers the existence of the term “heteroaryl” without a specified numerical range. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group may be designated as a “5-7 membered heteroaryl,” a “5-10 membered heteroaryl,” or similar designations. In various embodiments, the heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl 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, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0098] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group bonded as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0099] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or cyclic system containing only carbon atoms in its cyclic framework. If a carbocyclyl is a cyclic system, two or more rings may be bonded together by condensation, bridging, or spirobonding. Carbocyclyls can have any degree of saturation, provided that at least one ring in the cyclic system is non-aromatic. Therefore, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. A carbocyclyl group may have 3 to 20 carbon atoms, but this definition also covers the existence of the term “carbocyclyl” without a specified numerical range. A carbocyclyl group may also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is “C 3~6 Carbocyclyl (C 3-6 It may be designated as "carbocyclyl)" or a similar designation. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0100] "(Carbocyclyl)alkyl" refers to a carbocyclyl group bonded as a substituent via an alkylene group, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. 4~10 (Carbocyclyl)alkyl(C) 4-10 Examples include (carbocyclyl)alkyl groups. In some cases, the alkylene group is a lower alkylene group.

[0101] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0102] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein the ring in the ring system is not aromatic. One example is cyclohexenyl.

[0103] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in its ring skeleton. Heterocyclyls may be linked together by condensation, bridging, or spirobonding. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. The (one or more) heteroatoms may be present in either the non-aromatic or aromatic ring of the ring system. A heterocyclyl group may 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 covers the existence of the term “heterocyclyl” without a specified numerical range. A heterocyclyl group may also be a medium-sized heterocyclyl having 3 to 10 ring members. A heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as a "3-6 membered heterocyclyl" or a similar designation.

[0104] In various embodiments, the heterocyclil contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclil 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 6-membered monocyclic heterocyclil, the (1 or more) heteroatoms are selected from 1 to a maximum of 3 from O, N, or S, and in a preferred 5-membered monocyclic heterocyclil, the (1 or more) heteroatoms are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanil, imidazolinyl, imidazolidinyl, morpholinyl, oxylanil, oxepanil, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxynyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanil, hex Examples include, but are not limited to, sahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanil, 1,3-dithiolyl, 1,3-dithiolanil, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanil, indolinyl, isoindolinyl, tetrahydrofuranil, tetrahydropyranil, tetrahydrothiophenyl, tetrahydrothiopyranil, tetrahydro-1,4-thiadinyl, thiamorpholinil, dihydrobenzofuranil, benzimidazolidinyl, and tetrahydroquinoline.

[0105] "(heterocyclyl)alkyl" refers to a heterocyclyl group bonded as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0106] As used herein, “acyl” refers to -C(=O)R (wherein R is hydrogen, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 carbocykyl, an aryl, a 5-10 membered heteroaryl, and a 5-10 membered heterocyclyl, as defined herein). Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylic.

[0107] The "O-carboxy(O-carboxy)" group refers to the "-OC(=O)R" group (wherein R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0108] The "C-carboxy" group refers to the "-C(=O)OR" group (wherein R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocykyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein). A non-limiting example is carboxyl (i.e., -C(=O)OH).

[0109] The "cyano" group refers to the "-CN" group.

[0110] The "cyanato" group refers to the "-OCN" group.

[0111] The "isocyanato" group refers to the "-NCO" group.

[0112] The "thiocyanato" group refers to the "-SCN" group.

[0113] The "isothiocyanato" group refers to the "-NCS" group.

[0114] The "sulfinyl" group refers to the "-S(=O)R" group (wherein R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0115] The "sulfonyl" group refers to the "-SO2R" group (wherein R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0116] The "S-sulfonamido" group refers to the "-SO2NRARB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0117] The "N-sulfonamido" group is defined as the "-N(RA)SO2RB" group (wherein RA and Rb are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein).

[0118] The "O-carbamyl" group refers to the "-OC(=O)NRARB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyrill, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein).

[0119] The "N-carbamyl" group refers to the "-N(RA)OC(=O)RB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0120] The "O-thiocarbamyl" group is defined as the "-OC(=S)NRARB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyrill, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein).

[0121] The "N-thiocarbamyl" group is defined as the "-N(RA)OC(=S)RB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0122] The "C-amide" group refers to the "-C(=O)NRARB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein).

[0123] The "N-amide" group refers to the "-N(RA)C(=O)RB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl as defined herein).

[0124] The "amino" group refers to the "-NRARB" group (wherein RA and RB are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyryl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein).

[0125] The "aminoalkyl" group refers to an amino group bonded via an alkylene group.

[0126] The term "alkoxyalkyl" refers to alkoxy groups that are linked via an alkylene group, such as "C2-8 alkoxyalkyl".

[0127] As used herein, substituted groups are derived from unsubstituted parent groups in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise specified, when a group is considered "substituted", it means that the group is a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocykyl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocykyl-C1-C6-alkyl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and (and may be substituted with C1-C6 haloalkoxy), 5-10 member heterocyclyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, and may be substituted with C1-C6 haloalkoxy), 5-10 member heterocyclyl-C1-C6-alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and may be substituted with C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and (may be substituted with C1-C6 haloalkoxy), aryl(C1-C6)alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl(C1-C6)alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl and C1-C6 haloalkoxy (may be substituted), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (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-carbamyl, N-carbamyl,This means that the group is substituted with one or more substituents independently selected from O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," that group may be substituted with any of the substituents listed above.

[0128] In some embodiments, the (one or more) substituted group is substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen groups.

[0129] It should be understood that the naming conventions for certain radicals can include either monoradicals or diradicals, depending on the context. For example, a substituent is understood to be a diradical if it requires two bonding sites with the rest of the molecule. Substituents identified as alkyls that require two bonding sites include diradicals such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2-. Other radical naming conventions clearly indicate that a radical is a diradical, such as "alkylene" or "alkenylene".

[0130] In some embodiments, the compound of formula (I) described herein is administered in a composition. In some embodiments, the concentration of the compound of formula (I) in the composition is about 0.1 mM to about 10 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is about 0.2 mM to about 5 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is about 0.3 mM to about 2 mM. In some embodiments, the concentration of the compound of formula (I) in the composition is about 0.5 mM to about 1 mM.

[0131] Cyclodextrin In some embodiments, the compositions described herein, comprising a compound of formula (I), further comprise a cyclodextrin. In some embodiments, the cyclodextrin in the composition is a cyclodextrin described in International Publication No. 2022 / 093652. In some embodiments, the cyclodextrin is an alkylated cyclodextrin. As used herein, “alkylated cyclodextrin” is a cyclodextrin in which one or more hydrogen atoms on a hydroxy substituent on the cyclodextrin are replaced by an alkyl group which may be substituted by other substituents. In one embodiment, the alkylated cyclodextrin for use described herein has the structure of formula (II): [ka]

[0132] or a pharmaceutically acceptable salt thereof (wherein p is 4, 5, or 6, and R1 is independently selected in each occurrence from -OH and optionally substituted -O-C1~C8 alkyl groups, with at least one R1 being an optionally substituted alkyl group).

[0133] Optional substituents for substituting -O-C1~C8 alkyl include C1~C6 alkenyl, C1~C6 alkynyl, C1~C6 heteroalkyl, C3~C7 carbocyclyl (may be substituted with halo, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 haloalkyl, and C1~C6 haloalkoxy), C3~C7-carbocyclyl-C1~C6-alkyl (may be substituted with halo, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 haloalkyl, and C1~C6 haloalkoxy), 5~10 member heterocyclyl (halo, (may be substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heterocyclyl-C1-C6-alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (may be substituted with halo, C1-C6 alkyl, C1- C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy (may be substituted), 5-10 member heteroaryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl (C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1 ~C6) alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1~C6) alkyl (e.g., -CF3), halo(C1~C6) alkoxy (e.g., -OCF3), C1~C6 alkylthio, arylthio, amino, amino(C1~C6) alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato,Examples include sulfinyl, sulfonyl, and oxo (=O).

[0134] In some embodiments, p is 5 (i.e., the cyclodextrin is β-cyclodextrin). In some embodiments, the alkylated cyclodextrin is sulfoalkyl ether-β-cyclodextrin. For example, in some embodiments, at least one R1 is O-(C2~C6 alkylene)-SO3 - -T (wherein T is independently selected in each occurrence from pharmaceutically acceptable cations). Suitable examples of T include, among others, H+, alkali metals (e.g., Li+, Na+, K+), alkaline earth metals (e.g., Ca+2, Mg+2), ammonium ions and amine cations, such as (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines and (C4-C8)-cycloalkanolamines, as well as combinations thereof.

[0135] In some embodiments, alkylated cyclodextrin has the structure of formula (III): [ka]

[0136] (In the formula, each R is independently -H or -(CH2)4-SO3-Na) + It has -(CH2)4-SO3-Na in all cyclodextrin molecules in the composition. + The average degree of substitution is 6 to 7.1. For example, in some embodiments, the alkylated cyclodextrin may be CAPTISOL®.

[0137] In the compositions described herein, individual cyclodextrin molecules in the composition may have varying degrees of substitution with respect to a given substituent. Therefore, it is common to characterize such compositions by their average degree of substitution (ADS) with respect to a given substituent. Thus, for example, an ADS of 6–7.1 indicates that each cyclodextrin molecule in the composition has an integer degree of substitution with respect to a given substituent, but there is a distribution of such substitutions within the composition, resulting in an average of 6–7.1.

[0138] Further exemplary sulfoalkyl ether (SAE)-CD derivatives include: [Table 1]

[0139] (wherein x represents the average degree of substitution). In some embodiments, the alkylated cyclodextrin is formed as a salt.

[0140] Various embodiments of sulfoalkyl ether cyclodextrin include eicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, and heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin. Other known alkylated cyclodextrins containing a sulfoalkyl moiety include sulfoalkylthio and sulfoalkylthioalkyl ether derivatives, such as octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[(2-sulfoethyl)thio]propyl]-β-cyclodextrin], and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.

[0141] In some embodiments, the alkylated cyclodextrin composition of the present disclosure is a sulfoalkyl ether-β-cyclodextrin composition having 2-9, 4-8, 4-7.5, 4-7, 4-6.5, 4.5-8, 4.5-7.5, 4.5-7, 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7.1, 6.5-7.1, 6.2-6.9, or 6.5 ADS per alkylated cyclodextrin, the remaining substituent being -H.

[0142] In some embodiments, R of formula (II) 1 The alkyl group is either -OH or an unsubstituted -O-C1~C8 alkyl group. Such alkylated cyclodextrins are known as alkyl ether (AE)-CDs. Exemplary AE-CD derivatives include: [Table 2]

[0143] (In the formula, ME represents methyl ether, EE represents ethyl ether, PE represents propyl ether, BE represents butyl ether, PtE represents pentyl ethyl ether, HE represents hexyl ether, and y represents the average degree of substitution.)

[0144] In some embodiments, at least one R1 of formula (II) is a hydroxyl-substituted -O-C1~C6 alkyl (e.g., hydroxypropyl-β-cyclodextrin). Further exemplary hydroxyalkyl ether (HAE)-CD derivatives include: [Table 3]

[0145] (In the formula, 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.)

[0146] In some embodiments, alkylated cyclodextrins having mixed substituents (e.g., including both sulfoalkyl ether substituents and alkyl ether substituents (SAE-AE-CD)) are provided. Specific embodiments of such derivatives include: 1) the alkylene moiety of SAE having the same number of carbon atoms as the alkyl moiety of AE; 2) the alkylene moiety of SAE having a different number of carbon atoms than the alkyl moiety of AE; 3) the alkyl and alkylene moieties being independently selected from the group consisting of linear or branched moieties; 4) the alkyl and alkylene moieties being independently selected from the group consisting of saturated or unsaturated moieties; 5) the ADS of the SAE group being greater than or approximately equal to the ADS of the AE group; or 6) the ADS of the SAE group being smaller than the ADS of the AE group. Some embodiments include SAE-HAE-CD.

[0147] Alkylated cyclodextrins 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, halo-derivativeated cyclodextrin, amino-derivativeated cyclodextrin, nitrile-derivativeated cyclodextrin, aldehyde-derivativeated cyclodextrin, carboxylate-derivativeated cyclodextrin, sulfate-derivativeated cyclodextrin, sulfonate-derivativeated cyclodextrin, mercapto-derivativeated cyclodextrin, alkylamino-derivativeated cyclodextrin, or succinyl-derivativeated cyclodextrin.

[0148] In some embodiments, alkylated cyclodextrins, such as mixed ether alkylated cyclodextrins, include, for example, those listed in Table 4 below: [Table 4]

[0149] TIFF2026515818000021.tif235160

[0150] TIFF2026515818000022.tif191161

[0151] Further 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 entirety of which is incorporated herein by reference.

[0152] In a given alkylated cyclodextrin composition, the substituents of the (one or more) alkylated cyclodextrins may be the same or different. For example, the SAE moiety or HAE moiety may have the same or different types of alkylene (alkyl) radicals in each appearance in the alkylated cyclodextrin composition. In such embodiments, the alkylene radical of the SAE moiety or HAE moiety may be ethyl, propyl, butyl, pentyl, or hexyl in each appearance in the alkylated cyclodextrin composition.

[0153] Alkylated cyclodextrins can differ in the degree of substitution by functional groups, the number of carbon atoms in the functional groups, their molecular weights, the number of glucopyranose units contained in the base cyclodextrin used to form the derivatized cyclodextrin, and / or their substitution patterns. Furthermore, the derivatization of cyclodextrins by functional groups occurs in a non-precise but controlled manner. For this reason, the degree of substitution is actually a number representing the average number of functional groups per cyclodextrin (e.g., SBE7-β-CD has an average of 7 substitutions per cyclodextrin). Thus, this has an average degree of substitution ("ADS") of 7. In some embodiments, ADS can be determined by techniques including capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, or a combination thereof. Furthermore, the regiochemistry of hydroxyl group substitutions in cyclodextrins is variable with respect to the substitution of specific hydroxyl groups on the hexose ring. For this reason, different hydroxyl group substitutions can occur during the production of derivatized cyclodextrins, and certain derivatized cyclodextrins have a preferred substitution pattern, although it is neither exclusive nor specific. Considering the above, the molecular weight of a particular derivatized cyclodextrin composition may vary from batch to batch.

[0154] A single parent cyclodextrin molecule has 3v+6 hydroxyl moieties available for derivatization. When v=4 (α-cyclodextrin), the degree of substitution "y" of that moiety can range from 1 to 18. When v=5 (β-cyclodextrin), the degree of substitution "y" of that moiety can range from 1 to 21. When v=6 (γ-cyclodextrin), the degree of substitution "y" of that moiety can range from 1 to 24. In general, "y" is also in the range of 1 to 3v+g, and g is in the range of 0 to 5. In some embodiments, "y" is in the range of 1 to 2v+g, or 1 to 1v+g.

[0155] The degree of substitution ("DS") of a particular moiety (e.g., SAE, HAE, or AE) is a measure of the number of SAE (HAE, or AE) substituents attached to individual cyclodextrin molecules, in other words, the number of moles of substituents per mole of cyclodextrin. Thus, each substituent has a specific DS for each alkylated cyclodextrin species. The average degree of substitution ("ADS") of substituents is a measure of the total number of substituents present per cyclodextrin molecule for the distribution of alkylated cyclodextrins in the alkylated cyclodextrin composition of this disclosure. Thus, SAE4-CD has an ADS (per CD molecule) of 4.

[0156] Some embodiments of the present disclosure include: 1) alkylated cyclodextrin in which more than half of the hydroxyl moiety is derivatized; 2) alkylated cyclodextrin in which half or less than half of the hydroxyl moiety is derivatized; 3) alkylated cyclodextrin in which the substituents are the same in each occurrence; 4) alkylated cyclodextrin in which the substituents include at least two different substituents; or 5) alkylated cyclodextrin in which the substituents include one or more substituents selected from the group consisting of unsubstituted alkyl, substituted alkyl, halide (halo), haloalkyl, amine (amino), aminoalkyl, aldehyde, carbonylalkyl, nitrile, cyanoalkyl, sulfoalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl, unsubstituted alkylene, substituted alkylene, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0157] Alkylated cyclodextrin compositions can contain multiple alkylated cyclodextrin molecules with different degrees of substitution. For example, an alkylated cyclodextrin molecule may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more hydroxyl groups of a parent cyclodextrin functionalized with substituents, such as sulfoalkyl ethers. In such compositions, the average degree of substitution (ADS) can be calculated based on the relative amount of alkylated cyclodextrin molecules having a particular degree of substitution, as described herein. As a result, the ADS of SAE in an SAE-CD derivative composition represents the weighted average of the degrees of substitution of individual SAE-CD molecules in the composition. For example, SAE 5.2 -CD composition, multiple SAE x The formula includes a distribution of -CD molecules (wherein "x" (for the DS of the SAE group) can be an integer ranging from 1 to 12 for each individual cyclodextrin molecule), but the population of SAE-cyclodextrin molecules is such that the mean value of "x" (for the ADS of the SAE group) is 5.2.

[0158] Alkylated cyclodextrin compositions can have high, medium, or low ADS. Alkylated cyclodextrin compositions can also have a broad or narrow "span," which is the number of alkylated cyclodextrin molecules with different degrees of substitution within the alkylated cyclodextrin composition. For example, an alkylated cyclodextrin composition containing a single species of alkylated cyclodextrin 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 would be equal to the ADS of that alkylated cyclodextrin composition. For example, the electrophoresis of an alkylated cyclodextrin with a span of 1 should have only one alkylated cyclodextrin species in terms of degree of substitution. An alkylated cyclodextrin composition with a span of 2 contains two individual alkylated cyclodextrin species with different degrees of substitution, and its electrophoresis would, for example, show two different alkylated cyclodextrin species with different degrees of substitution. Similarly, the span of an alkylated cyclodextrin composition having a span of 3 includes three individual alkylated cyclodextrin species with different degrees of substitution. The span of an alkylated cyclodextrin composition is typically in the range of 5 to 15, or 7 to 12, or 8 to 11.

[0159] The parent cyclodextrin contains secondary hydroxyl groups at the C-2 and C-3 positions of the glucopyranose residue that forms the cyclodextrin, and a primary hydroxyl group at the C-6 position of the same glucopyranose residue. Each of these hydroxyl moieties is available for derivatization with substituent precursors. Depending on the synthetic methodology used, the substituent moieties can be distributed randomly or somewhat regularly among the available hydroxyl positions. The positional isomerism of the substituent derivatization can also be varied as desired. The positional isomerism of each composition is independently selected. For example, most of the substituents present can be located on either or both of the primary or secondary hydroxyl groups of the parent cyclodextrin. In some embodiments, the primary distribution of substituents is C-3>C-2>C-6, and in other embodiments, the primary distribution of substituents is C-2>C-3>C-6. Some embodiments of this disclosure include alkylated cyclodextrin molecules in which a small number of substituent moieties are located at the C-6 position, and most of the substituent moieties are located at the C-2 and / or C-3 positions. Further embodiments of the present disclosure include alkylated cyclodextrin molecules in which substituent portions are substantially uniformly distributed between the C-2, C-3, and C-6 positions.

[0160] Alkylated cyclodextrin compositions contain a distribution of multiple individual alkylated cyclodextrin species, each having an individual degree of substitution ("IDS"). The content of each cyclodextrin species in a particular composition can be quantified using capillary electrophoresis. The analytical method (e.g., capillary electrophoresis in the case of charged alkylated cyclodextrins) is sufficiently sensitive to distinguish a composition containing as little as 5% of one alkylated cyclodextrin and 95% of another alkylated cyclodextrin from a starting alkylated cyclodextrin composition containing a single alkylated cyclodextrin.

[0161] The aforementioned variations among individual species of alkylated cyclodextrins in their distribution can lead to changes in the complexation equilibrium constant K1:1, which in turn affects the required molar ratio of derivatized cyclodextrin to the activator. The equilibrium constant also varies somewhat with temperature, and a tolerance in the ratio is required to ensure that the drug remains solubilized during temperature fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant can also vary with pH, ​​and a tolerance in the ratio may be required to ensure that the drug remains solubilized during pH fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant can also change due to the presence of other excipients (e.g., buffers, preservatives, antioxidants). Therefore, to compensate for the aforementioned variability, the ratio of derivatized cyclodextrin to the activator can be varied from the ratio shown herein.

[0162] In some embodiments, the compositions described herein contain a compound of formula (I) and a cyclodextrin, such as alkylated cyclodextrin, in a predetermined molar ratio. In various embodiments, the molar ratio of cyclodextrin to the compound of formula (I) has lower limits 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 upper limits 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 approximately 20:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 18:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 15:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 12:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 10:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 8:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 5:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 4:1.In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 3:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 2:1. In some embodiments, the molar ratio of cyclodextrin to the compound of formula (I) is approximately 1:1.

[0163] Various amounts of the compound of formula (I) can be administered to one eye in a single dose. In some embodiments, human subjects are administered approximately 7.5 μg to approximately 50 μg of the compound of formula (I) in a single dose to one eye. In some embodiments, human subjects are administered approximately 5.0 μg to approximately 10 μg or approximately 7.5 μg of the compound of formula (I) in a single dose to one eye. In some embodiments, approximately 20 μg to approximately 30 μg or approximately 25 μg of the compound of formula (I) is administered to one eye in a single dose. In some embodiments, approximately 40 μg to approximately 60 μg or approximately 50 μg of the compound of formula (I) is administered to one eye in a single dose. In some embodiments, a single dose of the compound of formula (I) in an amount of approximately 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, or 100 μg is administered to one eye. In some embodiments, a single dose of less than 5 μg of the compound of formula (I) is administered to one eye. In some embodiments, a single dose of more than 100 μg of the compound of formula (I) is administered to one eye.

[0164] composition The compositions provided herein, comprising a compound of formula (I) and, in some embodiments, a cyclodextrin, may be provided as solid or liquid formulations. For example, a solid formulation suitable for reconstitution with a diluent before administration to a subject may be provided. Suitable diluents for reconstitution include, for example, sterile water or saline solution. When provided as a liquid formulation, or when reconstituting a solid formulation, the composition may be an aqueous solution or suspension.

[0165] The liquid formulations of this disclosure can be converted into solid formulations for reconstitution. The reconstituteable solid composition according to this disclosure comprises an activator (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 liquid formulation to be stored. The composition may include a mixture of solid derivatized cyclodextrin, an activator-containing solid, and optionally at least one solid pharmaceutical excipient (with minimal or no inclusion complexes), such that the majority of the activator is not complexed with the derivatized cyclodextrin before reconstitution. Alternatively, the composition may include a solid mixture of derivatized cyclodextrin and an activator, such that the majority of the activator is complexed with the derivatized cyclodextrin before reconstitution. The reconstituteable solid composition may also include a derivatized cyclodextrin and an activator, wherein substantially all or at least the majority of the activator is complexed with the derivatized cyclodextrin.

[0166] Reconstituteable solid compositions can be prepared according to any of the following processes: First, prepare a liquid formulation of the present disclosure, and then form a solid by lyophilization (freeze-drying), spray-drying, spray freeze-drying, poor solvent precipitation, sterile spray-drying, various processes utilizing supercritical or near-supercritical fluids, or other methods known to those skilled in the art for producing solids for reconstitution.

[0167] The liquid vehicles contained in the formulations of this disclosure may include aqueous liquid carriers (e.g., water), aqueous alcohols, aqueous organic solvents, non-aqueous liquid carriers, and combinations thereof.

[0168] The compositions disclosed herein may contain one or more pharmaceutical excipients, such as conventional preservatives, defoamers, antioxidants, buffers, acidifiers, alkalizers, complexing enhancers, cryoprotectants, electrolytes, glucose, emulsifiers, oils, plasticizers, solubility enhancers, stabilizers, tonicity modifiers, diluents, complexing agents, other excipients known to those skilled in the art for use in formulations, and combinations thereof.

[0169] As used herein, the term “alkalizing agent” is intended to mean a compound used to provide an alkaline medium for product stability. Examples of such compounds include, but are not limited to, ammonia solutions, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine bases, alkaline amino acids and trolamine, as well as others known to those skilled in the art.

[0170] As used herein, the term “acidifying agent” is intended to mean 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 others known to those skilled in the art.

[0171] As used herein, conventional preservatives are compounds used to at least slow the rate at which bioburden increases, but to maintain bioburden stably or reduce bioburden after contamination. Examples of such compounds include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercury nitrate, phenylmercury acetate, thimerosal, metacresol, myristylgamma-picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methylparaben, ethylparaben, propylparaben or butylparaben, as well as others known to those skilled in the art.

[0172] As used herein, the term “antioxidant” is intended to mean an agent used to inhibit oxidation and thus prevent deterioration of a preparation by an oxidation process. Examples of such compounds include, but are not limited to, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylhydroxyanisole, butylhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite, as well as others known to those skilled in the art.

[0173] As used herein, the term “buffering agent” is intended to mean a compound used to resist changes in pH during dilution or the addition of an acid or alkali. 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, monobasic sodium phosphate, dibasic sodium phosphate, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, Tris, sodium tartrate, as well as anhydrous sodium citrate and sodium citrate dihydrate, and others known to those skilled in the art.

[0174] Complexation enhancers may be added to the compositions of this disclosure. If such agents are present, the cyclodextrin / activator ratio may be varied. The complexation enhancer is one or more compounds that enhance the complexation of the activator (e.g., the compound of formula (I)) with the cyclodextrin. Suitable complexation enhancers include one or more pharmacologically inert water-soluble polymers, hydroxy acids, and other organic compounds typically used in preservative formulations to enhance the complexation of a particular agent with cyclodextrin.

[0175] Hydrophilic polymers can be used as complexing enhancers, solubility enhancers, and / or water activity reducers to improve the performance of compositions containing cyclodextrin. Suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (such as water-soluble derivatives of cellulose), and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g., sodium alginate), and agar, as well as polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose, mixed ethers thereof such as hydroxypropylmethylcellulose, as well as other mixed ethers such as hydroxyethyl-ethylcellulose and hydroxypropylethylcellulose, hydroxypropylmethylcellulose phthalate, and carboxymethylcellulose and its salts, particularly sodium carboxymethylcellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycol) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone, and polystyrene sulfonate), as well as various copolymers of acrylic acid (e.g., carbomers). Other natural, semi-synthetic, and synthetic polymers not listed herein that meet the criteria of water solubility, pharmaceutically acceptable, and pharmacological inertness are also considered to be within the scope of this disclosure. Further exemplary polymers are described, for example, in International Publication No. 2022 / 093652.

[0176] As used herein, the term “stabilizer” is intended to mean a compound used to stabilize a therapeutic agent against physical, chemical, or biochemical processes that reduce the therapeutic activity of the therapeutic agent. Suitable stabilizers include, but are not limited to, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophan, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate and sodium saccharin, and others known to those skilled in the art.

[0177] As used herein, the term “tonicity modifier” is intended to mean a compound that can be used to adjust the tonicity of a liquid formulation of the composition described herein. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and others known to those skilled in the art. In some embodiments, the tonicity of the liquid formulation approximates that of blood or plasma.

[0178] In some embodiments, the liquid formulations described herein include buffers and / or tonicity modifiers to achieve properties suitable for injection into the eye. For example, in various embodiments, the pH of such liquid composition may be in the range of 6.0–8.0, 6.0–7.5, 6.0–6.8, 6.5–7.5, or 6.8–7.2. In various embodiments, the weight osmolality of such liquid composition may be in the range of 200 mOsm–500 mOsm, 200 mOsm–400 mOsm, or 250 mOsm–350 mOsm.

[0179] As used herein, the term “antifoaming agent” is intended to mean a compound that prevents or reduces the amount of foaming that forms on the surface of a liquid formulation of a composition described herein. Suitable antifoaming agents include dimethicone, simethicone, octoxynol, and others known to those skilled in the art.

[0180] As used herein, the term “cryoprotectant” is intended to mean 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 others known to those skilled in the art.

[0181] As used herein, the terms “emulsifier” or “emulsifying agent” are intended to mean a compound added to one or more phase components of an emulsion for the purpose of stabilizing droplets of the inner phase within 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, tyroxapol, tragacanth, xanthan gum, acacia, agar, alginic acid, sodium alginate, bentonite, carbomer, sodium carboxymethylcellulose, cholesterol, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, octoxynol, oleyl alcohol, polyvinyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, and others known to those skilled in the art.

[0182] A solubility enhancer may be added to the composition of this disclosure. The solubility enhancer is one or more compounds that enhance the solubility of an activator (e.g., a compound of formula (I)) when it is in a liquid formulation. If such an agent is present, the cyclodextrin / activator ratio may be changed. Suitable solubility enhancers include one or more organic solvents, detergents, soaps, surfactants, and other organic compounds typically used in parenteral formulations to enhance the solubility of specific agents.

[0183] Suitable organic solvents include, for example, ethanol, glycerin, polyethylene glycol, propylene glycol, poloxamer, and others known to those skilled in the art.

[0184] The compositions of the present disclosure may include oils (e.g., non-volatile 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 glycers, acetylated fatty acid glycers, and combinations thereof. The compositions of the present disclosure may also include alcohols (e.g., ethanol, isopropanol, hexadecyl alcohol, glycerol, propylene glycol, etc.), glycerol 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.

[0185] In various embodiments of the compositions described herein, the compound of formula (I) may be entirely or substantially entirely in a cis configuration or a trans configuration. In various embodiments, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% of the molecules of formula (I) in the composition are in a trans configuration. In various other embodiments, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% of the molecules of formula (I) in the composition are in a cis configuration.

[0186] In some embodiments, compositions are provided in which more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 99%, or more than 99.5% of the compound of formula (I) is complexed with cyclodextrin, and the remaining amount of the compound is in a free, uncomplexed form. In some embodiments, compositions are provided in which less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% of the compound is complexed with cyclodextrin. In some embodiments, a composition is provided in which a first percentage of the compound of formula (I) is complexed with cyclodextrin, and then, when this is exposed to light, a composition is produced in which a second, lower percentage of the compound of formula (I) is complexed with cyclodextrin.

[0187] All references cited herein, including patents, patent applications, papers, textbooks, etc., and references cited within them, are incorporated herein by reference in their entirety unless they already exist.

[0188] [Examples] [Example 1] Phase 1b Clinical Trial An open-label, single-dose escalation trial was conducted in two non-randomized cohorts. A summary of the study design is shown in Figure 1 (evaluation dates are shown only for Cohort 1).

[0189] Test design. Cohort 1 included patients with no light perception (NLP) / bare light perception (BLP). Cohort 2 included patients with counting fingers (CF) / hand motion (HM) vision. The cohorts were subjected to a single intravitreal (IVT) injection of KIO-301 per eye. The primary outcome evaluation items included adverse events (AE), pharmacokinetics (PK), and test results. The secondary outcome evaluation items included object identification, intensity, and contrast evaluation, and the evaluation days were repeated for each eye in each cohort. Representative results are discussed below.

[0190] Results - Subject 1 - 01 Systemic and ocular safety evaluation. No AE was reported. By slit - lamp examination, it was revealed that the subject had abnormal baseline keratopathy. Intraocular pressure (IOP) was normal at baseline. When dilated fundus photography was performed within 6 hours and on the 29th day after injection, it showed an abnormal baseline. Electrocardiogram was normal at baseline. No clinically significant change was observed from baseline for safety parameters.

[0191] Intensity and contrast evaluation. A series of six visual stimuli were presented to the subject, and the subject was asked to indicate (both verbally and physically) when a shape or object was perceived. The results are shown in Figures 2A - 2C. Figures 2A and 2B show the % accuracy of the subject's perception of shape or object by the right eye or left eye, respectively. Figure 2C shows the light response index of the subject with respect to light intensity. As shown in the results, there was a promising increase in activity from baseline up to 48 hours. The subject responded to low - level light (3×10 14 photons / cm 2 ·s).

[0192] Dynamic visual field. The dynamic visual field was evaluated with a Goldmann Haag - Streit perimeter. The evaluation was performed by a vision therapist. The total horizontal visual field degree and the total vertical visual field degree were measured. The results are shown in Figures 3A and 3B.

[0193] Window positioning. The subjects' ability to determine direction was tested up to 30 days after injection. Subjects were asked to identify a randomized "window" at a given location eight times. The results are shown in Figure 4. An increasing trend in % accuracy was observed, and the effect appeared to decrease over time. The results were consistent with the subjects' reported outcomes.

[0194] Functional MRI – Qualitative overlap of three visual paradigms. Functional MRI was performed on subjects at baseline and on days 2, 14, and 28. Results are shown in Figure 5. Increased striated (V1) and non-striated (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 functional measurements of vision.

[0195] Functional MRI - Quantitative Increase: Checkerboard. Functional MRI was performed on subjects stimulated with a checkerboard. The results are shown in Figure 6. The blue area indicates an increase at p<0.05.

[0196] Quality of Life Survey - VFQ-25. Participants completed the National Ophthalmological Society's 25-item Visual Function Questionnaire 25 (VFQ-25) at baseline and 29 days post-injection. An increase of 2-4 points is generally considered clinically significant. The results are shown in Figure 7. The overall increase was caused by increases in the subscales of vision-specific questions (mental health and role-related difficulties) and eye pain.

[0197] Results - Subject 1-02. Subject 1-02 is in their 40s, has an unknown genetic mutation, and has had NLP for more than 10 years.

[0198] Systemic and ocular safety assessments were conducted. No adverse events (AEs) were reported. Slit-lamp examination results showed no change from baseline. Intraocular pressure (IOP) was normal at baseline and did not change from baseline. Dilated fundus photography was abnormal at baseline and did not change from baseline. Spectral-domain optical coherence tomography (SD-OCT) showed no macular edema and no thinning.

[0199] Intensity and contrast evaluation. As described above, a series of six visual stimuli were presented to the target at various light levels. The results are shown in Figures 8A-8C, which demonstrate an increase in light perception over the first two weeks after injection. High levels of light (5 × 10⁻¹⁰) 15 photon / cm 2 • (less than cloudy) was perceived.

[0200] Dynamic visual field. The dynamic visual field was tested as described above. The results are shown in Figures 9A and 9B. During right eye movement, a blue level 2 was observed in the far peripheral area.

[0201] Functional MRI – Qualitative overlap of three visual paradigms. Functional MRI was performed as described above. The results are shown in Figure 10. Compared to baseline, a clear increase in striate (V1) activity was observed on days 2 and 14. By day 28, activity returned to similar levels to baseline. The more unilateral increase in V1 activity was consistent with other functional measures of vision.

[0202] Subject Feedback: The subject perceived more light in both eyes and was confident that they saw small flashes of light periodically. While not yet 100% clear in light / dark perception, the subject reported greater confidence in their own light / dark orientation and was able to see a lit phone screen in the dark. 48 hours post-injection during functional MRI, the subject reported consistently seeing flashes of light in their right eye upon stimulus presentation. Observations from Subject 1-02 are consistent with the dynamics of Subject 1-01, and confirmatory functional MRI data are consistent with a stronger unilateral response.

Claims

1. A method for treating human subjects suffering from retinal disorders, comprising a compound of formula (I): 【Chemistry 1】 A method comprising the step of administering a composition comprising either or a pharmaceutically acceptable salt thereof (the azo bond in the structure may be cis or trans) to the eye of the subject via intravitreal injection.

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

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

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

5. The method according to claim 1, wherein the retinal disorder is colloideremia.

6. The method according to any one of claims 1 to 5, wherein the compound of formula (I) is 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 administration to one eye of the subject brings a therapeutic effect to both eyes of the subject.

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

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

11. The method according to any one of claims 7 to 9, wherein the administration to one eye is a first administration, and the method further comprises a second administration, the second administration comprising administering the compound of formula (I) to the eye opposite to the subject about three to five weeks after the first administration.

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

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

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

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

16. The method according to any one of claims 1 to 15, wherein the treatment in a human subject comprises stimulating striatal (V1) and non-striatal (V2 and / or V3) cortical activity in the subject as measured by functional MRI.

17. The method according to any one of claims 1 to 16, wherein the treatment for a human subject includes increasing the tolerance of glare and photosensitivity in the subject.

18. The method according to any one of claims 1 to 17, wherein the treatment in a human subject includes increasing a measure of functional vision.

19. The method according to any one of claims 1 to 18, wherein the treatment in a human subject reduces random electrical activity of nonspecific non-stimulation generation in the retina.

20. The method according to any one of claims 1 to 19, wherein the composition further comprises cyclodextrin.

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

1.

22. The method according to claim 20 or 21, wherein the molar ratio of cyclodextrin in the composition to the compound of formula I is 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 in the composition to the compound of formula I 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 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 about 0.2 mM to about 5 mM.

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

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

28. A method for treating human subjects suffering from retinal disorders, A first administration of the subject to one eye via intravitreal injection of a composition containing the compound of formula (I); and a second administration of the subject to the other eye via intravitreal injection of a composition containing the compound of formula (I); or A first administration of the subject to one eye via intravitreal injection of a composition containing the compound of formula (I); and a second administration of the subject to the same eye via intravitreal injection of a composition containing the compound of formula (I). Includes, The compound of formula (I) has the following structure: 【Chemistry 2】 A method comprising 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 opposite eye is simultaneous with, substantially simultaneously with, or immediately after the first administration.

30. The method according to claim 28, wherein the second administration to the opposite eye occurs approximately three weeks to five weeks after the first administration.

31. The method according to claim 28, wherein the second administration to the same eye occurs approximately three weeks to five weeks after the first administration.

32. A method for increasing tolerance to glare and photosensitivity in human subjects suffering from retinal disorders, A first administration of the subject to one eye via intravitreal injection of a composition containing the compound of formula (I); and a second administration of the subject to the other eye via intravitreal injection of a composition containing the compound of formula (I); or A first administration of the subject to one eye via intravitreal injection of a composition containing the compound of formula (I); and a second administration of the subject to the same eye via intravitreal injection of a composition containing the compound of formula (I). Includes, The compound of formula (I) has the following structure: 【Transformation 3】 A method comprising a pharmaceutically acceptable salt thereof, wherein the azo bond in the structure may be cis or trans.

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