Compositions and methods of use of cannabinol compounds in neuroprotection

Abstract

This document provides methods and compositions for neuroprotection. The neuroprotective composition may be or includes 4-chlorobutylcannabinol (4-chlorobutyl-CBN) or a derivative thereof and / or a pharmaceutically acceptable salt thereof. The neuroprotective composition may be used to treat neurodegenerative diseases. The neuroprotective composition may be used to protect retinal neurons in subjects in need from degeneration, such as for the treatment of age-related macular degeneration.

Description

Background Technology

[0001] Neurodegeneration is a potential symptom of a variety of diseases affecting the central and peripheral nervous systems. Neurodegeneration includes the induction of neuronal atrophy, axonal degeneration (e.g., Wallerian and / or Wallerian-like degeneration), and necrotizing or programmed cell death mechanisms. Different types of programmed cell death, such as apoptosis, autophagy, pyroptosis, and dysapoptosis, have been demonstrated in neurons. Mechanisms by which stimuli such as physical injury, oxidative stress, excitotoxicity, mitochondrial dysfunction, inflammation, iron accumulation, and protein aggregation contribute to neurodegeneration have been shown.

[0002] Neurodegenerative eye diseases include age-related macular degeneration (AMD). AMD affects approximately 14%–24% of people aged 65 to 74 and approximately 35% of people over 75 worldwide, causing impaired or lost vision in the central visual field (macula) due to damage to the retina and / or related neurons. AMD is a cause of vision loss and potential blindness in people over 50. The two main forms of AMD are atrophic (non-exudative or “dry”) AMD and neovascular (exudative or “wet”) AMD. Atrophic AMD is characterized by geographic atrophy (GA) in the central macula during the later stages of AMD, and vision can slowly deteriorate over many years due to the loss of photoreceptors and the development of GA. Neovascular AMD is a more severe form of AMD and is characterized by neovascularization (e.g., choroidal neovascularization) during the later stages of AMD, which can rapidly lead to blindness. Neovascular AMD affects more than 30 million patients worldwide and is a leading cause of vision loss in people aged 60 or older. If AMD remains untreated, patients may lose central vision in the affected eye within 24 months of disease onset. Approximately 90% of AMD patients have the dry form, and about 10% develop neovascular AMD.

[0003] Neuroprotection is the ability to salvage or restore the nervous system, its cells, structures, and / or functions, or to provide resistance to neurodegenerative stimuli. Neuroprotective compositions can be used to treat various diseases that cause or lead to neurodegeneration, such as age-related macular degeneration, or to alleviate the symptoms of these diseases. Despite significant advances in understanding the underlying mechanisms of neurodegeneration, there remains a need for methods and compositions for neuroprotection.

[0004] Cannabinoids, their salts, and derivatives possess several properties with therapeutic potential. Activation or blockade of CB1 and / or CB2 receptors with cannabinoids can modulate downstream signaling and metabolic pathways, subsequently affecting synaptic transmission, including the transmission of pain and other sensory signals, immune responses, and inflammation in the periphery. Therefore, there is considerable interest in using natural or non-natural cannabinoids for therapeutic purposes. Summary of the Invention

[0005] This document describes compounds, pharmaceutical compositions, and methods of using thereof. In one or more embodiments, these compounds and pharmaceutical compositions are neuroprotective. A compound or a pharmaceutical composition containing a compound (e.g., a compound of formula I) can contact neurons to provide neuroprotection. In one or more embodiments, this contact is made by administering the compound (e.g., a compound of formula I) or a pharmaceutical composition containing such a compound (e.g., a compound of formula I) to a subject in need. The compound (e.g., a compound of formula I), the pharmaceutical composition containing such a compound (e.g., a compound of formula I), and the associated methods can be used to provide neuroprotection and, in some embodiments, can be used to treat various ocular neurodegenerative diseases. In one or more embodiments, a compound (e.g., a compound of formula I) and a pharmaceutical composition containing such a compound (e.g., a compound of formula I) are provided for inducing neuroprotection in, for example, retinal neurons. For example, a compound (e.g., a compound of formula I) or a pharmaceutical composition comprising such a compound (e.g., a compound of formula I) may be administered topically or systemically to a subject to induce neuroprotective effects in retinal neurons, for example, to treat ocular neurodegenerative diseases such as AMD (including, for example, atrophic (non-exudative or "dry") AMD and neovascular (exudative or "wet") AMD). In some embodiments, the compound or pharmaceutical composition prevents or treats neurodegeneration in neurons, including neurodegeneration caused by or resulting from: neuronal atrophy, axonal degeneration (e.g., Wallerian and / or Wallerian-like degeneration) and / or induction of necrotic or programmed cell death mechanisms (including, for example, programmed cell death in neurons, such as apoptosis, autophagy, pyroptosis, and edema); and / or prevents or treats neurodegeneration caused by physical damage, oxidative stress, excitotoxicity, mitochondrial dysfunction, inflammation (including neuroinflammation), iron accumulation, and / or protein aggregation. Cannabinoids (including compounds of formula I) are involved in the transmission of pain and other sensory signals, immune responses, and inflammation in the periphery. The compounds of the first or second aspect (and any embodiments thereof) or the pharmaceutical compositions of the third aspect (and any embodiments thereof) may be used to prevent or treat the conditions described in this paragraph.

[0006] In a first aspect, a compound of formula I is provided: I (named 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol or 4-chlorobutyl-cannabinol or 4-chlorobutyl-CBN), or derivatives thereof; and / or pharmaceutically acceptable salts thereof. In one or more embodiments, a compound of formula I is provided as a derivative thereof. In one or more embodiments, a derivative of a compound of formula I is a prodrug of formula I.

[0007] In a second aspect, a compound of formula I is provided: I, Or a pharmaceutically acceptable salt thereof. In one or more embodiments, the compound of formula I is not provided as a pharmaceutically acceptable salt.

[0008] In a third aspect, a pharmaceutical composition is provided comprising a compound of formula I: I, Or its derivatives; and / or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. In one or more embodiments, a pharmaceutical composition is provided comprising a compound according to the following formula I: ; I, And pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a derivative thereof; and / or a pharmaceutically acceptable salt thereof; and the pharmaceutically acceptable excipient comprises ethanol. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a derivative thereof; and / or a pharmaceutically acceptable salt thereof; and the pharmaceutically acceptable excipient does not contain ethanol. In some embodiments, the pharmaceutically acceptable excipient consists only of ethanol. In some embodiments, the pharmaceutically acceptable excipient consists of more than one component of ethanol.

[0009] In a fourth aspect, a method is provided to protect neurons from neurodegeneration or to treat neurodegeneration in neurons, the method comprising contacting the neurons with a compound of the first or second aspect (and any embodiment thereof) or a pharmaceutical composition of the third aspect (and any embodiment thereof) in an amount (or concentration) sufficient to inhibit neurodegeneration in a subject in need. In one or more embodiments, the contact is in vitro. In one or more embodiments, the contact is in vivo. In one or more embodiments, the contact comprises administering the compound or pharmaceutical composition to a subject in need. In one or more embodiments, the neurons are retinal neurons (e.g., retinal ganglia). In one or more embodiments, the contact comprises administering a compound of the first or second aspect (and any embodiment thereof) or a pharmaceutical composition of the third aspect (and any embodiment thereof), for example as an intravitreal (IVT) injection. Intravitreal injection may target the posterior part of the eye, such as... Figure 1As shown (arrow). In one or more embodiments, the compound of Formula I is not provided as a pharmaceutically acceptable salt. In one or more embodiments, the compound of Formula I is 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (i.e., not a derivative thereof or a pharmaceutically acceptable salt). In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma, nor to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject with glaucoma. In some or any embodiments, the method is not used to lower intraocular pressure in a subject with glaucoma.

[0010] In a fifth aspect, a method is provided to protect a subject from neurodegeneration or to treat neurodegeneration in a subject, the method comprising administering to a subject in need a compound of the first or second aspect (and any embodiment thereof) or a pharmaceutical composition of the third aspect (and any embodiment thereof). In one or more embodiments, the pharmaceutical composition is adapted to achieve a neuroprotective dose of 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug). In one or more embodiments, the compound of the first or second aspect (and any embodiment thereof) or the pharmaceutical composition of the third aspect (and any embodiment thereof) is formulated for application to the eye and for protecting neurons from neurodegeneration or treating neurodegeneration in neurons. In one or more embodiments, the compound of the first or second aspect (and any embodiment thereof) or the pharmaceutical composition of the third aspect (and any embodiment thereof) is formulated to achieve a concentration of about 0.15 µM to less than about 20 µM of 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neuronal cells. In one or more embodiments, the ocular neurons are retinal neurons or other neuronal cells (e.g., including but not limited to retinal ganglia and photoreceptors). In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma, nor to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject with glaucoma. In some or any embodiments, the method is not used to lower intraocular pressure in a subject with glaucoma.

[0011] In a sixth aspect, the use of the compounds of the first or second aspect (and any embodiments thereof) or the pharmaceutical composition of the third aspect (and any embodiments thereof) for treating neurodegeneration in a subject in need is provided, preferably using the pharmaceutical composition described herein or the method described herein according to one or more of the foregoing aspects (in the fourth and fifth aspects) and any embodiments thereof. In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma nor to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject suffering from glaucoma. In some or any embodiments, the method is not used to lower intraocular pressure in a subject suffering from glaucoma.

[0012] In a seventh aspect, a method for treating age-related macular degeneration is provided, the method comprising administering to a subject in need a compound of the first or second aspect (and any embodiment thereof) or a pharmaceutical composition of the third aspect (and any embodiment thereof).

[0013] In an eighth aspect, a method is provided to improve the integrity of the retinal pigment epithelium (RPE) and reduce autofluorescent deposits (a hallmark of dry AMD) in subjects with AMD, the method comprising administering to a subject in need a compound of the first or second aspect (and any embodiment thereof) or a pharmaceutical composition of the third aspect (and any embodiment thereof). In one or more embodiments, a method is provided in which an amount is administered, and such amount is sufficient to improve the integrity of the retinal pigment epithelium.

[0014] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), contact and / or application comprises local application to a subject in need. For example, application to a subject suffering from a neurodegenerative disease (e.g., neurodegenerative disease of the eye). In one or more embodiments, contact and / or application comprises application to a subject suffering from a neurodegenerative disease (e.g., neurodegenerative disease of the eye). In one or more embodiments, contact and / or application comprises application to a subject suffering from AMD. In one or more embodiments, contact and / or application comprises application to a subject diagnosed with AMD. In one or more embodiments, the method comprises simultaneously or sequentially contacting and / or applying to the subject in need an additional active agent for treating AMD. In some or any embodiments, the subject suffers from glaucoma. In some or any embodiments, the subject does not suffer from glaucoma.

[0015] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), the amount is an amount (or concentration) sufficient to reduce the amount or rate of apoptosis in a population of neurons in contact with the compound or pharmaceutical composition. In one or more embodiments, the amount (or concentration) sufficient to inhibit neurodegeneration is an amount (or concentration) sufficient to reduce the progression of age-related macular degeneration or associated vision loss. In one or more embodiments, the compound of formula I is not provided as a pharmaceutically acceptable salt. In one or more embodiments, the compound of formula I is 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (i.e., not a derivative thereof or a pharmaceutically acceptable salt). In one or more embodiments, the amount (or concentration) sufficient to inhibit neurodegeneration is sufficient to protect retinal neurons, protect retinal tissue, protect photoreceptor cells, prevent or reduce the accumulation of autofluorescent extracellular debris, and prevent or treat neuroinflammation. In one or more embodiments, the amount (or concentration) sufficient to inhibit neurodegeneration is sufficient to prevent or treat neuroinflammation. In some or any of the embodiments, the subject has glaucoma. In some or any implementation scheme, the subjects did not have glaucoma.

[0016] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), the amount (or concentration) sufficient to inhibit neurodegeneration or sufficient to improve the integrity of the retinal pigment epithelium is about 0.15 µM to less than about 20 µM of 4-chlorobutyl-CBN (or a pharmaceutically acceptable salt or derivative thereof, e.g., a prodrug); in some embodiments, the amount is an amount of 4-chlorobutyl-CBN that is neither a salt nor a prodrug. In one or more embodiments, the amount (or concentration) sufficient to inhibit neurodegeneration or sufficient to improve the integrity of the retinal pigment epithelium is an amount that results in a concentration of 4-chlorobutyl-CBN selected from about 0.3 µM to less than or equal to about 15 µM in the vitreous fluid, in the ocular tissues of the eye, and / or in contact with ocular neurons. In one or more embodiments, an amount (or concentration) sufficient to inhibit neurodegeneration or sufficient to improve the integrity of the retinal pigment epithelium is an amount that results in a concentration of 4-chlorobutyl-CBN greater than or equal to about 0.5 µM and less than or equal to about 15 µM in the vitreous fluid, ocular tissues of the eye, and / or in contact with ocular neurons, such as concentrations selected from about 1 µM to about 15 µM, about 2 µM to about 15 µM, about 3 µM to about 15 µM, about 2 µM to about 12 µM, about 3 µM to less than about 12 µM, about 3 µM to less than about 11 µM, about 3 µM to about 10 µM, or 3 µM to 10 µM. In one or more embodiments, the compound of formula I is not provided as a pharmaceutically acceptable salt. In one or more embodiments, the compound of formula I is 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (i.e., not a derivative thereof or a pharmaceutically acceptable salt). In one or more embodiments, the amount is based on a compound excluding any pharmaceutically acceptable salts. In some or any embodiments, the subject has glaucoma. In some or any embodiments, the subject does not have glaucoma.

[0017] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), an amount (or concentration) sufficient to inhibit neurodegeneration or sufficient to improve the integrity of the retinal pigment epithelium is an amount that results in a concentration of 4-chlorobutyl-CBN, its pharmaceutically acceptable salt, or a derivative thereof (e.g., a prodrug) selected from about 0.15 µM to less than about 20 µM (such as selected from about 0.5 µM to less than about 15 µM, selected from greater than about 2 µM to less than about 12 µM, 2 µM to 12 µM, selected from about 3 µM to less than about 12 µM, selected from about 3 µM to less than about 11 µM, selected from about 3 µM to about 10 µM, or selected from 3 µM to 10 µM). In one or more embodiments, the subject has AMD. In some or any embodiments, the subject has glaucoma. In some or any embodiments, the subject does not have glaucoma.

[0018] In one or more embodiments, the amount (or concentration) sufficient to inhibit neurodegeneration or sufficient to improve the integrity of the retinal pigment epithelium is an amount that produces a concentration range, the lower limit of which is selected from any one of 0.15, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, and 9 µM, and the upper limit of which is selected from any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 µM, wherein the lower and upper limits form a mathematically permissible range, and the concentration is the concentration of 4-chlorobutyl-CBN, its pharmaceutically acceptable salt, or a derivative thereof (e.g., a prodrug) in vitreous fluid, ocular tissues of the eye, and / or in contact with ocular neuronal cells. In one or more embodiments, the subject has AMD. In some or any of the embodiments, the subject has glaucoma. In some or any of the embodiments, the subject does not have glaucoma.

[0019] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), the final concentration (in vivo) of the compound of Formula I in the pharmaceutical composition is about 1 / 10 (one-tenth) of the initial concentration of the compound of Formula I. In one or more embodiments, the final concentration (in vivo) of the compound of Formula I in the pharmaceutical composition is 1 / 10 of the initial concentration of the compound of Formula I. In one or more embodiments, the initial concentration is the concentration of 4-chlorobutyl-CBN (or a pharmaceutically acceptable salt thereof, or a derivative thereof) in the pharmaceutical composition. In one or more embodiments, wherein when the pharmaceutical composition is an intravitreal injection, the initial concentration is the concentration of 4-chlorobutyl-CBN (or a pharmaceutically acceptable salt thereof, or a derivative thereof) in the intravitreal injection. In one or more embodiments, the final concentration is the concentration of 4-chlorobutyl-CBN (or a pharmaceutically acceptable salt thereof, or a derivative thereof) in the vitreous fluid, in the ocular tissues of the eye, and / or in contact with ocular neuronal cells. In one or more embodiments, the final concentration is the concentration of 4-chlorobutyl-CBN (or a pharmaceutically acceptable salt thereof, or a derivative thereof) in vitreous fluid. In one or more embodiments, the compound of Formula I is not provided as a pharmaceutically acceptable salt. In one or more embodiments, the compound of Formula I is 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (i.e., not a derivative thereof or a pharmaceutically acceptable salt). In one or more embodiments, the concentration is based on a compound excluding any pharmaceutically acceptable salt.

[0020] In one or more embodiments, 4-chlorobutyl-CBN is provided in the form of a sustained-release formulation. In one or more embodiments, the formulation comprises: a) a delivery carrier comprising a cellulose polymer and an anionic polysaccharide; and b) nanoparticles comprising an amphiphilic non-ionizable block copolymer and 4-chlorobutyl-CBN, wherein the formulation has a gelation point of about 30°C to about 37°C.

[0021] In one or more embodiments of any of the fourth, fifth, sixth, seventh, and eighth aspects (and any embodiments thereof), contact and / or application includes systemic administration. In one or more embodiments, systemic administration includes intravenous injection. In one or more embodiments, systemic administration includes oral administration. In one or more embodiments, systemic administration includes transdermal administration. In one or more embodiments, systemic administration includes intravitreal injection. In one or more embodiments, the compound of formula I is not provided as a pharmaceutically acceptable salt. In one or more embodiments, the compound of formula I is 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (i.e., not a derivative thereof or a pharmaceutically acceptable salt). In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma, nor to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject suffering from glaucoma. In some or any implementation, this method is not used to lower intraocular pressure in subjects with glaucoma.

[0022] In one or more embodiments of any of aspects four, five, six, seven, and eight (and any embodiments thereof), contact and / or application includes topical application. In one or more embodiments, contact and / or application is directed directly at the eye. For example, contact and / or application is on the eye (e.g., as eye drops, such as in the form of microemulsion eye drops or ophthalmic gel). As another example, contact and / or application is administered directly into the eye or the posterior part of the eye (e.g., via intravitreal injection or pump). In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma, nor is it used to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject with glaucoma. In some or any embodiments, the method is not used to lower intraocular pressure in a subject with glaucoma.

[0023] Incorporate by reference All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. Attached Figure Description

[0024] Figure 1 A partial sectional view of an eye according to one or more embodiments of the present invention is shown, indicating the various parts of the eye and illustrating the site where an intravitreal injection is performed to treat age-related macular degeneration.

[0025] Figure 2A The results of a flash electroretinography (fERG) test are presented, showing the response of photoreceptors in the eye to a light stimulus of intensity (luminance) of 0.01 cd*s / m^2. The alpha wave amplitude (µV) represents the photoreceptor response, and luminance (cd*s / m^2) represents the intensity of the flash. Control: Healthy animals without light damage (LD) and untreated. Medium: Light damage treated with sterile dilution buffer.

[0026] Figure 2B The results of a flash electroretinography (fERG) test are shown, illustrating the response of photoreceptors in the eye to a light stimulus of intensity (luminance) of 0.01 cd*s / m^2. The % α-wave amplitude is shown relative to healthy animals (CTRL or control = 100%). Control: Healthy animals without light damage and untreated. Medium: Light damage treated with dilution buffer.

[0027] Figure 3A Results of flash electroretinography (fERG) are presented, showing the response of photoreceptors in the eye to light stimuli of increased intensity. A-wave amplitude (µV) represents the photoreceptor response, and luminance (cd*s / m^2) represents the intensity of the flash. For eyes injected with 4-chlorobutyl-CBN, an increase in a-wave amplitude was observed for the corresponding light stimulus (measured in luminance) compared to the medium. For eyes injected with CBN, no overall improvement in a-wave amplitude was observed compared to the medium. Control: Healthy animals without photodamage and untreated. Medium: Photodamage treated with dilution buffer.

[0028] Figure 3B It shows an intensity of 0.01 cd*s / m^2 (from... Figure 3A The a-wave amplitude is plotted to better represent the increase in a-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show a-wave amplitude in µV (left) and % a-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0029] Figure 3C It shows an intensity of 0.1 cd*s / m^2 (from... Figure 3AThe a-wave amplitude is plotted to better represent the increase in a-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show a-wave amplitude in µV (left) and % a-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0030] Figure 3D It shows an intensity of 1 cd*s / m^2 (from Figure 3A The a-wave amplitude is plotted to better represent the increase in a-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show a-wave amplitude in µV (left) and % a-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0031] Figure 3E It shows an intensity of 10 cd*s / m^2 (from Figure 3A The a-wave amplitude is plotted to better represent the increase in a-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show a-wave amplitude in µV (left) and % a-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0032] Figure 3F It shows an intensity of 100 cd*s / m^2 (from Figure 3A The a-wave amplitude is plotted to better represent the increase in a-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show a-wave amplitude in µV (left) and % a-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0033] Figure 4A Results of flash electroretinography (fERG) are presented, showing the response of the inner retina in the eye to light stimuli of increased intensity. b-wave amplitude (µV) represents the inner retinal response, and luminance (cd*s / m^2) represents the intensity of the flash. For eyes injected with 4-chlorobutyl-CBN, an increase in b-wave amplitude was observed for the corresponding light stimulus (measured in luminance) compared to the medium. For eyes injected with CBN, no overall improvement in b-wave amplitude was observed compared to the medium. Control: Healthy animals without light damage and untreated. Medium: Light-damaged animals treated with dilution buffer.

[0034] Figure 4B It shows an intensity of 0.1 cd*s / m^2 (from... Figure 4A The b-wave amplitude is plotted to better represent the increase in b-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show b-wave amplitude in µV (left) and % b-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0035] Figure 4C It shows an intensity of 1 cd*s / m^2 (from Figure 4A The b-wave amplitude is plotted to better represent the increase in b-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show b-wave amplitude in µV (left) and % b-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0036] Figure 4D It shows an intensity of 10 cd*s / m^2 (from Figure 4A The b-wave amplitude is plotted to better represent the increase in b-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show b-wave amplitude in µV (left) and % b-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0037] Figure 4E It shows an intensity of 100 cd*s / m^2 (from Figure 4A The b-wave amplitude is plotted to better represent the increase in b-wave amplitude that occurs during treatment with 4-chlorobutyl-CBN. Histograms show b-wave amplitude in µV (left) and % b-wave amplitude normalized relative to healthy animals (right) (CTRL or control = 100%). Controls: Healthy animals without photodamage and untreated. Media: Photodamage treated with dilution buffer.

[0038] Figure 5Results of flash electroretinography (fERG) are presented, showing the response of the inner retinal circuitry in the eye to light stimuli of increased intensity levels (primarily due to rod bipolar cells and A11 / A17 amacrine cells). Oscillatory potential (OP) amplitude (µV) represents the inner retinal response, and luminance (cd*s / m^2) represents the intensity of the flash. For eyes injected with 4-chlorobutyl-CBN, an increase in OP amplitude was observed for the corresponding light stimulus (measured in luminance) compared to the medium. For eyes injected with CBN (30 µM), an increase in OP amplitude was observed at 100 cd*s / m^2 (dark-vision stimulus) compared to the medium, while no overall improvement in OP amplitude was observed for other light stimuli compared to the medium. For eyes injected with CBN (100 µM), no overall improvement in OP amplitude was observed for any applied light stimulus compared to the medium. Controls: Healthy animals without light damage and untreated. Medium: Light-damaged animals treated with dilution buffer.

[0039] Figure 6A In vivo imaging of the inner retinal layer structure in a rat model of photodamage is presented. The imaging shows the outer nuclear layer (ONL), inner nuclear layer (INL), and ganglion cell layer (GCL) in cells treated with 4-chlorobutyl-CBN (3 µM). Controls: healthy animals without photodamage and untreated. Medium: photodamage treated with dilution buffer.

[0040] Figure 6B In vivo imaging with reverse (negative) exposure of the inner retinal layer structure is presented. This imaging shows the outer nuclear layer, inner nuclear layer, and ganglion cell layer in cells treated with 4-chlorobutyl-CBN (3 µM). Control: Healthy animals without photodamage and untreated. Medium: Photodamage and treatment with dilution buffer.

[0041] Figure 7A The a-wave amplitude in response to different dose levels of 0.3 µM, 1 µM, 3 µM, and 10 µM (intraocular) of 4-Cl-butyl-CBN is shown. An overall increase in a-wave response was observed in eyes treated with 3 µM and 10 µM of 4-Cl-butyl-CBN compared to the mediator. Control: Healthy animals without photodamage and untreated. Mediator: Photodamage treated with dilution buffer.

[0042] Figure 7BThe b-wave amplitude in response to different dose levels of 0.3 µM, 1 µM, 3 µM, and 10 µM (intraocular) of 4-Cl-butyl-CBN is shown. An overall increase in b-wave response was observed in eyes treated with 3 µM and 10 µM of 4-Cl-butyl-CBN compared to the mediator. Control: Healthy animals without photodamage and untreated. Mediator: Photodamage treated with dilution buffer.

[0043] Figure 7C The oscillating potential (OP) amplitudes in response to different dose levels of 0.3 µM, 1 µM, 3 µM, and 10 µM (intraocular) of 4-Cl-butyl-CBN are shown. An overall increase in OP response was observed in eyes treated with 3 µM and 10 µM of 4-Cl-butyl-CBN compared to the mediator. Control: Healthy animals without photodamage and untreated. Mediator: Photodamage treated with dilution buffer.

[0044] Figure 8A Histological imaging of the retina to measure outer nuclear layer (ONL) thickness is shown. Scale bar: 200 µm.

[0045] Figure 8B The ONL:retinal thickness ratio is shown at various locations along the superior and inferior retina. Data are presented as mean + / - SE. Statistical analysis is performed between the medium and 4-Cl-butyl-CBN (3 µM). t Tests (n=7 / group). *p<0.05; ***p<0.001, relative to the medium. An increase in ONL: retinal thickness was observed for 4-Cl-butyl-CBN compared to the medium.

[0046] Figure 8C A schematic diagram of a frozen section of the retina is shown, illustrating the retinal folds along the superior and inferior retina. Figure 8B The location of the retina is shown in the image. ON = optic nerve.

[0047] Figure 9A Histological imaging of autofluorescence (AF) extracellular deposits was presented. A reduction in extracellular deposits was observed for 4-Cl-butyl-CBN compared to the mediator.

[0048] Figure 9B The amount of AF deposits is shown. A statistically significant reduction in extracellular deposits was observed with 4-Cl-butyl-CBN compared to the mediator. Data are shown as mean + / - SE. Statistical analysis was performed between the mediator and 4-Cl-butyl-CBN (3 µM). t Test (n=7 / group). **p<0.01, relative to the medium.

[0049] Figure 10A Histological imaging of retinal pigment epithelium (RPE) with anti-RPE65 was presented. Improved RPE integrity was observed with 4-Cl-butyl-CBN compared to the mediator.

[0050] Figure 10B The normalized RPE length relative to the control is shown. A statistically significant increase in RPE length was observed between 4-Cl-butyl-CBN and the control. Data are shown as mean + / - SE. Statistical analysis was performed between the mediator and 4-Cl-butyl-CBN (3 µM). t Tests (n=7 / group). ***p<0.001, relative to the medium. These data indicate that 4-Cl-butyl-CBN improves the RPE length in the AMD model.

[0051] Figure 11A Immunostaining of retinal cross-sections of IBA-1 is shown. Scale bar: 50 µm. A reduction in retinal inflammation was observed with 4-Cl-butyl-CBN compared to the mediator.

[0052] Figure 11B The number of IBA-1(+) cell counters in the outer retina (subretinal, outer nuclear layer, outer plexiform layer) from the upper to the lower edge of the retina is shown. A reduction in retinal inflammation was observed with 4-Cl-butyl-CBN compared to the mediator. Data are shown as mean + / - SE. Statistical analysis was performed using the student's law between the mediator and 4-Cl-butyl-CBN (3 µM). t Test (n=7 / group). *p<0.05; **p<0.01, relative to the medium.

[0053] Figure 11C The number of IBA-1(+) cells in the upper retina is shown. A statistically significant reduction in inflammation in the upper retina was observed with 4-Cl-butyl-CBN compared to the mediator. Data are shown as mean + / - SE. Statistical analysis was performed using the student's law between the mediator and 4-Cl-butyl-CBN (3 µM). t Test (n=7 / group). *p<0.05; **p<0.01, relative to the medium.

[0054] Figure 11D The number of IBA-1(+) cells in the inferior retina is shown. A statistically significant reduction in inflammation in the inferior retina was observed with 4-Cl-butyl-CBN compared to the mediator. Data are shown as mean + / - SE. Statistical analysis was performed using the student's law between the mediator and 4-Cl-butyl-CBN (3 µM). tTest (n=7 / group). *p<0.05; **p<0.01, relative to the medium.

[0055] Figure 11E The number of IBA-1(+) cells in the upper and lower retina is shown. A statistically significant reduction in retinal inflammation was observed with 4-Cl-butyl-CBN compared to the mediator. Data are shown as mean + / - SE. Statistical analysis was performed using the student's law between the mediator and 4-Cl-butyl-CBN (3 µM). t Test (n=7 / group). *p<0.05; **p<0.01, relative to the medium.

[0056] Figure 12 The concentrations of 4-Cl-butyl-CBN applied topically in rabbits or administered via IVT in rats are shown. Increased concentrations in the retina / RPE / choroid were observed in rats after IVT administration compared to topical application in rabbits. Detailed Implementation

[0057] This document describes compounds (e.g., compounds of Formula I) and pharmaceutical compositions thereof, as well as methods for using such compounds (e.g., compounds of Formula I) and pharmaceutical compositions to protect neurons from one or more cytotoxic stimuli. In one or more embodiments, the method includes contacting neurons with a compound (e.g., a compound of Formula I) or a pharmaceutical composition thereof, such as by administering the compound or pharmaceutical composition to a subject in need. The methods, compounds (e.g., compounds of Formula I) and pharmaceutical compositions thereof described herein are particularly suitable for (but not limited to) protecting retinal neurons. In some cases, the methods, compounds (e.g., compounds of Formula I) and pharmaceutical compositions thereof described herein can be used for neuroprotection of retinal neurons in a subject (e.g., a subject with age-related macular degeneration). In this way, these methods, compounds (e.g., compounds of Formula I) and pharmaceutical compositions thereof can be described as neuroprotective. In one or more embodiments, the neurons are damaged, including but not limited to photodamaged neurons. In one or more embodiments, the compound (e.g., a compound of Formula I) and pharmaceutical compositions thereof comprise 4-chlorobutyl-CBN. In some cases, the method includes contacting retinal neurons with 4-chlorobutyl-CBN, such as by administering 4-chlorobutyl-CBN (or a pharmaceutical composition thereof) to a subject in need. In one or more embodiments, the method is used to protect a subject from AMD or to treat AMD in a subject in need. In some or any embodiments, the method is used to protect a subject from glaucoma or to treat glaucoma in a subject. In some or any embodiments, the method is not used to protect a subject from glaucoma, nor to treat glaucoma in a subject. In some or any embodiments, the method is used to lower intraocular pressure in a subject with glaucoma. In some or any embodiments, the method is not used to lower intraocular pressure in a subject with glaucoma.

[0058] In one or more embodiments, the compound is 4-chlorobutyl-CBN having formula I: I.

[0059] In one or more embodiments, the compound is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0060] The pharmaceutical composition may be or may contain 4-chlorobutyl-CBN having the formula I: I.

[0061] In one or more embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable excipient. In one or more embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0062] In one or more embodiments, the compound or pharmaceutical composition is or may contain a compound of Formula I or a pharmaceutically acceptable salt thereof as a prodrug. For example, the compound or pharmaceutical composition is or may contain 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof as a prodrug.

[0063] In some cases, the prodrug is an ester of 4-chlorobutyl-CBN (according to formula I) or a pharmaceutically acceptable salt thereof. In some cases, the prodrug is a D-(-)-glycerate of 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof. Further prodrug strategies for the compounds described herein can be found in the following literature: US Patent Publications 2016 / 0228490; 2011 / 0052694; 2015 / 0197484; 2008 / 0076789; 2009 / 0143462; 2012 / 0289484; 2009 / 0036523; 2009 / 0156814 and 2008 / 0008745; and Adelli et al., Investigative Ophthalmology & Visual Science, April 2017, Vol. 58, No. 4, p. 2168; and Upadhye et al., AAPS PharmSciTech, Vol. 11, No. 2. June 2010, page 509, the contents of these documents are hereby incorporated in their entirety for all purposes, and in particular the 4-chlorobutyl-CBN prodrugs and pharmaceutical compositions comprising them, and the methods of using and / or administering such prodrugs.

[0064] As used herein, the term "prodrug" refers to a derivative of a prodrug compound that, upon administration, releases a bioactive compound in vivo via some chemical or physiological process (e.g., upon reaching physiological pH or through enzymatic action, the prodrug is converted into a bioactive compound). The prodrug itself may lack or possess the desired biological activity. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some cases, prodrugs possess improved physical and / or delivery properties relative to the parent compound from which they are derived. Prodrugs generally have advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7–9, 21–24). A discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and EB Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987). Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as enhanced drug stability for long-term storage.

[0065] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when administered to a subject. Prodrugs of therapeutically active compounds as described herein can be prepared by modifying one or more functional groups present in a therapeutically active compound (i.e., a compound of formula I or a pharmaceutically acceptable salt thereof) and other therapeutically active compounds used in or included in a pharmaceutical composition according to one or more embodiments, in a manner such that the modification is cleaved in routine operation or in vivo to produce the parent therapeutically active compound. Prodrugs include compounds of formula I in which a hydroxyl group is covalently bonded to any group that is cleaved to form a free hydroxyl group when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, formate or benzoate derivatives of alcohols that can be used in the reaction.

[0066] In some cases, the prodrug includes 3,6,9,12-tetraoxatridecyl ester; N,N-dimethylglycyl ester; 3,6,9,12-tetraoxatridecyl carbonate; N-formylglycyl ester; N-formyldodecylsarcosine ester; 3,6,9,12-tetraoxatridecyl oxalate; hemisuccinate; 4-aminobutylcarbamate; prolyl ester; 3-dimethylaminopropionate; glycolic acid ester; (D)-ribonucleate; ammonium phosphate; (R)-2,3-dihydroxypropyl carbonate; 3-hydroxy-2-(hydroxymethyl)-2-methylpropionate; glycine ester; β-alanine ester; (S)-2,3-dihydroxypropionate; (S)-2,3-dihydroxypropyl carbonate; or (R)-2,3-dihydroxypropyl carbonate.

[0067] Similarly, if the disclosed compound or its pharmaceutically acceptable form contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6))alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkanoylcarbonyloxymethyl, N(C1-C6)alkanoylcarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, aryl acyl and α-aminoyl or α-aminoyl-α-aminoyl, wherein each α-aminoyl group is independently selected from naturally occurring L-amino acids P(O)(OH)2, P(O)(O(C1-C6)alkyl)2 or glycosyl (a group generated by removing the hydroxyl group of a carbohydrate in the form of a hemiacetal).

[0068] The use of prodrug systems is described in T. Järvinen et al., “Design and Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook (SC Gad, editor, Wiley-Interscience, Hoboken, NJ, 2005), Chapter 17, pp. 733-796. Other alternatives for prodrug construction and use are known in the art. When a prodrug or other therapeutically active agent comprising cannabinol or 4-chlorobutyl-CBN is used in a method or pharmaceutical composition according to one or more embodiments, the prodrug and active metabolite of the compound can be identified using techniques known in the art. See, for example, Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992).

[0069] Exemplary prodrugs that can be used in one or more embodiments of this disclosure include, but are not limited to, the following prodrugs of compounds of formula I or pharmaceutically acceptable salts thereof: ; X and Y may be the same or different, and are selected from the group consisting of: hydrogen, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium); and cations of pharmaceutically acceptable organic amines (e.g., quaternized or protonated amines, including alkylamines, hydroxyalkylamines, monoamines, diamines and naturally occurring amines). Examples of pharmaceutically acceptable organic bases of this class include choline, betaine, caffeine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, hydrabamine, isopropylamine, methylglucosamine, morpholine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, tetramethylammonium hydroxide, benzyltrimethylammonium hydroxide, tris(hydroxymethyl)aminomethane (TRIS), N-(2-hydroxyethyl)pyrrolidine, piperazine, glucosamine, arginine, lysine, and histidine. In one or more embodiments, X and Y are different substituents. In one or more embodiments, X and Y are the same substituent. In one or more embodiments, X and Y may both be part of the same functional group, such as piperazine. In one or more embodiments, the phosphate ester is selected from the group consisting of diphosphates and triphosphates.

[0070] In one or more embodiments, the prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof; ; Where R 4 It is an alkyl, alkoxyalkyl, alkylamino, hydroxyalkyl, or hydroxyalkylamino; in one or more embodiments, R 4 Contains 1 to 12 carbons and optionally contains no more than 4 substituents; in one or more embodiments, R 4 It contains 1 to 6 carbons and optionally contains no more than 2 substituents.

[0071] In one or more embodiments, the prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof; ; Where R 4 It is an alkyl, alkoxyalkyl, alkylamino, hydroxyalkyl, or hydroxyalkylamino; in one or more embodiments, R 4 Contains 1 to 12 carbons and optionally contains no more than 4 substituents; in one or more embodiments, R 4 It contains 1 to 6 carbons and optionally contains no more than 2 substituents.

[0072] In one or more embodiments, the prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof; ; Where R 4 It is an alkyl, alkoxyalkyl, alkylamino, hydroxyalkyl, or hydroxyalkylamino; in one or more embodiments, R 4 Contains 1 to 12 carbons and optionally contains no more than 4 substituents; in one or more embodiments, R 4 It contains 1 to 6 carbons and optionally contains no more than 2 substituents.

[0073] In one or more embodiments, the prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof; Where R 4 It is an alkyl, alkoxyalkyl, alkylamino, hydroxyalkyl, or hydroxyalkylamino; in one or more embodiments, R 4 Contains 1 to 12 carbons and optionally contains no more than 4 substituents; in one or more embodiments, R 4 It contains 1 to 6 carbons and optionally contains no more than 2 substituents.

[0074] Prodrugs that can be used in one or more embodiments of this disclosure include, but are not limited to, the following prodrugs of compounds of formula I or pharmaceutically acceptable salts thereof: Prodrugs that can be used in one or more embodiments of this disclosure include, but are not limited to, the following prodrugs of compounds of formula I or pharmaceutically acceptable salts thereof: .

[0075] Prodrugs that can be used in one or more embodiments of this disclosure include, but are not limited to, the following prodrugs of compounds of formula I or pharmaceutically acceptable salts thereof: or In one or more embodiments, the aforementioned prodrug can be advantageously formulated with cyclodextrin (such as atactic methylated β-cyclodextrin, 2-hydroxypropyl β-cyclodextrin or sulfobutyl ether β-cyclodextrin).

[0076] The pharmaceutical composition may contain additional active agents. In one or more embodiments, the pharmaceutical composition may contain 4-chlorobutyl-CBN, a pharmaceutically acceptable salt thereof or a derivative thereof, and additional cannabinoids or terpenoids. In one or more embodiments, the pharmaceutical composition may contain additional active agents for treating age-related macular degeneration.

[0077] Currently, different classes of therapeutic agents are used to treat age-related macular degeneration, including but not limited to: micronutrient supplements, vascular endothelial-derived growth factor (VEGF)-A antagonists (anti-VEGF agents or VEGF inhibitors), and photodynamic therapy.

[0078] Useful micronutrient supplements include, but are not limited to, vitamin C, zinc, vitamin E, copper, and beta-carotene. Useful anti-VEGF agents include, but are not limited to, ranibizumab, aflibercept, buxizumab, farexizumab, and bevacizumab. Useful photodynamic therapy agents include, but are not limited to, verteporfin. In one or more embodiments, different therapeutic agents may be combined.

[0079] In one or more embodiments, the compounds and pharmaceutical compositions described herein (e.g., containing 4-chlorobutyl-CBN or a pharmaceutically acceptable salt or derivative thereof) allow for lower doses or lower frequencies of administration of one or more therapeutic agents for the treatment of age-related macular degeneration.

[0080] definition When referring to the compounds provided herein, unless otherwise stated, the following terms have the following meanings. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. If a term has multiple definitions herein, the definition in this section shall prevail unless otherwise stated. Unless otherwise stated, when a term is defined as substituted, the groups in the list of substituents are themselves unsubstituted.

[0081] The term “about” as used herein includes (and describes) variations relating to that value or parameter itself. For example, a description of “about X” includes a description of “X”. As used herein, and unless otherwise stated, the terms “about” and “approximately”, when used in conjunction with the temperature, dose, amount, or weight percentage of an ingredient in a composition or dosage form, mean a dose, amount, or weight percentage that a person skilled in the art would consider to provide a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. Specifically, when used in this context, the terms “about” and “approximately” contemplate a dose, amount, or weight percentage within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dose, amount, or weight percentage.

[0082] Unless the context clearly specifies otherwise, the term “a / an” as used herein means one or more / a kinds. For example, “pharmaceuticalally acceptable excipient” means “one or more pharmaceutically acceptable excipients”.

[0083] As used herein, "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having one to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. In one or more embodiments, the alkyl group is a (C1-C6) alkyl group.

[0084] As used herein, "alkoxy" refers to an -OR group, where R is an alkyl group as defined herein. In one or more embodiments, the alkoxy group is a (C1-C6)alkoxy group.

[0085] As used herein, “(C1-C6)alkyloxymethyl” refers to -CH2OC(O)R, where R is a (C1-C6) alkyl group as defined herein.

[0086] As used in this article, "1-((C1-C6))alkanoyloxy)ethyl" refers to , where R is a (C1-C6) alkyl group as defined herein.

[0087] As used in this article, "1-methyl-1-((C1-C6)alkanoyloxy)ethyl" refers to , where R is a (C1-C6) alkyl group as defined herein.

[0088] As used herein, “(C1-C6)alkoxycarbonyloxymethyl” refers to -CH2OC(O)R, where R is (C1-C6)alkoxy as defined herein.

[0089] As used herein, “N(C1-C6)alkoxycarbonylaminomethyl” refers to -CH2NHC(O)R, where R is (C1-C6)alkoxy as defined herein.

[0090] As used in this article, "succinyl" refers to -C(O)CH2CH2C(O)OH.

[0091] As used herein, “(C1-C6)alkyl” refers to -C(O)R, where R is a (C1-C6)alkyl group as defined herein.

[0092] As used herein, “α-amino(C1-C4)alkyl” refers to -C(O)R, where R is an alkyl group substituted with -NH2.

[0093] As used in this article, "aryl acyl" refers to -C(O)phenyl or -C(O)naphthyl.

[0094] As used herein, “alkoxyalkyl” means an alkyl group as defined herein that is substituted with one or two alkoxy groups as defined herein.

[0095] As used herein, “alkylamino” means an alkyl group as defined herein that is substituted with one or two -NH2 groups.

[0096] As used herein, “hydroxyalkyl” means an alkyl group as defined herein that is substituted with one or two hydroxyl groups.

[0097] As used herein, “hydroxyalkylamino” means -NHR, where R is a hydroxyalkyl group as defined herein.

[0098] As used in this article, "subjects in need" refers to mammals, with humans being the preferred group.

[0099] As used in this article, “4-chlorobutyl-cannabinol”, “4-chlorobutyl-CBN”, “4-Cl-butyl-CBN” or “4-Cl-CBN” refers to 3-(4-chlorobutyl)-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol.

[0100] “Salt” means an acid or base salt of a compound used in one or more methods of this disclosure. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0101] Therefore, when a therapeutically active agent (such as, but not limited to, 4-chlorobutyl-CBN or its derivatives), alone or contained in a pharmaceutical composition according to this disclosure, has a sufficiently acidic functional group, a sufficiently basic functional group, or both sufficiently acidic and sufficiently basic functional groups, the one or more of these groups can accordingly react with a number of inorganic or organic bases and any of inorganic and organic acids to form a pharmaceutically acceptable salt of 4-chlorobutyl-CBN. Examples of pharmaceutically acceptable salts include those prepared by reacting a pharmacologically active compound with a mineral or organic acid or inorganic base, such as sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, isobutyrates, hexanoates, heptarates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, etc. Salts including salts of fumarate, maleate, butyn-1,4-diate, hexyn-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, or pyranoside such as glucuronic acid or galacturonic acid, or α-hydroxy acids such as citric acid, tartaric acid, or amino acids such as aspartic acid, glutamic acid, or aromatic acids such as benzoic acid, cinnamic acid, or sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. If the pharmaceutically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free acid with inorganic or organic bases such as amines (primary, secondary, or tertiary), alkali metal hydroxides, or alkaline earth metal hydroxides, etc. Illustrative examples of suitable salts include: organic salts derived from amino acids (such as glycine and arginine), ammonia, primary amines, secondary amines and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0102] "Pharmaceutical acceptable" means that the salt, carrier, diluent, or excipient is compatible with the other components of the composition and is harmless to its recipients.

[0103] "Pharmaceutically acceptable excipients" are substances that facilitate the administration of the active agent to a subject and / or facilitate the absorption of the active agent by a subject. Pharmaceutical excipients that can be used in this disclosure include, but are not limited to, buffers, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorings. Those skilled in the art will recognize that other pharmaceutical excipients are useful in this disclosure.

[0104] In some cases, a protecting group may be included in the compound used in the method according to this disclosure or in the compound according to this disclosure. The use of such a protecting group can prevent subsequent hydrolysis or other reactions that may occur in vivo and degrade the compound. Protectable groups include alcohols, amines, carbonyl groups, carboxylic acids, phosphoric acids, and terminal alkynes. Protecting groups that can be used to protect alcohols include, but are not limited to, acetyl, benzoyl, benzyl, β-methoxyethoxyethyl ether, dimethoxytriphenylmethyl, methoxymethyl ether, methoxytriphenylmethyl, p-methoxybenzyl ether, methylthiomethyl ether, neopentanoyl, tetrahydropyranyl, tetrahydrofuran, triphenylmethyl, silyl ether, methyl ether, and ethoxyethyl ether. Protecting groups that can be used to protect amines include benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, toluenesulfonyl, trichloroethyl chloroformate, and sulfonamide. Protecting groups that can be used to protect carbonyl groups include acetals, ketals, acyl groups, and dithianes. Protecting groups that can be used to protect carboxylic acids include methyl esters, benzyl esters, tert-butyl esters, esters of 2,6-disubstituted phenols, silyl esters, orthoesters, and oxazolines. Protecting groups that can be used to protect phosphate groups include 2-cyanoethyl and methyl. Protecting groups that can be used to protect terminal alkynes include propargyl alcohol and silyl groups. Other protecting groups are known in the art.

[0105] As used herein, the term "prodrug" refers to a derivative of a prodrug compound that, upon administration, releases a bioactive compound in vivo via some chemical or physiological process (e.g., upon reaching physiological pH or through enzymatic action, the prodrug is converted into a bioactive compound). The prodrug itself may lack or possess the desired biological activity. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some cases, prodrugs possess improved physical and / or delivery properties relative to the parent compound from which they are derived. Prodrugs generally have advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7–9, 21–24). A discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and EB Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987). Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as enhanced drug stability for long-term storage.

[0106] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when administered to a subject. Prodrugs of therapeutically active compounds as described herein can be prepared by modifying one or more functional groups present in a therapeutically active compound (including 4-chlorobutyl-CBN or 4-chlorobutyl-CBN derivatives) and other therapeutically active compounds used in or included in pharmaceutical compositions according to this disclosure, in a manner such that the modification is cleaved in conventional operation or in vivo to produce the parent therapeutically active compound. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is covalently bonded to any group that, when administered to a subject as a prodrug of the active compound, is cleaved to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, formate or benzoate derivatives of alcohols or acetamides, formamide or benzamide derivatives of therapeutically active agents having amine functional groups that can be used for the reaction, etc. In some cases, the prodrug is a protected derivative of the compound, such as a protected derivative of 4-chlorobutyl-CBN or a protected derivative of 4-chlorobutyl-CBN.

[0107] Similarly, if the disclosed compound or its pharmaceutically acceptable form contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6))alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkanoylcarbonyloxymethyl, N(C1-C6)alkanoylcarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, aryl acyl and α-aminoyl or α-aminoyl-α-aminoyl, wherein each α-aminoyl group is independently selected from naturally occurring L-amino acids P(O)(OH)2, P(O)(O(C1-C6)alkyl)2 or glycosyl (a group generated by removing the hydroxyl group of a carbohydrate in the form of a hemiacetal).

[0108] The use of prodrug systems is described in T. Järvinen et al., “Design and Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook (SC Gad, editor, Wiley-Interscience, Hoboken, NJ, 2005), Chapter 17, pp. 733-796. Other alternatives for prodrug construction and use are known in the art. When a prodrug or other therapeutically active agent comprising 4-chlorobutyl-CBN is used or included in a pharmaceutical composition according to the methods of this disclosure, conventional techniques known in the art can be used to identify the prodrug and active metabolite of the compound. See, for example, Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992).

[0109] As used herein, the terms “therapeutically effective quantity,” “therapeutically effective dose,” or “therapeutically effective amount” refer to a dose of one or more compounds or a pharmaceutical composition described herein that produces the therapeutic effect of administration thereto. The precise dose will depend on the therapeutic purpose and will be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1–3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0110] cannabinoids Cannabinoids are a group of chemical substances known to activate cannabinoid receptors throughout the body's cells, including the skin. Phytocannabinoids are cannabinoids derived from the cannabis plant. They can be isolated from the plant or synthesized. Endocannabinoids are endocannabinoids naturally produced by human cells. Classic phytocannabinoids are ABC tricyclic terpenoid compounds with a benzopyran moiety.

[0111] Cannabinoids exert their effects by interacting with cannabinoid receptors present on the cell surface. To date, two types of cannabinoid receptors have been identified: the CB1 receptor and the CB2 receptor. These two receptors share approximately 48% amino acid sequence identity, are distributed in different tissues, and have different cell signaling mechanisms. They also differ in their sensitivity to agonists and antagonists.

[0112] In some cases, cannabinoids or their precursors may be purified, derivatized (e.g., to form prodrugs or salts, or to form target cannabinoids from precursors) and / or formulated into pharmaceutical compositions.

[0113] Cannabinoids include, but are not limited to, phytocannabinoids. In some cases, cannabinoids include, but are not limited to, cannabinol, cannabidiol, and Δ... 9 -Tetrahydrocannabinol (Δ 9-THC), non-natural cannabinoid HU-210 (6a) R ,10a R )-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloct-2-yl)-6 H ,6a H 7 H 10 H ,10a H -benzo[ c Isochre-1-ol), HU-308 ([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctyl-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol), HU-433 (enantiomer of HU-308), cannabidiol (CBDV), cannabinoid (CBC), cannabinoid (CBCV), cannabinol (CBG), cannabinol (CBGV), cannabinol serotonin (CBE), cannabicyclophenol (CBL), cannabinol (CBV), and cannabitriol (CBT). Other cannabinoids include tetrahydrocannabinol (THCV) and cannabinol monomethyl ether (CBGM). Additional cannabinoids include cannabinoid-1-ol (CBCA), Δ... 9 -Tetrahydrocannabinolic acid (THCA); and cannabidiolic acid (CBDA); these other cannabinoids are characterized by the presence of a carboxylic acid group in their structure.

[0114] Other cannabinoids include nabilone, rimonabant, JWH-018 (naphthyl-1-yl-(1-pentylindol-3-yl)methyl ketone), JWH-073 (naphthyl-1-yl-(1-butylindol-3-yl)methyl ketone), CP-55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctane-2-yl)phenol), dimethylheptylpyran, and HU-331 (3-hydroxy-2-[(1 R )-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone), SR144528 (5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl] -N -[(1 S ,2 S 4 R )-1,3,3-trimethylbicyclo[2.2.1]heptane-2-yl]-1 H- Pyrazole-3-carboxamide), WIN 55,212-2 ((11 R)-2-methyl-11-[(morpholin-4-yl)methyl]-3-(naphthalene-1-carbonyl)-9-oxa-1-azatricyclic [6.3.1.0] 4 , 12 [Dodeca-2,4(12),5,7-tetraene), JWH-133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran), levonatradol and AM-2201 (1-[(5-fluoropentyl)-1 H [-indole-3-yl]-(naphth-1-yl)methyl ketone). Other cannabinoids include Δ 8 -Tetrahydrocannabinol (Δ 8 -THC), 11-hydroxy-Δ 9 -Tetrahydrocannabinol, Δ 11 -Tetrahydrocannabinol and 11-hydroxy-tetrahydrocannabinol.

[0115] In another alternative, analogues or derivatives of these cannabinoids can be obtained by providing precursor cannabinoids and further derivatizing them (e.g., by synthetic means). Non-natural cannabinoids include, but are not limited to, those described in the following documents: U.S. Patent No. 9,394,267 to Attala et al.; U.S. Patent No. 9,376,367 to Herkenroth et al.; U.S. Patent No. 9,284,303 to Gijsen et al.; U.S. Patent No. 9,173,867 to Travis; U.S. Patent No. 9,133,128 to Fulp et al.; U.S. Patent No. 8,778,950 to Jones et al.; U.S. Patent No. 7,700,634 to Adam-Worrall et al.; U.S. Patent No. 7,504,522 to Davidson et al.; U.S. Patent No. 7,294,645 to Barth et al.; U.S. Patent No. 7,109,216 to Kruse et al.; U.S. Patent No. 6,825,209 to Thomas et al.; and U.S. Patent No. 6,284,788 to Mittendorf et al.

[0116] In one or more embodiments, the compound disclosed herein is a cannabinoid. The cannabinoid according to this disclosure can bind at least partially and selectively to either a CB2 cannabinoid receptor or a CB1 cannabinoid receptor. In one or more embodiments, the cannabinoid binds to both CB1 and CB2 cannabinoid receptors. In some cases, the cannabinoid according to this disclosure is selective for the CB1 cannabinoid receptor and acts as a partial agonist. In some other cases, the cannabinoid according to this disclosure is selective for the CB2 cannabinoid receptor and acts as a partial agonist. In some cases, the cannabinoid binds to both CB1 and CB2 receptors, thereby acting as a partial agonist of both receptors, but not necessarily with... Similar potency with a higher affinity for the CB2 receptor. In some cases, one of the cannabinoids in the cannabinoid or mixture of cannabinoids is an antagonist or inverse agonist of the CB1 and / or CB2 receptors. As an antagonist or inverse agonist, the cannabinoid can bind to the CB1 and / or CB2 receptors but can induce a pharmacological response opposite to that of an agonist. In some cases, the cannabinoids in the pharmaceutical compositions and methods according to this disclosure have partial selectivity for the CB2 cannabinoid receptor. In some cases, in an in vitro competitive assay, the cannabinoid or mixture of cannabinoids exhibits K+ α-reactivity to the CB2 receptor. i It can be up to 1 / 3 of the Ki expressed for the CB1 receptor, and has a generally higher binding affinity for CB2.

[0117] Pharmaceutical Composition The pharmaceutical compositions described herein are typically formulated for administration. Therefore, this document describes pharmaceutical compositions comprising 4-chlorobutyl-CBN, formulated for administration with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0118] Pharmaceutical compositions can be prepared using well-known and readily available ingredients through known procedures.

[0119] Pharmaceutical compositions containing 4-chlorobutyl-CBN can be formulated for administration to subjects via one of a variety of standard routes (e.g., ocular, oral, topical, parenteral, inhalation or spray, rectal or vaginal) in dose units containing conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, excipients and / or mediators.

[0120] As used herein, the term parenteral administration includes, in one or more embodiments, subcutaneous, intradermal, intra-articular, intravenous, intramuscular, intravascular, intrasternal, intrathecal, and infusion techniques. Pharmaceutical compositions are typically formulated in a form suitable for administration to a subject via a chosen route (e.g., as eye drops, long-acting ophthalmic preparations, syrups, elixirs, tablets, troche, lozenges, hard or soft capsules, pills, suppositories, oily or aqueous suspensions, dispersible powders or granules, emulsions, injections, or solutions).

[0121] In one or more embodiments, the pharmaceutical composition is formulated for administration via a systemic route (e.g., intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, or oral).

[0122] Pharmaceutical compositions intended for oral use can be prepared in solid or liquid unit dosage forms. Fluid unit dosage forms can be prepared according to procedures known in the art for manufacturing pharmaceutical compositions, and such pharmaceutical compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically palatable formulation. Efficacy can be prepared using an aqueous alcohol (e.g., ethanol) medium with a suitable sweetener (such as sugar or saccharin) and aromatic flavoring agents, as well as other preparation techniques. Suspensions can be prepared using an aqueous medium with the aid of suspending agents such as gum arabic, tragacanth, methylcellulose, etc. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a derivative thereof; and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient comprising ethanol. In some embodiments, the pharmaceutical composition comprises a compound of formula I or a derivative thereof; and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient not comprising ethanol. In some embodiments, the pharmaceutically acceptable excipient consists only of ethanol. In some embodiments, the pharmaceutically acceptable excipient consists of more than one component of ethanol.

[0123] Solid pharmaceutical compositions (including, but not limited to, tablets, gels, or chewable tablets) contain an active ingredient and a mixture of non-toxic, pharmaceutically acceptable excipients suitable for manufacturing the solid pharmaceutical composition. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc; as well as other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and similarly functional materials. Solid pharmaceutical compositions may be uncoated, or they may be coated using known techniques. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0124] Pharmaceutical compositions intended for oral use may also be present as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium (e.g., medium-chain triglyceride oil (MCT oil), medium-chain fatty acid (MCFA), liquid paraffin, coconut oil, palm kernel oil, olive oil, or in some cases peanut oil). Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable inert oil (such as vegetable oil, light liquid petrolatum, MCT oil, MCFA, coconut oil, palm kernel oil, peanut oil, or other inert oil).

[0125] Aqueous suspensions contain an active ingredient mixed with one or more excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanol), condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides (e.g., polyvinyl sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., ethylparaben or n-propylparaben), one or more colorants, one or more flavoring agents, or one or more sweeteners (such as sucrose or saccharin).

[0126] Oily suspensions are formulated by suspending the active ingredient in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, as described above, may be added to provide a palatable oral preparation. These pharmaceutical compositions may be preserved by adding antioxidants such as ascorbic acid.

[0127] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0128] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifiers may be naturally occurring gums (e.g., gum arabic or tragacanth), naturally occurring phospholipids (e.g., soybean lecithin), and esters or metaesters derived from fatty acids and hexyl anhydrides (e.g., sorbitan monooleate), as well as condensation products of such metaesters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also optionally contain sweeteners and flavoring agents.

[0129] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents (such as those mentioned above) as known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenteral acceptable non-toxic diluents or solvents, for example, as a solution in 1,3-butanediol. Other acceptable media and solvents include, for example, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile fixed oils may be used as solvents or suspending media. A variety of mild, non-volatile oils known to be suitable for this purpose may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may be used in the preparation of injectables. Adjuvants such as local anesthetics, antiseptics, and buffers may also optionally be included in the injectable solutions or suspensions.

[0130] The pharmaceutical composition may contain pharmaceutically acceptable excipients, such as buffers. In one or more embodiments, the buffer is a sterile buffer. In one or more embodiments, the buffer is a PBS buffer. In one or more embodiments, the buffer contains a polysorbate-type nonionic surfactant, such as polysorbate 20 or polysorbate 80. In one or more embodiments, the polysorbate-type nonionic surfactant is present in an amount of 0.01 to 1% (w / v) of the buffer, such as 0.02 to 0.4% (w / v) or 0.03% (w / v). In one or more embodiments, the buffer contains a sugar, such as sucrose. In one or more embodiments, the sugar is present in an amount of 1 to 10% (w / v) of the buffer, such as 2 to 8% (w / v), 4 to 6% (w / v), or 5% (w / v). In one or more embodiments, the buffer contains a solvent, such as dimethyl sulfoxide (DMSO). In one or more embodiments, the amount of DMSO present is 0.1 to 1% (w / v) of the buffer solution, such as 0.1 to 0.5% (w / v) or 0.2 to 0.3% (w / v).

[0131] Other pharmaceutical compositions and methods for preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy” (originally “Remington's Pharmaceutical Sciences”); Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, Pa. (2000).

[0132] The concentration of compounds (e.g., 4-chlorobutyl-CBN) in the pharmaceutical composition will vary depending on the condition to be treated and / or the method of administration.

[0133] method This article describes a method for protecting neurons from neurodegenerative stimulation. Typically, this method involves contacting the neurons with an effective amount of 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof, or a 4-chlorobutyl-CBN derivative (e.g., a prodrug). This method can be an in vitro method. Alternatively, this method can be at least partially in vivo, such as by administering the compound or pharmaceutical composition to a subject. Administration can be performed via systemic (e.g., intravenous or subcutaneous) or local injection. For example, local injection can include intravitreal injection. Administration can be performed via non-invasive local application methods. For example, local application to retinal neurons (such as retinal ganglia) can include administering an eye drop pharmaceutical composition, such as a hydrogel (see, for example, WO 2018 / 205022) or a microemulsion (see, for example, U.S. Patent Nos. 8,968,775 and 9,149,453).

[0134] As described in US 8,968,775 and US 9,149,453, an eye drop pharmaceutical composition may include: a drug carrier suitable for topical application to the eye, the drug carrier comprising: an oil-in-water microemulsion comprising (i) an oil selected from the group consisting of isopropyl myristate, isopropyl palmitate, and medium-chain triglycerides; (ii) a pair of surfactants selected from the group consisting of two polysorbates, polysorbate and propylene glycol, polysorbate and glycerol, polysorbate and 1,2,3-triacetoxypropane, polyethoxylated castor oil and 1,2,3-triacetoxypropane, and polyethoxylated castor oil and propylene glycol; and (iii) water, wherein: water constitutes about 50% to 95% of the drug carrier. (w / w), the oil and a pair of surfactants substantially comprise all the remaining portion of the drug carrier; and the ratio of the percentage (w / w) of the pair of surfactants to the percentage (w / w) of the oil is at least about 10:1.

[0135] The pharmaceutical composition may comprise a lipophilic active pharmaceutical ingredient (API) and the aforementioned drug carrier, wherein the pharmaceutical composition is formulated for topical application to the eye.

[0136] In one or more embodiments, the eye drop pharmaceutical composition comprises a compound of formula I.

[0137] In one or more embodiments, the compound or its pharmaceutical composition is administered for a period of less than six weeks. In one or more embodiments, the compound or its pharmaceutical composition is administered for a period of approximately one to four weeks. In one or more embodiments, such as for the treatment of neurodegenerative diseases like age-related macular degeneration, the duration of administration of the compound or its pharmaceutical composition is extended, such as for several years, or for the duration of the patient's remaining life. The compound or its pharmaceutical composition may be administered every two months (every other month), monthly, weekly, every other day, daily, twice daily, or three times daily.

[0138] A compound or a pharmaceutical composition thereof may be administered to treat the eye of a subject requiring treatment to protect retinal neurons (e.g., optic nerve fibers). For example, the subject may have age-related macular degeneration. In some or any of the embodiments, the subject may have glaucoma. In some or any of the embodiments, the subject does not have glaucoma. If a compound or a pharmaceutical composition thereof is administered to protect neurons, such as retinal neurons, the compound or the pharmaceutical composition thereof may be administered at a dose that provides a peak, median, or trough (preferably peak) neuroprotective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neuronal cells. In one or more embodiments, the target neurons are retinal neurons. In one or more embodiments, the target neurons are peripheral neurons. In one or more embodiments, the target neurons are central neurons. In one or more embodiments, the compound or a pharmaceutical composition thereof is administered to treat the eye of a subject requiring treatment to protect retinal tissues, such as the retina and / or retinal pigment epithelium (RPE). In one or more embodiments, the compound or a pharmaceutical composition thereof is administered to treat the eye of a subject requiring treatment to protect photoreceptor cells (photoreceptors). In one or more embodiments, the compound or a pharmaceutical composition thereof is administered to treat the eye of a subject requiring treatment to prevent or reduce the accumulation of autofluorescent extracellular debris. In one or more embodiments, the compound or a pharmaceutical composition thereof is administered to treat the eye of a subject requiring treatment to prevent neuroinflammation (in some embodiments, the subject has AMD; in some embodiments, the subject has glaucoma; in some embodiments, the subject does not have glaucoma).

[0139] In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is less than about 25 µM, less than about 20 µM, less than about 15 µM, less than about 14 µM, less than about 13 µM, less than about 12 µM, or less than about 10 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN, its pharmaceutically acceptable salt, or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is greater than about 0.15 µM to less than about 25 µM, or greater than 0.15 µM to less than 25 µM, or at least about 0.15 µM to less than about 25 µM, or at least 0.15 µM to less than 25 µM, or greater than about 0.15 µM to less than about 20 µM, or greater than 0.15 µM to less than 20 µM, or at least about 0.15 µM to less than about 20 µM, or at least 0.15 µM to less than 20 µM.

[0140] In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is greater than about 0.15 µM to less than about 15 µM, or greater than 0.15 µM to less than 15 µM, or at least about 0.15 µM to less than 15 µM, or at least 0.15 µM to less than 15 µM, or greater than about 0.15 µM to less than about 12 µM, or greater than 0.15 µM to less than 12 µM, or at least about 0.15 µM to less than about 12 µM, or at least 0.15 µM to less than 12 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) is at least about 0.5 µM to less than about 25 µM, or at least about 0.5 µM to less than 25 µM, or at least about 0.5 µM to less than about 20 µM, or at least 0.5 µM to less than 20 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) is at least about 0.5 µM to less than about 15 µM, or at least about 0.5 µM to less than about 15 µM, or at least about 0.5 µM to less than about 12 µM, or at least 0.5 µM to less than 12 µM.

[0141] In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is less than about 25 µM, less than about 20 µM, less than about 15 µM, less than about 14 µM, less than about 13 µM, less than about 12 µM, or less than about 10 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is greater than about 0.15 µM to less than about 25 µM, or greater than 0.15 µM to less than 25 µM, or at least about 0.15 µM to less than about 25 µM, or at least 0.15 µM to less than 25 µM, or greater than about 0.15 µM to less than about 20 µM, or greater than 0.15 µM to less than 20 µM, or at least about 0.15 µM to less than about 20 µM, or at least 0.15 µM to less than 20 µM.

[0142] In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye, and / or in contact with ocular neurons is greater than about 0.15 µM to less than about 15 µM, or greater than 0.15 µM to less than 15 µM, or at least about 0.15 µM to less than 15 µM, or at least 0.15 µM to less than 15 µM, or greater than about 0.15 µM to less than about 12 µM, or greater than 0.15 µM to less than 12 µM, or at least about 0.15 µM to less than about 12 µM, or at least 0.15 µM to less than 12 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) is at least about 0.5 µM to less than about 25 µM, or at least about 0.5 µM to less than 25 µM, or at least about 0.5 µM to less than about 20 µM, or at least 0.5 µM to less than 20 µM. In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) is at least about 0.5 µM to less than about 15 µM, or at least about 0.5 µM to less than about 15 µM, or at least about 0.5 µM to less than about 12 µM, or at least 0.5 µM to less than 12 µM.

[0143] In one or more embodiments, the neuroprotective effective concentration of the compound (e.g., 4-chlorobutyl-CBN or a pharmaceutically acceptable salt thereof or a derivative thereof (e.g., a prodrug)) in vitreous fluid, in ocular tissues of the eye and / or in contact with ocular neurons is greater than about 0.15 µM to less than about 10 µM, or greater than 0.15 µM to less than 7.5 µM, or at least about 0.15 µM to less than about 10 µM, or at least 0.15 µM to less than 7.5 µM, or greater than about 0.15 µM to about 5 µM, or greater than 0.15 µM to 5 µM, or at least about 0.15 µM to about 5 µM, or at least 0.15 µM to 5 µM.

[0144] For example, the compound or pharmaceutical composition thereof may be administered orally, intrathecally, intravenously, topically, or by injection, and / or directly to the site of a target neuron or a group of target neurons. In one or more embodiments, the neuroprotective effective concentration is achieved by systemic doses of about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 13 mg / kg. Repeated administration is possible, for example, once every two months, once a month, once a week, every other day, once a day, or twice a day.

[0145] The compound or pharmaceutical composition thereof may be administered intrathecally, intravenously, or by injection, or directly to the eye, such as by topical eye drops or intravitreal injection or infusion. In one or more embodiments, for ocular administration of an ocular indication (e.g., to treat age-related macular degeneration), the systemic dose may be from 1 mg / kg to 20 mg / kg. It may be repeatedly administered, for example, once every two months, once a month, once a week, every other day, once daily, or twice daily. In one or more embodiments, for systemic administration of an ocular indication (e.g., to treat age-related macular degeneration), the systemic dose may be from 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. It may be repeatedly administered, for example, once every two months, once a month, once a week, every other day, once daily, or twice daily. In one or more embodiments, for systemic administration in peripheral indications (e.g., to treat peripheral neuropathy and / or peripheral nerve damage or injury), the dose may be from 1 mg / kg to 20 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. Repeated administration is possible, for example, once every two months, once a month, once a week, every other day, once a day, or twice a day. In one or more embodiments, for systemic administration in central indications (e.g., to treat central nervous system damage or injury), the dose may be from 1 mg / kg to 20 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. Repeated administration is possible, for example, once a week, once a day, or twice a day.

[0146] In one or more embodiments, for ocular application in an ocular indication (e.g., for the treatment of age-related macular degeneration), the ocular dose may be 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.5 mg to 5 mg, or 1 mg to 5 mg, applied to the eye, such as in the form of eye drops or ocular gel. It may be repeatedly administered, for example, once every two months, once a month, once a week, every other day, once a day, or twice a day. In one or more embodiments, for ocular application in an ocular indication (e.g., for the treatment of age-related macular degeneration), the ocular dose may be 0.05 mg to 2 mg, 0.05 mg to 1.5 mg, 0.05 mg to 1 mg, 0.1 mg to 2 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.05 mg to 0.5 mg, or 0.1 mg to 0.5 mg, applied to the eye, such as by intravenous injection or infusion. Repeated administration is possible, such as once every two months, once a month, once a week, every other day, once a day, or twice a day.

[0147] In one or more embodiments, the compound or its pharmaceutical composition is administered within about 0-48 hours of damage affecting retinal neurons, photoreceptors, retinal pigment epithelium, neuroinflammation, and / or the accumulation of autofluorescent extracellular deposits. In one or more embodiments, the compound or its pharmaceutical composition is administered within about 2-24 hours of damage affecting retinal neurons, photoreceptors, and / or retinal pigment epithelium. In one or more embodiments, the compound or its pharmaceutical composition is administered within about 3-12 hours of damage affecting retinal neurons, photoreceptors, and / or retinal pigment epithelium. In one or more embodiments, the compound or its pharmaceutical composition is administered within about 3-5 hours of damage affecting retinal neurons, photoreceptors, and / or retinal pigment epithelium.

[0148] In one or more embodiments, the compound or a pharmaceutical composition thereof is administered to a subject suffering from AMD.

[0149] The method may include, or may further include, the simultaneous or sequential administration of an additional active agent (e.g., a second drug) in combination with the compound or a pharmaceutical composition thereof. In some cases, the additional active agent is a therapeutic agent for treating age-related macular degeneration. In one or more embodiments, the additional active agent is an anesthetic. In one or more embodiments, the additional active agent is a VEGF inhibitor. In one or more embodiments, the additional active agent is an anti-VEGF protein or compound. For example, the method may include anesthetizing the subject prior to administration of the compound or pharmaceutical composition of one or more embodiments. In another instance, in the method of one or more embodiments, the subject is anesthetized prior to contact (the administration step).

[0150] Example Materials and methods Animals and experimental groups Sprague Dawley (SD) albino rats were born and housed under dim, cyclical light conditions (12 hours of light, 12 hours of darkness) with an ambient light level of approximately 5 lux. Animals had free access to food and water. Experiments were conducted on adult animals aged 2–4 months. Treatment was administered via intravitreal injection in both eyes one day prior to light exposure, and potential retinal protection was assessed by fERG recordings seven days after light exposure.

[0151] Preparation of pharmaceutical compositions and intravitreal injection 4-Chlorobutyl-CBN was prepared through a combination of biosynthesis and chemical synthesis. In short, 5-chlorovalerate was "feeded" to… brewing yeast This strain was engineered to convert acid analogs into 4-chlorobutyl-olanolic acid. .

[0152] 4-Chlorobutyl-olanol analogues were recovered from the culture medium by extraction with ethyl acetate. From 4-chlorobutyl-olanol, the final product 4-chlorobutyl-CBN was generated using two different pathways. For pathway "A", 4-chlorobutyl-olanol was decarboxylated to 4-chlorobutyl-ol: It then combines with citral (chemical isopentenylation) to generate 4-chlorobutyl-CBC: It is oxidized to 4-chlorobutyl-CBN. In a different pathway (“B”), 4-chlorobutyl oleuropenic acid is “feeded” to… brewing yeastA strain engineered to overproduce gerany-bisphosphate precursor (GPP) and express heterologous genes encoding isopentenyltransferase and synthase. The biotransformation strain converts 4-chlorobutyl-olanolic acid analogs to 4-chlorobutyl-THCA. It is recovered from yeast cells by ethyl acetate extraction. Then, 4-chlorobutyl-THCA is decarboxylated and oxidized to generate 4-chlorobutyl-CBN. 4-chlorobutyl-CBN can also be prepared by chemical synthesis. Alternatively, methods similar to those described in US-2023-0063396-A1 can be used to prepare 4-chlorobutyl-CBN.

[0153] 15 mM or 30 mM stock solutions of 4-Cl-butyl CBN in 100% DMSO were diluted in sterile dilution buffer (0.03% polysorbate (Tween) 20, 5% sucrose in PBS) to obtain final formulation concentrations of approximately 100 µM, 30 µM, and 10 µM at a final DMSO concentration of 0.2–0.4%, for intravitreal injection administration. Formulations were prepared by serial dilution, ensuring that they contained similar levels of DMSO at different dose levels. Buffer solutions were prepared by dissolving 0.03% polysorbate (Tween) 20, 5% sucrose in PBS buffer. For buffer solutions used in the mediator and control (or injectable formulation), the buffer solutions were diluted with DMSO to an appropriate level (to match the buffer solutions used in the corresponding concentration / dilution stock solutions, but without cannabinoids / APIs). Regarding the DMSO in the buffer solution, the injectable formulation contains DMSO from a 4-chlorobutyl-CBN stock solution; for example, when the stock solution is diluted to 100 µM for injection into the eye, the 4-chlorobutyl-CBN concentration is 10 µM. Therefore, DMSO is added to the buffer solution used for the media and control experiments to match the DMSO concentration of the corresponding injectable formulation. The buffer solution is used in the media and control as described below. After dissolving the excipient, the buffer solution is filtered through a 0.2 µM filter to prepare a sterile buffer for formulation preparation. The DMSO stock solution is diluted in the buffer solution to obtain final formulations at concentrations of approximately 100 µM, 30 µM, and 10 µM. The mixture is then vortexed at a high setting for 30 seconds or longer. The final concentration in the vitreous fluid is 1 / 10 of the injection concentration. For example, an initial concentration of 1 / 10 of 100 µM is a final concentration of 10 µM (see figure); similarly, an initial concentration of 1 / 10 of 30 µM is a final concentration of 3 µM (see figure); further, an initial concentration of 1 / 10 of 3 µM is a final concentration of 0.3 µM (see figure); and so on. The final expected concentration of the buffer components in the eye is 0.003% polysorbate (tween) 20, 0.5% sucrose, and approximately 0.02% to 0.04% DMSO.

[0154] For surgical intervention, rats were anesthetized by intraperitoneal injection of ketamine / toluidine (10 mg / 100 g–1.2 mg / 100 g). Under completely aseptic conditions, 2.0 μL of the compound was injected into both eyes using a Hamilton syringe (2). Controls: Healthy animals without light damage (LD) and untreated. Mediator: Light-damaged animals treated with dilution buffer. The mediator did not induce any change in fERG response compared to the light-damaged, untreated eyes. Therefore, the light-damaged group was not included in the analysis.

[0155] Light damage Animals were placed in individual Plexiglas cages with food on the floor and water in plastic bottles. They were acclimatized to darkness overnight and exposed to 1000 lux at 9 a.m. for 24 hours (LD24h). Afterward, they were returned to dim, cyclical light conditions for 7 days to recover from acute stress caused by light exposure.

[0156] Electroretinography (ERG) recording fERG was recorded under dark-adapted conditions in response to a single flash of white light (scotopic) delivered by a standard Ganzfeld stimulator (Biomedica Mangoni, Pisa, Italy). Prior to fERG, rats were anesthetized by intraperitoneal injection of ketamine / toluidine (10 mg / 100 g–1.2 mg / 100 g), fixed to a stereotaxic apparatus, and their body temperature maintained at 37.5 °C. The cornea was anesthetized with one drop of procaine (NOVOCAINE), and the pupils were dilated with visumidriatic 1.0% tropicamide. Simultaneous recording was performed on both eyes using gold electrode rings (2.0 mm in diameter) placed on the cornea. A reference electrode was subcutaneously inserted near the eye, and a ground electrode was inserted into the forehead scalp between the eyes. Responses were recorded at increased light intensities (ranging from 0.001 cd*s / m² to 100 cd*s / m²). At the end of the recording session, the traces were bandpass filtered between 0.3 and 500 Hz. The a-wave amplitude (μV) and b-wave amplitude (μV) for the corresponding brightness were measured. Oscillation potential (OP) analysis was also performed by calculating the sum of the amplitudes of OP1, OP2, OP3, and OP4.

[0157] Statistical analysis For statistical analysis, one-way ANOVA was performed among CBN, 4-chlorobutyl-CBN, and the mediator group, followed by Dunnett post-hoc comparisons; for analyses excluding the CBN group, Student's post-hoc comparisons were performed between the 4-chlorobutyl-CBN and the mediator group. t Tests. Statistical analysis was performed using SigmaPlot 12.0 software (Systat Software, San Jose, CA, USA). Data are presented as mean ± standard error of mean. (4-Cl-CBN: n=14; CBN 30: n=17; CBN 100: n=13; medium: n=17) (*p<0.05, relative to medium).

[0158] Example 1: Intravitreal injection of 0.3 µM 4-chlorobutyl-CBN In separate experiments, in vivo studies were conducted in a rat model of AMD by intravitreal injection of 3 µM (final intraocular concentration of 0.3 µM) 4-chlorobutyl-CBN in the mediator and 3 µM (final intraocular concentration of 0.3 µM) CBN in the mediator. The mediator alone and the control were tested and compared separately. Intravitreal injection was performed in the posterior segment of the eye, as... Figure 1 As shown by the arrow. The results of this study are presented in Figure 2A and 2B middle.

[0159] from Figure 2A and 2B As can be seen, CBN with a final concentration of 0.3 µM appears to be superior to 4-chlorobutyl-CBN with a final concentration of 0.3 µM. However, there is a student-like difference between the CBN and 4-Cl-CBN groups. t The test result was p=0.46; therefore, there was no statistically significant difference between the two groups. In this study, a final concentration of 0.3 µM 4-chlorobutyl-CBN was tested in a small number of animals. Therefore, these results may not be statistically significant.

[0160] Example 2: Intravitreal injection of 3 µM 4-chlorobutyl-CBN In vivo studies were conducted in a rat model of AMD by intravitreal injection of 30 µM (final 3 µM) 4-chlorobutyl-CBN, 30 µM (final 3 µM) CBN, and 100 µM (final 10 µM) CBN in separate experiments. Individual mediators and controls were tested and compared separately. Intravitreal injection was performed in the posterior segment of the eye, as shown in the figure. Figure 1 As shown by the arrow. The results of this study are presented in Figures 3A to 3F (a-wave amplitude), 4A to 4E (b-wave amplitude), and 5A (OP amplitude).

[0161] The amplitude of the alpha wave indicates the response of photoreceptors to light stimuli. For example... Figures 3A to 3F As shown, for the increase in a-wave amplitude (µV), at brightness (light intensity) of 0.01, 0.1, 1, 10, and 100 cd*s / m^2, 3 µM (final concentration) of 4-chlorobutyl-CBN was superior to both 3 µM (final concentration) and 10 µM (final concentration) of CBN. These results indicate that a statistically significant increase in a-wave amplitude was observed at intensities of 0.01, 0.1, and 100 cd*s / m^2.

[0162] The amplitude of the b-wave indicates the overall response of the inner retina to increased light stimulation. For example... Figures 4A to 4EAs shown, for the increase in b-wave amplitude (µV), at brightness (light intensity) of 0.001, 0.01, 0.1, 1, 10, and 100 cd*s / m^2, 3 µM (final concentration) of 4-chlorobutyl-CBN was superior to both 3 µM (final concentration) and 10 µM (final concentration) of CBN. These results indicate that a statistically significant increase in b-wave amplitude was observed at intensities of 0.1, 1, 10, and 100 cd*s / m^2.

[0163] The amplitude of the oscillating potential (OP) indicates the response of the inner retinal circuitry to light stimulation (primarily due to rod bipolar cells and A11 / A17 amacrine cells). Figure 5 As shown, for OP amplitude (µV), at brightness (light intensity) of 0.001, 0.01, 0.1, 1 and 10 cd*s / m^2, 3 µM (final concentration) 4-chlorobutyl-CBN is superior to 3 µM (final concentration) CBN and 10 µM (final concentration) CBN.

[0164] Example 3: Imaging At the end of the electroretinography recording, the eyes were enucleated for morphological analysis, fixed in 4% paraformaldehyde for 6 h, and washed in 0.1 M phosphate-buffered saline (PBS, pH 7.4). The cornea and lens were removed, and the remaining eye cups were cryoprotected by immersing them in 30% sucrose. They were then embedded in a Tissue Tek OCT compound (optimal cutting temperature, Valencia, CA, USA), frozen, and stored at -20°C. Frozen sections of 20 μm thickness were obtained using a Leica CM1850 cryostat (GmbH, Nussloch, Germany) and collected on gelatin and poly-L-lysine-coated slides. Sections passing through the optic nerve were selected for subsequent immunofluorescence analysis.

[0165] Microglia, astrocytes, and Müller cells were identified using immunofluorescence. Specifically, nonspecific binding sites were blocked with 5% bovine serum albumin (BSA) at room temperature (RT) for 1 h. Sections were then incubated overnight at 4°C with primary antibodies (anti-IBA-1 for detecting microglia, Wako Chemicals, #019-19741, astrocytes, and Müller cells (anti-GFAP, Cell Signaling, #3670)). Sections were then incubated with a 1:300 dilution of secondary antibodies (anti-mouse or anti-rabbit IgG conjugated with red or green fluorescent dyes) (Alexa Fluor 594 or 488; Molecular Probes, Invitrogen, Carlsbad, CA, USA) at 37°C for 2 h. Cell nuclei were labeled with bisbenzoimide nuclear dye (Hoechst) to identify the retinal layer. Images were then acquired using fluorescence microscopy. Results are shown in [Figure number missing]. Figure 6A In. Figure 6B The image is provided as a shadow to show the contrast.

[0166] The photodamage model of AMD is characterized by thinning of the outer nuclear layer where photoreceptors reside. This is typically a feature of photoreceptor degeneration associated with AMD. With photoreceptor death, glial proliferation events occur in the retina, leading to (i) the invasion of microglia (which are present in the inner retina under physiological conditions) into the outer nuclear layer, and (ii) the responsiveness of astrocytes and Müller cells, characterized by the upregulation of GFAP markers.

[0167] Based on this, analysis of retinal cryosections investigated whether the application of 3 µM 4-Cl-butylCBN prevented the aforementioned harmful events. In summary, morphological analysis showed that 4-Cl-butylCBN can prevent photoreceptor death and glial proliferation in the photoreceptor-damaged retina.

[0168] Specifically, the treatment provides the following protective outcomes: (i) The outer core layer is thicker than that of the medium; (ii) Invasion of IBA-1(+) cells in the outer nuclear layer was inhibited; and (iii) GFAP expression was suppressed throughout the retinal layer compared to the mediator.

[0169] Example 4. Comparison between 4-chlorobutyl-CBN and control animals To better evaluate the degree of functional protection provided by 4-chlorobutyl-CBN in a photodamage model, student studies were conducted between eyes treated with 4-chlorobutyl-CBN and control (eyes of healthy animals). tTest analysis. As shown in Table 12, there were no significant differences between the 18 fERG conditions studied and the control and treated eyes.

[0170] Table 1: Comparison of 4-chlorobutyl-CBN with control animals t Test and comparison

[0171] The results showed that 4-chlorobutyl-CBN (at a final concentration of 3 µM as described above) significantly prevented retinal functional impairment due to light damage, as evidenced by the amplitudes of the a-wave, b-wave, and oscillatory potential (OP) compared to the mediator. Typically, 4-chlorobutyl-CBN retained fERG values ​​similar to those in healthy, undamaged animals. The functional protection of 4-chlorobutyl-CBN was evident for both b-wave and OP, suggesting greater protection of the inner retina compared to the outer retina. Additionally, a slight improvement in retinal function also occurred in response to 100 cd*s / m^2 of CBN (when used at 3 µM). In other words, in these tests, there was little difference between the control (healthy eyes, unexposed to light) and eyes treated with 4-chlorobutyl-CBN when exposed to light.

[0172] Example 5: In vivo concentration 4-Cl-butyl-CBN (intraocular) was tested at concentrations of 0.3 µM, 1 µM, 3 µM, and 10 µM. Compared with the mediator, concentrations of 3 µM and 10 µM of 4-Cl-butyl-CBN improved the amplitude of the a-wave, which indicates a photoreceptor response, suggesting that this treatment exerts a neuroprotective effect against photodamage to photoreceptors. Control: Healthy animals without photodamage and untreated. Mediator: Photodamage treated with dilution buffer. The results of these tests are shown in... Figure 7A middle.

[0173] 4-Cl-butyl-CBN (intraocular) at concentrations of 0.3 µM, 1 µM, 3 µM, and 10 µM was tested. Compared to the mediator, concentrations of 3 µM and 10 µM of 4-Cl-butyl-CBN improved the b-wave amplitude, which indicates the overall response of the inner retina after light stimulation, suggesting that this treatment protected against retinal functional impairment. Control: Healthy animals without light injury and untreated. Mediator: Light injury treated with dilution buffer. The results of these tests are shown in... Figure 7B middle.

[0174] 4-Cl-butyl-CBN (intraocular) was tested at concentrations of 0.3 µM, 1 µM, 3 µM, and 10 µM. Compared to the mediator, concentrations of 3 µM and 10 µM of 4-Cl-butyl-CBN improved the amplitude of the oscillating potential (OP), an indicator of inner retinal circuit function, suggesting that this treatment exerted retinal neuroprotective effects and inhibited inner retinal function. Control: Healthy animals without light damage and untreated. Mediator: Light damage treated with dilution buffer. The results of these tests are shown in... Figure 7C middle.

[0175] Electrophysiological results obtained from photodamaged animals treated with intravitreal injections of 4-Cl-butyl CBN and CBN demonstrated that, compared to eyes treated with the medium, 3 µM 4-Cl-butyl CBN exhibited superior functional protection, exceeding that of CBN at the same concentration, at least as... Figure 3A and 4A As shown.

[0176] Example 6: Histological and Molecular Analysis Representative retinal slices from all experimental groups were stained with the nuclear dye Hoechst (blue), as follows: Figure 8A As shown. The control group refers to healthy rats without light damage. The vector group refers to animals with light damage (illness) and treated with injected buffer.

[0177] The red line highlights the outer nuclear layer thickness (ONL). Determine the ratio of ONL to retinal thickness, such as... Figure 8B As shown, where Figure 8C Specific locations on the upper and lower retina are shown, at which points are determined. Figure 8B The thickness ratio. These data indicate that 4-Cl-butyl-CBN improves the outer core layer thickness in the AMD model.

[0178] Autofluorescence (AF) extracellular deposits in retinal cryopreserved sections were evaluated using a 594 nm excitation wavelength. Figure 9A As shown (AF deposits are shown in red). For example... Figure 9B As shown, the number of AF deposits was counted in the entire retinal slice. These data indicate that 4-Cl-butyl-CBN reduces extracellular deposits in the AMD model.

[0179] The integrity of the retinal pigment epithelium (RPE) was assessed in retinal cryosections stained with anti-RPE65 immunostaining. Figure 10A As shown (immunostaining shows red). Frozen sections passing through the optic nerve were selected for analysis, and the integrity of the RPE was measured at the dorsal retina. White segmented lines delineate the complete RPE. Figure 10BAs shown, the RPE65(+) length was measured. These data indicate that 4-Cl-butyl-CBN improves the RPE length in the AMD model.

[0180] Photodamage models demonstrate the loss of RPE integrity, including the loss of RPE cell-cell junction integrity (Miralles de Imperial-Ollero et al. 2021, Cachafeiro et al. 2013 and Geiger et al. 2015).

[0181] like Figure 11A As shown, microglia were labeled with anti-IBA-1 (green) in retinal frozen sections from all experimental groups. Figure 11B As shown, IBA-1(+) cells were counted from the upper edge to the lower edge of the retina at the outer retina (subretinal, outer nuclear layer, outer plexiform layer). The locations on the upper and lower retina where data were collected are... Figure 8C The same as shown. The number of IBA-1(+) cells in the upper retina, lower retina, and the entire retina (upper and lower) are shown in the figures. Figure 11C-11E These data indicate that 4-Cl-butyl-CBN reduces inflammation in the retina in the AMD model.

[0182] Example 7: Receptor Interaction Study The interactions of 4-Cl-butyl-CBN with different receptors were evaluated using various assay methods. Assays were performed by Eurofins using its standard bioassay protocols.

[0183] The interaction of 4-Cl-butyl-CBN with CB1 and CB2 receptors, using cAMP as a biomarker, was assessed using the HitHunter® cAMP assay. In short, cAMP Hunter cell lines expressing CB1 or CB2 receptors were evaluated using the DiscoverX HitHunter cAMP XS+ assay. To assess agonist behavior (Gs agonist form), cells were incubated with the sample to induce a response, the medium was aspirated and replaced with HBSS / Hepes buffer containing cAMP XS+ Ab reagent, and then 5 µL of 4X sample was added to the cells and incubated at 37°C or room temperature for 30 or 60 min, with a medium concentration of 1%. To assess agonist behavior (Gi agonist form), cells were incubated in the presence of EC80 leucovorin to induce a response. The medium was aspirated and replaced with HBSS / Hepes buffer containing cAMP XS+ Ab reagent. Then, 5 µL of 4X sample compound containing 4X EC80 leucovorin was added to the cells, and the cells were incubated at 37°C or room temperature for 30 or 60 minutes, with a mediator concentration of 1%. To assess antagonist behavior, cells were pre-incubated with the sample, then agonist-activated at EC80 concentration. The medium was aspirated and replaced with HBSS / Hepes buffer containing cAMP CS+ Ab reagent. Then, 5 µL of 4X sample compound was added to the cells and incubated at 37°C or room temperature for 30 minutes. Then, 5 µL of EC80 agonist was added and the cells were incubated at 37°C or room temperature for 30 or 60 minutes, with a mediator concentration of 1%. For GI-coupled GPCRs, EC80 leucovorin was included in the antagonist assay. For signal detection in either assay, add 20 µL of cAMP XS + ED / CL lysis mixture and incubate for one hour, then add 20 µL of cAMP CS + EA reagent and incubate at room temperature for three hours. Read the microplate for chemiluminescence detection.

[0184] The interaction of 4-Cl-butyl-CBN with CB1 and CB2 receptors was assessed using the PathHunter® β-inhibitor assay from Eurofins DiscoverX Corp., which uses inhibitory protein as a marker.

[0185] The interactions of 4-Cl-butyl-CBN with PPARγ, PPARα, and PPARδ were assessed using the PathHunter® nuclear hormone receptor protein interaction (Pro) assay. Briefly, for agonist determination, PathHunter NHR cell lines were incubated with the sample, followed by the addition of 5 µL of 5X sample to the cells and incubation at 37°C or room temperature for 3–16 hours, with a final mediator assay concentration of 1%. For antagonist determination, cells were pre-incubated with the antagonist, followed by agonist activation at EC80 concentration, then 5 µL of 5X sample was added to the cells and incubated at 37°C or room temperature for 60 minutes, with a final mediator assay concentration of 1%. Then, 5 µL of EC80 agonist in assay buffer was added and incubated at 37°C or room temperature for 3–16 hours. Assay signals were generated by adding 12.5 or 15 µL of the PathHunter assay reagent mixture and incubating at room temperature for one hour, followed by reading the microplate for chemiluminescent detection.

[0186] A similar analysis was performed on the GPR55 receptor β-inhibitory protein pathway.

[0187] Data on receptor interactions are provided in Table 2 below: Table 2: 4-Cl-Butyl-CBN receptor interaction data

[0188] These data indicate that 4-Cl-butyl-CBN is a selective (biased) CB1 and CB2 agonist and antagonist, as well as a GPR55 agonist. These data further suggest that 4-Cl-butyl-CBN is an agonist of the cAMP pathway and an antagonist of the β-repressor pathway.

[0189] Example 8: 4-Cl-Butyl-CBN Levels in the Retina Following Local and IVT Delivery Topical eye drop formulations of 4-Cl-butyl-CBN were administered topically to rabbits in two formulations and compared with IVT levels in rats, as shown in Figure 13.

[0190] IVT delivery in rats was performed in a disease model, as previously described in Example 1. Animals were euthanized 24 hours after IVT injection, and retinal / RPE / choroidal tissue was collected from each animal. Compound concentrations were measured using qualified LC-MS / MS bioanalytical methods. The microemulsion formulation for topical delivery in rabbits was based on the methods previously described in U.S. Patent Nos. 8,968,775 and 9,149,453. In the topical delivery study in rabbits, animals received two 40 µL topical doses (1% formulation) twice daily in both eyes for 8 days. On day 8, animals were euthanized, and retinal / RPE / choroidal tissue was collected from each animal. Compound concentrations were measured using qualified LC-MS / MS bioanalytical methods.

[0191] Example 9: Local delivery of 4-Cl-butyl-CBN to the retina in a Sprague Dawley rat model Prior to photodamage, Sprague Dawley albino rats were given topical application of the compound via eye drops (10 µl) twice daily (approximately 12 hours later) for seven days, and this continued for an additional seven days after the injury. At the endpoint, retinal function was assessed by fERG recordings, and RPE / retinal protection was investigated by the following histological evaluations: RPE integrity, accumulation of autofluorescent deposits, and retinal thickness.

[0192] Example 10: Comparative analysis of in vivo treatment of AMD with 4-Cl-butylCBN and CBN Ocular tissue was extracted from rats treated with 4-Cl-butyl CBN or CBN for further morphological and molecular analysis of AMD pathology, as described below.

[0193] 1. Protection of the retinal pigment epithelium (RPE) Retinal pigment epithelial cell death is an integral part of the pathogenesis of AMD (Kim et al., 2021), and it is also reproduced in light damage models (Jaadane et al., 2017; Tisi et al., 2020a). Evaluating the efficacy of 4-Cl-butyl CBN or CBN compounds in preventing retinal pigment epithelial degeneration on retinal cryosections immunolabeled with the selective RPE cell marker (RPE65) allows for the assessment of the therapeutic effect on maintaining the integrity of the retinal pigment epithelium.

[0194] 2. Photoreceptor (PR) neuroprotection Photoreceptor cell death is another event in AMD (Mitchell et al., 2018) and is also induced by photodamage in albino rats. Photoreceptor neuroprotection was investigated by quantifying outer nuclear layer thickness and by measuring the length of degenerated regions on frozen sections of the retina stained with bisbenzoimide nuclear dye (Tisi et al., 2019). Greater outer nuclear layer thickness and reduced length of degenerated regions indicated photoreceptor protection.

[0195] 3. Accumulation of extracellular deposits Another AMD event is the accumulation of extracellular material visible on fundus imaging, i.e., drusen and lipofuscin (Ach et al., 2014; Davis et al., 2005). Furthermore, in photodamage models, autofluorescent (AF) extracellular debris accumulates alongside degeneration of the retinal pigment epithelium and photoreceptors (Tisi et al., 2020b). Therefore, quantifying autofluorescent extracellular debris on frozen retinal sections using fluorescence microscopy, and a reduction in AF extracellular debris deposits in treated eyes, indicates retinal protection.

[0196] 4. Nerve inflammation Neuroinflammatory events are a driving factor in AMD. Retinal neuroinflammation involves the responsiveness of microglia and macroglia (astrocytes and Müller cells) (Gupta et al., 2003; Dhodapkar et al., 2022). Glial markers (IBA-1 for microglia and GFAP for astrocytes and Müller cells) are used to investigate neuroinflammatory events based on the expression of IBA-1(+) cells and GFAP throughout the retinal layer. A decrease in the number of microglia and GFAP expression in the photodamaged retina indicates a reduction in neuroinflammation.

[0197] The above data further demonstrate the neuroprotective effect on photoreceptors and improved photoreceptor function, reduced extracellular AF deposits, and preserved RPE integrity in an in vivo rat model of photodamage. Additionally, 4-Cl-butyl-CBN represents a compound capable of crossing the blood-brain barrier and entering systemic circulation, and can be delivered via topical eye drops or in vitro transdermal transfer (IVT) formulations.

[0198] References * * * The invention described herein can be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted expansively and non-limitingly. Furthermore, the terminology and expressions used herein are used as descriptive rather than restrictive terms, and there is no intention to exclude any equivalents or any part thereof shown and described herein, and it should be recognized that various modifications are possible within the scope of the claimed invention.

[0199] Therefore, it should be understood that although the invention has been specifically disclosed by way of preferred embodiments and optional features, modifications and variations can be made to the invention disclosed herein by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention disclosed herein. The invention has been described broadly and generally herein. Each species and subgenus falling within the general scope of the disclosure is also part of these inventions. This includes a general description of each invention with incidental conditions or negative limitations to remove any subject matter from the genus regardless of whether the removed material is particularly present therein.

[0200] Furthermore, since features or aspects of the invention have been described in accordance with the Markush group, those skilled in the art will recognize that the invention has also been described in accordance with any individual member or subgroup of the Markush group. It should also be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art upon review of the above description. Therefore, the scope of the invention should not be determined by reference to the above description, but rather by reference to the appended claims together with the full scope of their equivalents. All disclosures in articles and references (including patent publications) are incorporated herein by reference.

Claims

1. A compound of formula I: I， Or its derivatives and / or its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein it is based on: 。 3. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, wherein the amount (or concentration) is sufficient to inhibit neurodegeneration in the subject, wherein the amount (or concentration) sufficient to inhibit neurodegeneration is sufficient to protect retinal neurons, protect retinal tissue, protect photoreceptor cells, prevent or reduce the accumulation of autofluorescent extracellular debris, and prevent neuroinflammation.

5. The pharmaceutical composition according to claim 3 or 4, wherein the compound of formula I is present in an amount of about 0.3 µM to less than or equal to about 20 µM; in some embodiments, about 2 µM to less than or equal to about 12 µM; in some embodiments, about 3 µM to less than or equal to about 10 µM; in some embodiments, about 3 µM to less than or equal to about 15 µM; or in some embodiments, about 10 µM to less than or equal to about 15 µM.

6. The pharmaceutical composition according to any one of claims 3 to 5, wherein the pharmaceutically acceptable excipient comprises a sterile buffer.

7. The pharmaceutical composition according to claim 6, wherein the sterile buffer is PBS buffer or saline.

8. The pharmaceutical composition according to claim 6 or 7, wherein the sterile buffer comprises a polysorbate-type nonionic surfactant and sucrose.

9. The pharmaceutical composition according to claim 8, wherein the polysorbate-type nonionic surfactant is polysorbate 20.

10. The pharmaceutical composition according to any one of claims 3 to 9, comprising: Delivery carriers containing cellulose polymers and anionic polysaccharides; and Nanoparticles comprising amphiphilic non-ionizable block copolymers and compounds of formula I according to claim 1 or 2, The pharmaceutical composition said therein has a gel point of about 30°C to about 37°C.

11. The pharmaceutical composition according to any one of claims 3 to 10, wherein the pharmaceutical composition is for topical application.

12. The pharmaceutical composition according to any one of claims 3 to 11, wherein the pharmaceutical composition is intended for direct application to the eye.

13. The pharmaceutical composition according to any one of claims 3 to 12, wherein the pharmaceutical composition is for direct application to the posterior part of the eye.

14. The pharmaceutical composition according to any one of claims 3 to 13, wherein the pharmaceutical composition is an intravitreal injection.

15. The pharmaceutical composition according to any one of claims 3 to 13, wherein the pharmaceutical composition is an eye drop pharmaceutical composition.

16. The pharmaceutical composition according to any one of claims 3 to 15, wherein the pharmaceutical composition is administered every two months, monthly, weekly, every other day, daily, twice daily, or three times daily.

17. A method for protecting neurons from neurodegeneration or a method for treating neurodegeneration in neurons, the method comprising contacting the neurons with an amount (or concentration) of the compound according to claim 1 or 2 or a pharmaceutical composition according to any one of claims 3 to 16 sufficient to inhibit neurodegeneration in a subject in need.

18. A method for treating age-related macular degeneration, the method comprising administering a compound according to claim 1 or 2 or a pharmaceutical composition according to any one of claims 3 to 16 to a subject in need.

19. A method for improving the integrity of the retinal pigment epithelium, comprising administering a compound according to claim 1 or 2 or a pharmaceutical composition according to any one of claims 3 to 16 to a subject in need.

20. The method according to any one of claims 17 to 19, wherein the contact or application is directed at the eye of the subject in need.

21. The method according to any one of claims 17 to 20, wherein the method is used to protect neurons from neurodegeneration, and said neurons are retinal neurons.

22. The method according to any one of claims 17 to 21, wherein the method comprises simultaneously administering the compound or pharmaceutical composition and an additional active agent for treating age-related macular degeneration to the neuron or contacting the neuron with the compound or pharmaceutical composition and an additional active agent for treating age-related macular degeneration.

23. The method according to any one of claims 17 to 22, wherein the method comprises sequentially administering the compound or pharmaceutical composition and an additional active agent for treating age-related macular degeneration to the neuron or contacting the neuron with the compound or pharmaceutical composition and an additional active agent for treating age-related macular degeneration.

24. The method according to any one of claims 17 to 23, wherein the desired subject is a mammal.

25. The method according to any one of claims 17 to 24, further comprising anesthetizing the subject in need prior to the contact or application.

26. The method according to any one of claims 17 to 25, further comprising dilating the pupil of the subject in need prior to the contact or administration, optionally wherein, for claim 25, the dilation step is performed before or simultaneously with the anesthesia step.

27. The method according to any one of claims 17 to 26, wherein the method is used to protect neurons from neurodegeneration, and the neurons are photodamaged.

28. The method according to any one of claims 17 to 27, wherein the amount applied is sufficient to inhibit neurodegeneration.

29. The method of claim 28, wherein the amount (or concentration) sufficient to inhibit neurodegeneration is an amount (or concentration) sufficient to reduce the progression of age-related macular degeneration or associated vision loss.

30. The method according to any one of claims 19 to 26, wherein the method is used to improve the integrity of the retinal pigment epithelium and / or reduce autofluorescent deposits.

31. The method of claim 30, wherein an amount is applied and said amount is sufficient to improve retinal pigment epithelial integrity and / or reduce autofluorescent deposits.

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