Cannabinoid compounds and their use for treating neurological disorders

Abstract

Provided herein are 3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6- (alkenyl)benzoic acid compounds of Formula (I), pharmaceutical compositions thereof, and methods for neuroprotection, stimulating neurogenesis, improving basal and motor activity, anxiety-related behaviors, cognitive function and memory, sound awareness, downregulating markers of inflammation, and / or upregulating markers of neuronal function. The compounds of Formula (I) and pharmaceutical compositions comprising the same can be used to treat neurodegenerative diseases, as well as to promote neurite elongation and / or restore neurite formation in a patient in need thereof.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 545,361, filed October 23, 2023, and U.S. Provisional Patent Application Serial No. 63 / 573,398, filed April 2, 2024, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Approximately 100 million Americans will develop neurological and brain disorders at some point in their lives. These diseases are often devastating, with exorbitant physical, emotional, and economic costs. In fact, according to the U.S. Centers for Disease Control and Prevention (CDC), in 2010, the cost of treating Alzheimer's disease alone was estimated between $159 billion and $215 billion. By 2040, these costs are projected to jump to between $379 billion and $500 billion annually. Unfortunately, currently available treatments for neurodegenerative diseases may alleviate some of the associated symptoms, but there is no known cure.

[0003] Neurodegenerative diseases typically involve neuronal atrophy, axonal degeneration (e.g., Wallerian degeneration and / or Wallerian-like degeneration), axonal demyelination, and necrotizing or programmed cell death. Different types of programmed cell death, such as apoptosis, autophagy, pyroptosis, and cytoplasmosis, have been demonstrated in neurons. Therefore, methods and compositions that block or reverse these processes and thus promote neuroprotection will effectively prevent, reverse, or delay the symptoms of neurodegenerative diseases.

[0004] Cannabis plants produce many compounds, including cannabinoids, some of which may have significant medical implications. In fact, some cannabidiol extracts have shown beneficial effects in the treatment of brain injury (see, for example, U.S. Patent No. 9,205,063). Furthermore, there are numerous anecdotal reports of potential therapeutic effects. However, many cannabinoids and their derivatives do not exhibit detectable neuroprotective effects at physiological concentrations, while others have been shown to cause excitotoxicity at physiological concentrations. Given the potentially documented effects of cannabinoids, their therapeutic potential in Alzheimer's disease and other conditions is primarily attributed to the effects of THC and CBD, as well as other cannabinoid compounds (see, for example, U.S. Patent Publications 2017 / 0273914 and 2018 / 0169035). Indeed, THC and CBD have been proposed as free radical scavenging antioxidants and neuroprotective agents (see, for example, U.S. Patent No. 6,630,507).

[0005] Given the numerous symptoms and manifestations of neurodegenerative diseases, there remains a need in the art for improved compounds, compositions, and methods for treating neurodegenerative diseases, such as Alzheimer's disease, with cannabinoid compounds. These and other needs will become clear from the detailed description below. Summary of the Invention

[0006] This document describes cannabinoid compounds, compounds of formula I, pharmaceutical compositions comprising these compounds, and methods for treating neuronal diseases, including those characterized by neurodegeneration and / or those requiring or benefiting from neurogenesis. Without being bound by theory, the compounds of formula I disclosed herein can inhibit or slow the progression of neurodegenerative diseases by reducing cytotoxicity in affected neuronal populations. Furthermore, and notably, compounds of formula I can also be used to promote neurite elongation and / or restore neurite formation in damaged neurons and in patients in need. Compared to other cannabinoid compounds, compounds of formula I can be used in methods for neuroprotection, neurogenesis stimulation, improvement of basic and motor activity, improvement of anxiety-related behaviors, improvement of cognitive function and memory, improvement of phonological awareness, downregulation of inflammatory markers, and / or upregulation of neuronal functional markers in patients in need.

[0007] In a first aspect, a method for treating a patient suffering from neuronal disease or a method for inducing neurogenesis is provided, the method comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound of formula I is based on: (I) in R 1 yes , where the bond a is either cis (Z) or trans (E); R 2 yes , where the bond b is either cis (Z) or trans (E); m is an integer selected from 1 to 6; and R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

[0008] In a second aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula I: (I) Or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier thereof; wherein R 1 yes , where the bond a is either cis (Z) or trans (E); R 2 yes , where the bond b is either cis (Z) or trans (E); m is an integer selected from 1 to 6; and R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

[0009] In one or more embodiments of the first and second aspects, the compound of formula I is a compound of any one of formulas II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of formula II. In one or more embodiments, the cannabinoid compound is a compound of formula C4 (4-pentenyl-cannabinophenolic acid or 4-pentenyl-CBGA), a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof.

[0010] In a third aspect, methods are provided for treating patients with neuronal disorders that benefit from neurogenesis, comprising administering to a patient in need a therapeutically effective amount of a compound of formula I, II, or any embodiment thereof, or administering to a patient in need a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I, II, or any embodiment thereof, wherein the compound stimulates neurogenesis. In one or more embodiments, the compound of formula I is a compound of any one of formula II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of formula II. In one or more embodiments, the cannabinoid compound is formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof.

[0011] In one or more embodiments, such as the first aspect, the neuronal condition is a central nervous system (CNS) or peripheral nervous system (PNS) condition. In one or more embodiments, the CNS condition is selected from the group comprising or consisting of: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In one or more embodiments, the CNS condition is AD. In one or more embodiments, the PNS condition is selected from the group comprising or consisting of: trapped neuropathy (e.g., carpal tunnel syndrome); thoracic outlet syndrome; brachial plexus injury (e.g., as seen in motorcycle upper limb traction injury); direct open traumatic injury; diabetic neuropathy; Guillain-Barré syndrome; hereditary sensory and autonomic neuropathy (HSAN) (e.g., familial autonomic dysfunction). The compounds of formulas I and II disclosed herein, or any embodiments thereof, and pharmaceutical compositions may be administered locally or systemically to a subject to inhibit or slow the progression of neurodegenerative diseases and / or stimulate neurogenesis in the subject. In one or more embodiments, the conditions benefiting from neurodevelopment are selected from the group comprising or consisting of: Alzheimer's disease (AD), axonal injury, ischemic stroke, schizophrenia, Down syndrome, autism spectrum disorder (ASD), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, spinal muscular atrophy, motor neuron disease, chronic hearing loss, tinnitus, hyperacusis, age-related hearing loss, and balance disorders associated with cochlear synaptic lesions and vestibular synaptic lesions. In one or more embodiments, these methods further include the simultaneous or sequential application of one or more additional active agents.

[0012] In a fourth aspect, methods for promoting neurite elongation and / or restoring neurite formation are provided for patients in need, including administering a therapeutically effective amount of a cannabinoid compound as described herein. In one or more embodiments, the cannabinoid compound is a compound of any one of formulas I, II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof. In one or more embodiments, the cannabinoid compound is a compound of formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof. Patients requiring neurite elongation and / or restoration of neurite formation may include, for example, those with Alzheimer's disease (AD), axonal injury, ischemic stroke, schizophrenia, Down syndrome, autism spectrum disorder (ASD), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, spinal muscular atrophy, motor neuron disease, chronic hearing loss, tinnitus, hyperacusis, age-related hearing loss, and those with balance disorders associated with cochlear synaptic lesions and vestibular synaptic lesions.

[0013] One or more embodiments include the use of cannabinoid compounds of formulas I, II, B3, C2, C3, C4, D5, E6, and F7 for the treatment of neurodegeneration in patients in need. One or more embodiments include the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof for the treatment of neurodegeneration in patients in need. One or more embodiments include the use of cannabinoid compounds of formulas I, II, B3, C2, C3, C4, D5, E6, and F7 for the promotion of neurite elongation and / or restoration of neurite formation in patients in need. One or more embodiments further include the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof for the promotion of neurite elongation and / or restoration of neurite formation in patients in need.

[0014] In one or more embodiments, the cannabinoid compound and the pharmaceutical composition containing the cannabinoid compound may be administered via intraventricular (ICV) injection, which may be once every two weeks, once a week, twice a week, three times a week, once a day, or twice a day. In one or more embodiments, the cannabinoid compound and the pharmaceutical composition containing the cannabinoid compound may be administered systemically, such as intravenously. In one or more embodiments, systemic administration includes transdermal administration. In one or more embodiments, the compound of formula I or II, or any embodiment thereof, or the pharmaceutical composition containing the compound of formula I or II, or any embodiment thereof, may be administered orally, for example as a pill, sustained-release capsule, or sublingual spray or film. In one or more embodiments, the compound of formula I or II, or any embodiment thereof, or the pharmaceutical composition containing the compound of formula I or II, or any embodiment thereof, may be administered topically. In another embodiment, the compound of formula I or II, or any embodiment thereof, or the pharmaceutical composition containing the compound of formula I or II, or any embodiment thereof, may be administered directly to the brain.

[0015] In one or more embodiments, pharmaceutical compositions are provided comprising a compound of formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof. In one or more embodiments, the cannabinoid compound is a compound of any one of formulas I, II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof. The pharmaceutical composition may be an injectable formulation, an injectable microemulsion or nanoparticle formulation, an intravenous formulation, an intranasal spray, a sublingual spray or film formulation, or an oral formulation.

[0016] In one or more embodiments, a compound of any one of formulas I, II, B3, C2, C3, C4, D5, E6, and F7 is provided as a sustained-release formulation, wherein it can be applied topically for peripheral neuropathy. In one or more embodiments, formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, its derivatives, its prodrug, or a combination thereof is provided as a sustained-release formulation, wherein it can be applied topically for peripheral neuropathy. In one or more embodiments, a compound of any one of formulas I, II, B3, C2, C3, C4, D5, E6, and F7 is provided as an injectable microemulsion or nanoparticle formulation. In one or more embodiments, formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, its derivatives, its prodrug, or a combination thereof is provided as an injectable microemulsion or nanoparticle formulation.

[0017] In one or more embodiments, this document provides compounds of formula I, II or any embodiment thereof, pharmaceutical compositions thereof, and methods thereof for neuroprotection, stimulating neurogenesis, improving basic and motor activity, anxiety-related behavior, cognitive function and memory, phonological awareness, downregulating inflammatory markers, and / or upregulating neuronal functional markers.

[0018] 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

[0019] Figure 1 The comparative neuroprotective effect of compound I (4-pentenyl-CBGA) on differentiated SH-SY5Y human neurons in an in vitro β-amyloid-induced cytotoxicity model was illustrated compared to CBGA and CBGVA. 4-pentenyl-CBGA, CBGA, and CBGVA were shown in the presence of 5 µM Aβ1-42 (“Aβ”). Assays were normalized relative to Aβ (0%), where Aβ (5 µM) was in NH4OH (0.5%) and ethanol (0.25%). Data are presented as a reduction in cell death (%) relative to the 5 µM Aβ + solvent control (0%). Figure 1 4-Pentenyl-CBGA was shown to exhibit neuroprotective effects and be biologically active in differentiated SH-SY5Y human neurons. Compared with CBGA, 4-pentenyl-CBGA provided greater reductions in cell death at doses of 15 µM and 20 µM. Figure 1 The results show that CBGVA does not provide neuroprotection.

[0020] Figure 2 illustrates the comparative neuroprotective effects of compound I in an in vitro β-amyloid-induced cytotoxicity model using differentiated SH-SY5Y human neurons. 1-pentenyl-CBGA and 4-pentenyl-CBGA are shown in the presence of 5 µM Aβ1-42 (“Aβ”). Assays were normalized relative to Aβ (0%), where Aβ (5 µM) was in NH4OH (0.5%) and ethanol (0.25%). Data are presented as a reduction in cell death (%) normalized relative to Aβ (5 µM), where Aβ was in… Figure 2a The value is 0%, and in Figure 2b The middle value is 100%. Figure 2a and 2b1-Pentenyl-CBGA and 4-pentenyl-CBGA, respectively, demonstrated neuroprotective and bioactive effects in differentiated SH-SY5Y human neurons. The assay using 4-pentenyl-CBGA provided a greater reduction in cell death at doses of 10 µM, 15 µM, 20 µM, and 25 µM compared to the assay using 1-pentenyl-CBGA. **p<0.01; ***p<0.001.

[0021] Figure 3 The effects of compound I on neurogenesis compared to CBGA are illustrated. Differentiated SH-SY5Y cells (control) were treated with CBGA and 4-pentenyl-CBGA (5 µM to 15 µM) for 24 hours. After treatment, phase-contrast micrographs of SH-SY5Y cells were obtained using a Leica microscope with 10x objectives, and total neurite length was analyzed using the NeuronJ plugin of ImageJ software to detect neurite length. Compared with control cells, cells treated with CBGA and 4-pentenyl-CBGA (5 µM to 15 µM) showed an increase in total neurite length. When compared with CBGA, cells treated with 4-pentenyl-CBGA (5 µM to 15 µM) showed a further improvement in total neurite extension. For statistical analysis, approximately 100 to 150 cells were analyzed from multiple images, and the average total neurite length of each image was expressed as neurite length. The results are illustrated in [Figure / Image / Text - 100 µM]. Figure 3 middle.

[0022] Figure 4 The ratio of 4-pentenyl-CBGA concentration in the brain to that in plasma (brain / plasma) is plotted. Figure 4 The ratio of 4-pentenyl-CBGA was approximately 0.55 (brain / plasma) at 30 minutes post-administration, approximately 0.30 to approximately 0.35 (brain / plasma) at 75 minutes post-administration, and approximately 0.25 (brain / plasma) at 240 minutes post-administration. These results indicate that 4-pentenyl-CBGA initially enters the brain and then decreases in concentration in the brain compared to its plasma concentration for at least 4 hours post-administration.

[0023] Figure 5 illustrates the differences in behavior between control (healthy, wild-type) and TG mice treated with 4-pentenyl-CBGA in an open field-single-fence environment. Figure 5aThe image shows a three-dimensional view of the open field – a single enclosure (left), a top-down perspective view of the enclosure (right), and results of basic and kinetic activities (bottom). Mice were placed in the open field apparatus and allowed to move freely back and forth between the center 503 or the inner wall 501 of the enclosure according to their own preferences. Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with mutations in five genes that cause Alzheimer’s disease and treated with a solvent control (VC: 10% DMSO, 10% Tween, and 80% phosphate-buffered saline). Control mice were wild-type (normal, disease-free) and treated with VC. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. "4-pentenyl-CBGA (high)" mice are TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween and 80% phosphate buffered saline. Figure 5b The control mice spent more relative time near the inner wall 501 of the enclosure, which is their normal behavior. Untreated TG mice spent more relative time at the center 503 compared to control mice. TG mice treated with 4-pentane-CBGA (low) showed a tendency towards behavior similar to untreated TG mice compared to control mice, while TG mice treated with 4-pentane-CBGA (high) showed behavior similar to control mice and tended to differ from untreated TG mice with increasing dose (n=4 to 6 per group).

[0024] Figure 6 illustrates the behavior and results of control mice and TG mice treated with 4-pentenyl-CBGA in the elevated cross (+) maze behavior test. Figure 6a A 3D view of the elevated cross-shaped maze is displayed, and Figure 6bResults of behavioral tests, including anxiety-related behaviors, are shown. The elevated maze comprises open arms 601 serving as an open platform (e.g., without protective sides or walls) and closed arms 603 serving as enclosed spaces (e.g., with protective sides or surrounded by lateral barriers). The two open arms extend across the structure as a single long arm, and the two closed arms extend outward from either side of the center point of the open arms, forming a pattern of a cross (+) symbol. Mice were placed on the top surface of the elevated maze test and allowed to move freely back and forth between the open and closed arms according to their own preferences. Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with five gene mutations that cause Alzheimer’s disease and treated with VC. Control mice were wild-type (normal, disease-free) and treated with VC. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice are TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween and 80% phosphate buffered saline. Figure 6b The results showed that control mice spent more relative time in the closed arm 603, which is their normal behavior. Untreated TG mice spent more relative time in the open arm 601 compared to control mice. TG mice treated with 4-pentane-CBGA (low) showed behavior that was substantially the same as control mice, and TG mice treated with 4-pentane-CBGA (high) showed behavior similar to controls, but tended to differ from untreated TG mice with increasing dose (n=4 to 6 per group).

[0025] Figure 7 illustrates the 2-hour object recognition test. Figure 7a The mouse is shown being trained to recognize normal objects in its environment 701 (left). Figure 7a The image shows the introduction of the new object 703 into the mouse's environment (right). Figure 7bThe results of the object recognition behavior in the 2-hour study are shown, including tests of cognitive function and memory (bottom). Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with five gene mutations that cause Alzheimer’s disease and treated with VC. Control mice were wild-type (normal, disease-free) and treated with VC. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice were TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. Overall, control (WT) mice spent more time on the new object compared to the old object, and untreated TG mice showed a lower preference for the new object compared to control mice. Compared with control mice or untreated TG mice, TG mice treated with 4-pentenyl-CBGA (low) showed a lower preference for novel objects. With increasing dose, TG mice treated with 4-pentenyl-CBGA (high) showed similar behavior to control (WT) mice (n=4 to 6 per group).

[0026] Figure 8 illustrates the 24-hour object recognition test. Figure 8a The icons representing training mice (left) and testing mice (right) are shown. Figure 8b The test results are shown, including 24-hour cognitive function and memory (bottom). Figure 8a The mouse is shown being trained to recognize normal objects in its environment 801 (left). Figure 8a The image shows the introduction of the new object 803 into the mouse's environment (right). Figure 8bThe results of the object recognition behavior in the 24-hour study are shown, including tests of cognitive function and memory (bottom). Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with five gene mutations that cause Alzheimer’s disease and treated with VC. Control mice were wild-type (normal, disease-free) and treated with VC. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice were TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. Overall, control (WT) mice spent more time on new objects compared to old objects, and untreated TG mice showed a lower preference for new objects compared to control mice. TG mice treated with 4-pentyl-CBGA (low) and 4-pentyl-CBGA (high) showed similar preferences for novel objects, which were largely the same as those in the control group (n=4 to 6 in each group).

[0027] Figure 9 Observations from pre-pulse inhibition (PPI) and auditory startle response are illustrated. Results are shown as % PPI 78 dB SPL. Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with mutations in five genes leading to Alzheimer’s disease and treated with VC. Control mice were wild-type (normal, disease-free) and treated with VC. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice were TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. Untreated TG mice showed a reduced PPI for auditory sounds compared to control mice. Compared with untreated TG mice, both TG mice treated with 4-pentyl-CBGA (low) and 4-pentyl-CBGA (high) showed improved PPI (n=4 to 6 per group).

[0028] Figure 10 The levels of glial fibrillary acidic protein (GFAP) in treated mice are illustrated. Figure 10Optical density measurements of GFAP protein are shown, and results are compared between control mice, TG mice, TG mice treated with 4-pentenyl-CBGA (low), and TG mice treated with 4-pentenyl-CBGA (high). Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with mutations in five genes leading to Alzheimer's disease and treated with vitamin C. Control mice were wild-type (normal, disease-free) and treated with vitamin C. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice were TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. After euthanasia, the brain was collected and the cortex was isolated. Increased GFAP expression in the cortex was shown in untreated TG mice compared to control mice. Both TG mice treated with low-4-pentyl-CBGA and those treated with high-4-pentyl-CBGA showed improved GFAP levels in the brain. As the dose increased from low-4-pentyl-CBGA to high-4-pentyl-CBGA, GFAP protein expression became close to that in control mice.

[0029] Figure 11 The concentrations of β-amyloid protein in the cortex of control mice, untreated TG mice (5XFAD transgenic mice), TG mice treated with 4-pentenyl-CBGA (low), and TG mice treated with 4-pentenyl-CBGA (high) are plotted. Results shown are normalized relative to controls. Transgenic (TG) mice (also referred to herein as “5XFAD” or “5XFAD transgenic” mice) were bred with mutations in five genes leading to Alzheimer's disease and treated with vitamin C. Control mice were wild-type (normal, disease-free) and treated with vitamin C. “4-pentenyl-CBGA (low)” mice were TG mice treated with 10 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. “4-pentenyl-CBGA (high)” mice were TG mice treated with 40 mg / kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% phosphate-buffered saline. Compared with TG mice, both 4-pentyl-CBGA (low) mice and 4-pentyl-CBGA (high) mice resulted in lower β-amyloid protein concentrations in the cortex. Detailed Implementation

[0030] 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.

[0031] References to “about” values ​​or parameters herein include (and describe) variations of 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 refer to a dose, amount, or weight percentage that a person skilled in the art would consider to provide an equivalent pharmacological effect to that obtained from a specified dose, amount, or weight percentage. Specifically, when used in this context, the terms “about” and “approximately” consider doses, amounts, or weight percentages that differ from a specified dose, amount, or weight percentage by no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or no more than 0.5%.

[0032] Unless the context clearly specifies otherwise, the term “a / an” as used herein means one or more.

[0033] As used in this article, terms such as “patient,” “subject,” and “subject in need” refer to mammals, preferably humans.

[0034] As used herein and unless otherwise stated (i.e., as with respect to compounds), "alkyl" means a straight-chain or branched hydrocarbon group having one to twenty carbon atoms. In one or more embodiments, the alkyl group has one to twelve carbon atoms. In one or more embodiments, the alkyl group has one to six carbon atoms. In one or more embodiments, the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc.

[0035] As used herein, “alkoxy” means –OR group, where R is an alkyl group as defined in this section.

[0036] As used herein, “alkoxycarbonyl” means -C(O)OR group, where R is an alkyl group as defined herein.

[0037] As used herein, “alkoxycarbonyloxy” means -OR group, where R is an alkoxycarbonyl group as defined herein.

[0038] As used herein, “alkoxycarbonyloxymethyl” means -CH2OR group, where R is an alkoxycarbonyl group as defined herein.

[0039] As used herein, “alkoxycarbonyloxyethyl” means -CH2CH2-OR group, where R is an alkoxycarbonyl group as defined herein.

[0040] As used herein, “alkoxycarbonylamino” means -NR group, where R is an alkoxycarbonyl group as defined herein.

[0041] As used herein, “alkoxycarbonylaminomethyl” means -CH2NR group, where R is an alkoxycarbonyl group as defined herein.

[0042] As used herein, “alkoxycarbonylaminoethyl” means -CH2CH2-OR group, where R is an alkoxycarbonyl group as defined herein.

[0043] As used herein, "alkanoyl" means -C(O)R group, where R is an alkyl group as defined herein.

[0044] As used herein, “alkanoyloxy” means -OR group, where R is an alkanoyl group as defined herein.

[0045] As used herein, “alkanoyloxymethyl” means -CH2OR group, where R is an alkanoyl group as defined herein.

[0046] As used herein, “alkanoyloxyethyl” means -CH2CH2OR group, where R is an alkanoyl group as defined herein.

[0047] As used in this article, "succinyl" refers to the -C(O)-CH2CH2-C(O)- group.

[0048] As used in this article, "amino" refers to the -NH2 group.

[0049] As used herein, “aryl acyl” means a -C(O)R group, where R is an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, tolyl, and xylyl.

[0050] As used herein, "aminoacyl" means -C(O)R group, where R is an amino group as defined herein.

[0051] As used herein, “alkylamino” means -NHR group, where R is an alkyl group as defined in this section.

[0052] As used herein, “alkylaminoalkyl” means an alkylamino group substituted with an alkyl group as defined in this section.

[0053] The term "geraniyl" in this article refers to the functional group derived from geraniol (i.e., geraniol without a terminal -OH group). Geraniyl can also be referred to as a 2-(3,7-dimethyloctyl-2,6-dien-1-yl) group and can be cis (Z) or trans (E).

[0054] As used in this article, "CBGA" or "cannabinoid acid" refers to 3-[(2 E 3,7-Dimethyloctyl-2,6-dienyl]-2,4-dihydroxy-6-pentylbenzoic acid.

[0055] As used herein, “3-but” and “3-butenyl” (e.g., on 3-but-CBGA and 3-butenyl-CBGA) refer to but-3-en-1-yl.

[0056] As used herein, “4-pentyl” and “4-pentenyl” (e.g., on 4-pent-CBGA and 4-pentenyl-CBGA) refer to pent-4-en-1-yl.

[0057] As used herein, “3-pentyl” and “3-pentenyl” (e.g., on 3-pent-CBGA and 3-pentenyl-CBGA) refer to pent-3-en-1-yl.

[0058] As used herein, “2-pentyl” and “2-pentenyl” (e.g., on 2-pent-CBGA and 2-pentenyl-CBGA) refer to pent-2-en-1-yl.

[0059] As used herein, “1-pentyl” and “1-pentenyl” (e.g., on 1-pent-CBGA and 1-pentenyl-CBGA) refer to pent-1-en-1-yl.

[0060] As used herein, “5-hex” and “5-hexenyl” (e.g., on 5-hex-CBGA and 5-hexenyl-CBGA) refer to hex-5-en-1-yl.

[0061] As used herein, “6-heptane” and “6-heptenyl” (e.g., on 6-hept-CBGA and 6-heptenyl-CBGA) refer to hept-6-en-1-yl.

[0062] As used herein, “7-octyl” and “7-octenyl” (e.g., on 6-oct-CBGA and 7-octenyl-CBGA) refer to oct-7-en-1-yl.

[0063] “Salt” means an acid salt 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.

[0064] Therefore, when a therapeutically active agent (such as, but not limited to, a compound having any of formulas I, II, B3, C2, C3, C4, D5, E6, and F7 or a derivative thereof) alone or as included in a pharmaceutical composition according to this disclosure has a sufficiently acidic, sufficiently basic, or both sufficiently acidic and sufficiently basic functional group, this or these groups can accordingly react with a variety of inorganic or organic bases, and any of inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include those prepared by reacting a pharmacologically active compound with an inorganic or organic acid or inorganic base, such as salts including: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, isobutyrates, hexanoates, heptanates, propargylates, oxalates, malonates, succinates, and octanoic acid. Salts, sebacic acid salts, fumarate salts, maleates, butyn-1,4-diacid salts, hexyn-1,6-diacid salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0065] If the active pharmaceutical 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.

[0066] If a pharmacologically 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 an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary, 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.

[0067] "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.

[0068] "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 colorants. Those skilled in the art will recognize that other pharmaceutical excipients can be used in this disclosure.

[0069] As used herein, the terms “therapeutic effective quantity,” “therapeutic effective dose,” or “therapeutic effective amount” refer to the dose of one or more compounds described herein or the dose by which a pharmaceutical composition is administered to produce a therapeutic effect. The exact dose will depend on the purpose of treatment and will be determined by someone 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 ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0070] Cannabinoids Cannabinoids are a group of chemical substances known to activate cannabinoid receptors in cells throughout the human body, 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 tricyclic terpenoid compounds with a benzopyran moiety.

[0071] Cannabinoids include, but are not limited to, plant cannabinoids. In some cases, cannabinoids include, but are not limited to, cannabinol (CBN), cannabidiol (CBD), 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 [Isochrome-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), cannabichromene (CBC), cannabichromevarin (CBCV), cannabigerol (CBG), cannabipolyphenolic acid (CBGA), cannabigerovarin (CBGV), cannabielsoin (CBE), cannabicyclol (CBL), cannabivarin (CBV), and cannabitriol (CBT). Other cannabinoids include tetrahydrocannabinol (THCV) and cannabinol monomethyl ether (CBGM). Other cannabinoids include cannabinoid-3-hydroxycorticoline (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.

[0072] 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.

[0073] Cannabinoids exert their effects by interacting with cannabinoid receptors present on cell surfaces. To date, two types of cannabinoid receptors, CB1 and CB2, have been identified. These two receptors share approximately 48% amino acid sequence identity, are distributed in different tissues, and have different cell signaling mechanisms. Their sensitivities to agonists and antagonists also differ, and the numerous cannabinoids that affect one or sometimes both receptors extensively make functional generalization difficult. Notably, recent studies have shown that cannabinoid-based agonists of the CB2 receptor can induce neuronal damage (Wojcieszak et al., J. Mol. Neurosci. (2016) 58:441-445), and thus determining the appropriate type and / or level of cannabinoid receptor interactions in neuronal tissue has proven difficult to achieve until now.

[0074] Unbound by theory and contrary to the findings of Wojcieszak et al. as previously described herein, in one or more embodiments, compounds of formulas I and II of this disclosure, or any embodiment thereof, may selectively bind to the CB2 cannabinoid receptor and act as a partial or complete agonist. In one or more embodiments, compounds of formulas I and II of this disclosure, or any embodiment thereof, may bind to both CB1 and CB2 receptors, but exhibit a higher affinity for the CB2 receptor. In one or more embodiments, compounds of formulas I and II of this disclosure, or any embodiment thereof, may downregulate the expression of the CB1 receptor and / or modulate the translocation of CB1R to the neuronal membrane. In one or more embodiments, compounds of formulas I and II of this disclosure, or any embodiment thereof, may upregulate the expression of the CB2 receptor and / or increase the translocation of CB2R to the membrane. In one or more embodiments, compound I is according to formula II.

[0075] Unbound by theory, compounds of Formula I or II of this disclosure, or any embodiment thereof, can increase neurite ingrowth and / or enhance the expression of neuronal microtubule-associated protein (MAP2) in cells and neurites, thereby providing stability to neurons. In one or more embodiments, compounds of Formula I or II of this disclosure, or any embodiment thereof, can enhance the expression of microtubule structural units (e.g., Tuj1 protein), thereby stabilizing axonal structure and dendrites to improve neuronal communication.

[0076] In one or more embodiments, the structures in this disclosure include double bonds, including as... and As depicted in the text. In such structures, the double bonds (bond a or bond b) can be either E or Z configurations, unless the context otherwise specifies, for example, when R... 3 When it is H. In one or more embodiments, each double bond is independently of the E configuration.

[0077] Implementation Scheme 2. In the implementation schemes of the first, second, third, or fourth aspects, the compound of formula I is the compound of formula II: (II) Or its pharmaceutically acceptable salt.

[0078] Implementation Plan 3. In the implementation plan of the first, second, third, or fourth aspect, or in Implementation Plan 2, R 2 It contains a total of 4, 5, 6, 7 or 8 carbon atoms.

[0079] Implementation Plan 4. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 3, R 2 It contains a total of 5, 6, 7 or 8 carbon atoms.

[0080] Implementation Plan 5. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 4, R 2 It contains a total of 5 carbon atoms.

[0081] Implementation Plan 6. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 5, R 3 It is H.

[0082] Implementation Plan 7. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 5, R 3 It is CH3.

[0083] Implementation Plan 8. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 5, R 3 It is CH2CH3.

[0084] Implementation Plan 9. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 8, R 2 The double bond in it is trans.

[0085] Implementation Plan 10. In the implementation plan of the first, second, third, or fourth aspect, or in any of Implementation Plans 2 to 8, R 2 The double bond in it is cis.

[0086] Implementation Scheme 11. In the implementation schemes of the first, second, third, or fourth aspect, the compound of formula (I) is selected from the group consisting of: (B3); (C2); (C3); (C4); (D5); (E6) and (F7); Or its pharmaceutically acceptable salt.

[0087] Implementation Scheme 12. In the implementation schemes of the first, second, third, or fourth aspect, the compound of formula (I) is selected from the group consisting of: (C2); (C3) and (C4); Or its pharmaceutically acceptable salt.

[0088] Implementation Scheme 13. In the implementation schemes of the first, second, third, or fourth aspect, the compound of formula (I) is: (C4); Or its pharmaceutically acceptable salt.

[0089] Implementation Scheme 14. In any of the implementation schemes of the first, second, third or fourth aspects or any of implementation schemes 1 to 13, the compound of formula (I) or (II) is not a pharmaceutically acceptable salt.

[0090] Implementation Scheme 15. In any of the implementation schemes of the first, second, third or fourth aspects or any of implementation schemes 1 to 13, the compound of formula (I) or (II) is a pharmaceutically acceptable salt thereof.

[0091] Implementation Scheme 16. In the implementation scheme of the first, third, or fourth aspect, or in any one of implementation schemes 1 to 15, the method includes inducing neurogenesis.

[0092] Implementation Scheme 17. In the implementation scheme of the second aspect or any of Implementation Schemes 2 to 15, the concentration of the compound in contact with the target neuron or target neuron population is 1 to 30 µM.

[0093] Implementation Scheme 18. In the implementation scheme of the second aspect or any of Implementation Schemes 2 to 15, the concentration of the compound is a systemic concentration of about 0.5 mg / kg to about 6 mg / kg.

[0094] In one or more embodiments, the systemic administration concentration is the concentration applied to provide an appropriate concentration of the compound in contact with the target neuron or group of target neurons.

[0095] Implementation Scheme 19. In the implementation schemes of the first, third, or fourth aspects, or any of Implementation Schemes 2 to 15, the neuronal symptom is Alzheimer's disease.

[0096] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula B3: B3.

[0097] Formula B3 is (E)-6-(but-3-en-1-yl)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxybenzoic acid or 3-butenyl-CBGA.

[0098] In one or more embodiments, compounds according to formula C1 are provided: C1 It is named 3-((E)-3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-((E)-pent-1-en-1-yl)benzoic acid or 1-pentenyl-CBGA.

[0099] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula C2: C2.

[0100] Formula C2 is 3-((E)-3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-((E)-pent-2-en-1-yl)benzoic acid or 2-pentenyl-CBGA.

[0101] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula C3: C3.

[0102] Formula C3 is 3-((E)-3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-((E)-pent-3-en-1-yl)benzoic acid or 3-pentenyl-CBGA.

[0103] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula C4: C4.

[0104] Formula C4 is (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-(pent-4-en-1-yl)benzoic acid or 4-pentenyl-CBGA.

[0105] In one or more embodiments, the compound or derivative of formula I or II is a compound according to formula C4: C4.

[0106] Formula C4 is (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-(pent-4-en-1-yl)benzoic acid or 4-pentenyl-CBGA.

[0107] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula D5: D5.

[0108] Formula D5 is (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-6-(hex-5-en-1-yl)-2,4-dihydroxybenzoic acid or 5-hexenyl-CBGA.

[0109] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula E6: E6.

[0110] Formula E6 is (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-6-(hept-6-en-1-yl)-2,4-dihydroxybenzoic acid or 6-heptenyl-CBGA.

[0111] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound according to formula F7: F7.

[0112] Formula F7 is (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2,4-dihydroxy-6-(oct-7-en-1-yl)benzoic acid or 7-octenyl-CBGA.

[0113] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound selected from the group consisting of: (B3); (C2); (C3); (C4); (D5); (E6) and (F7); And / or its pharmaceutically acceptable salts.

[0114] In one or more embodiments including the first, second, third, and fourth aspects, the compound or derivative of formula I or II is a compound selected from the group consisting of: (C2); (C3) and (C4); And / or its pharmaceutically acceptable salts.

[0115] In some cases, a Formula I compound or its precursor may be purified, derivatized (e.g., to form a prodrug or salt, or to form a target cannabinoid from the precursor) and / or formulated into a pharmaceutical composition.

[0116] 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.

[0117] 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 cannabinoids, such as 4-pentenyl-CBGA or 4-pentenyl-CBGA derivatives, and other therapeutically active compounds used in or included in compositions according to this disclosure, in such a manner 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, cleaves 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 a cannabinoid compound, such as a protected derivative of 4-pentenyl-CBGA or a protected derivative of 4-pentenyl-CBGA.

[0118] For example, if a therapeutic agent or a pharmaceutically acceptable form of a therapeutic agent contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing a hydrogen atom of the carboxylic acid group with a group such as C 1-8 Alkyl, C 2-12 Alkyloxymethyl, 1-(alkoxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkoxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, and methyl-1-(alkoxycarbonyl)ethyl having 4 to 10 carbon atoms. The atom is 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalyl, 4-crotonyl lactone, γ-butyrolactone-4-yl, di-N,N(C1-C2)alkylamino(C2-C3)alkyl (such as (3-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di-(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidinyl-, pyrrolidine-, or morpholino(C2-C3)alkyl.

[0119] In some cases, the therapeutic agent or a pharmaceutically acceptable form of the therapeutic agent is a compound of formula I, and the prodrug comprises 3,6,9,12-tetraoxatridecyl ester; N,N-dimethylglycyl ester; 3,6,9,12-tetraoxatridecyl carbonate; N-formylglycyl ester; N-formyldodecylsarcosinate ester; 3,6,9,12-tetraoxatridecyl oxalate; hemisuccinate; 4-aminobutylcarbamate; prolyl ester; 3-dimethylaminopropionate; glycolate; (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.

[0120] In some cases, the therapeutic agent, or its pharmaceutically acceptable form, is 4-pentenyl-CBGA. (i.e., containing a carboxylic acid functional group), and the prodrug contains 3,6,9,12-tetraoxatridecyl ester; N,N-dimethylglycyl ester; 3,6,9,12-tetraoxatridecyl carbonate; N-formylglycyl ester; N-formyldodecylsarcosinate ester; 3,6,9,12-tetraoxatridecyl oxalate; hemisuccinate; 4-aminobutylcarbamate; prolyl ester; 3-dimethylaminopropionate; glycolate; (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 derivatives.

[0121] Similarly, the prodrug can be formed by replacing the hydrogen atom of the alcohol group of the compound of formula I 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 from the hemiacetal form of a carbohydrate).

[0122] 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 cannabinoid phenolic acid 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 metabolites 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, Advanced Drug Discovery Reviews (Elsevier Press 1992); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., editors, 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).

[0123] Exemplary prodrugs that can be used in compositions and methods according to one or more embodiments of this disclosure include, but are not limited to, the following compounds according to formula II-A or II-B (in one or more embodiments, the prodrug of formula II includes, but is not limited to, a prodrug of 4-pentenyl-CBGA):

[0124] Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans form at bond b; and Where R 1a It is a prodrug portion; and wherein 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, the P(=O)(OX)(OY) group is selected from the group consisting of diphosphates and triphosphates. In one or more embodiments, the compound is in the form of a salt of a diphosphate or triphosphate. In one or more embodiments, the compound is according to one of the following formulas: III Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans form at bond b; and Where R 4a It is a straight-chain or branched substituted or unsubstituted alkyl group or R 4a It is an alkoxyalkyl, alkylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R 4a Containing 1 to 12 carbon atoms and optionally no more than 4 substitutions, more preferably wherein R 4a It contains 1 to 6 carbon atoms and optionally no more than 2 substitutions; IV Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans form at bond b; and Where R 4a It is a straight-chain or branched substituted or unsubstituted alkyl group or R 4a It is an alkoxyalkyl, alkylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R 4a Containing 1 to 12 carbon atoms and optionally no more than 4 substitutions, more preferably wherein R 4a It contains 1 to 6 carbon atoms and optionally no more than 2 substitutions; V Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans form at bond b; and Where R 4a It is a straight-chain or branched substituted or unsubstituted alkyl group or R 4a It is an alkoxyalkyl, alkylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R 4a Containing 1 to 12 carbon atoms and optionally no more than 4 substitutions, more preferably wherein R 4a It contains 1 to 6 carbon atoms and optionally no more than 2 substitutions; VI Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans form at bond b; and Where R 4a It is a straight-chain or branched substituted or unsubstituted alkyl group or R 4aIt is an alkoxyalkyl, alkylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R 4a Containing 1 to 12 carbon atoms and optionally no more than 4 substitutions, more preferably wherein R 4a It contains 1 to 6 carbon atoms and optionally no more than 2 substitutions.

[0125] Prodrugs that can be used in compositions and methods according to one or more embodiments of this disclosure include, but are not limited to, prodrugs of the following formula G: G Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

[0126] 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.

[0127] Prodrugs that can be used in compositions and methods according to one or more embodiments of this disclosure include, but are not limited to, prodrugs of the following formula H: H Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

[0128] Prodrugs that can be used in compositions and methods according to one or more embodiments of this disclosure include, but are not limited to, prodrugs of the following formula J: J Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3It is H, and there is no cis or trans at the b key.

[0129] Prodrugs that can be used in compositions and methods according to one or more embodiments of this disclosure include, but are not limited to, prodrugs of the following formula K: K Where R 2 yes Where the key b is either a forward (Z) or a reverse (E) expression; m is an integer selected from 1 to 6; R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

[0130] Further prodrug strategies for the cannabinoid compounds described herein can be found in (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7-9, 21-24). Discussions of prodrugs are provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and EB Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987). The contents of these documents are hereby incorporated in their entirety for all purposes, particularly for the purposes of cannabinoid prodrug compositions and formulations, and methods of manufacturing, using, and / or administering such prodrug compositions described herein.

[0131] In one or more embodiments, these cannabinoid analogs or derivatives can be obtained by providing a precursor cannabinoid and further derivatizing it (e.g., by synthetic methods). Non-natural cannabinoids include, but are not limited to, 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.

[0132] In some cases, a protecting group may be included in the compound used in the method according to this disclosure or in the composition according to this disclosure. This protecting group is used to prevent subsequent hydrolysis or other reactions that can 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.

[0133] The compounds disclosed herein may be at least partially selective for binding to the CB2 cannabinoid receptor, CB1 cannabinoid receptor, TRPV receptor, GPR (G protein-coupled receptor) 18, GPR 55, GPR 119 and / or other cellular receptors. In one or more embodiments, the compounds disclosed herein are selective for binding to one or more of the CB2 cannabinoid receptor, CB1 cannabinoid receptor, TRPV receptor, GPR18, GPR 55 and GPR 119.

[0134] Pharmaceutical Composition In one or more embodiments, this document provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one or more embodiments, the compound is a pharmaceutically acceptable salt. In one or more embodiments, the concentration of the compound in the pharmaceutical composition that contacts a target neuron or a group of target neurons is 1 to 30 µM.

[0135] The pharmaceutical compositions described herein are generally formulated for administration. Therefore, pharmaceutical compositions comprising a compound of formula I or II or any embodiment thereof (e.g., 4-pentenyl-CBGA, its derivatives, or combinations thereof) are also described herein, formulated for administration with one or more pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical compositions can be prepared using well-known and readily available ingredients through known procedures.

[0136] Pharmaceutical compositions comprising cannabinoid compounds of formulas I and II, and of any embodiment thereof, may be formulated for administration to a subject in dose units containing conventionally nontoxic, pharmaceutically acceptable carriers, adjuvants, excipients, and / or mediators via one of a variety of standard routes, such as intraventricular, intrathecal, intranasal, ocular, oral, topical, parenteral, inhalation or spray, rectal, or vaginal.

[0137] 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 into forms suitable for administration to a subject via a chosen route, such as as injectables, eye drops, ophthalmic receptacle preparations, syrups, elixirs, tablets, lozenges, tablets, hard or soft capsules, pills, oral disintegrating films, nasal sprays, suppositories, oily or aqueous suspensions, dispersible powders or granules, emulsions, injectable formulations, or solutions.

[0138] In one or more embodiments, the pharmaceutical composition is formulated for administration via a systemic route, such as intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, or oral.

[0139] Pharmaceutical compositions for intranasal administration may also be available as aerosols. Pharmaceutical compositions for oral mucosal sprays may also be administered buccally, sublingually, or oropharynx. Pharmaceutical compositions for sublingual use may also be presented as liquid tinctures, lozenges, soft lozenges, tablets, sugar lozenges, or as oral disintegrating films applied sublingually. Oral, mucosal, oral mucosal spray, intranasal, pulmonary, topical, and transdermal routes of administration of cannabinoids have been described (see, for example, Bruni et al., ...). Molecules , 23: 2478; doi:10.3390 / molecules23102478 and WO2007032962A2).

[0140] Pharmaceutical compositions intended for oral use can be prepared in solid or fluid 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 can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically aesthetically pleasing and palatable formulation. Efficacy can be prepared using a hydroalcoholic (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.

[0141] Solid pharmaceutical compositions (including, but not limited to, tablets, gels, or chewable tablets) contain an active ingredient and a blend of non-toxic, pharmaceutically acceptable excipients suitable for manufacturing the 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. Tablets may be uncoated, or they may be coated using known techniques. For other reasons, coated solid pharmaceutical compositions, such as coated tablets, can delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0142] Pharmaceutical compositions for oral use can also be present as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium such as peanut oil, 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 the compound with a slurry of 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.

[0143] 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).

[0144] 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 (such as those listed earlier in this document) and flavoring agents may be added to provide a palatable oral preparation. These pharmaceutical compositions may be preserved by adding antioxidants such as ascorbic acid.

[0145] 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 illustrated by those already mentioned herein. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0146] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. 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 hexitols (dehydrated forms) (e.g., sorbitan monooleate), as well as condensation products of such metaesters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). These emulsions may also optionally contain sweeteners and flavorings.

[0147] Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents (such as those mentioned above) as known in the art. Sterile injectable preparations can 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 that can be used include, for example, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile fixed oils can be used as solvents or suspending media. A variety of mild, non-volatile oils known to be suitable for this purpose can be used, including non-natural monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can 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.

[0148] 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. (2003).

[0149] The concentration of compounds (e.g., 4-pentenyl-CBGA) in the pharmaceutical composition will vary depending on the symptoms to be treated and / or the mode of administration.

[0150] How to use In one or more embodiments, this document provides a method for treating a patient with neuronal disease, the method comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0151] This article describes methods for protecting neurons from neurodegeneration, as well as methods for stimulating neurogenesis, such as by promoting neurite elongation and / or restoring neurite formation. Typically, these methods involve contacting the affected neuronal population with a therapeutically effective amount of a compound of formula I, a single stereoisomer or mixture of stereoisomers thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, a prodrug thereof, or a combination thereof. The method may be an in vitro method. Alternatively, the method may be at least partially in vivo, such as by administering a neuroprotective composition to a subject. Administration can be intranasal, sublingual, systemic (intravenous), or local (intraventricular or subcutaneous) administration. Administration can be performed via non-invasive local application methods. For example, local application can be directly to the brain.

[0152] In one or more embodiments, the compound is administered for a period of less than twenty weeks. In one or more embodiments, the compound is administered for a period of less than 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6 weeks. In one or more embodiments, the compound is administered for a period of approximately one to sixteen weeks. In one or more embodiments, the compound is administered for a period of approximately one to twelve weeks. In one or more embodiments, the compound is administered for a period of approximately one to eight weeks. In one or more embodiments, the compound is administered for a period of approximately one to four weeks. In one or more embodiments, such as for the treatment of neurodegenerative diseases such as AD, PD, ALS, HD, MS, the duration of compound administration is extended, such as for several years, or for the duration of the patient's remaining lifespan. The compound may be administered every two weeks, once a week, twice a week, three times a week, every other day, once a day, twice a day, or three times a day.

[0153] Cannabinoid compounds can be administered to treat the brain of subjects requiring treatment to protect brain neurons. For example, the subject may have already suffered “damage” to brain neurons, such as from physical injury. As another example, the subject may have already been diagnosed with Alzheimer's disease (AD) (preclinical stage) or may have mild to severe clinical symptoms of AD. If cannabinoid compounds are administered to protect neurons, such as brain neurons, a dose can be given that provides a peak concentration (e.g., C10) of the cannabinoid compound (e.g., 4-pentenyl-CBGA or its pharmaceutically acceptable salts, derivatives, prodrugs, or combinations thereof) in contact with the target neuron or group of target neurons. max ), median (e.g., steady state) or valley (e.g., C) 谷The target neuron is preferably at a peak neuroprotective effective concentration. In one or more embodiments, the target neuron is a brain neuron. In one or more embodiments, the target neuron is a peripheral neuron. In one or more embodiments, the target neuron is a central neuron.

[0154] In one or more embodiments, the neuroprotective effective concentration of the cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, its derivatives, its prodrugs, or combinations thereof) in contact with the target neuron or target neuron population is less than about 30 µM, 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, less than about 11 µM, less than about 10 µM, less than about 5 µM, less than about 1.5 µM, less than about 0.5 µM, or less than about 0.15 µM. In one or more embodiments, the neuroprotective effective concentration of the cannabinoid compound (e.g., 4-pentenyl-CBGA or its pharmaceutically acceptable salt, derivatives thereof, prodrug thereof, or combination thereof) in contact with the target neuron or target neuron population is greater than about 0.15 µM and less than about 30 µM, or greater than about 0.15 µM and less than 30 µM, or at least about 0.15 µM and less than about 30 µM, or at least 0.15 µM and less than 30 µM, greater than about 0.15 µM and less than about 25 µM, or greater than about 0.15 µM and less than 25 µM, or at least about 0.15 µM and less than 25 µM, or greater than about 0.15 µM and less than about 20 µM, or at least about 0.15 µM and less than about 20 µM, or at least about 0.15 µM and less than about 20 µM, or at least 0.15 µM and less than 20 µM. µM, or greater than about 0.15 µM to less than about 15 µM, or greater than about 0.15 µM to less than 15 µM, or at least about 0.15 µM to less than about 15 µM, or at least 0.15 µM to less than 15 µM, 0.15 µM to less than about 10 µM, or greater than about 0.15 µM to less than 10 µM, or at least about 0.15 µM to less than 10 µM, 0.15 µM to less than about 5 µM, or greater than about 0.15 µM to less than 5 µM, or at least about 0.15 µM to less than 5 µM, or at least 0.15 µM to less than 5 µM.

[0155] In one or more embodiments, the amount of a cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, its derivatives, its prodrugs, or combinations thereof) sufficient to inhibit or slow the progression of neurodegenerative diseases is an amount resulting in a concentration of about 0.15 µM to about 15 µM, about 0.15 µM to about 10 µM, about 0.15 µM to about 7.5 µM, or about 0.15 µM to about 5 µM for contact with neurons. In one or more embodiments, the amount of a cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, its derivatives, its prodrugs, or combinations thereof) sufficient to inhibit or slow the progression of neurodegenerative diseases is an amount resulting in a concentration of about 0.5 µM to about 15 µM, about 0.5 µM to about 10 µM, about 0.5 µM to about 7.5 µM, or about 0.5 µM to about 5 µM for contact with neurons.

[0156] In one or more embodiments, for ICV administration in indications of neurodegenerative diseases (e.g., for the treatment of AD), the ICV dose may be about 11 µg to about 1.4 mg, about 11 µg to about 1.0 mg, about 11 µg to about 0.5 mg, about 11 µg to about 0.25 mg, about 11 µg to about 0.125 mg, about 5.5 µg to about 1.0 mg, about 5.5 µg to about 0.5 mg, about 5.5 µg to about 0.25 mg, or about 5.5 µg to about 0.125 mg, administered to the brain (in vitro) in the form of an injectable formulation. The dose may be repeated, for example, once every two weeks, once a week, twice a week, three times a week, every other day, once a day, or twice a day. In one or more embodiments, for ICV administration in indications of neurodegenerative diseases (e.g., for AD), the brain dose may be 1.1 µg to about 0.14 mg, 1.1 µg to about 0.10 mg, 1.1 µg to about 0.05 mg, 1.1 µg to about 0.025 mg, or 1.1 µg to about 0.0125 mg, administered to the brain in the form of an ICV injection or via a pump. The dose may be repeated, for example, once every two weeks, once a week, twice a week, three times a week, every other day, once a day, or twice a day.

[0157] In one or more embodiments, the systemic dose level (the concentration of the cannabinoid compound in the composition according to one or more embodiments) is 5 to 50 mg / kg (e.g., for intraperitoneal injection in mice). In one or more embodiments, the systemic dose level is about 1 mg / kg to about 50 mg / kg, such as 1 mg / kg to 50 mg / kg (e.g., for intraperitoneal injection in mice). In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in mice) is about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 50 mg / kg, about 5 mg / kg to about 40 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 40 mg / kg, about 20 mg / kg to about 40 mg / kg, about 30 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 50 mg / kg, or about 5 mg / kg to about 10 mg / kg.

[0158] In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in mice) is within a range having a lower limit selected from any one of 1, 5, 10, 15, 20, 25, 30, 35, 40, or 45 mg / kg; and an upper limit selected from any one of 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / kg; wherein the lower limit and the upper limit form a mathematically permissible range.

[0159] In one or more embodiments, the systemic dose level is 0.8 to 4.5 mg / kg (e.g., for intraperitoneal injection in humans). In one or more embodiments, the systemic dose level is about 0.5 mg / kg to about 6 mg / kg, such as 0.5 mg / kg to 6 mg / kg (e.g., for intraperitoneal injection in humans). In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in humans) is about 0.6 mg / kg to about 5 mg / kg, about 0.8 mg / kg to about 5 mg / kg, about 0.6 mg / kg to about 4.5 mg / kg, about 0.8 mg / kg to about 4.5 mg / kg, about 1 mg / kg to about 4.5 mg / kg, about 2.0 mg / kg to about 4.5 mg / kg, about 3.5 mg / kg to about 4.5 mg / kg, about 0.6 mg / kg to about 4 mg / kg, about 0.8 mg / kg to about 4 mg / kg, about 1 mg / kg to about 4 mg / kg, about 2 mg / kg to about 4 mg / kg, about 3 mg / kg to about 4 mg / kg, about 0.6 mg / kg to about 3.5 mg / kg, about 0.8 mg / kg to about 3.5 mg / kg, about 1 mg / kg to about 3.5 mg / kg, or about 2 mg / kg to about 3.5 mg / kg.

[0160] In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in humans) is within a range having a lower limit selected from any one of 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 1.0, 1.5, 2.0, 2.5, or 3.0 mg / kg; and an upper limit selected from any one of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 mg / kg; wherein the lower limit and the upper limit form a mathematically permissible range.

[0161] In one or more embodiments, a cannabinoid compound or a preparation thereof is administered to a subject suffering from AD. In one or more embodiments, a cannabinoid compound or a preparation thereof is administered to a subject suffering from ALS, HD, PD, or MS. In one or more embodiments, a cannabinoid compound or a preparation thereof is administered to a subject with mild to severe AD symptoms.

[0162] Cannabinoid compounds can be administered to treat subjects requiring treatment to protect peripheral neurons. For example, the subject may have already suffered damage to one or more peripheral nerves, such as from physical injury. As another example, the subject may have a disease or condition characterized by peripheral nerve degeneration. Extracerebral and extraspinal PNS conditions that would benefit from this disclosure also include entrapment neuropathy, such as carpal tunnel syndrome; brachial plexus injury, such as that seen in motorcycle upper limb traction injuries; and direct open traumatic injuries. Peripheral neuropathy distorts or disrupts the transmission of information between the brain and other parts of the body and may affect one or more nerves. Some are the result of other conditions, such as diabetic neuropathy. Others, such as Guillain-Barré syndrome, occur after a viral infection. Still others are due to nerve compression, such as carpal tunnel syndrome or thoracic outlet syndrome. In some cases, such as complex regional pain syndrome and brachial plexus injury, the problem begins after the injury. Some peripheral neuropathy conditions are hereditary. A group of hereditary conditions, such as hereditary sensory and autonomic neuropathy (HSAN), are caused by PNS dysfunction. One such condition, familial autonomic dysfunction, is caused by a mutation in the IKBKAP gene.

[0163] Cannabinoid compounds can be administered to treat subjects in need of treatment to protect central neurons. For example, the subject may already have damage to neurons in the central nervous system (CNS). As another example, the subject may have a disease or condition characterized by central nervous system degeneration.

[0164] The method may include, or further include, the simultaneous or sequential application of a second active agent in combination with a cannabinoid compound provided herein. In some cases, the second active agent is a therapeutic agent used to treat Alzheimer's disease.

[0165] The pharmaceutical composition may contain additional active agents. In one or more embodiments, the pharmaceutical composition may contain 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, its derivatives, its prodrug, or a combination thereof, as well as additional cannabinoids or terpenoids. In one or more embodiments, the pharmaceutical composition may contain additional active agents for the treatment of AD, PD, ALS, HD, and MS, or additional active agents for the treatment of neurodegenerative diseases.

[0166] Currently, different classes of therapeutic agents are used to treat and reverse Alzheimer's disease (AD), including but not limited to: FDA-approved drugs for AD that are designed to relieve symptoms such as memory loss for a limited time. These drugs (including Aricept, Exelon, Razadyne, Galantamine, Donepezil, Tacrine, and Rivastigmine) are acetylcholinesterase inhibitors that increase levels of acetylcholine, a neurotransmitter that sends signals from one brain cell to another.

[0167] Namenda works by modulating the activity of the neurotransmitter glutamate. Namzaric combines two approaches. Neither of these drugs prevents damage to brain cells; they can alleviate memory problems in the short term by modulating neurotransmitters. Currently, there are >120 potential drugs in clinical trials designed to treat the underlying cause of Alzheimer's disease, rather than its symptoms. J147 is promising as an experimental anti-aging mitochondrial ATP synthase modulator. Nevertheless, any therapeutic agent suitable for treating AD can be used in synergy with compounds of formulas I, II, B3, C2, C3, C4, D5, E6, and F7. Nevertheless, any therapeutic agent suitable for treating AD can be used in synergy with compounds of formula I, their pharmaceutically acceptable salts, their derivatives, their prodrugs, or combinations thereof.

[0168] In one or more embodiments, the pharmaceutical compositions described herein, such as those containing 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, derivatives thereof, prodrug thereof, or combinations thereof, allow for lower doses or lower frequencies of administration of one or more therapeutic agents for the treatment of AD.

[0169] Compounds of Formula I, II, or any of their formulations can also be administered to stimulate neurogenesis in patients in need. Neuroogenesis ensures proper synaptic development, axonal guidance, and neuronal function, and can play a role in ischemic stroke (Arvidsson et al., 2002; Zhang et al., 2004) and spinal cord injuries leading to axonal damage or neurodegeneration. Inadequate neurogenesis is also a potential cause of various neurodevelopmental disorders, such as (Cellular and Molecular Life Sciences (2020) 77:1511–1530) schizophrenia, Down syndrome, and autism spectrum disorder (ASD). Degeneration and loss of spinal motor neurons can also lead to progressive and fatal motor neuron diseases such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and spinal muscular atrophy. This article also considers the use of the subject compounds, compositions, and methods in regenerative therapies for motor neuron disease (Cells 2020, 9(4), 934; https: / / doi.org / 10.3390 / cells9040934) and for regenerative therapies for chronic hearing loss, tinnitus, hyperacusis, age-related hearing loss, or balance disorders associated with cochlear and vestibular synaptic lesions.

[0170] Example Example 1: Protection of differentiated SH-SY5Y neurons Cell culture and differentiation: The SH-SY5Y human neuronal cell line was derived from neuroblastoma cells established from metastatic bone tumors (patients with neuroblastoma). Cells were maintained in DMEM:F-12 medium (growth medium) supplemented with 10% FBS and 1% antibiotic-antifungal penicillin / streptomycin under a humid atmosphere of 5% CO2 at 37°C. To induce neuronal differentiation of SH-SY5Y cells, the medium was replaced with growth medium containing retinoic acid (RA), and the cells were cultured for 5 days at a humid atmosphere of 5% CO2.

[0171] Compounds and drug formulations used in animal studies: 4-Pentenyl-CBGA was prepared via biosynthesis. In short, 5-hexenoic acid was "feeded" into a *Saccharomyces cerevisiae* strain engineered to convert the acid analog to 4-pentenyl-oleucic acid. The oleucic acid analog was recovered from the culture medium by ethyl acetate extraction. Then, 4-pentenyl-oleucic acid was "feeded" into a *Saccharomyces cerevisiae* strain engineered to overproduce gerany-bisphosphate precursor (GPP) and express a heterologous gene encoding isopentenyltransferase. The biotransformation strain converted the oleucic acid analog to 4-pentenyl-CBGA, which was recovered from the yeast cells by ethyl acetate extraction and purified by preparative reversed-phase HPLC. 4-Pentenyl-CBGA can also be synthesized chemically.

[0172] A stock solution of 4-pentenyl CBGA in 100% DMSO was diluted in 10% Tween and 80% PBS to achieve the desired formulation concentration of approximately 10% DMSO for intraperitoneal administration. This yielded the compound 4-pentenyl-CBGA, consistent with the formulation of the solvent control (VC): approximately 10% DMSO, 10% Tween, and 80% phosphate-buffered saline.

[0173] For a one-day injection, dilute the DMSO stock solution in Tween, vortex mix, and then add PBS buffer to the mixture to produce a sufficient volume of formulation for administration. Vortex mix for 30 seconds or longer at the highest setting on the mixer.

[0174] For in vitro studies, Ethanol (100%) was used as the solvent to prepare stock solutions (10 mM) (e.g., for CBGA, CBGVA, and 4-pentenyl-CBGA). β-amyloid stock solutions (1 mM) were prepared in ammonium hydroxide (NH4OH). Treatment solutions were prepared directly in control medium (DMEM: F12 + 5% FBS + 1% antibiotic-antifungin) using appropriate stock solutions. Treatment concentrations of CBGA and CBGVA were prepared at 5 µM, 10 µM, 15 µM, and 20 µM. Treatment concentrations of 4-pentenyl-CBGA were prepared at 5 µM, 10 µM, 15 µM, 20 µM, and 25 µM.

[0175] Assessment of cytotoxicity and neuroprotectionThe neuroprotective and cytotoxic effects of the test compounds on differentiated SH-SY5Y human neurons were assessed by an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Initially, the cytotoxic and neuroprotective effects of the test compounds were evaluated in a primary screening assay in the absence of damaging agents that induce cytotoxicity. Subsequently, test compounds exhibiting “borderline” cytotoxicity were selected and subjected to secondary screening in the presence of damaging cytotoxic agents such as β-amyloid (Aβ1-42) peptide. SH-SY5Y neurons differentiated from retinoic acid (RA) in DMEM:F12 complete medium were seeded into 96-well plates (10,000 cells / well). Cells differentiated for 5 days in the presence of RA. Post-differentiation cells were treated with Aβ1-42 (24 h) and the test compounds, and an MTT assay was performed.

[0176] MTT assay: For MTT assays, differentiated SH-SY5Y neurons were treated with various concentrations of the test compound for 24 hours in the presence of 5 µM Aβ1-42 peptide, and treatment was performed to determine cytotoxicity. Briefly, a stock solution of 5 mg / mL methylthiazolyl diphenyltetraazolium bromide (Sigma-Aldrich) was prepared in PBS. After treating SH-SY5Y neurons with the test compound for 24 hours, the cells were incubated with 20 μL of the MTT stock solution in 200 μL of DMEM at 37°C for 2 hours. Following washing with PBS, 200 μL of isopropanol was added to the wells. The color change resulting from the dissolution of formazan salt was immediately quantified using a spectrophotometer (BMGLabtech) at 570 nm. The data were normalized relative to β-amyloid protein containing 0.5% NH4OH and 0.25% ethanol and expressed as % cell death. Results are plotted on [image / image / etc.]. Figure 1 and 2 in.

[0177] like Figure 1 As shown, 4-pentenyl-CBGA and CBGA confer effective neuroprotective effects against Aβ1-42-induced cytotoxic damage to SH-SY5Y neurons. Figure 1The neuroprotective effects of CBGA, 4-pentenyl-CBGA, and CBGVA against Aβ1-42-induced cytotoxicity in differentiated SH-SY5Y cells were compared. Co-exposure to CBGA at concentrations of 10 µM, 15 µM, and 20 µM protected cells from Aβ1-42-induced damage. Co-exposure to 4-pentenyl-CBGA at concentrations of 10 µM, 15 µM, and 20 µM protected cells from Aβ1-42-induced damage in a dose-dependent manner. CBGVA at 10 µM or 15 µM did not confer neuroprotection against Aβ1-42-induced cytotoxic damage to SH-SY5Y neurons and induced cytotoxicity. However, co-exposure to CBGVA at a concentration of 20 µM slightly protected cells from Aβ1-42-induced damage.

[0178] like Figure 2a As shown, 1-pentenyl-CBGA, in a dose-dependent manner at 5 µM, 10 µM, and 15 µM, conferred potent neuroprotection against Aβ1-42-induced cytotoxic damage to SH-SY5Y neurons; however, 1-pentenyl-CBGA induced cytotoxicity at 20 µM and 25 µM. Figure 2b As shown, 4-pentenyl-CBGA provides neuroprotection against Aβ1-42-induced cytotoxic damage to SH-SY5Y neurons at 10 µM, 15 µM, 20 µM and 25 µM, and is dose-dependent up to 15 µM.

[0179] Overall, these data indicate that the beneficial therapeutic range of 4-pentenyl-CBGA against Aβ1-42 damage is from about 10 µM to about 25 µM (or greater); and the beneficial therapeutic range of 1-pentenyl-CBGA against Aβ1-42 damage is from about 5 µM to about 15 µM. These results suggest that the R of compound I... 2 The location of the double bond may play a role in neuroprotection. For comparison, these data indicate that the beneficial therapeutic range of CBGA against Aβ1-42 lesions is approximately 10 µM to approximately 20 µM (or greater).

[0180] Example 2: Effects of Formula I compounds on neurogenesis Neurogenesis specifically involves the maturation of adult neurons and the transmission of their connections to link with other neurons. Therefore, neurogenesis distinguishes mature neurons from general neuronal growth. Changes in neurite length following treatment with compounds of Formula I were determined in a dose-dependent manner. In WO2022082313A1, CBGA was found to significantly increase neurogenesis in SH-SY5Y cells in a dose-dependent manner. To initiate neuronal differentiation, cells were seeded in pre-coated matrix gel (10 mg / mL, BD Bio-science, San Jose, CA, USA) and grown for 5 days in medium containing retinoic acid (10 µM, Sigma; St. Louis, MO, USA). SH-SY5Y cells (control) were treated with 4-pentane-CBGA (5 µM–15 µM) for 24 hours. All experiments were performed using cells from passages 14–22. Phase-contrast micrographs of SH-SY5Y cells were obtained using a Leica microscope with a 10x objective after treatment. Total neurite length was analyzed from multiple images of the cells. In short, we used the NeuronJ plugin for ImageJ software to detect neurite length and track neurites to quantify their corresponding lengths. For statistical analysis, approximately 100-150 cells were analyzed from multiple images, and the average total neurite length for each image was expressed as the neurite length. The results are plotted in... Figure 3 middle.

[0181] like Figure 3 As shown, in this study, 4-pentenyl-CBGA was found to improve neurogenesis in SH-SY5Y cells compared to CBGA at 5 µM, 10 µM, and 15 µM. Although... Figure 3 The differences shown are small, but in the tested in vitro system, the neurites only grow to a certain length. For example, the growth of the neurites in the tested in vitro system is also very small, so small that the differences are sufficient to identify neurogenesis.

[0182] Example 3: Presence of Formula I compounds in the brain and plasma The concentration of 4-pentaeno-CBGA in plasma and brain samples was determined using an Exion LC-AD liquid chromatograph coupled to a Sciex 7500QQQ mass spectrometer via HQP-LC-MS. A total of nine male 10-week-old B6.Cg-Tg mice received a single intraperitoneal injection of 40 mg / kg. Two animals were administered a control solvent (10% DMSO and 10% Tween in 80% phosphate-buffered saline). Animals were euthanized, and brain tissue and blood were collected at 30, 75, and 240 minutes after IP injection (n=3). Blood samples were immediately processed to separate plasma and stored at -80°C until analysis. Plasma and brain samples were processed for further bioanalytical analyses. Figure 4 As shown, at 30 minutes after administration, the ratio of 4-pentenyl-CBGA in brain to plasma was approximately 0.55. At 75 minutes after administration, the ratio of 4-pentenyl-CBGA in brain to plasma decreased to the range of approximately 0.30 to approximately 0.35. At 240 minutes after administration, the ratio of 4-pentenyl-CBGA in brain to plasma decreased to approximately 0.25.

[0183] Example 4: In vivo behavioral testing In vivo study design: For in vivo experiments, TG mice (5XFAD transgenic male mice) were purchased from JAX / MMRRC and housed in MBF, UBC. TG mice exhibited AD pathological conditions such as rapid β-amyloid plaque deposition, neurodegeneration, and cognitive impairment. Five-week-old mice were acclimatized to light and dark cycles, and at 8 weeks of age, administration of the appropriate solvent and / or compound of formula I was initiated. Mice were treated three times weekly for 8 weeks, followed by twice weekly treatment for another 5 weeks, with behavioral tests performed at week 21. In these tests, n = 4 to 6 per group.

[0184] Compound 4-pentane-CBGA (stock solution 125 mg / ml) was prepared in 10% DMSO and 10% Tween in 80% phosphate-buffered saline (6.25 mg / ml). A total of seven male 8-week-old B6.Cg-Tg mice received repeated intraperitoneal doses of 4-pentane-CBGA [10 mg / kg (low) and 40 mg / kg (high)] (twice or three times weekly) for three months. Seven male WT mice and seven TG mice were also administered solvent controls. Between 4 and 5 months of age, a series of behavioral tests were performed on wild-type (WT) controls and TG mice, including open field (OFT), elevated cross maze (EPM), novel object recognition (NORT), and auditory startle response assessment. These tests were designed to establish a comprehensive baseline relative to the experimental timeline.

[0185] Behavioral Test 1: Open Field - Single Fence (Basic and Motor Activities) To establish baseline basal and motor activity, control (normal, wild-type) and TG mice were observed after being placed in an open field—a single-fence enclosure. The open field was used as a tool to assess anxiety-like responses in mice exposed to an unshaded, expansive area. The open field apparatus consisted of a 72 x 72 cm square of plexiglass bounded by a 36 cm high wall. Mice were positioned in one corner of the space and allowed to navigate the area for a duration of 7 minutes. Indicators of anxiety-like responses, such as the duration spent in the center of the field, were recorded. Mouse movement was recorded and analyzed using a video tracking system (ezTrack). Control mice were observed to spend more time near the wall throughout the test and less time near the center, with a relative proportion of time spent near the center of the enclosure of 0.06. TG mice were observed to spend a relative proportion of time near the center of the enclosure of 0.14. Next, TG mice treated with 4-pentane-CBGA (low) were tested, and their relative proportion of time spent near the center was observed to be from approximately 0.08 to approximately 0.1. 4-pentane-CBGA (high) TG mice were tested, and the relative time proportion near the center was observed to be approximately 0.04 to approximately 0.06. These results are presented in... Figure 5b Medium. N: Control = 5; TG = 5; 4-pentane-CBGA (low) = 6; 4-pentane-CBGA (high) = 4. 5XFAD mice: male, age: 4.5 months. Error bars: standard error of the mean (SEM).

[0186] Based on these tests, the results showed that, compared with TG mice, mice treated with 4-pentenyl-CBGA improved basal and motor activities in a dose-dependent manner. Furthermore, TG mice treated with high levels of 4-pentenyl-CBGA met or exceeded the results exhibited by healthy control mice. Unbound by theory, these tests indicated that, compared with controls, TG mice treated with high levels of 4-pentenyl-CBGA exhibited the same or increased anxiety-like behaviors, while TG mice exhibited fewer anxiety-like behaviors.

[0187] Behavioral Test 2: Elevated Cross Maze Test (Anxiety-Related Behaviors) An elevated cruciform maze was used to determine the effects of Formula I compound on anxiety-related behaviors. The maze consisted of four arms radiating from a central square (5 x 5 cm) (each arm measuring 30 x 5 cm). The structure was 45 cm above the ground. Two of these arms were surrounded by 15 cm high lateral barriers (referred to as closed arms), while the other two had no barriers (referred to as open arms). During a phase, mice were positioned in the center of the maze, facing the open arms, and allowed to traverse the maze over a 7-minute time span. Observations associated with anxiety-like behaviors, such as the duration spent in the open and closed arms, were noted. Mouse movement was recorded and analyzed using a video tracking system (ezTrack). Control mice (normal, wild-type) and TG mice were observed after being placed on the platform. Control mice moved toward the closed arms (protected, laterally enclosed) of the enclosure. Thus, the relative proportion of time spent by control mice (normal, wild-type) in the open arms of the elevated maze was observed to be approximately 0.15. The relative proportion of time spent by untreated TG mice in the open arms was observed to be approximately 0.2 to approximately 0.25. TG mice treated with 4-pentane-CBGA (low) were tested, and their relative time proportion in the open arm was observed to be approximately 0.15. TG mice treated with 4-pentane-CBGA (high) were tested, and their relative time proportion in the open arm was observed to be approximately 0.1 to approximately 0.15. These results are presented in... Figure 6b Medium. N: Control = 6; TG = 4; 4-pentyl-CBGA (low) = 6; 4-pentyl-CBGA (high) = 4. 5XFADF mice; male; age: 4.5 months.

[0188] These results showed that anxiety-related behaviors in TG mice treated with 4-pentenyl-CBGA increased to or exceeded those in the healthy control group compared with the untreated TG group. A dose-dependent improvement was observed.

[0189] Behavioral Test 3: 2-Hour New Object Recognition (Cognitive Function and Memory) To determine the effect of compound I on short-term and long-term memory impairment in TG mice, a novel object recognition test (NORT) was performed. Mice were placed in an open, transparent box containing two identical objects for 10 minutes to allow them to become familiar with the objects. Observations were recorded and presented. Figure 7b (Comparison with the old object). Short-term memory assessment was performed two hours later. During this phase, the mice were placed in the box again with one of their familiar objects and the new object for five minutes. Observations were recorded and presented. Figure 7b (Control Novel Object). Novel objects were tested using control mice (normal, wild-type; "Control Novel Object"), untreated TG mice ("TG Novel Object"), TG mice treated with 4-pentyl-CBGA (low), and TG mice treated with 4-pentyl-CBGA (high); observations were recorded and presented. Figure 7bMedium. N: Control = 6; TG = 4; 4-pentyl-CBGA (low) = 6; 4-pentyl-CBGA (high) = 4. 5XFAD mice: male, age: 4.5 months. Error bars: SEM. Untreated TG mice did not show a preference for novel objects (number of visits); however, they spent less total time on novel objects compared to control (normal, wild-type) mice.

[0190] The control group with the old object spent the same amount of time on the object in the environment, approximately 1.0 relative time compared to the previous old object control. The control group with the new object spent more time on the new object in the environment than on the old object, or approximately 1.6 relative time compared to the control with the old object. Compared to the control group with the new object, the untreated TG group (TG new object) spent less time on the new object; compared to the control with the old object, the TG group (untreated) spent approximately 1.2 relative time. In other words, the TG mice (untreated) showed little or no preference between the old and new objects. When the new object was placed in the treatment group environment, the TG mice treated with 4-pentane-CBGA (low) performed similarly to the control mice with the old object (approximately 1.0 relative time compared to the control with the old object), and the TG mice treated with 4-pentane-CBGA (high) performed similarly to the healthy control mice with the new object (control new object) (approximately 1.4 relative time compared to the control with the old object).

[0191] These results show that control (wild-type) mice (control new object) showed a greater preference for new objects compared to untreated TG mice (TG new object). Without being bound by theory, this observed behavior may be due to the exploratory nature of mice. Untreated TG mice (TG new object) exhibited a lower preference for new objects compared to control (wild-type) mice (control new object) because they spent less total time on new objects. TG mice treated with 4-pentyl-CBGA (high) exhibited similar behavior to wild-type mice (control old object). Therefore, increased doses of 4-pentyl-CBGA (high) were observed to improve cognition, function, and memory (after 2 hours of exposure) compared to 4-pentyl-CBGA (low) mice.

[0192] Behavioral Test 3: 24-Hour New Object Recognition (Cognitive Function and Memory) Cognitive function and memory tests were performed 24 hours after initial familiarization (familiarization with the object at time zero). Mice were reintroduced into a box containing the original object and a new object different from the one used in the short-term memory assessment. Memory was measured as a preference for the amount of time spent exploring the new object relative to the amount of time spent exploring the old object (new object preference). Exploration was defined as the time the mouse paused and sniffed the object. Results are plotted on... Figure 8bIn this study, novel objects were tested using control mice (healthy, wild-type), untreated TG mice, TG mice treated with low 4-pentane-CBGA, and TG mice treated with high 4-pentane-CBGA; observations were recorded and presented. Figure 8b Medium. N: Control = 6; TG = 4; 4-pentyl-CBGA (low) = 4; 4-pentyl-CBGA (high) = 3. 5XFAD mice: male, 4.5 months old. Error bars: SEM. Untreated TG mice did not show a preference for novel objects in terms of the number of visits; however, they spent less time on object(s).

[0193] The control group with the old object spent the same amount of time on the object in their environment, approximately 1.0 relative time compared to the previous old object control. The control group with the new object spent more time on the new object in their environment compared to the old object, or approximately 1.2 to approximately 1.4 relative time compared to the old object control. The untreated TG group spent less time on the new object (control new object) compared to the control group; and approximately 0.8 to approximately 1.0 relative time compared to the old object control. In other words, the untreated TG mice showed little or no preference between the old and new objects. When the new object was placed in the treatment group environment, both the 4-pentyl-CBGA (low) and 4-pentyl-CBGA (high) TG mice performed similarly to the control new object mice (approximately 1.2 to approximately 1.4 relative time compared to the old object control).

[0194] These results further confirm that healthy wild-type mice showed a greater preference for novel objects compared to untreated TG mice. Untreated 5XFAD (TG) mice exhibited a lower preference for novel objects compared to healthy wild-type mice, as they spent less total time on novel objects. 4-Pentenyl-CBGA (low) and 4-Pentenyl-CBGA (high) TG mice remembered objects they had observed before the novel objects were placed in their environment, and they exhibited similar behavior to healthy wild-type mice. Therefore, TG mice treated with 4-pentenyl-CBGA at doses ranging from 10 to 40 mg / kg showed improved cognition, as well as function and memory (24 hours after exposure).

[0195] Behavioral Test 4: Auditory Startle (Sound Awareness) To determine the impact of hearing loss in conjunction with Alzheimer's disease, prepulse inhibition or auditory startle (vocal awareness) tests were performed. Prepulse inhibition of the auditory startle reflex is a tool for measuring the detection threshold in conscious animals. In these tests, hearing loss is associated with neuronal loss. The auditory startle test was used to assess the startle response to auditory signals and to evaluate sensorimotor gating, known as prepulse inhibition. Mice were placed in a compact holding chamber within a large startle apparatus. They were then exposed to auditory cues in the range of 70–120 dB to elicit a startle response, determined based on their movement. Prepulse inhibition was determined using paired auditory cues, where a lower intensity sound immediately preceded a higher intensity sound. Prepulse inhibition was characterized by a reduced startle response to subsequent sounds compared to their response to the same sound presented itself. Mice underwent a single test phase lasting 16 minutes, during which 32 trials characterized by different auditory signals were performed. Hearing impairment was measured by the maximum startle response (Vmax) and the percentage of pre-pulse inhibition (PPI), calculated using the formula 100 - [(Vmax of the PPI test / Vmax of the startle test alone) × 100]. Results are plotted in... Figure 9 middle.

[0196] like Figure 9 As shown, in these experiments, untreated TG mice tested at approximately 25-30% PPI (78 dB SPL) compared to control mice, which tested at approximately 50-55% PPI. 4-pentenyl-CBGA (low) mice and 4-pentenyl-CBGA (high) TG mice tested at approximately 40-50% PPI (78 dB SPL). In summary, TG mice showed improved startle response when treated with 4-pentenyl-CBGA, suggesting a reduction in neuronal loss in the olfactory cortex of the brain. N = 4-6 animals per group. Error bars: SEM.

[0197] Example 5: RNA sequence profile To determine whether the RNA sequence profiles of the brain samples were consistent with the results of the 4-pentenyl-CBGA treatment, several genes associated with Alzheimer's disease were found to have statistically significant alterations, and their changes (e.g., upregulation, downregulation, etc.) were observed.

[0198] Methodology: RNA isolation and quality control: Total RNA was extracted from cortical brain tissue using the Qiagen RNeasy kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Quality control assessment for RNA integrity and purity was performed using an Agilent 2100 Bioanalyzer. Samples with an RNA integrity number (RIN) of 9 or greater were used.

[0199] RNA-seq library preparation and transcriptome analysis: mRNA libraries were prepared using the Illumina® Chain-Linked mRNA Library Preparation Kit (catalog number 20040534). miRNA libraries were prepared using the OTTR cDNA Library Construction Kit. Libraries were sequenced using the high-throughput Illumina NextSeq 550 sequencing platform to generate paired-end reads (2 x 150 bp). Read quality was controlled using the FastQC tool. Reads were mapped to the genome using TopHat2 (UCSC hg38), and transcripts were quantified using Cufflinks. Differential expression (DE) analysis was performed using Cuffdiff2 to identify AD-related genes differentially expressed among control (healthy, wild-type) mice, untreated TG mice, and 4-pentane-CBGA-treated TG mice. Based on evidence involving specific toxicological genomic targets, the study targeted genes involved in inflammation and neuronal health.

[0200] Pathway enrichment analysis: GSEA was used to perform gene set enrichment analysis on differentially expressed genes to detect enriched biological and cellular pathways.

[0201] The RNAs in these sequence profiles are associated with inflammatory genes and neuronal health. When untreated TG mice were tested, higher concentrations (upregulated) of inflammation-related RNAs were found compared to controls (healthy, wild-type). In untreated TG mice, lower concentrations (downregulated) of RNAs associated with neuronal health were found compared to controls (healthy, wild-type). In other words, control mice retained wild-type gene and RNA production, while untreated TG mice exhibited RNA production similar to that of Alzheimer's disease.

[0202] In TG mice treated with 4-pentenyl-CBGA (4-pentenyl-CBGA (low) mice and 4-pentenyl-CBGA (high) mice), RNA sequencing revealed that, compared with untreated TG mice, inflammatory pathways were downregulated (downregulation of inflammatory markers) and neuronal health pathways were upregulated (upregulation of neuronal function markers). Specifically, compared with control (normal wild-type) mice, the untreated TG group showed increased pro-inflammatory genes and decreased neuronal function genes. The 4-pentenyl-CBGA (low) group showed decreased pro-inflammatory genes compared to TG. The 4-pentenyl-CBGA (high) group showed decreased pro-inflammatory genes and increased neuronal function genes compared to untreated TG. These data are consistent with behavioral study data. These results also indicate that neural pathways are preserved in 4-pentenyl-CBGA-treated mice.

[0203] The results of the behavioral test described in Example 4 were confirmed to be supported by the RNA sequence profiling study.

[0204] Example 6: GFAP levels in the brain GFAP is associated with inflammatory responses in Alzheimer's disease. For example, in the presence of β-amyloid, glial cells are activated and an inflammatory response releases GFAP in the brain. In these studies, the concentration of glial fibrillary acidic protein (GFAP) in the brain was compared among control mice (normal, wild-type), untreated TG mice, TG mice treated with 4-pentane-CBGA (low), and TG mice treated with 4-pentane-CBGA (high). After treatment, mouse brains were collected and dissected to isolate cortical regions. Tissue was washed in cold phosphate-buffered saline (PBS) and lysed using lysis buffer (10% v / v) containing a mixture of protease-phosphatase inhibitors (1% v / v). The homogenate was centrifuged, the supernatant was collected, and protein concentrations were determined using the Bio-Rad protein assay (Bio-Rad Laboratories, Mississauga, ON, Canada). Whole-cortical tissue lysate (15 μg protein) was dissolved in Laemmli sample buffer (Bio-Rad Laboratories, Mississauga, ON, Canada) containing 5% β-mercaptoethanol, fractionated by SDS-PAGE, and transferred to a nitrocellulose membrane. The membrane was blocked for 1 hour at room temperature with 5% skim milk in Tris-buffered saline containing 0.2% Tween 20 and incubated overnight with GFAP antibody (1:500). After incubation, the membrane was washed and incubated at room temperature (RT) for 2 hours with species-specific (HRP) conjugated secondary antibody (1:1000). The membrane was washed and developed with HRP-chemiluminescent substrate and photographed using FluorChem software on an Alpha Innotech imaging system (AlphaInnotech, San Jose, CA, USA). β-actin (1:5000) was used as a loading control, and densitometric analysis was performed using FluorChem software. Results ( Figure 10 The study showed that administration of 4-pentenyl-CBGA to TG mice reduced GFAP concentration in the brain in a dose-dependent manner.

[0205] Example 7: β-amyloid protein concentration in the cortex The concentration of β-amyloid protein in the cortex was compared among control mice (normal, wild-type), untreated TG mice, 4-pentane-CBGA (low) treated TG mice, and 4-pentane-CBGA (high) treated TG mice. Following in vivo treatment, mouse brains were collected and dissected to isolate the cortical regions. Tissue was washed in cold PBS and lysed using lysis buffer (10% v / v) containing a protease-phosphatase inhibitor mixture (1% v / v). The homogenate was centrifuged, the supernatant was collected, and protein concentration was determined using the Bio-Rad protein assay (Bio-Rad Laboratories, Mississauga, ON, Canada). ELISA was performed according to the manufacturer's instructions (FastScan™ β-amyloid (1-40) ELISA Kit No. 20882). Briefly, 50 μL of sample or positive control was added to the corresponding well, followed by 50 μL of antibody mixture. The plate was incubated at room temperature on a plate shaker set to 400 rpm for 1 hour. After incubation, the plate was washed three times, and 100 μL of LTMB substrate was added to the wells, followed by 100 μL of stop solution to terminate the reaction. The plate was read at 450 nm using a spectrophotometer (BMG Labtech) within 30 minutes of adding the stop solution. The results were normalized relative to the control, as shown below. Figure 11 As shown, treatment with 4-pentenyl-CBGA in TG mice resulted in a dose-dependent reduction in β-amyloid concentration in the cortex. Furthermore, the 4-pentenyl-CBGA (low) and 4-pentenyl-CBGA (high) treatments showed less accumulation of β-amyloid in the mouse brain.

[0206] Example 8: PS19 Tau Model Long-term studies include behavioral tests to determine, for example, cognitive function and memory, as well as other biological (molecular) endpoints. Appropriate in vivo Alzheimer's disease models are used, such as PS19 mice (also known as B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle / J; The Jackson Lab: Stock No. 008169). These animals in the 1–3 month age group represent a stage without plaque or NFT formation, while animals aged 3–6 months exhibit tau inoculation activity and further tau accumulation as an early phenotype in this model (Holmes et al., 2014). Furthermore, cognitive impairment, including spatial learning and memory impairment (Takeuchi et al., 2011), motor deficit progression, and paralysis have been observed at 7–10 months (Yoshiyama et al., 2007).

[0207] For cannabinoid administration, sex- and age-matched genotypes and their wild-type littermates (age group 1-3 months) should be given the optimal cannabinoid dose via intraperitoneal (ip) injection or oral administration every other day for 3-6 months.

[0208] Six- and nine-month-old PS19 and wild-type mice injected with cannabinoids were used to compare behavioral changes (spatial learning and memory) and motor responses associated with progressive shifts in AD pathogenesis.

[0209] To establish the functional and pathological correlation between AD and the endocannabinoid system, ELISA, immunohistochemistry, and Western blotting were used to analyze Tau hyperphosphorylation and CB1R / CB2R expression in cortical and hippocampal tissue extracts in 3, 6, and 9-month-old control and cannabinoid-infused PS19 and wild-type mice.

[0210] To assess neuroinflammation, ELISA analysis was used to determine the levels of hippocampal cytokines IL-1β, IL-6, and TNFα, as well as microglial proliferation, in 3, 6, and 9-month-old pS19 mice and age-matched wild-type (WT) mice treated with solvent or 4-pentane-CBGA.

[0211] RNA-seq analysis was performed to determine changes in the expression of genes such as CLDN11, ATP8B1, ITGA3, CD9, CRIM1, and NTN4, as indicators of neuronal functional integration into the hippocampal trisynaptic circuit and neuronal recovery from NFT-induced neuronal damage in wild-type and AD transgenic mice. Furthermore, immunofluorescence immunochemistry in mouse brain slices was used to determine the expression of microtubule-binding proteins (such as synaptophysin Lis-1, DCX, and Map2c) that help bind microtubules in growing neurites.

[0212] Example 9: Receptor interaction studies The interactions of 4-pentenyl-CBGA with different receptors were evaluated using various assay methods.

[0213] The interaction of 4-pentenyl-CBGA with CB1 and CB2 receptors, using cAMP as a marker, was assessed using the HitHunter® cAMP assay. In short, cAMP Hunter cell lines expressing CB1 or CB2 receptors were evaluated via the DiscoverX HitHunter cAMP XS+ assay. To assess agonist behavior (Gs agonist form), cells were incubated with the sample to induce a reaction, the medium was aspirated and replaced with HBSS / Hepes buffer containing cAMP XS+ Ab reagent, and then 5 µL of the 4X sample was added to the cells and incubated at 37°C or room temperature at a 1% solvent concentration for 30 or 60 minutes. To assess agonist behavior (Gi agonist form), cells were incubated in the presence of EC80 forskolin to induce the reaction. 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 forskolin was added to the cells, and the cells were incubated at 37°C or room temperature for 30 or 60 minutes at a 1% solvent concentration. To assess antagonist behavior, cells were pre-incubated with the sample, followed by agonist stimulation 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. Subsequently, 5 µL of EC80 agonist was added and the cells were incubated at 37°C or room temperature for 30 or 60 minutes at a 1% solvent concentration. For GI-coupled GPCRs, EC80 forskolin was included in the antagonist assay. For signal detection in any assay, add 20 µL of cAMP XS + ED / CL lysis mixture and incubate for 1 hour, followed by adding 20 µL of cAMP CS + EA reagent and incubating for 3 hours at room temperature. Read the microplate for chemiluminescence detection.

[0214] The interaction of 4-pentenyl-CBGA with CB1 and CB2 receptors was evaluated using the PathHunter® β-inhibitor assay from Eurofins DiscoverX Corp., with the inhibitor protein as a assay marker.

[0215] The interaction of 4-pentenyl-CBGA with PPARγ, PPARα, and PPARδ was 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 was performed at 37°C or room temperature with a final solvent assay concentration of 1% for 3–16 hours. 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 incubation was performed at 37°C or room temperature with a final solvent assay concentration of 1% for 60 minutes. Subsequently, 5 µL of EC80 agonist in assay buffer was added, and incubation was performed 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 1 hour, followed by reading the microplate for chemiluminescent detection.

[0216] Data on receptor interactions obtained using Eurofins bioassays are provided in Table 1 below: Table 1: 4-Pentenyl-CBGA receptor interaction data

[0217] Inactive – Inactive during testing Interestingly, these data show that 4-pentenyl-CBGA is a selective (biased) CB1R and CB2R agonist targeting the cAMP signaling pathway, with a strong bias towards CB2R. However, it is neither a CB1R nor CB2R agonist nor an antagonist targeting the β-repressor protein signaling pathway. Furthermore, it is a PPARγ agonist but a PPARα and δ antagonist.

[0218] Previously, CBGA has been shown to be a strong CB1R agonist targeting the cAMP signaling pathway and a weak agonist targeting the β-repressor protein signaling pathway, while being a weak CB2R agonist targeting both cAMP and β-repressor protein signaling pathways. Furthermore, CBGA is a PPARα and PPARγ agonist. THC has been shown to be a strong CB1R and CB2R agonist targeting the β-repressor protein signaling pathway. THC is also a strong CB1R agonist targeting the cAMP signaling pathway, but a weak CB2R agonist. THC is also a PPARγ agonist. In contrast to THC, CBD is a weak CB1R and CB2R agonist targeting both cAMP and β-repressor protein signaling pathways, as well as a PPARγ agonist. (Navarro et al. Pharmacological Research. 2020; 159:104940; O'Sullivan et al. BBRC. 2005;337(3):824–831; Khosropoor et al. Phytomedicine 2023; 114:154771).

[0219] These data and publications demonstrate a Formula I compound that can potentially cross the blood-brain barrier via systemic delivery through oral ingestion; exhibit neuroprotection and neurogenesis in vitro; and demonstrate improvements in motor function, cognition, and memory, reduced neuroinflammation, and increased neuronal function in vivo. Furthermore, 4-pentenyl-CBGA exhibits reduced cytotoxicity.

[0220] * * * 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.

[0221] 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.

[0222] 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 description herein is intended to be illustrative rather than restrictive. Many embodiments will be apparent to those skilled in the art upon reading this description. Therefore, the scope of the invention should not be determined by reference to the description herein, but rather by reference to the appended claims and the full scope of their equivalents. All disclosures in articles and references (including patent publications) are incorporated herein by reference.

Claims

1. A method for treating a patient with neuronal disorders, a method for protecting neurons from neurodegeneration, or a method for inducing neurogenesis, said method comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound of formula I is based on: (I)， in R 1 yes , where the bond a is either cis (Z) or trans (E); R 2 yes , where the bond b is either cis (Z) or trans (E); m is an integer selected from 1 to 6; and R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

2. The method of claim 1, wherein the compound of formula I is a compound of formula II: (II), Or its pharmaceutically acceptable salt.

3. The method as described in claim 1 or 2, wherein R 2 It contains a total of 4, 5, 6, 7 or 8 carbon atoms.

4. The method according to any one of claims 1 to 3, wherein R 2 It contains a total of 5, 6, 7 or 8 carbon atoms.

5. The method according to any one of claims 1 to 4, wherein R 2 It contains a total of 5 carbon atoms.

6. The method according to any one of claims 1 to 5, wherein R 3 It is H.

7. The method according to any one of claims 1 to 5, wherein R 3 It is CH3.

8. The method according to any one of claims 1 to 5, wherein R 3 It is CH2CH3.

9. The method according to any one of claims 1 to 8, wherein R 2 The key 'b' in the equation is trans.

10. The method according to any one of claims 1 to 8, wherein R 2 The key 'b' in the formula is cis.

11. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: (B3) (C2) (C3) (C4) (D5) (E6) and (F7); Or its pharmaceutically acceptable salt.

12. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: (C2) (C3) and (C4); Or its pharmaceutically acceptable salt.

13. The method of claim 1, wherein the compound of formula (I) is: (C4)； Or its pharmaceutically acceptable salt.

14. The method according to any one of claims 1 to 13, wherein the compound of formula (I) or (II) is not a pharmaceutically acceptable salt.

15. The method according to any one of claims 1 to 13, wherein the compound of formula (I) or (II) is a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1 to 15, wherein the method includes inducing neurogenesis.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I: (I)， Or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier thereof; in, R 1 yes Where bond a is cis (Z) or trans (E); R 2 yes , where the bond b is either cis (Z) or trans (E); m is an integer selected from 1 to 6; and R 3 It is H, CH3, or CH2CH3, provided that R is 1. 3 It is CH3 or CH2CH3; and R is present in it. 3 It is H, and there is no cis or trans at the b key.

18. The pharmaceutical composition of claim 17, wherein the compound of formula I is a compound of formula II: (II), Or its pharmaceutically acceptable salt.

19. The pharmaceutical composition of claim 17 or 18, wherein R 2 It contains a total of 4, 5, 6, 7 or 8 carbon atoms.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein R 2 It contains a total of 5, 6, 7 or 8 carbon atoms.

21. The pharmaceutical composition according to any one of claims 17 to 20, wherein R 2 It contains a total of 5 carbon atoms.

22. The pharmaceutical composition according to any one of claims 17 to 21, wherein R 3 It is H.

23. The pharmaceutical composition according to any one of claims 17 to 21, wherein R 3 It is CH3.

24. The pharmaceutical composition according to any one of claims 17 to 21, wherein R 3 It is CH2CH3.

25. The pharmaceutical composition according to any one of claims 17 to 24, wherein R 2 The key 'b' in the equation is trans.

26. The pharmaceutical composition according to any one of claims 17 to 24, wherein R 2 The key 'b' in the formula is cis.

27. The pharmaceutical composition of claim 17, wherein the compound of formula (I) is selected from the group consisting of: (B3) (C2) (C3) (C4) (D5) (E6) and (F7); Or its pharmaceutically acceptable salt.

28. The pharmaceutical composition of claim 17, wherein the compound of formula (I) is selected from the group consisting of: (C2) (C3) and (C4); Or its pharmaceutically acceptable salt.

29. The pharmaceutical composition of claim 17, wherein the compound of formula (I) is: (C4)； Or its pharmaceutically acceptable salt.

30. The pharmaceutical composition of any one of claims 17 to 29, wherein the compound of formula (I) or (II) is not a pharmaceutically acceptable salt.

31. The pharmaceutical composition according to claims 17 to 29, wherein the compound of formula (I) or (II) is a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition of any one of claims 17 to 31, wherein the concentration of the compound in contact with the target neuron or group of target neurons is 1 to 30 µM.

33. The pharmaceutical composition of any one of claims 17 to 31, wherein the concentration of said compound is a systemic concentration of about 0.5 mg / kg to about 6 mg / kg.

34. The method of any one of claims 1 to 16, wherein the neuronal condition is Alzheimer's disease.

35. The method of any one of claims 1 to 16 and 34, wherein a therapeutically effective amount of the pharmaceutical composition of any one of claims 17 to 33 is administered.

Images