Novel halogenated cannabinoid derivatives

Abstract

(I) [Refer to original abstract doc for image] The invention related to novel halogenated cannabinoid derivatives of formula (I), wherein R1 and R2 are independently selected from a halogen or a hydro

Description

FIELD OF THE INVENTION

[0001] The present invention relates to novel halogenated cannabinoid derivatives. The invention consists of derivatives of the non-psychoactive cannabinoid cannabidiol (CBD) which have been halogenated to improve their properties. The invention further relates to the method of synthesis of the novel compounds and their use as medicaments. BACKGROUND TO THE INVENTION

[0002] The compound cannabidiol (CBD) was first isolated from the cannabis plant in 1940 by Roger Adams and its structure was elucidated by Raphael Mechoulam in 1963 (Burstein, 2015). CBD is part of a class of compounds described as cannabinoids which are compounds found within the cannabis plant (as phytocannabinoids), in most animal organisms (as endocannabinoids) or can be prepared synthetically.

[0003] CBD occurs naturally in the cannabis plant, however for many decades it was largely thought to be inactive, and much research was undertaken on the psychoactive compound tetrahydrocannabinol (THC) which also occurs naturally in cannabis plants and was found to bind to the cannabinoid type 1 (CB1) and type 2 (CB2) receptors that are found within the human body.

[0004] Synthetic THC was approved as a medicament by the FDA in 1985 as dronabinol and is indicated as an appetite stimulant in patients with HIV / AIDS and cancer it is additionally approved to treat chemotherapy-induced nausea and vomiting.

[0005] Plant-derived THC and CBD are the active ingredients in nabiximols which was approved by the MHRA in 2010 to treat neuropathic pain, spasticity, and overactive bladder in patients with multiple sclerosis.

[0006] Semi-synthetic CBD, sold as Epidiolex(RTM), was approved by the FDA in 2018 for the treatment of two rare childhood epilepsy disorders, Dravet syndrome and Lennox-Gastaut syndrome and has since been approved to treat an additional rare epilepsy syndrome tuberous sclerosis complex.

[0007] CBD was described as an anti-epileptic as early as 1843 by W.B. O’Shaughnessy, though it wasn’t until the early 1980’s that researchers tested CBD in animal models of epilepsy. In more recent years there has been a large increase in the understanding of this cannabinoid however it’s mechanism of action as an anticonvulsant remains unknown.

[0008] A review published in 2016 describes the human metabolites of CBD (Ujvary and Hanus, 2016). The first CBD metabolites to be identified were isolated from rat liver homogenate and their structures were determined as a primary alcohol derived from the oxidation at the allylic C- 7 methyl group on the cyclohexene moiety (7-OH-CBD). The 7-OH CBD is further oxidised to form CBD-7-oic acid (7-COOH CBD).

[0009] In general, the most abundant metabolites are hydroxylated 7-carboxy derivatives of CBD. These are excreted either intact or as glucuronide conjugates.

[0010] According to the Epidiolex patient information leaflet, CBD is metabolised in the liver and the gut by CYP2C19 and CYP3A4 enzymes in addition to UGT1A7, UGT1A9 and UGT2B7 isoforms to the metabolite 7-hydroxy-cannabidiol (7-OH CBD) which is further converted to 7-COOH CBD.

[0011] The patient information leaflet additionally describes 7-OH CBD as being found to be active in preclinical models of seizure whereas the final metabolite 7-COOH CBD was not active.

[0012] The synthetic production of CBD derivatives including 7-OH CBD is disclosed in WO 01 / 95899, the patent details data to show the compound was effective in a model of inflammation.

[0013] The patent EP3,160,457 details data demonstrating the anti-convulsant activity of 7-OH CBD and 7-OH CBDV in an animal model of seizure at lower doses than the parent compounds.

[0014] Due to the efficiency of the CYP and UGT enzymes the active metabolite 7-OH CBD is very quickly further metabolised to the inactive 7-COOH CBD final metabolite. In consequence 7-OH CBD would not be considered a useful target for drug development.

[0015] For over 20 years, organo-fluorine molecules have represented one of the fastest growing classes of organic compounds, indeed the role of fluorine in the design of pharmaceutical drugs has been recognised.

[0016] The introduction of fluorine into a molecule may be able to improve conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties of a compound however drug-metabolizing enzymes can cleave the C-F bond resulting in the formation of unwanted metabolites and subsequent safety and toxicity issues.

[0017] In 2021, the FDA approved nine new fluorine-containing drugs to treat diseases including multiple myeloma, migraines, and non-small cell lung cancer, confirming the safety and efficacy of these fluorinated medicaments.

[0018] Breuer et al. (2016) describes fluorination of the cannabinoid CBD to produce three different fluorinated CBD derivatives. These compounds were tested in behavioural assays and in some cases were found to be more potent that CBD however some were found to be not effective suggesting that halogenation of compounds, including cannabinoids, does not necessarily increase the potency of the drug and in some cases can render the drug ineffective.

[0019] Since the publication of Breuer several patent applications have detailed the halogenation of CBD for various potential uses. For example WO2021 / 076939 describes Markush structures which include halogenated CBD, these compounds were designed to avoid the P450 metabolism in the liver. The document US2023 / 100890 describes various Markush compounds one of which being halogenated CBD which is suggested to be of use in the treatment of migraine. EP4089084 again details a range of compounds via a Markush which may be useful for a range of indications and diseases, however no data is presented to support the medical use of these compounds except some PK data in rats for several of the compounds. The document WO222 / 222923 describes halogenated CBD for use in the treatment of inflammatory skin conditions, whereas the halogenated CBD of WO2022 / 133544 is described as being of potential use as an anti-microbial agent. WO207 / 008136 describes various fluorinated CBD type compounds in addition to data on these compounds in rodent anxiety models.

[0020] In contrast to the prior art the applicant has synthesised and tested novel halogenated CBD derivatives. These derivates originate from metabolites of CBD, such as 6-OH CBD and 7-OH CBD. These compounds have been tested in an animal model of epilepsy and surprisingly it was found that halogenation of CBD metabolites increased the efficacy of the compounds in comparison to CBD. In addition in silica modelling was undertaken on these compounds and these data showed improved properties over CBD.

[0021] Such a finding provides a distinct contribution to the field of epilepsy as the data presented is indicative of an improved compound that could be used to treat epilepsy. BRIEF SUMMARY OF THE DISCLOSURE

[0022] In accordance with a first aspect of the present invention there is provided a compound of Formula I or a salt thereof, Formula I wherein: R1 and R2 are independently but not mutually selected from a halogen or H; R3 is CH3 or CH2-OH; R4 is H or OH; and R5 is a straight or branched chain alkyl containing between one and nine carbons, wherein the compound of Formula I does not include the compound where R3 is CH3 and R4 is OH and R5 is a straight chain alkyl containing three carbon atoms.

[0023] Preferably the compound of Formula I or a salt thereof is defined by any one of the compounds in Table 1.

[0024] Preferably the compound of Formula I or a salt thereof is such that R1 and R2 are independently but not mutually fluorine.

[0025] Preferably the compound of Formula I or a salt thereof is such that R3 is CH2-OH.

[0026] More preferably both R1 and R2 are independently but not mutually fluorine and R3 is CH2-OH.

[0027] In accordance with a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound of Formula I or a salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0028] In accordance with a third aspect of the present invention there is provided a compound of Formula I or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a salt thereof for use as a medicament.

[0029] In accordance with a fourth aspect of the present invention there is provided a compound of Formula I or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a salt thereof for use in the treatment of epilepsy.

[0030] In accordance with a fifth aspect of the present invention there is provided a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or salt thereof.

[0031] In accordance with a sixth aspect of the present invention there is provided a method of synthesising a compound of Formula I. DEFINITIONS

[0032] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8 alkyl) or one to six carbon atoms (C1-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ferf-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0033] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0034] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkenyl groups containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl). Exemplary alkenyl groups include ethenyl ( / .e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0035] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkynyl groups containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0036] “Ester” refers to a functional group -COO and may also be referred to as an “ester link”. Esters are formed by the condensation reaction between an alcohol and a carboxylic acid.

[0037] The term “halo” or, alternatively, “halogen” means fluoro or fluorine, chloro or chlorine, bromo or bromine and iodo or iodine.

[0038] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocycle, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, a heterocycloalkyl, an aromatic and heteroaromatic moiety.

[0039] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0040] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0041] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0042] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0043] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0044] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0045] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0046] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0047] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration. In addition, such certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.

[0048] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0049] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0050] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. DETAILED DESCRIPTION OF THE INVENTION

[0051] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. Compounds

[0052] The compound of the present invention is one or more compounds with the Markush formula provided in Formulas I, and la.

[0053] In embodiments, the present disclosure provides a compound of Formula I, Formula la or a salt thereof: Formula I wherein: R1 and R2 are independently but not mutually selected from a halogen or H; R3 is CH3 or CH2-OH; R4 is H or OH; and R5 is a straight or branched chain alkyl containing between one and nine carbons. Formula la wherein: R1 and R2 are independently but not mutually selected from a halogen or H; R3 is CH3 or CH2-OH; R4 is H or OH; and R5 is a straight or branched chain alkyl containing between one and nine carbons.

[0054] Specifically disclaimed is the compound of Formula I wherein R3 is CH3 and R4 is OH and R5 is a straight chain alkyl containing three carbon atoms.

[0055] In further embodiments R5 is any alkyl, including a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups. The alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl). The alkyl of R4 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ferf-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The R5 alkyl group is attached to the rest of the molecule by a single bond. The alkyl group is optionally substituted by one or more substituents. 5

[0056] In selected embodiments, provided herein is one or more compounds selected from Table 1.

[0057] In embodiments, provided herein is one or more pharmaceutically acceptable salts of a compound selected from Table 1.

[0058] The compounds of the invention may be used as their salts, polymorphs or deuterated 10 forms. Furthermore, the compounds may occur as an epimer, the cis-isomer, the trans-isomer or a racemate of the two. The compounds of the invention may be present or administered in the form of a prodrug of the active compound. Table 1. Compounds of the invention Compound ID SMILES Structure SNS-101 CCCCCC1=C(F)C(O)=C(C2C=C(CO)CCC 2C(C)=C)C(O)=C1 JX SNS-103 CCCC1=C(C(O)=C(C(O)=C1)C2C=C(CC C2C(C)=C)CO)F ^OH OH OH SNS-107-1 CCCCCC1=CC(O)=C([C@@H]2C=C(C)[C @@H](O)C[C@H]2C(C)=C)C(O)=C1 F Av r UH SNS-107-2 CCCCCC1=CC(O)=C([C@@H]2C=C(C)[C @H](O)C[C@H]2C(C)=C)C(O)=C1 F U, O X__ / \__ / V- Compositions

[0059] The compounds described herein may be formulated as a pharmaceutical composition. A pharmaceutical composition may comprise: (i) a compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0060] In embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone. In embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier. Other suitable carriers, diluents, or excipients are well-known to those in the art. (See, e.g., Gennaro (ed.), Remington's Pharmaceutical Sciences (Mack Publishing Company, 19th ed. 1995).) Formulations can further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc.

[0061] Pharmaceutical compositions comprising a compound of Formula I ora pharmaceutically acceptable salt thereof, may also contain one or more additional ingredients including, but not limited to, a mucoadhesive compound, a buffering agent, a plasticizing agent, a stabilizing agent, a taste-masking agent, a flavoring agent, a coloring agent, an antiseptic, an inert filler agent, a preservative, and combinations thereof.

[0062] In embodiments, the formulations may comprise one or more solubilizing agents that increase the solubility of active compounds in the formulation. Suitable solubilizing agents include, for example, complexing agents, surfactants, and the like. Suitable complexing agents include unsubstituted cyclodextrins (such as alpha-cyclodextrin, beta-cyclodextrin) and substituted cyclodextrins, (such as hydroxypropyl beta-cyclodextrin, sulfobutylether-beta-cyclodextrin). Suitable surfactants include polyoxyethylene sorbitan monolaurate (for example, Tween 20), polyoxyethylene sorbitans molooleate (for example, Tween 80), polyethylene glycol (15)-hydroxystearate (for example, Kolliphor® HS 15), PEG-35 castor oil (for example, Kolliphor® EL) and PEG-60 hydrogenated castor oil (for example, Cremophor® RH 60).

[0063] In embodiments, the formulations comprise one or more buffer agents that maintain the pH of the IV solution within a pharmaceutically acceptable range. In certain embodiments, the buffer maintains the pH of the IV solution between about 5 and 9. In specific embodiments, the buffer maintains the pH of the IV solution at about 7.4. Suitable buffers include, for example, citrates, lactate, acetate, maleate, phosphates, and the like. In embodiments, the formulations comprise one or more density modifiers that are used to control the density of the IV formulation. Suitable density modifiers include, for example, dextrose. In embodiments, the formulations comprise one or more isotonicity modifiers that provide a formulation that is iso-osmotic with tissue to prevent pain and irritation when the formulation is administered. Suitable isotonicity modifiers include, for example, electrolytes, monosaccharides, and disaccharides. Examples of isotonicity modifiers include glycerin, dextrose, potassium chloride, and sodium chloride.

[0064] In embodiments, the formulations comprise one or more viscosity enhancers. Suitable viscosity enhancers include, for example, povidone, hydroxyethylcellulose, polyvinyl alcohol, and carbomer (such as, acrylic acid homopolymers and acrylic acid copolymers).

[0065] In embodiments, the formulations comprise one or more preservatives that increase the stability of active compounds in the formulation and / or provide antimicrobial activity. Suitable preservatives include, for example, antimicrobial agents and antioxidants. Examples of antimicrobial agents include benzyl alcohol, methyl paraben, propyl paraben, phenol, cresol, methyl paraben, chlorbutanol, sodium metabisulphite, sodium bisulphite, benzethonium chloride, and benzalkonium chloride. Examples of antioxidants include sodium bisulphite and other sulfurous acid salts, ascorbic acid, salts of ethylenediaminetetraacetic acid (including sodium), alpha tocopherol, butylated hydroxyl hydroxytoluene, and butylated hydroxyanisole.

[0066] A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof; may be formulated in a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form, a liquid, a lozenge, a fast disintegrating tablet, a lyophilized preparation, a film, a spray (including a nasal spray, an oral spray, or a topical spray), or a mucoadhesive. The oral unit dosage form may be selected from the group consisting of: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays.

[0067] The compounds of Formula I or a pharmaceutically acceptable salt thereof can be administered to subjects by a variety of administration modes, including, for example, by intramuscular, subcutaneous, intravenous, intra-atrial, intra-articular, parenteral, intranasal, intrapulmonary, transdermal, intrapleural, intrathecal, and oral routes of administration. For prevention and treatment purposes, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a subject in a single bolus delivery, via continuous delivery (e.g., continuous transdermal delivery) over an extended time period, or in a repeated administration protocol (e.g., on an hourly, daily, weekly, or monthly basis).

[0068] Pharmaceutical compositions comprising a compound of Formula I ora pharmaceutically acceptable salt thereof can be supplied as a kit comprising a container that comprises the pharmaceutical composition as described herein. A pharmaceutical composition can be provided, for example, in the form of an injectable solution for single or multiple doses, or as a sterile powder that will be reconstituted before injection. Alternatively, such a kit can include a dry-powder disperser, liquid aerosol generator, or nebulizer for administration of a pharmaceutical composition. Such a kit can further comprise written information on indications and usage of the pharmaceutical composition. Therapeutic Use

[0069] The compounds of Formula I may be of use as a medicament. Moreover the compounds of Formula I may of use in the treatment of epilepsy or as an anti-convulsant. EXAMPLES

[0070] The applicant has synthesised and tested novel halogenated CBD derivatives. These derivates originate from metabolites of CBD, such as 6-OH CBD and 7-OH CBD. These compounds have been tested in an animal model of epilepsy and surprisingly it was found that halogenation of CBD metabolites increased the efficacy of the compounds in comparison to CBD. In addition in silica modelling was undertaken on these compounds and these data showed improved properties over CBD.

[0071] Such a finding provides a distinct contribution to the field of epilepsy. The data presented herein indicates that the improved compounds of the invention would able to be dosed at a lower amount than CBD and as such would be less of a burden on the liver of patients taking CBD. Furthermore the in silica modelling data presented indicates that the compounds of the invention are likely to have a better safety profile than CBD enabling patients to be treated more effectively and without so many side effects or drug-drug interactions with other commonly used anti-seizure medications and other drugs.

[0072] The examples below detail in Example 1 the synthetic route of the compounds detailed in Table 1. Example 2 describes the efficacy of these compounds in an animal model of seizure, the mini-MEST model. Example 3 describes the in silica modelling data for these compounds. EXAMPLE 1: SYNTHESIS OF COMPOUNDS General experimental Information NMR

[0073] 1H spectra were collected on 400 MHz NMR spectrometers (Bruker AVANCE III HD). Chemical shifts for protons are reported in parts per million (ppm) and are referenced to residual protonated solvent (CHCI3 = 5 7.27; DMSO = 5 2.50). LCMS UPLC-1 SQD General Conditions:

[0074] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using a Waters Acquity Classic UPLC with PDA and SQ mass detection.

[0075] Unless otherwise Stated:

[0076] UV: 220 nm - 400 nm

[0077] Mass spec: 100-800 m / z Method 2A

[0078] Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 pm

[0079] Column Temp: 50 °C

[0080] Flow rate: 0.6 mL / min.

[0081] Eluents: A: H2O, 0.1% formic acid, B: MeCN

[0082] Gradient: 0.0-1.8 min 2-98% B, 1.8-2.1 min 98% B, 2.1-2.5 98% A. Method 8A

[0083] Column: Acquity UPLC BEH C18 2.1x50 mm 1.7 pm

[0084] Column Temp: 50 °C

[0085] Eluents: A: H2O, 0.1% formic acid, B: MeCN

[0086] Flow Rate: 0.6 mL / min

[0087] Gradient: 0.5-6.5 min 2-98% B, 6.5-7.6 min 98% B, 7.6-8.0 98% A. UPLC-3 QDA General Conditions:

[0088] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using a Waters Acquity H-Class UPLC with PDA and QDA mass detection.

[0089] Unless otherwise Stated:

[0090] UV: 210nm-400nm

[0091] Mass spec: 100-800 m / z Method 2A

[0092] Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 pm

[0093] Column Temp: 50 °C

[0094] Flow rate: 0.8 mL / min.

[0095] Eluents: A: H2O, B: MeCN, C: 50% H20150% MeCN + 2.0% formic acid

[0096] Gradient: 0.0 -1.7 mins 0-95% B, 5% C; 1.7-2.1 mins 95% B, 5% C

[0097] 2.1-2.5 mins 95% A, 5% C. Method 8A

[0098] Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 pm

[0099] Column Temp: 50 °C

[00100] Flow rate: 0.8 mUmin.

[00101] Eluents: A: H2O, B: MeCN, C: 50% H20 1 50% MeCN + 2.0% formic acid

[00102] Gradient: 0.0 - 0.5 mins 95% A, 5% C; 0.5-6.5 mins 0-95% B, 5% C;

[00103] 6.6-7.5 mins 95% B, 5% C; 7.5-7.6 mins 0-95% A, 5% C; 7.6-8.0 mins 95 % A, 5% C. Synthesis of 2-[(3R,4R)-7-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-pentylresorcinol: SNS-101

[00104] Olivetol (5) was fluorinated with selectfluor in moderate yield, and then the bicycle was formed using the same method as above, providing a mixture of separable regioisomers (4 and 7), each of which were confirmed by 2D-NMR. OH Selectfluor MeCN Sc(OTf), allyl alcohol DCM 6 57% 28% -30%

[00105] Methylation of the required isomer gave the fluoro-dimethyl-CBD (8) in good yield. 8 81%

[00106] Epoxidation of the more substituted alkene provided the epoxide 9 as a mixture of diastereoisomers. Epoxide opening with commercial pre-formed LDA was applied, providing the ring opened product 10 in good yield.

[00107] A 1-pot formal isomerisation using methanesulfonyl chloride from alcohol 10 to alcohol 13 provided the required exocyclic alcohol, but as a mixture with the exocyclic chloride. This is assumed to have occurred by substitution of the mesylate intermediate with the 5 nucleophilic chloride ion prior to addition of aq. NaHCOs. 25% 18%

[00108] To avoid the chlorine substitution, methanesulfonyl chloride was replaced with methansulfonyl anhydride (methanesulfonic acid being a weaker nucleophile than the chloride). 10 This successfully formed the formal-rearranged product 13 in good yield. This was then demethylated using MeMgl to afford SNS-101 (26 mg at +95% purity).

[00109] The complete synthetic scheme to SNS-101 is shown below. Selectfluor MeCN ' 6 57% Sc(OTf), allyl alcohol, DCM Ms2O, EtaN, NaHCOs THF 63% SNS-101 20%

[00110] SNS-101 was purified and was confirmed by LC-MS and NMR as follows:

[00111] A mixture of [(3R,4R)-3-(3-fluoro-2,6-dimethoxy-4-pentyl-phenyl)-4-isopropenyl-cyclohexen-1-yl]methanol (140 mg, 0.372 mmol) and methylmagnesium iodide (3 M in ether) (3 M, 619.738 pL) was concentrated under heating and nitrogen flow. The reaction was then heated to 190°C for 1 h. The reaction was cooled to rt and diluted with THF (5 mL) the reaction was carefully quenched with NH4CI (5 mL) and diluted with water (20 mL). The aq. phase was extracted with DCM (2 x 40 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo.

[00112] Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in petrol afforded impure material by NMR. Re-purification by chromatography on silica eluting with a gradient of 50 to 60% Et20 in petrol afforded 4-fluoro-2-[(1 R,6R)-3-(hydroxymethyl)-6-isopropenyl-cyclohex-2-en-1-yl]-5-pentyl-benzene-1,3-diol (26 mg, 0.075 mmol, 20.067% yield) as a pale yellow oil.

[00113] LC-MS-3 (Method 8A): Rt 4.20 mins; MS m / z 331.3 = [M-H2O+H]+ (96% @ 254nm).

[00114] 1H NMR (400 MHz, CDCI3) 6 6.18 (d, J = 6.3 Hz, 1H), 5.81 (s, 1H), 5.37-4.97 (m, 2H), 4.60 (s, 1H), 4.48 (s, 1H), 4.18 - 4.06 (m, 2H), 4.02 - 3.94 (m, 1H), 2.62 - 2.46 (m, 3H), 2.30 - 2.22 (m, 2H), 1.94-1.74 (m, 2H), 1.70 (s, 3H), 1.56 (d, J = 8.6 Hz, 2H), 1.41 (t, J = 6.0 Hz, 1H), 1.38-1.26 (m, 4H), 0.89 (t, J = 6.7 Hz, 3H). Synthesis of 2-[(3R,4R)-7-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-propylresorcinol: SNS-103

[00115] SNS-103 was synthesised using th© routs developed for SNS-101, although starting from 5-propylbenzene-1,3-diol (14), which incurred no unexpected issues. This provided 33 mg of SNS-103 at +95% purity. The reaction scheme summary is shown below.

[00116] SNS-103 was purified and was confirmed by LC-MS and NMR as follows:

[00117] A mixture of [(3R,4R)-3-(3-fluoro-2,6-dimethoxy-4-propyl-phenyl)-4-isopropenyl-cyclohexen-1-yl]methanol (197 mg, 0.565 mmol) and methylmagnesium iodide (3 M in ether) (3 M, 942.268 pL) was warmed under flow of N2 to remove the Et20. The reaction was then heated to 190 °C for 1h. The reaction was cooled to rt, diluted with THF (6 mL) and carefully quenched with NH4CI (3 mL). The reaction was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo.

[00118] Purification by chromatography on silica, eluting with a gradient of 0 to 50% EtOAc in petrol afforded impure material. Repurification by chromatography on silica eluting with a gradient of 0 to 20% EtOAc in DCM also afforded impure material. Repurification by C18 reverse phase chromatography eluting with a gradient of 20 to 60% MeCN in water (no additive) afforded impure material. Re-purification by chromatography on silica eluting with a gradient of 50 to 60% Et20 in petrol afforded 4-fluoro-2-[(1R,6R)-3-(hydroxymethyl)-6-isopropenyl-cyclohex-2-en-1-yl]-5-propyl-benzene-1,3-diol (33 mg, 0.099 mmol, 17.489% yield, 96% purity) as a pale orange oil.

[00119] LC-MS-1 (Method 8A): Rt 3.60 mins; MS 319.4 = [M-H]- (96% @ TAC).

[00120] 1H NMR (400 MHz, CDCI3) 3 6.18 (d, J = 6.3 Hz, 1H), 5.81 (s, 1H), 5.36-4.96 (m, 2H), 4.60 (s, 1H), 4.48 (s, 1H), 4.19 - 4.05 (m, 2H), 4.05 - 3.95 (m, 1H), 2.52 (m, 3H), 2.31 -2.19(m, 2H), 1.96-1.74 (m, 2H), 1.70 (s, 3H), 1.61 (q, J = 7.5 Hz, 2H), 1.42 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H). Synthesis of 2-[(3R,4R)-6-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-pentylresorcinol: SNS-107

[00121] From intermediate 4, SNS-107 diastereoisomers were synthesised following literature reports (WO2022 / 238701). Acylation of 4 was achieved in moderate yield, and oxidation in a comparable yield to that of the literature, providing 22.

[00122] Reduction using UAIH4 of 22 was undertaken, providing a -9:1 mixture of diastereoisomer based on crude NMR data. Separation of the isomers and their purification followed. UAH4, Et2O SNS-107-1 SNS-107-2 -9:1 mixture SNS-107-1

[00123] Two normal phase purifications provided +90 mg of SNS-107-1 at 92% purity (including 2 wt% Et20), and -150 mg of material at -90% purity by LCMS. The main impurity in this material is believed to be compound related, and has the same LCMS retention time as SNS-107-2. This second batch was purified by reverse phase chromatography with a neutral liquid phase, to give 34 mg of clean SNS-107-1. SNS-107-2

[00124] This material was subjected to 2 normal phase purifications, providing -25 mg of material. On standing, a later running impurity appeared by LCMS. This material was transferred into a final vial, and dried (25 mg at 85% purity by NMR).

[00125] The full scheme for the SNS-107 diastereoisomers is shown below. Selectfluor MeCN ' Sc(OTf), allyl alcohol DCM 6 57% 4 28% AcCI, EtgN, DMAP, DCM Mn(OAc)3, t-BuOOH, EtO Ac LiAH,, Et SNS-107-1 5% (clean) SNS-107-2 4%

[00126] SNS-107 was purified and was confirmed by LC-MS and NMR as follows: 2-[(3R,4R)-6-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-pentylresorcinol: SNS-107

[00127] To a solution of Lithium aluminium hydride (2.4 M in THF) (2.4 M, 2.919 mL) in Et20 (28 mL) was slowly added a solution of [3-acetoxy-4-fluoro-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]-5-pentyl-phenyl] acetate (718 mg, 1.668 mmol) in Et20 (7 mL). After 30 min at rt the reaction was cooled in an ice bath, and carefully quenched with water (14 mL) then diluted with HCI (2 M, 14 mL). The organic phase was separated then the aq. phase was re-extracted with DCM (2 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica, eluting with a gradient of 5 to 30% EtOAc in petrol afforded two impure fractions. 2-[(3R,4R,6S)-6-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-pentylresorcinol SNS-107-1

[00128] The above was purified by chromatography on silica eluting with a gradient of 0 to 10% EtOAc in DCM affording +90 mg of material at 92% pure (containing 2 wt% Et20). Purification of less pure fraction by reverse phase chromatography eluting with a gradient of 25 to 65% MeCN in water afforded 4-fluoro-2-[(1R,4S,6R)-4-hydroxy-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-benzene-1,3-diol (34 mg, 0.098 mmol, 5.851% yield) [APEX-000166-72-1] as a white solid.

[00129] LC-MS-3 (Method 8A): Rt 1.67 mins; MS 347.1 = [M-H]- (97% @ 280 nm).

[00130] 1H NMR (400 MHz, DMSO) 6 9.00 - 8.54 (m, 2H), 6.03 - 5.93 (m, 1H), 5.08 (s, 1H), 4.60 (d, J =6.6 Hz, 1H), 4.48 - 4.45 (m, 1H), 4.43 - 4.38 (m, 1H), 4.08 (s, 1H), 3.89 - 3.82 (m, 1H), 3.23-3.12 (m, 1H), 2.45-2.34 (m, 2H), 1.94-1.85 (m, 1H), 1.63 (s, 3H), 1.58 (s, 4H), 1.54-1.42 (m, 2H), 1.33 - 1.22 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H). 2-[(3R,4R,6R)-6-Hydroxy-p-mentha-1,8-dien-3-yl]-4-fluoro-5-pentylresorcinol SNS-107-2

[00131] The above was purified by chromatography on silica eluting with a gradient of 0 to 10% EtOAc in DCM affording material ~90% pure. The material was concentrated into a vial to afford 4-fluoro-2-[(1R,4R,6R)-4-hydroxy-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-benzene-1,3-diol (25 mg, 0.072 mmol, 4.302% yield) [APEX-000166-72-2] as a yellow solid at +85% purity.

[00132] LC-MS-3 (Method 2A): Rt 1.71 mins; MS 347.2 = [M-H]- (77% @ 280 nm).

[00133] 1H NMR (400 MHz, DMSO) 6 8.90 - 8.49 (m, 3H), 6.01 (d, J = 6.0 Hz, 1H), 5.18 (s, 1H), 4.56 (d, J = 4.8 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.44 (s, 1H), 3.87 (s, 1H), 3.79 - 3.71 (m, 1H), 3.28-3.22 (m, 1H), 2.44-2.34 (m, 2H), 1.77-1.64 (m, 5H), 1.57 (s, 3H), 1.53-1.42 (m, 2H), 1.38 - 1.21 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H). EXAMPLE 2: MAXIMAL ELECTROSHOCK SEIZURE THRESHOLD (MEST) TEST IN THE MOUSE

[00134] The aim of the study was to investigate the potential anticonvulsant effect of SNS-101, SNS-103, SNS-107-1, SNS-107-2 and CBD in the maximal electroshock seizure threshold (MEST) model of generalised seizures in mice.

[00135] The maximal electroshock seizure threshold (MEST) test is widely utilized preclinically to evaluate pro- or anti-convulsive properties of test compounds (Loscher etal., 1991). The MEST test is typically conducted in rodents. An increase in seizure threshold is indicative of an anticonvulsant effect. Antiepileptic drugs including diazepam and sodium valproate with clinically proven efficacy against generalised tonic-clonic seizures exhibit anticonvulsant properties in this test in the mouse. Conversely, a reduction in seizure threshold is indicative of a proconvulsive effect as observed with known convulsive agents (e.g., Picrotoxin).

[00136] The ability of a test compound to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hind limb extensor convulsions, is assessed in the MEST. The outcome of the presence (+) or absence (0) of tonic hind limb extensor convulsions observed from a current to produce tonic hind limb extension in 50% of animals in the treatment group (CC50) determines the seizure threshold for the treatment group and the effects were then compared to the CC50 of the vehicle control group. Study details:

[00137] Naive mice [42 male C57BL / 6J mice from Charles River UK, approximately aged 6-7 weeks (upon arrival), weight range 20-25g (upon arrival)] were acclimatised to the procedure room in their home cages for at least 7 days following arrival to the test facility, with food and water available ad libitum.

[00138] All animals were assigned to vehicle (1:2:17 EthanokKolliphor HS15:Water), diazepam 2.5 mg / kg (positive control, 30 min pre-treatment time), or SNS-101 at 80 mg / kg (60 min pre-treatment time), SNS-103 at 80 mg / kg (60 min pre-treatment time), SNS-107-1 at 80 mg / kg (60 min pre-treatment time), SNS-107-2 at 80 mg / kg (60 min pre-treatment time) or CBD at 80 mg / kg (60 min pre-treatment time) (n=6 / group) based on a mean distribution of body weight across groups. All the animals were dosed at 10 mUkg via intraperitoneal injection.

[00139] Animals were individually assessed for the production of a tonic hind limb extensor convulsion at 60 min post-dose for vehicle (1:2:17 Ethanol:Kolliphor HS15:Water), SNS-101, SNS-103, SNS-107-1, SNS-107-2 and CBD, or 30 min post-dose for diazepam 2.5 mg / kg (i.p.), from a single electroshock.

[00140] The first animal within a treatment group was given a shock at the expected or estimated CC50 current. For subsequent animals, the current was lowered or raised depending on the convulsion outcome from the preceding animal.

[00141] Data generated from each treatment group were used to calculate the CC50 and 95% Cl values. Doses and pre-treatment times were based on previous pharmacokinetic data.

[00142] Each animal was humanely killed immediately after production of a convulsion or within 10s following electroshock (whichever is earlier) by concussion of the brain from striking the cranium, followed by decapitation. No tissues were collected for this study.

[00143] The data for each treatment group were recorded as the number of +'s and O's at each current level employed and this information was then used to calculate the CC50 value ± SEM (Kimball et al., 1957). Treatment effects were calculated as % change in CC50 from the vehicle control group. Significant differences between drug-treated animals and controls were assessed using the method described in Litchfield and Wilcoxon, 1949. Results

[00144] The data generated in the MEST study by the four test compounds, CBD and the positive control are detailed in Table 2. Table 2. Summary of data from MEST study Treatment Dose (mg / kg) Route Ptt (mins) n CC50 (mA) 95% Cl (mA) % change from control Vehicle i.p. 60 6 23.3 23.1-23.6 n / a Diazepam 2.5 i.p. 30 6 261.8 236.1-290.3 1024% SNS-101 80 i.p. 60 6 >200.0 n / a >758% SNS-103 80 i.p. 60 6 84.7 78.4-91.6 264% SNS-107-1 80 i.p. 60 6 >200.0 n / a >758% SNS-107-2 80 i.p. 60 6 185.3 182.3-188.4 695% CBD 80 i.p. 60 6 92.9 91.4-94.4 299%

[00145] The positive control, diazepam (2.5 mg / kg), administered at 30 min before testing (10 mL / kg, i.p.) produced an increase in seizure threshold. The study is therefore valid. 5

[00146] All of the tested compounds increased CC50 ranging from 264% to >758%, this study therefore provides evidence of the anticonvulsant property of the test compounds.

[00147] For compound SNS-101 and SNS-107-1 the CC5o is described as greater than 200mA as for these test articles there were no animals which displayed tonic hind limb seizures at any currents up to the maximum of 200mA therefore the actual figure cannot be recorded. 10 Conclusion

[00148] The data presented in this example is very significant as it provides evidence that the halogenation of metabolites of CBD to produce novel compounds can increase the anti-15 seizure efficacy in comparison to CBD. EXAMPLE 3: IN SILICO MODELLING OF TEST COMPOUNDS

[00149] This example details the in silica modelling undertaken on the four synthesized test articles SNS-101, SNS-103 SNS-107-1, SNS-107-2 in addition to CBD to determine the predicted properties of the compounds in comparison to CBD. 5 Results

[00150] Tables 3 to 5 below detail the results of the in silica modelling. Table 3. In silico modelling data - Part A Comp ound Formul a MW MR TP SA Consensu s Log P ESOL Log S ESOL Class Ali Log S Ali Class Gl absorpt ion CBD C21H3 002 314 .46 99. 85 40. 46 5.2 -5.69 Mod erate I y soluble -7.17 Poorly soluble High SNS-101 C21H2 9FO3 348 .45 100 .97 60. 69 4.73 -5.1 Moderate! y soluble -6.4 Poorly soluble High SNS-103 C19H2 5FO3 320 .4 91. 35 60. 69 4.03 -4.39 Mod erate I y soluble -5.28 Moderatel y soluble High SNS-107-1 C21H2 9FO3 348 .45 100 .97 60. 69 4.68 -5.14 Mod erate I y soluble -6.36 Poorly soluble High SNS-107-2 C21H2 9FO3 348 .45 100 .97 60. 69 4.67 -5.14 Mod erate I y soluble -6.36 Poorly soluble High 10 Table 4. In silico modelling data - Part B Compo und BBB permeant Pgp substrate CYP1A2 inhibitor CYP2C19 inhibitor CYP2C9 inhibitor CYP2D6 inhibitor CYP3A4 inhibitor CBD Yes No No Yes Yes Yes Yes SNS-101 Yes No No No No Yes Yes SNS-103 Yes No No No No Yes No SNS-107-1 Yes No No No No Yes Yes SNS-107-2 Yes No No No No Yes Yes 15 Table 5. In silico modelling data - Part C Molecul e log Kp (cm / s) Lipinski ♦violations Ghose ♦violations Bioavailability Score PAINS ♦alerts Synthetic Accessibility CBD -3.59 1 1 0.55 0 4.05 SNS-101 -4.61 0 0 0.55 0 4.26 SNS-103 -5.21 0 0 0.55 0 4.01 SNS- 107-1 -4.64 0 0 0.55 0 4.48 SNS- 107-2 -4.64 0 0 0.55 0 4.48

[00151] As can be seen in Table 3, apart from SNS-103havea higher molecular weight than CBD and all compounds appear to be more soluble than CBD. Similarly to CBD all compounds are predicted to have a high Gl absorption.

[00152] Table 4 details that all compounds appear to be able to penetrate the blood-brain barrier and are substrates of Pgp. However there are some significant differences between CBD and the SNS test compounds. CBD is shown to be an inhibitor of both the CYP2C19 and CYP2C9 cytochrome P450 enzymes, whereas the SNS are predicted to not inhibit these enzymes.

[00153] Table 5 details that CBD violates 1 of Lipinski’s rules and I of Ghose’s rules, whereas the SNS compounds are not predicted to violate these rules. Conclusion

[00154] These data are significant as they predict that the SNS compounds would potentially have less side effects and less drug-drug interactions than CBD. For example, CBD is a known CYP2C19 inhibitor whereas the SNS compounds are not predicted to inhibit the CYP2C19 enzyme. CYP2C19 is the principal enzyme involved in the hepatic metabolism of 5-10% of all drugs currently in use, including antimalarials (proguanil), oral anticoagulants (R-warfarin), chemotherapeutic agents (cyclophosphamide), anti-epileptics (S-mephenytoin, diazepam, phenobarbitone, clobazam), antiplatelets (clopidogrel), proton pump inhibitors (omeprazole, pantoprazole, lansoprazole, rabeprazole), antivirals (nelfinavir), and antidepressants (amitriptyline, clomipramine).

[00155] The prescribing information for Epidiolex (CBD) states that CBD is an inhibitor of CYP2C19 and dose reductions of substrates of CYP2C19, such as clobazam and diazepam, both drugs used in the treatment of seizures, should be considered.

[00156] It is also known that co-administration of CBD and clobazam causes a 3-fold increase in the plasma concentration of the active metabolite of clobazam which increases adverse effects of both of the drugs such as hepatocellular injury caused by transaminase elevations. It has also been found that the rate of associated sedation with taking Epidiolex was higher in patients co-administered clobazam, 46% vs 32%.

[00157] The data presented in this example demonstrates that the SNS compounds are likely to be safer to use due to less side effects and drug-drug interactions with commonly used drugs.

[00158] The data additionally suggests that the SNS compounds are likely to possess 5 better drug-like qualities than CBD as they do not violate any of Lipinski or Ghose’s rules. Reassuringly all compounds are predicted to be blood-brain barrier penetrants and able to be absorbed through the Gl tract making them suitable for oral dosing of a CNS active drug.

Claims

A compound of Formula I or a salt thereof,Formula Iwherein:R1 and R2 are independently but not mutually selected from a halogen or H;R3 is CH3 or CH2-OH;R4 is H or OH; andR5 is a straight or branched chain alkyl containing between one and nine carbons, wherein the compound of Formula I does not include the compound where R3 is CH3 and R4 is OH and R5 is a straight chain alkyl containing three carbon atoms.

2. A compound of Formula I or a salt thereof according to claim 1, wherein the compound is defined by any one of the compounds in Table 1.

3. A compound of Formula I or a salt thereof according to claim 1 or claim 2, wherein R1 and R2 are independently but not mutually fluorine.

4. A compound of Formula I or a salt thereof according to any of claims 1 to 3, wherein R3 is CH2-OH.

5. A compound of Formula I or a salt thereof according to claim 3 or claim 4, wherein R1 and R2 are independently but not mutually fluorine and R3 is CH2-OH.

6. A pharmaceutical composition comprising a compound of Formula I or a salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

7. A compound of Formula I or a salt thereof, or a pharmaceutical composition comprising5 the compound of Formula I or a salt thereof for use as a medicament.

8. A compound of Formula I or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a salt thereof for use in the treatment of epilepsy.10 9. A method of treatment comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula I or salt thereof.

10. A method of synthesising a compound of Formula I.Application No: GB2410164.4Examiner: Dr Radhe ShyatnClaims searched: 1-10Date of search: 30 October 2024Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X 1,3,6-10 US 2019 / 0084909 Al (MECHOULAM et al.) See example 5 on page 16 for the synthesis (HU-474) and example 7 for animal testing, see para [0004] and compound HU-474 on page 1 right hand column X 1,3,6-10 US 2015 / 0344403 Al (MECHOULAM et al.) See example 1, para [0084] and the structure of the compound X 1,3,6-10 Wikipedia.com, [online], Available from: https : / / en. wikipedia. org / w / index. php?title=4%27-Fluorocannabidiol&oldid=l 188194074[Accessed 29 October 2024] See whole document. X 1, 3, 6-10 WO 2018 / 222923 Al (PHYTECS INC) See para [0186] and the structure of F-CBD. Also see the compound HUF-101 in para [0405] and [0418] X 1,3-5 US 2023 / 0100890 Al (BABAN) See whole document particularly page 19: third structure on the right hand column and fourth structure on left column of page 22 X 1,3-5 WO 2021 / 076936 Al (NATURAL EXTRACTION SYS LLC) See whole document, particularly Markush structure of formula (II) X 1,3-5 WO 2017 / 011210 Al (NORAMCO INC) See whole document, particularly Markush structure of formula (VI) on page 8Categories:X Document indicating lack of novelty or inventive step A Document indicating technological background and / or state of the art. Y Document indicating lack of inventive step if P Document published on or after the declared priority date but combined with one or more other documents of same category. before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.Field of Search:Search of GB, EP, WO &US patent documents classified in the following areas of the UKCX :Worldwide search of patent documents classified in the following areas of the IPCC07C_____________________________________________________The following online and other databases have been used in the preparation of this search report INTERNET, CAS ONLINE, SEARCH-PATENT, SEARCH-NPLInternational Classification:Subclass Subgroup Valid From C07C 0039 / 42 01 / 01 / 2006 A61K 0031 / 055 01 / 01 / 2006 A61P 0025 / 08 01 / 01 / 2006 C07C 0037 / 055 01 / 01 / 2006