Cannabinoid derivatives as pharmaceutically active compounds and methods for their preparation

Abstract

The present invention relates to novel compounds, methods for producing them, and the use of these compounds as research tools and pharmaceuticals. The novel compounds are analogs of cannabidiol (CBD). CBD is a non-psychoactive cannabinoid that has been used to treat various diseases and disorders. While such treatments are promising, there remains a need in the art for more effective treatments, which has been provided by novel cannabidiol compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is related to and claims the benefit of GB2019786.9, filed December 15, 2020 (15.12.2020); GB2104278.3, filed March 26, 2021 (26.03.2021); and GB2110512.7, filed July 21, 2021 (21.07.2021), the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to novel compounds, methods for making them, and the use of these compounds as research tools and pharmaceuticals.

[0003] The novel compounds are analogs of cannabidiol (CBD). CBD is a non-psychoactive cannabinoid that has been used to treat a variety of diseases and disorders. While such treatments are promising, there remains a need in the art for more effective treatments, which has been provided by novel cannabidiol compounds. [Background technology]

[0004] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to constituents of the cannabis plant or to endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. The only natural way in which these compounds are produced is by the cannabis plant. Cannabis is a genus of flowering plants in the Cannabaceae family that includes the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis (sometimes considered part of Cannabis sativa).

[0005] The cannabis plant contains an extremely complex mixture of compounds. At least 568 unique molecules have been identified. These compounds include cannabinoids, terpenoids, sugars, fatty acids, flavonoids, other hydrocarbons, nitrogenous compounds, and amino acids.

[0006] Cannabinoids exert their physiological effects through various receptors, including, but not limited to, adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. The primary cannabinoids present in the cannabis plant are the cannabinoid acids Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and cannabidiolic acid (CBDA), along with small amounts of their respective neutral (decarboxylated) cannabinoids. Additionally, cannabis may contain lower levels of other minor cannabinoids.

[0007] There are currently four approved cannabinoid-based pharmaceutical products on the market: dronabinol (Marinol®), a synthetic tetrahydrocannabinol (THC) approved for the treatment of anorexia in AIDS and severe nausea and vomiting caused by cancer chemotherapy; nabilone (Cesamet®), a synthetic cannabinoid and THC analog approved for the treatment of nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional antiemetics; nabiximols (Sativex®), a mixture of two cannabis plant extracts approved for the treatment of neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis; and highly purified botanical CBD (Epidiolex®), approved in the United States for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in children over 2 years of age and adults.

[0008] As can be seen from the above, cannabinoids are a class of compounds that can be obtained naturally from the cannabis plant or can be produced semi-synthetically or synthetically through chemical synthesis.

[0009] Over 100 different cannabinoids have been identified. These cannabinoids can be divided into different groups: phytocannabinoids, endocannabinoids, and synthetic cannabinoids (which may be novel cannabinoids or synthetically produced versions of phytocannabinoids or endocannabinoids). The Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3-15, details the cannabinoids known to date.

[0010] Cannabidiol (CBD) is the major cannabinoid constituent of cannabis species, such as the hemp plant (Cannabis sativa). Unlike other cannabinoids, such as THC, cannabidiol does not bind to CB1 or CB2 receptors, or its binding to the receptors is negligible with respect to inducing pharmacological effects. Therefore, cannabidiol does not elicit central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychotropic (cannabimimetic) activity, and its molecular structure and properties differ substantially from those of other cannabinoids.

[0011] The administration of cannabidiol has been the subject of research in an attempt to provide alternative treatments for various diseases and disorders that may respond to such treatment.

[0012] While publications such as Gong et al. (2019) describe possible synthetic routes to produce C4'-substituted derivatives of CBD, providing a wide range of compounds that could potentially be produced and tested, no data are provided to suggest the efficacy of such compounds, let alone that any particular compound is particularly beneficial compared to others in treating disease.

[0013] It is with these considerations in mind that the present invention has been devised. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] The Handbook of Cannabis, Roger Pertwee, Chapter 1, pp. 3-15 [Non-patent document 2] "Pharmaceutical Salts: Properties, Selection, and Use", 2nd edition, 2002, Stahl and Wermuth (eds.), Wiley-VCH, Weinheim, Germany [Non-patent document 3] Remington: The Science and Practice of Pharmacy, 20th edition, 2000, published by Lippincott, Williams & Wilkins [Non-patent document 4] Handbook of Pharmaceutical Excipients, 2nd edition, 1994 [Non-patent document 5] The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986 Summary of the Invention [Means for solving the problem]

[0015] Most generally, the present invention relates to synthetic cannabinoid compounds that are biologically active and therefore useful in the treatment of diseases. Such novel compounds can be administered by a variety of routes, including, but not limited to, oral, transdermal, buccal, nasal, pulmonary, rectal, or ocular. Such compounds can be used to treat or prevent medical conditions such as epilepsy.

[0016] In a first aspect of the present invention, there is provided a compound of formula (I) or a salt thereof,

[0017] [ka]

[0018] In the formula, X is

[0019] [ka]

[0020] [ka]

[0021] The present invention provides a compound or a salt thereof selected from the following:

[0022] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and one or more additional ingredients selected from carriers, diluents (e.g., oils), excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, colorants, flavoring agents, and sweetening agents.

[0023] Preferably, the pharmaceutical composition of the second aspect is in a form selected from liquids, solutions, suspensions, emulsions, syrups, electuaries, mouthwashes, drops, tablets, granules, powders, lozenges, pastilles, capsules, cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0024] In a third aspect of the invention, there is provided a compound of the first aspect, or a pharmaceutical composition of the second aspect, for use in a method of treatment.

[0025] Preferably, the method of treatment in the third aspect is a method of treating epilepsy, generalized seizures or tonic-clonic seizures.

[0026] In a fourth aspect of the present invention, there is provided a compound of the first aspect, or a pharmaceutical composition of the second aspect, for use as a medicament.

[0027] Preferably, the medicament of the fourth aspect is a medicament for treating epilepsy, generalized seizures or tonic-clonic seizures.

[0028] In 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 the first aspect or a pharmaceutical composition of the second aspect.

[0029] In a sixth aspect of the present invention, there is provided a method for preparing a compound of formula (I), comprising the steps of: (1a) reacting a compound of formula (II) with a compound of formula (III) Including,

[0030] [ka]

[0031] During the ceremony, R 1 and R 2 is OH; or R 1 and R 2 together to form -OC(Me)2C(Me)2O-; X 1 is defined below, a method is provided.

[0032] In a seventh aspect of the present invention, there is provided a method for preparing a compound of formula (I), comprising the steps of: (2a) reacting a compound of formula (II) with bis(pinacolato)diboron; and (2b) reacting the product of step (2a) with a compound of formula (IV) Including,

[0033] [ka]

[0034] During the ceremony, X 2 is defined below, a method is provided.

[0035] In an eighth aspect of the present invention there is provided an intermediate for use in the preparation of a compound of formula (I), the intermediate having formula (II):

[0036] [ka]

[0037] An intermediate is provided which is a compound of the formula:

[0038] These and other aspects and embodiments of the invention are described in more detail below.

[0039] Embodiments of the present invention are further described below with reference to the accompanying drawings. [Brief explanation of the drawings]

[0040] [Figure 1] FIG. 1 shows the effect of Compound 1 in the mini-MEST test in mice. [Figure 2] FIG. 1 shows the effects of compounds 2 and 3 in the mini-MEST test in mice. [Figure 3] FIG. 1 shows the effects of compounds 4 and 5 in the mini-MEST test in mice. [Figure 4] FIG. 1 shows the effect of compound 12 in the mini-MEST test in mice. [Figure 5] FIG. 1 shows the effect of compound 42 in the mini-MEST test in mice. [Figure 6] FIG. 1 shows the effect of compound 43 in the mini-MEST test in mice. [Figure 7] FIG. 1 shows the effect of Compound 1 in the MEST test in mice. [Figure 8] FIG. 1 shows the effect of compound 6 in the mini-MEST test in mice. [Figure 9] FIG. 1 shows the effect of compound 13 in the mini-MEST test in mice. [Figure 10] FIG. 1 shows the effects of compounds 22 and 38 in the mini-MEST test in mice. [Figure 11] FIG. 1 shows the effects of compounds 26, 28 and 33 in the mini-MEST test in mice. [Figure 12] FIG. 1 shows the effect of compound 46 in the mini-MEST test in mice. [Figure 13] FIG. 1 shows the effect of compound 36 in the mini-MEST test in mice. DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention relates to synthetic cannabinoid compounds that are biologically active and therefore useful in the treatment of disease.

[0042] Synthetic cannabinoids The present invention provides a compound of formula (I):

[0043] [ka]

[0044] In the formula, X is

[0045] [ka]

[0046] [ka]

[0047] The dashed lines indicate the points of attachment to the rest of the molecule.

[0048] In a preferred embodiment, X is

[0049] [ka]

[0050] is selected from.

[0051] salt In some embodiments, the compound of Formula (I) is provided in free base form.

[0052] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, e.g., a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in "Pharmaceutical Salts: Properties, Selection, and Use", 2nd ed., 2002, Stahl and Wermuth (eds.), Wiley-VCH, Weinheim, Germany.

[0053] Thus, in some embodiments, compounds of Formula (I) are provided as salts, eg, in protonated form with a suitable counteranion.

[0054] Suitable counter anions include both organic and inorganic anions. An example of a suitable inorganic anion is chloride (Cl). - ), bromide ion (Br - ), iodine ion (I - ), sulfate ions (SO4 2- ), sulfite ions (SO3 2- ), nitrate ions (NO3 - ), nitrite ion (NO2 - ), phosphate ions (PO4 3- ), and phosphite ions (PO3 3-Examples of suitable organic anions include those derived from inorganic acids, including 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, phenylsulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartrate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannic acid and carboxymethylcellulose.

[0055] Alternatively, in some embodiments, the compound of formula (I) is provided as a salt, eg, in deprotonated form, with a suitable counter cation.

[0056] Suitable counter cations include both organic and inorganic cations. An example of a suitable inorganic cation is Na + and K. + Alkali metal ions such as Ca 2+ and Mg 2+ alkaline earth cations such as Al 3+ Examples of suitable organic cations include ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 +Examples of substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + is.

[0057] solvate In some embodiments, the compound of formula (I) is provided in a desolvated form, for example a dehydrated form.

[0058] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound.

[0059] Thus, in some embodiments, the compound of formula (I) is provided in the form of a solvate (a complex of a solute (e.g., a compound, a salt of a compound) and a solvent). Examples of solvates include hydrates, such as monohydrates, dihydrates, and trihydrates.

[0060] N-oxide The compounds of formula (I) may, for example, have sp 2 If it contains a nitrogen atom (-N=), (-N + (O - It may be convenient to prepare, purify, and / or handle the corresponding N-oxide (-N(→O)=), also designated as )=).

[0061] Thus, in some embodiments, certain compounds of Formula (I) are provided in the form of an N-oxide, for example, pyridine may be substituted to form a pyridine N-oxide.

[0062] Certain isomers Certain compounds of Formula (I) may exist in one or more particular optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, or conformational forms, including, but not limited to, D- and L-forms; d- and l-forms; (+)- and (-)-forms; syn- and anti-forms; axial- and equatorial-forms; boat-, chair-, twist-boat-, envelope-, and half-chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" or "isomeric forms."

[0063] Structural or constitutional isomers (i.e., isomers that differ solely by the position of their atoms in space and not by the bonding between their atoms) are specifically excluded from the term "isomer" as used herein. For example, a reference to a methoxy group, -OCH, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CHOH. Similarly, a reference to 2-pyridinyl is not to be construed as a reference to its structural isomer, 3-pyridinyl.

[0064] The above exclusion does not relate to tautomers, such as keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol, imine / enamine, amide / iminoalcohol, nitroso / oxime, lactam / lactim.

[0065] The term "isomer" includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H may be any isotope, including T; C may be 12 C. 13 C, and 14 It can be any isotope, including C; O can be 16 O and 18 It may be any isotope, including O, etc.

[0066] Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic mixtures and other mixtures.

[0067] Synthesis method Methods for the synthesis of compounds of formula (I) are described in the Examples. Additional information regarding the synthesis of synthetic cannabinoids can be found in Gong et al. (2019).

[0068] Method 1 The present invention provides a first method for preparing a compound of formula (I), comprising: (1a) reacting a compound of formula (II) with a compound of formula (III) Including,

[0069] [ka]

[0070] During the ceremony, R 1 and R 2 is OH; or R 1 and R 2 together to form -OC(Me)2C(Me)2O-; X 1 teeth,

[0071] [ka]

[0072] [ka]

[0073] The method is selected from the following:

[0074] In a preferred embodiment, R 1 and R 2 together to form -OC(Me)C(Me)O- (boronic acid pinacol ester).

[0075] Preferably, step (1a) comprises reacting a compound of formula (II) with a compound of formula (III) and a palladium catalyst. Suitable palladium catalysts include Pd(dppf)Cl2 and SPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

[0076] Preferably, step (1a) further comprises reacting a compound of formula (II) with a compound of formula (III) and a base. Suitable bases include sodium carbonate (Na2CO3), cesium carbonate (Cs 12 CO3).

[0077] Typically, step (1a) is carried out in a solvent. Suitable solvents include dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), and water.

[0078] Optionally, certain additives may be used in step (1a). Suitable additives include cesium fluoride (CsF).

[0079] Step (1a) is typically carried out at elevated temperatures (above room temperature, about 20° C.). Methods for providing heat during the reaction are known and include, for example, the use of a reaction vessel with an external heating jacket or the use of microwave heating.

[0080] Typically, step (1a) comprises reacting a compound of formula (II) with a compound of formula (III) at a temperature of from 60°C to 140°C, preferably from 80°C to 140°C, more preferably from 80°C to 120°C.

[0081] Step (1a) may be carried out for a time sufficient to form the desired amount of coupling product. Typically, step (1a) is carried out until substantially all of the compound of formula (II) is consumed.

[0082] Typically, step (1a) involves reacting a compound of formula (II) with a compound of formula (III) for a period of from 1 hour to 24 hours.

[0083] Method 2 The present invention also provides a second process for preparing a compound of formula (I), comprising: (2a) reacting a compound of formula (II) with bis(pinacolato)diboron; and (2b) reacting the product of step (2a) with a compound of formula (IV) Including,

[0084] [ka]

[0085] During the ceremony, X 2 teeth,

[0086] [ka]

[0087] [ka]

[0088] The method is selected from the following:

[0089] Preferably, step (2a) comprises reacting the compound of formula (II) with bis(pinacolato)diboron and a palladium catalyst. Suitable palladium catalysts include Pd(dppf)Cl2 and SPhos-Pd-G2.

[0090] Preferably, step (2a) further comprises reacting the compound of formula (II) with bis(pinacolato)diboron and a base. Suitable bases include potassium acetate.

[0091] Typically, step (2a) is carried out in a solvent. Suitable solvents include dioxane and water.

[0092] Step (2a) typically involves reacting the compound of formula (II) with bis(pinacolato)diboron at a temperature of from 60°C to 140°C, preferably from 80°C to 140°C, more preferably from 80°C to 120°C.

[0093] Step (2a) may be carried out for a time sufficient to form the desired amount of coupling product. Typically, step (2a) is carried out until substantially all of the compound of formula (II) is consumed.

[0094] Typically, step (2a) involves reacting the compound of formula (II) with bis(pinacolato)diboron for a period of from 1 hour to 24 hours.

[0095] Preferably, step (2b) comprises reacting the product of step (2a) with a compound of formula (IV) and a palladium catalyst. Suitable palladium catalysts include Pd(dppf)Cl2 and SPhos-Pd-G2.

[0096] Preferably, step (2b) further comprises reacting the product of step (2a) with a compound of formula (IV) and a base. Suitable bases include sodium carbonate (Na2CO3), cesium carbonate (Cs 12 CO3).

[0097] Typically, step (2b) is carried out in a solvent. Suitable solvents include dioxane and water.

[0098] Optionally, certain additives may be used in step (2b). Suitable additives include cesium fluoride (CsF).

[0099] Step (2b) typically involves reacting the product of step (2a) with a compound of formula (IV) at a temperature of from 60°C to 140°C, preferably from 80°C to 140°C, more preferably from 80°C to 120°C.

[0100] Step (2b) may be carried out for a time sufficient to form the desired amount of coupled product.

[0101] Typically, step (2b) involves reacting the product of step (2a) with a compound of formula (IV) for a period of from 1 hour to 24 hours.

[0102] Intermediates The present invention provides intermediates useful in the preparation of compounds of formula (I). The intermediates of the present invention are compounds of formula (II).

[0103] [ka]

[0104] Pharmaceutical Composition While it is possible for a compound of formula (I) to be administered alone, it is preferable to administer a pharmaceutical composition (e.g., formulation, preparation, or medicament) comprising a compound of formula (I) together with one or more other pharmaceutically acceptable ingredients.

[0105] Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, together with one or more pharmaceutically acceptable ingredients.

[0106] Suitable pharmaceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) can be found in standard pharmaceutical textbooks, such as Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, published by Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 2nd Edition, 1994.

[0107] Examples of suitable pharmaceutically acceptable ingredients include pharmaceutically acceptable carriers, diluents (e.g., oils), excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents.

[0108] In a preferred embodiment, the pharmaceutical composition comprises one or more excipients selected from among a carrier, an oil, a disintegrant, a lubricant, a stabilizer, a flavoring agent, an antioxidant, a diluent, and another pharmaceutically active compound.

[0109] The pharmaceutical composition may be in any suitable form. Examples of suitable forms include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), syrups, electuaries, mouthwashes, drops, tablets (including coated tablets), granules, powders, lozenges, pastilles, capsules (including hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0110] In a preferred embodiment, the form of the pharmaceutical composition is selected from tablets, capsules, granules, powders for inhalation, sprinkles, oral solutions and suspensions.

[0111] medical treatment The present inventors have found that the compound of formula (I) is biologically active. The examples demonstrate that the compound of formula (I) exhibits anticonvulsant activity in a mouse model. Therefore, the compound of formula (I) and its salts, as well as pharmaceutical compositions containing the compound of formula (I) or its salts, may be useful in medical treatment.

[0112] Thus, the present invention provides a compound of formula (I) or a salt thereof for use in a method of therapy, for example in a method of treatment of the human or animal body by therapy (ie treatment).

[0113] The present invention also provides a compound of formula (I) or a salt thereof for use as a pharmaceutical.

[0114] The present invention also provides a method of treatment comprising the step of administering a therapeutically effective amount of Compound (I) or a salt thereof to a subject in need of treatment.

[0115] The present invention also provides the use of Compound (I) or a salt thereof for the manufacture of a medicament.

[0116] Condition being treated The present inventors have found that the compound of formula (I) exhibits anticonvulsant activity in a mouse model of generalized seizures. Accordingly, the compound of formula (I), its salts, and pharmaceutical compositions comprising the compound of formula (I) or its salts may be useful in the treatment of certain conditions associated with seizures.

[0117] Similarly, compounds of formula (I), salts thereof, and pharmaceutical compositions comprising compounds of formula (I) or salts thereof will be useful as medicaments (and in the manufacture of medicaments for the treatment of) certain conditions related to seizures.

[0118] In a preferred embodiment, the seizure-related condition is epilepsy.

[0119] In one embodiment, the seizure-related condition is a generalized seizure, such as a generalized seizure associated with epilepsy.

[0120] In one embodiment, the seizure-related condition is a tonic-clonic seizure, for example a tonic-clonic seizure associated with epilepsy.

[0121] Subjects / patients The method of treatment typically involves administering to a subject or patient a compound of formula (I) or a salt thereof.

[0122] The subject / patient may be a chordate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human. Furthermore, the subject / patient may be in any of its developmental forms, such as an infant or child.

[0123] In a preferred embodiment, the subject / patient is a human, more preferably an adult human.

[0124] The subject / patient may also be a non-human mammal used in experimental research, such as a rodent, including rats, mice, guinea pigs, and chinchillas.

[0125] Administration route The method of treatment may involve administering to a subject a compound of formula (I) or a salt thereof by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0126] Routes of administration may be oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using aerosols, etc., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular.

[0127] dose The method of treatment typically involves administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0128] Appropriate doses of compounds of formula (I), their salts, and pharmaceutical compositions containing compounds of formula (I) or their salts may vary from patient to patient. Determining the optimal dose will generally involve balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dose level will depend on a variety of factors, including, but not limited to, the activity of the particular compound of formula (I), the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other active agents, compounds, and / or substances used in combination, the severity of the condition, and the patient's race, sex, age, weight, condition, general health, and medical history. While the dose and route of administration are ultimately at the discretion of the clinician, generally, the dose will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial adverse or harmful side effects.

[0129] Administration can be in one dose, continuously or at intervals (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Single or multiple administrations can be carried out, with dosage levels and pattern being selected by the treating clinician.

[0130] Other Aspects and Embodiments Any and all compatible combinations of the above-described embodiments are expressly disclosed herein as if each and every combination were individually and expressly recited.

[0131] Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.

[0132] When used, "and / or" is considered a specific disclosure of each associated component or feature alone, as well as a specific disclosure of combinations of components or features. For example, "A and / or B" is considered a specific disclosure of i) A, ii) B, and iii) each of A and B, as if each were individually listed.

[0133] Unless the context dictates otherwise, the above feature descriptions and definitions are not limited to any particular aspect or embodiment of the present invention, but apply equally to all aspects and embodiments described.

[0134] definition To aid in the understanding of the present invention, the following terms are defined below.

[0135] "Cannabinoids" is a group of compounds that includes endocannabinoids, phytocannabinoids, and compounds that are neither endocannabinoids nor phytocannabinoids (hereinafter "syntho-cannabinoids").

[0136] "Endocannabinoids" are endogenous cannabinoids that are high-affinity ligands for CB1 and CB2 receptors.

[0137] A "phytocannabinoid" is a cannabinoid that can be found naturally in the cannabis plant. Phytocannabinoids may be present in extracts containing the botanical drug substance, may be isolated, or may be synthetically reproduced.

[0138] "Syntho-cannabinoids" are compounds that are not found endogenously or in the cannabis plant. Examples include WIN 55212 and rimonabant.

[0139] An "isolated phytocannabinoid" is one that has been extracted from the cannabis plant and purified to the extent that all additional components, such as secondary and minor cannabinoids and non-cannabinoid fractions, have been removed.

[0140] A "synthetic cannabinoid" is one produced by chemical synthesis. The term includes the modification of an isolated phytocannabinoid, for example, by forming a pharmaceutically acceptable salt thereof.

[0141] A "substantially pure" cannabinoid is one that is present in a purity of greater than 95% (w / w), more preferably greater than 96% (w / w), through 97% (w / w), 98% (w / w), up to 99% (w / w) or greater.

[0142] Epilepsy is considered to be a brain disorder defined by any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart; (2) a likelihood of further seizures occurring over the next 10 years, similar to one unprovoked (or reflex) seizure and a general risk of recurrence (at least 60%) after two unprovoked seizures; (3) a diagnosis of an epilepsy syndrome (practical clinical definition of epilepsy by the International League Against Epilepsy (ILAE), 2014).

[0143] The term “generalized seizures” (or “generalized onset seizures”) refers to seizures conceptualized as originating from one point in the brain and rapidly interlocking into bilaterally distributed networks ( Operational Classification of Seizure Types by ILAE, 2017 ).

[0144] "Tonic-clonic seizures" occur in two stages: a tonic stage, which typically involves muscle stiffening and loss of consciousness, and a clonic stage, which typically involves rhythmic jerking of the limbs.

[0145] The term "pharmaceutically acceptable" refers to compounds, ingredients, substances, compositions, dosage forms, etc., which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a target patient (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each ingredient (e.g., carrier, diluent, excipient, etc.) must also be "acceptable" in the sense of being compatible with the other ingredients of the composition.

[0146] The term "therapeutically effective amount" refers to the amount of a compound, or substance, composition, or dosage form containing a compound, that, when administered in accordance with a desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio. [Example]

[0147] Certain aspects and embodiments of the present invention will now be described by way of example and with reference to the figures described above.

[0148] Example 1 Synthetic methods for producing CBD derivatives This example describes synthetic methods used to generate novel analogs of canonical CBD (1-48) that exhibited pharmacological activity. Schemes 1a and 1b below describe the initial routes for preparing intermediates (1aa, 1ab, and 1ba), and Schemes 2a-2r describe the subsequent generation of CBD derivatives 1-48 formed from either Scheme 1a or 1b, or via several intermediates obtained from the designated starting materials (Schemes 2p, 2q, 2r).

[0149] Scheme 1a: Synthetic route for preparing intermediates 1aa and 1ab

[0150] [ka]

[0151] The intermediate in Scheme 1a was prepared according to the method of Gong et al. (2019).

[0152] Scheme 1b: Synthetic route for preparing intermediate 1ba

[0153] [ka]

[0154] A solution of 5-bromobenzene-1,3-diol (20.88 g, 110 mmol) and p-toluenesulfonic acid monohydrate (10.51 g, 55.2 mmol) in a mixture of 2-methyltetrahydrofuran (132 mL) and dichloromethane (465 mL) was cooled to 0 °C in an ice / brine bath under nitrogen. (4R)-4-Isopropenyl-1-methyl-cyclohex-2-en-1-ol (13 mL, 77.5 mmol) was added, and the resulting solution was stirred for 5 min. The cooling bath was removed, and the colorless solution was stirred for 2 h while warming to 20 °C. The mixture was diluted with dichloromethane (200 mL) and basified to pH 8 by careful addition of saturated aqueous sodium bicarbonate (300 mL). The organic layer was separated, washed with water (50 mL) and saturated brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo to give a colorless gum. This was purified by column chromatography on silica (800 g, Interchim cartridge) eluting with 0-50% diethyl ether in cyclohexane to give the title compound (2.53 g) as a colourless gum, which was repurified by column chromatography on silica gel (40 g, 15 micron Interchim column) eluting with 5-20% diethyl ether in cyclohexane to give the title compound (0.92 g) and some impurities.

[0155] The first column also yielded recovered 5-bromobenzene-1,3-diol (8.17 g) as a colorless gum, which solidified upon standing. This was dissolved in a mixture of 2-methyltetrahydrofuran (55 mL) and dichloromethane (185 mL), treated with (4R)-4-isopropenyl-1-methyl-cyclohex-2-en-1-ol (4.9 mL, 30.3 mmol), and cooled to 0 °C in an ice / brine bath under nitrogen. p-Toluenesulfonic acid monohydrate (4.11 g, 21.6 mmol) was added, and the resulting solution was stirred for 5 minutes. The cooling bath was removed, and the colorless solution was stirred for 2 hours while warming to 20 °C. The mixture was diluted with dichloromethane (100 mL) and basified to pH 8 by careful addition of saturated aqueous sodium bicarbonate (300 mL). The organic layer was separated, washed with water (50 mL) and saturated brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo to give a colorless gum. The residue was purified by column chromatography on silica (40 g, Interchim cartridge) eluting with 0-50% diethyl ether in cyclohexane to give the title compound as a colorless gum. This was combined with the impurity material from the first reaction and purified by column chromatography on silica (40 g, Interchim cartridge) eluting with 5-20% diethyl ether in cyclohexane to give the title compound as a colorless gum (2.10 g, 91% LCMS purity).

[0156] The total yield of 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (1ba) obtained was 3.02 g (8.5%).

[0157] The analytical data for compound 1ba are as follows: 1H NMR (400 MHz, DMSO) δ 9.37 (s, 2H), 6.38 (s, 2H), 5.08 (s, 1H), 4.49 (d, J=2.8 Hz, 1H), 4.44 (dd, J=1.6, 2.8 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.06 - 2.98 (m, 1H), 2.12 - 2.07 (m, 1H), 1.96 - 1.92 (m, 1H), 1.63 - 1.59 (m, 8H).

[0158] Formation of biaryl compounds from aryl bromides (1ba) and triflates (1aa and 1ab) can be achieved using one of several sets of conditions, as illustrated by Schemes 2a-2o below. Schemes 2p-2r illustrate synthetic routes to analogs from other designated starting materials.

[0159] Scheme 2a

[0160] [ka]

[0161] 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol), [3,5-dihydroxy-4-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]trifluoromethanesulfonate (200 mg, 0.510 mmol), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (147 mg, 0.663 mmol), and sodium carbonate (216 mg, 2.04 mmol) in 1,4-dioxane (3 mL) and water (1 mL) were heated in a sealed tube at 100 °C for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (20 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (10 mL), dried (Phase Separator paper), and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 34 as an off-white solid (20.5 mg, 12%).

[0162] The same method was used with the appropriate boronic acid pinacol ester to generate compounds 1 and 5-17.

[0163] Scheme 2b

[0164] [ka]

[0165] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol), 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (100 mg, 0.309 mmol), 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (106 mg, 0.402 mmol), and sodium carbonate (131 mg, 1.24 mmol) in 1,4-dioxane (2 mL) and water (0.70 mL) were heated in a sealed tube at 100° C. for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (30 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (20 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried (phase separator paper) and concentrated in vacuo. The residue was purified by preparative HPLC to give compound 35 as an off-white solid (55.9 mg, 48%).

[0166] The same method was used with the appropriate boronic acid pinacol ester to generate compounds 2, 3, 18-23, 35, and 48.

[0167] Scheme 2c

[0168] [ka]

[0169] A solution of (1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (119 mg, 0.368 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (130 mg, 0.553 mmol), cesium carbonate (360 mg, 1.10 mmol), and SPhos (6.0 mg, 0.0146 mmol) in tetrahydrofuran (1.70 mL) and water (170 µL) was degassed with nitrogen, treated with SPhos Pd G2 (6.0 mg, 8.33 µmol), and heated at 80 °C overnight. The reaction mixture was partitioned between diethyl ether (5 mL) and water (5 mL). The layers were separated and the aqueous layer was further extracted with diethyl ether (3 × 3 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate in dichloromethane to give compound 37 as a light brown solid (47 mg, 35%).

[0170] The same method was used with the appropriate boronic acid pinacol ester to generate compound 41.

[0171] Scheme 2d

[0172] [ka]

[0173] A solution of (1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (150 mg, 0.464 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (151 mg, 0.603 mmol), cesium carbonate (464 mg, 1.39 mmol), and SPhos Pd G2 (6.7 mg, 9.28 μmol) in N,N-dimethylformamide (4.0 mL) and water (1.0 mL) was degassed with nitrogen and treated with SPhos (7.6 mg, 0.0186 mmol). The reaction mixture was heated in a microwave reactor at 140 °C for 90 min, then diluted with water (10 mL) and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined and concentrated in vacuo. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate in cyclohexane followed by reverse-phase preparative HPLC to give compound 38 as an off-white solid (88.5 mg, 51%).

[0174] Scheme 2e

[0175] [ka]

[0176] A solution of (1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (150 mg, 0.464 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (147 mg, 0.603 mmol), and sodium carbonate (148 mg, 1.39 mmol) in N,N-dimethylformamide (4.0 mL) and water (1.0 mL) was degassed with nitrogen and treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (19 mg, 0.023 mmol) in dichloromethane. The reaction mixture was heated in a microwave reactor at 140 °C for 90 min, then diluted with water (10 mL) and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined and concentrated in vacuo. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate in cyclohexane followed by reverse-phase preparative HPLC to give compound 39 as an off-white solid (36.9 mg, 24%).

[0177] Scheme 2f

[0178] [ka]

[0179] A solution of (1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (80 mg, 0.248 mmol), [3-[(dimethylamino)methyl]phenyl]boronic acid (44 mg, 0.248 mmol), and cesium fluoride (113 mg, 0.743 mmol) in 1,4-dioxane (2.00 mL) and water (1.00 mL) was degassed with nitrogen and treated with [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (9.2 mg, 0.012 mmol). The reaction mixture was heated at 90 °C for 60 min, then diluted with ethyl acetate (25 mL), washed with water (25 mL), dried (phase separation filter paper), and concentrated in vacuo. The residue was purified by column chromatography eluting with 0-50% ethyl acetate / ethanol / NH3 75:25:1 in cyclohexane to give compound 40 as a beige solid (32.6 mg, 32%).

[0180] The same method was used with the appropriate boronic acid pinacol ester to generate compound 43.

[0181] Scheme 2g

[0182] [ka]

[0183] (1'R,2'R)-4-Bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (100 mg, 0.254 mmol) was dissolved in dry 1,4-dioxane (3 mL) and degassed with nitrogen. 2-Methyl-5-(tributylstannyl)oxazole (104 mg, 0.279 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) were added, and the reaction mixture was heated at 100 °C overnight. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through Celite, and washed with water (10 mL) and 1 M aqueous potassium fluoride solution (3 × 20 mL). The organic layer was separated, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% diethyl ether in cyclohexane followed by reverse phase preparative HPLC to give compound 24 as an off-white solid (19.4 mg, 23%).

[0184] Scheme 2h

[0185] [ka]

[0186] A solution of (1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (100 mg, 0.309 mmol), bis(pinacolato)diboron (94 mg, 0.371 mmol), and potassium acetate (61 mg, 0.619 mmol) in dioxane (4.0 mL) was degassed with nitrogen, treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol), and heated at 100°C overnight. The reaction mixture was cooled to room temperature and treated with 2-bromo-5-methyl-1,3,4-oxadiazole (53 mg, 0.325 mmol), cesium carbonate (202 mg, 0.619 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol). The reaction mixture was heated at 100°C for 5 hours. Additional 2-bromo-5-methyl-1,3,4-oxadiazole (53 mg, 0.325 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol) were added, and the reaction mixture was heated at 100°C overnight. The mixture was diluted with ethyl acetate (3 mL) and washed with water (4 mL) and brine (2 mL). The combined aqueous phases were extracted with ethyl acetate (2 × 3 mL) and the combined organic phases were washed with water (4 mL) and brine (2 mL), dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC followed by column chromatography on silica eluting with 0-10% methanol in dichloromethane to give compound 29 as an off-white solid (30.3 mg, 30%).

[0187] The same method was used with the appropriate boronic acid pinacol ester to generate compound 4.

[0188] Scheme 2i

[0189] [ka]

[0190] A solution of (1'R,2'R)-2,6-dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (200 mg, 0.510 mmol), bis(pinacolato)diboron (194 mg, 0.765 mmol), potassium acetate (200 mg, 2.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) in 1,4-dioxane (5 mL) was heated in a sealed tube at 100°C for 24 hours. The reaction mixture was cooled to room temperature, and water (2 mL), cesium fluoride (310 mg, 2.04 mmol), 5-bromo-1-methyl-1H-imidazole (107 mg, 0.663 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (19 mg, 0.025 mmol) were added. The mixture was heated in a sealed tube at 100 °C for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (30 mL). The filtrate was washed with saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried (phase separator paper) and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 32 as an off-white solid (0.5 equiv. formate salt) (4.76 mg, 3%).

[0191] The same method was used with the appropriate boronic acid pinacol ester to generate compound 25.

[0192] Scheme 2j

[0193] [ka]

[0194] 5-Bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (100 mg, 0.309 mmol), bis(pinacolato)diboron (118 mg, 0.464 mmol), potassium acetate (121 mg, 1.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.0155 mmol) in 1,4-dioxane (3 mL) were heated in a sealed tube at 100°C for 24 hours. The reaction mixture was cooled to room temperature, and water (1 mL), cesium fluoride (188 mg, 1.24 mmol), 3-bromo-1-methyl-1H-1,2,4-triazole (65 mg, 0.402 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol) were added. The reaction mixture was heated in a sealed tube at 100 °C for 24 hours. The mixture was cooled to room temperature, and 3-bromo-1-methyl-1H-1,2,4-triazole (65 mg, 0.402 mmol), sodium carbonate (131 mg, 1.24 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol) were added. The mixture was heated in a sealed tube at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (30 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried (phase separator paper) and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 33 as an off-white solid (6.96 mg, 7%).

[0195] The same method was used with the appropriate boronic acid pinacol ester to generate compound 42.

[0196] Scheme 2k

[0197] [ka]

[0198] (1'R,2'R)-2,6-Dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (975 mg, 2.16 mmol) was dissolved in toluene (10 mL) and dry 1,4-dioxane (6.0 mL) and degassed with nitrogen. Bis(pinacolato)diboron (604 mg, 2.38 mmol), potassium acetate (636 mg, 6.49 mmol), and XPhos Pd G3 (37 mg, 0.043 mmol) were added, and the mixture was stirred at 95 °C overnight. The reaction was poured into water (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic phase was dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-20% diethyl ether in cyclohexane to give the title compound as a colourless gum (172 mg, 13%, NMR showed 40% pinacol contamination).

[0199] A solution of (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (172 mg, 60% pure, 0.279 mmol), 4-bromo-1-methyl-1H-imidazole (0.028 mL, 0.279 mmol), and sodium carbonate (118 mg, 1.11 mmol) in 1,4-dioxane (2.0 mL) and water (0.50 mL) was degassed with nitrogen and treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol). The reaction mixture was heated at 100° C. overnight and then treated with additional 4-bromo-1-methyl-1H-imidazole (0.056 mL, 0.558 mmol), cesium carbonate (91 mg, 0.279 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.0139 mmol). The reaction mixture was heated at 100° C. for an additional 6 h and then partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (20 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 28 as an off-white solid (7.1 mg, 7.9%).

[0200] Scheme 2l

[0201] [ka]

[0202] A degassed solution of tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) and Me4tButylXphos (22 mg, 0.046 mmol) in toluene (2.50 mL) and 1,4-dioxane (0.50 mL) was heated to 120 °C and stirred for 10 min. After cooling to room temperature, (1'R,2'R)-2,6-dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (150 mg, 0.382 mmol), potassium phosphate tribasic (243 mg, 1.15 mmol), and 1,2,4-triazole (26 mg, 0.382 mmol) were added, and the mixture was degassed, heated to 120 °C, and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0 to 100% ethyl acetate in cyclohexane followed by reverse-phase preparative HPLC to give compound 31 as an off-white solid (1 equivalent of trifluoroacetate salt) (8.75 mg, 7.4%).

[0203] The same method was used with the appropriate boronic acid pinacol ester to generate compound 26.

[0204] Scheme 2m

[0205] [ka]

[0206] (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diylbis(2,2-dimethylpropanoate) (200 mg, 0.357 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and potassium carbonate (99 mg, 0.713 mmol) in dioxane (5.0 mL) and water (1.0 mL) were treated with tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol). The mixture was heated at 140 °C in a microwave reactor for 30 minutes and concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with water (5 mL). The organic layer was dried (hydrophobic frit) and concentrated in vacuo to give crude (1'R,2'R)-5'-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diylbis(2,2-dimethylpropanoate) (149 mg). This was dissolved in toluene (5.0 mL) and treated with methylmagnesium bromide (3 M in tetrahydrofuran, 0.57 mL, 1.71 mmol). The reaction mixture was heated to 110 °C for 7 h. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution (2 mL). The mixture was extracted with dichloromethane (2 × 25 mL). The combined organic phases were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound 36 as a colourless solid (21 mg, 18%).

[0207] The same method was used with the appropriate boronic acid pinacol ester to generate compound 27.

[0208] Scheme 2n

[0209] [ka]

[0210] A solution of 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (300 mg, 0.928 mmol) and pyridinium p-toluenesulfonate (47 mg, 0.186 mmol) in dichloromethane (6.0 mL) was treated with 3,4-dihydro-2H-pyran (0.25 mL, 2.78 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), and brine (20 mL), dried (magnesium sulfate), and concentrated in vacuo to give crude 2,2'-(((1'R,2'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(tetrahydro-2H-pyran) as a yellow oil (391 mg, 86% crude yield).

[0211] A portion of this material (50 mg, 0.102 mmol) was dissolved in DMSO (0.5 mL) and treated with 2-hydroxypyridine (12 mg, 0.122 mmol), potassium carbonate (42 mg, 0.305 mmol), 4,7-dimethoxy-1,10-phenanthroline (4.9 mg, 0.0203 mmol), and copper(I) iodide (1.9 mg, 0.010 mmol). The reaction mixture was heated in a microwave reactor at 120° C. and stirred for 5 hours, then treated with additional 2-hydroxypyridine (12 mg, 0.122 mmol) and copper(I) iodide (1.9 mg, 0.010 mmol) and heated at 150° C. for an additional 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried (magnesium sulfate) and concentrated to give crude 1-((1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-2,6-bis((tetrahydro-2H-pyran-2-yl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one as a brown oil (35 mg). This was dissolved in methanol (1.0 mL) without further purification, treated with p-toluenesulfonic acid monohydrate (2.4 mg, 0.013 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 30 as an off-white solid (2.0 mg, 5.8%).

[0212] Scheme 2o

[0213] [ka]

[0214] A degassed solution of (1'R,2'R)-2,6-dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (200 mg, 0.510 mmol), 3-aminopyridine (58 mg, 0.612 mmol), JohnPhos (7.6 mg, 0.025 mmol), and potassium phosphate tribasic (325 mg, 1.53 mmol) in tetrahydrofuran (2.50 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.55 μmol). The mixture was degassed and heated at 85 °C for 3 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0-60% 3:1 ethyl acetate / ethanol in cyclohexane to give compound 45 as a brown solid (44 mg, 26%).

[0215] The same method was used with the appropriate boronic acid pinacol ester to generate compound 46.

[0216] Scheme 2p

[0217] [ka]

[0218] Methyl 3,5-dihydroxyphenylacetate (5.25 g, 28.8 mmol) was dissolved in tetrahydrofuran (20 mL) and diluted with dichloromethane (80 mL). p-Toluenesulfonic acid monohydrate (548 mg, 2.88 mmol) was added, and the mixture was cooled to 4 °C. (1S,4R)-4-Isopropenyl-1-methyl-cyclohex-2-en-1-ol (5.8 mL, 36.0 mmol) was added in one portion, and the mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (20 mL) was added, and the mixture was stirred for 10 minutes and diluted with water (40 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0–70% diethyl ether in cyclohexane to give 75% pure methyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)acetate (3.2 g, 20%) as a yellow oil.

[0219] Methyl 2-[3,5-dihydroxy-4-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate (75%, 3.13 g, 7.42 mmol) was dissolved in tetrahydrofuran (72 mL). Water (12.00 mL) was added, followed by lithium hydroxide monohydrate (996 mg, 23.7 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with 2 M HCl (10.5 mL). Water (75 mL) and EtOAc (75 mL) were added, and the organic layer was separated and washed with 1:1 brine:water (60 mL). The organic phase was dried (hydrophobic frit) and concentrated in vacuo. The aqueous phase was further extracted with EtOAc (60 mL). The organic phase was dried (hydrophobic frit) and the solvent was concentrated in vacuo. The residues were combined and purified by column chromatography on silica, eluting with 50–100% diethyl ether in cyclohexane to give 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)acetic acid (2.0 g, 91%) as a yellow oil.

[0220] 2-((1'R,2'R)-2,6-dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl)acetic acid (100 mg, 0.331 mmol) was dissolved in tetrahydrofuran (4 mL) and cooled to 0°C. N,N'-Dicyclohexylcarbodiimide (75 mg, 0.364 mmol) and 1-hydroxybenzotriazole (49 mg, 0.364 mmol) were added, and the mixture was stirred at 0°C for 3.5 hours. N-Hydroxyacetimidamide (25 mg, 0.331 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0°C, and insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a dark brown oil. This was dissolved in dioxane (5 mL), and the mixture was heated at 110° C. for 7 hours, cooled to room temperature, and stirred overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0 to 100% diethyl ether in cyclohexane, followed by reverse-phase preparative HPLC to give compound 44 as an off-white solid (32 mg, 29%).

[0221] Scheme 2q

[0222] [ka]

[0223] 2,2,6,6-Tetramethyl-3,5-heptanedione (0.54 mL, 2.59 mmol) was added to a stirred mixture of 3-bromopyridine (2.5 mL, 25.9 mmol), 3,5-dimethoxyphenol (2 g, 13.0 mmol), cesium carbonate (12.7 g, 38.9 mmol), and copper(I) iodide (247 mg, 1.30 mmol) in 1-methyl-2-pyrrolidinone (80 mL). The reaction was degassed for 5 minutes and heated at 140° C. for 24 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with diethyl ether (150 mL) and washed with brine (5×30 mL). The organic layer was separated, dried (hydrophobic frit), and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0-100% ethyl acetate in cyclohexane to give 3-(3,5-dimethoxyphenoxy)pyridine (2.2 g, 73%) as a yellow oil.

[0224] Boron tribromide (30 mL, 29.8 mmol, 1.0 M in dichloromethane) was added dropwise to a stirred solution of 3-(3,5-dimethoxyphenoxy)pyridine (2.3 g, 9.95 mmol) in dichloromethane (50 mL) at -10 °C. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was cooled to 0 °C and quenched with methanol (10 mL, 0.247 mol). The mixture was diluted with dichloromethane (50 mL) and neutralized to pH 8 with aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were combined, dried (hydrophobic frit), and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0-20% methanol in dichloromethane to give 5-(pyridin-3-yloxy)benzene-1,3-diol (900 mg, 44%) as a light brown solid.

[0225] Boron trifluoride diethyl etherate (0.35 mL, 2.87 mmol) was added to a stirred mixture of 5-(pyridin-3-yloxy)benzene-1,3-diol (530 mg, 2.61 mmol) in tetrahydrofuran (20 mL) at 0 °C. (1S,4R)-4-Isopropenyl-1-methyl-cyclohex-2-en-1-ol (0.51 mL, 3.13 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h and then warmed to room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0–80% ethyl acetate in cyclohexane, followed by reverse-phase preparative HPLC to give compound 47 as an off-white solid (7.4 mg, 0.8%).

[0226] Scheme 2r

[0227] [ka]

[0228] A solution of (1'R,2'R)-5'-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (300 mg, 0.925 mmol) in methanol (10 mL) was treated with palladium on carbon (10%, 98 mg, 0.0925 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered through a pad of Celite, washing with methanol. The filtrate was concentrated in vacuo, and the residue was purified by reverse-phase preparative HPLC to give compound 36 as an off-white solid (32 mg, 10%).

[0229] Compounds 1~48

[0230] [ka]

[0231] [ka]

[0232] [ka]

[0233] [ka]

[0234] Compounds 1-48 were prepared by one of the synthetic routes in Schemes 2a-2r, substituting the appropriate boronic acid, boronic ester, tributylarylstannane, aryl bromide, or nitrogen heterocycle. Table 1 below details the synthetic route and analytical data for each compound.

[0235] Note: Compounds 22 and 23 were formed as a mixture of epimers from the racemic boronic ester and separated by chiral SFC.

[0236] [Table 1-1]

[0237] [Table 1-2]

[0238] [Table 1-3]

[0239] [Table 1-4]

[0240] [Table 1-5]

[0241] Table 1-6

[0242] Table 1-7

[0243] Table 1-8

[0244] Table 1-9

[0245] Table 1-10

[0246] Table 1-11

[0247] Table 1-12

[0248] Table 1-13

[0249] Table 1-14

[0250] Table 1-15

[0251] [Table 1-16]

[0252] [Table 1-17]

[0253] Example 2 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in a mouse model with minimal sample size (mini MEST) The efficacy of 1-5 exemplary cannabinoid derivatives was tested in a novel mouse model of generalized seizures, the mini-MEST (maximum electroshock seizure threshold) test (using a lower n number than typically used).

[0254] The maximal electroshock seizure threshold (MEST) test is widely used preclinically to assess the proconvulsant or anticonvulsant properties of test compounds (Loscher et al., 1991).

[0255] In the MEST test, the ability of a drug to modify the seizure threshold current required to induce hind limb tonic extensor convulsions is measured according to the "up-and-down" method of shock titration (Kimball et al., 1957). An increase in seizure threshold indicates an anticonvulsant effect. Antiepileptic drugs, including sodium channel blockers with clinically proven efficacy against generalized tonic-clonic seizures (e.g., lamotrigine), all exhibit anticonvulsant properties in this test in mice.

[0256] Conversely, a reduction in the seizure threshold indicates a proconvulsant effect, such as that observed with known convulsants such as picrotoxin.

[0257] The ability of test compounds to modify stimulus intensity, expressed as the current (mA) required to induce the presence of a tonic hindlimb extension spasm, is assessed in the MEST. The current (CC) required to produce a tonic hindlimb extension in 50% of the animals in the treatment group is 50 The presence (+) or absence (0) of tonic hindlimb extensor convulsions observed from the CC group was used to determine the seizure threshold for the treatment group, and the effect was then compared to the CC of the vehicle control group. 50 Compared to.

[0258] method Exam Details: Naive mice were acclimated to the treatment room in their home cages for up to 7 days with free access to food and water.

[0259] All animals were weighed at the beginning of the study and randomly assigned to treatment groups based on the average distribution of body weights across groups. All animals were dosed with vehicle, 5-50 mg / kg test compound, or 2.5 mg / kg diazepam via intraperitoneal (ip) injection at 10 mL / kg.

[0260] Animals were individually assessed for the development of tonic hindlimb extensor convulsions from a single electric shock 30 min post-dosing for vehicle, 15-30 min (depending on compound) post-dosing for test compounds, and 30 min post-dosing for diazepam.

[0261] The first animal in a treatment group was assigned a predicted or estimated CC 50 A current shock was administered, and for subsequent animals the current was decreased or increased depending on the outcome of the seizure from the previous animal in logarithmic intervals.

[0262] Using the data generated from each treatment group, CC of the treatment group 50 Values ​​were calculated ±SEM.

[0263] Test Compound: Vehicle: (5% ethanol in 85% saline, 10% solutol) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60° C. in 17 mL saline (1:2:17).

[0264] Positive control: diazepam was used at 2.5 mg / kg.

[0265] The test compounds used were 1, 2, 3, 4, and 5. Test compounds were administered at 5-50 mg / kg (ip) in a 1:2:17 ethanol:solutol:saline formulation.

[0266] Sample Collection: Immediately after the onset of convulsions, each animal was humanely killed by a blow to the skull to destroy the brain, followed by decapitation to ensure permanent cessation of blood circulation, in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain samples were taken after decapitation.

[0267] Blood was collected into lithium-heparin tubes and centrifuged at 1500 × g for 10 minutes at 4°C. The resulting plasma was removed (>100 μL) and divided into two aliquots in 0.5 mL Eppendorf tubes containing 10 μL of ascorbic acid (100 mg / mL) for stabilization. Brains were removed, washed with saline, and halved. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen in a cardis.

[0268] statistical analysis Data for each treatment group was recorded as the number of +s and 0s at each current level used, and this information was then used to calculate CC 50 Values ​​(current required for 50% of animals to show seizure behavior) ± standard error were calculated.

[0269] The effects of test compounds were also assessed by comparing CC from the vehicle control group. 50 was calculated as a percentage change in

[0270] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0271] result Figures 1-3 and Tables 2-4 describe the data generated in this experiment.

[0272] In the vehicle group, CC 50 The value was calculated to be 22.5 to 25.0 mA.

[0273] In the diazepam (2.5 mg / kg) treatment group, administered ip 30 min before the test, CC 50 Values ​​ranged from 75.0 to 89.0 mA. These results were statistically significant (p<0.001) compared to their respective vehicle controls.

[0274] In the test compound treatment groups administered i.p. 15–30 min before testing, all five compounds demonstrated statistically significant CC1 / CC2 / CC3 / CC4 / CC5 / CC6 / CC7 / CC8 / CC9 / CC10 / CC11 / CC12 / CC13 / CC14 / CC15 / CC25 / CC16 / CC17 / CC18 / CC19 / CC20 / CC21 / CC22 / CC19 / CC21 / CC18 / CC22 / 50 brought value.

[0275] Such data indicate that these compounds may be therapeutically beneficial.

[0276] [Table 2]

[0277] [Table 3]

[0278] [Table 4]

[0279] conclusion These data demonstrate the therapeutic efficacy of the compounds.

[0280] These data are important because they provide previously unknown evidence that these novel cannabinoid derivatives may have therapeutic value.

[0281] The compounds tested were those detailed as Compound 1, Compound 2, Compound 3, Compound 4 and Compound 5. Such compounds are examples of cannabinoid analogs of general formula I.

[0282] Clearly, such therapeutic efficacy can be attributed to the cannabinoid analogues of general formula I of the present invention, since all compounds showed efficacy in the mini-MEST test.

[0283] Example 3 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice with minimal sample size (mini-MEST) The efficacy of exemplary cannabinoid derivatives 12, 42, and 43 was tested in a novel mouse model of generalized seizures, the mini-MEST (maximal electroshock seizure threshold) test (using a lower n number than typically used).

[0284] method Study details, sampling and statistical analysis The protocol according to Example 2 was followed.

[0285] Test Compound: Vehicle: (5% ethanol in 85% saline, 10% solutol) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60° C. in 17 mL saline (1:2:17).

[0286] Positive control: diazepam was used at 2.5 mg / kg.

[0287] The test compounds used were 12, 42, and 43. Test compounds were administered at 5-50 mg / kg (ip) in a 1:2:17 ethanol:solutol:saline formulation.

[0288] result Figures 4-6 and Tables 5-7 describe the data generated in this experiment.

[0289] In the vehicle group, CC 50 The value was calculated to be 26.5 to 29.7 mA.

[0290] In the diazepam (2.5 mg / kg) treatment group, administered ip 30 min before the test, CC 50 Values ​​ranged from 97.8 to 128.0 mA. These results were statistically significant (p<0.001) compared to their respective vehicle controls.

[0291] In the test compound treatment groups administered i.p. 15–30 min before testing, all three compounds demonstrated statistically significant CC increases compared to vehicle at at least one dose. 50 For 50 mg / kg of Compound 12, CC 50 Although statistical significance could not be determined because the dose did not reach 0.01, no animals had seizures at this dose, indicating clear anticonvulsant activity.

[0292] Such data indicate that these compounds may be therapeutically beneficial.

[0293] [Table 5]

[0294] [Table 6]

[0295] [Table 7]

[0296] conclusion These data demonstrate therapeutic efficacy of the compound at at least one concentration tested.

[0297] These data are important because they provide previously unknown evidence that these novel cannabinoid derivatives may have therapeutic value.

[0298] The compounds tested were those detailed as Compound 12, Compound 42, and Compound 43. Such compounds are examples of cannabinoid analogs of general formula I.

[0299] Clearly, such therapeutic efficacy can be attributed to the cannabinoid analogues of general formula I of the present invention, since all compounds showed efficacy in the mini-MEST test.

[0300] Example 4 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice The efficacy of 1 cannabinoid derivative was tested in a mouse model of generalized seizures, the maximum electroshock seizure threshold (MEST) test.

[0301] method Study details, sampling and statistical analysis The protocol according to Example 2 was followed, with the current decreasing or increasing in 5 mA intervals instead of logarithmic scale intervals.

[0302] Test Compound: Vehicle: (5% ethanol, 10% solutol, 85% saline) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60° C. in 17 mL saline (1:2:17).

[0303] Positive control: diazepam was used at 2.5 mg / kg.

[0304] Test Compound 1 was administered at 1, 5 and 50 mg / kg (ip) in a 1:2:17 ethanol:solutol:0.9% saline formulation.

[0305] result Figure 7 and Table 8 describe the data generated in this experiment.

[0306] In the vehicle group, CC 50 The value was calculated to be 26.0 mA.

[0307] In the diazepam (2.5 mg / kg) treatment group, administered ip 30 min before the test, CC 50 The value was 84.2 mA, which was statistically significant (p<0.001) compared to the vehicle control.

[0308] In the test compound treatment groups administered i.p. 15–30 min before testing, Compound 1 significantly reduced CC1 activity compared to vehicle at all three doses of the compound. 50 brought value.

[0309] Such data indicate that this compound may be therapeutically beneficial.

[0310] [Table 8]

[0311] conclusion These data demonstrate the therapeutic efficacy of Compound 1 and reaffirm the anticonvulsant effects shown in Example 2 (Table 2).

[0312] Clearly, the compound produced a dose-related increase in MEST, with significant effects observed at all doses from 1 to 50 mg / kg compared to vehicle.

[0313] Example 5 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice with minimal sample size (mini-MEST) The efficacy of exemplary cannabinoid derivatives 6, 13, 22, 26, 28, 33, 38 and 46 was tested in a novel mouse model of generalized seizures, the mini-MEST (maximum electroshock seizure threshold) test (using a lower n number than typically used).

[0314] method Study details, sampling and statistical analysis The protocol according to Example 2 was followed.

[0315] Test Compound: Vehicle: (5% ethanol in 85% saline, 10% solutol) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60° C. in 17 mL saline (1:2:17).

[0316] Positive control: diazepam was used at 2.5 mg / kg.

[0317] The test compounds used were 6, 13, 22, 26, 28, 33, 38, and 46. Test compounds were administered at 5-50 mg / kg (ip) in a 1:2:17 ethanol:solutol:saline formulation.

[0318] result Figures 8-12 and Tables 9-13 describe the data generated in this experiment.

[0319] In the vehicle group, CC 50 The value was calculated to be 22.5 to 26.5 mA.

[0320] In the diazepam (2.5 mg / kg) treatment group, administered ip 30 min before the test, CC 50Values ​​ranged from 75.0 to 106.5 mA. These results were statistically significant (p<0.001) compared to their respective vehicle controls.

[0321] In the test compound treatment groups administered i.p. 15–30 min before testing, seven compounds demonstrated statistically significant CC effects compared to vehicle at at least one dose. 50 brought value.

[0322] Such data indicate that these compounds may be therapeutically beneficial.

[0323] [Table 9]

[0324] [Table 10]

[0325] [Table 11]

[0326] [Table 12]

[0327] [Table 13]

[0328] conclusion These data demonstrate therapeutic efficacy of the compound at at least one concentration tested.

[0329] These data are important because they provide previously unknown evidence that these novel cannabinoid derivatives may have therapeutic value.

[0330] The compounds tested were those detailed as Compound 6, Compound 13, Compound 22, Compound 26, Compound 28, Compound 33, Compound 38 and Compound 46. Such compounds are examples of cannabinoid analogs of general formula I.

[0331] Clearly, such therapeutic efficacy can be attributed to the cannabinoid analogues of general formula I of the present invention, since the compounds have shown efficacy in the mini-MEST test.

[0332] Example 6 Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice with minimal sample size (mini-MEST) The efficacy of 36 exemplary cannabinoid derivatives was tested in a novel mouse model of generalized seizures, the mini-MEST (maximal electroshock seizure threshold) test (using a lower n number than typically used).

[0333] method Study details, sampling and statistical analysis The protocol according to Example 2 was followed.

[0334] Test Compound: Vehicle: (5% ethanol in 85% saline, 10% solutol) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60° C. in 17 mL saline (1:2:17).

[0335] Positive control: diazepam was used at 2.5 mg / kg.

[0336] The test compound used was 36. The test compound was administered at 5 and 50 mg / kg (ip) in a 1:2:17 ethanol:solutol:saline formulation.

[0337] result Figure 13 and Table 14 describe the data generated in this experiment.

[0338] In the vehicle group, CC 50 The value was calculated to be 25.5mA.

[0339] In the diazepam (2.5 mg / kg) treatment group, administered ip 30 min before the test, CC 50 The value was 107.0 mA. This result was statistically significant (p<0.001) compared to the vehicle control.

[0340] In the test compound treatment group, administered ip 15–30 min before testing, Compound 36 significantly reduced CC compared to vehicle. 50 brought value.

[0341] Such data indicate that this compound may be therapeutically beneficial.

[0342] [Table 14]

[0343] conclusion This data demonstrates the therapeutic efficacy of the compound.

[0344] This data is important because it provides previously unknown evidence that this novel cannabinoid derivative may have therapeutic value.

[0345] The compound tested was the compound detailed as Compound 36. Such compounds are examples of cannabinoid analogs of general formula I.

[0346] Clearly, such therapeutic efficacy can be attributed to the cannabinoid analogues of general formula I of the present invention, since the compounds have shown efficacy in the mini-MEST test.

[0347] References Several publications are cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. Full citations for these references are provided below. The contents of each of these references are incorporated herein. 1. Gong et al., “Synthesis of CBD and Its Derivatives Bearing Various C4'-Side Chains with a Late-Stage Diversification Method”, J. Org. Chem, 2020, Vol. 85, pp. 2704-2715.

Claims

1. A compound of formula (I) or a salt thereof, 【Chemistry 1】 In the formula, X is 【Chemistry 2A】 【Chemistry 2B】 A compound or a salt thereof, which is one of the following:

2. 10. The compound of claim 1 provided in free base form.

3. 10. The compound of claim 1 provided as a pharmaceutically acceptable salt.

4. 10. The compound of claim 1 provided in a dehydrated form.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

6. 6. The pharmaceutical composition of claim 5, further comprising one or more additional ingredients selected from carriers, diluents (e.g., oils), excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, colorants, flavoring agents, and sweetening agents.

7. 7. The pharmaceutical composition of claim 6, in a form selected from liquids, solutions, suspensions, emulsions, syrups, electuaries, mouthwashes, drops, tablets, granules, powders, lozenges, pastilles, capsules, cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

8. 7. The pharmaceutical composition according to claim 6, wherein the form of the pharmaceutical composition is selected from tablets, capsules, granules, powders for inhalation, sprinkles, oral solutions and suspensions.

9. 6. The pharmaceutical composition of claim 5 for use in the treatment of epilepsy.

10. 6. The pharmaceutical composition of claim 5 for use in the treatment of generalized seizures.

11. 6. The pharmaceutical composition of claim 5 for use in the treatment of generalized tonic-clonic seizures.

12. 10. The pharmaceutical composition of claim 9, wherein the use is in a human subject.

13. 10. Use of the compound of claim 1 or a salt thereof in the manufacture of a medicament.

14. 14. The use according to claim 13, wherein the medicament is used to treat epilepsy, to treat generalized seizures, or tonic-clonic seizures.

15. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 4, comprising: (1a) reacting a compound of formula (II) with a compound of formula (III) Including, 【Transformation 3】 The compound of formula (III) 【Chemistry 4】 and; X 1 teeth, [Chemistry 5A] 【Chem.5B】 A method selected from the following.

16. 16. The method of claim 15, wherein step (1a) comprises reacting a compound of formula (II) with a compound of formula (III) and a palladium catalyst.

17. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 4, comprising: (2a) reacting a compound of formula (II) with bis(pinacolato)diboron; and (2b) reacting the product of step (2a) with a compound of formula (IV) Including, 【Transformation 6】 During the ceremony, X 2 teeth, 【Chemical 7A】 【Chemistry 7B】 A method selected from the following.

18. 18. The method of claim 17, wherein step (2a) comprises reacting the compound of formula (II) with bis(pinacolato)diboron and a palladium catalyst.

19. 18. The method of claim 17, wherein step (2b) comprises reacting the product of step (2a) with a compound of formula (IV) and a palladium catalyst.

20. 5. An intermediate for use in the preparation of a compound of formula (I) as defined in any one of claims 1 to 4, comprising a compound of formula (II): 【Transformation 8】 An intermediate compound of the formula:

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