Cannabinoid derivatives as pharmaceutically active compounds and methods for preparing same

Abstract

The present invention relates to cannabinoid derivatives as pharmaceutically active compounds and methods for preparing the same. The cannabinoid derivatives of the present invention 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 is provided by the cannabinoid derivatives of the present invention.

Description

[Technical Field]

[0001] Related Applications This application is related to and claims the benefit of GB2019784.4, filed on December 15, 2020 (15.12.2020), the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to cannabinoid derivatives as pharmaceutically active compounds and methods for their preparation.

[0003] The cannabinoid derivatives of the present invention 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 the cannabinoid derivatives of the present invention provide. [Background technology]

[0004] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to the constituents of the cannabis plant or to endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. The only way in nature for these compounds to be 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. Among these compounds are 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 major cannabinoids present in the cannabis plant are the cannabinoid acids Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and cannabidiolic acid (CBDA), along with smaller amounts of their corresponding neutral (decarboxylated) cannabinoids. In addition, cannabis may contain lower levels of other minor cannabinoids.

[0007] There are currently four cannabinoid-based pharmaceutically approved 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 that does not respond 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 derived naturally from the cannabis plant or produced synthetically, either semi-synthetically or 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 primary cannabinoid component of cannabis species, including hemp (Cannabis sativa). Unlike other cannabinoids, such as THC, cannabidiol does not bind to CB1 or CB2 receptors, or its binding to these 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 (cannabis-like) 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 a variety of diseases and disorders that may respond to such treatment.

[0012] While publications such as Gong et al. (2019) describe possible synthetic routes for producing C4'-substituted derivatives of CBD and indicate a wide range of compounds that could potentially be produced and potentially tested, they do not provide data suggesting the efficacy of such compounds, let alone data suggesting that any particular compound is particularly beneficial compared to others in treating disease.

[0013] The present invention was conceived from this perspective. [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 ed., 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] A practical clinical definition of epilepsy by the International League Against Epilepsy(ILAE), 2014 [Non-patent document 6] Operational Classification of Seizure Types by the ILAE, 2017 [Non-Patent Document 7] 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] The cannabidiol derivative of the present invention is (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, referred to throughout as the compound of formula (I) or Compound 1.

[0017] In a first aspect of the present invention, there is provided a compound of formula (I) or a salt thereof:

[0018] [ka]

[0019] In a second aspect of the 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.

[0020] Preferably, the pharmaceutical composition of the second aspect is in a form selected from a liquid, solution, suspension, emulsion, syrup, electuary, mouthwash, drop, tablet, granule, powder, lozenge, troche, capsule, cachet, pill, ampoule, bolus, suppository, pessary, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, and aerosol.

[0021] 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.

[0022] Preferably, the method of treatment in the third aspect is a method of treating epilepsy, generalized seizures or generalized tonic-clonic seizures.

[0023] 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.

[0024] Preferably, the medicament of the fourth aspect is a medicament for treating epilepsy, generalized seizures or generalized tonic-clonic seizures.

[0025] 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.

[0026] These and other aspects and embodiments of the invention are described in further detail below.

[0027] Embodiments of the present invention are further described below with reference to the accompanying drawings. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 shows the evaluation of test compounds of formula (I) in the MEST test in mice, as described in Example 2. [Figure 2] FIG. 1 shows the pharmacokinetics of Compound 1 in rats, as described in Example 3. [Figure 3] FIG. 1 shows the specific PK parameters A) AUClast and B) Cmax of Compound 1 in rats, as described in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention provides synthetic cannabinoid compounds that are biologically active and therefore useful in the treatment of disease.

[0030] Synthetic cannabinoids The present invention provides compounds of formula (I):

[0031] [ka]

[0032] The compound of the present invention is (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.

[0033] salt In some embodiments, the compound of Formula (I) is provided in free base form.

[0034] 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.

[0035] Thus, in some embodiments, compounds of Formula (I) are provided as salts, eg, in protonated form with a suitable counteranion.

[0036] Suitable counter anions include both organic and inorganic anions. An example of a suitable inorganic anion is chloride (Cl). - ), bromide (Br - ), iodide (I - ), sulfuric acid (SO4 2- ), sulfurous acid (SO32- ), nitric acid (NO3 - ), nitrite (NO2 - ), Phosphate (PO4 3- ), and phosphorous acid (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, lactate, 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.

[0037] Alternatively, in some embodiments, the compound of formula (I) is provided as a salt, eg, in deprotonated form, with an appropriate countercation.

[0038] Suitable countercations include both organic and inorganic cations. Examples of suitable inorganic cations include 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 ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NHR + , NH2R 2+ , 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.

[0039] solvate In some embodiments, the compound of formula (I) is provided in a desolvated form, for example a dehydrated form.

[0040] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound.

[0041] 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.

[0042] Synthesis method Methods for synthesizing compounds of formula (I) are described in the Examples. Further information related to the synthesis of synthetic cannabinoids can be found in Gong et al. (2019).

[0043] 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.

[0044] 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.

[0045] 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 ed., 2000, published by Lippincott, Williams & Wilkins, and Handbook of Pharmaceutical Excipients, 2nd ed., 1994.

[0046] 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.

[0047] 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.

[0048] The pharmaceutical composition may be in any suitable form, including 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, e.g., coated tablets), granules, powders, lozenges, troches, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0049] In a preferred embodiment, the form of the pharmaceutical composition is selected from tablets, capsules, granules, inhalable powders, sprinkles, oral solutions and suspensions.

[0050] Drug 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.

[0051] Thus, the present invention provides a compound of formula (I) or a salt thereof for use in a method of therapy, for example a method of treatment of the human or animal body by therapy (ie a method of therapy).

[0052] The present invention also provides a compound of formula (I) or a salt thereof for use as a pharmaceutical.

[0053] 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.

[0054] The present invention also provides the use of Compound (I) or a salt thereof for the manufacture of a medicament.

[0055] 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 containing the compound of formula (I) or its salts may be useful in the treatment of certain conditions associated with seizures.

[0056] 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 treating) certain conditions associated with seizures.

[0057] In a preferred embodiment, the seizure-related condition is epilepsy.

[0058] In one embodiment, the seizure-related condition is a generalized seizure, such as a generalized seizure associated with epilepsy.

[0059] In one embodiment, the seizure-related condition is a tonic-clonic seizure, such as a tonic-clonic seizure associated with epilepsy.

[0060] Subjects / patients The methods of treatment typically involve administering a compound of formula (I) or a salt thereof to a subject or patient.

[0061] 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 forms of development, for example, an infant or child.

[0062] In a preferred embodiment, the subject / patient is a human, more preferably an adult.

[0063] The subject / patient may be a non-human mammal used in laboratory research, such as a rodent, including rats, mice, guinea pigs, and chinchillas.

[0064] Route of administration The method of treatment may comprise 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., the desired site of action).

[0065] Routes of administration can be oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., by inhalation or insufflation therapy used 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, intrathecal, intracapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0066] Dosage The method of treatment typically involves administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0067] The appropriate dosage of the compound of Formula (I), its salts, and pharmaceutical compositions containing the compound of Formula (I) or its salts may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on various 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 materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, general health, and medical history. While the dosage and route of administration are ultimately at the discretion of the clinician, generally, the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or toxic side effects.

[0068] Administration can be accomplished in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Single or multiple administrations can be carried out with dose levels and pattern being selected by the treating clinician.

[0069] Other Aspects and Embodiments Any and all compatible combinations of the above embodiments are expressly disclosed herein as if each and every combination were individually and expressly set forth.

[0070] Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.

[0071] The use of "and / or" is to be construed as a specific disclosure of each associated element or feature alone, as well as a specific disclosure of any combination of elements or features. For example, "A and / or B" is to be construed as a specific disclosure of i) A, ii) B, and iii) each of A and B, as if each were individually listed.

[0072] Unless the context dictates otherwise, the feature descriptions and definitions set forth above are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0073] definition The following definitions are provided to aid in the understanding of the present invention.

[0074] "Cannabinoids" is a group of compounds that includes endocannabinoids, phytocannabinoids, and compounds that are neither endocannabinoids nor phytocannabinoids (hereinafter "syntho-cannabinoids").

[0075] "Endocannabinoids" are endocannabinoids that are high affinity ligands for CB1 and CB2 receptors.

[0076] "Phytocannabinoids" are cannabinoids that are naturally occurring and can be found in the cannabis plant. Phytocannabinoids may be present in extracts containing botanical drug substances, may be isolated, or may be synthetically reproduced.

[0077] "Synthocannabinoids" are compounds that are not found endogenously in the cannabis plant. Examples include WIN55212 and rimonabant.

[0078] "Isolated phytocannabinoids" are those that have 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.

[0079] A "synthetic cannabinoid" is one produced by chemical synthesis. The term includes modifying an isolated plant cannabinoid, for example, by forming a pharmaceutically acceptable salt thereof.

[0080] A "substantially pure" cannabinoid is defined as a cannabinoid present in a purity of greater than 95% (w / w), more preferably greater than 96% (w / w) to 97% (w / w) to 98% (w / w) to 99% (w / w) and greater.

[0081] 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) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures occurring over the next 10 years; or (3) a diagnosis of an epilepsy syndrome (A practical clinical definition of epilepsy by the International League Against Epilepsy (ILAE), 2014).

[0082] The term “generalized seizures” (‘generalized onset seizures’) refers to seizures conceptualized as originating from one point in the brain and involving a network that rapidly distributes bilaterally (Operational Classification of Seizure Types by the ILAE, 2017).

[0083] A "tonic-clonic seizure" occurs in two phases: a tonic phase, usually accompanied by muscle stiffening and loss of consciousness, and a clonic phase, usually accompanied by rhythmic jerking of the limbs.

[0084] The term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject (e.g., human) in question without excessive 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.

[0085] The term "therapeutically effective amount" relates to the amount of a compound, or material, 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]

[0086] Certain aspects and embodiments of the present invention will now be described by way of example and with reference to the figures described above.

[0087] (Example 1) Method for synthesizing CBD derivatives This example describes a novel synthetic method that was used to generate novel analogs of CBD that exhibit pharmacological activity. Scheme 1 below describes the three steps of the reaction used to generate CBD derivatives, which are formed via several intermediates.

[0088] The cannabidiol derivative of the present invention is (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, referred to throughout as the compound of formula (I) or Compound 1.

[0089] The analytical data for compound 1 are as follows: 1 H NMR (500 MHz, DMSO) δ 8.88 (s, 2H), 7.81 (s, 1H), 7.53 (s, 1H), 6.32 (s, 2H), 5.11 (m, 1H), 4.51 (m, 1H), 4.42 (dd, J = 3.0, 1.6 Hz, 1H), 3.86 (m, 1H), 3.80 (s, 3H), 3.05 (ddd, J = 13.2, 10.5, 2.8 Hz, 1H), 2.09 (m, 1H), 1.97 (m, 1H), 1.69 (m, 1H), 1.63 (m, 1H), 1.56 (s, 3H), 1.55 (s, 3H). MS (ES+): m / z 325.2 (M+1). HPLC purity 99.2%. Scheme 1: Synthesis of CBD derivatives

[0090] [ka]

[0091] [Table 1]

[0092] (1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (menthadienol) was coupled with phloroglucinol using BF3-OEt2 to give the trihydroxybenzene derivative in moderate yield.

[0093] Treatment with trifluoromethanesulfonic anhydride afforded the aryl triflates in good yields via regioselective triflation.

[0094] Aryl triflates and pyrazole boronates were coupled in a palladium-catalyzed Suzuki reaction. The title compounds were obtained in good yields after IMS crystallization.

[0095] Example 2: Evaluation of cannabinoid derivatives for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice The efficacy of cannabinoid derivatives according to formula (I) was tested in a mouse model of generalized seizures, the Maximum Electroshock Seizure Threshold (MEST) test.

[0096] The maximal electroshock seizure threshold (MEST) test is widely used preclinically to evaluate the proconvulsant or anticonvulsant properties of test compounds (Loscher et al., 1991).

[0097] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce a hindlimb tonic extensor seizure is measured according to the "up and down" method of shock titration (Kimball et al., 1957). An increase in the seizure threshold indicates an anticonvulsant effect. All antiepileptic drugs, including sodium channel blockers (e.g., lamotrigine) with clinically proven efficacy against generalized tonic-clonic seizures, exhibit anticonvulsant properties in this test in mice.

[0098] Conversely, a lowering of the seizure threshold indicates a proconvulsant effect such as that observed with known convulsants such as picrotoxin.

[0099] The ability of test compounds to alter stimulus intensity, expressed as the current (mA) required to induce the presence of a tonic hindlimb extensor spasm, is assessed in the MEST. 50 The presence (+) or absence (0) of tonic hindlimb extensor spasms observed from currents producing tonic hindlimb extensor spasms in 50% of animals in the 100% 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.

[0100] method Research details: Naive mice were acclimated to the procedure room in their home cages for up to 7 days with food and water available ad libitum.

[0101] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the average distribution of body weights by group. All animals received either vehicle, 2, 20, or 200 mg / kg test compound, or 2.5 mg / kg diazepam via intraperitoneal injection at 10 mL / kg.

[0102] Animals were individually assessed for the occurrence of tonic hindlimb extensor convulsions from a single electric shock 30 minutes after administration of vehicle, 30 minutes after administration of test compound, and 30 minutes after administration of diazepam.

[0103] The first animal in a treatment group was given a predicted or estimated CC 50 For subsequent animals, the current was decreased or increased at 5 mA intervals depending on the outcome of the convulsion from the previous animal.

[0104] Using data from each treatment group, CC for the treatment group 50 Values ​​were calculated ±SEM.

[0105] 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).

[0106] Positive control: diazepam was used at 2.5 mg / kg.

[0107] The test compound, described herein as Compound 1, is shown as Formula (I). The test compound was administered at 2, 20, and 200 mg / kg (ip) in a 1:2:17 ethanol:solutol:0.9% saline formulation.

[0108] Sample Collection: Each animal was humanely killed immediately after convulsions by a blow to the skull to destroy the brain, followed by decapitation to ensure permanent cessation of circulation under The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain were collected after decapitation.

[0109] 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, each in a 0.5 mL Eppendorf tube containing 100 μL of ascorbic acid (100 mg / mL) for stabilization. The brains were removed, washed with saline, and halved. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0110] 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 The value (current required for 50% of the animals to exhibit seizure behavior) ± standard error is calculated.

[0111] The effect of the test compound was assessed by comparing CC from the vehicle control group. 50 The rate of change was also calculated.

[0112] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0113] result Figure 1 and Table 1 describe the data obtained in this experiment.

[0114] In the vehicle group, CC 50 The value was calculated to be 24.3 mA.

[0115] In the diazepam (2.5 mg / kg) treatment group, which was administered intraperitoneally 30 minutes before the test, CC 50 The value was 78.5 mA. This result was statistically significant compared to the vehicle control (p<0.001). One animal in the diazepam group was not medicated due to welfare issues caused by fighting.

[0116] In the test compound treatment groups administered intraperitoneally 30 minutes before testing, Compound 1 demonstrated statistically significant CC1 reductions compared to vehicle at all three doses of the compound. 50 The value was obtained.

[0117] Such data indicate that this compound is therapeutically beneficial.

[0118] [Table 2]

[0119] conclusion These data demonstrate the therapeutic efficacy of compounds of formula (I).

[0120] These data are important because they provide previously unknown evidence that this novel cannabinoid derivative may have therapeutic value.

[0121] Clearly, the compound produced a dose-dependent increase in MEST, suggesting that the compound exhibits anticonvulsant properties. Significant effects were observed at 2, 20, and 200 mg / kg when compared to vehicle.

[0122] Example 3: Evaluation of pharmacokinetic properties of cannabinoid derivatives The plasma pharmacokinetics of Compound 1 was evaluated after oral administration to male Wistar Han rats.

[0123] method Research details: Wistar Han rats were selected as the animal model for this study because they are a rodent species accepted by regulatory agencies for preclinical toxicity testing. Animals were socially housed (up to three animals from the same group) in polycarbonate cages equipped with water bottles and containing appropriate bedding. Unless contraindicated by study procedures, they may be provided with items such as hiding devices, paper, and / or chewing objects. Pelleted rodent chow was provided ad libitum throughout the study, except during designated procedures.

[0124] The nine male animals were 8 to 10 weeks old at the start of dosing.

[0125] Test Compound: Vehicle: 1% ethanol / 12% Kolliphor HS-15 / 87% saline (w / w / v).

[0126] Dosage formulations were prepared as follows: The test item was dissolved in ethanol. Kolliphor HS-15 and saline were separately heated to 60°C, and the required amount of heated Kolliphor HS-15 was added to the test article / ethanol solution. The mixture was stirred at 60°C until homogeneous. Hot saline was added to the mixture to meet the dose level requirements and stirred at 60°C until a homogeneous solution was achieved. Prior to release, the formulation was cooled to below 40°C. The formulation was then stored at room temperature until dosing.

[0127] Treatment: Groups 1, 2 and 3: Test items were administered to appropriate animals by oral gavage. A single dose was given using a plastic feeding tube.

[0128] [Table 3]

[0129] Sample Collection: PK Sample Collection: Blood was collected from animals in Groups 1-3 according to the PK sample collection table (outlined in Table 3). Approximately 0.2 mL of blood samples were collected from the jugular vein, collected in tubes containing K2 EDTA as an anticoagulant, and stored on ice.

[0130] Sample processing and storage: Whole blood was processed to plasma by centrifugation (3000 g, 10 min at 5° C.) within 1 h of collection. Plasma samples were transferred to labeled polypropylene tubes and stored below −75° C. until shipment.

[0131] [Table 4]

[0132] result Figures 2-3 and Table 4 show the data obtained in this study. Bioavailability was 0.01 mg / kg at 1 hour for the 15 and 45 mg / kg dose groups. max The results showed that the concentration of α-glucan in the α-glucan was higher across the range of exposure and C max increases linearly with dose in rats (Figure 3).

[0133] [Table 5]

[0134] conclusion The data presented in this example allowed for the determination of the intrinsic pharmacokinetics of the test compound (Compound 1) and allowed for its proper characterization. The favorable pharmacokinetic data demonstrate the suitability of this novel compound as a treatment option for seizure-related conditions.

[0135] (References) TIFF0007727733000009.tif21169

Claims

1. A compound of formula (I) or a salt thereof 【Chemical 1】 。 2. The compound of claim 1, wherein the compound of formula (I) is provided in free base form.

3. The compound of claim 1, wherein the compound of formula (I) is provided as a pharmaceutically acceptable salt.

4. The compound of claim 1, wherein the compound of formula (I), or a salt thereof, is provided in a dehydrated form.

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

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, troches, 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 pharmaceutical composition is in a form selected from the group consisting of tablets, capsules, granules, inhalable powders, 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. The pharmaceutical composition of claim 9 for use in human subjects.

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 for use in the treatment of epilepsy, for use in the treatment of generalized seizures, or for use in the treatment of generalized tonic-clonic seizures.

15. A method for producing a cyclohexan-2-en-1-ol comprising the steps of: a) coupling (1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol with benzene-1,3,5-triol to obtain (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4,6-triol; b) reacting (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4,6-triol with trifluoromethanesulfonic anhydride to produce (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; and c) coupling (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 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the compound of formula (I); 5. A process for preparing a compound according to any one of claims 1 to 4, comprising:

16. The method of claim 15, further comprising converting the compound of formula (I) produced in step c) into a pharmaceutically acceptable salt of the compound of formula (I).

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