6-Hydroxy-Cannabidiol-C4

Abstract

The present invention relates to pharmaceutically active compounds and their preparation methods. The compound of the present invention is 6-hydroxy-cannabidiol-C4 (6-OH-CBD-C4). The compound of the present invention is related to cannabidiol (CBD). CBD is a non-psychotropic cannabinoid that has been used to treat various diseases and disorders. Although these treatments are promising, there is still a need in the art for more effective treatments, which has been realized by the compounds of the present invention.

Description

[Technical field]

[0001] Related Applications This application is related to and claims priority to GB 2106789.7, filed May 12, 2021 (12.05.2021), the contents of which are incorporated by reference in their entirety.

[0002] The present invention relates to novel pharma- ceutical active compounds and methods for their preparation. In particular, the present invention relates to 6-hydroxy-cannabidiol-C4 (6-OH-CBD-C4) and its use in the treatment of epilepsy. [Background technology]

[0003] Epilepsy occurs in approximately 1% of the population worldwide (Thurman et al., 2011), of whom 70% can adequately control their symptoms with currently available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) have not been able to achieve seizure freedom with available AEDs and are therefore referred to as suffering from refractory or "treatment-resistant epilepsy" (TRE).

[0004] Refractory or treatment-resistant epilepsy was defined by the International League Against Epilepsy (ILAE) in 2009 as “the failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately selected and used AED schedules (whether monotherapy or combination therapy)” ( Kwan et al., 2009 ).

[0005] Individuals who develop epilepsy during the first few years of life are often difficult to treat and are therefore often referred to as treatment-resistant. Children who experience frequent seizures during childhood often suffer neurological damage that can cause cognitive, behavioral, and motor delays.

[0006] Childhood epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000 people, which is twice the number of adults with epilepsy per population.

[0007] When a child or young adult presents with seizures, an investigation is usually carried out to find out the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so a diagnosis for these children may take some time.

[0008] The main symptom of epilepsy is recurrent seizures. An investigation is carried out regarding the type of seizures the patient is experiencing to determine the type of epilepsy or epilepsy syndrome the patient suffers from. Clinical observations and electroencephalography (EEG) tests are performed and the type of seizures is classified according to the ILEA classification.

[0009] Generalized seizures, in which seizures arise within and rapidly involve bilaterally distributed networks, can be divided into six subtypes: tonic-clonic (grand mal); absence (petit mal); clonic; tonic; atonic; and myoclonic.

[0010] Focal seizures (partial seizures), where the seizures occur within a network restricted to only one cerebral hemisphere, are also divided into subcategories. Here, the seizures are characterized according to one or more characteristics of the seizure, including auditory, motor, autonomic, and cognitive / responsive. If a seizure begins as a focal seizure and rapidly evolves to become distributed within a bilateral network, it is called a bilateral convulsive seizure. This term was proposed as an alternative to secondary generalized seizures (generalized seizures that evolve from focal seizures and are no longer focal).

[0011] Focal seizures in which the subject's awareness / responsiveness is altered are referred to as focal seizures with impairment, whereas focal seizures in which the subject's awareness or responsiveness is not impaired are referred to as focal seizures without impairment.

[0012] Cannabidiol (CBD), a non-psychotropic derivative derived from the cannabis plant, has demonstrated anticonvulsant properties in several case reports, preclinical studies, and clinical trials in both animal models and humans. Three randomized controlled trials have demonstrated the efficacy of a purified pharmaceutical preparation of CBD in patients with Dravet and Lennox-Gastaut syndromes.

[0013] Based on these three trials, a plant-derived purified CBD preparation (Epidiolex®) was approved by the FDA in June 2018 and by the EMA in September 2019 for the treatment of seizures associated with Dravet and Lennox-Gastaut syndromes. In July 2020, the FDA approved the drug for the treatment of seizures associated with tuberous sclerosis complex.

[0014] Cannabidiol-C4 (CBD-C4), also known as norcannabidiol, is a short-chain homolog of CBD shortened by one methylene bridge. It is a naturally occurring cannabinoid found in small amounts in the cannabis plant. This cannabinoid can also be produced by synthetic means.

[0015] Previously, the Applicant has shown in WO 2020 / 104796 that the compound CBD-C4 exhibits anticonvulsant activity. Therapeutic efficacy was demonstrated in the MES model of generalized seizures, while a series of toxicity screenings demonstrated that the toxicity of the compound was tolerable. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] WO 2020 / 104796 [Non-patent literature]

[0017] [Non-Patent Document 1] "Pharmaceutical Salts: Properties, Selection, and Use", 2nd Edition, 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany [Non-Patent Document 2] Remington: The Science and Practice of Pharmacy, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press [Non-Patent Document 3] International League Against Epilepsy (ILAE) Practical Clinical Definition of Epilepsy, 2014 [Non-Patent Document 4] ILAE operational classification of epileptic seizure types, 2017 Summary of the Invention [Problem to be solved by the invention]

[0018] It is with these considerations in mind that the present invention has been devised.

[0019] Most generally, the present invention relates to the surprising discovery that the novel compound 6-OH-CBD-C4 is biologically active and therefore useful in the treatment of disease. This novel compound can be administered by a variety of routes, including but not limited to oral, transdermal, buccal, intranasal, pulmonary, rectal, or ocular. This compound can be used to treat or prevent medical conditions, such as epilepsy. [Means for solving the problem]

[0020] In a first aspect of the present invention there is provided a compound of formula (I) or a salt thereof:

[0021] [ka]

[0022] In one embodiment, the compound of the first aspect is a pure compound, an isolated compound, or a synthetic compound.

[0023] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt thereof.

[0024] In one embodiment, the pharmaceutical composition of the second aspect comprises one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g. wetting agents), masking agents, colorants, flavorants, and sweeteners.

[0025] In one embodiment, the pharmaceutical composition of the second aspect is in a form selected from liquids, solutions, suspensions, emulsions, syrups, lozenges, 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.

[0026] In a third aspect of the invention there is provided a compound of formula (I) or a salt thereof for use as a medicament, for example for the treatment of epilepsy.

[0027] In a fourth aspect of the invention there is provided a compound of formula (I) or a salt thereof for use in a method of treatment, such as a method of treating epilepsy.

[0028] In a fifth aspect of the invention, there is provided a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0029] In one embodiment, the compounds of formula (I) or salts thereof are used in combination with one or more co-administered antiepileptic drugs (AEDs).

[0030] In one embodiment, the dose of the compound of formula (I) is 1-2,000 mg / kg.

[0031] According to a sixth aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), comprising the steps of: i) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol with acetic anhydride to produce 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; ii) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with acetic anhydride and sodium dichromate dihydrate to produce 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; and iii) treating 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with lithium aluminum hydride to produce the compound of formula I.

[0032] In a seventh aspect of the invention, there is provided an intermediate formed in the process for the preparation of a compound of formula (I).

[0033] [ka]

[0034] These and other aspects and embodiments of the invention are described in further detail below.

[0035] The invention will now be described with reference to the drawings listed below. [Brief description of the drawings]

[0036] [Figure 1] 1 shows the evaluation of a test compound, designated Compound I, in the mini-MEST test in mice as described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The present invention relates to the compound 6-OH-CBD-C4, which is biologically active and therefore useful in the treatment of diseases.

[0038] Compound I The present invention provides a compound of formula (I):

[0039] [ka]

[0040] The compound of formula (I) is (1'R,2'R,4'S)-4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4,6-triol, which is referred to herein as the compound of formula (I) or Compound I.

[0041] salt In some embodiments, the compound of formula (I) is provided in the form of a free base.

[0042] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, e.g., a pharma- ceutically acceptable salt. Examples of pharma-ceutically acceptable salts are described in "Pharmaceutical Salts: Properties, Selection, and Use", 2 ndEdition, 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany.

[0043] Thus, in some embodiments, the compound of formula (I) is provided as a salt, for example in a protonated form with a suitable counter anion.

[0044] Suitable counter anions include both organic and inorganic anions. Examples of suitable inorganic anions include chloride anion (Cl - ), bromine anion (Br - ), iodine anion (I - ), sulfate anion (SO4 2- ), sulfite anion (SO3 2- ), nitrate anion (NO3 - ), nitrite anion (NO2 - ), phosphate anion (PO4 3- ), and the phosphite anion (PO3 3- Examples of suitable organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, Examples of suitable polymeric organic anions include 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 anions derived from tannins and carboxymethylcellulose.

[0045] Alternatively, in some embodiments, the compound of formula (I) is provided as a salt, for example in a deprotonated form with a suitable counter cation.

[0046] Suitable counter cations 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 the ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NH3R + , 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 ions derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + It is.

[0047] solvate In some embodiments, the compound of formula (I) is provided in a desolvated form, for example a dehydrated form.

[0048] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound.

[0049] 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.

[0050] Synthesis method The present invention provides a process for the preparation of a compound of formula (I) comprising the steps of: i) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol with an acylating agent to produce 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; ii) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with an oxidizing agent to produce 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; and iii) treating 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with a reducing agent to produce the compound of formula I.

[0051] Suitable acetylating agents include acetic anhydride, acetyl chloride, N-succinimidyl acetate, 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine, and N-acetylimidazole. In a preferred embodiment, acetic anhydride is used.

[0052] Optionally, a base is used in step i). Suitable bases include organic bases such as pyridine, dimethylbenzylamine, imidazole, benzimidazole, methylimidazole, triethylamine, tributylamine, diisopropylethylamine, tetramethylethylenediamine, DABCO, etc. In a preferred embodiment, pyridine is used.

[0053] Suitable oxidizing agents include chromium species such as sodium dichromate dihydrate with acetic anhydride. In a preferred embodiment, acetic anhydride and sodium dichromate dihydrate are used.

[0054] Suitable reducing agents include lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (red-Al), diborane, and sodium borohydride. In a preferred embodiment, lithium aluminum hydride is used.

[0055] Intermediates The present invention provides intermediates formed in the processes for preparing compounds of formula (I).

[0056] [ka]

[0057] Pharmaceutical Compositions 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) that includes a compound of formula (I) in combination with one or more other pharma- ceutically acceptable ingredients.

[0058] Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, together with one or more pharma- ceutically acceptable ingredients.

[0059] Suitable pharma- ceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) can be found in standard pharmaceutical textbooks, e.g., Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press.

[0060] Examples of suitable pharma- ceutically acceptable ingredients include pharma- ceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavors, and sweeteners.

[0061] In a preferred embodiment, the pharma- ceutically acceptable ingredients are selected from carriers, oils, disintegrants, lubricants, stabilizers, flavorings, antioxidants, and diluents, and may optionally include other pharma- ceutically active compounds.

[0062] The pharmaceutical compositions may be in any suitable form, including, for example, liquids, solutions (aqueous and non-aqueous), suspensions (aqueous and non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), syrups, lozenges, mouthwashes, drops, tablets (including, for example, coated tablets), granules, powders, lozenges, troches, capsules (including, for example, hard and soft gelatin capsules), cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0063] In preferred embodiments, the pharmaceutical compositions may be in the form of tablets, capsules, granules, powders for inhalation, sprinkles, oral solutions, and suspensions.

[0064] Medical treatment The present inventors have discovered that the compound of formula (I) is biologically active. In the examples, it is demonstrated that the compound of formula (I) exhibits anticonvulsant activity in a mouse model of seizures.Therefore, the compound of formula (I), its salt, and pharmaceutical compositions comprising the compound of formula (I) or its salt will be useful in medical treatment.

[0065] The present invention therefore provides a compound of formula (I) or a salt thereof for use in a method of treatment, for example for use in a method of treatment of the human or animal body by therapy (ie a therapeutic method).

[0066] The present invention also provides a compound of formula (I) or a salt thereof for use as a medicine.

[0067] The present invention also provides a method of treatment, comprising the step of administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0068] The present invention also provides the use of a compound of formula (I) or a salt thereof for the manufacture of a medicament.

[0069] The invention also provides the use of a compound of formula (I), or a salt thereof, in a method of treatment.

[0070] Condition being treated The present inventors have discovered that the compound of formula (I) exhibits anticonvulsant activity in a mouse model of generalized seizures.Therefore, the compound of formula (I), its salt, and pharmaceutical compositions containing the compound of formula (I) or its salt will be useful in treating certain conditions associated with seizures.

[0071] 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 associated with seizures.

[0072] In a preferred embodiment, the seizure-related condition is epilepsy.

[0073] In one embodiment, the seizure-related condition is generalized seizures, such as generalized seizures associated with epilepsy.

[0074] In one embodiment, the seizure-related condition is focal onset seizures, for example focal onset seizures associated with epilepsy.

[0075] In one embodiment, the seizure-related condition is a tonic-clonic seizure, for example a tonic-clonic seizure associated with epilepsy.

[0076] Subjects / Patients Typically, the method of treatment comprises the step of administering to a subject or patient a compound of formula (I) or a salt thereof.

[0077] The subject / patient can 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.

[0078] The subject / patient may be in any of its forms of development, for example, the subject / patient may be an infant or a child.

[0079] In a preferred embodiment, the subject / patient is a mammal, more preferably a human, and even more preferably an adult human.

[0080] 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.

[0081] Route of administration The method of treatment may involve administering to the subject a compound of formula (I) or a salt thereof by any convenient route of administration, whether systemic / peripheral or local (ie, at the site where the effect is desired).

[0082] Routes of administration can 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 nose drops); intraocular (e.g., by eye drops); intrapulmonary (e.g., by inhalation therapy or insufflation therapy, e.g., using an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); intravaginal (e.g., by pessary); parenteral, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal, e.g., by injection or infusion.

[0083] Dosage Typically, the method of treatment comprises the step of administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0084] The appropriate dosage of the compound of formula (I), its salt, and pharmaceutical compositions containing the compound of formula (I) or its salt may vary from patient to patient. In general, determining the optimal dosage involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level depends on a variety of factors, including, but not limited to, the activity of the compound of formula (I), the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other effective drugs, compounds, and / or materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, physical condition, general health, and previous medical history. Although the dosage and route of administration are ultimately at the discretion of the clinician, generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing significant adverse side effects.

[0085] In some embodiments, the dose of the compound of formula (I) is 1-2,000 mg / day. In preferred embodiments, the dose is 20-1,000 mg / day, more preferably 50-500 mg / day.

[0086] Administration can be effected in one dose continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the treatment period. Single or multiple administrations can be administered, with dosage levels and patterns being selected by the treating clinician.

[0087] Simultaneous administration The method of treatment may include administering to a subject a compound of formula (I) or a salt thereof in the absence of other medications.

[0088] In some embodiments, the methods of treatment comprise administering to a subject a compound of formula (I) or a salt thereof in combination with one or more co-administered antiepileptic drugs (AEDs).

[0089] Suitable AEDs include rufinamide; lamotrigine; topiramate; felbamate, stiripentol, clobazam, and valproic acid.

[0090] The administration may be simultaneous or sequential.

[0091] Other Aspects and Embodiments Every compatible combination of the above embodiments is expressly disclosed herein just as if every combination was individually and explicitly set forth.

[0092] Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.

[0093] When used, "and / or" should be considered a specific disclosure of each associated component or feature individually as well as a specific disclosure of combinations of such components or features. For example, "A and / or B" should be considered a specific disclosure of i) A, ii) B, and ii) each of A and B as if each were individually set forth.

[0094] Unless otherwise dictated by context, 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.

[0095] definition Definitions of some of the terms used to describe this invention are set out below.

[0096] The compounds described in this application are listed below.

[0097] [Table 1]

[0098] Epilepsy is considered to be a brain disorder defined by any of the following criteria: (1) the occurrence of at least two unprovoked (or reflex) seizures separated by more than 24 hours; (2) the occurrence of one unprovoked (or reflex) seizure followed by a 10-year seizure recurrence rate similar to the general risk of recurrence after two unprovoked seizures (at least 60%); (3) the diagnosis of an epilepsy syndrome (International League Against Epilepsy (ILAE) practical clinical definition of epilepsy, 2014).

[0099] The term "focal seizures" ("focal onset seizures") refers to seizures that occur within a network limited to one cerebral hemisphere. Seizures may be discretely localized or more widely distributed. Focal seizures may occur in subcortical structures (ILAE Operational Classification of Epileptic Seizure Types, 2017).

[0100] The term “generalized seizures” (‘generalized onset seizures’) refers to seizures conceptualized as originating at any point in the brain and rapidly involving bilaterally distributed networks (ILAE Operational Classification of Epileptic Seizure Types, 2017).

[0101] The term "pharmacologically 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 in question (e.g., human) and are free of undue toxicity, irritation, allergic response, or other problem or concern, 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.

[0102] The term "therapeutically effective amount" refers to an amount of a compound, or a material, composition, or dosage form containing a compound, that is effective to produce some desired therapeutic effect when administered in accordance with a desired treatment regimen, and is commensurate with a reasonable benefit / risk ratio.

[0103] "Tonic-clonic seizures" occur in two phases: a tonic phase, which usually involves muscle stiffening and loss of consciousness, and a clonic phase, which usually involves rhythmic muscle contractions of the limbs.

[0104] The human equivalent dose (HED) can be estimated using the following formula:

[0105]

number

[0106] Rat K m is 6, and the human K m is 37. Thus, for a human of about 60 kg, a dose of 200 mg / kg in rats would equate to a human daily dose of about 2,000 mg. EXAMPLES

[0107] Certain aspects and embodiments of the present invention will now be described by way of example and with reference to the above-mentioned drawings.

[0108] Example 1 Synthetic Method for Preparing Compound I In this example, a novel synthetic methodology is described that was used to prepare a novel compound that exhibited pharmacological activity. In Scheme 1 below, a three-step reaction is described that was used to prepare the novel compound that was formed through several intermediates.

[0109] The novel compound of the present invention is (1'R,2'R,4'S)-4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol, and is referred to throughout as the compound of formula I or Compound I.

[0110] Scheme 1 below shows a synthetic route to compound I in three steps.

[0111] Scheme 1: Synthesis of Compound I

[0112] [ka]

[0113] [Table 2]

[0114] Step 1: Preparation of compound b A solution of (1'R,2'R)-4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (250 mg, 0.832 mmol) in pyridine (3.0 mL) was treated with acetic anhydride (0.24 mL, 2.5 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (80 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was passed through hydrophobic filter paper and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (40 g silica cartridge, eluted with 5-10% ethyl acetate in cyclohexane) to give (1'R,2'R)-4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate as a colorless viscous oil (236 mg, 74%).

[0115] Step 2: Preparation of compound c A solution of (1'R,2'R)-4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate (230 mg, 0.597 mmol) in acetic acid (1.0 mL) was treated with acetic anhydride (0.25 mL, 2.69 mmol) and sodium dichromate dihydrate (214 mg, 0.717) and the reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers were washed with brine (20 mL), passed through hydrophobic filter paper and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (25 g silica cartridge, eluted with 20–30% ethyl acetate in cyclohexane) to give (1'R,2'R)-4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate as a colorless oil (111 mg, 47%).

[0116] Step 3: Preparation of Compound I To a solution of lithium aluminum hydride (1.1 mL, 1.1 mmol, 1.0 M in diethyl ether) in dry diethyl ether (3 mL) cooled to 0° C. was added dropwise a solution of (1'R,2'R)-4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate (105 mg, 0.263 mmol) in diethyl ether (3.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was recooled to 0° C. and water (1 mL) was carefully added followed by 2 M hydrochloric acid (5 mL). The mixture was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (20 mL), passed through hydrophobic filter paper and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (12 g silica cartridge, eluting with 10-50% ethyl acetate in cyclohexane) followed by reverse phase preparative HPLC to give compound I as an off-white solid (23 mg, 28%).

[0117] Example 2 Evaluation of novel compounds for anticonvulsant activity using the maximal electroshock seizure threshold (MEST) test in mice using minimal sample size (mini-MEST) The efficacy of novel compounds of formula I was tested in a novel mouse model of generalized seizures by the mini-MEST (maximal electroshock seizure threshold) test, using a smaller n number than typically used.

[0118] 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).

[0119] The MEST test measures the ability of drugs to alter the seizure threshold current required to induce hindlimb extensor tonic seizures according to an "up-down" shock titration method (Kimball et al., 1957). An increase in the seizure threshold indicates an anticonvulsant effect. Any antiepileptic drug with clinically proven efficacy against generalized tonic-clonic seizures, including sodium channel blockers (e.g., lamotrigine), is anticonvulsant in mice in this test.

[0120] Conversely, a decrease in seizure threshold is indicative of the proconvulsant effect observed with known convulsants such as picrotoxin.

[0121] The ability of test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the presence of hindlimb extensor tonic convulsions is evaluated in the MEST. The results are the presence (+) or absence (0) of hindlimb extensor tonic convulsions observed with a current that produces a hindlimb tonic convulsion in 50% of the animals within a treatment group (CC 50 ) to determine seizure thresholds in the treatment groups and then compare these effects with those in the vehicle control group CC 50 Compared to.

[0122] method Exam details: Naïve mice were acclimated to the procedure room in their home cages for up to 7 days with food and water available ad libitum.

[0123] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the mean weight distribution among groups. All animals received vehicle, test compound at 100 mg / kg (Compound I) or 150 mg / kg (Compound II), or diazepam at 2.5 mg / kg via intraperitoneal injection (ip) at 10 mL / kg.

[0124] Animals were individually assessed for the occurrence of hindlimb extensor tonic convulsions induced by a single electric shock 30 minutes after administration of vehicle, test compound, and diazepam.

[0125] The first animal in a treatment group had a predicted or estimated CC 50 The animals were shocked with a current that was either decreased or increased in logarithmic intervals in subsequent animals depending on the outcome of the seizure from the preceding animal.

[0126] Using the data generated from each treatment group, CC of the treatment group was calculated. 50 Values ​​were calculated ±SEM.

[0127] Test Compounds: Vehicle: (5% ethanol in 85% saline, 10% solutol) was prepared as follows: 1 mL ethanol, 2 mL solutol were heated to 60° C. in 17 mL saline (1:2:17).

[0128] Positive control: diazepam was used at 2.5 mg / kg.

[0129] The test compound, described herein as Compound I, is shown as Formula I. Test compounds were administered at 150 mg / kg (ip) in a 1:2:17 ethanol:Solutol:0.9% saline formulation.

[0130] Sample Collection: Immediately after the onset of convulsions, each animal was humanely killed by destruction of the brain via a skull blow followed by decapitation to ensure permanent cessation of circulation under "Humaneous killing of animals under Schedule 1" of the Animals (Scientific Procedures) Act 1986. Peripheral blood and brain samples were taken after decapitation.

[0131] Blood was collected into lithium-heparin tubes and centrifuged at 1500xg for 10 min at 4°C. The resulting plasma was removed (>100 μL) and divided into two aliquots into 0.5 mL Eppendorf tubes containing 10 μL of stabilizing ascorbic acid (100 mg / mL). Brains were removed, washed in saline, and divided in half. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0132] statistical analysis Data for each treatment group was recorded as the number of +'s and 0's at each current level used, and this information was then used to calculate the CC 50 The value (current required for 50% of the animals to show seizure behavior) ± standard error is calculated.

[0133] The effect of the test compound was also compared with the CC group from the vehicle control group. 50 The change was calculated as a percentage of

[0134] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0135] result FIG. 1 and Table 1 list the data generated in this experiment.

[0136] In the vehicle group, CC 50 The value was calculated to be 25.0 mA.

[0137] In the group treated with diazepam (2.5 mg / kg) administered intraperitoneally 30 min before the test, CC 50 The value was 97.8 mA. This result was statistically significant compared to the vehicle control (p<0.001).

[0138] Compound I, administered intraperitoneally 30 min before testing, produced a clear increase in seizure threshold compared to vehicle, and CC at 150 mg / kg. 50 >131mA. Exact values ​​could not be calculated because no "+" hindlimb tonic convulsions were observed among the six animals tested. CC 50 Although the efficacy of compound I in treating rheumatoid arthritis was not established, compound I demonstrated a clear increase in seizure threshold in the mini-MEST. No animals in this treatment group exhibited convulsions, demonstrating the clear activity of compound I.

[0139] These data indicate that this compound has therapeutic potential.

[0140] [Table 3]

[0141] conclusion Data generated using the mini-MEST model demonstrate the therapeutic efficacy of this compound. Compound I exhibits potent therapeutic efficacy and CC 50 was increased by over 159% compared to vehicle controls.

[0142] This data is important because it provides previously unknown evidence that this novel compound may be therapeutically beneficial.

[0143] Example 3 Bioanalysis of new compounds Bioanalytical experiments were performed to determine quantitative measurements of Compound I in plasma and brain.

[0144] method Six mice were dosed with Compound I at 150 mg / kg by intraperitoneal (ip) injection. Sample analysis was performed 30 min after dosing using a sample volume of 40 μL. After addition of an internal standard (in acetonitrile) and isopropanol, samples were protein precipitated by addition of acetonitrile. Samples were centrifuged and the supernatants were transferred to clean 96-well plates (with the addition of Tween to minimize non-specific binding to the plate material), evaporated to dryness, and then reconstituted in a suitable solvent. Extracts were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS / MS).

[0145] result Table 2 shows the data generated in this experiment. High concentrations of Compound I were detected in plasma and brain.

[0146] [Table 4]

[0147] conclusion This data confirms that Compound I is present in plasma and the brain.

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】

2. 10. The compound of claim 1 as a pure, isolated, or synthetic compound.

3. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof. 【Chemistry 2】

4. 4. The pharmaceutical composition of claim 3 in a form selected from liquids, solutions, suspensions, emulsions, syrups, lozenges, mouthwashes, drops, tablets, granules, powders, lozenges, troches, capsules, cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

5. 5. The pharmaceutical composition of claim 3 or 4, comprising one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g. wetting agents), masking agents, colorants, flavorants, and sweeteners.

6. 4. A pharmaceutical composition according to claim 3 for use as a medicament.

7. 7. The pharmaceutical composition for use according to claim 6, wherein the medicament is for treating epilepsy.

8. 8. The pharmaceutical composition for use according to claim 6 or 7, wherein the medicament is for treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

9. 4. The pharmaceutical composition of claim 3 for use in a method of treatment.

10. 10. The pharmaceutical composition for use according to claim 9, wherein the method of treatment is a method of treating epilepsy.

11. 11. The pharmaceutical composition for use according to claim 9 or 10, wherein the method of treatment is a method of treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

12. A pharmaceutical composition for use according to claim 9 or 10, wherein the compound is used in combination with one or more co-administered antiepileptic drugs (AEDs).

13. 13. The pharmaceutical composition for use according to claim 12, wherein the AED is selected from rufinamide, lamotrigine, topiramate, felbamate, stiripentol, clobazam, and valproic acid.

14. The pharmaceutical composition for use according to claim 9 or 10, wherein the dose of the compound is from 1 to 2,000 mg / day, such as from 20 to 1,000 mg / day, such as from 50 to 500 mg / day.

15. Use of a compound of formula (I) or a salt thereof for the manufacture of a medicament. 【Chemistry 3】 16. The use of claim 15, wherein the medicament is for treating epilepsy.

17. The use of claim 15 or 16, wherein the medicament is for treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

18. A method for preparing a compound of formula (I), comprising the steps of: i) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol with an acylating agent to produce 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; ii) treating 4-butyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with an oxidizing agent to produce 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate; and iii) treating 4-butyl-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate with a reducing agent to produce a compound of formula I: 【Chemistry 4】 。

19. 19. The method of claim 18, wherein the acylating reagent is selected from acetic anhydride, acetyl chloride, N-succinimidyl acetate, 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine, and N-acetylimidazole; such as acetic anhydride.

20. 20. The process according to claim 18 or 19, wherein the base is selected from pyridine, dimethylbenzylamine, imidazole, benzimidazole, methylimidazole, triethylamine, tributylamine, diisopropylethylamine, tetramethylethylenediamine, DABCO; for example pyridine.

21. 20. The method according to claim 18 or 19, wherein the oxidizing agent is a chromium oxidizing agent, such as acetic anhydride and sodium dichromate dihydrate.

22. 20. The method of claim 18 or 19, wherein the reducing agent is selected from lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (red-Al), diborane, and sodium borohydride; for example, lithium aluminum hydride.

23. A compound of formula (I): 【Chemistry 5】 An intermediate formed in the process of claim 1, selected from the following: 【Chemistry 6】

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