Resorcinol derivative as pharmaceutically active compound and method of preparation thereof

Abstract

To provide a resorcinol derivative as a pharmaceutically active compound, and a method of preparation thereof.SOLUTION: Resorcinol derivatives have been used to treat various diseases and disorders. While such treatments hold promise, there remains a need in the art for more effective treatments, which is fulfilled by the resorcinol derivative of the present invention.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application is related to and claims the benefit of GB2106786.3, filed May 12, 2021 (May 12, 2021), the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to resorcinol derivatives as pharmaceutically active compounds, research tools, and methods for their preparation. [Background technology]

[0003] Resorcinol is widely known as a versatile chemical compound that is widely used in the development of advanced chemicals and technologies (Durairaj, 2005). It has been used in a wide range of applications from medicine to chemistry, including the production of resins, plastics, dyes, drugs, and many other organic chemical compounds.

[0004] Resorcinol occurs as white crystals or powder, has a faint, characteristic aromatic odor with a sweet-bitter taste, and is readily soluble in water and alcohol. Other names for this compound include resorcinol, meta-dihydroxybenzene, 1,3-dihydroxybenzene, 1,3-benzenediol, and 3-hydroxyphenol, and its theoretical formula is C6H6O2. Structurally, this compound has two hydroxyl groups in an aromatic ring structure, positioned meta to each hydroxyl group. The high reactivity of resorcinol is primarily related to the location of these two hydroxyl groups within the benzene ring; the hydrogen atom adjacent to the hydroxyl group is particularly reactive.

[0005] Resorcinol can be produced via synthetic routes, either using natural resins such as Brazilwood distillates, by dissolving any of a number of resins (such as galbanum and asafoetida) and combining this with potassium hydroxide, or by several synthetic methods. One synthetic method of production is the sulfonation of benzene with sulfuric acid, fusing the resulting benzenedisulfonic acid with sodium hydroxide, and then extracting the resorcinol.

[0006] One of the uses of resorcinol is its role as a chemical intermediate for synthesizing pharmaceuticals and other organic compounds. For example, it is used in the production of diazo dyes and plasticizers and as a UV absorber in resins. As a medicine, resorcinol is used as an antiseptic and disinfectant in topical pharmaceutical products to treat skin disorders and infections such as acne, seborrheic dermatitis, eczema, psoriasis, corns, calluses, and warts. Resorcinol exerts keratolytic activity, thereby helping to remove hard, scaly, or rough skin. However, its primary use is in the production of resins. Reaction with formaldehyde produces resins used to make rayon and nylon suitable for impregnation with rubber and as adhesives. [Prior art documents] [Non-patent literature]

[0007] [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, 20th edition, 2000, pub. Lippincott, Williams & Wilkins [Non-patent document 3] Handbook of Pharmaceutical Excipients, 2nd Edition, 1994 [Non-patent document 4] Animals (Scientific Procedures) Act 1986 [Non-patent document 5] Duermueller et al., NeuroReport, Vol. 4, No. 6, pp. 683-686, 1993 [Non-patent document 6] J. Pharmacol. Exp. Ther. 107, pages 273-283, 1953 Summary of the Invention [Problem to be solved by the invention]

[0008] Most generally, the present invention relates to novel resorcinol derivatives that are biologically active and therefore useful in the treatment of diseases. Such novel compounds can be administered by a wide 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, including, but not limited to, epilepsy. [Means for solving the problem]

[0009] In a first aspect of the present invention, a compound of formula (I):

[0010] [ka]

[0011] or a salt or stereoisomer thereof.

[0012] In one embodiment, the compound of formula (I) is (1'R,2'R,4'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol or a salt thereof.

[0013] In one embodiment, the compound of formula (I) is (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol or a salt thereof.

[0014] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect together with one or more additional ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents.

[0015] Preferably, the pharmaceutical composition of the second aspect is in a form selected from liquid, solution, suspension, emulsion, syrup, electuary, mouthwash, drops, tablets, granules, powder, lozenges, pastilles, capsules, cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0016] 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.

[0017] Preferably, the method of treatment of the third aspect is a method of treating epilepsy, generalized seizures, focal onset seizures, or tonic-clonic seizures.

[0018] 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.

[0019] Preferably, the medicament of the fourth aspect is a medicament for treating epilepsy, generalized seizures, focal onset seizures, or tonic-clonic seizures.

[0020] In a fifth aspect of the present invention, there is provided a method of treatment comprising administering a therapeutically effective amount of a compound of the first aspect, or a pharmaceutical composition of the second aspect, to a subject in need of treatment.

[0021] According to a sixth aspect of the present invention, a method for producing a medicament for the preparation of ... i) reacting 5-bromobenzene-1,3-diol with 4-isopropenyl-1-methyl-cyclohex-2-en-1-ol; ii) treating the resulting compound 5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol with acetic anhydride; iii) further treating the resulting compound [3-acetoxy-5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate with manganese acetate dihydrate; iv) thereafter adding sodium borohydride to the compound [3-acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]phenyl]acetate obtained, followed by the subsequent steps to prepare the compound of formula (I). There is provided a process for the preparation of a compound of formula (I), comprising:

[0022] These and other aspects and embodiments of the invention are described in further detail below.

[0023] The present invention will now be described with reference to the figures listed below. [Brief explanation of the drawings]

[0024] [Figure 1] 1 shows the evaluation of test compounds in the mouse mini-MEST test as described in Example 2. [Figure 2] 1 shows the evaluation of test compounds in the MEST test in mice as described in Example 3. [Figure 3]1 shows the percentage (%) of mice with wild running when Compound I was administered in a mouse audiogenic seizure test (positive control: valproate; negative control: vehicle) as described in Example 4. [Figure 4] 1 shows the percentage (%) of mice with clonic convulsions when Compound I was administered in a mouse audiogenic seizure test (positive control: valproate; negative control: vehicle) as described in Example 4. [Figure 5] 1 shows the latency to clonic convulsions upon administration of Compound I in a mouse audiogenic seizure test as described in Example 4 (positive control: valproate; negative control: vehicle). [Figure 6] 1 shows the percentage (%) of mice with tonic extension when Compound I was administered in a mouse audiogenic seizure test (positive control: valproate; negative control: vehicle) as described in Example 4. [Figure 7] 1 shows the latency to tonic extension upon administration of Compound I in the mouse audiogenic seizure test as described in Example 7 (positive control: valproate; negative control: vehicle). [Figure 8] 1 shows the percentage (%) of mortality upon administration of Compound I in a mouse audiogenic seizure test (positive control: valproate; negative control: vehicle) as described in Example 4. [Figure 9] 1 shows the evaluation of test compounds in a 6 Hz psychomotor test in mice as described in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides novel resorcinol derivatives that are biologically active and therefore useful in the treatment of disease.

[0026] New resorcinol The present invention relates to a compound of formula (I):

[0027] [ka]

[0028] The present invention provides a compound of the formula:

[0029] The compound of formula (I) exists as isomers (epimers). Two isomers of the novel resorcinol of the present invention are (1'R,2'R,4'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol, which will be referred to as Isomer 1, and (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol, which will be referred to as Isomer 2. Isomers 1 and 2 will be collectively referred to as the compound of formula I or Compound I.

[0030] In one embodiment, the compound of formula (I) is (1'R,2'R,4'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Isomer 1).

[0031] In one embodiment, the compound of formula (I) is (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (isomer 2).

[0032] salt In some embodiments, the compound of formula (I) is provided in the form of a free base.

[0033] 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.

[0034] Thus, in some embodiments, compounds of Formula (I) are provided as salts, eg, in protonated form, with a suitable counteranion.

[0035] Suitable counter anions include both organic and inorganic anions. An example of a suitable inorganic anion is chloride (Cl). - ), bromide (Br - ), iodide (I - ), sulfate (SO4 2- ), sulfite (SO3 2- ), nitrate (NO3 - ), nitrite (NO2 - ), phosphate (PO4 3- ), and phosphite (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.

[0036] Alternatively, in some embodiments, the compound of formula (I) is provided as a salt, for example in deprotonated form, with an appropriate countercation.

[0037] Suitable countercations 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 ions (i.e., NH4 + ) 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.

[0038] solvate In some embodiments, the compound of formula (I) is provided in a desolvated form, eg, a dehydrated form.

[0039] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound.

[0040] 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.

[0041] Synthesis method The present invention also relates to a method for producing a method for manufacturing a semiconductor device comprising the steps of: i) reacting 5-bromobenzene-1,3-diol with 4-isopropenyl-1-methyl-cyclohex-2-en-1-ol; ii) treating the resulting compound 5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol with acetic anhydride; iii) further treating the resulting compound [3-acetoxy-5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate with manganese acetate dihydrate; iv) thereafter adding sodium borohydride to the compound [3-acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]phenyl]acetate obtained, followed by the subsequent steps to prepare the compound of formula (I). The present invention provides a process for the preparation of a compound of formula (I), comprising:

[0042] Intermediates The present invention also provides an intermediate formed in the process for preparing a compound of formula (I),

[0043] [ka]

[0044] to provide an intermediate,

[0045] 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.

[0046] 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.

[0047] Suitable pharmaceutically 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 ed., 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 2nd ed., 1994.

[0048] 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, flavors, and sweeteners.

[0049] In a preferred embodiment, the pharmaceutical composition comprises one or more excipients selected from a carrier, an oil, a disintegrant, a lubricant, a stabilizer, a flavoring agent, an antioxidant, a diluent, and another pharmaceutically active compound.

[0050] 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, e.g., coated tablets), granules, powders, lozenges, pastilles, 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.

[0051] In a preferred embodiment, the form of the pharmaceutical composition is selected from tablets, capsules, granules, inhalable powders, sprinkles, oral solutions, and suspensions.

[0052] 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, are useful for medical treatment.

[0053] Thus, the present invention 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 (i.e., a method of treatment).

[0054] The present invention also provides a compound of formula (I), or a salt thereof, for use as a pharmaceutical.

[0055] The present invention also provides a method of treatment comprising administering a therapeutically effective amount of Compound (I), or a salt thereof, to a subject in need of treatment.

[0056] The present invention also provides use of Compound (I), or a salt thereof, for the manufacture of a medicament.

[0057] Symptoms to be 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 are useful for treating certain symptoms associated with seizures.

[0058] Similarly, compounds of formula (I), salts thereof, and pharmaceutical compositions comprising compounds of formula (I) or salts thereof are useful as medicaments (and in the manufacture of medicaments for the treatment) of certain symptoms associated with seizures.

[0059] In a preferred embodiment, the seizure-related condition is epilepsy.

[0060] In one embodiment, the seizure-related condition is a generalized seizure, for example, a generalized seizure associated with epilepsy.

[0061] In one embodiment, the seizure-related condition is a tonic-clonic seizure, for example, a tonic-clonic seizure associated with epilepsy.

[0062] Subjects / patients The methods of treatment typically involve administering a compound of formula (I), or a salt thereof, to a subject or patient.

[0063] 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. Furthermore, the subject / patient can be in any of its forms of development, for example, an infant or child.

[0064] In a preferred embodiment, the subject / patient is a human, more preferably an adult.

[0065] The subject / patient may also be a non-human mammal used in laboratory research, such as a rodent, which includes rats, mice, guinea pigs, and chinchillas.

[0066] Route of administration The method of treatment may involve administering a compound of formula (I), or a salt thereof, to a subject systemically / peripherally or locally (i.e., at the site of desired action) by any convenient route of administration.

[0067] 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), ophthalmic (e.g., by eye drops), pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., used through the mouth or nose), rectal (e.g., by suppository or enema), vaginal (e.g., by vaginal suppository), 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., subcutaneously or intramuscularly.

[0068] Dosage The methods of treatment typically involve administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt thereof.

[0069] 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 toxic side effects. The selected dosage 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 materials used in combination, the severity of the symptoms, and the patient's species, sex, age, weight, symptoms, general health, and previous 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.

[0070] Administration can be 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 the dose level and pattern being selected by the treating clinician.

[0071] Other Aspects and Embodiments All compatible combinations of the above embodiments are expressly disclosed herein as if each and every combination were individually and expressly set forth.

[0072] Various important aspects and embodiments of the present invention will be apparent to those skilled in the art in light of this disclosure.

[0073] When used, "and / or" should be construed as a specific disclosure of each associated component or feature individually, as well as a specific disclosure of combinations of components or features. For example, "A and / or B" should be construed as a specific disclosure of i) A, ii) B, and ii) each of A and B, as if each were individually listed.

[0074] Unless otherwise indicated by context, the preceding feature descriptions and definitions are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0075] definition The following definitions are provided to aid in the understanding of the present invention.

[0076] "Resorcinol" is a compound having the following structure, or any superstructure containing such a structure within it:

[0077] [ka]

[0078] Epilepsy is considered to be a brain disorder defined by any of the following symptoms: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure occurring over the next 10 years and a probability of further seizures similar to the general risk of recurrence after two unprovoked seizures (at least 60%), or (3) a diagnosis of an epilepsy syndrome (practical clinical definition of epilepsy by the International League Against Epilepsy (ILAE), 2014).

[0079] The term “generalized seizures” (or “generalized onset seizures”) refers to seizures conceptualized as originating from a point in the brain and rapidly involving bilaterally distributed networks ( Operational Classification of Seizure Types by ILAE, 2017 ).

[0080] "Tonic-clonic seizures" occur in two phases: the tonic phase is typically accompanied by muscle stiffening and loss of consciousness, and the clonic phase is typically accompanied by rhythmic jerking of the limbs.

[0081] The term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject (e.g., a human) of interest 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.

[0082] The term "therapeutically effective amount" refers to an 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]

[0083] Certain aspects and embodiments of the present invention are described, by way of example only, and with reference to the above figures.

[0084] Example 1 Synthetic production method of resorcinol derivatives This example describes a novel synthetic method used to prepare a novel resorcinol that demonstrated pharmacological activity. Scheme 1 below illustrates the four steps of the reaction used to prepare the novel resorcinol, which was formed via multiple intermediates.

[0085] The two novel resorcinol isomers of the present invention are (1'R,2'R,4'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol, which will be referred to as Isomer 1 of Compound I, and (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol, which will be referred to as Isomer 2 of Compound I; Isomer 1 and Isomer 2 will be referred to collectively throughout as the compound of Formula I or Compound I.

[0086] The analytical data for Isomer 1 of Compound I are as follows: 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 2H), 6.39 (s, 2H), 5.17 (s, 1H), 4.63 - 4.58 (m, 1H), 4.51 (s, 1H), 4.47 - 4.46 (m, 1H), 4.08 - 4.01 (m, 1H), 3.87 (s, 1H), 3.74 - 3.72 (m, 1H), 2.01 (d, J=5.0 Hz, 1H), 1.70 - 1.53 (m, 7H).

[0087] The analytical data for isomer 2 of compound I are as follows: 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.32 (s, 1H), 6.43 - 6.36 (m, 2H), 5.07 - 5.05 (m, 1H), 4.62 (d, J=6.7 Hz, 1H), 4.49 - 4.44 (m, 2H), 4.12 - 4.06 (m, 1H), 3.88 - 3.84 (m, 1H), 3.20 - 3.12 (m, 1H), 1.90 (ddd, J=2.4, 5.7, 12.0 Hz, 1H), 1.66 - 1.63 (m, 3H), 1.63 - 1.55 (m, 4H).

[0088] Scheme 1: Synthesis of novel resorcinols

[0089] [ka]

[0090] [Table 1]

[0091] Step 1: Formation of compound c A solution of 5-bromobenzene-1,3-diol (20.88 g, 0.110 mol, 1.00 equiv.) and p-toluenesulfonic acid monohydrate (10.51 g, 55.2 mmol, 0.500 equiv.) 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, 0.701 equiv.) 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, warming to 20 °C. The mixture was diluted with dichloromethane (200 mL) and basified to pH 8 by careful addition of 300 mL of saturated aqueous NaHCO3. The organic layer was separated and washed with water (50 mL), brine (50 mL), then dried (MgSO), filtered, and concentrated in vacuo to give a colorless gum, which was purified by column chromatography on silica gel (800 g, Interchim cartridge) eluting with 0-50% diethyl ether in cyclohexane to give 2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (2.53 g, ca. 6% yield) as a colorless gum / glass. This was repurified by column chromatography on silica gel (40 g, 15 micron Interchim column) eluting with 5-20% diethyl ether in cyclohexane in vacuo to give 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (0.92 g) and some impurities.

[0092] The initial column also yielded 5-bromobenzene-1,3-diol (8.17 g, approximately 39% recovery) as a colorless gum that 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, 0.701 equiv.), and cooled to 0 °C in an ice / brine bath under nitrogen. p-Toluenesulfonic acid monohydrate (4.11 g, 21.6 mmol, 0.500 equiv.) 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, warming to 20 °C. The mixture was diluted with dichloromethane (100 mL) and basified to pH 8 by careful addition of 300 mL of saturated aqueous sodium bicarbonate. The organic layer was separated and washed with water (50 mL), saturated brine (50 mL), then dried (MgSO), filtered, and concentrated in vacuo to give a colorless gum. The residue was purified by column chromatography on silica gel (40 g Interchim cartridge) eluting with 0-50% diethyl ether in cyclohexane to give the title compound (1.33 g, 7% yield, 81% LCMS purity) as a colorless gum. This was combined with the impurity material from the first reaction and purified by column chromatography on silica gel (40 g Interchim cartridge) eluting with 5-20% diethyl ether in cyclohexane to give 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (2.10 g, 91% LCMS purity) as a colorless gum.

[0093] The total yield of 5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol obtained was 3.02 g (9.34 mmol, 8.5%).

[0094] Analytical data for compound c: 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).

[0095] Step 2: Formation of compound d 5-Bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (1305 mg, 4.04 mmol, 1.00 equiv.) in acetonitrile (30 mL) was treated with cesium carbonate (3289 mg, 10.1 mmol, 2.50 equiv.) followed by acetic anhydride (0.95 mL, 10.1 mmol, 2.50 equiv.). The reaction mixture was stirred for 1 hour and then partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic phases were filtered through hydrophobic filter paper and concentrated in vacuo to give the title compound (1.60 g, 93.4%) as an orange gum, which was used in the next reaction without further purification.

[0096] Analytical data for compound d: 1 H NMR (400 MHz, CDCl3) δ, 7.07 (s, 2H), 5.15 (s, 1H), 4.56 (s, 1H), 4.44 - 4.44 (m, 1H), 3.55 - 3.50 (m, 1H), 2.67 - 2.60 (m, 1H), 2.24 - 2.16 (m, 7H), 2.07 - 2.00 (m, 1H), 1.84 - 1.64 (m, 5H), 1.58 - 1.57 (m, 3H).

[0097] Step 3: Formation of compound e [3-Acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate (1560 mg, 3.83 mmol, 1.00 equiv) and molecular sieves (3 Å, 5000 mg) in ethyl acetate (31.92 mL) were treated with manganese(III) acetate dihydrate (103 mg, 0.383 mmol, 0.100 equiv), followed by a 5.5 M solution of tert-butyl hydroperoxide in nonane (3.5 mL, 19.2 mmol, 5.00 equiv). The reaction mixture was stirred overnight at 20 °C, then diluted with ethyl acetate (50 mL) and filtered through a pad of Celite. The filtrate was washed with saturated aqueous sodium thiosulfate (30 mL) and water (30 mL), separated, dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0 to 100% diethyl ether in cyclohexane to give the title compound (561 mg, 34.8%) as an off-white solid.

[0098] Analytical data for compound d: 1 H NMR (400 MHz, DMSO) δ 7.39 (s, 2H), 6.38 (t, J=1.8 Hz, 1H), 4.56 (s, 1H), 4.50 (s, 1H), 4.04 (td, J=2.3, 10.6 Hz, 1H), 3.20 - 3.11 (m, 1H), 2.85 - 2.76 (m, 1H), 2.35 - 2.19 (m, 7H), 1.71 (dd, J=1.5, 2.5 Hz, 3H), 1.62 (s, 3H).

[0099] Step 4: Formation of Isomer 1 of Compound I and Isomer 2 of Compound I To a solution of [3-acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]phenyl]acetate (1.10 g, 2.61 mmol, 1.00 equiv.) in methyl alcohol (25.0 mL) at 0 °C, sodium borohydride (0.22 g, 5.74 mmol, 2.20 equiv.) was added in four equal portions over a 30 minute period, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (75 mL) and water (75 mL). The layers were separated, and the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0 to 80% ethyl acetate in cyclohexane to give (1'R,2'R,4'R)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (200 mg, 22.5%) as a white solid and (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (508 mg, 57.4%) as a white solid.

[0100] Example 2 Evaluation of novel resorcinols for anticonvulsant activity using the mouse maximal electroshock seizure threshold (MEST) test with minimal sample size (mini-MEST) The efficacy of the novel resorcinol compounds of Formula I was tested in a novel mouse model of generalized seizures, the mini-MEST (maximum electroshock seizure threshold) test, which uses a lower n number than typically used.

[0101] 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).

[0102] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce a tonic extensor hindlimb spasm 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.

[0103] Conversely, a lowering of the seizure threshold indicates a proconvulsant effect such as that observed with known convulsants such as picrotoxin.

[0104] The MEST assesses the ability of test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the presence of a tonic hindlimb extensor spasm. The current (CC) that evokes a tonic hindlimb extensor spasm in 50% of the animals in the treatment group is used. 50 The seizure threshold of the treatment group was determined by the presence (+) or absence (0) of tonic hindlimb extensor spasms observed from the CC group, and the effect was then compared to that of the vehicle control group. 50 Compared to.

[0105] method Research details: Naive mice were habituated to the procedure room in their home cages for up to 7 days and allowed free access to food and water.

[0106] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the average distribution of body weights across groups. All animals were dosed with either vehicle, 50 mg / kg test compound, or 2.5 mg / kg diazepam via intraperitoneal (ip) injection at 10 mL / kg.

[0107] Animals were individually assessed for the development of tonic hindlimb extensor convulsions from a single electric shock 30 minutes after administration of vehicle, test compound, and diazepam.

[0108] The first animal in a treatment group was assigned a predicted or estimated CC50 Shocks were administered with electrical current, which for subsequent animals was decreased or increased in logarithmic intervals depending on the outcome of the seizure from the previous animal.

[0109] Using the data generated from each treatment group, CC of the treatment group 50 Values ​​were calculated ±SEM.

[0110] Test Compound: Vehicle: (5% ethanol, 10% solutol in 85% saline) was prepared as follows: 1 mL ethanol, 2 mL solutol were warmed to 60°C in 17 mL saline (1:2:17).

[0111] Positive control: diazepam was used at 2.5 mg / kg.

[0112] The test compound, referred to herein as Compound I, is as shown in Formula I. The test compound was administered at 50 mg / kg (ip) in a 1:2:17 ethanol:solutol:0.9% saline formulation.

[0113] Sample Collection: Each animal was humanely killed immediately after the onset of convulsions due to brain destruction from the blow to the skull, followed by confirmation of complete cessation of circulation by decapitation in accordance with The Humane Killing of Animals, Schedule 1 of the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection was performed following decapitation.

[0114] 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 over the heart.

[0115] 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 show seizure behavior) ± standard error is calculated.

[0116] The effect of test compounds was also assessed by comparing CC from the vehicle control group. 50 was calculated as a percentage change in

[0117] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0118] result Figure 1 and Table 1 illustrate the data obtained in this experiment.

[0119] In the vehicle group, CC 50 The value was calculated to be 23.5 mA.

[0120] In the group treated with diazepam (2.5 mg / kg) administered ip 30 min before the test, CC 50 The value was 89.0 mA, which was statistically significant compared to the vehicle control (p<0.001).

[0121] Test compounds administered ip 30 min before testing produced a clear increase in seizure threshold compared to vehicle, and CC 50was greater than 114 mA at 50 mg / kg. The exact value could not be calculated because no "+" tonic hindlimb convulsions were observed in the six animals tested. CC 50 Although the seizure threshold was not determined, Compound I demonstrated a clear increase in the seizure threshold in the mini-MEST. Animals in this treatment group did not experience convulsions, demonstrating the clear activity of Compound I.

[0122] Such data indicate that this compound may have therapeutic benefit.

[0123] [Table 2]

[0124] conclusion The data obtained using the mini-MEST model demonstrate a strong therapeutic effect for Compound I, demonstrating CC 50 increased by more than 385% compared to the vehicle control, a rate of change even higher than that produced by the positive control.

[0125] This data is important because it provides previously unknown evidence that this novel resorcinol may have therapeutic value.

[0126] Example 3 Evaluation of novel resorcinols for anticonvulsant activity using the mouse maximal electroshock seizure threshold (MEST) test The efficacy of the novel resorcinol compounds of formula I was tested in a mouse model of generalized seizures, namely the maximal electroshock seizure threshold (MEST) test.

[0127] 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).

[0128] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce a hindlimb tonic-extension convulsion 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.

[0129] Conversely, a lowering of the seizure threshold indicates a proconvulsant effect such as that observed with known convulsants such as picrotoxin.

[0130] The MEST assesses the ability of test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the presence of a tonic hindlimb extension spasm. The current (CC) that evokes tonic hindlimb extension in 50% of the animals in the treatment group is used. 50 The seizure threshold of the treatment group was determined by the presence (+) or absence (0) of tonic hindlimb extensor convulsions observed from the CC group, and the effect was then compared with that of the vehicle control group. 50 Compared to.

[0131] method Research details: Naive mice were habituated to the procedure room in their home cages for up to 7 days and allowed free access to food and water.

[0132] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the average distribution of body weights across groups. All animals were dosed via intraperitoneal (ip) injection at 10 mL / kg with either vehicle, 1, 5, 20, 50, 100, and 200 mg / kg of test compound, or 2.5 mg / kg of diazepam.

[0133] Animals were individually assessed for the occurrence of tonic hindlimb extensor convulsions following a single electric shock, 60 minutes after vehicle administration, 15-60 minutes after test compound administration, and 30 minutes after diazepam administration.

[0134] The first animal in a treatment group was assigned a predicted or estimated CC 50 The animals were shocked with a current that was decreased or increased in 5 mA intervals for subsequent animals depending on the outcome of the seizure from the previous animal.

[0135] Using the data generated from each treatment group, CC of the treatment group 50 Values ​​were calculated ±SEM.

[0136] Test Compound: Vehicle: (5% ethanol, 5% Kolliphor® EL, 90% saline) was prepared as follows: 2 mL ethanol, 2 mL Kolliphor® EL were warmed to 60° C. in 36 mL saline (1:1:18).

[0137] Positive control: diazepam was used at 2.5 mg / kg.

[0138] The test compound, referred to herein as Compound I, is as shown in Formula I. The test compound was administered at 1, 5, 20, 50, 100, and 200 mg / kg (ip) in a 1:2:17 ethanol:solutol:0.9% saline formulation.

[0139] Sample Collection: Each animal was humanely killed immediately after the onset of convulsions due to brain destruction from the blow to the skull, followed by confirmation of complete cessation of circulation by decapitation in accordance with The Humane Killing of Animals, Schedule 1 of the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection was performed following decapitation.

[0140] 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 100 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 on dry ice.

[0141] 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 show seizure behavior) ± standard error is calculated.

[0142] The effect of test compounds was also assessed by comparing CC from the vehicle control group. 50 was calculated as a percentage change in

[0143] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0144] result Figure 2 and Table 2 illustrate the data obtained in this experiment.

[0145] In the vehicle group, CC 50 The value was calculated to be 23.7 mA.

[0146] In the diazepam (2.5 mg / kg) treatment group, which was administered ip 30 min before the test, CC 50 The value was 130.0 mA, which was statistically significant compared to the vehicle control (p<0.001).

[0147] Test compounds administered ip 15-60 min before testing showed statistically significant CC increases compared to vehicle at 1, 5, 20, 50, and 100 mg / kg. 50values ​​suggesting that this compound exhibits anticonvulsant properties.

[0148] At 200 mg / kg, Compound I produced a significant increase in the seizure threshold compared to vehicle, and CC 50 The CC values ​​were greater than 300 mA. The 12 animals tested did not show a "+" tonic hindlimb twitch, so the exact values ​​could not be calculated. 50 Although the effect of 200 mg / kg on the seizure threshold was not determined, the seizure threshold was significantly increased in the MEST.

[0149] Such data indicate that this compound has therapeutic benefit.

[0150] [Table 3]

[0151] conclusion These data, generated using the MEST model, demonstrate the therapeutic efficacy of compounds of formula I, CC 50 is increased at all doses compared to the vehicle control.

[0152] These data are important because they provide previously unknown evidence that this novel resorcinol may have therapeutic value.

[0153] Clearly, this compound produced a dose-related increase in MEST, suggesting that this compound exhibits anticonvulsant properties. A significant effect was observed when compared to vehicle.

[0154] Example 4 Evaluation of novel resorcinols for anticonvulsant activity using the DBA / 2 mouse audiogenic seizure test. The DBA / 2 audiogenic seizure test to detect anticonvulsant activity follows that described by Duermueller et al. (NeuroReport, Vol. 4, No. 6, pp. 683-686, 1993).

[0155] method Research details: Sixty male DBA / 2 mice (3-4 weeks old) were included in the study (weight range 8-11 g at the start of the experiment). Animals were allowed to acclimate to the testing facility for 1 day after birth and then randomly housed in groups of five in Makrolon cages on wooden bedding with free access to food and water.

[0156] The animal house was maintained under artificial lighting (12 h) between 7:00 and 19:00 at a controlled room temperature of 22 ± 2°C and relative humidity of 30–70%.

[0157] Mice were individually transferred (at 3-5 min intervals) from the preparation room to an adjacent experimental room, where their body temperature was measured using a rectal thermometer. Immediately thereafter, they were placed in a Plexiglas jar (diameter = 40 cm, height = 35 cm) equipped with an electric bell. Upon activation of the bell, the incidence and latency of wild running, clonic, and tonic seizures were measured. Mortality was also recorded. The bell was activated until a tonic seizure occurred or for a maximum of 60 s.

[0158] The experiment included 6 groups (10 mice studied per group). The experimenter was blinded to the treatment groups.

[0159] Test substances were evaluated at four doses (10 mL / kg) administered i.p. 30 or 60 minutes before the test and compared to a vehicle control group. Doses and pretreatment times were based on previous pharmacokinetic data.

[0160] [Table 4]

[0161] Test Compound: Test compound: Compound I dissolved in 5% ethanol, 10% Kolliphor HS15, 85% saline.

[0162] Vehicle control: 5% ethanol, 10% Kolliphor HS15, 85% saline.

[0163] Reference: valproate (180 mg / kg) dissolved in 5% ethanol, 10% Kolliphor HS15, and 85% saline.

[0164] statistical analysis Data were tested for normality using d'Agostino-Pearson and were found not to follow a normal distribution. No behavioral outliers were identified, and therefore no statistical outliers were identified or removed.

[0165] Quantitative data (latencies) for test substances were analyzed by comparing treatment groups with vehicle controls using the Kruskal-Wallis test followed by Dunn's multiple comparison test. Quantitative data for reference substances were analyzed using the Mann-Whitney U test.

[0166] Quantitative data (frequencies) were analyzed by comparing treatment groups with vehicle controls using Fisher's exact test.

[0167] result Figures 3-8 and Tables 4-7 describe the data generated in this experiment.

[0168] For the negative control of the experiment, vehicle control was administered i.p. 30 min before testing. All mice exhibited wild running (see Figure 3, leftmost column at 100%), clonic convulsions (Figure 4 shows 100%), and tonic convulsions (Figure 6). Four of the 10 mice tested died (Figure 8). The median latency to wild running was 3.3 s (IQR 2.7-4.0) (Table 4), the median latency to clonic convulsions was 6.6 s (IQR 6.1-7.7) (Table 5), and the median latency to tonic convulsions was 10.7 s (IQR 9.6-12.1) (Table 6).

[0169] As a positive control for the experiment, valproate (180 mg / kg) administered i.p. 30 min before testing suppressed wild running (see Figure 3, second column from the left at 0%), clonic convulsions (Figure 4 shows 0%), and tonic convulsions (Figure 6) compared to vehicle controls (-100%, p<0.001 for each parameter). Valproate significantly increased the corresponding latencies compared to vehicle controls (+1718%, +809%, and +461%, respectively, p<0.001 for each parameter) (Tables 4-6). No deaths were observed in valproate-treated animals (Figure 8 and Table 9). No adverse symptoms were observed in valproate-treated animals.

[0170] Four mice in each group dosed with Compound I at 100 and 200 mg / kg had rectal temperatures below 35.0° C. These mice were excluded from all analyses. Tremors were observed in five mice treated with 100 mg / kg and three mice treated with 200 mg / kg.

[0171] Compound I at 50, 100, and 200 mg / kg significantly reduced the number of mice exhibiting wild running (-50%, p<0.05, -100%, p<0.001, and -80%, p<0.01, respectively). See Figure 3.

[0172] There was a statistically significant main effect of Compound I dose on the latency to wild running compared to vehicle (p<0.001, see Table 4). Dunn's multiple comparison test showed that 50, 100, and 200 mg / kg Compound I significantly increased the latency to wild running compared to vehicle (mean ranks -19.10, p<0.01, -26.55, p<0.001, and -23.22, p<0.001, respectively).

[0173] Compound I at 50, 100, and 200 mg / kg significantly reduced the number of mice exhibiting clonic seizures (-60%, p<0.05, -100%, p<0.001, and -80%, p<0.01, respectively). See Figure 4.

[0174] There was a statistically significant main effect of Compound I dose on the latency to clonic convulsions compared to vehicle (p<0.001, see Figure 5). Dunn's multiple comparison test showed that 20, 50, 100, and 200 mg / kg Compound I significantly increased the latency to clonic convulsions compared to vehicle (mean ranks -13.10, p<0.05; -21.20, p<0.001; -26.70, p<0.001; and -22.53, p<0.001, respectively).

[0175] As shown in Figure 6, at all doses, Compound I significantly reduced the number of mice exhibiting tonic convulsions (-60% at 20 mg / kg, p<0.05; -100% at other doses, p<0.001).

[0176] There was a statistically significant main effect of Compound I dose on the latency to tonic convulsion compared with vehicle (p<0.001) (FIG. 7). Dunn's multiple comparison test showed that Compound I at 20, 50, 100, and 200 mg / kg significantly increased the latency to tonic convulsion compared with vehicle (mean rank: -16.20 for 20 mg / kg, p<0.01; -22.80 for the last three doses, p<0.001).

[0177] As evidenced by Figure 8 and Table 7, Compound I had no effect on mortality at any dose.

[0178] [Table 5]

[0179] [Table 6]

[0180] [Table 7]

[0181] [Table 8]

[0182] conclusion Valproate exhibited anticonvulsant activity in this model, and therefore the experiment was considered valid. The results demonstrate the presence of anticonvulsant activity for Compound I over the dose range of 20-200 mg / kg i.p. in the DBA / 2 mouse audiogenic seizure test.

[0183] Neither valproate nor Compound I caused a significant change in the number of deaths, providing evidence of the safety of Compound I.

[0184] Example 5 Evaluation of novel resorcinols for anticonvulsant activity using the mouse 6Hz psychomotor test. The 6 Hz psychomotor test to detect anticonvulsant activity follows that described by Brown et al. (J. Pharmacol. Exp. Ther. 107, 273-283, 1953).

[0185] method Research details: Male RjOrl:Swiss mice, 5 weeks old, weighing 28–38 g at the start of the experiment. Animals were allowed to acclimate to the testing facility for at least 5 days after birth and were randomly housed in groups of 3–4 in Makrolon cages on wooden bedding with free access to food and water.

[0186] The animal house was maintained under artificial lighting (12 h) between 7:00 and 19:00 at a controlled room temperature of 22 ± 2°C and relative humidity of 30–70%.

[0187] Before transcorneal stimulation, one drop of tetracaine solution (2%) was applied to each eye of the mouse for local anesthesia. Between 1 and 10 minutes after the pretreatment time specified for the test compound, the mouse was administered a square-wave current (44 mA, square pulse: 0.2 ms pulse width, 3 s duration, 6 Hz) via a corneal electrode connected to a constant-current shock generator.

[0188] The number of seizures reflected by forelimb clonus was recorded immediately after current administration and was scored as absent (0 = no forelimb clonus), mild (1 = clonus in one forelimb), and strong (2 = clonus in both forelimbs).

[0189] Fifteen mice were studied per group. Experimenters were blinded to the treatments. Cages were randomly assigned to treatment codes, each designating one treatment group.

[0190] Compound I was administered intraperitoneally at 20 and 50 mg / kg 30 minutes before testing, and at 100 and 200 mg / kg 60 minutes before testing, and compared to vehicle control (5% ethanol, 10% Kolliphor EL, 85% saline).

[0191] Valproate (300 mg / kg ip) administered 30 min before the test was used as a reference substance and compared with a vehicle control (5% ethanol, 10% Kolliphor HS15, 85% saline).

[0192] [Table 9]

[0193] Test Compound: Test compound: Compound I dissolved in 5% ethanol, 10% Kolliphor HS15, 85% saline.

[0194] Vehicle control: 5% ethanol, 10% Kolliphor HS15, 85% saline.

[0195] Reference: valproate (300 mg / kg) dissolved in 5% ethanol, 10% Kolliphor HS15, and 85% saline.

[0196] Statistical analysis: Because data is assumed to be non-normally distributed based on validation data, non-parametric tests are used.The quantitative data (scores) of test substance are analyzed by comparing treatment groups with corresponding vehicle controls using the Kruskal-Wallis test together with Dunn's multiple comparison test if the Kruskal-Wallis test is significant.The quantitative data of reference substance are analyzed using the Mann-Whitney U test.

[0197] result Figure 9 and Table 9 illustrate the data obtained in this experiment.

[0198] For the negative control, vehicle control administered i.p. 30 minutes before testing, 5 mice had a forelimb seizure score of 0, 8 mice had a forelimb seizure score of 1, and 2 mice had a forelimb seizure score of 2 (see Figure 9, far left).

[0199] For the positive control, valproate (300 mg / kg) administered i.p. 30 min before testing significantly reduced the mean forelimb seizure score (-88%, p<0.001) compared to vehicle control (Figure 9, second from left). One of 15 mice tested showed slight sedation.

[0200] Two mice in the 100 mg / kg Compound I group and one mouse in the 200 mg / kg Compound I group were excluded due to incorrect dosing. Two of the 14 mice in the 200 mg / kg Compound I group showed tremors, and all mice showed mild (12 mice) to moderate (2 mice) sedation. Two of the 13 mice in the 100 mg / kg Compound I group showed slight sedation.

[0201] There were statistically significant differences in the Kruskal-Wallis test for forelimb seizure scores among all Compound I dose groups compared to vehicle (p<0.01) (see Table 9).

[0202] Compound I (100 mg / kg) administered ip 60 minutes before testing significantly reduced forelimb seizure scores (-88%, p<0.01) compared to vehicle controls (Figure 9).

[0203] [Table 10]

[0204] conclusion The results suggest the presence of anticonvulsant effects for Compound I at 100 mg / kg ip, with a similar trend at 200 mg / kg, in the 6 Hz (44 mA) psychomotor seizure test in mice.

[0205] (References) A number of publications have been 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.

[0206] Durairaj 2005. “Resorcinol Structure and Physical Properties.” Resorcinol. Springer, Berlin, Heidelberg. https: / / doi.org / 10.1007 / 3-540-28090-1_1

Claims

1. Formula (I): 【Chemistry 1】 or a salt or stereoisomer thereof.

2. A compound of formula (I) which is (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol.

3. 10. A pharmaceutical composition comprising a compound of claim 1 or 2 together with one or more additional ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavors, and sweeteners.

4. 4. The pharmaceutical composition of claim 3, in a form selected from liquid, solution, suspension, emulsion, syrup, electuary, mouthwash, drops, tablets, granules, powders, lozenges, pastilles, capsules, cachets, pills, ampoules, intravenous bolus, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

5. 3. A compound according to claim 1 or 2 for use as a medicine.

6. 6. The compound for use according to claim 5, wherein the medicament is a medicament for treating epilepsy.

7. 7. The compound for use according to claim 5 or 6, wherein the medicament is for treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

8. 10. A compound according to claim 1 or 2 for use in a method of treatment.

9. 9. The compound for use according to claim 8, wherein said method of treatment is a method of treating epilepsy.

10. 10. The compound for use according to claim 8 or 9, wherein said method of treatment is a method of treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

11. 10. A method of treatment comprising administering a therapeutically effective amount of a compound of claim 1 or 2 to a subject in need of treatment.

12. 12. The method of treatment of claim 11, which is a method of treating epilepsy.

13. 13. The method of treatment of claim 11 or 12, which is a method of treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

14. A process for the preparation of a compound of formula (I), comprising: The following steps: i) reacting 5-bromobenzene-1,3-diol with 4-isopropenyl-1-methyl-cyclohex-2-en-1-ol; ii) treating the resulting compound 5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol with acetic anhydride; iii) Further, the resulting compound [3-acetoxy-5-bromo-2-[6-isopropenyl-3-methyl-cyclohex-2-en-1-yl ]phenyl]acetate with manganese acetate dihydrate; iv) The compound [3-acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl ]phenyl]acetate, followed by the subsequent steps to prepare a compound of formula (I). A method comprising:

15. An intermediate formed in the process for preparing a compound of formula (I), 【Chemistry 2】 That is, an intermediate.

Images