Terpene phenol compounds and their use

Abstract

This disclosure describes terpene-phenolic compounds and their use in medicine. This disclosure also describes perottetinene-like compounds, their preparation, formulations containing them, and their use in medicine. Such compounds include (1'R,2'R)-5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET) or (1'R,2'R)-4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET-OH).

Description

Technical Field

[0001]

[0001] The present invention relates to terpene phenol compounds and their use in medicaments. More specifically, the present invention relates to perrottetinene-like compounds, their production, formulations containing them, and their use in medicaments.

Background Art

[0002]

[0002] Perrottetinene (PET) is a naturally occurring compound found in mosses of the genus Radula native to Japan, New Zealand, and Costa Rica, namely Radula perrottetii, Radula marginata, and Radula laxiramea.

[0003]

[0003] This is a terpene phenol compound containing a terpenoid moiety (A), a substituted or unsubstituted phenol or resorcinol moiety (B), and a substituted or unsubstituted phenylethylarene side chain (C).

[0004]

[0004] Its structure is illustrated below:

[0005]

Chemical Formula

[0006]

[0005] Alternatively, (B) and (C) may together be referred to as bibenzyl or dihydrostilbenoid, and in this case, the compound may be called terpene-bibenzyl or terpene-dihydrostilbenoid.

[0007]

[0006] This can be produced as cis or trans isomers or as a racemic mix of cis or trans isomers.

[0007] A recent paper by Chicca et al., Sci Adv 2018, compared the activities of bibenzyl (-) cis - perrottetinine (cis - PET) and bibenzyl (-) trans - perrottetinine (trans - PET) with those of the cannabinoids trans - delta - 9 - tetrahydrocannabinol (trans - THC) and cis - delta - 9 - tetrahydrocannabinol (cis - THC).

[0008]

[0008] Applicants postulate that perrottetinene - like compounds, defined as bis - phenyl or biphenyl having a 2 - carbon bridge (saturated or unsaturated) or cannabinoid - like molecules containing a substituted or unsubstituted phenylethylarene side chain (C), may have interesting pharmacological and pharmaceutical activities.

[0009]

[0009] Applicants further postulate that considering the chemical structure of perrottetinene was similar to that of the cannabinoid trans - delta - 9 - tetrahydrocannabinol (THC), other "perrottetinene - like" compounds having a terpenoid moiety (A), a substituted or unsubstituted phenol or resorcinol moiety (B), and a substituted or unsubstituted phenylethylarene side chain (C) may be regarded as cannabinoid - like compounds.

[0010]

[0010] As previously mentioned, (B) and (C) may, alternatively, be referred to together as bibenzyl or dihydrostilbenoid.

[0011] These compounds in which the terpenoid moiety is attached to a substituted or unsubstituted dihydropinosylvin * were postulated to possibly have interesting pharmacological and pharmaceutical activities. Another chemical name representing dihydropinosylvin is 5 - phenethylbenzene - 1,3 - diol; 5 - (2 - phenylethyl)benzene - 1,3 - diol or 3,5 - dihydroxybibenzyl.

[0011]

[0012] These perrottetinene-like compounds include a closed-ring structure (similar to cannabinoid tetrahydrocannabinol THC and cannabinol (CBN)) and an open-ring structure (similar to cannabinoid cannabidiol (CBD), cannabigerol (CBG) and cannabichromene (CBC)).

[0012]

[0013] The structures of THC and CBD are illustrated below along with the structures of the other major types of cannabinoids CBG, CBC and CBN.

[0013]

Table 1

[0014]

[0014] One such perrottetinene-like compound is perrottetinene (PET) or a CBD analog of 5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol. This is i) the (-) trans isomer, (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, ii) the (+) trans isomer, (1’S,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, iii) the (-) cis isomer, (1’R,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, or iv) the (+) cis isomer, (1’S,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol which may be produced and hereinafter collectively referred to as "CBD-PET".

[0015]

[0015] Another perrottetinene-like compound is a CBD analog of PET-OH or 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol. This is i) the (-) trans isomer, (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, ii) the (+) trans isomer, (1’S,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, iii) the (-) cis isomer, (1’R,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, or iv) the (+) cis isomer, (1’S,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol and may be produced as, hereinafter collectively referred to as "CBD-PET-OH".

[0016]

[0016] The literature search for CBD analogs of PET was conducted by Crombie in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972~1999) (1988), (5), 1263~70, as well as

[0017] EP2314580;

[0018] US2019023680;

[0019] WO2014177593;

[0020] WO2017011210;

[0021] WO2017181118; and

[0022] WO2017216362 Some patent references including the above were identified.

Summary of the Invention

Problems to be Solved by the Invention

[0017]

[0023] The object of the present invention is to identify, manufacture and test perrottetinen-like compounds that may be used as pharmaceuticals.

Means for Solving the Problems

[0018]

[0024] Two such compounds described herein, designated CBD-PET and CBD-PET-OH, were manufactured and tested as potential drugs and were found to have potentially useful pharmacological effects.

[0019]

[0019] All publications, published patent applications, patents and other patent documents cited herein are hereby incorporated by reference in their entirety. This specification incorporates by reference the content and drawings of the US Provisional Patent Application (No. 63 / 003270) for which priority is claimed and which was filed on March 31, 2020.

[0020]

[0025] According to a first aspect of the present invention, there is provided a compound which is 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET) or 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET-OH), or a salt or hydrate thereof.

[0021]

[0026] In one aspect, CBD-PET is the (-) trans form, namely (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET) or (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0022]

[0027] In another aspect, CBD-PET is the (+) trans form, namely (1’S,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0023]

[0028] In yet another aspect, CBD-PET is the (-) cis form (1’R,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0024]

[0029] In yet another aspect, CBD-PET is the (+) cis form, namely (1’S,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0025]

[0030] In one aspect, CBD-PET-OH is the (-) trans form, namely (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0026]

[0031] In another aspect, CBD-PET-OH is the (+) trans form, i.e., (1’S,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0027]

[0032] In yet another aspect, CBD-PET-OH is the (-) cis form, i.e., (1’R,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0028]

[0033] In yet another aspect, CBD-PET-OH is the (+) cis form, i.e., (1’S,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol.

[0029]

[0034] Preferably, CBD-PET and / or CBD-PET-OH are of pharmaceutical grade.

[0035] As used herein, pharmaceutical grade means that CBD-PET and / or CBD-PET-OH are in a form required by the pharmaceutical regulatory authorities of the jurisdiction. Preferably, CBD-PET and / or CBD-PET-OH have a purity of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, more preferably at least 98%, and most preferably at least 99%.

[0030]

[0036] In one aspect, CBD-PET and / or CBD-PET-OH are present mostly as the p-isomer.

[0037] In another aspect, CBD-PET and / or CBD-PET-OH are present mostly as the o-isomer.

[0031]

[0038] By "substantially" is preferably meant that more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, and more preferably more than 95% of the compound is present in the specified isomeric form.

[0032]

[0039] In a further aspect, CBD-PET and / or CBD-PET-OH are present as a racemic mix of either the trans or cis isomer and / or the two position p or o-isomers, in the (+) or (-) form. Preferably, the mix is in a controlled ratio, for example, between a ratio of 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3 or 2:1 to 1:2.

[0033]

[0040] According to a second aspect of the invention, CBD-PET and / or CBD-PET-OH are provided for use in a medicament or as a medicine.

[0041] In a first aspect, CBD-PET and / or CBD-PET-OH is the (-) trans isomer.

[0034]

[0042] In a second aspect, CBD-PET and / or CBD-PET-OH is the (+) trans isomer.

[0043] In a third aspect, CBD-PET and / or CBD-PET-OH is a racemic mix of the (-) trans and (+) trans isomers.

[0035]

[0044] In a fourth aspect, CBD-PET and / or CBD-PET-OH is the (-) cis isomer.

[0045] In a fifth aspect, CBD-PET and / or CBD-PET-OH is the (+) cis isomer.

[0036]

[0046] In a sixth aspect, CBD-PET and / or CBD-PET-OH is a racemic mix of the (-) cis and (+) cis isomers.

[0047] In a preferred first embodiment, the compound is CBD-PET (Figure 2f), more specifically (-)-trans-CBD-PET (Figure 2b).

[0037]

[0048] Alternatively, this may be (+) trans-CBD-PET (Figure 2c), (-)-cis-CBD-PET (Figure 2d) or (+)-cis-CBD-PET (Figure 2e), or a racemic mixture of the respective (+) and (-) isomers.

[0038]

[0049] In a preferred second embodiment, the compound is CBD-PET-OH (Figure 3f), more specifically (-)-trans-CBD-PET-OH (Figure 3b).

[0050] Alternatively, this may be (+) trans-CBD-PET-OH (Figure 3c), (-)-cis-CBD-PET-OH (Figure 3d) or (+)-cis-CBD-PET-OH (Figure 3e) (+) and (-) isomers, or a racemic mixture of the respective (+) and (-) isomers.

[0039]

[0051] In both preferred embodiments, the para (p) isomer was preferentially selected over the other ortho (o) isomer. However, in further embodiments, the ortho (o) isomer may be preferentially selected over the other para (p) isomer.

[0040]

[0052] The compounds of preferred embodiments 1 and 2 may exist as pure or substantially pure isomers, or as a racemic mixture having the respective isomers in a specified ratio. As used herein, substantially pure may mean that the isomer has a purity of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, and more preferably at least 98%, and most preferably at least 99%.

[0041]

[0053] Most preferably, the substantially pure isomer is (-) trans as opposed to the (+) trans isomer.

[0054] In yet another aspect, metabarriants of CBD-PET and / or CBD-PET-OH can be generated or selected.

[0042]

[0055] According to a third aspect of the invention, there is provided a pharmaceutical composition comprising CBD-PET and / or CBD-PET-OH, preferably together with one or more pharmaceutically acceptable excipients.

[0043]

[0056] CBD-PET and / or CBD-PET-OH can exist as (-) or (+) trans or (-) or (+) cis isomers, or as racemic mixtures of their respective (+) or (-) trans or (+) or (-) cis forms.

[0044]

[0057] The compound can exist, for example, as a salt, hydrate, free acid or base, or other form in order to improve its bioavailability or other characteristics.

[0058] The composition can be formulated for delivery by any standard pharmaceutical route including parenteral (intraperitoneal, intravenous, intramuscular and subcutaneous), oral, nasal including nasogastric, intraocular, transmucosal (oral, intravaginal and rectal) and / or transdermal.

[0045]

[0059] The identified active pharmaceutical agent, namely CBD-PET and / or CBD-PET-OH and / or a pharmaceutically acceptable salt or hydrate thereof, is particularly suitable for treating seizures and / or epilepsy. This is based on results obtained in two well understood animal models of seizures.

[0046]

[0060] The pentylenetetrazole (PTZ) model (PTZ is a GABA receptor antagonist) is a model of generalized seizures (as opposed to partial or focal seizures). It generates absence (petit mal) seizures, tonic seizures, or myoclonic seizures during the interictal period. As a generalized seizure model, it has features that distinguish it from the maximal electroshock (MES) seizure model (which is also a model of generalized seizures).

[0047]

[0061] In epilepsy, myoclonic seizures usually cause abnormal movements simultaneously on both sides (left and right) of the body. They occur in various epilepsy syndromes with different characteristics.

[0048]

[0062] Juvenile myoclonic epilepsy (JME): The seizures usually involve the neck, shoulders, and upper arms. In many patients, the seizures most often occur soon after waking up. They usually begin around puberty or sometimes in early adulthood in people with a normal range of intelligence. In most cases, these seizures can be well controlled with medication but must be continued throughout life.

[0049]

[0063] Lennox–Gastaut syndrome (LGS): This is a rare syndrome that usually includes other types of seizures. It begins in early childhood. Myoclonic seizures usually involve the neck, shoulders, upper arms, and often the face. They can be extremely strong and difficult to control.

[0050]

[0064] Progressive myoclonic epilepsy (PME): Rare syndromes in this category are characterized by a combination of myoclonic seizures and tonic seizures. Treatment usually is not very successful over the long term because the patient deteriorates over time.

[0051]

[0065] On the other hand, the maximal electroshock (MES) model is categorized as a model of generalized tonic seizures. When screening antiepileptic drug candidates, the MES model is an excellent tool for evaluating antiseizure characteristics compared to focal or partial seizures (psychomotor seizures).

[0052]

[0066] Tonic-clonic seizures can begin in one or both sides of the brain.

[0067] When they begin in both sides of the brain, they are called generalized onset motor seizures or generalized tonic-clonic seizures. Both terms mean the same thing.

[0053]

[0068] When they begin in one side of the brain and spread to affect both sides, the term focal onset bilateral tonic-clonic seizure is used.

[0069] Based on the statistically significant data obtained in these two seizure models, both compounds exhibit antiseizure activity.

[0054]

[0070] Both CBD-PET and CBD-PET-OH have been shown to be effective in the PTZ model. CBD-PET showed activity against both clonic and tonic seizures, and CBD-PET-OH was particularly effective against tonic seizures. The results were statistically significant.

[0055]

[0071] CBD-PET-OH was effective in the MES model and also showed statistically significant activity against clonic and / or tonic-clonic seizures.

[0072] In both cases, CBD-PET and CBD-PET-OH were used at a mouse dose of 200 mg / Kg, which is equivalent to a human equivalent dose of 200×0.08 = 16 mg / Kg, or a dose of 960 mg in a "typical" adult of 60 Kg body weight, based on the FDA conversion factor - see https: / / www.fda.gov / media / 72309 / download (incorporated by reference).

[0056]

[0073] Based on this initial data, it may be possible to predict the human dosage to be on the order of 8 mg / Kg to 32 mg / Kg, or as an intermediate dosage between, for example, 480 mg to 1920 mg for a 60 Kg patient or 12 mg / Kg to 24 mg / Kg, or as a dosage of 720 mg to 1440 mg for a 60 Kg patient.

[0057]

[0074] According to a fourth aspect of the invention, there is provided a method of treating a subject, the method comprising administering to a patient an effective amount of CBD-PET and / or CBD-PET-OH in a unit dosage form.

[0058]

[0075] The patient may be an adult, pediatric, neonatal or infant or adult or juvenile animal, particularly a companion animal such as a dog or cat or horse.

[0076] In one aspect, the dosage is in the form of parenteral (intraperitoneal, intravenous, intramuscular and subcutaneous), oral, nasal including nasogastric, intraocular, transmucosal (oral, intravaginal and rectal), or transdermal.

[0059]

[0077] Preferably, the method of treatment is for treating seizures and / or epilepsy.

[0078] Seizures are classified as in the ILAE seizure classification 2017 as reproduced in the following table:

[0060]

Chemical formula

[0061]

[0079] The seizures to be treated may include one or more of the general onset seizures including myoclonic seizures, myoclonic-tonic-clonic seizures, tonic-clonic seizures, tonic seizures and / or tonic-clonic seizures.

[0062]

[0080] Epilepsy or epilepsy-related syndromes include, but are not limited to, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy.

[0063]

[0081] In one aspect, an effective dose for humans is a dose from 8 mg / Kg to 32 mg / Kg, or for a 60 Kg patient a dose from 480 mg to 1920 mg or an intermediate dose therebetween such as 12 mg / Kg to 24 mg / Kg, or for a 60 Kg patient a dose from 720 mg to 1440 mg.

[0064]

[0082] For companion animals such as dogs, cats and horses, the dose can be determined using standard conversion factors available to those skilled in the art.

[0083] A method for producing a perrottetinene-like compound according to a fifth aspect of the present invention, the method comprising reacting p-menthadienol with dihydropinosylvin or dihydroresveratrol in the presence of a Lewis acid, characterized in that the Lewis acid is zinc triflate.

[0065]

[0084] The applicant has surprisingly determined that zinc triflate and other Lewis acids can be more effective as catalysts providing much larger conversions, whereby a substantially larger yield of the desired enantiomer can be obtained.

[0066]

[0062] The present invention provides the following: [1] A compound which is (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET) or (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH). [2] The compound of [1], which is (-)-trans-CBD-PET. [3] The compound of [1], which is (-)-trans-CBD-PET-OH. [4] A compound according to any one of [1] to [3], which is substantially a pure p-isomer. [5] A compound according to any one of [1] to [3], which is substantially a pure o-isomer. [6] A compound according to any one of [1] to [3], which is a mixture of both p- and o-isomers. [7] A compound according to [4] or [5], wherein the isomer has a purity of more than 95%. [8] A compound according to [6], wherein the two isomers forming the mixture are present together with a purity of more than 95%. [9] A compound according to any one of [1] to [8] for use in a medicament.

[10] A pharmaceutical composition for treating a condition of seizure or epilepsy in a patient, the pharmaceutical composition comprising a compound according to any one of [1] to [8].

[11] A method for treating a condition of seizure or epilepsy in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of [1] to [8].

[12] A compound according to any one of [1] to [8] for use in the treatment of a condition of seizure or epilepsy in a patient.

[13] Use of a compound according to any one of [1] to [8] for the purpose of manufacturing a medicament for treating a condition of seizure or epilepsy in a patient.

[14] The pharmaceutical composition according to

[10] , the method according to

[11] , the compound for use according to

[12] or the use according to

[13] , wherein the condition to be treated is generalized epilepsy.

[15] The pharmaceutical composition according to

[10] , the method according to

[11] , the compound for use according to

[12] or the use according to

[13] , wherein the condition to be treated is myoclonic seizure.

[16] The pharmaceutical composition according to

[10] , the method according to

[11] , the compound for use according to

[12] or the use according to

[13] , wherein the condition to be treated is juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy.

[17] The pharmaceutical composition of

[10] , the method of

[11] , the compound for use according to

[12] , or the use of

[13] , wherein the state to be treated is an absence seizure, a tonic seizure, or a tonic - clonic seizure.

[18] The pharmaceutical composition according to any one of

[10] -

[17] , the method according to any one of

[11] -

[17] , the compound for use according to any one of

[12] -

[17] , or the use according to any one of

[13] -

[17] , wherein the compound is packaged or delivered in an effective dose via one of the following routes: parenteral, oral, nasal including nasogastric, intraocular, transmucosal, or transdermal.

[19] The pharmaceutical composition according to any one of

[10] -

[18] , the method according to any one of

[11] -

[18] , the compound for use according to any one of

[12] -

[18] , or the use according to any one of

[13] -

[18] , wherein the patient is a human patient.

[20] The pharmaceutical composition according to any one of

[10] -

[19] , the method according to any one of

[11] -

[19] , the compound for use according to any one of

[12] -

[19] , or the use according to any one of

[13] -

[19] , wherein the compound is administered to the patient at a dose of at least 8 mg / Kg.

[21] A method for producing a perrottetinene - like compound, comprising reacting menthadienol with dihydropinosylvin or dihydroresveratrol in the presence of, for example, a Lewis acid (step).

[22] The method of

[21] , wherein the Lewis acid is a zinc - based acid.

[23] The method of

[22] , wherein the zinc - based acid is zinc triflate.

[24] The method of

[23] , wherein the initial amount of zinc triflate is 0.01 - 0.05 molar equivalents of menthadienol.

[25] The method according to any one of

[21] -

[24] , wherein the reaction of menthadienol with dihydropinosylvin or dihydroresveratrol occurs at a temperature in the range of 80 - 120°C.

[26] When menthadienol reacts with dihydropinosylvin, a method according to any one of

[21] to

[24] wherein the perrottetinene-like compound is (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET).

[27] When menthadienol reacts with dihydroresveratrol, a method according to any one of

[21] to

[24] wherein the perrottetinene-like compound is (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH).

[28] The method of

[27] , further comprising the step of generating dihydroresveratrol by hydrogenating trans-resveratrol in the presence of palladium on carbon (Pd / C).

[0067]

[0063] The present invention also provides the following: [1a] (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET) or (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH). [2a] CBD-PET as described in [1a], which is (-)-trans-CBD-PET (Figure 2). [3a] CBD-PET-OH as described in [1a], which is (-)-trans-CBD-PET-OH (Figure 3). [4a] CBD-PET or CBD-PET-OH as described in any of [1a] to [3a], present as a substantially pure p-isomer. [5a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [3a], existing as a substantially pure o-isomer. [6a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [3a], existing as a mix of both p and o isomers. [7a] CBD-PET or CBD-PET-OH as described in [4a] or [5a], where the isomer exists with a purity of more than 95%. [8a] CBD-PET or CBD-PET-OH as described in [6a], where the two isomers forming the mix exist together with a purity of more than 95%. [9a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [8a], for use in a medicament. [10a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [9a], where CBD-PET or CBD-PET-OH is packaged or delivered in an effective dose by one of the following routes: parenteral, oral, nasal including nasogastric, intraocular, transmucosal or transdermal. [11a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [10a], for use in the treatment of seizures or epilepsy. [12a] CBD-PET or CBD-PET-OH as described in [11a], for use in the treatment of generalized epilepsy. [13a] CBD-PET or CBD-PET-OH as described in [12a], for use in the treatment of myoclonic seizures. [14a] CBD-PET or CBD-PET-OH as described in [13a], for use in the treatment of juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy. [15a] CBD-PET or CBD-PET-OH as described in [12a], for use in the treatment of absence, tonic or tonic-absence seizures. [16a] CBD-PET or CBD-PET-OH as described in any of [1a] to [15a], delivered at a dose of at least 8 mg / Kg. [17a] A pharmaceutical composition comprising CBD-PET or CBD-PET-OH together with one or more pharmaceutical excipients. [18a] A method of treating a subject, the method comprising administering to a patient an effective amount of CBD-PET or CBD-PET-OH in a unit dosage form. [19a] The method as described in [18a], wherein the subject is an adult, pediatric, neonatal or infant or adult or juvenile animal, particularly a companion animal such as a dog. [20a] A method for producing a perrottetinene-like compound, the method comprising reacting p-menthadienol with dihydropinosylvin or dihydroresveratrol in the presence of a Lewis acid, characterized in that the Lewis acid is zinc triflate.

[0068]

[0064] [1b] The following structure

[0069]

Chemical formula

[0070] 5'-Methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Figure 2f) having the following structure The following structure

[0071]

Chemical formula

[0072] 4-(4-Hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Figure 3f) having the following structure A compound selected from any one of the group consisting of, or a pharmaceutically acceptable salt or hydrate thereof. [2b] The following structure

[0073]

Chem.

[0074] The compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof, which is 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET) (Figure 2f). [3b] 4-(4-Hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET-OH) (Figure 3f)

[0075]

Chem.

[0076] The compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof, which is as follows. [4b] (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((−)trans-CBD-PET) (Figure 2b)

[0077]

Chem.

[0078] The compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof, which is as follows. [5b] (1’S,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+)-cis-CBD-PET) (Figure 2c)

[0079]

Chem.

[0080] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [6b] (1’R,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((−)cis-CBD-PET) (Figure 2d)

[0081]

Chemical formula

[0082] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [7b] (1’S,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+)cis-CBD-PET) (Figure 2e)

[0083]

Chemical formula

[0084] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [8b] (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((−)trans-CBD-PET-OH) (Figure 3b)

[0085]

Chemical formula

[0086] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [9b] (1’S,2’S)-4-(4-Hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+) cis-CBD-PET-OH) (Figure 3c)

[0087]

Chem.

[0088] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [10b] (1’R,2’S)-4-(4-Hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((-) cis-CBD-PET-OH) (Figure 3d)

[0089]

Chem.

[0090] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [11b] (1’S,2’R)-4-(4-Hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+) cis-CBD-PET-OH) (Figure 3e)

[0091]

Chem.

[0092] is the compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof. [12b] Structure:

[0093]

Chem.

[0094] The compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof, which is the o-isomer of trans-CBD-PET having [13b] Structure:

[0095] [Chemical formula]

[0096] The compound of [1b], or a pharmaceutically acceptable salt or hydrate thereof, which is the o-isomer of trans-CBD-PET-OH having [14b] A compound according to any one of [1b] to [13b], which exists as a substantially pure isomer. [15b] A compound according to any one of [1b] to [13b], which exists as a racemic mixture of isomers. [16b] A compound according to any one of [1b] to [13b], which is a substantially pure p-isomer. [17b] A compound according to any one of [1b] to [13b], which is a substantially pure o-isomer. [18b] A compound of [16b] or [17b], wherein the isomer has a purity of more than 95%. [19b] A compound according to any one of [1b] to [13b], which is a mixture of both p- and o-isomers. [20b] A compound of [19b], wherein the two isomers forming the mixture are present together with a purity of more than 95%. [21b] A compound according to any one of [1b] to [20b] for use in a medicament. [22b] A pharmaceutical composition for treating a condition of seizure or epilepsy in a patient, comprising a compound according to any one of [1b] to [20b]. [23b] A method for treating a condition of seizure or epilepsy in a patient, comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of [1b] to [20b]. [24b] A compound according to any one of [1b] to [20b] for use in the treatment of a condition of seizure or epilepsy in a patient. [25b] Use of a compound according to any one of [1b] to [20b] for the manufacture of a medicament for treating a condition of seizure or epilepsy in a patient. [26b] The medicament composition of [22b], the method of [23b], the compound for use according to [24b] or the use of [25b], wherein the condition to be treated is general epilepsy. [27b] The medicament composition of [22b], the method of [23b], the compound for use according to [24b] or the use of [25b], wherein the condition to be treated is myoclonic seizure. [28b] The medicament composition of [22b], the method of [23b], the compound for use according to [24b] or the use of [25b], wherein the condition to be treated is juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy. [29b] The medicament composition of [22b], the method of [23b], the compound for use according to [24b] or the use of [25b], wherein the condition to be treated is absence seizure, tonic seizure or tonic-absence seizure. [30b] The medicament composition according to any one of [22b] to [29b], the method according to any one of [23b] to [29b], the compound for use according to any one of [24b] to [29b] or the use according to any one of [25b] to [29b], wherein the compound is packaged or delivered in an effective dose via one of the following routes: parenteral, oral, nasal including nasogastric, intraocular, transmucosal or transdermal. [31b] The medicament composition according to any one of [22b] to [30b], the method according to any one of [23b] to [30b], the compound for use according to any one of [24b] to [30b] or the use according to any one of [25b] to [30b], wherein the patient is a human patient. [32b] A pharmaceutical composition in accordance with any one of [22b] to [31b], a method in accordance with any one of [23b] to [31b], a compound for use in accordance with any one of [24b] to [31b], or a use in accordance with any one of [25b] to [31b], wherein the compound is administered to a patient at a dose of at least 8 mg / Kg. [33b] A method for producing a perrottetinene-like compound, the method comprising reacting menthadienol with dihydropinosylvin or dihydroresveratrol in the presence of a Lewis acid. [34b] The method of [33b], wherein the Lewis acid is a zinc-based acid. [35b] The method of [34b], wherein the zinc-based acid is zinc triflate. [36b] The method of [35b], wherein the initial amount of zinc triflate is 0.01 to 0.05 molar equivalents of menthadienol. [37b] The method according to any one of [33b] to [36b], wherein the reaction of menthadienol with dihydropinosylvin or dihydroresveratrol occurs at a temperature in the range of 80 to 120 °C. [38b] The method according to any one of [33b] to [36b], wherein when menthadienol reacts with dihydropinosylvin, the perrottetinene-like compound is (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET). [39b] The method according to any one of [33b] to [36b], wherein when menthadienol reacts with dihydroresveratrol, the perrottetinene-like compound is (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH). [40b] The method of [39b], further comprising the step of producing dihydroresveratrol by hydrogenating trans-resveratrol in the presence of palladium on carbon (Pd / C). A method according to any one of [33b] to [40b], wherein the menthadienol is p-menthadienol.

[0097]

[0085] Hereinafter, aspects of the present invention will be further described with reference to the accompanying drawings.

Brief Description of the Drawings

[0098]

Figure 1

[0086] FIG. 1 is a general scheme for the synthesis of analogs including but not limited to CBD-PET and hydroxy-substituted variants and subsequent ring closure to produce THC-PET and THC-PET-OH.

Figure 2a

[0087] FIG. 2a is a scheme for the synthesis of CBD-PET.

Figure 2b

[0088] FIG. 2b illustrates the (-) trans isomer.

Figure 2c

[0089] FIG. 2c illustrates the (+) trans isomer.

Figure 2d

[0090] FIG. 2d illustrates the (-) cis isomer.

Figure 2e

[0091] FIG. 2e illustrates the (+) cis isomer.

Figure 2f

[0092] FIG. 2f illustrates CBD-PET without stereochemistry.

Figure 3a

[0093] FIG. 3a is a scheme for the synthesis of CBD-PET-OH.

Figure 3b

[0094] FIG. 3b illustrates the (-) trans isomer.

Figure 3c

[0095] FIG. 3c illustrates the (+) trans isomer.

Figure 3d

[0096] FIG. 3d illustrates the (-) cis isomer.

Figure 3e

[0097] FIG. 3e illustrates the (+) cis isomer.

Figure 3f

[0098] FIG. 3f illustrates CBD-PET-OH without stereochemistry.

Figure 4

[0099] Figure 4 is a bar graph showing the latency to tonic hindlimb seizures for test compounds versus CBD as well as negative (vehicle) and positive control (phenytoin) in the MES mouse model of seizures.

Figure 5

[0100] Figure 5 is a bar graph showing the latency to interictal seizures for test compounds versus CBD as well as negative (vehicle) and positive control (diazepam) in the PTZ mouse model of seizures.

Figure 6

[0101] Figure 6 is a bar graph showing the latency to tonic hindlimb seizures for test compounds versus CBD as well as negative (vehicle) and positive control (diazepam) in the PTZ mouse model of seizures.

Figure 7

[0102] Figure 7 is HPLC data for (-)-trans-CBD-PET (p isomer).

Figure 8

[0103] Figure 8 is HPLC data for (-)-trans-CBD-PET (o isomer).

Figure 9

[0104] Figure 9 is HPLC data for (-)-trans-CBD-PET-OH (p isomer).

Figure 10

[0105] Figure 10 is HPLC data for (-)-trans-CBD-PET-OH (o isomer). DETAILED DESCRIPTION OF THE INVENTION

[0099] Compound

[0075] The present invention relates to the following structure

[0100]

Chemical formula

[0101] 5'-Methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Figure 2f) having the following structure The following structure

[0102]

Chem.

[0103] 4-(4-Hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Figure 3f) having Provided is a compound selected from the group consisting of, or a pharmaceutically acceptable salt or hydrate thereof. These compounds may hereinafter be collectively referred to as the compounds of the present invention or the inventive compounds.

[0104]

[0076] In one aspect, the compounds of the present invention have the following structure

[0105]

Chem.

[0106] 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET) (Figure 2f) having, or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compounds of the present invention are 4-(4-Hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET-OH) (Figure 3f)

[0107]

Chem.

[0108] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((−)-trans-CBD-PET) (Figure 2b)

[0109]

Chemical formula

[0110] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’S,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+)-cis-CBD-PET) (Figure 2c)

[0111]

Chemical formula

[0112] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’R,2’S)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((−)-cis-CBD-PET) (Figure 2d)

[0113]

Chemical formula

[0114] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’S,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+)-cis-CBD-PET) (Figure 2e)

[0115]

Chemical formula

[0116] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((-) trans-CBD-PET-OH) (Figure 3b)

[0117]

Chemical formula

[0118] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’S,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+) cis-CBD-PET-OH) (Figure 3c)

[0119]

Chemical formula

[0120] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’R,2’S)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((-) cis-CBD-PET-OH) (Figure 3d)

[0121]

Chemical formula

[0122] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is (1’S,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol ((+) cis-CBD-PET-OH) (Figure 3e)

[0123]

Chemical formula

[0124] or a pharmaceutically acceptable salt or hydrate thereof. In one aspect, the compound of the present invention is as follows:

[0125]

Chemical formula

[0126]

Chemical formula

[0127]

Chemical formula

[0128]

Chemical formula

[0129] Any one or at least one thereof, or a pharmaceutically acceptable salt or hydrate thereof may be used. In one aspect, the compound of the present invention is as follows:

[0130]

Chemical formula

[0131]

Chemical formula

[0132]

Chemical formula

[0133]

Chemical formula

[0134] Any one or at least one thereof, or a pharmaceutically acceptable salt or hydrate thereof may be used. In one aspect, the compound of the present invention may be (-)-trans-CBD-PET or (-)-trans-CBD-PET-OH.

[0135]

[0077] The compounds of the present invention may be substantially pure p-isomers or substantially pure o-isomers. As used herein, substantially pure means that the isomer has a purity of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, more preferably at least 98%, and most preferably at least 99%. The compounds of the present invention may be a mixture of both p- and o-isomers. When in a mixture of p- and o-isomers, each of the two isomers forming the mixture is, together, present at a purity of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, more preferably at least 98%, and most preferably at least 99%, preferably with a purity of more than 95%.

[0136]

[0078] Examples of pharmaceutically acceptable salts of the compounds of the present invention include alkali metal salts such as salts of sodium, potassium and lithium; alkaline earth metal salts such as salts of calcium and magnesium; metal salts such as salts of aluminum, iron, zinc, copper, nickel, cobalt, etc.; ammonium salts; organic amine salts such as salts of t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, piperazine, tetramethylammonium, tris(hydroxymethyl)aminomethane; hydrogen halide salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts and hydroiodide salts; inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonate salts such as methanesulfonate salts, trifluoromethanesulfonate salts and ethanesulfonate salts; aryl sulfonate salts such as benzenesulfonate salts and p-toluenesulfonate salts; organic acid salts such as acetate salts, malate salts, fumarate salts, succinate salts, citrate salts, tartrate salts, oxalate salts, maleate salts; and amino acid salts such as salts of glycine, lysine, arginine, ornithine, glutamic acid and aspartic acid. These salts can be produced by known methods. Alternatively, the compounds of the present invention contained in the compositions of the present invention may be in the form of their hydrates. Medical use

[0079] As demonstrated in the examples, the compounds are useful for treating a plurality of conditions. Accordingly, the present invention provides the compounds of the present invention for use in a medicament. In particular, for treating conditions which are seizures or epilepsy, the present invention provides: (a) A pharmaceutical composition for treating a condition which is a seizure or epilepsy in a patient, the pharmaceutical composition comprising a compound of the present invention, namely CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof. (b) A method for treating a patient in a seizure or epilepsy state, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, namely CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof. (c) A compound of the present invention, namely CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment of a seizure or epilepsy state in a patient. (d) Use of a compound of the present invention, namely CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof, for the purpose of manufacturing a medicament for treating a patient in a seizure or epilepsy state.

[0137]

[0080] In one aspect, the pharmaceutical composition of (a) may further comprise a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" as used herein includes any substance used as a vehicle for delivering the active ingredient to a subject, and any substance added to the active ingredient, for example, to improve its handling properties or to enable the resulting composition to be formed into an orally deliverable unit dose having the desired shape and viscosity. Excipients include, by way of illustration and not limitation, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, flow promoters, substances added to mask or counteract an unpleasant taste or odor, flavoring agents, dyes, substances added to improve the appearance of the dosage form, and any other substance other than the active ingredient conventionally used in the preparation of oral dosage forms.

[0138]

[0081] In one aspect, for the pharmaceutical composition of (a), the method of (b), the compound for use according to (c) or the use of (d), the condition to be treated may be generalized epilepsy or juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy.

[0139] In another aspect, for the pharmaceutical composition of (a), the method of (b), the compound for use according to (c), or the use of (d), the condition to be treated may be myoclonic seizures, absence seizures, tonic seizures, or tonic-clonic seizures.

[0140] For the pharmaceutical composition of (a), the method of (b), the compound for use according to (c), or the use of (d), the administration may be determined by one of ordinary skill in the art according to the specific condition being treated and the patient. Exemplary routes include intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, oral administration, tissue administration, transdermal administration, and the like. In one aspect, the composition of the present invention of (a) or the compound of the present invention may be administered via a parenteral, oral, nasal including nasogastric, intraocular, transmucosal, or transdermal route.

[0141] Also, the dosage forms available for the composition of the present invention of (a) or the compound of the present invention are not particularly limited and include, for example, injectables, injections, oral agents, drip agents, creams, inhalants, ointments, lotions, and the like.

[0142] The patient to be treated by the pharmaceutical composition of (a), the method of (b), the compound for use according to (c), or the use of (d) is not particularly limited and includes humans; domestic animals such as female cows, sheep, horses, goats, llamas, kangaroos, and pigs; pet animals such as dogs, cats, rabbits, and birds; and zoo animals such as lions, elephants, giraffes, and bears. In one aspect, the patient to be treated is a human.

[0143]

[0086] The appropriate dosage for administering the compounds of the present invention can be determined by those skilled in the art based on the descriptions and data provided herein. Guidance for converting appropriate dosages for animal models to appropriate dosages for humans is known to those skilled in the art. Examples of such dosage conversions are provided in Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, July 2005). Specifically, a dosage of 200 mg / Kg for mice for CBD-PET and CBD-PET-OH is equivalent to a human equivalent dosage of 200×0.08 = 16 mg / Kg, or a dosage of 960 mg for an "average" adult weighing 60 Kg. Based on this initial data, the human dosage might be predicted to be on the order of 8 mg / Kg to 32 mg / Kg, or an intermediate dosage between, for example, 480 mg to 1920 mg for a 60 Kg patient or 12 mg / Kg to 24 mg / Kg, or a dosage of 720 mg to 1440 mg for a 60 Kg patient. Dosages for heavier human patients or lighter patients such as children can be appropriately determined based on the disclosure provided herein. In one aspect, the compounds of the present invention can be administered to a patient at a dosage of at least 8 mg / Kg.

[0144]

[0087] The pharmaceutical composition of (a) may further contain a pharmaceutically acceptable carrier. The concentration of the compound of the present invention contained in the pharmaceutical composition of (a) may vary depending on the type of carrier, etc., and is suitably in the range of 0.1 nM to 100 μM, preferably in the range of 1 nM to 10 μM, more preferably in the range of 10 nM to 1 μM.

[0145]

[0088] In addition to the compounds of the present invention, the pharmaceutical composition of (a) may further contain one or more pharmaceutically acceptable additives. Examples of such additives are emulsifying aids (e.g., fatty acids having 6 to 22 carbon atoms and their pharmaceutically acceptable salts, albumin and dextran), stabilizers (e.g., cholesterol and phosphatidic acid), isotonic agents (e.g., sodium chloride, glucose, maltose, lactose, sucrose, trehalose), and pH adjusters (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide and triethanolamine). One or more of these additives can be used. The content of the additive in the composition of the present invention is suitably 90 wt% or less, preferably 70 wt% or less, more preferably 50 wt% or less. Synthesis method

[0089] The present invention provides a synthesis method for producing a perrottetinene-like compound such as the compound of the present invention, which comprises reacting menthadienol with dihydropinosylvin or dihydroresveratrol in the presence of, for example, a Lewis acid (step). The step (hereinafter referred to as the "alkylation step") enables the alkylation of menthadienol with dihydropinosylvin or dihydroresveratrol, thereby producing a perrottetinene-like compound.

[0146]

[0090] In one aspect, when menthadienol reacts with dihydropinosylvin, the perrottetinene-like compound produced by the method of the present invention is (1’R,2’R)-5’-methyl-4-phenethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET). In one aspect, when menthadienol reacts with dihydroresveratrol, the perrottetinene-like compound produced by the method of the present invention is (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH). In one aspect, menthadienol is para (p-) menthadienol.

[0147]

[0091] The Lewis acid used is H + 、K + 、Zn 2+ 、Mg 2+ 、Fe 3+ 、BF3、Sc 3+ 、CO2、SO3、RMgX (wherein R is a hydrocarbon radical such as CH3, C2H5 or C6H5, and X is a halogen atom such as chlorine, bromine or iodine), AlCl3 and Br2. Further examples of Lewis acids used in the method include Zn(OTf)2, p-TsOH.H2O, BF3OEt2, BF3OEt2 - Al2O3; and Sc(OTf)3. In one aspect, the Lewis acid used in the synthesis method may be a zinc (or BF3) - containing or base acid. In a further aspect, the zinc-based acid may include zinc triflate (Zn(OTf)2).

[0148]

[0092] In one aspect, the initial or starting amount of the Lewis acid (added in the alkylation step) may be 0.005 to 0.10, 0.005 to 0.09, 0.005 to 0.08, 0.005 to 0.07, 0.005 to 0.06, 0.005 to 0.05, 0.005 to 0.04, 0.005 to 0.03, 0.005 to 0.025, 0.01 to 0.10, 0.01 to 0.09, 0.01 to 0.08, 0.01 to 0.07, 0.01 to 0.06, 0.01 to 0.05, 0.01 to 0.04, 0.01 to 0.03, 0.01 to 0.025, 0.015 to 0.10, 0.015 to 0.09, 0.015 to 0.08, 0.015 to 0.07, 0.015 to 0.06, 0.015 to 0.05, 0.015 to 0.04, 0.015 to 0.03 or 0.015 to 0.025 molar equivalents of menthadienol. In one aspect, the initial amount of the Lewis acid added in the alkylation step may be 0.02 molar equivalents of menthadienol.

[0149]

[0093] In one aspect, the alkylation step, i.e., the reaction of menthadienol with dihydropinosylvin or dihydroresveratrol, occurs at a temperature below the range of 60 to 140 °C, 60 to 130 °C, 60 to 120 °C, 70 to 140 °C, 70 to 130 °C, 70 to 120 °C, 80 to 140 °C, 80 to 130 °C, 80 to 120 °C, 90 to 110 °C or 95 to 105 °C. In one aspect, the alkylation step occurs at a temperature in the range of 80 to 120 °C. In one aspect, the alkylation step occurs at a temperature of 100 °C.

[0150]

[0094] When the perrottetinene-like compound produced by the method of the present invention is (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET-OH), the method of the present invention may further include the step of producing dihydroresveratrol by hydrogenating trans-resveratrol in the presence of palladium on carbon (Pd / C).

Examples

[0151]

[0106] The first step was to prepare CBD-PET and CBD-PET-OH.

[0107] The compounds of the present invention were generated by the general scheme approach illustrated in Figure 1, as well as the schemes and compounds shown in Figures 2a-f and 3a-f, respectively. General methodology

[0108] Initial target compounds: i) (-) trans-CBD-PET, and ii) (-) trans-CBD-PET-OH The main step in the preparation of was preferably the Friedel-Crafts alkylation of p-menthadienol with the required resorcinol / biphenyl compound.

[0152]

[0109] Dihydropinosylvin was commercially available, but dihydroresveratrol required the hydrogenation of readily available resveratrol under standard conditions. Process-Scheme 1 described in Figure 1 produced approximately equal amounts of p and o-isomers and required extensive chromatography to separate them from each other and other minor by-products.

[0153]

[0110] Finally, the synthesis of (-)-trans-THC-PET was carried out by the boron trifluoride diethyl etherate-mediated cyclization of (-)-trans-CBD-PET, which affected the formation of the pyran ring.

[0154]

[0100] Hereinafter, the present invention will be described in more detail with reference to the following examples, but it should not be considered limited thereto. Example 1 Preparation of (-) trans-CBD-PET

[0101] The initial preparation of (-) trans-CBD-PET was ·Zn(OTf)2; ·p-TsOH.H2O; ·BF3OEt2; ·BF3OEt2 - Al2O3; and ·Sc(OTf)3 Based on the use of a number of different Lewis acids including , the reaction conditions for the coupling of dihydropinosylvin and p-menthadienol are literature-based (Figure 2 - Scheme 2).

[0155]

[0102] The use of the original Crombie et al. conditions (p-TsOH·H2O in toluene); reference: J. Chem. Soc. Perkin. Trans I, 1988, 1263 - 1270 was carried out, but only 25% of the selected (-)-trans-CBD-PET (p-isomer) was produced along with 10% of another o-isomer.

[0156]

[0103] The Lewis acids commonly used for this transformation, boron trifluoride diethyl etherate (BF3·OEt2) and BF3·OEt2-alumina (reference: Tet. Lett. 1985, 26, 1083 - 1086) were examined and found to give less than 30% yields of the desired product. The alumina-mediated conditions produced unknown isomeric compounds which did not match the 1H NMR of any of the compounds reported in the literature.

[0157]

[0104] The use of Sc(OTf)3 (reference: WO2007041167) at either 20 °C or below 0 °C gave yields comparable to p-TsOH and BF3·OEt2 and another o-isomer.

[0158] The use of Zn(OTf)2 in toluene at 100 °C with added excess dihydropinosylvin (see WO2019046806) led to complete consumption of p-menthadienol, but some dihydropinosylvin remained. LCMS analysis showed the presence of multiple peaks with m / z = 349 corresponding to the desired product and several peaks with m / z = 497 consistent with bis-alkylation by-products. After flash chromatography purification, two main spots were isolated and characterized. Based on their 1H NMR spectra, which were consistent with published data (Crombie et al., J. Chem. Soc. Perkin. Trans I, 1988, 1263 - 1270), the less polar spot was identified as the desired (-)-trans-CBD-PET (p-isomer), and the more polar spot was confirmed as the o-isomer of (-)-trans-CBD-PET. This initial reaction provided 42% of the desired p-isomer and 39% of the o-isomer.

[0159]

[0106] This Lewis acid, Zn(OTf)2, has proven to be significantly more efficient than others referenced in the literature and was used in the production. Preparation of (-)-trans-CBD-PET for in vivo testing

[0107] The 2 L three-necked reactor was equipped with a magnetic stirrer, a reflux condenser, a thermocouple, and a nitrogen inlet. Dihydropinosylvin (116.1 g, 0.54 mol, 1.10 eq) was charged into the reactor as a solid under a nitrogen atmosphere, followed by toluene (750 mL, 10 volumes). The resulting solution was heated to 80 °C over 20 minutes, then Zn(OTf)2 (3.6 g, 0.010 mol, 0.020 eq), followed by p-menthadienol (75.0 g, 0.490 mol, 1.00 eq) in toluene (375 mL, 5.0 volumes) were added. The reaction mixture was then heated to 100 °C and the progress was monitored by TLC. After 1 hour at 100 °C, complete consumption of p-menthadienol was observed and the batch was cooled to 50 - 55 °C. The reaction was quenched by the slow (5 - 10 minutes) addition of water (150 mL), then cooled to 20 °C. The mixture was stirred at 20 °C for an additional 5 - 10 minutes, then the layers were separated. The aqueous layer was discarded and the organic solvent was removed under reduced pressure. The resulting crude oil was purified by flash column chromatography on silica gel in two batches eluting slowly with 0 - 30% EtOAc / heptane [gradient: 1 × 2 L of 100% heptane; 1 × 2 L of 5% EtOAc - heptane; 1 × 2 L of 12% EtOAc - heptane (start of p-isomer elution); 2 × 2 L of 10% EtOAc - heptane (end of p-isomer elution); 1 × 2 L of 15% EtOAc - heptane; 1 × 2 L of 20% EtOAc - heptane (start of o-isomer elution); 1 × 4 L of 25% EtOAc - heptane (end of o-isomer elution)] (Biotage KP-SIL 75-L cartridge; 1 kg of silica). The fractions containing the product (p-isomer) were combined and the solvent was removed under reduced pressure to give 60 g of (-)-trans-CBD-PET with 94% purity as a clear viscous oil. This material was further purified in three batches by combiflash (HP silica gel, 330 g gold cartridge) chromatography to yield (-)-trans-CBD-PET (40.3 g, 24% yield; lot number GSR-D-31-1-Figure 7) with 99.3% HPLC purity.Fractions from the Biotage column containing the o-isomer were pooled and concentrated under reduced pressure to give a transparent viscous oil (57.9 g, 34% yield; lot number GSR-D-31-2-Figure 8) of o-(-)-trans-CBD-PET with a purity of 99.1%. Identity was confirmed by 1H and 13 C NMR (500 MHz, CDCl3) after drying the material under high vacuum for 60 hours.

[0160] Example 2 Preparation of (-) trans-CBD-PET-OH The Zn(OTf)2 conditions utilized above for the preparation of CBD-PET were adapted for the synthesis of the 4-hydroxyphenethyl analog (CBD-PET-OH; (1’R,2’R)-4-(4-hydroxyphenethyl)-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2,6-diol, Figure 3 - Scheme 3). Commercially available resveratrol (1.0 equivalent) was hydrogenated in the presence of 10% Pd-C (2 wt%) using the reported procedure (US20160367498), resulting in a complete and clean conversion of resveratrol to dihydroresveratrol. In the first coupling trial, treatment of dihydroresveratrol (0.5 g) with p-menthadienol in the presence of Zn(OTf)2 (0.02 equivalent) under the same conditions showed a similar TLC reaction profile with complete consumption of p-menthadienol in 1 hour. LCMS analysis of the isolated crude product confirmed the presence of two peaks with m / z = 365 (M+1) representing the desired product (p-isomer) and byproduct (o-isomer), in addition to two additional peaks with m / z = 499 indicating the dialkylated product. The crude (-)-trans-CBD-PET-OH was purified by silica gel chromatography eluting with 0 - 40% EtOAc / heptane to yield (-)-trans-CBD-PET-OH (37% yield) and another o-isomer of (-)-trans-CBD-PET-OH (28% yield) as clear viscous oils. The structures of the isomers were assigned based on comparison of their NMR spectra with those reported in the literature (Crombie et al., J. Chem. Soc. Perkin. Trans I, 1988, 1263 - 1270). The main distinguishing feature of the 1H NMR spectrum of the selected p-isomer was the broadened signals of the 3’ and 5’ protons due to slow exchange involving rotation of the p-menthadienol core (see Scheme 1 for atom numbering). Similarly, the corresponding carbon atoms also showed broadened peaks in 13C NMR with significantly reduced peak heights. Consistent with the literature, such exchange or broadening of the proton or carbon signals was not observed for the more hindered o-position isomer. Preparation of (-)-trans-CBD-PET-OH for in vivo testing Step 1: Preparation of dihydroresveratrol

[0109] To a solution of trans-resveratrol (75.0 g, 0.33 mol, 1.00 equivalent) in EtOH (1120 mL, 15 volumes) in a metal pressure reactor was added 10% Pd / C (1.75 g, 0.0015 mol, 0.050 equivalent). The flask was purged with nitrogen to create an inert atmosphere and then with hydrogen gas. The reaction mixture was stirred at 20 °C for 16 h under a hydrogen (40 psi) atmosphere. Upon complete consumption of resveratrol, the mixture was filtered through a short pad of celite to remove Pd / C. The celite pad was washed with additional EtOH [3 × 300 mL (2 volumes)]. The combined filtrates were concentrated under reduced pressure to afford a clear oil which solidified to an off-white solid upon further drying under high vacuum. The identity of dihydroresveratrol (149.3 g, yield = 98%) was confirmed by 1H NMR and was consistent with the reported 1H NMR data in US20160367498. Step 2: Preparation of (-)-trans-CBD-PET-OH

[0110] The 2 L three-necked reactor was equipped with a magnetic stirrer, a reflux condenser, a thermocouple and a nitrogen inlet. Dihydroresveratrol (127 g, 0.550 mol, 1.10 eq) was added to the reactor as a solid under a nitrogen atmosphere, followed by toluene (800 mL). The mixture was heated to 80 °C over 20 min, and Zn(OTf)2 (3.84 g, 0.011 mol, 0.02 eq) was added, followed by p-menthadienol (80.0 g, 0.52 mol, 1.0 eq) in toluene (400 mL). The reaction mixture was then heated to 95 - 100 °C and the progress was monitored by TLC. After 1 h, TLC analysis showed complete consumption of p-menthadienol. The reaction mixture was cooled to 50 - 55 °C and quenched by the slow addition of water (160 mL). The batch was then further cooled to 20 °C. The mixture was stirred at 20 °C for an additional 5 - 10 min, then the layers were separated and the organic layer was collected. The solvent was removed under reduced pressure. The crude product was split into two batches and purified by flash chromatography using a Biotage KP-SIL 75 L column eluting slowly with 0 - 30% EtOAc - heptane [gradient: 2 x 2 L of 100% heptane; 2 x 2 L of 10% EtOAc - heptane; 2 x 2 L of 12% EtOAc - heptane; 3 x 4 L of 15% EtOAc - heptane (p-isomer elution); 2 x 4 L of 20% EtOAc - heptane (o-isomer elution); 1 x 4 L of 25% EtOAc - heptane; 1 x 2 L of 30% EtOAc - heptane]. Fractions containing the product (p-isomer) were combined and the solvent was removed under reduced pressure to yield p-(-)-trans-CBD PET-OH (39.3 g, 20% yield; lot number GSR-D-37-7) as a clear viscous oil with 97.4% purity by HPLC (Figure 9). Similarly, fractions containing the other o-isomer were pooled and concentrated under reduced pressure to give o-(-)-trans-CBD-PET-OH (43.9 g, 22% yield; lot number GSR-D-37-8) as a clear viscous oil with 99.3% purity by HPLC (Figure 10). Identity was confirmed by 1H NMR and 13C NMR (500 MHz, CDCl3) after drying the material under high vacuum for 60 h.

[0161]

[0111] Two exemplary compounds: A - (-)-trans - CBD - PET (p - isomer); and B - (-)-trans - CBD - PET - OH (p - isomer) were subjected to PK studies and tested in two exemplary seizure models, namely the PTZ and MES models of seizures. Animals

[0112] Species: Mouse Strain: ICR:CD - 1 Source of animals: Charles River Age or weight: 8 - 10 weeks Sex: Male Randomization: Animals were randomly assigned to treatment groups Blinding of the study: Investigators were blinded to the treatment. Housing and feeding

[0113] Acclimation / conditioning For more than 3 days Housing: Mice will be housed on a 12 - hour light / dark cycle (lights on at 7:00 AM) No more than 4 mice per cage depending on size Ventilated cage rack system Diet: Standard rodent solid diet and water ad libitum Design parameters PK study

[0114] Route of administration: Intraperitoneal (i.p.) Dose volume: 10 ml / kg Formulation: Vehicle for test compound and CBD: 1:1:18 ethanol:Cremophor (polyoxyl castor oil) EL:0.9% saline Dose level: 100 mg / kg Dose frequency: Once Study duration: 1 day

[0115] Time points for blood sampling: IP administration: 0.5 hour (30 minutes), 1 hour, 2 hours, Number of animals per group: 3 Number of samples for analysis: Nine blood samples per compound Total of 18 samples Total number of animals: 6

[0116] The above is summarized in Table 1 below:

[0162]

Table 2

[0163] The conversion of mouse dosage to human equivalent dosage in mg / Kg is by multiplying the mouse dosage by 0.08. MES study

[0117] Route of administration: Intraperitoneal (i.p.) and oral (p.o.) (phenytoin) Dosage volume: 10 ml / kg Formulation: Vehicle for test compound: 1:1:18 ethanol:Cremophor (polyoxyl castor oil) EL:0.9% saline Vehicle for phenytoin: 0.5% MC in water Dosage levels: 100 - 200 mg / kg (Table 2), phenytoin 60 mg / kg Dosage frequency: Once Study duration: 1 day Interval between dosing and evaluation: 30 minutes for test article and phenytoin, 60 minutes for CBD Number of animals per group: 10 Number of groups: 5 Total number of animals: 50

[0118] The above is summarized in Table 2 below.

[0164]

Table 3

[0165] PTZ study

[0119] Route of administration: Intraperitoneal (i.p.) and oral (p.o.) (diazepam) Dosage volume: 10 ml / kg Formulation: Vehicle for the test compound: 1:1:18 ethanol:Cremophor (polyoxyl castor oil) EL: 0.9% saline Vehicle for diazepam: 0.5% MC in water, 0.1% Tween 80 Dose levels: 100 - 200 mg / kg (Table 3), phenytoin 60 mg / kg Dose frequency: once Study duration: 1 day Interval between dosing and evaluation: 30 minutes for the test article and diazepam, 60 minutes for CBD Number of animals per group: 10 Number of groups: 5 Total number of animals: 50

[0120] The above is summarized in Table 3 below:

[0166]

Table 4

[0167] Method PK study

[0121] For the test of each compound, six CD-1 mice were divided into two groups of three mice each. The test agent was administered to the animals via the i.p. route, and blood was collected at 30, 60, and 120 minutes. The administration was as outlined in Table 1. Blood samples were collected into microcentrifuge tubes coated with EDTA, inverted, placed on an ice pack, and then centrifuged and stored at -70°C. The samples were extracted using the acetonitrile / protein precipitation method, and the levels of the test agent were analyzed by LC / MS / MS. Maximal electroshock (MES)

[0122] Animals were administered a vehicle, phenytoin, CBD, or a test compound, and overall behavioral observations were made over a 30-minute period. Proparacaine hydrochloride ophthalmic solution (Butler AHS, Dublin, OH) was applied approximately 10 minutes prior to the test to paralyze the eyes. Thirty to 60 minutes after administration of the vehicle, phenytoin, CBD, or test compound, 0.9% aqueous saline solution (sodium chloride in water) was applied to both eyes, and electroconvulsions were induced by alternating current delivered via corneal electrodes by a rodent shock generator (Harvard Apparatus, Holliston, MA) at a frequency of 60 Hz. Parameters for ICR:CD1 mice were a stimulus duration of 0.2 seconds at an intensity of 25 mA. The criterion for seizure occurrence was the presence of tonic hindlimb extension defined as extension beyond a 90-degree angle to the plane of the body. A 20-second cutoff latency was used for mice that did not seize. Any seizure activity prior to tonic hindlimb seizure (i.e., interictal seizure defined as rapid spasms or jerky movements of the limbs) was recorded as the presence of a seizure (noted as 1 - yes, 0 - no). After seizure presentation or a 20-second timeout, the mice were euthanized by cervical dislocation. PTZ-induced seizure

[0123] Mice were acclimated to the surgery room for at least 30 minutes. Pentylenetetrazol (PTZ; Sigma Aldrich) was formulated in water at a concentration of 20 mg / ml. PTZ was injected at a volume of 5 ml / kg to produce a final dose of 100 mg / kg. The PTZ injection was i.p. Diazepam was formulated at a concentration of 2 mg / ml and administered at a volume of 10 ml / kg to produce a final dose of 20 mg / kg. The time to the first myoclonic and tonic hindlimb extension responses was measured. A 10-minute maximum latency to seizure was imposed. Bioanalytical method development and sample bioanalysis

[0124] The bioanalytical detection method was developed using LC / MS / MS (ABI 5000 or 5500). Standard curves of the test agent were prepared in an appropriate biological matrix (plasma). The levels of the test article were measured as in the method developed in plasma. The level was determined by extrapolating the concentration from the standard curve using linear regression analysis. Method development and bioanalysis were performed by the partner company Keystone Bioanalytical (North Wales, PA, US). Data analysis

[0125] Data were expressed as mean + SEM. Statistical analysis using one-way ANOVA with Fisher's LSD post hoc test was used to determine statistical significance compared to vehicle-treated animals. Results PK study

[0126] Animals were treated according to Table 1, and the time course of (-)-trans-CBD-PET was illustrated by the measured concentration (ng / ml) of (-)-trans-CBD-PET in plasma after administration of 100 mg / kg i.p.

[0168]

Table 5

[0169]

[0127] Animals were treated according to Table 1, and the time course of (-)-trans-CBD-PET-OH was illustrated by the measured concentration (ng / ml) of (-)-trans-CBD-PET-OH in plasma after administration of 100 mg / kg i.p.

[0170]

[0128]

[0171]

Table 6

[0172] MES study

[0129] The results of the MES study are illustrated in Figure 4: MES: latency in seconds for seizures occurring in mice. Animals were treated according to Table 2. A 20-second time-out was recorded for any mouse that did not exhibit a tonic seizure. Data were expressed as arithmetic mean ± SEM. Data were analyzed by one-way ANOVA, followed by Fisher's LSD post hoc test. *** P < 0.001, * P < 0.05, n = 1 PTZ study

[0130] The results of the PTZ study are illustrated in Figure 5: PTZ: latency to myoclonic seizures. Animals were treated according to Table 3. Each bar graph represents the mean latency (seconds) + / − SEM. * P < 0.05, **** P < 0.0001, one-way ANOVA, followed by Fisher's LSD test, compared to vehicle-treated animals, n = 10 / group.

[0173]

[0131] In Figure 6: PTZ: latency to tonic hindlimb seizures. Animals were treated according to Table 3. Each bar graph represents the mean latency (seconds) + / − SEM. *** P < 0.001, **** P < 0.0001, one-way ANOVA, followed by Fisher's LSD test, compared to vehicle-treated animals, n = 10 / group. Conclusion

[0132] Pharmacokinetic time-course analysis for (−)-trans-CBD-PET and (−)-trans-CBD-PET-OH demonstrated that the maximum concentration in plasma was achieved 30 minutes after injection. The pretreatment time for (−)-trans-CBD-PET and (−)-trans-CBD-PET-OH for the MES and PTZ studies was determined to be 30 minutes.

[0174]

[0133] In the MES study, (-)-trans-CBD-PET was inactive. The (-)-trans-CBD-PET-OH effect was significantly different from the vehicle (p < 0.05). Phenytoin, the positive control for the study, demonstrated 100% protection from seizures (p < 0.05).

[0175]

[0134] PTZ administration produced clonic and tonic hindlimb seizures in animals treated with vehicle. Diazepam, the positive control for the study, produced significant protection from seizures (100%, Figures 5 and 6, p < 0.05).

[0176]

[0135] Administration of (-)-trans-CBD-PET produced significant protection from clonic seizures compared to vehicle-treated animals (p < 0.05).

[0136] Administration of (-)-trans-CBD-PET and (-)-trans-CBD-PET-OH produced a significant effect in protecting from tonic hindlimb seizures (p < 0.05).

[0177]

[0137] 100 mg / kg of cannabidiol administered 60 minutes before MES and PTZ did not produce a significant effect in the model (p > 0.05). The present invention includes, without limitation, the following aspects. [Aspect 1] The following structure

Chemical formula

Chemical formula

Claims

1. The following structure 【Chemical 1】 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol having the formula: [Chemical 2] and a pharmaceutically acceptable salt or hydrate thereof A compound selected from the group consisting of any one of the above.

2. 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (p-CBD-PET-OH): 【Chemical Formula 3】 or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

3. (1'R,2'R)-4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((−)trans-CBD-PET-OH): 【Chemical Formula 4】 or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

4. (1'S,2'S)-4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((+)cis-CBD-PET-OH): 【Chemical Formula 5】 or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

5. (1'R,2'S)-4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((−)cis-CBD-PET-OH): 【Chemical Formula 6】 or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

6. (1'S,2'R)-4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((+)cis-CBD-PET-OH): [Chemical Formula 7] or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

7. 【Fig. 8】 or a pharmaceutically acceptable salt or hydrate thereof, the compound according to claim 1.

8. Structure [Chemical Formula 9] or 【Chemical 10】 The compound according to claim 1, which is the o-isomer of CBD-PET-OH having the following, or a pharmaceutically acceptable salt or hydrate thereof.

9. The compound according to any one of claims 1 to 8, which exists as a racemic mixture of the respective (+) or (-) trans or (+) or (-) cis isomers.

10. The compound according to any one of claims 1 to 9, or the following structure 【Chemical Formula 11】 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol having the following, or 【Chemical Formula 12】 or a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients, a pharmaceutically acceptable salt or hydrate thereof.

11. 【Fig. 13】 Or the pharmaceutical composition according to claim 10, comprising a pharmaceutically acceptable salt or hydrate thereof.

12. 【Fig. 14】 Or the pharmaceutical composition according to claim 10, comprising a pharmaceutically acceptable salt or hydrate thereof.

13. A pharmaceutical composition for treating a condition of seizure or epilepsy in a patient, the compound according to any one of claims 1 to 9, or the following structure 【Chemical Formula 15】 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol having the following, or 【Chemical Formula 16】 , or the pharmaceutical composition as described above, comprising a pharmaceutically acceptable salt or hydrate thereof.

14. 【Fig. 17】 Or the pharmaceutical composition according to claim 13, comprising a pharmaceutically acceptable salt or hydrate thereof.

15. 【Fig. 18】 Or the pharmaceutical composition according to claim 13, comprising a pharmaceutically acceptable salt or hydrate thereof.

16. The compound according to any one of claims 1 to 9, or the following structure 【Chemical 19】 5'-methyl-4-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol having the following, or 【Chemical 20】 Or use for manufacturing a medicament for treating a condition of seizure or epilepsy of a pharmaceutically acceptable salt or hydrate thereof.

17. The use according to claim 16, wherein the compound is 【Chemical 21】 or a pharmaceutically acceptable salt or hydrate thereof, said use.

18. The use according to claim 16, wherein the compound is 【Chemical 22】 or a pharmaceutically acceptable salt or hydrate thereof, said use.

19. The pharmaceutical composition according to any one of claims 13 to 15, wherein the state to be treated is general epilepsy.

20. The pharmaceutical composition according to any one of claims 13 to 15, wherein the state to be treated is myoclonic seizure.

21. The pharmaceutical composition according to any one of claims 13 to 15, wherein the state to be treated is juvenile myoclonic epilepsy, Lennox–Gastaut syndrome and / or progressive myoclonic epilepsy.

22. The pharmaceutical composition according to any one of claims 13 to 15, wherein the state to be treated is absence seizure, tonic seizure and / or tonic–clonic seizure.

23. The pharmaceutical composition according to any one of claims 13 to 15 and claims 19 to 22, wherein the compound is packaged or delivered in an effective dose via one of the following routes: parenteral, oral, nasal including nasogastric, intraocular, transmucosal or transdermal.

24. The pharmaceutical composition according to any one of claims 13 to 15 and claims 19 to 23, wherein the patient is a human patient.

25. The pharmaceutical composition according to any one of claims 13 to 15 and claims 19 to 24, wherein the compound is administered to the patient at a dose of at least 8 mg / Kg.

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