Ternphenolic compounds and uses thereof

Abstract

The present disclosure describes terpenophenolic compounds and their use in medicine. The present disclosure also describes a Graptopetalum scapiforme-like compound, its preparation, formulations containing it, and its use in medicine. Such compounds include (1'R,2'R)-5'-methyl-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] The present invention relates to terpenophenolic compounds and their use in medicine. More particularly, the present invention relates to perrottetinene-like compounds, their manufacture, formulations containing them and their use in medicine. BACKGROUND

[0003] Perrottetinene (PET) is a naturally occurring compound found in native Radula species liverworts from Japan, New Zealand and Costa Rica, namely Radula perrottrtii, Radula marginata and Radula laxiramea.

[0004] It is a terpenophenolic compound comprising a terpenoid moiety (A), a substituted or unsubstituted phenol or resorcinol moiety (B) and a substituted or unsubstituted phenethylaryl side chain (C).

[0005] Its structure is shown below:

[0006]

[0007] Alternatively, (B) and (C) can be together referred to as a bibenzyl or dihydrostilbene, in which case the compound can be referred to as a terpenylated bibenzyl or terpenylated dihydrostilbene.

[0008] It can be prepared as a cis or trans isomer or as a racemic mixture of cis or trans isomers.

[0009] A recent paper Chicca et al. Sci Adv 2018 compared the activity of the bibenzyl (-) cis-perrottetinene (cis-PET) and the bibenzyl (-) trans-perrottetinene (trans-PET) with the cannabinoids trans-delta-9-tetrahydrocannabinol (trans-THC) and cis-delta-9-tetrahydrocannabinol (cis-THC).

[0010] Applicants speculate that perrottetinene-like compounds can have interesting pharmacology and pharmaceutical activity, which applicants define as (saturated or unsaturated) bis-phenyls or biphenyls with a 2-carbon bridge, or cannabinoids molecules containing a substituted or unsubstituted phenethylaryl side chain (C).

[0011] Applicants also speculate that given the chemical structure of pinobanksin is similar to the cannabinoid trans-delta-9-tetrahydrocannabinol (THC), other "pinobanksin-like" compounds can be considered as cannabinoid-like compounds, with a terpenoid moiety (A), a substituted or unsubstituted phenol or resorcinol moiety (B), and a substituted or unsubstituted phenethyl aryl side chain (C).

[0012] As previously mentioned (B) and (C) can alternatively be referred to together as a bibenzyl or dihydrostilbene.

[0013] It is speculated that these compounds, where the terpenoid moiety is attached to a substituted or unsubstituted dihydropinosylvin, can have interesting pharmacology and medicinal activity. Dihydropinosylvin has alternative chemical names of: 5-phenylethylbenzene-1,3-diol; 5-(2-phenylethyl)benzene-1,3-diol or 3,5-dihydroxybibenzyl.

[0014] These pinobanksin-like compounds include both a closed ring structure (similar to the cannabinoids tetrahydrocannabinol THC and cannabinol (CBN)) and an open ring structure (similar to the cannabinoids cannabidiol (CBD), cannabigerol (CBG) and cannabichromene (CBC)).

[0015] The structures of THC and CBD are shown below, along with the structures of other major cannabinoid types CBG, CBC and CBN.

[0016]

[0017]

[0018] One such pinobanksin-like compound is a CBD analog of pinobanksin (PET) or 5'-methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol. It can be prepared as:

[0019] i) the (-) trans isomer, (1'R,2'R)-5'-methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol;

[0020] ii) the (+) trans isomer, (1'S,2'S)-5'-methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol;

[0021] 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

[0022] 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

[0023] hereinafter generally referred to as "CBD-PET".

[0024] Another plagioccephalene-like compound is CBD-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. It can be prepared as:

[0025] 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;

[0026] 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;

[0027] 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

[0028] 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;

[0029] hereinafter generally referred to as "CBD-PET-OH".

[0030] A literature search for CBD analogs of PET found a paper by Crombie in Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry (1972-1999) (1988), (5), 1263-70, and several patent references, including:

[0031] EP2314580;

[0032] US2019023680;

[0033] WO2014177593;

[0034] WO2017011210;

[0035] WO2017181118; and

[0036] WO2017216362.

[0037] It is an object of the present invention to identify, make and test plagiogynin-like compounds for potential use as pharmaceuticals.

[0038] Two such compounds, described herein and referred to as CBD-PET and CBD-PET-OH, were made and tested as potential pharmaceuticals, and were found to have potentially useful pharmacology. SUMMARY

[0040] All publications, published patent applications, patents, and other patent documents cited in this specification are incorporated herein by reference in their entirety. The specification of this application hereby incorporates by reference the content of the specification and drawings of, and claims priority to, U.S. Provisional Patent Application (No. 63 / 003270) filed on March 31, 2020.

[0041] According to a first embodiment of the present invention, there is provided the compound 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.

[0042] In one embodiment, the CBD-PET is in the (-) trans form, i.e. (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.

[0043] In another embodiment, the CBD-PET is in the (+) trans form, i.e. (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.

[0044] In yet another embodiment, the CBD-PET is in the (-) cis form, i.e. (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.

[0045] In yet another embodiment, the CBD-PET is in the (+) cis form, i.e. (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.

[0046] In one embodiment, the CBD-PET-OH is in the (-) trans form, i.e. (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.

[0047] In another embodiment, the CBD-PET-OH is in 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.

[0048] In yet another embodiment, the CBD-PET-OH is in 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.

[0049] In yet another embodiment, the CBD-PET-OH is in the (+) cis form, i.e. (1'S,2'R)-4-(4-hydroxyphenylethyl)-5'-methyl-2'-(prop-1 -en-2-yl)-1 ',2',3',4'-tetrahydro-[1,1 '-biphenyl]-2,6-diol.

[0050] Preferably, the CBD-PET and / or CBD-PET-OH is pharmaceutical grade.

[0051] As used herein, pharmaceutical grade means that the CBD-PET and / or CBD-PET-OH is in a form as required by the drug regulatory authorities in the jurisdiction. Suitably, the CBD-PET and / or CBD-PET-OH 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 still at least 98%, and most preferably still at least 99%.

[0052] In one embodiment, the CBD-PET and / or CBD-PET-OH is predominantly present as the para isomer.

[0053] In another embodiment, the CBD-PET and / or CBD-PET-OH is predominantly present as the ortho isomer.

[0054] Predominantly suitably means 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.

[0055] In yet another embodiment, the CBD-PET and / or CBD-PET-OH is present as a racemic mixture of the (+) or (-) form of the or trans or cis isomer and / or the two regio-para or ortho isomers. Preferably, the mixture is in a controlled ratio, for example a ratio of between 5:1 to 1 :5, 4:1 to 1 :4, 3:1 to 1 :3, or 2:1 to 1 :2.

[0056] According to a second embodiment of the present application, there is provided CBD-PET and / or CBD-PET-OH for use in medicine or as a medicament.

[0057] In a first embodiment, the CBD-PET and / or CBD-PET-OH is the (-) trans isomer.

[0058] In a second embodiment, the CBD-PET and / or CBD-PET-OH is the (+) trans isomer.

[0059] In a third embodiment, the CBD-PET and / or CBD-PET-OH is a racemic mixture of the (-) trans and (+) trans isomers.

[0060] In a fourth embodiment, the CBD-PET and / or CBD-PET-OH is the (-) cis isomer.

[0061] In a fifth embodiment, the CBD-PET and / or CBD-PET-OH is the (+) cis isomer.

[0062] In a sixth embodiment, the CBD-PET and / or CBD-PET-OH is a racemic mixture of the (-) cis and (+) cis isomers.

[0063] In a preferred first embodiment, the compound is CBD-PET ( Figure 2f ), and more particularly (-)-trans-CBD-PET ( Figure 2b ).

[0064] Alternatively, it can be (+) trans CBD-PET ( Figure 2c ), (-)-cis-CBD-PET ( Figure 2d ), or (+)-cis-CBD-PET ( Figure 2e ) or a racemic mixture of the (+) and (-) isomers, respectively.

[0065] In a preferred second embodiment, the compound is CBD-PET-OH ( Figure 3f ), and more particularly (-)-trans-CBD-PET-OH ( Figure 3b ).

[0066] Alternatively, it can be (+) trans CBD-PET-OH ( Figure 3c ), (-)-cis-CBD-PET-OH ( Figure 3d ), or (+)-cis-CBD-PET-OH ( Figure 3e ) the (+) and (-) isomers or a racemic mixture of the (+) and (-) isomers, respectively.

[0067] In two preferred embodiments, the para (p) isomer is selected over the other ortho (o) isomer. However, in another embodiment, the ortho (o) isomer can be selected over the other para (p) isomer.

[0068] The preferred compounds of embodiments 1 and 2 can exist as pure or substantially pure isomers, or as racemic mixtures with the respective isomers in defined proportions. As used herein, substantially pure can 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%, more preferably also at least 98%, and most preferably also at least 99%.

[0069] Most preferably, the substantially pure isomer is the (-) trans and not the (+) trans isomer.

[0070] In yet another embodiment, meta variants of CBD-PET and / or CBD-PET-OH can be prepared or selected.

[0071] According to a third embodiment of the present application, there is provided a pharmaceutical composition comprising CBD-PET and / or CBD-PET-OH, suitably together with one or more pharmaceutically acceptable excipients.

[0072] The CBD-PET and / or CBD-PET-OH can exist as (-) or (+) trans or (-) or (+) cis isomers, or as racemic mixtures of the respective (+) or (-) trans or (+) or (-) cis forms.

[0073] The compounds can exist as salts, hydrates, free acids or bases or other forms, for example to improve their bioavailability or other characteristics.

[0074] The compositions can be formulated for delivery by any standard pharmaceutical route, including parenteral (intraperitoneal, intravenous, intramuscular and subcutaneous), oral, nasal including nasogastric, ocular, transmucosal (buccal, vaginal and rectal) and / or transdermal.

[0075] The identified active pharmaceutical agent, i.e. CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof, is particularly suitable for the treatment of seizures and / or epilepsy. This is based on the results obtained in two well-understood animal models of seizures.

[0076] The pentylenetetrazol (PTZ) model (PTZ is a GABA receptor antagonist) is a model of generalized seizures (as opposed to partial or focal seizures). It produces clonic, tonic-clonic, or myoclonic seizures that mimic absence (petit mal) seizures. As a model of generalized seizures, it has features that distinguish it from the maximal electroshock (MES) seizure model (also a model of generalized seizures).

[0077] In epilepsy, myoclonic seizures often cause abnormal movements on both sides of the body (left and right) at the same time. They exist in various epilepsy syndromes with different characteristics.

[0078] Juvenile myoclonic epilepsy (JME): The seizures usually involve the neck, shoulders, and upper limbs. In many patients, the seizures most often occur shortly after waking up. They usually begin around puberty, or sometimes in early adulthood in people with normal intelligence. In most cases, these seizures can be well controlled with medication, but must be taken for life.

[0079] Lennox-Gastaut syndrome (LGS): This is an uncommon syndrome that usually also 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 very intense and difficult to control.

[0080] Progressive myoclonic epilepsy (PME): Rare syndromes in this category are characterized by a combination of myoclonic and tonic-clonic seizures. Treatment is usually not successful for long, as patients worsen over time.

[0081] On the other hand, the maximal electroshock (MES) model is classified as a model of generalized tonic-clonic seizures. The MES model is an excellent tool for assessing antiseizure characteristics compared to focal or partial seizures (psychomotor seizures) when screening anticonvulsant candidates.

[0082] Tonic-clonic seizures can begin on one side or both sides of the brain.

[0083] When they begin on both sides of the brain, they are called generalized onset motor seizures or generalized tonic-clonic seizures. The two terms mean the same thing.

[0084] When they begin on one side of the brain and spread to affect both sides, the term focal to bilateral tonic-clonic seizures is used.

[0085] Based on statistically significant data obtained in both of these seizure models, both compounds exhibited antiseizure activity.

[0086] CBD-PET and CBD-PET-OH were both 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. This result was statistically significant.

[0087] CBD-PET-OH was effective in the MES model, again showing statistically significant activity against tonic and / or tonic-clonic seizures.

[0088] In both cases, CBD-PET and CBD-PET-OH were used at a mouse dose of 200 mg / Kg, which is based on the FDA conversion factor - see https: / / www.fda.gov / media / 72309 / download (incorporated by reference) is equivalent to a human equivalent dose of 200 x 0.08 = 16 mg / Kg, or a dose of 960 mg for an "average" adult human of 60 Kg.

[0089] Based on this early data, one can anticipate human doses of approximately 8 mg / Kg to 32 mg / Kg or as a dose for a 60 Kg patient from 480 mg to 1920 mg, or intermediate values therebetween, such as 12 mg / Kg to 24 mg / Kg or as a dose for a 60 Kg patient from 720 mg to 1440 mg.

[0090] According to a fourth embodiment of the application, it provides a method of treating a subject, comprising administering to the patient a therapeutically effective amount of CBD-PET and / or CBD-PET-OH in unit dosage form.

[0091] The patient can be an adult, a child, a neonate or an infant, or an adult or young animal, in particular a companion animal, such as a dog, a cat or a horse.

[0092] In one embodiment, the dose is in parenteral (intraperitoneal, intravenous, intramuscular and subcutaneous), oral, nasal including nasogastric, ocular, transmucosal (buccal, vaginal and rectal) or transdermal form.

[0093] Preferably, the method of treatment is to treat seizures and / or epilepsy.

[0094] The following table reproduces the classification of seizures according to the ILAE 2017 seizure classification:

[0095] ILAE 2017 seizure type classification extended 1

[0096]

[0097] The seizures to be treated can include one or more of the following: generalized onset seizures, including clonic seizures, clonic-tonic-clonic seizures, tonic seizures and / or tonic-clonic seizures.

[0098] The epilepsy or syndrome associated with epilepsy includes, but is not limited to: juvenile myoclonic epilepsy; Lennox-Gastaut syndrome or progressive myoclonic epilepsy.

[0099] In one embodiment, the effective dose for humans is a dose of 8 mg / Kg to 32 mg / Kg or from 480 mg to 1920 mg as a dose for a 60 Kg patient, or intermediate values therebetween, for example 12 mg / Kg to 24 mg / Kg or from 720 mg to 1440 mg as a dose for a 60 Kg patient.

[0100] For companion animals such as dogs, cats and horses, the dose can be determined using standard conversion factors available to the skilled person.

[0101] According to a fifth embodiment of the present application, there is provided a method of manufacturing a plagiogyrine-like compound comprising the step of reacting p-menthadienol with dihydrodehydrodiconiferyl alcohol or dihydroaurones in the presence of a Lewis acid, characterised in that the Lewis acid is zinc triflate.

[0102] Applicants have surprisingly determined that the use of zinc triflate and other Lewis acids as catalysts can be more effective, providing higher conversion rates, thereby providing substantially greater yields of the enantiomer of interest.

[0103] The present application provides the following:

[0104] [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).

[0105] [2] The compound of [1] which is (-)-trans CBD-PET.

[0106] [3] The compound of [1] which is (-)-trans CBD-PET-OH.

[0107] [4] The compound according to any one of [1] to [3] which is the substantially pure para isomer.

[0108] [5] The compound according to any one of [1] to [3] which is the substantially pure ortho isomer.

[0109] [6] The compound according to any one of [1] to [3] which is a mixture of both the para and ortho isomers.

[0110] [7] The compound of [4] or [5] wherein the isomer is greater than 95% pure.

[0111] [8] The compound of [6], wherein the two isomers forming the mixture are present together in greater than 95% purity.

[0112] [9] A compound according to any one of [1] to [8] for use in medicine.

[0113]

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

[0114]

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

[0115]

[12] A compound according to any one of [1] to [8] for use in treating a seizure or seizure disorder in a patient.

[0116]

[13] Use of a compound according to any one of [1] to [8] in the manufacture of a medicament for treating a seizure or seizure disorder in a patient.

[0117]

[14] The pharmaceutical composition of

[10] , the method of

[11] , the compound for use according to

[12] , or the use of

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

[0118]

[15] The pharmaceutical composition of

[10] , the method of

[11] , the compound for use according to

[12] , or the use of

[13] , wherein the disorder to be treated is myoclonic seizures.

[0119]

[16] The pharmaceutical composition of

[10] , the method of

[11] , the compound for use according to

[12] , or the use of

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

[0120]

[17] The pharmaceutical composition of

[10] , the method of

[11] , the compound for use according to

[12] , or the use of

[13] , wherein the disorder to be treated is clonic, tonic, or clonic-tonic seizures.

[0121]

[18] The pharmaceutical composition according to any one of

[10] to

[17] , the method according to any one of

[11] to

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

[12] to

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

[13] to

[17] , wherein the compound is packaged for delivery, or delivered at an effective dose, by one of the following routes: parenteral, buccal, nasal including nasogastric, ocular, transmucosal, or transdermal.

[0122]

[19] The pharmaceutical composition according to any one of

[10] to

[18] , the method according to any one of

[11] to

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

[12] to

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

[13] to

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

[0123]

[20] The pharmaceutical composition according to any one of

[10] to

[19] , the method according to any one of

[11] to

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

[12] to

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

[13] to

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

[0124]

[21] A method of manufacturing a plagioclavatol-like compound, comprising (steps:) reacting menthadienol with dihydro- pinobanksin or dihydro-bibutanol, such as in the presence of a Lewis acid.

[0125]

[22] The method of

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

[0126]

[23] The method of

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

[0127]

[24] The method of

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

[0128]

[25] The method according to any one of

[21] to

[24] , wherein the reaction of menthadienol with dihydro-pinobanksin or dihydro-bibutanol occurs at a temperature range of 80-120 °C.

[0129]

[26] The method according to any one of

[21] to

[24] , wherein when menthadienol is reacted with dihydro-pinobanksin, the plagioclavatol-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).

[0130]

[27] The method according to any one of

[21] to

[24] , wherein when menthadienol is reacted with dihydro-bibutanol, the plagioclavatol-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).

[0131]

[28] The method of

[27] , further comprising the step of preparing dihydro-bibutanol by hydrogenation of trans-bibutanol in the presence of palladium on carbon (Pd / C).

[0132] The present application also provides the following:

[0133] [1a] CBD-PET as described in [1a] which is (-)-trans CBD-PET (Figure 2).

[0134] [2a] CBD-PET as described in [1a] which is (-)-trans CBD-PET (Figure 2).

[0135] [3a] CBD-PET-OH as described in [1a] which is (-)-trans CBD-PET-OH (Figure 3).

[0136] [4a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [3a] which is present as the substantially pure para isomer.

[0137] [5a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [3a] which is present as the substantially pure ortho isomer.

[0138] [6a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [3a] which is present as a mixture of both para and ortho isomers.

[0139] [7a] CBD-PET or CBD-PET-OH as described in [4a] or [5a] wherein the isomer is present in greater than 95% purity.

[0140] [8a] CBD-PET or CBD-PET-OH as described in [6a] wherein the two isomers forming the mixture are present together in greater than 95% purity.

[0141] [9a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [8a] for use in medicine.

[0142] [10a] CBD-PET or CBD-PET-OH as described in any one of [1a] to [9a] wherein the CBD-PET or CBD-PET-OH is packaged for delivery, or delivered in an effective dose, by one of the following routes: parenterally, buccal, nasal including nasogastric, ocular, transmucosally or transdermally.

[0143] [11a] The CBD-PET or CBD-PET-OH of any one of [la] to [10a] for use in the treatment of seizures or epilepsy.

[0144] [12a] The CBD-PET or CBD-PET-OH of [11a] for use in the treatment of generalized epilepsy.

[0145] [13a] The CBD-PET or CBD-PET-OH of [12a] for use in the treatment of myoclonic seizures.

[0146] [14a] The CBD-PET or CBD-PET-OH of [13a] for use in the treatment of juvenile myoclonic epilepsy, Lennox-Gastaut syndrome or progressive myoclonic epilepsy.

[0147] [15a] The CBD-PET or CBD-PET-OH of [12a] for use in the treatment of clonic, tonic or tonic-clonic seizures.

[0148] [16a] The CBD-PET or CBD-PET-OH of any one of [la] to [15a] delivered at a dose of at least 8 mg / Kg.

[0149] [17a] A pharmaceutical composition comprising CBD-PET or CBD-PET-OH together with one or more pharmaceutical excipients.

[0150] [18a] A method of treating a subject comprising administering to the patient an effective amount of CBD-PET or CBD-PET-OH in unit dosage form.

[0151] [19a] The method of [18a] wherein the subject is an adult, a child, a neonate or an infant, or an adult or young animal, in particular a companion animal, such as a dog.

[0152] [20a] A method of manufacturing a cannabigerun-like compound comprising the step of reacting p-menthadienol with dihydrodehydrodiconiferyl alcohol or dihydro-ferulic acid in the presence of a Lewis acid, characterized in that the Lewis acid is zinc triflate.

[0153] [1b] A compound which is any one selected from the group consisting of:

[0154] 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 structure

[0155]

[0156] 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 having the structure

[0157]

[0158] or a pharmaceutically acceptable salt or hydrate thereof.

[0159] [2b] The compound of [1b] 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 having the structure

[0160]

[0161] or a pharmaceutically acceptable salt or hydrate thereof.

[0162] [3b] The compound of [1b] which is 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

[0163]

[0164] or a pharmaceutically acceptable salt or hydrate thereof.

[0165] [4b] The compound of [1b] 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 ((-) trans-CBD-PET) Figure 2b

[0166]

[0167] or a pharmaceutically acceptable salt or hydrate thereof.

[0168] [5b] The compound of [1b] which 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

[0169] ​​​

[0170] or a pharmaceutically acceptable salt or hydrate thereof.

[0171] [6b] The compound of [1b] which 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 )

[0172]

[0173] or a pharmaceutically acceptable salt or hydrate thereof.

[0174] [7b] The compound of [1b] which 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 )

[0175]

[0176] or a pharmaceutically acceptable salt or hydrate thereof.

[0177] [8b] The compound of [1b] which 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 )

[0178]

[0179] or a pharmaceutically acceptable salt or hydrate thereof.

[0180] [9b] The compound of [1b] which 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 )

[0181]

[0182] or a pharmaceutically acceptable salt or hydrate thereof.

[0183] [10b] The compound of [1b] which 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 )

[0184]

[0185] or a pharmaceutically acceptable salt or hydrate thereof.

[0186] [11b] The compound of [1b] which 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 )

[0187]

[0188] or a pharmaceutically acceptable salt or hydrate thereof.

[0189] [12b] The compound of [1b] which is the ortho isomer of trans-CBD-PET having the structure:

[0190]

[0191] or a pharmaceutically acceptable salt or hydrate thereof.

[0192] [13b] The compound of [1b] which is the ortho isomer of trans-CBD-PET-OH having the structure:

[0193]

[0194]

[0195] or a pharmaceutically acceptable salt or hydrate thereof.

[0196] [14b] The compound according to any one of [1b] to [13b] which is present as a substantially pure isomer.

[0197] [15b] The compound according to any one of [1b] to [13b] which is present as a racemic mixture of isomers.

[0198] [16b] The compound according to any one of [1b] to [13b] which is a substantially pure para isomer.

[0199] [17b] The compound of any one of [lb] to [13b], which is a substantially pure ortho isomer.

[0200] [18b] The compound of [16b] or [17b], wherein the isomer is greater than 95% pure.

[0201] [19b] The compound according to any one of [lb] to [13b], which is a mixture of both para and ortho isomers.

[0202] [20b] The compound of [19b], wherein the two isomers forming the mixture are together present in greater than 95% purity.

[0203] [21b] A compound according to any one of [lb] to [20b] for use in medicine.

[0204] [22b] A pharmaceutical composition for treating a condition that causes seizures or epilepsy in a patient, comprising a compound according to any one of [lb] to [20b].

[0205] [23b] A method for treating a condition that causes seizures or epilepsy in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of [lb] to [20b].

[0206] [24b] A compound according to any one of [lb] to [20b] for use in treating a condition that causes seizures or epilepsy in a patient.

[0207] [25b] Use of a compound according to any one of [lb] to [20b] in the manufacture of a medicament for treating a condition that causes seizures or epilepsy in a patient.

[0208] [26b] The pharmaceutical 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 generalized epilepsy.

[0209] [27b] The pharmaceutical 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 seizures.

[0210] [28b] The pharmaceutical 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.

[0211] [29b] The pharmaceutical 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 clonic seizures, tonic seizures, or tonic-clonic seizures.

[0212] [30b] The pharmaceutical composition according to any one of [22b]-[29b], the method according to any one of [23b]-[29b], the compound for use according to any one of [24b]-[29b], or the use according to any one of [25b]-[29b], wherein the compound is packaged for delivery, or delivered in an effective dose, by one of the following routes: parenteral, buccal, nasal including nasogastric, ocular, transmucosal, or transdermal.

[0213] [31b] The pharmaceutical composition according to any one of [22b]-[30b], the method according to any one of [23b]-[30b], the compound for use according to any one of [24b]-[30b], or the use according to any one of [25b]-[30b], wherein the patient is a human patient.

[0214] [32b] The pharmaceutical composition according to any one of [22b]-[31b], the method according to any one of [23b]-[31b], the compound for use according to any one of [24b]-[31b], or the use according to any one of [25b]-[31b], wherein the compound is administered to the patient at a dose of at least 8 mg / Kg.

[0215] [33b] A method of manufacturing a plauanel-like compound, comprising the step of: reacting menthadienol with dihydrodehydrodiconiferyl alcohol or dihydro- piceatannol in the presence of a Lewis acid.

[0216] [34b] The method of [33b], wherein the Lewis acid is a zinc-based acid.

[0217] [35b] The method of [34b], wherein the zinc-based acid is zinc triflate.

[0218] [36b] The method of [35b], wherein the starting amount of zinc triflate is 0.01-0.05 molar equivalents of menthadienol.

[0219] [37b] The method according to any one of [33b] to [36b], wherein the reaction of menthadienol with dihydrodehydrodiconiferyl alcohol or dihydro-piceatannol occurs at a temperature range of 80-120 °C.

[0220] [38b] The method according to any one of [33b] to [36b], wherein when menthadienol is reacted with dihydrodehydrodiconiferyl alcohol, the plauanel-like compound is (1’R,2’R)-5’-methyl-4-phenylethyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’- tetrahydro-[1,1’-biphenyl]-2,6-diol (CBD-PET).

[0221] [39b] The method of any one of [33b] to [36b], wherein when menthadienol is reacted with dihydrorelaxinol, the peltatoside-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).

[0222] [40b] The method of [39b], further comprising the step of preparing dihydrorelaxinol by hydrogenation of trans-relaxinol in the presence of palladium on carbon (Pd / C).

[0223] [41b] The method of any one of [33b] to [40b], wherein the menthadienol is p-menthadienol.

[0224] BRIEF DESCRIPTION OF THE DRAWINGS

[0225] Embodiments of the application are further described below with reference to the accompanying drawings, in which:

[0226] Figure 1 A general scheme for the synthesis of CBD-PET and analogs, including but not limited to hydroxyl substituted variants and subsequent ring closure to produce THC-PET and THC-PET-OH;

[0227] Figure 2a A scheme for the synthesis of CBD-PET;

[0228] Figure 2b Example (-) trans isomer;

[0229] Figure 2c Example (+) trans isomer;

[0230] Figure 2d Example (-) cis isomer;

[0231] Figure 2e Example (+) cis isomer;

[0232] Figure 2f Example CBD-PET without stereochemistry;

[0233] Figure 3a A scheme for the synthesis of CBD-PET-OH;

[0234] Figure 3b Example (-) trans isomer;

[0235] Figure 3c Example (+) trans isomer;

[0236] Figure 3d Example (-) cis isomer;

[0237] Figure 3e Example (+) cis isomer;

[0238] Figure 3f Example CBD-PET-OH without stereochemistry;

[0239] Figure 4 Bar graph showing latency to tonic hind limb clonus in a MES mouse seizure model for test compounds relative to CBD and negative control (vehicle) and positive control (phenytoin).

[0240] Figure 5 Bar graph showing latency to clonic convulsions in a PTZ mouse seizure model for test compounds relative to CBD and negative control (vehicle) and positive control (diazepam).

[0241] Figure 6 Bar graph showing latency to tonic hind limb clonus in a PTZ mouse seizure model for test compounds relative to CBD and negative control (vehicle) and positive control (phenytoin).

[0242] Figure 7 HPLC data for (-)-trans-CBD-PET (para isomer);

[0243] Figure 8 HPLC data for (-)-trans-CBD-PET (ortho isomer);

[0244] Figure 9 HPLC data for (-)-trans-CBD-PET-OH (para isomer); and

[0245] Figure 10 HPLC data for (-)-trans-CBD-PET-OH (ortho isomer).

[0246] DETAILED DESCRIPTION

[0247] Compounds

[0248] The present invention provides a compound selected from:

[0249] 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 structure

[0250]

[0251] 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 having the structure

[0252]

[0253] or a pharmaceutically acceptable salt or hydrate thereof.

[0254] These compounds can be collectively referred to hereinafter as the compound of the present invention or the compound of the invention.

[0255] In one embodiment, the compound of the present invention can be 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 the structure

[0256]

[0257] or a pharmaceutically acceptable salt or hydrate thereof.

[0258] In one embodiment, the compound of the present invention can be 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

[0259]

[0260] or a pharmaceutically acceptable salt or hydrate thereof.

[0261] In one embodiment, the compound of the present invention can be (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

[0262]

[0263] or a pharmaceutically acceptable salt or hydrate thereof.

[0264] ​​In one embodiment, the compound of the application can be (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 )

[0265]

[0266] or a pharmaceutically acceptable salt or hydrate thereof.

[0267] In one embodiment, the compound of the application can be (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 )

[0268]

[0269] or a pharmaceutically acceptable salt or hydrate thereof.

[0270] In one embodiment, the compound of the application can be (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 )

[0271]

[0272] or a pharmaceutically acceptable salt or hydrate thereof.

[0273] In one embodiment, the compound of the application can be (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 )

[0274]

[0275] or a pharmaceutically acceptable salt or hydrate thereof.

[0276] In one embodiment, the compound of the application can be (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 )

[0277]

[0278] or a pharmaceutically acceptable salt or hydrate thereof.

[0279] In one embodiment, the compound of the application can be (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 3d )

[0280]

[0281] or a pharmaceutically acceptable salt or hydrate thereof.

[0282] In one embodiment, the compound of the application can be (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 3e )

[0283]

[0284] or a pharmaceutically acceptable salt or hydrate thereof.

[0285] In one embodiment, the compound of the application can be any one or at least one of the following:

[0286] (-)-trans-CBD-PET vicinal isomer

[0287]

[0288] (1'R,2'R)-5'-methyl-6-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro- [1,1'-biphenyl]-2,4-diol

[0289] (+)-trans-CBD-PET vicinal isomer

[0290] (+)-trans-CBD-PET vicinal isomer

[0291] (1'S,2'S)-5'-methyl-6-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol

[0292] (-)-cis-CBD-PET ortho isomer

[0293]

[0294] (1'R,2'S)-5'-methyl-6-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol

[0295] (+)-cis-CBD-PET ortho isomer

[0296]

[0297] (1'S,2'R)-5'-methyl-6-phenethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol

[0298] or a pharmaceutically acceptable salt or hydrate thereof.

[0299] In one embodiment, the compound of the present application can be any one or at least one of the following:

[0300] (-)-trans-CBD-PET-OH ortho isomer

[0301]

[0302] (1'R,2'R)-6-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol

[0303] (+)-trans-CBD-PET-OH ortho isomer

[0304]

[0305] (1'S,2'S)-6-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol

[0306] (-)-cis-CBD-PET-OH ortho isomer

[0307]

[0308] (1 'R,2'S)-6-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1 -en-2-yl)-1 ',2',3',4'- tetrahydro-[1,1 '-biphenyl]-2,4-diol

[0309] (+)-cis-CBD-PET-OH ortho isomer

[0310]

[0311] (1 'S,2'R)-6-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1 -en-2-yl)-1 ',2',3',4'- tetrahydro-[1,1 '-biphenyl]-2,4-diol

[0312] or a pharmaceutically acceptable salt or hydrate thereof.

[0313] In one embodiment, the compound of the application can be (-)-trans-CBD-PET or (-)-trans-CBD-PET-OH.

[0314] The compound of the application can be substantially pure para isomer or substantially pure ortho isomer. As used herein, substantially pure means that the isomer has at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98% purity, more preferably also at least 98%, and most preferably also at least 99%. The compound of the application can be a mixture of both para and ortho isomers. When in a mixture of para and ortho isomers, each of the two isomers forming the mixture are present together in at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98% purity, more preferably also at least 98%, and most preferably also at least 99%, preferably, in greater than 95% purity.

[0315] Examples of the pharmaceutically acceptable salt of the compound of the present application include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts and the like; ammonium salts; organic amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glycinamide salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris(hydroxymethyl)aminomethane salts; hydrogen halide salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts and hydroiodide salts; inorganic acid salts such as nitrate salts, perchlorate salts, sulfate salts, phosphate salts and the like; lower alkane sulfonic acid salts such as methanesulfonate salts, trifluoromethanesulfonate salts and ethanesulfonate salts; aryl sulfonic acid 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 the like; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts and aspartic acid salts. These salts can be produced by known methods. Alternatively, the compound of the present application contained in the composition of the present application can be in the form of a hydrate thereof.

[0316] Medical use

[0317] The compound of the present application is useful for the treatment of various disorders as demonstrated in the examples. Thus, the present application provides the compound of the present application for use in medicine. In particular, for the treatment of disorders of seizure or epilepsy, the present application provides the following:

[0318] (a) a pharmaceutical composition for use in the treatment of a disorder of seizure or epilepsy in a patient, comprising the compound of the present application, i.e. CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof.

[0319] (b) a method for the treatment of a disorder of seizure or epilepsy in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present application, i.e. CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof.

[0320] (c) use of the compound of the present application, i.e. CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of a disorder of seizure or epilepsy in a patient.

[0321] (d) use of the compound of the present application, i.e. CBD-PET and / or CBD-PET-OH, and / or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of a disorder of seizure or epilepsy in a patient.

[0322] In one embodiment, the pharmaceutical composition of (a) further comprises a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" herein includes any substance used as a carrier for delivering an active ingredient to a subject, and any substance added to an active ingredient, for example, to improve its handling properties or to permit the formed composition to be delivered in a form having a desired shape and consistency for oral delivery. Excipients can include, by way of example and not limitation, diluents, disintegrants, binders, humectants, lubricants, glidants, additives to mask or counteract unpleasant taste or odor, flavorings, colorings, additives to improve the appearance of the dosage form, and any other substance conventionally used in the manufacture of oral dosage forms other than the active ingredient.

[0323] In one embodiment, 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 can be generalized epilepsy, or juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, or progressive myoclonic epilepsy.

[0324] In another embodiment, 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 can be myoclonic seizures, clonic seizures, tonic seizures, or tonic-clonic seizures.

[0325] For the pharmaceutical composition of (a), the method of (b), the compound for use according to (c), or the use of (d), administration can be determined by the skilled person depending on the particular condition to be treated and the patient. Exemplary routes include intravenous administration, arterial administration, intramuscular administration, subcutaneous administration, oral administration, tissue administration, transdermal administration, and the like. In one embodiment, the composition of the application of (a) or the compound of the application can be administered by parenteral, oral, nasal including nasogastric, ocular, transmucosal, or transdermal routes.

[0326] Further, the dosage form usable for the composition of the application of (a) or for the compound of the application is not particularly limited, and includes, for example, infusion agents, injection agents, oral agents, instillation agents, creams, inhalants, ointments, lotions, and the like.

[0327] 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, however, includes humans, domestic animals such as cattle, sheep, horses, goats, alpacas, kangaroos, and pigs, pets such as dogs, cats, rabbits, and birds, and zoo animals such as lions, elephants, giraffes, and bears. In one embodiment, the patient to be treated is a human.

[0328] Suitable dosages for administration of the compounds of the present application can be determined by the skilled artisan based on the description and data provided herein. Guidance for conversion of suitable dosages from animal models to suitable dosages for humans is known to the skilled artisan. An example of such dosage conversion is 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), July 2005 Pharmacology and Toxicology). Specifically, for CBD-PET and CBD-PET-OH, a dose of 200 mg / Kg in mice is equivalent to a comparable dose of 200 x 0.08 = 16 mg / Kg in humans, or a dose of 960 mg for an "average" adult human of 60 Kg in weight. Based on this early data, one can expect human dosages of approximately 8 mg / Kg to 32 mg / Kg or as a dose for a 60 Kg patient from 480 mg to 1920 mg, or intermediate values therebetween, such as 12 mg / Kg to 24 mg / Kg or as a dose for a 60 Kg patient from 720 mg to 1440 mg. Dosages for heavier human patients or for lighter patients such as children can be appropriately determined based on the disclosure provided herein. In one embodiment, the compounds of the present application can be administered to a patient at a dose of at least 8 mg / Kg.

[0329] The pharmaceutical composition of (a) can further comprise a pharmaceutically acceptable carrier. The concentration of the compound of the present application contained in the pharmaceutical composition of (a) can vary depending on the kind of the carrier and the like, and is suitably in the range of 0.1 nM to 100 μΜ, preferably in the range of 1 nM to 10 μΜ, and more preferably in the range of 10 nM to 1 μΜ.

[0330] The pharmaceutical composition of (a) can contain one or more pharmaceutically acceptable additives in addition to the compound of the present application. Examples of such additives are co-emulsifiers (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 control agents (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 additives in the composition of the present application is suitably 90% by weight or less, preferably 70% by weight or less, and more preferably 50% by weight or less.

[0331] Synthetic method

[0332] The present application provides a synthetic method of manufacturing, for example, the compound of the present application, a plagioccephalene-like compound, which comprises (a step) reacting menthadienol with dihydroquercetin or dihydroaurone, for example, in the presence of a Lewis acid. This step (hereinafter referred to as "alkylation step") allows menthadienol to be alkylated with dihydroquercetin or dihydroaurone, thereby producing a plagioccephalene-like compound.

[0333] In one embodiment, when menthadienol is reacted with dihydroquercetin, the plagioccephalene-like compound produced by the method of the present application 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 embodiment, when menthadienol is reacted with dihydroaurone, the plagioccephalene-like compound produced by the method of the present application 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 embodiment, the menthadienol is para (p-) menthadienol.

[0334] The Lewis acid used can be selected from the group consisting of H + , K + , Zn 2+ , Mg 2+ , Fe 3+ , BF3, Sc 3+, CO2, SO3, RMgX (where R is a hydrocarbon group such as CH3, C2H5, or C6H5, and X is a halogen atom such as chlorine, bromine, or iodine), A1C13, and Br2. Further examples of Lewis acids used in the method include Zn(OTf)2, p-TsOH.H2O, BF3OEt2, BF3OEt2-AI2O3, and Sc(OTf)3. In one embodiment, the Lewis acid used in the synthesis method can be a zinc (or BF3) containing or based acid. In another embodiment, the zinc based acid can include zinc triflate (Zn(OTf)2).

[0335] In one embodiment, the initial or starting amount of Lewis acid (to be added in the alkylation step) can be 0.005-0.10, 0.005-0.09, 0.005-0.08, 0.005-0.07, 0.005-0.06, 0.005-0.05, 0.005-0.04, 0.005-0.03, 0.005-0.025, 0.01-0.10, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, 0.01-0.025, 0.015-0.10, 0.015-0.09, 0.015-0.08, 0.015-0.07, 0.015-0.06, 0.015-0.05, 0.015-0.04, 0.015-0.03, or 0.015-0.025 molar equivalents of menthadienol. In one embodiment, the initial amount of Lewis acid to be added in the alkylation step can be 0.02 molar equivalents of menthadienol.

[0336] In one embodiment, the alkylation step, i.e., the reaction of menthadienol with dihydromatairesinol or dihydroanagallol, occurs at or within a temperature range of 60-140 °C, 60-130 °C, 60-120 °C, 70-140 °C, 70-130 °C, 70-120 °C, 80-140 °C, 80-130 °C, 80-120 °C, 90-110 °C, or 95-105 °C. In one embodiment, the alkylation step occurs at a temperature range of 80-120 °C. In one embodiment, the alkylation step occurs at a temperature of 100 °C.

[0337] When the plagiogynolene-like compound prepared by the method of the present application 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 application can further comprise the step of preparing dihydroresveratrol by hydrogenation of trans-resveratrol in the presence of palladium on carbon (Pd / C).

[0338] The first step is the manufacture of CBD-PET and CBD-PET-OH.

[0339] The compounds of the present application are prepared by the general schemes shown in Figure 1 and, respectively, Schemes and compounds in Figure 2a -f and Figure 3a -f.

[0340] General methodology

[0341] The key step to prepare the initial target compounds is:

[0342] i) (-)-trans CBD-PET, and

[0343] ii) (-)-trans CBD-PET-OH

[0344] is the Friedel-Crafts alkylation of p-menthadienol with the desired resorcinol / biphenyl compound.

[0345] Dihydromatairesinol is commercially available, but dihydroresveratrol needs to be hydrogenated from the readily available resveratrol under standard conditions. Figure 1 The steps described in Scheme 1 produce almost equal amounts of the p- and o- isomers and require extensive chromatographic work to separate them from each other and from other minor side products.

[0346] Finally, the synthesis of (-)-trans-THC-PET is performed by a boron trifluoride diethyl ether complex mediated cyclization of (-)-trans-CBD-PET to affect the formation of the pyran ring.

[0347] In the following, the present application will be described in more detail with reference to the following examples, without being restricted thereto.

[0348] Example 1 - Preparation of (-)-trans CBD-PET

[0349] The initial preparation of (-)-trans CBD-PET was based on the use of a number of different Lewis acids, which included:

[0350] • Zn(OTf)2;

[0351] • p-TsOH.H2O;

[0352] • BF3OEt2;

[0353] • BF3OEt2-Al2O3; and

[0354] • Sc(OTf)3

[0355] and reaction conditions for the coupling of dihydrokaempferol with p-menthadienol based on published reports (Figure 2 - Scheme 2).

[0356] The original Crombie et al. conditions (p-TsOH.H2O in toluene) were used; ref: J. Chem. Soc. Perkin. Trans I, 1988, 1263-1270, but only gave 25% of (-)-trans-CBD-PET (p-isomer) along with 10% of another o-isomer.

[0357] A Lewis acid commonly used for such transformations, trifluoroborate ether complex (BF3.OEt2) and BF3.OEt2-alumina (ref: Tet. Lett. 1985, 26, 1083-1086) were tested and found to provide less than 30% yield of the desired product. The alumina mediated conditions produced an unknown isomerised compound which did not match the1H NMR of any compound reported in the literature.

[0358] The use of Sc(OTf)3at 20 °C or below (ref: WO2007041167) provided comparable yields to p-TsOH and BF3.OEt2along with another o-isomer.

[0359] The use of Zn(OTf)2in toluene at 100 °C with excess dihydrokaempferol (see WO2019046806) consumed the p-menthadienol completely but left some dihydrokaempferol remaining. LCMS analysis showed multiple peaks with m / z = 349 corresponding to the desired product and several peaks with m / z = 497 matching the bis-alkylated by-product. After purification by flash chromatography, two major spots were isolated and characterised. 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 based on their matching1H NMR spectra to published data (Crombie et al.; J. Chem. Soc. Perkin. Trans I, 1988, 1263-1270). The initial reaction provided 42% of the desired p-isomer and 39% of the o-isomer.

[0360] Zn(OTf)2, this Lewis acid proved significantly more effective than other Lewis acids mentioned in the literature and was used in the preparation.

[0361] Preparation of (-)-trans-CBD-PET for in vivo testing

[0362] A 2 L three-necked reactor was equipped with a magnetic stirrer, reflux condenser, thermocouple, and nitrogen inlet. Dihydrodehydrodiconiferyl alcohol (116.1 g, 0.54 mol, 1.10 equiv) was charged as a solid into the reactor followed by toluene (750 mL, 10 vol) under a nitrogen atmosphere. The resulting solution was heated to 80 °C for 20 min, followed by the addition of Zn(OTf)2(3.6 g, 0.010 mol, 0.020 equiv) followed by p-menthadienol (75.0 g, 0.490 mol, 1.00 equiv) in toluene (375 mL, 5.0 vol). The reaction mixture was then heated to 100 °C and the progress was monitored by TLC. After 1 h at 100 °C, complete consumption of p-menthadienol was observed and the batch was cooled to 50-55 °C. The reaction was quenched by slow (5-10 min) addition of water (150 mL) followed by cooling to 20 °C. The mixture was stirred at 20 °C for an additional 5-10 min before allowing the layers to separate. 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 (Biotage KP-SIL 75-L column; 1 kg silica) in two batches, eluting slowly with 0-30% EtOAc / heptane [gradient: 1 x 2 L of 100% heptane; 1 x 2 L 5% EtOAc-heptane; 1 x 2 L 12% EtOAc-heptane (p-isomer elution begins); 2 x 2 L 10% EtOAc-heptane (p-isomer elution ends); 1 x 2 L 15% EtOAc-heptane; 1 x 2 L 20% EtOAc-heptane (o-isomer elution begins); 1 x 4 L 25% EtOAc-heptane (o-isomer elution ends)]. Fractions containing product (p-isomer) were combined and the solvent was removed under reduced pressure to provide 60 g of (-)-trans-CBD-PET, 94% pure, as a clear viscous oil. This material was further purified by Combiflash (HP silica, 330 g gold cartridges) chromatography in three batches to provide (-)-trans-CBD-PET (40.3 g, 24% yield; batch # GSR-D-31-1 - GSR-D-31-3) with 99.3% HPLC purity. Fractions containing the o-isomer from the Biotage column were combined and concentrated under reduced pressure to provide o-(-)-trans-CBD-PET (57.9 g, 34% yield; batch # GSR-D-31-2 - GSR-D-31-4) with 99.3% HPLC purity. Figure 7 Figure 8 ​clear viscous oil, 99.1% purity. After drying the material under high vacuum for over 60 h, the identity was confirmed by1H and 13 C NMR (500 MHz, CDC13) confirmed identity.

[0363] Example 2 - Preparation of (-)-trans-CBD-PET-OH

[0364] The above Zn(OTf)2conditions for the preparation of CBD-PET were adapted for the synthesis of the 4-hydroxyphenethyl analogue (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, Scheme 3, Figure 3). Using the reported procedure (US20160367498) commercial available resveratrol (1.0 eq) was hydrogenated in the presence of 10% Pd-C (2 wt%) and resulted in a complete and clean conversion of resveratrol to dihydroresveratrol. In an initial coupling attempt, dihydroresveratrol (0.5 g) was treated with p-menthadienol in the presence of Zn(OTf)2(0.02 eq) under the same conditions, showed a similar TLC reaction profile with complete consumption of p-menthadienol within 1 h. LCMS analysis of the isolated crude confirmed the presence of two peaks with m / z = 365 (M+1) representing the desired product (p-isomer) and a side product (o-isomer), in addition to two further peaks with m / z = 499 representing a bis-alkylated product. The (-)-trans-CBD-PET-OH crude was purified by silica gel chromatography eluting with 0-40% EtOAc / heptane to provide (-)-trans-CBD-PET-OH (37% yield) and another o-isomer of (-)-trans-CBD-PET-OH (28% yield) as a clear viscous oil. The structure of the isomers was determined based on the comparison of their NMR spectra with those reported in the literature (Crombie et al.; J. Chem. Soc. Perkin. Trans I, 1988, 1263-1270). The key distinguishing feature of the1H NMR spectrum of the selected p-isomer was the broadened signals of the 3' and 5' protons, which is due to slow exchange involving rotation of the p-menthadienol nucleus (see atom numbering in Scheme 1). Similarly, the corresponding carbon atoms also showed broadened peaks with significantly reduced peak height in the13C NMR. In line with the literature, no such exchange or broadening of the proton or carbon signals was observed in the more hindered and o-regioisomer.

[0365] Preparation of (-)-trans-CBD-PET-OH for in vivo testing

[0366] Step 1: Preparation of dihydroresveratrol

[0367] To a solution of trans-resveratrol (75.0 g, 0.33 mol, 1.00 equiv) in ethanol (1120 mL, 15 vol) in a metal pressure reactor was charged 10% Pd / C (1.75 g, 0.0015 mol, 0.050 equiv). The flask was purged with nitrogen to create an inert atmosphere, followed by purging with hydrogen. The reaction mixture was stirred at 20 °C for 16 h under an atmosphere of hydrogen (40 psi). Once resveratrol was consumed completely, the mixture was filtered through a short pad of celite to remove the Pd / C. The celite pad was washed with additional EtOH [3 x 300 mL (2 vol)]. The combined filtrate was concentrated under reduced pressure to provide a clear oil which turned off-white solid upon further drying under high vacuum.1H NMR confirmed the identity of dihydroresveratrol (149.3 g, yield = 98%) and matched the1H NMR data reported in US20160367498.

[0368] Step 2: Preparation of (-)-trans-CBD-PET-OH

[0369] 2 L three necked reactor equipped with magnetic stirrer, reflux condenser, thermocouple and nitrogen inlet. Under nitrogen atmosphere, dihydrolawsonia (127 g, 0.550 mol, 1.10 equiv) was charged as a solid into the reactor followed by toluene (800 mL). The mixture was heated to 80 °C for 20 min and Zn(OTf)2(3.84 g, 0.011 mol, 0.02 equiv) was charged followed by p-menthadienol (80.0 g, 0.52 mol, 1.0 equiv) 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 slow addition of water (160 mL). The batch was then further cooled to 20 °C. The mixture was stirred for an additional 5-10 min at 20 °C before layering to collect the organic layer. The solvent was removed under reduced pressure. The crude was divided into two batches and purified using Biotage KP-SIL 75L column eluting with 0-30% EtOAc-heptane slowly [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] by flash chromatography. The fractions containing the product (p-isomer) were combined and the solvent was removed under reduced pressure to provide p-(-)-trans-CBD-PET-OH (39.3 g, 20% yield; batch # GSR-D-37-7) as a clear viscous oil with 97.4% HPLC purity ( Figure 9 Figure 10 ). Similarly, the fractions containing the other o-isomer were pooled and concentrated under reduced pressure to provide o-(-)-trans-CBD-PET-OH (43.9 g, 22% yield; batch # GSR-D-37-8) as a clear viscous oil with 99.3% HPLC purity ( Figure 10 ). The identity was confirmed by1H NMR and13C NMR (500 MHz, CDCI3) after drying the material under high vacuum for over 60 h.

[0370] Two exemplary compounds:

[0371] i) A-(-)-trans-CBD-PTE (p-isomer); and

[0372] ii) B-(-)-trans-CBD-PTE-OH (p-isomer)

[0373] ​PK studies were performed and tested in two exemplary seizure models (i.e., PTZ and MES models of seizure).

[0374] Animals

[0375] Species: Mouse

[0376] Strain: ICR: CD-1

[0377] Source of Animals: Charles River

[0378] Age or Weight: 8-10 weeks

[0379] Sex: Male

[0380] Randomization: Animals were randomly assigned to treatment groups

[0381] Investigator Blinding: The investigator was blinded to treatment.

[0382] Housing and Feeding

[0383] Acclimation / Adjustment

[0384] Not less than three days

[0385] Housing:

[0386] Mice will be housed in 12 hr light / dark cycle (lights on at 7:00 AM)

[0387] Not more than 4 mice per cage depending on size

[0388] Ventilated cage rack system

[0389] Diet:

[0390] Standard rodent chow and water ad libitum

[0391] Design Parameters

[0392] PK Studies

[0393] Route of Administration: Intraperitoneal (i.p.)

[0394] Dose Volume: 10 ml / kg

[0395] Formulation:

[0396] Vehicle for test compound and CBD: 1 : 1 : 18 Ethanol: Cremophor (Kolliphor) EL: 0.9% saline

[0397] Dose Levels: 100 mg / kg

[0398] Dose Frequency: Once

[0399] Duration of study: 1 day

[0400] Blood collection time points:

[0401] IP administration: 0.5h (30min), 1h, 2h,

[0402] Number of animals per group: 3

[0403] Number of samples for analysis:

[0404] 9 blood samples per compound

[0405] Total of 18 samples

[0406] Total number of animals: 6

[0407] The above is summarized in Table 1 below:

[0408] [Table 1]

[0409]

[0410] Conversion of mouse doses to human equivalent doses is done by multiplying the mouse dose by 0.08 expressed in mg / Kg.

[0411] MES study

[0412] Route of administration: intraperitoneal (i.p.) or oral (p.o.) (phenytoin)

[0413] Dose volume: 10 ml / kg

[0414] Formulation:

[0415] Vehicle for test compounds: 1 : 1 : 18 ethanol: Kolliphor EL: 0.9% saline

[0416] Vehicle for phenytoin: 0.5% MC in water

[0417] Dose levels: 100-200 mg / kg (Table 2), phenytoin 60 mg / kg

[0418] Dose frequency: once

[0419] Duration of study: 1 day

[0420] Interval between dose and assessment: 30 min for test article and phenytoin, 60 min for CBD

[0421] Number of animals per group: 10

[0422] Number of groups: 5

[0423] Total number of animals: 50

[0424] This is summarized in Table 2 below:

[0425] [Table 2]

[0426]

[0427] PTZ study

[0428] Route of administration: intraperitoneal (i.p.) or oral (p.o.) (diazepam)

[0429] Dose volume: 10 ml / kg

[0430] Formulation:

[0431] Vehicle for test compound: 1 : 1 : 18 ethanol: polyoxyethylated castor oil (Kolliphor) EL: 0.9% saline

[0432] Vehicle for diazepam: 0.5% MC, 0.1% Tween 80 in water

[0433] Dose levels: 100-200 mg / kg (Table 3), phenytoin 60 mg / kg

[0434] Dose frequency: once

[0435] Study duration: 1 day

[0436] Interval between dose and assessment: 30 min for test article and diazepam, 60 min for CBD

[0437] Number of animals per group: 10

[0438] Number of groups: 5

[0439] Total number of animals: 50

[0440] This is summarized in Table 3 below:

[0441] [Table 3]

[0442]

[0443] Methods

[0444] PK study

[0445] To test each compound, six CD-1 mice were divided into 2 groups of 3. The animals were administered the test agent via the i.p. route and blood was collected at 30, 60, 120 min, administration is outlined in Table 1. Blood samples were collected in EDTA-coated microfuge tubes, inverted and placed on ice packs prior to centrifugation, and stored at -70°C. Samples were extracted using the acetonitrile / protein precipitation method and analyzed for test agent levels by LC / MS / MS.

[0446] Maximal electroshock (MES)

[0447] Animals were administered vehicle, phenytoin, CBD or test compound and observed for 30 minutes for gross behavioural observations. Approximately 10 minutes prior to testing, the eyes were made sluggish using proparacaine hydrochloride eye drops (Butler AHS, Dublin, OH). Thirty to sixty minutes after administration of vehicle, phenytoin, CBD or test compound, 0.9% saline solution (sodium chloride in water) was applied to both eyes and electrical convulsions were induced by delivering alternating current through corneal electrodes at a frequency of 60 Hz using a Rodent Shocker generator (Harvard Apparatus, Holliston, MA). The parameters for ICR:CD1 mice were a duration of stimulation of 0.2 s at an intensity of 25 mA. The criterion for seizure occurrence was the presence of tonic hind limb extension, defined as extension at an angle greater than 90 degrees to the plane of the body. A 20 s cut-off latency was used for mice that did not seize. Any seizure activity prior to the tonic hind limb seizure (i.e. clonic seizures defined as rapid jerking or twitching movements of the limbs) was recorded as a seizure (scored as 1 - yes, 0 - no). After exhibiting a seizure or after the 20 s cut-off, mice were euthanized by cervical dislocation.

[0448] PTZ-induced seizures

[0449] Mice were acclimatized to the procedure room for at least 30 minutes. Pentyltetrazol (PTZ; Sigma Aldrich) was prepared in water to a concentration of 20 mg / ml. PTZ was injected at a volume of 5 ml / kg to give a final dose of 100 mg / kg. PTZ injections were i.p. Diazepam was prepared to a concentration of 2 mg / ml and administered at a volume of 10 ml / kg to give a final dose of 20 mg / kg. The time to initial myoclonic and tonic hind limb extension responses were measured. The maximum latency to seizure was set at 10 minutes.

[0450] Bioanalytical method development and sample bioanalysis

[0451] Bioanalytical detection methods were developed using LC / MS / MS (ABI 5000 or 5500). Standard curves were prepared for the test reagents in the appropriate biological matrix (plasma). The levels of the test articles were measured in plasma according to the developed methods.

[0452] The levels were determined by extrapolating the concentrations from the standard curves using linear regression analysis. Method development and bioanalysis were performed by the contract company Keystone Bioanalytical (North Wales, PA, US).

[0453] Data analysis

[0454] Data are presented as mean ± SEM. Statistical analysis using one-way ANOVA with post-hoc Fisher’s LSD test was used to determine statistical significance compared to vehicle treated animals.

[0455] Results

[0456] PK study

[0457] Animals were treated according to Table 1 and the time course of (-)-trans CBD-PET is illustrated in Table 4, measured concentrations (ng / ml) of (-)-trans CBD-PET in plasma after -i.p. administration of 100 mg / kg.

[0458] [Table 4]

[0459]

[0460] Animals were treated according to Table 1 and the time course of (-)-trans CBD-PET -OH is illustrated in Table 5, measured concentrations (ng / ml) of (-)-trans CBD-PET-OH in plasma after -i.p. administration of 100 mg / kg.

[0461] [Table 5]

[0462]

[0463] MES study

[0464] Figure 4 Results of the MES study are illustrated in Table 6: MES: Latency to onset of a seizure in mice in seconds. Animals received treatment according to Table 2. A 20 second timeout was recorded for any mouse that did not exhibit a tonic seizure. Data are presented as mean ± SEM. Data were analyzed by one-way ANOVA followed by post-hoc Fisher’s LSD test. ***P < 0.001, *P < 0.05, n = 1.

[0465] PTZ study

[0466] Figure 5 Results from the PTZ study: PTZ: Latency to myoclonic seizures. Animals received treatment according to Table 3. Each bar represents the mean latency (sec) + / - SEM. *P<0.05, ****P<0.0001, one-way ANOVA followed by Fisher’s LSD test, compared to vehicle-treated animals, n=10 / group.

[0467] Figure 6 Results from the PTZ study: PTZ: Latency to myoclonic seizures. Animals received treatment according to Table 3. Each bar represents the mean latency (sec) + / - SEM. *P<0.05, ****P<0.0001, one-way ANOVA followed by Fisher’s LSD test, compared to vehicle-treated animals, n=10 / group.

[0468] ***P<0.001, ****P<0.0001, one-way ANOVA followed by Fisher’s LSD test, compared to vehicle-treated animals, n=10 / group.

[0469] Conclusions

[0470] Pharmacokinetic time course analysis of (-)-trans CBD-PET and (-)-trans CBD-PET-OH demonstrated that the maximum concentration in plasma was reached at 30 min post-injection. The pre-treatment time for (-)-trans CBD-PET and (-)-trans CBD-PET-OH for the MES and PTZ studies was determined to be 30 min.

[0471] In the MES study, (-)-trans CBD-PET was inactive. The effect of (-)-trans CBD-PET-OH was significantly different from vehicle (p<0.05). The positive control of the study, phenytoin, demonstrated 100% protection from seizures (p<0.05).

[0472] The administration of PTZ produced myoclonic and tonic hind limb seizures in animals treated with vehicle. The positive control of the study, diazepam, produced a significant protection from seizures (100%, p<0.05). Figure 5 and 6 , p<0.05).

[0473] The administration of (-)-trans CBD-PET produced a significant protection from myoclonic seizures compared to vehicle-treated animals (p<0.05).

[0474] The administration of (-)-trans CBD-PET and (-)-trans CBD-PET-OH produced a significant effect, protecting from tonic hind limb seizures (p<0.05).

[0475] Administration of 100 mg / kg cannabidiol 60 min prior to MES and PTZ did not produce a significant effect in the model (p>0.05).

Claims

1. Use of the compound in the preparation of a medicament for treating epilepsy in patients, said compound being: 5'-Methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol has the following structure Or 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, having the following structure Or its pharmaceutically acceptable salts or hydrates.

2. Use of the compound in the preparation of a medicament for treating seizures in patients, said compound being: 5'-Methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol has the following structure Or 4-(4-hydroxyphenethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, having the following structure Or its pharmaceutically acceptable salts or hydrates.

3. The use according to claim 1 or 2, wherein the compound is 5'-methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET) having the following structure Or its pharmaceutically acceptable salts or hydrates.

4. The use according to claim 1 or 2, wherein the compound is 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 its pharmaceutically acceptable salts or hydrates.

5. The use of claim 1 or 2, wherein the compound is (1'R,2'R)-5'-methyl-4-phenylethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((-)trans-CBD-PET). Or its pharmaceutically acceptable salts or hydrates.

6. The use of claim 1 or 2, wherein the compound is (1'R,2'R)-4-(4-hydroxyphenylethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((-)trans-CBD-PET-OH) Or its pharmaceutically acceptable salts or hydrates.

7. The use of claim 2, wherein the attack is a generalized attack.

8. The use of claim 2, wherein the seizure is a tonic seizure.

9. The use of claim 2, wherein the compound is CBD-PET or (-)trans-CBD-PET, and wherein the seizure is a myoclonic or clonic seizure.

10. The use of claim 2, wherein the compound is CBD-PET-OH or (-)trans-CBD-PET-OH, and wherein the seizure is a tonic seizure.

11. The use of claim 1, wherein the epilepsy is juvenile myoclonic epilepsy, Lennox-Gasto syndrome, or progressive myoclonic epilepsy.

12. The use of claim 2, wherein the seizure comprises one or more: a generalized onset seizure selected from myoclonic seizures, myoclonic-tonic-clonic seizures, clonic seizures, tonic seizures, or tonic-clonic seizures.

13. Use according to any one of claims 1, 2, 7-12, wherein the compound is packaged for delivery or delivered in an effective dose, said delivery being via one of the following routes: parenteral, oral, nasal (including nasogastric feeding), ocular, transmucosal, or transdermal.

14. Use according to any one of claims 1, 2, 7-12, wherein the patient is a human patient.

15. Use according to any one of claims 1, 2, 7-12, wherein the compound is administered to a patient at a dose of at least 8 mg / kg.

16. Compound 4-(4-hydroxyphenylethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (CBD-PET-OH) Or its pharmaceutically acceptable salts or hydrates.

17. Compound (1'R,2'R)-4-(4-hydroxyphenylethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ((-)trans-CBD-PET-OH) Or its pharmaceutically acceptable salts or hydrates.

18. A pharmaceutical composition comprising a compound according to claim 16 or 17 and one or more pharmaceutically acceptable excipients.

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