Use of 8,9-dihydrocannabidiol compounds

Abstract

The present invention provides a method for treating or reducing epileptic seizures, the method comprising a compound as described herein.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 815,735, filed on March 8, 2019, which is hereby incorporated by reference in its entirety for all purposes. Background of the Invention

[0003] There may be a fine line between therapeutic intervention and drug abuse, and there may be no better example than herbal cannabis and its products. Therapies involving cannabis have been a last resort in treating some intractable epilepsy cases, which is also one of the most powerful medical justifications for cannabis legalization. To circumvent the sedative effects of Δ 9 -tetrahydrocannabinol (THC), some studies have focused on its less intoxicating cannabidiol (CBD) isomer. However, like all natural cannabinoids, CBD is a controlled substance in most countries / regions and can be easily converted to THC using common chemicals. Alternatives to CBD include 8,9 - dihydrocannabidiol (H2CBD) and its analogs. H2CBD is a fully synthetic CBD analog prepared from inexpensive non - cannabis - derived compounds. Studies have found that H2CBD is comparable to CBD in reducing the number and severity of pentylenetetrazole - induced seizures in rats. Finally, H2CBD cannot be converted to THC through any reasonable synthetic pathway and can thus be freely sold without the possibility of abuse.

[0004] There is currently a great deal of research activity surrounding the potential of plant cannabinoids, i.e., compounds that occur naturally in the cannabis plant (Cannabis spp.), to treat various medical conditions, including anxiety, glaucoma, epilepsy, spasticity, inflammation, neurodegenerative diseases, mood disorders, and even cancer. However, the opportunities for the therapeutic potential of cannabinoids are weighed against a number of drawbacks, including adverse health effects, the potential for abuse, cognitive and motor impairments, psychiatric disorders, legal issues, and the environmental impact of cannabis cultivation. In addition, herbal cannabis has been shown to contain over 500 chemical entities, including approximately 100 cannabinoids as well as various other terpenes, phenols, flavonoids, lipids, and steroids, the toxicity and mutagenicity of which have largely not been explored. Of the two main cannabinoids present in cannabis, namely Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), the adverse effects (intoxication, ataxia, tachycardia, drowsiness, dry mouth, and excessive swallowing) are mainly attributed to the former, and for this reason, CBD is often singled out for pharmacological research.

[0005] CBD is extracted from the cannabis plant. There may be a range of impurities and there are growing concerns about pesticide contamination, especially in the current very erratic climate. Even if pure CBD is sold, it is technically trivial to chemically convert CBD to THC. If CBD becomes freely available, this could lead to a culture similar to the "meth labs" phenomenon of pseudoephedrine to methamphetamine, except that "hash labs" would involve a much simpler chemically conversion logically. Pure THC, without CBD to counteract its psychoactive effects, is a potentially dangerous drug. An attendant responsibility of extracting CBD from cannabis is the cultivation of cannabis, which has potential environmental impacts in terms of high water use and pesticide / herbicide effluent burden.

[0006] Among the potential therapeutic indications of cannabis, its most notable use can be considered as an anti-epileptic drug. Epilepsy is a collective term for a range of disorders characterized by recurrent, unpredictable seizures, the consequences of which often have a profound impact on quality of life. Historical and anecdotal evidence, as well as a large number of case studies documenting the actual unique efficacy of cannabis in treating refractory epilepsy cases, have led to strong support for the legalization of cannabis. The clinical data supporting the therapeutic potential of CBD as an anti-epileptic drug, while encouraging, are limited in terms of the number of studies and the subjects involved. On the other hand, there is preclinical evidence of broad anti-convulsant activity of CBD and THC in acute animal models of seizures.

[0007] One advantage of H2CBD is that, although it is similar to CBD, it is not present in cannabis extracts and is therefore not a controlled substance. Perhaps more importantly, in stark contrast to CBD itself, there is no reasonable synthetic route to convert H2CBD to THC because H2CBD lacks the double bond that enables the conversion of CBD to THC. Although H2CBD has been prepared from natural CBD, H2CBD can also be prepared by a highly efficient, total synthesis method to avoid being an intermediate of any listed substance, thus also avoiding the need to grow cannabis to supply H2CBD. What is needed are analogs of H2CBD and methods of using these compounds to treat epilepsy and other disorders. Surprisingly, the present invention meets this need and other needs. Summary of the Invention

[0009] In one embodiment, the present invention provides a method of treating or alleviating seizures, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] which does not produce a hypnotic effect on the subject, thereby treating seizures, wherein: n is 1 or 2; R 1a and R1d each independently is -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, wherein R 1a or R 1d at least one of which is methyl or isopropyl; R 1b and R 1c each independently is hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; or, R 1b combines with R 1d and the atoms to which they are attached to form a C 4-8 cycloalkyl, wherein the cycloalkyl is substituted with 1 - 3 R 1e groups; R 1e is H, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2a is -OR 2f 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2b and R 2c each independently is hydrogen, halogen, -OR 2f or -NR 2f R 2g ; R 2d and R 2e each independently is -OH, -OC(O)R 2f 、-OR 2f 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; or, R 2d and R 1a combine with the atoms to which they are attached to form a C 6-12 heterocycloalkyl; or, R 2d and R 1b combine with the atoms to which they are attached to form a C 5-12 heterocycloalkyl; R 2f and R 2g each independently is hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; the dotted lines a, b, and c each independently are none or a chemical bond, wherein when n is 2, the dotted line a is none, wherein when R 1b is oxygen and does not bond with R 1aWhen forming an epoxide ring, the dashed line b is a chemical bond, where when R 1c is oxygen, the dashed line c is a chemical bond; and the dashed circle d is none or 1, 2, or 3 chemical bonds.

[0012] In another embodiment, the present invention provides a method for reducing the frequency of epileptic seizures, comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, without causing a hypnotic effect on the subject, thereby reducing the frequency of epileptic seizures.

[0013] In another embodiment, the present invention provides a method for alleviating the hypnotic effect of cannabidiol in treating epileptic seizures, comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, thereby alleviating the hypnotic effect of cannabidiol in treating epileptic seizures.

[0014] In another embodiment, the present invention provides a compound of formula IA-1:

[0015]

[0016] wherein n is 1 or 2; R 1a is -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 1b is hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; R 1d is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2a is -OR 2d 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2d and R 2e are each independently -OH, -OC(O)R 2f 、-O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2f is hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20Alkynyl; and the dashed circle d is none or 1, 2 or 3 chemical bonds; wherein when R 1a is methyl, R 1d is isopropyl, R 2d and R 2e are both -OH, and R 2a is C 1-20 alkyl, then the compound is not

[0017]

[0018] and

[0019] wherein when R 1a is methyl, R 1d is propyl, R 2b is pentyl, and R 2a and R 2e are both -OH, then the compound is not

[0020]

[0021] Brief Description of the Drawings

[0022] Figure 1 Shows the chemical structures of THC, CBD, and H2CBD.

[0023] Figure 2 A - D in -1 shows the effects of H2CBD on acute, PTZ - induced primary generalized seizures in rats. Vehicle, H2CBD (50, 100, and 200 mg kg -1 ) and CBD (200 mg kg Figure 2 ) treatments were followed by PTZ administration. The proportion of animals ( Figure 2 in A) showing tonic - clonic seizures (gray - shaded area) and the median (middle bar), inter - quartile range (upper and lower bars), and individuals (●) of the maximum seizure severity ( Figure 2 in B) were affected. * = P < 0.05; *** = P < 0.001. The error bars in ( Figure 2 in B) show SEM. In each case, n = 12 animals per group. The brain ( Figure 2 in C) and blood concentrations (

[0024] Figure 3 of H2CBD (50, 100, and 200 mg / kg) and CBD (200 mg / kg) Figure 2 in D) were evaluated from autopsy samples obtained 90 minutes after cannabinoid administration. n ≥ 5 animals per group. The figure shows the results of the median (middle bar), inter - quartile range (upper and lower bars), and individual animals (●). * = P < 0.05; ** = P < 0.01.A - C therein shows the spontaneous activity in the open field within 30 minutes starting from 45 minutes after drug or vehicle injection. The horizontal plane movement ( Figure 3 in A), vertical plane movement ( Figure 3 in B), and time in the center of the open field ( Figure 3 in C) of the drug group and the vehicle group are shown.

[0025] Figure 4 The comparison between the positive control CBD (left) and H2CBD (right) in preventing PTZ - induced seizures in mice is shown. The dose of both drugs is 200 mg / kg -1 , while the dose of PTZ is 85 mg / kg -1 . For tonic - clonic seizures, running was observed, followed by no hind - limb extension. For tonic extension, running was observed followed by hind - limb extension. Clonus refers to involuntary, rhythmic muscle contractions and relaxations. Twitch refers to sudden, involuntary muscle contractions. Compared with the vehicle group, *P = 0.025, **P = 0.004, ***P = 0.0002. DETAILED DESCRIPTION

[0026] I. General

[0027] The present invention provides a method for treating or alleviating seizures, and a method for reducing the seizure frequency and alleviating the hypnotic effect produced by treating seizures with cannabidiol using H2CBD and its analogs. The present invention also provides new cannabidiol derivatives.

[0028] II. Definitions

[0029] Unless otherwise specifically stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. In addition, any method or material similar or equivalent to the methods or materials described in the present invention can be used in the implementation of the present invention. For the purposes of the present invention, the following terms are defined.

[0030] "A", "an", or "the" includes not only aspects with a single member, but also aspects with more than one member. For example, the singular forms of "a", "an", or "the", unless clearly stated otherwise herein, include the plural forms. Thus, for example, a reference to "a cell" includes a plurality of such cells, a reference to "a pharmaceutical agent" includes one or more pharmaceutical agents known to those skilled in the art, and so on.

[0031] "Alkyl" refers to a straight - chain or branched - chain saturated aliphatic group having the indicated number of carbon atoms. Alkyl can include any number of carbons, such as C 1-2 , C 1-3 , C1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. The alkyl group may be substituted or unsubstituted.

[0032] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one double bond. The alkenyl group may include any number of carbon atoms, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 . The alkenyl group may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatriene. The alkenyl group may be substituted or unsubstituted.

[0033] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. The alkynyl group may include any number of carbon atoms, such as C2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 . Examples of propargyl groups include, but are not limited to, ethynyl, propargyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. The alkynyl group may be substituted or unsubstituted.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms or the specified number of atoms. The cycloalkyl group may include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyls include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl is a saturated monocyclic C 3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic C 3-6When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl can be substituted or unsubstituted.

[0035] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms of N, O, and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -. Heterocycloalkyl can include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), ethylene oxide, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl can also be fused with an aromatic or non-aromatic ring system to form members including, but not limited to, dihydroindole. Heterocycloalkyl can be unsubstituted or substituted. For example, heterocycloalkyl can be substituted by C 1-6 alkyl or oxo (=O), etc.

[0036] "Epoxide" refers to a three-atom cyclic ether having the following structure:

[0037]

[0038] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0039] "Isomer" refers to compounds having the same chemical formula but different ways of connecting atoms in the molecule, resulting in different chemical structures. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and regioisomers. Examples of stereoisomers include, but are not limited to, diastereoisomers and enantiomers.

[0040] "Pharmaceutically acceptable salts" refers to salts of a compound where the compound is suitable for administration to a subject. Representative pharmaceutically acceptable salts include acetate, ascorbate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, ethanedisulfonate, fumarate, gentisate, gluconate, glucuronate, glutamate, hippurate, hydrobromide, hydrochloride, isethionate, lactate, lactobionate, maleate, malate, mandelate, mesylate, mucate, naphthalenesulfonate, naphthalene-1,5-disulfonate, naphthalene-2,6-disulfonate, nicotinate, nitrate, orotate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, tosylate, and xinafoate salts, among others.

[0041] "Cannabidiol", also known as CBD, refers to a compound having the following structure:

[0042]

[0043] "H2CBD" or "dihydrocannabidiol" refers to a compound having the following structure:

[0044]

[0045] "Hypnotic effect" or "anesthetic effect" refers to the induction of sleep. Drugs that can cause a hypnotic effect include psychotropic drugs that can induce sleep. Types of hypnotic drugs include, but are not limited to, cannabinoids, benzodiazepines, quinazolinones, imidazopyridines, and barbiturates.

[0046] "Subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0047] "Alleviate" refers to a decrease or reduction in the severity of a disorder or symptom.

[0048] "Treat", "treating", "treatment" refers to any indication of success in the treatment or alleviation of an injury, abnormality, disorder, or symptom (e.g., pain), including any objective or subjective parameter, such as elimination; remission; reduction in the severity of symptoms or making the patient more tolerant of the symptoms, injury, abnormality, or disorder; decreasing the frequency or duration of the symptoms or disorder; or, in some cases, preventing the onset of symptoms. Treatment or alleviation of symptoms can be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0049] "Administer" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device such as a microosmotic pump, to a subject.

[0050] "Therapeutically effective amount or dose" or "therapeutically sufficient amount or dose" or "effective amount or sufficient amount or dose" means a dose that, when administered thereto, produces a therapeutic effect. The exact dose will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1 - 3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Lippincott, Williams and Wilkins). In sensitized cells, the therapeutically effective dose is generally lower than the conventional therapeutically effective dose for non - sensitized cells.

[0051] "Subject" means an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0052] III. Methods of Treatment

[0053] The compounds of the present invention can be used to treat or reduce seizures. The compounds of the present invention can also be used to reduce the frequency of seizures. The compounds of the present invention can also be used to reduce the hypnotic effect of cannabidiol in treating seizures.

[0054] In some embodiments, the compounds of the present invention are used to treat or reduce convulsive effects. In some embodiments, the compounds of the present invention are used to treat or reduce seizures. In some embodiments, the compounds of the present invention are used to treat or reduce epilepsy. In some embodiments, the compounds of the present invention have anticonvulsant properties.

[0055] A. Method for treating or reducing epileptic seizures

[0056] In some embodiments, the present invention provides a method of treating or reducing epilepsy or seizures, comprising administering to a subject in need thereof a therapeutically effective amount of a low - abuse - potential cannabinoid.

[0057] In some embodiments, the present invention provides a method for treating or alleviating epilepsy or epileptic seizures, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. In some embodiments, the present invention provides a method for treating or alleviating epileptic seizures, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof.

[0058] In some embodiments, the present invention provides a method for treating or alleviating epileptic seizures, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0059]

[0060] which does not produce a hypnotic effect on the subject, thereby treating epileptic seizures, wherein: n is 1 or 2; R 1a and R 1d are each independently -CO 2 R 1e , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, wherein at least one of R 1a or R 1d is methyl or isopropyl; R 1b and R 1c are each independently hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; or, R 1b combines with R 1d and the atoms to which they are attached to form a C 4-8 cycloalkyl, wherein the cycloalkyl is substituted with 1 - 3 R 1e groups; R 1e is H, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2a is -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2b and R 2c are each independently hydrogen, halogen, -OR 2f or -NR 2f R 2g ; R 2d and R 2e are each independently -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl, C2-20 an alkenyl or C 2-20 alkynyl; or, R 2d and R 1a combine with the atoms to which they are attached to form a C 6-12 heterocycloalkyl; or, R 2d and R 1b combine with the atoms to which they are attached to form a C 5-12 heterocycloalkyl; R 2f and R 2g are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; the dashed lines a, b, and c are each independently none or a chemical bond, where when n is 2, the dashed line a is none, where when R 1b is oxygen and does not combine with R 1a to form an epoxide ring, the dashed line b is a chemical bond, where when R 1c is oxygen, the dashed line c is a chemical bond; and the dashed circle d is none or 1, 2, or 3 chemical bonds.

[0061] In some embodiments, the present invention provides a method for treating or alleviating seizures, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

[0062]

[0063] which does not produce a hypnotic effect on the subject, thereby treating seizures, wherein: n is 1 or 2; R 1a and R 1d are each independently -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, wherein at least one of R 1a or R 1d is methyl or isopropyl; R 1b and R 1c are each independently hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; or, R 1b combines with R 1d and the atoms to which they are attached to form a C 4-8 cycloalkyl, wherein the cycloalkyl is substituted with 1 - 3 R 1e groups; R 1e is H, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R2a is -OR 2f 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2b and R 2c are each independently hydrogen, halogen, -OR 2f or -NR 2f R 2g ; R 2d and R 2e are each independently -OH, -OC(O)R 2f 、-O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2f and R 2g are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; the dotted lines a, b, and c are each independently none or a chemical bond, where when n is 2, a is none, where when R 1b is oxygen and does not combine with R 1a to form an epoxide ring, the dotted line b is a chemical bond, where when R 1c is oxygen, the dotted line c is a chemical bond; and the dotted circle d is none or 1 or 2 chemical bonds.

[0064] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0065] In some embodiments, R 1a and R 1d are each independently -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, where at least one of R 1a or R 1d is methyl or isopropyl; R 1b and R 1c are each independently hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; or, R 1b combines with R 1d and the atoms to which they are attached to form a C 4-8Cycloalkyl, wherein the cycloalkyl is substituted by 1 to 3 R 1e groups; R 1e is H, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl.

[0066] In some embodiments, R 1a and R 1d are each independently -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 1a and R 1d are each independently C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 1a and R 1d are each independently C 1-20 alkyl or C 2-20 alkenyl. In some embodiments, R 1a and R 1d are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl. In some embodiments, R 1a and R 1d are each independently methyl, ethyl, propyl, isopropyl. In some embodiments, R 1a is methyl. In some embodiments, R 1d is isopropyl. In some embodiments, R 1a is methyl and R 1d is isopropyl.

[0067] In some embodiments, R 1b and R 1c are each independently hydrogen or oxygen. In some embodiments, R 1b is oxygen, or R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring. In some embodiments, R 1b combines with R 1d and the atoms to which they are attached to form a C 4-8 cycloalkyl. In some embodiments, R 1b is oxygen. In some embodiments, R 1b is hydrogen. In some embodiments, R 1c is oxygen. In some embodiments, R 1c is hydrogen.

[0068] In some embodiments, R 2a is -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2b and R 2c are each independently hydrogen, halogen, -OR 2f or -NR 2f R 2g ; R 2d and R 2e are each independently -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; and R 2f and R 2g are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl.

[0069] In some embodiments, R 2a is -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 2a is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 2a is C 1-20 alkyl. In some embodiments, R 2a is C 4-15 alkyl. In some embodiments, R 2a is C 4-10 alkyl. In some embodiments, R 2a is butyl, pentyl, isopentyl, hexyl, 2-methylhex-2-yl, heptyl, 3-methylhept-2-yl or octyl. In some embodiments, R 2a is pentyl, isopentyl, hexyl, 2-methylhex-2-yl, heptyl or 3-methylhept-2-yl.

[0070] In some embodiments, R 2b and R 2c are each independently hydrogen, halogen, -OR 2f or -NR 2f R 2g . In some embodiments, R 2b and R2c Each independently is hydrogen, a halogen, or -OR 2f . In some embodiments, R 2b and R 2c each independently is hydrogen, F, Cl, -OH, or -O-C 1-6 alkyl. In some embodiments, R 2b and R 2c each independently is hydrogen or F. In some embodiments, R 2b and R 2c are both hydrogen. In some embodiments, R 2b and R 2c are both F.

[0071] In some embodiments, R 2d and R 2e each independently is -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl. In some embodiments, R 2d and R 2e each independently is -OH, -OC(O)R 2f , or -OR 2f . In some embodiments, R 2d and R 2e each independently is -OH, -OC(O)Me, -OC(O)Et, -OMe, -OEt, -OPr, or -OBu. In some embodiments, R 2d and R 2e each independently is -OH, -OC(O)Me, or -OMe. In some embodiments, R 2d and R 2e are both -OH.

[0072] In some embodiments, R 2f and R 2g each independently is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl. In some embodiments, R 2f and R 2g each independently is hydrogen, C 1-20 alkyl, or C 2-20 alkenyl. In some embodiments, R 2f and R 2g each independently is hydrogen or C 1-20 alkyl. In some embodiments, R 2f and R 2gEach independently is hydrogen, methyl, ethyl, propyl or isopropyl. In some embodiments, R 2f and R 2g Each independently is hydrogen or methyl. In some embodiments, R 2f and R 2g Are both hydrogen. In some embodiments, R 2f and R 2g Are both methyl.

[0073] In some embodiments, the dashed lines a, b and c are each independently none or a chemical bond, wherein when n is 2, the dashed line a is none, wherein when R 1b Is oxygen and does not combine with R 1a To form an epoxide ring, the dashed line b is a chemical bond, and when R 1c Is oxygen, the dashed line c is a chemical bond.

[0074] In some embodiments, the dashed line a is none or a chemical bond. In some embodiments, a is none. In some embodiments, when n is 2, a is none. In some embodiments, in some embodiments, the dashed line b is none or a chemical bond. In some embodiments, b is none. In some embodiments, b is a chemical bond. In some embodiments, when R 1b Is oxygen and does not combine with R 1a To form an epoxide ring, the dashed line b is a chemical bond. In some embodiments, the dashed line c is none or a chemical bond. In some embodiments, c is none. In some embodiments, c is a chemical bond. In some embodiments, when R 1c Is oxygen, the dashed line c is a chemical bond.

[0075] In some embodiments, the dashed circle d is none, 1, 2 or 3 chemical bonds. In some embodiments, the dashed circle d is none, 1 or 2 chemical bonds. In some embodiments, the dashed circle d is none or 1 chemical bond. In some embodiments, the dashed circle d is none. In some embodiments, the dashed circle d is 1 chemical bond. In some embodiments, the dashed circle d is 2 chemical bonds. In some embodiments, the dashed circle d is 3 chemical bonds.

[0076] In some embodiments, the present invention provides a method, wherein the compound is of formula Ia or a pharmaceutically acceptable salt thereof:

[0077]

[0078] In some embodiments, the present invention provides a method, wherein the compound is of formula Ib or a pharmaceutically acceptable salt thereof:

[0079]

[0080] In some embodiments, the present invention provides a method, wherein the compound is of formula Ic or a pharmaceutically acceptable salt thereof:

[0081]

[0082] In some embodiments, the present invention provides a method, wherein the compound is of formula Id or a pharmaceutically acceptable salt thereof:

[0083]

[0084] In some embodiments, the present invention provides a method, wherein the compound is of formula Ie or a pharmaceutically acceptable salt thereof:

[0085]

[0086] In some embodiments, the present invention provides a method, wherein the compound is of formula If or a pharmaceutically acceptable salt thereof:

[0087]

[0088] In some embodiments, the present invention provides a method, wherein the compound is of formula Ig or a pharmaceutically acceptable salt thereof:

[0089]

[0090] In some embodiments, the present invention provides a method, wherein the compound is of formula Ih or a pharmaceutically acceptable salt thereof:

[0091]

[0092] In some embodiments, the present invention provides a method, wherein the compound is of formula Ii or a pharmaceutically acceptable salt thereof:

[0093]

[0094] wherein R 2a1 、R 2a2 and R 2a3 are each independently C 1-19 alkyl, C 2-19 alkenyl or C 2-19 alkynyl. In some embodiments, R 2a1 、R 2a2 and R 2a3 are each independently C 1-19 alkyl. In some embodiments, R 2a1 、R 2a2 and R 2a3 are each independently C 1-10Alkyl. In some embodiments, R 2a1 , R 2a2 and R 2a3 are each independently C 1-5 alkyl.

[0095] In some embodiments, the present invention provides a method wherein the compound is of formula Ij or a pharmaceutically acceptable salt thereof:

[0096]

[0097] wherein R 2d is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl.

[0098] In some embodiments, the present invention provides a method wherein the compound is of formula Ik or a pharmaceutically acceptable salt thereof:

[0099]

[0100] wherein R 2a is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl.

[0101] In some embodiments, the present invention provides a method wherein the compound is:

[0102]

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the present invention provides a method wherein the compound of formula I is 8,9-dihydrocannabidiol:

[0105]

[0106] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, electroencephalogram (EEG), high-density electroencephalogram, computed tomography (CT) scan, magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), subtraction-ictal SPECT co-registered with MRI (SISCOM), statistical parametric mapping (SPMJ), curry analysis, and magnetoencephalogram (MEG) can be used to determine treatment or alleviation of seizures.

[0108] In some embodiments, animal epilepsy models can be used to determine the treatment or alleviation of seizures. In some embodiments, the animal epilepsy model can be, but is not limited to, a generalized epilepsy model, a limbic epilepsy model, a unique epilepsy model of an animal that develops epilepsy through kindling, a chronic epilepsy model, and a model in which an animal is electrically shocked and includes tonic convulsions. In some embodiments, the animal epilepsy model can be, but is not limited to, a maximal PTZ epilepsy model, a 6Hz model, a corneal kindling mouse model, a pilocarpine-induced status epilepticus model, and a maximal electroshock model.

[0109] B. Method for reducing the frequency of epileptic seizures

[0110] In some embodiments, the present invention provides a method for reducing epilepsy. In some embodiments, the present invention provides a method for reducing the frequency of epileptic seizures.

[0111] In some embodiments, animal studies can be used to determine the reduction of the frequency of epileptic seizures. In some embodiments, animal studies include, but are not limited to, rodents, rats, mice, zebrafish. In some embodiments, animal studies include administering the compound of the present invention about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours before administering a convulsant drug. In some embodiments, animal studies include administering the compound of the present invention about 1 hour before administering a convulsant drug.

[0112] In some embodiments, animal epilepsy models can be used to determine the reduction of the frequency of epileptic seizures. In some embodiments, the animal epilepsy model can be, but is not limited to, a generalized epilepsy model, a limbic epilepsy model, a unique epilepsy model of an animal that develops epilepsy through kindling, a chronic epilepsy model, and a model in which an animal is electrically shocked and includes tonic convulsions. In some embodiments, the animal epilepsy model can be, but is not limited to, a maximal PTZ epilepsy model, a 6Hz model, a corneal kindling mouse model, a pilocarpine-induced status epilepticus model, and a maximal electroshock model.

[0113] In some embodiments, the present invention provides a method for reducing the frequency of epileptic seizures, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, which does not produce a hypnotic effect on the subject, thereby reducing the frequency of epileptic seizures.

[0114] C. Method for reducing hypnotic effects

[0115] It is known that many cannabinoids cause a hypnotic effect. In some embodiments, the present invention provides a method for alleviating the hypnotic effect of cannabidiol in the treatment of epilepsy or epileptic seizures. In some embodiments, the present invention provides a method for alleviating the hypnotic effect of cannabidiol in the treatment of epilepsy.

[0116] In some embodiments, motor activity can be used to determine the reduction of the hypnotic effect of cannabidiol treatment of epilepsy or seizures. In some embodiments, motor activity can be measured by, but not limited to, movement in the horizontal plane, movement in the vertical plane, and time in the center of an open field.

[0117] In some embodiments, administration of the compounds of the invention causes minimal or no behavioral changes. Examples of behavioral changes include, but are not limited to, hypnotic effects and sedative effects. In some embodiments, treatment with high doses of the compounds of the invention causes minimal or no behavioral changes.

[0118] In some embodiments, the invention provides a method for reducing the hypnotic effect of cannabidiol treatment of epilepsy, comprising administering to a subject in need thereof a therapeutically effective amount of the claimed compound of the invention or a pharmaceutically acceptable salt thereof, thereby reducing the hypnotic effect of cannabidiol treatment of epilepsy.

[0119] IV. Compounds

[0120] In some embodiments, the invention provides a compound of formula IA-1:

[0121]

[0122] wherein n is 1 or 2; R 1a is -CO 2 R 1e , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 1b is hydrogen or oxygen; or, when R 1b is oxygen, R 1b combines with R 1a and the atoms to which they are attached to form an epoxide ring; R 1d is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2a is -OR 2d , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2d and R 2e are each independently -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; R 2f is hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C2-20 Alkynyl; and the dashed circle d is none or 1, 2 or 3 chemical bonds; wherein when R 1a is methyl, R 1d is isopropyl, R 2d and R 2e are both -OH, and when R 2a is C 1-20 alkyl, then the compound is not

[0123]

[0124] And

[0125] Wherein when R 1a is methyl, R 1d is propyl, R 2b is pentyl, and R 2a and R 2e are both -OH, then the compound is not

[0126]

[0127] In some embodiments, when R 1a is methyl, R 1d is isopropyl, R 2d and R 2e are both -OH, and when R 2a is C 1-20 alkyl, then the compound is not

[0128]

[0129] And

[0130] Wherein when R 1a is methyl, R 1d is propyl, R 2b is pentyl, and R 2a and R 2e are both -OH, then the compound is not

[0131]

[0132] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0133] In some embodiments, R 1a is -CO 2 R 1e 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R1a is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 1a is C 1-20 alkyl. In some embodiments, R 1a is C 1-8 alkyl. In some embodiments, R 1a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl. In some embodiments, R 1a is methyl, ethyl, propyl or isopropyl. In some embodiments, R 1a is methyl.

[0134] In some embodiments, R 1b is hydrogen or oxygen. In some embodiments, R 1b is hydrogen. In some embodiments, R 1b is oxygen.

[0135] In some embodiments, R 1d is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 1d is C 1-20 alkyl or C 2-20 alkenyl. In some embodiments, R 1d is C 1-10 alkyl or C 2-10 alkenyl. In some embodiments, R 1d is C 5-8 alkenyl. In some embodiments, R 1d is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl. In some embodiments, R 1d is methyl, ethyl, propyl or isopropyl. In some embodiments, R 1d is isopropyl. In some embodiments, R 1d is 6-methylhex-5-en-2-yl.

[0136] In some embodiments, R 2a is -OR 2d 、C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 2a is C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 2ais C 1-20 alkyl. In some embodiments, R 2a is C 4-15 alkyl. In some embodiments, R 2a is C 4-10 alkyl. In some embodiments, R 2a is butyl, pentyl, isopentyl, hexyl, 2-methylhex-2-yl, heptyl, 3-methylhept-2-yl or octyl. In some embodiments, R 2a is pentyl, isopentyl, hexyl, 2-methylhex-2-yl, heptyl or 3-methylhept-2-yl.

[0137] In some embodiments, R 2d and R 2e are each independently -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl; and R 2f is hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl.

[0138] In some embodiments, R 2d and R 2e are each independently -OH, -OC(O)R 2f , -OR 2f , C 1-20 alkyl; and R 2f is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl. In some embodiments, R 2d and R 2e are each independently -OH, -OC(O)R 2f or -OR 2f ; and R 2f is C 1-6 alkyl. In some embodiments, R 2d and R 2e are each independently -OH, -OC(O)Me, -OC(O)Et, -OMe, -OEt, -OPr or -OBu. In some embodiments, R 2d and R 2e are each independently -OH, -OC(O)Me or -OMe. In some embodiments, R 2d and R 2e are both -OH.

[0139] In some embodiments, R2f is hydrogen, C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl. In some embodiments, R 2f is hydrogen, C 1-20 alkyl or C 2-20 alkenyl. In some embodiments, R 2f is hydrogen or C 1-20 alkyl. In some embodiments, R 2f is hydrogen or C 1-10 alkyl. In some embodiments, R 2f is hydrogen, methyl, ethyl, propyl or isopropyl. In some embodiments, R 2f is hydrogen or methyl. In some embodiments, R 2f is hydrogen. In some embodiments, R 2f is methyl.

[0140] In some embodiments, the dashed circle d is absent or is 1, 2 or 3 chemical bonds. In some embodiments, the dashed circle d is absent or is 1 or 2 chemical bonds. In some embodiments, the dashed circle d is absent or is 1 chemical bond. In some embodiments, the dashed circle d is absent. In some embodiments, the dashed circle d is 1 chemical bond. In some embodiments, the dashed circle d is 2 chemical bonds. In some embodiments, the dashed circle d is 3 chemical bonds.

[0141] In some embodiments, the present invention provides a compound, wherein the compound is of formula (IA-1a) or a pharmaceutically acceptable salt thereof:

[0142]

[0143] In some embodiments, the present invention provides a compound, wherein the compound is of formula (IA-1b) or a pharmaceutically acceptable salt thereof:

[0144]

[0145] In some embodiments, the present invention provides a compound, wherein the compound is of formula (IA-1c) or a pharmaceutically acceptable salt thereof:

[0146]

[0147] In some embodiments, the present invention provides a compound, wherein the compound is of formula (IA-1d) or a pharmaceutically acceptable salt thereof:

[0148]

[0149] In some embodiments, the present invention provides a compound, wherein the compound is of formula (IA-1e) or a pharmaceutically acceptable salt thereof:

[0150]

[0151] In some embodiments, the compounds of the present invention include, but are not limited to:

[0152]

[0153]

[0154]

[0155] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0156]

[0157] V. Formulations and Administration

[0158] The pharmaceutical compositions of the present invention can be formulated into various oral, parenteral and topical dosage forms. Oral formulations include tablets, pills, powders, capsules, liquids, lozenges, cachets, gels, syrups, pastes, suspensions, etc. suitable for ingestion by a patient. The compositions of the present invention can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal injection. In addition, the compositions described herein can be administered by inhalation, such as intranasal administration. In addition, the compositions of the present invention can be administered transdermally. The compositions of the present invention can also be administered by intraocular, intravaginal and intrarectal routes, including suppositories, insufflations, powders and aerosol formulations (e.g., steroid inhalers, see Rohatagi, J Clin.Pharmacal., 35:1187-1193, 1995; Tjwa, Ann.Allergy Asthma lmmunol., 75:107-111, 1995). Thus, the compositions of the present invention can also be administered by thin film drug delivery methods.

[0159] For the preparation of pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also function as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Formulation and administration techniques are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. ("Remington's").

[0160] The compounds of the present invention may also be in the form of salts, for example acid or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Co., Easton, Pa., 1985, which is incorporated herein by reference.

[0161] Pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, i.e., cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methylammonium salts.

[0162] Similar acid addition salts, such as those of inorganic acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided that a basic group (such as a pyridyl group) forms part of the structure.

[0163] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in conventional manner. The parent form of the compound differs in certain physical properties, such as solubility in polar solvents, from the various salt forms, but otherwise, for the purposes of the present invention, these salts are equivalent to the parent form of the compound.

[0164] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain from 5% to 70% or from 10% to 70% of the compounds of the present invention.

[0165] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting waxes; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol or sorbitol, starches from corn, wheat, rice, potato or other plants; cellulose such as methylcellulose, hydroxymethylcellulose or sodium carboxymethylcellulose; and gums including gum arabic and tragacanth; and proteins including, but not limited to, gelatin and collagen. If desired, disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate may be added.

[0166] The dragee cores have suitable coatings (such as concentrated sugar solutions), and such dragees may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gels, polyethylene glycol and / or titanium dioxide, shellac and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coatings for product identification or to characterize the amount (i.e., dose) of the active compound. The pharmaceutical formulations of the present invention can also be used orally, such as push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and coatings such as glycerol or sorbitol. The push-fit capsules may contain the compounds of the present invention mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In the soft capsules, the compounds of the present invention may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin or liquid polyethylene glycol, with or without stabilizers.

[0167] To prepare suppositories, first melt a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, and then uniformly disperse the compounds of the present invention therein by stirring. Then pour the molten homogeneous mixture into a mold of appropriate size and allow it to cool so as to solidify.

[0168] Formulations in liquid form include solutions, suspensions and emulsions, such as aqueous or water / propylene glycol solutions. For parenteral injection, the liquid formulations may be formulated in solutions in aqueous polyethylene glycol.

[0169] An aqueous solution suitable for oral use can be prepared by dissolving the compound of the present invention in water and adding, if desired, suitable colorants, flavorants, stabilizers, and thickeners. An aqueous suspension for oral use can be prepared by finely dispersing the active ingredient with a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and acacia, and a dispersing or wetting agent such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate) in water. The aqueous suspension may also contain one or more preservatives such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate, one or more colorants, one or more flavorants, and one or more sweeteners such as sucrose, aspartame, or saccharin. The formulation can be adjusted for osmotic pressure.

[0170] The formulations also include solid forms that are intended to be converted shortly before use into a liquid form for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizers, etc.

[0171] An oily suspension can be formulated by suspending the compound of the present invention in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin; or a mixture of these. The oily suspension may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents can be added to provide a palatable oral formulation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by adding an antioxidant such as ascorbic acid. For examples of injectable oil carriers, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be the above vegetable oil or mineral oil or a mixture thereof. Suitable emulsifying agents include natural gums (e.g., acacia and tragacanth), natural phospholipids (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydride (e.g., sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweetening agents and flavorants, as in the formulation of syrups and elixirs. Such formulations may also contain demulcents, preservatives, or colorants.

[0172] The compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be formulated for administration by intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12: 857-863, 1995); or, as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). Transdermal and intradermal routes can provide sustained delivery for weeks or months.

[0173] In some embodiments, the pharmaceutical compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or an organ cavity. The formulations for administration generally comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents that can be used include water and Ringer's solution, isotonic sodium chloride. In addition, sterile, fixed oils can generally be used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these formulations can vary widely and will be selected primarily based on the fluid volume, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For IV administration, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. Such suspensions can be formulated using those suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (such as a 1,3-butanediol solution).

[0174] In some embodiments, the formulations of the compositions of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using ligands attached to liposomes or directly to oligonucleotides that bind to cell surface membrane protein receptors and cause endocytosis. By using liposomes, especially when the liposome surface carries ligands specific for target cells or is otherwise preferentially targeted to specific organs, the compositions of the present invention can be concentrated and delivered in vivo to target cells. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0175] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the compound of the present invention. The unit dosage form can be a packaged formulation that contains discrete quantities of the formulation, such as tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be the capsule, tablet, cachet, or lozenge itself, or can be any of these in a suitable number of packaged forms.

[0176] The compounds of the present invention can be present in any suitable amount and can depend on a variety of factors, including but not limited to the weight and age of the subject, the disease state, etc. Suitable dosage ranges for the compounds of the present invention include from about 0.1 mg to about 10,000 mg, or from about 1 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 250 mg. Suitable doses of the compounds of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg.

[0177] The compounds of the present invention can be administered at any suitable frequency, interval, and duration. For example, the compounds of the present invention can be administered once an hour, or twice, three times, or more times an hour, once a day, or twice, three times, or more times a day, or once every 2, 3, 4, 5, 6, or 7 days to provide a preferred dose level. When the compounds of the present invention are administered more than once a day, representative intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, as well as 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present invention can be administered one, two, three, or more times, and the administration can last for 1 hour, 1 - 6 hours, 1 - 12 hours, 1 - 24 hours, 6 - 12 hours, 12 - 24 hours, 1 day, 1 - 7 days, one week, 1 to 4 weeks, one month, 1 - 12 months, one year, or longer, even indefinitely.

[0178] The composition can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful for modulating the glucocorticoid receptor, or in combination with adjuvants that may be ineffective alone but can contribute to the efficacy of the active agent.

[0179] The compounds of the present invention can be co - administered with another active agent. Co - administration includes administering the compound of the present invention and the active agent separately within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours. Co - administration also includes administering the compound of the present invention and the active agent simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or in any order sequentially. In addition, the compound of the present invention and the active agent can each be administered once a day, or twice, three times, or more times a day to provide a preferred dose level per day.

[0180] In some embodiments, co - administration can be accomplished by co - formulating, i.e., preparing a single pharmaceutical composition containing the compound of the present invention and the active agent. In other embodiments, the compound of the present invention and the active agent can be formulated separately.

[0181] The compounds and active agents of the present invention can be present in the compositions of the present invention in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). The compounds of the present invention and other active agents can be present in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1 or 100:1 (w / w). Other dosages and dosage ratios of the compounds and active agents of the present invention are applicable to the compositions and methods of the present invention.

[0182] VI. Examples

[0183] For the compounds of the present invention that display an asterisk (*) next to a stereocenter, the stereochemistry indicated represents the relative stereochemistry at that atom, rather than the absolute stereochemistry. For example, for the H2CBD compound shown by the following formula:

[0184]

[0185] The asterisk (*) indicates that the compound is trans at that atom and can be the (S,S) or (R,R) enantiomers, or a mixture thereof:

[0186]

[0187] In another example, for the H4CBD compound shown as follows:

[0188]

[0189] The asterisk (*) indicates that the compound can be either stereoisomeric form, retaining the relative stereochemistry, as shown below:

[0190]

[0191] Other compounds of the present invention that display an asterisk (*) represent the relative stereochemistry of the designated atom, rather than the absolute stereochemistry as described above.

[0192] In some embodiments, the compounds containing an asterisk (*) can have an enantiomeric excess (ee) of 0% to 100%. In some embodiments, the ee is 0% to about 90%. In some embodiments, the ee is 0% to about 70%. In some embodiments, the ee is 0% to about 50%. In some embodiments, the ee is 0% to about 30%. In some embodiments, the ee is 0%.

[0193] Example 1. Preparation of H2CBD

[0194] A solution of oleanol (1.72 g, 9.54 mmol) and food-grade α-phellandrene (1.41 g, 10.4 mmol, 1.09 eq) in benzene (5 mL) was treated with p-toluenesulfonic acid monohydrate (0.545 g, 2.87 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using gradient elution (100% hexane to a hexane solution of 10% diethyl ether) to give H2CBD (2.14 g, 71%) as a dark yellow oil. Spectral data ( 1 H-NMR, 13 C-NMR) were in complete agreement with the literature.

[0195] Example 2. 2-(6-Isopropyl-3-methylcyclohex-2-en-1-yl)-5-pentylbenzene-1,3-diol (8,9-dihydro cannabidiol, H2CBD)

[0196]

[0197] A 150 mL round-bottom Schlenk flask was equipped with a magnetic stir bar and a rubber septum. The flask was purged with nitrogen and oleanol (3.00 g, 16.6 mmol), toluene (50 mL), and p-toluenesulfonic acid monohydrate (190 mg, 6 mol%) were added. The flask was placed in a preheated (70 °C) oil bath and stirred for 15 min, then α-phellandrene (2.80 mL, 2.38 g, 17.4 mmol) was injected through the septum within 1 min. After 25 min, the reaction was quenched by pouring it into a mixture of saturated NaHCO 3 aqueous solution (20 mL) and ice (10 g). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give the crude product (5.25 g). The column was packed with 100 g of silica gel and equilibrated with a mixture of dichloromethane (15%) and hexane (85%). The crude product was loaded onto the column and eluted with 4 column volumes of the solvent mixture. Then the method was changed to gradient elution, and within the next 6 column volumes, the DCM content was gradually increased to 50%. The fractions containing the product were combined and the solvent was evaporated to give H 2 CBD (3.24 g, 62%) as a viscous pale yellow oil. 1 H NMR (400 MHz, CDCl 3)δ6.21(br s,3H),5.52(s,1H),4.71(s,1H),3.82(br d,J=9.8Hz,1H),2.44(t,J=7.8Hz,2H),2.12 - 2.10(m,2H),1.82 - 1.76(m,4H,incl.1.77s,3H),1.63 - 1.55(m,4H),1.45 - 1.27(m,6H),0.91 - 0.85(m,9H). 13 C NMR(101MHz,CDCl 3 )δ156.3(br),154.4(br),143.1,140.2,125.0,114.1,109.9(br),107.5(br),43.8,35.6(2C),31.7,30.85,30.8,28.0,23.8,22.7,22.2,21.8,16.5,14.2.MS(ESI):316[M,18%],273(8%),246(23%),231(100%).

[0198] Example 3. 5-Isopropyl-2-methyl-9-pentyl-3,4,5,6-tetrahydro-2H-2,6-methano-1-benzoxocin-7-ol (8,9-dihydro-iso-THC) Example 4. 4-(6-Isopropyl-3-methylcyclohex-2-en-1-yl)-5-pentylbenzene-1,3-diol (8,9-dihydro-

[0199]

[0200] Charge the round - bottom flask (50 mL) with oleanol (600 mg, 3.33 mmol), benzene (10 mL), p - toluenesulfonic acid monohydrate (40 mg, 6 mol%), and α - phellandrene (0.55 mL, 470 mg, 3.5 mmol). Heat the mixture under reflux for 1 h while removing water azeotropically using a Dean - Stark apparatus. After cooling to room temperature, quench the reaction into saturated NaHCO 3 aqueous solution, separate the organic phase, and extract the aqueous phase with ethyl acetate (2×10 mL). Wash the combined organic phases with water and brine, dry over magnesium sulfate, and evaporate the solvent. Purify the crude product by vacuum distillation to obtain 8,9 - dihydro - iso - THC as a colorless glass (780 mg, 74%), bp 192 - 198 °C / 200 mTorr. 1 H NMR(600MHz,CDCl 3) δ 6.28 (d, J = 4.5 Hz, 1H), 6.12 (d, J = 4.5 Hz, 1H), 4.54 (d, J = 4.4 Hz, 1H), 3.33 (br q, J = 2.9 Hz, 1H), 2.45 (dd, J = 7.0, 3.1 Hz, 2H), 1.95 - 1.70 (m, 3H), 1.63 - 1.48 (m, 7H), 1.36 - 1.25 (m, 9H, incl. 1.33 s, 3H), 1.09 (t, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 5.7 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 157.46, 152.08, 142.44, 111.71, 107.80, 106.05, 74.47, 44.34, 35.70, 34.98, 31.59, 30.79, 30.52, 29.35, 27.79, 26.24, 22.57, 22.07, 21.13, 20.52, 14.05. MS (ESI): 316 [M, 26%], 273 (7%), 260 (24%), 231 (100%).

[0201] Example 6. 2-Cyclohexyl-5-pentylbenzene-1,3-diol o-Cannabidiol, iso-H 2 CBD)

[0202]

[0203] A 100 mL round - bottom Schlenk flask was equipped with a magnetic stir bar and a rubber septum. The flask was purged with nitrogen and olive alcohol (1.80 g, 10.0 mmol), toluene (30 mL), p - toluenesulfonic acid monohydrate (60 mg, 3 mol%), and α - phellandrene (1.76 mL, 1.50 g, 11.0 mmol) were added. The reaction was stirred at room temperature for 6 h and quenched with saturated NaHCO 3 aqueous solution (20 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give the crude product (3.10 g). The column was packed with 100 g of silica gel and equilibrated with a mixture of dichloromethane (30%) and hexane (70%). The crude product was loaded onto the column and eluted with 6 CV of the solvent mixture. The fraction containing H 2 CBD (1.10 g, 34%) was evaporated. Then the column was further eluted with pure DCM, the fractions containing the product were combined, and the solvent was evaporated to give iso - H 2 CBD (1.40 g, 44%) as a viscous pale yellow oil. 1 H NMR (600 MHz, CDCl3 ) δ 6.24 (s, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 5.47 (s, 1H), 4.80 (s, 1H), 3.44 (d, J = 10.8 Hz, 1H), 2.66 (ddd, J = 15.0, 9.5, 6.0 Hz, 1H), 2.44 - 2.31 (m, 1H), 2.27 - 2.05 (m, 2H), 1.81 - 1.70 (m, 5H, incl. 1.77 s 3H), 1.56 - 1.48 (m, 3H), 1.37 - 1.30 (m, 5H), 0.91 - 0.87 (m, 3H), 0.84 (d, J = 9.9, 3H), 0.82 (d, J = 9.9, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 156.56, 154.55, 144.09, 139.95, 125.13, 120.24, 108.60, 102.47, 42.93, 38.30, 34.24, 31.90, 31.29, 30.60, 27.27, 23.65, 22.57, 22.16, 21.92, 16.79, 14.07. MS (ESI): 316 [M, 42%], 246 (67%), 231 (100%), 189 (44%).

[0204] Example 5. 2-(2-Isopropyl-5-methylcyclohexyl)-5-pentylbenzene-1,3-diol (tetrahydrocannabinol, H 4 CBD)

[0205]

[0206] A 250 mL autoclave was equipped with a magnetic stir bar and charged with H 2 CBD (6.00 g, 19.0 mmol), glacial acetic acid (100 mL), and platinum oxide (150 mg). The vessel was purged with H 2 and the reaction mixture was stirred at 400 psi H 2 for 12 h. Methanol (100 mL) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by vacuum distillation to give H 4 CBD (5.68 g, 94%) as a colorless glass, bp 194 - 196 °C at 200 mTorr. 1 H NMR (600 MHz, CDCl 3)δ6.18(s,1H),6.12(s,1H),4.62(d,J=3.3Hz,2H),2.99(td,J=11.4,3.7Hz,1H),2.42(t,J=7.9Hz,2H),2.09-1.96(m,1H),1.86-1.46(m,8H),1.36-1.25(m,4H),1.12-1.02(m,4H),0.91-0.86(m,6H),0.84(d,J=7.0Hz,3H),0.71(d,J=7.0Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ155.81,154.42,142.30,115.46,109.45,108.50,45.00,40.56,38.50,35.80,35.63,33.89,31.96,30.97,28.98,25.75,22.91,22.86,22.06,16.13,14.40.MS(ESI):318[M,27%],262(12%),233(58%),193(100%).

[0207] Example 7. 2-[6-(1,5-Dimethylhex-4-en-1-yl)-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-

[0208]

[0209] A 100 mL round-bottom flask was equipped with a magnetic stir bar and a rubber septum. To the flask was added oleanol (1.00 g, 5.55 mmol), cyclohexanol (1.70 g, 16.6 mmol) and 85% orthophosphoric acid (3 mL). The flask was sealed and the mixture was heated at 90 °C for 12 h with stirring. The reaction was cooled, the pressure was released, and the reaction was heated again at 130 °C for 1 h under a nitrogen stream. After cooling, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and the solvent was evaporated to give the crude product (1.2 g). Column chromatography on 40:60 dichloromethane:hexane gave 2-cyclohexyl-5-pentylbenzene-1,3-diol (470 mg, 33%) as a white crystalline solid, mp 57 - 58 °C. 1 H NMR(400MHz,CDCl 3)δ6.16(s,2H),4.57(s,2H),3.19 - 2.86(m,1H),2.43(t,J=7.8Hz,2H),2.01(dd,J=12.5,3.4Hz,2H),1.82(d,J=12.5Hz,2H),1.73 - 1.70(m,3H),1.62 - 1.49(m,2H),1.43 - 1.14(m,7H),0.89(t,J=6.7Hz,3H).. 13 C NMR(101MHz,CDCl 3 )δ154.71,142.20,116.95,108.93,77.36,35.57,35.39,31.70,30.80,30.64,27.53,26.36,22.69,14.17.MS(ESI):262[M,62%],219(70%),206(64%),137(100%).

[0210] 1,3-diol diacetate)

[0211]

[0212] A 150 ml round - bottomed Schlenk flask was equipped with a magnetic stir bar and a rubber septum. The flask was purged with nitrogen and olive alcohol (2.00 g, 11.1 mmol), toluene (35 mL) and p - toluenesulfonic acid monohydrate (125 mg, 6 mol%) were added. Then the flask was placed in a pre - heated (70 °C) oil bath and stirred for 15 minutes, and then a commercial ginger oil with 48 - 50% zingiberene content (5.40 mL) was injected through the septum within 1 minute. After 25 minutes, the reaction was quenched by pouring it into a mixture of saturated NaHCO 3 aqueous solution (20 mL) and ice (10 g). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give the crude product (6.00 g). The column was packed with 100 g of silica gel and equilibrated with a mixture of dichloromethane (10%) and hexane (90%). The crude product was loaded onto the column and eluted with 7 column volumes of the solvent mixture. Then the method was changed to gradient elution, and within the next 8 column volumes, the DCM content was gradually increased to 40%. The fractions containing the product were combined and the solvent was evaporated to give 2 - [6 - (1,5 - dimethylhex - 4 - en - 1 - yl) - 3 - methylcyclohex - 2 - en - 1 - yl] - 5 - pentylbenzene - 1,3 - diol (1.80 g, 42%) as a viscous pale yellow oil. 1 H NMR(400MHz,CDCl 3) δ 6.26 - 6.15 (br m, 2H), 6.01 (br s, 1H), 5.53 (s, 1H), 4.89 (t, J = 7.3 Hz, 1H), 4.51 (br s, 1H), 3.82 (d, J = 10.5 Hz, 1H), 2.45 (t, J = 7.8 Hz, 2H), 2.12 - 2.08 (m, 2H), 1.82 - 1.72 (m, 7H, incl. 1.77 s, 6H), 1.61 - 1.55 (m, 5H, incl 1.57 s, 3H), 1.42 - 1.18 (m, 8H), 0.90 - 0.83 (m, 7H). 13 C NMR (101 MHz, CDCl 3 ) δ 154.18 (br), 142.90, 139.94, 130.99, 124.97, 124.67, 113.78, 109.94 (br), 107.34 (br), 41.39, 35.77, 35.51, 35.36, 32.50, 31.60, 31.57, 30.84, 30.71, 25.99, 25.60, 23.66, 22.56, 22.47, 17.56, 14.55, 14.03. MS (ESI): 384 [M, 15%], 277 (10%), 246 (21%), 231 (100%).

[0213] Example 8. 2-(6-Isopropyl-3-methylcyclohex-2-en-1-yl)-5-pentyl-1,3-benzenediyl diacetate (H 2 CBD Example 9. 2-(3-Isopropyl-6-methyl-7-oxabicyclo[4.1.0]hept-2-yl)-5-pentyl-1,3-benzenedi

[0214]

[0215] At room temperature, acetic anhydride (1.24 mL, 1.34 g, 13.1 mmol) was added to a stirred solution of H 2 CBD (1.60 g, 5.06 mmol) and pyridine (1.65 mL, 1.61 g, 20.0 mmol) in dichloromethane (100 mL). After 12 h, the reaction mixture was poured into water (20 mL). The organic phase was separated, washed with saturated NaHCO 3 aqueous solution and brine, dried over magnesium sulfate, then passed through a silica gel plug (30 g), and subsequently washed with additional DCM (50 mL). Evaporation of the solvent gave H 2 CBD diacetate (1.82 g, 90%). 1 H NMR (400 MHz, CDCl 3) δ 6.73 (s, 2H), 5.14 (s, 1H), 3.43 (d, J = 8.6 Hz, 1H), 2.70 - 2.45 (m, 2H), 2.21 (s, 6H), 2.10 - 2.00 (m, 2H), 1.90 - 1.77 (m, 2H), 1.66 - 1.59 (m, 4H, incl. 1.65 s, 3H), 1.49 - 1.41 (m, 1H), 1.37 - 1.25 (m, 5H), 0.89 (t, J = 6.4 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 169.30, 150.06, 142.21, 133.33, 126.49, 125.11, 121.06 (br), 42.87, 37.57, 35.36, 31.69, 30.92, 30.52, 28.04, 23.55, 22.62, 22.49, 21.70, 21.11, 16.20, 14.15. MS (ESI): 400 [M, 56%], 357 (40%), 315 (38%), 273 (55%), 231 (100%).

[0216] acetate (epoxy-H2CBD diacetate) Example 10. 9-Isopropyl-6-methyl-3-pentyl-5a,6,7,8,9,9a-hexahydrodibenz[b,d]furan-1,

[0217]

[0218] In an ice bath, m-chloroperbenzoic acid (75% w / w, 1.00 g, 4.35 mmol) was added to a stirred solution of H 2 CBD diacetate (1.35 g, 3.37 mmol) in dichloromethane (500 mL). After 12 hours, the reaction was poured into water (20 mL), and the organic phase was separated and washed with aqueous sodium bisulfite, NaHCO 3 aqueous solution and brine, then dried over magnesium sulfate. Evaporation of the solvent gave 2-(3-isopropyl-6-methyl-7-oxabicyclo[4.1.0]hept-2-yl)-5-pentyl-1,3-benzenediacetate (1.14 g, 84%) with 94% GC purity as a pale yellow oil. After purification by column chromatography (silica gel, pure DCM as eluent), a more pure product (97+ by GC analysis) was obtained as a pale yellow oil (470 mg, 35%). 1 H NMR (400 MHz, CDCl 3)δ ppm 6.76 (s, 1H), 6.78 (s, 1H), 3.09 (d, J = 11.1 Hz, 1H), 2.88 (s, 1H), 2.56 (t, J = 7.9 Hz, 2H), 2.30 (s, 6H), 2.11 (d, J = 15.3 Hz, 1H), 1.72 - 1.56 (m, 3H), 1.38 - 1.15 (m, 11H, incl. 1.34 s, 3H), 0.90 - 0.86 (m, 3H), 0.72 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 )δ 168.99, 168.90, 149.78, 149.54, 142.86, 124.89, 121.09, 119.83, 64.07, 58.41, 43.12, 36.65, 35.37, 31.58, 31.08, 30.43, 27.86, 23.08, 22.52, 21.53, 21.42, 21.11, 17.98, 15.95, 14.06. MS (ESI): 426 [M, 4%], 374 (9%), 313 (48%), 271 (100%).

[0219] 6-diol Example 11. 5-(1,1-Dimethylpentyl)-2-(6-isopropyl-3-methylcyclohex-2-en-1-yl)benzene-1,3-

[0220]

[0221] 1 M KOH solution (1.81 mL, 1.81 mmol) was added to a solution of 2-(3-isopropyl-6-methyl-7-oxabicyclo[4.1.0]hept-2-yl)-5-pentyl-1,3-benzenedicarboxylate (470 mg, 1.13 mmol) in methanol (15 mL). After 30 minutes, the reaction was diluted with water (70 mL) and extracted with ethyl acetate (3 × 20 mL). The extract was washed with an aqueous NaHCO 3 solution and brine, and then dried over magnesium sulfate. Evaporation of the solvent gave 9-isopropyl-6-methyl-3-pentyl-5a,6,7,8,9,9a-hexahydrodibenz[b,d]furan-1,6-diol as a pale yellow oil (368 mg, 98%). 1 H NMR (400 MHz, CDCl 3)δ6.31(s,1H),6.17(d,J=1.3Hz,1H),5.00(br s,1H),4.05(dd,J=5.3,1.6Hz,1H),3.12(dd,J=11.2,5.3Hz,1H),2.57-2.39(m,2H),2.05-2.00(m,2H),1.81-1.63(m,2H),1.60-1.54(s,2H),1.45(s,3H),1.43-1.38(m,2H),1.35-1.28(m,4H),1.20-1.15(m,1H),0.94(d,J=6.9Hz,3H),0.88(t,J=6.8Hz,3H),0.84(d,J=6.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ160.96,151.91,144.54,117.65,108.91,103.47,90.82,69.93,46.30,40.58,36.13,35.10,31.68,31.09,28.25,27.38,22.68,21.92,17.50,15.76,14.16.

[0222] diol Example 12. 5-(1,1-Dimethylheptyl)-2-(6-isopropyl-3-methylcyclohex-2-en-1-yl)benzene-1,3-

[0223]

[0224] A 100 mL round-bottom Schlenk flask was equipped with a magnetic stir bar and a rubber septum. The flask was purged with nitrogen and charged with 5-(1,1-dimethylpentyl)benzene-1,3-diol (1.58 g, 7.59 mmol), toluene (23 mL), and p-toluenesulfonic acid monohydrate (86 mg, 6 mol%). The flask was placed in a preheated (70 °C) oil bath and stirred for 15 min, then α-phellandrene (1.28 mL, 1.09 g, 7.96 mmol) was injected through the septum in 1 min. After 25 min, the reaction was poured into saturated NaHCO 3The reaction was quenched in a mixture of aqueous solution (15 mL) and ice (5 g). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give the crude product (2.61 g). The crude product was dissolved in hexane (25 mL) and loaded onto a silica gel plug (30 g). The plug was eluted with hexane (100 mL) followed by a 250 mL mixture of dichloromethane:hexane (25:75). Evaporation of the solvent gave 5-(1,1-dimethylpentyl)-2-(6-isopropyl-3-methylcyclohex-2-en-1-yl)benzene-1,3-diol (2.21 g, 85%) as a viscous pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.40 (s, 1H), 6.25 (s, 1H), 4.62 (s, 1H), 3.33 (d, J = 3.1 Hz, 1H), 1.89 (dd, J = 13.2, 2.6 Hz, 1H), 1.85 - 1.82 (m, 1H), 1.75 (dd, J = 13.6, 3.5 Hz, 1H), 1.61 - 1.56 (m, 2H), 1.54 - 1.48 (m, 4H), 1.36 (s, 3H), 1.32 - 1.27 (m, 1H), 1.24 - 1.19 (m, 8H, incl. 1.21 s, 6H), 1.10 (d, J = 6.5 Hz, 3H), 1.07 - 1.03 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 157.27, 151.92, 149.87, 111.51, 105.81, 104.01, 74.63, 44.45, 44.42, 37.53, 35.14, 30.64, 29.52, 28.97, 28.95, 27.90, 27.09, 26.37, 23.54, 22.20, 21.26, 20.69, 14.25.

[0225] diol Example 13. 2,4-Dihydroxy-3-(6-isopropyl-3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid

[0226]

[0227] A 100 mL round-bottom Schlenk flask is equipped with a magnetic stir bar and a rubber septum. The flask is purged with nitrogen and charged with 5-(1,1-dimethylheptyl)benzene-1,3-diol (1.50 g, 6.44 mmol), toluene (20 mL), and p-toluenesulfonic acid monohydrate (74 mg, 6 mol%). The flask is placed in a preheated (70 °C) oil bath and stirred for 15 minutes, then α-phellandrene (1.08 mL, 921 mg, 6.75 mmol) is injected through the septum within 1 minute. After 25 minutes, the reaction is quenched by pouring it into a mixture of saturated NaHCO 3 (10 mL) aqueous solution and ice (5 g). The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (2 × 20 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated to give the crude product (2.38 g). The crude product is dissolved in hexane (20 mL) and loaded onto a silica plug (30 g). The plug is eluted with hexane (100 mL) followed by a 250 mL mixture of 25:75 dichloromethane:hexane. Evaporation of the solvent gives 5-(1,1-dimethylheptyl)-2-(6-isopropyl-3-methylcyclohex-2-en-1-yl)benzene-1,3-diol (1.86 g, 78%) as a viscous pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.40 (s, 1H), 6.25 (s, 1H), 4.48 (s, 1H), 3.32 (d, J = 3.1 Hz, 1H), 1.89 (dd, J = 13.2, 2.6 Hz, 1H), 1.85 - 1.79 (m, 1H), 1.77 - 1.69 (m, 1H), 1.61 - 1.55 (m, 2H), 1.53 - 1.47 (m, 4H), 1.35 (s, 3H), 1.30 - 1.26 (m, 1H), 1.24 - 1.16 (m, 12H, incl. 1.21 s, 6H), 1.11 (d, J = 6.5 Hz, 3H), 1.08 - 1.04 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 157.30, 151.90, 149.91, 111.47, 105.86, 104.00, 44.70, 44.46, 35.15, 31.94, 30.64, 30.18, 30.17, 29.53, 28.99, 28.95, 27.92, 26.38, 24.79, 22.84, 22.21, 21.28, 20.70, 14.25, 14.25. MS (ESI): 372 [M, 22%], 3163 (9%), 288 (100%).

[0228] (H2CBDA) Example 14. Antiepileptic research

[0229]

[0230] Magnesium metal (0.765 g, 31.6 mmol) was refluxed in anhydrous methanol (15 mL) for 1 hour, at which point the metal was completely consumed. The solvent was evaporated and the magnesium methoxide product was redissolved in anhydrous DMF (10 mL). The mixture was placed in an ice bath and stirred, and solid carbon dioxide (1.4 g, 32 mmol) was introduced in one portion. After 30 minutes, a solution of H 2 CBD (1.00 g, 3.16 mmol) in DMF (2 mL) was added, and the mixture was heated in an oil bath at 120 °C for 3 hours. The reaction was quenched by pouring into a mixture of ice (20 g), water (50 mL), and concentrated hydrochloric acid (3.8 mL). After stirring for 10 minutes, the mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gave the crude product (1.10 g), which was purified by flash chromatography using 85:15 hexane:ethyl acetate to give 2,4-dihydroxy-3-(6-isopropyl-3-methylcyclohex-2-en-1-yl)-6-pentylbenzoic acid (175 mg, 39%), as a viscous yellow oil, and unreacted H 2 CBD (610 mg, 61%) which solidified on standing. 1 H NMR (600 MHz, CDCl 3 ) δ 11.91 (s, 1H), 6.74 (s, 1H), 6.28 (s, 1H), 5.51 (s, 1H), 4.00 (d, J = 9.8 Hz, 1H), 3.04 - 2.90 (m, 1H), 2.88 - 2.78 (m, 1H), 2.19 - 2.08 (m, 2H), 1.85 - 1.76 (m, 4H, incl. 1.78, s, 3H), 1.67 - 1.51 (m, 4H), 1.47 - 1.40 (m, 1H), 1.40 - 1.24 (m, 6H), 0.93 - 0.84 (m, 10H). 13 C NMR (101 MHz, CDCl 3 ) δ 176.10, 164.26, 161.30, 147.68, 140.67, 124.51, 114.89, 112.25, 102.59, 43.78, 36.57, 35.07, 32.04, 31.28, 30.54, 27.84, 23.69, 22.53, 22.02, 21.71, 16.56, 14.07.

[0231] Figure 2

[0232] Animals: Male Wistar Han rats (70 - 110 g; Harlan, Bicester, UK) were housed on a 12-hour light-dark cycle with food and water ad libitum. All experiments were conducted in accordance with the UK Animals (Scientific Procedures) Act 1986 and the ARRIVE guidelines for reporting experiments involving animals; a total of 60 rats were used.

[0233] Drug administration: Animals were randomly divided into 5 groups of 12 animals each and received vehicle (ethanol, polyoxyethylene castor oil Cremophor EL, and saline (0.9% w / v NaCl), 2:1:17), positive control (cannabidiol; CBD; 200 mg kg max ; Sigma-Aldrich, UK) or 8,9-dihydrocannabidiol (H2CBD; 50, 100, or 200 mg kg -1 ; Sigma-Aldrich, UK) by intraperitoneal injection 1 hour before administration of the convulsant to achieve brain cannabinoid T -1 ). One hour after drug or vehicle treatment, the convulsant pentylenetetrazole (PTZ; 85 mg kg -1 ) in 0.9% w / v NaCl was injected intraperitoneally. Seizure activity was video-recorded for 30 minutes and the video recordings were blinded before offline review and coding using a modified Racine scale (0, normal behavior; 0.5, abnormal behavior; 1, isolated myoclonus; 2, atypical clonic seizure; 3, bilateral forelimb clonus; 3.5, bilateral forelimb clonus with body torsion; 4, tonic-clonic seizure, tonic phase suppressed; 5, fully developed tonic-clonic seizure).

[0234] Assessment of bioanalytes: Chemicals and reagents. 4,4'-Dichlorodiphenyltrichloroethane (DDT, CAS: 50 - 29 - 3) was used as an internal analytical standard (IS). HPLC-grade hexane, acetonitrile, water, and ascorbic acid were purchased from Sigma-Aldrich (UK) and Fisher Scientific.

[0235] Analysis of plasma and brain samples: Stock standard solutions of CBD, H2CBD, and DDT were prepared in acetonitrile (5 mg / ml and 1 mg / mL) and stored at -20 °C until use. They were further diluted in acetonitrile:water (62:38) to achieve calibration concentrations of 0.1, 0.2, 0.5, 1, 5, 10 μg / mL. Plasma samples for HPLC were prepared using a previously validated method. Briefly, DDT (50 μg / mL) was added to 150 μL of rat plasma samples as an internal standard, and plasma proteins were precipitated by adding 600 μL of ice-cold acetonitrile, followed by water (600 μL), with vortexing for 1 minute between additions. n-Hexane (3 mL) was added to each tube, and after vortexing for 5 minutes, the tubes were centrifuged at 1160 x g for 15 minutes at 10 °C, and the upper organic layer was carefully decanted using a glass pipette and retained. The organic layer was evaporated to dryness under a nitrogen stream at room temperature and redissolved in 150 μL of a mixture of acetonitrile and water (62:38) prior to HPLC analysis.

[0236] For brain analysis, the brains were weighed and 1.5× the volume of ice-cold solvent (90% acetonitrile; 10% water; 0.1% ascorbic acid) (w / v) was added, followed by homogenization for 1 minute. DDT (50 μg / ml) was added to each homogenized brain tissue as an internal standard, the samples were mixed, and equilibrated overnight at -20 °C. The samples were then centrifuged at 3500 rpm for 15 minutes, and the top layer was retained. The samples were dried at room temperature using a SpeedVac concentrator (Savant SPD131DDA, ThermoFisher Scientific, UK) and reconstituted in 150 μL of a mixture of acetonitrile and water (62:38) for HPLC analysis.

[0237] HPLC analysis: Analysis was performed using an Agilent 1200 series HPLC equipped with a photodiode array detector (Hewlett-Packard, Palo Alto, CA, USA). All samples were injected at 30 μl, and separation was achieved using an ACE C18-PFP 150 mm × 4.6 mm, 3 μm particle size column (Hichrom Ltd, Reading, UK), protected by an ACE C18-PFP 3 μm guard column. The mobile phase was a mixture of acetonitrile and water in a ratio of 62:38 (v / v). The flow rate was set at 1 mL / min, and the column temperature was maintained at 55 °C. Absorbance of all target compounds (CBD and DH-CBD) was monitored at 220 nm.

[0238] Statistics: Statistical procedures were performed using GraphPad Prism 7 (GraphPad Software, Inc., San Diego, CA, USA). The D'Agostino and Pearson normality tests showed that the data describing the maximum seizure severity and bioanalyte concentrations were not normally distributed. Therefore, the Kruskal-Wallis test and post hoc Dunn's test were used to evaluate the differences within these data types of groups. The effect of the drugs on the percentage of animals showing tonic-clonic seizures was evaluated by the chi-squared test and post hoc Fisher's exact test.

[0239] H2CBD has previously been the subject of a limited number of studies involving cannabinoid pharmacology. Like CBD, H2CBD has shown 1) an inhibitory effect on cytochrome P450, which can be measured by the formation of CO complexes during the metabolism of H2CBD in liver microsomes, and 2) antioxidant activity, which is quantified by the inhibition of the production of reactive oxygen intermediates, nitric oxide, and tumor necrosis factor in murine macrophages. Compared with CBD, H2CBD has shown little evidence of sedative activity.

[0240] In this study, 60 male Wistar Han rats were randomly divided into 5 groups of 12 animals each and received, by intraperitoneal injection, 1 hour before administration of the convulsant pentylenetetrazole (PTZ; 85 mg kg -1 in 0.9% w / v saline), vehicle (ethanol, Cremophor EL, 0.9% w / v saline; 2:1:17), vehicle plus positive control (CBD; 200 mg kg -1 ), or vehicle plus H2CBD (50, 100, or 200 mg kg -1 ).

[0241] An overall effect of treatment on the percentage of animals showing tonic-clonic seizures was found (χ 2 (4)=10.48; P = 0.033), where pairwise comparisons showed that animals receiving CBD (200 mg kg -1 ) and H2CBD (200 mg kg -1 ) showed a significant reduction in tonic-clonic seizures compared with the vehicle-treated group (P < 0.05 in both cases) ( Figure 2 ). In addition, the maximum seizure severity was also affected by treatment (H = 18.96; P < 0.001), where pairwise comparisons showed that animals receiving CBD (200 mg kg -1 ) and H2CBD (200 mg kg -1) The animals showed significantly reduced seizures according to the Racine scale coding compared to the vehicle treatment group (vehicle median: 5 (4.25 - 5 IQR), H2CBD 20 mg kg -1 : 2 (0.25 - 4.25 IQR), CBD 200 mg kg -1 : 2 (0.25 - 3.75) IQR), P < 0.001 in both cases).

[0242] Analysis of blood and brain tissues obtained post - mortem from rats in each treatment group showed that administration caused an overall effect on blood (H = 17.00; P = 0.0019) and brain tissue (H = 15.76; P = 0.0034) detected at significant concentrations of H2CBD (100 mg / kg: P < 0.05 (blood); 200 mg / kg: P < 0.01 (blood); P < 0.01 (brain)) and CBD (200 mg / kg: P < 0.01 (brain)) compared to the vehicle treatment group( Figure 3 ).

[0243] The results clearly show that H2CBD exhibits a dose - dependent anticonvulsant effect in acute, PTZ - induced generalized seizures in rats, and its maximum protective effect is comparable to the matched dose of the established anticonvulsant CBD. Although these preliminary data provide clear indications for using H2CBD as an anticonvulsant, further work will determine the inherent pharmacokinetic characteristics of H2CBD. For the purposes of this preliminary study, although the bioanalytical results suggest comparable anticonvulsant effects, there are differences in plasma and brain concentrations at the matched dose (200 mg kg -1 ), but H2CBD is assumed to be the same as CBD. This may indicate that the degree of the anticonvulsant effect of H2CBD may be attenuated by sub - optimal dosing intervals, preventing the evaluation of the effect at maximum drug concentrations.

[0244] The effects of H2CBD on rodent behavior were then evaluated. Multiple studies have demonstrated the anxiolytic / sedative properties of CBD, and recent work has proposed possible mechanisms for this effect. It was previously found that when CBD was exposed to simulated gastric fluid, CBD showed almost complete degradation within 1 hour (mainly Δ 8 - and Δ 9 -THC), indicating that oral CBD may expose patients to THC levels above the induction anesthesia threshold. In the absence of behavioral studies on H2CBD in the dose range used in the current work, the activity of H2CBD was evaluated relative to the vehicle in the EPM and open - field tests.

[0245] Twelve adult male Sprague Dawley rats were randomly divided into two groups of six animals each and administered an intraperitoneal injection of either a vehicle (Kolliphor RH-40, dmso, 0.9% w / v saline, 1:2:7) or the vehicle plus H2CBD (200 mg kg -1 ). In this case, the vehicle was different from that used in the antiepileptic study to avoid potential confounding effects of alcohol. The number of animals was also limited to the minimum required to establish an effect at the maximum drug dose. Forty-five minutes after injection of the vehicle and the drug, the rats were placed in the center of the EPM and the time spent on the open and closed arms of the maze was recorded. After a two-week interval, the same twelve rats were again randomly divided into two groups of six animals each and administered as above. Forty-five minutes after injection, spontaneous locomotor activity was measured by placing the animals in the center of a 16"×16" arena. They were allowed to move freely for 30 minutes and the activity was recorded using an automated activity monitoring system.

[0246] The EPM data were analyzed by analysis of variance. No statistically significant differences were found between the drug-treated and vehicle-treated groups in terms of the percentage of time spent on the open arms (F 1,10 = 0.50, p = 0.49). In the open field test, there were no statistically significant differences between the drug-treated and vehicle-treated groups in terms of the horizontal travel distance (F 1,10 = 0.005, P = 0.95), vertical activity (F 1,10 = 1.52, p = 0.25) or time in the center of the arena (F 1,10 = 2.55, p = 0.14) ​ ). Since H2CBD cannot be converted to THC by any mechanistically plausible pathway, the above data are consistent with the hypothesis that CBD itself has no inherent anxiolytic or sedative activity, but in vivo conversion to THC may be the cause of this effect. In any case, the data indicate that H2CBD does not produce measurable behavioral effects at a high dose (200 mg kg -1 ).

[0247] In summary, it has been demonstrated that prophylactic administration of H2CBD (200 mg kg -1) It can significantly reduce the incidence of tonic-clonic seizures and the maximum seizure severity without producing behavioral changes. The advantages of H2CBD as a potential anti-epileptic drug compared to CBD are summarized as follows: 1) H2CBD is fully synthetic and not a controlled substance, thus avoiding the legal issues surrounding cannabis-based therapies. 2) The preparation method of H2CBD is efficient, inexpensive, and scalable. Different from CBD which has to be separated from a mixture of other extracts and may be contaminated by pesticides, synthetic H2CBD can be easily obtained in pure form. 3) H2CBD can be used as a high-dose drug without anesthetic side effects. 4) Compared with CBD, there is no practical synthetic pathway from H2CBD to THC. 5) Preparing H2CBD from readily available non-cannabis-based precursors eliminates the need to grow cannabis and its accompanying problems. Therefore, assuming that the main medical reason for adopting cannabis-based therapies is their extraordinary anti-convulsant activity and that all other indications (anxiety, chronic pain, nausea, anorexia, etc.) can be effectively controlled with uncontroversial drugs, the often-cited case for legalizing cannabis based on the advantages of this treatment may be questioned.

[0248] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications can be made within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the extent as if each reference was individually incorporated by reference. When there is a conflict between this application and the reference documents provided herein, this application shall prevail.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or reducing seizures without causing hypnotic effects in a subject:

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