Therapeutic uses for epimers of hexahydrocannabivarin, hexahydrocannabidivarin, hexahydrocannabinol, hexahydrocannabidiol, and other hydrogenated cannabinoids

Abstract

The present disclosure concerns compositions comprising hexahydrocannabinol (HHC), hexahydrocannabidiol (H4CBD), hexahydrocannabidivarin (H4CBDV), and derivatives thereof. The present disclosure also concerns pharmaceutical compositions comprising the compositions. Methods of treating various diseases and disorders by administering the pharmaceutical compositions are also disclosed.

Description

THERAPEUTIC USES FOR EPIMERS OF HEXAHYDROCANNABIVARIN, HEXAHYDROCANNABIDIVARIN, HEXAHYDROCANNABINOL, HEXAHYDROCANNABIDIOL, AND OTHER HYDROGENATED CANNABINOIDSBACKGROUND

[0001] This application claims priority of U.S. Provisional Patent Application No. 63 / 583,689, filed September 19, 2023, which is hereby incorporated by reference in its entirety.Field of the Invention

[0002] Aspects of the present disclosure relate to the fields of organic chemistry and medicinal chemistry.Background

[0003] Hydrogenated cannabinoids are semi-synthetic cannabinoids made or extracted from naturally occurring cannabinoids or via traditional synthetic organic chemistry. Certain pure diastereomers of hydrogenated cannabinoids, such as (R) and (S) diastereomers of the hexahydrocannabivarin (HHCV), hexahydrocannabidivarin (H4CBDV), hexahydrocannabinol (HHC), and hexahydrocannabidiol (THD / H4CBD), hexahydrocannabivarin-quinone (HHCVQ), hexahydrocannabinol-quinone (HHCQ), hexahydrocannabidiol-quinone (H4CBDQ), hexahydro- cannabidivarin-quinone (H4CBDVQ) and related analog scaffolds have shown better antiinflammatory properties than their counterparts. There remains a need for synthesis and characterization, including biological characterization, of additional chiral diastereomers of the hydrogenated cannabinoids, such as those that cannot be synthesized directly from the naturally occurring cannabinoids, as well as therapeutic and prophylactic methods of use thereof such as in the treatment or prevention of various disease states.SUMMARY

[0004] Aspects of the present disclosure are directed to cannabinoid derivatives and therapeutic uses thereof.

[0005] Some embodiments concern a compound of formula I:where X is H, halogen, substituted or unsubstituted alkyl, or OR2; R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacentY are taken together to form a 3-membered cycloalkyl or heterocylcoalkyl ring, or two adjacentY are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen; Z is H, halogen, or OR4; R4is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, any natural or non-natural amino acid linked through its carboxy or amino terminus, -OC(O)(CH2)nC(O)O-gemcitabine, -OC(O)(CH=CH)nC(O)O-gemcitabine, -OCO(2,4- dinitrophenol) ester, -OCH nitroimidazole), -CO-TEMPO, -CO2-TEMPO, -COCEECEECCEEt, or -COCH2CH2COOH, where n is an integer from 1-20; R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, benzyl, substituted or unsubstituted aryl, -S-C1-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR3; and R5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula I is further defined as a compound of formula IV or a compound of formula V:

[0006] Some embodiments are directed to a compound of formula II:where A is O, S, CH2, NH, or N-alkyl; X is H, halogen, substituted or unsubstituted alkyl, or OR2; R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacent Y are taken together to form a 3 -membered cycloalkyl or heterocylcoalkyl ring, or two adjacent Y are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen; Z is H, halogen, or OR4; R4is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, -OC(O)(CH2)nC(O)O-gemcitabine, or -OC(O)(CH=CH)nC(O)O-gemcitabine, wherein n is an integer from 1-20; -OCO(2,4- dinitrophenol) ester, -OCH2(nitroimidazole), -CO-TEMPO, -CO2-TEMPO, -COCH2CH2CO2Et, -COCH2CH2COOH, or any natural or non-natural amino acid linked through its carboxy or amino terminus; R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkynyl, benzyl, substituted or unsubstituted aryl, -S-C1-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR5; and R5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula II is further defined as a compound of formula VI or a compound of formula VII:

[0007] Some embodiments of the disclosure are directed to a compound of formula III:where A is O, S, CH2, NH, or N-alkyl; X is H, halogen, substituted or unsubstituted alkyl, or OR2; R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacent Y are taken together to form a 3 -membered cycloalkyl or heterocylcoalkyl ring, or two adjacent Y are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen; R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, benzyl, substituted or unsubstituted aryl, -S-C1-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR5; and R5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; L is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, any natural or non-natural amino acid linked through its carboxy or amino terminus, -OCO(2,4-dinitrophenol) ester, -OCH2(nitroimidazole), -CO- TEMPO, -CO2-TEMPO, -COCH2CH2CO2Et, -COCH2CH2COOH, -OC(O)(CH2)nC(O)O- gemcitabine, or -OC(O)(CH=CH)nC(O)O-gemcitabine, where n is an integer from 1-20; or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula III is further defined as a compound of formula VIII or a compound of formula IX:

[0008] In some embodiments, a compound of formula I, a compound of formula II, and / or a compound of formula III is provided as a pharmaceutical composition. In some embodiments, apharmaceutical composition comprising a compound of formula I, a compound of formula II, and / or a compound of formula III is administered to a subject in order to treat a disease or disorder. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I, a therapeutically effective amount of compound of formula II, and / or a therapeutically effective amount of compound of formula III.

[0009] Some embodiments are directed to a method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula I, a compound of formula II, and / or a compound of formula III to a subject in need thereof, wherein the disease or disorder is selected from the group consisting of epilepsy, including epilepsy types that present as different types of seizures, including cluster seizures, refractory seizures, atypical absence seizures, atonic seizures, clonic seizures, myoclonic seizures, tonic seizures, tonic-clonic seizures, simple partial seizures, complex partial seizures, secondary generalized seizures, febrile seizures, nonepileptic seizures, gelastic and dacrystic seizures, and absence seizures, diabetes mellitus of different types, including type-1 diabetes, type-2 diabetes, and maturity onset diabetes of the young (MODY), including M0DY1, M0DY2, MODY3, M0DY4, M0DY5, M0DY6, M0DY7, M0DY8, M0DY9, MODY10, and M0DY11, nonalcoholic steatohepatitis (NASH), depressive disorders, including major depression, dysthymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, and situational depression, glaucoma, metabolic syndromes, including increased blood pressure, high blood sugar level, excess body fat around the waist, and abnormal cholesterol levels, autoimmune disorders including Addison disease, celiac disease, dermatomyotis, Graves’ disease, Hashimoto thyroiditis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, lupus, insulin resistance disease, sleep apnea, hypertension, kidney disease, obesity, inflammation disease, and disease resulting in knee-joint complications. In some embodiments, administration of a compound of formula I to a subject leads to a time-dependent increase in systemic concentration of the compound of formula I in the subject. In some embodiments, administration of a compound of formula II to a subject leads to a time-dependent increase in systemic concentration of the compound of formula II in the subject. In some embodiments, administration of a compound of formula III to a subject leads to a time-dependent increase in systemic concentration of the compound of formula III in the subject. In some embodiments, a moleculartarget of any of the compounds disclosed herein is selected from the group consisting of CB1 , CB2, GPR55 receptors, and combinations thereof

[0010] Some aspects of the disclosure are directed to a pharmaceutical composition comprising a compound as disclosed herein. The terms delta-8 tetrahydrocannabinol, delta-8 THC, D8 THC, A8-tetrahydrocannabinol, and A8-THC are used interchangeably herein. The terms delta-9 tetrahydrocannabinol, delta-9 THC, D9 THC, A9-tetrahydrocannabinol, A9-THC, and THC are used interchangeably herein. The terms tetrahydrocannabivarin, THCV, D9-THCV, and D8-THCV are used interchangeably herein. (R)-H4CBD, and (R)-THD are used interchangeably herein. (S)-H4CBD, and (S)-THD are used interchangeably herein. The terms hexahydrocannabidivarin, and H4CBDV are used interchangeably herein. The terms (R)- H4CBDV, and (R)- hexahydrocannabidivarin are used interchangeably herein. The terms (S)- H4CBDV, and (S)- hexahydrocannabidivarin are used interchangeably herein. The terms hexahydrocannabinol and HHC are used interchangeably herein. The terms (R)-HHC, and (R)- Hexahydrocannabinol are used interchangeably herein. The terms (S)-HHC and (S)- Hexahydrocannabinol are used interchangeably herein. The term “semi-synthetic” is defined as a method that employs natural compounds or compounds derived from natural compounds as starting materials to produce different compounds.

[0011] Some aspects relate to methods of synthesizing any of the compounds disclosed herein, such as any of the hydrogenated cannabinoids disclosed herein. In some aspects, the method comprises saturating, such as through hydrogenation, a double bond in a cannabinoid scaffold. The cannabinoid scaffold may be derived from hemp, Cannabis saliva. Cannabis indica, Echinacea purpurea, Echinacea angustifolia, Acntella oleracea, Helichrysum umbraculigerum, and / or Radula marginata, or any other source containing a cannabinoid scaffold. In some aspects, the cannabinoid scaffold comprises cannabinol, tetrahydrocannabinol, cannabidiol, and / or cannabidivarin.

[0012] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method.

[0013] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0014] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0015] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0016] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0017] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0019] FIGS. 1A-1B Plasma concentration vs time profiles for H4CBDV (FIG. 1A) and H4CBD (FIG. IB) in CD1 mice.

[0020] FIG. 21H NMR of HHC.

[0021] FIGS. 3 A-3B Nuclear Overhauser Effect Spectroscopy (NOESY) NMR spectra of (R)- HHC (FIG. 3A) and (S)-HHC (FIG. 3B).DETAILED DESCRIPTION

[0022] Aspects of the present disclosure are based, at least in part, on the therapeutic use of derivatives of (R) and (S) diastereomers of hexahydrocannabivarin (HHCV), hexahydrocannabinol (HHC), hexahydrocannabidiol (H4CBD) and hexahydrocannabidivarin (H4CBDV), and various derivatives thereof, for the treatment of a number of diseases and disorders.Chemical Definitions

[0023] When used in the context of a chemical group: “hydrogen” means — H; “hydroxy” means — OH; “oxo” means =0; “carbonyl” means — C(=O) — ; “carboxy” means — C(=O)OH (also written as — COOH or — CO2H); “halo” means independently — F, — Cl, — Br or — I; “amino” means — NH2; “hydroxyamino” means — NHOH; “nitro” means — NO2; imino means =NH; “cyano” means — CN; “isocyanate” means — N=C=O; “azido” means — N3; in a monovalent context “phosphate” means — OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means — OP(O)(OH)O — or a deprotonated form thereof; “mercapto” means — SH; and “thio” means =S; “sulfonyl” means — S(O)2 — ; and “sulfinyl” means — S(O) — .

[0024] In the context of chemical formulas, the symbol “ — ” means a single bond, “=” means a double bond, and “= ’ means triple bond. The symbol “ - ” represents an optional bond, which if present is either single or double. The symbol ” represents a single bond or a double bond. Thus, for example, the formulaincludesIt is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “ — ”, when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it cover all stereoisomers as well as mixtures thereof.

[0025] The symbol “ ' / vvx”, when drawn perpendicularly across a bond indicates a point of attachment of the group. It is noted that the point of attachment is typically identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol means a single bond where the group attached to the thick end of the wedge is “out of the page.” The symbolmeans a single bond where the group attached to the thick end of the wedge is “into the page”. The symbol “' / vvv” means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended.

[0026] The term “alkyl” when used without the “substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, and no atoms other than carbon and hydrogen. Thus, as used herein cycloalkyl is a subset of alkyl, with the carbon atom that forms the point of attachment also being a member of one or more non-aromatic ring structures wherein the cycloalkyl group consists of no atoms other than carbon and hydrogen. As used herein, the term does not preclude the presence of one or more alkyl groups attached to the ring or ring system. Non-limiting examples of cycloalkyl groups include cyclopropyl and cyclohexyl. The groups — CH3 (Me), — CH2CH3 (Et), — CH2CH2CH3 (n-Pr or propyl), — CH(CH3)2 (i-Pr, iPr or isopropyl), — CH(CH )2 (cyclopropyl), — CH2CH2CH2CH3 (n-Bu), — CH(CH3)CH2CH3 (sec-butyl), — CH2CH(CH3)2(isobutyl), — C(CH3)3 (tert-butyl, t-butyl, t-Bu or tBu), — CH2C(CH3).3 (neo-pentyl), cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups. When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, — F, —Cl, — Br, —I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH,— OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3 — N(CH3)2, — C(O)NH2, — OC(O)CH3, or — S(O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: — CH2OH, — CH2CI, — CF3, — CH2CN, — CH2C(O)OH, — CH2C(O)OCH3, — CH2C(O)NH2, — CH2C(O)CH3, — CH2OCH3, — CH2OC(O)CH3, — CH2NH2, — CH2N(CH3)2, and — CH2CH2CI. The term “haloalkyl” is a subset of substituted alkyl, in which one or more hydrogen atoms has been substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present. The group, — CH2CI is a non-limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present. The groups, — CH2F, — CF3, and — CH2CF3 are non-limiting examples of fluoroalkyl groups.

[0027] The terms “alkene” “olefin” and “alkenyl” when used without the “substituted” modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carboncarbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: — CH=CH2(vinyl), — CH=CHCHi, — CH=CHCH2CH3, — CH2CH=CH2(allyl), — CH2CH=CHCH3, and — CH=CHCH=CH2. When any of these terms are used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, — I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH?)2, — C(O)NH2, — OC(O)CH3, or — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example. The groups, — CH=CHF, — CH=CHC1 and — CH=CHBr, are non-limiting examples of substituted alkenyl groups.

[0028] The terms “alkyne” and “alkynyl” when used without the “substituted” modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups, — C=CH, — OCCH3, and — CH2OCCH3, are non-limiting examples of alkynyl groups. When any of these terms are used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, — F, —Cl, — Br, —I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH,— OCH3, — OCH2CH3, — C(0)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — 0C(0)CH3, or — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0029] The term “aryl” when used without the “substituted” modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, — C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl. When the term is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, — I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — OC(O)CH3, — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0030] The term “heteroaryl” when used without the “substituted” modifier refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and / or aralkyl groups attached to the aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. When the term is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, —I, NH2, NO2, CO2H, — CO2CH3, — CN, — SH, — OCH3, OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — OC(O)CH3, — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0031] The terms “heterocyclyl” is defined as a 4-, 5- or 6-membered monocyclic or a 8-, 9- or 10-membered bi- or tri-cyclic heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from N, O and S, and wherein the N and S heteroatoms may be optionally oxidized, and the N heteroatom may be optionally quaternized. A heterocyclyl group includes a carbon atom or nitrogen atom as the point of attachment. Examples of heterocyclyl rings include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, aza-bicyclo[2.2.2]octyl, hexahydro-pyrrolo[3,4- c]pyrrolyl, pyrrolidinonyl, piperidinonyl, oxazolidinonyl, imidazolidinonyl, piperazinonyl, pyrrolyl, pyrrazolyl, imidazolyl, dihydroimidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl and dithianyl-5-oxide, wherein said pyrrolyl, pyrrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl may be condensed with a phenyl, pyridyl, pyrrolyl, pyrrazolyl ,and imidazolyl.

[0032] The term “heterocycloalkyl” when used without the “substituted” modifier refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl groups attached to the ring or ring system. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. When the term is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, — I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3,— OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — OC(O)CH3, — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0033] The term “alkoxy” when used without the “substituted” modifier refers to the group — OR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkoxygroups include: — OCH3 (methoxy), — OCH2CH3 (ethoxy), — OCH2CH2CH3 (propoxy), — OCH2CH2CH3, — OCH(CH3)2 (isopropoxy), — O(CH.)3 (tert-butoxy), — OCH(CH2)2, — O- cyclopentyl, and — O-cyclohexyl. The terms “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as — OR, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, —Cl, — Br, —I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — 0C(0)CH3, or — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0034] The term “alkylamino” when used without the “substituted” modifier refers to the group — NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: — NHCH3 and — NHCH2CH3. The term “dialkylamino” when used without the “substituted” modifier refers to the group — NRR', in which R and R' can be the same or different alkyl groups. The terms “alkoxyamino”, “alkenylamino”, “alkynyl amino”, “arylamino”, “aralkylamino”, “heteroarylamino”, “heterocycloalkylamino” and “alkylsulfonylamino” when used without the “substituted” modifier, refers to groups, defined as — NHR, in which R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is — NHCeHs. The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group — NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is — NHC(O)CH3. The term “alkylimino” when used without the “substituted” modifier refers to the divalent group =NR, in which R is an alkyl, as that term is defined above. The term “alkylaminodiyl” refers to the divalent group — NH-alkanediyl-, — NI I-alkanediyl-NH — , or - alkanediyl-NH-alkanediyl-. When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, — I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — OC(O)CH3, or — S(O)2NH2, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example. The groups — NHC(O)OCH3 and — NHC(O)NHCH3 are non-limiting examples of substituted amido groups.

[0035] When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by — OH, — F, — Cl, — Br, — I, — NH2, — NO2, — CO2H, — CO2CH3, — CN, — SH, — OCH3, — OCH2CH3, — C(O)CH3, — NHCH3, — NHCH2CH3, — N(CH3)2, — C(O)NH2, — OC(O)CH3, — S(O)2NH2, or — C(O)OC(CH3)3 (tertbutyloxycarbonyl, BOC), an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, for example.

[0036] The terms delta-8 tetrahydrocannabinol, delta-8 THC, D8 THC, A8- tetrahydrocannabinol, and A8-THC are used interchangeably herein. The terms delta-9 tetrahydrocannabinol, delta-9 THC, D9 THC, A9-tetrahydrocannabinol, A9-THC, and THC are used interchangeably herein. The terms tetrahydrocannabivarin, THCV, D9-THCV, and D8- THCV are used interchangeably herein. The terms hexahydrocannabinol and HHC are used interchangeably herein. The terms hexahydrocannabidiol, H4CBD, and THD are used interchangeably herein. The terms hexahydrocannabidivarin, and H4CBDV are used interchangeably herein. The terms H4CBDQ, (9R)-H4CBDQ, (9S)-H4CBDQ, H4CBDVQ, HHCQ, (9R)-HHCQ, and (9S)-HHCQ are used interchangeably herein to describe quinone derivative of H4CBD, (9R)-H4CBD, (9S)-H4CBD, H4CBDV, HHC, (9R)-HHC, and (9S)-HHC. The term “semi-synthetic” is defined as a method that employs natural compounds or compounds derived from natural compounds as starting materials to produce different compounds.

[0037] A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chiralityfor which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non- racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains <15%, more preferably <10%, even more preferably <5%, or most preferably <1% of another stereoisomer(s).

[0038] Compounds employed in methods of the invention may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S- or the R-configuration, as defined by the IUPAC 1974 Recommendations. Compounds may be of the D- or L-form, for example. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic form, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.

[0039] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0040] Various forms of palladium catalyst useful for the reaction are discussed by Blaser et. al., Supported palladium catalysts for fine chemicals synthesis in Journal of Molecular Catalysis A: Chemical, 2001, v. 172, p. 3-18, the entirety of which is incorporated by reference.General Pharmaceutical Compositions

[0041] The phrases “pharmaceutical” and “pharmacologically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, such as a human, as appropriate. The preparation of a pharmaceuticalcomposition comprising a compound of formula I, a compound of formula II, and / or a compound of formula III will be known to those of skill in the art in light of the present disclosure. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by FDA Office of Biological Standards. The phrases “pharmaceutical composition” and “therapeutic agent” refer to compositions that comprise a compound of formula I, a compound of formula II, and / or a compound of formula III. The phrase “active compound” refers to a compound of formula I, a compound of formula II, and / or a compound of formula III.

[0042] “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2- naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l- carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. The compositions disclosed herein may be formulated into a neutral or salt form. Additional examples ofpharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0043] “Prodrug” means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have activity with respect to a given molecular target. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

[0044] As used herein, “pharmaceutically acceptable carrier” includes any and all aqueous solvents (e.g., water, alcoholic / aqueous solutions, saline solutions, parenteral vehicles, such as sodium chloride, Ringer’s dextrose, etc.), non-aqueous solvents (e.g., propylene glycol, polyethylene glycol, vegetable oil, and injectable organic esters, such as ethyloleate), dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial or antifungal agents, anti-oxidants, chelating agents, and inert gases), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, fluid and nutrient replenishers, such like materials and combinations thereof, as would be known to one of ordinary skill in the art. The pH and exact concentration of the various components in a pharmaceutical composition are adjusted according to well-known parameters.

[0045] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0046] A pharmaceutical composition can include a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In some embodiments, the surfactant comprises tween, polysorbate, saponin, tocofersolan (TPGS), lecithin (including sunflower or soy lecithin), sodium stearoyl lactylate, or a combination thereof. The prevention of the action of microorganisms can be brought about by various anti-bacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0047] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization or an equivalent procedure. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.Therapeutic Methods

[0048] Certain aspects of the disclosure concern pharmaceutical compositions that comprise a compound of formula I, a compound of formula II, and / or a compound of formula III. The pharmaceutical compositions may be used in methods for the treatment of epilepsy, including epilepsy types that present as different types of seizures, including cluster seizures, refractory seizures, atypical absence seizures, atonic seizures, clonic seizures, myoclonic seizures, tonicseizures, tonic-clonic seizures, simple partial seizures, complex partial seizures, secondary generalized seizures, febrile seizures, nonepileptic seizures, gelastic and dacrystic seizures, and absence seizures, diabetes mellitus of different types, including type-1 diabetes, type-2 diabetes, and maturity onset diabetes of the young (MODY), including M0DY1, M0DY2, M0DY3, M0DY4, M0DY5, M0DY6, M0DY7, M0DY8, M0DY9, MODYIO, and M0DY11, nonalcoholic steatohepatitis (NASH), depressive disorders, including major depression, dysthymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, and situational depression, glaucoma, metabolic syndromes, including increased blood pressure, high blood sugar level, excess body fat around the waist, and abnormal cholesterol levels, autoimmune disorders including Addison disease, celiac disease, dermatomyotis, Graves’ disease, Hashimoto thyroiditis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, lupus, insulin resistance disease, sleep apnea, hypertension, kidney disease, obesity, inflammation disease, and disease resulting in knee-joint complications.

[0049] As used herein, “treat,” “treating,” or “treatment” or equivalent terminology refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the growth, development, or spread of one or more symptoms or manifestation of a disease or condition. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treatment” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The results of treatment can be determined by methods known in the art, such as determination of reduction of, e.g., tumor burden, determination of restoration of function, or other methods known in the art.

[0050] As used herein, “prevent,” and similar words such as “prevented,” “preventing,” etc., indicate an approach for preventing, inhibiting, or reducing the likelihood of the occurrence orrecurrence of, a disease or condition, e.g., obesity. It also refers to delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition. As used herein, “prevention” and similar words also includes reducing the intensity, effect, symptoms and / or burden of a disease or condition prior to onset or recurrence of the disease or condition. Prevention may be considered complete when onset of a disease, disorder, or condition has been delayed for a predefined period of time.

[0051] The therapies provided herein may comprise administration of a therapeutic agent comprising one or a combination of a compound of formula I, a compound of formula II and / or a compound of formula III. When multiple therapies are provided, the different therapies may be administered in one composition or in more than one composition, such as 2 compositions, 3 compositions, or 4 compositions. Various combinations of the agents may be employed.

[0052] The therapeutic agents of the disclosure may be administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the antibiotic is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage may be determined based on the type of disease to be treated, severity and course of the disease, the clinical condition of the individual, the individual's clinical history and response to the treatment, and the discretion of the attending physician.

[0053] The treatments may include various “unit doses.” Unit dose is defined as containing a predetermined-quantity of the therapeutic composition. The quantity to be administered, and the particular route and formulation, is within the skill of determination of those in the clinical arts. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. In some embodiments, a unit dose comprises a single administrable dose.

[0054] In some embodiments, the therapy is administered at a dose of between 1 mg / kg and 5000 mg / kg. In some embodiments, the therapy is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 11 1, 112, 1 13, 1 14, 115, 116, 117, 118, 1 19, 120, 121, 122,123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141,142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179,180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198,199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217,218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236,237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255,256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312,313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331,332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350,351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369,370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388,389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407,408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445,446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464,465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483,484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502,503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521,522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559,560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 mg / kg.

[0055] In some embodiments, a single dose of a compound of formula I, a compound of formula II, or a compound of formula III, or a single dose that comprises any combination thereof is administered. In some embodiments, multiple doses of the compound of formula I, compoundof formula II, and / or compound of formula III are administered. In some embodiments, the compound of formula I, compound of formula II, and / or compound of formula III is administered at a dose of between 1 mg / kg and 100 mg / kg. In some embodiments, the compound of formula I, compound of formula II, and / or compound of formula III is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / kg.

[0056] The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain embodiments, it is contemplated that doses in the range from 10 mg / kg to 200 mg / kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 pg / kg, mg / kg, pg / day, or mg / day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and / or on multiple days, weeks, or months.

[0057] In certain embodiments, the effective dose of the pharmaceutical composition is one which can provide a blood level of about 1 pM to 150 pM. In another embodiment, the effective dose provides a blood level of about 4 pM to 100 pM.; or about 1 pM to 100 pM; or about 1 pM to 50 pM; or about 1 pM to 40 pM; or about 1 pM to 30 pM; or about 1 pM to 20 pM; or about 1 pM to 10 pM; or about 10 pM to 150 pM; or about 10 pM to 100 pM; or about 10 pM to 50 pM; or about 25 pM to 150 pM; or about 25 pM to 100 pM; or about 25 pM to 50 pM; or about 50 pM to 150 pM; or about 50 pM to 100 pM (or any range derivable therein). In other embodiments, the dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 pM or any range derivable therein. In certain embodiments, the therapeutic agent that is administered to a subject is metabolized in the body toa metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent.

[0058] Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.

[0059] It will be understood by those skilled in the art and made aware that dosage units of pg / kg or mg / kg of body weight can be converted and expressed in comparable concentration units of pg / ml or mM (blood levels), such as 4 pM to 100 pM. It is also understood that uptake is species and organ / tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.

[0060] In certain instances, it will be desirable to have multiple administrations of the composition, e.g., 2, 3, 4, 5, 6 or more administrations. The administrations can be at 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9, 10, 11, or 12 week intervals, including all ranges there between.

[0061] The phrases “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal or human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in immunogenic and therapeutic compositions is contemplated. Supplementary active ingredients, such as other anti-infective agents and vaccines, can also be incorporated into the compositions.

[0062] The therapeutic agents can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, or intraperitoneal routes. Typically, such compositions can be prepared as either liquid solutions or suspensions; solid forms suitablefor use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and, the preparations can also be emulsified.

[0063] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0064] A pharmaceutical composition can include a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, cyclodextrin, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various anti-bacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0065] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization or an equivalent procedure. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile inj ectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0066] Upon formulation, solutions may be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.

[0067] In certain aspects, the compositions or therapeutic agents for use in the methods, such as a compound of formula I, compound of formula II, and / or compound of formula III, are suitably contained in a pharmaceutically acceptable carrier. The carrier may be non-toxic, biocompatible and may be selected so as not to detrimentally affect the biological activity of the agent. The agents in some aspects of the disclosure may be formulated into preparations for local delivery (i.e. to a specific location of the body, such as nervous or other tissue) or systemic delivery, in solid, semisolid, gel, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections allowing for oral, parenteral or surgical administration. Certain aspects of the disclosure also contemplate local administration of the compositions by coating medical devices and the like.

[0068] Suitable carriers for parenteral delivery via injectable, infusion or irrigation and topical delivery include distilled water, physiological phosphate-buffered saline, normal or lactated Ringer's solutions, dextrose solution, Hank's solution, or propanediol. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any biocompatible oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The carrier and agent may be compounded as a liquid, suspension, polymerizable or non-polymerizable gel, paste or salve.

[0069] The carrier may also comprise a delivery vehicle to sustain (i.e., extend, delay or regulate) the delivery of the agent(s) or to enhance the delivery, uptake, stability or pharmacokinetics of the therapeutic agent(s). Such a delivery vehicle may include, by way of nonlimiting examples, microparticles, microspheres, nanospheres or nanoparticles composed of proteins, liposomes, carbohydrates, synthetic organic compounds, inorganic compounds, polymeric or copolymeric hydrogels and polymeric micelles.

[0070] In certain aspects, the actual dosage amount of a composition administered to a patient or subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0071] Solutions of pharmaceutical compositions can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions also can be prepared in glycerol, liquidpolyethylene glycols, mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0072] In certain aspects, the pharmaceutical compositions are advantageously administered in the form of injectable compositions either as liquid solutions or suspensions; solid forms suitable or solution in, or suspension in, liquid prior to injection may also be prepared. These preparations also may be emulsified. A typical composition for such purpose comprises a pharmaceutically acceptable carrier. For instance, the composition may contain 10 mg or less, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like.

[0073] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate. Aqueous carriers include water, alcoholic / aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc. Intravenous vehicles include fluid and nutrient replenishers. Preservatives include antimicrobial agents, antifungal agents, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to well-known parameters.

[0074] Additional formulations are suitable for oral administration. Oral formulations include such typical excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, cyclodextrins, magnesium carbonate and the like. The compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.

[0075] An effective amount of the pharmaceutical composition is determined based on the intended goal. The term “unit dose” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined-quantity of the pharmaceutical composition calculated to produce the desired responses discussed above in association with its administration, i.e., the appropriate route and treatment regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the protection or effect desired.

[0076] Precise amounts of the pharmaceutical composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g.,alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance.Examples

[0077] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.EXAMPLE 1SYNTHESIS, SEPARATION, AND CHARACTERIZATION OF (R) AND (S) DIASTEREOMERS OF HHC, HHCV, H4CBD, AND H4CBDV

[0078] The synthesis of (R) and (S)-HHC and H4CBD was followed by general procedure. A 20 L flask equipped with a reflux condenser and an addition funnel was purged with argon for 10 min at 1 bar. Pd / C (0.1 molar %) was added to the reaction slowly using a powder funnel under argon. The flask was then purged with argon for 10 min at 1 bar. Ethanol (1 L) was added slowly to avoid sparking the solvent. THC (100 g) was dissolved in ethanol (300 mb). The solution was added to the flask under argon and purged for 10 min at 1 bar. Afterward, the atmosphere of argon was stopped, and an atmosphere of hydrogen (1 bar) was introduced. The reaction was then stirred at 25 °C for 3 h or until complete by high performance liquid chromatography (HPLC) with a diode array detector. Upon completion, the reaction was purged with argon for 10 min at 1 bar. The reaction mixture was poured over 1-3 -micron filter paper on a Buchner funnel and then concentrated in vacuo. The crude oil was then dissolved in hexane and purified over silica (0%- 5% ethyl acetate). The fractions of interest were concentrated in vacuo and then distilled to afford a mixture of R and S diastereomers of HHC as a yellow oil.1H nuclear magnetic resonance (NMR) (500 MHz, CD3CN) 8 6.72 (s, 1H), 6.13 (d, J = 1.7 Hz, 1H), 6.08 (d, J= 1.7 Hz, 1H), 3.11 to 3.03 (m, 1H), 2.45 to 2.34 (m, 3H), 2.18 (s, 1H), 1.87 to 1.79 (m, 2H), 1.63 to 1.48 (m, 2H), 1.42 to 1.23 (m, 5H), 1.31 (s, 3H), 1.19 to 1.03 (m, 3H), 1.00 (s, 3H), 0.95 to .85 (m, 5H), and 0.64 (dt,J = 12.8, 11.4 Hz, 1H).13C NMR (101 MHZ, CD3CN) 5 157.07, 155.91, 143.39, 118.36, 1 11.32, 109.96, 108.38, 77.53, 64.22,50.26, 39.81, 36.40, 36.06, 33.69, 32.37, 31.70, 28.83, 28.14, 25.68, 23.31, 23.04, 19.37, 14.43, 2.01, 1.80,1.60, 1.39, 1.19, 0.98, and 0.77.

[0079] Chiral separation of (R) and (S) HHC: The diastereomers of HHC were separated by supercritical fluid chromatography (SFC). SFC is used in the industry primarily for the separation of chiral molecules, and uses the same columns as standard HPLC systems and CO2 as the mobile phase. HHC (5 g) was submitted for diastereomeric resolution. The analytical and preparative SFC methods described below were used for the purification.

[0080] Analytical SFC method: Column 4.6 x 100 mm Chiralpak AD-H from Chiral Technologies (West Chester, PA); CO2 Co-solvent (Solvent B) Isopropanol; Isocratic Method 25% Co-solvent at 4 mL / min System Pressure 125 bar; Column Temperature 40 °C; and Sample Diluent Isopropanol

[0081] Preparative SFC method: Column 2.1 x 25.0 cm Chiralpak AD-H was procured from Chiral Technologies (West Chester, PA); CO2 Co-solvent (Solvent B) isopropanol; isocratic method 30% Co-solvent at 80 g / min; system pressure 100 bar; column temperature 25°C; and sample diluent isopropanol.HHCV and H4CBDV were synthesized according to the general procedure above. HHCV: HPLC (C18): 5.85, 5.447 min.1H NMR (FIG. 2, 500 MHz, CD3CN) 5 6.75 (1H), 6.167 (2H), 2.44 (3H), 1.86 (1H), 1.61 (3H), 1.44 (1H), 1.35 (4H), 1.15 (2H), 1.07 (2H), 1.06 (2H), 0.95 (6H). H4CBD: HPLC (C18): 4.610, 4.697 min, 'H NMR (500 MHz, CD CN) 5 6.25 (2H), 6.21 (1H), 6.19 (1H), 5.42 (1H), 3.10 (1H), 2.48 (3H), 2.25 (1H), 1.84 (1H), 1.62 (4H), 1.54 (3H), 1.4 (6H), 1.15 (2H), 0.96 (7H), 0.91 (4H), 0.78 (4H).EXAMPLE 2FORMULATION DATA

[0082] Formulation and dosing information used for pharmacokinetic experiments is provided in Table 1 below. The solutions were sonicated, vortexed, and slightly heated resulting in a clear purple liquid.Table 1 Formulation of compounds(HP-P-CD = 2-hydroxypropyl-beta-cyclodextrin)EXAMPLE 3PHARMACOKINETICS AND PHARMACODYNAMICS

[0083] Pharmacokinetic data was produced by administering CD1 male mice with H4CBD or H4CBDV. Each compound was formulated and administered as shown in Example 2. Plasma was sampled from the IV administered mice at 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr post dose. Plasma was sampled from the PO administered mice at 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr post dose. Plasma concentrations of each compound were measured in each mouse by HPLC-MS. The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 10 pL of working solutions (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) were added to 10 pL of the blank male CD1 mice plasma to achieve calibration standards of 0.5-1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 20 pL. Six quality control samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL and 800 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards. 20 pL standards, 20 pL QC samples and 20 pL unknown samples (10 pL plasma with 10 pL blank solution) were added to 200 pL of methanol containing internal standard (IS) mixture for precipitating protein respectively. The samples were vortexed for 30 seconds then centrifuged at 4 °C, 4,000 rpm for 15 min. The supernatants were diluted with water at a ratio of 1 :2. 15 pL of each diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0084] A summary of H4CBD pharmacokinetic parameters when administered IV are shown in Table 2. A summary of H4CBD pharmacokinetic parameters when administered PO are shown in Table 3. A summary of H4CBDV pharmacokinetic parameters when administered IV are shown in Table 4. A summary of H4CBDV pharmacokinetic parameters when administered PO are shown in Table 5.Table 2 H4CBD pharmacokinetic parameters when administered IVTable 3 H4CBD pharmacokinetic parameters when administered POTable 4 H4CBDV pharmacokinetic parameters when administered IVTable 5 H4CBDV pharmacokinetic parameters when administered POEXAMPLE 4TOXICITY STUDIES

[0085] To determine potential maximum tolerated dosages, 3.12, 6.25, 10, and 12.5 mg / kg of H4CBDV, for 2, 2, 1, and 1 doses respectively, were administered to mice. No toxicity was observed for the 3.12, 6.25, and 10 mg / kg doses. 12.5 mg / kg administered mouse showed partial toxicity (tremors) for H4CBD and acute toxicity for H4CBDV (strong tremors and weight loss). Mice were then administered higher doses of H4CBD and H4CBDV.

[0086] For H4CBD, a 31.25 mg / kg dose of caused a mouse to stop moving after about 5-10 minutes and have seizure-like symptoms; the mouse took another 30-45 minutes to start moving / breathing normally. The mouse was administered daily 31.25 mg / kg doses for two additional days with the same presentation and displayed tail vein toxicity on day 3. At day 4 the mouse did not receive any dose. At each of days 5, 6, and 7, the mouse received a 15.63 mg / kg dose and also had seizure-like symptoms but recovered more quickly (around 30 minutes) for each day. A 39.06 mg / kg dose killed a mouse in about 5 minutes. A 46.87 mg / kg dose killed a mouse almost immediately after administration.

[0087] For H4CBDV, a 31.25 mg / kg dose of caused a mouse to stop moving after about 2 minutes and have seizure-like symptoms; the mouse took another 30-45 minutes to start moving / breathing normally. The mouse was administered daily 31.25 mg / kg doses for two additional days with the same presentation and displayed tail vein toxicity on day 2. At day 4 the mouse did not receive any dose. At each of days 5, 6, and 7, the mouse received a 15.63 mg / kg dose and also had seizure-like symptoms but recovered more quickly (around 30 minutes) eachday. A 39.06 mg / kg dose killed a mouse immediately. A 46.87 mg / kg dose killed a mouse immediately.* * *

[0088] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.REFERENCESThe following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.1. Thapa, D. et al., Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis, European Journal of Pharmacology 2011, 650 (1), 64-71.2. PCT Patent Application No. PCT / US22 / 74047 - A method for preparing hexahydrocannabinol .3. Cruces, W., Ray, K. P, Jagtap, P. G., Cannabinoid Analogs and methods of use for Treatment and Prevention of Cancer, Patent Pending, 63 / 411,506, September 29, 2022.4. Collins, A. C., Ramirez, G. A., Tesfatsion, T. T., Ray, K. P, Caudill, S., Cruces, W., Synthesis and Characterization of the Diastereomers of Hexahydrocannabinol (HHC) and Hexahydrocannabidiol (H4CBD), Nat. Prod. Comm. 2023, 18(3), 1-6.5. Seccamani, P. et al., Photochemistry of Cannabidiol (CBD) Revised. A Combined Preparative and Spectrometric Investigation, Journal of Natural Products 2021, 84 (11), 2858-2865.6. U.S. Patent Application Publication No. 2019 / 0030102 - Hydrogenation of cannabis oil.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I:whereinX is H, halogen, substituted or unsubstituted alkyl, or OR2;R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacent Y are taken together to form a 3-membered cycloalkyl or heterocyl coalkyl ring, or two adjacent Y are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen;Z is H, halogen, or OR4;R4is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, -OC(O)(CH2)nC(O)O-gemcitabine, or -OC(O)(CH=CH)nC(O)O-gemcitabine, wherein n is an integer from 1-20; -OCO(2,4-dinitrophenol) ester, -OCH2(nitroimidazole), -CO-TEMPO, -CO2-TEMPO, -COCH2CH2CO2Et, -COCH2CH2COOH, or any natural or non-natural amino acid linked through its carboxy or amino terminus;R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, benzyl, substituted or unsubstituted aryl, -S-C1-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR5; andR is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof.

2. The compound of formula I, wherein the compound is further defined as a compound of formula IV:

3. The compound of formula I, wherein the compound is further defined as a compound of formula V:

4. A method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula I to a subject in need thereof, wherein the disease or disorder is selected from the group consisting of epilepsy, diabetes, nonalcoholic steatohepatitis (NASH), depression, glaucoma, a metabolic syndrome, an autoimmune disorder, insulin resistance disease, sleep apnea, hypertension, kidney disease, obesity, inflammation, and disease resulting in knee-joint complications.

5. The method of claim 4, wherein administration of the compound of formula I leads to a time-dependent increase in systemic concentration of the compound of formula I in the subject.

6. A compound of formula II:whereinA is O, S, CH2, NH, or N-alkyl;X is H, halogen, substituted or unsubstituted alkyl, or OR2;R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacent Y are taken together to form a 3 -membered cycloalkyl or heterocylcoalkyl ring, or two adjacent Y are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen;Z is H, halogen, or OR4;R4is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, -OC(O)(CH2)nC(O)O-gemcitabine, or -OC(O)(CH=CH)nC(O)O-gemcitabine, wherein n is an integer from 1-20; -OCO(2,4-dinitrophenol) ester, -OCH2(nitroimidazole), -CO-TEMPO, -CO2-TEMPO, -COCH2CH2CO2Et, -COCH2CH2COOH, or any natural or non-natural amino acid linked through its carboxy or amino terminus;R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, benzyl, substituted or unsubstituted aryl, -S-C1-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR5; andR5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof.

7. The compound of formula II, wherein the compound is further defined as a compound offormula VI:

8. The compound of formula II, wherein the compound is further defined as a compound of formula VII:

9. A method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula II to a subject in need thereof, wherein the disease or disorder is selected from the group consisting of epilepsy, diabetes, nonalcoholic steatohepatitis (NASH), depression, glaucoma, a metabolic syndrome, an autoimmune disorder, insulin resistance disease, sleep apnea, hypertension, kidney disease, obesity, inflammation, and disease resulting in knee-joint complications.

10. The method of claim 9, wherein administration of the compound of formula II leads to a time-dependent increase in systemic concentration of the compound of formula II in the subject.

11. A compound of formula III:whereinA is 0, S, CH2, NH, or N-alkyl;X is H, halogen, substituted or unsubstituted alkyl, or OR2;R2is substituted or unsubstituted alkyl; each Y is independently H, substituted or unsubstituted alkyl, or two adjacent Y are taken together to form a 3 -membered cycloalkyl or heterocylcoalkyl ring, or two adjacent Y are taken together to form a 3-membered ring optionally substituted with one or two R3; each R3is independently H or halogen;R is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, benzyl, substituted or unsubstituted aryl, -S-Ci-6 alkyl-CH=CH2, substituted or unsubstituted heteroaryl, or OR5; andR5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;L is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, -OC(O)(CH2)nC(O)O-gemcitabine, or -OC(O)(CH=CH)nC(O)O-gemcitabine, wherein n is an integer from 1-20; -OCO(2,4-dinitrophenol) ester, -OCH2(nitroimidazole), -CO-TEMPO, -CO2-TEMPO, -COCH2CH2CO2Et, -COCH2CH2COOH, or any natural or non-natural amino acid linked through its carboxy or amino terminus; or an enantiomer, diastereomer, epimer, racemate, or pharmaceutically acceptable salt thereof.

12. The compound of formula III, wherein the compound is further defined as a compound of formula VIII:

13. The compound of formula III, wherein the compound is further defined as a compound of formula IX:

14. A method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula III to a subject in need thereof, wherein the disease or disorder is selected from the group consisting of epilepsy, diabetes, nonalcoholic steatohepatitis (NASH), depression, glaucoma, a metabolic syndrome, an autoimmune disorder, insulin resistance disease, sleep apnea, hypertension, kidney disease, obesity, inflammation, and disease resulting in knee-joint complications.

15. The method of claim 8, wherein administration of the compound of formula III leads to a time-dependent increase in systemic concentration of the compound of formula III in the subject.

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