Fluorinated phytocannabinoids, and compositions comprising and methods of producing and using same

Abstract

Fluorinated phytocannabinoids, and compositions comprising and methods of producing and using same.

Description

[0001] FLUORINATED PHYTOCANNABINOIDS, AND COMPOSITIONS COMPRISING AND METHODS OF PRODUCING AND USING SAME

[0002] BACKGROUND

[0003] Phytocannabinoids are cannabinoids derived from the cannabis plant. The two most abundant phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0004] SUMMARY

[0005] A first aspect of the present disclosure relates to a fluorinated phytocannabinoid of any one of Formulae 1-11:

[0006] wherein: Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and R2 is an aliphatic sidechain.

[0007] In some embodiments of the first aspect, Ri is -COOH.

[0008] In some embodiments of the first aspect, Ri is H.

[0009] In some embodiments of the first aspect, Ri is an ester.

[0010] In some embodiments of the first aspect, Ri is CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group.

[0011] In some embodiments of the first aspect, R2 is methyl, ethyl, n-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

[0012] In some embodiments of the first aspect, the fluorinated phytocannabinoid is:

[0013] In some embodiments of the first aspect, the fluorinated phytocannabinoid is:

[0014] A second aspect of the present disclosure relates to a composition comprising a fluorinated phytocannabinoid of the first aspect.

[0015] In some embodiments of the second aspect, the composition comprises at least one pharmaceutically acceptable carrier.

[0016] A third aspect of the present disclosure relates to a method comprising contacting cells with a fluorinated phytocannabinoid of the first aspect, wherein the contacting reduces cell viability in at least one of the cells.

[0017] In some embodiments of the third aspect, the cells are in vitro cells.

[0018] In some embodiments of the third aspect, the cells are in vivo cells.

[0019] In some embodiments of the third aspect, the cells are ex vivo cells.

[0020] In some embodiments of the third aspect, the cells are cancer cells.

[0021] In some embodiments of the third aspect, the cancer cells are leukemia cells.

[0022] In some embodiments of the third aspect, the cells are activated T cells.

[0023] In some embodiments of the third aspect, the cells are in a subject and the contacting comprises administering the fluorinated phytocannabinoid to the subject.

[0024] In some embodiments of the third aspect, the administering comprises systemic administration.

[0025] In some embodiments of the third aspect, the systemic administration comprises one or more of enteral administration and parenteral administration.

[0026] In some embodiments of the third aspect, the subject is a mammal, and optionally is a human.

[0027] In some embodiments of the third aspect, the subject has a cancer.

[0028] In some embodiments of the third aspect, the cancer is leukemia.

[0029] In some embodiments of the third aspect, the method further comprises administering, to the subject, one or more of a surgical regimen, a radio-therapy regimen, and a chemotherapy regimen.

[0030] In some embodiments of the third aspect, the subject has an autoimmune condition. A fourth aspect of the present disclosure relates to a method comprising contacting cells with a composition of the second aspect, wherein the contacting reduces cell viability in at least one of the cells.

[0031] In some embodiments of the fourth aspect, the cells are in vitro cells.

[0032] In some embodiments of the fourth aspect, the cells are in vivo cells.

[0033] In some embodiments of the fourth aspect, the cells are ex vivo cells.

[0034] In some embodiments of the fourth aspect, the cells are cancer cells.

[0035] In some embodiments of the fourth aspect, the cancer cells are leukemia cells.

[0036] In some embodiments of the fourth aspect, the cells are activated T cells.

[0037] In some embodiments of the fourth aspect, the cells are in a subject and the contacting comprises administering the fluorinated phytocannabinoid to the subject.

[0038] In some embodiments of the fourth aspect, the administering comprises systemic administration.

[0039] In some embodiments of the fourth aspect, the systemic administration comprises one or more of enteral administration and parenteral administration.

[0040] In some embodiments of the fourth aspect, the subject is a mammal, and optionally is a human.

[0041] In some embodiments of the fourth aspect, the subject has a cancer.

[0042] In some embodiments of the fourth aspect, the cancer is leukemia.

[0043] In some embodiments of the fourth aspect, the method further comprises administering, to the subject, one or more of a surgical regimen, a radio-therapy regimen, and a chemotherapy regimen.

[0044] In some embodiments of the fourth aspect, the subject has an autoimmune condition.

[0045] A fifth aspect of the present disclosure relates to a method of producing a fluorinated phytocannabinoid, comprising: providing a phytocannabinoid; and hydrofluorinating the phytocannabinoid to produce a fluorinated phytocannabinoid of the first aspect.

[0046] In some embodiments of the fifth aspect, hydrofluorinating the phytocannabinoid comprises reacting the phytocannabinoid with hydrogen fluoride pyridine.

[0047] BRIEF DESCRIPTION OF DRAWINGS

[0048] FIG. 1 is a graph showing % cell death at 72-hour timepoint of 9- Fluorohexahydrocannabinol (9F HHC). FIG. 2 is a graph showing % cell death at 72-hour timepoint of 9- Fluorohexahydrocannabinolic acid (9F HHCA).

[0049] FIG. 3 is a graph showing % cell death at 72-hour timepoint of 9- Fluorohexahydrocannabidivarin (9F HHCV)

[0050] DETAILED DESCRIPTION

[0051] Definitions

[0052] As used herein, a “phytocannabinoid” refers to a multi-ring phenolic compound derived from a plant of the Cannabis (Cannabaceae) genus. A phytocannabinoid may include a dibenzopyran ring and a hydrophobic alkyl chain. Phytocannabinoids are known to interact with the cannabinoid CBi and CB2 receptors, which belong to the Class A (rhodopsin (Rho) family) of G-protein coupled receptors (GPCRs). Example phytocannabinoids include A9- tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THQ, cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), A9- tetrahydrocannabivarin (THCV), cannabivarin (CBV), cannabidivarin (CBDV), cannabinodiol (CBND), cannabielsion (CBE), cannabicyclol (CBL), and cannabitriol (CBT).

[0053] As used herein, a “fluorinated phytocannabinoid” refers to a phytocannabinoid that has had at least one moiety substituted for at least one fluorine atom. In some instances, a , fluorinated phytocannabinoid may be a “hydrofluorinated phytocannabinoid,” meaning a phytocannabinoid having an alkene that has undergone a hydrofluorination reaction. That is, the alkene is replaced by an alkane in which one of the carbon atoms has been bonded to a fluorine atom and the other carbon atom has been bonded to a hydrogen atom.

[0054] As used herein, an “aliphatic sidechain" refers to a chain of carbon atoms having one or more alkane and / or one or more alkene bonds. Example aliphatic sidechains include methyl, etiiyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0055] As used herein, “alkyl” refers to a Ci-Cis hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, — CHs), etiiyl (Et, — CH2CH3), 1- propyl (n-Pr, n-propyl, — CH2CH2CH3), 2-propyl (i-Pr, i-propyl, — CH(CHa)2), 1-butyl (n- Bu, n-butyl, — CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, — CH2CH(CHa)2), 2- butyl (s-Bu, s-butyl, — CH(CHJ)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, — C(CHa)3), 1- pentyl (n-pentyl, — CH2CH2CH2CH2CH3), 2-pentyl ( — CH(CHI)CH2CH2CH3), 3-pentyl ( — CH(CH2CH3)2), 2-methyl-2-butyl (— C(CH3)2CH2CH3), 3-mcthyl-2-butyl (— CH(CH3)CH(CH3)2), 3-methyl-l-butyl (— CH2CH2CH(CH3)2), 2-methyl-l-butyl (— OHCHCCH3X^HzCH3), 1-hexyl (— CH2CH2CH2CH2CH2CH3), 2-hexyl (— CH(CH3)CH2CH2CH2CH3), 3-hexyl (— CHCCH2CH3XCH2ahCH2)), 2-methyl-2-pentyl (— C(CH3)2CH2CH2CH3), 3-methy!-2-pentyl (— CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (— CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (— C(CH3XCH2CH3)2), 2-methyl-3-pentyl (— CH(CH2CH3X3H(CH3)2), 23-dimethyl-2-butyl (— C(CH3)2CH(CH3)2), and 3,3-dimethyl- 2-butyl (— CH(CH3XXCH3)3).

[0056] As used herein, “alkenyl" refins to a C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation (i.e., a carbon- carbon, sp2double bond). Examples include, but are not limited to, ethylene or vinyl ( — CH=CH2), allyl ( — CH2CH=CH2), cyclopentenyl ( — C5H7), and 5-hexenyl ( — CH2CH2CH2CH2CH=CH2).

[0057] As used herein, “alkynyl" refers to a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation (i.e., a carbon-carbon, sp triple bond). Examples include, but are not limited to, acetylenic ( — C^CH) and propargyl ( — CH2OCH).

[0058] As used herein, “alkylene” refers to a saturated, branched, or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Example alkylene radicals include, but are not limited to, methylene ( — CH2 — ) 1,2- ethyl (— CH2CH2— ), 1,3-propyl (— CH2CH2CH2— ), 1,4-butyl (— CH2CH2CH2CH2— ), and the like. Examples of a C1-C10 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, ocytylene, nonylene and decalene.

[0059] As used herein, “alkenylene” refers to an unsaturated, branched, or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Example alkenylene radicals include, but are not limited to, 1,2-ethylene (— CH=CH— ).

[0060] As used herein, “alkynylene” refers to an unsaturated, branched, or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Example alkynylene radicals include, but are not limited to, acetylene ( — OC — ), propargyl ( — CH2OC — ), and 4-pentynyl ( — ClfcCTbCHzC^CH — ). As used herein, “aryl” refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Example aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0061] As used herein, “arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Example arylalkyl groups include, but are not limited to, benzyl, 2- phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms (e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms).

[0062] As used herein, “heteroarylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl radical. Exapmle heteroarylalkyl groups include, but are not limited to, 2- benzimidazolylmethyl, 2-fuiylethyl, and the like. The heteroarylalkyl group comprises 6 to 20 carbon atoms (e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). The heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).

[0063] As used herein, “substituted alkyl”, “substituted aryl", and “substituted arylalkyl" refer to alkyl, aryl, and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent Example substituents include, but are not limited to, — X, — R, —OR, —SR, — S~, — NR2, — NRa, =NR, — CX3, — CN, — OCN, — SCN, — N=C=O, — NCS, —NO, — NQz, =^2, —Na, NC(=O)R, — C(=O)R, — C(=O)NR2, — SO3H, — S(=O)2R, — OS(=O)2OR, — S(=O)2NR, — S(=O)R, — OP(=OXOR)2, — P(=OXOR)2, — PO- a, — PO3H2, — C(=O)R, — C(=O)X, — C(=S)R, — CO2R, — CO2 " — C(=S)OR, — C(=O)SR, — C(=S)SR, — C(=O)NR2, — C(=S)NR2, — C(=NR)NR2, where each X is independently a halogen (i.e., F, Cl, Br, or I) and each R is independently — H, C2- C18 alkyl, C6-C20 aryl, C3-C14 heterocycle, protecting group, or prodrug moiety). Alkylene, alkenylene, and alkynylene groups as described above may also be similarly substituted. As used herein, “heteroaryl” and “heterocycle” refer to a ring system in which one or more ring atoms is a heteroatom (e.g., nitrogen, oxygen, and sulfur). The heterocycle radical comprises 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). Examples of heterocycles include, but are not limited to, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis- tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H- pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0064] As used herein, “carbocycle” refers to a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cycloheptyl, and (tyclooctyl.

[0065] As used herein, “arylene” refers to an aryl group which has two covalent bonds and can be in the ortho, meta, or para configurations as shown in the following structures:

[0066] in which the phenyl group can be unsubstituted or substituted with up to four groups including, but not limited to, — C1-C8 alkyl, — O — (C1-C8 alkyl), -aryl, — C(O)R', — OC(O)R', — C(O)OR', — C(O)NH2, — C(O)NHR', — C(O)N(R')2- NHC(O)R', — S(O)2R', — S(O)R', —OH, -halogen, —Na, — NHa, — NH(R'), — N(R')2 and — CN, where each R' is independently selected from H, — C1-C8 alkyl, and aryl.

[0067] Fluorinated Phytocannahinoids

[0068] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 1 :

[0069] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0070] R2 is an aliphatic sidechain.

[0071] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have tiie structure of Formula 2:

[0072] where:

[0073] R1 is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0074] R2 is an aliphatic sidechain.

[0075] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 3: where:

[0076] R1 is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0077] R2 is an aliphatic sidechain. In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 4: where:

[0078] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0079] R2 is an aliphatic sidechain.

[0080] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 5 : where:

[0081] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0082] R2 is an aliphatic sidechain.

[0083] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 6: where:

[0084] R1 is -CChH, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0085] Ra is an aliphatic sidechain.

[0086] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 7: where:

[0087] R1 is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0088] R2 is an aliphatic sidechain.

[0089] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 8: where:

[0090] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0091] Rz is an aliphatic sidechain.

[0092] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 9: where:

[0093] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0094] R2 is an aliphatic sidechain.

[0095] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 10: where:

[0096] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0097] R3 is an aliphatic sidechain.

[0098] In some embodiments, a fluorinated phytocannabinoid of the present disclosure may have the structure of Formula 11: where:

[0099] Ri is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, and

[0100] R2 is an aliphatic sidechain.

[0101] An example of a fluorinated phytocannabinoid of the present disclosure is:

[0102] Another example of a fluorinated phytocannabinoid of the present disclosure is:

[0103] A further example of a fluorinated phytocannabinoid of the present disclosure is: Another example of a fluorinated phytocannabinoid of the present disclosure is:

[0104] Treatment and Risk Reduction

[0105] As used herein, the terms “treat”, “treated”, or “treating” when used with respect to a disease or condition may refer to a prophylactic treatment that decreases the likelihood of a cell or subject developing the disease or condition, and also may refer to a treatment after the cell or subject has developed the disease or condition, in order to eliminate or ameliorate the disease or condition, prevent the disease or condition from becoming more advanced and / or severe, and / or slow the progression of the disease or condition compared to progression in the absence of the therapy.

[0106] Certain methods of the present disclosure include a treatment regimen comprising administering to a cell or subject identified as having, or at risk of having, a disease or condition, one or more fluorinated phytocannabinoids. Certain embodiments may include (1) identifying a cell or subject at risk of having a disease or condition or a cell or subject that has the disease or condition, (2) selecting a regimen to be administered to the cell or subject identified in step (1); and (3) administering the selected regimen to the cell or subject identified as in need of the selected therapeutic regimen. It will be understood that the terms “administered,” “administering," and “administer" may be used interchangeably with the terms “contacted with," “contacting with,” and “contact with”, respectively, when used in reference to administering one or more fluorinated phytocannabinoids of the present disclosure.

[0107] The present disclosure, in part, includes methods of reducing a cell and / or subject’s risk of developing a disease or condition. Certain embodiments of risk reduction include administering one or more fluorinated phytocannabinoids to a cell and / or subject identified as at risk of developing a disease or condition. In some embodiments, an agent administered to the subject is a fluorinated phytocannabinoid agent (e.g., a fluorinated phytocannabinoid within the scope of the present disclosure) that is administered in an amount effective to reduce the cell’s and / or subject’s risk of developing the disease or condition. Efficacy of a method of the present disclosure to reduce a cell’s or subject’s risk may be determined by comparing results of administering a fluorinated phytocannabinoid agent to a cell or subject with control results. In some embodiments, a fluorinated phytocannabinoid agent administered to a cell or subject reduces the cell’s or subject’s risk, respectively, of developing a disease or condition compared to a control risk of developing the disease or condition, wherein the control risk is a risk of a cell or subject in essentially identical circumstances developing the disease or condition in the absence of the administered fluorinated phytocannabinoid agent.

[0108] Identifying a cell or subject at risk of developing a disease or condition may be based, at least in part, on factors such as but not limited to: the source of the cell, the medical history of the subject; genetic background of the subject; a prior, current, or future activity of the subject; and a prior, current, or future exposure of the subject to an agent or element believed to be a possible causative factor in the development of the disease or condition, etc.

[0109] In addition to activities or future activities that may indicate a level of risk of a cell or subject developing a disease or condition, the presence of an existing symptom or physiological indicator in a cell or subject may indicate a risk of the cell or subject developing a disease or condition. For example, though not intended to be limiting, a subject’s age may assist in identifying the subject as being at risk for a disease or condition. Additional examples of physiological conditions or events that may assist in identifying a cell or subject at risk of having or as having a disease or condition include, but are not limited to, CNS inflammation and / or infection, traumatic brain injury, repetitive brain injury, or an autoimmune condition (e.g., Human Immunodeficiency Virus (HIV), Addison disease, Celiac disease - sprue (gluten-sensitive enteropathy), dermatomyositis, Amyotrophic Lateral Sclerosis (ALS), Graves disease, Hashimoto thyroiditis, inflammatory bowel disease (Crohn disease, ulcerative colitis), multiple sclerosis, myasthenia gravis, etc.).

[0110] A fluorinated phytocannabinoid agent of the present disclosure could be used to prevent or treat

[0111] Labelling

[0112] A fluorinated phytocannabinoid of the present disclosure or a composition comprising a fluorinated phytocannabinoid of the present disclosure can be used alone or in conjugates with other molecules such as targeting agents and / or labeling agents in methods of the present disclosure. Targeting agents useful according to the methods of the present disclosure are those that direct a fluorinated phytocannabinoid of the present disclosure to a specific cell type to be treated such as, but not limited to liver cells, muscle cells, cardiac cells, circulatory cells, neuronal cells, glial cells, fat cells, skin cells, hematopoietic cells, epithelial cells, sperm, oocytes, muscle cells, adipocytes, kidney cells, hepatocytes, and pancreatic cells. A targeting compound of choice will depend upon the nature of the disease or condition to be treated. In some instances, it may be desirable to target the fluorinated phytocannabinoid of the present disclosure to skeletal muscle, cardiac muscle, kidney, liver, or brain, etc. Those of ordinary skill in the art will be aware of and able to select and use suitable targeting agents for use in methods of the present disclosure.

[0113] Labeling agents may be used in methods of the present disclosure to determine the location of a fluorinated phytocannabinoid of the present disclosure in cells and tissues and also, may be used to assess the cell, tissue, or organ location of a fluorinated phytocannabinoid of the present disclosure that has been delivered to a cell or administered to a subject. Procedures for attaching and utilizing labeling agents such as enzymatic labels, dyes, radiolabels, etc. are well known in the art. A detectable label attached to a fluorinated phytocannabinoid of the present disclosure and / or used in a method of the present disclosure may be a detectable marker such as a colorimetric marker, enzymatic marker, radioactive marker, etc. whose presence and location in a subject can be detected by standard imaging techniques.

[0114] As used herein, the term “detectable label" means a label or tag chemically bound to a fluorinated phytocannabinoid of the present disclosure or composition comprising a fluorinated phytocannabinoid of the present disclosure. In some embodiments a detectable label may be an affinity label, including one or more of biotin, digoxigenin, and a hapten. In some embodiments, a detectable label comprises a visible component, as is typical of a dye or fluorescent molecule, a luminescent label, a radiolabel, an enzymatic label, a contrast agent, a heavy metal, or a heavy element such as bromine or iodine, or metals such as gold, osmium, rhenium, etc.; however, any signaling means used by the label is also contemplated.

[0115] In some embodiments, a fluorinated phytocannabinoid of the present disclosure and / or fluorinated phytocannabinoid composition of the present disclosure may be labelled, or otherwise modified, to permit detection. Such labeled compounds and / or compositions can be used for real-time in vivo imaging using a sample that remains within (e.g., is not removed from) a subject or for in vitro imaging using a sample that is removed from a subject. Detectable labels that can be used in conjunction with a fluorinated phytocannabinoid compound or composition comprising a fluorinated phytocannabinoid of the present disclosure may be any that do not substantially interfere with the therapeutic function to treat the disease or condition, but that allow external detection. Examples of detectable labels and methods suitable for use in in vitro treatment methods of the present disclosure are described in detail elsewhere herein. Suitable in vivo detectable labels may include those that may be detected by X-radiography, NMR, or MRI. For X-radiographic techniques, suitable detectable labels include any radioisotope that emits detectable radiation but that is not overtly harmful to the patient, such as barium or cesium, for example. Suitable detectable labels for NMR and MRI generally include those with a detectable characteristic spin, such as deuterium.

[0116] The size of the subject, and the imaging system used, will determine the quantity of imaging moiety needed to produce vivo images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of technetium-99m. The labeled fluorinated phytocannabinoid of the present disclosure or composition comprising a fluorinated phytocannabinoid of the present disclosure will then preferentially accumulate at the location of cells to which the compound and / or composition, respectively, was delivered. The labeled fluorinated phytocannabinoid of the present disclosure or composition comprising a fluorinated phytocannabinoid of the present disclosure can then be detected using art-known techniques.

[0117] Effective Amounts

[0118] Methods of the present disclosure comprise administering an agent to a cell or subject (a non-limiting example of which is a fluorinated phytocannabinoid agent) in an amount effective to treat a disease or condition. An effective amount is a dosage of the agent sufficient to provide a medically desirable result. It should be understood that pharmacological agents of the present disclosure are used to treat or prevent diseases or conditions, that is, in some embodiments they may be used to treat an existing disease or condition in a cell or subject, and they may also be administered prophylactically to a cell or subject at risk of developing a disease or condition. An effective amount is that amount that can lower a risk of, slow or perhaps prevent altogether the development of a disease or condition in a cell or subject.

[0119] Factors involved in determining an effective amount are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of a pharmacological agent of the present disclosure be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a subject (also referred to herein as a patient) may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0120] The therapeutically effective amount of a pharmacological agent of the present disclosure is that amount effective to treat the disease or condition. For example, the desired response may be inhibition of the progression of the disease or condition and / or reducing the severity and / or the level of the disease or condition. This may involve only slowing the progression of the disease or condition temporarily, although it may include halting the progression of the disease or condition permanently. This can be monitored by routine diagnostic methods known to those of ordinary skill in the art. A desired response to a method of the present disclosure to treat a disease or condition may, in some embodiments, be preventing the onset of the disease or condition.

[0121] In some embodiments, a therapeutically effective amount refers to that amount of the agent (a non-limiting example of which is a fluorinated phytocannabinoid agent) being administered to a cell or subject that is sufficient to prevent progression of a disease or condition. Administration of the agent in an amount effective to reduce a disease or condition in a cell or subject may reduce the risk of the cell or subject developing the disease or condition by at least 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%, compared to the percent control risk of the cell or subject developing the disease or condition. In a non-limiting example, if a cell or subject’s risk of developing a disease or condition based on medical history, genetic analysis, etc. is 20%, administering an effective amount of a fluorinated phytocannabinoid agent to the cell or subject may reduce the cell or subject’s 20% risk down to less than 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% risk, or to 0% risk.

[0122] In some embodiments, a therapeutic regimen comprising administration of one or more agents to a cell or subject determined to be in need such treatment may include administration of one or more agents once, or multiple times. Multiple administrations of an agent means the agent is administered to a cell or subject 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. It will be understood that administration of an agent may be done in combination with additional treatments for a disease or condition.

[0123] Treatment Selection

[0124] As described herein, a therapeutic regimen (also referred to herein as a treatment) may be selected for a cell or subject based at least in part on the identification that the cell or subject is at risk of having or that the cell or subject has a disease or condition. In some embodiments, selection of a treatment may be based, at least in part, on the severity of a disease or condition in a cell or subject. In some embodiments, a selected treatment may include administering to the cell or subject an effective amount of one or more agents. In some embodiments, the administered agent is a fluorinated phytocannabinoid agent.

[0125] Certain embodiments of the present disclosure include administering a fluorinated phytocannabinoid agent and administering one or more additional treatments appropriate for the specific disease or condition in the cell or subject. As a non-limiting example, an additional treatment for a cell or subject identified as having or at risk of having a disease or condition includes one or more of physical therapy, surgery, administration of one or more additional therapeutic agents, dietary modification, etc. Upon a determination of the presence of, or a risk of, a disease or condition in a cell or subject, a practitioner will, without undue experimentation, be aware of and able to select one or more treatments that may be administered to a cell or subject in addition to the administration of an agent, a non-limiting example of which is a fluorinated phytocannabinoid agent.

[0126] Therapeutic Compositions and Methods and Monitoring Efficacy

[0127] Methods of the present disclosure include producing, in a cell or subject in need of such treatment, a therapeutic effect against a disease or condition. The term “therapeutic effect” as used herein in reference to an agent (e.g., a fluorinated phytocannabinoid agent) means a clinically beneficial effect of the agent against the disease or condition when it is administered to a cell or subject in need of such treatment. A therapeutic effect of an agent can be determined, for example, by detecting one or more physiological effects of the treatment, such as the decrease or lack of symptoms of the disease or condition following administration of the treatment. Additional means of monitoring and assessing a disease or condition in a cell or subject, and ways to assess and determine one or more of a level, severity, change in severity, etc. of a disease or condition in cell or subject are known in the art and can be used to assess the condition in a cell or subject following a treatment method of the present disclosure.

[0128] Methods and compositions of the present disclosure may be used to treat a disease or condition. As used herein, the terms “treat," “treated,” or “treating” when used in relation to a disease or condition may refer to a prophylactic treatment that decreases the likelihood or risk of a cell or subject developing the disease or condition, and may be used to refer to a treatment after a cell or subject has developed a disease or condition in order to eliminate or ameliorate the disease or condition, prevent the disease or condition from becoming more advanced or severe, and / or to slow the progression of the disease or condition compared to the progression of the disease or condition in the absence of a therapeutic method of the present disclosure.

[0129] Subjects and Cells

[0130] The term “subject” may refer to human or non-human animals, including mammals and non-mammals, vertebrates and invertebrates, and may also be any multicellular organism or single-celled organism such as a eukaryotic (including plants and algae) or prokaryotic organism, archaeon, microorganisms (e.g., bacteria, archaea, fungi, protists, viruses), and aquatic plankton. A subject may be considered a normal subject or may be a subject known to have or suspected of having a disease or condition. In some embodiments, an organism is a genetically engineered organism, which may also be referred to herein as a genetically modified organism.

[0131] A cell of the present disclosure may be an in vitro cell, in vivo cell, or ex vivo cell. Cells, tissues, or other sources or samples may include a single cell, a variety of cells, or organelles. It will be understood that a cell sample comprises a plurality of cells. As used herein, the term “plurality” means more than one. In some instances, a plurality of cells is at least 2, 10, 100, 1,000, 10,000, 100,000, 500,000, 1,000,000, 5,000,000, or more cells. A plurality of cells used in a method of the present disclosure may be a population of cells. A plurality of cells may include cells that are of the same cell type. In some embodiments, one or a plurality of cells used in a method of the present disclosure is a healthy normal cell, which is not known to have a disease, disorder, or abnormal condition. In some embodiments, one or a plurality of cells used in a method of the present disclosure includes cell(s) having a known or suspected disease or condition or other abnormality, for example, a cell obtained from a subject diagnosed as having a disorder, disease, or condition, including, but not limited to a degenerative cell, a neurological disease-bearing cell, a cell that is a cell model of a disease or condition, an injured cell, etc. In some embodiments, a cell is an abnormal cell obtained from cell culture, a cell line known to include a disorder, disease, or condition. Non- limiting examples of diseases or conditions include anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome-related disorders, autoimmune disorders (e.g., Human Immunodeficiency Virus (HIV), Addison disease, Celiac disease - sprue (gluten-sensitive enteropathy), dermatomyositis, Amyotrophic Lateral Sclerosis (ALS), Graves disease, Hashimoto thyroiditis, inflammatory bowel disease (Crohn disease, ulcerative colitis), multiple sclerosis, myasthenia gravis, etc.), traumatic brain injury, concussion, stroke, autism, PTSD, depression, opiate addiction, and macular degeneration. Incorporated herein by reference in its entirety is Caprari, C., Ferri, E., Vandelli, M.A. et al. An emerging trend in Novel Psychoactive Substances (NPSs): designer THC. J Cannabis Res 6, 21 (2024), which provides a review of the medical applications of cannabinoids.

[0132] In some embodiments of the present disclosure, a plurality of cells is a mixed population of cells, meaning all cells are not of the same cell type. Cells may be obtained from any organ or tissue of interest, including but not limited to brain, CNS, PNS, breast, blood, blood vessel (e.g., artery or vein), fat, pancreas, liver, muscle, gastrointestinal tract, heart, etc. In some embodiments, a cell is a control cell. In various embodiments, a cell used in a method of the present disclosure may be a genetically modified cell or a cell that is not genetically modified.

[0133] The effects of cannabinoids at the cellular level are known. See Abyadeh et al., “A Protomic View of Cellular and Molecular Effects of Cannabis," Biomolecules, 2021 Oct; 11(10): 1411, the entire contents of which is incorporated herein by reference.

[0134] In some embodiments, a cell or a plurality of cells used in a method of the present disclosure is obtained directly from a subject. Non-limiting examples of sources of cells that may be contacted with a fluorinated phytocannabinoid of the present disclosure are blood, saliva, lymph, cerebrospinal fluid, brain tissue, neuronal tissue, vitreous humor, aqueous humor, mucous, tissue, a surgical specimen, biopsy specimen, tissue explant, organ culture, biological fluid or any other tissue or cell preparation, or fraction or derivative thereof or isolated therefrom, etc. In some embodiments of the present disclosure, a cell is obtained from primary cells, cell lines, freshly isolated cells or tissues, frozen cells or tissues, paraffin embedded cells or tissues, fixed cells or tissues, and / or laser dissected cells or tissues. A cell contacted with a fluorinated phytocannabinoid of the present disclosure can be obtained (isolated) from a subject, or other source according to methods known in the art. A cell culture or subject from which cell or cells are obtained may be a cell culture comprising genetically engineered cells or a genetically engineered subject, respectively.

[0135] Assessments and Controls

[0136] A disease or condition in a subject can be detected using an art-known method. Methods that may be used to detect a disease or condition include, but are not limited to, identifying the presence of one or more physiological characteristics or symptoms of the disease or condition in a subject, assessing genetic characteristics of a subject, histological and / or imaging methods applied to a subject, etc. Characteristics of a disease or condition detected in a subject can be compared to control values of the characteristics of the disease or condition. A control value may be a predetermined value, which can take a variety of forms. It can be a single cut-off value, such as a median or mean. It can be established based upon comparative groups, such as in groups of individuals having the disease or condition, groups of individuals who have been administered a treatment for the disease or condition, groups of individuals who have not been administered a treatment for the disease or condition, etc. Another example of comparative groups may be groups of subjects having one or more symptoms of or a diagnosis of the disease or condition and groups of subjects without the one or more symptoms of or a diagnosis of the disease or condition. A predetermined value will depend upon the particular population selected. Accordingly, the predetermined value selected may take into account a category in which an individual falls. Non-limiting examples of categories are a subject’s age, a subject’s genetic background, etc. Appropriate categories can be selected and utilized with no more than routine experimentation by those of ordinary skill in the art.

[0137] Controls can be used in methods of the present disclosure to compare characteristics of different control groups, characteristics of a cell or subject with those of a control group, etc. Comparisons between cells or subjects and controls, one control with another control, etc. may be based on relative differences. For example, though not intended to be limiting, a physiological symptom in a subject treated with an agent in a therapeutic method of the present disclosure, can be compared to the physiological symptom of a control subject or subject group that has not been administered the agent. In some embodiments, a suitable control is a subject not treated with a treatment method of the present disclosure. A comparison of a treated versus a control may include comparing disease severity differences between a treated subject and a selected control. In some instances, severity of symptoms or physiological effects of a disease or condition in a subject treated with a method of the present disclosure may be determined to be less relative to a selected control, with the comparison indicating up to a 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% reduction in severity of one or more physiological effects and symptoms of the disease or condition in the subject as compared to the control.

[0138] In some embodiments, a level of severity of a treated subject’s disease or condition is less than 100% of a control severity level of the disease or condition. In certain embodiments, the severity of one or physiological symptoms of the disease or condition in a subject treated according to a method of the present disclosure is less than or equal to 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%. 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the control level of severity of the one or more physiological symptoms, respectively, of the disease or condition.

[0139] It will be understood that controls may be, in addition to predetermined values, samples of materials tested in parallel with the experimental materials. Examples include samples from control populations or control samples generated through manufacture to be tested in parallel with the experimental samples; and a control may be a sample from a subject prior to, during, or after a treatment with an embodiment of a method or composition of the present disclosure. Thus, one or more characteristics determined for a subject having a disease or condition may be used as “control” values for those characteristics in that subject at a later time.

[0140] Preparation and Administration of Pharmacological Agents

[0141] The pharmacological agents used in the methods of the present disclosure are preferably sterile and contain an effective amount of a fluorinated phytocannabinoid agent for producing the desired response in a unit of weight or volume suitable for administration to a subject. In some embodiments, an agent (a non-limiting example of which is a fluorinated phytocannabinoid agent) is delivered in a composition formulated to cross into the brain (e.g., formulated to cross the blood-brain barrier). Doses of pharmacological agents administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. The dosage of a pharmacological agent may be adjusted by the individual health-care provider or veterinarian, particularly in the event of any complication. A fluorinated phytocannabinoid agent may also be referred to herein as a pharmacological agent.

[0142] The amount of a treatment administered to a subject may be varied for example by increasing or decreasing the amount of one or more agents administered to the subject. Changes in a treatment of the present disclosure may include one or more of changing the therapeutic composition administered, changing the route of administration, changing the dosage timing and so on. An effective amount of a composition of the present disclosure will vary with the particular disease or condition being treated, the age and physical condition of the subject being treated, the severity of the disease or condition, the duration of the treatment, the specific route of administration, and other art-known factors within the knowledge and expertise of a health practitioner.

[0143] Various modes of administration known to the skilled artisan can be used to effectively deliver a pharmaceutical composition of the present disclosure comprising a fluorinated phytocannabinoid agent to a subject in an amount effective to produce a desired therapeutic effect against a disease or condition in the subject. Administration methods that may be used to deliver a composition or pharmaceutical compound of the present disclosure to a subject include, but are not limited to, topical, intravenous, oral, intracavity, intrathecal, intrasynovial, buccal, sublingual, intranasal, transdermal, intravitreal, inhalation, subcutaneous, intramuscular, and intradermal administration.

[0144] The present disclosure is not limited by the particular modes of administration disclosed herein. Standard references in the art (e.g., Remington, The Science and Practice of Pharmacy, Editor: Adeboye Adejare, 23rdEdition, Elsevier, 2020) provide modes of administration and formulations for delivery of various pharmaceutical preparations and formulations in pharmaceutical carriers. Other protocols that are usefill for the administration of pharmacological agents of the present disclosure will be known to one of ordinary skill in the art, in which the dose amount, schedule of administration, sites of administration, mode of administration and the like vary from those presented herein.

[0145] Treatment compositions and treatment agents of the present disclosure are also referred to herein as pharmaceutical agents. Treatment compositions of the present disclosure may be administered to mammals other than humans (e.g., for testing purposes or veterinary therapeutic purposes), and such administrations may be carried out under substantially the same conditions as described herein. It will be understood that methods and compositions of the present disclosure are applicable to both human and animal diseases. Thus, the present disclosure is intended to be used in husbandry and veterinary medicine as well as in human therapeutics.

[0146] When administered, the pharmaceutical preparations of the present disclosure are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the present disclosure. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. A pharmacological agent or composition of the present disclosure may be combined, if desired, with a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” as used herein means one or more compatible solid or liquid fillers, diluents, or encapsulating substances which are suitable for administration into a human. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the pharmacological agents of the present disclosure, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0147] The pharmaceutical compositions may contain suitable buffering agents, non-limiting examples of which are acetate, phosphate, citrate, glycine, borate, carbonate, bicarbonate, hydroxide (and other bases) and pharmaceutically acceptable salts of the foregoing compounds. The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal.

[0148] The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0149] Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, pills, lozenges, each containing a predetermined amount of the active compound(s) [e.g., a fluorinated phytocannabinoid(s)]. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir, an emulsion, or a gel. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Non-limiting examples of suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers (e.g., EDTA) for neutralizing internal acid conditions or may be administered without any carriers.

[0150] For a pharmacological agent the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the fluorinated phytocannabinoid agent or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0151] The treatment agents of the present disclosure, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) with an added preservative. The compositions of the present disclosure may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0152] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds (e.g., fluorinated phytocannabinoids) in water-soluble form. Suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0153] Pharmacological agent(s), including but not limited to a fluorinated phytocannabinoid agent, may be provided in particles. The term “particles” as used herein means nano or microparticles (or in some instances larger particles) that can consist in whole or in part of a fluorinated phytocannabinoid agent as described herein. The particles may contain the pharmacological agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The pharmacological agent(s) also may be dispersed throughout the particles. The pharmacological agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the pharmacological agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, credible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the fluorinated phytocannabinoid agent in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0154] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the pharmacological agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules, (1993) 26:581-587, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexyhnethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0155] A pharmacological agent of the present disclosure may be contained in controlled- release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non- immediate release formulations including but not limited to sustained-release and delayed- release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels and / or tissue levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” Use of a long-term sustained-release implant may be particularly suitable for treatment of chronic diseases or conditions and / or chronic risk of developing a disease or condition. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the pharmacological agent(s) of the present disclosure for at least 7 days, and / or from 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0156] The present disclosure also contemplates the use of kits. In some aspects of the present disclosure, the kit can include one or more pharmaceutical preparation vial, a pharmaceutical preparation diluent vial, and a fluorinated phytocannabinoid agent. A vial containing the diluent for the pharmaceutical preparation is optional. A diluent vial may contain a diluent such as physiological saline for diluting what could be a concentrated solution or lyophilized powder of the a fluorinated phytocannabinoid agent. The instructions can include instructions for mixing a particular amount of the diluent with a particular amount of the concentrated pharmaceutical preparation, whereby a final formulation for injection or infusion is prepared. The instructions may include instructions for treating a subject with effective amounts of the fluorinated phytocannabinoid agent. It also will be understood that the containers containing the preparations, whether the container is a bottle, a vial with a septum, an ampoule with a septum, an infusion bag, and the like, can contain indicia such as conventional markings that change color when the preparation has been autoclaved or otherwise sterilized.

[0157] Examples

[0158] Example 1. Hydrofluorination of Δ9-tetrahydrocannabinol

[0159] In a plastic polyethylene tube, a solution of Δ9-tetrahydrocannabinol (368 mg, 1.17 mmol) in dichloromethane (5 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma-Aldrich, -30% pyridine / ~70% HF, 3 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product (338 mg, 86.44%), whose structure was confirmed by proton, carbon, and fluorine NMR as an isomeric mixture of (9R)- and (9S) fluorohexahydrocannabinol (HHC).

[0160] In aplastic polyethylene tube, a solution of A9-tetrahydrocannabivarin (327 mg, 1.14 mmol) in dichloromethane (3 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma-Aldrich, -30% pyridine / ~70% HF, 1.5 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product as an orange oil (353 mg, 91.7%) and whose structure was confirmed by proton, carbon, and fluorine NMR and GCMS as an isomeric mixture of (97?)- and (9S)- isomers of 9-Fluorohexahydrocannabidivarin (HHCV).

[0161] Example 3. Hydrofluorination of A9-tetrahydrocannabinolic acid

[0162] In a plastic polyethylene tube, a solution of A9-tetrahydrocannabinolic acid (439 mg, 1.226 mmol) in dichloromethane (3 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma- Aldrich, -30% pyridine / ~70% HF, 1.5 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product as a white solid (416 mg, 89.69%) and whose structure was confirmed by proton, carbon, and fluorine NMR as an isomeric mixture of (97?)- and (9S)- fluorohexahydrocannabinolic acid.

[0163] Example 4. Hydrofluorination of Cannabidiol

[0164] In a plastic polyethylene tube, a solution of cannabidiol (407 mg, 1.226 mmol) in dichloromethane (3 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma- Aldrich, -30% pyridine / ~70% HF, 1.5 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product as an orange oil (425 mg, 97.97%) and whose structure was confirmed by proton, carbon, and fluorine NMR as an isomeric mixture of (97?)- and (95)- fluorohexahydrocannabinol (HHC).

[0165] Example 5. Hydrofluorination of Cannabigerol

[0166] In a plastic polyethylene tube, a solution of cannabigerol (319 mg, 1.226 mmol) in dichloromethane (3 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma- Aldrich, -30% pyridine / ~70% HF, 1.5 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product as a yellow oil (325 mg, 96.72%) and whose structure was confirmed by proton, carbon, and fluorine NMR as an isomeric mixture of (47?)- and (45)-isomers of 2-(4- fluoro-4-methylpentyl)-2-methyl-7-pentylchroman-5-ol.

[0167] Example 6. Hydrofluorination of Cannabidivarin

[0168] In a plastic polyethylene tube, a solution of cannabidivarin (360 mg, 1.26 mmol) in dichloromethane (3 mLs) cooled to 0 °C was treated with hydrogen fluoride pyridine (Sigma- Aldrich, -30% pyridine / ~70% HF, 1.5 mLs) dropwise via plastic syringe. The reaction mixture turned dark brown. Stirred at 0 °C for 1 hour and then warmed to room temperature. After an hour stirring at room temperature, a saturated aqueous solution of sodium bicarbonate (10 mLs) was added with stirring. The biphasic mixture was transferred to a separatory funnel and the dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent by evaporation on rotary evaporator afforded the desired product as an orange oil (365 mg, 94.8%) and whose structure was confirmed by proton, carbon, and fluorine NMR and GCMS as an isomeric mixture of (97?)- and (95)- isomers of 9-Fluorohexahydrocannabidivarin (HHCV).

[0169] Example 7. Use of Fluorinated Phytocannabinoids to Inhibit Cellular Activity

[0170] In some studies, a fluorinated phytocannabinoid of the present disclosure is contacted with pro-inflammatory cytokine-releasing cell and it is determined that the contact of the cell by the fluorinated phytocannabinoid inhibits the cell’s release of the cytokines.

[0171] In certain studies, a cell is contacted with one or more fluorinated phytocannabinoids of the present disclosure and the resulting inhibition of the cell’s release of cytokines is determined and compared to a control level of inhibition. In some embodiments, the control level of inhibition is a level of inhibition of release of the cytokines by a cell contacted with a non-fluorinated phytocannabinoid.

[0172] Studies may be performed to assess effects of one or more fluorinated phytocannabinoids of the present disclosure on CB1 and / or CB2 receptor-mediated activity. CB1 receptors mediate most of the psychoactive effects of cannabinoids, whereas CB2 receptors are principally involved in anti-inflammatory and immunosuppressive actions. In certain studies, one or more fluorinated phytocannabinoids of the present disclosure are contacted with a reporter cell(s) for CB1 and / or CB2 receptor activity. In some studies, for example, a fluorinated phytocannabinoid of the present disclosure is contacted with an HEK293T cell that expresses CB1 and / or CB2 receptors and a level of activity of the CB1 and / or CB2 receptor(s) in the contacted cell(s) is determined. In some studies, a fluorinated phytocannabinoid of the present disclosure is contacted with an HEK293T cell that expresses CB1 and / or CB2 receptors and is a reporter for CB1 and / or CB2 activity. Results of the study demonstrate the contact with the fluorinated phytocannabinoid of the present disclosure reduces activity of CB1 and / or CB2 receptors and reduces the level of the cell’s cytokine release.

[0173] In some studies, toxicity and / or side effects of a fluorinated phytocannabinoid of the present disclosure is determined. In certain studies, the resulting toxicity and / or side effect data is compared with control data. In some studies, the control data is a level of toxicity and / or side effects resulting from contacting a substantially similar cell with a non-fluorinated phytocannabinoid, and results indicate a lower level of toxicity and / or side effects of the fluorinated phytocannabinoids of the present disclosure compared to the control level of toxicity and / or side effects, respectively.

[0174] Example 8. Jurkat Cell Death Assays

[0175] The Jurkat cell line is an immortalized T lymphocyte cell line that was isolated in 2003 from the peripheral blood of a 14 -year- old, male patient with leukemia and is widely used in models to study cancer, HIV, and cardiovascular disease in humans. Jurkat cells can be induced to undergo apoptosis (programmed cell death) by various stimuli that include chemical insults, such as anticancer chemotherapeutic drugs such as Doxorubicin and 5- Fluorouracil.

[0176] Jurkat T cells used herein were maintained in Roswell Park Memorial Institute (RPMI) media with 5% fetal bovine serum and 1% penicillin / streptomycin. Incubation of cells occurred at 37°C with 5% CO2. Hydrofluorinated compounds from Examples 1, 3, and 6 of the present disclosure were solubilized in DMSO to a stock concentration of lOmM and stored at -20°C until use. The Jurkat cells were treated with the indicated dose of specific compounds or a vehicle control for 72 hours in experimental triplicate. At that time, the Jurkat cells were collected and stained for flow cytometry using live / dead fixable cell stain kit (Invitrogen, Massachusetts, USA) per manufacturer instructions. Samples were run on the Agilent Novocyte 3000 and acquired and analyzed with the Agilent NovoExpress Software. Further compound analysis and graphing was performed in GraphPad Prism and depicted in FIGS. 1-3 for the 72-hour timepoint. Bars represent means + / - standard deviation. Student t tests were used to compare two groups at a time. *p<0.05.

[0177] Further Definitions and Construction of Terms

[0178] The titles, headings, and subheadings provided herein should not be interpreted as limiting the various aspects of the disclosure. Accordingly, the terms defined herein are more fully defined by reference to the specification in its entirety. All references cited herein are incorporated by reference in their entirety.

[0179] Unless otherwise defined, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.

[0180] In this application, the use of “or” means “and / or” unless stated otherwise. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim in the alternative only.

[0181] It is further noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” and any singular use of any word, include plural referents unless expressly and unequivocally limited to one referent.

[0182] As used herein, the term “about,” means approximately. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Illustratively, the use of the term “about” indicates that values slightly outside the cited values (i.e., plus or minus 0.1% to 10%), which are also effective and safe are included in the value. Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5).

[0183] As used herein, the terms “comprising” (and any form of comprising, such as “comprise,” “comprises,” and “comprised"), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), and “containing" (and any form of containing, such as “contains" and “contain") are inclusive or open-ended and do not exclude additional, un-recited elements or method steps. Additionally, a term that is used in conjunction with the term “comprising" is also understood to be able to be used in conjunction with the term “consisting of’ or “consisting essentially of.”

[0184] Method steps described in this disclosure can be performed in any order unless otherwise indicated or otherwise clearly contradicted by context

[0185] For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present disclosure may occur in combination with any other embodiment of the same aspect of the present disclosure. In addition, insofar as is practicable it is to be understood that any preferred or optional embodiment of any aspect of the present disclosure should also be considered as a preferred or optional embodiment of any other aspect of the present disclosure.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A fluorinated phytocannabinoid of any one of Formulae 1-11:wherein:R1 is -CO2H, H, an ester, or CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group, andR2 is an aliphatic sidechain.

2. The fluorinated phytocannabinoid of claim 1, wherein Ri is -COOH.

3. The fluorinated phytocannabinoid of claim 1, wherein Ri is H.

4. The fluorinated phytocannabinoid of claim 1, wherein Ri is an ester.

5. The fluorinated phytocannabinoid of claim 1 , wherein Ri is CO2R, where R is an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, and alkenylene group, an alkynylene group, an aryl group, an arylalkyl group, a heteroarylalkyl group, a substituted alkyl group, a substituted aryl group, a substituted arylalkyl group, a heteroaryl group, a carbocycle group, or an arylene group.

6. The fluorinated phytocannabinoid of claim 1, wherein R2 is methyl, ethyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

7. The fluorinated phytocannabinoid of claim 1, wherein the fluorinated phytocannabinoid is:

8. The fluorinated phytocannabinoid of claim 1 , wherein the fluorinated phytocannabinoid is:

9. A composition comprising the fluorinated phytocannabinoid of claim 1.

10. The composition of claim 9, further comprising at least one pharmaceutically acceptable carrier.

11. A method comprising contacting cells with the fluorinated phytocannabinoid of claim 1, wherein the contacting reduces cell viability in at least one of the cells.

12. The method of claim 11, wherein the cells are in vitro cells.

13. The method of claim 11, wherein the cells are in vivo cells.

14. The method of claim 11, wherein the cells are ex vivo cells.

15. The method of claim 11 , wherein the one or more cells are cancer cells.

16. The method of claim 15, wherein the cancer cells are leukemia cells.

17. The method of claim 11, wherein the cells are activated T cells.

18. The method of claim 11 , wherein the cells are in a subject and the contacting comprises administering the fluorinated phytocannabinoid to the subject.

19. The method of claim 18, wherein the administering comprises systemic administration.

20. The method of claim 19, wherein the systemic administration comprises one or more of enteral administration and parenteral administration.

21. The method of claim 18, wherein the subject is a mammal, and optionally is a human.

22. The method of claim 18, wherein the subject has a cancer.

23. The method of claim 22, wherein the cancer is leukemia.

24. The method of claim 22, further comprising administering, to the subject, one or more of a surgical regimen, a radio-therapy regimen, and a chemotherapy regimen.

25. The method of claim 18, wherein the subject has an autoimmune condition.

26. A method comprising contacting cells with the composition of claim 9, wherein the contacting reduces cell viability in at least one of the cells.

27. The method of claim 26, wherein the cells are in vitro cells.

28. The method of claim 26, wherein the cells are in vivo cells.

29. The method of claim 26, wherein the cells are ex vivo cells.

30. The method of claim 26, wherein the cells are cancer cells.

31. The method of claim 30, wherein the cancer cells are leukemia cells.

32. The method of claim 26, wherein the cells are activated T cells.

33. The method of claim 26, wherein the cells are in a subject and the contacting comprises administering the fluorinated phytocannabinoid to the subject.

34. The method of claim 33, wherein the administering comprises systemic administration.

35. The method of claim 34, wherein the systemic administration comprises one or more of enteral administration and parenteral administration.

36. The method of claim 33, wherein the subject is a mammal, and optionally is a human.

37. The method of claim 33, wherein the subject has a cancer.

38. The method of claim 37, wherein the cancer is leukemia.

39. The method of claim 37, further comprising administering, to the subject, one or more of a surgical regimen, a radio-therapy regimen, and a chemotherapy regimen.

40. The method of claim 33, wherein the subject has an autoimmune condition.

41. A method of producing a fluorinated phytocannabinoid, comprising: providing a phytocannabinoid; and hydrofluorinating the phytocannabinoid to produce the fluorinated phytocannabinoid of claim 1.

42. The method of claim 41 , wherein hydrofluorinating the phytocannabinoid comprises reacting the phytocannabinoid with hydrogen fluoride pyridine.

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