Cannabinoid derivatives and their use in the treatment of inflammation, pain or obesity

Abstract

The present invention provides cannabinoid derivatives, methods for their preparation, compositions containing them, and their use in the treatment of inflammation and / or pain and / or obesity. [Representative diagram] None

Description

[Technical Field]

[0001] The present invention relates to cannabinoid derivatives and their uses in the treatment of inflammation and / or pain and / or obesity. [Background technology]

[0002] Cannabidiol (CBD) is the primary non-psychotropic cannabinoid in most cannabis extracts, such as hashish and marijuana. However, because CBD does not bind to the known cannabinoid receptors CB1 or CB2 and therefore does not elicit the central or peripheral effects mediated by these receptors, CBD does not produce any of the psychotropic effects typical of Δ9-tetrahydrocannabinol (Δ9-THC). Nevertheless, CBD has been shown to produce numerous pharmacological effects in in vitro assays, as well as in vivo assays in animals and some preliminary human studies, some of which have significant potential therapeutic value.

[0003] Thus, for example, CBD has been found to offer several potential therapeutic benefits in anxiety and psychiatric disorders in animal models as well as in patients with neurological diseases. CBD has also been shown to be a neuroprotective antioxidant.

[0004] Other reports have described in vitro effects of CBD on immune cells, such as the inhibition of nitric oxide (NO) production by mouse peritoneal macrophages and the suppression of TNF-α, IL-1α, and IFNγ by human peripheral blood mononuclear cells.

[0005] These in vitro studies confirm previous reports of CBD's analgesic and anti-inflammatory effects in animals. CBD was found to be significantly more potent than aspirin in the phenylbenzoquinone-induced writhing test in mice, a standard analgesic activity assay. In tetradecanoylphorboacetate (TPA)-induced mouse ear erythema (a standard anti-inflammatory activity assay), CBD produced a 92% suppression of the inflammatory response when applied at a 100 pg / ml solution.

[0006] Several studies have provided CBD, resorcinol, and other cannabinoid derivatives with a wide range of applications. [1-24] U.S. Patent No. 3,661,919 provided resorcinol derivatives exhibiting bactericidal and antifungal activity. U.S. Patent No. 4,018,777 provided resorcinol derivatives useful as sedatives, analgesics, sedative-hypnotics, and anticonvulsants. U.S. Patent No. 6,274,635 provided 5-alkyl-resorcinol derivatives, cannabinol derivatives, cannabidiol derivatives, and cannabigerol derivatives for treating immune system disorders. U.S. Patent Application No. 2002 / 0137802 provided cannabinoid or resorcinol derivatives for inhibiting platelet activation and / or aggregation. U.S. Patent No. 6,566,560 provided resorcinol derivatives for attenuating neoplastic growth. U.S. Patent Application No. 2003 / 0232101 provided cannabinol derivatives, Δ9-THC derivatives, cannabichromene derivatives, cannabidiol derivatives, and cannabigerol derivatives for preventing HIV transmission. U.S. Patent Application No. 7,105,685 and U.S. Patent Application No. 2007 / 0179135 provided cannabinol derivatives and pharmaceutical preparations thereof. U.S. Patent Application No. 2004 / 0034108, WO 2004 / 016246, and UK Patent No. GB 2392093 provided cannabinoid derivatives for administration via pump-action sprays. U.S. Patent Nos. 7,179,800 and 7,285,687, and WO 2003 / 091189 provided cannabidiol derivatives useful for treating pain, inflammation, and autoimmune diseases. US Patent No. 6,630,507 and WO1999 / 53917 provided cannabinoid derivatives as antioxidants and neuroprotective agents.

[0007] U.S. Patent Nos. 4,282,248 and 6,410,588, U.S. Patent Application Nos. 2003 / 0166727 and 2007 / 0082954, and WO 2005 / 023741 and WO 2001 / 095899, which are incorporated in their entireties as if fully set forth herein, teach cannabidiol derivatives, some of which have been synthesized and biologically evaluated [25, 21], some of which have been shown to have anti-inflammatory activity. Summary of the Invention [Means for solving the problem]

[0008] The present invention provides a compound represented by the following general formula (I), or a stereoisomer, solvate, or salt thereof:

[0009] [ka]

[0010] During the ceremony, [ka]

[0011] is a single or double bond, R1 is selected from CH3 and CH2, R2 and R3 are selected from OH, O(C1-C3 alkyl), straight or branched chain C3-C10 alkyl, R4 is straight or branched chain C1-C5 alkyl, R5 is selected from OH, straight or branched chain C3-C10 alkyl, and R6 is selected from H, straight or branched chain C1-C5 alkyl, provided that:

[0012] [ka]

[0013] is a double bond, then at least one of R2 and R3 is different from OH or R6 is different from H; if R3 and R5 are both OH, then R2 is C5 alkyl and R4 is C1-C5 alkyl.

[0014] In some embodiments

[0015] [ka]

[0016] is a single bond.

[0017] In some embodiments

[0018] [ka]

[0019] is a single bond, and R2 and R3 are both OH.

[0020] In some embodiments, R2 and R3 are each O(C1-C3 alkyl).

[0021] In some embodiments, R2 is a straight or branched chain C3-C10 alkyl.

[0022] In some embodiments, R3 and R5 are both OH.

[0023] In some embodiments, R3 and R5 are both OH, R2 is a straight or branched chain C3-C10 alkyl, and R4 is a straight or branched chain C1-C5 alkyl.

[0024] In some embodiments, R4 and R6 are each C1-C5 alkyl.

[0025] In some embodiments, the compound of formula (I) is (1'S,2'S)-2'-isopropyl-3,5'-dimethyl-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-217),

[0026] [ka]

[0027] (1R,2R)-2',6'-dimethoxy-3',5-dimethyl-4'-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl (HUM-219),

[0028] [ka]

[0029] (1'R,2'R)-5,5'-dimethyl-6-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol (HUM-229),

[0030] [ka]

[0031] (1'R,2'R)-3,5,5'-trimethyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-236)

[0032] [ka]

[0033] is selected from.

[0034] In some embodiments, the compound of general formula (I) is a compound of general formula (I'), wherein the substituents R1-R6 are defined as above.

[0035] [ka]

[0036] The present invention further provides a compound represented by the following general formula (V), or a stereoisomer, solvate, or salt thereof:

[0037] [ka]

[0038] During the ceremony,

[0039] [ka]

[0040] is a single bond or a double bond, R16 is selected from linear or branched C1-C5 alkyl and linear or branched C2-C8 alkenyl, R17 to R21 are each selected from H, linear or branched C1-C5 alkyl, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, amine, halo, haloalkyl, OH, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, carboxy, amido, thioamide, thioimide, and CN, R22 and R26 are each selected from OH and O(C1-C3 alkyl), and R23, R24, and R25 are each selected from linear or branched C1-C5 alkyl and H.

[0041] [ka]

[0042] is a double bond, then at least one of R22 and R26 is different from OH and R25 is different from H; at least one of R18 to R21 is different from H; and when R24 and R26 are both OH, then R22 is C5 alkyl and R23 is C1-C5 alkyl.

[0043] In some embodiments, the compound of formula (V) is a compound of the general formula (V'):

[0044] [ka]

[0045] In the formula, R16 to R26 are each defined as above.

[0046] The present invention further provides a compound represented by the following general formula (II), or a stereoisomer, solvate, or salt thereof:

[0047] [ka]

[0048] wherein R7 and R8 are each selected from OH, O(C1-C3 alkyl), and OC(=O)R16; R9 is selected from H or C1-C3 alkyl; R10 is a straight or branched C3-C10 alkyl; and R16 is a C1-C5 alkyl optionally substituted with at least one morpholino (O(CH2CH2)2NH) derivative, provided that when both R7 and R8 are OH, R9 is different from a C1 alkyl.

[0049] In some embodiments, at least one of R7 and R8 is O(C1-C3 alkyl).

[0050] In some embodiments, at least one of R7 and R8 is OC(=O)R16, where R16 is a C1-C5 alkyl optionally substituted with at least one morpholino (O(CH2CH2)2NH) derivative.

[0051] In some embodiments, both R7 and R8 are O(C1-C3 alkyl).

[0052] In some embodiments, the compound of general formula (II) is (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-(2-methyloctan-2-yl)phenol (HUM-223),

[0053] [ka]

[0054] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-pentylphenyl 3-morpholinopropanoate (HUM-233),

[0055] [ka]

[0056] (E)-4-(3-(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-pentylphenoxy)-3-oxopropyl)morpholin-4-ium (Z)-3-carboxyacrylate (HUM-234),

[0057] [ka]

[0058] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-dimethoxy-4-methyl-5-pentylbenzene (HUM-235)

[0059] [ka]

[0060] is selected from.

[0061] The present invention further provides a compound represented by the following general formula (III), or a stereoisomer, solvate, or salt thereof:

[0062] [ka]

[0063] wherein R13, R14 and R15 are each selected from H, straight or branched C1-C10 alkyl, with the proviso that when R13 is CH3, then R15 is different from H.

[0064] In some embodiments, R13 is CH3.

[0065] In some embodiments, R13 is H.

[0066] In some embodiments, R15 is CH3.

[0067] In some embodiments, R15 is H.

[0068] In some embodiments, R14 is a straight or branched C3-C10 alkyl.

[0069] In some embodiments, the compound of general formula (III) is 2,8-dimethyl-2-(4-methylpent-3-en-1-yl)-7-pentyl-2H-chromen-5-ol (HUM-238).

[0070] [ka]

[0071] The present invention further provides a compound represented by the following general formula (IV), or a stereoisomer, solvate, or salt thereof:

[0072] [ka]

[0073] wherein R27 and R30 are each selected from OH, O(C1-C3 alkyl), and R28 and R29 are each independently a straight or branched chain C1-C10 alkyl.

[0074] In some embodiments, at least one of R27 and R30 is OH. In other embodiments, R27 and R30 are both OH.

[0075] In some embodiments, the compound of general formula (IV), including any stereoisomers, solvates, or salts, is a compound of general formula (IV').

[0076] [ka]

[0077] In some embodiments, the compound of general formula (IV) is 4-methyl-5-pentyl-2-((2R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)benzene-1,3-diol (HUM-231).

[0078] [ka]

[0079] The present invention further provides a compound represented by the following general formula (IV), or a stereoisomer, solvate, or salt thereof, wherein R27 and R30 are each selected from OH, O(C1-C3 alkyl), and C1-C10 alkyl, and R28 and R29 are each independently straight-chain or branched-chain OH, and C1-C10 alkyl.

[0080] In some embodiments, the compound of the invention is 4-methyl-5-pentyl-6-((2R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)benzene-1,3-diol (HUM-332).

[0081] [ka]

[0082] The present invention provides pharmaceutical compositions comprising at least one compound of general formula (I), (II), (III) and (IV) as disclosed herein above and below.

[0083] The present invention further provides a method for treating a condition, disease or disorder associated with inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of general formula (I), (II), (III), and (IV) as disclosed herein above and below.

[0084] In some embodiments, the medical condition, disease, or disorder associated with inflammation is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, psoriasis, type 1 diabetes mellitus (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immune deficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung disease, hypersensitivity pneumonitis, delayed hypersensitivity, interstitial lung disease. (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis or other inflammatory diseases), scleroderma, dermatitis (including atopic dermatitis and eczematous dermatitis), iritis, conjunctivitis, keratoconjunctivitis, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, polychondritis, Graves' ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory bowel disease, celiac disease, Alzheimer's disease, prion-related diseases, and cancer metastasis.

[0085] In some embodiments, the medical condition, disease or disorder is selected from the group consisting of rheumatoid arthritis, atherosclerosis, Crohn's disease and multiple sclerosis.

[0086] In some embodiments, the treatment with at least one compound of the present invention is abuse-free treatment.

[0087] The present invention further provides a method of treating pain in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of general formula (I), (II) and (III) as disclosed herein above and below.

[0088] Reference to "pain" should be understood to refer to any type of pain, including temporary, persistent, chronic, acute, idiopathic pain, etc. Pain that may be treated includes pain caused by any condition, disease, or disorder, for example, until a noxious stimulus is removed or the underlying injury or pathology is healed, as well as several painful conditions such as rheumatoid arthritis, peripheral neuropathy, cancer, any type of trauma, surgery, inflammation, childbirth, etc.

[0089] The present invention further provides a method for treating an obesity-related condition, disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of general formula (I), (II), (III), and (IV) as disclosed herein above and below.

[0090] The present invention provides a method for treating conditions, diseases, or disorders associated with inflammation, pain, obesity, and any combination thereof, comprising administering to a subject in need thereof a compound represented by the following general formula (I), or a stereoisomer, solvate, or salt thereof:

[0091] [ka]

[0092] During the ceremony, [ka]

[0093] is a single or double bond, R1 is selected from CH3 and CH2; R2 and R3 are selected from OH, O(C1-C3 alkyl), straight or branched C3-C10 alkyl, R4 is straight or branched C1-C5 alkyl, R5 is selected from OH, straight or branched C3-C10 alkyl, and R6 is selected from H, straight or branched C1-C5 alkyl.

[0094] The present invention provides a method for treating conditions, diseases, or disorders associated with inflammation, pain, obesity, and any combination thereof, comprising administering to a subject in need thereof a compound represented by the following general formula (II), or a stereoisomer, solvate, or salt thereof:

[0095] [ka]

[0096] wherein R7 and R8 are each selected from OH, O(C1-C3 alkyl), and OC(=O)R16; R9 is selected from H or C1-C3 alkyl; R10 is a straight or branched chain C3-C10 alkyl; and R16 is a C1-C5 alkyl optionally substituted with at least one of morpholino and (O(CH2CH2)2NH) derivatives.

[0097] The present invention provides a method for treating conditions, diseases, or disorders associated with inflammation, pain, obesity, and any combination thereof, comprising administering to a subject in need thereof a compound represented by the following general formula (III), or a stereoisomer, solvate, or salt thereof:

[0098] [ka]

[0099] wherein R13, R14 and R15 are each selected from H, straight or branched chain C1-C10 alkyl.

[0100] The present invention provides a method for treating conditions, diseases, or disorders associated with inflammation, pain, obesity, and any combination thereof, comprising administering to a subject in need thereof a compound represented by the following general formula (IV), or a stereoisomer, solvate, or salt thereof:

[0101] [ka]

[0102] wherein R27 and R30 are each selected from OH, O(C1-C3 alkyl), and R28 and R29 are each selected from straight or branched chain C1-C10 alkyl. [Brief explanation of the drawings]

[0103] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, the invention, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read in connection with the accompanying drawings.

[0104] [Figure 1A] 1A and 1B show swelling (1A) and pain (1B) results for various doses of HUM-216 compared to CBD. [Figure 1B] 1A and 1B show swelling (1A) and pain (1B) results for various doses of HUM-216 compared to CBD. [Figure 2A] 2A and 2B show swelling (2B) and pain (2C) results for various doses of HUM-223 and HUM-219 compared to CBD and CBG. [Figure 2B] 2A and 2B show swelling (2B) and pain (2C) results for various doses of HUM-223 and HUM-219 compared to CBD and CBG. [Figure 3A] 1 shows the TNF-α results for various doses of HUM-216 compared to CBD, and the results for various doses of HUM-218 and HUM-223 compared to CBG. [Figure 3B] 1 shows the TNF-α results for various doses of HUM-216 compared to CBD, and the results for various doses of HUM-218 and HUM-223 compared to CBG. [Figure 4] 1 shows the change in weight bearing of the affected knee compared between CBD and HUM-216. Higher amounts mean more pain, lower amounts mean less pain.

[0105] It should be understood that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE INVENTION

[0106] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, those skilled in the art will understand that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0107] Embodiments of the present invention further include any stereoisomers, prodrugs, solvates, hydrates and / or pharmaceutically acceptable salts of the compounds described herein.

[0108] As used herein, the term "stereoisomer" refers to isomers that have identical constitution but differ in the arrangement of their atoms in space. In the context of the present invention, this term includes enantiomers, diastereomers, racemates, non-racemic mixtures, (+) / (-)-isomers, (D) / (L)-isomers, (R) / (S)-isomers, cis-trans isomers, E / Z-isomers, and any combination thereof.

[0109] The term "prodrug" refers to an agent that is converted into an active compound (active parent drug) in vivo. Prodrugs are typically useful for facilitating administration of the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility compared to the parent drug in pharmaceutical compositions. Prodrugs are also often used to achieve sustained release of an active compound in vivo. Examples of prodrugs include, but are not limited to, compounds described herein that have one or more carboxylic acid moieties and are administered as esters ("prodrugs"). Such prodrugs are hydrolyzed in vivo to provide the free compound (parent drug). The selected ester can affect both the solubility characteristics and the rate of hydrolysis of the prodrug.

[0110] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a compound of the invention) and a solvent, whereby the solvent does not interfere with the biological activity of the solute. Suitable solvents include, for example, ethanol, acetic acid, and the like.

[0111] The term "hydrate" refers to a solvate, as defined above, wherein the solvent is water.

[0112] The phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counterion, which is typically used to modify the solubility characteristics of the parent compound and / or reduce any significant irritation to an organism by the parent compound, while not abolishing the biological activity and properties of the administered compound. Examples of pharmaceutically acceptable salts include, but are not limited to, carboxylate anions and cations, such as, but not limited to, ammonium, sodium, potassium, and the like.

[0113] As is well known in the art, the phrase "acid addition salt" describes a complex of two ionizable moieties, a base and an acid, that, when interacted under suitable conditions in specific stoichiometric proportions, form a salt containing one or more cations of the base moiety and one or more anions of the acid moiety. As used herein, the phrase "acid addition salt" refers to a complex in which the base moiety is an amine, such that the salt includes the cationic form of the amine (ammonium) and the anionic form of the acid.

[0114] Depending on the stoichiometric ratio of base to acid in the salt complex, as detailed below, the acid addition salts can be either mono- or poly-addition salts.

[0115] The phrase "mono-addition salt," as used herein, refers to a salt complex in which the stoichiometric ratio of acid anion to amine cation is 1:1, such that the acid addition salt contains one molar equivalent of acid per one molar equivalent of conjugate.

[0116] The phrase "polyaddition salt," as used herein, refers to a salt complex in which the stoichiometric ratio of acid anion to amine cation is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., such that the acid addition salt 15 contains two or more molar equivalents of acid per molar equivalent of conjugate.

[0117] The stoichiometric ratio between base and acid of the salt complex, according to some embodiments of the invention, ranges from 6:1 to 1:6 base:acid equivalents, 4:1 to 1:4 base:acid equivalents, 3:1 to 1:3 base:acid equivalents, or 1:1 to 1:3 base:acid equivalents.

[0118] Thus, the acid addition salt of the chemical conjugate according to the present invention is a complex formed between one or more amino groups of the compound and one or more equivalents of an acid.Accordingly, acid addition salts include, but are not limited to, halogen acids such as hydrochloric acid to provide hydrochloric acid addition salts (as well as bromide and iodide salts), acetic acid to provide acetic acid addition salts, ascorbic acid to provide ascorbic acid addition salts, benzoic acid to provide benzoic acid addition salts (benzoates), benzenesulfonic acid to provide benzenesulfonic acid addition salts, camphorsulfonic acid to provide camphorsulfonic acid addition salts, naphthylsulfonic acid to provide naphthylsulfonic acid addition salts, toluenesulfonic acid (p-toluenesulfonic acid) to provide toluenesulfonic acid addition salts (tosylates), Various organic and inorganic acids can be included, such as trifluoroacetic acid to provide trifluoroacetic acid addition salts, citric acid to provide citric acid addition salts, maleic acid to provide maleic acid addition salts (maleates), methanesulfonic acid to provide methanesulfonic acid (mesylate or methanesulfonate) addition salts, naphthalenesulfonic acid to provide napsylate addition salts, oxalic acid to provide oxalic acid addition salts, phosphoric acid to provide phosphoric acid addition salts, succinic acid to provide succinic acid addition salts (succinate), sulfuric acid to provide sulfuric acid addition salts, and tartaric acid to provide tartaric acid addition salts. Each of these acid addition salts can be either a mono- or poly-acid addition salt, as these terms are defined above.

[0119] As used herein, the term "alkyl" describes an aliphatic hydrocarbon, including straight-chain and branched-chain groups. According to some embodiments, the alkyl group has 1 to 10 carbon atoms, according to other embodiments, 1 to 5 carbon atoms, according to still other embodiments, 6 to 10 carbon atoms, and according to still other embodiments, 4 to 6 carbon atoms. When a numerical range, e.g., "1 to 10," is mentioned herein, it means that the group, in this case, the alkyl group, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms. Alkyl can be substituted or unsubstituted. If substituted, the substituent can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halogen (halo), hydroxy, oxo, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, haloalkyl, amine, carbonyl, carboxyl, amide, thioamide, cyano, and carbamate, as these terms are defined herein.

[0120] The term "alkyl," as used herein, also encompasses saturated or unsaturated hydrocarbons, and thus, the term further encompasses alkenyl and alkynyl.

[0121] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be unsubstituted or substituted with one or more substituents, as described above for alkyl.

[0122] The term "alkynyl," as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl can be unsubstituted or substituted with one or more substituents, as described above for alkyl.

[0123] As used herein, the term "amine" describes the group --NR'R" where each of R' and R" is independently hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl, or heteroaryl, as these terms are defined herein.

[0124] As used herein, the terms "halo," "halogen," and "halide," referred to interchangeably herein, describe atoms of fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, bromide, and iodide.

[0125] The term "haloalkyl" describes an alkyl group, as defined above, that is further substituted with one or more halide groups.

[0126] The terms "hydroxy" or "hydroxyl," used interchangeably herein, refer to an --OH group.

[0127] The term "alkoxy" describes an --OR' group, where R' is as defined herein.

[0128] The term "aryloxy," as used herein, refers to the group --OR" where R" is aryl.

[0129] The term "thiohydroxy" as used herein refers to a -SH group.

[0130] The term "thioalkoxy" describes a -SR' group, where R' is as defined herein.

[0131] The term "thioaryloxy" describes a group -SR', where R" is aryl.

[0132] The term "carbonyl" or "ketone," as used herein, refers to a -(C=O)H or -(C=O)-R group, where R is as defined herein. An exemplary carbonyl is a formyl group, where R' is hydrogen. Another exemplary carbonyl is an acetyl group, where R' is methyl.

[0133] The term "oxo" refers to the (=O) group, ie, an oxygen attached by a double bond, which in the case of a carbon substituent constitutes a carbonyl.

[0134] The terms "carboxy," "carboxyl," or "carboxylate," as used herein, refer interchangeably to -C(=O)-OR, where R can be absent (as in a carboxylate anion) or can be selected from the group consisting of hydrogen (e.g., a carboxylic acid), alkyl (e.g., an ester), cycloalkyl, heteroalicyclic, aryl, or heteroaryl, as these terms are defined herein.

[0135] The term "amide" describes a -C(=O)-NRR", where R is as defined herein.

[0136] The term "thioamide" describes a -C(=S)-NRR" where R is as defined herein.

[0137] The term "thioimide" describes a -C(=NR)-SR", where R and R'' are as defined herein.

[0138] The term "cyano," as used herein, refers to a -C=N group.

[0139] The term "carbamate" describes an --OC(.dbd.O)--NR'R", where R' and R" are as defined herein.

[0140] A particular exemplary carbamate is obtained when the amine is protected with a Boc protecting group to give the tert-butyl carbamate.

[0141] Another exemplary carbamate is obtained when the amine is protected with an Fmoc protecting group to give (9H-fluoren-9-yl)methyl carbamate.

[0142] Furthermore, these cannabinoid derivative compounds include, for example: (1'R,2'R)-3,5'-Dimethyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-216)

[0143] [ka]

[0144] (1'S,2'S)-2'-Isopropyl-3,5'-dimethyl-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-217)

[0145] [ka]

[0146] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-4-methyl-5-pentylbenzene-1,3-diol (HUM-218)

[0147] [ka]

[0148] (1R,2R)-2',6'-dimethoxy-3',5-dimethyl-4'-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl (HUM-219)

[0149] [ka]

[0150] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-(2-methyloctan-2-yl)phenol (HUM-223)

[0151] [ka]

[0152] (1'R,2'R)-5,5'-Dimethyl-6-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol (HUM-229)

[0153] [ka]

[0154] (E)-4-(3,7-dimethylocta-2,6-dien-1-yl)-6-methyl-5-pentylbenzene-1,3-diol (HUM-330)

[0155] [ka]

[0156] 4-Methyl-5-pentyl-2-((2R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)benzene-1,3-diol (HUM-231)

[0157] [ka]

[0158] 2,6-Dimethyl-2-(4-methylpent-3-en-1-yl)-7-pentyl-2H-chromen-5-ol

[0159] [ka]

[0160] (E)-4-(3-(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-pentylphenoxy)-3-oxopropyl)morpholin-4-ium-3-ide (HUM-233)

[0161] [ka]

[0162] It is part of a group of compounds including

[0163] Thus, according to another aspect of the present invention, there is provided a method of treating a medical condition, disease, or disorder associated with inflammation, affected by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds presented herein, and their enantiomers, hydrates, solvates, prodrugs, or any pharmaceutically acceptable salts as defined above.

[0164] According to some embodiments of the present invention, there is provided a method of treating a medical condition, disease, or disorder associated with inflammation by administering to a subject in need thereof a therapeutically effective amount of any one of the compounds set forth in Table I presented in the Examples section below, and any one or more of their enantiomers, hydrates, solvates, prodrugs, or any pharmaceutically acceptable salts as defined above.

[0165] As used herein, the terms "treat" and "treatment" include arresting, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0166] Thus, another aspect of the present invention provides the use of one or more of the compounds presented herein, and one or more of their enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts as defined above, in the preparation of a medicament.

[0167] According to some embodiments of the invention, the medicament is for the treatment of a medical condition, disease or disorder associated with inflammation.

[0168] According to some embodiments of the present invention, there is provided the use of any one of the compounds set forth in Table I presented in the Examples section below, and any one or more of any enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof as defined above, in the preparation of a medicament for the treatment of a medical condition, disease or disorder associated with inflammation.

[0169] Inflammation is the body's protective response to injury. As used herein, the term "inflammation" includes, but is not limited to, medical conditions, diseases, and disorders associated with inflammation.

[0170] Thus, representative examples of inflammation-related diseases or disorders that can be treated by using one or more of the compounds described in the present invention include, but are not limited to, idiopathic inflammatory diseases or disorders, chronic inflammatory diseases or disorders, acute inflammatory diseases or disorders, autoimmune diseases or disorders, infectious diseases or disorders, inflammatory malignant diseases or disorders, inflammatory transplant-related diseases or disorders, inflammatory degenerative diseases or disorders, hypersensitivity-related diseases or disorders, inflammatory cardiovascular diseases or disorders, inflammatory cerebrovascular diseases or disorders, peripheral vascular diseases or disorders, inflammatory glandular diseases or disorders, inflammatory gastrointestinal diseases or disorders, inflammatory skin diseases or disorders, inflammatory liver diseases or disorders, inflammatory neurological diseases or disorders, inflammatory musculoskeletal diseases or disorders, inflammatory renal diseases or disorders, inflammatory reproductive diseases or disorders, inflammatory systemic diseases or disorders, inflammatory connective tissue diseases or disorders, inflammatory tumors, necrosis, inflammatory implant-related diseases or disorders, inflammatory aging processes, immunodeficiency diseases or disorders, proliferative diseases or disorders such as cancer, and inflammatory lung diseases or disorders, as detailed below.

[0171] Non-limiting examples of hypersensitivity include type I hypersensitivity, type II hypersensitivity, type III hypersensitivity, type IV hypersensitivity, immediate hypersensitivity, antibody-mediated hypersensitivity, immune complex-mediated hypersensitivity, T lymphocyte-mediated hypersensitivity, delayed hypersensitivity, helper T lymphocyte-mediated hypersensitivity, cytotoxic T lymphocyte-mediated hypersensitivity, TH1 lymphocyte-mediated hypersensitivity, and TH2 lymphocyte-mediated hypersensitivity.

[0172] Non-limiting examples of inflammatory cardiovascular diseases or disorders include occlusive diseases or disorders, atherosclerosis, valvular heart disease, stenosis, restenosis, in-stent stenosis, myocardial infarction, coronary artery disease, acute coronary syndrome, congestive heart failure, angina pectoris, myocardial ischemia, thrombosis, Wegener's granulomatosis, Takayasu's arteritis, Kawasaki syndrome, anti-factor VIII autoimmune disease or disorder, necrotizing small vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, microimmune focal necrotizing glomerulonephritis, crescentic glomerulonephritis, antiphospholipid syndrome, antibody-induced heart failure, thrombocytopenic purpura, autoimmune hemolytic anemia, cardiac autoimmunity, Chagas' disease or disorder, and anti-helper T lymphocyte autoimmunity.

[0173] Stenosis is an occlusive disease of the vascular system, commonly caused by atherosclerotic plaque and enhanced platelet activity, most significantly affecting the coronary vasculature.

[0174] Restenosis is the progressive re-occlusion that often follows a reduction in occlusion in stenotic vasculature. When vasculature patency requires the mechanical support of a stent, in-stent stenosis can occur, re-occluding the treated vessel.

[0175] Non-limiting examples of cerebrovascular diseases or disorders include stroke, cerebrovascular inflammation, cerebral hemorrhage, and vertebral artery insufficiency.

[0176] Non-limiting examples of peripheral vascular diseases or disorders include gangrene, diabetic angiopathy, ischemic bowel disease, thrombosis, diabetic retinopathy, and diabetic nephropathy.

[0177] Non-limiting examples of autoimmune diseases or disorders include all diseases caused by immune responses, such as autoantibodies or cell-mediated immunity against autoantigens. Representative examples include rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis / dermatomyositis, Sjogren's syndrome, Behcet's disease, multiple sclerosis, autoimmune diabetes, Hashimoto's disease, psoriasis, primary myxedema, pernicious anemia, myasthenia gravis, chronic active hepatitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, uveitis, vasculitis, and heparin-induced thrombocytopenia.

[0178] Non-limiting examples of inflammatory glandular diseases or disorders include pancreatic diseases or disorders, type I diabetes, thyroid diseases or disorders, Graves' disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxoma, ovarian autoimmunity, autoimmune antispermia, autoimmune prostatitis, and type I autoimmune polyglandular syndrome.

[0179] Non-limiting examples of inflammatory gastrointestinal diseases or disorders include colitis, ileitis, Crohn's disease, chronic inflammatory bowel disease, inflammatory bowel syndrome, chronic inflammatory bowel disease, celiac disease, ulcerative colitis, ulcers, skin ulcers, pressure ulcers, gastric ulcers, gastrointestinal ulcers, buccal ulcers, nasopharyngeal ulcers, esophageal ulcers, duodenal ulcers, and peptic ulcers.

[0180] Non-limiting examples of inflammatory skin diseases or disorders include acne and autoimmune bullous skin diseases.

[0181] Non-limiting examples of inflammatory liver diseases or disorders include autoimmune hepatitis, cirrhosis, and biliary cirrhosis.

[0182] Non-limiting examples of inflammatory neurological diseases or disorders include multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barré syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological diseases or disorders, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff-body syndrome, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham chorea, Gilles de la Tourette syndrome, autoimmune polyendocrine deficiency, immunodeficiency neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS-related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis, stroke, inflammatory retinal diseases or disorders, inflammatory eye diseases or disorders, optic neuritis, spongiform encephalopathy, migraine, headache, cluster headache, and stiff-body syndrome.

[0183] Non-limiting examples of inflammatory connective tissue diseases or disorders include autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune diseases or disorders, myositis, tendonitis, ligament inflammation, chondritis, arthritis, synovitis, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, skeletal inflammation, autoimmune ear diseases or disorders, and autoimmune diseases or disorders of the inner ear.

[0184] Non-limiting examples of inflammatory kidney diseases or disorders include autoimmune interstitial nephritis and / or renal cancer.

[0185] Non-limiting examples of inflammatory reproductive diseases or disorders include recurrent fetal loss, ovarian cysts, or menstrual-related diseases or disorders.

[0186] Non-limiting examples of inflammatory systemic diseases or disorders include systemic lupus erythematosus, systemic sclerosis, septic shock, toxic shock syndrome, and cachexia.

[0187] Non-limiting examples of infectious diseases or disorders include chronic infectious diseases or disorders, subacute infectious diseases or disorders, acute infectious diseases or disorders, viral diseases or disorders, bacterial diseases or disorders, protozoal diseases or disorders, parasitic diseases or disorders, fungal diseases or disorders, mycoplasmal diseases or disorders, gangrene, sepsis, prion diseases or disorders, influenza, tuberculosis, malaria, acquired immune deficiency syndrome, and severe acute respiratory syndrome.

[0188] Non-limiting examples of inflammatory transplant-related diseases or disorders include graft rejection, chronic graft rejection, subacute graft rejection, acute graft rejection, hyperacute graft rejection, and graft-versus-host disease or disorder. Exemplary implants include artificial implants, breast implants, silicone implants, dental implants, penile implants, cardiac implants, artificial joints, fracture repair devices, bone replacement implants, drug delivery implants, catheters, pacemakers, artificial hearts, artificial heart valves, drug-releasing implants, electrodes, and respiratory tubes.

[0189] Non-limiting examples of inflammatory tumors include malignant tumors, benign tumors, solid tumors, metastatic tumors, and non-solid tumors.

[0190] Non-limiting examples of inflammatory lung diseases or disorders include asthma, allergic asthma, emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis, and bronchitis.

[0191] According to some embodiments of the present invention, exemplary medical conditions, diseases, and disorders associated with inflammation include multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, psoriasis, type 1 diabetes mellitus (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immune deficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung disease, hypersensitivity pneumonitis, delayed hypersensitivity disease, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis or other inflammatory diseases), scleroderma, dermatitis (including atopic dermatitis and eczematous dermatitis), iritis, conjunctivitis, keratoconjunctivitis, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, polychondritis, Graves' ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory bowel disease, celiac disease, Alzheimer's disease, prion-related diseases, and cancer metastasis.

[0192] According to some embodiments of the invention, the inflammatory disorder comprises rheumatoid arthritis, atherosclerosis, Crohn's disease, multiple sclerosis, Alzheimer's disease, prion-related diseases, and cancer metastasis.

[0193] As used herein, the phrase "therapeutically effective amount" describes that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the condition being treated.

[0194] As demonstrated in the Examples section below, exemplary therapeutically effective amounts of the compounds of the invention range between about 0.1 mg / kg and about 100 mg / kg of body weight.

[0195] In any of the methods and uses described herein, the cannabinoid derivative compounds of the present invention may be utilized by themselves or, according to some embodiments, as part of a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.

[0196] Thus, according to a further aspect of the present invention there is provided a pharmaceutical composition comprising one or more compounds having general formula I as defined above and a pharmaceutically acceptable carrier.

[0197] According to some embodiments of the present invention, there is provided a pharmaceutical composition comprising any one of the compounds set forth in Table I, presented in the Examples section below, and a pharmaceutically acceptable carrier, and one or more of any enantiomers, hydrates, solvates, prodrugs, or any pharmaceutically acceptable salts thereof, as defined above.

[0198] As used herein, a "pharmaceutical composition" refers to a preparation of a compound presented herein with other chemical components, such as suitable pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0199] Hereinafter, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abolish the biological activity and properties of the administered compound. Examples of carriers include, but are not limited to, propylene glycol, saline, emulsions, and mixtures of organic solvents and water, as well as solid (e.g., powdered) and gaseous carriers.

[0200] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0201] Techniques for drug formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0202] Thus, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and adjuvants that facilitate processing of the compounds into pharmaceutically usable preparations. The appropriate formulation depends on the route of administration selected. The dosage can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in consideration of the patient's condition (see, e.g., Fingl et al., 1975, "The Pharmacological Basis of Therapeutics," Ch. Ip. I). Pharmaceutical compositions can be formulated for administration by any one or more routes, depending on whether local or systemic treatment or administration is selected and the area to be treated. Administration can be orally, by inhalation, or parenterally, for example, by infusion or intraperitoneal, subcutaneous, intramuscular, or intravenous injection, or topically (by eye, vaginally, rectally, intranasally, etc.).

[0203] Formulations for topical administration may include, but are not limited to, lotions, ointments, gels, creams, suppositories, drops, liquids, sprays, and powders.

[0204] Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0205] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, caplets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.

[0206] Formulations for parenteral administration may include sterile solutions which may contain, but are not limited to, buffers, diluents, and other suitable additives. Sustained release compositions are contemplated for therapeutic use.

[0207] The amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0208] The compositions of the present invention may, if desired, be provided in a pack or dispenser device, such as an FDA (U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, but is not limited to, comprise metal or plastic foil, such as a blister pack or a pressurized container (for inhalation). The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the composition form for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert.

[0209] Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of a medical condition, disease, or disorder associated with inflammation, as detailed above.

[0210] Thus, according to one embodiment of the present invention, the pharmaceutical compositions of the present invention are packaged in packaging material and identified in printing in or on the packaging material for use in treating a medical condition, disease, or disorder associated with inflammation, as defined above.

[0211] According to further embodiments of any of the methods, uses, and compositions provided herein, the compounds of the present invention may be combined with other active ingredients commonly used to treat inflammation-related diseases and disorders.

[0212] Reference to "abuse-free treatment" should be understood to refer to treatment with at least one compound that does not subject a patient administered said compound to substance abuse, drug abuse, in any amount administered in a manner harmful to the individual or others.

[0213] Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as described herein and as claimed in the claims section below finds experimental support in the following examples. [Example]

[0214] Reference is now made to the following examples, which together with the above description illustrate the invention in a non-limiting fashion.

[0215] Example 1 Chemical Synthesis

[0216] Materials and Methods:

[0217] AU chemical reagents were purchased from Sigma-Aldrich.

[0218] Organic solvents were purchased from Bio-Lab.

[0219] Cannabinoids (e.g., cannabidiol) were extracted from cannabis plants as previously described [Gaoni, Y. and Mechoulam, R. (1971) J. Amer. Chem. Soc. 93, 217-224].

[0220] Standard Carboxylation Reaction

[0221] Based on the procedure described by Ben-Zvi et al.

[26] , 20 mmol of cannabinoid compound was dissolved in 30 mL of 2 M methylmagnesium carbonate (MMC) solution in DMF (60 mmol). A condenser was attached and the reaction was heated to 120 °C for 2 h and monitored by TLC.

[0222] The reaction was worked up by pouring into ice-cold 10% w / v HCl solution. The aqueous phase was extracted three times with diethyl ether (EtO). The organic phase was then dried over anhydrous magnesium sulfate (MgSO) and evaporated to give a dark purple syrup-like crude product. CBDA was purified by silica gel column chromatography using ethyl acetate (EA):methanol:acetic acid (10%:2%:1%, respectively) in petroleum ether (approximate yield: 35%).

[0223] Standard reduction of carboxylic acids to methyl groups

[0224] Based on a method previously published by H. Edery et al.

[27] . 3.04 mmol of the carboxylic acid was dissolved in dry THF under nitrogen. The solution was then slowly added to a flask containing a pre-cooled suspension of 79.01 mmol of LiAlH4 in dry THF (30 mL, cooled to -20 °C). A condenser was attached, and the reaction was heated to reflux for 3 h and monitored by TLC. After complete consumption of the starting material, the reaction was cooled to -20 °C for workup. Ethyl acetate was added dropwise to neutralize the remaining LiAlH4, followed by the addition of ethanol, methanol, and ice until no visible reaction of LiAlH4 was observed in the flask. The reaction suspension was washed with 10% w / v HCl solution to pH 1. The aqueous phase was extracted three times with ethyl acetate, washed with saturated NaHCO3 to pH 10, and washed with brine to neutral pH. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by silica gel column chromatography (approximate yield 95%).

[0225] Preparation of H2-CBD: 5 grams (15.92 mmol) of cannabidiol and 250 mg (1.1 mmol, 5% w / w) of platinum oxide were added to a pressure flask and dissolved in ethyl acetate. The reaction flask was then evacuated and pressurized to 15 psi with hydrogen gas. The reaction flask was placed on an automatic shaker and the pressure was maintained for 1.5 minutes. The hydrogen was then removed by vacuum. The mixture was gravity filtered and evaporated. The crude product was purified by silica gel column chromatography (0-3% Et2O in petroleum ether).

[0226] [ka]

[0227] Synthesis of HUM-216: 2 g of LiAlH4 was added portionwise to 100 ml of dry THF at -15°C under a nitrogen atmosphere, followed by the slow addition of 700 mg of CBDA dissolved in 50 ml of dry THF. The reaction mixture was allowed to warm to room temperature and then refluxed for 5 hours. The mixture was then cooled back to -15°C, and ethyl acetate was slowly added dropwise until the LiAlH4 stopped reacting. Several drops of ethanol, methanol, and water were then added to ensure that the LiAlH4 was no longer active. The product (98% yield) was extracted with five portions of ethyl acetate, washed to neutrality, dried over MgSO4, and purified by silica gel chromatography using 5% diethyl ether in petroleum ether.

[0228] Synthesis of HUM-217: HUM-217 was prepared from H2-CBD in exactly the same yield (approximately 30%) as HUM-216 from CBD.

[0229] Preparation of CBG: To 2 g of olivetol dissolved in 200 ml of dry dichloromethane, 80 mg of paratoluenesulfonic acid was added under a N2 atmosphere, and the reaction was cooled to 0 °C. 3 g of geraniol dissolved in 100 ml of dry DCM was added slowly over 10 min. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction suspension was then washed with 10% w / v NaHCO3 solution until neutral, and the aqueous phase was extracted three times with DCM and dried over MgSO4. The product (30% yield) was purified by silica gel chromatography using 7% diethyl ether in petroleum ether.

[0230] Synthesis of HUM-218: HUM-218 was prepared from CBG in the same manner as HUM-216 from CBD, with the exact same yield (approximately 30%).

[0231] Synthesis of HUM-219: To 280 mg of HUM-216 (0.85 mmol) and 0.75 g of K2CO3 in 10 ml of dry DMF, 500 μl of excess methyl iodide (approximately 7.5 mmol) was added dropwise under a N2 atmosphere. The reaction was stirred overnight. The reaction suspension was washed with 10% w / v HCl solution until neutral. The aqueous phase was extracted three times with ethyl acetate and dried over MgSO4. The product (approximately 90% yield) was purified by silica gel chromatography using 3% diethyl ether in petroleum ether.

[0232] Preparation of CBG-DMH: To 1.84 g of dimethylheptylresorcinol (DMHR) dissolved in 100 ml of dry dichloromethane, 80 mg of paratoluenesulfonic acid was added under a N atmosphere, and the reaction was cooled to 0 °C. 1.2 g of geraniol dissolved in 50 ml of dry DCM was added slowly over 10 min. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction suspension was then washed with 10% w / v NaHCO solution until neutral, and the aqueous phase was extracted three times with DCM and dried over MgSO. The product (30% yield) was purified by silica gel chromatography using 5% diethyl ether in petroleum ether.

[0233] Synthesis of HUM-223: To 2.4 g of CBG-DMH and 1.34 g of K2CO3 in 20 ml of dry DMF, 406.1 μL of methyl iodide (1 equivalent) was added dropwise under a N2 atmosphere. The reaction was stirred overnight. The reaction suspension was washed with 10% w / v HCl solution until neutral. The aqueous phase was extracted three times with ethyl acetate and dried over MgSO4. The product (yield approximately 40%) was purified by silica gel chromatography using 3% diethyl ether in petroleum ether.

[0234] Methods developed during this project

[0235] [ka]

[0236] Preparation of the (+-)CBC derivative via citral coupling

[28] : 0.5 grams of olivetolaldehyde (2.4 mmol) and 0.5 mL of citral (2.9 mmol) were dissolved in anhydrous toluene at room temperature under a nitrogen atmosphere. 86 mg of ethylenediamine diacetate (EDDA) was added to the solution, still at room temperature. A water condenser was then attached, and the reaction was refluxed and monitored by TLC (5% EA in PE). After 4 hours, the reaction was cooled to room temperature on an ice bath. The solvent was removed by evaporation under vacuum to give a dark orange oily crude product. The product was purified by flash column chromatography using an EtO:PE gradient. The product eluted with 1.25% EtO. The product was obtained as a light yellow oil.

[0237] Olivetol formylation reaction

[29] : 15 mL of phosphoryl chloride (0.123 mol) was dissolved dropwise in ice-cold anhydrous DMF (43 mL) under a nitrogen atmosphere. A 24 mL solution of 8.8 g (0.05 mol) of olivetol in anhydrous DMF was added dropwise. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was cooled on ice and added dropwise to 72 mL of ice-cold water. While still on ice, a 20% solution of sodium hydroxide was added to the reaction until a pH of 10 was reached. The reaction was then refluxed for 10 minutes. The reaction was then acidified with concentrated hydrochloric acid until a pH of 1 was reached. The aqueous reaction solution was extracted four times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and the solvent was evaporated under vacuum. The crude oil was dry-loaded onto silica gel and purified by column chromatography using an EA:PE gradient. The product was eluted with 15% EA:PE. The starting material was eluted with 30% EA:PE. The product was obtained as a pale yellow solid. The NMR spectrum (CDCl3) was consistent with previously published literature.

[0238] Aldehyde reduction reaction

[30] : 0.1 grams of aldehyde (0.48 mmol) was dissolved in anhydrous toluene under a nitrogen atmosphere and cooled on an ice bath for 5 minutes. To the cold suspension, 0.5 mL of a 60% Red-Al® solution in toluene was added. The reaction was then refluxed overnight. The reaction was cooled on an ice bath, and 5 mL of brine was added dropwise to prevent overflow. The mixture was partitioned between ether and water, and the aqueous phase was acidified to pH 1 using 20% sulfuric acid solution. The now acidic aqueous phase was then extracted three times with ether. The combined extracts were washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. The evaporated crude product was purified by column chromatography using an EA:PE gradient. Yield: 75%. The NMR spectrum (CDCl3) was consistent with previously published literature.

[0239] Synthesis of an alternative method for HUM-216 and its unusual derivative, HUM-229: 1.5 g of methyl-olivetol and 1.2 g of paramentadienol were dissolved in 50 ml of dry DCM, and 1 g of dry MgSO4 was added under a N2 atmosphere. The reaction mixture was cooled to 0 °C, and 50 μL of BF3 etherate was added. The reaction mixture was mixed for 1.5 hours, washed with 10% w / v NaHCO3 solution until neutral, and the aqueous phase was extracted three times with DCM and dried over MgSO4. The crude product was purified by silica gel chromatography using 5% → 30% diethyl ether in petroleum ether. HUM-216 was obtained in 45% yield, and HUM-229 in 35% yield.

[0240] Synthesis of an alternative method for HUM-218 and an unusual derivative, HUM-230: To 1.51 g of methyl-olivetol dissolved in 25 ml of dry dichloromethane, 140 mg of paratoluenesulfonic acid was added under a N2 atmosphere, and the reaction mixture was cooled to 0 °C. 1.2 g of geraniol dissolved in 20 ml of dry DCM was added slowly over 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction suspension was then washed with 10% w / v NaHCO3 solution until neutral, and the aqueous phase was extracted three times with DCM and dried over MgSO4. The crude product was purified by silica gel chromatography using 5% → 30% diethyl ether in petroleum ether. HUM-218 was obtained in 45% yield, and HUM-229 in 30% yield.

[0241] Synthesis of HUM-231 and HUM-229: To 500 mg of methyl-olivetol dissolved in 70 ml of dry dichloromethane, 40 mg of paratoluenesulfonic acid was added under a N2 atmosphere, and the reaction mixture was cooled to 0 °C. 242 mg of verbenol dissolved in 15 ml of dry DCM was added slowly over 10 min. The reaction mixture was stirred at 0 °C for 1 h. The reaction suspension was then washed with 10% w / v NaHCO3 solution until neutral, and the aqueous phase was extracted three times with DCM and dried over MgSO4. The crude product was purified by silica gel chromatography using 5% → 30% diethyl ether in petroleum ether. HUM-231 was obtained in 45% yield, and HUM-229 in 25% yield.

[0242] Example 2 Biological activity

[0243] Preparation of Mouse Macrophages for Anti-Inflammatory Activity Assay: The anti-inflammatory activity of exemplary cannabidiol derivatives according to some embodiments of the present invention was tested using mouse macrophages. Peritoneal exudate macrophages from 8-9 week-old C57BL / 6 female mice were collected 4 days after injection of 1.5 ml of 3% thioglycollate medium. Peritoneal macrophages were cultured in 96-microwell flat-bottom plates. After 2 hours, cells were rinsed to remove non-adherent cells and then activated with LPS (1 pg / ml). Exemplary cannabinoid derivatives were diluted to various concentrations in DMEM and added to the cell preparation. After 24 hours of incubation, supernatants were collected and stored at -20°C until assayed for TNF-α and NO.

[0244] Determination of plasma TNF-α levels in endotoxemic mice: Cannabidiol derivatives were dissolved in 1 part DMSO, 1 part TWEEN® 80, and 4 parts PBS, and controls were treated with the same vehicle. Male C57B16 / J mice were pretreated with the indicated exemplary cannabidiol derivative 45 minutes prior to intraperitoneal injection of 1 mg / kg LPS. After an additional 90 minutes, mice were decapitated and trunk blood was collected for determination of TNF-α levels.

[0245] Reactive oxygen intermediate (ROI) assay: RAW264.7 cells suspended in phenol red-free HBSS were distributed into plastic luminometer tubes. A cannabidiol derivative was added to the sample, followed by 10 μl of luminol and 30 μl of zymosan. The chemiluminescence peak was then recorded in a luminometer.

[0246] Nitric oxide (NO) measurement assay: Nitric oxide levels were measured by measuring the nitrite accumulation in the supernatant of peritoneal macrophages treated with cannabidiol derivatives, prepared as described above.

[0247] TNF-α determination assay: TNF-α (pg / ml) in cell culture supernatants or mouse plasma was determined by the "sandwich" ELISA technique. ELISA reagents were used according to the manufacturer's protocol (R&D Systems).

[0248] result

[0249] The results of the biological activity assay are shown in Figures 1 to 4.

[0250] As can be seen in Figures 1-4, exemplary compounds according to embodiments of the present invention, HUM-216, HUM-217, HUM-218, and HUM-223, all exhibited significant anti-inflammatory activity.

[0251] It will be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0252] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

[0253] References: 1. Cardillo, B., et al., Gazzetta Chimica Italiana 1973.103(1-2):p.127-39. 2.Carlini,EA,et al.,Res Commun Chem Pathol Pharmacol,1975.12(1):p.1-15. 3.Weiner,BZ,et al,European Journal of Medicinal Chemistry,1975.10(1):p.79-83. 4.Knaus,EE,et al.,Journal of Chromatographic Science 1976.14(11):p.525-30. 5.Hendriks,Hv et al.,Pharmaceutisch Weekblad,1978.113(17):p.413-24. 6.Consroe,P.,et al.,J Clin Pharmacol,1981.21(8-9 Suppl):p.428S-436S. 7.Jorapur,VS,et al,Chemistry Letters 1982.3:p.299-302. 8.Jorapur,VS,et al.,J Med Chem,1985.28(6):p.783-7. 9.Martin,BR,etal,NIDA Res.Monogr.,1987.79:p.108-22. 10.Mechoulam,Rv et al,NIDA Res Monogr,1987.79:p.15-30. 11.Yamamoto,I.,et al.,Journal of Pharmacobio-Dynamics 1989.12(8):p.488-94. 12.Compton,DR,et al.,Journal of Medicinal Chemistry 1990.33(5):p.1437-43. 13.Baek,SH,et al.,Bulletin of the Korean Chemical Society,1992.13(2):p.117-18. 14.Baek,SH,et al.,Archives of Pharmacal Research,1992.15(1):p.5-8. 15. Inoue, S., et al. 16.Baek,SH,Bulletin of the Korean Chemical Society,1993.14(1):p.144-6 17.Baek,SH,et al,Bulletin of the Korean Chemical Society,1993.14(2):p.272-4. 18.Tius,MA,et al.,Tetrahedron,1993.49(16):p.3291-304. 19.Baek,SH,et al.,Bulletin of the Korean Chemical Society,1994.15(6):p.07-8. 20.Wiley,JL,et al,J Pharmacol Exp Ther,2002.301(2):p.679-89. 21.Summary,PF,et al.,Arthritis Rheum,2004.50(3):p.985-98. 22.Hanus,LO,et al.,Org Biomol Chem,2005.3(6):p.1116-23. 23.Mechoulam,Rv et al.,Phytochemistry Reviews 2005.4(1):p.11-18. 24. Padgett, LW, Life Sci, 2005.77(14):p.1767-98. Org Lett, 2000.2(21):p.3301-3. 26. R. Mechoulam, Z. Ben-Zvi, J. Chem.Soc.D Chem.Commun.1969,343. 27. H. Edery, Y. Grunfeld, G. Porath, Z. Ben-Zvi, A. Shani, R. Mechoulam, Arzneimittelforschung.1972, 22, 1995-2003. 28.RLYong,X.Wang,Bull.Korean Chem.Soc.2005,DOI 10.5012 / bkcs.2005.26.12.1933. 29. H. Lin, T. Annamalai, P. Bansod, Y.-C. Tse-Dinh, D. Sun, nd, DOI 10.1039 / c3md00238a. 30.M.Cerny,J.Malek,Collect.Czechoslov.Chem.Commun.1970,DOI 10.1135 / cccc19702030.

[0254] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit and scope of the invention.

Claims

1. A compound represented by the following general formula (I), or a stereoisomer, solvate, or salt thereof: During the ceremony, is a single bond or a double bond, R1 is selected from CH3 and CH2; R2 and R3 are selected from OH, O(C1-C3 alkyl), straight or branched C3-C10 alkyl; R4 is a straight or branched C1-C5 alkyl; R5 is selected from OH, straight or branched C3-C10 alkyl; R6 is selected from H, straight or branched chain C1-C5 alkyl. however, is a double bond, then at least one of R2 and R3 is different from OH or R6 is different from H; if R3 and R5 are both OH, then R2 is C5 alkyl and R4 is C1-C5 alkyl.

2. The compound described in claim 1, wherein is a single bond.

3. is a single bond, The compound of claim 1, wherein R2 and R3 are both OH.

4. 2. The compound of claim 1, wherein R2 and R3 are each O(C1-C3 alkyl).

5. The compound of claim 1, wherein R2 is a straight or branched C3-C10 alkyl.

6. The compound of claim 1, wherein R3 and R5 are both OH.

7. R3 and R5 are both OH; R2 is a straight or branched C3-C10 alkyl; 2. The compound of claim 1, wherein R4 is a straight or branched C1-C5 alkyl.

8. 2. The compound of claim 1, wherein R4 and R6 are each C1-C5 alkyl.

9. (1'S,2'S)-2'-isopropyl-3,5'-dimethyl-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-217), (1R,2R)-2',6'-dimethoxy-3',5-dimethyl-4'-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl (HUM-219), (1'R,2'R)-5,5'-dimethyl-6-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4-diol (HUM-229), 2. The compound of claim 1, selected from (1'R,2'R)-3,5,5'-trimethyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (HUM-236).

10. A compound represented by the following general formula (II), or a stereoisomer, solvate, or salt thereof: During the ceremony, R7 and R8 are each selected from OH, O(C1-C3 alkyl), OC(=O)R16; R9 is selected from H or C1-C3 alkyl; R10 is a linear or branched C3 to C10 alkyl; R16 is a C1-C5 alkyl optionally substituted with at least one of morpholino (O(CH2CH2)2NH). However, when both R7 and R8 are OH, R9 is different from C1 alkyl.

11. 11. The compound of claim 10, wherein at least one of R7 and R8 is O(C1-C3 alkyl).

12. At least one of R7 and R8 is OC(=O)R16; 11. The compound of claim 10, wherein R16 is C1-C5 alkyl optionally substituted with at least one of morpholino.

13. 11. The compound of claim 10, wherein both R7 and R8 are O(C1-C3 alkyl).

14. (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-4-methyl-5-pentylbenzene-1,3-diol (HUM-218), (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-(2-methyloctan-2-yl)phenol (HUM-223), (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-pentylphenyl 3-morpholinopropanoate (HUM-233), (E)-4-(3-(2-(3,7-dimethylocta-2,6-dien-1-yl)-3-methoxy-5-pentylphenoxy)-3-oxopropyl)morpholin-4-ium (Z)-3-carboxyacrylate (HUM-234), 11. The compound of claim 10, selected from (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-dimethoxy-4-methyl-5-pentylbenzene (HUM-235).

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14.

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