WO2008107879A1 - Novel cannabidiol derivatives and their use as anti-inflammatory agents - Google Patents

Novel cannabidiol derivatives and their use as anti-inflammatory agents Download PDF

Info

Publication number
WO2008107879A1
WO2008107879A1 PCT/IL2008/000281 IL2008000281W WO2008107879A1 WO 2008107879 A1 WO2008107879 A1 WO 2008107879A1 IL 2008000281 W IL2008000281 W IL 2008000281W WO 2008107879 A1 WO2008107879 A1 WO 2008107879A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
unsubstituted
group
disease
substituted
Prior art date
Application number
PCT/IL2008/000281
Other languages
French (fr)
Inventor
Raphael Mechoulam
Natalya Kogan
Ruth Gallily
Aviva Breuer
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Publication of WO2008107879A1 publication Critical patent/WO2008107879A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention in some embodiments thereof, relates to novel derivatives of cannabidiol, pharmaceutical compositions comprising same and uses thereof as anti-inflammatory agents.
  • CBD cannabidiol
  • ⁇ 9 -THC cannabinoid receptors
  • CBD does not bind to the known cannabinoid receptors CBl or CB2, and therefore does not cause the central or peripheral effects mediated by these receptors.
  • CBD has been shown in in vitro assays, as well as in in vivo assays in animals and in some human, preliminary trials, to produce numerous pharmacological effects, some of which are of high potential therapeutic value.
  • CBD has been found to produce several, potentially therapeutic, effects in animal models, as well as in patients with neurological diseases, in anxiety and psychosis.
  • CBD was also foimd to be a neuroprotective antioxidant.
  • CBD 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- ⁇ , IL-Ia and IFN ⁇ by human peripheral blood mononuclear cells.
  • NO nitric oxide
  • TNF- ⁇ , IL-Ia and IFN ⁇ human peripheral blood mononuclear cells.
  • CBD was found much more potent than aspirin in the phenylbenzoquinone writhing test in mice in a standard analgesic activity assay.
  • TPA tetradecanoylphorbolacetate
  • U.S. Patent No. 3,661,919 provided resorcinol derivatives exhibiting bactericidal and fungicidal activities.
  • U.S. Patent No. 4,018,777 provided resorcinol derivatives useful as tranquilizers, 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 diseases of the immune system.
  • U.S. Patent No. Patent No. Patent No. 3,661,919 provided resorcinol derivatives exhibiting bactericidal and fungicidal activities.
  • U.S. Patent No. 4,018,777 provided resorcinol derivatives useful as tranquilizers, analgesics, sedative-hypnotics and anticonvulsants.
  • U.S. Patent No. 6,566,560 provided resorcinol derivatives to attenuate the growth of a neoplasm.
  • U.S. Patent Application No. 20030232101 provided cannabinol derivatives, Delta8-THC derivatives, cannabichromene derivatives, cannabidiol derivatives and cannabigerol derivatives for preventing the transmission of HIV.
  • U.S. Patent No. 7,105,685 and U.S. Patent Application No. 20070179135 provided cannabinol derivatives and pharmaceutical preparations thereof.
  • the present invention in some embodiments thereof, provides novel cannabidiol derivatives wherein at least one of the hydroxyl substituent groups is converted to a stable form thereof, and to processes of preparing the same.
  • the present invention further provides pharmaceutical compositions containing these cannabidiol derivatives and uses thereof in the treatment of inflammation.
  • A is selected from the group consisting of an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heteroalicyclic, an unsubstituted or substituted aryl and an unsubstituted or substituted heteroaryl;
  • R 1 and R 2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen, provided that at least one OfR 1 and R 2 is not hydrogen;
  • R 3 is selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy and an aryloxy;
  • D 1 is selected from the group consisting OfNR 4 , O and S
  • D 2 is selected from the group consisting of NR 5 , O and S;
  • R 4 and R 5 are each independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
  • the compound(s) described herein exhibit anti-inflammatory activity. According to further features in some embodiments of the invention described herein, each OfD 1 and D 2 is O.
  • A is an unsubstituted or substituted cycloalkyl.
  • the cycloalkyl is selected from the group consisting of a monocyclic unsubstituted or substituted cycloalkyl and a bicyclic unsubstituted or substituted cycloalkyl.
  • the bicyclic unsubstituted or substituted cycloalkyl is pinene.
  • the monocyclic unsubstituted or substituted cycloalkyl has general Formula II:
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, hydroxyl, alkoxy, carboxyl, carbonyl, formyl, acetyl and amine. whereas: a dashed line is a single or double bond; and a wavy line is a bond having an R or an S stereo-configuration.
  • R 1 and R 2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen.
  • R 1 and R 2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 4 to 10 carbon atoms and hydrogen.
  • R 1 and R 2 are each independently selected from the group consisting of a substituted, branched or linear alkyl having from 3 to 10 carbon atoms and hydrogen.
  • R 1 and R 2 are each independently unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and R 7 is carboxyl.
  • R 6 is methyl.
  • each OfR 1 and R 2 is methyl.
  • R 3 is 1-pentyl, and A is 2-yl-4-methylcyclohex-3-enyl)acrylic acid.
  • A is 3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, 2- yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, JV-Boc-ethanamine-2-yl, JV-
  • R 2 is selected from the group consisting of 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, JV-Boc-ethanamine-2-yl, JV-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl and acetonitrile-2-yl.
  • R 3 is selected from the group consisting of 1-pentyl and 1,1-dimethylheptyl-l- yi.
  • A is selected from the group consisting of an unsubstituted or substituted heteroalicyclic and an unsubstituted or substituted heteroaryl.
  • A is selected from the group consisting of an unsubstituted or substituted five- membered ring, an unsubstituted or substituted six-membered ring and an unsubstituted or substituted seven-membered ring.
  • the unsubstituted or substituted five-membered ring is selected from the group consisting of dihydropyrrole (pyrroline), tetrahydropyrrole (pyrrolidine), dihydrofuran, tetrahydrofurane, dihydrothiophene, tetrahydrothiophene furane, pyrrole, thiophene, oxazole, isoxazole, thiazole, thiazole, oxatriazole and oxatriazole.
  • the unsubstituted or substituted six-membered ring is selected from the group consisting of piperidine, pyridine, tetrahydropyran, pyran, thiane, thiine (thiapyrane), piperazine, diazine, oxazine, thiazine, triazine, dithiane and dioxane.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, acetyl, 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, N-Boc-ethanamine-2-yl, N-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl, acetonitrile-2-yl, 4-formyl-butanoic acid, 4-formyl-but-2-enoic acid and propan-2-one-l-yl.
  • the compound(s) described herein exhibit anti-inflammatory activity.
  • composition which includes, as an active ingredient, the compound(s) presented herein.
  • the pharmaceutical composition is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation.
  • a method of treating a medical condition, disease or disorder associated with inflammation which is effected by administering to a subject in need thereof a therapeutically effective amount of the compound(s) presented herein.
  • the medicament is used in the treatment of a medical condition, disease or disorder associated with inflammation.
  • the medical condition, disease or disorder associated with inflammation is selected from the group consisting of 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 I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type 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
  • the medical condition, disease or disorder is selected from the group consisting of rheumatoid arthritis, atherosclerosis, Crohn's disease and multiple sclerosis.
  • composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.
  • the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • the present invention in some embodiments thereof, provides novel cannabidiol derivatives.
  • the present invention further provides pharmaceutical compositions containing these cannabidiol derivatives and uses thereof in the treatment of inflammation.
  • the present embodiments provide some novel cannabinoid derivatives, which can be prepared at much improved yields, and show improved anti-inflammatory activity.
  • A is selected from the group consisting of an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heteroalicyclic, an unsubstituted or substituted aryl and an unsubstituted or substituted heteroaryl;
  • R 1 and R 2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen, provided that at least one OfR 1 and R 2 is not hydrogen;
  • R 3 is selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy and an aryloxy;
  • D 1 is selected from the group consisting OfNR 4 , O and S;
  • D 2 is selected from the group consisting of NR 5 , O and S; and
  • R 4 and R 5 are each independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
  • the present embodiments further encompass any enantiomers, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of the compounds described herein.
  • enantiomer refers to a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other. Enantiomers are said to have "handedness” since they refer to each other like the right and left hand. Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems.
  • prodrug refers to an agent, which is converted into the active compound (the active parent drug) in vivo.
  • Prodrugs are typically useful for facilitating the administration of the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions. Prodrugs are also often used to achieve a sustained release of the active compound in vivo.
  • An example, without limitation, of a prodrug would be a compound as described herein, having one or more carboxylic acid moieties, which is administered as an ester (the "prodrug"). Such a prodrug is hydrolyzed in vivo, to thereby provide the free compound (the parent drug).
  • the selected ester may affect both the solubility characteristics and the hydrolysis rate of the prodrug.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the compound of the present 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.
  • hydrate refers to a solvate, as defined hereinabove, where the solvent is water.
  • phrases "pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
  • An example, without limitation, of a pharmaceutically acceptable salt would be a carboxylate anion and a cation such as, but not limited to, ammonium, sodium, potassium and the like.
  • a compound in which D 1 and D 2 are both O, R 1 is an alkyl substituted with a carboxyl group and R 2 is hydrogen exhibits an improved bioavailability profile by being highly soluble in aqueous media in concentrations much higher than those of the previously known cannabidiol derivatives.
  • cannabidiol derivative can be readily converted into an anion of many pharmaceutically acceptable salts having cations such as, for example, sodium, potassium, ethylenediamine, ethanolamine, calcium, deanol, magnesium, zinc, piperazine, diethanolamine, pyrrolidine, betaine, tromethamine, choline, lysine, morpholine, triethanolamine, arginine, N-methylglucamine and the likes.
  • the parent compound can be ionized so as to be positively charged and hence be a cation of a salt.
  • a compound which contains an amine group either on one of R 1 or R 2 , or on A can be converted to a cation of a pharmaceutically acceptable acid addition salt.
  • the phrase "acid addition salt” describes a complex of two ionizable moieties, a base and an acid, which, when interacted in a particular stoichiometric proportion and under suitable conditions, form a salt that comprises one or more cations of the base moiety and one or more anions of the acid moiety.
  • the phrase “acid addition salt” refers to such a complex, in which the base moiety in amine, such that the salt comprises a cationic form of the amine (ammonium) and an anionic form of an acid.
  • the acid additions salts can be either mono addition salts or poly addition salts.
  • the phrase "mono addition salt”, as used herein, refers to a salt complex in which the stochiometric ratio between the acid anion and amine cation is 1:1, such that the acid addition salt includes one molar equivalent of the acid per one molar equivalent of the conjugate.
  • poly addition salt refers to a salt complex in which the stochiometric ratio between the acid anion and the amine cation is greater than 1:1 and is, for example, 2:1, 3:1, 4:1 and so on, such that the acid addition salt includes two or more molar equivalents of the acid per one molar equivalent of the conjugate.
  • the stoichiometric proportions between the base and the acid of the salt complex ranges from 6:1 to 1:6 base:acid equivalents, from 4:1 to 1:4 base:acid equivalents, from 3:1 to 1:3 base:acid equivalents or from 1:1 to 1:3 base:acid equivalents.
  • the acid addition salts of a chemical conjugate according to the present invention are therefore complexes formed between one or more amino groups of the compound and one or more equivalents of an acid.
  • the acid addition salts may therefore include a variety of organic and inorganic acids, such as, but not limited to, halogen acids such as hydrochloric acid which affords an hydrochloric acid addition salt (as well as salts of bromide and iodide), acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzoic acid which affords a benzoic acid addition salt (benzoate), benzenesulfonic acid which affords a benzenesulfonic acid addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, naphthylsulfonic acid which affords a naphthylsulfonic acid addition salt, toluenelsulfonic acid (p-toluenes
  • each of these acid addition salts can be either a mono acid addition slat or a poly acid addition salt, as these terms are defined hereinabove.
  • cannabidiol derivative compounds as presented herein, which contain one or more -OH (hydroxyl) or an -NH 2 (amine) groups either on one OfR 1 or R 2 , or on A, can be converted to into a prodrug by coupling to, for example, a succinic, fumaric, maleic acids and other suitable acids to form prodrugs, which can be enzymatically hydrolyzed in the body by, for example, esterases or amidases. All of the cannabidiol derivative compounds presented herein (namely ethers, esters, salts, prodrugs, etc.) are considerably more soluble in aqueous media as compared to the previously described derivatives.
  • A is a cyclic moiety which can be saturated, partly saturated or aromatic (cycloalkyl or aryl), can have one or more heteroatom as part of the ring (heteroalicyclic or heteroaryl), and can further be unsubstituted or substituted.
  • cycloalkyl describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system.
  • the cycloalkyl may be unsubstituted or substituted by one or more substituents.
  • the substituent can be, for example, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a halogen (halo), a hydroxy, an alkoxy, an aryloxy, a thiohydroxy, a thioalkoxy, a thioaryloxy, a haloalkyl, an amine, a carbonyl, a carboxyl, an amide, a thioamide, a cyano and a carbamate, as well as combinations thereof, as these terms are defined herein.
  • heteroalicyclic describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl.
  • heteroalicyclics include, without limitation, piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.
  • aryl describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • the aryl group may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • a representative group of moieties which can embody A in Formula I include, according to some embodiments of the present invention and without limitation, 4-, 5- , 6- and 7-membered substituted or unsubstituted heteroalicyclics and heteroaryls such as [l,2]diazocan-3-one, [l,3]diazocan-2-one, [l,4]diazocane, [l,4]oxazepane, 1,2,3- triazine, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2-diazepine, 1,2-oxathiepane, 1,2-oxathiolane, 1,2-oxazine, 1,2-thiazine, 1,3, 5 -triazine, 1,3-diazepine, 1,3- dioxolane, 1,3-dioxolene, 1,3-oxazine, 1,3-thiazine, 1,3-thiazole, 1,4
  • each of R 1 and R 2 can independently be an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
  • alkyl describes an aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 10 carbon atoms, according to other embodiments, 1 to 5 carbon atoms, according to yet other embodiments, 6 to 10 carbon atoms, and according to still other embodiments, 4 to 6 carbon atoms.
  • a numerical range e.g., "1-10” is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkyl can be substituted or unsubstituted.
  • the substituent can be, for example, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a halogen (halo), a hydroxy, an oxo, an alkoxy, an aryloxy, a thiohydroxy, a thioalkoxy, a thioaryloxy, a haloalkyl, an amine, a carbonyl, a carboxyl, an amide, a thioamide, a cyano and a carbamate, as these terms are defined herein.
  • alkyl also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.
  • 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 by one or more substituents, as described hereinabove for alkyl.
  • alkynyl is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl may be unsubstituted or substituted by one or more substituents, as described hereinabove for alkyl.
  • amine describes a -NR'R" group where each of R' and R" is independently hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl or heteroaryl, as these terms are defined herein.
  • halo As used herein, the terms "halo”, “halogen” and “halide”, which are referred to herein interchangeably, describe an atom of a fluorine, chlorine, bromine or iodine, also referred to herein as fluoride, chloride, bromide and iodide.
  • haloalkyl describes an alkyl group as defined above, further substituted by one or more halide(s).
  • hydroxy or "hydroxyl”, as used herein interchangeably, refers to an -OH group.
  • alkoxy describes a -OR' group, where R' is as defined herein.
  • aryloxy refers to an —OR” group wherein R" is aryl.
  • thiohydroxy refers to an -SH group.
  • thioalkoxy describes a -SR' group, where R' is as defined herein.
  • thioarylkoxy describes a -SR" group, where R" is aryl.
  • An exemplary carbonyl is a formyl group, wherein R is hydrogen.
  • Another exemplary carbonyl is an acetyl group, wherein R is methyl.
  • cyano refers to a -C ⁇ N group.
  • an acetonitrile substituent group is a cyano group attached to a molecule via a -CH 2 - group, constituting a -CH 2 -C ⁇ N group.
  • a particular exemplary carbamate is afforded when an amine is protected with a Boc protecting group, affording a tert-butyl carbamate.
  • R 1 and/or R 2 can each be unsubstituted or substituted with a number of groups as presented hereinabove, as well as combinations thereof, and the same definition applies to any variable which is defined as unsubstituted or substituted, regardless of the definition for each of the particular chemical groups.
  • R 3 can be an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy or an aryloxy.
  • the group which is equivalent to the R 3 variable in Formula I is optionally 1-pentyl.
  • this group can be, for example, 1 ,2-dimethylheptyl, 1,1- dimethylheptyl and the likes.
  • R 3 can be a straight (linear) or branched alkyl of 5 to 12 carbon atoms; a group -O-alkyl, where the alkyl is straight (linear) or branched having 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; a group -(CH 2 )n-O-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms.
  • the novel compounds presented herein are derivatives of cannabidiol (CBD).
  • CBD cannabidiol
  • A can be a substituted six-membered cycloalkyl.
  • one or both OfD 1 and D 2 are O (oxygen).
  • A is a moiety having general Formula II:
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, hydroxyl, alkoxy, carboxyl, carbonyl, formyl, acetyl and amine, as there terms are defined hereinabove.
  • Each of the dashed lines in Formula II represents a single or double bond, and each of the wavy lines represents a bond having an R or an S stereo-configuration.
  • each of R 6 and R 7 can be attached to main part of the moiety having general Formula II via a single bond or a double bond, depending on the nature thereof and the valency of the atom these groups are attached to.
  • the compounds according to some embodiments of the present invention share many structural features of the naturally occurring CBD molecule.
  • these compounds were designed and selected such that their preparation and their bioavailability are improved by virtue of the particular substituents at any of variables Ri-R 7 , and in addition when the resulting compound can be ionized at physiological pH, namely an acid or a base that can be turned into a salt thereof.
  • R 7 can be a carboxyl group, allowing the compound to be turned into a carboxylate anion at certain pH levels.
  • R 1 is a substituted linear short alkyl, having, for example, 1 to 5 carbon atoms.
  • the alkyl is substituted by, for example, one or more of oxo, hydroxy, carboxy, amine and nitrile.
  • D 1 and D 2 are each O, and A is 3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl, as in CBD, while R 1 is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc-ethanamme-2-yl, iV-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl and acetonitrile-2-yl; and R 2 is selected from the group consisting of 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc- ethanamine-2-yl, iV-Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl and acetonitrile-2-yl;
  • variable R 3 is 1-pentyl
  • these CBD derivative compounds are part of a group of compounds which include, for example:
  • variable ring A in Formula I can be any five-, six- or seven-membered substituted or unsubstituted, aromatic, partly saturated or saturated ring.
  • Exemplary unsubstituted or substituted five-membered ring moieties which can be represented by A in Formula I include, without limitation, dihydropyrrole
  • Exemplary unsubstituted or substituted six-membered ring moieties which can be represented by A in Formula I include, without limitation, piperidine, pyridine, tetrahydropyran, pyran, thiane, thiine (thiapyrane), piperazine, diazine, triazine, oxazine, thiazine, dithiane and dioxane.
  • Exemplary unsubstituted or substituted seven-membered ring moieties which can be represented by A in Formula I include, without limitation, oxepine, azepine, thiepine, oxazepine, diazepine, triazepine, thiaazepine and thiadiazepine.
  • each of R 1 -R 2 can be independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, including, but not limited to, hydrogen (for only one of R 1 and R 2 ), methyl, ethyl, propyl, butyl, acetyl, 2-yl- acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, N-Boc-ethanamine-2-yl, N- Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl, acetonitrile-2-yl, 4-formyl-butanoic acid, 4-formyl-but-2-enoic acid and propan-2-one-l-yl.
  • cannabidiols are plant derived, a large family thereof contains a pinene moiety, which is one of the more ubiquitous natural transformation of l-methyl-4-(prop-l-en-2-yl)cyclohex-l-ene moiety, as found in some of the compounds according to some embodiments of the present invention, particularly those wherein A is having general Formula II.
  • the chemical compound pinene is a bicyclic terpene, also known as a monoterpene, which is found both in the ⁇ -pinene configuration and the ⁇ -pinene configuration (systematic names are (lS,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene and (1S,5S)- 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane, respectively), which can be metabolized or synthetically produced from, for example, a l-methyl-4-(isopropen-2- yl)cyclohexene carbocation intermediate, as illustrated in Scheme 1 below.
  • a method of treating a medical condition, a disease or a disorder associated with inflammation which is effected by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds as presented herein, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove.
  • a method of treating a medical condition, a disease or a disorder associated with inflammation which is effected by administering to a subject in need thereof a therapeutically effective amount of one or more of any one of the compounds presented in Table 1 which is presented in the Examples section that follows hereinbelow, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • another aspect of the present invention provides a use of one or more of the compounds as presented herein, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove, in the preparation of a medicament.
  • the medicament is for the treatment of a medical condition, a disease or a disorder associated with inflammation.
  • Inflammation is a protective response of the body to an injury.
  • the term "inflammation” includes without limitation, medical conditions, diseases and disorders which are associated with inflammation.
  • representative examples of diseases or disorders associated with inflammation include, without limitation, 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 transplantation-related diseases or disorders, inflammatory degenerative diseases or disorders, diseases or disorders associated with a hypersensitivity, 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 cutaneous diseases or disorders, inflammatory hepatic diseases or disorders, inflammatory neurological diseases or disorders, inflammatory musculo-skeletal 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 connective tissue diseases or disorders, inflammatory connective tissue diseases or disorders,
  • Type II hypersensitivity Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity, delayed type hypersensitivity, helper T lymphocyte mediated hypersensitivity, cytotoxic T lymphocyte mediated hypersensitivity, THl lymphocyte mediated hypersensitivity, and TH2 lymphocyte mediated hypersensitivity.
  • Non-limiting examples of inflammatory cardiovascular disease or disorder include occlusive diseases or disorders, atherosclerosis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, myocardial infarction, coronary arterial disease, acute coronary syndromes, 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 vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune 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.
  • Stenosis is an occlusive disease of the vasculature, commonly caused by atheromatous plaque and enhanced platelet activity, most critically affecting the coronary vasculature.
  • Restenosis is the progressive re-occlusion often following reduction of occlusions in stenotic vasculature.
  • in-stent-stenosis may occur, re-occluding the treated vessel.
  • cerebrovascular diseases or disorders include stroke, cerebrovascular inflammation, cerebral hemorrhage and vertebral arterial insufficiency.
  • Non-limiting examples of peripheral vascular diseases or disorders include gangrene, diabetic vasculopathy, ischemic bowel disease, thrombosis, diabetic retinopathy and diabetic nephropathy.
  • Non-limiting examples of autoimmune diseases or disorders include all of the diseases caused by an immune response such as an autoantibody or cell-mediated immunity to an autoantigen and the like.
  • Representative examples are chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, Bechet'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, vasculitides and heparin induced thrombocytopenia.
  • 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 myxedema, ovarian autoimmunity, autoimmune anti-sperm infertility, autoimmune prostatitis and Type I autoimmune polyglandular syndrome.
  • Non-limiting examples of inflammatory gastrointestinal diseases or disorders include colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, inflammatory bowel syndrome, chronic inflammatory bowel disease, celiac disease, ulcerative colitis, an ulcer, a skin ulcer, a bed sore, a gastric ulcer, a peptic ulcer, a buccal ulcer, a nasopharyngeal ulcer, an esophageal ulcer, a duodenal ulcer and a gastrointestinal ulcer.
  • Non-limiting examples of inflammatory cutaneous diseases or disorders include acne, and an autoimmune bullous skin disease.
  • Non-limiting examples of inflammatory hepatic diseases or disorders include autoimmune hepatitis, hepatic cirrhosis, and biliary cirrhosis.
  • Non-limiting examples of inflammatory neurological diseases or disorders include multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydeham chorea, Gilles de Ia Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis, stroke, an inflammatory
  • Non-limiting examples of inflammatory connective tissue diseases or disorders include autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune disease or disorder, myositis, tendinitis, a ligament inflammation, chondritis, a joint inflammation, a synovial inflammation, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, a skeletal inflammation, an autoimmune ear disease or disorder, and an autoimmune disease or disorder of the inner ear.
  • Non-limiting examples of inflammatory renal diseases or disorders include autoimmune interstitial nephritis and/or renal cancer.
  • Non-limiting examples of inflammatory reproductive diseases or disorders include repeated fetal loss, ovarian cyst, or a menstruation associated disease or disorder.
  • Non-limiting examples of inflammatory systemic diseases or disorders include systemic lupus erythematosus, systemic sclerosis, septic shock, toxic shock syndrome, and cachexia.
  • Non-limiting examples of infectious disease or disorder include chronic infectious diseases or disorders, a subacute infectious disease or disorder, an acute infectious disease or disorder, a viral disease or disorder, a bacterial disease or disorder, a protozoan disease or disorder, a parasitic disease or disorder, a fungal disease or disorder, a mycoplasma disease or disorder, gangrene, sepsis, a prion disease or disorder, influenza, tuberculosis, malaria, acquired immunodeficiency syndrome, and severe acute respiratory syndrome.
  • Non-limiting examples of inflammatory transplantation-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 a prosthetic implant, a breast implant, a silicone implant, a dental implant, a penile implant, a cardiac implant, an artificial joint, a bone fracture repair device, a bone replacement implant, a drag delivery implant, a catheter, a pacemaker, an artificial heart, an artificial heart valve, a drag release implant, an electrode, and a respirator tube.
  • Non-limiting examples of inflammatory tumors include a malignant rumor, a benign tumor, a solid tumor, a metastatic tumor and a non-solid tumor.
  • Non-limiting examples of inflammatory pulmonary diseases or disorders include asthma, allergic asthma, emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis and bronchitis.
  • Exemplary medical conditions, diseases and disorders which are 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 I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type 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
  • the inflammatory disorders include rheumatoid arthritis, atherosclerosis, Crohn's disease, multiple sclerosis, Alzheimers's disease, prion associated disease and cancer metastases.
  • therapeutically effective amount describes an amount of the compound being administered which will relieve to some extent one or more of the symptoms of the condition being treated.
  • an exemplary therapeutically effective amount of the compounds of the present invention ranges between about 0.1 mg/kg body and about 100 mg/kg body.
  • cannabidiol derivative compounds of the present embodiments can be utilized either per se or, according to some embodiments, as a part of a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises one or more compounds having general Formula I, as defined hereinabove, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises one or more of any one of the compounds presented in Table 1 which is presented in the Examples section that follows hereinbelow, and a pharmaceutically acceptable carrier, as well as any enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove.
  • a "pharmaceutical composition” refers to a preparation of the compounds presented herein, with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients examples include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • Proper formulation is dependent upon the route of administration chosen.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).
  • the pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically
  • Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.
  • 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.
  • Formulations for parenteral administration may include, but are not limited to, sterile solutions which may also contain buffers, diluents and other suitable additives.
  • compositions are envisaged for treatment.
  • the amount of a composition to be 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.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the 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, comprise metal or plastic foil, such as, but not limited to 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 be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • 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 treatment of a medical condition, disease or disorder associated with inflammation, as is detailed hereinabove.
  • the pharmaceutical composition of the present invention is being packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation, as is defined hereinabove.
  • the compounds of the present invention can be combined with other active ingredients which are commonly used to treat inflammation-associated diseases and disorders.
  • Organic solvents were purchased from Bio-Lab. Cannabinoids (such as cannabidiol) were extracted from Cannabis sativa plant as previously described [Gaoni, Y. and Mechoulam, R. (1971) J. Amer. Chem. Soc. 93, 217-224].
  • Ethyl 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l -en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetate was prepared from plant-derived cannabidiol as illustrated in Scheme 2 below.
  • Cannabidiol (1 mmol) was dissolved in dry acetone, and potassium carbonate anhydrous (1 mmol) and a catalytic amount of sodium iodide were added thereto. The solution was stirred in inert atmosphere for 10 minutes, and thereafter ethylbromoacetate (1 mmol) was added thereto. The reaction mixture was refluxed overnight, cooled, filtered, concentrated and purified by column chromatography to afford ethyl 2-(3 -hydroxy-2-((6R)-3-methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 - pentylphenoxy)acetate (HU-409) at 43 % yield.
  • HU-409 was dissolved in an aqueous solution of KOH (5 %) in methanol, and refluxed for 30 minutes under inert atmosphere. Thereafter the solution was converted under reduced pressure to afford 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l- en-2-yl)cyclohex-2-enyl)-5-pentylphenoxy)acetic acid (HU-410) at 100 % yield.
  • HU-429 HU-428 A solution of HCl/dioxane (1.45 ml, 4 M) in a 5 ml round-bottom flask equipped with a magnetic stir-bar was cooled by an ice bath under nitrogen. HU-429 (0.07 mmol) was added in one portion with stirring. The ice-bath was removed and the mixture was kept stirred. After 30 minutes, TLC indicted that the reaction was completed. Thereafter the reaction mixture was concentrated under reduced pressure and the residue was purified on column chromatography using 2 % methanol in chloroform as eluent to afford the free amine, HU-428.
  • CBD (1 equivalent, 0.1 mmol) was dissolved in dry acetone (3 ml) and K 2 CO 3 (4 equivalents, 0.4 mmol) was added thereto under dry nitrogen. The mixture was refluxed for 30 minutes and the solution became violet. Thereafter a solution of protected bromo-amine (1 equivalent, 0.1 mmol) in dry acetone was added in one portion followed by addition of the TSTaI (3 equivalents, 0.3 mmol) dissolved in dry acetone, and the reaction was refluxed for 4 days under nitrogen.
  • Cannabidiol-cyanomethyl ether (HU-431, 1 mmol) was mixed with an excess of LiAlH 4 in dry ether and refluxed for 3 hours. Thereafter the workup with saturated MgSO 4 the solution was concentrated and purified with 100 % ethyl acetate to afford HU-427 at a yield of 89 %.
  • Cannabidiol (1 mmol) was dissolved in dry acetone (10 ml) under a nitrogen atmosphere.
  • K 2 CO 3 (2 mmol) and iodoacetonitrlie (1 mmol) were added and the reaction mixture was allowed to refluxed overnight.
  • the reaction mixture was filtered, concentrated and purified on a silica gel column with 5 % ethylacetate in petroleum ether to afford HU-431 at a yield of 30 %.
  • HU-431 (1 mmol) was mixed with an excess of LiAlH 4 in dry ether and refluxed for 3 hours. Thereafter the resulting product was washed with saturated MgSO 4 and the solution was concentrated and purified with 100 % ethyl acetate to afford HU-427 at a yield of 89 %.
  • Cannabidiol (I 5 1.12 grams, 3.5 mmol) was dissolved in pyridine (4 ml). Acetic anhydride (2 ml) was added thereto and the reaction mixture was stirred at room temperature for 1.5 hours. Thereafter the reaction was monitored by TLC (1:10; ether: petroleum ether) until the starting material was fully consumes. Then the solution was extracted with ether (150 ml). The organic phase was washed with HCl (1 M) several times, then with saturated NaHCO 3 and brine and dried on MgSO 4 . The solvent was removed under vacuum to give 1.26 grams cannabidiol diacetate compound I at a yield of 93 %.
  • Cannabidiol diacetate-10-oic acid (V, 200 mg, 0.46 mmol) was dissolved in methanol (8 ml). A solution Of Na 2 CO 3 (138 mg) in water (3 ml) was added, under N 2 , and the mixture was stirred at room temperature for 2 hours, and thereafter evaporated under reduced pressure to remove the methanol, and then diluted with water. The resulting solution was slowly acidified with HCl IM while cooling in an ice bath to afford a weakly acidic solution. The mixture was extracted with ether, dried over MgSO 4 and evaporated to afford 152 mg of cannabidiol-10-oic acid, compound VI, at yield of 96 %.
  • Cannabidiol-10-oic acid (VI, 150 mg, 0.43 mmol) was dissolved in DMF (2.5 ml). Thereafter K 2 CO 3 (482 mg) and CH 3 I (0.5 ml) were added and the reaction mixture was stirred at room temperature over night. Thereafter water (20 ml) was added and the solution was extracted with ether. The organic phase was washed with brine until it was neutralized, dried over MgSO 4 and evaporated to afford an oil which was separated on column of silica gel, to afford 116 mg of dimethoxy cannabidiol- 10- oic acid methyl ester, compound VII, at a yield of 70 %.
  • Dimethoxy cannabidiol-10-oic acid, methyl ester (VII, 100 mg, 0.25 mmol) was dissolved in ethanol (2 ml). A solution of NaOH (60 mg) in water (0.5 ml) was added, under N 2 , and the mixture was stirred at room temperature for 72 hours. Thereafter the reaction mixture was then evaporated under reduced pressure to remove the ethanol, and then diluted with water.
  • a maleate salt of HU-435 (HU-436) was effected by the stirring a solution of maleic acid (0.247 mmol) and HU-435 (0.247 mmol) in 2- propanol at room temperature for 2.5 hours. Thereafter the solvent was evaporated under reduced pressure and the oil obtained was crystallized from ethyl acetate and ether to afford the salt HU-436 (melting point 110-112 0 C) at a yield of 80 %.
  • exemplary cannabidiol derivatives were tested using murine macrophages.
  • Peritoneal exudate macrophages from 8- week-old to 9-week-old C57BL/6 female mice were harvested 4 days after injection of 1.5 ml of 3 % thioglycolate medium.
  • Peritoneal macrophages were cultured in 96-microwell flat bottomed plates. Two hours later, the cells were rinsed to remove unattached cells, and thereafter activation with LPS (1 ⁇ g/ml).
  • the exemplary cannabinoid derivatives were diluted to various concentrations with DMEM and added to the cell preparations.
  • RAW 264.7 cells suspended in HBSS without phenol red, were distributed in plastic luminometer tubes.
  • the cannabidiol derivatives were added to the samples followed by addition of 10 ⁇ l of luminol and 30 ⁇ l of zymosan.
  • the chemiluminescence peak was then recorded by a luminometer.
  • Nitric oxide levels were determined by measuring the accumulated nitrite in the supernatants of cannabidiol derivative-treated peritoneal macrophages, prepared as described hereinabove.
  • TNF- ⁇ (pg/ml) in cell culture supematants or in mouse blood plasma was determined by the "sandwich" ELISA technique. ELISA reagents were used according to the manufacturer's protocol (R & D Systems).

Abstract

Novel derivatives of cannabidiol, having one or two of the hydroxyl groups substituted, exhibiting improved production yield, solubility, stability and bioavailability, are provided. Also provided are pharmaceutical compositions comprising same and uses thereof as anti-inflammatory agents.

Description

NOVEL CANNABIDIOL DERIVATIVES AND THEIR USE AS ANTIINFLAMMATORY AGENTS
FIELD AND BACKGROUND OF THE INVENTION The present invention, in some embodiments thereof, relates to novel derivatives of cannabidiol, pharmaceutical compositions comprising same and uses thereof as anti-inflammatory agents.
Cannabidiol (CBD) is the major non-psychotropic cannabinoid in most cannabis preparations, such as hashish and marihuana. However, CBD causes none of the psychotropic effects typical of Δ9-tetrahydrocannabinol (Δ9-THC) since CBD does not bind to the known cannabinoid receptors CBl or CB2, and therefore does not cause the central or peripheral effects mediated by these receptors. Nonetheless CBD has been shown in in vitro assays, as well as in in vivo assays in animals and in some human, preliminary trials, to produce numerous pharmacological effects, some of which are of high potential therapeutic value.
Thus, for example, CBD has been found to produce several, potentially therapeutic, effects in animal models, as well as in patients with neurological diseases, in anxiety and psychosis. CBD was also foimd to be a neuroprotective antioxidant.
Some reports describe the 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-Ia and IFNγ by human peripheral blood mononuclear cells. These in vitro studies lend support to earlier reports on analgesic and antiinflammatory effects of CBD in animals. CBD was found much more potent than aspirin in the phenylbenzoquinone writhing test in mice in a standard analgesic activity assay. In the tetradecanoylphorbolacetate (TPA) induced erythema of mouse ear (a standard anti-inflammatory activity assay) CBD caused 92 % inhibition of the inflammation response on application of a 100 μg/ml solution.
Some studies provided CBD, resorcinol and other cannabinoid derivatives with a wide scope of indications [1-24]. U.S. Patent No. 3,661,919 provided resorcinol derivatives exhibiting bactericidal and fungicidal activities. U.S. Patent No. 4,018,777 provided resorcinol derivatives useful as tranquilizers, 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 diseases of the immune system. U.S. Patent
Application No. 20020137802 provided cannabinoid or resorcinolic derivatives for inhibiting the activation and/or aggregation of blood platelets. U.S. Patent No. 6,566,560 provided resorcinol derivatives to attenuate the growth of a neoplasm. U.S. Patent Application No. 20030232101 provided cannabinol derivatives, Delta8-THC derivatives, cannabichromene derivatives, cannabidiol derivatives and cannabigerol derivatives for preventing the transmission of HIV. U.S. Patent No. 7,105,685 and U.S. Patent Application No. 20070179135 provided cannabinol derivatives and pharmaceutical preparations thereof. U.S. Patent Application No. 20040034108, WO 2004016246 and British Patent No. GB2392093 provided cannabinoid derivatives for administration via a pump action spray. U.S. Patent Nos. 7,179,800 and 7,285,687 and WO 2003091189 provided cannabidiol derivatives useful in the treatment of pain, inflammation and autoimmune disease. U.S. Patent No. 6,630,507 and WO 199953917 provided cannabinoid derivatives as antioxidants and neuroprotectants. U.S. Patent Nos. 4,282,248 and 6,410,588, U.S. Patent Application Nos.
20030166727 and 20070082954, as well as WO 2005023741 and WO 2001095899, which are incorporated in their entirety as if fully set forth herein, teach cannabidiol derivatives, some of which have been synthesized and biologically evaluated [25, 21], and some of which have been shown to possess anti-inflammatory activity,.
SUMMARY OF THE INVENTION
The present invention, in some embodiments thereof, provides novel cannabidiol derivatives wherein at least one of the hydroxyl substituent groups is converted to a stable form thereof, and to processes of preparing the same. The present invention further provides pharmaceutical compositions containing these cannabidiol derivatives and uses thereof in the treatment of inflammation.
Thus, according to one aspect of the present invention there is provided a compound having general Formula I:
Figure imgf000004_0001
an enantiomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof; wherein:
A is selected from the group consisting of an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heteroalicyclic, an unsubstituted or substituted aryl and an unsubstituted or substituted heteroaryl;
R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen, provided that at least one OfR1 and R2 is not hydrogen;
R3 is selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy and an aryloxy;
D1 is selected from the group consisting OfNR4, O and S; D2 is selected from the group consisting of NR5, O and S;
R4 and R5 are each independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
According to some embodiments of the invention, the compound(s) described herein exhibit anti-inflammatory activity. According to further features in some embodiments of the invention described herein, each OfD1 and D2 is O.
According to further features in some embodiments of the invention described herein, A is an unsubstituted or substituted cycloalkyl.
According to further features in some embodiments of the invention described herein, the cycloalkyl is selected from the group consisting of a monocyclic unsubstituted or substituted cycloalkyl and a bicyclic unsubstituted or substituted cycloalkyl. According to further features in some embodiments of the invention described herein, the bicyclic unsubstituted or substituted cycloalkyl is pinene.
According to further features in some embodiments of the invention described herein, the monocyclic unsubstituted or substituted cycloalkyl has general Formula II:
Figure imgf000005_0001
Formula II wherein:
R6 and R7 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, hydroxyl, alkoxy, carboxyl, carbonyl, formyl, acetyl and amine. whereas: a dashed line is a single or double bond; and a wavy line is a bond having an R or an S stereo-configuration. According to further features in some embodiments of the invention described herein, R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen.
According to further features in some embodiments of the invention described herein, R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 4 to 10 carbon atoms and hydrogen.
According to further features in some embodiments of the invention described herein, R1 and R2 are each independently selected from the group consisting of a substituted, branched or linear alkyl having from 3 to 10 carbon atoms and hydrogen.
According to further features in some embodiments of the invention described herein, R1 and R2 are each independently unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and R7 is carboxyl. According to further features in some embodiments of the invention described herein, R6 is methyl.
According to further features in some embodiments of the invention described herein, each OfR1 and R2 is methyl. According to further features in some embodiments of the invention described herein, R3 is 1-pentyl, and A is 2-yl-4-methylcyclohex-3-enyl)acrylic acid.
According to further features in some embodiments of the invention described herein, A is 3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl.
According to further features in some embodiments of the invention described herein, R1 is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, 2- yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, JV-Boc-ethanamine-2-yl, JV-
Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl and acetonitrile-2-yl; and R2 is selected from the group consisting of 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, JV-Boc-ethanamine-2-yl, JV-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl and acetonitrile-2-yl.
According to further features in some embodiments of the invention described herein, R3 is selected from the group consisting of 1-pentyl and 1,1-dimethylheptyl-l- yi.
According to further features in some embodiments of the invention described herein, A is selected from the group consisting of an unsubstituted or substituted heteroalicyclic and an unsubstituted or substituted heteroaryl.
According to further features in some embodiments of the invention described herein, A is selected from the group consisting of an unsubstituted or substituted five- membered ring, an unsubstituted or substituted six-membered ring and an unsubstituted or substituted seven-membered ring.
According to further features in some embodiments of the invention described herein, the unsubstituted or substituted five-membered ring is selected from the group consisting of dihydropyrrole (pyrroline), tetrahydropyrrole (pyrrolidine), dihydrofuran, tetrahydrofurane, dihydrothiophene, tetrahydrothiophene furane, pyrrole, thiophene, oxazole, isoxazole, thiazole, thiazole, oxatriazole and oxatriazole.
According to further features in some embodiments of the invention described herein, the unsubstituted or substituted six-membered ring is selected from the group consisting of piperidine, pyridine, tetrahydropyran, pyran, thiane, thiine (thiapyrane), piperazine, diazine, oxazine, thiazine, triazine, dithiane and dioxane.
According to further features in some embodiments of the invention described herein, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, acetyl, 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, N-Boc-ethanamine-2-yl, N-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl, acetonitrile-2-yl, 4-formyl-butanoic acid, 4-formyl-but-2-enoic acid and propan-2-one-l-yl.
According to another aspect of the present invention there are provided compounds selected from the group consisting of:
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetate (HU-409);
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetic acid (HU-410); 3-(2-hydroxyethoxy)-2-((6R)-3-methyl-6-(prop-l -en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-411); tert-butyl 2-(3 -hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex~2-enyl)- 5 -pentylphenoxy)ethylcarbamate (HU-412) ; tert-butyl 2-(3 -hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-(2-methyloctan-2-yl)phenoxy)ethylcarbamate (HU-420);
3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-427);
2-(3 -methoxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 - pentylphenoxy)ethanamine (HU-428) ; tert-butyl 2-(3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)ethylcarbamate (HU-429);
2-(3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)- 5 -pentylphenoxy)ethanamine (HU-430) ;
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431);
2-((lR)-2-(2,6-dimethoxy-4-pentylphenyl)-4-methylcyclohex-3-enyl)acrylic acid (HU-434); 3 -methoxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 - pentylphenyl 3-morpholinopropanoate (HU-435);
3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-morpholinopropanoate maleate (HU-436); 2-(3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431A); and
2-(3 -(acetonitrile-2-oxy)-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)acetonitrile (HU-432); and any enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.
According to some embodiments of the invention, the compound(s) described herein exhibit anti-inflammatory activity.
According to another aspect of the present invention there is provided a pharmaceutical composition which includes, as an active ingredient, the compound(s) presented herein.
According to further features in some embodiments of the invention described herein, the pharmaceutical composition is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation. According to another aspect of the present invention there is provided a method of treating a medical condition, disease or disorder associated with inflammation, which is effected by administering to a subject in need thereof a therapeutically effective amount of the compound(s) presented herein.
According to another aspect of the present invention there is provided a use of the compound(s) presented herein in the preparation of a medicament.
According to further features in some embodiments of the invention described herein, the medicament is used in the treatment of a medical condition, disease or disorder associated with inflammation.
According to further features in some embodiments of the invention described herein, the medical condition, disease or disorder associated with inflammation is selected from the group consisting of 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 I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type 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 anemia, idiopathic thrombocytopenia, polychondritis, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory intestinal disease, celiac disease, Alzheimers's disease, prion associated disease and cancer metastases.
According to further features in some embodiments of the invention described herein, the medical condition, disease or disorder is selected from the group consisting of rheumatoid arthritis, atherosclerosis, Crohn's disease and multiple sclerosis.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The term "comprising" means that other steps and ingredients that do not affect the final result can be added. This term encompasses the terms "consisting of and "consisting essentially of.
The phrase "consisting essentially of means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method. As used herein, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof. Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
As used herein throughout the term "about" refers to + 10 %. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention, in some embodiments thereof, provides novel cannabidiol derivatives. The present invention further provides pharmaceutical compositions containing these cannabidiol derivatives and uses thereof in the treatment of inflammation.
Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. As discussed hereinabove, some cannabidiol derivatives have been described in U.S. Patent Nos. 4,282,248 and 6,410,588, U.S. Patent Application Nos. 20030166727 and 20070082954, WO 2005023741 and WO 2001095899. Although some of these known cannabidiols have been described as being active as anti- inflammatory agents [25, 21], these compounds have been produced at low yields in a multi-step synthesis, and had rather limited bioavailability and a poor pharmacokinetic profile in terms of stability and the capacity to be used in a prodrug form thereof.
The present embodiments provide some novel cannabinoid derivatives, which can be prepared at much improved yields, and show improved anti-inflammatory activity.
While reducing the present invention to practice, it was found that introduction of some substituents to one or both of the hydroxyl group positions present in cannabidiol, affords active compounds whose solubility and stability is considerably improved as compared to that of cannabidiol and other cannabidiol derivatives known in the art. Furthermore, the yield of their synthesis is considerably improved as compared to the known compounds. These novel cannabidiol derivatives therefore represent a significant improvement in terms of therapeutic value.
Thus, according to one aspect of the present invention, there is provided a compound having general Formula I:
Figure imgf000011_0001
wherein:
A is selected from the group consisting of an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heteroalicyclic, an unsubstituted or substituted aryl and an unsubstituted or substituted heteroaryl;
R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen, provided that at least one OfR1 and R2 is not hydrogen; R3 is selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy and an aryloxy; D1 is selected from the group consisting OfNR4, O and S; D2 is selected from the group consisting of NR5, O and S; and R4 and R5 are each independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
As can be discerned from the structure of the compound represented by Formula I, when D1 and D2 are identical, R1 and R2 are indistinguishable due to the symmetry of the central aryl ring. It is therefore sufficient to state the various options for each of R1 and R2 once for each in order to define a specific embodiment of a compound according to Formula I, or in other words, a specific description of R1=X while R2=Y is equivalent to a description OfR1=Y while R2=X.
The present embodiments further encompass any enantiomers, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of the compounds described herein.
As used herein, the term "enantiomer" refers to a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other. Enantiomers are said to have "handedness" since they refer to each other like the right and left hand. Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems.
The term "prodrug" refers to an agent, which is converted into the active compound (the active parent drug) in vivo. Prodrugs are typically useful for facilitating the administration of the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions. Prodrugs are also often used to achieve a sustained release of the active compound in vivo. An example, without limitation, of a prodrug would be a compound as described herein, having one or more carboxylic acid moieties, which is administered as an ester (the "prodrug"). Such a prodrug is hydrolyzed in vivo, to thereby provide the free compound (the parent drug). The selected ester may affect both the solubility characteristics and the hydrolysis rate of the prodrug. The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the compound of the present 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.
The term "hydrate" refers to a solvate, as defined hereinabove, where the solvent is water.
The phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound. An example, without limitation, of a pharmaceutically acceptable salt would be a carboxylate anion and a cation such as, but not limited to, ammonium, sodium, potassium and the like. For example, a compound in which D1 and D2 are both O, R1 is an alkyl substituted with a carboxyl group and R2 is hydrogen (see for example, HU-410, in the Examples section that follows) exhibits an improved bioavailability profile by being highly soluble in aqueous media in concentrations much higher than those of the previously known cannabidiol derivatives. Furthermore, such a cannabidiol derivative can be readily converted into an anion of many pharmaceutically acceptable salts having cations such as, for example, sodium, potassium, ethylenediamine, ethanolamine, calcium, deanol, magnesium, zinc, piperazine, diethanolamine, pyrrolidine, betaine, tromethamine, choline, lysine, morpholine, triethanolamine, arginine, N-methylglucamine and the likes. In another example, a compound in which one or both D1 and D2 is N
(nitrogen), namely a secondary or a tertiary amine, the parent compound can be ionized so as to be positively charged and hence be a cation of a salt.
In yet another example, a compound which contains an amine group either on one of R1 or R2, or on A, can be converted to a cation of a pharmaceutically acceptable acid addition salt.
As is well known in the art, the phrase "acid addition salt" describes a complex of two ionizable moieties, a base and an acid, which, when interacted in a particular stoichiometric proportion and under suitable conditions, form a salt that comprises 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 such a complex, in which the base moiety in amine, such that the salt comprises a cationic form of the amine (ammonium) and an anionic form of an acid. Depending on the stochiometric proportions between the base and the acid in the salt complex, as is detailed hereinbelow, the acid additions salts can be either mono addition salts or poly addition salts.
The phrase "mono addition salt", as used herein, refers to a salt complex in which the stochiometric ratio between the acid anion and amine cation is 1:1, such that the acid addition salt includes one molar equivalent of the acid per one molar equivalent of the conjugate.
The phrase "poly addition salt", as used herein, refers to a salt complex in which the stochiometric ratio between the acid anion and the amine cation is greater than 1:1 and is, for example, 2:1, 3:1, 4:1 and so on, such that the acid addition salt includes two or more molar equivalents of the acid per one molar equivalent of the conjugate.
The stoichiometric proportions between the base and the acid of the salt complex, according to some embodiments of the present invention, ranges from 6:1 to 1:6 base:acid equivalents, from 4:1 to 1:4 base:acid equivalents, from 3:1 to 1:3 base:acid equivalents or from 1:1 to 1:3 base:acid equivalents.
The acid addition salts of a chemical conjugate according to the present invention are therefore complexes formed between one or more amino groups of the compound and one or more equivalents of an acid. The acid addition salts may therefore include a variety of organic and inorganic acids, such as, but not limited to, halogen acids such as hydrochloric acid which affords an hydrochloric acid addition salt (as well as salts of bromide and iodide), acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzoic acid which affords a benzoic acid addition salt (benzoate), benzenesulfonic acid which affords a benzenesulfonic acid addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, naphthylsulfonic acid which affords a naphthylsulfonic acid addition salt, toluenelsulfonic acid (p-toluenesulfonic acid) which affords a toluenesulfonic acid addition salt (tosylate), trifluoroacetic acid which affords a trifluoroacetic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition salt (maleate), methanesulfonic acid which affords a methanesulfonic acid (mesylate or methanesulfonate) addition salt, naphthalenesulfonic acid which affords a napsylate addition salt, oxalic acid which affords an oxalic acid addition salt, phosphoric acid which affords a phosphoric acid addition salt, succinic acid which affords a succinic acid addition salt (succinate), sulfuric acid which affords a sulfuric acid addition salt and tartaric acid which affords a tartaric acid addition salt. Each of these acid addition salts can be either a mono acid addition slat or a poly acid addition salt, as these terms are defined hereinabove. In another example, cannabidiol derivative compounds, as presented herein, which contain one or more -OH (hydroxyl) or an -NH2 (amine) groups either on one OfR1 or R2, or on A, can be converted to into a prodrug by coupling to, for example, a succinic, fumaric, maleic acids and other suitable acids to form prodrugs, which can be enzymatically hydrolyzed in the body by, for example, esterases or amidases. All of the cannabidiol derivative compounds presented herein (namely ethers, esters, salts, prodrugs, etc.) are considerably more soluble in aqueous media as compared to the previously described derivatives.
As described hereinabove, A is a cyclic moiety which can be saturated, partly saturated or aromatic (cycloalkyl or aryl), can have one or more heteroatom as part of the ring (heteroalicyclic or heteroaryl), and can further be unsubstituted or substituted.
The term "cycloalkyl", as used herein, describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl may be unsubstituted or substituted by one or more substituents. When substituted, the substituent can be, for example, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a halogen (halo), a hydroxy, an alkoxy, an aryloxy, a thiohydroxy, a thioalkoxy, a thioaryloxy, a haloalkyl, an amine, a carbonyl, a carboxyl, an amide, a thioamide, a cyano and a carbamate, as well as combinations thereof, as these terms are defined herein. The term "heteroalicyclic" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl.
Representative examples of heteroalicyclics include, without limitation, piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.
The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl.
The term "heteroaryl" describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. The heteroaryl group may be unsubstituted or substituted by one or more substituents, as described hereinabove for cycloalkyl. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
A representative group of moieties which can embody A in Formula I include, according to some embodiments of the present invention and without limitation, 4-, 5- , 6- and 7-membered substituted or unsubstituted heteroalicyclics and heteroaryls such as [l,2]diazocan-3-one, [l,3]diazocan-2-one, [l,4]diazocane, [l,4]oxazepane, 1,2,3- triazine, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2-diazepine, 1,2-oxathiepane, 1,2-oxathiolane, 1,2-oxazine, 1,2-thiazine, 1,3, 5 -triazine, 1,3-diazepine, 1,3- dioxolane, 1,3-dioxolene, 1,3-oxazine, 1,3-thiazine, 1,3-thiazole, 1,4-diazapane, 1,4- diazepine, 1,4-oxazepane, 1,4-oxazine, 1,4-thiazine, 2-isoxazoline, 5,6,7,8-tetrahydro- lH-azocin-2-one, acridine, azaspirodecan, azepine, azetidine, aziridine, azirine, azocane, azocane-2-one, benzimidazole, benzofuran, benzothiazole, benzothiophene, benzoxazole, carbazole, cinnoline, cyclohexyl, diaziridine, diazirine, dioxane, dioxazine, dioxazole, dioxin, dioxolane, dioxole, dithiane, ditliiazine, dithiazole, dithiolane, furan, imidazole, imidazolidine, imidazoline, indazole, indole, indoline, indolizine, isoindole, isoquinoline, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolidine, isoxazoline, ketopiperazine, morpholine, napthyridine, oxadiazine, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxaziridine, oxazole, oxirane, oxocan-2-one, oxocane, phenazine, phenothiazine, phenoxazine, phenyl, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, quinazoline, quinoline, quinolizine, quinoxaline, tetrahydrofuran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, thianaphthalene, thiatriazole, thiazine, thiazole, thiazolidine, thiazoline, thienyl, thietan, thiomoφholine, thiophene, thiopyran, triazine, triazole and trithiane.
As presented in Formula I, each of R1 and R2 can independently be an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
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 yet other embodiments, 6 to 10 carbon atoms, and according to still other embodiments, 4 to 6 carbon atoms. Whenever a numerical range; e.g., "1-10", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkyl can be substituted or unsubstituted. When substituted, the substituent can be, for example, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a halogen (halo), a hydroxy, an oxo, an alkoxy, an aryloxy, a thiohydroxy, a thioalkoxy, a thioaryloxy, a haloalkyl, an amine, a carbonyl, a carboxyl, an amide, a thioamide, a cyano and a carbamate, as these terms are defined herein.
The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.
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 by one or more substituents, as described hereinabove for alkyl.
The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be unsubstituted or substituted by one or more substituents, as described hereinabove for alkyl. As used herein, the term "amine" describes a -NR'R" group where each of R' and R" is independently hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl or heteroaryl, as these terms are defined herein.
As used herein, the terms "halo", "halogen" and "halide", which are referred to herein interchangeably, describe an atom of a fluorine, chlorine, bromine or iodine, also referred to herein as fluoride, chloride, bromide and iodide.
The term "haloalkyl" describes an alkyl group as defined above, further substituted by one or more halide(s).
The term "hydroxy" or "hydroxyl", as used herein interchangeably, refers to an -OH group.
The term "alkoxy" describes a -OR' group, where R' is as defined herein.
The term "aryloxy", as used herein, refers to an —OR" group wherein R" is aryl.
The term "thiohydroxy", as used herein, refers to an -SH group. The term "thioalkoxy" describes a -SR' group, where R' is as defined herein.
The term "thioarylkoxy" describes a -SR" group, where R" is aryl.
The term "carbonyl", or "ketone", as used herein, refers to-(C=O)H or -(C=O)-R' group, wherein R' is as defined herein. An exemplary carbonyl is a formyl group, wherein R is hydrogen. Another exemplary carbonyl is an acetyl group, wherein R is methyl.
The term "oxo" refers to a (=0) group, namely an oxygen bound by a double bond, which in the case of a carbon substituent constitutes a carbonyl.
The terms "carboxy", "carboxyl" or "carboxylate", as used herein, refer interchangeably to a -C(=O)-O-R', where R' can be absent (as in the case of a carboxylate anion), or selected from the group consisting of hydrogen (for example, carboxylic acid), alkyl (for example, ester), cycloalkyl, heteroalicyclic, aryl or heteroaryl, as these terms are defined herein.
The term "amide" describes a -C(=0)-NR'R", where R' is as defined herein and R" is as defined for R'. The term "thioamide" describes a -C(=S)-NR'R", where R' is as defined herein and R" is as defined for R'.
The term "thioimide" describes a -C(=NR')-SR", where R' and R" are as defined herein. The term "cyano", as used herein, refers to a -C≡N group. For example an acetonitrile substituent group is a cyano group attached to a molecule via a -CH2- group, constituting a -CH2-C≡N group.
The term "carbamate" describes an -OC(=O)-NR'R", with R' and R" as defined herein.
A particular exemplary carbamate is afforded when an amine is protected with a Boc protecting group, affording a tert-butyl carbamate.
Another exemplary carbamate is afforded when an amine is protected with an Fmoc protecting group, affording a (9H-fluoren-9-yl)methyl carbamate. It is therefore noted that unless stated otherwise, R1 and/or R2 can each be unsubstituted or substituted with a number of groups as presented hereinabove, as well as combinations thereof, and the same definition applies to any variable which is defined as unsubstituted or substituted, regardless of the definition for each of the particular chemical groups. As presented in Formula I, R3 can be an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy or an aryloxy. In CBD and in compounds according to some embodiments of the present invention, the group which is equivalent to the R3 variable in Formula I is optionally 1-pentyl. In other exemplary cannabinoids and in compounds according to some embodiments of the present invention, this group can be, for example, 1 ,2-dimethylheptyl, 1,1- dimethylheptyl and the likes.
Alternatively, R3 can be a straight (linear) or branched alkyl of 5 to 12 carbon atoms; a group -O-alkyl, where the alkyl is straight (linear) or branched having 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; a group -(CH2)n-O-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms.
According to some embodiments of the present invention, the novel compounds presented herein are derivatives of cannabidiol (CBD). In some of these embodiments, A can be a substituted six-membered cycloalkyl. Similarly, in some embodiments, one or both OfD1 and D2 are O (oxygen).
According to other embodiments, A is a moiety having general Formula II:
Figure imgf000020_0001
Formula II wherein:
R6 and R7 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, hydroxyl, alkoxy, carboxyl, carbonyl, formyl, acetyl and amine, as there terms are defined hereinabove.
Each of the dashed lines in Formula II represents a single or double bond, and each of the wavy lines represents a bond having an R or an S stereo-configuration.
It is noted herein that each of R6 and R7, independently, can be attached to main part of the moiety having general Formula II via a single bond or a double bond, depending on the nature thereof and the valency of the atom these groups are attached to.
It is further noted that the feasibility of each of the variables in Formula II, namely A, D1, D2 and R1-R7, the bonds variables located at the indicated positions as well as their optional substituents, depends on the valency and chemical compatibility of the participating variable, bond or substituent, the substituted position and other neighboring substituents. Hence, compounds represented by general formulae according to some embodiments of the present invention, are aimed at encompassing only the chemically feasible molecules, having only the chemically feasible substituents for any given position.
According to some embodiments of the present invention, when each of D1 and D2 is O, and A is a moiety having general Formula II, the compounds according to some embodiments of the present invention share many structural features of the naturally occurring CBD molecule. In order to improve the pharmaceutical profile and yet maintain a viable and scaleable synthesis, these compounds were designed and selected such that their preparation and their bioavailability are improved by virtue of the particular substituents at any of variables Ri-R7, and in addition when the resulting compound can be ionized at physiological pH, namely an acid or a base that can be turned into a salt thereof. Thus, for example, R7 can be a carboxyl group, allowing the compound to be turned into a carboxylate anion at certain pH levels. Such a compound is described in the Example section that follows, wherein D1 and D2 are each O, R1 is an 7V-Boc- ethanamine-2-yl, R2 is hydrogen, R3 is 1-pentyl and A is 2-(2-yl-4-methylcyclohex-3- enyl)acrylic acid (2-((lR)-2-(2,6-dimethoxy-4-pentylphenyl)-4-methylcyclohex-3- enyl)acrylic acid, also denoted HU-434).
In some embodiments of the present invention, R1 is a substituted linear short alkyl, having, for example, 1 to 5 carbon atoms. The alkyl is substituted by, for example, one or more of oxo, hydroxy, carboxy, amine and nitrile. Alternatively, D1 and D2 are each O, and A is 3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl, as in CBD, while R1 is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc-ethanamme-2-yl, iV-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl and acetonitrile-2-yl; and R2 is selected from the group consisting of 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc- ethanamine-2-yl, iV-Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl and acetonitrile- 2-yl.
Further, when the variable R3 is 1-pentyl, and according to an aspect of the present invention, these CBD derivative compounds are part of a group of compounds which include, for example:
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetate (HU-409);
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetic acid (HU-410); 3-(2-hydroxyethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-411); tert-butyl 2-(3 -hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5 -pentylphenoxy)ethylcarbamate (HU-412) ; tert-butyl 2-(3 -hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-(2-methyloctan-2-yl)phenoxy)ethylcarbamate (HU-420);
3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-427); 2-(3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)ethanamine (HU-428); tert-butyl 2-(3-memoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)ethylcarbamate (HU-429); 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431) ;
2-((lR)-2-(2,6-dimethoxy-4-pentylphenyl)-4-methylcyclohex-3-enyl)acrylic acid (HU-434);
3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-morpholinopropanoate (HU-435);
3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-morpholinopropanoate maleate (HU-436);
2-(3 -(2-aminoethoxy)-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-pentylphenoxy)ethanamine (HU-430); 2-(3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431A); and
2-(3 -(acetonitrile-2-oxy)-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)acetonitrile (HU-432); all of which are presented in the Examples section that follows. According to other embodiments of the present invention, compounds of other combinations of ring A, D1-D2 and substituents R1-R3 are encompassed herein. For example, variable ring A in Formula I can be any five-, six- or seven-membered substituted or unsubstituted, aromatic, partly saturated or saturated ring.
Exemplary unsubstituted or substituted five-membered ring moieties which can be represented by A in Formula I include, without limitation, dihydropyrrole
(pyrroline), tetrahydropyrrole (pyrrolidine), dihydrofuran, tetrahydrofurane, dihydrothiophene, tetrahydrothiophene furane, pyrrole, thiophene, oxazole, isoxazole, thiazole, thiazole, oxatriazole and oxatriazole.
Exemplary unsubstituted or substituted six-membered ring moieties which can be represented by A in Formula I include, without limitation, piperidine, pyridine, tetrahydropyran, pyran, thiane, thiine (thiapyrane), piperazine, diazine, triazine, oxazine, thiazine, dithiane and dioxane. Exemplary unsubstituted or substituted seven-membered ring moieties which can be represented by A in Formula I include, without limitation, oxepine, azepine, thiepine, oxazepine, diazepine, triazepine, thiaazepine and thiadiazepine.
In any of the above compounds, wherein variable ring A in Formula I is any five-, six- or seven-membered substituted or unsubstituted, aromatic, partly saturated or saturated ring, each of R1-R2 can be independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, including, but not limited to, hydrogen (for only one of R1 and R2), methyl, ethyl, propyl, butyl, acetyl, 2-yl- acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, N-Boc-ethanamine-2-yl, N- Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl, acetonitrile-2-yl, 4-formyl-butanoic acid, 4-formyl-but-2-enoic acid and propan-2-one-l-yl.
As many of the presently known and widely studied cannabidiols are plant derived, a large family thereof contains a pinene moiety, which is one of the more ubiquitous natural transformation of l-methyl-4-(prop-l-en-2-yl)cyclohex-l-ene moiety, as found in some of the compounds according to some embodiments of the present invention, particularly those wherein A is having general Formula II. Briefly, the chemical compound pinene is a bicyclic terpene, also known as a monoterpene, which is found both in the α-pinene configuration and the β-pinene configuration (systematic names are (lS,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene and (1S,5S)- 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane, respectively), which can be metabolized or synthetically produced from, for example, a l-methyl-4-(isopropen-2- yl)cyclohexene carbocation intermediate, as illustrated in Scheme 1 below.
Scheme 1
Figure imgf000023_0001
β-pinene Some compounds wherein A is a substituted or unsubstituted α-pinene moiety, and wherein D1 and D2 are each oxygen, have been described previously in, for example, U.S. Patent No. 4,282,248, and are therefore excluded from the scope of the present invention. However, compounds wherein at least one of D1 and D2 is not oxygen, or wherein A is a substituted or unsubstituted β-pinene, or wherein at least one of R1 and R2 is a substituted or unsubstituted alkyl having more than 5 carbon atoms have not been described previously and are therefore encompassed by some of the present embodiments. As described and demonstrated in the Examples section that follows, the compounds according to embodiments of the present invention have been tested for their anti-inflammatory activity, and were indeed found to be highly potent candidates for anti-inflammatory agents and drugs.
Thus, according to another aspect of the present invention, there is provided a method of treating a medical condition, a disease or a disorder associated with inflammation, which is effected by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds as presented herein, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove. According to some embodiments of the present invention, there is provided a method of treating a medical condition, a disease or a disorder associated with inflammation, which is effected by administering to a subject in need thereof a therapeutically effective amount of one or more of any one of the compounds presented in Table 1 which is presented in the Examples section that follows hereinbelow, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove.
As used herein, the terms "treating" and "treatment" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
Accordingly, another aspect of the present invention provides a use of one or more of the compounds as presented herein, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove, in the preparation of a medicament.
According to some embodiments of the present invention the medicament is for the treatment of a medical condition, a disease or a disorder associated with inflammation.
According to some embodiments of the present invention, there is provided a use of one or more of any one of the compounds presented in Table 1 which is presented in the Examples section that follows hereinbelow, as well as any enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove, in the preparation of a medicament for the treatment of a medical condition, a disease or a disorder associated with inflammation.
Inflammation is a protective response of the body to an injury. As used herein, the term "inflammation" includes without limitation, medical conditions, diseases and disorders which are associated with inflammation. Thus, representative examples of diseases or disorders associated with inflammation, and are therefore treatable by using one or more of the compounds described in the present invention include, without limitation, 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 transplantation-related diseases or disorders, inflammatory degenerative diseases or disorders, diseases or disorders associated with a hypersensitivity, 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 cutaneous diseases or disorders, inflammatory hepatic diseases or disorders, inflammatory neurological diseases or disorders, inflammatory musculo-skeletal 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 and disorders, such as cancer, and inflammatory pulmonary diseases or disorders, as is detailed hereinbelow. Non-limiting examples of hypersensitivities 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 type hypersensitivity, helper T lymphocyte mediated hypersensitivity, cytotoxic T lymphocyte mediated hypersensitivity, THl lymphocyte mediated hypersensitivity, and TH2 lymphocyte mediated hypersensitivity.
Non-limiting examples of inflammatory cardiovascular disease or disorder include occlusive diseases or disorders, atherosclerosis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, myocardial infarction, coronary arterial disease, acute coronary syndromes, 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 vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune 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.
Stenosis is an occlusive disease of the vasculature, commonly caused by atheromatous plaque and enhanced platelet activity, most critically affecting the coronary vasculature.
Restenosis is the progressive re-occlusion often following reduction of occlusions in stenotic vasculature. In cases where patency of the vasculature requires the mechanical support of a stent, in-stent-stenosis may occur, re-occluding the treated vessel.
Non-limiting examples of cerebrovascular diseases or disorders include stroke, cerebrovascular inflammation, cerebral hemorrhage and vertebral arterial insufficiency.
Non-limiting examples of peripheral vascular diseases or disorders include gangrene, diabetic vasculopathy, ischemic bowel disease, thrombosis, diabetic retinopathy and diabetic nephropathy.
Non-limiting examples of autoimmune diseases or disorders include all of the diseases caused by an immune response such as an autoantibody or cell-mediated immunity to an autoantigen and the like. Representative examples are chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, Bechet'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, vasculitides and heparin induced thrombocytopenia.
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 myxedema, ovarian autoimmunity, autoimmune anti-sperm infertility, autoimmune prostatitis and Type I autoimmune polyglandular syndrome. Non-limiting examples of inflammatory gastrointestinal diseases or disorders include colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, inflammatory bowel syndrome, chronic inflammatory bowel disease, celiac disease, ulcerative colitis, an ulcer, a skin ulcer, a bed sore, a gastric ulcer, a peptic ulcer, a buccal ulcer, a nasopharyngeal ulcer, an esophageal ulcer, a duodenal ulcer and a gastrointestinal ulcer.
Non-limiting examples of inflammatory cutaneous diseases or disorders include acne, and an autoimmune bullous skin disease.
Non-limiting examples of inflammatory hepatic diseases or disorders include autoimmune hepatitis, hepatic cirrhosis, and biliary cirrhosis. Non-limiting examples of inflammatory neurological diseases or disorders include multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydeham chorea, Gilles de Ia Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis, stroke, an inflammatory retinal disease or disorder, an inflammatory ocular disease or disorder, optic neuritis, spongiform encephalopathy, migraine, headache, cluster headache, and stiff-man syndrome.
Non-limiting examples of inflammatory connective tissue diseases or disorders include autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune disease or disorder, myositis, tendinitis, a ligament inflammation, chondritis, a joint inflammation, a synovial inflammation, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, a skeletal inflammation, an autoimmune ear disease or disorder, and an autoimmune disease or disorder of the inner ear.
Non-limiting examples of inflammatory renal diseases or disorders include autoimmune interstitial nephritis and/or renal cancer.
Non-limiting examples of inflammatory reproductive diseases or disorders include repeated fetal loss, ovarian cyst, or a menstruation associated disease or disorder.
Non-limiting examples of inflammatory systemic diseases or disorders include systemic lupus erythematosus, systemic sclerosis, septic shock, toxic shock syndrome, and cachexia.
Non-limiting examples of infectious disease or disorder include chronic infectious diseases or disorders, a subacute infectious disease or disorder, an acute infectious disease or disorder, a viral disease or disorder, a bacterial disease or disorder, a protozoan disease or disorder, a parasitic disease or disorder, a fungal disease or disorder, a mycoplasma disease or disorder, gangrene, sepsis, a prion disease or disorder, influenza, tuberculosis, malaria, acquired immunodeficiency syndrome, and severe acute respiratory syndrome.
Non-limiting examples of inflammatory transplantation-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 a prosthetic implant, a breast implant, a silicone implant, a dental implant, a penile implant, a cardiac implant, an artificial joint, a bone fracture repair device, a bone replacement implant, a drag delivery implant, a catheter, a pacemaker, an artificial heart, an artificial heart valve, a drag release implant, an electrode, and a respirator tube. Non-limiting examples of inflammatory tumors include a malignant rumor, a benign tumor, a solid tumor, a metastatic tumor and a non-solid tumor.
Non-limiting examples of inflammatory pulmonary diseases or disorders include asthma, allergic asthma, emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis and bronchitis.
Exemplary medical conditions, diseases and disorders which are associated with inflammation, according to some embodiments of the present invention 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 I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type 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 anemia, idiopathic thrombocytopenia, polychondritis, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory intestinal disease, celiac disease, Alzheimers's disease, prion associated disease and cancer metastases.
According to some embodiments of the present invention, the inflammatory disorders include rheumatoid arthritis, atherosclerosis, Crohn's disease, multiple sclerosis, Alzheimers's disease, prion associated disease and cancer metastases. As used herein, the phrase "therapeutically effective amount" describes an amount of the compound being administered which will relieve to some extent one or more of the symptoms of the condition being treated.
As demonstrated in the examples section that follows, an exemplary therapeutically effective amount of the compounds of the present invention ranges between about 0.1 mg/kg body and about 100 mg/kg body.
In any of the methods and uses described herein, the cannabidiol derivative compounds of the present embodiments can be utilized either per se or, according to some embodiments, as a part of a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.
Thus, according to additional aspects of the present invention, there is provided a pharmaceutical composition, which comprises one or more compounds having general Formula I, as defined hereinabove, and a pharmaceutically acceptable carrier.
According to some embodiments of the present invention, there is provided a pharmaceutical composition, which comprises one or more of any one of the compounds presented in Table 1 which is presented in the Examples section that follows hereinbelow, and a pharmaceutically acceptable carrier, as well as any enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, as defined hereinabove.
As used herein a "pharmaceutical composition" refers to a preparation of the compounds presented herein, with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
Hereinafter, the term "pharmaceutically acceptable carrier" refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Examples, without limitations, of carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.
Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences" Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).
The pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically
(including ophtalmically, vaginally, rectally, intranasally).
Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.
Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
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.
Formulations for parenteral administration may include, but are not limited to, sterile solutions which may also contain buffers, diluents and other suitable additives.
Slow release compositions are envisaged for treatment. The amount of a composition to be 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.
Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the 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, comprise metal or plastic foil, such as, but not limited to 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 be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
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 treatment of a medical condition, disease or disorder associated with inflammation, as is detailed hereinabove.
Thus, according to an embodiment of the present invention, the pharmaceutical composition of the present invention is being packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation, as is defined hereinabove.
According to further embodiments of the any of the methods, uses and compositions presented herein, the compounds of the present invention can be combined with other active ingredients which are commonly used to treat inflammation-associated diseases and disorders.
Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily 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 delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. EXAMPLES
Reference is now made to the following examples, which together with the above descriptions; illustrate the invention in a non limiting fashion.
EXAMPLE l
CHEMICAL SYNTHESES Materials and methods:
All chemical reagents were purchased from Sigma-Aldrich.
Organic solvents were purchased from Bio-Lab. Cannabinoids (such as cannabidiol) were extracted from Cannabis sativa plant as previously described [Gaoni, Y. and Mechoulam, R. (1971) J. Amer. Chem. Soc. 93, 217-224].
Preparation of ethyl 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl)-5-pentylphenoxy)acetate (HU-409):
Figure imgf000033_0001
HU-409
Ethyl 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l -en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetate (HU-409) was prepared from plant-derived cannabidiol as illustrated in Scheme 2 below.
Cannabidiol (1 mmol) was dissolved in dry acetone, and potassium carbonate anhydrous (1 mmol) and a catalytic amount of sodium iodide were added thereto. The solution was stirred in inert atmosphere for 10 minutes, and thereafter ethylbromoacetate (1 mmol) was added thereto. The reaction mixture was refluxed overnight, cooled, filtered, concentrated and purified by column chromatography to afford ethyl 2-(3 -hydroxy-2-((6R)-3-methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 - pentylphenoxy)acetate (HU-409) at 43 % yield.
Preparation of 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)acetic acid (HU-410):
Figure imgf000034_0001
HU-410
2-(3 -Hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetic acid (HU-410) was prepared from ethyl 2-(3-hydroxy-2-((6R)- 3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 -pentylphenoxy)acetate (HU-409) as illustrated in Scheme 2 below.
Scheme 2
Figure imgf000034_0002
2 % KOH in methanol, reflux
30 minutes
Figure imgf000034_0003
HU-409 was dissolved in an aqueous solution of KOH (5 %) in methanol, and refluxed for 30 minutes under inert atmosphere. Thereafter the solution was converted under reduced pressure to afford 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l- en-2-yl)cyclohex-2-enyl)-5-pentylphenoxy)acetic acid (HU-410) at 100 % yield.
Preparation of 3-(2-hydroxyethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl)-5-pentylphenol (HU-411):
Figure imgf000035_0001
HU-411
3-(2-Hydroxyethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-411) was prepared according to procedures presented herein.
General Procedure for Boc removal:
The general procedure for the removal of a Boc protecting group from a substituent on a cannabidiol derivative, according to some embodiments of the present invention, is demonstrated in Scheme 3 in the example of deprotection of HU-429 to HU-428, as described hereinbelow.
Scheme 3
Figure imgf000035_0002
HU-429 HU-428 A solution of HCl/dioxane (1.45 ml, 4 M) in a 5 ml round-bottom flask equipped with a magnetic stir-bar was cooled by an ice bath under nitrogen. HU-429 (0.07 mmol) was added in one portion with stirring. The ice-bath was removed and the mixture was kept stirred. After 30 minutes, TLC indicted that the reaction was completed. Thereafter the reaction mixture was concentrated under reduced pressure and the residue was purified on column chromatography using 2 % methanol in chloroform as eluent to afford the free amine, HU-428.
Preparation of tert-butyl 2-(3-hydroxy-2-((6R)-3-methyI-6-(prop-l-en-2- yl)cyclohex-2-enyl)-5-pentylphenoxy)ethylcarbamate (HU-412):
2-(3-hydroxy-2-((6R)-3-methyl-6-(ρroρ-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)ethylcarbamate (HU-412) was prepared from plant-derived cannabidiol as illustrated in Scheme 4 below.
Scheme 4
CBD (1 equivalent, 0.1 mmol) was dissolved in dry acetone (3 ml) and K2CO3 (4 equivalents, 0.4 mmol) was added thereto under dry nitrogen. The mixture was refluxed for 30 minutes and the solution became violet. Thereafter a solution of protected bromo-amine (1 equivalent, 0.1 mmol) in dry acetone was added in one portion followed by addition of the TSTaI (3 equivalents, 0.3 mmol) dissolved in dry acetone, and the reaction was refluxed for 4 days under nitrogen.
After 4 days the solution was cooled to room temperature and the acetone was evaporated under reduced pressure. The residue was dissolved in water then extracted with diethyl ether (3 time 10 ml), the combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was evaporated to afford a crude oil which was purified on column chromatography with 3 % ethyl acetate in petroleum ether to afford HU-412 at a 50 % yield as an pure oily product. Preparation of 3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl)-5-pentylphenol (HU-427):
Figure imgf000037_0001
HU-427
3-(2-Aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-427) was prepared by the reduction of HU-431 (see below) to the corresponding dimethylene amine as follows.
Cannabidiol-cyanomethyl ether (HU-431, 1 mmol) was mixed with an excess of LiAlH4 in dry ether and refluxed for 3 hours. Thereafter the workup with saturated MgSO4 the solution was concentrated and purified with 100 % ethyl acetate to afford HU-427 at a yield of 89 %.
Preparation of 2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy) acetonitrile (HU-431) :
Figure imgf000037_0002
HU-431
Cannabidiol (1 mmol) was dissolved in dry acetone (10 ml) under a nitrogen atmosphere. K2CO3 (2 mmol) and iodoacetonitrlie (1 mmol) were added and the reaction mixture was allowed to refluxed overnight. The reaction mixture was filtered, concentrated and purified on a silica gel column with 5 % ethylacetate in petroleum ether to afford HU-431 at a yield of 30 %.
Preparation of 3-(2~aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl)-5-pentylphenol (HU-427):
Reduction of the cannabidiol-cyanomethyl ether (HU-431) to the cannabidiol dimethylene amine (HU-427) was carried out as illustrated in Scheme 5 below.
Scheme 5
Figure imgf000038_0001
HU-431 HU-427
HU-431 (1 mmol) was mixed with an excess of LiAlH4 in dry ether and refluxed for 3 hours. Thereafter the resulting product was washed with saturated MgSO4 and the solution was concentrated and purified with 100 % ethyl acetate to afford HU-427 at a yield of 89 %.
Preparation of 2-((lR)-2-(2,6-dimethoxy-4~pentylphenyl)-4-methylcyclohex- 3-enyl)acrylic acid (HXJ -434): 2-((lR)-2-(2,6-dimethoxy-4-pentylphenyl)-4-methylcyclohex-3-enyl)acrylic acid (HU-434) was prepared as illustrated in Scheme 6 below, starting from the plant- derived cannabidiol (CBD). Scheme 6
Figure imgf000039_0001
Cannabidiol (I5 1.12 grams, 3.5 mmol) was dissolved in pyridine (4 ml). Acetic anhydride (2 ml) was added thereto and the reaction mixture was stirred at room temperature for 1.5 hours. Thereafter the reaction was monitored by TLC (1:10; ether: petroleum ether) until the starting material was fully consumes. Then the solution was extracted with ether (150 ml). The organic phase was washed with HCl (1 M) several times, then with saturated NaHCO3 and brine and dried on MgSO4. The solvent was removed under vacuum to give 1.26 grams cannabidiol diacetate compound I at a yield of 93 %.
A solution of cannabidiol diacetate (II, 1 grams, 2.5 mmol) in CH2Cl2 (6 ml) was added to a suspension of SeO2 (55 mg, 0.5 mmol) and tBuOOH (70 %, 0.68 ml, 5 mmol) in CH2Cl2 (6 ml). The mixture was stirred at room temperature over night (TLC eluent 3:10; etheπpetroleumether). The solution was extracted with ether (150 ml), the organic phase was washed with 10 % KOH, saturated NaS2O5, saturated NaHCO3 and brine. It was then dried on MgSO4 and the solvent was removed under vacuum to afford an oil which was purified on a column of silica gel to afford 305 mg of compound III at a yield of 30 %. Dry pyridine (0.44 ml) was added to a solution of 4:1 CH2C12:DMF (5.5 ml) followed by the addition of CrO3 (280 mg). The resulting mixture was stirred at room temperature for 15 minutes. Thereafter a solution of compound III (300 mg) in 4:1 CH2C12:DMF (1.4 ml) was added, and the reaction mixture was stirred at room temperature overnight. Ethanol (0.5 ml) was added and the mixture was stirred for 10 minutes, the reaction mixture was filtered through a column with silica gel with a layer of anhydrous Na2SO4 on top. Elution with ethyl acetate (140 ml) gave a solution which was dried on MgSO4. The solvent was removed under vacuum to afford an oil which was purified on column of silica gel, to afford 240 mg of cannabidiol diacetate-10-al compound IV at a yield of 80 %.
To a mixture of cannabidiol diacetate-10-al (IV, 200 mg, 0.48 mmol), 2- methyl-2-butene (1.07 ml), saturated KH2PO4 (0.64 ml), and t-butanol (10.5 ml), NaClO2 (234 mg) was gradually added, while stirring. The reaction mixture was stirred over night, and then water (30 ml) was added and the mixture was extracted several times with ethyl acetate, dried over MgSO4 and evaporated to give 205 mg of cannabidiol diacetate-10-oic acid, compound V, at a yield of 100 %.
Cannabidiol diacetate-10-oic acid (V, 200 mg, 0.46 mmol) was dissolved in methanol (8 ml). A solution Of Na2CO3 (138 mg) in water (3 ml) was added, under N2, and the mixture was stirred at room temperature for 2 hours, and thereafter evaporated under reduced pressure to remove the methanol, and then diluted with water. The resulting solution was slowly acidified with HCl IM while cooling in an ice bath to afford a weakly acidic solution. The mixture was extracted with ether, dried over MgSO4 and evaporated to afford 152 mg of cannabidiol-10-oic acid, compound VI, at yield of 96 %.
Cannabidiol-10-oic acid (VI, 150 mg, 0.43 mmol) was dissolved in DMF (2.5 ml). Thereafter K2CO3 (482 mg) and CH3I (0.5 ml) were added and the reaction mixture was stirred at room temperature over night. Thereafter water (20 ml) was added and the solution was extracted with ether. The organic phase was washed with brine until it was neutralized, dried over MgSO4 and evaporated to afford an oil which was separated on column of silica gel, to afford 116 mg of dimethoxy cannabidiol- 10- oic acid methyl ester, compound VII, at a yield of 70 %.
Dimethoxy cannabidiol-10-oic acid, methyl ester (VII, 100 mg, 0.25 mmol) was dissolved in ethanol (2 ml). A solution of NaOH (60 mg) in water (0.5 ml) was added, under N2, and the mixture was stirred at room temperature for 72 hours. Thereafter the reaction mixture was then evaporated under reduced pressure to remove the ethanol, and then diluted with water. The resulting solution was slowly acidified with HCl IM while cooling in an ice bath to afford a weakly acidic solution, which was extracted with ether, dried over MgSO4 and evaporated to afford an oil which was separated on column of silica gel to afford 60 mg of 2-(2-(2,6-Dimethoxy- 4-pentylphenyl)-4-methylcyclohex-3-enyl)acrylic acid (HU-434) at a yield of 61 %.
Preparation of 3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenyl 3-morpholinopropanoate (HU-435):
Figure imgf000041_0001
HU-435
3-Methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-morpholinopropanoate (HU-435) was prepared from plant-derived cannabidiol which was converted to mono-methoxy CBD, as described in [25, 21] Dicyclohexylcarbodiimide (DCC, 32 mmol) was added to 4-morpholino propionic acid (3.2 mmol), mono-methoxy CBD (1.6 mmol) and pyrrolidino pyridine (0.32 mmol) in dry CH2Cl2 (20 ml). The reaction mixture was stirred at room temperature overnight (formation of dicyclohexylurea, DCU, was seen within 10 minutes). The DCU was filtered and the solution was concentrated and purified on silica gel column (15 grams) using 50 % ether in petroleum ether as eluent. HU-435 was afforded at a 16 % yield.
Preparation of 3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenyl 3-morpholinopropanoate maleate (HU-436):
Figure imgf000042_0001
HU-436
The preparation of a maleate salt of HU-435 (HU-436) was effected by the stirring a solution of maleic acid (0.247 mmol) and HU-435 (0.247 mmol) in 2- propanol at room temperature for 2.5 hours. Thereafter the solvent was evaporated under reduced pressure and the oil obtained was crystallized from ethyl acetate and ether to afford the salt HU-436 (melting point 110-112 0C) at a yield of 80 %.
The above presented as well as other exemplary cannabinoid derivative compounds which were prepared according to the procedures presented hereinabove, according to embodiments of the present invention, are presented in Table 1 hereinbelow.
Table 1
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
EXAMPLE 2 BIOLOGICAL ACTIVITY Preparation of murine macrophages for Anti-inflammatory activity measurement assays:
The anti-inflammatory activity of exemplary cannabidiol derivatives, according to some embodiments of the present invention, was tested using murine macrophages. Peritoneal exudate macrophages from 8- week-old to 9-week-old C57BL/6 female mice were harvested 4 days after injection of 1.5 ml of 3 % thioglycolate medium. Peritoneal macrophages were cultured in 96-microwell flat bottomed plates. Two hours later, the cells were rinsed to remove unattached cells, and thereafter activation with LPS (1 μg/ml). The exemplary cannabinoid derivatives were diluted to various concentrations with DMEM and added to the cell preparations. After 24 hours incubation, the supernatants were collected and stored at -20 0C until assayed for TNF-α and NO. Determination of plasma TNF-a levels in endotoxemic mice; The cannabidiol derivatives were dissolved in one part DMSO, one part TWEEN 80, and four 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 an intraperitoneal injection of 1 mg/kg LPS. After an additional 90 minutes, the mice were decapitated, and trunk blood was collected for determination of TNF-α levels. Reactive oxygen intermediate (ROI) assay:
RAW 264.7 cells, suspended in HBSS without phenol red, were distributed in plastic luminometer tubes. The cannabidiol derivatives were added to the samples followed by addition of 10 μl of luminol and 30 μl of zymosan. The chemiluminescence peak was then recorded by a luminometer.
Nitric oxide (NO) Determination assay:
Nitric oxide levels were determined by measuring the accumulated nitrite in the supernatants of cannabidiol derivative-treated peritoneal macrophages, prepared as described hereinabove.
TNF-a determination assay:
TNF-α (pg/ml) in cell culture supematants or in mouse blood plasma was determined by the "sandwich" ELISA technique. ELISA reagents were used according to the manufacturer's protocol (R & D Systems).
RESULTS
The results of the biological activity assays are presented in Table 2 hereinbelow.
Table 2
Figure imgf000047_0001
As can be seen in Table 2, the exemplary compounds according to embodiments of the present invention, HU-409 and HU-410, both exhibited notable anti-inflammatory activity.
It is appreciated 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. Although the 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. AU publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein 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.
References cited by numerals
(Other references are cited in the text)
1. Cardillo, B., et al, Gazzetta Chimica Italiana 1973. 103(1-2): p. 127-39.
2. Carlini, E.A., et al, Res Commun Chem Pathol Pharmacol, 1975. 12(1): p. 1-15.
3. Weiner, B.Z., etal, European Journal of Medicinal Chemistry, 1975. 10(1): p. 79-83.
4. Knaus, E.E., et al, Journal of Chromatographic Science 1976. 14(11): p. 525-30.
5. Hendriks, H., et al, Pharmaceutisch Weekblad, 1978. 113(17): p. 413-24.
6. Consroe, P., etal, J Clin Pharmacol, 1981. 21(8-9 Suppl): p. 428S-436S.
7. Jorapur, V.S., et al, Chemistry Letters 1982. 3: p. 299-302.
8. Jorapur, V.S., et al, J Med Chem, 1985. 28(6): p. 783-7.
9. Martin, B.R., et al, NIDA Res. Monogr., 1987. 79: p. 108-22.
10. Mechoulam, R., et al, NIDA Res Monogr, 1987. 79: p. 15-30.
11. Yamamoto, L, et al, Journal of Pharmacobio-Dynamics 1989. 12(8): p. 488-94.
12. Compton, D.R., et al, Journal of Medicinal Chemistry 1990. 33(5): p. 1437-43.
13. Baek, S.H., et al, Bulletin of the Korean Chemical Society, 1992. 13(2): p. 117-18.
14. Baek, S.H., et al, Archives of Pharmacal Research, 1992. 15(1): p. 5-8.
15. Inoue, S., et al, Nippon Kagaku Kaishi, 1992. 1: p. 45-52.
16. Baek, S.H., Bulletin of the Korean Chemical Society, 1993. 14(1): p. 144-6.
17. Baek, S.H., et al, Bulletin of the Korean Chemical Society, 1993. 14(2): p. 272-4.
18. Tius, M.A., et al, Tetrahedron, 1993. 49(16): p. 3291-304.
19. Baek, S.H., et al, Bulletin of the Korean Chemical Society, 1994. 15(6): p. 507-8.
20. Wiley, J.L., et al , J Pharmacol Exp Ther, 2002. 301(2): p. 679-89.
21. Sumariwalla, P.F., et al, Arthritis Rheum, 2004. 50(3): p. 985-98.
22. Hanus, L.O., et al. , Org Biomol Chem, 2005. 3(6): p. 1116-23.
23. Mechoulam, R., et al, Phytochemistry Reviews 2005. 4(1): p. 11-18.
24. Padgett, L.W., Life Sci, 2005. 77(14): p. 1767-98.
25. Tchilibon, S., et al, Org Lett, 2000. 2(21): p. 3301-3.

Claims

WHAT IS CLAIMED IS:
1. A compound having general Formula I:
Figure imgf000050_0001
an enantiomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof; wherein:
A is selected from the group consisting of an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heteroalicyclic, an unsubstituted or substituted aryl and an unsubstituted or substituted heteroaryl;
R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen, provided that at least one OfR1 and R2 is not hydrogen;
R3 is selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms, an alkoxy and an aryloxy;
D1 is selected from the group consisting OfNR4, O and S;
D2 is selected from the group consisting of NR5, O and S;
R4 and R5 are each independently an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms.
2. The compound of claim 1, having an anti-inflammatory activity.
3. The compound of claim 1, wherein each OfD1 and D2 is O.
4. The compound of claim 3, wherein A is an unsubstituted or substituted cycloalkyl.
5. The compound of claim 4, wherein said cycloalkyl is selected from the group consisting of a monocyclic unsubstituted or substituted cycloalkyl and a bicyclic unsubstituted or substituted cycloalkyl.
6. The compound of claim 5, wherein said bicyclic unsubstituted or substituted cycloalkyl is pinene.
7. The compound of claim 5, wherein said monocyclic unsubstituted or substituted cycloalkyl has general Formula II:
Figure imgf000051_0001
Formula II wherein:
R6 and R7 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, hydroxyl, alkoxy, carboxyl, carbonyl, formyl, acetyl and amine. whereas: a dashed line is a single or double bond; and a wavy line is a bond having an R or an S stereo-configuration.
8. The compound of claim 7, wherein R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and hydrogen.
9. The compound of claim 7, wherein R1 and R2 are each independently selected from the group consisting of an unsubstituted or substituted, branched or linear alkyl having from 4 to 10 carbon atoms and hydrogen.
10. The compound of claim 7, wherein R1 and R2 are each independently selected from the group consisting of a substituted, branched or linear alkyl having from 3 to 10 carbon atoms and hydrogen.
11. The compound of claim 7, wherein R1 and R2 are each independently unsubstituted or substituted, branched or linear alkyl having from 1 to 10 carbon atoms and R7 is carboxyl.
12. The compound of claim 11 , wherein R6 is methyl.
13. The compound of claim 11, wherein each OfR1 and R2 is methyl.
14. The compound of claim 12, wherein R3 is 1-pentyl, and A is 2-yl-4- methylcyclohex-3 -enyl)acrylic acid.
15. The compound of claim 7, wherein A is 3-methyl-6-(prop-l-en-2- yl)cyclohex-2-enyl.
16. The compound of claim 15 , wherein:
R1 is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, 2- yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc-ethanamine-2-yl, N- Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl and acetonitrile-2-yl; and
R2 is selected from the group consisting of 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, iV-Boc-ethanamine-2-yl, iV-Fmoc-ethanamine-2-yl, 3- morpholinopropanoyl and acetonitrile-2-yl.
17. The compound of claim 16, wherein R3 is selected from the group consisting of 1-pentyl and 1,1-dimethylheptyl-l-yl.
18. The compound of claim 1, wherein A is selected from the group consisting of an unsubstituted or substituted heteroalicyclic and an unsubstituted or substituted heteroaryl.
19. The compound of claim 18, wherein A is selected from the group consisting of an unsubstituted or substituted five-membered ring, an unsubstituted or substituted six-membered ring and an unsubstituted or substituted seven-membered ring.
20. The compound of claim 18, wherein said unsubstituted or substituted five-membered ring is selected from the group consisting of dihydropyrrole (pyrroline), tetrahydropyrrole (pyrrolidine), dihydrofuran, tetrahydrofurane, dihydrothiophene, tetrahydrothiophene furane, pyrrole, thiophene, oxazole, isoxazole, thiazole, thiazole, oxatriazole and oxatriazole.
21. The compound of claim 18, wherein said unsubstituted or substituted six-membered ring is selected from the group consisting of piperidine, pyridine, tetrahydropyran, pyran, thiane, thiine (thiapyrane), piperazine, diazine, oxazine, thiazine, triazine, dithiane and dioxane.
22. The compound of any of claims 19-21, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, acetyl, 2-yl-acetic acid, 2-yl-acetate, ethanol-2-yl, ethanamine-2-yl, N-Boc- ethanamine-2-yl, N-Fmoc-ethanamine-2-yl, 3-morpholinopropanoyl, acetonitrile-2-yl, 4-formyl-butanoic acid, 4-formyl-but-2-enoic acid and propan-2-one-l-yl.
23. A compound selected from the group consisting of:
2-(3 -hydroxy-2-((6R)-3 -methyl-6-(ρrop- 1 -en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetate (HU-409);
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetic acid (HU-410);
3-(2-hydroxyethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-411); tert-butyl 2-(3-hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-pentylphenoxy)ethylcarbamate (HU-412); tert-butyl 2-(3 -hydroxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-(2-methyloctan-2-yl)phenoxy)ethylcarbamate (HU-420);
3 -(2-aminoethoxy)-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5- pentylphenol (HU-427);
2-(3-methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)ethanamine (HU-428); tert-butyl 2-(3 -methoxy-2-((6R)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)ethylcarbamate (HU-429);
2-(3 -(2-aminoethoxy)-2-((6R)-3 -metliyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)- 5-pentylphenoxy)ethanamine (HU-430);
2-(3-hydroxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431);
2-((lR)-2-(2,6-dimethoxy-4-pentylphenyl)-4-methylcyclohex-3-enyl)acrylic acid (HU-434);
3-methoxy-2-((6R)-3-metliyl-6-(piOp-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-moφholinopropanoate (HU-435);
3-methoxy-2-((6R)-3-methyl-6-(piOp-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenyl 3-morpholinopropanoate maleate (HU-436);
2-(3-metlioxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5- pentylphenoxy)acetonitrile (HU-431A); and
2-(3-(acetonitrile-2-oxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2- enyl)-5-pentylphenoxy)acetonitrile (HU-432); and any enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising, as an active ingredient the compound of any of claims 1-22.
25. The pharmaceutical composition of claim 24, being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation.
26. A method of treating a medical condition, disease or disorder associated with inflammation, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1-
22.
27. Use of the compound of any of claims 1-22 in the preparation of a medicament for the treatment of a medical condition, disease or disorder associated with inflammation.
28. A pharmaceutical composition comprising, as an active ingredient, the compound of claim 23.
29. The pharmaceutical composition of claim 28, being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a medical condition, disease or disorder associated with inflammation.
30. Use of the compound of claim 23 in the preparation of a medicament.
31. The use of claim 30, wherein said medicament is for the treatment of a medical condition, disease or disorder associated with inflammation.
32. A method of treating a medical condition, disease or disorder associated with inflammation, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 23.
33. The composition, method or use of any of claims 29-32, wherein said medical condition, disease or disorder associated with inflammation is selected from the group consisting of 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 I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type 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 anemia, idiopathic thrombocytopenia, polychondritis, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory intestinal disease, celiac disease, Alzheimers's disease, prion associated disease and cancer metastases.
34. The composition, method or use of claim 33, wherein said medical condition, disease or disorder is selected from the group consisting of rheumatoid arthritis, atherosclerosis, Crohn's disease and multiple sclerosis.
PCT/IL2008/000281 2007-03-05 2008-03-05 Novel cannabidiol derivatives and their use as anti-inflammatory agents WO2008107879A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US90480607P 2007-03-05 2007-03-05
US60/904,806 2007-03-05
US99035607P 2007-11-27 2007-11-27
US60/990,356 2007-11-27

Publications (1)

Publication Number Publication Date
WO2008107879A1 true WO2008107879A1 (en) 2008-09-12

Family

ID=39387753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2008/000281 WO2008107879A1 (en) 2007-03-05 2008-03-05 Novel cannabidiol derivatives and their use as anti-inflammatory agents

Country Status (1)

Country Link
WO (1) WO2008107879A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009018389A1 (en) * 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US8435556B2 (en) 2000-12-22 2013-05-07 Alltranz, Llc Transdermal delivery of cannabidiol
WO2014178048A1 (en) 2013-05-02 2014-11-06 Mor Research Applications Ltd. Cannabidiol for the prevention and treatment of graft-versus-host disease
WO2015162610A1 (en) * 2014-04-21 2015-10-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
WO2017132526A1 (en) * 2016-01-29 2017-08-03 University Of Mississippi Biologically active cannabidiol analogs
US9889100B2 (en) 2013-05-02 2018-02-13 Mor Research Applications Ltd. Cannabidiol for treatment of severe and refractory graft-versus-host disease
WO2018091551A1 (en) * 2016-11-15 2018-05-24 Full Spectrum Laboratories Ltd Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
WO2019220324A3 (en) * 2018-05-14 2020-01-02 Buzzelet Development And Technologies Ltd Terpene-enriched cannabinoid compositions and uses thereof in the treatment of infectious conditions
CN113087599A (en) * 2020-01-08 2021-07-09 成都百裕制药股份有限公司 Cannabidiol derivative, preparation method and medical application thereof
CN113440508A (en) * 2021-07-27 2021-09-28 昆明理工大学 New application of cannabidiol derivative
WO2021245676A1 (en) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Cannabidiolic acid (cbda) derivatives and uses thereof
CN113896616A (en) * 2020-07-06 2022-01-07 复旦大学 Preparation method of cannabidiol
CN114315680A (en) * 2022-03-07 2022-04-12 中国农业科学院农产品加工研究所 Cannabidiol-2-pyrrolidine acid ester and application thereof
WO2022104245A3 (en) * 2020-11-16 2022-06-23 SYNERGY LIFE SCIENCE, Inc. Cannabinoid emulsifier
WO2023057982A1 (en) * 2021-10-07 2023-04-13 Oxiteno S.A. Indústria E Comércio Alkoxylation of cannabidiol & other cannabinoids
EP4034100A4 (en) * 2019-09-26 2023-10-11 Firstlight Pharmaceuticals LLC Cannabinoid prodrug compounds
CN116983265A (en) * 2023-09-28 2023-11-03 中国农业科学院农产品加工研究所 Embedding system of dihydro cannabidiol dioxypiperazine formate, preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053917A1 (en) * 1998-04-21 1999-10-28 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
WO2001032169A1 (en) * 1999-10-31 2001-05-10 Yissum Research Development Company Of The Hebrew University Agonists specific for the peripheral cannabinoid receptor
WO2003091189A1 (en) * 2002-04-25 2003-11-06 Virginia Commonwealth University Cannabinoids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053917A1 (en) * 1998-04-21 1999-10-28 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
WO2001032169A1 (en) * 1999-10-31 2001-05-10 Yissum Research Development Company Of The Hebrew University Agonists specific for the peripheral cannabinoid receptor
WO2003091189A1 (en) * 2002-04-25 2003-11-06 Virginia Commonwealth University Cannabinoids

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8435556B2 (en) 2000-12-22 2013-05-07 Alltranz, Llc Transdermal delivery of cannabidiol
US8449908B2 (en) 2000-12-22 2013-05-28 Alltranz, Llc Transdermal delivery of cannabidiol
WO2009018389A1 (en) * 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US8293786B2 (en) 2007-07-30 2012-10-23 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
US9956182B2 (en) 2013-05-02 2018-05-01 Mor Research Applications Ltd. Cannabidiol for the prevention and treatment of graft-versus-host disease
US11357740B2 (en) 2013-05-02 2022-06-14 Stero Biotechs Ltd. Cannabidiol for enhancing the therapeutic effect of a steroid
US9889100B2 (en) 2013-05-02 2018-02-13 Mor Research Applications Ltd. Cannabidiol for treatment of severe and refractory graft-versus-host disease
US10660865B2 (en) 2013-05-02 2020-05-26 Mor Research Applications Ltd. Cannabidiol for the prevention and treatment of graft-versus-host disease
WO2014178048A1 (en) 2013-05-02 2014-11-06 Mor Research Applications Ltd. Cannabidiol for the prevention and treatment of graft-versus-host disease
US10058515B2 (en) 2013-05-02 2018-08-28 Mor Research Applications Ltd. Cannabidiol for treatment of severe and refractory graft-versus-host disease
WO2015162610A1 (en) * 2014-04-21 2015-10-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
CN106232588A (en) * 2014-04-21 2016-12-14 耶路撒冷希伯来大学伊萨姆研究发展有限公司 Cyclohexenyl group compound, the compositions comprising it and application thereof
US11149014B2 (en) 2014-04-21 2021-10-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Method for treating pain or associated condition or symptom
US10239848B2 (en) 2014-04-21 2019-03-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
EP3786158A1 (en) * 2014-04-21 2021-03-03 Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. Cyclohexenyl compounds, compositions comprising them and uses thereof
US11337952B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11596617B2 (en) 2016-01-29 2023-03-07 University Of Mississippi Biologically active cannabidiol analogs
EP3407973A4 (en) * 2016-01-29 2019-09-11 The University Of Mississippi Biologically active cannabidiol analogs
WO2017132526A1 (en) * 2016-01-29 2017-08-03 University Of Mississippi Biologically active cannabidiol analogs
US11344525B2 (en) 2016-01-29 2022-05-31 University Of Mississippi Biologically active cannabidiol analogs
US10709681B2 (en) 2016-01-29 2020-07-14 University Of Mississippi Biologically active cannabidiol analogs
US11337950B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
US11337951B2 (en) 2016-01-29 2022-05-24 University Of Mississippi Biologically active cannabidiol analogs
IL266636A (en) * 2016-11-15 2019-07-31 C Peet Richard Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
US20180201560A1 (en) * 2016-11-15 2018-07-19 Full Spectrum Laboratories Ltd. Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
US20190345087A1 (en) * 2016-11-15 2019-11-14 Teewinot Technologies Limited Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
US10384997B2 (en) * 2016-11-15 2019-08-20 Teewinot Technologies Limited Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
WO2018091551A1 (en) * 2016-11-15 2018-05-24 Full Spectrum Laboratories Ltd Bio-stable cannabinoid compounds and methods for enhancing their physiological concentration
WO2019220324A3 (en) * 2018-05-14 2020-01-02 Buzzelet Development And Technologies Ltd Terpene-enriched cannabinoid compositions and uses thereof in the treatment of infectious conditions
EP4034100A4 (en) * 2019-09-26 2023-10-11 Firstlight Pharmaceuticals LLC Cannabinoid prodrug compounds
CN113087599A (en) * 2020-01-08 2021-07-09 成都百裕制药股份有限公司 Cannabidiol derivative, preparation method and medical application thereof
WO2021245676A1 (en) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Cannabidiolic acid (cbda) derivatives and uses thereof
CN113896616A (en) * 2020-07-06 2022-01-07 复旦大学 Preparation method of cannabidiol
WO2022104245A3 (en) * 2020-11-16 2022-06-23 SYNERGY LIFE SCIENCE, Inc. Cannabinoid emulsifier
CN113440508B (en) * 2021-07-27 2023-10-27 昆明理工大学 New application of cannabidiol derivative
CN113440508A (en) * 2021-07-27 2021-09-28 昆明理工大学 New application of cannabidiol derivative
WO2023057982A1 (en) * 2021-10-07 2023-04-13 Oxiteno S.A. Indústria E Comércio Alkoxylation of cannabidiol & other cannabinoids
CN114315680A (en) * 2022-03-07 2022-04-12 中国农业科学院农产品加工研究所 Cannabidiol-2-pyrrolidine acid ester and application thereof
CN116983265A (en) * 2023-09-28 2023-11-03 中国农业科学院农产品加工研究所 Embedding system of dihydro cannabidiol dioxypiperazine formate, preparation method and application thereof
CN116983265B (en) * 2023-09-28 2023-12-19 中国农业科学院农产品加工研究所 Embedding system of dihydro cannabidiol-2, 6-dioxopiperazine formate and preparation method and application thereof

Similar Documents

Publication Publication Date Title
WO2008107879A1 (en) Novel cannabidiol derivatives and their use as anti-inflammatory agents
Lin et al. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 3. Aromatic amine analogs
RU2532546C2 (en) Oxidised lipid compounds and their application
JPH07228558A (en) Stilbene derivative and carcinostatic agent containing the same
US20100152238A1 (en) Novel quinonoid derivatives of cannabinoids and their use in the treatment of malignancies
US20130217674A1 (en) Ship1 modulators and related methods
US20230002425A1 (en) Cannabidiol derivatives, preparation method thereof and use thereof
US20230059087A1 (en) Cannabidiol derivatives, preparation method thereof and use thereof
SA519401049B1 (en) Condensed thiophene derivatives useful as napi-iib inhibitors
WO2008062830A1 (en) Spiroquinone compound and pharmaceutical composition
EP2880024A1 (en) Griseofulvin derivatives
JPH02745A (en) New hmg-coa reductase inhibitor
US20240116883A1 (en) Cannabinoid derivatives and their use the treatment of inflammation and/or pain and/or obesity
FR2521992A1 (en) NOVEL PYRIDINE COMPOUNDS USEFUL AS MEDICAMENTS
WO2019182904A1 (en) Phosphonamidate butyrophilin ligands
JP2002530394A (en) Novel agarofuran derivatives, their preparation, pharmaceutical compositions containing them and their use as medicaments
JP2012097003A (en) Bixin derivative and cytoprotective agent
FI66607B (en) FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC EQUIPMENT 1,2-5,6-DIANHYDRO-HEXITOLER
KR920002143B1 (en) 5-substituted uridine derivatives and intermediates for their preparation
JPWO2018143162A1 (en) Compound which is a prodrug of hydroxamic acid or a salt thereof, lyophilized preparation, LpxC inhibitor and antibacterial agent
EP2694058B1 (en) New indolinone protein kinase inhibitors
US20230227482A1 (en) Tetrahydrocannabinol derivatives, preparation method thereof and use thereof
US11400079B2 (en) Antibacterial monobactams
CN115043879A (en) Dihydroartemisinin derivative and preparation method thereof
EP3099661B1 (en) Clostrubins

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08710270

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08710270

Country of ref document: EP

Kind code of ref document: A1