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WO2012011112A1 - Cannabinoïdes non psychoactifs et leurs utilisations - Google Patents

Cannabinoïdes non psychoactifs et leurs utilisations Download PDF

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Publication number
WO2012011112A1
WO2012011112A1 PCT/IL2011/000586 IL2011000586W WO2012011112A1 WO 2012011112 A1 WO2012011112 A1 WO 2012011112A1 IL 2011000586 W IL2011000586 W IL 2011000586W WO 2012011112 A1 WO2012011112 A1 WO 2012011112A1
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WIPO (PCT)
Prior art keywords
branched
straight
alkyl
compound according
disease
Prior art date
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PCT/IL2011/000586
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English (en)
Inventor
Ruth Gallily
Raphael Mechoulam
Marc Feldmann
Christeen Haj
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Kennedy Trust for Rheumatology Research
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Mathilda and Terence Kennedy Institute of Rheumatology Trust
Kennedy Institute of Rheumotology
Yissum Research Development Co of Hebrew University of Jerusalem
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Application filed by Mathilda and Terence Kennedy Institute of Rheumatology Trust, Kennedy Institute of Rheumotology, Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Mathilda and Terence Kennedy Institute of Rheumatology Trust
Publication of WO2012011112A1 publication Critical patent/WO2012011112A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • 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
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • 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

  • This invention relates to non-psychoactive cannabinoid derivatives and uses thereof for the manufacture of medicaments for the treatment of inflammation and/or inflammatory relates diseases, disorders and /or symptoms.
  • CBD cannabidiol
  • the invention provides a compound having the general formula (I):
  • R 2 is a straight or branched Q-Cs alkyl
  • R 5 is selected from a straight or branched C 6 -C 12 alkyl, a straight or branched C 5 - C 9 alkoxy, a straight or branched C!-C 7 ether, each being optionally substituted by at least one substituent selected from -OH, -NH 3 , straight or branched C -Cs amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
  • R ⁇ is a straight or branched C ! -C 5 alkylene
  • R 8 , and R 9 are independently selected from H, OH, straight or branched Q-Cs alkyl, straight or branched Cj-Csalkoxy, -NH 3 , straight or branched C C 5 amine;
  • R 10 is selected from H, a straight or branched C C alkyl
  • Rn and R 12 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C ⁇ -Cs alkoxy, -NH 3 , straight or branched C Cs amine.
  • the invention provides a compound having the general formula (II):
  • R 2 is a straight or branched Q-Cs alkyl
  • R 5 is selected from a straight or branched C 6 -C 12 alkyl, a straight or branched C 5 - C 9 alkoxy, a straight or branched Q-O7 ether, each being optionally substituted by at least one substituent selected from -OH, -NH 3 , straight or branched Cj-Cs amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
  • Ci-C 5 alkylene is a straight or branched Ci-C 5 alkylene
  • R 8 , and R 9 are independently selected from H, OH, straight or branched C ⁇ -Cs alkyl, straight or branched Q-Csalkoxy, -NH 3 , straight or branched Q-Cs amine;
  • R 10 is selected from H, a straight or branched Cj-Cs alkyl; and
  • Rn and R 12 are independently selected from H, OH, straight or branched C C 5 alkyl, straight or branched C ⁇ -Cs alkoxy, -NH 3 , straight or branched C ⁇ -Cs amine.
  • R 2 is a straight or branched C ⁇ -Cs alkyl
  • R 5 is selected from a straight or branched C 6 -C 12 alkyl, a straight or branched C 5 - C 9 alkoxy, a straight or branched C!-C 7 ether, each being optionally substituted by at least one substituent selected from -OH, -NH 3 , straight or branched C -Cs amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
  • Re is a straight or branched C ⁇ -Cs alkylene
  • R , and R 9 are independently selected from H, OH, straight or branched C ⁇ -Cs alkyl, straight or branched Q-Csalkoxy, -NH3, straight or branched Cj-C 5 amine;
  • R 10 is selected from H, a straight or branched Q-C5 alkyl; and Rn and R 12 are independently selected from H, OH, straight or branched C C 5 alkyl, straight or branched Q-Cs alkoxy, -NH 3 , straight or branched C C 5 amine.
  • Rn and R 12 are independently selected from H, OH, straight or branched C C 5 alkyl, straight or branched Q-Cs alkoxy, -NH 3 , straight or branched C C 5 amine.
  • (II) or (III) is a double bond.
  • said one double bond a compound of any one of formulae (I) or (II) is between carbon 1 and 2.
  • said one double bond a compound of any one of formulae (I) or (II) is between carbon 3 and 4.
  • said one double bond a compound of any one of formulae (I) or (II) is between carbon 5 and 6.
  • said one double bond a compound of any one of formulae (I) or (III) is between carbon 2 and 3.
  • said one double bond a compound of any one of formulae (I) or (III) is between carbon 4 and 5.
  • said one double bond a compound of any one of formulae (I) or (III) is between carbon 6 and 1.
  • (II) is a double bond.
  • 1 6 of a compound of any one of formulae (I) or (III) is a double bond.
  • all other bonds, other than the ones indicated in embodiments herein above, are single bonds.
  • R ⁇ is -ReOR 7 ;
  • R6 is a straight or branched C C 5 alkylene; and
  • R 7 is H.
  • Ri 0 is selected from H, a straight or branched C1-C5 alkyl; and
  • R 12 is selected from H, OH, straight or branched -Cs alkyl, -NH 3 , straight or branched Ci-C 5 amine.
  • R 5 is a straight or branched C 6 -C 12 alkyl.
  • the invention encompasses a compound having the general formula (IV):
  • R 3 , R 4 and R 5 are as defined herein above.
  • the invention encompasses a compound having the general formula (V):
  • R3, R 4 and R 5 are as defined herein above.
  • one of of a compound of any one of formulae (IV) or (V) is a double bond.
  • said one double bond a compound of any one of formula (IV) is between carbon 1 and 2.
  • said one double bond a compound of any one of formula (IV) is between carbon 3 and 4.
  • said one double bond a compound of any one of formula (IV) is between carbon 5 and 6.
  • said one double bond a compound of any one of formula (V) is between carbon 2 and 3.
  • said one double bond a compound of any one of formula (V) is between carbon 4 and 5.
  • said one double bond a compound of any one of formula (V) is between carbon 6 and 1.
  • 1 2 of a compound of formula (IV) is a double bond.
  • 1 6 0 f a compound of formula (V) is a double bond.
  • all other bonds, other than the ones indicated in embodiments herein above, are single bonds.
  • R 10 is selected from H, a straight or branched C C 5 alkyl; and
  • R 12 is selected from H, OH, straight or branched C ⁇ -C$ alkyl, -NH 3 , straight or branched C ⁇ -C * , amine.
  • R 5 is selected from a straight or branched C 6 -C 12 alkyl.
  • a compound of the invention is (-)-8,9-dihydro-CBD-7- oic acid diacetate (HU-444), having the formula:
  • a compound of the invention is (-)-8,9 dihydro-CBD-7-oic acid (HU-445), having the formula:
  • alkyl refers to a straight or branched chain hydrocarbon having from one to five carbon atoms, or from one to seven carbon atoms, or from five to nine carbon atoms, or from six to twelve carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, n-butyl, n- pentyl, isobutyl, and isopropyl, tert-butyl, and the like.
  • alkylene refers to a saturated, divalent, branched or straight hydrocarbon group having from one to five carbon atoms.
  • C 1-5 -alkylene groups include, methylene, ethylene, 1,2-propylene, 1,3- propylene, butylene, isobutylidene, pentylene, hexylene and the like.
  • esters is meant to encompass an -COOR group wherein R is an alkyl as defined herein above.
  • ether refers to an -R'OR group, wherein R' is a C1-C7 straight or branched alkylene group and R is a C1-C7 straight or branched alkyl group.
  • alkoxy refers to an RO- group, where R is alkyl as defined above.
  • C1-C7 amide refers to a monoalkyl amide (-CONHR) or dialkyl amide (-CONRR), wherein R and R' are independently a C C 7 straight or branched alkyl.
  • C1-C5 amine refers to an -NHR or -NRR' group wherein R and R' are independently a C ⁇ -Cs straight or branched alkyl.
  • C7-C5 alkoxy refers to a -OR group wherein R is a Ci- C 5 alkyl.
  • substituents such as for example those specified above, -OH, -NH 3 , straight or branched Q-C 5 amine, phenyl, substituted phenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen (-F, - CI, -Br, -I).
  • substituents may be the same or different and said substitution may occur at any position on the substituted group (i.e. at a terminal or any mid-chain position or both).
  • a compound of the invention is intended or indicated for use in the treatment of a condition, disease, disorder or symptom associated with inflammation.
  • inflammation as used herein is meant to encompass any response of vascular tissues to stimuli, such as pathogens, damaged cells, or irritants. Inflammation can be either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
  • Causes of inflammation or any associated disease, disorder or symptom include but are not limited to: burns, chemical irritants, frostbite, toxins, infection by pathogens, physical, blunt or penetrating, immune reactions due to hypersensitivity, ionizing radiation, foreign bodies, including splinters, dirt and debris etc.
  • said condition, disease, disorder or symptom associated with inflammation is selected from multiple sclerosis, rheumatoid arthritis, liver inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, psoriasis, diabetes (Type I and Type II diabetes (IDDM) including the protection of beta cells from destruction), 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 derma), derma
  • a compound of the invention is intended or indicated for use in the treatment of a disease or disorder selected from cardiac disfunction in diabetic cardiopathy nephrotoxicity (in some embodiments due to the use of anti-cancer agents), hepatic ischemia/reperfusion injury, cardiac ischemia/reperfusion injury, brain ischemia/reperfusion injury, cancer (in some embodiments breast cancer) and any combinations thereof.
  • a disease or disorder selected from cardiac disfunction in diabetic cardiopathy nephrotoxicity (in some embodiments due to the use of anti-cancer agents), hepatic ischemia/reperfusion injury, cardiac ischemia/reperfusion injury, brain ischemia/reperfusion injury, cancer (in some embodiments breast cancer) and any combinations thereof.
  • a compound of the invention is intended or indicated for use in suppressing the generation of at least one of reactive oxygen species, nitric oxygen species, TNFa and any combinations thereof.
  • a compound of the invention is intended or indicated for use in at least one of enhancing adenosine uptake, 5-HT(lA) activation, PPAR activation and any combinations thereof.
  • PPAR activation when referring to the enhancement of adenosine uptake, 5-HT(l A) activation, PPAR activation it should be understood to encompass it should be understood to include any qualitative or quantitative change in at least one of the anti- inflammation related processes and cascades in a patient suffering therefrom, administered with a compound or composition of the invention. Such effects are demonstrated in vitro and in vivo in the below described experimental section of the invention.
  • the invention provides a composition comprising at least one compound according to the invention.
  • said composition is a pharmaceutical composition.
  • composition of the invention is intended or indicated for use in the treatment of a condition, disease, disorder or symptom associated with inflammation.
  • composition of the invention is intended or indicated for use in suppressing the generation of at least one of reactive oxygen species, nitric oxygen species, TNFa and any combinations thereof.
  • a composition of the invention is intended or indicated for use in at least one of enhancing adenosine uptake, 5-HT(lA) activation, PPAR activation and any combinations thereof.
  • pharmaceutical compositions comprising a compound of the subject invention it should be understood to encompass admixtures of a compound of the invention, with any pharmaceutically acceptable auxiliaries known to a person skilled in the art, and optionally other therapeutic agents.
  • auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant.
  • the compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent.
  • Auxiliary agent(s), also named accessory ingredient(s) include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents, anti-oxidants, and wetting agents.
  • compositions of the invention suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste.
  • the compositions can further be processed into a suppository or enema for rectal administration.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.
  • compositions include aqueous and nonaqueous sterile injection.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use.
  • compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
  • compositions of the invention will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
  • treatment refers to the administering of a therapeutic amount of a composition or compound of the invention which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.
  • the term "effective amount" means that amount of a composition or compound of the invention that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the effective amount for purposes disclosed herein is determined by such considerations as may be known in the art.
  • the amount must be effective to achieve the desired therapeutic effect as described above, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime.
  • the effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount.
  • an effective amount depends on a variety of factors including the affinity of a ligand to a receptor, its distribution profile within the body, a variety of pharmacological parameters such as half life in the body, on undesired side effects, if any, on factors such as age and gender, etc.
  • terapéuticaally effective amount means any amount of a composition or compound of the invention which, as compared to a corresponding subject who has not received such amount of a composition or compound of the invention, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • the invention provides a use of a compound of the invention, for the manufacture of a medicament.
  • the invention provides a use of a compound of the invention, for the manufacture of a medicament for the treatment of a condition, disease, disorder or symptom associated with inflammation.
  • the invention provides a use of a compound of the invention, for the manufacture of a medicament for suppressing the generation of at least one of reactive oxygen species, nitric oxygen species, TNFa and any combinations thereof.
  • the invention provides a use of a compound of the invention, for the manufacture of a medicament for at least one of enhancement of adenosine uptake, 5-HT(l A) activation, PPAR activation and any combinations thereof.
  • the invention further encompasses a method of treating a condition, disease, disorder or symptom associated with inflammation in a subject in need thereof, said method comprising administering to said subject an effective amount of at least one compound of the invention.
  • the invention further provides a method of suppressing the generation of at least one of reactive oxygen species, nitric oxygen species, TNFa and any combinations thereof, said method comprising administering to a subject in need thereof, an effective amount of at least one compound of the invention.
  • Fig. 1 is a scheme of the synthesis of (-) 8,9 dihydro-CBD- 7-oic acid, diacetate
  • Figs. 2A-2B show the respective ROI inhibition of HU-444 (2A) and HU-445 (2B) in various concentrations (10, 20, and 40 g/ml).
  • Figs. 3A-3C show the respective ROI inhibition of HU-444 (3A and 3B) and HU-445 (3C) in various concentrations (1, 2.5, 5, 10, 20, 40 and 60 ⁇ g/ml).
  • Figs. 4A-4B show respectively the inhibition of THP-1 cell migration toward MCP-1 with HU-444 at concentration of 20 and 10 ⁇ g/ml (4 A) and the effect of HU- 445 (at 40, 20, 10, 5, 2.5, 1 ⁇ g/ml respectively) on TNF levels (4B).
  • Figs. 5A-5B show the respective inhibiting effect of HU-444 (5 A) and HU-445 (5B) on TNF production in the mice.
  • Fig. 6 shows the incidences of arthritis in DBA/1 mice immunized with chicken type II collagen.
  • Fig. 7 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on weight of DBA/1 mice with established chicken type II collagen-induced arthritis. The effect was compared with vehicle and CBD.
  • Fig. 8 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen- induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 9 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen- induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 10 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 11 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 12 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 13 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 14 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. Paw thickness (raw data) over ten days.
  • Fig. 15 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 16 shows the incidences of arthritis in DBA/1 mice immunized with chicken type II collagen (performed for experiment with 15 mg/kg HU-444).
  • Fig. 17 shows the effect of treatments with HU-444 (15 mg/kg) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle.
  • Fig. 18 shows the effect of treatments with HU-444 (15 mg/kg) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 19 shows the effect of treatments with HU-444 (15 mg/kg) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle.
  • Fig. 20 shows the effect of treatments with HU-444 (15 mg/kg) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 21 shows the joints composite profile (categorized as normal, mild, moderate or severe) of DBA/1 mice with established chicken type II collagen-induced arthritis treated with 15 mg/kg of HU-444 and compared with vehicle.
  • Fig. 22 shows the joints composite protected vs. damaged profile of DBA/1 mice with established chicken type II collagen-induced arthritis treated with 15 mg/kg of HU-444 and compared with vehicle.
  • Fig. 23 shows the effect of HU-444 on levels of alanine transferase enzyme in serum of CON-A treated mice. The effect is shown relative to control group.
  • Fig. 24 shows the effect of HU-444 in various doses (2.5mg, 5mg, lOmg) on the levels of tumour necrosis factor (TNF) in serum of CON-A treated mice. The effect is shown relative to control group.
  • Example 1 Synthesis of 8,9 dihydro-CBD- 7-oic acid, diacetate (HU-444) and 8.9 dihvdro-CBD-7-oic acid (HU-445) (see also Fig. 1):
  • (-)-CBD was isolated from Cannabis sativa resin.
  • CBD (0.544 g, 1.73 mmol) in ethylacetate (10 ml), Pt (0.021 g), was hydrogenated at 10 psi, for 30 min.
  • the mixture was purified by silica gel chromatography, using petroleum ether and ether as an eluent (0.534 g), Yield (97.5%).
  • Example 2 In vitro and In vivo effect of HU-444 and HU-445
  • Raw 264.7 cells a monocytic-macrophage cell line derived from BALB/c mice, were obtained from the Addiction Technology Transfer Center (ATTC, Rockville, MD, USA). The cells were cultured in Dulbecco's modified Eagle medium (DMEM) suplemented with 5% fetal calf serum (FCS) and sodium pyrovate, glutamine and antibutics. For activation, the cells were incubated with LPS (E. coli ⁇ g/ml for 24 hs, Sigma, Israel). ROI production by RAW 264.7 cells
  • Raw 264.7 cells were removed by cell scraper, washed and re-suspended in Hanks' balanced salt solution (without phenol red).
  • Hanks' balanced salt solution without phenol red
  • chemiluminescence 0.5 ml of cell suspension (5 x 10 5 cells) was added to each luminometer tube, together with various doses of cannabinoids derivative of the invention tested (dissolved in ethanol and diluted with Hanks). The cells were incubated for 20-24 hs and then, 10 ⁇ of luminol (Sigma) and 30 ⁇ of zymosan (Sigma) were added to the tubes, and the chemiluminescence was measured immediately in a luminometer (Biolumate LB 95, Berhold, Wilbad, Germany[8].
  • Peritoneal cells were harvested from C57BL/6 female mice four days after intraperitoneal injection of 1.5 ml of thioglycollate medium (Difco). The cells were washed with phosphate-buffered saline, re-suspended in DMEM and supplement, containing 5% FCS, and plated flat-bottom 96-microwell plates at a concentration of 1.2 x 10 5 cells per well. Following 2-3 h of incubation at 37°C, the non-adherant cells were removed by intensive rinsing. About 95% of the adherent cells were macrophages. Treatment of macrophages with cannabinoids
  • the cannabinoid derivatives of the invention were first dissolved in absolute ethanol (1 mg/50-100 ⁇ ethanol), and the solutions were further diluted with DMEM medium. For each cannaboid compound, various nontoxic concentrations were added to the macrophages, followed by addition of 1 ⁇ g/ml of lipopolysaccharide (LPS, e. coli, Sigma) for activation. The macrophages were then cultivated in a humid atmosphere with 5% C0 2 for 24 hs. The supernatant fluids were harvested and kept at -20°C until assayed for NO and TNFa.
  • LPS lipopolysaccharide
  • NO generation was determined by measuring the nitrite accumulated in the supernatants (100 ⁇ ) of the cannabinoid-treated macrophages as follows. An equal volume (100 ⁇ ) of Griess reagent (1% sulphanilamide, 0.1% naphthalene diamine HCl, 2% H 3 P0 4 ) was added to each supernatant. Following 10 min of incubation at room temperature, the color production was measured at 550 nm with an ELISA reader. The concentration of the nitrit was calculated according to a standard curve [8].
  • TNFain-vitro TNFa in the supernatants of the cannabinoid-treated (40, 20, 10, 5,and 1 ⁇ /ml) LPS-activated macrophages was determined by ELISA (R&D) according to manufactore instructions.
  • mice were injected IP with 100 ⁇ g LPS, Cannabinoid derivative of the invention was administrated IP simultaneously. Mice were bled 90 min later and TNF in the plasma was measured by Elisa. IN VITRO RESULTS
  • Fig. 2 A shows that the reduction in ROI (oxygen radicals) was 61% and 38% at HU-444 concentration of 40 ⁇ g/ml and 20 ⁇ g/ml, respectively.
  • Fig. 2B shows that the reduction in ROI (oxygen radicals) was 60% , 30% and 39% at HU-445 concentrations of 40 ⁇ g/ml, 20 ⁇ g/ml and 10 ⁇ g/ml, respectively.
  • Figs. 3A and 3B show that the presence of HU-444 reduced NO generation of RAW cells in the two performed experiments (3A and 3B), by 62-73% and 50-70% at 60 ⁇ g/ml and 40 ⁇ g/ml HU-444, respectively.
  • Fig. 3C shows that the presence of HU-445 reduced NO generation of RAW cells, by 78%, 58% and 22% at 40 ⁇ g/ml, 20 ⁇ g/ml and 10 ⁇ g/ml HU-445, respectively.
  • FIG. 4A shows that HU-444 at concentration of 20 and 10 ⁇ ⁇ inhibited THP-1 cell migration toward MCP-1 by 43% and 35% respectively.
  • Fig. 4B shows that HU-445 affected TNF levels by 80%, 40% and 27% at 40 ⁇ g/ml , 20 ⁇ g/ml and 10 ⁇ g/ml respectively.
  • Fig. 5B shows that HU-445 affected TNF levels by 55% at 10 ⁇ g/ml.
  • Example 3 Effect of HU-444 on the treatment of established chicken type II collagen-induced arthritis in DBA/1 mice
  • mice Male DBA/1 mice were immunized at 16 weeks of age with an emulsion of purified chicken type II collagen and Freund's complete adjuvant (CFA) at the base of the tail, in a single intra dermal injection. No booster was used in this experiment.
  • CFA complete adjuvant
  • mice In the group receiving 15mg/kg of HU-444 there were twenty male DBA/1 mice immunized with a single i.d. injection of purified chicken type II collagen emulsified in Freund's complete adjuvant and kept in IVC over a 20 h light/dark cycle. They were fed with tap water and laboratory chow ad libitum.
  • mice were regularly monitored from day 14 post immunization and mice developing clinical signs of arthritis, as characterised by inflammation in any of their paws were randomly recruited into the different treatment groups.
  • mice were scored for degree of redness & inflammation in every paw daily and given a clinical score from 0-3.
  • Hind paw thickness was measured in (mm) using a caliper on day of monitoring & Rx.
  • Results presented as raw data of mean ⁇ SEM values of n 9 per group.
  • normalised data in relation to dl of CIA are presented as the means ⁇ SEM. Further results were plotted as an average ⁇ sem of number of mice per group vs day of arthritis.
  • mice in all treatment groups were weighed before recruitment into groups and at the end of the experiment, following treatments. Data was plotted as a change in weight.
  • Fig. 6 shows the incidences of arthritis in DBA/1 mice immunized with chicken type II collagen.
  • Fig. 7 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on weight of DBA/1 mice with established chicken type II collagen-induced arthritis. The effect was compared with vehicle and CBD.
  • Fig. 8 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen- induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 9 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen- induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 10 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA 1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 11 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 12 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD.
  • Fig. 13 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 14 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA 1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. Paw thickness (raw data) over ten days.
  • Fig. 15 shows the effect of treatments with HU-444 (in 2.5, 5, 10 mg/kg dosages) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 16 shows the incidences of arthritis in DBA/1 mice immunized with chicken type II collagen (performed for experiment with 15 mg/kg HU-444).
  • Fig. 17 shows the effect of treatments with HU-444 (15 mg/kg) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle.
  • Fig. 18 shows the effect of treatments with HU-444 (15 mg/kg) on clinical arthritis score of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 19 shows the effect of treatments with HU-444 (15 mg/kg) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle.
  • Fig. 20 shows the effect of treatments with HU-444 (15 mg/kg) on paw thickness (mm) of DBA/1 mice with established chicken type II collagen-induced arthritis, over ten days. The effect was compared with vehicle and CBD. The effect is shows as the change in clinical score from day 1 (normalised data) over ten days.
  • Fig. 21 shows the joints composite profile (categorized as normal, mild, moderate or severe) of DBA/1 mice with established chicken type II collagen-induced arthritis treated with 15 mg/kg of HU-444 and compared with vehicle.
  • Fig. 22 shows the joints composite protected vs. damaged profile of DBA/1 mice with established chicken type II collagen-induced arthritis treated with 15 mg/kg of HU-444 and compared with vehicle.
  • Study groups comprised of 8-9 weeks old 16 mice were injected with 25mg/kg CON- A intravenously.
  • Group A Four mice injected with 2.5 mg/kg HU-444.
  • Group B Four mice injected with 5.0 mg/kg HU-444.
  • Group C Four mice injected with 10.0 mg/kg HU-444.
  • Group D Four mice injected with the vehicle (mixture of ethanol, cremophor and saline in a 1 : 1 : 18 ratio).
  • mice were bled 22hrs later for determination of liver enzyme (alanine transaminase) as well as for tumor necrosis factor (TNF) levels in the serum.
  • liver enzyme alanine transaminase
  • TNF tumor necrosis factor
  • Fig. 23 shows decrease in levels of alanine transferase enzyme of between about
  • Fig. 24 shows decrease in tumour necrosis factor (TNF) in serum for all groups administered with HU-444 of about 50%.
  • HU-444 and HU-445 were demonstrated to posses potent anti-inflammatory properties. Both HU-444 and HU-445 suppressed by 60-80% the generation of reactive oxygen species (ROS) and nitric oxygen species (NOS), as well as the production of tumor necrosis factor alfa (TNFa) by mouse macrophages. In the in vivo system, HU- 444 and HU-445 inhibited TNFa production by 60-70%, when applied intraperitoneally to mice.
  • ROS reactive oxygen species
  • NOS nitric oxygen species
  • TNFa tumor necrosis factor alfa
  • HU-444 markedly suppressed, by 60-70%, the arthritis symptoms when given either intraperitoneally or orally to DBA/1 mice in a murine collagen- induced arthritis model.
  • HU-444 inhibited markedly the destruction of the livers by inflammation as well as reduced the aminotransaminases levels up to 90%.

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Abstract

La présente invention concerne des composés dihydro CBD de formule (I) et leurs dérivés, des compositions les comprenant et leurs utilisations dans la fabrication de médicaments pour le traitement d'états, maladies, troubles ou symptômes associés à l'inflammation.
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WO2021173130A1 (fr) 2020-02-26 2021-09-02 Vitality Biopharma, Inc. Nouveaux glycosides cannabinoïdes et leurs utilisations
US11207291B2 (en) 2017-05-09 2021-12-28 Graphium Biosciences, Inc. Antimicrobial compositions comprising cannabinoids and methods of using the same
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