Title of Invention

"CANNABIDOL DERIVATIVE AND A PROCESS FOR PREPARING THE SAME"

Abstract

The present invention relates to cannabidiol derivatives and to pharmaceutical compositions comprising cannabidiol derivatives being antiinflammatory agents having analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity. The present invention also relates to a process for the preparation of cannabidiol derivatives. It also relates to the use of cannabidiol derivatives and pharmaceutical compositions comprising same in the preparation of a medicament, in a method of the treatment of human beings with cannabidiol derivatives or with a pharmaceutical preparations comprising same.

Full Text

FIELD OF THE INVENTION The present invention relates to cannabidiol derivative and a process for preparing the same. More specifically, the present invention relates to cannabidiol derivative and pharmaceutical composition comprising cannabidiol derivatives being antiinflammatory agents having analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity. BACKGROUND AND PRIOR ART Cannabidiol (CBD, la) is the major non-psychotropic cannabinoid in most Cannabis preparations, such as hashish and marihuana.CBD causes none of the psychotropic effects typical ofA9-tetrahydrocannabinol (A9-THC) (Martin, Pharmacol. Rev., 38, 45-74 1986). CBD does not bind to the known cannabinoid receptors CB1 or CB2, and therefore does not cause the central or peripheral effects mediated by these receptors. However it has been shown in in vitro assays, in animal tests, as well as in some human, preliminary trials, to produce numerous pharmacological effects, some of which are of potential therapeutic value. Thus, recent 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. IL-lα and IFNγ by human peripheral blood mononuclear cells (Coffey etal., Intern. J.Immunopharmacol., 18. 749-752 [1996]; Watzl etal.. Int. J. Immunopharmicol., 13, 1091-1093 [1991];Srivastava etal., Immunopharmacol., 179-185 [1998]; for a review see Klein etal., Immunol. Today, 19.373-381 [1998])and"Malfait etal., Proc. Natl. Acad. Sci.fU. S. A.], 97,9561-9566[2000].". These in vitro studies lend support to earlier reports on analgesic andantiinflammatory effects in animals. Formukong etal., (inflammation 12, 361-371 [1988]) have found that CBD is much more potent than aspirin in thephenylbenzoquinone writhing test in mice (a standard analgesic assay). In the tetradecanoylphorbolacetable (TPA) induced erythema of mouse ear (anantiinflammatory assay) CBD caused 92% inhibition of the inflammation response on application of a lOOµg/ml solution. CBD has been found to produce several, potentially therapeutic, effects in animal models, as well as in patients with neurological diseases (for a review seeConsroe,(Neurobiol. Disease,^ 534-551 [1998]). in anxiety (Guimaraes etal.,Gen.Pharmacol., 25, 161-164[1994] : Zuardi etal., Psychopharmacology [Berlin], 76 245-250 [1982]) and in psychosis (Zuardi etal., J. Clin. Psychiatry,56, 485-486 [1995]). Hampson etal., (Proc. Natl. Acad. Sci. USA, 95,8268-8273 [1998]) have found that CBD is an neuroprotective antioxidant. Surprisingly, while the enantiomeric THC's differ in their biological activity (Mechoulam et al.,"Marijuana/cannabinoids: neurobiology and neurophysiology" ed. L. Murphy and A. Bartke, CRC Press, Boca Raton, Florida, pp 1-33[1992]), both CBD enantiomers have the same anticonvulsive and certain hormonal profiles (Leite etal., Pharmacol., 124, 141-146 [1982]; Cordova et al., Psychoneuroendocrinology, 5, 53-62[1980]). However the comparative pharmacology of CBD enantiomers has not been further explored. Also the syntheses and the pharmacology of CBD metabolites are unknown. Said syntheses and the pharmacology have now been explored and it has surprisingly been found that compounds of general formula I (Formula Removed) in which R' stands for COOH or CH2OH; and R" stands for a. straight or branched alkyl of 5 to 12 carbon atoms; b. a group-O-R'", where R'" is straight or branched alkyl of 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; c. 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; where R" is not C5H11 and pharmaceutic compositions comprising same, are anti-inflammatory agents and which have analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity. The present invention thus consists in pharmaceutical preparations comprising compounds of general formula being antiinflammatory agents, which have analgesic, antianxiety.anticonvulsive, neuroprotective, antipsychotic and anticancer activity comprising as active ingredient a compound of general formula I. The compounds of general formula I excluding those in which R"stands for C5H11 are novel and are within the scope of the present invention. The pharmaceutical preparations according to the present invention may have any suitable form, e.g. be a tablet, a capsule, a granule, a suspension, a solution, etc. They may comprise in addition to the active ingredient an excipient, such as a carrier, a disintegrant, a lubricant, a stabilizer, a flavoring agent and even an other pharmaceutical effective compound. The pharmaceutical preparations according to the present invention may be prepared by conventional methods. They comprise the various ingredients in the required amounts. The compounds of general formula and the pharmaceutical preparations comprising same are advantageously provided to the patient in a daily dosage of the compound in between 0.01 and 20mg/kg. The present invention consists also in the use of a compound of general formula I and pharmaceutical composition comprising same in the preparation of a medicament. The present invention also consists in a method for the treatment of human beings with a compound of general formula I or with a pharmaceutical preparation comprising same. The present invention consists also in processes for the preparation of compounds of general formula I. The process for the preparation of compounds of general formula I in which R'=CH2OH and R"= a. straight or branched alkyl of 5 to 12 carbon atoms; b. a group-O-R'", where R'" is straight or branched alkyl of 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; c. a group- (CH2)n-0-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms; and where R" is not C5H11; involves 8 steps starting from a compound of general formula I, in which R'=CH3 and R" is one of the substituents indicated above. The process involves blocking of the phenolic groups in order to allow further chemical transformations (step a) followed by selective epoxidation of the ring double bond (step b), selective opening of the epoxide ring to form an allylic alcohol (c), then several steps (d, e, f, g) which by allylic rearrangement lead to the dimethoxy derivative of the desired compound. The final step (h) involves demethoxylation under harsh conditions to form the desired allylic alcohol. The specific process for the preparation of a compound of general formula I in which R' stands for CH2OH and R" stands for 1', 1'-dimethylheptyl (DMH) comprises: a. reacting CBD or the dimethyl heptyl homologue thereof with methyliodide and potassium carbonate in DMF; b. reacting the dimethylether obtained with 3-chlorobenzoic acid to obtain the corresponding epoxide; c. the epoxide obtained being reacted with methyl magnesium N-cyclohexyl- isopropylamide in toluene ; d. the compound obtained in step c being acetylated ; e. the acetylate obtained being reacted with t-butyldimethylsilybromide ; f. the bromide obtained being reacted with(nBu) 4NH4Oac in acetone to obtain the allyl acetate diether; and g. the ether obtained being heated in a sodium hydroxide solution; and h. the compound obtained being heated with methylmagnesium iodide to obtain the required compound. The process for the preparation of compounds of general formula I in which R'=COOH and R"= a. straight or branched alkyl of 5 to 12 carbon atoms; b. a group-O-R'", where R'" is straight or branched alkyl to 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; c. 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 and where R" is not C5 H11 ; involves as starting material an intermediate compound (general formula 6) obtained in the synthesis described in Figs. 3A and 3B. It is exemplified in Figs 3A, 3B and 4, by (6 a) or (6b) in which R" = DMH. The first steps involves demethoxylation of the phenolic groups (step a), followed by acetylation (b). The triacetate with general formula (12) can be rearranged and brominated in a single step (c) to yield a bromide (13) which by oxidation (d, e) andhydrolysis (f) leads to the desired compound. The specific process for the preparation of a compound of general formula I, in which R' stands for COOH and R" stands for DMH comprises: a. the compound obtained in step d above being reacted with methyl magnesium iodide; b. the triol obtained being acetylated ; c. the acetylate obtained being rearranged and brominated to obtain the corresponding bromide; d. the bromide obtained being oxidized with potassium chromate in hexamethylphosphoric triamide; e. the aldehyde obtained being oxidized with sodium chlorite and reacted with an aqueous solution of sodium hydroxide to obtain the desired compound. The above specific processes are illustrated in Figs. 3A, 3B and 4. The starting material of the compounds of general formula I in which R' stands for CH3 and R" stands for a. straight or branched alkyl of 5 to 12 carbon atoms; b. a group-O-R'", where R'" is straight or branched alkyl of 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group; c. a group-(CH2) n-0-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms; and where R" is not C6H11; were prepared of the process exemplified in Fig. 5 in which mentha-2,8-diene-1-ol is condensed with a resorcinol substituted in position 5 (Leite etal.). The present invention will now be illustrated with reference to the following examples and experiments without being limited by same. The references to figures refer to those annexed to the specification. I Examples In all the examples, 1H NMR spectra were measured on a Varian VXR-300S spectrophotometer using TMS as the internal standard. All chemical shifts are reported in ppm. Specific rotations were detected with a Perkin-Elmer 141 polarimeter. Column chromatography was performed with ICN silica gel 60A. Organic solutions were dried over anhydrous magnesium sulfate. Example 1 Dimethoxy-CBD (4a) CBD 1a, (3g, 9.95 mmol) was dissolved in DMF (55 ml). K2C03 (7.35g, 53.3 mmol) and CH3I (2.3 ml, 36.9 mmol) were added and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC (10% Ether/P.E.) till the starting material was disappeared. Then 200ml of water were added and the solution was extracted with Ether. The organic phase was washed with brine till neutral pH, dried on MgS04 and filtered. Removal of the solvent under reduced pressure afforded 3.2 g of the product (yield 98%). (4a): 1H-NMR 8 6.344 (2H, s, Ar), 5.220 (1H, s, olefin), 4.460-4.436 (2H, d, J=7.2 Hz), 4.023-3.971 (1H, m, benzyl), 3.741 (6H, s, OCH3), 2.960-2.869 (1H, td, J=11.5, 4.5 Hz, allyl), 2.717-2.569 (2H, t, J=7.5 Hz, benzyl), 2.259-2.144 (1H, m), 2.018-1.960 (1H, m), 1.789-1.722 (1H, m), 1.678 (3H, s, allyl CH3), 1.568 (6H, br s), 1.352 (4H, m) 0.936-0.890 (3H, t, J=6.8 Hz, terminal CH3). IR: 2875, 1600, 1570, 1440, 1410, 1220, 1100, 880 cm-1. [α]D -96.8 ° (c 12.19 mg/ml, CHCI3) Example 2 Dimethoxy-CBD-DMH (4b) Prepared with the same procedure reported for (4a), with CBD-DMH as starting material. (4b): 1H-NMR 5 6. 449 (2H, s, Ar), 5.238 (1H, s, olefin), 4.422-4.382 (2H, d, J=12.0 Hz), 4.120-3.901 (1H, m, benzyl), 3.784 (6H, s, OCH3), 2.933-2.801 (1H, m, benzyl), 2.270-2.086 (1H, m, allyl), 2.048-1.924 (1H, m), 1.781-1.501 (10H, m), 1.253-1.185 (10H, m), 1.105-0.962 (2H, m) 0.849-0.8816 (3H, t, J=6.8 Hz, terminal CH3). IR: 2900, 1600, 15780, 1440, 1400, 1100 cm-1. [α]D -98.1° (c 2.04 mg/ml, CHCI3) Example 3 1,2 Oxido-dimethoxy-hexahydrocannabinol (5a)3-Chloro-perbenzoic acid (70% pure 1.2 g, 4.85 mmol) was dissolved in 50 ml CH2CI2 and the solution was cooled to 0°C. A solution of (4a) (1.65 g, 4.82 mmol) in 10ml CH2CI2 was slowly injected. The reaction mixture was stirred at 0°C for 30 min and monitored by TLC (10% E:ther/P.E.). The reaction was quenched by addition of a saturated aqueous solution of NaHC03 and the organic phase was separated by a separatory funnel, then the aqueous phase was extracted with ether. The combine organic extracts were washed with brine, dried over MgS04 and filtered. Removal of the solvents under reduced pressure afforded a residue that was flash chromatographed (7% Ether/P.E) to give the epoxy-derivative (5a) (yield 65%). (5a): 1H-NMR S 6.348-6.322 (2H, d, J=7.7 Hz, Ar), 4.369 (1H, s, olefin), 4.159 (1H, s, olefin), 3.-803 (3H, s, OCH3), 3.714 (3H, s, OCH3), 3.612-3.571 (1H, d, J=12.2, Hz, H on epoxide ring), 2.574-2.522 (2H, t, J=7.9 Hz, benzyl), 2.293-2.201 (1H, m), 2.081-1.995 (1H, m), 1.882-1.757 (1H, m), 1.628-1.585 (6H, m), 1.364-1.313 (9H, m), 0.936-0.890 (3H, t, J=6.5 Hz, terminal CH3). IR: 2900, 1610, 1580, 1460, 1420, 1120, 760 cm-1. Example 4 1,2 Oxidodimethoxyhexahydrocannabinol DMH (5b) Prepared with the same procedure reported for (5a), but the yield was slightly better (70%). (5b): 1H-NMR 5 6.466-6.442 (2H, d, J=7.2 Hz, Ar), 4.358 (1H, s, olefin), 4.121 (1H, s, olefin), 3.805 (3H, s, OCH3), 3.719 (3H, s, OCH3), 3.591-3.555 (1H, d, J=10.8, Hz, H on epoxide ring), 2.235-2.193 (1H, m, benzyl), 2.105-1.995 (1H, m, allyl), 1.907-1.761 (1H, m), 1.745-1.514 (10H, m), 1.369 (3H, s, allyl CH3), 1.268-1.180 (10H, m), 1.081-0.942 (2H, m.), 0.856-0.812 (3H, t, J=6.5 Hz, terminal CH3). IR: 2900, 1600, 1580, 1460, 1450, 1210, 1110, 750 cm-1. Example 5 (3R,4R)-3-[2,6-Dimethoxy-4-pentylphenyl]-2-hydroxy-4-isopropenyl-1-methylene cyclohexane (6a) Butyllithium in hexane (5.6 ml, 14 mmol) was added to a 0°C solution of N-cyclohexylisopropylamine (1.85 ml, 11.3 mmol) in anhydrous toluene (10 ml, distilled over sodium) under N2 atmosphere. After 15 min, methylmagnesium bromide in ether (3.8 ml, 11.4 mmol) was injected, and the reaction mixture was stirred for 45 min at room temperature. A solution of (5a) (1g, 2.79 mmol) in dry toluene (3 ml) was added, and the mixture was heated to 40°C and stirred for two hours. Then the reaction was cooled to 0°C and quenched by the slow addition of 5M HCI. The organic phase was separated by a separatory funnel, and then the aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried over MgS04 and filtered. Removal of the solvents under reduced pressure afforded a residue that on TLC (20% Ether/P.E.) showed only one spot, and by 1H-NMR was proved to be (6a) (yield 97%). (6a): 1H-NMR 5 6.332 (2H, s, Ar), 5.083 (1H, s, olefin), 4.821 (1H, s, olefin), 4.662-4.622 (1H, d, J=11.8 Hz, CHOH), 4.387 (1H, s, olefin), 4.379 (1H, s, olefin), 3.798 (3H, s, OCH3), 3.745 (3H, s, OCH3), 3.200-3.154 (1H, td, J=11.2, 3.0 Hz, benzyl), 2.564-2.452 (3H, m), 2.255-1.625 (1H, m), 1.754-1.707 (1H, m), 1.609-1.350 (4H, m), 1.432 (3H, s, allyl CH3), 1.350-1.313 (4H, m), 0.924-0.878 (3H, t, J=6.5 Hz. terminal CH3). IR: 3400, 2920, 1590, 1450, 1120, 900, 730 cm-1. [α]D +62.3 ° (c 15.36 mg/ml, CHCI3) Example 6 (3R,4R)-3-[4-(1 ',1' Dimethylheptyl)-2,6-dimethoxyphenyl]-2- hydroxy- 4-isopropenyl-1-methylenecyclohexane (6b) Prepared with the same procedure reported for (6a). (6b): 1H-NMR 5 6.440 (2H, s, Ar), 5.080 (1H, s, olefin), 4.821 (1H, s, olefin), 4.655-4.621 (1H, d, J=9.0 Hz, CHOH), 4.448 (1H, s, olefin), 4.338 (1H, s, olefin) 3.802 (3H, s, OCH3), 3.744 (3H, s, OCH3), 3.215-3.127 (1H, td, J=11.7, 3.0 Hz, benzyl), 2.505-2.444 (1H, dt, J=12.6, 3.0 Hz allyl), 2.255-2.182 (1H, td, J=9.0, 3.0 Hz), 1.740-1.688 (2H, m), 1.555-1.423 (8H, m), 1.301-1.177 (10H, m), 1.025-0.955 (2H, m), 0.859-0.814 (3H, t, J=6.5 Hz, terminal CH3). IR: 3400, 2900, 1600, 1560, 1450, 1400, 1110, 750 cm-1. [α]D +47.6 ° (c 1.05 mg/ml, CHCI3) Example 7 (3R,4R)-3-[2,6-Dimethoxy-4-pentylphenyl]-2-acetoxy-4 isopropenyl-1 -methylenecyclohexane (7a) (6a) (0.9 g, 2.5 mmol) was dissolved in pyridine (2 ml) and acetic anhydride (2 ml) and the reaction was stirred for 18 hours at room temperature. Then the solution was poured onto iced water (20 ml) and extracted with ether. The combined organic extracts were washed successively with 1N HCI, aqueous sodium bicarbonate and brine, dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded an oily residue that on TLC (20% Ether/P.E.) showed only one spot, that by 1H-NMR was proved to be (7a) (yield -100%). (7a): 1H-NMR 5 6.281-6.267 (2H, d, J=4.2 Hz, Ar), 5.967-5.931 (1H, d, J=10.8 Hz, olefin), 4.767-4.721 (2H, d, J=13.7 Hz, olefin), 4.535 (1H, s, olefin), 4.419 (1H, s, olefin), 3.793 (3H, s, OCH3), 3.745 (3H, s, OCH3), 3.491-3.416 (1H, t, J=11.4 Hz), 3.286-3.197 (1H, td, J=11.4, 2.7, Hz, benzyl), 2.533-2.469 (2H, t, J=7.2 Hz), 2.325-2.249 (1H, m), 1.717 (3H, s, OAc), 1.625-1.447 (6H, m), 1.404-1.250 (6H, m), 0.924-0.878 (3H, t, J=6.5 Hz, terminal CH3). IR: 2910, 1750, 1450, 1360, 1240, 1120, 890 cm-1. Example 8 (3R,4R)-3-[4-(1 ',1 '-Dimethylheptyl)-2,6-dimethoxyphenyl] -2- acetoxy-1 -methylenecyclohexane (7b) Prepared with the same procedure reported for (7a). (7b): 1H-NMR 5 6.409-6.377 (2H, d, J=8.1 Hz, Ar), 5.980-5.931 (1H, d, J=14.5 Hz, CHOAc), 4.768-4.717 (2H, d, J=15.2 Hz, olefin), 4.521 (1H, s, olefin), 4.405 (1H, s, olefin), 3.802 (3H, s, OCH3), 3.754 (3H, s, OCH3), 3.268-3.181 (1H, m, benzyl), 2.522-2.459 (1H, m, allyl), 1.781-1.717 (1H, m), 1.695 (3H, s, OAc), 1.540-1.484 (6H, m), 1.239-1.171 (14H, m), 0.980-0.923 (2H, m), 0.854-0.809 (3H, t, J=6.7 Hz, terminal CH3). IR: 290, 1750, 1450, 1360, 1240, 1120, 880 cm-1. Example 9 7-Bromo-dimethoxy CBD (8a) (7a) (1g, 2.5 mmol) was dissolved in dry CH2CI2 (50 ml, distilled over CaH2) under nitrogen atmosphere and TMSBr (1.6 ml, 12.1 mmol) was added. The reaction was stirred at r.t. for 4 hours, then it was shaken with a saturated aqueous solution of NaHC03 and the organic phase was separated by a separatory funnel, then the aqueous phase was extracted with ether. The combine organic extracts were washed with brine, dried over MgS04 and filtered. Removal of the solvents afforded a residue that 1H-NMR and TLC (20% Ether/P.E.) showed predominantly a single component, that was used immediately with no purification. (8a): 1H-NMR 6 6.322 (2H, s, Ar), 5.736 (1H, s, olefin), 4.767 (1H, s, olefin), 4.454), 4.535 (1H, s, olefin), 4.006 (2H, s, CH2Br), 3.736 (6H, s, OCH3), 2.853-2.767 (1H, td, J=11.9, 3.2 Hz, benzyl), 2.565-2.512 (1H, t, J=7.9, Hz, benzyl), 2.397-2.359 (1H, m), 2.277-2.183 (1H, m), 1.870-1.662 (2H, m), 1.619 (3H, s, allyl CH3), 1.439-1.237 (7H, m), 0.928-0.882 (3H, t, J=6.6 Hz, terminal CH3). IR: 2900, 1580, 1460, 1230, 1120 cm-1. Example 10 7-Bromo-dimethoxy CBD DMH (8b) Prepared with the same procedure reported for (8a). (8b): 1H-NMR 5 6.431 (2H, s, Ar), 5.602 (1H, s, olefin), 4.821-4.337 (4H, m, CH2Br + olefin), 4.042-3.961 (1H, m, olefin), 3.720 (6H, s, OCH3), 3.116-3.010 (1H, m, benzyl), 2.842-2.762 (1H, allyl), 1.782-1.517 (9H, m), 1.247-1.178 (10H, m), 1.010 (2H, br s), 0.831 (3H, br s, terminal CH3). IR: 2910,1580, 1460, 1230, 1120 cm-1 Example 11 7-Acetoxy-dimethoxy CBD (9a) (8a) (570 mg, 1.35 mmol) was dissolved in acetone (15ml, stored on 4A° molecular sieves) and tetrabutylammonium acetate (450 mg, 1.49 mmol). The mixture was stirred, refluxed and monitored by TLC (20% Ether/P.E.). After 2 hours there was no ore starting material. The acetone was removed under reduced pressure, and the residue was diluted with water (20 ml) and extracted with ether. The combine organic extracts were washed with aqueous sodium bicarbonate and brine, dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded 520 mg of an oily residue (96% yield). (9a): 1H-NMR 5 6.320 (2H, s, Ar), 5.581 (1H, s, olefin), 4.492-4.386 (4H, m, CH2OAc + olefin), 4.040-3.986 (1H, m, benzyl), 3.715 (6H, s, OCH3), 2.853-2.801 (1H, m), 2.195-2.071 (2H, m), 2.060 (3H, s, OAc), 1.823-1.695 (2H, m), 1.605 (5H, br s), 1.323 (4H, br s), 0.921-0.875 (3H, t, J=6.7 Hz, terminal CH3). IR: 2900, 1720, 1580, 1440, 1110 cm-1. [α]D -135.2 ° (c 15.95 mg/ml, CHCI3) Example 12 7-Acetoxy-dimethoxy CBD DMH (9b) Prepared with the same procedure reported for (9a), but the yield was slightly worse (90 %). (9b): 1H-NMR 5 6.440 (2H, s, Ar), 5.609 (1H, s, olefin), 4.498-4.343 (4H, m, CH2OAc + olefin), 4.041-3.965 (1H, m, benzyl), 3.719 (6H, s, OCH3), 2.845-2.763 (1H, m, allyl), 2.193-2.099 (2H, m), 2.061 (3H, s, OAc), 1.796-1.776 (2H, m), 1.594-1.518 (7H, m), 1.254-1.179 (10H, m), 1.015 (2H, brs), 0.856-0.861 (3H, t, J=6.4 Hz, terminal CH3). IR: 2900, 1720, 1600, 1580, 1450, 1410, 1220 cm-1. [ab -90.5° (c 2.53 mg/ml, CHCI3) Example 13 7-Hydroxy-dimethoxy CBD (10a) (9a) (500 mg, 1.25 mmol) was dissolved in ethanol (20ml) and NaOH 1N (2 ml) was added and the reaction was refluxed for 1 hour. The ethanol was removed under reduced pressure, and the residue was diluted with water (20 ml) and HCI 2N was added till acid pH. The solution was extracted with ether. The combine organic extracts were washed brine, dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded 430 mg of an oily residue (96% yield). (10a): 1H-NMR 5 6.328 (2H, s, Ar), 5.510 (1H, s, olefin), 4.458-4.414 (2H, d, J=13.2 Hz, olefin), 4.010 (2H, br s, CH2OH), 3.728 (6H, s, OCH3), 2.858-2.806 (1H, m, benzyl), 2.566-2.508 (2H, t, J=7.5 Hz, benzyl), 2.213 (2H, m), 1.817-1.582 (7H, m), 1.451-1.259 (5H, m), 0.924-0.878 (3H, t, J=6.5 Hz, terminal CH3). IR: 3300, 2900, 1580, 1440, 1220, 1110 cm-1. MS m/z (relative intensity): 358 (M+, 7), 327 (52), 290 (80), 221 (100), 152 (33). Exact mass calculated for C25H38O3: 358.25080, found 358.2511. Example 14 7-Hydroxy-dimethoxy CBD DMH (10b) Prepared with the same procedure reported for (10a). (10b): 1H-NMR 5 6.446 (2H, s, Ar), 5.528 (1H, s, olefin), 4.434-4.367 (2H, d, J=20.1 Hz, olefin), 4.010 (3H, br s, CH2OH + OH), 3.729 (6H, s, OCH3), 2.905-2.785 (1H, m, benzyl), 2.248-2.105 (2H, m), 1.759-1.704 (2H, m), 1.535 (3H, s, allyl CH3), 1.495-1.460(4H, m) 1.360-1.120 (10H, m) 0.980-0.9875 (2H, m), 0.797-0.752 (3H, t, J=6.5 Hz, terminal CH3). IR. 3300, 2900, 1600, 1570, 1420, 1400, 1230, 1110, 750 cm-1. [α]D -135.2 ° (c 15.95 mg/ml, CHCI3) MS m/z (relative intensity): 414 (M+, 14), 396 (8), 383 (100), 346 (43), 277 (50), 119 (7). Exact mass calculated for C27H42O3: 358.31340, found 358.3136. Example 15 7-Hydroxy CBD (2a) A Grignard reagent was prepared with magnesium (100 mg, 4.17 mmol) and CH3I (0.26 ml, 4.17 mmol) in dry ether (3ml, distilled over sodium) under N2 atmosphere. (10a) (420 mg, 1.17 mmol) in ether (1 ml) was slowly added to the stirred solution and the ether was distilled off. The residue was heated under N2 atmosphere till 210°C for 45 min. Then the flask was cooled till room temperature and the reaction was quenched with ice water. The aqueous solution was extracted with ether several times. The combine organic extracts were dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded a residue that was chromatographed on silica gel (25% Ether/P.E.) to give 150 mg of the pure (2a) (yield 40 %). (2a): 1H-NMR 5 6.200 (2H, s, Ar), 5.822 (1H, s, olefin), 4.629 (1H, s, olefin), 4.518 (1H,.s, olefin), 4.075 (2H, s, CH2OH), 3.962-3.923 (1H, m, benzyl), 2.567-2.484 (1H, td, J=13.3, 2.7 Hz, allyl), 2.435-2.384 (2H, t, J=7.5 Hz, benzyl), 1.882-1.734 (2H, m), 1.660 (6H, s. allyl CH3), 1.584-1.487 (2H, m), 1.285-1.248 (6H, m), 0.886-0.843 (3H, t, J=6.3 Hz, terminal CH3). IR: 3300, 2900, 1620, 1580, 1440, 1240, 1020, 730 cm-1. [α]D -67.3 ° (c 19.51 mg/ml, CHCI3) MS m/z (relative intensity): 330 (M+, 10), 312 (44), 299 (53), 284 (44), 244 (100), 231(56), 187(29), 147(13). Exact mass calculated for C21H30O3: 330.21949, found 330.2231. Example 16 7-Hydroxy CBD-DMH (2b) Prepared with the same procedure reported for (2a). (2b): 1H-NMR 5 6.335 (2H, s, Ar), 5.863 (1H, s, olefin), 4.652 (1H, s, olefin), 4.538 (1H, s, olefin), 4.108 (2H, s, CH2OH), 3.920-3.889 (1H, d, J = 9.3 Hz, benzyl), 2.498-2.433 (1H, m, allyl), 2.228 (2H, brs), 2.064-1.715 (2H, m), 1.648-1.428 (7H, m), 1.312-1.168 (12H, m), 0.853-0.808 (3H, t, J=6.5 Hz, terminal CH3). IR: 3300, 2900, 1620, 1580, 1420, 1210, 1020, 750 cm-1. [Α]D-61.1 ° (c 1.8 mg/ml, CHCI3) MS m/z (relative intensity): 386 (M+, 24), 369 (30), 368 (30), 355 (100), 300 (43), 287 (510), 283 (34), 249 (38), 233 (22), 187 (10). Exact mass calculated for C25H3803: 386.28210, found 386.2825. Effects of CBD (1a), 7-hydroxy-CBD (2a) (Example 15) and of 7-hydroxy-CBD-DMH (2b) (Example 16) and of indomethacin 30 min after arachidonic acid (A' A) induced, as shown in Fig. 1, swelling of the ear. Mice (female Sabra) were treated with 4.5 mg A' A (in 5 ul EtOH) dispersed on the inner surface of one of the ears. The other ear was treated with 5 ul of EtOH. Ear swelling was assessed by measuring ear thickness with a dial thickness gauge (Mitutoyo, Japan) just before treatment and 30 min after A; A application. The drugs (40 mg/kg for the cannabinoids and 20 mg/kg for indomethacin) were injected i.p. 60 min before the A' A treatment. *** indicates p Example 17 (3R,4R)-3-[2,6-Dihydroxy-4-pentylphenyl]-2-hydroxy-4-isopropenyl-1-methylene cyclohexane (11a) A Grignard reagent was prepared with magnesium (84 mg, 3.5 mmol) and CH3I (0.2 ml, 3.5 mmol) in dry ether (1 ml, distilled over sodium) under N2 atmosphere. (6a) (360 mg, 1 mmol) in ether (0.5 ml) was added to the stirred solution and the ether was distilled. The residue was heated under N2 atmosphere till 210°C for 45 min. Then the flask was cooled till room temperature and the reaction was quenched with ice water. The aqueous solution was extracted several times with ether. The combined organic extracts were dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded a residue that was chromatographed on silica gel (25% Ether/ P.E.) to give 132 mg of the pure (11a) (yield 40 %). (11a): 1H-NMR 8 6.156-6.097 (2H, d, J= 17.7 Hz, Ar), 5.612 (1H, s, OH), 5.370 (1H, s, OH), 5.092 (1H, s, olefin), 4.847 (1H, s, olefin), 4.684-4.625 (2H, m, CHOH + olefin), 4.462 (1H, s, olefin), 3.300-3.205 (1H, td, J=12.7, 2.7 Hz, benzyl), 3.128-3.058 (1H, t, J=10.5, Hz, allyl), 2.270-2.141 (1H, m), 2.122-2.049 (1H, br s, OH), 1.767-1.712 (1H, m), 1.534-1.48 (5H, m), 1.290-1.183 (4H, m), 0.895-0.881 (3H, t, J=6.6 Hz, terminal CH3). IR: 3350, 2900, 1620, 1580, 1420, 1160, 1000, 750 cm-1. Example 18 (3R,4R)--3-[4-(1',1'-Dimethylheptyl)-2,6-dihydroxyphenyl]-2-hydroxy-4-isopropen yl-1-methylenecyclohexane (11b) Prepared with the same procedure reported for (11a), but the yield was slightly better (45%). (11b): 1H-NMR 8 6.295 (1H, s. Ar), 6.229 (1H, s, Ar), 5.786 (1H, s, OH), 5.546 (1H, s, OH), 5.127 (1H, s, olefin), 4.861 (1H, s, olefin), 4.751-4.716 (1H, d, J=3.3 Hz, CHOH), 5.127 (1H, s, olefin), 4.444 (1H, s, olefin), 3.421-3.276 (1H, m, benzyl), 3.132-3.062 (1H, t, J=10.5, Hz, allyl), 2.502-2.459 (1H, d, J=12.9 Hz), 2.251-2.175 (2H, m), 1.780-1.739 (1H, m), 1.528 (3H, s, allyl CH3) 1.460-1.433 (4H, m), 1.251-1.170 (10H, m), 0.954 (2H, brs) 0.845 (3H, br s, terminal CH3). IR: 3300, 2900, 1620, 1580, 1410, 1210, 750 cm-1. [α]D +47.3 ° (c 1.48 mg/ml, CHCI3) if. Example 19, (3R,4R)-3-[2,6-Diacetoxy-4-pentylphenyl]-2-acetoxy-4-isopropenyl-1-methylenec yclohexane (12a) (11a) (100 mg, 0.3 mmol) was dissolved in pyridine (0.5 ml) and acetic anhydride (0.5 ml) and the reaction was stirred for 18 hours at room temperature. Then the solution was poured onto iced water (10 ml) and extracted with ether. The combine organic extracts were washed successively with 1N HCI, aqueous sodium bicarbonate and brine, dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded 136 mg of an oily residue that by NMR was proved to be (12a) (yield ~100%). (12a): 1H-NMR 8 6.861 (1H, s, Ar), 6.696 (1H, s, Ar), 5.725-5.688 (1H. d, J=11.1 Hz, CHOAC), 4.083 (1H, s, olefin), 4.689 (1H, s, olefin), 4.540-4.515 (2H, d, J= 7.5 Hz, olefin), 3.180-3.105 (1H, t, J=11.3 Hz, benzyl), 2.893-2.802 (1H, td, J=11.3, 3.2 Hz, allyl), 2.563-2.513 (2H, t, J=7.5, Hz, benzyl), 2.374 (3H, s, OAc), 2.280 (3H, s, OAc), 1.798 (3H, s, OAc), 1.614-1.470 (5H, m), 1.286-1.246 (8H, m), 0.886-0.844 (3H, t, J=6.3 Hz, terminal CH3). IR: 2910, 1750, 1410, 1350, 1180, 1130, 890 cm-1. Example 20 (3R,4R)-3-[2,6-Diacetoxy-4-(1 \1' dimethylheptyl)phenyl]-2-acetoxy- 4-isopropeny 1-1 -methylenecyclohexane (12e) Prepared with the same procedure reported for (12a). (12b): 1H-NMR 5 6.947 (1H, s, Ar), 6.795 (1H, s, Ar), 5.732-5.695 (1H, d, J=11.0 Hz, CHOAC), 4.798 (1H, s, olefin), 4.691 (1H, s, olefin), 4.540-4.515 (2H, d, J= 7.5 Hz, olefin), 3.167-3.095 (1H, t, J=11.3 Hz, benzyl), 2.854-2.816 (1H, m, allyl), 2.561-2.515 (1H, d, J=13.8, Hz, benzyl), 2.372 (3H, s, OAc), 2.287 (3H, s, OAc), 2.230-2.195 (1H, m), 1.825-1.770 (4H, m), 1.538-1.424 (6H, m), 1.224-1.151 (12H, m), 0.955-0.945 (2H,m) 0.840-0.799 (3H, t, J=6.1 Hz, terminal CH3). IR: 2900, 1750, 1410, 1360, 1180, 1130,890 cm-1. Example 21 7-Bromo-diacetate CBD (13a) (12a) (100 mg, 0.2 mmol) was dissolved in dry CH2CI2(10 ml, distilled over CaH2) under nitrogen atmosphere. TMSBr (0.13 ml, 1 mmol) and Znl2 (3.4 mg, 0.01 mmol) were added. The reaction was stirred at r.t. for 4 hours, then it was shaken with a saturated aqueous solution of NaHCO3 and the organic phase was separated by a separatory funnel, then the aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried over MgS04 and filtered. Removal of the solvents afforded a residue that was used immediately with no purification. (13a): 1H-NMR 5 6.764 (2H, s, Ar), 5.456 (1H, s, olefin), 4.901 (1H, s, olefin), 4.752 (1H, s, olefin), 3.930- 3.903 (2H, m, CH2Br), 3.784-3.756 (1H, d, J= 8.2 Hz, benzyl), 2.592-2.643 (2H, m,), 2.306 (6H, s, OAc), 2.198-2.131 (2H, t, J=10.2 Hz), 1.708 (3H, s, allyl CH3), 1.698-1.472 (4H, m), 1.439-1.194 (5H, m), 0.090-0.865 (3H, t, J=5.3 Hz, terminal CH3). IR: 2900, 1750, 1360, 1200, 1020, 900, 720 cm-1. Example 22 7-Bromo-diacetate CBD DMH (13b) Prepared with the same procedure reported for (13a). (13b): 1H-NMR 5 6.816 (2H, s, Ar), 5.645 (1H, s, olefin), 4.557 (1H, s, olefin), 4.448 (1H, s, olefin), 4.016 - 3.966 (2H, m, CH2Br), 3.483-3.405 (1H, m, benzyl), 2.655-2.459 (1H, m, allyl), 2.220 (6H, s, OAc), 1.883-1.637 (4H, m), 1.510 (3H, s, allyl CH3), 1.485-1.426 (4H, m), 1.410-1.176 (10H, m), 1.010-0.995 (2H,m) 0.853-0.807 (3H, t, J=6.5 Hz, terminal CH3). IR: 2900, 1750, 1370, 1220, 1020, 900, 750 cm-1. Example 23 7-Nor-formyl-diacetate CBD (14a) ;(13a) (100 mg, 0.21 mmol), 18-Crown-16 (55.4 mg, 0.21 mmol) and K2Cr04 (50.9 mg, 0.26 mmol) were dissolved in anhydrous HMPT (2 ml, distilled under vacuum and stored over 4A° molecular sieves). The mixture was stirred and heated at 110°C for 2 hours. The reaction was cooled and quenched by addition of 1M HCI and the aqueous phase was extracted with ether. The organic phase was washed with brine, dried over MgSO4 and filtered. Removal of the solvent under reduced pressure afforded a residue that was chromatographed on silica gel (20% Ether/ PE.) to give 27.7 mg of the pure (14a) (yield 32 %). (14a): 1H-NMR 5 9.434 (1Hs CHO), 6.778 (2H, s, Ar), 6.638 (1H, s, olefin), 4.633 (1H, s, olefin), 4.489 (1H, s, olefin), 3.746-3.718 (1H, d, J= 8.4 Hz, benzyl), 2.686-2.552 (4H, m), 2.304-2.075 (6H, br s), 1.965-1.921 (1H, m), 1.754-1.590 (6H, m), 1.318-1.305 (5H, m), 0.909-0.865 (3H, t, J=6.2 Hz, terminal CH3). IR: 2900, 1750, 1670, 1160, 1020 cm-1. [α]D -111.5 ° (c 3.5 mg/ml, CHCI3) Example 24 7-Nor-formyl-diacetate CBD DMH (14b) Prepared with the same procedure reported for (14a), but the yield was slightly worse (28 %). (14b): 1H-NMR 5 9.420 (1Hs CHO), 6.861 (2H, s, Ar), 6.501 (1H, s, olefin), 4.611 (1H, s, olefin), 4.455 (1H, s, olefin), 3.705-3.671 (1H, m, benzyl), 2.667-2.552 (3H, m), 2.292-2.071 (6H, br s, OAc), 1.960-1.890 (2H, m), 1.601 (3H, s, allyl CH3), 1.590-1.485 (4H, m), 1.241-1.711(8H, m) 1.100 -0.931 (2H, m) 0.854-0.865 (3H, t, J=5.7 Hz, terminal CH3). IR: 2900, 1750, 1660, 1160, 1020 cm-1. [α]D -85.7 ° (c 1.4 mg/ml, CHCI3) Example 25 7-Nor-carboxy-diacetate CBD (15a) NaCI02 (80% pure 82.6 mg, 0.73 mmol) was added in small quantities to a stirred mixture of (14a) (70 mg, 0.17 mmol), 2-Methyl-2-butene (0.45 ml, 4.25 mmol), a saturated aqueous solution of KH2PO4(0.2 ml) in t-Butanol (4 ml). The reaction was stirred at room temperature for 5 hours, and monitored by TLC (50% Ether/ P.E.). Then water was added (20 ml) and the mixture was extracted several times with Ethyl Acetate. The organic phase was washed with brine, dried over MgS04 and filtered. Removal of the solvent under reduced pressure afforded a residue that was chromatographed on silica gel (30% Ether\ PE.) to give 61.8 mg of the (15a) (yield 85%). (15a): 1H-NMR 5 6.939 (1H, s, olefin), 6.770 (2H, s, Ar), 4.611 (1H, s, olefin), 4.462 (1H, s, olefin), 3.618-3.718 (1H, m, benzyl), 2.589-2.538 (3H, m, allyl + benzyl), 2.212 (6H, s, OAc), 1.961 -1.862 (1H, m), 1.858-1.641 (1H, m), 1.592 (5H, br s), 1.321-1.255 (7H, m), 0.903-0.858 (3H, t, J=6.8 Hz, terminal CH3). IR: 3300, 2900, 1750, 1270, 1020 cm-1. Example 26 7-Nor-carboxy-diacetate CBD DMH (15b) Prepared with the same procedure reported for (15a). (15b): 1H-NMR 8 6.946 (1H, s, olefin), 6.854 (2H, s, Ar), 4.592 (1H, s, olefin), 4.436 (1H, s, olefin), 3.635-3.590 (1H, m, benzyl), 2.605-2.455 (1H, m, allyl), 2.208 (6H, s, OAc), 1.950-1.803 (2H, m), 1.795-1.610 (2H, m), 1.574 (3H, s, hhallyl CH3), 1.529-1.475 (4H, m), 1.267-1.174 (10H, m), 1.022 (2H. br s), 0.845-0.805 (3H, t, J=6.6 Hz, terminal CH3). IR: 3300, 2900, 1750, 1270, 1020 cm-1. Example 27 7-Nor-carboxy CBD (3a) (15a) (50 mg, 0.12 mmol) was dissolved in ethanol (10ml) and 1N NaOH (0.5 ml) was added and the reaction was refluxed for 1 hour. The ethanol was removed under reduced pressure, and the residue was diluted with water (20 ml) and the mixture was acidified with 2N HCI. The solution was extracted with ether. The combine organic extracts were washed brine, dried on MgS04 and filtered. Removal of the solvents under reduced pressure afforded a residue that was chromatographed on silica gel (30% Ether\ PE.) to give 38.2 mg of the (3a) (yield 95%). (3a): 1H-NMR 5 7.085 (1H, s, olefin), 6.173 (2H, s, Ar), 4.604-4.566 (2H, d, J=11.4 Hz, olefin), 4.115-4.033 (1H, m, benzyl), 2.799-2.688 (1H, m, allyl), 2.623-2.541 (1H, ;fn), 2.444-2.391 (2H, t, J=7.5 Hz), 1.950-1.869 (1H, m), 1.803-1.669 (5H, m), '1.623-1.453 (4H, m), 1.309-1.178 (5H, m), 0.902-0.857 (3H, t, J=6.5 Hz, terminal CH3). IR: 3350, 2950, 1700, 1440, 1400, 1160, 920, 740 cm-1. [α]D-112.3°(c 1.87mg/ml, MeOH) Example 28 7-Nor-carboxy CBD DMH (3b) Prepared with the same procedure reported for (3a). (3b): 1H-NMR 5 7.121 (1H, s, olefin), 6.291 (2H, s, Ar), 4.619-4.555 (2H, d, J=19.1 Hz, olefin), 4.036-4.033 (1H, d, J=8.9 Hz, benzyl), 2.718-2.567 (2H, m), 2.378-2.274 (1H, m), 1.948-1.904 (1H, m), 1.828-1.765 (1H, m), 1.648 (3H, s, allyl CH3) 1.622-1.430 (4H, m), 1.236-1.189 (8H, m), 1.001-0.965 (2H, m), 0.878-0.837 (3H, t, J=6.2 Hz, terminal CH3). IR: 3330, 2900, 1700, 1420, 1160, 920, 740 cm-1. [α]D -86.7 ° (c 2.05 mg/ml, CHCI3) The effect of various doses of CBD-7-oic acid (3a) (Example 28), and of CBD-DMH-7-oic acid (3b) (Example 28) and of indomethacin (20 mg/kg) after arachidonic acid-induced swelling of the ear are shown in Fig.2. The effects were measured over 75 min after the administration of arachidonic acid. The experimental details are identical to those described for the testing of CBD (1a) and derivatives thereof. *** indicates p A. Cannabinoid dose 80 mg/kg; indomethacin 20 mg/kg B. Cannabinoid dose 40 mg/kg; indomethacin 20 mg/kg C. Cannabinoid dose 5 mg/kg; indomethacin 20 mg/kg II. Pharmacological Activity Antiinflammatory activity The results presented in Figs 1,2 indicate that the CBD metabolites 2a and 3a, as well as their dimethylheptyl homologs 2b and 3b are antiinflammatory. Fig 1 shows that the results with 2a and 2b significantly differ from those with the control solution. However both compounds (at 40 mg/kg) are less active than the potent antiinflammatory drug indomethacin (at 20 mg/kg). Fig 1 also indicates that the antiinflammatory effects of 2a and 2b (at 40 mg/kg), although lower than those of indomethacin (at 20 mg/kg), parallel its action for at least about 90 min. It has previously been shown that some cannabinoids exhibit biphasic effects in various assays (Sulcova et al., Pharmacol. Biochem. Behav. 59.1998). Hence we looked at the antiinflammatory effects of 3a and 3b over a wide range of doses (Fig 2). The effect of the acids at 40 mg/kg, i.p. was found to be essentially equivalent to that of indomethacin (20 mg/kg, i.p.). Both 3a and 3b at 80 mg/kg were less effective than indomethacin (20 mg/kg). However at 5 mg/kg, 3b fully suppressed the inflammation and was comparable to indomethacin (20 mg/kg). Compound 3a was less active than 3b at 5 mg/kg. In another line of experiments it was found that the above described compounds in particular cannabidiol-7-oic acid (15a) and cannabidiol- DMH- 7-oic acid (15b) inhibit in vitro up to 90% TNFα production by murine macrophages and by the monocytic cell line RAW 264.7. The inhibition is dose dependent (10 µg - 0.001 µg/ml). Tables of results are attached in following Tables A and B. Table A Effect of cannabidiol-DMH-7-oic acid on TNFα production by (A) Thioglycollate-elicited macrophages (TGMMφ) and (B) RAW 264.7 mouse monocytic cell line. A TGMφ TNFa Titer (S50) After 24 hrs. Agent Dose S50 % inhibition µg/ml LPS 629 LPS+ 10 159 81 HU-320* LPS+HU-320* 5 406 51 LPS+HU-320* 1 501 40 LPS+HU-320* 0.01 535 36 A representative experiment of 6 performed. *HU-320 is the code name for cannabidiol-DMH-7-Oic acid (15b in Fig. 4). Table B TNFa Titer. Agent Dose S50 % inhibition µg/ml LPS+HU-320* 10 615 91 4 2300 65 1 2384 63 0.1 357.6 45 0.01 5818 11 LPS 6543 *HU-HU-320 is the code name for cannabidiol-DMH-7-oic acid (15b in Fig 4). This anti TNFa effect is also seen in vivo. High levels of TNFa appear in serum of mice after ip injection of 5 mg/kg/mouse lipopolysaccharide (LPS). Administration of cannabidiol-DMH-7-oic acid (15b) in 2 different doses 0.5 and 5 mg/kg simultaneously with LPS, suppressed serum TNFa level. At the lower dose of 0.5 mg/kg 80% suppression of TNFa level was observed. The same effect was observed with other compounds described herewith. Thus 7-hydroxy-CBD (2a) in doses of 10 µg/kg i.p. suppressed serum TNFa in mice (30%). The above compounds in particular 7-hydroxy-cannabidiol (2a) and 7-hydroxy-cannabidiol-DMH (2b) also inhibit markedly nitric oxide (NO) generation by murine macrophages (up to 90%). Oxygen radicals intermediate (ROI) generation by macrophages, assayed by chemiluminescence, demonstrated almost total inhibition (up to 95%) when the cells were incubated with cannabidiol-7-oic acid (15a) and cannabidiol-DMH-7-oic acid (15b). Table of results are attached in following Table C. Table C HU-320 and HU-319 inhibit Zymusan-induced release of reactive oxygen intermediates by monocytic RAW 264.7 cells. Treatment of RAW Chemiluminescense Inhibition peak % (1) Zymosan 8915 Zymosan + HU-320*4 µg/ml 1524 83 Zymosan+ HU-320*10 µg/ml 432 95 (2). Zymosan 5992 Zymosan + HU-319**4 µg/ml 4139 31 Zymosan + HU-319** 10 µg/ml 1041 83 *HU-320 is the code name for cannabidiol-DMH-7-oic acid (15b in Fig. 4) **HU-319 is our code name for cannabidiol-7-oic acid (15a in Fig. 4) The experimental methods used have been described in Gallily et al. (Eur. J. Pharmacol. 406, R5-R7, 2000), Avron and Gallily (J. Leukocyte Biol. 57, 264-268, 1995) and Gallily et al. (J. Pharmacol. Exp. Ther. 283, 918-924, 1997). The above results indicate that 7-hydroxy-CBD (2a) and 7-hydroxy-CBD-DMH (2b) show antiinflammatory activity. The acids 3a and 3b are much more promising, with 3b (at 5 mg/kg) being as potent as indomethacin (at 20 mg/kg). Said acids show also some analgesic activity. In view of the potent activity of 7-hydroxy-CBD-DMH (2b) and in particular of CBD-DMH-7-oic acid (3b) numerous additional side chain homologs were prepared. They were synthesized according to Figs. 3A and 3B, the starting resorcinol derivatives being: 5-(1,2-dimethyl heptyl)-resorcinol 5-(1,2-dimethyloctyl) resorcinol 5-(1,2-dimethylhexyl) resorcinol 5-(1,1-dimethyl heptyl) resorcinol 5-(1-ethyl-2-methylpropyl) resorcinol 5-methylnonyl resorcinol 5-(1-methylnonyl) resorcinol 5-(1-methyloctyl) resorcinol 5-(1,2,4-trimethylhexyl) resorcinol 5-(1-ethylheptyl) resorcinol leading to CBD-type compounds derived from compound type 16. These were converted into the respective homologs 17 and 18, following the synthetic Figs. 3 and 4. There have also been used 5-substituted resorcinols in which the side-chain contains an ether such as OCH3, OC2H5, OC3H7(n), OC4H9(n), OCH(CH3)2, OCH(CH3)C2H5, OCH2CH(CH3) etc. A further group we used was based on 5 substituted resorcinols in which the alkyl group was substituted: 0-CH(CH3)(CH2)4CH3 0-CH(CH3)CH2CH2C6H5 0-CHCH3)CH2CH2CH2C6H5 Antinociceptive activity It has been found that 2a, 2b, 3a and 3b attenuate the late phase of pain behavior produced by formalin-induced chemical change. Thus mice injected with formalin (3.2% dissolved in saline) licked their paws 8 + 2 times over 5 min, recorded 30 min after the formalin administration. All four compounds, 2a, 2b, 3a, 3b (20 mg/kg each) fully blocked the licking. Antianxiety and anticonvulsive effects Preliminary data indicated that in addition to the antiinflammatory and analgesic effects the metabolites 2a and 3a and the homologs 2b and 3b have antianxiety and anticonvulsive effects. Preliminary data also indicate that compounds described herein, such as 1a, 1b, 2a and 2b prevent the uptake of endocannabinoids into neuronal cells and may thus prolong their activity. This action may explain the antianxiety and anticonvulsive activity of these compounds. Anticancer effects It has been found that cannabidiol and other compounds such as cannabidiol-DMH-7-oic acid (15b) described in this specification cause high rate of programmed cell death (apoptosis) in human HL-60 promyelecytic leukemia cells. The apoptosis was cannabinoid dose dependent (0.1 µg/ml to 8 µg/ml). Moreover a very marked.synergism reaching up to 85% of apoptosis was seen when HL-60 cells were irradiated by y ray (800 rad) and treated with cannabidiol and/or other compounds described. The method used, namely determination by the fluorescent Hoechst 33258 stain, is described by T.R.Chen (Cell Res. 104, 255-262,1977). A Table of results is appended in following Table D. Table D Apoptosis of HL-60 induced by CBD alone or together with y-irradiation Treatment with % apoptosis y-irradiation** % apoptosis canabinoid + cannabinoid (1). Control 15 Control 26 1µg/mlCBD 19 1 µg/ml CBD 28 4 µg/ml CBD 33 4 µg/ml CBD 45 8 µg/ml CBD 48 8 µg/ml CBD 85 (2). Control 10 Control 15 5 µg/ml HU-320*** 15 5 µg/ml HU-320 25 10 µg/ml HU-320*** 27 10 µg/ml HU-320 58 * The cells were incubated with the cannabinoid for 24h. ** Irradiation (800 rad) by Gammacell 220 Excel *** HU-320 is the code name for cannabidiol-DMH-7-oic acid (15b in Fig. 4). Ill Receptor Binding Assays The CB1 binding assays were performed with synaptosomal membranes prepared from rat brains (Devane et al., 1992). The CB2 assays were performed with transfected cells (Mechoulam et al., 1995). All assays were done in triplicate. The previously described probe [3H]HU-243 was employed in a centrifugation-based ligand binding assay (Devane et al., 1992a, Devane et al., 1992b). It has a Ki value of 45 + 7 pM. Animals and Drugs Female Sabra mice (2 months old, Harlan-Sprague Dawley, Jerusalem) were used for a series of tests and for the assays for inflammation and peripheral pain. Groups of mice were used in each experiment. Compounds 2a, 2b, 3a and 3b were dissolved in vehicle (ethanoliemulphorsaline=1:1:18) and injected intraperitoneally (i.p.) in volumes of 0.1 ml/10g in mice as previously described (Hanusetal., 1999). The experiments on animals were performed according to standards determined by the committee on ethics in animal research of the Hebrew University of Jerusalem. Arachidonic acid-induced ear inflammation in the mouse Ear inflammation was measured by assessing ear tissue swelling after topical application of arachidonic acid. Nonsteroidal anti- inflammatory drugs have been shown to reduce swelling in this model (Young et al., 1984). Sixty minutes after i.p. injections of the drug, namely the CBD derivatives or indomethacin, arachidonic acid was applied to the inner surface of one ear (4.5 mg in 5 µl ethanol). The opposite ear served as control (5 µl ethanol). Ear thickness was determined (in 0.01 mm units) every 15 min for 90 min starting immediately after arachidonic acid application using 3 dial thickness gauge (Mitutoyo, Japan). Peripheral pain Pain mediated by the peripheral nervous system, was tested in the 'formalin test' for cutaneous (peripheral) pain (Tjolson et al., 1992; Calignano et al., 1998; Jaggar et al, 1998). The compound tested (or vehicle) was injected i.p. Formalin (3.2% dissolved in saline) was injected s.c. in the plantar surface of the hind paw of a mouse (in 20µl volumes) 90 min after the drug. Immediately after formalin administration nociception was assessed (every 5 min for 1 hr) by the number of times the animal licks for formalin-injected paw. Statistical analyses Time curves were compared by two-way analyses-of-variance (ANOVA: time x dose). Differences from vehicle treatments were compared by one-way ANOVA.s, followed by post-hoc Newman-Keuls tests (Prism software from Graph Pad, San Diego). We claim: 1. A cannabidol derivative of general Formula I (Formula Removed) wherein R' stands for COOH or CH2OH and R" stands for a. straight or branched alkyl of 5 to 12 carbon atoms; b. a group-O-R"', where R'" is straight or branched alkyl of 5 to 9 carbon atoms, or a straight or branched alkyl of 5 to 12 carbon atoms substituted at the terminal carbon atom by a phenyl group; c. a group- (CH2) n-0-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms; and where R" is not C5H11. 2. A cannabidol derivative as claimed in claim 1, wherein R" stands for 1, 1 dimethylheptyl. 3. A cannabidol derivative as claimed in claim 1, wherein R" stands for 1. 2 dimethylheptyl. 4. A cannabidol derivative as claimed in claim 1, wherein R1 = CH2OH. 5. A cannabidol derivative as claimed in claim 1. wherein R'=CH20H and R"= l1, dimethylheptyl (DMH). 6. A cannabidol derivative as claimed in claim 1. wherein R-COOH. 7. A cannabidol derivative as claimed in claim 1, wherein R'=COOH and R"= l1, l1- dimethylheptyl (DMH). 8. A pharmaceutical composition comprising cannabidol derivative as claimed in claim 1. together with known excipients wherein the composition is in a physical form of a tablet, a capsule, a granule or a suspension. 9. A process for preparation of cannabidol derivative of general formula I as claimed in claim 5, comprising the steps of: a. reacting cannabidol or dimethyl heptyl homologue thereof with methyliodide and potassium carbonate in DMF to obtain a dimethylether; b. reacting the dimethylether with 3-chlorobenzoic acid to obtain corresponding epoxide; c. reacting the epoxide obtained with methyl magnesium N-cyclohexyl- isopropylamide in toluene; d. acylating the compound obtained in step c to obtain an acetate; e. reacting the acetate obtained with reacted with t- butyldimefhylsilybromide; f reacting the bromide obtained with (nBu)4NH40ac in acetone to obtain allyl acetate diether; and g. heating the ether obtained in a sodium hydroxide solution; and h. further heating the compound obtained in step g with methyl magnesium iodide to obtain the required compound.. 10. A cannabidol derivative of general Formula I as claimed in claim 1 and a process for preparation of cannabidol derivative as claimed in claim 9 substantially such as herein described with reference to the accompanying drawings and as illustrated in the foregoing examples.

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