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  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
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Definitions

• the present invention relates generally to compounds exhibiting cannabimimetic activity and is more particularly concerned with new and improved cannabimimetic compounds exhibiting preferentially high binding affinities for the CB2 cannabinoid receptor, methods of preparation of such compounds, pharmaceutical preparations employing these compounds and methods of administering therapeutically effective amounts of these compounds to provide a physiological effect.
• Classical cannabinoids such as the marijuana derived cannabinoid 9 -tetrahydrocannabinol, ( 9 -THC) produce their pharmacological effects through interaction with specific cannabinoid receptors in the body. So far, two cannabinoid receptors have been characterized: CB1 , a central receptor found in the mammalian brain and peripheral tissues and CB2, a peripheral receptor found only in the peripheral tissues. Compounds that are agonists or antagonists for one or both of these receptors have been shown to provide a variety of pharmacological effects.
• novel cannabimimetic compounds can be represented by the structural Formula I, physiologically acceptable salts, diasteromers, enantiomers, double bond isomers or mixtures thereof.
• R comprises C-,. 6 alkoxy; N-alkyl; S-alkyl; C ⁇ haloalkoxy; C ⁇ alkylketo; C
• R 1 comprises C ⁇ alkoxy; N-alkyl; S-alkyl; C ⁇ haloalkoxy; C ⁇ alkylketo; C,_ 6 alkylthioketo; CO 2 H; CONR 6 R 7 where R 6 and R 7 each independently comprise H, lower alkyl and carbalkoxyloweralkyl; ester; thioester; reversed ester; reversed thioester; reversed amide; wherein R5 comprises methoxy, ethoxy, propoxy, methyl, amino, methylamino, ethylamino, butylamino,
• R 2 and R 3 each independently comprise phenyl; benzyl; ⁇ -naphthyl; methylene- ⁇ -naphthyl; ⁇ -naphthyl; methylene- ⁇ -naphthyl; 5 or 6 membered heteroaromatic rings comprising 1 to 3 heteroatoms each independently selected from N, O, and S, provided that no more than 1 heteroatom is O or S; methylene- 5 or 6 membered heteroaromatic rings comprising 1 to 3 heteroatoms each independently selected from N, O, and S, provided that no more than 1 heteroatom is O or S; any of the above comprising up to 3 substituents independently selected from halo, hydroxyl, amino, lower alkyl amino, C ⁇ alkyl, C.,_ 6 alkoxy, C,_ 6 alkylthio, CN, CF 3 , CO 2 H, CONR 6 R 7 where R 6 and R 7 each independently comprise H, lower alkyl or carbalkoxyloweral
• each X independently comprises CH or N to yield either carbocyclic rings or heterocyclic rings. It should be understood that when each X is CH, the invention in any aspect encompasses the corresponding benzene derivatives i.e. 1 ,4- dihydrobenzenes.
• a preferred novel cannabimimetic compound can be represented by structural Formula II,
• R 4 and R 5 each independently comprise methoxy, ethoxy, propoxy, methyl
• R 2 and R 3 each comprise phenyl.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises N;
• R 4 comprises ethoxy
• R 5 comprises methyl, -O or or an enantiomer thereof
• R 2 and R 3 each comprise phenyl.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises N;
• R 4 and R 5 each comprise ethoxy
• R 2 and R 3 each independently comprise p-NO2 substituted phenyl, p-CI substituted phenyl, p-Br substituted phenyl, p-OMe substituted phenyl, o, p-dichloro substituted phenyl, 1 -napthyl or phenyl ketone.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises N;
• R 4 and R 5 each comprise ethoxy
• R 2 comprises phenyl
• R 3 comprises p-CI substituted phenyl or 1 -napthyl.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises N;
• R 4 and R 5 each comprise ethoxy
• R 2 comprises p-Br substituted phenyl
• R 3 comprises p-CI substituted phenyl.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises CH;
• R 4 and R 5 each comprise ethoxy
• R 2 and R 3 each comprise phenyl.
• a preferred novel cannabimimetic compound can be represented by structural Formula II wherein: X comprises N;
• R 4 and R 5 each comprise ethoxy
• R 2 and R 3 each comprise napthyl.
• the invention in any aspect also encompasses any of physiologically acceptable salts, diasteromers, enantiomers, double bond isomers and mixtures of the above inventive compounds.
• each X is CH
• the invention in any aspect encompasses the corresponding benzene derivatives i.e. 1 ,4-dihydrobenzenes.
• the compounds represented by structural Formula II are also encompassed within the broader invention represented by structural Formula I.
• alkyl refers to a linear, branched or cyclic alkyl group having from 1 to about 9 carbon atoms including, for example, methyl, ethyl, propyl, butyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclooctyl, vinyl and allyl.
• the alkyl group can be saturated or unsaturated and substituted or unsubstituted.
• lower-alcohol refers to the general formula alkyl-OH.
• alkoxy refers to the general formula -O-alkyl.
• alkylmercapto refers to the general formula -S- alkyl.
• alkylamino refers to the general formula -(NH)-alkyl.
• di-alkylamino refers to the general formula -N-(alkyl) 2 .
• an aromatic ring is an unsaturated ring structure, substituted or unsubstituted, that includes only carbon as ring atoms.
• a heteroaromatic ring is an unsaturated ring structure, substituted or unsubstituted, that has carbon atoms and one or more heteroatoms, including oxygen, nitrogen and/or sulfur, as ring atoms, for example, pyridine, furan, quinoline, and their derivatives.
• a carbocyclic ring is a saturated ring structure, substituted or unsubstituted, that includes only carbon as ring atoms, for example, cyclohexane.
• a heterocyclic ring is a saturated ring structure, substituted or unsubstituted, that has carbon atoms and one or more heteroatoms, including oxygen, nitrogen and/or sulfur, as ring atoms, for example, piperidine, morpholine, piperazine, and their derivatives.
• a terpene is an unsaturated hydrocarbon having the general formula C 10 H 16 and based on the isoprene (C 6 H 8 ) unit. As used herein a terpene may be acyclic, monocyclic or polycyclic and substituted or unsubstituted.
• Substituent groups for the above moieties useful in the invention are those groups that do not significantly diminish the biological activity of the inventive compound. Unless otherwise specifically defined, substituent groups that do not significantly diminish the biological activity of the inventive compound include, for example, -OH, -NH 2 , alkoxy, halogen, -CF 3 , -CN, -NCS, azido, -CONH, -NHCO, sulfonamide, lower alcohol. Some of the inventive cannabinoid compounds exhibit high affinity for the
• CB2 cannabinoid receptor Another aspect of the invention is use of at least one of the inventive compounds to interact with the CB2 cannabinoid receptor.
• inventive cannabinoid compounds show a surprisingly higher selectivity for the CB2 cannabinoid receptor.
• inventive selective compounds are able to interact with the CB2 cannabinoid receptor, without affecting the CB1 cannabinoid receptor to the same degree. Therefore, still another aspect of the invention is use of at least one of the inventive compounds to preferentially interact with the CB2 cannabinoid receptor.
• inventive cannabinoid compounds can act as high affinity modulators for the CB2 cannabinoid receptor.
• the inventive cannabinoid compounds therefore are potential therapeutic agents through the modulation of the CB2 cannabinoid receptor.
• novel cannabinoid compounds described herein may be agonists for the CB2 cannabinoid receptor.
• inventive cannabinoid agonists interact with the CB2 cannabinoid receptor binding site to initiate a physiological or a pharmacological response characteristic of that receptor. Therefore, a further aspect of the invention is use of at least one of the inventive compounds to initiate an agonistic response from a CB2 cannabinoid receptor.
• inventive cannabinoid compounds described herein, and physiologically acceptable salts thereof have pharmacological properties when administered in therapeutically effective amounts for providing a physiological response in individuals and/or animals.
• another aspect of the invention is the administration of a therapeutically effective amount of at least one of the inventive cannabimimetic compounds, or a physiologically acceptable salt thereof, to an individual or animal to provide a physiological response.
• inventive cannabinoid compounds have uniquely short and simple synthesis routes.
• methods of preparation of the inventive cannabinoid compounds are also provided.
• a "therapeutically effective amount" of a compound is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a discernible increase or decrease in stimulation of cannabinoid receptors.
• the discernible increase or decrease in stimulation of cannabinoid receptors provides a physiological response in the individual or animal.
• inventive compounds described herein, and physiologically acceptable salts thereof have pharmacological properties when administered in therapeutically effective amounts for providing a physiological response useful to: treat pain, peripheral pain, glaucoma, epilepsy and nausea such as associated with cancer chemotherapy; cancer, especially glioma and breast cancer; neurodegenerative diseases including Multiple Sclerosis, Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, reduce fertility; prevent or reduce diseases associated with motor function such as Tourette's syndrome; prevent or reduce inflammation; provide neuroprotection; to modulation of the immune system; or treat a combination of the above.
• a "therapeutically effective amount" of the novel cannabimimetic compounds may range from about 1 0 mg/day to about 1 ,000 mg/day.
• an "individual” refers to a human.
• An “animal” refers to, for example, veterinary animals, such as dogs, cats, horses and the like, and farm animals, such as cows, pigs and the like.
• the compound of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasal or topical). The form in which the compounds are administered will be determined by the route of administration.
• Such forms include, but are not limited to, capsular and tablet formulations (for oral and rectal administration), liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration).
• the formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives.
• Suitable physiologically to acceptable vehicles may include, for example, saline, sterile water, Ringer's solution, and isotonic sodium chloride solutions.
• the specific dosage level of compound will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.
• TABLE 1 illustrates some cannabinoids of the present invention (compounds 1 -25).
• Method A Concentrated sulfuric acid (50 mL, 96%) was slowly dropped into a solution of aniline (30 g. 0.32 mol) ill ethanol (280 mL) until the white precipitate newly formed disappeared again at 0-5 °C. To this mixture, isoamylnitrite (40 g, 0.34 mol) was slowly added with stirring. An equal volume of ethyl ether was added to precipitate the product. The mixture was filtered and the residue washed with ethanol :ether (1 : 1 , v/v) to provide a crude greenish solid of benzenediazonium sulfuric acid salt for the following reaction.
• Phenyl hydrazine hydrochloride (1 .45 g, 1 0 mmol) was suspended in water (5 mL) (the resulting mixture showed pH -4). To this mixture was added a solution of 2-chloro-2-ethoxyacetate (prepared from ethyl 2, 2- diethoxy acetate and acetyl chloride without further purification) in dioxane (1 2.5 mL) in small portions while cooling with tap water. After: 3 h, the reaction mixture was neutralized to pH-8 with sodium hydroxide solution and evaporated under vacuum to half its volume.
• Liquid ammonia was slowly added to a suspension of 5.1 (76 mg, 0.2 mmol) and sodium cyanide (1 mg, 0.02 mmol) in methanol (2 mL) in a sealing tube at -60 to about -80 °C for 2 min. After slow warming up to -20 °C, the reaction mixture was sealed, and warmed up to room temperature. After stirring at RT for two days, the reaction mixture was cooled down to -20 °C again for opening the seal, and then warmed up to RT for workup. The solvent was removed by rotary evaporation, and the residue was dissolved in ethanol for filtration.
• isopinocampheylamine 15 mg, 1 mmol
• LiHMDS 1.2 mL
• Sodiohexamethyldisilazane (0.2 mL, 1 M solution in THF) was added dropwise to a solution of 5.12 (26.1 mg, 0.1 mmol) and 5.13 (30.5 mg, 0.1 mmol) in THF (0.5 mL) at -40 °C.
• the reaction mixture changed from light yellow to reddish.
• the reaction was terminated by the addition of ammonium chloride aqueous solution, which followed by typical workup and silica gel flash column purification with petroleum ethe ⁇ ethyl acetate (25: 1 -10: 1 , v/v) as eluent provided the title compound 5.54 as an orange solid (36 mg.
• the mixture was cooled to 0 °C internal temperature with an ice bath and the precipitate collected by filtration.
• the precipitate was washed with 2 mL of dry methanol and 2 mL of dry ether, and dried under vacuum. Cooling the remaining mother liquor to -30 °C afforded a second smaller amount of product.
• the combined product was dissolved in anhydrous methylene chloride and filtered. After removal of the solvent, the filtrate afforded the title compound as an orange solid (1 .5 g, 41 %), mp 1 10-1 1 1 °C.
• ester 5.68 400 mg, 1 .72 mmol
• triethylammonium chloride 710 mg, 5.16 mmol
• binding affinity is represented by the IC 50 value which is the concentration of an analog required to occupy the 50% of the total number (Bmax) of the receptors. The lower the IC 50 value, the higher the binding affinity.
• a compound is said to have "binding selectivity" if it has higher binding affinity for one receptor compared to the other receptor; e.g. a compound that has an IC 50 of 0.1 nM for CB1 and 10 nM for CB2, is 100 times more selective for the CB1 receptor.
• the binding affinities (I ,) are expressed in nanomoles (nM).
• membranes were prepared from rat forebrain membranes according to the procedure of P.R. Dodd et al; A Rapid Method for Preparing Synaptosomes: Comparison with Alternative Procedures, Brain Res., 1 07 - 1 1 8 (1 981 ).
• the binding of the novel analogues to the CB1 cannabinoid receptor was assessed as described in W.A. Devane et al; Determination and Characterization of a Cannabinoid Receptor in a Rat Brain. Mol. Pharmacol., 34, 605 - 61 3 (1 988) and A.
• Membranes previously frozen at -80 °C, were thawed on ice. To the stirred suspension was added three volumes of TME (25mM Tris-HCI buffer, 5 mM MgCI 2 and 1 mM EDTA) at a pH 7.4. The suspension was incubated at 4 °C for 30 min.
• TME 25mM Tris-HCI buffer, 5 mM MgCI 2 and 1 mM EDTA
• the membranes were pelleted and washed three times with TME.
• the treated membranes were subsequently used in the binding assay described below. Approximately 30 ⁇ g of membranes were incubated in silanized 96-weII microtiter plate with TME containing 0.1 % essentially fatty acid-free bovine serum albumin (BSA), 0.8 nM [ 3 H] CP-55,940, and various concentrations of test materials at 30 °C for 1 hour. The samples were immediately filtered using a Packard Filtermate 1 96 and Whatman GF/C filterplates and washed with wash buffer (TME) containing 0.5% BSA.
• BSA bovine serum albumin
• Radioactivity was detected using MicroScint 20 scintillation cocktail added directly to the dried filterplates, and the filterplates were counted using a Packard Instruments Top-Count. Nonspecific binding was assessed using 1 00 nM CP-55,940. Data collected from three independent experiments performed with duplicate determinations was normalized between 1 00% and 0% specific binding for [ 3 H] CP-55,940, determined using buffer and 100 nM CP-55,940. The normalized data was analyzed using a 4-parameter nonlinear logistic equation to yield IC 50 values.
• Intracellular cyclic AMP (cAMP) levels are measured with a comparative protein binding assay (materials available from Diagnostic Products, Inc. of Carlsbad, Ca.) generally according to the method described in Tao, Q. and M.E. Abood; "Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G- protein coupling", J Pharmacol Exp Ther. 1 998, 285(2): pp. 651 -658, which is incorporated by reference herein.
• the inventive compounds are unique in having a high affinity for the CB2 receptor and relatively little affinity for the CB1 receptor. As can be seen from Table 1 , some of these compounds exhibit a high selectivity for the CB2 receptor of about 2 orders of magnitude.

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