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Cannabinoid derivatives, methods of making, and use thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Oxygen Containing Hetero Ring, The Hetero Ring Is Six-membered, Polycyclo Ring System Having The Hetero Ring As One Of The Cyclos, Tricyclo Ring System Having The Hetero Ring As One Of The CyclosCannabinoid derivatives, methods of making, and use thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070167514, Cannabinoid derivatives, methods of making, and use thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is a continuation of application Ser. No. 10/850,588, filed May 20, 2004, which application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/472,316 filed May 20, 2003, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates generally to cannabinoid derivatives of delta-8-tetrahydrocannabinol (.DELTA..sup.8-THC), delta-9-tetrahydrocannabinol (.DELTA..sup.9-THC), and delta-6a-10a-tetrahydrocannabinol (.DELTA..sup.6a-10a-THC) that are active as either agonists or antagonists of the cannibinoid receptor type-1 (CB-1) and/or cannabinoid receptor type-2 (CB-2), and their use for treating CB-1 or CB-2 mediated conditions. BACKGROUND OF THE INVENTION [0003] Delta-9-tetrahydrocannabinol (.DELTA..sup.9-THC) was isolated and identified as the major active constituent of marijuana in 1964 by Mechoulam and coworkers (Gaoni et al., J. Am. Chem. Soc. 86:1646 (1964)). In the following decades, the CB1 and CB2 receptors were discovered, characterized and shown to be responsible for the actions of .DELTA..sup.9-THC (Gernard et al., Biochem. J. 279:129 (1991); Skaper et al., Proc. Natl. Acad. Sci. USA 93:3984 (1996); Matsuda et al., Nature 346:61 (1990); Munro et al., Nature 365:61 (1993)). The CB1 and CB2 receptors have since gained attention as potential therapeutic targets for the development of antiobesity (Di Marzo et al., Nature 410:822 (2001)), anticancer (Palolaro et al., Prostaglandins Leukot. Essent. Fatty Acids 66:319 (2002)), analgesic (Palmer et al., Chem. Phys. Lipids 121:3 (2002)), and antiglaucoma agents (Porcella et al., Eur. J. Neurosci. 13:409 (2001); Chien et al., Arch. Ophthalmol. 121:87 (2003)). Efforts to develop therapeutic agents have resulted in the identification of a number of structurally distinct classes of compounds that bind to the cannabinoid receptors, these include the classical cannabinoids (.DELTA..sup.9-THC), the non-classical cannabinoids such as CP55,940 (Melvin et al., Med. Chem. 27:67 (1984)), the diarylpyrazoles such as AM-251 (Lan et al., J. Med. Chem. 42:769 (1999)), and aminoalkylindoles such as WIN-55212 (D'Ambra et al., J. Med. Chem. 35:124 (1992)). By far the most extensively studied cannabinoid analogs in terms of the pharmacology and SAR are the classical and non-classical cannabinoids. [0004] The binding affinity of the classical cannabinoids (CCBs) and non-classical cannabinoids to the CB1 receptor can generally be defined in terms of a three point and four point pharmacophore model, respectively (Seltzman, Curr. Med. Chem. 6:685 (1999)). The structural elements that form the three point pharmacophore of the CCB analogs are: (1) a phenolic group in the C1 position of the aromatic ring (Razdan, Pharmac. Rev. 38:75 (1986); Uliss et al., J. Med. Chem. 18:213 (1975)); (2) an unsaturated .DELTA..sup.8 or .DELTA..sup.9 C ring with an exocyclic C11 methyl or hydroxy methyl, or alternatively a saturated C ring containing a 9-.beta.-hydroxyl, 9-.beta.-hydroxy methyl, or 9-keto functional group (Thomas et al., Mol. Pharmacol. 40:656 (1991); Wilson et al., J. Med. Chem. 19:1165 (1976); Melvin et al., Mol. Pharmacol. 44:1008 (1993); Mechoulam et al., Experientia 44:762 (1988); and (3) a C3 aliphatic side chain ranging from 3 to 7 carbons wherein heptyl analogs represent the optimum side chain length. In addition to the basic pharmacophore model, substitution of the C3 side chain with 1',1'-dimethyl, 1',2'-dimethyl, and 1',1'-dithiolane generally enhances the activity of the CCBs (Huffman et al., Tetrahedron 53:1557 (1997); Huffman et al., Bioorganic Med. Chem. Lett. 7:2799 (1997); Guo et al., J. Med. Chem. 37:3867 (1994); Devane et al., J. Med. Chem. 35:2065 (1992); Tius et al., Life Sci. 56:2007 (2007); Huffman et al., J. Med. Chem. 39:3875 (1996)). [0005] The understanding of the interplay between the pharmacophoric elements of CCBs and the ligand binding pocket (LBP) have been significantly refined as a result of QSAR studies and site directed mutagenesis of the LBP. Computational studies have identified the requirement for a hydrogen bond donor/acceptor pair in the C1 region of CCBs (Thomas et al., Mol. Pharmacol. 40:656 (1991); Schmetzer et al., J. Computer-Aided Mol. Design. 11:278 (1997); Reggio et al., J. Med. Chem. 32:1630 (1989); Johnson et al., Cannabinoids as Therapeutic Agents, Boca Raton, Fla., CRC Press (1986)), a result proposed to correlate with an interaction of the C1 hydroxyl with a critical Lys192 in the CB1 receptor (Song et al., Mold. Pharmacol. 49:891 (1996); Chin et al., J. Neurochem. 70:280 (1998)). An additional donor/acceptor pair between Tyr275 and the CCBs containing a hydroxyl in the C9 region may be responsible for the increased CB1 affinity relative to .DELTA..sup.9-THC (McAllister et al., Biochem. Pharmacol. 63:2121 (2002), which is hereby incorporated by reference in its entirety). [0006] The intramolecular geometries of the C1 and C9 substituents are tightly defined by the rigid ring system of the CCBs, however QSAR studies indicate moderate to high conformational flexibility in the C3 side chains (Schmetzer et al., J. Computer-Aided Mol. Design. 11:278(1997); Papahatjis et al., J. Med. Chem. 41:1195 (1998); Ryan et al., Life Sci. 56:2013 (1995); Keimowitz et al., J. Med. Chem. 43:59 (2000). These studies clearly demonstrate the LBP of CB1 prefers a hydrophobic substituent at C3 but the requirement for conformational flexibility remains to be fully elucidated. Progress to this end has been reported in studies of a series of conformationally restricted .DELTA..sup.8-THC side chain analogs incorporating methylene and methyne functionalities (Keimowitz et al., J. Med. Chem. 43:59 (2000)) and 1'-cyclopropyl analogs (Papahatjis et al., Bioorg. Med. Chem. Lett. 12:3583 (2002)). The study suggests that the side chain adopts an orthogonal geometry relative to the plane of the aromatic ring with the tail of the side chain folding into a hydrophobic pocket. Despite the incorporation of unsaturation into the side chains, considerable flexibility remains in this set of molecules. The inherent computational limitations in predicting the conformation of a flexible side chain, in the absence of x-ray crystallographic or high resolution NMR data, somewhat limits the ability to predict the preferred side chain geometry and LBP steric requirements of the CB receptors. [0007] There still remains a need for identifying compounds that can be used for therapeutic purposes to affect treatment of conditions or disorders that are mediated by the CB-1 receptor and/or the CB-2 receptor. [0008] The present invention is directed to developing .DELTA..sup.8-THC, .DELTA..sup.9-THC, and .DELTA..sup.6a-10a-THC analogs that exhibit activity, either as an agonist or an antagonist, on the CB-1 receptor and/or the CB-2 receptor and can be used to treat conditions or disorders that are mediated by these receptors. SUMMARY OF THE INVENTION [0009] A first aspect of the present invention relates to cannabinoid analogs according to formula (I) below [0010] wherein the C ring contains a double bond at either the .DELTA..sup.8 position, the .DELTA..sup.9 position, or the .DELTA..sup.6a-10a position; [0011] X is selected from the group of C(CH.sub.3).sub.2, C(--Y(CH.sub.2).sub.nY--), CH.sub.2, C(O) [0012] Y is selected from the group of S and O; [0013] R.sub.1 is selected from the group of a C3 to C8 cycloalkyl, thiophenyl, furanyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, biphenyl, 2-napthyl, thiazolyl, benzthiazolyl, methyltetrazolyl, [0014] R.sub.2 and R.sub.3 are methyl for compounds containing a .DELTA..sup.8 or a .DELTA..sup.9 double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a .DELTA..sup.6a-10a double bond; [0015] R.sub.4 is selected from the group of methyl, methanol, --(CH.sub.2).sub.mCOOH, and --(CH.sub.2).sub.mCOH for compounds containing a .DELTA..sup.8 or a .DELTA..sup.9 double bond, or is methyl for compounds containing a .DELTA..sup.6a-10a double bond; [0016] R.sub.5 is selected from the group of H, OH, methoxy, and ethoxy; [0017] R.sub.6-R.sub.10 are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl; [0018] at least one of R.sub.11-R.sub.13 is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R.sub.11-R.sub.13 can optionally be H; [0019] n is an integer from 2 to 4; and [0020] m is an integer that is either 0 or 1. 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