Peripheral cannabinoid receptor (CB2) selective ligands Number:6,995,187 from the United States Patent and Trademark Office (PTO) owispatent

Title: Peripheral cannabinoid receptor (CB2) selective ligands

Abstract: Novel polycyclic cannabinoid analogs are presented which have preferentially high affinities for the cannabinoid CB2 receptor sites. The improved receptor affinity makes these analogs therapeutically useful as medications in individuals and animals for treatment of pain, glaucoma, epilepsy, nausea associated with chemotherapy.

Patent Number: 6,995,187 Issued on 02/07/2006 to Makriyannis,   et al.

---

Inventors:	Makriyannis; Alexandros (Watertown, MA); Khanolkar; Atmaram (Coventry, RI)
Assignee:	University of Connecticut (Farmington, CT)
Appl. No.:	110830
Filed:	October 18, 2000
PCT Filed:	October 18, 2000
PCT NO:	PCT/US00/28818
371 Date:	October 21, 2002
102(e) Date:	October 21, 2002
PCT PUB.NO.:	WO01/28329
PCT PUB. Date:	April 26, 2001

Current U.S. Class:	514/455; 549/280
Current Intern'l Class:	A61K 31/35.2  (20060101); C07D 311/78   (20060101)
Field of Search:	514/455 549/280

---

References Cited [Referenced By]

---

U.S. Patent Documents

3041343	Jun., 1962	Jucker et al.
3465024	Sep., 1969	Brownstein et al.
3573327	Mar., 1971	Miyano.
3577458	May., 1971	Brownstein et al.
3656906	Apr., 1972	Bullock.
3838131	Sep., 1974	Gauthier.
3886184	May., 1975	Matsumoto et al.
3897306	Jul., 1975	Vidic.
3915996	Oct., 1975	Wright.
3928598	Dec., 1975	Archer.
3944673	Mar., 1976	Archer.
3953603	Apr., 1976	Archer.
4036857	Jul., 1977	Razdan et al.
4054582	Oct., 1977	Blanchard et al.
4087545	May., 1978	Archer et al.
4087546	May., 1978	Archer et al.
4087547	May., 1978	Archer et al.
4088777	May., 1978	Archer et al.
4102902	Jul., 1978	Archer et al.
4152450	May., 1979	Day et al.
4171315	Oct., 1979	Ryan et al.
4176233	Nov., 1979	Archer et al.
4179517	Dec., 1979	Mechoulam.
4188495	Feb., 1980	Althuis et al.
4208351	Jun., 1980	Archer et al.
4278603	Jul., 1981	Thakkar et al.
4282248	Aug., 1981	Mechoulam et al.
4382943	May., 1983	Winter et al.
4395560	Jul., 1983	Ryan.
4497827	Feb., 1985	Nelson.
4550214	Oct., 1985	Mehta.
4758597	Jul., 1988	Martin et al.
4812457	Mar., 1989	Narumiya.
4876276	Oct., 1989	Mechoulam.
4885295	Dec., 1989	Bell et al.
5053548	Oct., 1991	Tanaka et al.
5068234	Nov., 1991	D'Ambra et al.
5147876	Sep., 1992	Mizuchi et al.
5223510	Jun., 1993	Gubin et al.
5284867	Feb., 1994	Kloog.
5324737	Jun., 1994	D'Ambra et al.
5434295	Jul., 1995	Mechoulam et al.
5440052	Aug., 1995	Makriyannis et al.
5462960	Oct., 1995	Barth et al.
5489580	Feb., 1996	Makriyannis et al.
5521215	May., 1996	Mechoulam.
5532237	Jul., 1996	Gallant et al.
5538993	Jul., 1996	Mechoulam.
5576436	Nov., 1996	McCabe et al.
5605906	Feb., 1997	Lau.
5607933	Mar., 1997	D'Ambra et al.
5618955	Apr., 1997	Mechoulam et al.
5624941	Apr., 1997	Barth et al.
5635530	Jun., 1997	Mechoulam.
5688825	Nov., 1997	Makriyannis et al.
5744459	Apr., 1998	Makriyannis et al.
5747524	May., 1998	Cullinan et al.
5804601	Sep., 1998	Kato et al.
5817651	Oct., 1998	D'Ambra et al.
5872148	Feb., 1999	Makriyannis et al.
5874459	Feb., 1999	Makriyannis et al.
5925628	Jul., 1999	Lee et al.
5925768	Jul., 1999	Barth et al.
5932610	Aug., 1999	Shohami et al.
5948777	Sep., 1999	Bender et al.
6013648	Jan., 2000	Rinaldi et al.
6028084	Feb., 2000	Barth et al.
6096740	Aug., 2000	Mechoulam.
6127399	Oct., 2000	Yuan.
6166066	Dec., 2000	Makriyannis et al.
6284788	Sep., 2001	Mittendorf et al.
6391909	May., 2002	Makriyannis et al.
6579900	Jun., 2003	Makriyannis et al.
6610737	Aug., 2003	Garzon et al.
2002/0119972	Aug., 2002	Leftheris et al.
2003/0120094	Jun., 2003	Makriyannis et al.
2003/0149082	Aug., 2003	Makriyannis et al.
2004/0077649	Apr., 2004	Makriyannis et al.
2004/0077851	Apr., 2004	Makriyannis et al.
2004/0087590	May., 2004	Makriyannis et al.
Foreign Patent Documents
0276732	Aug., 1988	EP.
0471609	Jun., 1993	EP.
0737671	Oct., 1996	EP.
0860168	Sep., 2001	EP.
2240003	May., 1975	FR.
2735774	Jan., 2000	FR.
2027021	Feb., 1980	GB.
57098228	Jun., 1982	JP.
2304080	Dec., 1990	JP.
WO 97/0086/0	Jan., 1997	WO.
WO 99/5710/7	Nov., 1999	WO.
WO 99/6438/9	Dec., 1999	WO.
WO 00/3220/0	Jun., 2000	WO.
WO 01/2849/7	Apr., 2001	WO.
WO 01/2849/8	Apr., 2001	WO.
WO 01/2855/7	Apr., 2001	WO.
WO 01/2900/7	Apr., 2001	WO.
WO 01/3216/9	May., 2001	WO.
WO 01/5886/9	Aug., 2001	WO.
WO 03/005960	Jan., 2003	WO.
WO 03/020217	Mar., 2003	WO.
WO 03/035005	May., 2003	WO.
WO 03/063758	Aug., 2003	WO.
WO 03/064359	Aug., 2003	WO.

Other References

Cancer and Metastasis Reviews (1998), 17(1), 91-106. Science (1999), vol. 286, 531-537. FDA mulls drug to slow late-stage Alzheimer's [online], [retrieved on Sep. 23, 2003]. Retrieved from the Internet, URL;http://www.cnn.com/2003/HEALTH/conditions/09/24/alzheimers.drug.ap/index.html>. U.S. Appl. No. 09/600,786, filed Nov. 24, 1999, Makriyannis et al. U.S. Appl. No. 09/701,989, filed Jun. 9, 1999, Makriyannis et al. U.S. Appl. No. 10/110,865, filed Oct. 18, 2000, Makriyannis et al. U.S. Appl. No. 10/110,812, filed Oct. 18, 2000, Makriyannis et al. U.S. Appl. No. 10/110,862, filed Oct. 18, 2000, Makriyannis et al. U.S. Appl. No. 10/111,059, filed Oct. 18, 2000, Makriyannis et al. U.S. Appl. No. 10/483,482, filed Jul. 11, 2002, Makriyannis et al. U.S. Appl. No. 10/493,093, filed Oct. 28, 2002, Makriyannis et al. U.S. Appl. No. 10/647,544, filed Aug. 25, 2003, Makriyannis et al. U.S. Appl. No. 10/790,498, filed Mar. 1, 2004, Makriyannis et al. Abadji V., Lin S., Taha G., Griffin G., Stevenson L.A., Pertwee R.G., Makriyannis A.; "(R)-Methanadamide: a chiral novel anandamide possessing higher potency and metabolic stability"; J. Med. Chem.; 37(12); 1889-1893; 1994; CODEN: JMCMAR; ISSN: 0022-2623; XP002040932. *1* Alo, B.I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.; and Snieckus, V. Sequential Directed Ortho Metalation-Boronic Acid Cross-Coupling Reactions. A general Regiospecific Route to Oxygenerated Dibenzo[b,d]pyran-6-ones Related to Ellagic Acid, J. Org. Chem. 1991, 56, 3763-3768. *1* Arnone M., Maruani J., Chaperon P, et al, Selective inhibition of sucrose and ethanol intake by SR141716, an antagonist of central cannabinoid (CB1) receptors, Psychopharmacal, (1997) 132, 104-106. (abstract only). *1* Barnett-Norris et al; "Exploration of biologically relevant conformations of anadamide, . . . "; J. Med. Chem.; vol. 41; 4861-4872; 1998. *1* Beak, P.; and Brown, R A., The Tertiary Amide as an Effective Director of Ortho Lithiation, J. Org. Chem. 1982, 47, 34-36. *1* Belgaonkar et al; "synthesius of isocoumarins"; Indian J. Chem; vol. 13; No. 4; 336-338; 1975 (abstract only). Beltramo M., Stella N., Calignano A., Lin S. Y., Makriyannis A., Piomelli D; "Functional Role Of High-Affinity Anandamide Transport, as Revealed By Selective Inhibition"; Science; vol. 277; 1094-1097; 1997. Beltramo M., Stella N., Calignano A., Lin S. Y., Makriyannis A., Piomelli D; "Identification and Functional Role of High Affinity Anandamide Transport"; The Neurosciences Institute (1 page). Berdyshev EV, Cannabinoid receptors and the regulation of immune response. Chem Phys Lipids. Nov. 2000; 108(1-2):169-90. Berglund et al; "Structural requirements for arachidonylethanolamide interaction with CB1 and CB2 cannabinoid receptors: . . . "; Prostanglandins, leukotrienes ands essential fatty acids; 59(2); 111-118; (1998). (abstract only). Bodnar, V.N., Lozinskii, M.O., Pel'kis, P.S.; "Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles and 1,4-dihydro-1,2,4,5-tetrazines"; Ukrainskii Khimicheskii Zhurnal (Russian Edition); 48(12); 1308-1311; 1982 (abstract only). Bracey, M et al, Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling. Science 2002; 298(5599): 1793-1796. *1* Brenneisen R, Pgli A, Elsohly MA, Henn V. Spiess Y: The effect of orally and rectally administered 9-tetrahydrocannabinol on spasticity, a pilot study with 2 patients. Int. J. Clin Pharmacol Ther. (1996) 34:446-452. (abstract only). *1* Brown et al; "Synthesis and hydroboration of (-)-2-phenylapopinene, Comparison of mono(2-phenylapoisopinocampheyl)borane with its 2-methyl and 2-ethyl analogues for the chiral hydroboration of representative alkenes"; J. Org. Chem.; 55(4); 1217-1223; (1990). *1* Buckley NE, McCoy KI, Mpzey E et al, "Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor"; Eur. J Pharmacol (2000) 396:141-149. *1* Burstein et al; "detection of cannabinoid receptors . . . "; Biochem. Biophys. Res. Commun.; vol. 176(1); 492-497; 1991 (abstract only). Busch-Peterson et al; "Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs"; J. Med. Chem.; 39; 3790-3796; (1996). *1* Calignano A, La Rana G. Diuffrida A, Piomelli D; "Control of pain initiation by endogenous cannabinoids"; Nature (1998) 394:277-291. (abstract only). Calignano A., La Rana G., Beltramo, M., Makriyannis A., Piomelli D; "Potentiation of Anandamide Hypotension by the Transport inhibitor, AM404"; Eur. J. Pharmacol.; 1997; 337 R1-R2. Calignano A., La Rana G., Makriyannis A., Lin S., Beltramo M., Piomelli D; "Inhibition of Intestinal Motility by Anadamide, an Endogenous Cannabinoid"; Eur. J. Pharmacol.; 1997; 340 R7-R8. Campbell FA et al; "Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review"; BMJ. Jul. 7, 2001;323(7303):13-6. *1* Charalambous A. et al; "5′-azido 8-THC: A Novel Photoaffinity Label for the Cannabinoid Receptor"; J. Med. Chem., 35, 3076-3079 (1992). *1* Charalambous A. et al; "Pharmacological evaluation of halogenated . . . "; Pharmacol. Biochem. Behav.; vol. 40; No. 3; 509-512; 1991. *1* Cheng et al; "Relationship Between the Inhibition Constant (K1) and the concentration of Inhibitor which causes 50% Inhibition (I50) of an Enzymatic Reaction"; Biochem. Pharmacol., 22, 3099-3102, (1973) (abstract only). Cherest M., Luscindi X.; "The action of acetyl chloride and of acetic anhydride on the lithium nitronate salt of 2-phenylnitroethane . . . "; Tetrahedron; 42(14); 3825-3840; 1986; in French with English abstract. Cherest M., Lusinchi X.; "A novel electrophilic N-amidation via electron deficient complexes: action of ferric chloride on N-acetyloxyamides"; Tetrahedron Letters; 30(6); 715-718; 1989. *1* Colombo G, Agabio R, Diaz G. et al; "Appetite suppression and weight loss after the cannabinoid antagonist SR141716"; Life Sci. (1998) 63-PL13-Pl117. (abstract only). *1* Compton et al; "Synthesis and pharmacological evaluation of ether and related analogues of delta8-. delta9- and delta9,11-tetrahydrocannabinol"; J. Med. Chem; vol. 34; No. 11; 3310-3316; 1991. *1* Consroe P, Musty R, Rein J, Tillery W, Pertwee R; "The perceived effects of smoked cannabis on patents with multiple sclerosis"; Eur. Neurol. (1997) 38-44-48. (abstract only). Coxon et al; "Derivatives of nopinone"; Aust. J. Chem.; 23; 1069-1071; (1970) (abstract only). *1* Crawley et al; "Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents"; Pharmacology Biochemistry and Behavior; vol. 46; 967-972; 1993. D'Ambra et al; "C-attached aminoalkylindoles: potent cannabinoid mimetics"; Bioorg. & Med. Chem. Lett., 1996, 6(1), 17-22. Demuynck L. et al; "Rearrangement of Indolo[2,3-a]quinolizidines to derivatives with E-azaaspidospermane skeleton"; Tetrahedron Letters; 30(6) 710-722; 1989; in French with English abstract. *1* DePetrocellis L, Melck D, Palmisano A. et al; "The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation"; Proc. Natl. Acad. Sci. USA (Jul. 1998) 95:8375-8380. Desarnaud F., Cadas H., Piomelli D.; "Anandamide amidohydrolase activity in rat brain microsomes"; J. Biol. Chem.; 270; 6030-6035; (1995). Deutsch D.G. et al; "Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to cannabinoid receptor"; Biochem. Biophys. Res. Commun. 231(1); 217-221; 1997; CODEN: BBRCA9; ISSN:0006-291X; XP002040933. Deutsch D.G., Chin S.A.; "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist"; Biochemical Pharmacology; 46(5); 791-796; 1993. *1* Devane, W.A. et al; "Determination and Characterization of a Cannabinoid Receptor in a Rat Brain"; Mol. Pharmacol., 34, 605-613 (1988). (abstract only). *1* Di Marzo, V., Melck, D., Bisogno, T., DePetrocellis, L.; "Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action"; Trends Neurosci. (1998) 21:521-528. *1* Dominiami et al; "Synthesis of 5-(tert-Alkyl)resorcinols"; J. Org. Chem. 42(2); 344-346; (1977). Drake et al, "classical/nonclassical hybrid cannabinoids"; J. Med. Chem.; vol. 41(19); 3596-3608 (1998). Edery et al; "Activity of novel aminocannabinoids in baboons"; J. Med. Chem.; 27; 1370-1373 (1984). Eissenstat et al; "Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics"; J. Med. Chem. 1995, vol. 38, No. 16, pp. 3094-3105; XP 000651090. Fahrenholtz, K. E., Lurie, M. and Kierstead, AR. W.; "The Total Synthesis of dl-Δ9-Tetrahydrocannabinol and Four of Its Isomers"; J. Amer. Chem. Soc. 1967, 89(23), 5934-5941. *1* Fahrenholtz; "The synthesis of 2 metabolites of (-)-delta eight-tetrahydrocannabinol"; J. Org. Chem.; vol. 37(13); 1972; XP002111824. Fisera, L., Kovac, J., Lesco, J., Smahovsky, V.; "Furan derivatives. Part CLVI. 1,3-dipolar cycloadditions of heterocycles. V. Reaction of C-acetyl-N-phenylnitrilimine with furan derivatives", Chemicke Zvesti; 35(1); 93-104 1981 (abstract only). *1* Fride, E. & Mechoulam, R.; "Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent"; European Journal of Pharmacology, vol. 231; 313-314; 1993. Galiegue S et al.; "Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations"; Eur J Biochem.; Aug. 15, 1995;232(1):5461. (abstract only). *1* Gareau, Y.; Dufresne, C.; Gallant, M.; Rochette, C.; Sawyer, N.; Slipetz, D. M.; Tremblay, N.; Weech, P. K.; Metters, K. M.; Labelle, M.; "Structure activity relationships of tetrahydrocannabinol analogs on human cannabinoid receptors"; Bioorg. Med. Chem. Lett. 1996, 6(2), 189-194. *1* Gold et al; "A comparison of the discriminative stimulus properties of delta9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys"; J. Pharmacol. Exp. Ther.; vol. 262(2); 479-486; 1992. *1* Hampson, A.J., Grimaldi M. Axpirod J. Wink D; "Cannabidiol and (-) 9 tetrahydrocannabinol are neuroprotective antioxidants"; Proc. Natl Acad Sci. USA (Jul. 1998) 95; 8268-8273. *1* Hargreaves, K. et al; "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia"; Pain; 32; 77-88; (1988) (abstract only). *1* Herzberg U, Eliav E, Bennett GJ, Kopin IJ; "The analgesic effects of R(+) WIN 55,212-2 mesylate, a high affinity cannabinoid agonist in a rat model of neuropathic pain"; Neurosci. Letts. (1997) 221; 157-160. Hillard C. J., Edgemond, W. S., Jarrahian W., Campbell, W. B; "Accumulation of N-Arachidonoylethanolamine (Anandamide) into Cerebellar Granule Cells Occurs via Facilitated Diffusion"; Journal of Neurochemistry; 69; 631-638 (1997). Horrevoets A.J.G et al; "Inactivation of Escherichia coli outer membrane phospholipase A by the affinity label hexadecanesulfonyl fluoride"; Eur. J. Biochem.; 198; 247-253; 1991. Horrevoets A.J.G et al; "Inactivation of reconstituted Escherichia coli outer membrane phospholipase A by membrane-perturbing peptides results in an increased reactivity towards the affinity label hexadecanesulfonyl fluoride"; Eur. J. Biochem.; 198; 255-261; 1991. Howlett et al; "Azido and isothicyanato substituted aryl pyrazoles bind covalently to the CB1 cannabinoid receptor and impair signal transduction"; Journal of Neurochemistry; vol. 74(5) (2000) 2174-2181; XP001097394. *1* Howlett et al; "Stereochemical effects of 11-OH-delta 8 tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor"; Neuropharmacology; vol. 29(2); 161-165; 1990. Huffman et al; "3-(1′,1′-dimethylbutyl)—deoxy-delta 8THC and related compounds: synthesis of selective ligands for the CB2 receptor"; Bioorganic and Medicinal Chemistry; vol. 7; 2905-2914; (1999). Huffman et al; "Stereoselective synthesis of the epimeric delta 7-tetrahydocannabinols"; tetrahedron; vol. 51(4); 1071-1032; (1995). *1* Huffman et al; "Synthesis of 5′,11 dihydroxy delta 8 tetrahydrocannabinol"; Tetrahedron, vol. 53(39), pp 13295-13306 (1997). *1* Huffman et al; "Synthesis of a tetracyclic, conformationally constrained analogue of delta8-THC"; Bioorganic & Medicinal Chemistry; vol. 6(12); 2281-2288; 1998; XP002123230. *1* Huffman et al; "Synthesis of both enantiomers of Nabilone from a common intermediate. Enantiodivergent synthesis of cannabinoids"; J. Org. Chem.; 1991, 56, 2081-2086. Kaminski NE; "Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors"; J. Neuroimmunol. Mar. 15, 1998;83(1-2):124-32. Kawase M. et al; "Electrophilic aromatic substitution with N-methoxy-N-acylnitrenium ions generated from N-chloro-N-methoxyamides: synthesis of nitrogen heterocyclic compounds bearing a N-methoxyamide group"; J. Org. Chem.; 54; 3394-3403; 1989. Khanolkar A., Abadji V., Lin S., Hill W., Taha G., Abouzid K., Meng Z., Fan P., Makriyannis A.; "Head group analogues of arachidonylethanolsamide, the endogenous cannabinoid ligand"; J. Med. Chem.; vol. 39(22); 4515-4519; (1996). Khanolkar et al; "Molecular probes for the cannabinoid receptors"; Chemistry and Physics of Lipids; 108; 37-52; (2000). Klein T.W. et al, "The cannabinoid system and cytokine network"; Proc Soc Exp Biol Med. Oct. 2000; 225(1):1-8; (abstract only). Klein TW et al, "Cannabinoid receptors and immunity"; Immunol Today; Aug. 1998; 19(8):373-81. Koutek B. et al; "Inhibitors of arachidonyl ethanolamide hydrolysis"; J. Biol. Chem.; 269(37); 22937-40; 1994; CODEN: JBCHA3; ISSN: 0021-9258; XP002040931. Kumar RN, et al; "Pharmacological actions and therapeutic uses of cannabis and cannabinoids"; Anesthesia, 2001, 56: 1059-1068 (abstract only). Lan, R et al; "Structure activity relationships of pyrazole derivatives as cannabinoid receptor antagonists"; J. Med. Chem.; vol. 42(4); 769-776; (1999). *1* Lavalle et al; "Efficient conversion of (1R, 5R)-(+)-alpha-pinene to (1S, 5R)-(-)-nopinene"; J. Org. Chem.; vol. 51(8); 1362-1365; (1986). Lin S., Khanolkar A., Fan P., Goutopolous A., Qin C., Papahadjis D., Makriyannis A.; "Novel Analogues of arachidonylethanolamide (anandamide): affinities for the CB1 and CB2 Cannabinoid Receptors and Metabolic Stability"; J. Med. Chem.; vol. 41; 5353; 1998. *1* Loev, B., Bender, P. E., Dowalo, F., Macko, E., and Fowler, P.; "Cannabinoids. Structure-Activity Studies Related to 1,2-Dimethylheptyl Derivatives"; J. Med. Chem.; vol. 16(11); 1200-1206; 1973. Lozinskii, M.O., Bodnar, V.N., Konovalikhin, S.V., D'yachenko, O.A., Atovmyan, L.O.; "Unusual transformations of arylhydrazonoyl chlorides of oxalic acid ethyl ester"; Izvestiya Akademii Nauk SSSr, Seriya Khimicheskaya; 11; 2635-2637; 1990 (abstract only). *1* Ludt, R.E. et al; "A comparison of the synthetic utility of n-butyllithium and lithium diisopropylamide in the metalations of N,N-dialkyltouamides"; J. Org. Chem.; 38(9); 1668-1674 (1973). Mackie K., Devane W.A., Hille B.; "Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells"; Mol. Pharmacol; 44; 498-0503 (1993). *1* Martin et al; "Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs"; Pharmacol. Biochem. Behav.; vol. 40(3); 471-478; 1991. *1* Martyn CN. Illis LS, Thom J.; "Nabilone in the treatment of multiple sclerosis"; Lancet (1995) vol. 345; pp. 579. *1* Matsumoto et al; "Cannabinoids 1.1-amino-and 1 mercapto-7,8,9,10-tetrahydro-6h-dibenzo[b,d]pyrans"; J. of Med. Chem.; vol. 20(1); 17-24; 1977; XP00211825. *1* Mavromoustakos, T. et al; "Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction"; Biochimica et Biophysica Acta; vol 1281(2); 1996; XP002111823. Mechoulam et al; "Stereochemical Requirements for cannabinoid activity"; J. Med. Chem.; 23(10); 1068-1072; (1980). Mechoulam et al; "Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative"; Tetrahedron Asymmetry; 1: 311-314; (1990) (abstract only). *1* Meltzer et al; "An improved synthesis of cannabinol and cannabiorcol"; Synthesis; 1981:985 (1981). Melvin et al; "Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs"; Mol. Pharmacol.; 44(5); 1008-1015 (1993). *1* Merck Index; 11th edition; "Tetrahydrocannabinols" compound No. 9142; 1989. Neunhoeffer O., Gottschlich R.; "Acylating activity of O-acylated hydroxylamine derivatives"; Justus Liebigs Ann. Chem.; 736; 100-109; 1970; in German with English abstract. *1* Novak, J et al; Cannabis, part 27, synthesis of 8-, 10- and 11-oxygenated cannabinoids; J. Chem. Soc. Perkin Trans.; 2867-2871; (1983) (abstract only). *1* Nye et al; "High affinity cannabinoid binding sites in brain membranes labelled with [H]-5′-trimethylammonium delta8-tetrahydrocannabinol"; J. Pharmacol. Exp. Ther.; vol. 234(3); 784-794; 1985. *1* Papahatjis et al; "A new ring-forming methodology for the synthesis of conformationally constrained bioactive molecules"; Chemistry Letters, 192; (2001). *1* Papahatjis et al; "Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1′-substituted delta8-tetrahydrocannabinols"; J. Med. Chem.; 41(7); 1195-1200; (1998). Pertwee et al; "AM630, a competitive cannabinoid receptor agonist"; Life Sci. 1995, 56(23/24), 1949-1955; XP 000653566. Pertwee et al; "Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens"; Eur. J. Pharmacol. 1995, 284, 241-247; XP-001041044. Petrov, M.L., Terent'eva, N.A., Potekhin, K.A., Struchkov, Yu. T.; ".alpha.,.beta.-unsaturated thiolates and their analogs in cycloaddition reactions. XVIII. Reaction of (2-phenylethynyl)tellurolates with C-ethoxycarbonyl-N-Phenylnitrilimine"; Zhurnal Organicheskoi Khimii; 29(7); 1372-1378; (1993) (abstract only). Piomelli D., Beltramo M., Glasnapp S., Lin S.Y., Goutopoulos A., Xiw X-Q., Makriyannis A.; "Structural determinants for recognition and translocation by the anandamide transporter"; Proc. Natl. Acad. Sci. USA; 96; 5802-5807; (1999). *1* Pitt et al; "The synthesis of Deuterium, carbon-14 and carrier free tritium labelled cannabinoids"; Journal of Labellled Compounds; vol. 11(4); 551-575; 1975; XP002123229. *1* Razdan et al; "Drugs derived from cannabinoids. 6. Synthesis of cyclic analogues of dimethylheptylpyran"; J. Med. Chem.; vol. 19(5); 719-721; 1976 (abstract only). *1* Reggio et al; "Characterization of a region of steric interference at the cannabinoid receptor using the active analog approach"; J. Med. Chem. United States; vol. 36(12); 1761-1771; 1993. *1* Rhee, M. H.; Vogel, Z.; Barg, J.; Bayewitch, M.; Levy, R.; Hanus, L.; Breuer, A.; and Mechoulam, R.; "Cannabinol Derivatives: Binding to Cannabinoid Receptors and Inhibition of Adenylcyclase"; J. Med. Chem. 1997, 40(20); 3228-3233. *1* Richardson JD, Aanonsen I, Hargreaves KM; "Antihyperalgesic effects of spinal cannabinoids"; Eur. J. Pharmacol. (1998) 346:145-153. *1* Richardson JD, Kilo S. Hargreaves KM; "Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors"; Pain (1998) 75:111-119. Rinaldi-Carmona et al; "Biochemical and pharmacological characterization of SR141716A, the first potent and selective brain cannabinoid receptor antagonist"; Life Sci.; vol. 56(23/24); 1941-1947 (1995). Rinaldi-Carmona et al; "SR141716A, a potent and selective antagonist of the brain cannabinoid receptor"; FEBS Lett.; 350; 240-244; (1994). *1* Rompp Chemie Lexikon; Falbe and Regitz; "band 1-A-C1, 8"; Aufl, Thieme Verlag; Stuttgart, S 569-570; 1989. Santus, Maria; "Studies on thioamides and their derivatives. IX. Synthesis of the derivatives of 1,2,4,5-tetrazine"; Acta Polonae Pharmaceutica; 50(2-3); 183-188; 1993 (abstract only). Schatz AR et al; "Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system"; Toxicol Appl Pharmacol. Feb. 1997; 142(2):278-87. Shawali, A.S., Albar, H.A.; "Kinetics and mechanism of dehydrochlorination of N-aryl-C-ethoxycarbonyl formohydrazidoyl chlorides"; Canadian Journal Of Chemistry; 64(5); 871-875; 1986 (abstract only). Shim et al; "Three-dimensional quantitative structure-activity relationship study of the cannabimimetic (aminoalkyl)indoles using comparative molecular field analysis"; J. Med. Chem.; 1998, 41(23); 4521-4532; XP-002212407. Shim et al; "Unified pharmacophoric model for cannabinoids and aminoalkylindoles derived from molecular superimposition of CB1 cannabinoid receptor agonists CP55244 and WIN55212-2"; ACS Symposium series, 1999 719 (rational drug design), 165-184; XP-001095771. Showalter et al; "Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands"; J. Pharmacol. Exp. Ther., 1996 278(3) 989-999; XP-001097918. *1* Smith P.B. et al; "The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice"; Journal of Pharmacology and Experimental Therapeutics; vol. 270(1):219-227; 1994. Tius et al; "Conformationally restricted hybrids of CP-55,940 and HHC: Steroeselective synthesis and activity"; Tetrahedron; 50 (9); 2671-2680; (1994) (abstract only). Twitchell, W. et al; "Cannabinoids inhibit N- and P/Q type calcium channels in cultured rat hippocampal neurons"; Journal of Neurophysiology; 78(1); 43-50; 1997 (abstract only). *1* Watanabe, T.; Miyaura, N.; and Suzuki, A.; "Synthesis of Sterically Hindered Biaryls via the Palladium Catalyzed Cross-Coupling Reaction of Arylboronic Acids or their Esters with Haloarenes"; Synlett 1992, 207-210. Wiley et al; "Structure activity relationships of indole and pyrrole derived cannabinoids"; J. Pharmacol. Exp. Ther. 1998, 285(3), 995-1004; XP-001097982. Wilson et al; "9-nor-delta8-tetrahydrocannabinol, a cannabinoid of metabolic interest"; J. Med. Chem.; 17(4); 475-476; (1974). Wilson et al; "Analgesic properties of the tetrahydrocannabinols, their metabolites and analogs"; J. Med. Chem.; 18(7); 700-703; (1975). Wilson et al; "9-nor-9-hydroxyhexahydrocannabinols. Synthesis, some behavioral and analgesic properties, and comparison with the tetrahydrocannabinols"; J. Med. Chem.; 19(9); 1165-1167; (1976). Yamada et al; "(Aminoalkyl)indole isothiocyanates as potentiual electrophilic affinity ligands for the brain cannabinoid receptor"; J. Med. Chem. 1996, vol. 39(10), 1967-1974. Yan, Guo et al; "Synthesis and pharmacological properties of 11-hydroxy-3-(1′-1′-dimethylheptyl)hexahydrocannabinol: a high affinity cannabinoid agonist"; J. Med. Chem.; vol. 37(16); 2619-2622; (1994). *1* Yan Guo et al; "(-)-11-hydroxy-7′-isothiocyanato-1′-1′dimethylheptyl-delta8-THC: a novel probe for the cannabinoid receptor in the brain"; J. Med. Chem.; 37(23); 3867-3870; (1994).

Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Anderson; Rebecca
Attorney, Agent or Firm: Alix, Yale & Ristas, LLP

---

Parent Case Text

---

This application is the National Stage of International Application No. PCT/US00/28818, filed Oct. 18, 2000, which claims the benefit of U.S. Provisional Application No. 60/160,146, filed Oct. 18, 1999.

---

Claims

---

What is claimed is:

1. A compound of the formula: ##STR13##

and physiologically acceptable salts thereof, wherein

R₁ is selected from H; OH; OCH₃; N₃; and NH₂;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

2. The compound of claim 1 wherein R₁ is OH and R₂ is 1,1-dimethylheptyl and R₃ is CH₃.

3. The compound of claim 1 wherein R₁ and R₃ are each OH and R₂ is 1,1-dimethylheptyl.

4. A method of preferentially stimulating the CB2 receptors in an individual or animal for the treatment of at least one of pain an peripheral pain comprising administering to the individual or animal a therapeutically effective amount of a compound having the formula: ##STR14##

and physiologically acceptable salts thereof, wherein

R₁ is selected from H; OH; OCH₃; N₃; and NH₂;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₆; C₃H₇; and C₄H₉.

5. A pharmaceutical composition containing a therapeutically effective amount of a compound having the formula: ##STR15##

and physiologically acceptable salts thereof, wherein

R₁ is selected from H; OH; OCH₃; N₃; and NH₂;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

6. The compound of claim 1 wherein:

R₁ is selected from OH and NH₂;

R₂ is C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; and

R₃ is selected from H and CH₃.

7. The compound of claim 1 wherein:

R₁ is selected from H; OH and OCH₃;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

8. The compound of claim 1 wherein:

R₁ is selected from H; N₃; and NH₂;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

9. The method of claim 4 wherein:

R₁ is selected from H; OH and OCH₃;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

10. The method of claim 4 wherein:

R₁ is selected from H; N₃; and NH₂;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

11. The pharmaceutical composition of claim 5 wherein:

R₁ is selected from H; OH and OCH₃;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃: C₂H₅; C₃H₇; and C₄H₉.

12. The pharmaceutical composition of claim 5 wherein:

R₁ is selected from H; N₃; and NH₂H;

R₂ is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; (CH₂)C≡CH where n is an integer from 3-5; and C≡C(CH₂)_nCH₃ where n is an integer from 2-4; and

R₃ is selected from H; CH₃; C₂H₅; C₃H₇; and C₄H₉.

---

Description

---

FIELD OF THE INVENTION

The present invention relates generally to cannabinoid compounds and is more particularly concerned with new and improved cannabinoid compounds exhibiting high binding affinities for the CB2 cannabinoid receptor, pharmaceutical preparations employing these analogs and methods of administering therapeutically effective amounts of the preparations to provide a physiological effect.

BACKGROUND OF THE INVENTION

Classical cannabinoids such as the marijuana derived cannabinoid Δ⁹-tetrahydrocannabinol, (Δ⁹-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. See, for example, Pertwee, R. G., Pharmacology of cannabinoid CB1 and CB2 receptors, Pharmacol. Ther., (1997) 74:129-180 and Di Marzo, V., Melck, D., Bisogno, T., DePetrocellis, L., Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action, Trends Neurosci. (1998) 21:521-528.

There is considerable interest in developing cannabinoid analogs possessing high affinity for the CB2 receptor. Cannabinoid analogs that preferentially stimulate the CB2 receptor, directly or indirectly, can provide clinically useful effects without affecting the subject's central nervous system. Such analogs may offer a rational therapeutic approach to a variety of disease states.

SUMMARY OF THE INVENTION

It has now been found that certain novel cannabinoids possess improved CB2 receptor affinity over known cannabinoids. In one aspect of the invention, novel cannabinoids can be represented by the following formula and physiologically acceptable salts thereof. ##STR1##

• wherein R₁ is selected from OH; H; OCH₃; N₃; NH₂; O(CH₂)_nN(CH₃)₂ and ##STR2##
  where n is an integer from 1-3;
• R2 is selected from (CH₂)_nCH₃, where n is an integer from 4-6; C(CH₃)₂(CH₂)_nCH₃, where n is an integer from 3-5; ##STR3##
  where each X is independently selected from C, O, S and NH and n is an integer from 3-5; (CH₂)_nC≡CH where n is an integer from 3-5;