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(12) United States Patent (10) Patent No.: US 9,365,534 B2 Mechoulam Et Al

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(12) United States Patent (10) Patent No.: US 9,365,534 B2 Mechoulam Et Al USOO9365534B2 (12) United States Patent (10) Patent No.: US 9,365,534 B2 Mechoulam et al. (45) Date of Patent: Jun. 14, 2016 (54) ARYLATED CAMPHENES, PROCESSES FOR (56) References Cited THER PREPARATION AND USES THEREOF U.S. PATENT DOCUMENTS (71) Applicant: Yissum Research Development 2,537,647 A 1/1951 Kitchen et al. Company of the Hebrew University of 2,647,152 A 7, 1953 Kitchen et al. Jerusalem Ltd., Jerusalem (IL) 3.284,359 A 11, 1966 Roth 3,800,051 A 3, 1974 Barnhart et al. 3,833,671 A 9/1974 Mardiguian et al. (72) Inventors: Raphael Mechoulam, Jerusalem (IL); 4,061,777 A 12/1977 Mardiguian Lital Magid, Jerusalem (IL); Esther 4,112,000 A 9/1978 Mardiguian Shohami, Mevasseret Zion (IL); Itai 5,648,352 A 7/1997 Bocket al. 6.242,386 B1 6/2001 Lukads et al. Bab, Carmei Yossef (IL) 7,514,583 B2 4/2009 Snow et al. 7,714,170 B2 5, 2010 Snow et al. (73) Assignee: YISSUM RESEARCH 8,722,938 B2* 5/2014 Mechoulam et al. ......... 568.327 DEVELOPMENT COMPANY OF 2007/0225.362 A1 9, 2007 Snow et al. THE HEBREW UNIVERSITY OF 2007/0276034 A1 1 1/2007 Esposito et al. 2011/OO15272 A1 1/2011 Snow et al. JERUSALEM LTD., Jerusalem (IL) 2011/O144124 A1 6, 2011 Snow et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. CL 19930O256 2, 1993 CL 2OOOO 1176 5, 2000 CN 18472O7 A 3, 2006 (21) Appl. No.: 14/230,267 DE 828394 C 1, 1952 DE 876241 C 5, 1953 (22) Filed: Mar. 31, 2014 GB 1548875. A 7/1979 JP S5O151856 A 12, 1975 (65) Prior Publication Data JP 2004513163 A 4/2004 JP 2004529852. A 9, 2004 US 2015/OO38728A1 Feb. 5, 2015 JP 2005531596. A 10/2005 RU 2233262 C1 T 2004 WO O224636 A2 3, 2002 WO O238542 A1 5, 2002 Related U.S. Application Data WO O3101927 A1 12/2003 (62) Division of application No. 13/504,167, filed as WO WO 2008,154083 A2 12/2008 application No. PCT/IL2010/000970 on Nov. 18, OTHER PUBLICATIONS 2010, now Pat. No. 8,722,938. Murry et al. Tetrahedron Letters, 24(10),979-982, 1983.* (60) Provisional application No. 61/262,677, filed on Nov. Tsukervanik, et al. STN Abstract of Zhurnal Obshchei Khimi 19, 2009. (1938), 8, 1899-1902.* Kitchen, Leland J. Journal of the American Chemical Society (1948), 70, 3608-10.* (51) Int. Cl. Herold et al. Chemische Berichte (1981), 114(1), 359-74.* CO7D 49.3/00 (2006.01) Ducloset al Tetrahedron Letters, 2008, 49,5587-5589.* CO7D 3II/94 (2006.01) Makriyannis A. “Bornyl- and Isobornyl-delta8-tetrahydrocan C07C39/23 (2006.01) nabinols: A Novel Class of Cannabinergic Ligands,” J. of Medicinal CD7C 43/25 (2006.01) Chemistry, Oct. 2008, pp. 6393-6399, vol. 51. CD7C 43/23 (2006.01) Duclos Ri, et al. “Synthesis and Characterization of 2-substituted Bornane Pharmacophores for Novel Cannabinergic Ligands'. Tetra C07C 45/70 (2006.01) hedron Letters, Sep. 2008, pp. 5587-5589, vol. 49, No. 39, Elsevier, C07C5L/00 (2006.01) Amsterdam, NL. C07C5L/09 (2006.01) Szabo, B. "Pharmacology of cannabinoid receptors.” Biotrend Rev 2 C07C 69/757 (2006.01) (2008): 1-13. CO7D 3II/80 (2006.01) (Continued) CO7D 3II/96 (2006.01) (52) U.S. Cl. Primary Examiner — Nizal Chandrakumar CPC .............. C07D 311/94 (2013.01); C07C39/23 (74) Attorney, Agent, or Firm — Browdy and Neimark, (2013.01); C07C 43/215 (2013.01); C07C PLLC 43/23 (2013.01); C07C45/70 (2013.01); C07C 51/00 (2013.01); C07C51/09 (2013.01); C07C (57) ABSTRACT 69/757 (2013.01); C07D 31 1/80 (2013.01); The present invention relates to arylated camphenes, pro C07D 311/96 (2013.01); C07C 2102/42 cesses for their preparation and uses thereof for the manufac (2013.01) ture of medicaments for the treatment of diseases, disorders (58) Field of Classification Search or conditions associated with, or benefiting from stimulation CPC ..................................................... CO7C 43/215 of CB2 receptors. USPC .......................................................... 5467279 See application file for complete search history. 4 Claims, 10 Drawing Sheets US 9,365,534 B2 Page 2 (56) References Cited 308: A Specific Agonist for CB2, a Peripheral Cannabinoid Recep tor'. 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McGeer PL., “Reduction of Human Allylboronsaureester chiraler Glycole” Chemische Berichte. Monocytic Cell Neurotoxicity and Cytokine Secretion by Ligands of 114:1:359-374 (1981). the Cannabinoid-type CB2 Receptor'. British J. Pharmacology, Jun. Albrecht Berkessel et al. “Synthesis and Configurational Assignment 2003, pp. 775-786, vol. 139, No. 4. of Chiral Salicylic Aldehydes: Novel Building Blocks for Asymmet Kogan NM, Mechoulam R. “The Chemistry of Endocannabinoids'. ric Catalysis' Europ. J of Organic Chemistry. 16:2800-2807 (2002). J. Endocrinological Investigation, 2006, pp. 3-14, vol. 29, Supp. 3. Arevalo-Martin A. Garcia-Ovejero D, Gomez O. Rubio-Araiz A. Kogan NM, Mechoulam R. “Cannabinoids in Health and Disease'. Navarro-Galve B, Guaza C. Molina-Holgado E. Molina-Holgado F. Dialogues in Clinical Neuroscience, 2007, pp. 413-430, vol. 9, No. 4. “CB2 Cannabinoid Receptors as an EmergingTarget for Demyelinat Lotersztajn S. Teixeira-Clerc F. Julien B, Deveaux V, Ichigotani Y. ing Diseases: From Neuroimmune Interactions to Cell Replacement Manin S, Tran-Van-Nhieu J, Karsak M. Zimmer A, Mallat A, “CB2 Strategies”. British J. Pharmacology., Jan. 2008, pp. 216-225, vol. Receptors as New Therapeutic Targets for Liver Diseases”. British J. 153, No. 2. Pharmacology, Jan. 2008, pp. 286-289, vol. 153, No. 2. Avraham Y. Israeli E. Gabbay E. Okun A, Zolotarev O, Silberman I. McMurray JE, Scott WJ, “A Method for the Regiospecific Synthesis Ganzburg V. Dagon Y. Magen I, Vorobia L. Pappo O. Mechoulam R. of Enol Triflates by Enolate Trapping”. Tetrahedron Letters, 1983, Ilan Y. Berry EM, "Endocannabinoids Affect Neurological and Cog pp. 979-982, vol. 24, No. 10. nitive Function in Thioacetamide-Induced Hepatic Mechoulam R. Braun P. Gaoni Y. “Synthesis of (Delta)1-THC and Related Cannabinoids”. J. Am. Chem. Soc., 1972, pp. 6159-6165. Encephalopathy'. Neurobiological Disease, Jan. 2006, pp. 237-245, vol. 94. vol. 21, No. 1. Mechoulam R. Sumariwalla PF, Feldmann M. Galilly R. "Can Ashton JC, Glass M. “The Cannabinoid CB2Receptor as a Target for nabinoids in Models of Chronic Inflammatory Conditions'. Inflammation-Dependent Neurodegeneration'. Current Phytochemistry Reviews, 2005, pp. 11-18, vol. 4. Neuropharmacology, Jun. 2007, pp. 73-80, vol. 5, No. 2. Ofek O. Karsak, M. Leclerc N, Fogel M. Frenkel B. Wright K. Tam Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M, J. Attar-Namdar M. Kram V, Shohami E, Mechoulam R. Zimmer A, Appleton I, "Cerebral Hypoxia-Ischemia and Middle Cerebral Artery Bab I. “Peripheral Cannabinoid Receptor, CB2, Regulates Bone Occlusion Induce Expression of the Cannabinoid CB2 Receptor in Mass'. Proceedings of the National Academy of Sciences (USA), the Brain'. Neuroscience Letters, Jan. 2007, pp. 114-117, vol. 412, Jan. 2006, pp. 696-701, vol. 103, No. 3. No. 2. Pacher P. Hasko G. Endocannabinoids and Cannabinoid Receptors in Bartlett PD, Knox LH, Org. Syn. Coll., 1973, p. 689, vol. 5. 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