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(12) United States Patent (10) Patent No.: US 8.492,564 B2 Beguin Et Al

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(12) United States Patent (10) Patent No.: US 8.492,564 B2 Beguin Et Al USOO8492.564B2 (12) United States Patent (10) Patent No.: US 8.492,564 B2 Beguin et al. (45) Date of Patent: Jul. 23, 2013 (54) SALVINORIN DERIVATIVES AND USES Béguin et al., “Differential signaling properties at the kappa opioid THEREOF receptor of 12-epi-Salvinorin A and its analogues. Bioorg Med Chem Lett. 22: 1023-1026, 2012. (75) Inventors: Cecile Beguin, Lexington, MA (US); Béguin et al., “Modification of the furan ring of salvinorin A: iden Justin Stephen Potuzak, Millis, MA tification of a selective partial agonist at the kappa opioid receptor.” 17: 1370-1380, Epub Dec. 14, 2008. (US); Thomas Anthony Munro, Béguinet al., "N-Methylacetamide Analog of Salvinorin A: A Highly Cambridge, MA (US); Katharine K. Potent and Selective K-Opioid Receptor Agonist with Oral Efficacy.” Duncan, San Diego, CA (US); William J. Pharmacol. Exp. Ther, 324; 188-195 (2008). A. Carlezon, Lincoln, MA (US); Bruce Béguin et al., “Synthesis and In Vitro Evaluation of Salvinorin A M. Cohen, Lexington, MA (US); Analogues: Effect of Configuration at C(2) and Substitution at Lee-yuan Liu-Chen, Media, PA (US) C(18).” Bioorg. Med. Chem. Lett. 16:4679-4685 (2006). Béguin et al., “Synthesis and InVitro Pharmacological Evaluation of (73) Assignees: The McLean Hospital Corporation, Salvinorin A Analogues Modified at C(2).” Bioorg. Med. Chem. Lett. Belmont, MA (US); Temple University 15:2761-2765 (2005). School of Medicine, Philadelphia, PA Bigham et al., “Divinatorins A-C, New Neoclerodane Diterpenoids from the Controlled SageSalvia divinorum,'.J. Nat. Prod 66: 1242 (US) 1244 (2003). Bikbulatov et al., “Short synthesis of a novel class of salvinorin A (*) Notice: Subject to any disclaimer, the term of this analogs with hemiacetalic structure.” Tetrahedron Lett. 49: 937-940, patent is extended or adjusted under 35 2008. U.S.C. 154(b) by 0 days. Butelman et al., “The Plant-Derived Hallucinogen, Salvinorin A. Produces K-Opioid Agonist-Like Discriminative Effects in Rhesus (21) Appl. No.: 13/133,824 Monkeys.” Psychopharmacol. 172:220-224 (2004). Carlezon et al., “Depressive-Like Effects of the K-Opioid Receptor (22) PCT Filed: Dec. 14, 2009 Agonist Salvinorin A on Behavior and Neurochemistry in Rats.” J. Pharmacol. Exp. Ther: 316:440-447 (2006). (86). PCT No.: PCT/US2009/067929 Chavkin et al., “Salvinorin A, an Active Component of the Halluci nogenic Sage Salvia divinorum Is a Highly Efficacious K-Opioid S371 (c)(1), Receptor Agonist: Structural and Functional Considerations. J. (2), (4) Date: Sep. 29, 2011 Pharmacol. Exp. Ther: 308: 1197–1203 (2004). Chuppet al., “Behavior of Benzyl Sulfoxides Toward Acid Chlorides. Useful Departures from the Pummerer Reaction.” J. Org. Chem. (87) PCT Pub. No.: WO2010/075045 49:4711-4716 (1984). PCT Pub. Date: Jul. 1, 2010 Communication from European Patent Application No. 05725639, dated Jul. 3, 2008. (65) Prior Publication Data Communication from European Patent Application No. 05725639 enclosing Supplementary Partial European Search Report for Euro US 2012/0010219 A1 Jan. 12, 2012 pean Patent Application No. 05725639, dated Feb. 29, 2008. Giroud et al., “Salvia divinorum: An Hallucinogenic Mint which Might Become a New Recreational Drug in Switzerland.” Forensic Sci. Int. 112:143-150 (2000). Related U.S. Application Data Harding et al., “Synthetic Studies of Neoclerodane Diterpenes from (60) Provisional application No. 61/122,668, filed on Dec. Salvia divinorum: Selective Modification of the Furan Ring.” Bioorg. Med. Chem. Lett. 16:3170-3174 (2006). 15, 2008. Harding et al., “Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Semisynthesis of Salvinicins A and B and Other (51) Int. Cl. Chemical Transformations of Salvinorin A. J. Nat. Prod. 69: 107 CO7D 409/00 (2006.01) 112 (2006). C07D 31 L/78 (2006.01) Huang et al., "Comparison of Pharmacological Activities of (52) U.S. Cl. Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a USPC ............................................. 549/60; 549/280 Potent Opioid Agonist.” J. Pharmacol. Exp. Ther: 297:688-695 (2001). (58) Field of Classification Search International Preliminary Report on Patentability for PCT/US05/ USPC .................................................... 549/60, 280 08603, dated Sep. 13, 2006. See application file for complete search history. International Preliminary Report on Patentability for PCT/US09/ 67929, dated Jun. 21, 2011. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Nizal Chandrakumar 2006, OO52439 A1 3/2006 Beguin et al. 2006, OO58264 A1 3, 2006 Prisinzano (74) Attorney, Agent, or Firm — Clark & Elbing LLP 2006, 0083679 A1 4/2006 Zawiony et al. (57) ABSTRACT FOREIGN PATENT DOCUMENTS The invention features Salvinorin compositions that are selec WO WO-02/49643 A1 6, 2002 tive for kappa opioid receptors; methods of treating mania by WO WO-2005/0897.45 A1 9, 2005 using a selective kappa receptor agonist; and methods of OTHER PUBLICATIONS treating mood disorders, such as depressive disorders and manic disorders, using salvinorin compositions. Beguin et al. Bioorganic & Medicinal Chemistry (2009), 17(3), 1370-1380. 12 Claims, 5 Drawing Sheets US 8.492.564 B2 Page 2 OTHER PUBLICATIONS Pogozheva et al., “Opioid Receptor Three-Dimensional Structures International Search Report for PCT/US05/08603, dated Jul. 11, from Distance Geometry Calculations with Hydrogen Bonding Con 2005. straints.” Biophy's. J. 75:612-634, 1998. Roth et al., “Salvinorin A: A Potent Naturally Occurring Non International Search Report for PCT/US09/67929, dated Apr. 14, nitrogenous KOpioid Selective Agonist.” Proc. Nat. Acad. Sci. U.S.A. 2010. 99: 11934-1 1939 (2002). Koreeda et al., “The Absolute Stereochemistry of Salvinorins.” Sheffler and Roth, “Salvinorin A: The Magic Mint Hallucinogen Chem. Lett. 19:2015-2018 (1990). Finds a Molecular Target in the Kappa Opioid Receptor.” Trends Lee et al., “Synthesis and InVitro Pharmacological Studies of C(4) Pharmacol. Sci. 24:107-109 (2003). Modified Salvinorin A Analogues.” Bioorg. Med Chem. Lett. Siebert, “Localization of Salvinorin A and Related Compounds in 15:4169-4173 (2005). Glandular Trichomes of the Psychoactive Sage, Salvia divinorum," Lee et al., “Synthesis and InVitro Pharmacological Studies of New Ann. Bot. 93: 763-771 (2004). Simpson et al., “Synthetic Studies of Neoclerodane Diterpenes from C(2) Modified Salvinorin A Analogues.” Bioorg. Med. Chem. Lett. Salvia divinorum: Preparation and Opioid Receptor Activity of 15:3744-3747 (2005). Salvinicin Analogues.” J. Med. Chem. 50:3596-3603 (2007). Ma et al., “Dynorphinergic GABA Neurons Are a Target of Both Spanagel et al., “Opposing Tonically Active Endogenous Opioid Typical and Atypical Antipsychotic Drugs in the Nucleus Accumbens Systems Modulate the Mesolimbic Dopaminergic Pathway.” Proc. Shell, Central Amygdaloid Nucleus and Thalamic Central Medial Natl. Acad. Sci. U.S.A. 89:2046-2050, 1992. Nucleus.” Neuroscience 121:991-998 (2003). Valdés et al., “Divinorin A, a Psychotropic Terpenoid, and Divinorin Mague et al., “Antidepressant-Like Effects of K-Opioid Receptor B from the Hallucinogenic Mexican Mint Salvia divinorum," J. Org. Antagonists in the Forced Swim Test in Rats.” J. Pharmacol. Exp. Chem. 49:4716-4720 (1984). Valdés et al., “Salvinorin C, a New Neoclerodane Diterpene from a Ther: 305:323-330 (2003). Bioactive Fraction of the Hallucinogenic Mexican Mint Salvia McCurdy et al., “Studies Directed toward Understanding the Opioid divinorum.” Org. Lett. 3:3935-3937 (2001). Receptor Recognition of Salvinorin A, a Non-Nitrogenous Natural Zdero et al., “Ent-Clerodanes and Other Constituents from Bolivian Product with Kappa Opioid Receptor Selectivity,” 2003 Narcotics Baccharis Species.” Phytochem. 28:531-542 (1989). Research Conference, Abstract #28, p. 51. Zhang et al., “Kappa Agonist Salvinorin A Induced Conditioned Munro et al., “Studies toward the Pharmacophore of Salvinorin A. A Place Aversion in C57BL/6J Mice. 2003 Narcotics Research Con Potent K Opioid Receptor Agonist.” J. Med Chem. 48:345-348 ference, Abstract #102, p. 70. (2005). Zhu et al., “Activation of the Cloned Human Kappa Opioid Receptor Munro and Rizzacasa, “Salvinorins D-F, New Neoclerodane by Agonists Enhances 35S]GTPYS Binding to Membranes: Deter Diterpenoids from Salvia divinorum, and an Improved Method for mination of Potencies and Efficacies of Ligands.” J. Pharmacol. Exp. the Isolation of Salvinorin A.J. Nat. Prod. 66:703-705 (2003). Ther: 282:676-684 (1997). Munro et al..."8-epi-Salvinorin B: Crystal Structure and Affinity at Written Opinion of the International Searching Authority for PCT/ the K Opioid Receptor.” Beilstein J. Org. Chem. 3:1-5 (2007). US05/08603, dated Jul 11, 2005. Pliakas et al., “Altered Responsiveness to Cocaine and Increased Written Opinion of the International Searching Authority for PCT/ Immobility in the Forced Swim Test Associated with Elevated cAMP US09/67929, dated Apr. 14, 2010. Response Element-Binding Protein Expression in Nucleus Accumbens,” J. Neurosci. 21:7397-7403 (2001). * cited by examiner U.S. Patent Jul. 23, 2013 Sheet 1 of 5 US 8.492,564 B2 Figure 1 0 U50,488 tle U50,488 - 10 M6 - - - - - - - - Test compound (M) U.S. Patent Jul. 23, 2013 Sheet 2 of 5 US 8.492,564 B2 Figure 2 12-epi-Salvinorin B n-butyl ether 12-epi-salvinorin Ballyl ether US 8,492,564 B2 1. SALVINORIN DERVATIVES AND USES THEREOF (I) A CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. national stage filing under 35 U.S.C. S371 of international application PCT/US2009/ 067929, filed Dec. 14, 2009, which claims benefit of the filing 10 date of U.S. Provisional Application No. 61/122,668, filed Dec. 15, 2008. BACKGROUND OF THE INVENTION 15 or a pharmaceutically acceptable salt thereof. In formula I. A The invention relates to the treatment of depressive disor is selected from C(O)Y, C(O)xis, CH(OR")X, CHZs, ders and mania. Stressors that cause symptoms of depression increase the R15 R15 activation of cAMP response element-binding protein R14 R14 (CREB) in the nucleus accumbens. CREB activation results e in the activation of the prodynorphin gene, which encodes the O O opioid peptide dynorphin.
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