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(12) United States Patent (10) Patent N0.: US 8,957,025 B2 Owen (45) Date of Patent: Feb

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(12) United States Patent (10) Patent N0.: US 8,957,025 B2 Owen (45) Date of Patent: Feb USOO8957025B2 (12) United States Patent (10) Patent N0.: US 8,957,025 B2 Owen (45) Date of Patent: Feb. 17, 2015 (54) ENKEPHALIN ANALOGUES OTHER PUBLICATIONS (75) Inventor: Dafydd Rhys Owen, Cambridge, MA Waldhoer, et al., “Opioid Receptors”, Annu. Rev. Biochem., vol. 73, (Us) pp. 953-990 (2004). Bileviciute-Ljungar, et al., “Peripherally Mediated Antinociception (73) Assignee: P?zer Inc., New York, NY (US) of the p-Opioid Receptor Agonist 2-[(4,501-Epoxy-3-hydroxy-14B methoxy- 1 7-methylmorphinan-6B-yl)amino]acetic Acid (HS-731) (*) Notice: Subject to any disclaimer, the term of this after Subcutaneous and Oral Administration in rats With Car patent is extended or adjusted under 35 rageenan-Induced Hindpaw In?ammation”, JPET, vol. 317(1), pp. U.S.C. 154(b) by 0 days. 220-227 (2006). Gordon, et al., “Activation of P-glycoprotein ef?uX transport amelio (21) Appl. No.: 14/125,690 rates opioid CNS effects Without diminishing analgesia”, Drug Dis covery Today: Therapeutic Strategies, vol. 6(3), pp. 97-103 (2009). (22) PCT Filed: Jun. 29, 2012 He, et al., “Methadone Antinociception is Dependent on Peripheral Opioid Receptors”, Journal of Pain, vol. 10(4), pp. 369-379 (2009). (86) PCT No.: PCT/IB2012/053327 Koppert, et al., Peripheral Antihyperalgesic Effect of Morphine to Heat, but Not Mechanical, Stimulation in Healthy Volunteers after § 371 (00)’ Ultraviolet-B Irradiation, Anesthesia & Analgesia, vol. 88(1), pp. (2), (4) Date: Dec. 12, 2013 117-122 (1999). Oeltjenbruns, et al., “Peripheral Opioid Analgesia: Clinical Applica (87) PCT Pub. No.: WO2013/008123 tions”, Current Pain and Headache Reports, vol. 9(1), pp. 36-44 PCT Pub. Date: Jan. 17, 2013 (2005). Stein, et al., “Attacking pain at its source: new perspective on opioids”, Nature Medicine, vol. 9(8), pp. 1003-1008 (2003). (65) Prior Publication Data Stein, et al., “Peripheral mechanisms of opioid analgesia”, Current US 2014/0121279 A1 May 1, 2014 Opinion in Pharmacology, vol. 9(1), pp. 3-8 (2009). Wenk, et al., “Morphine Directly Inhibits Nociceptors in In?amed Skin”, Journal of Neurophisiologyvol. 95(4), pp. 2083 -2097 (2006). Related US. Application Data Osterlund Modalen, et al., A Novel Molecule (Frakefamide) With Peripheral Opioid Properties: The Effects on Resting Ventilation (60) Provisional application No. 61/507,280, ?led on Jul. Compaired With Morphine and Placebo, Anesthesia & Analgesia, 13, 2011. vol. 100, pp. 713-717 (2005). DeHaven-Hudkins, et al., “Pherpherally Restricted Opioid Agonists Int. Cl. as Novel Analgesic Agents”, Current Pharmaceutical Design, vol. (51) 10(7), pp. 743-757 (2004). A61P 25/04 (2006.01) KapitZke, et al., “Endogenous opioid analgesia in peripheral tissues C07C 23 7/06 (2006.01) and the clinical implications for pain control”, Therapeutics and A61K 38/06 (2006.01) Clinical Risk Management, vol. 1(4), pp. 279-297 (2005). C07K 5/065 (2006.01) Koda, et al., “Comparison of the in vitro apparent permeability and A61K 31/165 (2006.01) stability of opioid mimetic compounds With that of the native A61K 38/00 (2006.01) peptide”, Bioorganic & Medicinal Chemistry Letters, vol. 17(7), pp. (52) US. Cl. 2043-2046 (2007). CPC ............. .. C07C 237/06 (2013.01); A61K38/06 (Continued) (2013.01); C07K 5/06078 (2013.01); A61K 31/165 (2013.01); A61K 38/00 (2013.01) Primary Examiner * Maury Audet USPC ....... .. 514/18.4; 514/185; 514/21.9; 530/331 Assistant Examiner * Fred Reynolds (58) Field of Classi?cation Search (74) Attorney, Agent, or Firm * A. Dean Olson None See application ?le for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to dipeptide enkephalin ana logues of Formula (I) and their tautomers, ionic forms and U.S. PATENT DOCUMENTS pharmaceutically acceptable salts, and their use in medicine, in particular as opioid agonists. 6,114,310 A 9/2000 Chamberland et al. 2011/0207654 A1* 8/2011 Barber et al. ................ .. 514/1.1 FOREIGN PATENT DOCUMENTS 0154234 9/1985 91/11172 8/1991 94/02518 2/1994 98/55148 12/1998 2008/047229 4/2008 CH3 0 CH3 NH2 2008/118758 10/2008 2008/135826 11/2008 2009/012242 1/2009 2010/079443 7/2010 2011104649 9/2011 5 Claims, No Drawings US 8,957,025 B2 Page 2 (56) References Cited Castiglione-Morelli, et al., “A 500-MHz Proton Nuclear Magnetic Resonance Study of u Opioid Peptides in a Simulated Receptor OTHER PUBLICATIONS Environment”, J. Med. Chem., vol. 30(11), pp. 2067-2073 (1987). 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Res., vol. 23, pp. 45(23), pp. 5081-5089 (2002). 341-343 (1991). Genco, et al., “Antimicrobial activity of magainin analogues against Konopinska, et al., “Role of guanidine group at the N-terminal anaerobic oral pathogens”, International Journal of Antimicrobial proctolin chain in cardioexcitatory effects in insects”, Int. J. Peptide Agents, vol. 21(1), pp. 75-78 (2003). Protein Res., vol. 35, pp. 12-16 (1990). Deguchi, et al., “Blood-Brain Barrier Permeability of Novel Delitala, et al., “Opioids Stimulate Growth Hormone (GH) Release in [D-Arg2]Dermorphin (1-4)Analogs Transport Property is Related to Man Independently of GH-Releasing Hormone”, J. Clin. Endocri the Slow Onset of Antinociceptive Activity in the Central Nervous nology and Metab., vol. 69(2), pp. 356-358 (1989). System”, JPET, vol. 310(1), pp. 177-184 (2004). Borges, et al., “Opioid peptides do not modulate atrial natriuretic Wolin, et al., “Novel glycine transporter type-2 reuptake inhibitors. peptide or aldosterone release under basal conditions in man”, Jour Part 1: 01-amino acid derivatives”, Biorganic & Medicinal Chemistry, nal ofEndocrinology, vol. 116, pp. 313-317 (1988). vol. 12(16), pp. 4477-4492 (2004). Marastoni, et al., “Opioid peptides. Biological Study of [D-Met02] Liu, et al., “Utilization of Combined chemical Modi?cations to Dermorphin Analogues in Relation to the Plurality of Opioid Recep Enhance the Blood-Brain Barrier Permeability and Pharmacological tors XI”, 11 Farmaco, vol. 42, pp. 125-131 (1987). Activity of Endomorphin-l”, JPET vol. 319(1), pp. 308-316 (2006). 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