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(12) United States Patent (10) Patent No.: US 9,040,552 B2 Arnelle Et Al

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(12) United States Patent (10) Patent No.: US 9,040,552 B2 Arnelle Et Al US009040552B2 (12) United States Patent (10) Patent No.: US 9,040,552 B2 Arnelle et al. (45) Date of Patent: May 26, 2015 (54) SELECTIVE OPIOID COMPOUNDS Cancer online, retrieved on Jul. 6, 2007. Retrieved from the internet, URL http://www.nlm.nih.gov/medlineplus/cancer.html>.* (71) Applicant: Alkermes, Inc. Cancer online, retrieved on Jul. 6, 2007. Retrieved from the internet, URL: http://en.wikipedia.org.wiki|Cancer.* (72) Inventors: Derrick Arnelle, Arlington, MA (US); Irritable Bowel Syndrome online). Retrieved on Nov. 4, 2014 from Daniel Deaver, Franklin, MA (US); the internet. URL http://digestive.niddk.nih.gov/ddiseases/pubs/ Reginald L. Dean, III, Boxborough, bSt. MA (US); Mark Todtenkopf, Franklin, MA (US) * cited by examiner (73) Assignee: Alkermes, Inc., Waltham, MA (US) Primary Examiner — Shawquia Jackson *) Notice: Subject to anyy disclaimer, the term of this (74) Attorney, Agent, or Firm — Elmore Patent Law Group, patent is extended or adjusted under 35 U.S.C. 154(b) by 97 days. P.C.; Roy P. Issac; Carolyn S. Elmore (21) Appl. No.: 13/693,662 (57) ABSTRACT (22) Filed: Dec. 4, 2012 The present invention relates to compounds of Formula I or II, (65) Prior Publication Data or pharmaceutically acceptable salts, esters, or prodrugs US 2014/OOO5215A1 Jan. 2, 2014 thereof: Related U.S. Application Data (62) Division of application No. 12/371,334, filed on Feb. (I) 13, 2009, now Pat. No. 8,354,534. (60) Provisional application No. 61/028,780, filed on Feb. 14, 2008, provisional application No. 61/087,295, filed on Aug. 8, 2008. (51) Int. Cl. A6 IK3I/485 (2006.01) A6 IK 45/06 (2006.01) CO7D 22 I/28 (2006.01) CO7D 489/00 (2006.01) CO7D 489/08 (2006.01) CO7D 47/08 (2006.01) (II) (52) U.S. Cl. CPC ............ C07D 489/08 (2013.01); A61K3I/485 (2013.01); A61K 45/06 (2013.01); C07D 471/08 (2013.01) (58) Field of Classification Search CPC ............................ C07D 471/08: C07D 489/08 USPC ...................................................... 546/44, 74 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS which relates to mophinan compounds useful as L., 8 and/or K 4,730,048 A 3/1988 Portoghese receptor opioid compounds and pharmaceuticals containing 5,739,145 A 4, 1998 Nagase et al. 8,772,308 B2 7/2014 Zhang et al. same that may be useful for mediating analgesia, combating 2006/0063792 A1 3f2006 Dolle et al. ................... 514,282 drug addiction, alcohol addiction, drug overdose, mental ill ness, bladder dysfunctions, neurogenic bladder, interstitial FOREIGN PATENT DOCUMENTS cystitis, urinary incontinence, premature ejaculation, inflam JP 61271275 A 12, 1986 matory pain, peripherally mediated and neuropathic pain, JP 2011512360 A 4/2011 cough, lung edema, diarrhea, cardiac disorders, cardioprotec WO 02080918 A 10, 2002 tion, depression, and cognitive, respiratory, diarrhea, irritable WO 2007/031284 A1 3, 2007 bowel syndrome and gastro-intestinal disorders, immuno OTHER PUBLICATIONS modulation, and anti-tumor agents. Cancer and Metastasis Reviews (1998), 17(1), 91-106.* Science (1999), vol. 286,531-536.* 14 Claims, 1 Drawing Sheet U.S. Patent May 26, 2015 US 9,040,552 B2 8 s saline Niarishine at s fx-s&S (st corpxts r is 33 risks, ip SO : O Saline Flphine ases of cosip at Eri- Rigg, is Fl PGE2 dose = 0.1mgkg Morphing dose = 1.0mgkg FIG 2 US 9,040,552 B2 1. 2 SELECTIVE OPOD COMPOUNDS candidates for preventing and/or treating post-Surgical and post-partum ileus. Of those, drugs that do not interfere with RELATED APPLICATIONS the effects of opioid analgesics in the CNS would be of special benefit in that they could be administered simultaneously for This application is a divisional of U.S. application Ser. No. 5 pain management with limited side effects. 12/371,334, filed Feb. 13, 2009 and claims the benefit of U.S. provisional application No. 61/028,780 filed Feb. 14, 2008 Peripheral opioid antagonists that do not cross the blood and 61/087.295 filed Aug. 8, 2008. The contents of the above brainbarrier into the CNS are known in the literature and have applications are incorporated herein by reference. been tested in relation to their activity on the GI tract. In U.S. 10 Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No. TECHNICAL FIELD 5,159,081, and U.S. Pat. No. 5,270,328, peripherally selec tive piperidine-N-alkylcarboxylate opioid antagonists are This invention relates to morphinan compounds useful as described as being useful in the treatment of idiopathic con L., Kand/or 6 receptor opioid compounds and pharmaceuticals stipation, irritable bowel syndrome, and opioid-induced con containing same that may be useful for mediating analgesia, 15 stipation. Some peripheral Lantagonists derived from the combating drug addiction, alcohol addiction, drug overdose, structure naltrexone have been reported in the literature (U.S. mental illness, bladder dysfunctions, neurogenic bladder, Pat. No. 4,806,556: Botros, et al., J. Med Chem. 1989, 32, interstitial cystitis, urinary incontinence, premature ejacula 2068-2071). In addition, U.S. Pat. No. 4,176,186 describes tion, inflammatory pain, peripherally mediated and neuro quaternary derivatives of noroxymorphone (i.e., methylmaltr pathic pain, cough, lung edema, diarrhea, cardiac disorders, exone) that are said to prevent or relieve the intestinal immo cardioprotection, depression, and cognitive, respiratory, diar bility side effect of narcotic analgesics without reducing anal rhea, irritable bowel syndrome and gastro-intestinal disor gesic effectiveness. U.S. Pat. No. 5,972,954 describes the use ders, immunomodulation, and as anti-tumor agents. of methylmaltrexone, enteric-coated methylmaltrexone, or 25 other quaternary derivatives of noroxymorphone for prevent BACKGROUND OF THE INVENTION ing and/or treating opioid- and/or nonopioid-induced side effects associated with opioid administration. Opioid drugs typically target three types of endogenous General opioid antagonists, such as naloxone and naltrex opioid receptors (i.e., LL, 8, and K receptors) in biological 30 one, have also been implicated as being useful in the treat systems. Many opiates. Such as morphine, are L opioid ago ment of GI tract dysmotility. For example, U.S. Pat. No. nists that are often used as analgesics for the treatment of 4,987,126 and Kreek, M. J. Schaefer, R. A., Hahn, E. F., severe pain due to their activation of Lopioid receptors in the Fishman, J. Lancet, 1983, 1,8319, 261 disclose naloxone and brain and central nervous system (CNS). Opioid receptors other morphinan-based opioid antagonists (i.e., naloxone, are, however, not limited to the CNS, and may be found in 35 maltrexone) for the treatment of idiopathic gastrointestinal other tissues throughout the body, i.e., peripheral to the CNS. dysmotility. In addition, naloxone has been shown to effec A number of side effects of opioid drugs may be caused by tively treat non-opioid induced bowel obstruction, implying activation of these peripheral receptors. For example, admin that the drug may act directly on the GI tract or in the brain istration of L opioid agonists often results in intestinal dys 40 (Schang, J. C., Devroede, G., Am. J. Gastroenerol., 1985, 80. function due to the large number of receptors in the wall of the 6, 407). Furthermore, it has been implicated that naloxone gut (Wittert, G., Hope, P. and Pyle, D., Biochemical and may provide therapy for paralytic ileus (Mack, D.J. Fulton, J. Biophysical Research Communications, 1996, 218, 877-881: D., Br. J. Surg., 1989, 76, 10, 1101). However, it is well Bagnol, D., Mansour, A., Akil. A. and Watson, S.J., Neuro known that activity of naloxone and related drugs is not science, 1997, 81, 579-591). Specifically, opioids are gener 45 limited to peripheral systems and may interfere with the anal ally known to cause nausea and Vomiting, as well as inhibition gesic effects of opioid narcotics. of normal propulsive gastrointestinal function in animals and Despite recent advances in peripherally acting opioids, man (Reisine, T., and Pasternak, G., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Ninth Edition, there is still a need for more effective and safe opioid com 50 pounds, with potent L. K. and/or 6 receptor agonist activities 1996, 521-555), resulting in side effects such as, for example, that produce essentially no central mechanism side effect, constipation. more particularly for the use in preventing or treating unde It would be of benefit to inhibit the natural activity of sirable side effects associated with administering exogenous endogenous opioids during and/or after periods of biological opioids with minimal impact on opioid agonist analgesia. stress, Such as Surgery and childbirth, so that ileus and related 55 forms of bowel dysfunction can be prevented and/or treated. SUMMARY OF THE INVENTION Currently, therapies for ileus include functional stimulation of the intestinal tract, stool softeners, laxatives, lubricants, The present invention relates to derivatives of morphinans intravenous hydration, and nasogastric decompression. and 3-carboxamido-6-amino-Substituted 4.5 epoxymorphin These prior art methods suffer from drawbacks, for example, 60 ans to target modulation of opioid receptor activity outside of as lacking specificity for post-Surgical or post-partum ileus. the CNS, particularly those receptors associated with the And these prior art methods offer no means for prevention. If gastrointestinal tract, by reducing the lipid permeability of the illeus could be prevented, hospital stays, recovery times,
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