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(12) United States Patent (10) Patent No.: US 9,102,636 B2 Mannion Et Al

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(12) United States Patent (10) Patent No.: US 9,102,636 B2 Mannion Et Al US009102636B2 (12) United States Patent (10) Patent No.: US 9,102,636 B2 Mannion et al. (45) Date of Patent: Aug. 11, 2015 (54) ANALGESIC COMPOUNDS, Zhou, et al., “N-Acetylcysteine Reduces Extinction Responding and COMPOSITIONS, AND USES THEREOF Induces Enduring Reductions in Cue- and Heroin-Induced Drug Seeking.” Biol Psychiatry, 2008, 63:338-340. (75) Inventors: James C. Mannion, Plainsboro, NJ Ng, et al., “Oxidative stress in psychiatric disorders: evidence base (US); Scott L. Dax, Landenberg, PA and therapeutic implications.” International Journal of (US) Neuropsychopharmacology, 2008, 11:851-876. Bhardwaj, et al., “A Randomized Controlled Trial of Antioxidant (73) Assignee: Galleon Pharmaceuticals, Inc., Supplementation for Pain Relief in Patients with Chronic Pancreatitis.” Gastroenterology, 2009, 136:149-159. Horsham, PA (US) Choi, et al., “The Structure-Activity Relationship of Flavonoids as (*) Notice: Subject to any disclaimer, the term of this Scavengers of Peroxynitrite.” Phytotherapy Research, 2002, 16:232 patent is extended or adjusted under 35 235. Olmos, et al., “Drugs Modulating the Biological Effects of U.S.C. 154(b) by 1014 days. Peroxynitrite and Related Nitrogen Species.” Medicinal Research Reviews, 2007, 27(1):1-64. (21) Appl. No.: 13/043,159 Muscoli, et al., “Therapeutic manipulation of peroxynitrite attenu ates the development of opiate-induced antinociceptive tolerance in (22) Filed: Mar. 8, 2011 mice.” The Journal of Clinical Investigation, Nov. 2007. (65) Prior Publication Data 117(11):3530-3539. Bryant, et al., “Spinal ceramide and neuronal apoptosis in morphine US 2011/0224269 A1 Sep. 15, 2011 antinociceptive tolerance.” Neuroscience Letters, 2009, 463:49-53. US 2012/020286O A2 Aug. 9, 2012 Lam, et al., “Analgesic and anti-arthritic effects of Lingzhi and San Miao San Supplementation in a rat model of arthritis induced by Related U.S. Application Data Freund's complete adjuvant.” Journal of Ethnopharmacology, 2008, 120:44-50. (60) Provisional application No. 61/312,482, filed on Mar. Sindrup, et al., “Efficacy of pharmacological treatments of 10, 2010, provisional application No. 61/378,781, neuropathic pain: an update and effect related to mechanism of drug filed on Aug. 31, 2010. action. Pain, 1999, 83:389-400. Kim, et al., “An experimental model for peripheral neuropathy pro (51) Int. Cl. duced by segmental spinal nerve ligation in the rat.” Pain, 1992, C07D 277/18 (2006.01) 50:355-363. (52) U.S. Cl. Jumbelic, “Deaths with Transdermal Fentanyl Patches.” Am J Foren CPC .................................... C07D 277/18 (2013.01) sic Med Pathol, Mar. 2010, 31(1):18-21. (58) Field of Classification Search Hargreaves, et al., “A new and sensitive method for measuring ther USPC .................................................. 548/190, 194 mal nociception in cutaneous hyperalgesia.” Pain, 1988, 32:77-88. See application file for complete search history. Whiteside, et al., “The Role of Central and Peripheral u Opioid Receptors in Inflammatory Pain and Edema: A Study Using Mor (56) References Cited phine and DiPOA (8-(3.3-Diphenyl-propyl)-4-oxo-1-phenyl-1,3,8- triaza-spiro4.5 dec-3-yl)-acetic Acid).” The Journal of Pharmacol U.S. PATENT DOCUMENTS ogy and Experimental Therapeutics, 2005, 314(3):1234-1240. 3,993,766 A * 1 1/1976 Behner et al. ................. 514,370 * cited by examiner 2010/0324096 A1* 12/2010 Hanyu et al. .................. 514,342 Primary Examiner — Laura L. Stockton FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Saul Ewing LLP. Kathryn WO WO-2006,131737 A2 * 12/2006 Doyle; Domingos J. Silva WO WO-2009,099.195 A1 * 8, 2009 (57) ABSTRACT OTHER PUBLICATIONS The invention relates to compounds, compositions, and meth Chemical Abstracts Registry No. 524705-05-3, indexed in the Reg ods for diminishing pain in a Subject in need thereof compris istry file on STN Jun. 3, 2003.* ing administering the compounds and compositions herein Madayag, et al., “Repeated N-Acetylcysteine Administration Alters described. Plasticity-Dependent Effects of Cocaine.” The Journal of Neuroscience, Dec. 19, 2007, 27(51): 13968-13976. 3 Claims, 31 Drawing Sheets U.S. Patent Aug. 11, 2015 Sheet 1 of 31 US 9,102,636 B2 -- Vehicle PM 5. Cmpd. 2 (3 mg/kg) -A- Cmpd. 2 (10 mg/kg) -- Cmpd, 2 (25 mg/kg) 1) N:5-6 (S s S Time (min) post-?entany Time (min) post-fentary Cmpd. 2 or Vehicle Fentanyl Fentanyl 25 g/kg AM 25 ug/kg PM Baseline First latency recording First latency recording smopom somnisomni 6O 120 18O 210 30 6O 90 120 150 Time in min post fentanyl Time in min post fentany Figure 1 U.S. Patent Aug. 11, 2015 Sheet 2 of 31 US 9,102,636 B2 Vehicle urg...: Crmpd, 2 (3 mg/kg) N 6 taken Cmpd. 2 (10 mg/kg) st Fentanyl dose r Cmpd. 2 (25 mg/kg) 2nd Fentany dose - 50 50 se w 3 y X s 4.- : 4. s i"" O 's 20--- . 's 20 10 time (min} post-eritany Time (min) post-fentany Cmpd. 2 or vehicle Fentany Fentanyl 25 g/kg 25 g/kg Baseliny res recording First latency recording w 5min 20 40 60 90 120 20 40 6O 90 120 Time in min post fentany Time in min post fentanyl Figure 2 U.S. Patent Aug. 11, 2015 Sheet 3 of 31 US 9,102,636 B2 Cmpd. 2 or Vehicle (25ug/kgS. t Fentanyl25 g/k (''g's)E: (25Fentanyl gig) (25Fentanyl gig) (25 g/kg) sk -- Cmnd. 2 1 *k k k. -e- Vehicle sk sk n=6 sk xk SS ---------- 4 & 8 esseg Time (min) post-fentanyl Figure 3 U.S. Patent Aug. 11, 2015 Sheet 4 of 31 US 9,102,636 B2 First dose of Fantany -e- Vehicle -- Cmpd. 2 Cmpd. 2 pretreatment 15-min before 1 dose offentanyl Second dose of Ferntary Second dose offentanyl 2.5 h later Third dose offentany 2.5 h later P P Time (min) post-fetary Figure 4 U.S. Patent Aug. 11, 2015 Sheet 5 of 31 US 9,102,636 B2 Vehicle or Compound 2 given 15 min only before the 1 fentanyl administration Feintany Fentanyl fetany Fentany (25 g/kg, IV) (25 g/kg, IW) (25 g/kg, V} (25 g/kg, IV) -er Vehicle - - Cmpd. 2 (25 mg/Kg) s'ssessessesss is sessessesss Time (min) post-fentanyl Figure 5 U.S. Patent Aug. 11, 2015 Sheet 6 of 31 US 9,102,636 B2 PM Day 1 - Vehicle - Cmpd. 2 (25 mg/Kg) O O Time (min post-?entary AMDay2 s O is is is 8 & 9 Time (nir post-?entary Time (nin post-?entary Figure 6 U.S. Patent Aug. 11, 2015 Sheet 7 of 31 US 9,102,636 B2 Fentanyl Fentanyi Fentanyl Fentanyl Fentany Fentanyl Fentanyl 25 g/kg 25 uglkg 25 g/kg 25 uglkg 25 uglkg 25 g/kg 25 uglkg 30 m 4.0h 4.0 h 4.0h 7 4,0h Pre l 20 40 60 90 120 Baseline Day 1 Day 2 Day 3 Hammam - - Day 3 40 k -e- Vehicle -- Cmpd. 2 30 kkk p40.001 *pC0.05 or a a at a O Pre 20 40 60 90 120 Time (min) post-fentanyl Figure 7 U.S. Patent Aug. 11, 2015 Sheet 8 of 31 US 9,102,636 B2 Vehicle or Compound 2 (25 mg/kg, IV) given 15 min before intra-plantar administration of capsaicin (30 ug) -O- Weh-Caps -- Cmpd. 2 - Caps. N-6 5151 O Time (min) post-capsaicin Figure 8 U.S. Patent Aug. 11, 2015 Sheet 9 of 31 US 9,102,636 B2 C2 = Compound 2 is & is is a w a Vehicle C2 MC Figure 9 A U.S. Patent Aug. 11, 2015 Sheet 10 of 31 US 9,102,636 B2 Veh Veh Veh Veh Cmpd.2 Cmpd. 2 Cmpd. 2 Cmpd. 2 IMC IMC IMC IMC Baseline Sturgery O 60 O SO el SO 24 2. 24h Compound2 = 25 mg/kg, IV, Indomethacin = 15 mg/kg, IV, n=6/group *pg.0.05, **p<0.01, ***p<0.001, compared to the vehicle time-point on the same day Figure 9 B U.S. Patent Aug. 11, 2015 Sheet 11 of 31 US 9,102,636 B2 C2 = Compound 2 24h post-susgery gy w w y w w y w w as w w y w w w a w w w w w wi O a ya a w w w s p as .. a is s a a a is a w w is w a t Figure 10 A U.S. Patent Aug. 11, 2015 Sheet 12 of 31 US 9,102,636 B2 Veh. Veh. Veh. C2 C2 C2 MC IMC MC r . 2. Compound 2 = 25 mg/kg, IV, Indomethacin - 15 mg/kg, IV, n=6/group *p<0.05 compared to vehicle time-point on the same day Figure 10 B U.S. Patent Aug. 11, 2015 Sheet 13 of 31 US 9,102,636 B2 Vehicle or Compound 2 (25 mg/kg, IV) given 15 min before the 1 administration of SIN-1 (1 mg/kg, IV) Sir-1 Sin- Sin 30min 2h 30min 2 h - 2 h Baseline Test 1 Test 2 Test 3 25 -- Vehicle 20 - Cmpd. 2 15 N-6 **p<0.01 O 5 O Baseline 2 3 Testing Figure 11 U.S. Patent Aug. 11, 2015 Sheet 14 of 31 US 9,102,636 B2 Figure 12 U.S. Patent Aug. 11, 2015 Sheet 15 of 31 US 9,102,636 B2 Figure 13 U.S. Patent Aug. 11, 2015 Sheet 16 of 31 US 9,102,636 B2 Figure 14 U.S. Patent Aug. 11, 2015 Sheet 17 of 31 US 9,102,636 B2 U.S.
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