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WO 2017/165558 Al 28 September 2017 (28.09.2017) P O P C T

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WO 2017/165558 Al 28 September 2017 (28.09.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/165558 Al 28 September 2017 (28.09.2017) P O P C T (51) International Patent Classification: [US/US]; 600 McNamara Alumni Center, 200 Oak Street A61K 31/485 (2006.01) C07D 257/04 (2006.01) SE, Minneapolis, Minnesota 55455-2020 (US). A61K 31/445 (2006.01) C07D 489/08 (2006.01) (74) Agents: LI, Yang et al; 7851 Metro Parkway, Suite, 325, (21) International Application Number: Bloomington, Minnesota 55425 (US). PCT/US2017/023647 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 22 March 2017 (22.03.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, English (25) Filing Language: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (30) Priority Data: MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, 62/3 11,781 22 March 2016 (22.03.2016) U S NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (71) Applicant: REGENTS OF THE UNIVERSITY OF RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, MINNESOTA [US/US]; 600 McNamara Alumni Center, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, 200 Oak Street SE, Minneapolis, Minnesota 55425 (US). ZA, ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (71) Applicants : WILCOX, George Latimer [US/US]; 600 kind of regional protection available): ARIPO (BW, GH, McNamara Alumni Center, 200 Oak Street SE, Minneapol GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, is, Minnesota 55455-2020 (US). BRUCE, Daniel John TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 600 McNamara Alumni Center, 200 Oak Street TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, SE, Minneapolis, Minnesota 55455-2020 (US). FAIRB¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, ANKS, Carolyn Ann [US/US]; 600 McNamara Alumni SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Center, 200 Oak Street SE, Minneapolis, Minnesota GW, KM, ML, MR, NE, SN, TD, TG). 55455-2020 (US). PORTOGHESE, Phillip S. [US/US]; 600 McNamara Alumni Center, 200 Oak Street SE, Min neapolis, Minnesota 55455-2020 (US). AKGUN, Eyup [Continued on nextpage] (54) Title: COMBINATION FOR TREATING PAIN Figure 5a Q i+ 00 1 fi o (57) Abstract: The invention provides compounds, compositions, and methods for treating pain. w o 2017/165558 Λ Ι llll II II 11III I II I III I I I I I I 11III II I II Published: COMBINATION FOR TREATING PAIN GOVERNMENT FUNDING This invention was made with government support under R01 DA015438 and R01 DA001533 awarded by the National Institutes of Health-NIDA. The government has certain rights in the invention. CROSS-REFERENCE TO RETATED APPLICATIONS This application claims priority to United States Provisional Application Number 62/3 11,781, filed March 22, 20 16. The entire content of the application referenced above hereby incorporated by reference herein. BACKGROUND OF THE INVENTION Conservative estimates in the United States alone suggest that approximately 100 million adults suffer from chronic pain, resulting in a societal cost of $600 billion dollars annually in medical costs and lost productivity (Institute of Medicine (US) Committee on Advancing Pain Research, Care and Education, 201 ). Despite this, current treatment paradigms for chronic pain are inadequate. Opioid analgesics are among the most powerful and extensively used therapeutics for the treatment of chronic pain, but long-term use is associated with a number of deleterious CNS effects, namely respiratory depression, tolerance, addiction, and hyperalgesia. Additionally, diversion of centrally acting opioids for non-therapeutic use is of major concern in present day North America. The OTC remedy for diarrhea, loperamide (Lo, trade name Imodium), is a highly efficacious, antidiarrheal, mu-opioid receptor (MOR) agonist that is excluded from the CNS; therefore, it has near zero abuse liability, befitting its OTC approval and availability. Although prescription opioid analgesics are the gold standard for management of chronic pain, diversion, addiction and respiratory depression constitute a significant problem. Because opioids' addiction potential derives from actions in the mesolimbic dopaminergic system and their respiratory depression from actions in the brainstem, restriction of pharmacodynamic action to the peripheral nervous system represents a simple and effective means to eliminate these liabilities. Peripheral and topical analgesia targeting MOR is not novel (Joris, J. L., R. Dubner and K. M. arg av s Anesth Analg, 66(12): 1277-1281, 1987; Levine, J. D. and Y. O. Taiwo, Neuroscience, 32(3): 571-575, 1989; and Stein, C , Anesth Analg, 76(1): 182-191, 1993); however, the study of analgesic combinations of opioid analgesics in the periphery is rare (Kolesnikov, Y. A., et al., Eur J Pharmacol, 65(8): 61-64, 2010). It has been reported that the delta-opioid receptor (DOR) agonist, oxymorphindole (OMI), synergized with the MOR agonist morphine when administered intrathecally in mice (Schuster, D. J., et al, Br J Pharmacol, 72(2): 642-653, 2015). It has also been shown that the synergy between certain analgesics does not generalize to multiple side effects, yielding an analgesic combination with therapeutic windows ranging from 5- to 50-fold larger than either drug given alone (LS Stone et al., PLoS One, 9(10):el09903, 2010). Currently there is a need for additional agents and methods that can be used to treat pain. Ideally, such agents and methods will produce reduced addiction, reduced respiratory depression, and/or fewer unwanted effects on GI transit conmpared to currently available therapies. SUMMARY OF THE INVENTION The invention provides compositions and methods that can be used to treat pain. The compositions and methods of the invention typically produce reduced addiction, reduced respiratory depression, and/or fewer unwanted effects on GI transit conmpared to currently available therapies. In one embodiment the invention provides a composition comprising 1) a mu-opioid receptor (MOR) agonist that is excluded from the CNS, 2) a delta-opioid receptor (DOR) agonist, and 3) a pharmaceutically acceptable carrier. The invention also provides a method for treating pain in an animal (e.g. a human) comprising administering 1) a mu-opioid receptor (MOR) agonist that is excluded from the CNS, and 2) a delta-opioid receptor (DOR) agonist to the animal. The invention also provides the compound N-benzyloxymorphindole, or a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical composition comprising N- benzyloxymorphindole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention also provides a method for treating pain in an animal (e.g. a human) comprising administering N-benzyloxymorphindole or a pharmaceutically acceptable salt thereof to the animal. The invention also provides a method for agonizing a delta-opioid receptor comprising contacting the receptor with N-benzyloxymorphindole or a pharmaceutically acceptable salt thereof. The invention also provides a composition of the invention for use in medical therapy. The invention also provides a composition of the invention for the prophylactic or therepeutic treatment of pain. The invention also provides the use of a composition of the invention to prepare a medicament for treating pain in an animal. The invention also provides the use of a mu-opioid receptor (MOR) agonist that is excluded from the CNS to prepare a medicament for treating pain in an animal in combination with a delta-opioid receptor (DOR) agonist. The invention also provides the use of a delta-opioid receptor (DOR) agonist to prepare a medicament for treating pain in an animal in combination with a mu-opioid receptor (MOR) agonist that is excluded from the CNS. The invention also provides N-benzyloxymorphindole, or a pharmaceutically acceptable salt thereof for use in medical therapy. The invention also provides N-benzyloxymorphindole, or a pharmaceutically acceptable salt thereof for the prophylactic or therepeutic treatment of pain. The invention also provides the use N-benzyloxymorphindole, or a pharmaceutically acceptable salt thereof to prepare a medicament for treating pain in an animal. BRIEF DESCRIPTION OF THE FIGURES Figures la- Id show antagonism studies of OMI and BOMI (6) in vivo from Example 2. Figure l a shows antagonism of OMI when administered intracerebroventriclarly. Figure l b shows antagonism of BOMI when administered intracerebroventriclarly. Figure l c shows antagonism of OMI when administered intrathecally. Figure Id shows antagonism of BOMI when administered intrathecally. Figures 2a-2c show calcium mobilization studies for Example 3. Figure 2a shows calcium mobilization of NTI. Figure 2b shows calcium mobilization of OMI (4). Figure 2c shows calcium mobilization of BOMI (6). Figure 3 shows potency data of OMI and BOMI when administered intrathecally from Example 4. Figure 4 shows potency data of OMI and BOMI when administered intrathecally from Example 4. Figures 5a and 5b show analgesic properties of loperamide, OMI or combination in naive animals. Figure 5a shows centrally-mediated thermal nociceptive responses in the hot water tail flick test. Subjects were given an intrathecal injection of loperamide, OMI, or combination, and post-drug response were analyzed as a % of maximum possible effect, which was used to generate dose-response curves. Note the 10-fold shift in potency for the combination.
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