(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 2013/056229 Al 18 April 2013 (18.04.2013) P O P C T (51) International Patent Classification: Marc C. [US/US]; 1120 Deer Run Court, Southampton, C07C 225/20 (2006.01) A61P 25/28 (2006.01) Pennsylvania 18966 (US). GOLDBERG, Michael E. C07C 237/02 (2006.01) A61P 25/00 (2006.01) [US/US]; 113 North Bread Street, Unit 9E, Philadelphia, C07D 295/155 (2006.01) A61K 31/133 (2006.01) Pennsylvania 19106 (US). C07D 295/145 (2006.01) A61K 31/122 (2006.01) (74) Agent: MAXWELL, Leslie-Anne; Cantor Colburn LLP, A61P 25/04 (2006.01) 20 Church Street, 22nd Floor, Hartford, Connecticut 06103 (21) International Application Number: (US). PCT/US2012/060256 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 15 October 2012 (15.10.2012) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, 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, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/547,336 14 October 201 1 (14. 10.201 1) US NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (71) Applicants: THE UNITED STATES OF AMERICA, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, AS REPRESENTED BY THE SECRETARY, DE¬ TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, PARTMENT OF HEALTH AND HUMAN SERVICES ZM, ZW. [US/US]; National Institutes of Health, Office of Techno (84) Designated States (unless otherwise indicated, for every logy Transfer, 601 1 Executive Boulevard, Suite 325, MSC kind of regional protection available): ARIPO (BW, GH, 7660, Bethesda, Maryland 20892-7660 (US). THE GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, COOPER HEALTH SYSTEM [US/US]; One Cooper UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Plaza, Camden, New Jersey 08103 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicants (for US only) :WAINER, Irving W. [US/US]; MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 3003 34th Street NW, Washington, District of Columbia TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 20008 (US). MOADDEL, Ruin [US/US]; 1208 Marston ML, MR, NE, SN, TD, TG). Drive, Bel Air, Maryland 21015 (US). BERNIER, Michel Declarations under Rule 4.17 : [US/US]; 9 Weyanoke Court, Pikesville, Maryland 21208 — as to applicant's entitlement to applyfor and be granted a (US). ZARATE, Carlos A. [US/US]; 135 11 Stonebridge patent (Rule 4.1 7(H)) Terrace, Germantown, Maryland 20874 (US). TORJMAN, [Continued on nextpage] (54) Title: THE USE OF (2R, 6R)-HYDROXYNORKETAMINE, (S)-DEHYDRONORKETAMINE AND OTHER STEREOISOMERIC DEHYD RO AND HYDROXYLATED METABOLITES OF (R,S)- KETAMINE IN THE TREATMENT OF DEPRESSION AND NEUROPATHIC PAIN © o (57) Abstract: The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehyd- ronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive o disorder, neuropathic and chronic pain, including complex regional pain disorder (CRPS) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment. w o 2013/056229 A l III 11 II II 11 I Illlll III lll l II I II III III II I II as to the applicant's entitlement to claim the priority of Published. THE USE OF (2R, 6R)-HYDROXYNORKET AMINE, (S)-DEHYDRONORKET AMINE AND OTHER STEREOISOMERS DEHYDRO AND HYDROXYLATED METABOLITES OF (R,S)- KETAMINE IN THE TREATMENT OF DEPRESSION AND NEUROPATHIC PAIN CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims priority from U.S. Provisional Application No. 61/547,336, filed October 14, 201 1, which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT SUPPORT [0002] The Intramural Research Program of the National Institute of Aging and the Nation Institute of Mental Health funded the subject matter of this disclosure. The United States Government has certain rights in this application. BACKGROUND [0003] Ketamine, a drug currently used in human anesthesia and veterinary medicine, has been shown in clinical studies to be effective in the treatment of several conditions, including the of treatment-resistant bipolar depression, major depressive disorder, neuropathic pain, and chronic pain, including complex regional pain syndrome (CRPS). [0004] In the current "ketamine paradigm", ketamine and norketamine (NK) are considered to be responsible for the antinociceptive response in CRPS patients. However the routine use of the drug is hindered by unwanted central nervous system (CNS) effects. Approximately 30% of patients do not respond to ketamine treatment. Additionally, ketamine treatment is associated with serious side effects due to the drug's anesthetic properties and abuse potential. [0005] Recent studies have demonstrated that in CRPS patients receiving a continuous 5- day infusion of (R,S)-ketamine the primary circulating metabolites were (R,S)- dehydronorketamine (DHNK) and (2S,6S;2R,6R)-hydroxynorketamine (HNK). The data suggest that downstream metabolites play a role in ketamine analgesic efficacy, although little is known about the metabolites' pharmacological activity. [0006] The need for therapeutics which exhibits the therapeutic properties of ketamine with efficacy in a higher percentage of patients, reduced anesthetic properties and reduced abuse liability exists. The present disclosure fulfills this need and provides additional advantages set forth herein. FIELD OF THE DISCLOSURE [0007] This disclosure demonstrates that an active agents responsible for the therapeutic response to ketamine in patients is primarily due to (2R,6R)-hydroxynorketamine and (S)- dehydronorketamine, ketamine metabolite. The disclosure provides pharmaceutical preparations containing ketamine metabolites and prodrug of ketamine metabolites. The disclosure also provides novel ketamine prodrugs. The disclosure provides methods of treating, bipolar depression, neuropathic and chronic pain, including complex regional pain synthetic pain syndrome (CRPS) by administering purified (2R,6R)-hydroxynorketamine or purified (S)- dehydronorketamine or a prodrug of these compounds directly to patients in need of such treatment. SUMMARY [0008] In a first aspect the disclosure provides a pharmaceutical composition comprising a compound of Formula I Formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient. Within Formula I the variables, e.g. R1-R4, carry the definitions set forth below. [0009] Ri is hydrogen, hydroxyl, or a group -A1B1 where Ai is -0-, -0(C=0)-, -(C=0)0-, -0(C=0)0, -0(C=0)NRs-, -OS(0) 2-, -OS(0) 3, or -OP(0) 3-, and Bi is Ci-C alkyl, C2-C8alkenyl, C2-C8alkynyl, (carbocycle)Co-C 4alkyl, (heterocycle)Co-C 4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C 4alkyl, Ci-C 4alkoxy, Ci-C alkylester, mono- and di-(Ci-C 4alkyl)amino, (C -C7Cycloalkyl)Co-C 2alkyl, (heterocycloalkyl)Co-C 2alkyl, Ci-C 2haloalkyl, and Ci- C2haloalkoxy. [0010] The six-membered ring to which Ri is bound contains a double bond when Ri is hydrogen and is fully saturated when Ri is hydroxyl or -A1B1 [001 1] R2 is hydrogen or -A2B2 where A2 is a bond, -0(C=0)-, -(C=0)0-, -S(0) 2-, - (S=0)NR6-, or -(C=0)NR 6-, B2 is Ci-C alkyl, C2-C alkenyl, C2-C alkynyl, C2-C6alkanoyl, (carbocycle)Co-C 4alkyl, (heterocycle)Co-C 4alkyl, or an amino acid or dipeptide covalently bound to A2 by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Ci-C4alkoxy, Ci- C alkylester, mono- and di-(Ci-C 4alkyl)amino, (C3 -C7Cycloalkyl)Co-C2alkyl, (heterocycloalkyl)Co-C 2alkyl, Ci-C2haloalkyl, and Ci-C2haloalkoxy. [0012] R3 is hydrogen or Ci-C alkyl. [0013] R 4 and R are 0 or 1or more substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Ci-C4alkoxy, mono- and di-Ci-C 4alkylamino, Ci- C2haloalkyl, and Ci-C2haloalkoxy. [0014] Re is hydrogen or Ci-C alkyl. [0015] Also included are prodrugs of ketamine metabolites, including prodrugs of all hydroxynorketamine diastereomers, including (2R,6R)-hydroxynorketamine, (R) and (S)- dehydronorketamine, and other stereoisomeric dehydro and hydroxylated ketamine metabolites.. These prodrugs carry the definition set forth above for compounds of Formula I however the following conditions may apply: [0016] Ri is not hydrogen or hydroxyl when R2 is hydrogen. [0017] Bi is methyl when Ai is -0-. [0018] A 1B 1 is not (4-methylphenyl)-S(0)20-. [0019] Bi is not methyl when Ai is a bond. [0020] B2 is not methyl when A2 is a bond or -(C=0)0-. [0021] In another aspect the disclosure provides a method of treating bipolar depression, major depressive disorder, schizophrenia, Alzheimer's dementia, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, or neuropathic pain comprising administering a pharmaceutical composition containing an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier to a patient in need of such treatment.