THE USE OF (2R, 6R)-HYDROXYNORKETAMINE, (S)-DEHYDRONORKETAMINE AND OTHER STEREOISOMERIC DEHYDRO AND HYDROXYLATED METABOLITES OF (R,S)- KETAMINE IN THE TREATMENT OF DEPRESSION AND NEUROPATHIC PAIN

摘要

The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, 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 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.;

主权项

1. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, where R1 is hydrogen, hydroxyl, or a group -A1B1 where A1 is —O—, —O(C═O)—, —(C═O)O—, —O(C═O)O, —O(C═O)NR6—, —OS(O)2—, —OS(O)3, or —OP(O)3—, and B1 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (carbocycle)C0-C4alkyl, or (heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C6alkylester, mono- and di-(C1-C4alkyl)amino, (C3-C7cycloalkyl)C0-C2alkyl, (heterocycloalkyl)C0-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; wherein the six-membered ring to which R1 is bound contains a double bond when R1 is hydrogen and is fully saturated when R1 is hydroxyl or -A1B1; R2 is hydrogen or -A2B2 where A2 is a bond, —O(C═O)—, —(C═O)O—, —S(O)2—, —(S═O)NR6—, or —(C═O)NR6—, B2 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C6alkanoyl, (carbocycle)C0-C4alkyl, (heterocycle)C0-C4alkyl, 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, C1-C4alkyl, C1-C4alkoxy, C1-C6alkylester, mono- and di-(C1-C4alkyl)amino, (C3-C7cycloalkyl)C0-C2alkyl, (heterocycloalkyl)C0-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; R3 is hydrogen or C1-C6alkyl; R4 and R5 are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; and R6 is hydrogen or C1-C6alkyl.