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
Inventors
Wainer, Irving W. • Moaddel, Ruin • Bernier, Michel • Zarate, Carlos A. • Torjman, Marc C. • Goldberg, Michael E. • Tanga, Mary J.
Assignees
SRI International Inc • Cooper Health System Inc • US Department of Health and Human Services
Publication Number
US-9650352-B2
Publication Date
2017-05-16
Expiration Date
2032-10-15
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Abstract
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.
Core Innovation
The invention provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, (R)- or (S)-dehydronorketamine, and other stereoisomeric dehydro or hydroxylated ketamine metabolites, as well as novel ketamine metabolite prodrugs. The disclosure includes methods of treating bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain syndrome (CRPS), by administering purified ketamine metabolites or their prodrugs directly to patients in need.
The problem being addressed arises from the current ketamine treatment paradigm where ketamine and norketamine are considered responsible for analgesic effects, but ketamine's use is limited by unwanted central nervous system (CNS) effects and a significant portion of patients (about 30%) do not respond to treatment. Ketamine also carries serious side effects due to its anesthetic properties and abuse potential. The invention addresses the unmet need for therapeutics that exhibit the therapeutic properties of ketamine with improved efficacy, reduced anesthetic effects, and reduced abuse liability.
Claims Coverage
The patent includes three independent claims focused on compounds of specific chemical formulas and their use in treating various disorders. Three main inventive features are identified based on these claims.
Compounds of defined chemical formulas
The invention claims compounds of Formula I and related sub-formulas with specific definitions of variables R1-R6, including various substituents and prodrugs thereof. These compounds include stereoisomeric hydroxynorketamine and dehydronorketamine metabolites with defined chemical structures and substituent options, including pharmaceutically acceptable salts.
Pharmaceutical compositions containing the claimed compounds
The invention covers pharmaceutical compositions comprising the compounds or their pharmaceutically acceptable salts along with pharmaceutically acceptable carriers. These compositions can be formulated for various routes, including oral, intravenous, and intramuscular administration, and include specified concentration ranges.
Methods of treatment using the compounds
The invention claims methods of treating bipolar depression, major depressive disorder, schizophrenia, Alzheimer's dementia, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, and neuropathic pain by administering an effective amount of the claimed compounds or salts to patients needing such treatment.
The claims collectively cover specific stereoisomeric ketamine metabolites and their prodrugs, compositions containing them, and their use in treating various neurological and pain-related disorders, emphasizing the chemical definitions, formulations, and therapeutic methods.
Stated Advantages
Increased therapeutic response rate compared to ketamine by direct administration of active ketamine metabolites.
Avoidance of treatment-limiting CNS side effects associated with ketamine due to lack of NMDA receptor activity in metabolites like (2R,6R)-hydroxynorketamine.
Long plasma half-life and oral bioavailability of the ketamine metabolites allowing for convenient oral formulations.
Documented Applications
Treatment of bipolar depression.
Treatment of major depressive disorder.
Treatment of schizophrenia.
Treatment of Alzheimer's dementia.
Treatment of amyotrophic lateral sclerosis.
Treatment of complex regional pain syndrome (CRPS).
Treatment of chronic pain.
Treatment of neuropathic pain.
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