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Publication Number
US-9963435-B2
Publication Date
2018-05-08
Expiration Date
Abstract
Chemical entities of Formula (I): Including enantiomers thereof, wherein R1 has any of the values described herein, and compositions comprising such chemical entities; their preparation; and their use in various methods, including the treatment of depression, pain, cognitive disorders, neurodegenerative disorders, and other neurological and peripheral disorders.
Core Innovation
The invention relates to chemical entities of Formula (I), including stereoisomers and enantiomers, and to pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, and metabolites. The compounds are defined on a 2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one scaffold, including variants described as amino-acid conjugates and carboxylic acid conjugates, with explicitly identified (1R,5R) and (1S,5S) forms.
The disclosed compounds include embodiments bearing a 5-(2-chlorophenyl) group with diverse amino, hydroxy, and heteroaryl-containing side chains, including indole-, pyrrolidine-, and imidazole-type substituents. The exemplified set further includes hydroxyethyl or aminomethyl substituents, as well as related acid, amide, and carboxylic acid functional group classes within the same scaffold framework.
The disclosure also discusses HNK release concepts and indicates that the Formula (I) compounds are directed to HNK-mediated pathways rather than NMDAR inhibition. Extensive therapeutic and medical indications are stated for use, and pharmaceutical formulation and administration considerations are described for the compounds, including use as medicaments for the indicated therapeutic purposes.
Claims Coverage
Independent claims cover Formula (I) compounds with broad, explicitly constrained R1 substituent classes, an explicitly enumerated set of (1R,5R)/(1S,5S) 2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one derivatives, and pharmaceutical compositions containing a therapeutically effective amount of the compounds with a pharmaceutically acceptable excipient. The inventive features are centered on the bicyclic scaffold, the 5-(2-chlorophenyl) substituent, and the selection of diverse side-chain motifs and functional-group patterns.
Formula (I) compounds with broad R1 substituent definitions
A compound, or pharmaceutically acceptable salt thereof, of Formula (I) in which R1 is selected from defined options including H; C1-6 alkyl optionally substituted with halo, hydroxy, alkoxy, amino, and carboxyl; C3-8 alkenyl or C3-8 alkynyl optionally substituted with halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, and amino; (CH2)n aryl, (CH2)n heteroaryl, (CH2)n cycloalkyl, or (CH2)n heterocycloalkyl optionally substituted with halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, and amino (n = 0-4); or carbonyl/amine/heteroatom-containing substituent patterns including COR2, CONR3R4, CR5R6NR7R8, CHR9R10, and C(OH)R11R12, with further defined substituent constraints.
Selected (1R,5R)/(1S,5S) 2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one derivatives
A compound selected from the group consisting of specified (1R,5R) and (1S,5S) 2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one derivatives that include a 5-(2-chlorophenyl) motif and named side-chain substitutions and functional groups such as amino, hydroxy, indolyl, imidazolyl, amide, acid, hydroselenoethyl, methylthio, and mercaptoethyl motifs, or pharmaceutically acceptable salts thereof.
Pharmaceutical composition with therapeutically effective amount and excipient
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The inventive coverage centers on Formula (I) compounds with broad but constrained substituent classes, an explicitly enumerated group of (1R,5R)/(1S,5S) 2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one derivatives bearing specified substituent patterns, and pharmaceutical compositions containing the compounds together with a pharmaceutically acceptable excipient.
Stated Advantages
The compounds are described as intended to engage HNK-mediated pathways rather than NMDAR inhibition.
Ketamine is described as having poor oral bioavailability and being associated with abuse liability and dissociative psychological effects, while HNK is described as providing an alternative pathway associated with fewer undesirable effects.
Documented Applications
Treating depression, pain, cognitive disorders, dementia, neurological disorders, and peripheral disorders.
Use of isotopically labeled compounds in PET/SPECT contexts.
Antidepressant evaluation using model sections including Forced Swim Test, Novelty Suppressed Feeding Test, and Learned Helplessness.
PK/PD assessment including pharmacokinetic profiles, LC/MS/MS assessment, and a randomized double-blind placebo-controlled 21-day study design in the context of major depressive disorder, together with CogState testing method.
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