Imidazolo derivatives, compositions and methods as orexin antagonists
Inventors
Mekonnen, Belew • Patel, Hemantbhai
Assignees
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Publication Number
US-12187737-B2
Publication Date
2025-01-07
Expiration Date
Abstract
This disclosure is directed to substituted Imidazolo[2,1-b]oxazole, Imidazolo[2,1-b]thiazole, Imidazolo[2,1-b]oxadiazole, Imidazolo[2,1-b]oxadiathiazole derivatives of compounds that are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or implicated. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
Core Innovation
The invention relates to compounds of formula I and to pharmaceutically acceptable salts, hydrates, solvates, isomers, and combinations thereof. The compounds are defined by extensive structural constraints including selected aromatic, aryl, and heteroaryl groups for R1 and R4, substituent options for R1a and R4a, and selections for R2 and R3 including optional halogen, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, and cycloalkyl features.
The structural definition includes R5 and X options that provide a pyrrolidine ring, a piperidine ring, or a morpholine ring, with optional absolute (S)-configuration at the carbon atom at position 2 for the piperidine ring or the pyrrolidine ring, and optional absolute (R)-configuration at the carbon atom at position 2 of the morpholine ring. The invention also specifies additional ring and heteroatom variables including Y and Z1 and Z2 selections.
The invention further defines specific heteroaryl and ring-linkage relationships through A-B-J-D-E and B-J-G-K-L, with defined assignments for D, E, A, B, J, G, K, and L under the linkage constraints. The described compounds are orexin receptor antagonists acting at orexin receptor type 1 and type 2, and the document includes in vitro evaluation using CHO cells expressing human OX1/OX2 receptors with FLIPR calcium imaging and IC50 measurement.
The document also provides pharmaceutical compositions comprising the compounds in pharmaceutically acceptable forms and describes therapeutic use for central nervous system disorders. The specified therapeutic coverage includes substance addiction or dependence, panic, anxiety, depression, PTSD, neurodegeneration, autism, schizophrenia, and Alzheimer disease.
Claims Coverage
The provided independent claim is directed to a compound of formula I, including specified fused-ring and substituent constraints, and pharmaceutically acceptable salts, hydrates, solvates, isomers, or combinations thereof. The main inventive features across the independent claim are the defined formula and the specified fused-ring and variable architecture, with related scope directed to composition and CNS treatment indications.
Formula I compound scaffold with constrained substituents and defined ring and heteroaryl linkages
A compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or combination thereof, having R1 and R4 selected from aromatic, aryl, or heteroaryl options with substitution by R1a or R4a groups, and having R2, R3, R5, R6, X, Y, Z1, and Z2 defined with corresponding selection and optional substitution constraints.
Optional stereochemical configuration at ring positions with ring selection via R5 and X
R5 and X are selected to provide either a pyrrolidine ring, a piperidine ring, or a morpholine ring, with optional absolute (S)-configuration at the carbon atom at position 2 of the piperidine ring or pyrrolidine ring, and optional absolute (R)-configuration at the carbon atom at position 2 of the morpholine ring.
Defined heteroaryl and ring selections through A-B-J-D-E and B-J-G-K-L assignment
The compound is defined such that A-B-J-D-E is a five-member heteroaryl and B-J-G-K-L is a five-member ring selected from aromatic, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, with defined assignments for A, B, J, G, K, L, D, and E under the linkage constraints.
Across the independent claim, coverage is directed to formula I compounds with specifically constrained substituent sets, defined ring-linkage patterns, and optional absolute stereochemical configuration at defined ring positions, with the document positioning these compounds as orexin receptor antagonists.
Stated Advantages
Compounds are orexin receptor antagonists acting at orexin receptor type 1 and type 2, as supported by in vitro evaluation using FLIPR calcium imaging and IC50 measurement.
Documented Applications
Therapeutic use for central nervous system disorders including substance addiction or dependence, panic, anxiety, depression, PTSD, neurodegeneration, autism, schizophrenia, and Alzheimer disease.
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