Imidazolo derivatives, compositions and methods as orexin antagonists
Inventors
Mekonnen, Belew • Patel, Hemantbhai
Assignees
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Publication Number
US-12187738-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 provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or combination thereof, defined by a substituted fused ring scaffold with A-B-J-D-E and B-J-G-K-L ring definitions and extensive substituent and ring-selection rules for R1, R2, R3, R4, R5, R6, X, Y, Z1, and Z2. The scaffold rules specify heteroaryl and ring atom identities together with defined constraints on substitution patterns for the aromatic, aryl, and heteroaryl groups.
The compound scope includes optional stereochemical configurations at defined ring positions, including an absolute (S)-configuration optionally at the carbon atom at position 2 of the piperidine ring or pyrrolidine ring, and an absolute (R)-configuration optionally at the carbon atom at position 2 of the morpholine ring. The disclosure further defines alternative ring realizations by selection of X, with pyrrolidine ring formation when X is absent and piperidine ring formation when X is CH2.
The document also includes pharmaceutical compositions that include the compounds of formula I together with pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle components, and it describes use in treating central nervous system (CNS) disorders.
Claims Coverage
The independent claim covers a broad chemical space comprising compounds of formula I, including pharmaceutically acceptable salts, hydrates, solvates, isomers, and combinations. The inventive features center on the detailed formula I scaffold and the enumerated substituent, ring, and stereochemical selection rules, with dependent claims further narrowing to specific formula embodiments, pharmaceutical compositions, and CNS treatment methods.
Compound defined by formula I and pharmaceutically acceptable forms
A compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or combination thereof.
Substituent and ring selection rules for aromatic and heteroaryl groups
R1, R2, R3, and R4 are defined by detailed groups and substitution limits, with options including aromatic, aryl, five- or six-member heteroaryl selections, defined permissible substituents, and defined halogen selections together with substitution counts for specified groups.
Ring framework controlled by X, Y, and stereochemical options
R5 and R6 are selected according to whether X is absent or X is CH2 to provide a pyrrolidine ring or a piperidine ring, respectively, 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; Y is defined as absent or selected from specified groups.
Terminal substituent selection via Z1 and Z2 together with scaffold atom assignments
Z1 and Z2 are each independently selected from specified groups, and the scaffold atom assignments are constrained so that A is N; A-B-J-D-E is a five-member heteroaryl; B-J-G-K-L is a five-member ring selected from specified ring types; D is C; E is C; B is C; J is N; G is C or N; K is C; and L is O or S.
Pharmaceutical composition administration for CNS disorders
A pharmaceutical composition including a compound as defined is used for treating a central nervous system (CNS) disorder in a subject, and the CNS disorder is further specified to include a listed set of conditions.
Claim coverage centers on a highly specified formula I compound scaffold with detailed substituent, ring, and optional stereochemical configuration constraints, and extends to pharmaceutical compositions for treating CNS disorders, including an enumerated set of CNS conditions.
Stated Advantages
Documented Applications
Treating central nervous system (CNS) disorders.
Treating or preventing neurological and psychiatric disorders implicated in orexin signaling, including addiction/dependence, PTSD, schizophrenia, panic/anxiety, autism, depression, cognitive impairment, and Alzheimer’s disease.
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