Pyrazole and imidazole derivatives, compositions and methods as orexin antagonists
Inventors
Mekonnen, Belew • Patel, Hemantbhai
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12275744-B2
Publication Date
2025-04-15
Expiration Date
Abstract
The present invention is directed to substituted Pyrazole and Imidazole 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, including but not limited to: 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 orexin receptor antagonist compounds having a formula selected from a group of defined chemical structures, including substituted fused imidazole and fused pyrazole ring-system derivatives and additional orexin receptor antagonist compounds with aromatic and heteroaryl substitution variability. The disclosed chemical structures include variable substituents R1 through R6, ring variables X, Y, Z1 and Z2, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and isomers.
The chemical scope further includes isotopically labeled and stereoisomeric variants of compounds having specific structural frameworks, including isotopes relevant to PET and SPECT, deuterium, and radioisotopes such as 3H, 14C, and 18F. The document also defines allowable solid-form and stereochemical variants, including enantiomers and diastereomers, and identifies structural elements as rings I, II, II-a/b/c/d, and III.
The compounds are described as orexin receptor antagonists that inhibit human orexin-1 and orexin-2 receptors. The disclosure includes pharmaceutical compositions comprising the compounds and at least one excipient, and states routes of administration together with therapeutic indication categories for CNS disorders and substance addiction/dependence.
Claims Coverage
The consolidated claims coverage includes three independent claim themes: a broad compound claim, a pharmaceutical composition claim, and a method claim. Across these claims, the core inventive features are the defined substituent framework, the ring-selection logic tied to X and R5, optional Y functionality, permitted chemical and stereochemical variants, and a method for preparing compounds associated with Examples 1 through 21.
Defined compound framework with aromatic and heteroaryl substitution
A compound having a formula selected from a group of structures in which R1 is aromatic and is unsubstituted, mono-substituted, or di-substituted by R1a; R2 and R3 are independently selected from H, halogen, alkyl, substituted alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, and cycloalkyl; and R4 is aromatic and is unsubstituted, mono-, di-, or tri-substituted by R4a.
Fused-ring compound formula with R5 ring selection via X
X is absent, CH2, or O, and R5 is selected so that when X is absent a pyrrolidine ring is provided, when X is CH2 a piperidine ring is provided, and when X is O a morpholine ring is provided.
Optional functionality via Y and defined R6
R6 is selected from H, halogen, alkyl, and substituted alkyl, and Y is absent or selected from NH, O, CH2O, CH2, and NR7 where R7 is H or alkyl; Z1 and Z2 are H.
Permitted chemical and stereochemical variants
The compound may be a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer with respect to a stereogenic center, or a combination thereof.
Pharmaceutical composition with excipient
A composition comprising the defined compound or a pharmaceutically acceptable form thereof and at least one excipient.
Method for preparing Example 1 through Example 21 compounds
A method for preparing a compound of Example 1 through Example 21, the method comprising a reaction selected from the group consisting of reactions recited in the claim.
Overall, the claims cover defined orexin receptor antagonist scaffolds with substituent variability, ring-selection logic that determines pyrrolidine, piperidine, or morpholine formation, optional Y and R6 features, pharmaceutically acceptable forms and stereogenic isomers, a pharmaceutical composition with excipient, and a preparation method for Example 1 through Example 21 compounds.
Stated Advantages
The compounds inhibit human orexin-1 and orexin-2 receptors.
IC50 values for orexin receptor inhibition are reported using a CHO-FLIPR calcium assay.
Documented Applications
Use as orexin receptor type 1 and/or type 2 antagonists.
Treating or preventing central nervous system (CNS) disorders including panic, anxiety, depression, posttraumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD).
Therapeutic use related to substance addiction and dependence.
Pharmaceutical compositions for CNS disorders and substance addiction/dependence.
Administration of orexin receptor antagonist pharmaceutical compositions.
Interested in licensing this patent?