Substituted pyrido[2,1-a]isoquinolines as VMAT2 inhibitors
Inventors
HARRIOTT, Nicole • Pagano, Nicholas • Boon, Byron A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11718618-B2
Publication Date
2023-08-08
Expiration Date
Abstract
This disclosure relates generally to VMAT2 inhibitor compounds of Formula (Ia): and pharmaceutically acceptable salts thereof, as well as compositions and methods related thereto.
Core Innovation
The disclosed subject matter relates to stereochemically defined pyrido[2,1-a]isoquinolin-2-ol compounds having a common core scaffold, including embodiments represented by Formula (I) and Formula (Ia), and specific numbered compounds. The series varies substituents at positions including R1, R2, 3-position, 9-position, and 10-position, with stereochemical variants such as 2R/2S, 3R/3S, and 11bR/11bS, while including pharmaceutically acceptable salts and, in some items, co-crystals, isotopic variants, and crystalline forms.
The substituent options include fluorinated ether groups, methoxy and hydroxyl-containing substituents, cycloalkyl, aryl, heteroaryl, ether, nitrile, and sulfonyl-related motifs, together with sub-variables R2A, R2B, and R2C. Example compounds and named compound embodiments are presented in numbered series, including compounds 4-1 through 4-121, with structural images, molecular weights, and related chemical structure disclosures.
The disclosure also characterizes selected compounds by crystalline and physicochemical data, including powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, and references crystalline Form I in connection with at least one exemplified compound. It further includes pharmaceutical compositions and formulations, packaging concepts, administration routes, and method-of-use claims directed to treatment of neurological and psychiatric disorders by administration of the disclosed compounds or pharmaceutically acceptable salts.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof. Across the provided items, the key inventive features also include specific named compound embodiments, pharmaceutical compositions including pharmaceutically acceptable excipients, and methods of treating neurological or psychiatric diseases or disorders; dependent narrowing is expressly provided for autism spectrum disorder and tardive dyskinesia.
Formula (Ia) compound or pharmaceutically acceptable salt
A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof.
Specific compound embodiment and pharmaceutically acceptable salt
The compound of claim 1 is the depicted compound, including Compound 4-27, or a pharmaceutically acceptable salt of that compound.
Method of treating neurological or psychiatric disease or disorder by administration
Treating a neurological or psychiatric disease/disorder by administering a compound of claim 1, or a pharmaceutically acceptable salt, to a subject in need thereof.
Autism spectrum disorder treatment limitation
The method is limited to cases where the condition is an autism spectrum disorder.
Tardive dyskinesia treatment limitation
The method is used where the hyperkinetic movement disorder is tardive dyskinesia.
Pharmaceutical composition including excipient
A pharmaceutical composition that includes at least one pharmaceutically acceptable excipient and the compound of claim 4, or a pharmaceutically acceptable salt of that compound.
Overall, the claim coverage is anchored by the Formula (Ia) compound family and its pharmaceutically acceptable salts, with specific named compound embodiments, therapeutic administration claims for selected neurological or psychiatric disorders, and pharmaceutical composition claims including pharmaceutically acceptable excipients. Dependent narrowing is explicitly provided for autism spectrum disorder and tardive dyskinesia.
Stated Advantages
The document describes limitations of tetrabenazine, including a short half-life and a narrow therapeutic window, together with side effects.
Reduces monoamines via VMAT2 inhibition for therapeutic treatment of neurological and psychiatric disorders.
Documented Applications
Treating neurological or psychiatric diseases or disorders by administering the disclosed compounds or pharmaceutically acceptable salts to a subject in need.
Treating neurological or psychiatric diseases or disorders including schizophrenia, schizoaffective disorder, mood disorders, tardive dyskinesia, Tourette's syndrome, obsessive-compulsive disorder (OCD), and treatment-refractory OCD.
Treating autism spectrum disorder.
Treating tardive dyskinesia as a hyperkinetic movement disorder.
Providing pharmaceutical compositions including at least one pharmaceutically acceptable excipient and the claimed compound or salt.
Pharmaceutical product packaging and administration concepts including blister pack formats, instructions for administration, and an informational package insert.
Interested in licensing this patent?