6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligands
Inventors
Chappie, Thomas Allen • Henderson, Jaclyn Louise • Young, Joseph Michael • Wager, Travis T. • Kormos, Bethany Lyn • Patel, Nandini Chaturbhai • Sciabola, Simone • Tuttle, Jamison Bryce • Verhoest, Patrick Robert • Tucker, Joseph Walter
Assignees
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Publication Number
US-10590128-B2
Publication Date
2020-03-17
Expiration Date
Abstract
The present invention provides compounds of Formula (I): and pharmaceutically acceptable salts thereof wherein the variables R1, R2, R3, R4, R5, a and A are as defined herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D3-mediated (or D3-associated) disorders including, e.g., substance addiction, substance abuse, schizophrenia (e.g., its cognitive symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD or PD), Parkinson's disease, mania, anxiety, impulse control disorders, sexual disorders and depression.
Core Innovation
The invention relates to compounds of Formula I and pharmaceutically acceptable salts thereof, defined by a pyrido[2,3-d]azepine framework and extensive substituent variables R1 through R8 together with a defined aromatic or heteroaryl group A. The structural scope includes halo, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, phenoxy, and fluoro-substituted motifs, as well as optional fused ring and linked substituent relationships.
A is defined as C6-C10 aryl or 5- to 10-membered heteroaryl, optionally substituted with 1 to 3 R6, and the substituent definitions include optional fluoro substitution patterns and ring-forming combinations such as R4 and R6 taken together being a C1-C3 alkylene or R5 and R6 together forming a fused 5- to 7-membered cycloalkyl or heterocycloalkyl ring. The described examples include substituted sulfonamide derivatives and related stereoisomeric variants built on a common fused-ring scaffold, including tetrahydro-pyrido[2,3-d]azepine-derived intermediates and final sulfonamides.
The invention is also described in a dopamine D3 receptor context, where the compounds are identified as D3 ligands, D3 antagonists, or partial agonists. The disclosure states that the compounds, pharmaceutical compositions, and related treatments are directed to disorders associated with dysregulated D3 receptor activation or D3-mediated disorders.
Claims Coverage
The consolidated claim coverage centers on one broad independent Formula I compound claim with pharmaceutically acceptable salts, one narrowing claim that defines A as phenyl or a 6-membered heteroaryl, and a patient-treatment claim for diseases associated with dysregulated D3 receptor activation. Across these independent claims, the main inventive features are the structurally defined Formula I scaffold, the narrowed aromatic or heteroaryl selection, and the therapeutic use tied to D3 receptor dysregulation.
Formula I compounds with defined substituent framework
A compound of Formula I, or a pharmaceutically acceptable salt thereof, defined by R1, R2, a, R3, R4, A, R5, R6, R7, and R8, including selectable substituent classes and ring-closure relationships such as R4 and R5 taken together as a C1-C3 alkylene, R4 and R6 taken together as a C1-C3 alkylene, or R5 and R6 together forming a fused 5- to 7-membered cycloalkyl ring or heterocycloalkyl ring, with A selected from C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with 1 to 3 R6.
A narrowed to phenyl or 6-membered heteroaryl
A compound of Formula I in which A is selected from phenyl or a 6-membered heteroaryl, where the 6-membered heteroaryl is optionally substituted with one R6, and the compound is a pharmaceutically acceptable salt thereof.
Patient treatment for dysregulated D3 receptor activation
A method of treating a patient by administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for a disease associated with dysregulated activation of the D3 receptor.
The claims collectively define a broad Formula I compound space with constrained substituent options, a narrower aromatic embodiment, and a treatment method for disorders associated with dysregulated D3 receptor activation.
Stated Advantages
Provides measurable dopamine D2 and dopamine D3 receptor binding activity as reported by hD3 and hD2 Ki values and activity/IC50-derived values.
Supports therapeutic use for diseases linked to dysregulated D3 receptor activation.
Treats D3-mediated disorders, including substance addiction, schizophrenia, Parkinson’s disease, impulse control disorders, sexual dysfunction, and depression.
Documented Applications
Human dopamine D2 and dopamine D3 receptor binding assays using radioligand saturation and competitive binding.
Treatment of diseases or disorders associated with dysregulated activation of the D3 receptor, including Parkinson's disease, schizophrenia, dementia, psychosis, depression, mania, anxiety, dyskinesias, substance addiction, pathological gambling, hypersexuality, compulsive shopping, eating disorder, renal insufficiency, and diabetes.
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