Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6H)-ones
Inventors
Branstetter, Bryan • Breitenbucher, James • Dyck, Brian • Gomez, Laurent • Hudson, Andrew Richard • Marrone, Tami Jo • Peters, Marco • VICKERS, Troy • Weinhouse, Michael I.
Assignees
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Publication Number
US-10376514-B2
Publication Date
2019-08-13
Expiration Date
Abstract
Described herein are compounds of Formula I and Formula II, methods of their synthesis, compositions comprising the compounds, and use of the compounds and compositions in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
Core Innovation
The disclosure describes substituted heterocyclic compounds with fused triazolo and pyrimidin-5-one scaffolds, including thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, and related fused heterocyclic compounds. The compounds are defined by specific chemical structures, embedded chemical structure depictions, and broad substituent scope, with recurring substituents including methoxy, bromo, fluoro, chloro, hydroxyl, morpholine, pyridine, morpholinomethyl, morpholinoethyl, and CF3-related substitutions.
The document presents synthesized examples, intermediates, analytical data, and structural verification for multiple compounds, including 1H NMR, LC-MS characterization, molecular formulae, yields, and example numbering. Specific compounds and analogs are referenced through tables, embedded images, and associated structure files, and the disclosed embodiments are repeatedly linked to characterized structures rather than to a single compound.
The disclosure also describes synthetic routes for preparing and diversifying the fused heterocycle compounds, including conversions involving bromothiophenes, thiophene carbaldehydes, furan-fused transformations, benzylic electrophile substitution, aldehyde formation, reductive amination, and other scheme-based transformations, with some procedural detail omitted for safety.
Claims Coverage
The provided claim sets are centered on three independent claims, each directed to a compound, or a pharmaceutically acceptable salt thereof, defined by a specific chemical structure depiction. Across the claims, the inventive features are structural and are narrowed by embedded chemical structure images/files and, in some cases, explicit element or substituent inclusion shown in the depictions.
Structure-defined compound with pharmaceutically acceptable salt
A compound, or a pharmaceutically acceptable salt thereof, having the structure as defined by the depicted chemical structure.
Structure-defined compound with depicted variant selection
A compound, or a pharmaceutically acceptable salt thereof, where dependent claims identify specific illustrated structure variants through embedded image and structure file identifiers.
Structure-defined compound with explicit substitution details
A compound, or a pharmaceutically acceptable salt thereof, where the structural definition includes explicit element or group entities such as Br, F, OH, O, N, and S.
Claim coverage is structural throughout: the independent claims recite compounds defined by exact chemical structure depictions, and the dependent claims narrow those compounds to particular depicted variants identified by embedded structure images/files and, in some instances, explicit substituent or element features.
Stated Advantages
Treating CNS disorders, including cognitive impairment, dementia, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and ADHD.
Treating neuronal degeneration and neurogenesis-related conditions.
Treating cardiovascular and vascular disorders such as atherosclerosis, restenosis, and pulmonary hypertension.
Treating renal disorders including renal artery stenosis, glomerulonephritis, and polycystic kidney disease.
Treating multiple sclerosis.
Exemplary compounds are selective for PDE1 enzymes.
Exemplary compounds show greater specificity for PDE1B versus PDE1A and PDE1C.
Improves memory formation and long-term memory performance, including contextual fear conditioning and trace fear conditioning.
Activates CREB-dependent neuronal plasticity pathways including neuronal genes and neurotrophic/neuroprotective factors.
Supports neurite outgrowth and neurogenic phenotypes associated with PDE1B involvement.
Reported to reduce blood pressure and includes brief cardiovascular functional observations; occasional QTc interval prolongation is noted in exemplary compound findings.
Documented Applications
Treating CNS disorders including cognitive impairment and dementia.
Treating neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Treating schizophrenia and ADHD.
Treating multiple sclerosis.
Treating vascular disorders including atherosclerosis, restenosis, and pulmonary hypertension.
Treating renal disorders including renal artery stenosis, glomerulonephritis, and polycystic kidney disease.
A PDE1B inhibitory assay context is described using IMAP TR-FRET with FAM-labeled cAMP, with compound potency summarized by pIC50 and evaluated for PDE1 enzyme selectivity including PDE1A and PDE1C.
Treatment of CNS disorders and cognitive impairment using PDE1 inhibition and related enhancement of Ca2+ and cAMP/cGMP signaling with CREB-dependent neuronal plasticity pathways.
Treatment of cognitive impairment in combination with augmented cognitive training (ACT) to reduce training sessions.
Therapeutic targeting described across cardiovascular, renal, hematological, gastrointestinal and liver, cancer disorders, and neurodegenerative disorders.
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