Substituted pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines, pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidines and/or [1,2,4]triazolo[1,5-c]pteridines for treatment of central nervous system diseases and disorders
Inventors
ALLAN, Amy • Branstetter, Bryan • Dyck, Brian • Gomez, Laurent • Marrone, Tami Jo • Peters, Marco • Weinhouse, Michael I.
Assignees
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Publication Number
US-9284335-B2
Publication Date
2016-03-15
Expiration Date
Abstract
Described herein are compounds and chemical entities of Formula (I), methods of their synthesis, compositions comprising them, and their use in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
Core Innovation
The disclosed chemical entities are compounds of Formula (I), including pharmaceutically acceptable salts, prodrugs, metabolites, isotopically labeled compounds, and derivative forms. The core structure is defined by Y and Z selected from —CH— and —N— with the proviso that at least one Y or Z member is —N—, M is 0, 1, 2, 3, 4, or 5, and substituent-defined variables R1, R3, R4, and R10–R13 are selected from enumerated chemical groups with optional substitution patterns on aryl, heteroaryl, and heterocycloalkyl fragments.
The disclosure describes substituted pyridine-fused azolopyrimidin-5-(6H)-one chemical entities, including pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one derivatives and closely related fused variants, with defined substituent patterns and examples bearing benzyl-type groups and amine-containing side-chain substituents. It also provides structural depictions and analytical characterization data for specific examples, including 1H NMR, LCMS, HPLC, and [M+H]+ mass values.
The patent further relates these compounds to PDE1 and PDE1B inhibition, PDE selectivity assay context, and therapeutic use in conditions spanning CNS cognitive impairments and neurodegenerative conditions as well as cardiovascular, renal, hematological, gastrointestinal/liver, and cancer indications. The mechanistic narrative links PDE1 inhibition to Ca2+ signaling, cAMP/cGMP/CREB signaling, neuronal plasticity, and neuroprotection, and includes memory-related and neurite outgrowth assays in the disclosure figure set.
Claims Coverage
The consolidated claim set contains multiple independent claim families. Across these claims, the inventive coverage centers on a Formula (I) chemical entity with constrained substituent variables, multiple selection-by-enumeration compound alternatives for specific fused heterocyclic scaffolds, and pharmaceutically acceptable salts, with dependent pharmaceutical composition language present in the source material.
Formula (I) chemical entity with constrained substituents
A chemical entity of Formula (I) wherein Y and Z are each independently —CH— or —N—, with the proviso that at least one Y or Z member is —N—; M is 0, 1, 2, 3, 4, or 5; and R1, R3, R4, and R10–R13 are defined by extensive enumerated substituent classes and ring-forming options, including pharmaceutically acceptable salts of compounds of Formula (I).
Selected compounds from substituted pyrido-triazolo-pyrimidinone and related fused variants
A compound, or pharmaceutically acceptable salt thereof, selected from enumerated groups of specific pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one compounds and closely related [1,2,4]triazolo[1,5-c]pteridin-5(6H)-one or pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one variants.
Enumerated substituted examples with defined benzyl and side-chain substituents
A compound, or pharmaceutically acceptable salt thereof, selected from specific examples including bromo-, methoxy-, benzyl-, halogenated benzyl-, fluorinated, trifluoromethyl, trifluoromethoxy, morpholino, piperazinyl, piperidinyl, and oxazepanyl-like substituents, with stereochemically defined 2,6-dimethylmorpholino motifs present in some examples.
The consolidated claim coverage spans broad Formula (I) structural definitions with Y/Z, M, and enumerated substituent constraints, together with narrower independent claims that directly enumerate specific substituted pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one and related fused variants, including pharmaceutically acceptable salts.
Stated Advantages
Treating CNS disorders with cognitive deficits, including conditions linked to cyclic nucleotide signaling and dopamine signaling.
Providing neuronal plasticity-related effects involving CREB.
Providing neuroprotection.
Proposed utility for cardiovascular, renal, hematological, gastrointestinal/liver, cancer, and neurodegenerative/neurogenesis/neurite outgrowth indications.
Documented Applications
Treating CNS disorders with cognitive deficits, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and ADHD.
Cardiovascular, renal, hematological, gastrointestinal/liver, cancer, and neurodegenerative/neurogenesis/neurite outgrowth indications.
PDE1b inhibitory assay context including IMAP TR-FRET assay and PDE selectivity assay panel results.
siRNA knockdown studies examining PDE1b effects on memory in contextual fear conditioning and trace fear conditioning.
Memory-related assays and neurite outgrowth assays referenced in the disclosure figure set.
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