Substituted thiophene- and furan-fused azolopyrimidine-5-(6H)-one compounds
Inventors
Branstetter, Bryan • Breitenbucher, James • Dyck, Brian • Gomez, Laurent • Hudson, Andrew Richard • Marrone, Tami Jo • Peters, Marco • VICKERS, Troy
Assignees
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Publication Number
US-10092575-B2
Publication Date
2018-10-09
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 invention relates to administering an effective amount of a chemical entity of Formula (I) to a subject in need of treatment. The chemical entity is selected from compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and isotopically labeled compounds, with extensive variable definitions and selection rules for X, Y, M, R-group substituents, ring-forming provisos, and substitution options that define the scope of Formula (I).
The chemical entities are linked to treating diseases or disorders selected from vascular disorders, renal disorders, CNS disorders, and injuries or diseases that result in neuronal degeneration. The disclosure also states use for cognitive impairment, where cognitive training is provided in conjunction with administration of a Formula (I) chemical entity to produce an improvement in performance of a cognitive function associated with the cognitive impairment, with repeated providing and administering steps and reduced training sessions relative to cognitive training alone.
Another aspect of the invention is a method of promoting neurogenesis by administering an effective amount of a chemical entity of Formula (I) to a subject in need of such treatment. The disclosure further relates the Formula (I) chemical entities to inhibition of PDE1, in particular PDE1b, and to modulation of cyclic nucleotide signaling, including cAMP and cGMP, with stated utility across CNS/cognitive deficits, neurological disorders, and other PDE1-mediated disorders.
Claims Coverage
The consolidated claim coverage includes three independent claims. Across the claims, the inventive features are centered on administering a chemical entity of Formula (I), including salts, prodrugs, metabolites, and isotopically labeled compounds, for disease treatment, combining cognitive training with Formula (I) administration to treat cognitive impairment while reducing training sessions, and promoting neurogenesis via Formula (I) administration.
Administering a formula (i) chemical entity for treating selected diseases or disorders
A method of treating a disease or disorder selected from vascular disorders, renal disorders, CNS disorders, and injuries or diseases that result in neuronal degeneration by administering to a subject in need an effective amount of a chemical entity of Formula (I), including pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and isotopically labeled compounds, with Formula (I) defined by specified variable selections and provisos.
Combining cognitive training with a formula (i) chemical entity for cognitive impairment
A method of treating cognitive impairment in an animal that includes providing cognitive training under conditions sufficient to produce an improvement in performance of a cognitive function associated with the cognitive impairment, administering in conjunction with the cognitive training a chemical entity of Formula (I), repeating the providing and administering steps one or more times, and reducing the number of training sessions sufficient to produce the improvement in performance relative to cognitive training alone.
Administering a formula (i) chemical entity to promote neurogenesis
A method of promoting neurogenesis by administering to a subject in need an effective amount of a chemical entity of Formula (I), including pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and isotopically labeled compounds.
All independent claims rely on administration of a chemically defined Formula (I) entity. The scope is distinguished by the stated therapeutic objective: treatment of selected disease or disorder categories, treatment of cognitive impairment with cognitive training and reduced training-session requirements, or promotion of neurogenesis.
Stated Advantages
Produces an improvement in performance of a cognitive function whose deficit is associated with cognitive impairment.
Reduces the number of training sessions sufficient to produce the improvement in performance relative to cognitive training alone.
Promotes neurogenesis.
Therapeutic efficacy is linked to PDE1 inhibition, in particular PDE1b inhibition, and modulation of cyclic nucleotide signaling, including cAMP and cGMP.
Documented Applications
Treating diseases or disorders including vascular disorders, renal disorders, CNS disorders, and injuries or diseases resulting in neuronal degeneration.
Treating cognitive impairment by combining cognitive training with administration of a Formula (I) chemical entity to improve cognitive performance and reduce required training sessions.
Promoting neurogenesis in a subject in need of such treatment.
Treating CNS/cognitive deficits, neurological disorders, and other PDE1-mediated disorders.
Augmenting cognitive/motor training, neurorecovery/rehabilitation, and neuroprotection.
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