Substituted [1,2,4]triazolo[1,5-A]pyrimidin-7-yl compounds as PDE2 inhibitors
Inventors
Breitenbucher, James • Freestone, Graeme • Gomez, Laurent • Lemus, Robert • Ly, Kiev • McCarrick, Margaret • Vernier, William • VICKERS, Troy
Assignees
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Publication Number
US-10501465-B2
Publication Date
2019-12-10
Expiration Date
Abstract
The invention provides a chemical entity of Formula (I): wherein R1, R2, X, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods as disclosed herein, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by PDE2 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, and dermatological disorders.
Core Innovation
The patent describes substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl compounds linked through carbonyl to morpholine or piperidine, including related substituted triazolo[1,5-a]pyrimidine carbonyl derivatives and pharmaceutically acceptable salts. The disclosed examples include arylmethyl, benzoyl, pyrazole-3-carbonyl, and other aryl or heteroaryl substituents, with multiple halogenated, alkoxy-substituted, and stereochemically defined members.
The invention relates to methods of inhibiting PDE2 activity by exposing PDE2 to an effective amount of at least one compound selected from the same structural group. A further method administers an effective amount of the selected compounds to a subject in need thereof to inhibit or relieve a neurological disorder or ameliorate a symptom of a neurological disorder, wherein the neurological disorder is cognitive impairment.
The disclosure also includes examples of substituted morpholine and piperidine derivatives bearing named aryl and carbonyl substituent patterns, including fused-ring and heteroaryl variants. Characterization data such as [M+H] values and 1H NMR data are provided for many examples, together with structural depictions and example numbering across multiple series.
Claims Coverage
Two independent claims are identified. The claims cover a PDE2 inhibition method and a neurological disorder method, both using an effective amount of selected substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl carbonyl compounds with morpholine or piperidine linkages and pharmaceutically acceptable salts. The neurological disorder is specified as cognitive impairment, and dependent claims narrow the compound set to particular named members and stereochemical variants.
PDE2 inhibition by exposing PDE2 to selected triazolo[1,5-a]pyrimidin-7-yl carbonyl compounds
A method of inhibiting PDE2 activity by exposing PDE2 to an effective amount of at least one compound selected from the group consisting of substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl morpholine and piperidine carbonyl derivatives, including pharmaceutically acceptable salts thereof.
Neurological disorder treatment for cognitive impairment
A method of inhibiting or relieving a neurological disorder or ameliorating a symptom of a neurological disorder by administering to a subject in need thereof an effective amount of a compound selected from the same compound group, wherein the neurological disorder is cognitive impairment.
Claim coverage is centered on the same substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl carbonyl scaffold linked to morpholine or piperidine, applied to PDE2 inhibition by exposure and to neurological disorder treatment by administration, with cognitive impairment explicitly named.
Stated Advantages
Inhibiting PDE2 activity.
Inhibiting or relieving a neurological disorder.
Ameliorating a symptom of a neurological disorder.
Cognitive impairment is specified as the neurological disorder.
Documented Applications
A method of inhibiting PDE2 activity by exposing PDE2 to an effective amount of selected compounds, including pharmaceutically acceptable salts.
A method of inhibiting or relieving a neurological disorder or ameliorating a symptom of a neurological disorder by administering an effective amount of selected compounds to a subject in need thereof, wherein the neurological disorder is cognitive impairment.
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