Substituted furanopyrimidine compounds as PDE1 inhibitors
Inventors
Bookser, Brett • Botrous, Iriny • Burns, Aaron • Chung, DeMichael • Dyck, Brian • Kleinke, Andrew • Kumar, Dange Vijay • McCarrick, Margaret • RAFFAELE, NICHOLAS • TRAN, Joe • Weinhouse, Michael
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12006325-B2
Publication Date
2024-06-11
Expiration Date
Abstract
Substituted furanopyrimidine chemical entities of Formula (I): wherein Ra has 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, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive therapies; modulating and treating disorders mediated by PDE1 activity or dopaminergic signaling; 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 cardiovascular, renal, hematological, gastroenterological, liver, cancer, fertility, and metabolic disorders.
Core Innovation
The invention relates to substituted furo[2,3-d]pyrimidine-5-carboxamide compounds and pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from specified furo[2,3-d]pyrimidine-5-carboxamide structures. The selected compounds share a 6-methyl-4-[(1-methylcyclopropyl)amino] furo[2,3-d]pyrimidine-5-carboxamide scaffold and vary in N-substituted heteroaryl or arylmethyl groups, with examples including thiazolylmethyl, pyrrolylmethyl, fluorophenylmethyl, pyrazolylmethyl, chloropyridinylmethyl, oxazolylmethyl, pyrazinylmethyl, and methoxypyrimidinylmethyl variants.
The disclosure provides multiple enumerated compound examples and structural characterization data, including 1H NMR, [M+H] values, LC/MS indicators, and structural depictions. It also describes additional substituted analogs and related heteroaromatic scaffolds supported by chemical structure illustrations and mass spectral values.
The invention further frames these compositions for cognitive-related therapeutic use. The claims and dependent claim refinements recite administration of an effective amount to enhance memory or treat cognitive impairment in a subject with a cognitive disorder, with narrower indications including Parkinson’s disease and Parkinson’s disease with mild cognitive impairment (PD-MCI).
Claims Coverage
The consolidated claim coverage centers on pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a selected furo[2,3-d]pyrimidine-5-carboxamide compound, or a pharmaceutically acceptable salt thereof, from several enumerated compound groups. Across the independent claims, the inventive features focus on the defined scaffold and specific N-substituted selections; dependent claim summaries further narrow the use to memory enhancement and treatment of cognitive impairment, including Parkinson’s disease and PD-MCI.
Pharmaceutical composition with selected furo[2,3-d]pyrimidine-5-carboxamide compounds
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from enumerated furo[2,3-d]pyrimidine-5-carboxamide compounds including 6-methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide, 6-methyl-4-[(1-methylcyclopropyl)amino]-N-(1H-pyrrol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide, N-[(2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, and N-[(6-chloropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.
Pharmaceutical composition with selected heterocycle-substituted furo[2,3-d]pyrimidine-5-carboxamide compounds
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from enumerated compounds including 6-methyl-N-{[5-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, 6-methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, 6-methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrazin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide, 6-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, and 6-methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,3-oxazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide.
Pharmaceutical composition with selected aryl- and pyrimidinyl-substituted furo[2,3-d]pyrimidine-5-carboxamides
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from enumerated compounds including N-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, N-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, N-{[1-(3-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, and N-[(6-methoxy-2-methylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.
Memory enhancement and cognitive impairment treatment
Dependent claims further cover administering an effective amount of the composition to enhance memory or treat cognitive impairment in a subject with a cognitive disorder, including Parkinson’s disease and Parkinson’s disease with mild cognitive impairment (PD-MCI).
Across the independent claims, the claim coverage is directed to pharmaceutical compositions containing a pharmaceutically acceptable carrier and one of several explicitly enumerated furo[2,3-d]pyrimidine-5-carboxamide compounds or pharmaceutically acceptable salts. The dependent claim refinements associate the compositions with administering an effective amount to enhance memory or treat cognitive impairment, with Parkinson’s disease and Parkinson’s disease with mild cognitive impairment (PD-MCI) as the stated cognitive disorder contexts.
Stated Advantages
Enhancing memory in a subject with a cognitive disorder.
Treating cognitive impairment in a subject with Parkinson’s disease.
Treating Parkinson’s disease with mild cognitive impairment (PD-MCI).
Providing compositions useful for memory enhancement and cognitive impairment treatment associated with Parkinson’s disease.
Treatment of neurological disorders via PDE1 inhibition, including cognitive impairment.
Enhance 24h memory.
Reverse haloperidol catalepsy.
Documented Applications
Memory enhancement in a subject with a cognitive disorder by administering an effective amount of the claimed pharmaceutical composition.
Treating cognitive impairment in a subject with Parkinson’s disease by administering an effective amount of the claimed pharmaceutical composition.
Treating or assessing Parkinson’s disease with mild cognitive impairment (PD-MCI).
Metabolic and reaction kinetic studies.
Detection and imaging techniques.
Radioactive therapies.
Treatment of neurological disorders including cognitive impairment, Parkinson’s disease, Alzheimer’s disease, and schizophrenia-related cognitive symptoms.
Stroke and traumatic brain injury (TBI) rehabilitation and augmented training/cognitive training.
Peripheral disorder treatment including cardiovascular, renal, hematological, gastrointestinal and liver diseases, cancer disorders, and fertility disorders.
Object recognition memory effects.
Contextual fear conditioning effects.
Haloperidol-induced catalepsy effects.
Interested in licensing this patent?