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
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Publication Number
US-11434247-B1
Publication Date
2022-09-06
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 document describes substituted furo[2,3-d]pyrimidine compounds of Formula (I), or pharmaceutically acceptable salts thereof, centered on a furo[2,3-d]pyrimidine scaffold with variable substituents L1, L2, and L3. The scope includes furo[2,3-d]pyrimidine-4-amine and furo[2,3-d]pyrimidine-5-carboxamide motifs, together with L4 and L5 taken together with the nitrogen to which they are attached to form a 3-15-membered heterocycloalkyl or 5-10-membered heteroaryl ring, and with detailed selection rules for m, Rb, Rc, and optional substitution patterns on heterocycloalkyl, heteroaryl, phenyl, benzyl, and related groups.
The disclosure further identifies specific substituted furo[2,3-d]pyrimidine-5-carboxamide compounds as members of selected groups, including named N-substituted analogs with 6-methyl and 4-[(1-methylcyclopropyl)amino] features and varied heteroaryl or heterocycloalkyl carboxamide substituents. The examples vary the N-substituent and other attached ring systems while maintaining the common furo[2,3-d]pyrimidine carboxamide framework, and are supported by reported ^1H NMR and [M+H] mass values.
The document also frames the disclosed chemistry as substituted furanopyrimidine compounds, including subformulas and stereoisomeric forms, and identifies the compounds as phosphodiesterase (PDE1) inhibitors. The stated therapeutic intent includes neuroplasticity, neuroprotection, and neurorecovery, together with treatment of central nervous system and neurological disorders, and the disclosure also provides pharmaceutical compositions containing the substituted furanopyrimidine compounds and pharmaceutically acceptable salts.
Claims Coverage
The consolidated claim coverage includes one broad Formula (I) compound claim and selected-list claims for specific substituted furo[2,3-d]pyrimidine carboxamide compounds, plus a method claim directed to enhancing memory. In total, the claims center on the furo[2,3-d]pyrimidine scaffold with defined variable substituent frameworks and one independently claimed therapeutic use.
Formula (I) furo[2,3-d]pyrimidine compound with variable L1, L2, and L3 substituents
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L1 is selected from specified N(Rb)-containing forms, heterocycloalkyl, or heteroaryl options; L2 is selected from specified linker, heteroatom, alkyl, cycloalkyl, aryl, and heteroaryl options; and L3 is selected from hydrogen, hydroxyl, cyano, amino, alkylamino, dialkylamino, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, carbonyl-containing, cycloalkyl, heterocycloalkyl, phenyl, benzyl, and heteroaryl options, with optional substitution as recited in the claims.
Ring formation by L4 and L5
L4 and L5 are taken together with the nitrogen to which they are attached to form a 3-15-membered heterocycloalkyl or 5-10-membered heteroaryl ring, optionally substituted with one to four R1D groups, with L6 selected from an enumerated substituent set.
Selected substituted furo[2,3-d]pyrimidine-5-carboxamide compounds
A compound selected from a group consisting of specifically named substituted furo[2,3-d]pyrimidine-5-carboxamide derivatives and pharmaceutically acceptable salts thereof, including members with 6-methyl and 4-[(1-methylcyclopropyl)amino] features and varied N-substituents.
Enhancing memory by administering the claim 1 compound
A method for enhancing memory in a subject comprising administering an effective amount of the compound of claim 1 to the subject.
The claims collectively cover a broad Formula (I) furo[2,3-d]pyrimidine scaffold with extensive substituent selection rules, selected enumerated furo[2,3-d]pyrimidine-5-carboxamide members, and a memory-enhancement method using the claimed compound.
Stated Advantages
Enhancing memory in a subject.
Documented Applications
A method for enhancing memory in a subject by administering an effective amount of the compound of claim 1.
Treatment of central nervous system and neurological disorders.
Neuroplasticity, neuroprotection, and neurorecovery.
Pharmaceutical compositions containing the substituted furanopyrimidine compounds and pharmaceutically acceptable salts.
Detection and imaging, and metabolic and reaction kinetic studies using detection/imaging techniques.
Memory enhancement in a subject, including object recognition and fear conditioning paradigms, with measures such as 24 hour memory and discrimination index.
Reduction/assessment of haloperidol-induced catalepsy in rodents as a behavioral readout.
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