Pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione derivatives
Inventors
Chenard, Bertrand L. • Gallaschun, Randall J.
Assignees
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Publication Number
US-9440973-B2
Publication Date
2016-09-13
Expiration Date
Abstract
This invention relates to novel Pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione derivatives of Formula (I): and their use as TRPC5 modulators, pharmaceutical compositions containing the same, and methods of using the same as agents for the treatment of TRPC5 receptor mediated disorders or conditions. R1, R2, R3 and R4 have meanings given in the description.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, including pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione derivatives and a broad class defined by substituent variables R1, R2, R3, R4, and R5. R1 is C2-C10 hydroxyalkyl optionally substituted with 1-3 C3-C10 cycloalkyls, and the remaining variables are defined by broad allowed chemical group classes with substituted aryl, heteroaryl, halo, hydroxyl, alkoxy, aryloxy, heterocycloalkyl, and carbonyl-containing groups among the listed options.
The compounds are positioned as TRPC5 modulators and TRPC5 antagonists that inhibit TRPC5-mediated ion flux and TRPC5-mediated inward currents and outward currents. The disclosure ties TRPC5 modulation to TRPC5 homomultimer and TRPC5 heteromultimer activity involving TRPC1/TRPC3/TRPC4.
The disclosure also includes synthetic preparation of specific compound examples within the Formula (I) framework, with reported LCMS data for the described steps and product. The compounds are framed in connection with TRPC5-mediated disorders, including neuropsychiatric and neurodegenerative disorders, nephropathy, seizure, pain-related conditions, and the listed disorders in the claims.
Claims Coverage
The claim coverage centers on one broad Formula (I) compound definition and TRPC5-related use claims, with a pharmaceutical composition formulation also indicated in the family summary. The inventive features are the compound class defined by R1-R5, cell-contacting TRPC5 inhibition, and treatment of TRPC5-mediated disorders.
Formula (I) compound definition
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is C2-C10 hydroxyalkyl optionally substituted with 1-3 C3-C10 cycloalkyls; R2, R3, and R4 are selected from the listed substituent classes including alkyl, alkenyl, alkynyl, acyl, cycloalkyl, alkoxy, cycloalkyloxy, halo, hydroxyl, alkylthio, thionyl, sulfonyl, sulfonamidyl, aryl, heteroaryl, aryl-alkyl, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, heterocycloalkyl, and carbonyl-containing groups, each optionally substituted with R5; and R5 is independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, alkoxy, aryl, heteroaryl, aryloxy, O-aryl-alkyl, O-alkyl-aryl, C(O)O-alkyl, C(O)-alkyl, C(O)OH, nitro, or cyano.
Cell-contacting TRPC5 inhibition
Inhibiting TRPC5 by contacting a cell with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
TRPC5-mediated disorder treatment
Treating a TRPC5-mediated disorder in a subject by administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, with disorders including depression, anxiety disorders, fear-related disorders, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, proteinuric kidney disease, or seizure disorder.
The claims collectively cover a broad Formula (I) compound class defined by R1-R5 substituent rules and TRPC5-related uses, namely cell-contacting inhibition and treatment of enumerated TRPC5-mediated disorders, with pharmaceutical composition/formulation aspects also noted in the family summary.
Stated Advantages
Inhibits TRPC5-mediated ion flux and/or TRPC5-mediated inward currents and outward currents.
Designed as TRPC5 antagonists for treating TRPC5-mediated disorders.
Documented Applications
Inhibiting TRPC5 by contacting a cell with the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Treating a TRPC5-mediated disorder in a subject by administering an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, including depression, anxiety disorders, fear-related disorders, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, proteinuric kidney disease, or seizure disorder.
A pharmaceutical composition formulation is included in the family summary provided with the relevant claims.
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