Thieno- and furo[2,3-d]pyrimidine-2,4[1H,3H]-dione derivatives
Inventors
Chenard, Bertrand L. • Gallaschun, Randall J.
Assignees
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Publication Number
US-9447114-B2
Publication Date
2016-09-20
Expiration Date
Abstract
This invention relates to novel Thieno- and Furo[2,3-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. A, R1, R2, R3 and R4 have meanings given in the description.
Core Innovation
The invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, including thieno[2,3-d]pyrimidine-2,4-dione derivatives and related scaffolds. A is S or O, and the compounds are defined by broad substituent sets for R1 through R4 with optional substitution by R5 and R6.
The compounds are stated to function as TRPC5 modulators, including TRPC5 antagonists, and to inhibit TRPC5-mediated ion flux with inward and/or outward currents. The disclosure ties the chemical structure class of Formula (I) to TRPC5 pharmacological activity and references inhibition and activity thresholds including IC50, nanomolar inhibition, and percent inhibition at 1 μM.
The compounds are useful for modulating TRPC5 and for treating TRPC5-mediated disorders and conditions. Explicitly named indications include neuropsychiatric and neurodegenerative disorders, nephropathy, seizure disorders, and pain-related disorders.
The disclosure includes pharmaceutical compositions containing the Formula (I) compounds and administration methods for TRPC5-targeted treatment. The compositions comprise a pharmaceutically acceptable excipient, diluent, or carrier, and the disclosed use includes pharmaceutically acceptable salt forms of the Formula (I) derivatives.
Claims Coverage
The provided material centers on one independent compound claim for a Formula (I) compound or pharmaceutically acceptable salt thereof, defined by broad substituent options for A, R1, R2, R3, and R4 with recursively defined R5 and R6 options. It also includes independent coverage for a pharmaceutical composition and for inhibiting TRPC5 by contacting a cell with the Formula (I) compound. Three inventive features are captured across the independent claims.
Formula (I) TRPC5 modulator scaffold
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is S or O; R1 is C2-C10 hydroxyalkyl with optional substitution by 1-3 R5; R2 is C1-C4 alkyl or C1-C4 hydroxyalkyl; R3 and R4 are defined by broad substituent sets with optional substitution by R5; and R5 and R6 are further defined by additional substituent option sets.
Pharmaceutical composition containing a Formula (I) compound
A pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent, or carrier.
TRPC5 inhibition by contacting a cell with a Formula (I) compound
A method of inhibiting TRPC5 by contacting a cell with the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
The claim coverage is directed to a broad Formula (I) chemical space configured as TRPC5 modulators, together with pharmaceutical compositions containing the compounds and a method of inhibiting TRPC5 by contacting cells with the compounds.
Stated Advantages
Modulates TRPC5-mediated ion flux and inhibits TRPC5-mediated inward and/or outward currents.
Used for TRPC5-targeted treatment of neuropsychiatric and neurodegenerative disorders, nephropathy, seizure disorders, and pain-related disorders.
Documented Applications
TRPC5-targeted treatment of neuropsychiatric disorders, including anxiety and fear-related disorders, post-traumatic stress disorder, panic disorder, depression, bipolar disorder, and Alzheimer’s disease.
TRPC5-targeted treatment of neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.
TRPC5-targeted treatment of nephropathy, including proteinuric kidney disease.
TRPC5-targeted treatment of seizure disorders.
TRPC5-targeted treatment of pain-related disorders, including nociceptive pain, inflammatory pain, neuropathic pain, fibromyalgia, and complex regional pain syndrome.
TRPC5 inhibition by contacting a cell with the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent, or carrier.
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