Quinazoline-2,4(1 H,3H)-dione derivatives
Inventors
Chenard, Bertrand L. • Gallaschun, Randall J.
Assignees
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Publication Number
US-9745272-B2
Publication Date
2017-08-29
Expiration Date
Abstract
This invention relates to novel Quinazoline-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 disclosure relates to TRPC5 antagonizing compounds defined by a general Formula (I), including pharmaceutically acceptable salt forms. The compounds are described as TRPC5 modulators, including TRPC5 antagonists, with inhibition of TRPC5-mediated ion flux and inward and outward currents associated with TRPC5. The scope includes broad Markush definitions for substituents in the Formula (I) scaffold, together with tautomeric, solvated, hydrated, and low pyrogen activity forms.
The invention additionally addresses quinazoline-2,4(1H,3H)-dione derivatives having a compound of Formula (I), with substituents R1 to R4 and R5/R6 defined by broad hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, heteroaryl, and related options. The disclosure further includes specific embodiment constraints, selected compound exemplars, and pharmaceutically acceptable salt forms. The compounds are described with potency criteria for TRPC5 antagonists, including IC50 values and inhibition levels at specified concentrations.
Pharmacological use is described for the TRPC5 antagonizing compounds in treatment or prevention of anxiety and fear-related disorders, neurodegenerative and neurological diseases, seizures, pain and pain-sensitivity conditions, and proteinuric kidney disease. The disclosure also mentions TRPC5 expression in podocytes, combination therapy with other drugs including analgesics such as opioids and NSAIDs, pharmaceutical compositions, dosage range discussion, and animal models and in vitro assay model frameworks for evaluating activity.
Claims Coverage
The claim coverage centers on one or more independent claims to a compound of Formula (I), including pharmaceutically acceptable salts, with broad Markush substituent definitions. The claims also include pharmaceutical composition coverage and narrower dependent limitations that select specific compounds or restrict particular substituents; at least eight inventive features are reflected across the merged claim set.
Formula (I) TRPC5 modulator with defined substituents
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the substituents are defined by the recited Markush ranges.
Formula (I) TRPC5 antagonizing compound with defined R1, R2, R3, and R4 substituents
A compound of Formula (I) in which R1, R2, R3, and R4 are defined by the specified substituent options, including the option that the compound is a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with excipient, diluent, or carrier
A pharmaceutical composition including at least one compound of Formula (I) or claim 1, together with a pharmaceutically acceptable excipient, diluent, or carrier.
Selected compound exemplar from the provided group
The compound is limited to one of the specific compounds shown in the provided selection group, or a pharmaceutically acceptable salt thereof.
Fixed substituent definition for R1
The compound of Formula (I) specifies that R1 is 3-hydroxypropyl.
Carbon-count constrained R2 substituent range
The compound of Formula (I) is defined such that R2 is a C1–C4 alkyl group.
Restricted R3 substituent set with optional halogen or —OCF3
The compound of Formula (I) is defined such that R3 is one of the specified substituents, with these substituents optionally substituted by fluorine or chlorine atoms or an —OCF3 group.
Substituent definition for R5 and R6
R5 and R6 are independently defined with the recited substituent options within the Formula (I) scaffold.
Overall claim coverage is anchored in a broad Formula (I) definition for TRPC5-modulating or TRPC5 antagonizing compounds, including pharmaceutically acceptable salts. The merged claim set further includes pharmaceutical composition coverage and narrower limitations that select specific exemplars or fix substituent choices such as R1 = 3-hydroxypropyl, R2 = C1–C4 alkyl, and R3 from a constrained set with optional halogen or —OCF3 substitution.
Stated Advantages
Low pyrogen activity, including discussion in terms of endotoxin and lipopolysaccharide (LPS).
Inhibition of TRPC5-mediated ion flux.
Inhibition of TRPC5-associated inward currents.
Inhibition of TRPC5-associated outward currents.
TRPC5 antagonists are described with IC50 ≤ 10 nM and ≥95% inhibition at ≤1 μM.
Documented Applications
Treatment or prevention associated with TRPC5 antagonism for anxiety and fear-related disorders, including post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, general anxiety disorder, obsessive-compulsive disorder, and separation anxiety.
Treatment or prevention of neurodegenerative and neurological diseases, including Parkinson’s disease, memory disorders, Alzheimer’s disease, amnesia, and stroke.
Treatment or prevention of seizures.
Treatment or prevention of pain and pain-sensitivity conditions, including nociceptive pain, inflammatory pain, neuropathic pain, osteoarthritis, rheumatoid arthritis, post-herpetic neuralgia, fibromyalgia, complex regional pain syndrome (CRPS), endometriosis, diabetic neuropathy, and migraine.
Treatment or prevention of proteinuric kidney disease, including reference to TRPC5 expression in podocytes.
Therapeutic use for TRPC5-mediated disorders, including neuropsychiatric/neurodegenerative conditions, nephropathy, and seizure disorders.
Combination therapy with other drugs including analgesics such as opioids and NSAIDs.
Pharmaceutical compositions for administration routes are described in the disclosure, including combination therapy examples.
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