Substituted phenyl sulfonyl phenyl triazole thiones and uses thereof
Inventors
Wrasidlo, Wolfgang J. • Stocking, Emily M. • Natala, Srinivasa Reddy • PRICE, Diana Luz
Assignees
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Publication Number
US-10501423-B2
Publication Date
2019-12-10
Expiration Date
Abstract
The present disclosure relates to substituted phenyl sulfonyl phenyl triazole thiones, pharmaceutical compositions containing them, and methods of using them.
Core Innovation
The patent describes a compound of Formula (I), wherein R1, R2, and R3 each independently are hydrogen, hydroxy, halogen, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, —CN, —C(O)Rx, —C(O)ORx, —S(O)2Rx, or —NRyRz. Rx, Ry, and Rz each independently are H or optionally substituted C1-4 alkyl, or Ry and Rz taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring; the invention includes the compound and pharmaceutically acceptable salts thereof.
The disclosure also describes sulfonyl-1,2,4-triazole-3-thione scaffolds and selected sulfonyl-1,2,4-triazole thione derivatives within the Formula (I) framework. Example embodiments include specific substituted analogs such as morpholine-substituted and multiple phenylsulfonyl variants with substituent patterns including chloro, methyl, CF3, methoxy, and dimethylamino.
The document further reports characterization data including LCMS, 1H NMR, NOESY/HMBC, PXRD, DSC, TGA, PLM, and SXRD, and refers to spray-dried formulations and spray dry dispersions (SDD). It also describes therapeutic uses for neurodegenerative diseases and other conditions associated with neurotoxic protein aggregation or accumulation and neuroinflammation, including Parkinson’s, Alzheimer’s, Lewy body disease, Huntington’s, ALS, and related conditions.
Claims Coverage
The claim coverage centers on 1 independent claim that defines a Formula (I) compound with variable substituents at R1, R2, and R3, including optional monocyclic heterocycloalkyl ring formation via Ry and Rz, together with pharmaceutically acceptable salts. Dependent claims refine this scaffold with selected sulfonyl-1,2,4-triazole-3-thione derivatives, specific substituent choices, and a pharmaceutical composition with an excipient.
Compound of Formula (I) with variable substituents and ring formation options
A compound of Formula (I) wherein R1, R2, and R3 are each independently hydrogen, hydroxy, halogen, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, —CN, —C(O)Rx, —C(O)ORx, —S(O)2Rx, or —NRyRz; Ry and Rz are each independently H or optionally substituted C1-4 alkyl, or Ry and Rz taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring; and pharmaceutically acceptable salts thereof.
Selected sulfonyl-1,2,4-triazole-3-thione derivatives and salts
The compound of Formula (I) is selected from a listed group of sulfonyl-1,2,4-triazole-3-thione derivatives, together with pharmaceutically acceptable salt forms.
R1 restricted to named heterocycle/amine substituents
Wherein R1 is morpholinyl, 4-methyl-piperazin-1-yl, piperidinyl, or pyrrolidinyl; together with the corresponding compound of Formula (I) and pharmaceutically acceptable salt thereof.
R2 specified as CF3
Wherein R2 is CF3; together with the corresponding compound of Formula (I) and pharmaceutically acceptable salt thereof.
R3 restricted to chloro
Wherein the substituent R3 is chloro; together with the corresponding compound of Formula (I) and pharmaceutically acceptable salt thereof.
Pharmaceutical composition including excipient
A pharmaceutical composition comprising at least one compound as defined by claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Overall, the claims cover a Formula (I) sulfonyl-linked 2,4-dihydro-1,2,4-triazole-3-thione scaffold with defined substituent variability at R1, R2, and R3, including amino substituents that can form an optionally substituted monocyclic heterocycloalkyl ring, and extend to pharmaceutically acceptable salts. The claim set further narrows to enumerated sulfonyl-1,2,4-triazole-3-thione derivatives, specific substituent choices such as R1 morpholinyl/4-methyl-piperazin-1-yl/piperidinyl/pyrrolidinyl, R2 CF3, and R3 chloro, and a pharmaceutical composition with an excipient.
Stated Advantages
Statistically significant reductions of α-synuclein deposits and PK-resistant ASYN in a Line 61 mThy1-α-synuclein transgenic mouse model are reported.
Statistically significant changes are reported for autophagy marker LC3 and motor performance/grip strength.
Neuroinflammation marker changes are reported, including TSPO (18 kDa) and GFAP.
Amyloid beta pathology changes are reported in a Line 41 APP transgenic mouse model, including β-amyloid plaques.
Documented Applications
Medicinal treatment of neurodegenerative diseases associated with neurotoxic protein aggregation or accumulation and/or neuroinflammation, including Parkinson’s, Alzheimer’s, Lewy body disease, Huntington’s, and ALS.
Treatment of conditions associated with protease-resistant protein aggregation or accumulation and decreasing neuroinflammation, involving alpha-synuclein, Aβ, tau, Huntingtin, and TDP-43.
Treatment-related efficacy findings in a Line 61 mThy1-α-synuclein transgenic mouse model, including effects on α-synuclein pathology, autophagy marker LC3, motor performance/grip strength, neuroinflammation markers TSPO and GFAP, and dopaminergic transporter DAT.
Treatment-related efficacy findings in a Line 41 APP transgenic mouse model, including effects on amyloid beta (β-amyloid) plaques.
Spray-dried formulations and spray dry dispersions (SDD) with solid-state characterization using PXRD, DSC, TGA, PLM, and SXRD for Compound 1.
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