PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases
Inventors
Colca, Gerard R. • Tanis, Steven P. • Larsen, Scott D.
Assignees
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Publication Number
US-8912335-B2
Publication Date
2014-12-16
Expiration Date
Abstract
The present invention relates to novel salts of thiazolidinediones and other pharmaceutical agents that are useful for treating and/or preventing metabolic diseases (e.g., diabetes, or neurodegenerative diseases (e.g., Alzheimer's Disease).
Core Innovation
The disclosure provides Formula I compounds and related Formula II/IIA/IIB and Formula III/IIIA/IIB/IVA/IVB compounds with defined substituent variables for ring A, R1, R2/R2′, R3, R4, and Q groups. Ring A includes phenyl and pyridinyl variants, and the substituent definitions include halo, alkyl, cycloalkyl, O-acyl, O-aroyl, O-heteroaroyl, phosphonate/phosphoryl motifs, and related O-linked substituent patterns. The embodiments are presented as representative structures and examples within the same general compound families.
The disclosure also presents sodium salt embodiments and other salt forms, including hydrogen chloride and dihydrogen sulfate salts, together with alkali earth metal salts. The compounds are shown in multiple structural variants with aromatic substitutions such as fluoro, chloro, methoxy, and trifluoromethyl, as well as stereochemical variants and different oxygen-linked or ester/carboxylate-related substituents. Tables and examples provide representative chemical structures for these salt forms and compound families.
The disclosure further describes co-crystal and pharmaceutical salt concepts, including salts or co-crystals of Formula I/II-related compounds with a phosphodiesterase inhibitor such as caffeine. The compounds are described as PPARγ-sparing agents with reduced PPARγ binding or activation and reduced PPARγ interaction, and the examples include characterization by XRPD, DSC, thermogravimetry, and moisture sorption. The disclosure also reports biological properties such as in vivo bioavailability studies, blood glucose lowering in diabetic KKAy mice, and PPARγ-related assay results.
Claims Coverage
The provided claim coverage repeatedly identifies one independent claim family directed to a sodium salt of a compound having a specific chemical structure. The inventive coverage centers on the sodium salt form and the structurally defined compound, with no additional independent claims or further extracted inventive refinements in the supplied content.
Sodium salt of a defined compound structure
A sodium salt of a compound having the structure defined in the claim.
Across the provided items, claim coverage is limited to a sodium salt of a compound defined by a specified chemical structure; no further inventive features are available in the partial claim text.
Stated Advantages
Sodium/potassium salts have significantly higher bioavailability than free base/free acid counterparts.
Reduced PPARγ binding, activation, or interaction.
Reduced side effects, including sodium reabsorption-related side effects.
Biological activity is described, including blood glucose lowering in diabetic KKAy mice.
Documented Applications
Treating or preventing metabolic diseases, including obesity and diabetes.
Treating neurodegenerative disorders, including Alzheimer’s disease and dementia.
In vivo bioavailability studies, including studies in cynomolgus monkeys and diabetic KKAy mice.
PPARγ-related assays, including binding/activation assay methodology and mitochondrial membrane competitive binding crosslinking results.
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