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-9126959-B2
Publication Date
2015-09-08
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 relates to Formula I compounds and potassium salt forms of compounds having specific chemical structures. The disclosed examples include multiple stereoisomeric, enantiomeric, and analog acid or metal-salt forms, together with structural depictions and representative substituent variations.
The chemical structures share related cores featuring aromatic ether/ester-linked scaffolds and sulfur-containing motifs, including thio-succinyl, thioamide, thiophene-like, and bicyclic or thiolactam-like features. The examples also show variable substituents such as F, Cl, methoxy, hydroxy, CF3, O-alkyl, phosphonate/phosphate/phosphoramidate-like moieties, sulfonamide moieties, and heteroaromatic groups including pyridine-like, thiazole, and imidazole-like rings.
The disclosure further specifies salt forms, including potassium salts and other salt classes such as sodium, HCl, dihydrogen sulfate, and alkali earth metal salt embodiments. The material also includes pharmaceutical compositions and co-crystals comprising acid salts of Formula I/II compounds combined with a phosphodiesterase inhibitor, together with characterization and comparison of salt forms by XRPD, DSC, thermogravimetry, moisture sorption, bioavailability comparison, and assay contexts related to PPARγ activation and mitochondrial membrane binding crosslinking.
Claims Coverage
The provided material centers on one independent claim in each excerpt, and the recurring independent claim coverage is a potassium salt of a compound defined by a specific chemical structure. No additional dependent-claim refinements are available in the supplied content.
Potassium salt of a structured compound
A potassium salt of a compound having the structure defined in the independent claim, including Formula I or the recited specific chemical structure.
The consolidated claim coverage is limited to potassium salts of compounds defined by specific chemical structures, with no further inventive features explicitly available from dependent claims in the supplied material.
Stated Advantages
PPARγ activity limitations relative to rosiglitazone and pioglitazone are stated for the disclosed co-crystals comprising acid salts with a phosphodiesterase inhibitor.
Reduced PPARγ binding and activation.
Avoidance of sodium reabsorption.
Reduced side effects versus higher-PPARγ-activity compounds.
Demonstrated hygroscopicity characterization for potassium salts versus other salt forms via moisture sorption and related solid-state analyses.
Improved bioavailability for potassium salt versus sodium salt forms is described.
Documented Applications
Pharmaceutical compositions are described, and co-crystals comprising acid salts of Formula I/II compounds with a phosphodiesterase inhibitor are described as pharmaceutical-related entities.
Treating and/or preventing metabolic diseases, including diabetes and obesity.
Treating and/or preventing neurodegenerative disorders such as Alzheimer’s Disease.
Bioavailability comparison of sodium vs potassium salt forms in vivo, including cynomolgus monkey data and AUC reference.
PPARγ-related evaluation using TR-FRET competitive binding assay context and GeneBLAzer PPARγ cell reporter assay context.
Mitochondrial membrane binding crosslinking assay context.
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