Synthesis for thiazolidinedione compounds
Inventors
Tanis, Steven P. • Parker, Timothy • Gadwood, Robert C. • Zeller, James R. • Artman, III, Gerald D. • Larsen, Scott D.
Assignees
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Publication Number
US-8946435-B2
Publication Date
2015-02-03
Expiration Date
Abstract
The present invention provides novel methods for synthesizing PPARγ sparing compounds, e.g., thiazolidinediones, that are useful for preventing and/or treating metabolic disorders such as diabetes, obesity, hypertension, and inflammatory diseases.
Core Innovation
The invention relates to thiazolidine compounds of Formula I and thiazolidinedione-containing scaffold compounds, including related substituent patterns on a pyridine/benzyl/oxy linkage system. The compounds are defined by R3 and by broad heteroaryl and heteroaralkyl substituent options, with optional substitution patterns and additional formula families including Formula 10A-10F and Formula 11A-11L/M.
The disclosure includes defined structural terms for heteroaliphatic, heteroaralkyl, cyclic and bridged bicyclic ring systems, with example ring systems such as adamantanyl, norbornanyl, and multiple bicyclo and tricyclo ring systems. It also includes leaving-group XA options including bromo, chloro, iodo, OMs, OTs, OTf, OBs, ONs, and OPO(OR4)2.
The document further describes synthetic interconversions among multiple chemical formulas, including acid and heat hydrolysis of Formula 2A to Formula I, reduction of Formula 7A to Formula 2A, and condensation and reduction steps connecting Formula 3B, 3A, 4A, 5A, 6A, 7A, and 8A. The compounds are also described as PPARγ sparing compounds with reduced PPARγ binding/activation relative to pioglitazone and rosiglitazone.
Claims Coverage
The independent claim set centers on compound selection defined by R3, with two inventive features that restrict R3 to hydrogen or an unsubstituted C1-6 alkyl and then further narrow it to specific unsubstituted alkyl groups.
R3 is hydrogen or an unsubstituted C1-6 alkyl
The compound is defined such that R3 is hydrogen or an unsubstituted C1-6 alkyl.
R3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl
R3 is further narrowed to methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each unsubstituted.
Overall, the claims restrict the Formula I compound by enforcing that R3 is either hydrogen or an unsubstituted C1-6 alkyl, and further narrow the covered embodiments to specific unsubstituted alkyl options.
Stated Advantages
Reduced PPARγ binding/activation relative to pioglitazone and rosiglitazone.
Diminished PPARγ-mediated sodium reabsorption side effects.
Documented Applications
Treating and/or preventing metabolic and inflammatory disorders.
Diabetes.
Hypertension.
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