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-8895748-B2
Publication Date
2014-11-25
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 patent describes PPAR-sparing thiazolidinedione (TZD) compounds of Formula I and a process for preparing them. The compounds are intended to reduce PPAR binding/activation versus pioglitazone/rosiglitazone and to diminish side effects such as sodium reabsorption while supporting the treatment/prevention of metabolic and inflammatory disorders.
The invention relates to a method for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, by converting a compound of Formula 2A to the compound of Formula I. The disclosure defines substituent ranges for R1 and R2, with R3 as hydrogen or an optionally substituted C1-6 alkyl, and describes this conversion as a post-functionalization conversion, including hydrolysis using acid treatment.
The description further provides intermediate conversion mapping among labeled formula compounds including Formula 7A, Formula 2A, Formula 8A, and Formula 4A/Formula 5A/Formula 6A, together with Formula 3A/Formula 3B, Formula 10A-10F, and Formula 11A-11M. It also describes formation of these intermediates from aldehydes, leaving groups such as halo or triflyl, and reagents including alkoxylamine derivatives, as part of the synthetic sequence leading to Formula I and its pharmaceutically acceptable salt.
Claims Coverage
The independent claim is directed to a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, by converting a compound of Formula 2A under substituent-defined structural constraints. Three inventive features are identified: the Formula 2A to Formula I conversion, the selection rules for R1 and R2, and the R3 constraint.
Method for preparing formula I via conversion of formula 2a
A method for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula 2A to a compound of Formula I.
Substituent selection for R1 and R2 in formula I
Each of R1 and R2 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 halo groups.
R3 constraint in formula I
R3 is hydrogen or an optionally substituted C1-6 alkyl.
The claimed core is a structured conversion of Formula 2A to Formula I, with Formula I defined by R1/R2 selection rules and the constraint that R3 is hydrogen or an optionally substituted C1-6 alkyl.
Stated Advantages
Reduced PPAR binding/activation versus pioglitazone/rosiglitazone.
Diminishing side effects such as sodium reabsorption.
Treatment/prevention of metabolic and inflammatory disorders.
Documented Applications
Treatment/prevention of metabolic and inflammatory disorders, including diabetes, obesity, hypertension, and dyslipidemia.
In vitro reduced PPAR activation criteria.
In vivo biomarker assessment in KKAy mice, including liver biomarker P2 (ectopic adipogenesis) and P2 expression.
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