Synthesis for thiazolidinedione compounds

Inventors

Zeller, James R. • Tanis, Steven P. • Larsen, Scott D. • Parker, Timothy

Assignees

Cirius Therapeutics Inc

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 disclosure provides substituted aromatic and heteroaryl intermediate compounds represented by Formula 2B, Formula 5A, Formula 6A, Formula 7A, Formula 8A, Formula 9A/10A, Formula 11A, Formula 12A, and Formula 13A, and describes preparation of novel thiazolidinedione derivatives represented by Formula I and related intermediate formulas. These structures include substituent definitions for R1, R2, R3, X, X1, X2, R5/R5′, R7, Y1, and Y2/PGO, with halo or other leaving-group options, O/S linkages, and protected or variable functional groups. The chemical scope is established through definitions of substituents, heterocycle rings, protecting-group variables, and leaving groups used in the synthetic sequence.

The document describes synthesis schemes including Scheme 2, Scheme 2A, and Scheme 3, and further frames ring-closure possibilities for N-substituents to form substituted 3–7-membered N-heterocycles within the defined structures. Formula 5A is transformed to Formula 2B through reaction with a Grignard reagent i-PrMgBr in combination with Formula 6A, Formula 8A is halogenated to form Formula 2A, Formula 7A is acylated with Formula 6A, and Formula 10A is hydrogenated to 3A. Formula I is also prepared by reacting Formula 2A with intermediates including leaving group X and condensation to form 10A.

The document presents example structures including thiazolidinedione scaffolds of Formula 11A/12A/13A and Formula ib/i, as well as substituted benzyl thiazolidinedione examples. It specifies nitrogen protecting group choices for Y1 including Cbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, trityl, and PMP, and oxygen protecting group choices for Y2 including silyl protecting groups and alternative alkyl or alkylcarbonyl oxygen-protecting groups. These options support the preparation and variation of substituted scaffolds bearing substituents R7 and leaving groups such as Cl, Br, and Ms.

The disclosure also frames biological characterization in terms of reduced PPARγ activation and reduced PPARγ binding/activation relative to pioglitazone and rosiglitazone, with assay context using a PPARγ ligand binding domain, luciferase reporter, and luciferase/galactosidase control. It also references measurements of P2 biomarker (ectopic adipogenesis) in KKAy mice and analytical information including HPLC and Table A values for example compounds.

Claims Coverage

The provided independent claim text is incomplete and does not state inventive features beyond general compound structures, so the claim coverage can only be described at a high level. Across the items, the claimed subject matter centers on substituted thiazolidinedione and related intermediate structures, but no substantive independent-claim elements are fully set out.

The claim coverage points to substituted thiazolidinedione scaffolds and related intermediates with defined substituents, protecting groups, and leaving groups, but the independent claim content provided remains incomplete.

Stated Advantages

Documented Applications