C17 polar-substituted heteroaromatic synthetic triterpenoids and methods of use thereof

Inventors

Jiang, Xin • Bender, Christopher F. • Do, Ha • SUN, Haizhou • Visnick, Melean

Assignees

Reata Pharmaceuticals Inc

Abstract

Disclosed herein are compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders, including those associated with inflammation and cancer.

Core Innovation

The patent describes steroid-like compounds and substituted triterpenoid compounds based on a substituted triterpenoid scaffold, including compounds bearing a nitrile group, substituted heterocycle features, and fluorinated substituents such as F, difluoro, CF3-type groups, CHF2, and related fluorine-containing side chains. The disclosure also presents polar-substituted heteroaromatic features such as oxadiazole and tetrazole ring substituents, together with variants such as fluoromethyl, aminomethyl, hydroxymethyl, aminoethyl, hydroxyethyl, and monofluoroalkyl forms.

The document provides structural depictions of multiple candidate compounds with steroid-like scaffolds and 1,3,4- or 1,2,4-oxadiazole motifs, including fused heteroaromatic ring motifs containing O and N atoms, and exact chemical drawings and stereochemistry for labeled variants. The compounds are identified with labels such as Compounds 26–33, 35–54, T7–T46, 58–90, and T11, T12, T34, T41–T46, together with related comparison compounds.

The compounds are described in an anti-inflammatory and oxidative-stress context, with stated relevance to inflammatory resolution, the Keap1/Nrf2/ARE pathway, and related factors such as NQO1 and HO-1, as well as inflammatory signaling components including NF-κB, STATs, iNOS, COX-2, and TNF-α. Biological evaluation is reported for nitric oxide suppression in RAW 264.7 macrophages stimulated with interferon-gamma, glutathione assays in mouse AML-12 cells, nitrite measurement using Griess reagent, viability assessment using WST-1, and comparative data including CYP3A4 inhibition and GSH EC50 values.

Claims Coverage

Across the independent claims, coverage centers on a specific structural formula with three main inventive features: R1 as a monopolar-substituted alkyl (C≤3) bearing a monopolar substituent of F, R2 as hydrogen or methyl, and R2′ as methyl. The claims also extend to pharmaceutically acceptable salts, with dependent claims narrowing to fluoromethyl at R1, specific illustrated structures including stereochemistry, and pharmaceutical compositions with excipients and specified administration routes.

Overall, the claim coverage is directed to formula-defined compounds with R1 restricted to a C≤3 monopolar-substituted alkyl having a monopolar substituent of F, R2 set as hydrogen or methyl, and R2′ methyl, with protection of pharmaceutically acceptable salts. Dependent coverage further narrows to fluoromethyl, specific illustrated structures and stereochemistry, and pharmaceutical compositions containing an excipient and formulated for a broad list of administration routes.

Stated Advantages

Documented Applications