Indene derivatives useful in treating pain and inflammation

Inventors

Harwig, Curtis • PETTIGREW, Jeremy D. • Cross, Jennifer • Seenisamy, Jeyaprakashnarayanan • Keregadde, Mahesh Narayan • KHER, Samir Satish

Assignees

Taro Pharmaceuticals Inc

Abstract

Compounds of formula (I) wherein, R1, R2, R3, R4a, R4b and R5 are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds are useful in treating inflammation and/or pain. Compositions comprising a compound of the invention are also disclosed, as are methods of using the compounds to treat inflammation and/or pain.

Core Innovation

The invention relates to a compound of formula (I) comprising an optionally substituted 5 to 14 membered fused N-heteroaryl fused to a cyclohexane. The N-heteroaryl contains 1 to 13 carbon atoms and 1 to 6 nitrogen, oxygen or sulfur atoms, and is optionally substituted by alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, carbonyl, amino, thio, and sulfoxide/sulfone-like groups. The variables R1 through R8 and Ri define additional substitution patterns, including direct bonds, alkylene chains, heteroarylalkyl moieties, and cases where two R8 groups together with the nitrogen form an optionally substituted N-heterocyclyl or N-heteroaryl.

The disclosure encompasses stereoisomers, enantiomers, tautomers, mixtures thereof, and pharmaceutically acceptable salts. The provided content also describes synthesis and characterization of multiple substituted fused heteroaryl/cyclohexane scaffold compounds and related stereochemically defined examples. Biological evaluation is described in terms of rat DRG excitability using Ca2+ imaging with electrical field stimulation, T cell proliferation and cytokine activity, human DRG excitability, in vivo pain and inflammation models, and liver microsome metabolism scoring.

Additional portions of the provided content describe synthetic sequences converting protected bicyclic/indazole scaffold intermediates into further functionalized analogs through olefination, reduction and oxidation, aldehyde-to-alcohol transformations, mesylation to azide substitution, azide-to-amine reductions, and late-stage heteroatom installation. The sequences also include conversions among quinoxaline, quinazoline, tetrahydroquinazoline, benzo[d][thiazole], benzo[c]isoxazole, and benzo[d][1,2,3]thiadiazole. The described examples include numerous numbered compound series members and functionalized amine or alcohol targets.

Claims Coverage

The claim coverage centers on one independent compound claim of formula (I) and an additional method claim for treating pain. The compound claim uses a broad fused N-heteroaryl/cyclohexane scaffold with extensive parameterized substituent definitions, while the method claim covers administration of the claimed compounds or compositions to a mammal in need.

The claim coverage is dominated by a broad formula (I) genus built on an optionally substituted fused N-heteroaryl/cyclohexane core, with detailed substituent, heteroarylalkyl, and N-heterocyclyl/N-heteroaryl alternatives, plus explicit stereoisomer, tautomer, enantiomer, and salt coverage. The supplied claims also include pain-treatment coverage by administration of the claimed compounds or compositions.

Stated Advantages

Documented Applications