Tetrazole Derivatives as TRPA1 Inhibitors for Treating Idiopathic Lung Disease or Cough

Abstract

Transient receptor potential channels (TRP channels) are a group of voltage-gated ion channels located mostly on the plasma membrane of numerous mammalian cell types. There are approximately 30 TRP channels sorted into several groups: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Transient receptor potential ankyrin 1 (TRPA1) is best known as a sensor for environmental irritants giving rise to somatosensory modalities such as pain, cold, and itch.TRPA1 is activated by a number of reactive, electrophilic stimuli and non-reactive compounds implicated in cough associated with asthma, chronic pulmonary obstructive disease (COPD), idiopathic pulmonary fibrosis (IPF), postviral cough, and chronic idiopathic cough. TRPA1 antagonists are effective in studies of atopic dermatitis, contact dermatitis, and psoriasis-associated itch.The present application describes a series of novel tetrazole derivatives as TRPA1 inhibitors for the treatment of idiopathic lung disease or cough. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.Definitions. A = phenyl, thienophenyl, benzothiophenyl, and benzofuranyl, unsubstituted or substituted with one or more member of the group R 1 selected from CN, halogen,