Preparation of 4-substituted N-hydroxybenzamides as HDAC inhibitors and therapeutic methods using them.

Abstract

Compds. of formula Cap-L-M [Cap = (un)substituted aliph. or arom. fused bicycle, (un)substituted aliph. or arom. 5-6 membered ring; AR2R3R4; L is attached to A; R2-4 = independently absent, H, alk(en)yl, (hetero)aryl, OH and derivs., etc.; L = absent, alkylene, heteroalkyl, etc.; M = CON(Rb)OH, N(OH)CORb, SO2NHRb, etc.; Rb = H, COMe, CF3, aryl, etc.], their pharmaceutically acceptable salts, hydrates and prodrugs, particularly hydroxybenzamides, e.g., 3-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indole (I), as histone deacetylases inhibitors (HDACIs) and compns. contg. them are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurol. disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed. Thus, I was prepd. by a multi-step procedure starting from tryptophol using 1-methylpiperazine and Me 4-(bromomethyl)benzoate. Many HDACIs of the invention exhibited selective inhibition of HDAC6 compared to other HDAC isoenzymes. [on SciFinder(R)]