5-PHENYL-ISOXAZOLE-3-CARBOXAMIDES MODULATING HSP90 WITH ANTITUMORAL ACTIVITIES

摘要

Disclosed herein are aryl isoxazole derivatives of formula I wherein: X is halogen, alkyl, alkenyl, haloalkyl, aryl, heteroaryl, benzyl, amino, alkylamino, or aminocarbonyl; Y and Z, the same or different, are halogen, nitro, haloalkyl, R3, OR3, amino, alkylamino, or aminocarbonyl; R1 is NHC(=O)ER4, NHC(=S)ER4, or NR5R6; R2 is NR8R9; and additional substituents are define in the specification; which exhibit inhibition of the molecular chaperone heat shock protein 90 (Hsp90) for use in the treatment of a neurodegenerative disease, inflammatory disease, cancer, autoimmune disease, cerebral ischemia, parasitemia including malaria. Examples of neurodegenerative diseases include Parkinson disease, Huntington disease, Alzheimer disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy or spinocerebellar ataxia. Examples of compounds claimed include: 4-acetylamino-5-(5-chloro-2,4-dihydroxy-phenyl)-isoxazole-3-carboxylic acid ethylamide; 5-(5-chloro-2,4-dihydroxy-phenyl)-4-(2,2-dimethyl- propionylamino)-isoxazole-3-carboxylic acid ethylamide; 1H-indole-6- carboxylic acid [5-(2,4-dihydroxy-5-isopropyl-phenyl)-3-ethyl carbamoyl- isoxazol-4-yl]-amide; 4-[(4-aminomethyl-cyclohexanecarbonyl)-amino]-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3- carboxylic acid ethylamide; and 5-(5-chloro-2,4-dihydroxy-phenyl)-4-(4-methoxy-benzoylaniino)-isoxazol-3-yl-(4-methylpiperazin-l-yl)-methanone.