SPIRO ISOBENZOFURANES AS NEUROPEPTIDE Y RECEPTOR ANTAGONISTS

摘要

Spiro compounds (I) are new. Spiro compounds of formula (I) and their salts and esters are new. [Image] A : linear 1-6C hydrocarbon chain optionally interrupted by N or O and optionally substituted by oxo, NH 2, NHAlk, N(Alk) 2, OH, OAlk, COOAlk, lower alkylene or R a; Alk : lower alkyl; Ar 1>arylene or heteroarylene both optionally substituted by halo, NO 2, oxo, Alk, lower haloalkyl, lower hydroxyalkyl, lower cycloalkyl, lower alkenyl, OAlk, lower haloalkoxy, NHAlk, N(Alk) 2, SAlk, COOH, COAlk, COOAlk or QAr 2>; Ar 2>aryl or heteroaryl both optionally substituted by halo, CN, Alk, lower haloalkyl, lower hydroxyalkyl, OH, OAlk, lower haloalkoxy, NHAlk, N(Alk) 2, COAlk or aryl; Q : bond or CO; R aAlk (optionally substituted by lower cycloalkyl, aryl or heteroaryl all optionally substituted by NH 2, NHAlk, N(Alk) 2or OH and F); R : H or lower alkylene attached to A; R 1, R 2, R 5H, Alk, aralkyl or aryl; R 3, R 4H, OH, Alk, aralkyl or aryl; T, U, V, W : N or methine (optionally substituted by halo, Alk, Oh or OAlk); X : N(SO 2R 1), N(COR 2) or CO; Y : CR 3R 4, O or NR 5; Z : N or CH 2; and n : not defined. Provided that at least 2 of T, U, V, W are not N. ACTIVITY : Hypotensive; Nephrotropic; Cardiant; Antiarteriosclerotic; Antidepressant; Tranquilizer; Anticonvulsant; Analgesic; Anabolic; Anxiolytic; Nootropic; Neuroprotective; Antialcoholic; Antiaddictive; Antidiabetic; Anorectic; Antilipemic; Antiinflammatory; Ophthalmological. MECHANISM OF ACTION : Neuropeptide-Antagonist-Y. In assays trans-N-[(S)-1-benzyl-2-(benzylamino)ethyl]-1-methanesulfonylspiro[indolin-3,1'-cyclohexane]-4'-carboxamide (Ia) had an IC 50value for human neuropeptide Y Y5 binding of 0.69 nM.