Isoquinoline und benzohisoquinoline derivatives, their preparation and their therapeutical application as antagonists of histamine H3 receptor .

摘要

Isoquinoline derivatives (I) and their acid addition salts, hydrates and solvates are new. Isoquinoline derivatives of formula (I) and their acid addition salts, hydrates and solvates are new. ring A : unsaturated carbocycle with double bonds, optionally substituted by one or two, same or different, halo, hydroxy, nitro, cyano, 1-2C perhaloalkyl, 1-3C alkyl or phenyl; l : 0-4; m : 0-3; n : 0-6; the groups bracketed by l, m and n : C x-y alkylidene, optionally substituted by 1-4, same or different, halo, hydroxy, nitro, cyano, amino, 1-2C perhaloalkyl, 1-3C alkyl or phenyl, or where l, m or n = zero, these groups are bonds; R1 : hydrogen, 1-3C alkyl, 1-6C alkylcarbonyl, 1-6C alkoxycarbonyl (all these optionally substituted by halo, hydroxy, 1-3C alkoxy, nitro, cyano, amino or aryl), also 1-3C alkyl-aryl, monocyclic heteroaryl, aryl, where the last two may be substituted by 1-4 of halo, hydroxy, nitro, cyano, amino (optionally substituted by one or two 1-3C alkyl), 1-3C (halo)alkyl, 1-2C perhaloalkyl, 1-3C alkoxy or 1-3C alkylidenedioxy; R2 : hydrogen, 1-6C alkyl or 3-6C cycloalkyl (both optionally substituted by 1-4 of halo, hydroxy, nitro, cyano, amino, (optionally substituted by one or two 1-3C alkyl), 1-3C haloalkyl, 1-2C perhaloalkyl, 1-3C alkoxy, 3-6C cycloalkyl, mono- or bi-cyclic heteroaryl or aryl (optionally substituted by 1-4 of halo, hydroxy, nitro, cyano, amino (optionally substituted by 1 or 2 1-3C alkyl),1-3C haloalkyl, 1-2C perhaloalkyl, 1-3C alkoxy or 1-3C alkylidenedioxy . An independent claim is included for a method for preparing (I). [Image] ACTIVITY : Nootropic; Neuroprotective; Antiparkinsonian; Tranquilizer; Anticonvulsant; Neuroleptic; Antidepressant; Antialcoholic; Antimigraine; Antiemetic; Anorectic; Antidiabetic. MECHANISM OF ACTION : Antagonism at histamine H3 receptors. The compound (2-cyclohexylmethyl)-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline oxalate has IC50 below 10 nM at the human H3 receptor (in a cAMP formation assay in CHO cells, by inhibiting the agonist properties of (R)-alpha -methylhistamine).