New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents

A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been pre pared in the search of novel antiallergic compounds. Synthesis of the desir ed ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation a fforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfu lly carried out by condensation of the corresponding acids or their N-aryl( methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyrid inium iodide. Efforts to improve the antiallergic potency of the title seri es by variation of the indole substituents (R-1, R-2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[ 1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.01 6 mu M. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 mu M) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 mu M, repectively. In vi vo antiallergic activity evaluation confirmed efficiency of 45 in sensitize d guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibitio n of microvascular permeability was assessed in two rhinitis models; ovalbu min and capsaicin-induced rhinorrhea could be prevented after topical appli cation of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 mu M); a nd it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.