New N-(Pyridin-4-yl)-(indol-3-yl)acetamides and Propanamides as Antiallergic Agents

Abstract

A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, 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 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.

Synthesis and spectral characterization of environmentally responsive fluorescent deoxycytidine analogs

“…A slight modification of the recently described protocol 27 starting with Sonogashira cross-coupling of 2-bromobenzo[b]furan (5) with trimethylsilylacetylene (TMS-acetylene), followed by the removal of the TMS protecting group under basic conditions furnished the alkyne 4d in 70% overall yield (Scheme 1). Indole-3-acetic acid (6) was esterified, 28 followed by the bromination at the 2 position 29 and Boc-protection of indole nitrogen. Ethyl 1-Boc-2-bromoindole-3-yl acetate (Scheme 1, 7) was obtained in 90% yield, based on ethyl 2-bromoindole-3-yl acetate.…”

“…28,29 Subsequently the alkyne functionality was installed in two steps. Ethyl 1-Boc-2-bromoindole-3-yl acetate (7, 3.8 g, 10 mmol) and TMS-acetylene (4.1 mL, 29.5 mmol) were mixed with diethylamine (6 mL) and dimethoxyethane (6 mL).…”

Synthesis, inhibition of NO production and antiproliferative activities of some indole derivatives

“…Thus they can influence processes involving free radical-injury [19][20]. They have also been found to inhibit lipid peroxidation [21] and to possess vasorelaxant, anticoagulant, anti-inflammatory [22], antitumoral and anti-allergic [23] activities. Thus, on the basis of these evidences we wish to report herein a easy synthesis of pyrano[3,2-e]indoles 6a-b and their precursors 4a-b and 5a-b using 5-hydroxyindole as a starting material.…”

Synthesis and Pharmacological Evaluation of (Indol-3-yl)alkylamides as Potent Analgesic Agents

“…On the other hand, its pfluoro counterpart 25 revealed more significant activity: 65 ± 11 %; its ID 50 in the same experimental conditions was 0.085 ± 0.021 mmol/kg. It has been previously stated [14] that this indolylacetamide 25 was an extremely strong inhibitor of the allergically induced histamine release from peritoneal mast cells; moreover it was able to inhibit IL-4 and IL-5 biosynthesis with IC 50 values in low micromolar ranges. These mediators contribute to bronchoconstriction but also to recruitment of inflammatory leucocytes and lymphocytes in atopic allergic disease.…”