Novel antiasthmatic agents with dual activities of thromboxane A2 synthetase inhibition and bronchodilation. 1. 2-[2-(1-Imidazolyl)alkyl]-1(2H)-phthalazinones

Abstract

A number of 4-substituted 2-[omega-(1-imidazolyl)alkyl]-1(2H)-phthalazinones were synthesized in order to develop agents possessing both thromboxane A2 synthetase inhibitory and bronchodilatory activities. The pharmacological evaluation of these compounds disclosed that they have both activities to various extents. Both activities were slightly dependent on the length of the 2-substituents and largely affected by the nature of the 4-substituents. Compounds bearing phenyl and thienyl groups exhibited relatively high and well-rounded activities. Among these compounds, 12j and 15f were found to be the most effective agents having well-rounded activities in vitro and in vivo. Introduction of a carboxyl group reduced both activities contrary to our expectation. 4-(3-Pyridyl)phthalazinone 18b was of particular interest because of unexpectedly high in vivo activities in spite of an absence of significant in vitro activities.

Near-monodisperse, catalytically active, imidazole-containing homooligomers: Synthesis by group transfer polymerization and solution characterization

“…In the first approach, imidazole was reacted with excess ethylene carbonate in the bulk at 80°C for 24 h and the product was distilled under reduced pressure. 14,15 In the second approach, imidazole was reacted with excess ethylene carbonate in toluene solution at 110°C until evolution of carbon dioxide ceased 16 ; a two-phase system resulted, toluene was removed by decantation, the bottom phase was treated with concentrated hydrochloric acid to decompose ethylene carbonate and neutralized with potassium carbonate. 2-imidazol-1-yl-ethanol was finally extracted with chloroform and recovered after solvent evaporation.…”

Synthesis of 2-[2-(1-Imidazolyl)ethyl]-4-phenylcycloalka[g]phthalazin-1(2H)-ones as Thromboxane A2 Synthase Inhibitors

“…1 H NMR spectra were recorded on a Varian UnityPlus 300 MHz spectrometer, IR spectra were obtained on an ATI Mattson FTIR instrument. Elemental analyses were performed at the Institute of Physical Chemistry (Microanalytical Laboratory), University of Vienna.…”

“…4-Arylphthalazin-1(2H)-ones bearing an imidazolylethyl substituent at N-2 have been found to be excellent inhibitors of thromboxane A 2 (TXA 2 ) synthase, and their potential usefulness as novel antiasthmatic drugs has been pointed out [1] . 2-[2-(1-Imidazolyl)ethyl]-4-phenylphthalazin-1(2H)-one (1) may be regarded as a lead compound in this class of agents and it has been subjected to various modifications, mainly focused on the side chain at position 2 as well as the 4-aryl substituent, in order to optimize biological activity [1][2][3][4][5][6] .…”

“…2-[2-(1-Imidazolyl)ethyl]-4-phenylphthalazin-1(2H)-one (1) may be regarded as a lead compound in this class of agents and it has been subjected to various modifications, mainly focused on the side chain at position 2 as well as the 4-aryl substituent, in order to optimize biological activity [1][2][3][4][5][6] . So far, little attention has been paid to the steric and lipophilic properties of the benzene part of the phthalazine skeleton in this context [3,4] .…”

Design and Synthesis of New Phthalazinone Derivatives Containing Benzyl Moiety with Anticipated Antitumor Activity

“…22) Phthalazin-1-(2H)-ones bearing a substituent at 4-position represent key intermediates in the synthesis of various compounds with high interesting pharmacological properties such as the blood platelet aggregation inhibitor 23) MV-5445 [1-(3-chloroanilino)-4-phenylphthalazine] which has been found to be a selective phosphodiesterase V inhibitor 24) or the thromboxane A 2 synthetase inhibitor or bronchodilator, 2-[2-(1-imidazolyl)-ethyl]-4-[3-pyridyl] phthalazine-1-(2H) one. 25) During the last two decades there is a growing interest in the synthesis of several phthalazines as promising drug candidates for the treatment of cancer. The latter research efforts have led to the discovery of several leading phthalazines with different cellular and enzymatic targets.…”