4-Benzylamino-1-chloro-6-substituted Phthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

Abstract

We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the 6-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.

Heteropoly Acid in Ionic Liquid - An Efficient Catalyst for the Preparation of 2H-Indazolo[2,1-b]Phthalazine-Triones

“…In order to show the general applicability of the protocol, we have applied this catalytic system for the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives from several types of aldehydes. Aromatic aldehydes carrying either electron donating or withdrawing substituents afforded high product yields with high purity ( 4 with respect to the amounts of the catalysts used, reaction times and yields of the products ( Table 4). Comparison of Keggin type heteropoly acid with these catalysts for this reaction show that activity of HTP/[bmim]BF 4 seems to be higher than or equal with other known catalysts ( Table 4).…”

“…Phthalazine derivatives were reported to possess vasorelaxant [2], cardiotonic [3], and anticonvulsant [4], activities. Therefore, a number of methods have been reported in the literature for the synthesis of phthalazine derivatives [4][5][6][7][8][9][10][11]. Unfortunately, many of these processes suffer from one or other limitations such as harsh reaction conditions, low product yields, tedious workup procedures, relatively long reaction times, and cooccurrence of several side products, and difficulty in recovery and reusability of the catalysts.…”

An Efficient Three Component Synthesis of 1H-Indazolo[2, 1-b]phthalazine-triones Catalyzed by Orthophosphoric Acid in Water-Phenol System

“…Amongst, nitrogen heterocyclic containing a phthalazine moiety was reported to possess anticonvulsant 10 , cardiotonic 11 , vasorelaxant 12 antimicrobial 13 , anti-inflammatory 14 , antifungal 15 and anticancer 16,17 activities. Newly, three-RESEARCH ARTICLE component reactions of dimedone (5,5- 23 , N-halo sulphonamides 24 , silica supported poly phosphoric acid 25 , 26 Mg(HSO 4 ) 2 , phosphor sulfonic acids 27 , nano silica sulphuric acid 28 , sulfonated polyethylene glycol 29 and boron sulfonic acid 30 .…”

Ionic Liquid 4-(3-Methyl-1-imidazolio)-1-butanesulfonic Acid Hydrogen Sulfate-catalyzed Synthesis of Phthalazinetrione Derivatives

“…Heterocycles containing the phthalazine moiety show some pharmacological and biological activities [3]. Phthalazine derivatives have been reported to possess anticonvulsant [4], cardiotonic [5], vasorelaxant [6], cytotoxic [7], antimicrobial [8], antifungal [9], anticancer [10], and anti-inflammatory activities [11]. In addition, these compounds show good promise as new luminescence materials and fluorescence probes [12].…”