Synthesis, saludiuretic, and antihypertensive activity of 6,7-disubstituted 1(2H)- and 3,4-dihydro-1(2H)-phthalazinones

Abstract

The synthesis of the isomeric series 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-1(2H)-phthalazinones (1 and 2) and 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-3,4-dihydo-1(2H)-phthalazinones (3 and 4), combining structural features characteristic to furosemide and hydralazine, is described, the mechanism of the formation of 1 and 2 is discussed, and their structure-activities relationships are studied. Preliminary screening in the rat shows that series 1 and 3 exhibit diuretic and saluretic activity similar to that of chlorothiazide with, however, Na+/K+ ratios more favorable than chlorothiazide and furosemide. The compounds of series 2 and 4 are practically inactive. All four series show initial antihypertensive activity lower than that of hydralazine. However, compounds 1a, 1c, and 4a show a higher activity at 8 and/or 24 h after administration and thus may offer a unique combination of a "loop" diuresis with direct long-acting peripheral vasodilating effects.

2-[(2,4,6-Trimethylbenzene)sulfonyl]phthalazin-1(2H)-one: crystal structure, Hirshfeld surface analysis and computational study

“…Phthalazin-1(2H)-one derivatives are a group of diazaheterobicycles that are noteworthy for their interesting medicinal applications. Thus, this class of compound has been reported to possess a wide variety of biological properties such as anti-diabetic (Mylari et al, 1992), anti-cancer (Menear et al, 2008), anti-inflammatory and analgesic (Pakulska et al, 2009), anti-histamine (Procopiou et al, 2011), anti-hypertensive and anti-thrombotic (Cherkez et al, 1986) activities. Some N-substituted phthalazinones have attracted attention as a result of their potential role as anti-asthmatic agents (Ukita et al, 1999), their ability to inhibit thromboxane A2 (TXA2) synthetase and to induce bronchodialation (Yamaguchi et al, 1993).…”

An Efficient Synthesis of Novel Bioactive Thiazolyl-Phthalazinediones under Ultrasound Irradiation

“…One of the most pivotal contributions of phthalazine derivatives is their antimicrobial activity. According to the literature, the most common substitution pattern of the target phthalazine skeleton is 1-,2- and 4- on the diazine part of the bicyclic system [ 10 , 11 , 12 ]. One extensive study illustrated the remarkable antifungal activity of 4-substituted-2-methylphthalazines, which as a result could be considered good lead compounds [ 13 ].…”

Synthesis of 3,4‐Dihydrobenzo[f]phthalazines via Iodine/tert‐Butyl Hydroperoxide‐Mediated Annulation Cascade of Yne‐Allenones

“…[1] Among these skeletons, substituent-diverse phthalazines represent an important structural motif commonly found in variety of natural products, pharmaceuticals, and other synthetics ( Figure 1). [2] Functional phthalazines have been found to exhibit a broad range of biological activities, such as anticonvulsant, antimicrobial, anti-inflammatory, antimycobacterial, and antitumor, etc.. [3] With these significant bioactivities, great efforts have been made to develop many reliable chemical methods for the construction of fused and functionalized phthalazines, mainly relying on conventional acid/base-mediated strategies, [4] or transition metal catalysis. [5] Despite much effort, efficient and atom-economic protocols have not been established to assemble functionalized fused phthalazines, especially metal-free version.…”

“…The yield of 4 a levelled off when the I 2 loading was further increased to 70 mol % (entry 3). Without either I 2 , H 2 O, or TBHP, the reaction did not work, indicating that these reagents are necessary for the success of this transformation (entries [4][5][6]. Decreasing the substrate ratio could promote the transformation, as the substrate ratio of 1 a and 2 a in 1:1.3 led to a remarkably higher yield of 53% (entry 7).…”