Cardiotonic agents. 7. Prodrug derivatives of 4-ethyl-1,3-dihydro-5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H-imidazol-2-one

Abstract

The cardiotonic agent 4-ethyl-1,3-dihydro-5-4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one (1) was found to have low bioavailability when administered orally to rats and dogs. A series of N-acyl derivatives, an underutilized prodrug of acidic NH compounds, has been synthesized and tested for their ability to improve the oral bioavailability of 1. Reaction of the monosodium salt of 1 with various anhydrides afforded the N-1 monoacylimidazolones with surprisingly high regioselectivity. In addition to the prodrugs, acylation of 1 with propionic or phenylacetic anhydride led to the novel 3H-pyrrolo[1,2-c]imidazole-3,5(2H)-diones 6. The prodrugs showed a significant increase in the partition coefficients with a minor decrease in the aqueous solubility. The benzoyl derivative 4b exhibited the highest stability in both pH 1.5 and 7.4 buffer solutions. Further evaluation of 4b showed rapid conversion to 1 in canine plasma (t1/2 = 38 min), and human plasma (t1/2 = 10 min). Oral studies indicated that the bioavailability of 4b was increased to greater than 75% (compared to less than 20% for 1), and hemodynamic studies demonstrated that the selective inotropic profile of 1 was retained.

Iron-Catalyzed Synthesis of 2H-Imidazoles from Oxime Acetates and Vinyl Azides under Redox-Neutral Conditions

“…2 H -Imidazoles are important motifs found in a broad spectrum of biologically active natural products as well as in organic synthesis . They could be used as chiral auxiliaries for organic synthesis reactions , and for detection of a diradical intermediate .…”

Methods for the synthesis of 1-substituted 1H-imidazol-2(3H)-ones

“…9 The interaction of the latter with various anhydrides produced N-monoacylimidazolones 1 with high regioselectivity. Trace amounts of diacetyl derivatives 20 were detected along with the major products 1.…”

“…2 Some representatives of 1-substituted imidazolones were found to enhance memory, 3 as well as were characterized with antioxidant, 3,4 vasodilatory, 4 angiotensive, 5 cytotoxic, 6 herbicidal, and insecticidal 7,8 activity. Among compounds of this type there are also growth regulators, 7 inotropic agents, 9 anticonvulsants, 4 dopamine receptor antagonists, 10,11 agonists of various receptors, 2,12 including CGRP 13 and prostaglandin receptors, 4 inhibitors of tyrosine phosphatase 14 and renin, 5 biosynthetic precursors to the cytostatic agelastatin alkaloids, 15,16 as well as stains used for human epithelial cells 17 (Fig. 1).…”

C−X (X = N, O) Cross-Coupling Reactions Catalyzed by Copper-Pincer Bis(N-Heterocyclic Carbene) Complexes

“…The N-arylazoles and biarylethers are among the most commonly found motifs in pharmaceuticals, biologically active molecules, crop-protection chemicals, and material science. A huge number of drugs contain N-arylimidazole moieties including cyclic AMP phosphodiesterase inhibitors (Sircar et al, 1987; Venuti et al, 1988; Güngör et al, 1992; Martinez et al, 1992; Sawanishi et al, 1997), thromboxane synthase inhibitors (Iizuka et al, 1981; Martinez et al, 1992; Cozzi et al, 1993; Nicolaï et al, 1993), topical antiglaucoma agents (Lo et al, 1992), and cardiotonic agents (Hagedorn et al, 1987; Erhardt et al, 1989; Shaw et al, 1992). In this regard, transition-metal catalyzed C-heteroatom coupling reactions have become one of the most important areas in modern chemical synthesis.…”