Synthesis and .ALPHA.-Adrenergic Binding Ligand Affinities of 2-Iminoimidazolidine Derivatives.

Abstract

Venous pathology may result from deficiency of the venous wall contractility. The increase in venous system pressure is due to three main factors: increase of Ca 2ϩ concentration in the smooth muscle cells, decrease of endothelial nitric oxide production and decrease of a-adrenergic receptors (a-AR) of the venous system. 1) Our research efforts to find potentially veinotonic molecules were oriented towards aadrenergic compounds, namely a 2-selective agonists, devoid of any vasoconstrictor side-effect due to a 1-AR activation, a 2-AR being relatively more abundant in veins than in arteries. 1-3) Furthermore, low lipophilicity was needed to avoid hematoencephalic resorption and thus to limit the molecules' central effects. It is also well known that imidazoline compounds enhance spontaneous mechanical activity in rat portal vein 4,5) and antagonize the relaxant effects of the K-channel openers. 4-7) Most a 2-adrenergic agonists belong to the classes of aralkylimidazoline and aryliminoimidazolidine derivatives, best represented by clonidine and moxonidine. With the structure-activity relationships of these aryliminoimidazolidine derivatives in mind, 8-11) we kept intact the 2-iminoimidazolidine fragment of the pharmacophore to preserve a good a 2-AR binding and we only modified the aromatic moiety. Among the various structures of the R moiety linked to the imino group (Chart 1) the choice was made between aliphatic moiety and aromatic moiety which could be ortho substituted. We had a special interest in benzopyranic structures because coumarin and flavonoids are usually used as phlebotomic as well as vascular protecting agents. 12-14) Chemistry The final compounds were obtained by condensation of various amines with imidazoline or imidazolidine (Chart 2) bearing adequate leaving groups in position 2 either pre-existent, as methylthio, or formed in situ as chloro. Starting from 2-imidazolidinethione, the hydriodide salt of 2methylmercaptoimidazoline was prepared by the action of iodomethane 15) and was heated with a moderate excess of a primary amine with or without solvent until the evolution of mercaptan was complete 16,17) (method 1). Starting from Nacetylimidazolidin-2-one, 18) the 2-chloro derivative formed in situ with POCl 3 17,19) was condensed with the primary amine and the acetyl protecting group was finally hydrolyzed (method 2). The initial primary amines were commercially available (series A, B) or prepared according to published procedures (series C). 20-27) The structures of all compounds were confirmed by IR, 1 H-NMR, 13 C-NMR and all final imidazolidine compounds were also confirmed by elemental analyses.

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

“…Imidazolidines are important building blocks in biologically active compounds [135][136][137][138] and carriers of pharmacologically active carbonyl compounds [139,140]. Mannich condensation of N-substituted 1,2-ethylenediamines 178 with 1 equiv.…”

C-N bond forming reactions in the synthesis of substituted 2-aminoimidazole derivatives

“…27 On the other hand, the synthesis of biologically active imidazolines, such as clonidine and indanazoline has been developed by Cussac et al through the condensation between primary amines and imidazolidin-2-ones or 2-methylsulfanyldihydroimidazoles. [28][29][30][31] Other procedures involve the condensation of amines with dihydroimidazol-3-ium-2-sulfonate 32 or with protected imidazolidine-2-thione, though the last procedure requires the use of mercury (II) chloride. 9 As part of our program to develop new procedures for the synthesis of heterocyclic systems, [33][34][35] we investigated several carbon-nitrogen bond forming reactions directed to the synthesis of 2-aminoimidazole derivatives.…”

“…Other solvents were used (EtOH, dioxane), but no reaction was observed under these conditions. Although the reaction of the unprotected 2-methylsulfanyldihydroimidazole 6 with various primary alkyl amines has been reported, 28 no reaction was obtained when 6 was treated with benzylamine or p-anisidine. Thus, the use of methylsulfanyl derivatives such as 7a allowed the amination reactions with aromatic amines under mild reaction conditions, but it required protection of the nitrogen atom of the imidazoline.…”

“…While this chemistry appears to work quite well, the alternative route of condensation of primary amines with N-acetylimidazolidin-2-one via its 2-chloro derivative formed in situ with POCl 3 only led to low to moderate yields (22-74%) of the N-acetylated imino derivatives. 28 We began by using the commercially available imidazolidin-2-one (1a) as substrate. We first tried the one-pot procedure developed by Cussac and col., in which the chloride 2a is generated in situ with POCl 3 in the presence of the amine.…”

Synthesis and conformational analysis of novel tertiary amides derived from N-[(S)-α-phenylethyl]-1,3-imidazolidine

“…Amide bond formation is one of the most often used transformations in organic synthesis, and amides are frequently employed as building blocks for the synthesis of biologically active compounds [1][2][3] such as antiinflammatory and analgesic agents, 4,5 fungicides antibiotics, parasiticides and antivirals. 6,7 The synthetic route used most frequently for amide formation involves the combination of an amine (including ammonia) with an activated carboxylic acid derivatives 8 or directly with the carboxylic acid in a reaction mediated by a coupling reagent.…”