Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type II Diabetes. 1. Synthesis and Biological Activities of N-Benzyl-N ‘-(arylalkyl)-2-(4‘,5‘-dihydro-1‘H-imidazol-2‘-yl)piperazines

Abstract

The physiopathology of non-insulin-dependent diabetes mellitus is associated with a dysfunction in the regulation of insulin secretion. The alpha 2-adrenoceptors have been reported to be involved in this alteration, although alpha 2-antagonists containing an imidazoline ring may stimulate insulin secretion independently of alpha 2-adrenoceptor blockage. Recently, a new "imidazoline-binding site" involved in the control of K(+)-ATP channels in the B cell has been proposed. In the course of searching for new antidiabetic agents, 1-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines, 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-alkylpiperazines, and 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines have been designed and evaluated as potential adrenoceptor antagonists. Pharmacological evaluation was performed in vivo using glucose tolerance tests performed on a rat model of type II diabetes obtained by injection of a low dose (35 mg/kg) of streptozotocin (STZ). For some compounds, binding experiments were performed on alpha 2 adrenoceptors and I1 and I2 imidazoline-binding sites. The biological and physicochemical data have been combined with molecular modeling studies to establish structure-activity relationships. The most active compound was 1-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)- 4-methylpiperazine (7f); intraperitoneal administration (100 mumol/kg) of 7f strongly improved glucose tolerance in STZ diabetic rats. This effect seemed at least partly mediated by a significant increase of insulin secretion. Other compounds of the same family (7b, 16f, 23b) have also shown potent activity. We found no correlation between in vivo antihyperglycemic properties and in vitro affinities for alpha 2-adrenoceptors or I1, and I2 binding sites. These compounds can be considered as antihyperglycemic agents potentially useful for treatment of type II diabetes and are currently under complementary investigation.

Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type II Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4‘,5‘-dihydro-1‘H- imidazol-2‘-yl)piperazines and Isosteric Analogues of Imidazoline

“…16,17 None of the compounds of this series presented a potent affinity for adrenoreceptors and I-PBS. 16 Moreover PMS 812 was considered as a very efficient glucose-independent insulin secretagogue acting through a novel imidazoline site, linked to K + channels, and distinct from I 1 -and I 2 -PBS. 18 In the continuation of this previous work, 16 we report here the synthesis and the biological evaluation of 1,4-dialkyl-, 1,4-dibenzyl-, and 1-alkyl-4-benzyl(or phenyl)-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine derivatives.…”

“…14,15 In a previous paper, 16 we described the syntheses and pharmaceutical evaluation of new antihyperglycemic 1,4-disubstituted-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)-piperazines having the following general formula:…”

Structure–activity relationships on adrenoceptors and imidazoline-preferring binding sites (I 1,2 -PBSs). Part 1: weak intramolecular H-bond and conformational flexibility in a new I 1 -PBS-selective imidazoline analogue, trans 1-(4′,5′-dihydro-1′ H -imidazol-2′-yl)methyl-2-hydroxyindane (PMS 952)

“…10 The deprotection has been occured during the treatment of the reaction from ester to imidazoline. 7 …”

“…7 The short range of pK a values around 8 units whatever the molecular skeleton of the analogue (here with an additional spacer that eliminates all electronic in¯uences) nulli®es a priori the in¯uence of this factor as a determinative parameter on the variations of the biological activity in an homogeneous series. Two other factors can be taken into account: (i) the local pH inside the site of interaction is unknown and assumed to be constant and (ii) if the imidazoline nitrogen is protonated, the positive charge is probably counterbalanced by electrostatic interaction with the carboxylate of an 0968-0896/00/$ -see front matter # 2000 Elsevier Science Ltd. All rights reserved.…”

Microwave-assisted facile synthesis of 2-substituted 2-imidazolines

“…Moreover 2-substituted imidazolines are synthetically important due to their use as a synthetic intermediates 1 , catalysts 2 , chiral auxiliaries 3 , chiral catalysts 4 and ligands for asymmetric catalysis 5 in various synthetic reactions. To date, there are several synthetic methods for 2-imidazolines starting mainly from aldehydes and ethylenediamine with NBS.…”