93537-38-3Relevant academic research and scientific papers
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
Le Bihan, Ga?lle,Rondu, Frédéric,Pelé-Tounian, Agnès,Wang, Xuan,Lidy, Sandrine,Touboul, Estéra,Lamouri, Aazdine,Dive, Georges,Huet, Jack,Pfeiffer, Bruno,Renard, Pierre,Guardiola-Lema?tre, Béatrice,Manéchez, Dominique,Pénicaud, Luc,Ktorza, Alain,Godfroid, Jean-Jacques
, p. 1587 - 1603 (2007/10/03)
Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl- 4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H- imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of α2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4',5'-dihydro-1'H-imidazol-2'- yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro- 1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 μmol/kg) as after ip administration and appears as a good candidate for clinical investigations.
Nucleophilic Addition to Substituted 1H-4,5-Dihydroimidazolium Salts
Salerno, Alejandra,Ceriani, Vanina,Perillo, Isabel A.
, p. 709 - 716 (2007/10/03)
1H-4,5-Dihydroimidazolium salts 1 react readily with nucleophilic reagents originating cyclic products which may be stable or become transformed into acyclic compounds maintaining the structural ethylenediamine unit. With methylmagnesium iodide compound le affords the expected imidazolidine, but in the case of substituted 1-aryl-3-methyl-2-phenyl salts 1b-d the N-aryl-N'-methylethylenediamines 3b-d and acetophenone (4) were isolated, the process representing the transfer of the C-2 unit to a nucleophilic carbon. With alkaline cyanides salts 1 react efficiently affording α,α-diaminonitriles 5. In these compounds the cyano group may be readily substituted by nucleophiles (hydroxyl anion, species with nucleophilic carbon and reagents that act by hydride ion transfer), in a way similar to the salts but with better yields.
Reduction of Substituted 1H-4,5-Dihydroimidazolium Salts
Salerno, Alejandra,Ceriani, Vanina,Perillo, Isabel A.
, p. 1725 - 1733 (2007/10/02)
Reactions of several substituted 1H-4,5-dihydroimidazolium salts 1 with nucleophilic and electrophilic reducing agents acting via hydride transfer were explored.Reaction of compounds 1 with lithium aluminum hydride in THF afforded the corresponding imidazolidines 2.When alkaline borohydrides (sodium borohydride, potassium borohydride, sodium cyanoborohydride) in ethanol at room temperature were used, partial or total over-reduction of compounds 2 leading to N,N,N'-trisubstituted ethylenediamines took place on occasion.Results may be explained taking into account that reductive cleavage of 2 proceeds via a stabilized iminium ion present in protic solvents.Treatment of compounds 1 with an excess of borane in THF afforded the corresponding imidazolidines 2 or their borane complexes, according to the substituent type.
