hydrogen and the -NCX group could be through the orbitals of the C=X bond. However, this formulation leaves unanswered the fact that only HNCO and HNCS are detected in the products, although under the conditions of our analysis, namely, at least 25% decomposition and in a 10-cm ir gas cell, this could be accounted for if the rate constant of isomerization of these species is at least twenty times larger as that for elimination. We plan to do more work along these lines and to extend the investigation to the isoselenocyanates.An indication of the degree of polarity of the reaction is obtained from Table VI where a similar effect of amethylation on rate is observed for isocyanates and isothiocyanates suggesting identity of mechanism. The absolute magnitude of this effect, although com-parable with that found in the acetates, is much less than in the case of alkyl halides, a reaction regarded as quasiheterolytic.19Experimental Section An all-glass apparatus of conventional design was used. The reaction vessel was a cylinder of about 380-ml capacity and fitted with a glass-diaphragm gauge which allowed the kinetics to be followed manometrically. The temperature of the fumance was kept constant within 0.2°b y means of an RT5 Mk.2 temperature controller from Associated Electrical Industries, England.Reagents.-Isopropyl and ieri-butyl isocyanates were laboratory reagents from K & K Laboratories, Inc., that had been (19) A. Maccoll, Chem. Rev,, 69, 32 (1969).
This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.
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