Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 µM) and partial PPARγ agonist (EC50=0.25 µM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

A new class of ammonium ylid for [2,3]-sigmatropic rearrangement reactions: ene-endo-spiro ylids.

The first examples of sigmatropic rearrangements of ene-endo-spirocyclic, tetrahydropyridine-derived ammonium ylids are reported. Thus, spiro[6.7]-ylids rearrange primarily by a [2,3]-pathway, whereas the analogous [6.6]-ylids rearrange by [1,2]- and [2,3]-mechanisms in roughly equal proportions. This method serves as a rapid entry to the core of a range of alkaloids bearing a pyrrolo[1,2-a]azepine or octahydroindolizidine nucleus.

First efficient and general copper-catalyzed [2,3]-rearrangement of tetrahydropyridinium ylids.

The factors affecting the copper-catalyzed rearrangement of ammonium ylids derived from tetrahydropyridines and diazoesters have been examined,and the first examples of high-yielding metal-catalyzed [2,3]-sigmatropic rearrangements of a wide range of such ylids are reported. The nature of the alpha-substituent in the diazo component of the reaction has a dramatic effect upon the yields of the reaction, with electron-withdrawing substituents enhancing the yield of the reaction. [reaction: see text]

Asymmetric [2,3]-rearrangement of glycine-derived allyl ammonium ylids.

The first examples of highly enantioselective [2,3]-sigmatropic rearrangements of acyclic allylic ammonium ylids are reported. Thus, a range of N-{2'-[(N'-allyl-N',N'-dialkyl)ammonium]}acetyl camphor sultams undergo rearrangement at 0 degrees C in DME solution with high diastereofacial control (up to 99:1 dr) to give allylglycines in generally high yield. The power of the method has been demonstrated in a rapid and efficient synthesis of (R)-allyl glycine.