Synthesis and evaluation of new phosphonated δ-lactam and glutarimide derivatives as angiotensin converting enzyme inhibitors

An efficient synthesis of new γ,δ-insaturated δ-lactam and glutarimide derivatives bearing a phosphonomethyl group from a common allylphosphonate precursor is described. Our approach is based on a two-step procedure involving the preparation of phosphonated-1,5-ketoester and −1,5-diester followed by an amidation–heterocyclization sequence. The first step proceeds via Michael's addition of ethyl acetoacetate and diethyl malonate on an allylphosphonate starting material. The second step consists of a base-promoted intramolecular amidation-cyclization sequence with primary amines, which accounts for the construction of δ-lactams and glutarimide skeletons. We performed the evaluation of angiotensin I-converting enzyme (ACE) inhibition using an in vitro enzyme assay on six new compounds. Five compounds showed potent ACE inhibitory activity, with IC₅₀ values ranging from 0.02 to 0.27 mg/ml. Compared with Captopril, used as a reference drug, two new glutarimide derivatives exhibited higher efficiency ACE inhibition activity.     

Synthetic Receptors with Micromolar Affinity for Chloride in Water

A water-soluble coordination cage was obtained by reaction of Pd(NO₃)₂ with a 1,3-di(pyridin-3-yl)benzene ligand featuring a short PEG chain. The cavity of the metal-organic cage contains one nitrate anion, which is readily replaced by chloride. The apparent association constant for chloride binding in buffered aqueous solution is K_a=1.8(±0.1)×10⁵ M⁻¹. This value is significantly higher than what has been reported for other macrocyclic chloride receptors. The heavier halides Br⁻ and I⁻ compete with binding or self-assembly, but the receptor displays very good selectivity over common anions such as phosphate, acetate, carbonate, and sulfate. A further increase of the chloride binding affinity by a factor of 3 was achieved using a fluorinated dipyridyl ligand.     

How Fast Is the Bandit?

Abstract

In this article we investigate the rate of convergence of the so-called two-armed bandit algorithm. The behavior of the algorithm turns out to be highly non standard: no central limit theorem, possible occurrence of two different rates of convergence with positive probability.     

Minimal arithmetic thickness connecting discrete planes

While connected arithmetic discrete lines are entirely characterized, only partial results exist for the more general case of arithmetic discrete hyperplanes. In the present paper, we focus on the three-dimensional case, that is on arithmetic discrete planes. Thanks to arithmetic reductions on a vector , we provide algorithms either to determine whether a given arithmetic discrete plane with as normal vector is connected, or to compute the minimal thickness for which an arithmetic discrete plane with normal vector is connected.     

An uncountable family of nonorbit equivalent actions of

For each , we construct an uncountable family of free ergodic measure preserving actions of the free group on the standard probability space such that any two are nonorbit equivalent (in fact, not even stably orbit equivalent). These actions are all ``rigid' (in the sense of Popa), with the IIfactors mutually nonisomorphic (even nonstably isomorphic) and in the class

     

A measurable-group-theoretic solution to von Neumann’s problem

We give a positive answer, in the measurable-group-theory context, to von Neumann’s problem of knowing whether a non-amenable countable discrete group contains a non-cyclic free subgroup. We also get an embedding result of the free-group von Neumann factor into restricted wreath product factors. D. Gaboriau’s research was supported by CNRS. R. Lyons’ research was supported partially by NSF grant DMS-0705518 and Microsoft Research.     

Local time and first return time for periodic semi-flows

We study Z^d-periodic semi-flows, which are versions in continuous time of Z^d-extensions of dynamical systems. These systems are defined by an underlying dynamical system, a step time (the time to wait before the system makes a move), and a step function (the displacement in Z^d at each step). We are interested in two statistics related to these semi-flows: the local time, i.e., the time spent in some subset, and the first return time to the origin. We get some partial results under spectral conditions on the transfer operator of the underlying dynamical system. If the underlying dynamics is Gibbs–Markov, and under additional constraints on the step time and step function, we get distributional asymptotics for the local time, and an equivalent of the tail of the first return time.     

Criteria of algebraic independence with multiplicities and interpolation determinants

We generalize Gel'fond's criterion of algebraic independence by taking into account the values of the derivatives of the polynomials, and show how the new criterion applies to proving results of algebraic independence using interpolation determinants. We also establish a new result of approximation of a transcendental number by algebraic numbers of bounded degree and size. It contains an earlier result of E. Wirsing and also a result announced by A. Durand.

     

Aitken's acceleration of the Restricted Additive Schwarz preconditioning using coarse approximations on the interface

An enhancement of the restricted Additive Schwarz (RAS) preconditioning, based on the Aitken's acceleration of the convergence of the Schwarz method, is proposed. Its numerical performance is compared with the RAS preconditioning on the two dimensional Helmholtz problem.     

Symplectic hypersurfaces in the complement of an isotropic submanifold

Using Donaldson's approximately holomorphic techniques, we construct symplectic hypersurfaces lying in the complement of any given compact isotropic submanifold of a compact symplectic manifold. We discuss the connection with rational convexity results in the K?hler case and various applications. Received: 9 January 2001 / Published online: 19 October 2001