Peter Kane

Inhibition of the tissue factor/factor VIIa complex — Lead optimisation using combinatorial chemistry

Following a high throughput screen (HTS) for the inhibition of the tissue factor/factor VIIa complex and the identification of a number of original hits a lead optimisation programme was initiated ...

A linker for amidines in solid phase synthesis

Abstract A range of linkers for the important amidine pharmacophore, cleavable using acid or light have been developed for use in library synthesis. The utility of these linkers is demonstrated by the solid phase synthesis of the Novartis (ex-Ciba) phase II compound CGS-25019C.

The Bohlmann–Rahtz route to functionalised pyridine scaffolds and their use in library synthesis

The Bohlmann-Rahtz reaction has been used to prepare 2,3,6-trisubstituted pyridines suitable for use in library synthesis. The synthesis of piperidine substituted nicotinic acid derivative 9 has been optimised and carried out on a large scale to give ca. 500 g of scaffold which was used in the generation of the pyridine library 11.

Solid‐Phase Synthesis of 2,4,6‐Triaminopyrimidines

A library of various 2,4,6-triaminopyrimidines was prepared by a solid-phase approach with a ring-activation/amination process (see scheme). Regio- and chemoselectivity could be controlled by a careful choice of leaving groups. The use of high temperature (140 °C) and neat amines show the advantages of solid-phase synthesis, since high purities and acceptable yields of substituted pyrimidines were obtained.

The preparation and utility of ethyl 2-(5′-O-t-butyldimethylsilyl-2′,3′-O-isopropylidene-β-D-ribofuranosyl)propenoate as a key intermediate for C-nucleoside synthesis

We describe a short route from D-ribose to compounds (Ib) and (Ic), which can be converted into the showdomycin derivative (IIb) and certain novel C-nucleosides, A key step in this synthetic sequence involved a stereoselective cyclisation facilitated by the use of phenylselenenyl chloride.

A new protecting-group strategy for indoles

The 2-phenylsulfonylethyl group is a useful alkyl protecting group for nitrogen during indole synthesis; it is readily removed from the indole nitrogen under basic conditions.

N–H Insertion reactions of rhodium carbenoids. Part 3. The development of a modified Bischler indole synthesis and a new protecting-group strategy for indoles

A modified version of the Bischler indole synthesis has been developed in which the key step is the N–H insertion reaction of rhodium carbene intermediates derived from α-diazo-β-ketoesters with anilines. Thus N-methylanilines 1 react with diazoketoesters 2 in the presence of dirhodium(II) acetate to give (N-arylamino)ketones 3, cyclisation of which using boron trifluoride–ethyl acetate or acidic ion exchange resin gives the indoles 4. In order to extend this method to the synthesis of N-unsubstituted indoles, a new protecting group strategy for indoles was developed. In this, anilines are reacted with α,β-unsaturated-esters or -sulfones to give the conjugate addition products 6 and 9, cyclisation of which gives indoles 8 and 11. The N-(2-ethoxycarbonylethyl)- and -(2-sulfonylethyl)- protecting groups are readily removed from indoles 8 and 11 by treatment with base.

the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.

The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position

A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds with low nanomolar potency and good selectivity for thrombin.

Amidine protection for solution phase library synthesis

The application of 4-methoxybenzyl-4-nitrophenylcarbonate as a reagent for the N-protection of amidinonaphthol has been demonstrated. The facile introduction of the 4-methoxybenzyloxycarbonyl group and the mildness of the deprotection conditions make this reagent well suited for the multiparallel solution phase synthesis of substituted benzamidines.