Kevin John Merchant

Potassium trimethylsilanolate mediated hydrolysis of nitriles to primary amides

Abstract Treatment of nitriles with potassium trimethylsilanolate under mild anhydrous conditions readily yields the corresponding primary amides after a simple aqueous workup.

Quinuclidine-based NK-1 antagonists I: 3-benzyloxy-1-azabicyclo[2.2.2]octanes

Abstract A series of 3-benzyloxy-derivatives of CP-96,345 has been evaluated and found to have significant affinity for the human NK1 receptor. 3,5-Disubstitution of the benzyl ether has been identified to be essential for high affinity.

Serine derived NK1 antagonists. 1: The effect of modifications to the serine substituents.

A series of novel serine derived NK1 antagonists is described. The effect of variations in the N-benzyl, O-benzyl and serine groups are used to define the elements which are necessary for binding.

Non-basic ligands for aminergic GPCRs: the discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders.

Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.

Synthesis of homochiral ketones derived from L-tryptophan : potent substance P receptor antagonists

Abstract The synthesis in 36% overall yield of (S)-2-amino-5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl-3-pentanone, the precursor to a novel class of substance P antagonists, is described.

The synthesis of 5- and 6-substituted quinuclidine-3-carboxylic esters: intermediates for novel muscarinic ligands

Quinuclidine-3-carboxylic esters bearing 5-hydroxy, 5-methyl and 6-methyl substituents are of interest as precursors to novel muscarinic ligands. All diastereoisomers of these disubstituted quinuclidines have been prepared, in each case using an appropriately substituted quinuclidin-3-one as the key intermediate. The keto ester 5a was obtained stereoselectively, either by intramolecular alkylation of a bromoacetylpiperidine, or by Dieckmann cyclisation of the differentially protected piperidine 18. 5-Methylquinuclidin-3-one was formed as a single isomer 24b by Dieckmann cyclisation. Piperidine-2,4-diester 33, in contrast, yielded a mixture of 2,5-disubstituted quinuclidine isomers 34 on cyclisation. Elaboration of the quinuclidinones gave the required esters, in several cases with high stereoselectivity. The stereochemical outcome of the Dieckmann cyclisation has been rationalised on the basis of molecular mechanics calculations.