Matthew J. Tozer

A CONVENIENT STRATEGY FOR REPLACEMENT OF THE ANOMERIC HYDROXYL GROUP BY DIFLUOROMETHYL FUNCTIONALITY IN CARBOHYDRATE-DERIVATIVES

A series of carbohydrate gem-difluoroenol ethers are readily prepared by the reaction of the corresponding lactones with dibromodifluoromethane, tris(dimethylamino)phosphine and zinc. Subsequent catalytic hydrogenation provides difluoromethyl C-glycoside analogues in which the exocyclic oxygen atom has been replaced by a difluoromethylene unit.

Histamine H3 receptor antagonists

The histamine H3 receptor provides a negative feedback mechanism for the release and synthesis of histamine. On non-histaminergic neurones the H3 receptor regulates the release of many other neurotransmitters. Blockade of stimulated H3 receptors results in the release of endogenous neurotransmitters. Possible indications for a histamine H3 receptor antagonist include attention-deficit hyperactivity disorder (ADHD), epilepsy, Alzheimer’s disease, narcolepsy, epilepsy, obesity, schizophrenia and respiratory diseases such as allergic rhinitis. Current H3 receptor antagonists fall into two classes, imidazole-containing and non-imidazole compounds, with there being far more examples of the former. The development of imidazole antagonists has produced the compound GT-2331 (Perceptin™, Gliatech), which has successfully passed early stage clinical trials. The search for non-imidazole antagonists is a burgeoning area, which may profit from the recent cloning of a human H3 receptor.

THE SYNTHESIS OF DIFLUOROMETHYLENE-LINKED C-GLYCOSIDES AND C-DISACCHARIDES

Novel difluoromethylene linked C-glycosides and C-disaccharides were prepared by intermolecular addition of nucleophilic and electrophilic radicals to carbohydrate gem-difluoroenol ethers.

4-Chlorobenzyl sulfonamide and sulfamide derivatives of histamine homologues: The design of potent histamine H3 receptor antagonists

4-Chlorophenylmethanesulfonamide and (4-chlorobenzyl)sulfamide derivatives of histamine homologues were prepared and found to be potent and selective histamine H3 receptor antagonists. High receptor affinity and low differences in the data from the bioassays were achieved with the imidazol-4-ylbutyl analogues.

From histamine to imidazolylalkyl-sulfonamides: The design of a novel series of histamine H3-receptor antagonists

Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.

CCK2 receptor antagonists containing the conformationally constrained phenylalanine derivatives, including the new amino acid Xic

The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2) over CCK(1) were observed for compounds 15a-e. The in vitro profile of the analogue containing the Nic residue (15d) was identical to that of compound 2, whereas the alternative conformational constraints resulted in a significant loss of affinity. The apparent advantage of Nic in the context of these CCK(2) ligands was subsequently demonstrated to be statistically significant.

Synthesis of conformationally constrained phenylalanine analogues via 7-, 8- and 9-endo Heck cyclisations

The novel conformationally constrained phenylalanine analogues 2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylic acid (Sic) 1, 1,2,3,4,5,6-hexahydro-3-benzazocine-2-carboxylic acid (Hic) 2 and 2,3,4,5,6,7-hexahydro-1H-3-benzazonine-2-carboxylic acid (Nic) 3 have been synthesised from commercially available 2-iodobenzyl alcohol in 20, 18 and 22% overall yield respectively via 7-, 8- and 9-endo Heck cyclisations.

Synthesis and structural analysis of dehydrophenylalanine cyclophanes

The syntheses and structures of three cyclophanes containing two (Z)-dehydrophenylalanine residues are reported; the length of the tethers between the two amino acid residues is easily altered and changing this parameter has a significant effect on the solid state structures of the cyclophanes.

ω-(Imidazol-4-yl)alkane-1-sulfonamides: a new series of potent histamine H3 receptor antagonists

Abstract ω-(1 H -Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H 3 receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1 H -imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide ( 16 ). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides.

A convenient method for replacement of the anomeric hydroxy group in carbohydrates by difluoromethyl functionality

Difluoromethylenation of carbohydrate lactones followed by catalytic hydrogenation provides a concise sequence for the title transformation.