Duncan Bruce Judd

A convenient procedure for the solution phase preparation of 2-aminothiazole combinatorial libraries

Abstract A convenient procedure for the solution phase preparation of 2-aminothiazole combinatorial libraries is described. The library preparation is simple, practical, and effective, generating compounds based around a known pharmacophore in high yield and purity. Furthermore, the procedure tolerates a diverse range of functionality in its substrates and is notable in allowing the preparation of compounds containing both free acids and bases without recourse to protection.

A generic approach for the catalytic reduction of nitriles

The scope of nickel boride mediated reduction of nitriles has been extended further to allow the preparation of Boc protected amines via a mild catalytic process. It is noteworthy that the toxicity of this procedure is greatly reduced due to its catalytic nature in nickel(II) chloride used in combination with excess sodium borohydride. The protocol is marked by its resilience towards air and moisture and hence an easy and general practical protocol.

Neuroprotective actions of GR89696, a highly potent and selective κ‐opioid receptor agonist

1 The effect of a novel, highly potent and selective κ‐opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2 In the Mongolian gerbil model, administration of GR89696 (3 to 30 μg kg−1, s.c.), immediately before and at 4h after insult, produced a dose‐dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7‐min bilateral carotid occlusion. Similar effects were obtained with two other κ‐agonists, GR86014 (1 mg kg−1, s.c.) and GR91272 (1 mg kg−1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mg kg−1, s.c. Repeated post‐treatment with GR89696 (100 μg kg−1, s.c.) or GR44821 (10 mg kg−1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia‐induced neurodegeneration. 3 In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 μg kg−1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 μg kg−1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4 The results indicate that the potent κ‐opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Convenient synthesis of protected primary amines from nitriles

Abstract Investigations into the use of nickel chloride and sodium borohydride for the reduction of nitriles showed the secondary amine dimers to be the major products under normal conditions. The addition of a suitable trapping agent, such as di-tert-butyl dicarbonate, allowed the isolation of the protected primary amines.

Trichlorophenol (TCP) sulfonate esters: A selective alternative to pentafluorophenol (PFP) esters and sulfonyl chlorides for the preparation of sulfonamides

2,4,6-Trichlorophenol (TCP) sulfonate esters undergo effective aminolysis under conventional heating and microwave irradiation; the reactivity of these species is such that chemoselective transformations of PFP sulfonate esters can be achieved.

SOLID PHASE SYNTHESIS OF 5-AMINOPYRAZOLES AND DERIVATIVES

Abstract The development of a novel solid phase synthesis of some 5-aminopyrazoles and derivatives is described. Reaction of hydrazines with solid supported β-keto-nitrile (1) affords 5-aminopyrazoles (2) the amino group of which is readily acylated or sulphonylated. Generation of the solid supported β-keto-nitrile (1) is non trivial and represents a key step in the overall synthesis.

Observations on the reactivity of pentafluorophenyl sulfonate esters

Studies on displacement reactions of alkyl pentafluorophenyl (PFP) sulfonates with amines are consistent with a mechanism involving an elimination-addition pathway; comparisons between the reactivity of PFP-sulfonates with sulfonyl chlorides and PFP-sulfonates with PFP-esters are also presented.