A series of new 2-phenylbenzothiazoles has been synthesized on the basis of the discovery of the potent and selective in vitro antitumor properties of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (8n; GW 610, NSC 721648). Synthesis of analogues substituted in the benzothiazole ring was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. Compounds were evaluated in vitro in four human cancer cell lines, and compound 8n was found to possess exquisitely potent antiproliferative activity (GI(50) < 0.1 nM for MCF-7 and MDA 468). Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. Structure-activity relationships established that the compound 8n stands on a pinnacle of potent activity, with most structural variations having a deactivating in vitro effect. Mechanistically, this new series of agents contrasts with the previously reported 2-(4-aminophenyl)benzothiazoles; compound 8n is not reliant on induction of CYP1A1 expression for antitumor activity.

The development and implementation of a robust process for the manufacture of metric ton quantities of the R2δ ligand imagabalin hydrochloride 4 is described. Key aspects of the synthesis include a chromatography-free, two-step telescoped process to prepare a mixture of Z:E-enamides 7 followed by a robust asymmetric hydrogenation with the rhodium-trichickenfootphos catalyst 8 to install the (3S)-stereocentre. Hydrolysis of the acetamide and ester protecting groups in the final step followed by isolation and recrystallisation of the hydrochloride salt gave high purity 4 in 40À50% overall yields.

The development of a highly efficient two-step process for the manufacture of the α2δ-ligand imagabalin hydrochloride 1 is described in 50% overall yield from (R)-3-methylhexanoic acid 2. Key aspects of this route include the development of a one-pot process for the synthesis of β-enamine ester 7 and its subsequent diastereoselective hydrogenation with a Ru-(S)-BINAP catalyst. The use of a combination of TFA, ammonium trifluoroacetate, and relatively low pressures in the asymmetric hydrogenation are novel conditions reported for this type of transformation. The simplified process described realised a 4-fold reduction in cost of goods compared with the previously described enabling route.