Synthesis of novel Riluzole analogues

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that is universally fatal. The only drug that is currently FDA approved for the treatment of ALS is Riluzole (Figure 1), which improves life expectancy by a few months via an unknown mechanism.
This thesis describes the preparation of novel Riluzole analogues with the overall aim of improving neuroprotective activity against ALS. Two libraries are reported based respectively on the incorporation of tetrahydropyridine and 1,4-substituted-1,2,3-triazole functionality to the benzothiazole ring. Both of these functional groups have been reported in pharmaceutically active drugs either already on the market or in late clinical trials related to the treatment towards motor neuron diseases. Tetrahydropyridine analogues were synthesised in a five step process by the generation of a diamine intermediate, followed by reaction with Zincke salt, cyclisation and reduction (Scheme 1).
1,4-Substituted-1,2,3-triazole analogues were synthesised by reaction of a terminal alkyne with an azide Riluzole analogue with substoichiometric amounts of CuI (Scheme 2). The azide analogue was generated by carrying out a diazotransfer reaction on the diamine intermediate followed by cyclisation with KSCN and Br2.