Patent Evaluation: Highly Potent 5HT_1D Agonists Containing a Pyrimidinylpiperazine

Summary

Novelty: 1,4-Disubstituted piperazines are claimed specifically for the treatment of migraine and vascular headache. The compounds are 5HT_1D receptor subtype agonists. In addition, it is notable that the compounds are similar to previously claimed 5HT reuptake inhibitors (EP-464604-A). It is possible that both of the above activities contribute to the overall ‘serotonergic’ character of the claimed compounds.

Biology: 5HT_1D affinity is demonstrated in competition-binding assays against 5HT in brain membranes. Most compounds exhibit IC₅₀ values less than 20 nM.

Chemistry: Three multistep synthetic schemes are presented, forming a subsidiary part of the claim. These processes are exemplified by approximately forty compounds and intermediates. Several compounds are specifically claimed, the preferred compound being 1-[3-(5-fluoro-1H-indol-3-yl)propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine.