Patent Evaluation: Benzo-isoquinoline derivatives as 5-HT_1A agonists and their potential use in therapeutics

Summary

Novelty: Novel benzo-isoquinoline derivatives are claimed to be 5-HT_1A agonists and dopamine antagonists. They are potentially useful as antidepressants and antipsychotics. They may also have utility in the treatment of hypertension and congestive heart failure.

Biology: Behavioural, psychological and biochemical tests were performed. In a CNS receptor binding assay 5-HT_1A inhibition was 15-99%, dopamine D₁ inhibition was 0-57% and dopamine D2 inhibition was 2-74%. In a dopamine cell firing assay, one compound demonstrated an ED50 value of 0.065 mg/kg. Data for sympathetic nerve discharge, metabolism and hypothermia are also given.

Chemistry: Over a hundred compounds are disclosed and are exemplified by synthesis. Preparations of intermediates are also given. Detailed reaction schemes are provided. Twenty-four compounds are specifically claimed, including (-)-10-cyano-1,2,3,4,4a,5,6,10b-octahydro-trans-3-N-propylbenzo[f]isoquinoline.