Patent Evaluation: Novel acetylcholinesterase inhibitors for treatment of cognitive disorders

Summary

Novelty: 3a,5-Cis and 3a,R-cis isomers of tetrahydroisoquinolinylcarbamates of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimemylpyrrolo[2,3-b]indole are claimed. The compounds are acetylcholinesterase inhibitors potentially useful in the treatment of cognitive disorders. They are claimed to have an improved pharmacological/pharmacokinetic profile in comparison with physostigmine.

Biology: A detailed comparison of the CNS and cardiovascular pharmacologies of the preferred compound and physostigmine is presented. While the two compounds are essentially equipotent in terms of in vitro inhibition of AChE, the preferred compound has increased stability, oral bioavailability, duration of action and therapeutic index. Unlike physostigmine, the preferred compound does not cause cardiovascular depression in dogs, an effect attributed to the ability of the new compound to enhance noradrenaline release in vitro and in vivo

Chemistry: Two compounds are exemplified by synthesis. (3a-Cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol(1,2,3,4-tetrahydroisoquinolinyl)carbamate is one of thirteen compounds specifically claimed.

Structure: