Synthesis of 1,2,3,4-Tetrahydroacridine and 5,6,7,8-Tetrahydroquinoline Derivatives as Potential Acetylcholinesterase Inhibitors

Abstract

This paper describes the synthesis of 1,3,4,5-tetrahydropyrazolo[3,4,5-kllacridine (2) and 11-amino-1,3,4,5-tetrahydroazepino[3,2-blquinolin-2-one (a) obtained by Schmidt reaction of 9-* amino-3,4-dihydroacridin-l(2H)-one (1) and the preparation of 4,5dihydro-3H-isoxazolo[3,4,5-kllacridine (1) obtained in the same manner starting from3,4-dihydroacridine-1,9(2H,lOH)-dione ( 6 ) .The correspondingpyrazolo[3,4,5-delquinoline (20) andisoxazolo[5,4,3delquinoline (18) are also reported.The compounds have been prepared with the aim of studying their possible activity as acetylcholinesterase inhibitors.The finding of a cholinergic deficit in the brain of patients with Alzheimer's disease, suggested that impaired cortical cholinergic transmission may be at least responsible for the symptoms of the disease.'In support of this suggestion it has been reported that physostigmine and 9-amino-1,2,3,4tetrahydroacridine (Tacrine), which potentiate the action of acetylcholine by inhibiting the degrading enzyme cholinesterase, can bring about memory 992 HETEROCYCLES.Val.34, Na. 5. 1992 improvement in Alzheimer's patients.?,) Physostiqmine however shows serious, potentially lethal side effects ( ~~' ~0 .6 mg/kg in mice) and is characterized by a short duration of action, while the main disadvantage of tacrine is its known liver toxicity.'Considerable attention has been recently focused on 9-amino-(or 9-benzylamino)-1,2,3,4-tetrahydroacridin-1-01s (HP-029 and HP-128, ~oechst-~oussel), both significantly less toxic than tacrine, which are in phase I1 clinical trials for the Alzheimer's disease.' Phy~ostigrnine Tacrine As continuation of our studies, directed towards the search of new tacrinelike compounds, in order to verify their activity as acetylcholinesterase inhibitor^,^ in this paper we describe the synthesis of some derivatives of 9-amino-3,4-dihydroacridin-l(2H)-one (I), 3,4-dihydroacridine-19(2H,lOH)dione ( 6 ) and 7,s-dihydroquinoline-4,5(1H,6H)-dione (16).Key intermediates(~)' and (6)' to our syntheses outlined in Scheme 1 were prepared as reported in the literature.Compound (I), when subjected to the Schmidt reaction with sodium azide in concentrated sulfuric acid, gave, in addition to the expected lactam 11-amino-1,3,4,5-tetrahydroazepino[3,2- blquinolin-2-one (2).also 1,3,4,5-tetrahydropyrazolo[3,4,5-kl]acridine (2), in approximate ratio of 4:l (312).By the same reaction compound (6) afforded only the 4,5-dihydro-3H-isoxazolo[3,4,5-kllacridine (1).