Synthesis of substituted 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-ones, a new class of agents for the improvement of cognition.

Bioorganic & Medicinal Chemistry Letters
1991.0

Abstract

The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests.Pyrazolo[1,5-a]pyrimidines have been reported in the literature to show activity as anxiolytics, antischistosomal agents, and phosphodiesterase inhibitors3. A series of substituted pyrazolo[1,5-a]pyrimidines studied in our laboratories had displayed good activity in our cognition screens; however, they were unstable and readily hydrolyzed back to the parent amides 2. In an effort to improve the stability of this template while retaining activity, we endeavored to synthesize the corresponding tricyclic ring system 3. This approach was particularly attractive since 3 resembles a ring-annelated pyrazolopyrimidine analog of guanine, and guanine nucleotides have recently been implicated in cellular receptor coupling mechanisms4 and receptor regulation in muscarinic neurons5, systems known to be affected in Alzheimer's Disease. As a result of this study we now describe the synthesis of a series of compounds with the previously unknown tricyclic 3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system, some of which possess significant biological activity in tests for the reversal of cognition deficits, and therefore may be useful in the treatment of conditions of impaired cognitive ability such as Alzheimer's disease.

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