Synthesis and biological activity of cocaine analogs. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones

Abstract

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.

Benzannulation for the Regiodefined Synthesis of 2-Alkyl/Aryl-1-naphthols: Total Synthesis of Arnottin I

“…To explore a tandem annulation for assembly of a benzo [d]naphtho- [b]pyranone motif, 1 was reacted with methylene homophthalate 26. 37 Expectedly, the reaction afforded benzonaphthopyranone 27 38 in 41% yield along with side product 28 in 26% yield. To determine the structure of the product 28, an independent synthesis of 28 was planned by the reaction of carbomethoxyphthalide 29 39 with homophthalate 26.…”

“…When the same reaction was performed with LHMDS, the yield improved to 67%. To explore a tandem annulation for assembly of a benzo[ d ]naphtho[ b ]pyranone motif, 1 was reacted with methylene homophthalate 26 . Expectedly, the reaction afforded benzonaphthopyranone 27 in 41% yield along with side product 28 in 26% yield.…”

Facile synthesis of 4‐alkoxycarbonylisoquinoline‐1,3‐diones and 5‐alkoxycarbonyl‐2‐benzazepine‐1,3‐diones via a mild alkaline cyclization

“…The anion of the homophthalic diester 2 obtained by treatment with LDA reacted with carbon dioxide according to Lazer et al . [9] to yield the methyl 2‐(2‐methoxycarbonylphenyl) malonate monoester 3 in 62% yield. Using activation with the BOP reagent [10], the corresponding amides 4a , 4b , 4c , 4d , 4e , 4g , 4h were synthesized with several alkyl, alkylaryl, aryl, benzyloxy amines, and glycine in satisfactory yields (52–85%).…”