The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease--the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (+/-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (+/-)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1 p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 microM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.

A novel synthesis of 3‐amino‐1,2‐benzisoxazole (3) from 2‐[(isopropylideneamino)oxy]benzonitrile (2) is described. This methodology was used to synthesize 3‐amino‐4‐hydroxy‐1,2‐benzisoxazole (10), which served as an intermediate for a number of isoxazolo[3,4,5‐ef][1,4]benzoxazepines.

A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl benzilate binding) and in vivo (reversal of scopolamine-induced dementia) as potential agents for the treatment of Alzheimer's disease. Compounds displaying significant activity were more broadly evaluated, which revealed the presence of a desirable adrenergic component of activity. The synthesis and structure-activity relationships for this series is presented, along with the biological profiles of selected compounds.

Two 2,3‐dihydro‐2‐(4‐pyridinyl)‐1H‐isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4‐chloropyridines. In addition, a number of 1‐alkyl‐2,3‐dihydro‐2‐(4‐pyridinyl)‐1H‐isoindoles 2c‐h were obtained from 2‐(4‐pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1‐alkylhydroxyisoindolones 6a‐f which, in two cases 6a,b, were dehydrated and subjected to three separate reductions to give targets 2c,d. In three cases, the intermediate hydroxyisoindolones 6c‐e were reduced in one step to the target compounds 2c‐g with lithium aluminum hydride‐aluminum chloride. When 6f, the product of the addition of phenyl Grignard to 5, was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane‐trifluoroacetic acid. The lithium aluminum hydride‐aluminum chloride conditions were successfully applied to the synthesis of a 1‐benzyl‐4‐piperidine derivative 21.

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