Several new potent acetylcholinesterase inhibitors have been synthesised as potential drugs for the treatment of Alzheimer's disease. Heptylphysostigmine (MF201) is a drug analogue of physostigmine under clinical evaluation. In order to obtain new physostigmine analogues, the methylcarbamoyloxy group was substituted with ω-morpholinoalkylcarbamoyloxy moieties of different chain lengths (C2-C12). Potent in vitro inhibition is seen when the chain length is composed of eight to twelve methylene groups. The inhibitory activity of the C10 and C11 is 7-fold greater with respect to heptylphysostigmine. The cholinergic approach in the treatment of Alzheimer's Disease (AD) has so far been the most studied and exploited. Multiple cholinergic abnormalities in AD have been demonstrated. Clinical studies indicate that acetylcholinesterase (AChE) inhibitors, such as tetrahydro-9-aminoacridine (THA) and physostigmine, may be useful in enhancing memory in patients with AD 1,2. However, THA induces a high incidence of liver toxicity 3, while physostigmine suffers from a short half-life, a variable bioavailability, and a narrow therapeutic index 4. That could account for its inconsistent clinical efficacy. Heptylphysostigmine (MF201), a derivative of physostigmine, which is significantly less toxic and retains its in vitro potency as inhibitor of AChE 4 is currently undergoing clinical evaluation for the treatment of AD. During our investigations of analogues of physostigmine as agents for the treatment of AD 5, we have prepared compounds which differ by their lipophilicity. The methyl group of physostigmine was substituted by aliphatic alkyl groups of increasing carbon chain length (from 2 to 12), which carries a terminal amino group. The morpholino group was chosen since its pKa (8.33 in aqueous solution) was expected to maintain the basicity of the inhibitors low enough to allow a sufficient rate of oral absorption and penetration of the blood-brain barrier. The new compounds were synthesised according to Schemes I and II.