9-Amino-1,2,3,4-tetrahydroacridin-1-ols. Synthesis and evaluation as potential Alzheimer's disease therapeutics

Abstract

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.

3,3,6,6-Tetramethyl-9-(2-nitrophenyl)-3,4,5,6,9,10-hexahydroacridine-1,8(2H,7H)-dione

“…Acetylcholinesterase inhibitors continue to be the therapeutic strategy of choice for patients with Alzheimer's disease (Shutske et al, 1989;Schipchandler & Mattingly, 1990;Reisch & Gunaherath, 1993). Among the variety of acetylcholinesterase inhibitors, the acridine derivatives are one of the most efficient drugs, since they display potent action with high tolerance.…”

The inhibitory avoidance test optimized for discovery of cognitive enhancers

“…These two distributions were partially overlapping in the single-trial acquisition protocol. We also demonstrated that the double-trial acquisition protocol was particularly sensitive to well-known acetylcholinesterase inhibitors such as tacrine and donepezil-drugs with demonstrated efficacy against scopolamine in this test (Dawson & Iversen, 1993;Pan et al, 2006;Saxena, Singh, Agrawal, & Nath, 2008;Shutske et al, 1989). Finally, we provided evidence about the reproducibility of the behavioral performance over a period of 3 years, showing reproducible scopolamine-induced long-term-memory impairments and the prevention of such a deficit by tacrine.…”

Lewis acid promoted Friedländer condensation reactions between anthranilonitrile and ketones for the synthesis of tacrine and its analogues

“…As depicted in Table 3 (entries 1 and 2), cyclopentanone (10) and cycloheptanone (12), delivered a lower yield of products 11 and 13, comparative to the six-membered ring substrate cyclohexanone (Tables 1 and 2). In this regard, there was no difference with the results reported in the literature.…”

“…16,18,19,21 We believe that the reaction may proceed through an initial imine-enamine tautomerism (whose preparation or isolation has been reported in some cases, depending upon the structure of the imine and enamine), activated by Lewis acid coordination under equilibrium conditions. 7,12,18,19 Next, we propose that the weakly basic nitrile of 7 is activated by Lewis acid coordination, followed by the intramolecular addition of the enamine carbon to the nitrile group to afford the intermediate 8. Next, an imine-enamine tautomerism should take place, during or prior to the alkaline hydrolysis work up, to afford 9.…”

“…Compared to tacrine, 6-fluoro-tacrin-1-ol (1c) has been reported to be slightly more potent, and 6-chlorotacrin-1-ol (1d), 30 times more potent. 12 In particular, 6-chlorotacrine (1e) has been found to be more potent than other substituted analogues ( Figure 1). 2,11,13 The importance of these compounds has led to the development of various methods for their synthesis.…”