Tacrine derivatives for treating Alzheimer's disease

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S297000, C546S106000

Reexamination Certificate

active

06194403

ABSTRACT:

FIELD OF INVENTION
This invention relates to the syntheses of a series of tacrine derivatives and the methods of treating Alzheimer's disease by these tacrine derivatives.
BACKGROUND OF THE INVENTION
Alzheimer's disease is critical and may be life threatening for human beings, especially for older people. Demographic data indicate that the percentage of elderly in the population is increasing. Therefore, the threat of Alzheimer's disease is greater and greater. Although there is not a real cure for this disease, there are several drugs for treating Alzheimer's disease, such as tacrine (Parke-Davis), Aricett (Pfizer-Eisai), and Excelon (Novartis).
Tacrine (Tetrahydroaminoacridine or THA,
FIG. 1
1
a
) functions as the acetylcholinesterase (AChE) inhibitor and was approved by the U.S. Food and Drug Administration (FDA) for treating Alzheimer's disease in recent year. It is marketed as Cognex® by Parke-Davis. (Crimson, M. L.
Ann. Pharmacother.
1994, 28, 744-751). However, there is considerable debate over some drawbacks of tacrine due to its many actions in the CNS and its serious toxicity (Watkins, P. B. et al.,
J. Am. Med. Assoc.
1994, 271, 992-998).
Therefore, it is very important to design and develop a more selective inhibitor of AChE as opposed to tacrine. Recently, tacrin-1-ol (velnacrine), one of the major metabolites of tacrine, was chosen for clinical trials in Alzheimer's disease (Puri, S. K. et al.,
J. Clin. Pharmacol.
1990, 30, 948-955). A series of substituted tacrin-1-ols were also developed and found to show more potent anti-AChE activities than did tacrine (Shutske, G. M. et al.,
J Med. Chem.
1989, 32, 1805-1813). 6-Chloro-tacrin-1-ol was reported to be almost 30 times as potent as tacrine and 6-fluoro-tacrin-1-ol was reported to be slightly more potent than tacrine. Another report revealed that 6-chlorotacrine (
1
b,
FIG. 1
) exhibited stronger binding strength toward AChE than did tacrine (Wlodek S. T. et al.,
Biopolymers
1996, 38, 109-117). In addition to the above monomeric derivatives of tacrine, Pang and coworkers disclosed a series of bis-tacrines as highly potent and selective inhibitors (
2
a,b
) of AChE (Pang, Y. P. et al.,
J. Biol. Chem.
1996, 271, 23646-23649). These bis-tacrines were up to 10,000-fold more selective and 1,000-fold more potent than tacrine in inhibiting rat AChE.
All these studies indicate that tacrine may be improved for it selectivity and potency. Based on the above findings, we are disclosing a series of innovative tacrine derivatives for the treatment of Alzheimer's disease.
BRIEF SUMMARY OF THE INVENTION
This invention discloses a series of tacrine derivatives for the treatment of Alzheimer's disease. Examples comprise chloro-substituted bis-tacrines and chloro-substituted tacrine derivatives. Based on the above references, these tacrine derivatives should have very good potential for treating Alzheimer's disease. To the best of our knowledge, none of the above references disclose a tacrine derivative that is the same as the tacrine derivatives disclosed in this invention.


REFERENCES:
patent: 5783584 (1998-07-01), Pang et al.

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